PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~7O&2~T'/czc HEARINGS BEFORE THE SUBCOMMIT.[EE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE NINETY-FOURTH CONGRESS SECOND SESSION QN PRESENT STATUS OF COMPETITION IN TIlE PHARMACEUTICAL INDUSTRY PART 31 NOVE3IBER 9, 10, 11, 18, AND 19, 1976 SAFETY AND EFFICACY OF ANTI-OBESITY DRUGS /0 0 Printed for the use of the Select Committee on Small Business t.S. GOVERNMENT PRINTING OFFICE 85-569 WASHINGTON: 1977 p L./ ~ 7 U For Sale by the Superintendent of Documents, U.S. Oovernment Printing ONce Washington, D.C. 20402 -I PAGENO="0002" SELECT COMMInEE ON SMALL BUSINESS (94th Cong., 2d seas.) GAYLORD NELSON, Wisconsin, Chairman JOHN SPARKMAN. Alabama THOMAS 3. McINTYRE, New Hampshire SAM NUNN, Georgia J, BENNETT JOHNSTON, Louisiana WILLIAM D. HATHAWAY, Maine JAMES ABOUREZ1~, South Dakota FLOYD K. HASKELL, Colorado WALTER P. MONDALE, Minnesota JOHN C. CULVER, Iowa THOMAS 3. McINTYRE, New Hampshire WILLIAM D. HATHAWAY, Maine JAMES ABOUREZIC, South Dakota FLOYD K. BASKELL. Colorado *Ex officio ineuit,er. JACOB K. JAV~TS, New York 7, GLENN BEALI, 3g., Maryland BILL BEOCK, Tennessee LOWELL P. WEICKER, Ja., Connecticut DEWEY P. BARTLETT, Oklahoma PAUL LAXALT, Nevada BOB PAcKWOOD, Oregon DEWEY F. BARTLETT, Oklahoma S. GLENN BEALL, JR., Maryland BOB PACKWOOD. Oregon JACOB K. JAVITS,' New York WILLIAM B. CHERKASEY, Staff Director BENJAMIN GoRDoN, Staff Economist JUDAR C. S0MMER, Minority Counsel KAREN YOUNG, Research Assist ant SUBCOMMITTEE ON MONOPOLY GAYLORD NELSON, Wisconsin, Chairman (II) PAGENO="0003" CONTENTS Testimony of- Chambers, Carl D., Ph. D., president of Personal Development Institute, and professor and director of the Institute for Public Pa~ Health Research, Antioch College at Columbia 14545 Crout, J. Richard, M.D., Director, Bureau of Drugs, Food and Drug Administration, accompanied by Richard A. Merrill, Chief Counsel, FDA; and William W. Vodra, Associate Chief Counsel, FDA 14566 Ellinwood, Everett H., Jr., M.D., professor of psychiatry, Duke University Medical Center, Durham, N.C 14499 Gellert, Thomas M., M.D., Huntington, N.Y 14551 Grinspoon, Lester, M.D., associate professor of psychiatry, Harvard Medical School, and director of information and evaluation, Mas- sachusetts Mental Health Center, Boston, Mass 14435 Henderson, John W. 1)., M.D., Ottawa, Canada l4.52~ Hicks, Larry, Teen Challenge Youth Center, Rehobeth, Md 14518 Jasinski, Donald R., M.D., Chief, Clinical Pharmacology Section, National Institute on Drug Abuse, Addiction Research Center, Lexington, Ky j44~~ Jolly, Eugene IL, M.D., Ph. D., president, Biometric Testing, Inc., Englewood Cliffs, N.J 14484 King, Edward A., Jr., A.C.S.W., deputy director, Town of Huntington Youth Bureau, Jluntington 14521 McGraw, Isaac It., president, Pharmaceutical Division of Pennwalt Corp., accompanied by Matthew Broderick 1461G Nora, James J., M.D., professor of pediatrics and director of pediatric cardiology, University of Colorado Medical Center, Denver, Colo_ 1444& Prout, Thaddeus E., M.D., associate professor of medicine, Johns llopkins University, and chief of medicine, Greater Baltimore Medical Center, Baltimore, Md 14454 Reynolds, Reverend Frank, national director of Teea Challenge Youth Centers, Springfield, Mo 14557 Rody, Frederick A., Jr., Acting Deputy Director, U.S. Department of Justice, Washington, D.C., accompanied by Robert J. Itosthal, Deputy Chief Counsel; Kenneth A. Durrin, Acting Director, Office of Compliance and Regulatory Affairs; Ernest A. Carabillo, Jr., Chief, Regiñatory Support DivIsion; am! Gerald Voylee, Special Agent In Charge, Lubbock, Ter - 14592 Scovillo, Barrett, M.D., of Washington, D.C 14478. Yaffe, Sumner J., M.D., professor of clinical pharmacology and pediatrics, University of Pennsylvania and director, division of clinical pharmacology, Children's Hospital, Philadelphia, Pa 14460 Yake, Reverend Reginald, executive director, Teen Challenge Training Center, Rehrersburg, Pa 14511 APPENDIX PREPARED STATEMENr5 Chambers, Carl D., Ph. D., president of Personal Development Institute, and professor and director of the Institute for Public Health Research, Antioch College at Columbia 14631 (UI) PAGENO="0004" `V Creiut, J Richard, M.D., Director, Bureau of Drugs, Food and Drug Page Administration 14640 Chart, total number of lix's for anorectic agents, 1964-76 1466,3 Chart, ratio of total DAWN mentions, total lix's (NPA), July 1973- December 1975 14664 Chart, ratio of total DAWN mentions, total lix's (NPA), nil DAWN facilities, by quarters, September 1973-December 1975 14665 Ellinwood, Everett H., Jr., M.1)., professor of psychiatry, Duke University Medical Center, Durham, N.C 14666 Iteferenc u;-~-~ 14683 Article, "Assault and homicide Associated With Amphetamine Abuse," by Everett 11. Ellinwood, Jr., M.D., from the Amer. J. Psychiat. 127.9, March 1971, pp. 90-95 14686 Gellert, Thorns-s M., Ml)., Huntington, N.Y 14691 Goldman, Allen S., M.D., director, The Teratology Center, Children's Ilospitalof Philadelphia, Philadelphia, Pa 14696 Grinspoon, Lester, M.l)., associate professor of psychiatry, Harvard Medical School and director of information and evaluation, Massa- ch.isetts Mental Health Center, Boston, Mass 14704 henderson, John W. D., M.D., Ottawa, Canada. 14729 Chart, methylphenidate, by dependence, social order, safety, health, andhenefits 14746 Table, designated drugs in Canada, manufactured or imported, 1967-76 14747 Chart, antiobesity market, 1971-73, source IMS Canada, LBR, Sept.1!, 1976 14748 Jasinski, Donald It, M.D., Chief, Clinical Pharmacology Section, National Institute on Dn'g Abuse Addiction Research Center, Lexington, Ky 14749 Table, equivalent euphorogenic doses, subcutaneous studies, oral studies 14736 Article, "Physiologic, Subjective, and Behavioral Effects of Ampheta- mine, Methamphetamine, Ephedrine, Phenmetrazine, and Methyl- phenidate in Man," by W. It. Martin, M.D., J. W. Sloan, B.S., J. D. Sapira, M.D., and 1). It Jasinski, M.D., from Clinical Phar- macology and Therapeutics, vol. 12, No. 2, pt. 1, pp. 245-258, March-April 1971 17457 Article, "Effeet.s of Diethylpropion and D-Amphetamine Subcutaneous and Oral Administration," by Donald R. Jasinski Ml)., John G. Nutt, M.D., and John D. Griffith, M.1)., from álinical Pharma- cology and Therapeutics,Vol. 16, No. 4, pp. 643-652, October 1974--- 14772 Article "A Comparison of Fentluramine and Amphetamine in Man by John 1). Griflith, M.D., John 0. Nutt, M.D., and Donald It. Jasiaski, M.l)., from Clinical Pharmacology and Therapeutics, vol. 18, No. 5, pt. 1, pp. 563-570, November 1975 14780 Progress Report on Studies from the Clinical Pharmacology Section of the Addiction Research Center, by Donald It. JasinsU, M.D., John D. Griffith, M.D., Jeffrey S. Pevnick, M.l)., and Stewart C. Clark, M.D., Ph.D 1478S Jolly, Eugene K, M.D., Ph. 1)., president, Biometric Testing, Inc., Engle- woodCliffs,N 14863 King, Edward A., Jr., A.C.S.W., deputy director, Town of huntington \outhflureau, huntington, N.Y 14880 McGraw, Isaac H., president, Pharmaceutical Division of Peanwalt Corp~ 14888 Noro, James J., M.l)., professor of pediatrics and director of pediatric cardiology, University of Colorado Medical Center, Denver, Cob 14913 lteferenc& 14919 Projit, Thaddeus H., M.D., associate profcssor of medicine, Johns Hopkins University arid chief of medicine, Greater Baltimore Medical Center, Baltimore, Md 14921 Reynolds, Reverend Frank, natIonal director of Teen Challenge Youth Cen- ters, Springfield, ~ 14934 Eody, Frederick A., Jr., Acting Deputy Director, U.S. Department of Justice, Washington, D.C 14942 PAGENO="0005" V flgt Scoville Barrett, M.D., of Washington, 110- 14961 Yaffe, ~umner J., M.D., professor of clinical pharmacology and pediatrics, University of Pennsylvania and director, Division of Clinical Pharma- cology, Children's hospital, Philadelphia, Pa 14967 Ynke, Reverend Reginald, executive director, Teen Challenge Training Cen- ter, Rehrersburg, Pa 14971 MATERIAL SUPPLIED FOR THE RECORD BY SENATOR NELSON ACTIONS BY THE FOOD AN!) DRUG ADMINISTRATION AND DRUG ENFORCEMENT AGENCY SINCE TERMINATION OF HEARINGS Letter dated Feb. 16, 1977, to Senator Gaylord Nelson, chairman, Senate Small Business Committee, from J. Richard Crout, M.D., Director, Bureau of Drugs, FDA 14975 Letter dated Jan. 28, 1977, to Benjamin Gordon, staff economist, Senate Small Business Committee, from J. Richard Crout, M,l)., Director, Bureau of Drugs, FDA 14977 Letter dated Dec. 20, 1976, to Sherwin Gardner, Acting Commissioner, Food and Drug Administration, from Peter B. Bensinger, Administrator, Drug Enforcement Administration, Department of Justice, with accom- panying enclosures_ 14979 ANTI-OnEsUry DRUGS-GENERAL Memorandum dated Feb. 5, 1964, to Ralph C. Smith, M.D., Acting Medical Director, from Robert 0. Knox, MI)., Medical Officer, FDA.~ 15052 Memorandum dated July 28, 1967, to Merle L. Gibson, MI)., Acting Director, Division of Neuroplininneological Drugs, from Robert 0. Knox, M.D., Me~ica1 Officer, FDA 15052 Memorandum dated May 19, 1969, to Merle L. Gibson, M.D., Director, Division of Nearopharmaeological Drugs, from Robert 0. Knox, M.D., Medical Officer, FDA 15052 Memorandum dated Nov. 18, 1969, to John Jennings, M.D., Acting Director, Bureau of Medlicine from Robert 0. Knox, M.D., Medical Officer, FDA 15054 Memorandum dated Fel,. 17, 1970, to John Jennings, Ml)., Acting Director, Burenu of Medicine, from Robert 0. Knox, Ml)., Medical Officer, FDA 15054 Memorandum dated Apr. 8, 1970, to John Jennings, M.D., Acting Direc- tor, Burenu of Drugs, from Robert 0. Knox, M.D., Medical Officer, FDA 150511 Memorandum dated Apr. 9, 1971, to Barrett Seoville, M.D., Deputy Director, from Dobert 0. Knøx, M.D., Medical Officer, FDA 15057 Memorandum dated Apr. 12, 1971, to Henry B. Simmons, M.D., Director, Bureau of Drugs, from Barrett Scoville, M.D., Deputy Director, FDA. 15058 Memorandum dated Apr. 19, 1971, to Dr. Marion Finkel, Deputy Direc- tor, Bureau of Drugs, from Leszek Ochota, M.D., FDA 15059 Memorandum dated Sept. 22, 1971, to the Commissioner, from Henry B. Simmons, Mi)., Director, Bureau of Drugs, FDA 15059 Paper, "The FDA Review of Anorectic Drugs: Background, Current Status, and Problem Areas," presented by Barrett Scovillie, M.I)., Deputy Director, and Elmer A. Gardner, Ml)., Director, Division of Neuropharmacological Drug Products, FDA, June 12, 1972 1506~ Final report to the Director, Burenu of Drugs, FDA, by Thaddeus B. Prout, M.D., Chairman, Consultants on Anorectic Drugs 13064 Memorandum dated Oct. 6, 1972, to the Commissioner, from Henry E. Simmons, M.D., Director, Bureau of Drugs, FDA 15066 Letter dated Mar. 26, 1973, to Delco Chemical Co., Inc., from Sherwin Gardner, Acting Commissioner, FDA, and John Ii Ingersoll, Director, Bureau of Narcotics and Dangerous Drugs 15063 Letter dated Sept. 28, 1974, te Dr. Alexander M. Schmidt, Commissioner, FDA, from Robert 0. Knox, M.D., Medical Officer, FDA 15069 Memorandum dated July 9, 1976, to Ed Melton, OLS, from Bill Crabbs, ITFD-120, FDA 1507~ Memorandum undated, to the Director, Bureau of Drugs, from J. Richard Crout, M.D., Acting Director, Office of Scientific Evaluation, FDA_~ 15070 PAGENO="0006" VI JOURNAL ARTICLES AND FEDERAL REGISTER NOTICES ~Artic1e, "Use, Misuse and Abuse of Amphetamine-type Drugs from the - Medical %iewpoint," by Maurice Seevers, Ph. D.,M.D., Department ~of Pharmacology University of Michigan Medical School, Ann Arbor, -.Mich., from the ~ational Institute on Amphetamine Abuse, Edwards- Pare `vile, III., 1966 15089 Article, "Amphetamines: A Dangerous Illusion," by George II. Edison, M.D., Salt Lake City, Utah, from the Annals of Internal Medicine, 74-005-610, 1971, pp. 605-610 15097 Article, "Drugs in Pregnancy," from the Medical Letter, 14:94-6, Dec. 8, 1972 15103 Article, "Amphetamines: Tighter Controls on the Horizon," by Constance 1-tolden, from the Science, vol. 194, pp. 1027-28, Dec. 3, 1976 15106 Notice, "Certain Anorectic Drugs-Drugs for human Use; Drug Efficacy Study Implementation," Food and Drug Administration, Department of Health, Education, and Welfare, from the Federal Register, vol. 35, No. 154, Aug. 8, 1970, pp. 12678-79 15108 Rules and regulations, "Title 21-Food and Drugs, Part 130-New Drugs," Food and Drug Administration, Department of health, Education, and Welfare, from the Federal Register, vol. 35, No. 154, Aug. 8, 1970, pp. 12652-53 10111 Rules and regulations, "Title 21-Food rind Drugs, Part 130-New Drugs, Amphetamines for Human Use," Food and Drug Administration, Department of Health, Education, and Welfare, from the Federal Register, vol. 38, No. 28, Feb. 12, 1973, pp. 4249-50 15113 Notice, "Certain Combination Anorectic Drugs-Opportunity for Hearing on Proposal to Withdraw Approval of New Drug Applications," Food and Drug Administration, Department of health, Education, and \Selfare, from the Federal Register, vol. 38, No. 28, Feb. 12, 1973, pp. 4279-82 15116 Notice, "Amphetamines for Human Use-Notice of Withdrawal of Ap- proval of New Drug Applications," Food and Drug Administration, Department of health, Education, and Welfare, from the Federal Register, vol. 38, No. 61, Mar. 30, 1973, pp. 8240-41 15123 Notice, "Certain Combination Anorectie Drugs-Final Order on Objections and Request I or a hearing Regarding Withdrawnl of Approval of New Drug Applications," Food and Drug Administration, Department of Health, Education, and Welfare, from the Federal Register, vol. 38, No. 185, Sept. 25, 1973 15126 Notice, "Drugs for Human Us~Drug Efficacy Study Implementation Certain Single Entity Oral Anorectic Drugs in Conventional or Con- trolled Release Dosage Forms," from the Federal Register, vol. 39, No. 140, July 19, 1974, pp. 26459-02 15128 Notice, "Bamadex Sequels-Denial of Hearing and Withdrawal of Ap- proval of New Drug Application," Food aud Drug Administration, Department of health, Education, and Welfare, from the Federal Register, vol. 40, No. 101, May 23, 1975, pp. 22570-75 15133 Memorandum dated Feb. 20, 1973, through Director, Division of Neuro- pharmacological Drug Products, from Barrett Scoville, M.D 15143 DEPARTMENT OF JUSTIcE, DRUG ENFORCEMENT AGENCY Memorandum dated Sept. 28, 1971, to Robert J. Rosthal, Acting Chief Counsel, from Kenneth A. Durrin, Chief, Compliance Investigations Divisions, Department of Justice 15146 Memorandum dated Oct. 8, 1971, to all domestic regional directors, from John It. Enright, Chief of Operations, Department of Justice 15148 Memorandum dated Oct. 8, 1971, to John R. Enright, Chief of Operations, from Kenneth A. Durrin, Chief, Compliance Investigations Division, Department of Justice 15154 Memorandum dated Nov. 22, 1971, to lion. John N. Mitchell, Attorney General, from John E. Ingersoll, Director, Bureau of Narcotics and Dangerous Drugs, Department of Justice 15151 Memorandum undated, to Andrew C. Tartaglino, Deputy Director for Operations, from Kenneth A. Durrin, Assistant Director for Compliance, Department of Justice 15159 PAGENO="0007" YII~ Order to show cause dated Jan. 14, 1972, In the Matter of Strasenburgh Page Prescription Products, Division of Pennwalt Corp 15164 Press release dated Jan. 27, 1972 15171 Memorandum dated Nov. 2, 1972, to Kenneth A. Durrin, Assistant Director for Compliance, from Larry Kerness, Chief, Regulatory En- forcement Division, Department of Justice 15173 Memorandum dnted Mar. 14, 1972, to Frederick M. Garfield, Assistant Director for Scientific Support, from Kenneth A. Durrin, Assistant Director for Compliance, Department of Justice 15177 Notice, "Controlled Substances in Schedules I and 11-1975 Final Aggre- gate Production Quotas," Department of Justice, from the Federal Register, voi. 40, No. 13, Jan. 20, 1975, p. 3225 15178 Report, "Drug Enforcement-Assault on Amphetamines," Department of Justice, Drug Enforcement Administration, winter 1975 15179 Notice, "Controlled Substances-Final 1975 Revised Aggregate Produc- tion Quotas in Schedules I and II," Department of Justice, from the Federal Register, vol. 40, No. 161, Aug. 19, 1975, pp. 36152-53 15202 Notice, "Controlled Substances i~ Schedules I and Il-Final 1976 Aggre- gate Production Quotas," Department of Justice, from the Federal Register, vol. 40, No. 210, Oct. 30, 1975, pp. 50547-48 15204 Notice, "Controlled Substances in Schedules I and Il-Final 1976 Revised Aggregate Production Quotas," Department of Justice, from the Federal Register, vol. 41, No. 132, July 8, 1976, p. 27980 15206 Annual statistics of psychotropIc substances, Form P, July 14, 1976..__. 15207 Notice, "Controlled Substances-Proposed Aggregate Production Quotas for 1077," Department of Justice, from the Federal Register, vol. 41, No. 190, Sept. 29, 1976, p.42965 15209 Notice, "Amphetamine-Aggregate Production Quota for 1974," Depart- ment of Justice, from the Federal Register, vol. 39, No. 117, June 17, 1974 15210 MATERIAL ON PrNNWAL'r Coup. flo3f Flits or Dnuo EfloucEMENr Aoncr, DarAnMENT OF JUSTICE Letter dated Aug. 13, 1970, to all field sales personnel, from Isaac II. McGraw, II, vice president, Pennwalt Corp 15211 Memorandum dated Aug. 20, 1970, to Drs. William F. Head and Aldo P. - Truant, from Elwood A. Garner, Pennwalt Corp 1o214 Memorandum dated Nov. 2, 1970, to all division and district managers, from J. Marion Meason, national sales manager, Peanwalt Corp 15220 Memorandum dated Nov. 5, 1970, to W. F. Head, A. P. Truant, I. It. McGraw, and E. ltahn, from Elwood A. Garner, Pennwalt Corp 15224 Letter dated Feb. 5, 1071, to an field sales personnel, from Isaac B. McGraw, IT, vice president, Pennwalt Corp 15229 Memorandum dated Mar. 11, 1971, to all division and district managers, from J. Marion Meason, national sales manager, Pennwalt Corp 15230 Letter dated May 20, 1971, to Dr. Barrett Scoville, Office of Scientific Evaluation, Bureau of Drugs, Food and Drug Administration, from W. F. Read, Jr., Ph. D., vice president, technical operations, Peanwalt Corp 15232 Memorandum dated May 25, 1971, to Isaac B. McGraw II, vice president, from J. Marion Meason, national sales manager, Pennwalt Corp 15240 Memorandum dated June 2, 1971, to all field sales personnel, from Isaac It. McGraw, II, vice presideat, Pennwalt Corp 15243 Letter dated June 25, 1971, to Dr. W. F. Head, Jr., director, quality con- trol, Pennwalt Corp., from Alan H. Kaplan of Kleinfeld and Kaplan, Washington, D.C 15246 Memorandum dated Sept. 20, 1971, to Isaac It. McGraw, II, vice president, - from J. Marion Meason, national sales manager, Peanwalt Corp 152o3 Letters undated, to "Dear Doctor," from Louis Cohen, Delco Chemical Co., Mount Vernon, N.Y 15256 Article, "Strasenburgh Quizzed on Amphotamines," from the Times-Union, Jan. 18, 1972 15256 Article, "Seize $1.5M Pep Pills," by Jeffrey Antevil, front the Daily News, Jan. 19, 1972 15257 Press release dated Jan. 21, 1972, of the Pennwalt Corp 15257 Telephone communication dated Jan. 27, 1972, to FDA memo file, from W. F. Read, Jr., Pennwalt Corp 15258 PAGENO="0008" VIII Article, "Drug Exporter to Quit Trade," from the Washington Post, Page Jan. 28, 1972 15259 Article, "New Drug Agency to Fight Pushers on Lower LeveLs," by Robert M. Smith, from the New York Times, Jan. 19, 1972 15260 Article, "United States Acts to Block Amphetamines From Mexico," by Harold M. Sehmeck, Jr., from the New York Times, Jan. 19, 1972 15261 Article, "Pennwalt Division's License to Export Amphetamine ChaUenged by Justice Unit," from the \Vall Street Journal, Jan. 19, 1972 15262 Letter dated May 15, 1972, to Isaac ft. McGraw, II, vice president, Pennwalt Corp., from John S. Canavis, Centre European de Recherches Therapeutiques Appliq~ees, S.A 15263 Letter datcd June 27, 1972, to Dr. Saverio Mecca, Eufarma Firenze, Italy, from Isaac ft. McGraw, It, vice president, Pennwalt dorp 15266 MATERIAL FROM FOOD AND Dnun ADMINISTRATION FILES ON BIPilnAMINE AND I0NA3LINE Summary of New Drug Application No. 11-013 by L. L. Phillips, Ph. D., original application date Dec. 2, 1957 15267 Memorandum dated Aug. 13, 1958, to Dr. DeF'elica, New Drug Branch, from E. I. Goldenthal, Division of Pharmacology, Food and Drug Administration 15268 Memorandum dated Feb. 17, 1959, to Dr. DeFelice, New Drug Branch, from B. I. Goldenthal, Division of Pharmacology, Food and Drug Administration 15269 Memorandum dated Jan. 16, 1964, to Dr. A. G. Pleron, Division of New Drugs, from Dr. William D'Aguannn, Division of Pharmacology, Food and Drug Administration 15269 Memorandum dated Oct. 29, 1965, to Dr. F. 0. ICelsey, Division of New Drugs, from Dr. S. usia, Drug Review Branch, Food and Drug Ad- ministration 15269 Memorandum of telephone interview dated Dec. 8, 1967, between ft. G. Eothwell, M.D.. medical director, Strasenburgh Laboratories, and Robert 31. Hodges, M.D., Director, Office of New Drugs, Food and Drug Admin- istration 15270 Letter dated Aug. 28, 1969, to Strasenburgh Laboratories, Rochester, N.Y., from Robert 0. Etiox, 31.1)., Medical Officer, Food and Drug Adnilu- istration 15270 New drug application Nos. 10-093, 11-538, and 11-613, July 1972 15272 Memorandum dated Aug. 30, 1972, to Barrett Scovilic, MD,, Division of Neuropharmaeological Drug Products, from Walter Sloboda, Division of Statistic Evaluation Branch, Food and Drug Administration 15273 Medical Summary of New Drug Application No. 11-S13 by Theresa T. Woo, M.D., Nov. 28, 1972 15275 Memorandum dated Jan. 24, 1973, to the Commissioner, from Henry E. Simmons, Ml)., M.P.II., Director, Bureau of Drugs, Food and Drug - Administration 1527o Review of a bioavailnbility study by Harold It. Murdock, Ph. D., May 30, 1973 15277 Medical Officer's Review of New Drug Application No. 11-013 by Theresa T. Woo, M.D., May 30, 1973 15277 Letter dated Feb. 19, 1974, to Alda P. Truant, Ph. D., Pcnnwalt Corp., from Barrett Scoville, MD., Deputy Director, Division of Neuropharmn- cological Drug Products, Fond and Drug Administration 15278 Memorandum of conference dated Oct. 3, 1974, between Dr. W. head, Dr. J. ft. McGraw, Dr. F. Leaders, Dr. J. E. Gicring, Penawalt Corp., and Dr. B. Scoville, Dr. T. Hayes, Dr. H. Murdock-, Dr. T. Woo, Mr. W. C. Crabl,s, Food and Drug Administration 15278 Letter dated Apr. 10, 1975, to Peter B. Manni, Ph. D., Pennwalt Corp., from Barrett Scoville, M.D., Director, Division of Neuropharmacological Drug Products, Fond and Drug Administration 15279 Supervisory review of review dated Feb. 17, 1976, by Thomas A. hayes, M.D 15279 Drug efficacy study of the National Academy of Sciences-National Re- search Council, NDA No. 10-093, Sept. 23, 1955 15280 Drug efficacy study of the National Academy of Sciences-National Research Council, NDA No. 11-613, May 14, 1959 15285 PAGENO="0009" Ix Drug Efficacy Study of the National Academy of Sciences-National "~ Research Council, NDA No. 11-538, Apr. 25. 1961 15290 Medical Officer's Review of New Drug Application No. 11-613, by Theresa T. Wood, M.D., Feb. 17, 1976 15294 Suannary of Reports on New Drug Application No. 11-613, by R. Kim- brougli, flD., Dec. 9, 1909 15296 MATERIAL FROM Fooi, AND Darn ADMINTSTRATI0N FILES ON CLORTERMINE-TRADE NAMR: \`oRANIL Letter dated Feb. 1, 1968, to William S. Westlin, M.D., clinical research section, CIBA Pharmaceutical Co., from Benjamin Simkin, M.D., University of Southern California Medical School 15302 Memorandum of telephone conversation dated Dec. 30, 1969, between George Ohye, director of drug compliance, CIBA Pharmaceutical Co., and William Dworkin, Food and Drug Officer 15303 Addendum to Medical Officer review of New Drug Application No. 16- SSU by Robert 0. Knox, M.D., Division of Neuropharmacological Drugs, Food and Drug Administration 1530-1 Memorandum dated Feb. 12, 1970, to John Jennings, M.D., from B. New- - berry Food and Drug Admialstratiou 1530o Letter dated Feb. 19, 1970, to Joseph S. Harun, M.D., CIBA Pharmaceu- tical Co., from John Jennings, M.D., Acting Director, Bureau of Medi- - cine, Food and Drug Administration 1a305 New Drug Application No. 16-880 15307 Memorandum undated, to Dr. Robert Knox, for Lawrence Hauptman, Food and Drug Administration 15307 MATERIAL FROM FOOD AND Daun ADMINISTRATION FILES ON FENFLURAMINE-TRADE NAME: PONDIMIN, PONDERER Chronology of new drug application No. 16-618 (Fcnfluramine (Pondimin, Pondercx)) 15308 Memorandum of telephone conversation dated June 7, 1968, between It. \V. Dent, Jr., M.D., A. 11. Robins Co., Inc., and Robert M. Hodges, M.D., Office of New Drugs, Food and Drug Administration 15309 Letter dated June 20, 1908, to It. Wiliinm Dent, Jr., M.J)., A. H. Robins Co., Inc., from Robert M. hodges, M.D., Director, Office of New Drugs, Bureau of Medicine, Food and Drug Administration 15309 Memorandum dated Aug. 9, 1968, to Acting Director, Division of Neuro- pharmacological Drugs, from Division of Statistics, Office of Medical Support, Foodand Drug Administration 15310 Memorandum of conference dated Sept. 11, 1968, I,etwcen R. Dent, Jr., M. 1.)., E. Woodward, Jr., M.D., It. Murphey, Ph. D., L. Preston, Jr., A. II. Robins Co., Inc., and M. L. Gibson, M.D., 11.0. Knox, M.D., P. James, Food and Drug Administration 15317 Memorandum dated Apr. 25, 1969, to Peter 0. James, Acting Chief, Statistical Analysis Branch, from Jacqueline 31. Tillman, Statistical Assistant, Food and Drug Administration 15317 Memorandum dated Apr. 25, 1969, to Robert 0. Knox, M.D., from Peter U. James, Food and Drug Administration 15318 ?ilerlieal Officer's review of New Drug Application No. 16-618 by Robert 0. Knox, 31.1)., Division of Neuropharmacological Drugs, MayO, 1969W 15320 Letter dated Sept. 8, 1969, to A. H. Robins Co., Inc., from RobertO. Knox, M.D., Medical Officer, Food and Drug Administration -- 15326 Medical Officer's review of New Drug Application No. 16-618 by James 31. Moser, Jr., M.D., Division of Neuropharmacological Drugs, Oct. 23, 1969 15327 Medical Officer's review of New Drug Application No. 10-4118 by James 31. Moser, Jr., M.D., Division of Neuropharmacological Drugs, Dec. 29, 1969 15334 Memorandum dated Feb. 17, 1970, to James M. Moser, Jr., M.D., Division of Neuropharmacological Drugs, from Peter 0. James, M.D., Acting Chief, Statistical Analysis Branch, Food and Drug Administration 15337 PAGENO="0010" x Medical Officer's review of New Drug Application NO. 16-618 by James M. ~ Moser, Jr., M.D., Division of Neuropharmneoiogicai Drugs, Mar. 25, 1970 15338 Letter dated July 9, 1970, to Charles E. Edwards, M.D., Commissioner, Food and Drug Administration, from E. Claihorne Robins, A. 11. Robins Co., Inc 15338 Memorandum dated Aug. 6 1970, to Dorothy S. Dobbs, M.D., Director, Bureau of Drugs, from M'artha M. Freeman, M.D., Division of Neuro- pharmacoiogicai Drugs, Food and Drug Administration 1o34l Memorandum dated Oct. 8, 1970, to all medical officers, Burea.u of Drugs, from Marvin Seife, M.D., Acting Director, Office of Scientific Evaluation - - Bureau of Drugs, Food and Drug Administration 1o34o Minutes of 47th meeting of the Research Committee, Bureau of Drugs, Food and Drug Administration, Oct. 29, 1970 10346 Letter dated Aug. 31, 1971, to the Food and Drug Administration, from F. A. Ciark, Jr., M.D 15347 Letter dated Mar. 7, 1975, to Alexander M. Schmidt, M.D., Commissioner, Food and Drug Administration, from Robert 0. Knox, M.D., Medical Officer, Division of Oncology and Radiopharmaceuticals, Food and Drug Administration 15318 Letter dated Mar. 13, 1975, to Alexander M. Schmidt M.D., Commissioner, Food and Drug Administration, from J. Richard trout, M.D., Director, - - Bureau of Drugs, Food and Drug Administration 1o3.,6 REARING DATES Nov. 9, 1976: Morning session 14433 Nov. 10, 1976: Morning session 14469 Nov. Il, 1976: Morning session 14499 Nov. 18, 1976: - Morning session 14u29 Nov. 19, 1976: Morning session 14063 PAGENO="0011" COMPETITIVE PROBLEMS IN TilE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) TUESDAY, NOVEMBER 9, 1976 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY or SELEcT Co3r3rInTE ON SMALL BUSINESS, TVasMngton, D.C. The subcommittee met, pursuant to notice, at 10 aim, in room 318,. Russell Senate Office Building, lion. Gaylord Nelson, chairman, presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Karen Young, research assistant. Senator NELSON. The Monopoly Subcommittee of the Senate Small Business Committee today commences 5 days of hearings on the anti- obesity drugs, which a.re generally amphetamines and amphetamine- related drugs. The latter include such drugs as phemnetrazine-Preludin-phen- termine - Tonamin - diethylpropion - Tenuate - chlortermine- Voranil-and others. Fenfluramine-Pondimin-appears to be more like the hallucinogens rather than amphetamines. At one time the amphetamines were the largest sellhig group of antiobesity drugs, but after being placed in schedule TI of the Con- trolled Substances List with an assigned quota, the demand shifted over to the amphetamine-related drugs, which remained in schedules III and IV. In 1975, 5.5 million prescriptions were written for the amphetamines and 19.9 million for the amphetamine-related antiohcsity drugs. Manufacturers' sales of antiohesity drugs for 1975 are estimated to be: Amphetamines ___ $20, ~ ooo Nonamphetamines 64, 594, 000 Total - S4,W~O.000 Estimated retail sales are in the vicinity of $170 million. Illegal street ~les would increase this amount considerably because of the hifther prices demanded. The amount of sales does not reflect the impact of these drugs on societv.As far back as 1969 the Economic and Social Council of the United Nations concluded that (a) "In some countries there is in- (14433 PAGENO="0012" 14434 COMPETITIVE PROBLEMS IN TI~ DRUG INDUSTRY creasing misuse, especially by young people, of central nervous system stimulants notably of the amphetamine type," and urged that (b) "Immediate action is necessary to combat this threat to the health of mankind.'' In 1910, U.S. legal production of amphetamines exceeded 10 billion P?hl~-tablets and capsules-in 1971, the figure probably exceeded 12 billion. In 1972, pr~liietion fell, because the amphetamines were given manu- factunng quotas, and former users were then diverted to ampheta- imne-related drugs. According to Dr. Lester Grinspoon's "The Speed Culture": Amphetamines were unique: never before had a powerful psychoactive drug been introduced in such quantities in so short a period of time, and never before Lad a drug with such a high addictive potential and capability of causing long- tern. or irreversible physical and psychological damage been so enthusiastically embraced by the medical profe~ton as a pana-~ea or so extravagantly promoted by the drug industry." Most studies have shown that these drugs as an adjunct to diet have a "trivial" advantage over diet alone. As a matter of fact, the weight loss occurs principally in the first few weeks und then levels off. The labeling calls for use for no more than "a few weeks." According to FDA's Advisory Committee on Metabolic and Endocrine Drugs, how- ever: The increased weight loss appears to be related to variables other than the drug prescribed, such as the physician-investigator, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss. In addition, the FDA Advisory Committee insisted that: The natural history of obesity is measured in years, whereas the studies cited are restricted to a few weeks duration; thus, the total impact of drug-Induced weight loss over that of diet must be considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors thherent In their use. The amphetamines have been widely abused in numerous popula- tions and evidence will be presented during these ~iearmngs that the newer drugs of the amphetamine family as well as the nonamphetamine drugs do not have higher benefits or lower risks than older available drugs. According to an article which appeared in Pediatrics of February 1978, and signed by the Committee on Drugs, its consultants and others of the American Academy of Pediatrics: More than ten years ago Japan banned the use of amphetamines. The United Kingdom restricted distribution of amphetamines to hospital pharmacies In 1968. Sweden categorized amphetamines as a narcotic in I~44 because of abuse: and in 1965, plienmetrazine (Preludia) and in 1968, methylphenidate (thtalin) were removed from the market. The health Protection Branch of the Department of National health and Welfare of Canada. with the endorsement of the Canadian Medical Association (and others) has moved to prohibit the use of amphetamines and related coin- pounds for weight reduction purposes as of September 1, 1972. The purpose of these hearings, therefore, is to ascertain whether the possible benefits of the antiohesity drugs outweigh the risks both to the individual and to society, and whether these drugs should con- timie to be marketed for the purposes claimed. PAGENO="0013" COMPETITIvE PROBLEMS IN THE DRUG INDUSTRY 14435 It has always been our policy that every viewpoint on all subjects before this committee is sought. These hearings are no exception to that rule. Representatives of the Pennwalt Corp., the largest manufacturer of these products will appear later in the hearings. Any other companies manufacturing these products are welcome to appear as witnesses upon their own request at anytime. We are pleased to have with us this morning a group of very dis- tinguished witnesses, Dr. Lester Grinspoon, associate professor of psy- chiatry, Harvard Medical School, and director of information and evaluation, Massachusetts Mental Health Center, Boston, 1~1ass. Dr. James J. Nora, professor of pediatrics and director of pediatric cardiology, University of Colorado Medical Center, Denver, Colt). Dr. Sumner Yaffe, professor of clinical pharmacology and pedi- atrics, University of Pennsylvania, and director, division of clinical pharmacology, Children's Hospital, Philadelphia, Pa. And Dr. Thaddeus Prout, associate professor of medicine, Johns Hopkins University and chief of medicine, Greater Baltimore Medi- cal Center, Baltimore, Md. Dr. Allen Goldman will not be here this morning, hut Dr. Yaffe will read Dr. Goldman's statement. Dr. Goldmn.n is associate professor of pediatrics, University of Pennsylvania, and director, teratology unit, Children's Hospital, Philadelphia, Pa. Our first witness this morning will be Dr. (irinspoon. Doctor, we are pleased to hear from you this morning. Your statement will be printed in full in the record.1 You may present it as you desire, and if you wish to expand upon it extemporaneously, you may do so. STATEMENT OF LESTER GRINSI'OON, M.D., ASSOCIATE PROFESSOR OF PSYCHIATRY, HARVARD MEDICAL SCHOOL, AND DIRECTOR * OP INFORMATION AND EVALUATION, MASSACHUSETTS MENTAL HEALTH CENTER, BOSTON, MASS. Dr. GRrNsrooN. Thank you, Mr. Nelson. First, as I said.I apologize for the length of my statement. I have provided up a brief history of amphetamines, and I simply summarize as follows: The drug was first synthesized in 18S7 by a German pharmacologist. Not much attention was paid to it, and it was pift back on the shelf, and it was not investigated until 1910 by U. Barger and Sir H. H. Dale, but again very little came of it until 1.928, when an American by the name of Dr. Gordon Alles, who was looking for a synthetic ephedrine substitute, that is, a synthetic amine substi- tute for ephedrine, began to experiment with it. Ephedrine was widely used in the treatment of asthma, and there was concern that the natural sources would soon be exhausted. Gordon Alles looked at amphetamine and dextro-amphetamine. and found through experimentation on himself that there drugs produced a sense of alertness that they combatted fatigue, and it gave a euphoric sense of confidence, even though they kept him awake late into the night. `See prepared statement of Dr. Grinspoon begthnlng at p. 14704. PAGENO="0014" 14436 COMPETITIVE PROBLEMS IN THE DittO INDVSDRY - lie u-as shortly approached by F. 13. Nabenhaner of a drug com- pany, which persuaded him to sell his patent rights. They were interested in this drug for their new "Benzedrine" in- haler. which they were about to market, and indeed, was marketed in 1932. At that time anybody could get the Benzedrine inhaler from grocerystores or drugstores without a prescription, and it was very shortly after that that it was discovered that this indeed could be abused. People would take the inhaler apart, and they could dissolve the contents in alcohol, or even swallow it whole, and discovered they could get qmte a high from it. The drug was packaged in pill form just a few years later, and -within a few years of that time 50 million units of the drug were being produced, and as I think I noted in your statement, by 1958 ~½ billion units were being produced in this country. and 10 years later. 8 billion, or enough for 35 to 50 pills for every man, woman and cluld in this * country. Now, World War II gave an enormous boost to the acceptance of these medicines in this country. but by far the most important factor in the enormous and widespread acceptance of these dni~s in this coun- -try was the way the medical profession perceived this class of drugs as -a panacea. As an illustration of this. in 1046 a physician by the name -of IV. II. Be-ft wrote an article in which lie asserted that there were 39 clinical utilities for this drug. Jt was a virtual panacea. It was said to be useful for such diverse syndromes as hiccups, irradiation sickness, hypertension, "caffeine mania." and schizophrenia. At the present time the medical profession is somewhat divided on what it believes are appropriate utilities of this drug. Certainly obesity is the condition for which amphetamines are most commonly prescribed, but before I discuss their efficacy in the treat- ment of this condition, I will briefly consider some of the toxic effects of emphetamines. Now, of all the myths surrounding the amphetamines, that of their alleged "non-a-ddictiveness" is today the most transparent, even thrnwh when these drugs were first introduced they were almost universally hailed as having little or no addictive potential. I am reading now from the bottom of page?. This is not surprising; almost even drug which is now condemned as addictive was vouchsafed by the official medical establishment as extremely useful and nonaddicting when it was first introduced. For example. when morplune was acetylated in 1898 the new drug was heralded as a nonaddictive cure for opium and morphine addictions. In fact-, enthusiasm was so high that the drug's name was taken from "hero"-it was called "heroin." Accordingly, the only surprising fact about the controversy over the addictiveness of the amphetamines is that it has persisted for so long. despite early strong evidence that these new drugs were substances which were especially euphorigenic. Indeed, cases of addiction were reported almost immediately, but the drug industry was so successful in reinforcing and sustaining early medical enthusiasm that even as late as 1958 0. D. Leake categorically PAGENO="0015" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14437 stated that "No clear case of addiction to d-amphetamine has been reported." However, Leake admitted at the very end of his book that he had not become aware of the Japanese situation until "this book was in galley proof." During World War II millions of Japanese soldiers, aviators, sail- ors, and civilians engaged in defense, munitions, and government woric took tons of "wake-amimies," especially methamphetamme-sold as "philipon." After the war military stockpiles of amphetamines flooded an exceedingly depressed and disillusioned but determined and growth- oriented cfvilian population, and the immediate result was the over- night eruption of an unprecedented epidemic of drug abuse and addiction. By 1954 it was estimated that there were 500,000 to 1.5 million Japanese amphetamine abusers, about half genuinely addicted. Despite the minimization of the amphetamine abstinence syndrome in the medical and lay press, and the parallel exaggeration of the un- pleasantness of the average heroin addict's abstinence syndrome, withdrawal from amphetamines can be most distressing. Since the individual who is "crashing" from high-dose amphetamine abuse appears to be sleeping well a good deal of the time, he is often considered to be merely exhausted. But the picture of the amphetamine abstinence syndrome that has recently emerged is as unpleasant and painful as the traditional rep- utation of heroin withdrawal. Extreme lethargy, fatigue, anxiety, terrifying nightmares, and suicidally severe depression are common. The individual is usually completely disoriented, bewildered and confused. He is apt to be extremely irritable and demanduig-which drives people away just when he most needs their help. His psychic disruption and loss of self-control may lead to violent acting out of aggressive impulses. He has headaches, he has trouble breathing, he sweats profusely, and his body is racked with alternat- ing sensations of extreme heat and cold and excruciating muscle cramps. He characteristically suffers painful gastrointestinal cramps. Espe- cially if he is alone, and despite his sometimes incredible hunger, he often lacks the strength to eat at all, aggravating his condition through mahiutrition. As early as 193.5 reports began to appear in medical journals sug- gesting that "Benzedrine" might cause serious cardiovascular disturb- ances. The following year the first such concrete evidence was published by K W. Anderson and W. C. 1sf. Scott, who administered "thetapeutic'! doses-b to 30 milligrams-of "Benzedrine" to 20 "physically fit" and "normal" subjects in a controlled laboratory experiment. Almost without exception their subject exhibited pallor and flush- ing, palpitations, and changes-usually marked increases-in pulse rate and blood pressure. - Now, 10 to 20 milligrams is not an uncommon dose for someone to take who is being treated for obesity. PAGENO="0016" 14438 COMPETITIVE PROBLEMB IN THE DRUG INDUSTRY In six cases the effects were more severe and included collapse, multi- plc extrasystoles, heart-block, and pain in the chest radiating into the left arm. From 1939 to 1962, at least 54 cases of acute physical amphetamine poisoning were published in the American and British literature, and many reports came in from nations like Japan and Sweden, where severe intravenous amphetamine epidemics broke out earlier than in this country. In addition, in 1962, B.IL Ong noted that in 1958 alone 38 separate cases of acute amphetamine poisoning in children under 5 years of a~e. had been reported to the Boston Poison Information Center. Similarly, 52 different cases of very young children suffering from acute physical reactions to amphetamine were admitted to one Toronto hospital from 1980 to 1968. P. II. Connell. searching for instances of amphetamine psychosis up to 1956, noted that all hut 10 of 92 cases also suffered moderate to severe physical sighs and symptoms, including flushing, pallor, cya- iiosis, fever, tachycardia, serious cardiac problems, markedly elevated blood pressure, hemmorhage or other "vascular accidents," nausea, vomiting, difficulty in breathing, tremor, ataxia, or loss of sensory abilities, twitchings, tetany, convulsions, loss of consciousness, and coma. Mr. Gounox. how do the children get the drugs? Dr. GRINSPOON. The children get the drugs accidentally; taking them out of medicine cabinets is the most common way. Mr. GoRDoN. But they are not prescribed for children? Dr. Gnxsroox. No, except for hyperkinetic children. Mostly they are accidentally ingested. Since high-ao.se and/or intravenous abuse of amphetamines has become increasingly more popular since the early 1960's, a whole new spectrum of serious physiological reactions have been reported. By 1966 cases of severe serum hepatitis resulting from intravenous abuse of amphetamines were being regarded as fairly common oc- currences: One physician reported that at least 11 cases had resulted from a 2-day "meth party" in Salt Lake City that year. At about this same time several independent Japanese, British, and American in- vestigators began to speculate that intravenous abuse of speed could cause permanent or long-term brain damage. In 1970, the first clinical evidence of this was reported by a team of California researchers headed by B. P. Citron, who had observed 14 young drug abusers suffering from "necrotizing angiitis." a disease characterized by widespread small blood vessel deterioration, includ- ing rupture of the vessels supplying the brain. Although the researchers could not conclusively prove that ineth- amphethmine was the only cause they did note that fill but two of the 14 admitted to intravenous abuse of methamphetamine, that one of the 14 had used speed exclusively, and. that all four of the patients who died had been heavy speed abusers. Mr. Gonnox. If I may interrupt, the FDA has prohibited paren- teral methamphet.amine to be marketed for obesity. Now, as I understand it, methamphetamine is soluble in water, is that correct? Mr. Gitzxsroox. That is correct. PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14439 Mr. GoimoN. How meaningful is this prohibition? Dr. GRINSFOON. Anybody who wants to abuse it intervenously can dissolve amphetamine n water and inject it. In fact, there is greater risk in doing that than there is with phar- maceutical materials which are sterile and carefully prepared. homemade intravenous injections are not, so there is more danger there. Not only can they inject only the amphetamines, but it may be couple.d with something else, and in fact, a number of young people have done this, and particles in the retina of the eye have appeared, which have been visualized on examination by ophthamologists. Furthermore, they pointed out that they had found no evidence of necrotizing angiitis in a number of similar young drug abusers who had not taken amphetamines, but had used equivalent amounts of all the other "hard" drugs reported by the 14. In late 1971, two papers by another group of California researchers led by C. L. Itumbaugh presented observations and experimental find- ings that have all but conclusively proved Citrons initial theory. These investigators subjected 19 multiple-drug abusers ranging in age from 16 to 39 to cerebral angiography, an X-ray technique in which a (lye is injected into a patient's circulatory system, allowing physicians to examine him for possible blockage of the arteries sup- plying his brain. Rumbaugh and others found that 14 of their 19 patients showed moderate to severe occlusion, and the other 5 showed at least minimal brain damage of this sort.. Although all of the patients either admitted to or were suspected of amphetamine abuse, they had abused so many other drugs that it was impossible to blame speed as the sole or primary etiological agent. Accordingly, Rumbaugh and others administered methamphetamine by needle to five monkeys at dosages roughly equivalent to 50 to 100 milligrams for humans. Ten minutes after the first injections the researchers noted decreased caliber of many of the smaller arteries supplying the brain, with either slowing or total blockage of blood flow in some arteries in four out of fice monkeys. At the end of 2 weeks of every-other-day injections, autopsies revealed irreversible damage to the brain. Riimhaugh has recently pointed out that these investigations and laboratory experi- ments strongly suggest that intravenous methamphetamine is the likely ~~aiise for the abnormally high incidence of "stroke" victims among the 15 to 25 age group in the TAOS Angeles area. Rumbaugh stresses that a stroke-type reaction may follow even low-dose oral use of ampheta. mines, because of the wide variations in susceptibility to the toxic ef- frets of amphetamines. It is perhaps easiest to grasp a sense of the real dimensions of the psychological dangers inherent in amphetamine use if we consider only the most serious and disruptive, effects. Although restlessness, dys- plioria. logorrhea (excessive talkativeness), insomina, some degree of confusion, dizziness, transient nausea., tension, anxiety, and fear to the point of acute panic have been reported by a large number of authors, these effects are probably best considered as inseparable components of the amphetamines' alerting, stimulating, and "euphoric" proper- ties. But amphetamine psychosis, even though it was once considered PAGENO="0018" 14440 COMPETITIvE PROBLEMS IN TEE DRUG INDUSTRY extremely rare, has undergone considerable reevaluation since 1058, when P. H. Connell published his now famous monograph. The first medical report to call attention to the possibility of am- phetamine psychosis was published in 1938 by D. Young and IV. B. Scoville. In the early 1940's there were a few similar reports from Switzerland and Germany, but very few evaluations of amphetamine psychosis had been published before Connell's pioneering work. Re- viewing all the French and English literature, he was able to find only 36 cases. 0. J. Kalant, in a subsequent review of the international medical literature up until the publication of CouncIl's book, uncovered 33 additional eases. But even if Connell had come across more reports, he probably would have persisted in his motivating insight regarding the strikingly close clinical symptomatology presented by patients suffering from am- phetamine psychosis and paranoid schizophrenia. Accordingly, he launched a personal 3-year investigation of patients admitted to five London hospitals, and discovered 4-2 unmistakeable cases of amphetamine psychosis that would have otherwise undoubt- edly gone undetected. In addition, colleagues who learned of his efforts reported another 1-1 substantiated cases to him. Connell stressed that, despite his earlier suspicions, he was quite surprised to find such a relatively high incidence of amphetamine psychosis. Connell's findings stirred interest and more exact diagnosis. In the 5-year period immediately following his book's publication, 118 more cases of amphetamine psychosis were reported. as compared with only 71 in the 20 years after Young and Scoville's initial report. Mr. GonnoN. Is there any way of ascertaining in advance a person's susceptibility to the toxic effects of amphetamine! Dr. GiaNspooN. There is none. Mr. GORDON. If not, then how can a physician who prescribes these drugs adhere to the medical doctrine of "Primum non nocëre"; that is, first do no harm? Dr. GuINspooN. Well, as T mention at the close of my statement. I think that is the way in which physicians have not been as responsible about these drugs as I believe they should be. flow. it is trne there are some people who are particularly vulnerable to the effects of amphetamines. For example. someone with a congenital vascular problem in the cerebral circulation; but generally speaking, these people arc unknown until an accident occurs. One just does not know it if the patient happens to be a person who is particularly susceptible; there is no way of knowing in advance. If he has a history of it. then you do know, but certainly a doctor who is quite knowledgeable about amphetamines certainly would not give them to such a person. - I should mention that amphetamine psychoses are so common now that people do notbotherto report them. Prior to Connell's work, it had usually been assumed that only per- sons who were in some peculiar way "latent schizophrenics" or "pre- psychotics" would ever develop psychoses after even massive and prolonged doses of amphetamines. PAGENO="0019" COMPETITIVE PROBLEMS Di THE DRUG INDUSTRY 14441 But Connell strongly opposed this assumption. At least 6 of the 40 patients for whom adequate personal psychiatric histories were avail- able appeared to have been perfectly normal prior to the development of their amphetamine psychoses, and a clear majority were described as "friendly and good mixers," certainly not schizoid personalities. That a psychosis may be induced in essentially normal people by amphetamines has been substantiated by at least two clinical experi- ments using human volunteers conducted by a group of researchers at the Vanderbilt Medical School. In the first experiment, four healthy males between the ages of 25 and 33, who had no previous history of amphetamine psychoses or schizophrenia, and were described by the investigators as having "warm, boyish personality traits" were administered hourly doses `Of 10 mg dextroamphetamine, unless some significant or potentially dangerous physiological changes were noted. Two of the patients were able to tolerate "relatively large" amounts of amphetamine for 24 hours, at which point they both developed severe psychoses. The other two patients were given amphetamine at a much slower rate, because they showed either slight hypertension or fever very early in the experiment. Since their dosages were low and infrequent, they were both able to withstand the psychosis production effects of amphetamine for 5 days. However, after 170 hours these two subjects also began to exhibit "unequivocal" and "florid" psychotic symptoms, whose onset was "abrupt" and which included "paranoid ideation which was fairly well organized." Soon afterward the same group of investigators repeated almost exactly the same clinical experiment, observing the reactions of six male volunteers, aged 25 to 27, who had been judged by an independent psychiatrist to be of normal intelligence and normal-nonschizoid and nonparanoid-personality. Furthermore, none showed any signs of brain damage or mental ab. normalities as judged by clinical examinations, clinical tests, and psy- chological examinations. The same procedure was followed as in the earlier experiment, ex- cept that doses ranged from 5 to 10mg per hour. Because two subjects had experienced a previous amphetamine psy- chosis, extra precautions were taken, and they were each limited to a total of 110 mgper day. One of these two subjects was the only one of the six who did not de- velop a severe amphetamine psychosis. The total cumulative doses of the other five ranged from 120 mg-l day-to 700 mg-S days. The psychoses were almost identical with those experienced by the initial group of subjects. In commenting on the implications of both studies, the researchers emphasized that even short-tern administration of dextroampheta- mine to persons who were nonpsychotic could precipitate a paranoid psehosis, and that their experiments definitely ruled out the up till then widely accepted hypothesis that only "previously borderline psy- chotics" would sustain an amphetamine psychosis. PAGENO="0020" 14442 co~rPETITwE PROBLEMS I~ THE DRUG INDUSTRY Senator NELSON. If I may interrupt, when the drug is withdrawn, what happens to the psychosis, what modification? Dr. GRINSPOON. Yes, the amphetamine psychosis is so close from a clinical point of view to a paranoid schizophrenic psychosis that they very often are confused by clinicians. Indeed, there are only two ways of making the diagnostic distinction. One is to get a history of use of ampliettimines, and it does not have to be at very high dosage. More constantly, it is a high dosage, and then for some reason there is usually an increment of dosage just before the psychosis; so if you get such a history, you get a urinalysis, and this has to be done within 48 hours .And I should say the third diagnostic criterion is that in the case of amphetamine psychoses, the psychosis usually disappears within 4 to 5 days. It is certainly gone within a week. Ijowever, there are some patients whose psychoses last much longer, and it appears to me that these are patients whose egos are already pretty fragile, and the straw that breaks the camel's back, so to speak, is the use of amphetamines. This is the exception. Generally speaking the person who has an acute amphetamine psychosis is one who is psy- chologically pretty well put together and the psychosis will disappear within a matter of days of withdrawal of amphetamines. Senator NELSON. I noticed in some of the literature before me, there is some indication that the paranoid psychotic may be dangerous to himself and to others under these circumstances. Dr. GRINSPO0N. Yes, that is certainly true. One of the things I was going to get to, which 1 will touch on very briefly, is that people have talked about a number of drugs, and their capacity for violent criminal behavior. The drug which is probably most dangerous from that point of view is actually amphetamines; alcohol is a close second, hut amphetamines seem to have as an inherent psychopharmacological property of the drug, a capacity to induce impulsiveness. paranoia. and the need to ex- press some kind of motor behavior, so that people who are paranoid, even before they become overtly psychotic, constitute a danger. I will skip over the next paragraph and address myself to the problems of obesity. Obesity continues to be the condition for which the largest amounts of legitimately obtained amphetamines are most casually and fre- quently prescribed. but despite enthusiastic early reports as to these drugs' efficacy in dietary regimens, expert medical opinion is gradually recognizing that obesity, far from being a semihuiuorous or cosmetic difficulty, is in fact a complex, long-term problem involving critical psychological and social determinants. No one really knows its causes. It is defined as a state in which fat accumulates because food intake, in terms of caloric content, is greater than energy output. Genetic, glandular, and other physical and physioloffical causes play a statistically small role in obesity-probably in less than 10 percent- usually the obese person simply overeats. According to one study, only 12 percent of 96 very obese patients attributed their condition to glandular disease; the rest admitted that overeating was the cause and referred to psychological factors like nervousness, family difficulties, and ingrained habits. PAGENO="0021" CoMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14443 Many investigators suggest that obese patients need psychotherapy; otherwise, no dietary regimen or chemotherapy will rectify or control their excessive eating. Apart from uncommon metabolic~ aberrations, the principal factors governing appetite are social and psychological. Sonie people are trained in childhood to overeat; others move in social and business circles where food and alcohol are present in abundance and one is expected to partake. With effort, habits can be broken and living circumstances altered. Emotional problems are far more. difficult to cleaT with. Chronic ten- sion and depression nnusiially strona oral drives, low capacity to delay gratification, and the substitution off ood for other forms of pleasure- all common in eases of obesity-increase the likelihood of becoming dependent on drugs, including amphetamines. Most troubled obese patients will not persist in their efforts to diet. The few who do and lose some weight regain it. A drug that re4iiçes appetite without requiring solving the patient's emotional problem seems a reasonable alternative to what would otherwise he the almost certain failure of these individuals to lose weight if they were to depend solely on willpower. But the wisdom of such a solution must he examined. Do clinical and experimental studies reliably establish that amphetamine and its congeners have a measureable anorectic effect If so, are the benefits great enough to justify their use despite the long-term adverse effects? For example. tins is such a common thing that people eat with cer- tain kinds of mild depression and anxiety. President Taft, as you niay know only weighed about 320 before lie entered the White louse, and then fie shot tip to 400 pounds. After his term in the White House, lie was able to go down to his subprcvious 320 pounds. There is still no real understanding of how amphetamine reduces appetite. Experiments with animals have demonstrated that it is not a function of local effects on the gastrointestinal tract. There is some tvidence that lesions in the hypothalamus may result in a substantial increase in appetite. If some obese people actually have a dysfunction of the hypo- thalamus, it is possible that amphetamines reduce appetite by their effect on tins area of the brain. however, if this mechanism exists at all, it is probably secondary to the central stimulating effect. It has been suggested that dinresis may cause some of the weight loss associated with the use of ampheta- mine. Both diuretic and antidiuretic effects have been reported, how- ever, and the role of dinresis in true weight loss is far from clear. i~!r. Gonnow. You are saving that even if these drugs were. effective, they do not really reach ~ut to tIme basic problem of obesity? Dr. (huxsvoox. That is absolutely correct. They do not solve the basic underlying problem. Mr. GoRDON. IVell, the studies that were done on these antiobesity drugs were short-term studies. 8 to 12 weeks. 1kw do we know whether the people who were using the anti- obesity drugs, did not go back to their former eating habits and regain weight? PAGENO="0022" 14444 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. GRiNspoox. As a matter of fact, I am about to get to that. In 1938 a research group led by Paul Bahnsen compared 100 normal subjects receiving amphetamine with an equal number receiving placebo; 19 of the active drug group and 1 control reported a reduc- tion in appetite. The first attempts to apply these observations to the clinical man- agement of obesity were made that same year by M. F. Lesses and A. Myerson, and by P. Rosenberg in 1939; both papers reported favor- able results. Since then a long series of reports and clinical studies has agreed with them. For example, S. C. Harris, A. C. Ivy, and L. K Searle found that seven obese patients lost more weight when taking am- phetamine than when taking placebo. Those who lost most were the ones who ate least, so the main cause of weight loss was apparently suppression of appetite rather than something like higher activity level. Harris also conducted another experiment in 1947 to investigate the possibility that weight can be lost with amphetamines even when caloric intake is maintained. Ten volunteer medical students agreed to eat 3.000 calories per day. During weeks 1 and 2, the students received no medication, and during weeks 3 and 4, they received placebo. During this control period totaling 26 days, there was an average weight loss of 0.7 pounds. This the authors attribute to the fact that for some of the subjects a 3,000-calorie diet was inadequate to maintain body weight. For study weeks 5 to 13, half of the students received 10 milligrams of 11-amphetamine before. each meal, and the other half received 5 milligrams. During week 5. the subjects in both groups lost an average of 1 pound. however, the amounts leveled off quickly, and the total average loss for the active medication phase was only 1.85 pounds. The authors concluded that reduction of caloric intake: not increase in motor activity or metabolic rate, is the essential variable in weight loss from amphetamines. Another useful study was conducted by D. Adlersberg andM. F. Mayer on 2~)9 obese patients who were being treated in a clinic of a large general hospital. Treatment groups were arranged as follows: Group A patients were treated with dietary restrictions alone; group B began with this, but after 2 to 5 months oral thyroid medication-2 to 3 grains desiccated thyroid daily-was adde~; and group C, after 3 months of dietary restriction, received amphetamine sulphate-5 to 10 mdli- grains twice daily, 1 to 2 hours before lunch and dinner. Although all three groups lost weight, group C-diet plus ampheta- mine-was the most successful. However, dosages had to be increased over time to maintain weight loss and overcome tolerance. A useful contribution of this study is the authors' attempt to differ- enti ate between long- and short-term results. - The most impressive weight losses for all three groups occurred in the first 1 or 2 months. Overall, amphetamines emerged as superior to the thyroid regime: but interestingly, in the long run diet alone compared favorably with diet and amphetamine. PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14445 Further data on tolerance are supplied by Gelvin and McGavack, who studied 27 obese patients attending, the Welfare Island dis- pensary. They took an initial dose of 15 milligrams of Dexednne per day, rapidly increased to a maximum of 30 milligrams, and were per- mitted to eat as they pleased. - After 8 weeks, 47 percent were maintaining a weight loss of 1 pound per week; after 12 weeks, only 23 percent continued to lose even that much. Twenty weeks after the beginning of treatment only one patient was still losing weight. The use of amphetamine to correct faulty eating habits has been suggested, but studies with animals have shown how difficult this is. Harris gave intramuscular injections-2.5 to 20 milligrams d-ampheta- mine sulphate-to dogs 1 hour before feeding, with the result that food intake was substantially decreased. In the case of one dog-Hi kilograms in weight-who was given in. jections of 10 milligrams per day, food consumption was reduced by 87 percent and body weight by 27.4percent within 32 days. After 30 days, an injection of saline solution was substituted for the amphetamine. The animals' appetite immediately increased greatly; obviously conditioning by the amphetamine regime could not be sus- tained without the anorectic effect of the drug itself. Similarly, the experience of most physicians treating patients for obesity suggests that little long-term learning effect can be attributed to the amphetamine regime; most patients, once they stop using amphetamines or become tolerant to them, resume their former eating habits. A second series of papers on obesity and amphetamines emerged in the 1050's, heralding the use of combination drugs in which am- phetamine was supplemented with a barbiturate, in most instances amobarbital. - The advantage was reported to be an easing of the emotional ex- tremes found iu obese patients. - These studies, most of them uncontrolled and methodologically un- sound, stated that patients lost weight, as with amphetamine alone, but also improved in mood. No data indicated that the combination drugs were any more effec- tive than amphetamines alone. In the late 1050's a third series of studies began to appear, deal- ing with the effectiveness of new amphetamine congeners or new forms-for example, "timed release" packaging-of already existing amphetamines. These drugs all share the same basic chemical skeleton and have effects, including adverse ones, very similar to amphetamine sulphate, although it was claimed for one drug after another that it had fewer ~Gside effects." W. Modell writes that: It seems unlikely that any minor structural change in this group which con- tinues the same theme will separate the action that may he cllnicaliy undesirable. Yet it Is preeiscly this which is Inferred from ninny claims made for these drugs, namely the recurrent claims for reduced Incidence of insomnia, anxiety, and nervousness, with potent anorectic effect. PAGENO="0024" 14445 COMPETITWE PROBLEMS ri~ THE DRUG INDUSTRY Still, they were sometimes compared with dextroamphetamine or a combination drug and found superior. I. ii. Kupersmith conducted what he termed a "comparative clinical investigation" in which he employed ephednne-ethylenediamine com- plex, d-amphet.aminc sulphate, d-amphetamine sulphate with a bar- biturate, and placebo. The weight changes per month in descending order were -11.3, T7-7' -3.0, and +1.~ pounds. In their eagerness to establish the supe- nonty of the new amphetamines many authors failed to build even minimal controls into their research designs. The Kupersmith data come from three different groups of subjects at different times and places. The only demographic data he includes are that they were "overweight subjects" or "overweight patients." From such data it seems likely that the most important independent variable was the researcher's desire for the results to come out as they did. - A 1959 article by S. C. Freed and E. B. hays on the drug lonamin is representative of the kind of anorectic drug evaluat ion reports that have appeared in reputable medical journals during the last 85 years. The authors do not indicate how their subjects were selected, hut it is apparent that they did not use any nondrug, placebo-administered, or even dextroamphetamine-treated control group or attempt to follow- lip their patients after cessation of Tonamin treatment. Furthermore, the data they present a.re sparse and incomplete; they do not even provide information on how obese any of their subjects were before beginning their drug and diet regimens. From the limited data they supply, we can calculate that one group of 00 patients treated with fairly high-30 milligrams daily-doses of Jonarnin lost an average of less than 7 pounds over the 1-month period. This is not very convincing when one considers that the weight of many people who are not taking any drugs or making any effort to lose weight may fluctuate almost as much as tins in a month and still be well within normal limits. The authors also minimized the "side reactions" to Tonamin. assert- ing, for example, that the insomnia often experienced was "somewhat different from that occurring during amphetamine therapy." in that and the psychological mipact of a new therapy. But even if we coil- pared to the. nervous overexhilaration which (has) * * * prevented sleep following amphetamine ~ If this statement deserves any credence-not that it necessarily does-it suggests that lonamin is more likely to lead to drug abuse. than racemic amphetamine; peop]e generally (10 not persist in taking drugs they consider unpleasant. Freed anti Hays claim that Tonamin is "chemically and pliarmaco- logically different from amphetamine." However, the following year IV. Modell emphasized that: Piienyitertlarybutyiamine resin advertised as not being an amphetamine drug, is a earboxylie acid-ty~w of exchange resin which contains substituted phenyibntyianilne moieties that are released in the gastrointestinal tract. As shown In the formulas, the amine Itself clearly belongs to the amphetamine series. Ten years later, lie devoted only two brief sentences to the alleged unique mode of action and value of Tonamin in his comprehensive and PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14447 objective edition of Drugs of Choice: "All systemic effects, therefore, stein from an aniplietamine-like action. There is no good evidence that this is in any way a superior member of the group." Not surprisingly, the drugs used by Freed and Hayes were supplied by the manufacturer. The vast majority of the clinical investigations on the anorect.ic effects of amphetamines yield, to one degree or another, favorable results. This judgment must be qualified, however, because excellent results are obtained in the early stages of almost all types of treatment because of the initial willingness of subjects to cooperate with a new physician and the psychological impact of a new therapy. But even if we con- sider amphetamines generally usef iii in this respect, and I certainly do not, we must still come to grips with the question of adverse effects. Much of the obesity literature minimizes the number and severity of these effects or actually states that there are none. Finch, for example, claims that: texedrine sulphate Is a liontoxie safe drug which may safely be used in ob- stetric patients to aid them In preventing excessive gain of weight. Studies like this have led to large-scale prescription of amphetamine to pregnant women when there is evidence that it may be a teratogenic agent. An amphetamine derivative called fenfluramine, sold in the United Kingdom, Europe, and Australia as "ponderax," seems to be a hia2hly specific appetite suppressant with low ONS-stimulating and euphor- ic properties and low-addictive potential. Even so, Oswald and Ins coworkers cautiously conclude only that it mag be preferred to other amphetamines. They emphasize that; Most sUmming pills are also "pep i.liis" and invite abuse. Past experience leads to scepticism when claims are made that a new appetite-reducing drug does not affect alertness or mood. Other clinicians, mindful of amphetamines' potential for harm, as- sert that iii weight reduction the exposure is limited to a relatively short. period. But, though tIns may be the intention, it often does not turn out that way. People who have problems controlling their iiecd for constant grati- fication, as indicated by compulsive eating. find it hard to put aside a. medication that makes them "feel good." What is more, many patients consider their attempt to lose weight doomed to failure once they have lost this "magic" potion that protects them from themselves. *%\Thien the dnig is discontinued, a psychological vacuum is created which has to be filled with food. On occasion, patients have gained back even more weight than they lost, a condition commonly known as the "rebound phenomenon." So, although short-term use of the drug causes a short-term weiØtt loss, it also helps the patient avoid the issue of changing his eating liahits I doubt the wisdom of using amphetamines for weight reduction under any circumstances. Although they can cause a 3- to 4-week eu- phoric "high" that may have as one of its "side effects" a diminished PAGENO="0026" 14448 COMPETITWE PROBLEMS JR `ItE DRUG INDUSTRY food intake and consequent weight loss, after this period they are no longer effective as anorectics unless the user increases the dose, thus initiating a pattern of abuse. And after use is discontinued, the average person quickly gains back the weight he lost-or more. In short, there seems to be few conditions whic?h justify the prescnb- ing of amphetamines; the exceptions are a very select group suffering from certain varieties of narcolepsy and a number of truly hyper- kinetic children, and in these cases amphetamines should be prescribed only after a careful weighing of their potential dangers against their possible value. Mr. Goitnox. Doctor, as far as the needs of the people with nar- colepsy, there are alternatives to amphetamines, are there not? Dr. GnnqspooN. That is correct. But it is not an antiobesity drug. It is not used as an antiobesity drug. I would suspect that if it might, one could then conceive of a drug company taking and promoting its anorectic factor, and using it in treatment of obesity. That is what has happened with so many of these drugs with what were originally considered to have so-called side effects; let us say a patient in the 1030's was treated for depression with amphetamines, and then it was noted that the drug had an anorectic effect. It was considered a side effect, a bad effect, because indeed you did not want to have a patient with this kind of depression, especially where `he was not eating, to have any of this side effect. Mr. GOP~DON. When -von referred to the amphetamines in your pres- eiitation, you also included amphetamine-related drugs? Dr. GRINSPO0N. Yes. Mr. Gonnox. Fenfinramine is a little different? Dr. Gnixsroox. Yes. Mr. GoRDoN. As a matter of fact, in an article that appeared in Clinical Pharmacology & Therapeutics in 1075- Dr. Gnrxspoox. Is that the Joim Griffith article? Mr. Gounox. It is by Griffith and Jasinslu. Dr. Gnixspoox. All right. Mr. Goimox. Dr. Jasinski is going to testify tomorrow. lie likens fenfiuramine to LSD rather than amphetamines. Dr. Gruxspoox. Yes. You see, one of the things I did not get into is that this simple molecule has an extraordinary way of being modi- fied in the laboratory. It is estimated there are potentially 2,000 amphetamine derivatives. lYe have only begun to open the door to these drugs. Now, one whole area of modifying this molecule is in the direction of the so-called hallucinogenic amphetamines. There are a number of drugs on the street now which are in fact, used by many people who are interested in psychedelic expenences, and some of these drugs are in fact amphetamine derivatives. Fenfluramine seems to be a drug which is sort of midway, pharma- cologically midway between the more established amphetamine drugs and halhicinogens. It seems to bridge those two general classes. Mr. Gonoox. Now, if it is so easy to concoct a lot of different ty~es of drugs that are related to amphetamines, would it not be your opmn- PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG rNDUSTRY 14449 ion that we better do something about these drugs right now, before they proliferate on the market? Dr. GRINsPooN. There is no question that something ought to be done about them, and there is no question that they will proliferate, not only in terms of numbers of any individual drug being available, but in terms of the actual kinds of drugs; new synthesized versions of these drugs are going to be around in the future, there is no question about it. The problem is what to do about it, because, you see, the other thing about the simplicity of this molecule is that anybody who has taken an organic chemistry course in college can buy some very simple equipment, for about $25 and set up what is called a garage speed laboratory, where illicit amphetamines are produced. It is very simple to produce it that way, and one cannot talk about banning the basic ingredients that are so commonly needed and used in industry; there is no way of preventing the development of illicit amphetamine laboratories. Let. me finish the last couple of sentences of my statement. Individual physicians-not only psychiatrists, but specialists in all areas, as well as general practitioners-who have overprescribed am- phetamines in the past should be willing to recognize how they may have denied a patient help for his real problem in the very act of complying with his overt request for a pill. The near-epidemic extent of amphetamine abuse which exists in this country today is at least in part a result of the medical com- munity's basic unwillingness to recognize that fulfillment of its first responsibility is not always identical with the most immediate alle- viation of pain and suffering. That concludes my prepared statement. Senator NELsoN. Thank you, Dr. Grinspoon. I have some questions which I think I will withhold for the whole panel until all of the testimony is in, so that each of you may wish to comment. Our next witness is Dr. James J. Nora, professor of pediatrics and director of pediatric cardiology, University of Colorado Medical Center, Denver, Colo.1 You may proceed, Dr. Nora. STATEMENT OP JAMES J~. NORA, M.D., PROFESSOR OP PEDIATRICS AND DIRECTOR OP PEDIATRIC CARDIOLOGY, UNIVERSITY OP COLORADO MEDICAL CENTER, DENVER, COLO. Dr. N0RA. Senator Nelson, Mr. Gordon, ladies and gentlemen, my charge, as I understand it. is to speak to the possible role that amphet- amines and related drugs may play in the production of birth defects. if there is exposure at a vulnerable period of embryonic or fetal devel- -opment, and if there are both a genetic predisposition to react ad- versely to these drugs and a genetic predisposition to some form of maldevelopment. All of the qualifications of the previous sentence must be applied to amphetamines and to most potential teratogens. I See prepared statement and attachments of Dr. Nora beginning at p. 14912. PAGENO="0028" 14450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - Mr. Gonnox. Is it possible to ascertain in advance whether a person is predisposed to react adversely to aniplietainines? Dr. Noiu. This is an area for the next couple of decades of work, determining who is at risk for development of the various birth defects, who is at risk to respond adversely to certain agents. I think that one area where it has been pursued a great deal, and must be pursued a great deal niore. is to find those things in the en- vironment that will produce coronary heart disease. It is not quite as lay advanced in the areas of birth defects, and in identifying the individuals at risk. Unfortunately, there is no simple skin test or blood test that would help us identify who would be at risk in taking amphetamines. Fortunately, there are few agents in our environment that possess the disastrous teratogenie. potential of thalidomide or rubella virus. And, conversely, under the right coumbination of genetic predisposi- tion and exposure at a vulnerable period of development, one could project that almost any agent that has pharmacologic activity could bo teratogenic. Between these extremes. I believe there exists a number of agents causing birth defects in enough susceptible individuals to constitute a significant health hazard. It is in tins latter category that I believe dextroainplietamine may belong. Sonic of my coworkers and I have devoted a not inconsequential portion of our reseaveh activity to investigating such teratogens, which are difficult to identify in the epidemiologic sense. To give an example: Thalidomide causes malformations, including a rare sentinel anomaly. phocoinelia. in ~30 to 80 percent of infants who have had a maternal exposure during the vulnerable period of embryogenesis. With these factors in favor of prompt detection of the teratogen, thalidoniide was on the market for over 2 years before the first suspi- cions about its safety were voiced. how much more difficult is it to implicate a "low risk agent" that causes maldevelopinent in only 1 percent of exposures? Yet, if the exposures are frequent, say, in 10 percent of pregnancies, then 3.000 malformed infants would he delivered in the United States each year as a result. of takin~ such a "low risk agent." Tlie pitfalls in conducting epidemiologic studies that will yield a confident answer as to whether or not an agent is teratogenic are many. In brief, precise verification is essential in both retrospective and prospective, studies. But, even with careful verification, the possibilities for systematic bias and the limitation in the type of data obtained-no population frequency rates-make retrospective studies less conclusive titan prospective ones. - The published studies of the potential teratogenicity of ampheta- mines are retrospective. Prospective studies, in which one. could he. more confident, have not been done. The reason is simply tins: Prospective studies require many more natients and no one to date has aecumnlated a large enough series to address this question prospectively. Senator NELSoN. Have there not been animal studies? PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14451 Dr. Non4t. Yes; and I will discuss tins in detail a little later, but the proper study of mankind is man and what one finds in an animal may not really relate too well. Senator NELSoN. It is difficult to conduct such studies on humans, but in the case of animals, is it not possible to get relevant data? Dr. N0RA. The traditional animal models do not always yield the data one desires. Thalidomide did not yield the patterns that were found, and in some species it was not teratogenic at all in these tradi- tional models, and yet it turned out to he (lisast ions in humans, so you can get sonic peripheral evidence, and I will discuss this in a little bit. Senator Nasox. It may not be relevant, and it may be a long time ago, but I recall in one of the cases where it was indicated there was very serious side effects of thalidomide, and they dropped these inves- tigators and got some others, and I do not recall what the investiga- tors found that aroused their suspicions to warn the company, but 1 do reca]l it was those investigators. 1)r. NonA. The investigators getting positive results probably were using an animal model appropriate to the study, and the best animal model is a primate of some sort which is niore closely related to a liurnam i\Ir. Gonnox. Is it not also correct that the results of animal studies resulted in the FDA's withholding marketing approval for thalid- omide? Dr. N0RA. That could be one of the influences. I am not privy to what went on at that time. We have considered that amphetamine provides a good model to illustrate the obstacles in the way of reaching confident conclusions about the presence or absence of teratogenic effect of a given agent. Our own experience with this drug may be summarized briefly. In 1962, the mother of an infant born with transpositioji of the great ves- sels-a complex and frequently fatal congenital malformation of the lieartr-expressed more than the usual concern about the cause of the heart defect in her infant son. She volunteered that she had taken amphetamine diet pills dii ring her pregnancy and asked directly if the amphetamine could have caused the problem. lYe were unable to find any evidence in the literature of such an association and so reassured the mother. Bitt within 2 weeks we encountered two more such cases of transposi- tion and first trimester exposure to atuplietamines. These three cases represented a very provociitiie epidemiologic cluster. At this point we began three studies: 1. A retrospective study to compare histories of maternal ex- posures to amphetamines in congenital heart patients and in nor- mal children; 2.An animal homology study to see if we could produce trans- position of the great vessels giving amphetamines to mice a~id chicks and P. A prospective study. ctartin~ with mothers prior to delivery who had documented amphetamine exposure in the first trimester and were awaiting the outcome of their pregnancies. PAGENO="0030" 14452 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY We reported the results of the animal studies in mouse first, and in mouse, chick, and drosophila later. Amphetamine produced malformations in all three models. But this doesn't mean it produces malformations in humans. The fact that three phyla were affected, and that two strains of one species were also affected was suggestive of the teratogenic potential of the drug. An unexpected finding that greatly influenced our thinking about the etiology of congenital heart diseases in general was that in one species of mouse we caused ventricular septal defect and in another species we caused atrial septal defect. We were unable to produce transposition. It appeared that amphetamines brought out the malformation to which the strain was predisposed. And it was this observation that led us to the belief that there must be a predisposition-a malfunction and a predisposition-to react adversely to an agent which must be given at the vulnerable period of development as the three essentials of teratogenesis. The first retrospective study of congenital heart patients was in-- conclusive. We did not find a statistical difference at the 0.05 level. After publishing these findings we redesigned our protocol, admitted younger patients into the study-to reduce material memory bias-~ and tightened our verification procedures. We tightened our verification procedures and made absolutely sure that there was adequate evidence from more than one source that the person did indeed have the drug at the time she was supposed to have taken it. After 2 more years we analyzed our new data, found a statistically significant difference between the congenital heart and control groups, and were forced to retract our previous report that there was no sig-- nificant amphetamine influence in congenital heart disease. Thus two studies by the same investigators led to opposite conclu- sions. We believe the second study to be the more reliable one. It has already been pointed out that retrospective studies are less conclusive than prospective ones, so we put our eggs in the basket of a large obstetrical practice that used amphetamines liberally. I carefully avoided telling the obstetricians which of the many drugs on our questionnaire we were most- interested in, hut- a medical student working with me spilled the beans and the obstetricians immediately stopped using amphetamines and lost interest in our project. By the way, that was at a time when malpractice insurance was S60- per year. You can imagine what a threat such studies are now. We did publish a small prospective study of 240 patients, eight of whom de- livered infants with malformations, three of which were associated with maternal exposure to amphetamines. The loss of a prospective study of sufficient size was probably of positive benefit to the patients. but it has obviated our reaching the confident conclusions we desired. Since I have brought up the subject of malpractice suits, I would like to call attention to a trend which I consider to be indefensible. From the number of communications I receive from legal firms all over the country regarding the role of maternal drug exposure in birth defects, it appears that some of our legal colleagues believe that the PAGENO="0031" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14453 way to demonstrate that a drug is a tèratogen is through passionate litigation rather than through dispassionate investigation. The idea has been fostered that one need only to demonstrate the possibility that a given agent could have caused a malformation in an individual. But as I have said, and I believe that most teratologists would agree, under the right conditions almost any drug can be tera- togenic. However, the question we are addressing here is whether or not am- phetamines cause birth defects to the extent that they represent a significant health hazard. From our retrospective data and the peripheral evidence from ex- perimental studies of mechanisms of action in animal models, I would give a qualified yes to the question. There have been a number of other retrospective studies published by other investigators of teratogenic effects attributed to ampheta- mines and related sympathomimetic drugs, such as phenmetrazine. Levin found a si~nificant increase in biliary atresia following ma- t.ernal exposure to amphetamines, and we have some confirmation of this in our study. Matera and coworkers reported an infant with exencephaly, which is one of the prominent malformations we found in our mouse studies, so here again animal studies offered supportive but not conclusive evi- dence. Nelson and Forfar in a retrospective study of 1,369 patients found an excess of infants with maternal exposure to appetite suppressants among those with abnormalities. Lenz found a case of diaphragmatic hernia and Powell and John- ston, two cases, following maternal phenmetrazine administration. Moss found limb anomalies in the infant of a mother who had taken phemnetrazine.. - It should be noted that all of these studies are retrospective and some are merely case reports. but they contribute to a sizable volume of evidence which supports the possibility that these drugs are tera- togenic, despite the fact that the definitive prospective study has not been performed. If appetite suppressants. which is just a polite tenn for "uppers". had a useful function in the medical armamentarium, one could not accept the present retrospective data as sufficient evidence to abrogate the use of these drugs. We are currently trying to resolve the problem of conflicting retro- spective data regarding birth defects and the "Pill" and various pro- gestogens and estrogens through a prospective study. The point is: The world needs the "Pill" or some agent that can per- form its function equally well. I am frankly unable to identify a similar need for amphetamines and related drugs. Mr. Chairman, the references to my prepared statement follow. Senator NELSON. Are you saying you find no need for amphetamines atall~ Dr. Nomt. I am not finding it the way the world needs the "Pill." I think there is no great need for appetite suppressants, but the type of need we have is for some medications that are for very specific indi- cations, such as narcolepsy and hyperkinesis. PAGENO="0032" 14454 COMPETITIVE PROBLEMS IX THE DRUG LNDUSTRY I think you have to look at the risk/benefit ratio. I think the risk/benefit ratio to the use of amphetamines as appetite suppressants is very, very unfavorable. Senator NELSoN. I will ask the panel to address that question when we conclude, the testimony. Dr. Nona. Thank you. Mr. Chairman. That concludes my prepared testimony. Senator NELSON. Our next witness will be Dr. Tliaddeus Prout, associate professor of medicine, Johns hopkins University and elf ef of medicine, Greater Baltimore. Medical Center, Baltimore, Md. Dr. Proi.it, you niav proceed. STATEMENT OF THADDEIJS E. flOUT, M.D., ASSOCIATE PROFESSOR OF MEDICINE, JOHNS HOPKINS UNIVERSITY, AND CHIEF OF MEDICINE, GREATER BALTIMORE MEDICAL CENTER, EALTI- MORE, MD. Dr. Prtotrr. Thank you, Mr. Chairman. I appreciate the opportunity of being here. In order to save time since I know you have a tight schedule, I will place my prepared statement on file, restrict my comments to one or two areas of importance. Senator NELSON. Your statement, Dr. Proiit, will be printed in full `in the record, and you may comment extemporaneously, or however you desire.' Dr. PEOn'. Thank you, sir. First, I place in the record the conclusions and the recommenda- tions of the Committee for the Evaluation of Anorectic Drugs of the FDA, of which I was chairman. The committee had recommended that all of the anorectic drugs with abuse potential be placed in schedule II of the Comprehensive Drug Abuse Act. Senator NELSON. You are talking about amphetamines that are a!- ready there. Are you also talking about the related drugs? Dr. PEon'. All of these drugs were not there at that time, and we were addressing ourselves to those that were not. We found no reason to conclude that they should not be placed in schedule II also. Senator NELSON. That was the recommendation? Dr. PEOn'. Yes. The study had been undertaken to study the pos- sible benefits of these drugs in obesity. Senator NELSON. Which conunittee is that? Dr. Paour. This was an ad hoc committee appointed by the FDA under my chairmanship. Senator NELSoN. When was that recommendation made? Dr. Puon'. In the fall of 1972. Senator NELSON. They are all related? Dr. Paon. All had abuse-potential with one exception. But some of the comments this morning were pointing that our knowledge niay change and fenfiuramine which was believed to be an exception may now come tinder the same suspicion. At that time it was a new mcdi- cation, and we did not have sufficient evidence to see that it might have an abuse potential as well. I See prepared etaten,ent of Dr. Prout beginning at p. 14921. PAGENO="0033" COMPETITIVE flOBLEMS IN THE DRUG INDUSTRY 14455 Fenfluramine is less of a central nervous system stimulant than the other drugs in this class. If anything, it appeared to have a depressing effect, hut that in itself raised the question of whether it might have abuse potential in some other Way. I think the comments this morning have pointed out that the continued surveillance of this drug class might have some merit-. Senator NELsoN. You said this is an ad hoc-panel? Dr. PROUT. Yes, an ad hoc committee of the FDA. Senator NELSoN. Selected by whom? Dr. PROUT. Selected by the Commissioner, I presume. It was selected in part from tie Committee on Endocine and Meta- bolic Drugs, of which I am also chairman. Senator NELSON. And the recommendation was that all of the am- phetamines and related drugs be put in schedule II? That was a unani- mous recommendation? Dr. Pnov'r. Yes, it was a unanimous recommendation. These recommendations, Senator Nelson, are listed verbatim on page 3 of my prepared statement. Senator ?.~ ELsox. Page 3? Dr. Pnorjr. Yes, of my prepared statement. Senator NELSON. And those recominendat ions were made in 1972? Dr. Piuou'r. Yes, in the fall of 1972. - Senator NELSON. So that is 4 years ago? Dr. Pnon'. Yes. Senator Nnsox. Has the FDA taken any action that you are await of in respect to those recommendations? Dr. PEOn'. Some, but not all of these medications have been placed in schedule II, and they appear to have drawn the line between those that had an abuse potential, and those already Imown to be tinder abuse in the street. The FDA apparently saw themselves as a surveillance agency that could in fact watch street traffic, and, if necessary act on the basis of new information by rescheduling the agents in III and IV to schedule II if necessary. Senator NELSON. You are identifying in your statement those that were placed on schedule II following the recommendations of the ad hoc committee, and those that were not? Do we have a list of them? Dr. PRour. Yes, we do. Senator NELSON. Are they in your statement? Dr. PnouT. No; the actual schedules are not in the statement, but they are readily available from the FDA. I could make a reason- ably accurate compilation of them, but I think you would prefer to go to the official record. Mr. GORDON. As I understand it. Mr. Chairman, the amphetamines, phenmetnzine..-_preludin_and methylphenidate_Rit~]in_~hicj~ Hi- talin incidentally is for weight control, were put in schedule II, and the so-called nonamphetamines such as lonamin, Pondimin, Tenuate, and others were put in schedules Til or IV. Dr. Prmov-r. Yes, all of the rest are eitherIII or IV, including the newer ones that were under study at that time. Senator Nasox. (lo ahead. Dr. PROtTT. I think that placing some of these drugs in schedule II had two effects. First, there was a fall in the sales of those which were L3-569-77-3 PAGENO="0034" 14456 COMPETITIVE PROBLEMS IN ~1IE DRUG INDUSTRY actually placed in schedule II. However, this did not completely pre- vent the abuse of all schedule II drugs. Preludin, for example, still seems to be high on the abuse list, and this is particularly true here in the District of Columbia. The second effect was predictable. Sales of amphetamine-like com- pounds which were not placed in schedule II had a marked increase in use with the expected rise in sales. One of these was cited on national television because of the particu- larly aggressive promotional techniques of one company and for its rather high increase in sales. These drugs are now know to be subject to street abuse. If you look back to the list of the recommendations of the committee for the FDA, my first recommendation would again be that all of these drugs with abuse potential be placed in schedule II. Second, it has been demonstrated that the amphetamines and their related compounds have such trivial effectiveness in the treatment of obesity, that we should loolc again at questions of whether or not obesity should continue as nn indication for their use. Obesity is the major medical excuse for the manufacture of am- phetamines. It now seems reasonable to state that the risk of over- production of the drugs and their excessive abuse far exceeds the benefits that might be cited in the treatment of obesity. Only a few patients in association with rigid dieting, believe that the so-called anorectie drugs were the causative agent in their weight reduction. Most patients get no benefit from their use and risk the development of addiction. I would, therefore, recommend that obesity be withdrawn as an in- dkation for the therapeutic use of these drugs. This action has in fact been taken by Canada and some other coun- tries, and in my own State of Maryland. Maryland has a model law that might be duplicated in the Federal statutes. Senator NELSON. Did you say the State of Maryland? Dr. Puou'r. The State of Maryland has withdrawn obesity as an indication for prescribing amphetamines. The effect of eliminating obesity as an indication for use and of.. putting these drugs on schedule II, would in effect take them off the market. Up to 90 percent of the medication appears to be prescribed for obesity and production could probably be reduced to 10 percent or less of present production rates. As a result there would be much less drug to spill over into the street. I believe tins would reduce the legitimate manufacture of these drugs by 85 to 90 percent. Senator Nrrsox. You are saying 85 to 90 percent of its current use is for obesity, that is, prescribed in the case of obesity? Dr. PROUT. That is correct. Of course, we do not know exactly where the product is g&nz and that is another reason for our prime concern. As has been brought out here this morning the production of these medications is far in excess of any use that we might be expected for treatment of obesity, and the other medical indication. Placing them in schedule II, and withdraw- ing obesity as an indication for their use, would in fact, make a very impressive impact on the amounts of medication available, and it could only be used for the other indicated medical uses from that time on. Senator. NiLsox. If I recollect correctly, there are some 70.000 PAGENO="0035" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14457 pounds produced amounting to 12 billion pills, was that somebody's testimony? Dr. PRou'r. The testimony this morning was S billion units, enough to give 35 doses to every man, woman and child in the United States. Dr. GRINSP00N. The figure is that it was estimated that it would go to 12 billion. Senator NELSoN. Twelve billion tablets? Dr. GR.rNerouN. Yes; by units, I mean tablets, capsules, what have you. Senator NELSON. And so you give a ballpark figure, you would be recommending a reduction from 12 billion to 1 billion? Dr. Pnout Yes; something in that order. The important thing is that it can be reduced within the year, or certainly by next year. Senator NELSON. What you are saying is leave it on the market for hyperkinesis and narcolepsy indications? Dr. PROUT. In the State of Maryland there is a third category of unusual and rare conditions, which is a legitimate use. This includes a few patients such as those with Parkinson's disease5 or other individuals with neurological problems, seen in large clinics, for individuals who have certain forms of pathological obesity, such as the Pickwickian syndrome and for which amphetamines might be used. This syndrome may include narcolepsy as a part of it. There are a number of other rare uses. Senator NELSON. I was wondenng how accurate are the figures that we have on the incidence of hyperkinesis and narcolepsy. Dr. Pnot"r. I do not think we have any hard data on the figures. esti- mates vary from various regions of the country, but the highest 1 have. seen is that 3 percent of schoolchildren may have a "hyperkinet.ie syndrome." Dr. GuxsrooN. There was one estimate by HEW, I believe they pro- jected there might be as many as 4 million children who suffered from hyperkinetic syndrome. I think that is a vast overstatement, but even if one took it as an outside figure, it is very difficult to assess. The closest we could come to for narcolepsy is a figure of something in the order of 20,000, and I think that is probably a liberal estimate. Senator Nasox. What are the estimates of the number of patients who are receiving amphetamines for weight control purposes? Dr. GRINsPoON. I do not know what that number is. Senator NELSON. Go ahead. Dr. Grnxsroox. When I said 4 million, that is the number of chil- dren who are not being treated. That is the estimate of the number who might be suffering from hvperkinetic syndrome. 3rr. Goimox. M impression is that these drugs are not indicated for hyperkinesis, but rather for minimum brain disfunction as evi- denced by hyperkinesis. There are a lot of kids that are hyperactive. Does that mean we have to give these kids drugs? Dr. Pnou'r. Are you asking me? I personally do not think so, and I think that the 400.000 estimate is probably about the same as the 3 percent. These schoolchildren are elementary schoolchildren and children in junior high school. PAGENO="0036" `14453 COMPETITIVE PROBLEMS IN THE DRUG IYPVSTRY The "hyperkinetic." or the "hyperactive," syndrome may disappear spontaneously. Dr. YArn. Not very many of these children in my opinion need drugs for their management. Senator NELSON. Go ahead, Dr. Prout. Dr. PRouT. I think when obesity is eliminated as an indication most of the amphetamines will be withdrawn from the market. Certainly nil of the combinations of drags including these amphetamines will be withdrawn, but this prohibition should be extended to the am- phetamme-like compound as well. Finally, I think if we are going to have any new preparation of these drugs, or any other substituted amines for the treatment of obesity that they must pass the test of efficacy and safety that the FDA requires, perhaps more rigidly based on FDA protocol in order to eliminate any trivial products. I think there is one further extension of tins that might actually be voiced here as well. The Federal Government spends an enormous amount of money and effort trying to take over-the-counter products for obesity off the market as well. There have been two suits, one by the FTC, and one by the U.S. Postal Service, related to propanolamine. This is a very wasteful way to spend the taxpayer's money, when we could in fact eliminate them all at once rather than drug by drug. As we chase each one of these manufacturers through their trade name, they have only to come back under a new name and a new trade name, to be back in business. That makes it very difficult to fight on a one-on-one basis, and Ithink the sweeping review of that whole area is we~li worth this committee's surveillance. This is where the original FDA Committee, in its earlier recom- mendations, fulfilled it charge in its single-purposed review of whether or not these drugs were or were not useful in the treatment of obesity-. But I now think we should probably also go to other considerations nnd this is the practice of the pharmaceutical companies of bulk shipping of these drugs directly to clinics. Senator NELSON. I did not understand that. This is what? Dr. Puorr. As noted in my prepared statement there is a practice in the pharmaceutical companies of making bulk shipments of these drugs directly to certain clinics. Kow, if these facilities will in the future be unable to stay in busl- ness if obesity is withdrawn as an indication for use it will be very bard to justify the sending, a bulk shipment of 100,000 doses to any single clinic or individuaL The risk here is in losing track of the drugs. Surveillance, even of the drugs in schedule II, would be very, very difficult to follow under these circumstances. A secoi~d important point to be reviewed is the whole basis of the Telatlonship of pharmaceutical houses to the medical profession which needs to be looked into. Indeed, Senator Nelson, you touched on it this morning when you noted that certain investigators who come up with "bad answers" may no longer be supported by drug companies for their "research." Or to state it positively, one finds that the pharma- ceutical companies are vet-v likely to support "research," "consulta- tion," "teaching," `~goodwill." or whatever other term might be used to describe the favor that they curry from these excess funds that PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14459 go into medical facilities. I think it is important that we have some way of looking into the total extent of this cash flow. In brief, I would say that we should have a better surveillance of the way pharmaceuti- cal companies support this kind of "research." Indeed, there are already ways in which pharmaceutical companies can contribute to a general research, and use acceptable protocols un- der tight surveillance, by utilizing review procedures by orgarnza- tions independent of pharmaceutical companies. Contributions to medical research are very much needed and I am sure there are ways in -which this can be done, but I believe we should look mto the ways in which their present tactics are tied in with the so-called "research." A third area of concern it seems to me actually brings up an area in winch I touched upon before tins committee in 1972. I had sug- gested at that time that Congress establish a committee of "blue-ribbon untouchables" very similar to the Council on Pharmacy and Chemistry previously active in the American Medical Association. This possibility deserves further thought and discussion, especially since it drew the fire of no less a spokesman of the AMA than the late Dr. Morris Fishbein. Such a committee I think would have a number of important func- tions, one of the things that seems to be- missing in the Federal Gov- ernment is that of having a responsible agency which authorizes, or looks into the way money is spent for drugs. Millions of dollars are spent on worthless drug products by the many medical facilities of the U.S. Government at this time, and I think we must look into this and eliminate the waste. - This committee could implement another thing that has been touched on this morning, and that is the necessity of having phase IV studies. We do not wish to impede the bringing of important new drugs into medical use. What we do wish to emphasize is the fact that many drugs come to medical use in winch the long-term effects are in fact not known. Dr. Nora and others have touched on the fact that long-term studies of a retrospective nature are not usually very productive. Phase IV study implies that continuing information is1ll be gathered after the drugs are put on the open market in order to retrieve long-term an- swers to the questions of efficacy and safety. It seems to me this needs to be looked into. - This "blue-ribbon" committee- should have one other function. As I had previously proposed, there is need for consumer information on drug usage, and a need for the production of a consumer package insert. This is also a recommendation I made before this coiiimittee in December 1972. I tlunk the people expect to have this kind of consumer education, and I do not believe it can wait until other antici- pated far-reaching legislation in the health insurance field comes down. Finally, there is a very difficult new area of concern w-hiichi I ran only look upon without definite knowledo~' of how it might be solved. Ihe pliarniaceutical houses have stepped into a void of continuing medical education. I am not sure- how we can again gain control of postgraduate education of the medical profession, but as we go into a period in which, the Federal Governnient becomes more and more interested in medical practice we must all look into this more carefully. PAGENO="0038" 14460 coI~xPETITivE PROBLEMS IN THE DRUG INDUSTRY There should be teaching programs which involve medical schools, community hospitals, and people that are knowledgeable in the medi- cal fields to bring new information into practice. I have gone into some detail in the submitted paper. Mr. Chairman, I have completed comment on my report to you. Briefly, I would hope: One, t-hat the former recommendations of the committee be implemented. Two, that obesity be eliminated as a- medical indication for the use of the agents under description in which the so-called anorectic prop- erty goes hand in hand with abuse potential. Three, that over-the-counter nostrums advertised for the purpose of reducing obesity be eliminated that are continuing to be used by the citizens in a worthless manner for large sums of money. Four, that the activities of the pharmaceutical industries be it- viewed as to the ways in which they influence the practice of medicine. - Five, that- consumer education be addressed. And, finally, six, that although there is no easy solution, the man- ner by which the medical profession and the Federal Government can replace thepharmaccutical manufacturers as the principal pur- veyors of postgraduate medical training be sought. - I have suggested that this might be done through a traineeship- type of program for clinical pharmaeologists. I believe that is the only way it can be done. Senator Nasox. What is that? Dr. PR0U'r. That this is the only way it might be done. Senator Xr.tsox. What might be done? Dr. Pnocr. That we might establish a method by which continuing medical education could be supported by something other than the pharmaceutical houses in order to prevent this continuing delusion of postgraduate medical education. Thank you. Senator NELsoN. Thank you very much, Dr. Prout. Our next witness is Dr. Sumner Yafl'e. professor of clinical phar- macology a-nd pediatrics, University of Pennsylvania, and director, Division of Clinical Pharmacology, Children's Hospital, Philadel- phia, Pa. - Dr. Yaffe is also to represent Dr. Allen Goldman, associate profes- sor of Pediatrics, University of Pennsylvania, and director, teratol- ogy unit, Children's hospital, Philadelphia, Pa.1 Please proceed, Dr. Yaffe. STATEMENT OF SD1~(NER 3'. ThrEE, M.D., PROFESSOR OP CLINICAL PHARMACOLOGY AND PEDIATRICS, UNIVERSITY OF PENNSYL- VANIA, AND DIRECTOR, DIVISION OP CLINICAL PHARMACOL- OGY, CHILDREN'S HOSPITAL, PHILADELPHIA, PA. Dr. 1AFFE. Senator Nelson, Mr. Gordon, I am delighted to be here. I have two roles as I understand it this morning. One is to introduce the testimony of Dr. Allen Goldman. who is as- sociate professor of pediatrics in my institution at the University of See prepared statement of Dr. floldman beginning at p. 14696. See also prepared state- ment of Dr. ta~e beginning at p. 14967. PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14461 Pennsylvania, and also director of the teratology unit at Children's Hospital in Philadelphia. Dr. Goldman's statement, I believe, is available. I would just like, if I may, rather than to read it, to highlight it, and to leave out certain portions. Senator NELSON. That would be fine, Dr. Yaffe. The statement by Dr. Goldman will be printed in full in the record, and you may comment on it, also. Dr. YArvE. Thank you. Dr. Goldman, at the very beginning of ins statement, mentions the continuing problem of birth defects, which I think is certainly worth- while in reiterating, and that birth defects cause about 560,000 deaths annually. lie points out that the survivors are afflicted with blindness, hearing impairments, heart or circulatory defects, mental retardation, and other malformations, lie then goes on to cite the continuing usage of drugs by pregnant women. This is on page 2. Paraphrasing some of this, he mentions the fact that despite the tragedy, women continue to take drugs, whether at the advice of their physicians, or over the counter, on their own ad- vice, they take large numbers of drugs during pregnancy. There are some data mentioned from several recent studies, one in the United Kingdom and Scotland, 1973, and another from Texas. An enormous number of drugs are taken by women while they are pregnant. I would guess that they continue to take the same drugs when they are not pregnant. I should also like to emphasize that these drugs were not taken to save the mother's life or to treat the fetus, but rather to relieve symptoms, and this is a very important point, that many of these symptoms are mild and innocuous. Therefore, in my opinion, the drugs need not he taken by the women, and, were this so, we would be in an era of very decreased drag administration, consumption during pregnancy, with probably a decrease in the rate of congenital malformations. Then Dr. Goldman goes on to discuss the problem of teratogenicity in general terms, mentioning the fact that in the usual production of anatomic mal- formations, it is only the first 2 or 3 months of pregnancy where we are concerned. Drugs that are known to cause human malformations fall into four categories, the first would be the anticancer, drugs, the second being the steroidal sex hormones, androgens, estrogens, and progestins. These hormones have been associated with very delayed and long-term effects of drugs. Fifteen or twenty years after the fetus received the drug, the effect was noted in the vagina in females exposed to these drugs, and more recently, we have seen effects in the male fetus now also in young adults. They have anatomic problems with their urinary system, and problems with infertility, decreased sperm production, and capability. I think the concept is that defects may appear many decades after the administration of a drug, and I think people now are not using these specific drugs as they did in the forties and fifties to treat women who are pregnant. Now, the third area that Dr. Goldman mentioned is alcohol, some- thing that for surprising reasons, has only been recently brought to our attention. A specific type of malformation has been reported. The final group which he mentioned is that characterized by thalidomide, PAGENO="0040" 14462 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY a drug which I do not have to mention here, lie then goes on to discuss what he calls hard teratogens, those exemplified by these four classes, and soft teratogens. He classifies the antiobesity drugs, the amphetamines, as soft, and points out the difficulties in ascertain- ment, when you have a low-level of frequency. Dr. Nora has expounded in much greater details, I will not repeat this, his opinions about the teratogens and the antiobesity drugs, but it is worthwhile to point out that one needs a minimum number of 18 cases of congenital heart disease per 1,000 exposed fetuses to be able to distinguish that from background- Mr. GolmoN. That is anatomical? Dr. YArn. Yes; and that leads me to the last point, which I would like to emphasize. of Dr. Goldman's, and that is possibility of a func- tional effect, that is, effect upon the central nervous system. Although we do not have any human evidence, we do hiow that dexampheta' mines administration can produce an effect on brain function, even though there is no congenital malformation. I bring to your attention the fact that these drugs are used to minimize weight gain, and (luring pregnancy this is not a proper use of the drugs, the indications are not proper. Dr. Prout mentioned that the limited evidence about the efficacy in the first place, but I do not even have to get into that, because I think weight gain during pregnancy is a physiological effect, some- tIming that really does not need treatment, un]ess it is perhaps extremely excessfve. I think obstetricians have changed their thinking from 10. 20. 30 years ago, when women were ordered not to gain very much weight, and now there is a more generous weight allowance during pregnancy, so that the state of nutrition of the fetus will not be compromised. Mr. GoRDoN. There are a number of days when a woman can lie pregnant without even knowing it, are there not? Dr. YArn. Absolutely. Now, that is niy interpretation of Dr. Goldman's remarks. Now, if I may, I would like to move into the other area, the other role, which I have been asked to testify by the d-amphetamine and related centra1 nervous system stimulants in children. The substance of my testimony is contained in the article which Senator Nelson mentioned in the introductory remarks. This article appeared in Pediatrics in February 1973, which was written while I was chairman of the Committee on Drugs of the American Academy of Pediatrics. Here again, I would like to give you some paraphrasing of this article, and underscore certain points which are contained in it. I might say at time outset that we were prompted to prepare this commentary as an educational resource for pediatricians, who are members of the Academy of Pediatricians. We were prompted to develop this commentary for two reasons, one, time rescheduling of several of these compounds into schedule II in 1972. which has been mentioned by Dr. Prout, and, second, that in our neighboring country, Canada, time use of amphetamines for the treatment of obesity was prohibited. We did have representation on the Committee on Drugs from tIme Health Protection Branch in Canada and in some way, the Canadians PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14463 were ahead of us, and had prohibited this indication for the prescrip- tion of this drug, and this class of drugs. Senator NELSON. What year was that? Dr. YArn. Year 1972. fall of 1972. Senator NELSON. And it is in the market for what specific purpose? 1)r: YAFFE. As far as I know, Senator, it is in the market for the two reasons in which we endorsed its prescription, that is for the hyperkinetic syndrome, minimal brain disfunction, which was men- tioned before, and, second, for the treatment of narcolepsy, which was also mentioned. . There is no other indication I would a~ree on, with the rare indica- tions, which Dr. Prout mentioned, in a8iilts, but for children, these two indications. I nught say, narcolepsy in children is a very, very rare disease. If you can use the record of the Mayo Clinic, they saw 400 children over a 7-year period, in which they had seen many of the children throughout certainly the Midwestern portion of tins coimtry. So it is a very rare disease, and hardly enough to warrant the large- scale production of amphetamines which has already been mentioned. Senator NELsoN. Let me ask one more question. . - Does Canada have the same system, the schedule II.type thing, and what is happening to the use of the drug in Canada? Do you have any statistics? Dr. YArn. I ant sorry, I do not know but I would think they would have some way to control production. Senator NELSoN. We will have some testimony on that, also. Dr. YArn. To continue, therefore as far as the hyperkinetic syndrome is concerned, I think Mr. Gordon mentioned this. I would support what lie said, that methvlphenidate. although still classed as an amphetamine, is probably the drug of choice among pediatricians in this country. That is a drug which has not been promoted as an antiobesity agent, so we then come in conclusion in this paper to a recommendation that-as others have made this morning-in 1973, amphetamines be removed as antiobesity drugs, and that the usage be limited to the two indications, one being narcolepsy, and the other being the hyperkinetic syndrome associated with minimal brain disfunction. Senator NELSON. That would be your recommendation? Dr. YArn. Yes. Senator Nn.sox. Would that be the judgment of your colleaoties who are knowledgeable in this field? Dr. YArn.. Yes. I would believe so, Senator. May I just add one other statement about obesity itself, which has been discussed in terms of the causation of obesity. This in my opinion is in many instances a disease. The antecedent for obesity begins probably in early infancy, and it is due to excessive feeding by many parents in our society. As a consequence the number of fat cells iii the body become increased. The very eloquent work of Dr. hirsch and Dr. TCnittle in New York. have clearly demonstrated that if you are overfed while an infant by your mother or father, you will have an increased number of fat cefls. There is very little `that can be done when you are an adult about your obesity. You have a drive to eat, and it seems to me that perhaps we should place the emphasis on PAGENO="0042" 14464 coI~1PETJTflt PROBLEMS IN THE DRUG INDUSTRY proper feeding habits of infants, rather than trying to treat adults with driws, because they overeat. Now, I would agree that there are ninny other emotional and psy- chological reasons for overeating, that may occur later on, but it is true there are a large number of obese adults that have their origin in infancy. In fact, I have just seen an article in the New England Journal of Medicine which was published this summer, from Roches- ter, N.Y., which has examined this point. This article which is entitled "Childhood Antecedents of Adult Obesity," with a subtitle, do chubby infants become obese adults. The authors state and prove an their summary of children whose records were available in the Rochester area, 15th 20 years after they were seen by their pediatrician, that the antecedents do begin in their infancy. If you are overweight as a young infant, chances are very great that you will be overweight as an adult. Than1 you. Senator Nasot Thank you very much. I would like to ask the panel a question, the 1962 law. known as the Kefauver amendments requires substantial evidence of effectiveness, based upon well.controlled scientific studies by qualified investigators. I think that is a fair paraphrase of the provision in the statute. I would like to hear your opinion on the following question: Based upon the knowledge we now have, and the understanding in the statute as to substantial evidence of effectiveness based upon well- controlled scientific studies by qualified investigators, would these amphetamines and amphetamine-related drugs meet the efficacy standard of the statute, to be admitted into the marketplace as a prescription drug for antiobesity tre.atment~ Well, Mr. Gordon reminds inc that the other aspect of the law is safety, but given the law as to safety and as to efficacy, I would like an opinion from each of you as to whether you believe that they are now qualified to be admitted under the law to be used for the purpose of treatment of obesity? Dr. YArn. I would like to give a qualified answer if I may. I thmk there as some evidence of children, in that in the short term, I urn now talking of several weeks, amphetamines are effective as antiobesity agents, but after 1 month the effect decreases markedly, and unless the dose is mcreased significantly, winch is not a good idea, because of the risk for side effects and abuse, then there will be little efficacy. Certainly there is not any substantial evidence of efficacy, certainly not m the way in which these drugs are used, on a chronic basis, there is no substantial evidence of efficacy, and the safety of course as Mr. Gordon mentioned, and as we have heard would hardly recommend these drugs for use in prescriptions. Senator Nnsow. You would say it is hardly recommended for what? Dr. YArn. I would hardly be induced to use these drugs for obesity because of their overriding toxicity. Senator NasoN. Dr. Grinspoon? Dr. Gnn~sroo~. Senator Nelson, I believe that this whole class of drugs would not rass the test of efficacy for the treatment of obesity, and that they would not be considered drugs which do not impose PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14465 significant risk, therefore, I would definitely say that they would not pass such a test. In fact, while I think the drugs are usable for narcolepsy and hyper- Idnetic syndrome, I would add then that where narcolepsy is con- cerned, it may very well be that it would be a struggle to get them by an efficacy criterion, because indeed, as was pointed out, if people who suffer the numerically largest form of narcolepsy, take a nap for 5 or 10 minutes, that is the best treatment of all. So the biggest risk to people with narcolepsy may `be *th~ taking of these drugs, so if they just take a nap, and they recognize the problem, as employers must, this usually works quite well, so that there is no reason to take drugs. As to the question of hyperkinetic children, I think at this moment, there are some children for whom it is efficacious, and the benefits exceed the risks; however, new treatments are coming along, there are other ways to approach it, and I look to the (lay when regarding the treatment of hyperkinet.ic children, we would question whether amphetamines is the best way. My concern about the treatment of hyperkinetic children right now is that many children do not suffer `from this very poorly defined syn- drome known as minimal braIn damage, and I think it is very im- portant for a physician to be quite responsible in diagnosing this illness. Senator NasoN. Dr. Nora? Dr. Noin. If I were in this hypothetica.l position of being able at this moment to accept or reject the use of this drug in the marketplace for antiobesity, I would certainly reject it. I do not think on the basis of its efficacy or safety, that it is a drug that should be admitted for thu.t purpose. I would have some more reservations about rejection for some other purposes, but I think that the problem of abuse enters the picture, and 1 am not sure that I see a great need for the drug in the physician's annatarium. The only exceptions perthaps are hyperkinesis and narcolepsy. Senator Nasow. Dr. Prout, do you want to answer that? Dr. Pnou'r. I think I have in a sense already answered it. Certainly in my own view, the trivial loss of weight seen with these drugs (toes not come up to evidence of efficacy. In the future, we will have to deal with the question of what is a reasonable amount of weight loss, for which the drug might be prescribed. Even if this were a small amount, a half a pound a week, but there was no risk, and did not require discontinuation of the drug, or you were able to contrnue the medication for a lifetime, then we would have & very efficacious drug. So the definition of efficacy and safety is easier perhaps in the drugs we have today. The measure of what would be efficacious and safe in the future, will lead us back to the necessity of making that judgment on the basis of phase IV studies, in addition to phase 111-type studies. Mr. Goimox. The phase IV long term studies? Dr. Pnov'r. The long term studies in which evidence of the lack of safety can be amassed over a period of time. Since obesity is a life- time problem, it is not sufficient to look at their effectiveness in periods of only 8 to 12 weeks. PAGENO="0044" 14466 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. In the earlier testimony as part of the Panel, you have recommended that at the least the obesity indication be removed and put on schedule TI. Do you or do you not believe that it would meet the standards of effieacy in tenus of the current statutory meaning that proof of efficacy imist. be based on well-controlled clinical trials by qualified investiga- tors and considering the safety question? Do you think that if the application were. now pending, and on the basis of what we know, would you approve these dnigs for the treatment of obesity? Dr. PROUT. I tiunk it would not now qualify, and I would recom- mend dint obesity be withdrawn a~' an indication for its use. Mr. Goirnox. I have a couple of quc stions. This is a quotation, an excerpt from an FDA document which we have, and I will read it. "Larger questions of long-standing remain unanswered such as the Tong-term effect on morbidity and mortality of the use of anorectics. These questions are of basic importance, since the usefulness of the drugs depends in large part upon the assumption that they somehow help prevent the adverse effects of obesity." This document also states: "In addition to evidence of abuse of amphetamines, evidence also exists in fair quantity for abuse of phenmetrazine-Preludin-and di- etltylpropion-Tenuate. For other anorectics evidence of abuse is scanty or lacking. Experience with other abusable drugs has shown, however, that documentation of abuse lags markedly behind abuse, and, when it appears, is only the tip of the iceberg." Do you agree that it is desirable to use pharmacologic and chemical data to predict abuse before it occurs? - Dr. PRot-T. I think this is the basis of our declaring that a drug has abuse potential. We were able to look at a large number of animal ex- periments in which the central nervous system stimulatoi-y effect of a drug was easily documented. From that point of view, one could pre- dict, since this is the effect that it was sought in the street. that as one group of drugs becomes more difficult to procure, the others will be tried and selected on the basis of their abuse usefuhiess. I think it is im- .portant not to wait until abuse is shown in the ~treet, but to predict that possihi7~ty on the basis of abuse potential, and it is the reason why the FDA Committee drew the line right there. Dr. GRINSPOON. I would agree; it seems to me ridiculous to wait until a drug is abused on the street. There is no question we can predict which drugs will be abused, and certainly the people who argue that a drug has certain characteristics such that it will not be abused. The burden of proof should he on them. In India about 10 years ago inethaqualone was sold, and there was a lot of experience in Britain, and it was brought to the United States and sold here about 4 years ago. It was very clear at that time that it could be abused, and it is being abused on the street now, it was some- thing absolutely predictable. Dr. Non~t. I would be in agreement with the others. * Dr. YArrz. Yes. * Mr. GORDON. One more question. In view of the "trivial," this is the word used by the Food and Drug Administration, benefits to a few individuals, and the danger to both PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14467 individuals and to the public, would you consider these. drugs, if they remain on the market, as a hazard to the public health? Dr. Gaixsroox. I would certainly consider them a hazard to the public health. There is no question iii my mind that there is far more harmfulness in the general use of amphetamines for the treatment of obesity in this country titan benefit from them, and, therefore, they are clearly a haz- ard to the general health. Dr. PE0U'r. I think the question has to be answered, Mr. Gordon, based on whether or not we can in fact control their use in any reason- able way. I think that we should work within the system as much as possible, because there are ]egitimate medical uses for these medications and we might use this group as a reasonable class to discuss tim process, and there might be ways by which their use could be brought to public benefit. I think that the sharp limitation quotas and withdrawal of obesity as an indication for use would allow us to use them in other ways. There is some experience, for example the Canadian experience. which we have not examined in detail before tins committee, and which I trust will be used to help to answer that question. Their experience will show that they have been able to control these drugs to some degree. 1 think we ought to focus on the fact that some of the problems, that .Japan, and particularly Sweden. has had in protecting their citizens against the abuse of drugs, has been in large part related to the fact that they have had very little help in the worldwide community. It seems to me we ought to look at this problem in the United Nations and elsewhere, as an important member for the world community. We must look at this problem on a worldwide basis. I think our posture here in the United States will be very important but we do have to learn how to control this problem in some way. Mr. GoRDoN. Then what is the answer? Is there an answer to it? Dr. Pnon'. The answer is there way be a hazard to the public, and there are abuses, and I think we have to learn how to control th°rn. Taking them off the market entirely, and eliminating their use. I think- is probably possible but there is a whole score of agents which arc used from this family, nose drops and sinus tablets, which are not un- der discussion, all of these things will have to be looked at. The drug abuse question has got to be seen in a broader sense. In my earlier testimony I was not able to go into this, but I think we will have to look at the whole family and the whole problem in a very realistic way. I believe scheduling has got to be puthied to the ultimate, as well as the establishment of quotas, the curtailment of influence of pharnia- ceutical houses, and their whole use of the medical profession but, the education of the public, and the education of the medical profession, are all part of that question. Mr. Gomorc. You said before that the antiobesity drugs should be taken off the market? Dr. PROUT. Obesity taken off as that indication for their use. This sharply curtails their use in that field. PAGENO="0046" 14468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GoimoN. There are many drugs that have no other indication. Dr. PitouT. Then by definition, that should come off the market. If obesity is withdrawn, then those agents which have no other proposed use would in fact be withdrawn from the market. Senator NELSON. Thank you very much, gentlemen, for your very valuable testimony. We certainly appreciate your taking the time to visit with us, and to come here to testify before the committee. The hearings will resume tomorrow in this room at 10 a.m. Thank you, gentlemen. The subcommittee stands in recess. [Whereupon, the subcommittee was recessed at 12:25 p.m.J PAGENO="0047" COMPETITIVE PROBLEMS IN TILE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) WEDNESDAY, NOVEMBER 10, 1976 U.S. SENATE, SuscoM3nrrEt ON MONOPOLY or nit San~cr COM3IIflEK ON SMALL Busi~ss, Washington, D.C. The subcommittee met, pursuant to recess, at 10 a.m., in room 318, Russell Senate Office Building, lion. Gaylord Nelson, chairman, presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Karen Young, research assistant. Senator NELsoN. The subcommittee will please come to order. Our first witness today is Dr. Donald R. Jasinski, chief of the clinical pharmacology section of the National Institute on Drug Abuse, Addiction Research Center, Lexington, Ky. Dr. Jasinski, we are pleased to have you here today, and appreciate your taking time to present your testimony. Your statement will be printed in full in the record, and you may present it however you desire. STATEMENT OP DOIQAID it JASTNSKI, M.D., CHIEF, CLINICAL PHARMACOLOGY SECTION, NATIONAL INSTITUTE ON DRUG ABUSE, ADDICTION RESEARCH CENTER, LEXINGTON, KY. Dr. JAsINsICI. I choose to read the statement. Senator NasoN. Fine. Then please proceed. - Dr. JAsINsICT. Mr. Chairman and members of the subcommittee, my name is Donald R. Jasinski. I am a physician who is a commissioned officer in the U.S. Public Health Service. I hold the posftion of Chief, Clinical Pharmacology Section, of the National Institute on Drug Abuse Addiction Research Center, Lexing- ton, Ky. F?r over 40 years, the Addiction Research Center has conducted studies in volunteer prisoner addicts to assess the abuse potential of psychoactive drugs proposed for introduction into therapeutics. Such studies with narcotic analgesics have proven to be a valid means of protecting the public health. (14469) PAGENO="0048" 14470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In the last 6 years. the comparative pharmacology of stimulant drugs has been studied in order to assess the abuse potential of these drugs relative to dextroamphetamine and to provide a basis for sched- iiling decisions under the Comprehensive Drug Abuse Prevention and Control Act of 1970. The principal underlying assessment for abuse potential is the identification of a prototype drug which has been abused and is judged to be a danger to the public health. All drugs having a similar mode of action and sharing the same profile of pharmacologic effects are viewed as having a potential for abuse. Amphetamine, the prototypic drug for antiobesity agents, produces characteristic and reproducible alterations in mood, feeling states, and perception in our addict population. Volunteers can distinaiiish these amphetamine-induced subjective states from those produced by agents such as morphine or pentobarbital. One type of change is "euphoria" or feelings of well-being and elation which are felt to be related to the ability of amphetamine to initiate and maintain drugtaking. In addition, amphetamine produces other characteristic effects in- cluding increases in blood pressure, decreases in pulse rate, increases in body temperature, decreases in the amount of food eaten, and a slight increase in pupil size. From our studies, d-metliamphetamtne, methyiphenidate, phenme- trazine, 1-ephedrine, diethylpropin, phentermine, and benzephetamine all produce typical amphetamine-like effects. These drugs differ from one another in milligram-for-milligram potencies. In sufficient doses, however, all can produce the same degree of effects. Please note the following table. [The table follows:] Equivaicut cup/torogenic doses Subcutaneous studies: Milligrams d-amphetamine 10 d.methamphetamlne 10 Metliyiphenidate 20 I'henmetrazlne 40 Ephedrine fliethyiproplon 140 a-amphetamine (oral) 10 Oral studies: d-amphetsmine 10 Phentermine 20 Benzphetamine 50 * 1-ephedrlne 50 Diethylpropion 70 Dr. .JAsixsIcT. In contrast, our studies also indicate that the appetite suppressants fenfluramine and chiorphentermine are not typical amphetamine-like agents. Feniluramine in low doses can produce feelings of well-being or elation. Large doses more characteristically produce unpleasant subjective states. PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14471 Subjects clearly distinguish the effects of amphetamine from fen- fluramine and more frequently identified fenfluramine as LSD or barbiturate-like substances. A further difference is that fenfluramine has little effect on blood pressure and body temperature, but produces a marked increase in pupil size. . `l'hree subjects had visual and olfactory hallucinations, distorted time sense, fleeting paranoia and sexual hallucinations. Mr. GORDON. Dr. Jasinski. what do you mean precisely when you say the amphetamines and their relatives all produce typical amphe- tamine-like effects? Do they also have the same potential for abuse? Is that what you mean? Dr. JAsIxsxr. We administer these drugs to subjects in single doses under double-blind circumstances. This means both the subject and the person making observations are unaware in that particu'ar circum- stance, of the dose, and the exact nature of the drug. The subjects are asked to relate the fee]ings which the drug produces and to identify the drug. Under these circumstances the subjects cannot distinguish these drugs from amphetamines. In addition, when one looks at other effects which are produced- such as decrease in the amount of food eaten, the changes in pupil size, the change- in body temperature, the change in blood pressure-all these drugs produce effects which are very similar to those of amphetamines. - - - - In addition, one characteristic effect is the well-being or euphoria which is seen in a population which has history of drug abuse. All these drugs, like amphetamines, produce these feelings. Mr. GorwoN. Fenfluramine is different; it is more like LSD, is that correct? Dr. JAsIxsIn. Some of our subjects said it was LSD. - We do riot have experimental data in this regard. This would require specific- experiments to answer this question which would involve -a direct comparison to LSD. We do not have this data. Mr. Gonnow. I read your article on comparison of fenfluramine and amphetamines in man, and Twill read this to you: - - In support of Levin's studies, fenfiuramine was observed to have hailucinogenic activity in three of five subjects who experienced syndromes characterized by visual hallucinations, sensory distortion, fleeting paranoia, derealization, deper- sonalized awareness, somatic symptomatology, labile mood, a modest increase in pulse rate and blood pressure, mydriasis, and hyperactive tendon reflexes-the last not measured systematically. This configuration resembles that produced by a number of hallucinogens, inL eluding LSD and certain ring-substitu~~ amphetamin~g This similarity, plus the' cases cited by Levin, suggests that LSD-lIke, rather than an amphetamlne.like a buss potential should be considered, This Issue aside, hallucinogenic and dys- phone symptoms may well urn_it the therapeutic utility of fenifuramine as ant anorexiant. - - Dr. JAsiNsKr. Yes, sir~ Mr. Goiwow. Then it seems you would agree that this drug should not be used for that purpose, is that correct? Dr. JA5IN5KI. No; I think the meaning of that statement was-some- what different, PAGENO="0050" 14472 COMPETITWE PROBLEMS IN TIlE DRUG INDUSTRY This drug, when used therapeutically by the physician may make the patient feel bad. Then patients will not take the drug, or will com- plain to the physician. As a result the physician will not lind this par- ticular drug useful. The meaning of that statement was that though this was not an amphetamine-like drug, these effects might limit fenfluramine's usefulness in therapeutics, and that- Mr. GonnoN. I do not understand this. Does fenfiuramine make you feel good, or does it make you feel bad? Dr. JASiNSKI. It will do both. In low doses, in some of our subjects, they felt good. ~iith the long-term administration, or with very large doses, pa- tients might feel bad. The literature on the use of fenfluramine has reported feeling states of sedation, and lethargy. The drug does not make people feel par- ticularly good when they take it therapeutically. I think that this may be a limitation on its usefulness as an appetite suppressant mainly because of consumer acceptance. Mr. GoitnoN. Please proceed. Dr. JAsIxssl. Ohlorphentermine markedly increases pupil size, pro- duces sedation which is regarded as unpleasant rather than euphoric. decreases appetite without producing increases in blood pressure or body temperature. Some subjects were grossly sedated by chlorphentermine, but no hallucinatory syndromes were observed. Abuse potential judgments from pharmacological studies can only be validated by comparison with actual incidences of abuse of available drugs. In this regard, methamphetamine, phenmatrizine and mcthylpheu- idate are three of the drugs pharmacologically equivalent to amphetamine. At times all have had a high incidence of abuse equaling that of amphetamine. On the other hand, three antiobesity drugs, diethylpro- pion, benzphetamine, and phentermine are also amphetamine-like drugs which are abused. - The incidence of abuse of these drugs is much less than that of amphetamine. One source of information on abuse incidence is the Drug Abuse Warning Network-Project DAWN-which is a program cosponsored by the National Institute on Drug Abuse and the Drug Enforcement Administration. This program tabulates drug mentions associated with drug-related deaths from medical examiners and drug-related medical or psycho- logical emergencies from hospital emergency rooms and crisis centers. In calendar year 1975, the number of mentions in Project DAWN for diethylpro~pion and phentermine were only 5 to 8 percent of those for amphetamine. According to the National Prescription Audit for this same period, the number of new prescriptions written for these drugs were 40 to 50 percent of those for amphetamine, suggesting that the lower incidence of abuse cannot be accounted for simply by differences in the relative amounts prescribed by physicians. PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14473 Similarly, the number of mentions for benzphetamine is only 1 per- cent of those for amphetamine, while the number of new prescriptions .are 6 percent of those for amphetamine. Senator NELSoN. May I ask you a question, Doctor? Dr. JASINSKI. Yes. Senator NELsoN. In the middle of page 3 you mention three anti- obesity-like drugs, and you name them. Are they also amphetamme. like druos? Do th~se three drugs that you mentioned have any indicated use for obesity? Dr. JASINSKL As far as I know, Senator, yes, they are only used as antiobesity drugs now. Senator NELSON. And you indicated they are subject to abuse, but innch less than amphetamines? Dr. JASINSICI. Yes. . . . Senator NELSON. Are you familiar with any studies indicating the `efficacy of these three drugs as antiobesity drugs? Dr. JAsINsin. The specific examples, I do not think I can quote offhand I know the literature in general, but I have not personally conducted Eny studies of the antiobesity effects of these agents, so my knowledge would only be from the literature. This is not my area of expertise, the area of obesity. Senator NELSoN. Doctor, you mentioned methylphenidate. I want to remind you it is not an antiobesity drug. It is not one of the indications. Dr. JA5IN5EI. Yes. Senator NELsoN. You state that the DAWN program tabulates drug mentions associated with drug-related deaths from medical examiners and drug-related medical or psychological emergencies from hospital emergency rooms and crisis centers. Why is this a good measure of drug abuse? Are you not assuming that abuse of a drug necessarily culminates in death or a hospitai emergency room? Dr. JASIN5ICI. I think there are a number of reservations about this data. The difficulty is that we have very few other systems which gather data itt abuse incidence. Its advantage is the large data base which is a very extensive survey from many sources. I think Pro3ect DAWN was instituted in 1973; however, the use of this data and its validity is just beginning to develop. It is about the only source of data we have, but I think it is cer- tainly characteristic of the situation. We do not have a particular sur- rev of the situation at the present time. `You must have an ongoing survey. The second issue is among what sources of populations does one look. Ilere I think the judgment is made, and I had nothing to do with Project DAWN, to examine public health problems and medical problems from people who would come into contact with the physicians... To collect epidemiological evidence on drug abuse becomes very difficult since it is usually a clandestine activity. These people generally only surface in contact with law en- forcement agencies, or when they come in contact with medical agen- cies, so it becomes a difficult problem in how to approach this. DAWN is the only ongoing data that we have. PAGENO="0052" 14474 coMrrrITIvE PROBLEMS IN THE DRUG iNDUSTRY Senator NELSoN. It does not measure drug abuse? Dr. .JAsiwsKI. No, it measures medical incidents which occur for the particular drug. It has been used as a crude index of drug abuse. Senator NasoN. Is there any way to extrapolate such figures from the statistics of those who end up requiring medical care, hospitaliza- lion-some of the consequences of drug abuse? Dr. JASINSK1. There is, for example, the Project DAWN reports prepared by the National Institute of Drug Abuse and the Drug En- forcement Agency which contain a profile on individual drugs. In this a number of questions are asked of the people who have been in trouble. Why they took the drug, the reason for taking the drug, the source of the drug-and I do not remember this exactly, for amphetamines, but I think-whether they took tins for pleasurable effects, or they felt they were dependent upon the drug. I know they had the age range of the patients broken down, and this data is published from the period of 1973. Senator NELSON. But do they intend to extrapolate from these statis- tics the total number of people who in fact use the drugs? Dr. JA5INSTU. No, I do not think they do this. If they do this, I am unaware of this. Whether they have attempted to do tins, I just don't know. An additional NIDA-sponsored survey conducted from October 1974 to May 1975 supports these conclusions from DAWN. In this study, 2.510 men representative of all men in the general population who were 20 to 30 years old in 1974, were surveyed for their nonmedical use of stimulant drugs. The specific stimulant drugs reported were amphetamine, meth- amphetamine, methylphenidate, phenmetrazine, and biphetamine. There were no mentions of diethyipropion, benzphetamine, or phentermine. Similar considerations also indicate a relatively low incidence of abuse of both fenfluramine and elorphentermine, two agents which are not pharmacologically equivalent to amphetamine. The assessment. studies in prisoner addicts are. valid measures of abuse potential; however, it must also be concluded that factors other than pharmacological equivalence determine the incidence of abuse of a drug. In the ease of drugs marketed as appetite suppressants, these factors are not known but experience suggests that at any point in time the incidence of abuse of a drug is determined by customs, fads, attit.ud~s. type of pharmaceutical preparation and knowledge of the drug's actions. In addition, certain properties of the drugs themselves may limit attractiveness to the drug abuser. For example. drugs which cannot easily be dissolved in water are less attractive to the addict who injects drugs. In retrospect. the comparative pharmacology and the incidence of abuse support the scheduling decisions made under the Comprehensive Drug Abuse Prevention and Control Act of 1970 concerning the anti- obesity drugs. PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14475 On the one hand, amphetamine, methamphetainine, phenmetrazine, and methylphenidate are recognized as having similar abuse potential, and as such have been placed in schedule IT. On the other hand, a number of other appetite suppressants have not been extensively abused to date. These drugs have been placed in schedules ITT or IV. Mr. Gounox. Doctor, you mentioned attitudes, they can change, can they not Dr. JA5INSET. Yes, sir. Mr. Goanox. I understand that Preludin has become one of the most widely used drugs in the District of Columbia area. rrlIe price in the street is about $10 per pill. We received a call from the Police Department of Louisville, Ky., that Preludin is the most popular street drug there, also. The price is about $8 per pill. In an undated FDA document, we have statements that documenta- tion of abuse lags markedly behind abuse, and when it appears, is only the tip of the iceberg. My question is, why wait until, there is an epidemic, why not use pharniacologic and chemical data to predict abuse before it occurs? Dr. jAsINsifI. I think this may be justified in certain instance from a historical perspective. It depends on how one directs one's thinking, and one's bias in the particular area. My particular bias is toward the practice of medicine, and making a rational scheduling policy such that scheduling does not affec.t the patient who may be using the drugs in legitimate circumstances and for legitimate needs. We know many drugs which have required uses in medicine, and which benefit the patients, also have other properties ]eading to self-ingestion. At times the people will use these drugs to such a point that they will experience toxic effects, or will engage in behaviors which our society condemns. In these instances we must, in my opinion, be as much concerned about not removing drugs from patients inappropriately. We must make decisions on a relatively rational basis. I think front a historical perspective, we have had a number of drugs which have been pharmacologically equivalent, but which have been used by physicians, and in a sense by people without creating major public health problems. \[r. Gonnox. Bitt it is not an antiobesity drug, so you are really cre- ating a straw man. We are talking about antiobesity drugs. We are not talking about that type of a drug. Now, given the very limited use, the FDA says that the benefits are clinically trivial, those were the exact words used by the FDA, by the advisory committee. Given these trivial benefits, and given the abuse potential, and other side effects. how (10 you figure the benefit-to-risk ratio? Dr. jxsxxsTcT. What I ant talking about is the relative risk. The data which I have bears on relative risk from a particular toxic effect, which is the ability to induce and maintain self-ingestion behavior. - Now. this is a risk which occurs with all the compounds. PAGENO="0054" 14476 COMPETITIVE PROBLEMS W THE DRUG INDUSTRY On the other hand, I have no data on the benefits. All of these deci-- sions come from benefit-to-risk ratios. I think tha.t within the Comprehensive Control Act, as I would see it, there is only one distinction. If one says these drugs are not thera- peutically useful, then all of the drugs would go to schedule I. The difference of schedules between II and III, and IV and 17, are not based on relative therapeutic ability of drugs. I think they only call for having an accepted medical use. If the drugs do not have approved medical utility, then I think all drugs would go into schedule I. Senator NELSON. If they have no efficacy at all, they should not be- on the market at all. Dr. JAsrNsIcI. That is right. Senator NELSON. So you would not permit them, in effect, on the market? * Dr. JAsINsICI. That is correct. I think in terms of the data, the de- cision to market these or not market these was not my mandate, nor- within my ability. Mine was only to assess the relative abuse potential and the risk to' public health from the ability to self-ingest, and I think the benefit part of the ratio factor is another question which I have an opinion, but I do not have expert testimony. Senator NELSON. Just so the record will be clear, then you, in evalu- ating these various drugs, in making judgments about abuse potential, you are not concerning yourself necessarily with the question of whether or not they meet the standards of the law of safety and efficacy? Dr. JASINSKL That is true. Senator NELSON. So you may have a drug on the marketplace that you conclude does not have much risk of being widely abused, but you are not reaching the conclusion whether or not it has any value for the treatment of any condition? Dr. JASIN5RI. That is true. Senator NELSON. You are dealing with abuse problems? Dr. JASINSKT. That is true. Senator NELSON. Unrelated to the question of efficacy of the drug in treating a particular condition? Dr. JAsINsET. That is true. Senator NELSON. All right. Dr. JAsINsICT. For c1a~ity, the scheduling of drugs, and the data which we generate, many times will affect questions of efficacy in an indirect way. It is obvious that if the drug is controlled on the basis: of pharmacological data in a very high schedule, the manufacturer may choose not to market the drug. If it is marketed, the physician may choose not to use this drug. and select an agent which is on a lower schedule, so our data does affect the pattern in which drugs are used. Some would argue that all drugs which have pharmacological equiv- alence to amphetamine should be placed in schedule II in order to pro- tect the public health. PAGENO="0055" COMPETITIVE PROBLEMS IN ThE DRUG INDUSTRY 14477 My own opinion is that this action would in certain instances be detrimental to the public health. The group most directly affected would be those patients using the drugs in a therapeutic situation since restrictive controls make them less available to the consumer. This situation is most clearly illustrated with ephedrine. In contrast to amphetamine, epliedrine is not used as an antiobesity drug, but is used mainly in the treatment of asthma to relieve spasms of the bron- chioles in the lungs. An amphetamine-like spectrum of pharmacologic effects, including euphoria, indicates that ephedrine has an abuse potential. Ephedrine is available in small amounts in a number of over-the- counter preparations and can be purchased without a prescription. The incidence of abuse of ephedrine is quite low and there is no evi- dence of danger to the public health. Under the present circumstances, the control of ephedrine is unwar- ranted, especially since the major consequences would be to decrease the availability and increase the cost to patients with chronic asthma. In conclusion, the utility and need for assessment studies to protect the public health is self-evident, especially in those instances where new agents are being introduced into therapeutics. It is in the interest of public health that we make rational schedul- ing decisions to forewarn the therapist of the dangers of the drugs he may prescribe and to assist him in their rational use. At the same time, inappropriate controls must be avoided since this would place unnecessary burdens on the patient. Our studies with stimulants have demonstrated that drugs which are structurally dissimilar to amphetamine can produce amphetamine- like effects and have abuse potential. A similar situation exists with substitutes for narcotics where a large number of synthetic and structurally unrelated drugs produce effects similar to morphine and heroin. Further, drugs which are structurally similar to amphetamine do not necessarily produce amphetamine-like effects. In this regard, we have only preliminary data on two recently intro- duced antiobesity agents, cloretermine and mazindol. We have not studied phendimetrazine. Unfortunately, further data on these agents will not be obtained. Mr. Chairman, this concludes my formal testimony. I will be pleased to answer any questions you and other members of the subcommittee may have. senator NasoN. We have asked all of the questions we have. Thank you very much, Doctor. Dr. JA5IN5KJ. Thank you very much. Senator Nasox. Dr. thomas M. Gellert of Huntington, N.Y. was to appear also this morning, and he has wired the committee that he would be unable to get here, so we hope to have him testify next week. Our next witness is Dr. Barrett Scoville of Washington, D.C. I believe he was formerly associated with the Food and Drug Administration. Would you please identify your work with the Food and Drug Administration? PAGENO="0056" 14478 COMPEflTIYE PROBLEMS IN THE DRUG rNDUSTRY STATEMENT OF BARRETT SCOVILLE, M.D., OF WASHINGTON, D.C. Dr. SCOVILLE. I formerly directed the Division of Neuropharmaco- logical Drug Products, which is one of the six FDA drug review divisions. Senator NELSON. Your statement will be printed in f till. You may present it in whatever way you desire. Dr. SC0VILLE. Thank you, sir. I will read the statement. Mr. Chairman, members of the subcommittee, I am here to provide you and the public with information on the decisions made about anorectic drugs-drugs used in treating obesity-during the time I worked in the Food and Drug Administration, and about my current personal opinions on what modifications of those decisions may be de- sirable, as well as on any other matters you wish to ask me about. I have testified before this committee in the past about the FDA review of drugs used in treating obesity. To recapitulate, in 1971 and 1972, the Food and Drug Administra- tion was confronted with decisions on the efficacy and safety of old and new anorectic drugs, some 11 chemical entities in all, over 130 drug products. The questions about efficacy included questions on the amount of weight loss, if any, associated with the use of anorectie drugs by obese patients, the duration of administration of the drugs, and possible dif- ferences in efficacy among the different chemical entities evaluated. The safety questions involved chiefly the public health hazards of a special toxicity, that of the potential of these drugs for producing de- pendence and for being abused. Data bearing on the efficacy questions included over 200 controlled trial involving almost 10.000 patients, trials carried out by drug man- ufacturers and submitted to FDA as part of various applications. The data on safety were a more heterogeneous assemblage of differ- ent sorts of evidence-chemical, animal, and human-which might have some bearing on abuse potential and other safety questions. The efficacy review involved an unprecedented reexamination of all individual patient data sheets, representing 70,000 patient visits, com- puterization of the data, and FDA reanalysis of the data, using its own computers and statisticians-who deserve much credit for the massive job. In making the final decisions on the drugs, the FDA was advised by a consultant panel headed by Dr. Thaddeus Prout. The former Council on Drugs of the American Medical Association, headed by Dr. Harry Shirkey, also gave us its opinion on the proposed actions. The institutional FDA decisions were embodied in a comprehensive memorandum proposing various alternatives with the pros and cons of each, the final decisions being initialed by the Commissioner of Food and Drugs. In carrying out the decisions, the FDA itself implemented decisions with respect to marketing approval and relabeling. Decisions on controls to be imposed because of abuse potential were and are the primary responsibility of the Bureau of Narcotics and Dangerous Drugs, now the Drug Enforcement Administration, al- PAGENO="0057" COMPETITIVE FROBLEMS IN THE DRUG INDUSTRY 14479 though the FDA does have major statutory responsibilities in this area, too. Recommendations were forwarded to the BNDD and controls were imposed by that agency. The results of our review, which ended in the latter half of 197~ with implementation of the decisions in early 1973, were as follows: First, a consistent policy and set of regulatory actions for all ano- rectics, based on a better characterization of their limited but une- quivocal superiority to nondrug therapy and including recommenda- tions that they be used only for short-term use as adjuncts to diet. Second, the elimination of a large number of combination drug products. Only two major combination products remain on the mar- ket, with litigation ongoing. The position of the manufacturer of these drugs, Smith, Kline & French, appears ethically and legally weakened by their failure to report important adverse information on the abuse potential of one of their products. Mr. GoRDoN. Could you elaborate on that, please? Dr. Scovnnj. This was pointed out in a Federal Register notice of 1973. The decision may have to be decided in court or in a hearing of this nature. Representatives of SKF came to FDA, bearing marketing studies which they felt supported their claim that their drug has little or no abuse. Independently, it also turned out they had in their possession a sep- arate study carried on by contract, showing that their drug was known and shown to be sold in the street. This was a study that they did not submit. This selective submission of evidence to the FDA seems to strike at the very basis of our current regulatory process. Mr. GoRDoN. I have sonic more questions along those lines. What finally happened? Is not this a violation of the law? Dr. Scovitrz. In my perception of the events, if they turn out to be true, it will be against the law. Mr. GonnoN. You said if it turns out to be true, you think there was a violation of the law? Dr. Scoviaa Yes. If the facts are correct, yes. Mr. GolmoN. If the facts are correctr-you think there was a viola- tion of the law Dr. ScOVILT.E. Yes. Mr. GORDON-. Has there been anything done about that as far as you know? Dr. ScOVJLT.E. Well, the FDA put this statement in what is called an opportunity for hearing, a proposal to withdraw approval of new drug applications. Mr. GomjoN. That was in 1973? Dr. SrnVILLE. Yes, sir. I am somewhat sympathetic with what appears to be the untimely response of the FDA, in that they are involved in large numbers of responses to notices of opportunity for hearings, for a very large num- her of drugs which are under the PEST review. I am sure they have a document in preparation dealing with this issue, but it has not to my knowledge been yet published. PAGENO="0058" 14480 COMPE'flTIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GoRDoN. Eskatrol, I think, is a $51/2 million a year item, so ob- viously the company would be very anxious to keep h on the market. Is Dexamyl the other one? Dr. ScovraE. Dexamvl is the other; yes, sir. Third, controls bearing on abuse potential were imposed on eight of these drugs for the first time, in a precedent-setting class action. Fourth, all injectable anorectics were eliminated from the market. You may wish to know what I think of these decisions with the benefit of hindsight, over 3 years after the fact. I believe that the basic efficacy decision remains a good one. Obesity remains a chronic disease, extremely difficult to treat, and even the limited efficacy of anorectic drugs is better than nothing. The safety decisions appear in need of revision. It is my under- standing that you will hear the Government data suggesting or show- ing that amphetamines remain the leading stimulant drug of abuse- with the possible exception of cocaine-in spite of the most restricted measures. If so, it would seem reasonable to withdraw approval of ampheta- mines for use in obesity, for which safer drugs are available. In a parallel fashion, the use of any other schedule II drugs in obe- sity should be examined to see if there may be a similar abuse problem. Senator NELsoN. On the question of efficacy, Dr. Prout testified yes-. terday, and he was the chairman of the special committee which was advisory to the FDA, and their conclusion after their studies was unanimous, which was that amphetamines should be removed from the market for purposes of treating obesity, because their effect, to use their words, was trivial, and the abuse widespread. You seem to be saying two tiungs, if there is abuse, somehow or other the abuse ought to stop, and that you think that it meets stand- ards of efficacy. Do you agree wit.h the FDA's special committee headed by Dr. Prout that they should not be used at all, or should be put in schedule II? Dr. ScovrntE. I think, sir, that the language of the group was that all of the anorectics produced about the same amount of weight loss, and so if that is so, and I believe it is. as far as data distinguished be- tween the drugs, their the question becomes one of relative safety. You might ask, why not get rid of the most dangerous and leave the safe ones available for us to treat obesity. I suggest it would seem to be reasonable for the Government to do that. Senator NELSON. Yesterday, I believe, all of the witnesses-possibly one had slight reservations-at least three of them agreed with Dri Prout-Drs. Grinspoon. Nora Prout and Yaffe-indicated that there ought not be indication for use of obesity, that that indication ought to be removed if the results were trivial, and three of them indicated that under today's standards of efficacy, they do not think the drug ouwht to be on the market in the first place. Dr. ScovrcLE. That is where I am personally disagreeing. Senator NELsoN. For purposes of treating obesity? Dr. ScovatE. I believe that the most dangerous, the most abusable of these drugs should be removed because of their abuse potNitial. There is a spectrum of abuse potentials, ranging from amphetamines on the one hand, down to some of the other drugs, perhaps those which have a substituted benzene ring, chlorphentermine perhaps, having PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14481 less abuse potential. It is my value judgment that obese people need treatment, that drugs are a reasonable form of short-term treatment of obesity, that the obese should not be deprived totally of drugs because of the abuse potential. Senator NELSoN. I guess I am still puzzled by this. You stated, it is my understanding, that amphetamines-Let me read this. It is my understanding that you wlu hear government data suggesting or showing that amphetamines remain the leading stimulant drug of abuse-with the possible exception of cocaine-in spite of the most restricted measures. If so, it would seem reasonable to withdraw approval of amphetamines for use in obesity * You are saying that if that abuse is statistically proven, which the testimony thus far asserts, that you would prohibit their use in the treatment of obesity, is that correct? I am referring to amphetamines. Dr. SCOVILLE. Yes, sir. Perhaps there is a confusion of tenninology. By some people amphetamines is used loosely to include all anorectic drugs. I am trying to use it in a more specific way as referring to one of approximately 11 chemicals, one which has the most abuse potential of any of the 11. My statement does not apply to all anorectic drugs, but only to a specific group among them. Amphetamines and anorectics are not synonomous in my terminology. Mr. Goimox. Amphetamines and anoreetics are not synonomous? Dr. Scovxrn. Not synonomous, yes. Senator Nrtsox. But I take it you are saying those amphetamines, cr any other-correct me if I am wrong-are subject to widespread abuse. If they are, they should not be in the marketplace for the mdi- .cated purpose of treating obesity? Dr. ScovitLr. That is my feeling. Senator Nasox. All right. Dr. ScovnLE. Along those lines, I go on to point out that the other anoreetics were quite difficult to evaluate for abuse or abuse potential in 1972. Data were scanty, and none had been subject to epidemic abuse. - We nonetheless recommended control on grounds of abuse potential. It is my understanding that in the interval, some of these drugs have been better tested, with confinnation of their abuse potential, and that observers of patterns of abuse have seen abuse potential turn into actual abuse in the street for some of these drugs. You have or will have obtained testimony on this problem from more expert witnesses than rue. If the data are as I suggest, they will support greater controls for some of the drugs currently in schedules III and IV. Thank you. Senator Nnsox. Thank you. Doctor Scoville. Mr. GORDoN. The Food and Drug Administration has made an overall study. They pooled several hundred studies, and then made on" hirr study out of it. They ran it through a computer, is that correct? Dr. SCOVILLE. It was analyzed, study by study. PAGENO="0060" 14482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We did so-to-speak place ail drug-treated patients and placebo- treated patients into two separate pools to see what happened, but that was not the basis for the decision. Mr. Gonnow. I have a document here that I ask be put in the record in the tippropriate place. Senator Nasox. So ordered without objection. Mr. Goanow. This is a document that was submitted by the Federal officer from the Food and Drug Administration to the HEW panel. In it, he states as follows: Of the 206 studIes reviewed, 122 were contained in Just three NDA's. As can be seen from tbe following tabulation derived from data accumulated by FDA statisticians, the reviewing physicians deemed less than half of the 122 to be adequate to permit valid conclusions: NDA numbarand name of drug Reviewing physician Does study permit valid conclusions? Yes Ito Uncertain Total 16-618--Ponditnin Dr. Freeman Dr. Wrigtt 16-680--Voranil Dr. Trilling 17-247-Mazindol Dr. Woo lotal 0 0 33 16 21 16 18 6 0 0 3 9 21 16 54 31 49 61 Ii 121 In spite of the above, the statisticians were instructed to include all 122 of their computer analysis. The above judgments of inadequacy were based primarily on the in- adequacies of, and deviations from, the clinical protocols; the objec- tions raised in my Medical Officer Reviews-copies of which were submitted to Commissioner Schmidt on March 7, 1975-included senous doubts as to the validity of some of the lab data and hence are additive, rather than merely corroborative of the above tabulation. Will you comment on that, please? Dr. Scovian. I do not suppose~he comments on what conclusions would be permitted by excluding the studies that were found in- adequate. Mr. Gonnox. The writer says the above judgments were based pri- manly on inadequancies of the data and deviation from the clinical protocol. And he goes on as T had read. Dr. ScoviaL. Well, that is his opinion. Subsequent to the medical officers' individual overall reviews, each individual patient was re- viewed, coded, key punched, and went through the computer. I know the medical officers did not and could not have looked at each data sheet on the scale subsequently done. Mr. GORDON. Actually he cites four physicians, four medical officers. They are Dr. Freeman. Dr. Wright. Dr. Trilling, and Dr. Woo. As I see it, they put it together, they took the reviews of these four physicians, so you have really five people making this claim, people who reviewed each of these drug applications. Dr. SCOVILLE. Well. I think Dr. Knox would agree that lie has fairly strong feelings about the uce of anorocties. which are known in- side the FDA and not on the outside. PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14483 In order to avoid bias on the part of medical officers, we took pains to analyze every single patient, and have somebody inspect every pa- tient data sheet before it was used in the analysis, and we tried to overcome personal bias by reviews. Mr. GonnoN. It is not just Dr. Knox. but it is four other physicians, so you would have to say five of them were biased. Dr. SCOViLLE. Well, it is hard to argue with those, without going hack and reviewing the ways the opinions were expressed, and the basis. I gratuitously suggest that even in the worst case, it is unlikely that all 22 studies on a single drug were invalid, which is what one of the medical officers proposed. Senator Nasow. I think tIns raises some important questions, but the Food and Drug Administration will appear. We do not expect you to recall off the top of your head all of these statistics without having them before you, so we will put these ques- tions to the Food and Drug Administration. Dr. SCOVILLE. Thank you. sir. Mr. GolmoN. &ow, in the FDA document dated February 17, the re- viewing medical officers claimed the total weight loss for those groups on diet plus drugs was small compared to those on diet alone. Twill read this: "It Is generally agreed that there Is a definite danger of abuse connected with the use of these drugs. - "While there is no unanimity of opinion as to the efficacy of these drugs, the following opinions merit careful consideration: "The British Medical Association has eoneluded that `These drugs should be avoided so far as possible in the treatment of obesity * * *~ "Arthur Grollinan has stated that ` . . . There is no evidence to Indicate that these agents suppress appetite as has been claimed, which is the basis usually for advocating their use. The only rationale for their use Is the hope that by counter- acting the depression Induced by hunger the patient Is better able to abstain from overeating. However, the anorerigenic agents have proven of little efficacy in actual praetice * ` "S S * The results obtained with anorexinnt agents therefore (1) are in many instances inferior to those obtained with unsnpplemented diets, (2) show the same marked variations present In the tabulated results of diet alone, and (3) indicate that the newer agents often compared poorly with the older ones whose de- ficiencies they presumably were Intended to correct. * * " * I stand With a minority of physicians in feeling that these drugs no longer have any place In the practice of medicine, with one or two rare excep- tions. -: - "I understand that one or two other countries have actually banned the use of those highly dangerous drugs. There is no justification for our continuing their `legal' use. To continue it would be simply to perpetuate one more massive in- consistency In our standards of morailty.*** "The present labeling fails to give the physician any idea of the degree of efficacy which has been demonstrated in the MhlAs for these compounds. It is unlikely that anyone reading the present labeilng would suspect that the sup- porting dnta in the MDAS revealed such a limited degree of efficacy. Although we customarily do not Include such information in package inserts, the am- phetamines constitute a special case and must -be dealt with accordingly. * * "I urge that the labeling of these compounds be revised to include. in each case, a factual tabulation of the actual amonnts of weight lose which have been reported by the various investigators, to include the duration of therapy, so that the physician will be In a better position to decide as to whether or not use of a sympathomimatie amine Is warranted. The common practice of expressing results In terms of rate of weight loss per week Is particularly objectionable and should he discontinued. * " PAGENO="0062" .~ 14484 COMPETITIVE PROBLEMS ~N THE DRUG rNDUSTRY What can you tell us about the quality of testing to establish ef- ficacy of antiobesity drugs, and would you say in retrospect, that they met the standards envisaged by the law? Dr. Scovmrz. The ones that were used in the review, in the opinion of those that had the studies computerized, did meet the standards of the law. I cannot give you details about individual investigators. I think we would have to go through case by case, if there were some suspicious things that anybody wished to bring up. I would have to say that in the general approach, the FDA reviews the documents, and anything suspicious is looked at more carefully. Occasionally field investigations are carried out. Mr. Goirnox. here is a letter signed by Dr. Jennings dated Feb- ruary 19, 1970, that the drug Voranil was not approvable. lie stated that "Bias has been introduced into the statistical analyses by delet- ing data from certain investigations in such a manner as to exclude unfavorable findings." Can you recall how often you found this kind of tactic? Dr.. Scovnj.~. I do not recall. May I ask the date of that? Mr. Goimox. February 19, 1970. Dr. ScovlaE. The general approach when bias is detected is to in- form the manufacturer of it, and a common response to such a state- ment is for the data to be resubmitted in a format determined by the FDA in a way in which the FDA tries to lay it all out so as to elimi- nate a potential for bias. It is to eliminate potential for bias that we went over every patient report form. Mr. Gonnox. Did you find this is a common thing, this type of with- holding of essential information, or using statistics in such a way that you get a favorable finding? Dr. Scovatn. It is hard to be sure of motives. In the case of inadequacy of statistical analysis, it is usually due to inferior motives or inferior abilities, and it is difficult to tell which. Mr. Gonnox. That is all. Senator NELsoN. Thank you very much, Dr. Scoville. We appreci- ate your taking the time to come and present your testimony this morning. Dr. SCOVITLE. Thank you very much. Senator NELSON. Our next witness is Dr. Eugene Jolly, president, Biometric Testing, Inc., Englewood, N.J. Dr. Jolly, we appreciate your taking the time to appear here this morning. Your testimony will be printed in full in the record. You may present it however you desire. STATEMENT OP EUGENE B. lOLL?, M.D., PH. B., PRESIDENT, BIOMETRIC TESTING, INC., ENOLEwOOD CLIPPS, NJ. Dr. JOLLY. Thank you, Senator. Senator Nelson, Mr. Gordon, it is a privilege to be here with you today to provide a summary of my findings resulting from clinical investigations of amphetamines and related drugs used as adjuncts in PAGENO="0063" COMPETITIVE PROBLEMS TN TIlE DRUG INDUSTRY 14485 the treatment of obesity and my thoughts in regard to the applicabil- ity of these drugs in clinical medicine. It is a particular honor to discuss these matters with you, Senator Nelson, one of the truly distinguished citizens of my home State. By way of introduction, Biometric Testing, Inc., is an independent testing laboratory, engaged in clinical research performed for the food, drug, cosmetic, and chemical industries on a contract basis. As a recognized clinical pharmacologist with over 20 years of ex- perience in drug research and development, my technical function is to design appropriate studies on test products, closely monitor their progress, evaluate responses to the test products and provide a com- prehensive interpretation of the data obtained. I should emphasize that I am a researcher and do not practice medi- cine. Our list of sponsors includes a wide sprectrurn of large, intermedi- ate, and small firms. Of particular interest is our work for the small drug manufacturers. It is probable that we have conducted more bio- availability comparisons with generic drugs than any other research group in the world. We are well known by both the industry and the Food and Drug Administration for our work in this field. Senator NasoN. How many personnel do you have, and what are their credentials? Dr. JoLLY. We have about 30 right now. Senator Nasox. Thirty? Dr. Join. About 30.' Well, actually my associate, he is an internist and gastroenterologist. Senator NasoN. You have an internist and a gastroenterologist? I)r. Join. Yes. We also have many physicians who assist us. There are specific tests, let us say we have a phase I test of a new drug, which requires constant physician monitoring, we will have outside physicians come in routinely. We have dermatologists who will do skin work. Senator NELSON. These would be specialists who are practicing, but are not employees of Biometric Testing? Dr. Jotty. That is right. Senator NELSON. And who work on a contract basis? Dr. JoLLY. Yes. Senator NasoN. Within your own organization, how many full- time employees do you have? Dr. JoLLY. About 30. Senator NasoN. What scientific, medical, and pharmacological specialties are represented? Dr. Join. At one time we had two nurses. We have a full.registered nurse, and at one time we had two, but our business decreased, and we have one now. Senator NELsoN. Full-time internist? Dr. JOLLY. The internist, Dr. Tessler, is on call at all times, but he is not on the premise at all times. Senator NELSON. Does he have a practice? I Dr. ~oiiy subsequently submitted the foliowing: "Actuai count 2~." PAGENO="0064" 14486 CO~1PETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. JOLLY. Yes, lie is on the staff with several hospitals in the city. We have several medical technicians, and then we have a few people who have been involved in research, who are not actually trained with medical-technical degrees and medical technologies, but they have been associated with research over the years. Until recently, we had a biophysicist, but he left us recently. Senator Nasox. Do you have any statisticians? Dr. JoLLY. We have a trainee statistician, and we employ Dr. Ilvman Menduke (Jefferson Medical College) on a retainer basis. We are attempting to improve our capabilities in this area. We do have computer time, and complete statistical assessments for drug houses, usually major drug firms will do their own analytical work, their own statistical analyses. They are better equipped for it. Senator Nasox. What exactly does your organization do? Do you do animal testing? Dr. JOLLY. No. Senator Nasox. You (10 testing at the human being level! Dr. JOLLY. Yes, volunteers. Senator Nasox. Pardon? Dr. Join. They are completely volunteers. Senator NELSON. But you are testing; do you do the chemical testing and the animal testing, anything like that? Dr. JOLLY. No. Senator NELSON. So you are doing the so-called clinical testing on human beings? Dr. JOLLY. Right. Senator Nasox. Where do you get your patients? Do you have doctors? Dr. JolLy. No. Senator Nasox. how do you find your patients? Dr. JOLLY. It is kind of grows like topsy. People enjoy doing re- search work, and when they find they are treated properly, and what they are doing is explained to them, they will tend to come in time and time again, and participate in tests, and it is good if you have a stable population; - but it keeps growing so long as you are in a oiven area. Some of them have been coming for die entire 7 years we have been in operation. They also are given monetary considerations. It is perfectly rea- sonable, rational and proper that they should be paid for their serv- ices, and they can make a little extra money. I like to think they enjoy it, and get a feeling of participation in the research. Senator Nasox. You do testing on ill patients? Dr. JOLLY. No. Senator Nasox. They are all healthy patients? Dr. JOLLY. Yes, with few exceptions. Obesity is a disease, but they are not sick people.- so we will accept the obesity state. We will test cold preparations, for example, these subjects are sick, but maybe not sick enough to go to a doctor. PAGENO="0065" CO~J1PETITWE PROBLEMS IN THE DRUG INDUSTRY 14487 If we find somebody, and we have on many occasions found some- body that requires medical attention, they will be referred or told to go to their own individual physician, and many times we will find people who are ill. Senator Nu~sox. So you are testing healthy patients. What are you testing for? Dr. Jouir. Mainly for safety. Sometimes for effectiveness, in the case of amphetamines, this is strictly for effectiveness. Senator NELSON. So in that testing, what was your protocol? Dr. JOLLY. The protocol was devised by the company. Very often I will design protocols for people, because I have had a wide experi- ence in this area. But the protocol I received was very, very well designed, and I think Dr. Scoville actually participated in some of the designs, or at least had a chance to review some of them, just to make sure that everything was covered. Senator NELSON. Did you do any bioavailabihty stuthes? Dr. JOLLY. That is another part of my presentation. We are probably the largest, we have done more studies than any- body in the world in this area. There are bioavailability comparisons on antibiotics, let's say, that are marketed, and we have done a tremendous number of those. Now, these studies, because we want to prove, or we want to deter- mine that the generic drug is equivalent to the referenced standard, and sometimes we find they are not, but most often they are. Senator NELSON. So if we have a generic producer, he wants to go into the marketplace on an unpatented drug or the patent runs out, and they come to you with their formulation, their Compollfld, you test it to determine whether it achieves a particular blood level or what the bioavailability is on a certain time schedule compared with the standard one in the marketplace, the brand name, is that what you do? Dr. Join. Yes. Senator NELSON. All right. Dr. JOLLY. Those are controlled studies as well. Senator Nrr.sox. But you do not do any testing on sick patients to determine the effectiveness of a particular drug against a particular target organism? Dr. Joay. No: we practice research only, but I will state this, we do outside clinical work at hospitals, at places overseas, in haiti we do some work. Senator NELSON. What do you mean outside hospital work? Dr. JOLLY. We do not do any clinical work for people and patients in our facility; however, we might conduct a study at New York Hos- pital, or someplace else. We do some work in Puerto Rico, and at a hospital under the direc- tion of doctors atthehospital. Now, what is our function? Our function is to monitor these studies, the thing is to make sure that they are completing the case reports, the way they were designed, that they are conducting the studies that were designed according to the protocol. Senator NELSON. That they are what? 85-569---77-----5 PAGENO="0066" 14488 crn~4PE'riTIvE PROBLEMS IN THE DRUG INDUSTRY Dr. Joar. That they are conducting the study designed according to protocol, that they maintain their records, their proper records, and that they maintain all of the data required by that protocol, and perhaps some I might feel would be of interest along with it. We have also done work in Haiti. These would be large-scale testing, vaccines, for example. Senator NELSON. Vaccines? Dr. JOLLY. 1~ Senator NELSON. Now is that on all healthy patients? Dr. JOLLY. Those are not specifically under our direction. They are under our direction, but they are conducted by physicians in these areas. We monitor them. Usually we will select physicians who arc certified. Senator NELSON. I take it you conduct studies and investigations to determine, then, whether the particular product meets the statutory standard of efficacy. I assume that is what you must have doue with the antiobesity drugs? Dr. JOLLY. Yes. Senator NElsoN. And so your studies complied with the statute which requires well controlled scientific studies by qualified investi- gators producing substantial evidence of efficacy? Dr. ,JOLLY. I am pleased to assure you of that. Senator NET.SON. So some of the studies involved questions of dli. cacy, some involved other bioavailability, that sort of thing? Dr. JOLLY. Basic safety; right. Can it be applied to the skin without producing sensitivity or irritation. Senator NELSoN. You do, I take it, studies on both prescription and nonprescription drugs? Dr. JOLLY. Cosmetics as well. Sometimes food. Sometimes we deter- mine the effects of food on situations, stomach acids, this sort of thing. Senator NELSON. Where is most of your work, insofar ~s drugs are concerned, in the field of prescriptions or nonprescriptions? Dr. Jor~Ly. About half and half. About half of our work I would say at the present time and during the last year or two has been the bloavailahility work, which has been a very important aspect of the Food and Drug Administration. All of us have been interested in generic drugs in the last 2 ye~~i~r~ That has been a very large section of our business. During the last few years we have been involved in phase I testing. This is the, test on drugs when they first come out of the laboratory, and these are again extremely complex, and very, very tightly designed tests. lYe keep subjects in the unit, during several days. They actually live in the unit, and are fed there. They will have around the clock nursing care and technical people with them. This is phase I work. Senator NELSON. In your own facility? Dr. JOLLY. Yes, sir. I have been told it is one of the finest clinical pharmacolo~~ units; best equipped in the country. PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14489 Senator NasoN. Did I understand you to say you have done more bio work than any other lab? Dr. JOLLY. I would say of all of the studies, that would be our greatest number. Senator Nasox. Were you involved in the studies on bibavailability of chioramphenicol? Dr. JOLLY. No; I missed that one. Other antibiotics have been tested by ~ Senator Nasox. Antibiotics for bioavailability? Dr. JOLLY. Yes; we still do a number of them. Senator NELSON. Does this mean for the purpose of determining for a producer whether or not it is an antibiotic he wants to market, that it achieves appropriate availability within certain time schedules? Dr. JOLLY. Sometimes. We do some for some of the larger companies, where they already are accepted, but they want to recheck their product. Senator NELSON. You are a clinical pharmacologist; do you have a degree in that field? Dr. JoLLY. I have a degree in medicine from the University of Michigan. I have a degree in pharmacology from the University of Wisconsin Senator NELSON. You say you are not a practicing physician? Dr. ,Jonx. That is correct. Senator Nrtsox. Do you have a license to practice? Dr. JOLLY. No; I never have. Senator NELSON. You have been in the research field at all times? Dr. JOLLY. I had been with the Food and Drug Administration for a while, way back. Senator NELSON. Go ahead. That was just so I could understand fa1rly well what it is you do. Go ahead. Dr. JOLLY. The amphetamine-like drugs fall into the general cate- gory of synipathomimetic agents. That is, they mimic a part or all of the responses seen from activation of the sympathetic nervous sys- tem, the so-called fight or flight mechanism of the body. These responses include: An increase in bloodflow to the heart, lungs, skeletal muscle and brain; stimulation of the heart with an Increase in cardiac output; dilatation of the bronchi and bronchioles of the lungs to allow more efficient oxygenation of the blood; and, central nervous system stimulation counteracting fatigue and increas- ing mental alertness. Metabolic effects include elevation in blood glucose and fatty acids and an increase in metabolism mainly through breakdown of fatty acids. It is important to recognize that there are numerous drugs in this category which produce sympathomimetic actions in various degrees. Therefore were amphetamine products, for example, to be removed from the market, other commercially available drugs could be substi- tuted for them. This question will be considered in our discussion as will the pos- sibility of imposing further restrictions on the distribution of some or all of these products. PAGENO="0068" 14490 COMPETITIVE PROBLEMS IN Tilt DRUG rNDUSTUY Of the series, methamphetamine and amphetamine are the most powerful central nervous system stimulants. The stimulant actions of one of these, amphetamine, were first described by Alles in 1933. In 1935, Prinzmetal and Bloomberg initiated clinical use of ampheta- mine for the treatment of narcolepsy, a disease characterized by in- ability to stay awake. Since that time, amphetamine products have been employed for a variety of conditions including chronic fatigue, parkinsomsm, epilepsy, childhood hyperkinesis, and poisoning by CNS depressants. Of course, the most popular use of amphetamine products today is in the treatment of obesity. Of the various clinical applications, experts still consider ampheta- mine as valuable in the treatment of patients with narcolepsy and for children with liyperkinesis in selected cases. This condition is very prevalent, experts estimating that some 5 percent of our children are affected to some degree. One of my children, for example, exhibited sufficient hyperactivity, lack of attention span, and associated be- havioral problems to require therapy. Similar symptoms were ex- hibited by some of my other children and drug therapy might have been useful. In retrospect, I probably also presented simi'iar symptoms during childhood. Ilyperkinesis in children requires more intensive study and greater recognition. It is frequently associated with learn- ing, speech, and other perceptual deficits. My own son suffered severe emotional problems related to the disease which one psychologist felt represented a borderline psychosis. The mental and emotional scars that are unavoidable sequellae represent the most damaging hazards associated with this disorder. Fortunately, the symptoms usually mod- crate with age and are seldom apparent in young adults. Obesity of course is the most prevalent disease in our society. Just from the cosmetic standpoint, the disease can represent a serious threat to well being, and we all appreciate the importance of the quality of life as opposed to its duration. The contribution of obesity to the in- cidence and severity of other diseases; particularly those involving the lungs, heart, and blood vessels are considered by most experts to he significant. However, epidemiological surveys suggest that re- markable influences on longevity are only seen with early onset obesity; dating back to the teenages, twenties, and early thirties. Conversely, moderate obesity does not appear to significantly change morbidity and mortality associated with pulmonary and cardiovascular disease when weight gains start in later years-after 40. Of course, severe obesity at any age represents a serious disease state which can adversely effect the function of all organ systems. There should be no question that amphetamine and related drugs are effective adjuncts in a therapeutic program for obesity. Their actions are clearcut and reproduceable. Senator Nnsox. Have you read the literature and the testimony yesterday of the four witnesses who recognize the recommendations of the FDA panel headed by Dr. Prout. that amphetamines' use indicated for obesity should he removed, that the results of treatment of obesity are "trivial," are you aware of it? Dr. JOLLY. I have become aware of that. Senator Nrtsox. Do you disagree? Dr. Jortr. No, not really. PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14491 My data came from very tightly controlled very definitive clinical investigation. I was trying to prove that these drugs produced significantly more weight loss than placebos. Senator NrLsoic. And was this short term? Dr. Joar. It is short-term, so I do not think the two can be com- pared, and I do not practice medicine, so I do not think I could argue with the results with Dr. Scoville, for example, who evaluated these drugs to a much greater degree than I. Senator Nasox. You are looking at it solely from the aspect of the short-term impact of amphetamine related to weight loss, and it was a double blind study? - Dr. Joux. Very tightly controlled, very rigid, in everything. Senator NELSON So your conclusion is only related to short-term use of the amphetamines in cases of obesity in connection with the diet, versus the placebo with diet? Dr. JOLLY. Right. Senator NELSON. And it has nothing to do with the long-term result? Dr. JOLLY. That is correct. - - My evaluation of the research work accomplished with amphet- amine-like drugs has been requested. With the disclaimer that specific projects cannot be evaluated with precision unless they are monitored and the data thoroughly reviewed, my general opinion is that the background of animal and clinical work on these drugs is both exten- sive and adequate to make a judgement of effectiveness under condi- tions of use. The actions of these drugs are clear-cut and even under relatively lax experimental conditions, should be reproduceable. Con- trolled studies to demonstrate effectiveness in comparison to placebos require hard work but no unusual skills. Study administrators may frequently be tempted to guess which patients are being treated with active drugs because of the side effects exhibited. This is a research problem common with the study of most pharmacologically active drugs. Experienced researchers discourage such speculation by the technical personnel. Those who do engage in guessing games will often find out that they were wrong. The actions of a placebo will often match and sometimes exceed those of an active material. Conversely, a very potent drug may not elicit any remarkable signs or symptoms in some individuals. Regardless, when objective endpoints are available, such as actual weight loss, assessments are simplified and data are more concrete. Moreover, when results obtained from a number of research sites prove essentially equivalent, it can be concluded that the findings are valid. On this basis, the effectiveness of amphetamine-like products as ad- juncts in the treatment of obesity has been generally accepted by ex- perth qualified by training and experience to make these judgements. Our data, confirmed by other investigators and resulting from separate investigations of amphetamine formulations and two related drugs can be summarized as follows: 1. Patients treated with amphetamines who complete the study re- quirements, weekly clinical visits, maintenance of the prescribed dos- age intake, continued diligence during study periods ranging from S to 1G weeks, on the average will lose more weight than patients who PAGENO="0070" 14492 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY are maintained on placebo medication during equivalent periods of time. 2. Weight loss in both placebo and treated groups are more notable when dietary plans are detailed and maximum caloric intakes are cal- culated for each patient on the basis of height and body build, in con- trast to~ weight losses associated with less rigid programs involving nonspecific dietary restrictions. 3. Fewer patients treated with placebo can maintain the personal motivation required to complete a weight reduction program, in com- parison to patients treated with an amphetamine formulation or re- lated product. There will he significantly more dropouts in the placebo group prior to completion of the study requirements. 4. The most important aspect in a weight reduction program is per- sonal motivation. Unless highly motivated an individual cannot stay on a diet and no program will be successful. 5. Patients do not appear to become resistant to the effects of amphetamine, rather they gradually lose motivation. 6. Very obese ~aticnts have great difficulty in reducing caloric in- take and losing significant amounts of weight with or without an am- phetamine crutch. Such individuals are often called compulsive eaters or food addicts. 7. The amount of attention paid to the trials and tribulations of obese subjects is directly proportional to the success attained. Review- ing progress, counseling, gentle persuasion and strong encouragement are important facets of a weight-reduction program. A rather dramatic illustration of the profound imfluence of the human psyche on eating habits is afforded by reviewing results of ad- ministration of sympathomimetic drugs to experimental animals. In the so-called lower forms these drugs are truly anorexigenic-appetite reducing-drugs. Most of us regard our canine friends as the most hedonistic of all creatures when it comes to food. Yet dogs given amphetamine will frequently stop eating entirely and literally starve themselves to death. The effects in rats and monkeys are a little less extreme but still remarkable. None require diet programs, motiva- tion, tender loving care or any of the other forms of psychological bolstering so important for humans. Clearly, if we resembled our animal predecessors just a little more closely, amphetamines might `be fine, reasonably safe drugs for treat- ment of obesity. True, they may produce numerous side effects such as anxiety, tenseness, restlessness, throbbing headaches, tremors, weak- ness, dizziness, and palpitations and, most important, difficulty in sleep- ing. But the side effects are usually controllable by dose reductions and tend to abate with continued use. Surprisingly, the stress which amphetamines induce on the system does not appear to produce any appreciable harm with moderate doses during short periods, except possibly to individuals with advanced cardiovascular disease. Rather the problem with the amphetamines as with many other drugs which affect the central nervous system relates to that intricate, mysterious, perverse tissue mass, the human brain; responsible for the indefinable human psyche. During a relatively short span of avail- ability, amphetamines have emerged as major drugs of abuse. PAGENO="0071" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 14493 In consideration of the number of very unpleasant side effects a reasonable question is why? Like most drugs subject to abuse, amphet- amines produce desirable responses that for some individuals out- weigh any associated discomfort or, in gross overdosage, physical distress. Compulsive users of amphetamines fall into roughly two categories. Individuals who consume therapeutic doses or doses only slightly in excess of therapeutic doses routinely, but not necessarily daily, fall into the first category. Such individuals have learned to rely on the drug to help them cope with the demands of their social environment. Amphetamines produce an elevation in mood and increased alertness. They counteract fatigue and improve the ability to concentrate. Physi- cal performance may be enhanced considerably at times. Perhaps the most insidious perceived benefit is an increase of initiative and self- confidence. Even though, on occasions, paradoxical responses occur, it is easy to understand how the student, the athlete, truckdrivers and other in- dividuals who receive rewards for either intense or prolonged efforts can be hooked. Consider also the overworked or harassed executive who finds that amphetamines improve the quality and quantity of his work output, while increasing self-confidence and the housewife who may use the drug simply to counteract boredom. Some of these mildly addicted individuals use the drug for years and don't present any remarkalbie social problem except occasional dis- tressing loquaciousness. With moderation, amphetamine effects sound good and have a definite appeal. Unfortunately all is not as rosy as it sounds. Users have difficulty sleeping and tend to either become ex- hausted or to use sedatives starting the classical "upper-downer" cycle. Some find alcohol an effective antidote for the stimulant side effects. Alcohol nnd sedatives as a whole are really more pleasant drugs and can become a far greater problem than the amphetamines. Actually people don't become physically dependent on amphetamines. They can stop use without any terribly unpleasant responses. But they can and do become physically dependent on alcohol and some even to the seda- tive hypnotic drugs. Other problems associated with- chronic use are less well defined; however, mental depression and gastrointestinal diseases appear to be relatively frequent concomitants of routine amphetamine intake. Nevertheless, the most important side effect of weight reduction pro- grams in which amphetamine is employed as an adjunct, is chronic compulsive use of moderate doses. . - - Experts regard even this form of abuse as more often a result of experimentation and subsequent reinforcement of a sensation of need for the drug in order to function, rather than as an iatrogenic medi- cafly induced problem. This pathway appears to be characteristic of all drugs of abuse. However, susceptibility to moderate abuse seems widespread and the risks involved are undoubtedly real, even during periods -of short-term use- adequately~ supervised by- competent physicians. - - - - - - - - - - - - Self-administration of gross overdoes of amphetamine-like products either orally, by inhalation or by intravenous injection represent a sec- ond and extremely hazardous form of abuse. Such activities are re- stricted preponderantly to members of our "drug culture." Individuals PAGENO="0072" 14494 COMPETITIVE PROBLEMS IT~ ThE DRUG INDUSTRY who employ large doses of amphetamine, methamphetamine or sim- ilar drugs usually abuse other central nervous system drugs including alcohol, opiates, barbiturates and marihuana. It seems that any mech- anism that can provide them with a means of escape from the expec- tations and impingement of society, their conscience and even con- sciousness, is subject to adaptation by these individuals. Amphetamines are valued because of a "rush" sensation produced particularly when injected. The exhilaration experienced reportedly resembles a sexual release. Cardiovascular and CNS side effects are of course magnified and it is difficult to understand how any degree of pleasure can compensate for the associated unpleasantness. I've only seen the results of acute amphetamine abuse on one occasion during a day-long visit at the home of a university professor, a psychologist by training. On arrival in the morning, his wife appeared to be float- ing on air. She remained that way until shortly before our departure in the evening, when she collapsed into a deep sleep. During the day s~he would not or could not maintain a given conversation or sit for any length of time. She was inordinately garrulous and obviously edgy. This response was purportedly the result of sniffing a quantity of dextroamphetamine. Most of us have seen the results of chronic, gross amphetamine abuse on TV, or at least read descriptions in the lay press. The anorexic ac- tions of the drugs are illustrated by the fact that chronic users gen- erally appear emaciated. But signs of mental disturbances are also obvious during periods of prolonged and repeated use. Diminished in- telligence level can be appreciated particularly in previously highly intelligent individuals. Delusions and frank hallucinations are com- mon. Feelings of persecution, suicidal urges, and even homicidal re- sponses are characteristic of this category of amphetamine addiction. Deaths resulting from amphetamine overdosage can occur, but most often are a result of administration of companion drugs. Actually, it is amazing how resistant the cardiovascular system of the human being is to this form of grievous assault; particularly when one consid- ers that the death rate from cardiovascular disease remains our lead- ing killer. Fortunately, when an amphetamine addict is "dried out" mental and physical pathology usually prove reversible. Nor do chronic, high dose, amphetamine abusers suffer withdrawal symptoms seen with ad- diction to depressant drugs; unless they happen to be addicted to any of these materials at the same time. Also, gross amphetamine abuse is usually episodic rather than continual as with classical opiate, seda- tive addiction. however, the property of tolerance to high doses is shared by this group. A dose of amphetamine which might prove fatal to a normal person may be employed routinely by some. Finally, it should be emphasized that this form of addiction to amphetamine is regarded by many experts to present the greatest potential for social aberrancies of a hazardous nature among the whole group of drug abuse problems. These individuals can be mutilators of children as well as adults, rapists and cold-blooded killers. One wonders for ex- ample, if the Manson cult were amphetamine freaks. The issue remains whether the risk to benefit ration associated with the therapeutic use of amphetamine for obesity, or any other disease, is PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14495 sufficiently low to justify their continued commercial availability. At present straight amphetamine and methamphetamines are included in schedule II of the Controlled Substances Act along with morphme, cocaine, and other drugs of abuse. Should these two drugs in particu- lar be relegated to category I, thereby prohibiting any form of com- mercial distribution? Should their use be restricted to cases of narcolepsy or childhood hyperkinesis in which they may well represent drugs of choice? Those who hold that an elevation to the category I status would be overkill point out that initial results obtained through imposing the category II restrictions have been moderately effective in diminishing the low-dose amphetamine abuse problem and that -with improved surveillance this form of moderate abuse will be effectively retarded. Many have doubts that a category I status would have any appreciable effect on severe abuse incidence in spite of increased effectiveness of our enforcement officials. The stre'~'t price of amphetamines, which rumor tells us is presently about $3 per dose would certainly increase which may afford some deterrent action; but, more likely, such an increase would prove of greater efficacy in supporting the ventures of organized crime. Speakmg to the pro-category I question. the therapeutic merit of amphetamine products are probably not sufficiently remarkable to dic- tate that they remain available even with further labeling restrictions. Senator NELSON. What are you saying? That they not be marketed at all? Dr. JOLLY. I think I am hedging a little. Senator NELsoN. All right. Dr. JOLLY. The next sentence I think really says what I mean. It seems unlikely that clinicians on the whole would strenuously object if the amphetamine products were completely banned; larticu- larly if they could be assured that deletion of these occasionally very useful drugs would not be an exercise in futility. Senator NELSON. You say it is unlikely? Dr. .JOLLY. I think so. You have seen that, obviously yesterday. Particularly I think many of them have some doutts about the value of taking drugs off the market realistically, because it seems to me it is frequently an exercise of futility. It really does not stop the horrible problems, and many of them feel that there ought to be better ways. An investigative reporter, with `cvhom I have become friendly re- cently disclosed to me that reliable information exists suggesting that other sympathomimetic drugs are presently achieving the widespread abuse category. He specifically designated the drug, phenteramine as a popular am- phetamine substitute. This drug is presently listed among the drugs with low abuse poten- tial in category IV. Our work at Biometric Testing, Inc., indicates that at effective therapeutic doses some of the syrnpathomimetic side effects may occur-.dry mouth, palpitations, nervousness-but that the mood-elevating, antifatigue actions associated with amphetamine and methainphetaniine are minimal. PAGENO="0074" 14496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Most investigators would discount a significant abuse potential for plienteramine and similar drugs on the basis of the data available in the literature. The drugs have just not proven to elicit sufficiently rewarding re- sponses in comparison to associated discomfort. Yet, we cannot sell the human animal short. A lesser crutch will frequently be acceptable if the parent is not available, even though it is reasonable to assume that unwanted side effects will be proportion- ately amplified with higher doses. Although not as extensively studied as amphetamine. phenteramine, and other drugs with similar activity have been well characterized pharmacologically. Jerome Jaffe in the standard test, Goodman & Gilman cites the work of Martin and his associates-Clin. Pharmacol. Ther. 12:245, 1971- which suggest that some representatives of the series can produce central nervous system stimulation in experimental animals compara- ble to that of amphetamine depending upon the dose administered. Since human investigations have been restricted to recommended doses, the relevancy of these data in humans cannot be defined. how- ever, as a response to the invitation to discuss this problem with you I have explored this possibility further. A former classmate and expert in the pharmacology of drug addic- tion, Dr. Gerald Deneau, and we have heard from Dr. Jasinski ou the same thing earlier, provided me with data showing that primates under given conditions will self-administer seine of these presumably less stimulant sympathomimetics. These data support the work of Martin, and others, and suggest that the appreciated amphetamine responses might be obtainable with elevated doses. It is difficult for me to judge what the relevancy of these data are. Any evidence suggesting a significant abuse potential requires criti- cal evaluation before conclusions are warranted. To achieve a conclusion that a given amphetamine-related product possesses abuse potential of an order to dictate added sanctions, it should be possible to document an increasing incidence of abuse. In contradiction to my reporter friend, another close observer has failed to note any remarkable or alarming upsurge in recreational, nonmedical use of the amphetamine-related drugs. He states that fenfiuramine, a new-er introduction more likely to produce drowsiness than stimulation, appears to present as many problems as some of the older products. Yet, on the basis of limited data, it seems that baboons, at least, do not enjoy fenfiuramine and will not self-administer the drug abnor- mally. Perhaps baboons are more discriminating than humans. Undoubtedly our flEA, regulatory officials will be able to provide us with more definitive information in regard to the current incidcnce of cases of confirmed abuse of amphetamine-related drugs; particu- larly the incidence associated with the inhalation and intravenous routes of administration. We do not know what the abuse potential is for these related drugs at this date. I think we have to find out. If indeed the related drugs prove to possess an abuse potential ap- proaching that of amphetamine, then clearly they should be placed in category II. PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14497 If new findings illustrate that a drug is favored by the "drug cul- ture" as an agent of gross abuse, it may well merit category I status. Under any circumstances, we should remain diligent in defining de- grees and hazards of abuse associated with these drugs retained on the market, and any potential substitutes should they be withdrawn. Thank you very much. Senator NELSON. Thank you, Dr. Jolly. We appreciate tour taking your time to come and to present your testimony here toaay. The hearings will recess until tomorrow morning at 10 a.m. in the same hearing room. So we stand in recess, and we do thank all of the witnesses for ap- pearing today. [Whereupon, the subcommittee was recessed at 11 :55 a.m.] PAGENO="0076" PAGENO="0077" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) THURSDAY, NOVE7LSEE 11, 1976 U.S. SEXATE, SuBconxrrrn~ ON MONOPOLr op rmi Srtzar C0MMFrrEE ON SMALL Busm'rss, Washington, D.C. The subcommittee met, pursuant to recess, at 10 a.m., in room 318, Russell Senate Office Building, lion. Gaylord Nelson, chairman, presiding. Present: Senator Nelson; Also present: Benjamin Gordon, staff economist; and Karen Young, research lissistant. Senator NELSON. The Monopoly Subcommittee of the Senate SmaU Business Committee will please come to order. Our first witness this morning is Dr. Everett Ellinwood, associate professor of psychiatry, Duke University Medical Center, Durham, We are pleased to have you here this morning. Your statement will be printed in full in the record.l You may present your statement however you desire. If you would pull the microphone up close, it would help, because the acoustics are very poor in this room. STATEMENT OP EVERETT U. ELLINWOOD, JR., M.D., PROFESSOR OP PSYCHIATRY, DUKE UNIVERSITY MEDICAL CENTER, DURHAM, N.e. Dr. ELLINWOOD. Thank you, Mr. Chairman. I have worked for many years now with most of the central nervous system stimulants, both in a clinical setting as well as in a basic re- search laboratory. In considering the anorectic drugs currently in use, it is important to distinguish between the central stimulant effects and anoreetic properties. The amphetamines are perhaps the best prototype of anorectic drugs, having strong central nervous system stimulant activity as well as anorectic properties. `See prepared statement and attachments of tr. ElHnwood beginning at p. 14666. (`4499 PAGENO="0078" 14500 COMPETITIVE PRoELnIS IN ~E DRUG D~DUSTRY I have a table, Mr. Chairman with a listing of the anorectic and stimulant drugs IThe table follows:] `lASh l.-DEA SCHEDULE, GENERIC EQUIVALENTS, AND TRADE NAMES OF PRESENTLY MARKETED STIMULANT DRUGS IN THE UNITED STATES DEA schedule Generic name Trade name I! II II III III III III III ~ lv lv iv Amphetamines: amphetamine Dexedrine, Obotam d,i amphetarrnne isomers Benzedrine, Biphetamine, Obetrot Metliamphetaimine - Desoxyn, Fetamin. d amphetamine+amobarbilal Dexamyl. d, 1 amphetamlne+PrOchIOrPeraZine Eskatrol. Other stimulant drugs: Methylplienidate Ritalin. Phenmetrazine Preludin. Benzpheta,nine Didrex. Chlorphentermine Pre-Sate. Clortermine Voranil. Mazindol Sanorex. Phendimetrazine Bonlrit, Melliat, abe-Nil, Bacarate. Diethyipropion Tenuate, Tepamil Fenflurarnine Pondimin. Phentermine lonamin, Fastin. Detcobese Strabobex, Dr. Ernxwoon. Methylphenidate and phenmetrazine: also have strong stimulating properties similar to the amphetamines. In considering the usefulness of these stimulant properties, there are two specific medical uses on which a consensus among physicians is held: (1) Their use in hyperkinetic children; and (2) Their use in narcolepsy. In both these conditions, one is faced with deficiencies in arousal and attention mechanisms. ilyperkinetic children demonstrate a remarkable inability to focus their attention on specific tasks or interests before them. They are especially distractable and susceptible to extraneous stimuli from the environment. In a school situation, they are incapable of handling the repetitious tasks requiring focused attention, such as reading and writing. Stimulants have also bcen generally accepted as a specific treatment for narcolepsy, an uncommon condition which is characterized by sudden attacks of sleep and weakness during normal waking hours, and unusual periodic sleep patterns at night. Stimulants, and especially amphetamine. have been found to change what is at times an incapacitating condition to an ability to return to work, to drive a car, and to carry out in a relatively normal fashion, tasks requiring vigilance and attention. Without the stimuhnts, the individual would periodically fall asleep as many as 6 to 20 times a day, and at times and conditions that would be compromising and dangerous. There is a disagreement over tIn' use of anorecties having pro- nounced stimulant properties in weight reduction regimes. This disagreement arises primarily because many individuals who have originally taken the stimulants for weight reduction appreciate the energizing and euphoric effects and continue to take the drugs for reasons other than weight reduction. PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14501 In my opinion, general long-term use of amphetamines or other stim- ulants for weight control should be discouraged strongly. The current practice of using the more potent stimulants for weight reduction during a 2- to 3-week startup period to allow the individual to gradually cut down his food intake patterns then discontinue the medication, needs also to be questioned. Several clinicians, Penick, 1969; Feinblatt, 1961; Fineberg, 1967, have specifically recommended this regime as being effective in a weight-control protocol. The Federal Drug Administration has previously reviewed the drug trial data on the effectiveness of the whole gamut of anorectic drugs in weight reduction regimes and it would appear that they are, in- deed, effective. In this unpublished study, Scoville, 1972, using 206 anorectic drug trials winch had been submitted to the FDA, the FDA researchers placed the raw data in a common format and subjected it to a total analysis; they indeed demonstrated that there was a significant effect- at least out to 16 weeks-of these anorectic drugs on weight loss. Usually, the weight loss amounted to 1 pound per week more than a simple diet alone with placebo. For the most part, the researchers at the FDA felt that the major- ity of the studies were well done, especially those accomplished on the basis of 8- and 6-week studies. The 1-year studies were not well-controlled and did not have good followup. Mr. Gorwox. May I interrupt at this point, Dr. Elliuwood. Dr. Scoville, whom you referred to, was here yesterday, and he was unaware that many of these studies on which you based your state- ment were found to be inadequate by at least tour or five of ~ medical officers. There has always been disagreement among the medical officers in the Food and Drug Administration concerning the efficacy or the adequacy of evidence showing that these drugs are effective. I would like t point out to you that this particular study is a pooled study which included many individual studies. In fact, more than half of them were inadequate, and apparently did not satisfy the law involving substantial evidence. Dr. ELLTNwOOD. I will have to leave that to the researchers at the FDA. Obviously one could question many clinical studies, but on the basis of the information I have, they have considered most of the studies to be adequate~.. I do think a word of caution is needed in that these studies are based on short-term effects of weight reduction, and if one follows any type pf treatment program for obesity for any length of time, the task of keeping weight down in these individuals is extremely discouraging. Most researchers-Stunkard and McLarenhume, 1959; Penick, 1969-report that only a small percentage of patients maintain their weight loss at the end of a year. Others-Penick, 1969-have cautioned against the total pessimistic view, in that treatments may have been effective in helping overweight patients from gaining even more weight. There is no hard data to support the issue one way or the other, and one could certainly conceive of anorectic drugs being used on a short- PAGENO="0080" 14502 C0~.LPETrrTvE PROBLEMS ]N THE DRUG INDUSTRY term basis in order to help the patient establish habit patterns or be- come involved in behavioral programs which would foster long-term weight reduction. The main question in evaluating anorectic drugs is not just their therapeutic effectiveness, but also the trade-off against the abuse poten- tial of these compounds. In a later section of this statement, we will discuss the point that the toxic impact of amphetamine-like stimulants on the individual, and indeed on society, is significant. We should strongly encourage attempts to reduce the use of com- pounds with potent stimulant properties. Another major question is whether there are anorectic drugs which have less of the stimulant abuse potential but which are still effective anorectics. - At this point it should be stated that none of the anorectics have been proven to be absolutely free of some form of a.buse potential, yet there may be a new group of relatively nonabused anorectics emerg- ing; that is, the ring-substituted amphetamine analogues. Now, I am not going to go into the chemical makeup of these sub- stitute compounds, except I think the evidence is accumulating that they may be different than the chain substituted compound. To date, the side-chain substituted amphetamine analogues, when tested in self-administration animal models, and in other tests for stimul ant properties, all appear to have some stimulant potency. Although weaker than dextroamphetamine and methamphetamine, as well as phenmetrazine. these compounds would appear to have suf- ficient stimulant properties to be abused by some individuals. Conversely, the major dependent abuse cycles have not been estab- lished with most of these compounds as has been noted with the above primary stimulants. The ring-substituted amphetamine analogues, fenuluramine and chlorphentermine, are amphetamine congeners which have anorectic effects apparently without major psychostimulant or sympathomi- metie effects, that is, cardiovascular stimulant effects. When tested in man, these drugs instead of producing a stimulant effect, appear to have more sedative properties. Studies using drug abusers to test for euphoric and arousal effects indicate that they do not perceive fenflura.mine or chlorphentermine as having the euphoric and arousal effects in the same way as most CNS stimulants. A word of caution is needed for fenfluramine, in that high doses induced psychotomimetic effects-Griffith, 1976; Gotestnm and Gunne, 1972-ithat is, visual and olfactory `hallucinations-Griffith, Nutt and Jasinski, 1975-rapid mood swings, distorted lime sense and fleeting paraiwia. The psychotomimetic effects of fenfiuramine should be evaluated carefully since there is one report in the literature-Levin, 1973- rndicatang that a South African group of drug abusers had used this compound for its hallucinogenic properties. Itemember, we are talking about a very high dose usage of this compouiid. There have not been similar reports, to my knowledge, in the United States. PAGENO="0081" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14503 With clilorphentermine, one needs to consider that there have been isolated reports of pulmonary hypertension, again which have not been reported, to my knowledge, in the United btates. Thus, these two ring-substituted compounds should be carefully examined, both in the basic research laboratories as well as clinically. Basic research with these two compounds has demonstrated a marked attenuation of stimulant properties as well as the indicators of abuse potential. In the case of fenfluramine, it is one~twentieth as potent as am- phetamine in elevating blood pressure in rats, and has no effect on body temperature-Bizzi and others, 1970. Fenlluramine, as well as ehlorphentermine, suppress feeding rn rats without the induction of locomotor stimulation-van Rossuin and Simons, 1969. In the self-administration technique for assessment of abuse poten- hal, fenfluramine has been demonstrated to be a compound for which neither rats-Baxter and others, 1973-nor monkeys-Gnffith, 1970; Woods and Tessel, 1974-will self-administer. Self-administration data for chiorphentermine is more equivocal, in that rats have been demonstrated to self-inject this compound as they do amphetamine, phemnatrazine, and diethyipropion-Baxter and others, 1973-however, monkeys show little evidence of self -admrn- istration-Yanagita, unpublished results. To continue the example with fenfluramine further, in actual prac- tice as an anoreetic, fenfluramine has been demonstrated to decrease food intake in many species, including man-see Stunkard and others, 1973. Those studies have demonstrated more of a sedative effect chroni- cally with fenfluramine than for either placebo or amphetamine when administered for weight reduction. Finally, although there is a report of the use of fenfluramine for its halluc~noge.nic properties, there have been no published reports of dependence patterns following several million prescriptions in the United States. I would like to present my recommendations on the basis of this statement, and then go into what I think is the major abuse potential of these compounds, the strong stimulant compounds, in man. In the light of these differences among anorectic compounds, a more rational approach to the abuse potential problem of anorectics would be to encourage discrinunatrng basic research and preclinical evalua- *tion of these compounds for the tradeoff for their anorectic properties and potential stimulant abuse properties. Furthennore, rescheduling the anorectics with stimulant proper- ties could encourage physicians to be more careful in their prescribing cntena. Tins observer would consider moving phentermine-lonamine and Fastin and diethylpropion Tenuate and Teparnil at least into sched- ule III. Mr. GoRDoN. May I interrupt. Why schedule III? It has no effect on medical practice. As a matter of fact, Dr. Grout in a document states as follows: "Schedule II of the CSA, the most restrictive for marketed drtws, requires nonre.flllable prescriptions, special records, and manufactur- 85-569--77-6 PAGENO="0082" 14504 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ing quotas, among other things; schedule III and IV have little but psychological impact on the practice of medicine, requiring only a special symbol on the labels and labeling and a practitioner's BNDD number on the irescription. The schedules of the act include three anorectics-methamphetainine, the amphetamines themselves, and phenmetrazine." Dr. ErnNwooD. That exactly will be my point. As I said, I will consider at least moving it into the III category. Let me go ahead and finish that. I think that will clarify your question. In addition, based on basic research in self-administration models or evidence of euphoriant effects in man, compounds such as benz- phetamine, clortermine, m.azindol, and phendimetrazine as well as diethylpropion and phentermine, might be considered for schedule II. Placing these compounds in schedule II would require that the physician explicitly write these prescnptions without refills. This would place considerably more emphasis on reevaluation f or subsequent prescription writing. The more potent stimulants such as dextroamphetamme, meth- amphetamine and phenmetrazine currently `under schedule II should be considered for possible discontinuance of their use as anoreetics. Certainly these compounds have been demonstrated to have con- siderable abuse potential. Use of potent stimulants for hyperactivity in children and narco- lepsy should be maintained. Senator NELsoN. You would remove `the indication for anorectic purposes from the drug labeling, I take it? Dr. EaINWOOD. For those compounds, for dextroamphetanfine, for phenmetrazine and methamphetamine. I think there are sufficient other compounds with less of the stimu- lating properties that one could use `for this. Finally, physicians might be encouraged to consider prescribing one of the ring.substituted compounds dependent on their evaluation of the patient for an initial weight reduction regime, at least before the more euphoriant and stimulating compounds are considered. Obviously, education of both physicians and the public is a major means of facilitating this process. I would like to go now into the impact of stimulant abuse on the individual and perhaps on society. In determining the impact of stimulant drugs on the individual and society, one can consider a host of potential changes including the morbidity and mortality rate among amphetamine abusers; the potential for an emotionally apathetic state following chronic abuse and withdrawal which has been described both in this country as we]l as Japan-Tatetsu, 1962; Utena, 1966; Ellinwood, 1073. In addition, there is evidence from chronic intoxication animal studies that nerve cell death takes place in brain areas which in part mediate alerting and emotional arousal-Escalante and Ellinwood, 1970. Studies in monkeys have demonstrated a long.term, perhaps perma- nent, depletion of an important neurotransmitter__dopamjne_which lasts for at least 3 to 6 months following high dose amphetamine main- tenance-Seiden and others, 1976.. PAGENO="0083" COMPETITIVE PROBLEMS IN TIlE DRUG n~DUSTRY 14505 Thus, there are clinical descriptions as ~ve1I as basic research indicat- ing that there may be long-term changes following chronic ainphet- amine intoxication. Senator NELSON. What is the effect of that, of whatever long-term changes that may occur? Dr. EaINwoon. You mean in humans? Senator NELSON. Yes. Dr. ELLINWOOD. Well, it is very difficult to document this, but there are many, many cases, reports, and histories of individuals, which report emotionally apathetic, fatigue states involving long-term use of amphetamines, at times some difficulty remembering. Now, I need to add, however, that critical studies of individuals with neurological tests have not demonstrated intellectual deficits, so I think one needs to consider that also. Perhaps the major issue relating to impact on society is that of criminal activity. Obviously, the drug marketplace is an unstable arena *in which crimes against property can become a part of the stimulant abuse pattern-Smith, 1972. One crucial question is whether stimulants specifically induce violence in abusers. In order to obtain a perspective of the effects of amphetamine on aggressive and violent behavior, one should compare them with the effects of other drugs. The concensus among those who work closely with problems of abuse is that opiates do not induce unwarranted violence and, in fact, are likely to inhibit tendencies toward violence, even though addicts are frequently involved in potentially explosive criminal situations-Kolb, 1925. On the other hand, for years alcohol and sedatives have been as- sociated with an increase in violence which is thought to be secondary to a lowering of impulse control-Guize, and others, 1962. Reports from law enforcement personnel and psychiatrists, as well as from drug users iheinselves, have indicated that high dose amphet- amine use may also be related to aggressive behavior-perhaps more specifically than some of the other groups of drugs. That is, such high dose use may actually facilitate aggressive be- havior rather than just lowering impulse control-Ellinwood, 1969, l971a; Kramer, 1909; Smith, 1972. Chronic high-dose use of amphetamines, which leads to behavioral aberrations including psychosis, is considered by clinical observers to be a volatile state and is the one not infrequently implicated in violent or assaultive behavior. In contrast, several survey studies, where arrestees are interviewed concerning their drug use-that is, the spectrum of low-dose and high- (lose use-indicate that amphetamine use per se is i-rot specifically related to violent crimes-Blum. 1069; Eckerman, and others, 1971; Greene, and others, 1973; Tinklenberg, and others, 1974. Thus, it appears that the violent activity most frequently appears not with low or moderate doses of amphetamine, but with the chronic high dose stage àf unstable and/or psychotic behavior. Often the amphetamine-induced paranoid ideation or emotional liability leads to the violent act or even overt homicide-Ellinwood, 1971b. PAGENO="0084" 14506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Not infrequently, the amphetamine abuser committing homicide is attacking an imaginary assailant or persecutor created m his paranoid delusional thinking. The violent act may take place in a state of terror or panic, often secondary to misinterpretation of events or delusions. Perhaps equally important is the influence of amphetamines in creating: 1. Impulsive or reactiveness, and `2. a liability of mood in which the user abruptly vacillates from a warm congeniality to fiercely hostile moods for the most trivial of reasons-Kramer, 1969; Ellinwood, 1971a. The drug subculture of amphetamine abuser, of course, is involved frequently in criminal activity in order to support drug use. The amphetamine abuser may suddenly panic and react violently while involved in an armed robbery. At times, this reaction is touched off by a bizarre feeling such as being suddenly and furiously angry because the storekeeper "smiled at me." In the study of amphetamine abusers committing homicide-which I carried out-Ellinwood, 1971a-7 of the 13 subjects were acutely psychotic and delusional at the time, and this disturbance of thought appeared to be directly related to the homicide. Four persons were primarily in an amphetamine-induced emo- tionally labile state. Paranoid ideation may have been involved in these cases, but it was not the most salient feature. Two persons with low impulse control had also been drinking at the time the homicide occurred. In two cases, homicide was associated with armed robbery and this appeared to be the primary contributing condition. Although the killers were high on amphetamines at the time, it is difficult to assess the relative importance of this and other factors since by far the most important factor was the flow of events associated with the armed robbery. Both of these men stated that they were obtaining money to buy drugs. Twelve of 13 persons committing homicide were carrying- concealed weapons at the time. Many speed users carry weapons, ostensibly for a variety of reasons including: 1. For use in armed robbery. `2. Because of their suspiciousness and fears-often he has "heard someone breaking in at night" or he becomes increasingly fearful of his persecution and begins carrying a gun~ and 3. There is a certain amoullt of "cowboy and Indian" braggadocio involved in carrying guns by speed users. Anyone working with amphetamine addicts will hear stories of individuals sitting all night with a loaded gun waiting for fantacized intruders to enter. Under these conditions, speed freaks have been Imown to shoot at hallucinated noises or images. Amphetamine facilitated violence is not peculiar to the United States; similar reports of bizarre aggression as well as homicide come~ from Sweden, Japan, and England. PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14507 Noda, 1050, reported that during the Japanese epidemic of amphet- amine abuse, in a 2-month period "1 of 60 convicted murderers had some connection with the misuse of amphetamines-Rylander, 1969- reports that there had been 3 murders, 1 manslaughter, and 21 assault and battery crimes committed by the 146 stimulant addicts admitted to his Swedish Forensic Psychiatry Climc. There had been 109 crimes committed against property sonic of these crimes were associated with aggression. - In his original monograph on amphetamine psychosis-Connell, 1058-states that hostile aggressive behavior was observed in 22 per- cent of the subjects included in his series from England. In a recent study by the-Kalant, 1976-examining deaths reported by the coroner in the Province of Ontario in 1972 and 1973 which were related to amphctamine use, they found that 17 of 26 were deaths of a violent nature. Seven were due to accidental violence, usually, due to poor judg- ment; seven to suicide; and three to homicide. Among the suicides, there was a high incidence of self-inflicted fatal gunshot wounds. Two suicides followed the killing of a police officer with subsequent impending capture by the police. One male was shot by a policeman after attacking him with a knife. From perusal of both the reported homicide cases and those of assault, it is apparent that many drug users move through three fairly distinct phases leading to the violent act. The three phases consist of: First, chronic amphetamine abuse; second, an acute change in the individual's state of emotional arousal; and third, a situation that triggers the specific events leading to the act of violenee-Ellinwood, 1971aL The phase of chronic abuse often sets the stage; it includes changes in the individual's frame of mind involving suspiciousness, paranoid thinking, and fearful regard of his environment. it is during this period that he obtains and begins to carry a concealed weapon. Armed robbery as a means of supporting the drug habit and conflicts over drug dealing also are segments of the setting that derives from chronic drug use. The second phase, involving a.sudden change in emotional arousal and/or a loss of intellectual control, is often secondary to a variety of factors, including a sudden increase in the dosage level-or acute use in a person with low tolerance-chronic loss of sleep, and the use of other drugs, especially sedatives and alcohol. In this emotional and cognitive framework, the person often mis- interprets his environment and becomes increasingly fearful. The emotional misinterpretation niay be quite su'btle; for instance, a sudden and overwhelming interpretation of a minor "clue" that fits into the person's delusional system. the other hand, it may be a very gross misinterpretation of the entire environment; strangers suddenly becomes sources of persecution. Often the person mistakes a stranger for a persecutor, or, alter- nately, for a frieml-Ellinwood, 1961; 1969. lins phase of sudden misinterpretation of the environment is associated with an intense sense of reality. PAGENO="0086" 14508 COMPETITIVE PROBLEMS IN Tilt DRUG INDUSTRY Within this framework, a minor incident can trigger the violent act. Often the threatening incident is half real and half misinterpreted. In nine of the cases in this study, the murder was committed on the basis of an instant decision or impulse secondary to a perceived danger. There were, however, four other cases in which sonic forethought was involved in the intent. One man "tracked down" his victim. Even within this context of pursuit of the victim, there is often a singular event that triggers the violence. In fact, in Smith's 1972 descriptions, nonfatal pursuits arc not uncommon-Kramer and others. 1967-have stated that these games are often only half serious. Thus, although chronic amphetamine abuse may set the stage for violence, it is the phase of acute changes in sensibilities that is actually associated with misinterpretation and the violent act. At this point, a note of caution is indicated. IJomicides related to amphetamine abuse certainly pale in significance when one considers the incidence relative to alcohol related violence. TIus does not mean that the fewer episodes of stimulant facilitated homicides are not critically important, but we should maintain a perspective with respect to alcohol. Finally, the question can be asked whether there are residual psychological changes that remain after one has developed the amphetamine psychosis. The amphetamine paranoid psychosis is a well-known phenomena associated with chronic amphetamine use-Connell, 1958; Kalant, 1966. Although single large doses of amphetamine can produce a toxic hallucinatory paranoid panic state, amphetamine psychosis most often results from chronic abuse and develops gradually; when seen by the examining physician, the process often has extended to the point where a picture of paranoid schizophrenic-like psychosis is present- Ellinwood, 1969, In fact, many patients have not infrequently been wrongly diag- nosed as such. The paranoid syndrome usually does not begin until after the ini- tial few weeks, or even months of amphetamine abuse. Mr. Goarox. Doctor, may I interrupt you just 1 second? You mentioned alcohol. In one of your journal articles you referred to poly-drug abuse, and you state: Reports on several persons who have committed quite serious assaults indi- cate that when combining amphetamines with other drugs, staggering amounts of alcohol or sedatives can often he consumed. Without the amphetamine TLSe, the individual would have passed out. Would you say this is an additional danger of amphetamines? Dr. Ernxwoon. Yes; I would say so. Mr. GoanoN. That you would consume much more alcohol? Dr. ELLINWOOD. Yes; and the combination often ends up with a fairly activated individual, who has lost a considerable amount of his judgment. Otherwise, a similar amount of alcohol, he would frequently pass out. PAGENO="0087" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14509 When the individual who had been taking amphetamines chronically combines it with alcohol, he loses a considerable amount of judgment. It tends to wax and wane depending on the drug cycle and dosage level. hallucinations tend to dissipate 2 or 3 days after cessation of am- phetamine use, yet delusions continue up to 2 weeks and have been noted in some patients for as long as 1 year or more. The amphetamine psychosis usually is a distinct syndrome char- acterized by delusions of persecution, ideas of reference, Visual and auditory hallucinations, changes in body image, hyperactivity, and excitation-Connell, 1958; Kalant, 1900; Ellinwood, 1907; 1969. Whereas the amphetamine psychotic process usually takes a rea- sonable period of time to develop into its more organized form, once established, moderately high doses can retrigger the psychosis rather rapidly in individuals who may have been abstinent from ampheta- mines for over a period of 1 year-Kramer, 1909; Bell, 1973; Ellin- wood, 1973. The Japanese-Utena, 1906-also describe a tendency for the psy- chotic symptoms to recur not only with subsequent amphetamine ad- ministration, but also under stress. Since the more aberrant behavior induced in animal models of chronic intoxication can also be triggered by single moderately high dosage-Ellinwood, 1971b-the clinical data needs to be taken seri- ously and examined further. This evidence, plus the observation of chronic delusions in some amphetamine addicts seriously raises the issue of chronic persistent behavioral effects. In summary, my recommendations are based on the fact that obesity is known to contribute to a decreased longevity; titus, it is important for clinicians to have means of estab] ishing weight reduc- tion regimes. - Many consider the development of an anorectic without stimulant abuse potential as a goal not only worthy, but obtainable. There is a considerable body of knowledge on the neuro-pharmacol- ogy and neurophysiology of eating behaviors. In addition, there are assessment techniques currently available for determining in the laboratory relative stimulant abuse potential for potential anorectic drugs. The total abolition of anorectic drugs would reduce the pharmaceu- tical industry's search for the nonabused anorectic. There are exam- ples of compounds currently on the market that appear to point in the right direction. Proper use of our current knowledge base. and further research will contribute to the goal of developing better nonabused anorectics. I would suggest establishing an independent FDA review committee that would provide guidelines for the basic and preclinical research needed to establish the therapeutic efficacy and abuse potential of new anorectic compounds. Use of our current knowledge could very accurately discriminate the compounds that will demonstrate abuse potential and those that will not. In the interim, I would recommend additional rescheduling of the anorectics with stimulant properties to encourage physicians to be more careful in their prescribing criteria. PAGENO="0088" 14510 coIsn'ETmvE PROBLEMS IN THE DRUG INDUSTRY This rescheduling would exclude at this time the ring-substituted anorectics until there is sufficient data to indicate that these coin- pounds have an abuse potential. The more potent stimulants, such as dextroamphetamine, metham- phetamine, and phenmetrazine, currently under schedule II should be considered for possible discontinuance of their use as anorectics. Finally, it would be helpful to have some means of monitoring and restricting physicians and/or obesity clinics that overprescribe the stimulant anorectics. Mr. Chairman, that concludes my statement. I have the references at the end of my prepared statement that I would like to have made a part of the record. Senator NasoN. Without objection, so ordered. Mr. Gonnox. Doctor, in Psychiatry in March 1971, you discussed the histories of persons that had marginal schizophrenia, and after taking amphetamines, they deteriorated rapidly. Now, this kind of condition would be contraindicated for the pre- scribing of amphetamines; is that correct? Dr. ELLTNW000. Certainly. Mr. Gonoox. Now, when a person goes to a so-called fat doctor, do you think he is going to be given a psychiatric examination? Dr. EwNwooD. Probably not. Mr. GORDON. So since violence and crime ensue, or can ensue, the consequence of amphetamine use can be very serious both to the indi- vidual and to society, as you stated before. You would agree with that, I presume? Dr. Ernxwoon; I would. Mr. GORDON. Now, three of the cases had low tolerance, had taken large amounts of amphetamine, and developed paranoia status. You also state it is not the amphetamine intake that is important, but it is the relationship to the level of tolerance. Now, is it possible or practicable for the prescribing physician to determine the level of tolerance for the patient? Dr. ELLINW000. No; I do not see that as being probable. lie could certainly determine the tolerance, but it is really not very feasible in standard medical practice. I want to emphasize one thing, that in describing the toxic effects of stimulants, we have been talking about the more potent complex that includes the dextroamphetamine, the methamphetamine and preludin. and I do not think we have any direct evidence that the com- pounds that fit in between those, or fit below those compounds in their stimulant potency have induced the chronic states that I have been describing. This is one of the reasons I have recommended that we take the compounds. the more potent stimulant compounds, out of the anorectic use category for these drugs. I ~m not, however, recommending taking out all of those compounds, because we do not have direct evidence that they caused these chronic problems that we have been describing. Mr. Gonnox. But can they cause them? We do not know. Before you put a drug on the market, shouldn't you have to show whether it causes this or does not cause that symptom? PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14511 Dr. ELLINWOOD. I think we could get evidence of that. I think the most important thing is whether they have sufficient euphoria prop- erties which indicate they will be abused. I think we do have tests now in both the clinical laboratories as well as basic research laboratories, that can provide us with fairly good evidence of the potency of these compounds in at least a few patterns of behavior. There are fairly good tests now, that can give you a reasonable pic- ture before they come on the market, but we do not have a complete picture for all of the compounds that are on the market. Mr. GoRDoN. Well, don't you think we should have a picture before we put a compound on the market, is that not required by law? Dr. ELLINw000. I think that is a reasonable assumption. Mr. GORDON. Thank you. Senator NasoN. The amphetamines, of course, have been on the marketplace long before the 1938 requirement of proof of safety, and much longer before the 1962 provision for efficacy. As to the amphet- amines, we are dealing with a drug that did not have to meet at that time a safety and efficacy standard. Are there any statistics available that would indicate, that would show what percentage of the drugs used for anorcctic purposes were in fact highly stimulating amphetamines? Dr. ELLINw0OD. What percentage! Senator NnsoN. Yes. People go to a physician for treatment of obesity, and get prescriptions for drugs. What percentage of those prescriptions for that purpose are in fact amphetamines, the highly active stimulants! Dr. ELuNw000. I think those prescribing habits have changed dra- matically, at least since 1968. There has been a shift in the prescribing habits. Senator NELsoN. That was because they were put on schedule II? Dr. ELLINWOOD. Yes, because they were put on schedule II, and the absolute production of these compounds was of course reduced. I think there has been a gradual shift to the less potent compounds, but I do not have statistics on that. Senator NELSON. We will ask the FDA when they appear next week. Mr. GoimoN. Mr. Chainnan, I ~sk that the two articles by Dr. Ellin- wood be placed in the record at the appropriate place. Senator NELSON. The two articles will be made a part of the record. We thank you very much, Dr. Ellinwood, for appearing and pre- senting your testimony. Dr.ErnNwoon. Thank you, Mr. Chairman. Senator NasoN. Our next witness will be Reverend Reginald Yake, executive director,Teen Challenge Training Center, Rehrersburg, Pa. Reverend Yake, your statement will be printed in full in the record. You may present it however you desire, and if you wish to make additions to the statement, extemporaneously, you may do so. STATEMENT OP REVEREfl REGINALD lAKE, EXECUTIVE DIREC- TOR, TEEN CHALLENGE TRAINING CEI4TER, REHRERSBURG, PA. Reverend YAXE. Thank you, Mr. Chairman. I ust wanted to state I am appearing for others. PAGENO="0090" 14512 COMPETITIVE PROBLEMS TN THE DRUG TNDUSTRY I am readinw their statements. It is not mine. It was advi~ed that they should not be present. They are presently in attendance at the Teen Challenge Training Center, and the Justice Department recommended along with yourself that possibly I appear in their stead because of damaging of their future, possibility of fu- hire incriminations from future work, or desires of their future plans, so as a result, the individuals that I am going to be ref errmg to are anonymous, and this is to protect them. Senator NELSON. But they are individuals who are now in your training center? Reverend YAKE. Yes. Senator NasoN. They are currently there? Reverend YAKE. Yes. Senator NELSON. So you are simply presenting on behalf of each of them their own statement about their involvement with amphet- amines? Reverend YMCE. Right. * Senator NELSON. Aaid do you have a statement of your own, obser- vations concerning your experience with them with your center? Reverend YAXE. Right. Senator NELSON. Go ahead. * Just be sure you identify what is your statement, your own state- ment and conclusions, so that the reporter has it correct in the record, distingu~slun~ between yourself and that of the individuals. Reverend YAKE. OK. This is a statement that we will call Mr. B. lie states as follows: In regards to the series of hearings on the antiobesity drugs which include amphetamines, I am sending you my story of involvement. My name is Mr. B, and I am 22 years of age. I am from the south ~hore of Massachusetts. I am presently in the Teen Challenge Train- ing Center in Rehrcrsburg, Pa. I was placed in the program on December 1. 1975, by the courts of Massachusetts for a drug-related crime, facing 21/2 years with another trial pending. My involvement with amphetamines was not as a user, but as a seller. At the time, my habit was with heroin, for 3 years at $25 a day, and sonic barbiturates. * Selling the speed only helped support my drug habit. The girl that I lived with at the time was also involved quite heavily with the flow of amphetamines. She was sentenced to a year imprisonment in De- Land County in Florida inthe year 1973. My involvement with speed began when I obtained the name of a doctor who was known to give out prescriptions for amphetamines quite freely. I bought this information for the price of 50 percent of my pills for the next three visits with the doctor. Senator NELSON. What information was that? The information where to get it? Reverend YAKE. Where to get it from thq doctor, yes, the informa- tion was to know the doctor's name. Senator NELSON. And so he paid somebody 50 percent of the sale value of the pills to get the doctor's name where he could go to get the amphetamine? PAGENO="0091" COMPETITIVE. PROBLEMS IN THE DRUG INDUSTRY 14513 ReverendYAgl. Yes. Later on in the statement, he refers to the fact that this is a saleable item on the street. [Mr. B continues:] The doctor that I was seeing was giving prescriptions for Biphet- amine ~20-Black Beauties-and lie, the doctor, would also direct me to a certain drugstore where I could have my prescription filled. The visit with the doctor would cost me $0 or $8 and the prescription itself about $7. With this small investment, I could turn the script over on the street for anywhere from $00 to $100. Demand was always greater than the supply with this particular drug-speed-and this always enabled me to get my price. Senator Nrtsox. lie sold the prescription? Reverend YAXE. No, he filled the prescriptions, and then he sold the drugs to make the money for his heroin habit. [Mr. B continues:] At the time I was getting this drug, I weighted 170 pounds and my height was 5 feet 8 inches. The doctor kept a record of this each time for Government records. My further involvement was when I obtained the name of another doctor in the area who also gave out prescriptions for speed. his pro- cedure was the same as the first doctor, but he gave out scripts for rhenmetHzine tablets. Senator NELsON. When he says scripts, does lie mean prescriptions? Reverend YAKE. Yes. Senator NELsoN. Isee. Mr. GoRnox. I think he is referring to phenmetrizine. Reverend YAKE. OK. [Mr. B continues:] The law states that these drugs are to be given out to the patient ~on]y once a month, 30 capsules or pills when overweight. As far as the second doctor is concerned, he was within the law, but I was seeing him three times a month under three different names with- out a disquise~. At the same time, I was still seeing the first doctor. As time went on, 1 started selling the name of the doctor to other people the same way I got it. only I got paid in cash. I also got the idea from a guy that. I often met in the doctor's office to bring along with me some girls to see the doctor for the same reasons as mine and have them get scripts or prescriptions for me to sell and in return for them, I would supply them with a very small amoimt for their present need. The guy-another dealer-who gave, me the idea of getting girls to work for me was presently doing this himself with various doctors. While in this business with speed, I came across the names of other doctors who also gave out freely prescriptions for speed, but I didn't have the time to bother with them. I.was busy enough with the doctors I.was already involved with. I might add though that there were several other doctors that I tried to obtain speed from and I was turned away with a flat no because they knewwhatlwasupto. . . The doctors that I dealt with were real quacks and I feel strongly that they knew what I was tip to, because I had gone as far as refusing to leave a doctor's office until he gave me what I wanted. PAGENO="0092" 14514 COMPETITIvE PEOflLEMS IN mz DRUG INDUStRY I hope and pray that this statement has some effect on the present situation in dealing with the leniency of giving out pharmaceutical prescriptions. I believe strongly that although restrictions may be tightened be- cause of the outcome of this investigation, this alone will not solve or even help solve the drug problem in this country until individuals- drug users-are dealt with individually as part o? this society and not as a problem that everyone wishes they could sweep under a rug and be rid of. The drug addicts, when dealt with, need to see and understand what the truth really is about this life here and to feel that they are a part of something. I feel the only cure for the individual to be able to see the real truth in life would be for someone to lead him or her to the truth of Jesus Christ. [End of Mr. B's statement.] Now, I talked to Mr. Gordon on the telephone, and I asked him if he could be a little more specific on some of the situations, in that he would not be appearing here for cross examination, and so there is another page, a subsequent page lie has written up. f Mr. B continues:] The doctor's office, at all times, would be packed with young people ranging in age from 18 to 35 or 40. From their conversations I could tell what their motive was for seeing the doctor. All of them were after prescriptions for speed, of which this was phenmetrizine. The people there were from different cities, Boston, Fall River, Brockton, and so forth. They traveled from all over to this doctor. How did they find out about this particular doctor News in the street travels fast. The other doctor who gave out biphetamines also had an office packed with patients, but lie also had some older folk that were there for rea- Sons other than to obtain speed. The people there for prescriptions for speed greatly outnumbered the older patients. I learned from being in this con game with doctors that there were various other ways to get other prescription drugs from doctors. For example, in order to get a certain drug, you would have to have a certain story for the doctor to believe, but not everybody knew these stories. I am talking about barbituates and Delada now. These stones would cost money along with certain doctors' names. I am just trying to show how easy it is for someone that is a good con to be able to get what he wants from certain lenient doctors. Also all of these doctors kept records of these visits for the Gov- ernment or the medical association to inspect if ever necessary, so I see that it is not on]y the doctors that are lenient but the people that are over them also. Most people using speed in the street do not see themselves as drug users because they are usually house mothers, college students study- ing for exams or just the good people m society that are very social. This speed, whidh they do not call it, is just something to pick them up; it does not make them silly or incapable of doing work, but in fact helps them. They do not realize its potency and effect on their lives until it is too late. PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14515 Then they find they cannot function without it, and w'hen they are deathly sick because of the lack of nutrition that they deprive their bodies of when they take these so-called diet pills, and then they find out they are a nervous wreck because of the abnormal effect of the drug, such as being able to stay awake for maybe 24 hours, 48 hours or eyen 72 hours at a time. Diet pills are being used for everything but dieting. Oh yeah, it is popular around heavy drinkers; speed allows the drmkers to drink in excess without falling all over the place. I have nothing against the medical profession or the laws of this country, but there is always one bad apple in every bunch, and the odor of this rotten apple is smelled by everyone and takes away the sweet fresh fragrance of the other good apples. [End of Mr. B's statement.] So yesterday I asked the individuals in the program, and the Teen Challenge Training Center-we presently have 130 fellows in resi- dence-if there were any others that had experiences, and I gave to Mr. Gordon this morning a briefer statemeiS from an individual from the Washington, D.C.-Baltimore area, and it is brief, and I will read it. [Statement read of other witness:] On or about the early part of 1970 myself and several friends were involved in the purchase of methadone in the southwestern part of Washington, D.C. We were able to purchase as much methadone, which on some days ranged up to the hundreds of dollars worth, as we were able to pay for. The doctor was completely aware of what was going on and made no effort to hide it. Not too far from this same location was another doc- tor who was doing the same exact thing. The drugs which were pur- chased were taken to Baltimore where they were sold on the streets for higher prices. From about the middle of 1973, up till the latter part of 1975, I was involved in the buying of pills through doctors in the Baltimore area. This was set up so that I had medical assistance and could go to various doctors during the day. I was able to purchase various types of drugs, including valium, parest, nembutal, seconal, tarinals, placidyalls, and many others, including class A narcotics. These doctors were aware that I was on a drug program, and still would prescribe drugs. The doctors, some, not all, were careful of how they dispensed the drugs. They would prescribe only enough for 1 month's supply, but would prescribe several different types of medi- cation. Other doctors would insist that several different people would come so they could prescribe to them, but I would receive the drug after we left the office. Some, though, would prescribe a large amount and tell you not to come back. On one occasion I can recall, I told a doctor I was strung out on valium, and needed to be detoxed off of them, I was told I could handle it myself if he could prescribe a large amount. lie did so willingly. This I did on several different occasions, to the same doctor. On another occasion in the Baltimore area, my girl friend was ap- proached while in a doctofs office and asked if she would exchange sex for an assorted amount of drugs. PAGENO="0094" 14516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY There are many, many instances I could give you of how doctors have sold drugs to myself and many of my friends, knowing they were being used illegally. [End of statement.] I have a third statement, but it is very brief, from tile fellow from the NewYork City area. Senator NELSON. Is hem your center? Reverend YAKE. Yes, all three of these individuals are in our train- ing center. [Statement read of additional witness:] I am here to inform you that I had the distasteful confrontation in meeting and dealing with the so-called doctors of this day and time. I am not referring to all doctors, but specifically some who should have their license terminated for a period of time. These particular doctors offer you any kind of drugs for a price, knowing that they are very dangerous to withdraw from. They offer you barbiturates in quantities;for cash money, I believe they should be under strict control in terms of dispensing these drugs. i was getting at from five different doctors while under the influence of alcohol and Methadone, this mixture will kill any creature on earth.. Today there are many young people that are turning to drugs be- cause they are very simple to get their hands on. I pray to God that there would be something done about this. We are dealing with precious lives. God bless you. [End of statement.] Senator NELSON. Concerning your center, is it for the care of only people who have drug addiction problems? Reverend YAKE. Primarily drugs, second alcohol, and third, troubled youth. Senator NELSON. And what is the incidence of amphetamine abuse among the individuals in your center? Reverend YAKE. Teen Challenge Training Center has been in opera- tion since 1902, and for many years our primary intake has been among the heroin users. -In fact, in our research that was conducted in 1968, we had 89 per. cent heroin users. I do not have statistics today to tell you of the breakdown of the various types of drugs, but I would say the majority of the fellows at the training center presently, and we have 130, is on the barbiturate- amphetamine area. - Senator NELSON. One or both? Reverend YAKE. One or both. Very seldom do you See a drug addict that is an abuser coming to our center that is strung out on one particular-type drug anymore. It is what they call the polydrug use, so it ends up one time he will take one type, and another time he will take another type. Senator NELSON. And that over half of your current census involves amphetamine and barbiturates? Reverend YAKE. I would be safe in saying that;- yes, well over half. Senator NELSON. This is riot particularly relevant to these hearings, but were these prescriptions prescribed in this fashion reported to the authorities by anyone? Reverend YAXE. No, we do not get involved with that as a rule. PAGENO="0095" COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY 14517 We have had a lot of unfortunate situations with guys coming in. We had a fellow that came in the Teen Challenge program in the Chi- cago area, he happened to be from Wisconsin, and this fellow had 2 years of college, but when he walked into the Teen Challenge Center in Chicago, lie could not write his own name, and if you were to ask mm what his birthday was, he told me afterward, he had said it was seven garbage cans in January, and he would have thought he was carrying on an mtelhgent conversation, he was so messed up with speed, and we had another fellow front Long Island, who likewise was in college, and he could not carry on a coherent conversation when lie came to Teen Challenge, because of the effects and abuses of the drugs. Senator NELSON. how successful is your program in permanently getting them off of the drugs? Reverend YAKI. Well, we made a research, as I said, in 1963, we stuck our neck out and put it on the line. For years, we had felt that Teen Challenge had a viable program, and the research was concluded last year. We are talking of 1968, which was primarily heroin, and we have not updated this as of now, bitt we were told that anyone who is off of drugs i years by society is cotisidered cured, so in 1973 we applied for a grant for 1968, and was turned down. We kept the same year of 1968, and we reapplied in 1974, and we were granted a grant by HEW, and it started in September of 1974. Now, we are getting feedback from this particular grant now, and if we take Goveritment standards of drug free after 7 years, taking 1968 graduates in 1975, we were 86 pcreent, but we do not consider that successful, because we feel that a guy cannot be an alcoholic and drink- ing a six pack, especially drinking on weekends, or to be a drug addict, he cannot be popping a few pills and smoking marijuana and likewise drinking a six pack. Our philosophy is complete abstinence, and we saw 70 percent after 7 years documented by NORC out of Chicago, were cured, *and had stayed cured from drugs. Senator NELsoN. Do you have any statistics on how the patients in your center were first introduced to the drugs? Reverend YAKE. No, we do not. Senator NELSON. Do you take a history when they come in? Reverend YAKE. Yes, we do, but we have never compiled them as such. I have a report that comes on my desk every month of the intake of fellows, like we have a group of fellows that come in every month, and a group that graduate every month, and it is an 8- to 9-month training program at the training center, and I have a list of all of the various types of drugs, how many years they have been in jail, how many yeats they have been on drugs, and this type of information, but we have never compiled it in statistics. Mr. GonnoN. You mention doctors as the original source. Now, is it your impression that the principal source of the drugs which are used for drug abuse comes from doctors? Reverend YAKE. As statements have been given to you and to us, I would say they are one of the very strong contributing factors. Now, the one fellow, I read his statement for you, from South Shore, Mass., his primary function was a drug pusher; however, the PAGENO="0096" 14518 COMPETITrVE PROBLEMS IN TEE DRUG INDUSThY other fellow from Baltimore, or Washington that I read to you his statement, after a period of time, lie started to buy drugs by bypassing doctors, and started to rip off drugstores himself, and so I would say many times individuals get started on this, or they get it on such easy accessibility of it in schools, or on the street, because of someone's abuse with the doctor, that, you know, this is hard to prove, but these guys are out pushing drugs oii the street, are getting it from doctors and other people are buying them from them. Senator NasoN. Thank you very much for taking time to come this morning and to testify. Reverend YAiut. Thank you. Senator NELsoN. Our next witness is Mr. Larry Hicks, Teen Chal- lenge Youth Center, Rehobeth, Md. STATEMENT OP LARRY HICKS, TEEN CHALLENGE YOUTH CENTER, BEHOBETH, MD. Mr. Hicxs. I do not have a prepared statement as such. I believe I was called here primarily to speak from a position of cx- drug user and dreg seller. I am currently living in the Bowie area of Maryland, and was work- ing as the director of Teen Challenge Center in Rehobeth, Md. Senator NELSON. As a director? Mr. llic~s. Yes, and became related to Teen Challenge, because I was paroled there from a conviction, a drug conviction! and from the Maryland Correctional Institution, and I guess, for all of my life, I used drugs for about 10 years, and when I say used, I also mean selling, and because I did not have to work that way, I could stay high longer. I became associated with amphetamines, or speed in 1967, and used it, as often as I could until 1971, and sold it whenever possible, because there was money in it. - It was a good drug to sell, and there was a large demand for it, it was quite popular, and from working in the Teen Challenge Center, it still is very popular today. It has not changed. My own personal experience with the drug, most of the ampheta- mines that are found coming from physicians, dextroamphetamine sulfates, dexedrine tablets, benzedrine tablets, biphetamines, bipheta- mine T-20's, dexoxyn, a pill made by Abbott, and in the realm of per- sonal use, most of these were secured in smaller quantities, most of the Smith-line products, dexedrine and benzedrine, things of that na- ture, we got from a friend's wife who worked in a doctor's office. Apparently the doctor must have received a lot of samples of these drugs, and she was able to take them home, and they had kind of a little drugstore at their house. You could get anything you wanted. The only drugs that were really available in quantities to sell for me personally were the dexoxyn tab- let made by Abbott, I believe, which was, it was i~ one-time thing, I would say there were several thousands of them available, and this was in Buffalo, N.Y., and a white pill with a mark on it, what I do not know who makes it, but we called them crossroads, that was available in tre- mendous quantities. Senator NasoN. Is that an amphetamine? PAGENO="0097" COMPETITIVE PROBLEMS I& ~E DRUG n~tunqtr 14519 Mr. liteRs. It was a stimulant. I do not know the ehethical nature of it. There was literally thousands of them available. Senator Nasow. Available how, where? Mr. Hicts. That came through a contact in North Carolina. I do not know how he secured them. - The only other pill that was available in any latge quantity oter any period of time is the black beauty, a biphetaS~e pill, I think it has always been around, as long as I was in the drug-selling busine~. Personally, when I lived in New York, I had a friend in Batavia, N.Y. which is about 30 miles outside of Buffalo, who was sellh~g Me the black beauties, and on one specific instance, he told me that I eould secure as much as 25,000 of them, and unfortunately, for Me at th~ time, I did not have the money to do it. I did purchase several thousand of them from the fellow at different times, 500 being the largest quantity atone time. He related to me that his contact got them from the factory, but I do not know personally about that. Mr. Gonriox. That is the Pennwalt Core. Mr. Hic~s. At the time they had MS on it, and then later on, When I moved down to the Washington area, and began buying the black beauties, at this time I tas securing them from a doctor, I noted they had a different symbol, I believe that was the Penn-walt Corp. - Mr. Gottoow. They changed the name. Senator NEr~soN. At what price were they? * Mr. Hicts. I cannot recall. I believe it was like 30 some cents a pill. Senator NElsoN. And what would they then sell for on the street? Mr. Hict. At that time, you could sell them for, depending on who you sold them to, anywhere horn 75 cents to a dollar. Now they are much higher. I do not know about them today, but in 1970, they had gone tip from a dollar to $3. Senator Nttsow. Sold on the street? Mr. Hica Yes, street value. Senator NELsoN. Do you recall what the price was if you bought them in a pharmacy? Mr. Hicics. I think when I got the script ifiled, it would cost me about $6 for 30 of them. Senator NELSON. How many a day would a drug user be likely to use? Mr. Hicus. It would depend on how lono~ he had been using them. The majority of the people I knew woula probably use maybe two or three of them per day. Other people I know at times I wa~ using them, I would be using 8 or 10 a day, because you nee&d niore later to stay up, otherwise you would go to sleep, and one of the things you did not want to do was go to sleep. Senator NElsoN. What w~ the main Source of these drugs that people such as yonr~elf would use and sell them? What tas the main source? Mr. Hxcxs. It would depend on which drug it was. The black beauties initially came from when I was living in Buffalo, came from an individual in Batavia, who said he secured them from a fellow at the factory. S5-569--77-------1 PAGENO="0098" 14520 COMPETFI'IYE PROBLEMS IX THE DRUG INDUSTRY I cannot verify that. In Washington, I secured them from a physi- cian, and the other drugs, as I said, I got them from a fellow who was, his wife worked for a doctor, and brought home the samples, the white cross. That came from a drug dealer, down in North Carolina.. I do not know where he secured them. Senator NELSoN. In the course of the period you were using and selling the drugs, was your source frequently or infrequently a physician? . Mr. Hicxs. Only a physician on one instance. - Senator NELSoN. Only in one instance? Mr. Hxci~s. Yes; I never had to rely on them before, and I was not that aware of the accessibility. I was usually looking for a larger quantity. From the physician you could always secure a script for usually 30 pUb, and we would have to go back the next month, and get another script, and go back the next month, and it seemed like too much hassle to go around and find 10 doctors to get enough pills, when you could find one person and buy them from him. Senator NELSON. What was the price you would pay per prescrip- tion, do you recall? Mr. Hxcxs. From the doctor, it cost $5 a visit. Now, you went in, and he took your blood pressure, and weighed you, and asked you what you would want, and you told him, and he wrote the script, and you gave the $5, and you had to go out and fill it. Senator NELSoN. He just asked you what you wanted, and he gave you what you asked for? Mr. ilicics, Yes. Senator NELSON. No quarrel about whether you needed it or not? Mr. Hicics. No. Senator Nasox. From your experience and that of others, how easy did it appear to be to go to this physician and get a prescription? Mr. Hicics. His office was always full, and I found out I was able to take several of my friends with me, and they secured them for themselves. At the time, it was a difficult period. I was not really dealing that heavily, and I had just been arrested, and I did not want to get ar- rested again, so I was laying a little low. Senator NELsoN. You are no longer associated with the Rehobet.h Teen Challenge? Mr. Hicics. I just `resigned and moved back to the Washington area, and I will be taking up a position of teaching a course in drug achnin- istry at a school being formed in Washington. Senator NELsoN. Thank you very much, Mr. Hicks, for taking the time to come. Mr. Ilicics. Thank you. Senator Nasox. Our next' witness is Ift. Edward King, deputy director, Town of Huntington Youth Bureau, Huntington, N.Y. Your statement will be printed in full in the record. PAGENO="0099" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14521 STATEMENT OP EDWARD A. KING, JR., A.C.S.W., DEPUTY DIREC- TOR,. TOWN OP HUNTINGTON YOUTH BUREAU, HUNTINGTON, N.Y. Mr. Kixe. Thank you. Mr. Chairman, I am deputy director of the Town of Huntington Youth Bureau, and program director of the town's community-based drug program. My testimony today is based on over 7 years ?~ experience in my present. position with Huntington township, which is a large Long Island suburb of New York City, with a population of 220,000 people. In 1968, the town of Huntington established the first town-level youth bureau in New York State, funded by the New York State Di- vision for Youth, and our youth bureau was among the very first agencies to receive State funds to operate a community-based program for the prevention and control of youthful drug abuse in 1910. In 1971, the town of Huntington instituted the first voluntary am phetamine ban in the United States. Senator NELSON. You say the town of Huntington instituted the first voluntary amphetamine ban in the United States. What does that mean Mr. ICixo. That means that physicians in the town of Huntington got together and agreed not to prescribe'amphetamines. Senator NELSON. All right. Mr. KING. Except in the very rare cases of narcolepsy and hyper- kinesis. At that time there were only two cases of narcolepsy identified in Suffolk County over a 2-year period. Senator NELsoN. How many cases of hyperkmnesis? Mr. Knco. A small number of hyperkinesis cases. The national incidence that year was about. 3 percent of all children between the ages of 5 and 12 that suffered from hyperkinesis. The town's comprehensive youth plan includes eight private, non- profit corporations known as youth development associations serving local neighborhoods within the township, and several support pro- grains in the areas of job development, summer camps, runaway place- ments, family, advocacy, and court diversion, as well as the dru6 program which consists of a hotline, counseling center, and outreact workers assigned to the local youth development associations. We feel that.our eight youth development associations on contract with the youth bureau provide the key to the development of program strategies, specific to reducing drug abuse. They are operated by local boards of community citizens-adults and youths-and are in the best positiorr to recognize local problems and their solutions in cooperation and coordination with our youth bureau professional staff. This elaborate system of citizen involvement in local government includes-in addition to local neighborhood boards-center councils4 task forces, special committees and program volunteers, working with PAGENO="0100" 14522 co~wnnin .PROBIXMS IN THE DRUG INDUSTRY the understanding and support of the appointed members of the youth board and the elected officials of the town council. We describe this grass-roots volunteer effort with obvious pride7 Mr. Chairman, to illustrate the importance of the work of this committee. With all of this local community concern and effort translated into quality programs and professional services, we will ultimately fail to tree ourselves of drug abuse unless institutionalized forms of drug abuse are addressed at the Federal level. Senator NELSoN. `What do you mean by institutionalized forms of driv' abuse? t~Fr. Kixo. I mean, particularly relevant to our discussion here to- day, the abuses of amphetamines by so-called weight clinics and weight doctors. I would go beyond that myself, in my own personal opinion, to include, for example, additives and preservatives in the foods we eat to make them more conveniently and more efficiently produced and marketed by big mdustries, to maintain their profit levels. Senator NELsoN. When you say institutionalized forms, you are it- ferring. I take it, to the legal prescribing? Mr. ICixo. Legitimized sources, yes. Senator NELSON. Legitimized sources of amphetamines? Mr. Kixe. Yes; and I would like to offer a very specific illustration at this time. In February of 1972, the town of huntington provided expert testimony in the person of Edward M. Gurowitz, Ph. D., then director of clinical services of the town's narcotic oiiidance council be- fore a Senate subcommittee chaired by Hon. Pau~ 0. Rogers, dealing with the very same concerns over amphetamine abuse which we are addressing here today. - - In that testimony, Dr. Gurowitz referred to a doctor with a "diet practice" with offices in the same building as our town's counseling center, and also housing the Suffolk County Methadone Maintenance Clinic. lie spoke of his difficulty in explaining this to young clients who saw long lines of people, many of them young, few of them obese, waiting to obtain drugs for wei~ht control. The situation was aggravate~ by the fact that many of these clients were court remanded for treatment after arrest and conviction for their illicit drug abuse, and had real feelings about the daily parade of "legitimized" drug traffic which they were witness to. The following steps were taken on the local level: The Suffolk County District Attorney's Office was alerted to the situation; the Suf- folk County Medical Society was informed-but the doctor was trot a member, and they could impose no effective sanction-the town's counseling center was moved to a new location; and, soon after, the county's methadone clinic moved away also. As of this writing, this same doctor remains under investigation of the Drug Enforcement Ad- ministration, and in active practice in the same location with an esti- mated weekly caseload of over 800 patients. In January of this year, one of those patients, a 20-year-old female, came to our counseling center with the hope of breaking a 1-year ad- diction to amphetamines. The pills were given to this client on a regular and unregulated ba- sis. She stated that she was given the pills directly by the doctor, and that she was able to get more than the usual weekly allotment of 21 pills with ease. PAGENO="0101" COMPETITIVE PROBLEMS E~ TEE DRUG ~DUSThY 14523 She further stated that? after the first visit, no significant examina- tion was made of her physical or emotional condition. During that year, before she came to us, she was often deeply de- pressed, had visual hallucinations, was delusional in her thinking, and attempted suicide on three separate occasions. She was hospitalized each time. On February 2 of this year, we referred her to a local detox unit, and they referred her to a local residential treatment program. She withdrew after 2 days, but our followup determined that she remained detoxified for 2 months before she returned to the doctor's office for more pills which she received. On May 4, in the presence of one our workers, she wrote a let- ter to the doctor, and told him of her addictive history with the pills he had been giving her, and pleaded with him to never give her pills even if she begged him. I wish that I could say that this is an atypical and overly dramatic case, Mr. Chairman, but this sad story is unusual only in the sense that this young woman came for help. When amphetamines are involved in an established pattern of drug abuse, deep depressions, aggressive acting out, paranolat suicidal ten- dencies and resistiveness to change are the common traits. Mr. OoRDoN. Mr. King, may I ask you a question concerning the doc- tor you mentioned. Does this practice include only obesity cases? Nr. KING. To the best of my knowledge, yes, sir. They are not really obesity cases in the sense that many of the clients seeing him are thin. He sees more people who you would characterize as underweight than you would characterize as overweight, in my opinion, from the people I have seen eoming and going from his office, and from the peo- pie he has seen who have come to us. This is only one doctor who illustrates the problem. He is not the only doctor who practices medicine in this fashion within our township. Mr. GomoN. And is he and the others also found to be the principal sources of speed? Mr. KING. Yes, sir, of the young people we have seen in the program, a very large majority of them who have problems with amphetamines, obtain their amphetamines from one of these three doctors. Some of them obtained their amphetamines from two or three of these doctors. Mr. Gorwox. How many cases have you had during the past year or so of amphetamine abuse? Mr. Kixo. Coincidentally, our capacity for our program in the course of the year, the number of clients we can effectively work with, is 800, which happens to be the weekly caseload of one of these doctors. Out of those 800 people, roughly 30 in the course of a year are char- acterized as having a problem with amphetamines in conjunction with other drugs. Out of those 30, only about 3 obtained their drugs illicitly. Senator NELSON. Of the 30 that came to your clinic, only 3? Ni'. KING. Yes. Of those we were able to contact through outreach and bring into our program. PAGENO="0102" 14524 COMPETITIVE PROBLEMS TN THE DRUG. INDUSTRY Senator NEL~ON. Only three of them obtained illicitly the drugs, were these all amphetamines, or was it a mix of various kinds? Mr. T~iwo. They were all taking amphetamines, or amphetamine- like stimulant drugs, that they had obtained through these doctors. The doctors used a variety of drugs, they do not use the same drug at all times. - The drug delcobese, known on the street as 697's, that is the drug enforcement number, seems to be the most common right now. Senator Nasox. Twenty-seven out of 30 received them through their physician? Mr. ICixo. Yes. Senator NELSON. Go ahead. Mr. ICixo. Just as these hearings on antiobesity drugs are part of a larger study of the development~ marketing, and distribution of pre- scription drugs in general, the abuse of amphetamines is usually com- bined with the abuse of tranquilizers, sedatives, and barbiturates obtained, far too often, from other doctors. Many adults in town, as well as young people, find themselves on a chemical roller coaster of "ups" and "downs." The suburban housewife seems to be a particularly high-risk pop- ulation for this kind of drug abuse. Some start with depressant drugs, develop tolerances, and then go to a "weight doctor" for amphetamines to help them get up in the morning. Others get "strung out" on their increased tolerance for ampheta- mines and ço to another doctor where they present the symptoms of extreme fatigue, anxiety, and tension, and tranquilizers or sedatives are prescribed. We have found very few amphetamine abusers in our township who have obtained their drugs from the street in recent years. This is not the case with tranquilizers, sedatives, and barbiturates, which are more common in general and more available in the illicit drug traffic. If we could somehow control the production of tranquilizers, seda- tives, and barbiturates so that tomorrow they would be available for only the appropriate medical uses, I would think twice before doing it. I certainly would not want to drive in heavy traflic the next day. The kind of human services necessary to enable less fortunate mem- bers of our society to cops in a healthy and responsible way with the stresses and anxieties of modern-day life are simply not in place. This is not tO say that depressant drugs are not grossly over- produced and overprescribed. They most certainly are, and Federal controls are urgently needed. However, these controls should be devel- oped caref ully and instituted with caution. A phase.in period of several years in which production limits would tighten in set steps would allow for the necessary ongoing evaluation which this effort would require. Amphetamines are a different story. The testimony of Dr. Gurowitz 5 years ago carefully established 1,200 kilos as a reasonable national production limit for amphetamines. This would provide an adequate supply to supplement the nonamphetamine drug of choice-Ritalin- for the treatment of the rare conditions of narcolepsy and hyper- kinesis. The latter condition is presently thought by many to be caused, PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14525 at least in part; by allergic reactions to dyes and preservatives in foods; yet another `form' of institutionalized substance abuse. It seems to me, Mr. Chairman, that amphetamines are the place to start with strict controls on production. While the abusers of depressant drugs are often self;medicating to control the symptoms of underlying emotional turmoil, amphetamines only aggravate and intensify those very same symptoms. - The person with underlying hostility becomes more hostile. The person with underlying depression becomes more depressed. The per- son with underlying psychosis breaks more completely with the reali- ties around him. The overall impact of this aggravated and intensified conflict on family life is beyond calculation, but most certainly widespread and tragic in its effect. We, in the town of huntington, are pleased and grateful that this committee is once again focusing attention on the critical need to cur- tail the overproduction of commonly abused prescription drugs by big industries throughout our Nation. By broadening the focus of our public concern over drug abuse in this way, we can talce real steps to demonstrate integrity in our na- tional effort. Young people abusing drugs obtained on the street have been scape- goated for too long in our so-called "war on drug abuse." young - people in general are extremely sensitive to* hypocrisy, and would be quick to recognize any real steps to deal fairly and squarely with institutionalized drug abuse as also being steps to reduce significantly the alienation young people feel from this national effort at the present time. Your leadership will go a long way toward uniting young and old alike in a national effort to find healthy and responsible ways to limit and control drug abuse and the closely related human abuses, of all kinds. We thank you for the opportunity to be a part of that process and stand ready to assist in any way possible. Thank you. ` Senator NELsoN. Do you have a residential center, or is this all outpatient? Mr. KING. This is all in the community, an outpatient, counseling program. Although one portion of our program is a clinical counseling center, where we do more intensified counseling, the backbone of the program is involving young people, both drug users and' nondrug users alike, in the governing of their local communities, in terms of developing programs and services for themselves and other people in the neighborhood. Senator Nasox. Did you say you have at any single time about 800 clients? Mr. ICING. That is an annual capacity. We work with, in the nei~h- borhood of 300, 315 or so at any one given time, at the present, with our present staff. Senator NasoN. You have about 300 enrolled at any one time? Mr. ICING. At any onetime, yes, sir. Senator Nasox. How long generally is the program? Mr. Kixe. The program has been in operation for 0 years now. PAGENO="0104" j4526 COMPZTITWE PROBLEMS IN TIlE DRUG INDUSTRY Senator Nu.soN. For the treatment of the individual? Mr. KING. It varies from person to person, Senator. The average is roughly in the neighborhood of 16 weeks, in terms of us counseling with them intensively, and working with other aspects of our comprehensive youth plan, in developing possibilities for in- volvement in constructive activities for that person to address himself to. Beyond that, we do not really measure as part of our drug program. Senator Nasow. Are all or most of the clients residents of the corn- niunity? Mr. KING. Yes; they are all residents of the community, with rare exceptions. When someone comes to us from outside the township, we see them, we do not turn them away, but I would say about 98 percent of the people we work with come from within the geographical township of Huntington. Senator Nasox. What is the population within the geographical area? Mr. Eat Two hundred and twenty thousand people. Senator Nasox. And ~within that township, do you know how many physicians prescribe? Mr. iCixo. Three who are outstanding, two doctors prescribe al- most exclusively amphetamines. They do not actually prescribe them, they give them away, and charge for the effice visit. Senator NELSoN. There is no particular indication for their use, for control of obesity, as you said earlier? Mr. Kr-wa. F~st oX all, I do not feel they have value in the control of obesity~ and, second, peop1e obtaining the drugs are not obese, and some of them are almost thm enough so you can see through them. Senator Nasow. What ia the age group you deal with mostly? Mr. ICING. Mostly between the ages of 12 and 22, with the largest majority being around the ages of 15,16,17. Senator Nasow. And in taking this history, how were those 12, 13,14,15 year olds introduced to the drug use? Mr. Kixo. With the amphetamine abusers, they are an older popqlation. Senator Nasow. It is an older population than the general popu- lation of drug abuse? Mr. Kr-wa. Yes, and I would say they are more toward the upper scale of the young people we deal with. They are in their late teens and early twenties, for the most part, and they were introduced to those drugs by doctors. That is particularly sad in a number of ways, especially in the sense of a young boy or girl, who is going through a lot of emotional and physical changes in adolescence. lie becomes overweight because of overeating, out of emotional need at one time or another, or just because of physiological change, they are awkward and clumsy at the time, and they are very highly motivated to do something about their overweight condition, and they really become sitting ducks for doctors who practice in this way. They go to the doctor, respecting his authority, respecting his position in society, and they go to him for medical help. They are doing the responsible thing, and through that treatment, they become PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14527 drug abusers, and, very often, they can become arrested for that drug abuse, if they happened to obtain the drug from a friend, who also goes to the same doctor, instead of from the doctor directly. Senator Nn~sox. Thank you very much, Mr. King, for taking the time to come here today to present your testimony. We do want to thank all of the witnesses for appearing at these hearings. The next hearing will be in this same room on Thursday, November 18, at 10 a.m. The subcommittee stands in recess. [Whereupon, the subcommittee was recessed at 11 :40 a.m.] PAGENO="0106" PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) THURSDAY, NOVflBER 18, 1976 ItS. Sz~nt, SvncoMMrn'rs ON MONOPOLY 01' THE SELtc'r ~0MMIT~EE ox SMALL BUSINESS, IVasltington, D.C. The subcommittee met, pursuant to recess, at 10 a.m., in room 318, Russell Senate O~ce Building, lion. Gaylord Nelson, chairman, presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Karen Young, research assistant. Senator NELSON. The subcommittee will please come to order. Our first witness today is Dr. John Henderson, of Ottawa, Canada. Dr. Henderson, the subcommittee is very pleased to have you here today to testify at these hearings. Your statement will be printed in full in the record. You may present it however you desire.' STATEMENT or JOHN W. B. HENDERSON, M.D., OTTAWA, CANADA Dr. HENDEES0N. Thank you very much, Mr. Chairman. Indeed, it ià a pleasure for me to come to Washington, and I would like to make one or two points prior to getting into the statement I have written. The first thing I would like to say is that I am a physician. I am not a public servant in Canada. I still practice medicine. My postgraduate work was done in Chicago and in Boston, and I now practice in Ottawa. I do not represent the Government of Canada, although I am a consultant to our Department of Health and Welfare. Many of the decisions we made some 4 years ago regarding the type of drugs we are interested in this morning, I was involved in, and, therefore, I must take some responsibility for them. I am also lere representing the Canadian Medical Association, for I am the chairman of the special committee of that organization con- cerning druz therapy; this is known as the Subcommittee on Pharma- cotherapy. Thus I would like to speak this morning more as a physician than as a representative of the Government of Canada, although what I want to talk about was very much a joint decision made by the medi- cal profession in my country, and the Government of Canada. 1 See prepared statement and attachments of Dr. Henderson beginning at 14120. (14529) PAGENO="0108" 14530 COMPETITIVE PROBLEMS ~N THE DEUG INDUSTRY Senator NELsoN. In the making of that decision, did you have an official role? Dr. 1-JENnEnsox. Yes, sir. I state in my statement that I was chair- man of the Special Amphetamine Ad 1-Joe Committee, which was a committee to look into the whole question of amphetamines and their place in medicine. - - I would like to say that I will try not to be presumptuous that we have the answers to the problem. . We made some decisions about amphetamine availability in 1972, and these became enacted in our laws in 1973. Some of the decisions we made in good faith at that time, we would not make now. Four years makes a big difference when one is looking at the potential for abuse of drugs, potential for misuse of drugs, and the incidence of side effects some of which we did not know about 4 years ago. I think that today we might make some different decisions. Senator NELSON. I did not hear that. Dr. I-JENDntsox. We were not aware 4 years ago of some of the side effects, some of the long-term effects, what people like to call today drug adverse effects, or drug adverse reactions. I have provided a table which was given me by our Department of Health and Welfare. It is labeled "Table J, Designated Drugs in Canada." On that sheet, we have demonstrated a series of numbers representing drugs either manufactured in Canada, or imported into tanada between the years 1967 and 1976. On the bottom half of the table are figures for the same drugs which have been- exported from Canada. - - We have made a decision in Canada that although there is a large number of drugs which one can call amphetamines, there are true amphetamines and amphetamine derivatives. lit 1972, we put those members of the family that seemed to us to have the greatest potential for misuse and abuse and harm to our society into a special restricted class. We chose amphetamines, meaning ihtL.form, dextroamphet- amine, benzphetamine, -- methamphetamine, phendimetrazine, and phenmetrazine. - - - - We decided to designate only these as "special amphetamines," Senator Nelson. Other members of the amphetamine class we chose to regard as potentially less harmful amphetamine congeners. The un- designated members include methyipherriclate or Ritalin, and a num- ber of drugs which are primarily prescribed for obesity. Since that there have been some new anorexiants introduced to the market. One is Imown as Mazindol, which although not chemically derived from amphetamine, shares several properties with amphetamines. You can see, therefore, that it is a large family. It is pharma- cologically correct to say they are all amphetamines, and, therefore, there should be no difference in regulations between the top group- very dangerous-and the bottom group-less dangerous-but for reasons I will come to a little later, we decided to draw a line some- where, and "designate" only those which I have shown on table I. After consultation with several expert members of the medical pro- fession in our country, and a survey of the world literature, we were still uncertain whether or not there are diagnoses for which these drugs are really indicated. If there are conditions for which these designated amphetamine drugs are prime choices, then obviously they PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14531 should be made available to the medical profession. Our first job in the special committee, therefore, was to have a look at the therapeutic indications for the use of these particular drugs. The way in which this control systbm was introduced in Canada, was through the political forum. Our then Minister of llealth and Welfare, 31 r. John Munro, stated in our House of Commons that he had been advised that only two diagnoses, narcolepsy and hyperkinetic disordei~s of childhood were true indications for these drugs. This was not the impression of many physicians in Canada. The committee, however, started from that viewpoint, and then began to look at other possibilities. We agreed unanimously that these drugs were not antidepressants but rather that they are stimulants; they do have anorectic properties, possibly as a side effect. Primarily, however, they are central nervous system stimulants, and have no real place in modern medicine as antidepressants. New antidepressant drugs have become available to medicine in the last few years which we feel are much more effective and safer than the amphetamines. It was the opinion of some that amphetamines can increase the physical activity and brighten the outlook of depressed people, but it was our impression from the literature of the time that increased activity in acutely depressed people sometimes in fact raises the possi- bibty of suicide, rather than decreases it. We felt that there was no place for these drugs, for maintenance of amphetamine.dependent persons. We did not feel that these designated drugs should be used for the treatment of obesity, especially as other drugs were available for this purpose. We also felt that these drugs should not be used for the treatment of disorders of the muscles and nerves-musculo-skeletal diseases. There were differehces of opinion about the use of these drugs in the condition known as idiopathic edema, swelling of the lower ex- tremities mainly in women; An increase in physical activity seems to benefit some of these patients, but we thought the vast majority of these people do not require amphetamines, and so we did not regard it an appropriate diagnosis for them. On page 4 of my statement, Senator Nelson, I mention nonnarcolep- tic hypersomnia. This means people who have an overwhelming prob- lem because they fall asleep at inopportune times. An alternative diagnosis often cannot be made. We are not entirely sure what this particular problem is, although it is seen in various disguises. In the Pickwick Papers of Charles Dickens, you may remember the fat boy who used to travel on the stagecoach, and who kept falling asleep. These people are obese, they have a great problem in breathing. They in fact ünderbreathe, and very often during sleep they stop breathing for short periods. They are blue in color, have muscle twitching, and they are forever asleep. It is a very distressing situation. It does appear that some of these people might be benefited by the fise of amphetamines. In recent years, however, it has been established that other drugs can also be used. PAGENO="0110" 14532 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY For example, female sex hormones may benefit some of these unfor- tunate persons. I believe we should await the results of considerable research being conducted now in the field of sleep. We chose not to include this diagnosis as a justification for treatment with amphetamines. Amphetamines have been combined with pain relieving medications for many years, especially in the treatment of painful menstrual cramps. I believe that has been an area of misuse, and many young women have become somewhat dependent on stimulants and ampheta- mines as a result of there being given these drugs for too long. Because nervous system stimulation is pleasant, the drugs that produce this effect begin to be used at times when there is no actual problem. It then can become a habit. This does not mean they have absolutely no place in pain relief. The amphetamines ~s a stimulant of the central nervous system distract people from some of their discomforts. however, we were concerned about the widespread use of amphetamines in our society by gyne- cologists and family physicians, and we felt the risks outweighed the benefits, and that therefore we should not approve this as a diagnosis. We, therefore, reached a consensus on a small number of diagnoses for which these amphetamine drugs could be legally prescribed by Cana- dian physicians. Mr. Gonnox. You are including the congeners? Dr. }lENDEnsox. I am talking purely at the moment of the ampheta- mines, benzphetamine, methamphetamine, phendimetrazine, and phenmetrazine. I am still talking about those drugs above the line which I drew. Narcolepsy is one diagnosis that we felt justified amphetamine drugs. There are conflicting reports about the number of people who have narcolepsy. In the United States the number varies from a few hundred to 20,000. Part of the problem is that we have no definite diagnostic criteria for this particular diagnosis. Many of these people do not need any drugs. They perhaps need special advice; they may require to have special consideration at work; and be allowed to take a nap in the middle of the day. However, some find this particular problem over- whelming, and falling asleep if you are working in a dangerous en- vironment could be extremely hazardous. So this diagnosis may well justify use of amphetamines. Our second approved condition is hyperkinetic disorders in chil- dren. I think, however, that there is almost more confusion here than there is about narcolepsy. I personally worry more about this diagnosis. I believe we have been too sloppy in our thinking about what is hyperactivity, or hyper- kinesis and what should be called the hyperkinetic syndrome, where the child's behavior is self-destructive, who cannot learn, and who is almost impossible to handle in the classroom. It is my opinion that the number of children with this particular syndrome is really quite small, whereas the number of hyperactive children is quite large. Some of them are hyperactive in school because they are bored. Children who are bright, with a high IQ, but who are bored, and cause classroom trouble, do not need drugs at all. PAGENO="0111" COMPETITIVE PROflLEMS IN THE DRUG INDUSTRY 14533 There are also drugs other than amphetamines which can be given to children with hyperkinetic disorders. Antidepressants can be used, but these too may create problems, for some of them may provoke an epileptic fit. Therefore, because there is no one universally effective drug for these children, we do need to have available to us a small number of amphetamines. - - We may, however, not need any of our designated ones. Below our line, there is methylphenidate and this can be used equally well for this diagnosis. * Allied to this diagnosis is the phrase minimal brain dysfunction, or minimal brain disorder. This is mixed to some extent with the hyper- kmet ic syndrome. We are not quite sure what is meant by it. Most of those children show some degree of mental retardation, usually minimal, and usually there is a slight abnormality in the electroencephalogram. * If they are badly retarded, or if there is quite a bit of brain dysfunc- tion, amphetamines may make the condition worse. There is no real way at the moment of telling in advance. Therefore, the only way to try to help these children is to use an amphetamine and see what happens. - Epilepsy. Some of our pediatricians, especially those interested in child neurology, felt there were some forms of epilepsy which benefit from amphetamines. Some stated that children taking other anti-epi- leptic drugs sometimes became quite retarded, and need a stimulant to counteract some of the slowing down side effects of the other neces- sary drugs. - I am not certain in 1976 whether this is still a fact worth consider- ing. Similarly, my fifth diagnosis is Parkinson's disease. Sometimes the stimulation provided by amphetamines does seem to improve their ability to move around, to walk, and to live a reasonable life. There are other uses which are related to anaesthesia where the amphetamines can be used to raise blood pressure. Mr. GoRDoN. Dr. henderson, may I interrupt you for a second? You stated that there are doctors who feel the drugs may increase mobility, and so forth. I was just wondering if this "feeling" is sufficient to approve a drug for a particular use by Canadiarr law; do you need adequate and well- controlled studies? Dr. ILENDEIt5ON. Yes; we try to evaluate studies, of course. We recognize, however, that therapeutics is not an exact science, and that we have to proceed on a preponderance of evidence handed to us. Most of the time we have some physicians saying one thing, and others saying another. We try to be as fair as possible, and we try to stay on the safe side by not taking away medication that might help some unfortunate people. In fact, for ParlcinAon's disease amphetamines are hardly ever used in our country. I feel that well-controlled studies are lacking in this particular area, and I am very doubtful about the efficacy of amphet- amines for this disease. If I were to go back now as chairman of the committee, I think I would have general agreement on that point. Senator Nelson, my table I demonstrates that when it became public knowledge in 1972 that steps were going to be taken to control PAGENO="0112" 14534 COMPETITiVE PBO$LEMS IN `rat DRUG INDUSTRY ths medical use of amphetamines, a sudden change occurred. You may ~ee the 756 kilograms imported in 1971, suddenly dropped in 1972 to 3244 kilograms. On January 1, 1973, our law designated the five conditions as the only medical diagnoses for which these drugs could be prescribed. Senator Nasol(. What conditions? Dr. jfrxpnjsoN. The five narcolepsy, hyperkinetic disorders in chil- dren, minimal brain dysf~mctjon, epilepsy, and Parkinsonism. You may see in table I, that 32.457 kilograms has dropped to 1.395 kilograms in 1973, and down to 0475 in 1975-.-less than a halt of 1 kilo- gram imported into Canada in 1 year. This, however, is quite adequate for the medical needs. I think the drop is quite dramatic. Senator NELsON. It is not manufactured in Canada? Dr. llnrnnsoN. No, sir. The only substance which is manufactured in Canada, phendlimetra- zine, winch although manufactured, is not marketed in Canada. It is all exported. Senator NELSON. Why is this not marketed in Canada? Dr. ilExorEsoN. It is not prohibited. It has never been put on the Canadian market. Thus, it is not being prescribed in Canada. Phen- dimetrazine is the only amphetamine derivative that has been manu- factured in our country. Mr. Gor~nox. What is the 1976 production for amphetamines? Dr. llnontsox. That is a purely chemical use; it has nothing to do with drugs. I cannot tell you which particular industry it was, but ampheta- mines are used as a basis for other chemicals. It was certainly non- medical. Senator Nnsow. All of these are amphetamines or related? Dr. IlENnutsox. No, sir, those shown on table I are the five we felt to be the most dangerous of the entire family. I will refer now to the question of obesity. You may see on the sec- ond long page, entitled "Antiobesity Market, 1971-75." The statistics hero were derived from ff5 Canada. * What we did here was to take the 1971 market as 100 percent. That was well before we changed our regulations. Thus the lefthand side represents percentage change. Senator NELsON. This is all for the treatment of obesity? Dr. }jENnntsox. Yes. In 1972 we had a drop in both the true amphetamines and ampheta- mine congeners, and in 1973, 1974, 1975, the amount of amphetamines of the type we have controlled in a rather drastic manner, has stayed very, very small. It is, however, obvious there has been an increase in prescnbing of the amphetamine congeners, and this would be about a 10-percent rise from 1973 to 1974 and about the same for 1974 ta 1975. I have looked at what is happening in 1976. It would seen there has been a rise, perhaps half the amount of the previous year. Mr. GoRDoN. The ban on prescribing amphetamines for obesity has brought about a shift in demand to the ncnamphetamines, the congeners; is that correct? * Dr. H~nr.x~sox. That is correct, Mr. Gothon. PAGENO="0113" COMPE'tITrVE PROBLEMS fl~ THE DRUG INDUSTRY 14535 What has happened is that physicians knowing that the drugs as Mazindol are not restricted, and not subject to the stnct regulations of the `top five of the amphetamines, are prescribing those. I do not know whether or not this increase, Senator Nelson, which is measured by the ThiS in terms of dollars spent, might be due to inflation, and not an actual increase in use of (the drugs. I also wonder whether or not the increased demand for these drugs might .be related to increase in populal ion. The population of Canada increased, dur- ing the years 1972-73, by 1.3 percent, between 1973-74, and this year it will be about 1.4 percent. Therefore, an crease in population may have to be considered, but it does not really erplam why more money is being expended for these amphetamine-derived anorexiants. Senator NaSON. What is the difference between the congeners and the amphetamines in terms of their effect on the user? Dr. HnnntsoN. The amount of stimulation, Mr. Nelson, is less, but chemically they are amphetamines. They `all demonstrate in a pharma- cological sense some central nervous system stimulation. Senator NasoN. Are they dramatically less stimulative? Dr. JIENDUtS0N. I would say measurably less, rather than dramatic- ally less. I think there have been improvements. An example ~s the drug fenfluramine. It may be true that this particular drug does not cause measurable euphoria in most persons who take it. It is the only one that I use in my own practice. Fenflurarnine. is a special kind of modified amphetamine which has hardly any notice- able stimulation. Possibly because of this the drug is unpopular in our country. People do not like it, people do not want repeat prescrip- tions of it, because they say it makes them drowsy. It does not "pick them up," and it causes in some people a degree of nausea, and some diarrhea. Therefore, the drug is rather unpleasant for the user. Peo- ple say that they would rather do without it. This is entirely different for dextroamphetamine, which causes a very measurable degree of euphoria. Senator NELSON. Is fenflurainjue indicated in Canadian medical practice for any other specific purpose other than as an antiobesity drugt Dr. HENDERSON. No, sir. Senator. NnsoK. What kind of studies have been done to show a~ effect on obesity Dr. HnrnERso~c. Most studies have been uncontrolled; this is a. great problem with most of the anoreotics. Most of them `haye consisted in measuring weight change over a period of weeks or months. Weight of course varies on its own. With almost any drug that you start witli~ people become enthusiastic, and during this period stick with their diet. People who are obese and having trouble are eating not because they are hungry. The stimulus for a person to raid the refrigerator at 12 o'clock at night is not really because of hunger. It is somehow or other they feel better after they have had something to cat. The eating in itself is a way of making them feel good. To take away physiological appetite by making a person feel nTausea, as one could do with, for example, table salt, is not the way to treat a person S5-569----77-g PAGENO="0114" 14536 COMPETITIVE PROBLEMS TN TUE DRUG INDUSTRY with a compulsive eating problem. Simply removing physiological hunger is not really a rational way of dealing with what is funda- mentally a psvehog~nic problem in over 80 percent of the people who are havintv serious trouble with their weight. SenatJ' NElsoN. But in the graph you lump toavt.her all of the amphetamines? Dr. HENDERSON. Yes, except fenfluramine. Also not rucluded is mazindol, because it has only very recently been released as a drug on our market. I have no real data for it. I looked at some other possibilities, and I would like to try to ex- plain why more money is being spent on these amphetamine congeners specifically marketed as appetite depressants or anorect.ants. In our country, we have a National llealth Service. Everybody, therefore, has access to a physician, without paying an extra fee. Under such a comprehensive prepaid medical insurance plan, more people go to their doctors, and tie doctors are busier than ever. More people are asking for all sorts of medication, and possibly this particular area of requests for drugs for weight problems is simply one of many such requests for drugs. The other point is that with the older drugs that we designated, the effects were good only for 4 to 8 weeks. The patients became tolerant, and this meant they had to take a higher dose of the drug, or they simply lost the anorexiant effect. Doctors did not like to see people increasing their dose because of the chance of side effects, such as some degree of irritability, tremor, possibly some change in blood pressure, and a raised heart rate. Newer drugs such as mazindol seem to have a much lower potential for tolerance. At least it takes a lot longer to become tolerant. The drug seems to be effective for up to 15 or even 30 weeks instead of the 6 to S weeks of the older ones. This means if a patient goes back to a physician, and says "Yes, I am doing well; I managed to stick to my diet reasonably easily and I am losing 2 pounds every week," the physician is more likely to represcribe. So the very fact that we have developed drugs which seem to be effective for long periods of time, means that any one patient probably receives more of them. Therefore, more money is be- ing spent on these particular drugs. Senator NELSON. Do any of these drugs shown on the dark part of the graph, the congeners, show an indication of the ldnd of addictive- ness that occurs as a consequence of the use of amphetamines? Dr. hENDERsoN. Yes, they do to some extent. We chose to exclude a few drugs from our strict restrictions on use because of the need for some degree of flexibility in the management of depression, not because of obesity. In about 1971 and 1972, as a result of a number of good scientific papers, we felt that amphetamines as such had no place in the treat- ment of depression. We felt that possibly there was some medical indi- cation for methylphenidate in the hands of skilled psychiatrists for some cases of depression where fast action was desirable. At that time it was our opinion that the congeners were not causing any medical or social problems, so to speak. That has changed since 1972. Last week I saw a large amount of thetliylpropion which bad been manufactured illicitly. It was not of PAGENO="0115" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14537 high quality, but nevertheless it was diethylpropion. The synthesis is apparently easy for anybody with some knowledge of chemistry. So we are indeed seeing abuse of at least one 9f these congeners which was legally marketed for obesity. I think it is quite obvious that no one will market an illicit drug ãf there is no "street" market for it. The stimulant properties of some of these congeners *see~ to be leading to nonmedical use of them. Therefore, there is now justification in Canada to reexamine whether or not the extent of our restrictions has been adequate, or now needs further tightening. We cannot really ignore the fact that drug abuse is beginning to appear with some of these amphetamine congeners. Senator NELSON. Are all of the congeners imported into Canada, or are some of these manufactured Dr. HENDERsON. None being manufactured that I know of. - Senator NELSON. Does the Canadian Government limit the amount imported! . Dr. HENDERSON. No, to my knowledge, it does not impose any quota on amounts. . They are controlled by the schedule which limits them to prescrip- tion, and other than over-the-counter sales that is about the loosest kind of control that exists! Senator NELSON. And all of these in the colored section of the graph are specifically indicated only for obesity? Dr. HENDERSON. Yes, they are approved for that purpose only; that is correct. Senator NELsON. If some of them are being used, as you put it, for nonmedical purposes, and if in fact it is found that they are widely used for that purpose, does their use for controlling obesity have a benefit-to-risk ratio sufficient to leave it in the market for that purpose? Or are the costs, so to speak, in the ratio too great to allow it to be in the market? Dr. IinmntsoN. In my own opinion, Senator Nelson, the risks are higher than the benefits. I would state however, that it is difficult to assess accurately the risk benefit, for in most cases medical opinion is divided. We have not been teaching a methodology of risk.benefit for drugs to our students or to our practicing physicians. It seems obvious that we should in the future. The only drug I prescribe for obesity is fenfiuramine. I think its potential for abuse is very small. After trying it patients prefer not to continue with it for long, but it does act as an anorectant for several weeks or a month or two. - I use it for people who have said they have tried all sorts of diets. Some have been in Weight Watcher-type organizations, but for one reason or other they have not succeeded in losing weight. Nothing has worked for them and they are depressed people. They do not like themselves as obese people. They really do want to lose weight, but they "cannot." Therefore they are, in their own eyes, failures, and they come virtually with tears in their eyes. It becomes important to try to persuade these patients, that it is a question of food intake that creates obesity. If one can demonstrate that he/she can lose weight, even a few pounds a week, if he sticks to PAGENO="0116" 14538 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a specific diet, perhaps just a low carbohydrate diet, without an in- crease in fat or protein, the first success has been achieved. After the second or third week, they may have lost C or 7 pounds. Suddenly the personality begins to pick up. Something at last is working for them. I make it clear to my patients they will not get it for longer than 8 or 4 weeks. It is purely to demonstrate they can and will lose weight if they maintain a specific diet regimen. I have not used the newer drug, mazindol. It may or may not have advantages over fenfluramine. I simply do not know. Mazindol is not an amphetamine derivative but has a separate molecular configuration. However, it has nil of the effects of amphetamines. Senator Naao~. All of the effects? Dr. HEImznsox. Yes. At the clinical level, it would be hard to say it is not an ampheta- mine, although chemically it is not. The advertising of the drug by the company tells doctors that it is the first nonamphetamine anorectant. It also declares that the side effects will be the same as the other amphetamine congeners. It is my suspicion that it will turn out to have the same potential for central nervous system stimulation as the rest. Mr. Goimoir. Dr. Henderson, if I may interrupt a second, we had testimony last week from Dr. Jasinski of the Addiction Research Center that he had done some work on fenfiuramine, and he found that it has the same effects as LSD. Will you comment on that? Dr. HENDERSON. It isa very peculiar drug. One could not have predicted much difference from other similar drugs from the original pharmacology. It affects various parts of the. brain, but in terms of air electro- encephalogram, it is obviously stimulating the subcortical area. It is a depressant on other parts of the brain. The overall effect is drowsiness rather than stimulation, but that does not mean that it is not a stimulant. It has some effects on sleep which are quits unusual. As you know, the amphetamines of all types can produce hallucinations, and fen- fluramine can do the same thing. This is why I am very cautious in my use of it. I never give it on a chronic basis. I do not give it to people who for one reason or an- other should not receive amphetamines of any kind.. There are mini- mal effects however on blood pressure and the heart. I could practice without it. I believe that no patient would really stiffer from its absence if it were not available. I am not sure that all physicians would agree with me. Some of them might think of fenfiuramine as a useful crutch, which at the moment has less potential for dependence or abuse than older amphetamine anorexiants. It is because physicians still find anorexiants to have some clinical use that both older and very new drugs like mazindol are widely prescribed. However, even the manufacturers of anorexiant drugs make it quite clear it will only work if the person maintains a strict diet at the same time. . . PAGENO="0117" COMPETITWE PROBLEMS IN TIlE DRUG INDUSTRY 14539 People who take these drugs unfortunately do not lose their interest in food. Senator NELSON. Of course, if they take an interest in their diet, and they stick to it, they would lose as much as if they did not take the drug at all. Dr. HENDERSoN. That is correct. These drugs act as distractors. They distract *a person's attention away from the fact they want more food. That is all they are doing in my opinion. It may even be questionable to say that they are anorectics, or that they are appetite depressants. A true anorexrant effect is seen in pa- tients who are taking one of the cardiac drugs, such as digitalis. Sometimes these patients, after they have built up their blood concen- tration, simply do not want to eat, and cannot eat. They are not inter- ested in food. Now, of course, there is no way digitalis could or should be marketed -as an nnorvctic,but indeed it has this effect-but itis a side effect. Amphetamines are not anor~etic in that senseç but beeunse of the distraction, md the feeliiw that life is fun, surronndinga are ~n)oyable and the person feels goo~ maybe for that period of time, he or she does not have to eat to feel content. Eating behavior however, has not been changed by these drugs~ Unless eating behavior, that is, one's attitude toward the cooking of food, and the eating of food does change then there is no long-term benefit from them. it is because of this, that I believe that these drugs have a very limited role to play in the management of obesity. Mr. GonnoN. I would like to read a statement from Dr. Jean Mayer, that he made before our committee 4 years ago, in 1972. This is on pages 1264 and 1265, and he says: flowever,as far as the general public is concerned, I think we would be delud- ing ourselves if we thought that even with this association of obesity and disease the health considerations were, in fact, the primary motivation of our federal citizens who seek to reduce. The primary motivation is a cosmetic one rather than a health one, and we have to address ourselves to the problem of obesity knowing that in the mind of a great many of its sufferers we are dealing with a cosmetic problem at least as much as we are dealing with a health problem, and that the almost desperate motivation of many of the sufferers in seeking relief has much more to do with benefits which they think will accrue to them here and now In terms of attractiveness to the other sex than because or the benefits to heaith In the long run. * I am stating all this by way of a background because I think we have to realize that the motivation in the mind of the patient is often very different from that which is discussed when one speaks of obesity as a purely medical problem. ¶ ` Would you like to comment on that? Dr. HENDERSON. Yes. Just 2 weeks ago. Mr. Gordon, I saw a uni- versity student who was grossly obese, who had said he had tried to diet, but had irot succeeded in losing anything more than 1 or 2 pounds. I asked him about his motivation for wanting to be thinner. In the jargon of the campus, he said that the real reason was that he was not "drawing the birds" as well as he had before. - I did not quite understand, so he explained that drawing the birds means drawing the attention of young ladies. The reason he wanted to lose weight was that he felt he was no longer physically attractive to the. coeds on the campus. I agree that a great deal of this need to be thin is cosmetic. Sometimes, however, cosmetic motivation is not PAGENO="0118" 14540 COMPETITWE PROBLEMS i2~ `THE DRUG INDUSTRY altogether a bad thing; for it can be turned around to good purposes. I think that most of us would agree that small amounts of obesity, 5 to 10 pounds overweight, does not matter much, and a lot of our obses- sion with slimness is a question of fashion more than with health. There is no doubt, however, that people who are 20 percent or more overweight, have a higher incidence of all kinds of problems. There is a health aspect to tins kind of obesity. To remedy this kind of obesity, some kind of lasting motivation is necessary. If I may, I would like to move into the question of s methodology of thinking about drugs. In medicine and in pharmacology, we tend to think of them as a medical scientist would, but I fully realize that is perhaps no longer enough. We have recently been faced with all sorts of drug problems, involv- ing drugs of licit and illicit origin and we are still concerned with alcohol, cannabis, many drugs which have their origin with illicit manufacturers-amphetamines--although many are not of illicit ori- gin but rather diversions from originally legal sources. I thought I would try to devise a method of looking at the social impact of drugs. In some cases, drugs as a family, and sometimes as individual drugs such as cannabis. I first toolc a look at benefits of the drug's availability. Of course, for many people, drugs do not have just medical benefits, but possess what they regard as recreational benefits. For example, alcohol does more harm to our society than any other drug, but prohibiting its use was a social failure. Obviously our cul- ture claims that in alcohol use there are recreational benefits. I have set down a number of questions about the availability of drugs made available to the public directly; or available through the practice of a physician's prescription. Does it cure anything? Or does it provide only temporary relief of a discomfort? Does this drug inter- fere with other drugs that may have to be taken, or even with dietary substances? Does it lack idiosyncratic or unpredictable reactions? How beneficial are the effects when compared with the toxicity? This is an important feature when one considers antiobesity amphet- amine-type drugs. Is it reasonably priced on the market? Are there any social benefits, or just various degrees of intoxication, when this drug is used? With regard to risks, I decided to look at it from several points of view. The first concerns various aspects of health. Does it impair learn- ing abilities, life skills, and formal education? Does it impair brain function in any way? * Does it lead to undeAirable conseqeunces of a chronic sensory dep- rivation? What does it do to us as a society if a high proportion of us shield ourselves from the "harsh" realities of life? Does it cause any other kinds of organic problems, for example, liver, kidneys, and so forth? Does it affect nutrition as alcohol does? Is it likely to he lethal if taken in overdose? What are the long- term effects if tins drug is used in recreation? From the viewpoints of personal and public safety, does it lead to any kind of deviant behavior? Does it lend to aggressive behavior- ineludin~r sexual aggression? Does it lead to any form of violent behavior? PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14541 I thihk that some of the amphetamines and drugs like cocaine have demonstrated increased aggressiveness. Is the drug associated with loss of psychomotor and judgment control? Is the criminal element in society involved in obtaining the sub- stance? The safety effect here is tied to guns, thefts, assaults, black- mail, and such other hazards. Does it lead to increased risk-taking behavior? Does it lead to flattening of effect, lack of emotional responses, in- cluding healthy anxiety, healthy concerns, justifiable fears? how great are the safety risks to individuals, communities, and larger society, when used recreationally? Many drugs do, including the amphetamines, make a person feel good-euphoria-and in this altered state may drive a car faster, and -so OIL * Risk-taking behavior leads to many problems. * We all need some degree of anxiety, and the taking of psychoactive drugs can lead to a situation that preclud~s benefits derived from emo- tional responses to life. More difficult to look at is the question of drugs as they affect the social order and culture. - Two countries have been brought to their present states by a great deal of hard work, perseverance, and guts. A "chemical" society that becomes reliant on uppers or downers-stimulants or tranquilizers- may change in terms of the character of its people. So.with that in mind, I ask more questions. Does chronic use of this drug lead to non- coping behavior or to low self reliance if the drug is withdrawn? Would widespread use lead to loss of productivity and creativeness? [s use of a drug associated with recruitment of nonusers? Can its use lead to a lowering of ethical and moral values within society? Is it itssociated with amotivitional states? Is it associated with economic losses to the community? Does a given drug lead to "anarchic" inclinations when used non- medically? What I mean by that is an attitude of hostility to au- thority-"no one is going to tell me what I can and can't do." Last but certainly not least, I have looked at the risks of psycho- active drugs in terms of potential for creation of states of dependence of addiction. I know of course that the Food and Drug Administration, and the Drug Enforcement Agency here in the United States, are extremely interested in this aspect - I have worked with several members of the U.S. Government within a committee of the World Health Organization, to try to develop ~nethodologies, whereby we can predict and assess the likelihood of states of psychological or physical dependence developing as a result of use of any psychoactive druc~. I believe that the emphetamines. and the antiobesity congeners should be looked at closely from this view- point. . . . Arrain I have asked a number of questions. Does dependence occur after regular low-dos. ~1ss? Does dependence occur only after heavy use? Is psvrhological dependence problematic? Does use result in physical addiction? PAGENO="0120" 14542 COMPETITIvE PROBLEMS rw THE DRUG UcDUSTRY How great are the reinforcing properties? I am using reinforce- ment here in its psychological sense. If & drug creates a pleasureable effect, so that after its use one feels great, we probably will want to use it again. Thus begins habituation. I am presently carrying out a psychoactive drug survey in which I have tried to answer these questions. One such profile that has been engendered is for the drug methyiphenidate as shown on the sheet `which I have made available to you. There are obviously some benefits, and because of this the drug is readily available. What about risks? There are probably some with respect to safety, especially in terms of risk-taking behavior. In terms of the social order, yes, there may be some, but certainly not of a high order. 1V[ethylphenidate is slightly different in a chemical sense from pure amphetamine, but it is a member of and as you probably know, that family. In the World Health Organization convention on psycho- tropic drugs, methyiphenidate is regarded in the same way as other amphetamines are. The recommendation of that particular convention is that methylphenidate should be regulated and subjected to the strin- gent controls used for amphetamines. With that, I agree. In summary, Senator Nelson, I would like to say that I am glad that Canada took some action in 1979 and 1973 to remedy overuse of am- phetamines. The drugs which we controlled have remained controlled. lYe set thera~'eutic guidelines for their use. We left the door slightly open to physicians in Canada by saying, "If you personally feel you need to use this drug for conditions outside of this list of approved conditions, get in touch with us and we will discuss the situation." We have had about 250 requests of this type from physicians per year since 1973. The number stays about constant. We have never ac- tually refused to allow a physician to employ amphetamines if in his best judgment he feels he has tried everything else, and this particular patient needs them, Despite various arguments from individual physicians. I do not think we want to increase our approved list in any way. The concept of restricting the number of diagnoses as indications for drugs is a new one for our country, and it was necessary to do a fair amount of selling of this to the Canadian Medical Association. Senator NElsoN. `When you say restrict, did you mean restricting in- dications for use? Dr. HENDERSON. Yes. For example, if a Canadian physician pre- scribes benzphetamine or methamplietamine as a stimulant for kids playing ice hockey, he is in fact doing something which is illegal. Amphetamines are not approved as a stimulant for say, truck drivers who drive all night and want something to stay awake. Neither are they to be used for obesity. A doctor is in fact breaking Canadian law by prescribing a designated amphetamine-for example, phen- inetrazine-for obesity. A physician is allowed to prescribe amphetamines only for the des- ignated conditions that I earlier outlined. Physicians in general do not like to be limited. They want to have total freedom to prescribe as we think is indicated. I just wish that medical knowledge in clinical pharmacology was a lot better. I think a lot of irrational prescribing was and is going on, PAGENO="0121" CO~WEflT1fl PROBLEMS IN ThE DRUG INDUSTRY 14543 and I say this repeatedly in my own country. Not only have I in mind this particular area of psychoactive drugs, but other drug groups such as antibiotics. We are obviously not doing as good a job as we should in our medical education, to teach rational therapeutics. I am more than a little embarrassed to see that Canadian physicians seem to be prescribing more and more of these amphetamine congeners for the treatment of obesity. They obviously are obeying the law. There is no problem there, but they seem to have fallen for the concept that there is a large place in practice for the congeners. * What we shall do next, I do not yet know. I would be happy to have another look at the whole situation, and I hope that in the next 2 or 3 months we will be reconvening our committee to formulate further recommendations. I personally feel we should make some changes in our older recom- mendàtions to the Government regarding amphetamine controls. These must be such however that they will not hurt any patients. We can indeed hurt people who have become dependent on drugs, when these are taken away from them in a sudden drastic manner. For this reason any curtailment of use of amphetamine congeners must be planned and introduced congeners. I would like to proceed thinking about drugs in terms of risks and benefits, and to introduce some of these concepts more thoroughly into our medical schools. Doctors in general have not taken sufficient regard to the social consequences of use of many classes of drugs, which are now widespread in our society. Senator NELSoN. For the National Health Prognm, Canada pro- duces a formulary of approved drugs? Dr. HENDERSON. No, sir. There has however been talk of that very thing. We presently use a book which is comparable to the Physicians' Desk Reference. In Canada it is known as the Compendium of Pharmaceuticals and Specialties. Senator Nnsow. Who publishes it? Dr. HnDERSON. The Canadian Pharmaceutical Association pub- lishes it. The book is derived from the approved product monographs of the companies. The publishers have an editorial board of physicians and clinical pharmacists. In some provinces there are special plans for people on welfare, old-age pensioners, and for these patients there are special lists of drugs that are available free. But there is no Canadian drug formulary. We have essentially the same number of prescribed drugs on our market as you have. They can all be prescribed for our patients with the one exception of the amphetamines, which can be prescribed only for five designated conditions. Senator Nasox. But the drugs in Canada are approved generally for the same uses as they are in this country; are they not? Dr. HENDERSON. Yes; that is true. Senator NElsoN. And when the Canadian panel decided to recoin- mend that amphetamines would no longer be indicated for obesity, you still had the congeners that could be used for weight control. PAGENO="0122" 14544 COm'ETITIVE PROBLEMS ~N THE DRUG TNDUSTRY If a number of the congeners are strongly stimulative also, in a simi- lar way as amphetamines, why did the panel permit the congeners to go on the market? Was it lack of knowledge? Dr. Hni~znsoN. In 1972, we were of the opinion that phentermine and a few other congeners did not have the potential for abuse that existed for say, phemnetrazine. We thus chose at that time to recom- mend that some congeners should remain uncontrolled at least for the time being. We said that we would attempt to review our decisions every 2 years. We knew we were making decisions which might not be long-lasting. It is only in the last year and a half that some of us have become convinced that a number of these congeners do have a risk of abuse. By asking the questions that I have outlined I have come to the con- clusion that the risks are greater than the benefit. As an example, the drug Benzphetamine-by trade name-was marketed in our country by Upjohn. The company however has simply withdrawn the drug from the market. They seemed to realize that am- phetamine prescribing was not really a logical way to treat obesity, 4nd now that Canadian law has so restricted its prescribing, the actual market is too small to be profitable. I wonder if at the level of the drug manufacturing companies, a number of them are not beginning to wonder whether or not these stimulant drugs really are a benefit. That is not to say that new drugs for obesity might uot be beneficial in the future. There is genuine interest and a genuine concern to find drugs with less toxicity, and with less potential for both abuse and for dependence. The new drug mazindol seems to be a step in this direction. Research is still going on in this area of appetite suppression. I am not very optimistic about any of these drugs, but on the other hand, I cannot say that a good appetite suppressant is either impossible or unwarranted. - Drugs can be a temporary crutch for some patients. But in addition to drugs that we need to achieve with our overweight patients is a better way of thinking, perhaps through group therapy such as that pro- vided by Weight Watchers. This is where in fact I send all of my over- weight patients. I persuade most of them to join one of these kinds of lay organizations, and two-thirds at least of them benefit from re- ferral. Senator NELSON. Well, thank you very much, Dr. Ilenderson, for your very thoughtful contributions. We appreciate your taking so much of your valuable time to come to testify. Dr. hENDERsON. Thank you. Senator NELSON. Our next witncss is Dr. Carl Chambers of Miami, Fla. Your statement will be printed in full in the record. You may present it however you desire. PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14545 STATEMENT OP CARL D. CHAMBERS, PH. D., PRESIDENT OP PERSONAL DEVELOPMENT INSTITUTE, AND PROFESSOR AND DIRECTOR OP THE INSTITUTE FOR PUBLIC HEALTH RESEARCH, ANTIOCH COLLEGE AT COLUMBIA Dr. ChAMBERS. Thank you, Mr. Chairman, members of the subcom- mittee. I am extremely grateful for your invitation to appear before your subcommittee to share with you my research on the patterns of use of amphetamines and related drugs. With your permission, I would like to share two types of research experiences with the subcommittee. First, I would like to share the experiences derived from conduct. ing some 35,000 face-to-face interviews with persons in 17 States and die District of Columbia. Senator NELSON. Were these 35,000 interviews conducted by you personally? Dr. CIIAMBEItS. I was the senior investigator, but I did not do all of them. Second, I would like to share the experiences derived from conduct- ing 935 interviews with imown drug abusers in nine cities from throughout the country. After a brief prepared statement of these experiences, I will be happy to answer any questions the subcommittee may have regarding these studies. Between 1970 and 1976, I was the senior investigator responsible for conducting substance use surveys within the statewide general populations of Arizona, Delaware, Florida, Indiana, Iowa, Minnesota, Mississippi, New Jersey, New York, North Dakota, North Carolina, South Carolina, South Dakota, Utah, and Wyoming. I have also been responsible for conducting the same surveys among the citizens re- siding throughout the District of Columbia and the citizens residing in selected multiple county areas of Arkansas and Pennsylvania. These surveys have resulted in some 35,000 interviews with persons carefully selected to represent the total populations age 14 and above ivlio resided in these areas. Each person was interviewed in private by trained interviewers concerning their use of prescription psycho- active drugs, nonprescription psychoactive drugs sold over the coun- ter, alcoholic beverages and illicit drugs. Viewing these data in the aggregate has brought us to the following conclusions: The use of amphetamines to diminish fatigue or for their energizing effects is significantly related to both sex and age. For example, our projections indicate some 63 percent of everyone who uses ampheta- mines as "pep pills" are males even though males represent only 46 percent of our population above the age of 13. Correspondingly, per- sons age 14 through 24 represent only about 26 percent of our total PAGENO="0124" 14546 co~pnxtyE PROBLEMS IN THE DRUG INDUSTRY population but contribute some 55 percent of all prescription "pep pill" users. Although there has been considerable discussion about the use of prescription "pep pills" among certain occupational groups such as truck drivers and students, our data suggests the highest rate of use of the prescription "pep pills" is probably among sales workers. Senator NELSON. May I ask you a question. You stated the persons in the age groups of 14 to 24 represent only about 2G percent of population, and some 55 percent of all prescriptions. Why would the physicians be prescribing pep pills to all groups of 14 to 25? Dr. CHAMBERS. I have no idea, sir. Senator Nasox. Why did those in that age group who were inter- viewed say that they sought prescriptions? Dr. Cnnxnns. Our task was not to determine "why". They were asked specifically about their use of "energizing pills", and where they got them. They did get them by prescription, and indeed, the vast majority paid for that prescription indicating the prescription was legally theirs. Senator Nasox. Which pills? Dr. CnnniEns. Dexadrene and Benzedrine primarily. Senator Nasox. That is not the indicated use for them anyway, is it? Dr. CHAMBERS. No, sir. Senator Nasmc. So you have a situation in which in this group, 55 percent of those who got prescriptions were made- Dr. CnA3mERS. We asked specifically, when we talked about am- phetamines with the respondents, if they sought the prescription for the energizing effects, or for diet pills, and these are all people who sought the pills for their energizing effects. Senator Nasoy. And these were people who in fact did not get them off the street, but got them through a prescription by a physician? Dr. CHAMBERS. Yes. however, in the majority of the cases they did not take the drug as it had been prescribed, but they did get it by prescription. Senator NELSON. What was the drug prescribed for Dr. CJInrnEns. We have not had access to such a prescription audit. The only thing we know is that the prescription was made out, and he received the drug. Senator Nztsox. This is 55 percent of all those who used pep pills among the 35,000 who were interviewed? Dr. CHAMBERS. Yes, sir. Unfortunately, neither other investigators nor I have been able to look closely at the relationship between one's work and the use of these prescription energizers. For example, I have some information that the use of these drugs among service and protective workers, migrant workers and those in competitive sports is considerably greater than current empirical data would suggest. The use of the amphetamines and amphetamine-containing diet pills ostensibly for their hunger suppressant effect is also significantly related to both sex and age. PAGENO="0125" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14547 If I was called upon to characterize the primary consumers of pre- scription "diet pills," unquestionably I would project then to be women between the ages of 18 and o4.. Senator NELSoN. Is this again from your list of 35,000? Dr. CHAMBERS. Yes, sir. I would further characterize then as house- wives who are not employed outside the home or women who are work- ing in sales or clerical jobs. Our data indicate that the vast majority of these women obtain these drugs through legal prescriptions but that they do not take them as they were prescribed. Substudies of these women show that regardless of why they begin to use these drugs, most ultimately begin to in- crease the prescribed dose or extend their use and take them because of the drugs production of a "sense of well being." The use of amphetamines as "pep pills" and as "diet pills" appears to be proportionately distributed throughout the race/ethnic groups. I believe some brief mention of the use of the nonprescription stim- ulánts sold over the counter should be made as there is some evidence that the use and abuse of these drugs is increasing and any controls placed on the prescription stimulants will probably compound these increases. The consumption of over the counter stimulants occur more among men than women and more among younger persons. The use of nonprescription stimulants appears to be proportionately distrib- uted throughout all of the socioeconomic and ethnic groups. Of sig- nificant concern to my colleagues and me, is our projeetion that the majority of the regular consumers of these over.the-counter drugs are workers who operate or are around machinery ftnd motor vehicles. Un- fortunately, the extended use of these stimulants only masks the fatigued state of the body and cannot fully restore the sensory per- ception and reflex action which has been lost through fatigue. I am sure the subcommittee is most interested in the precise number of people in this country who habitually use these drugs. Unfortu- nately, neither I nor any investigator I know can give you precise numbers. All any of us can give you will be projected numbers based upon various surveyed populations. With such a qualifier cleftrly un- derstood, let me give you the numbers our research would suggest. Assuming our some 35,000 people are representative of everyone in the country, we would project the following: Some 8 million people above the age of 13 have uted amphetamine "pep pills" with some 1,500,000 having done so recently and some 750,000 being current regular users of these drugs. Some 12 million people above the a~e of 13 have used amphetamine "diet pills" with some 3 million having done so recently and some 1,500,000 being current regular users of these drugs. Senator NELSON. Is this an extrapolation? Dr. CH.AMBEES. Yes. Senator NELSoN. How was your sample of 35,000 selected? Dr. CHAMBEUS. We picked tliem primarily by age group. We broke the population into five age cells, and once the interviewing is done, we. weigh the total back into the total population. Senator NELSoN. It was a random sample? Dr. CHAMBEES. Random down to the household, and then we in- terviewed specific age and sex groups within the households. Senator NElsoN. So what was that figure again, based on that, how many million have used them? PAGENO="0126" 14548 COMPETITIVE PROBLEMS 12i THE DRUG INDUSTRY Dr. CIJAMBEI1S. Six million have used them-above the age of 13- and l'/2 million have used the amphetamines recently. Senator NELSoN. Have used the prescription drugs? Dr. ChAMBERs. Prescriptions, yes, sir. A million and a half have done so recently, we believe within the last 30 days, and probably 750,000 now are currently regular users of these drugs. * Some 16 million people above the age of 13 have used nonprescrip- tion stimulants of whom as many as 3 million having done so recently. Probably as many as 500,000 people use one of the nonprescription stimulants every week. As I indicated in my introductory remarks, I would also like to share with the subcommittee my recent experiences in interviewing known drug users concerning their use of amphetamines and re- lated drugs. I believe the subcommittee should be aware of these users and the implications of this use as these users are normally excluded during even carefully designed general population surveys. If they are identified they are less likely to respond honestly to in- terviewers who are not known to them. Of equal importance, these types of users make no pretense to claims of use to diminish fatigue or to lose weight. They choose drugs to use solely for their potential for producing euphoria. During last year, Leon hunt, a mathematical epidemiologist and I were asked by the Drug Enforcement Administration's office Sci- ence and Technology to conduct a study among known drug abusers relative to the potential for abuse or nonmedical use of various legally manufactured psychoactive drugs including the amphetamines and related drugs. As the final report of this total research effort is avail- able to the subcommittee from the Drug Enforcement Administration, I won't take up your valuable time in a full elaboration of the study. I will abstract from the study those findings which I believe are most relevant to your current inquiry. In brief, the study called for us to review the drug history records and to interview random samples of narcotic abusers and abusers of nonnarcotic drugs who were undergoing treatment for this abuse in nine cities. Records were reviewed and drug abusers were inter- viewed in the following cities: Miami, Fla., Greensboro, N.C., Wash- ington, D.C., Atlantic City, N.J., New York City, N.Y., Des Moines, Iowa; Kansas City, Kans.; Phoenix7 Ariz.; and San Francisco, Calif. A total of 3,598 records were reviewed and 935 drug abusers were interviewed. Our analytic technique was first developed to describe the epidemic nature and spread of heroin in a community. The technique collects the year of first use of a drug and groups these experiences to deter- mine if the event is occurring randomly or is the result of contagious transmission from one user to another. The following results and gen- eralizations should be of special relevance to your current inquiry. Sixty-two percent of all the drug abusers we interviewed had his- tories of abusing amphetamines. However, among drug abusers whose primary drug of abuse was not heroin, the prevalence of amplletam1ne abuse was as high as 85 percent. Of interest, 63 percent of all abusers of amphetamines had been introduced to the drugs by their friends or PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1454~ peers and only 23 percent had been introduced to amphetamines by a drug dealer. Fifteen percent of all the drug abusers we interviewed had histories of abusing phenmetrazine-Preludin. Not unexpectedly those who abuse phenmetrazine were most frequently introduced to the drug by friends or peers. Amphetamine abuse in Miami has shown the epidemic character- istics since 1968. There is some evidence that the abuse of phenmetra- zine-Preludin-and phentermine-Jonamin and Fastin-may be becoming popular substitutes for the amphetamines.. Amphetamine abuse in Greensboro is an endemic or stable problem with drug dealers more frequently introducing new users than in any other city we studied. Phenmetrazine (Preludin) abuse has become a popular drug of abuse and appears to be primarily imported from the Washington area. The amphetamine epidemics Washington has experienced in the past may have been replaced by the abuse of phenmetrazine-Pre- ludin. - Amphetamine abuse in New York City is an endemic or stable problem when viewed in its totality with microepidemics occurring within neighborhoods. Our data are too sparse, however, to identify these neighborhoods in time and place. Amphetamine abuse in Atlantic City is an endemic or stable pro- blem. Phenxuetrazine--Preludin-abuse may also have become en- demic Amphetamine abuse in Des Moines was probably epidemic during the 1966-71 period when it probably became endemic. Phenmetrazine- Preludin-abuse has become epidemic. Des Moines was one of the few cities we studied which reflected considerable experimentation with a wide range of amphetamine related drugs. Amphetamine abuse in Kansas City is an endemic or stable pro- blem. Phenmetrazine-Preludin-abuse has, however, shown the char- acteristics of contagious transmission. Amphetamine abuse in Phoenix can be viewed as epidemic and probably has been since* lOGS. Phenmetrazine-Preluthn---abuse is probably endemic or stable. Amphetamine abuse in San Francisco can be viewed as epidemic and has been since 1966. Phenmetrazine-Preludin-abuse is probably endemic or stable. In summary, our study among known drug abusers indicates the continued popularity of the amphetamines as drugs of abuse. In addition, the abuse Of phenmetrazine-Preludin--has become epi- demic in some cities and appears to be spreading into others. Senator NElsoN. You are saying 2 million used the amphetamines? Dr. CJIAMBERS. Ostensibly for weight control. Senator NrLsoN. But in fact as a stimulant? Dr. CusMBER5. Yes, sir. They made them feel good. Mr.. GoRDoN. Do you have any figures showing the use of these drugs by income groups? Dr. CHAMBERs. I have by socioeconomic group. The groups break the population by parental education, income and occupational. This is in a sense "economic," and it appears that am- phetamines prescribed for their energizer effect, do show major social- PAGENO="0128" 14550 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY economic differences. The bulk of their use occurring in the middle range of the socioeconomic groups. SYith the diet pills, there is a vir- tual exclusion of the very low classes, but widely distributed otherwise. Senator NELSoN. Over what period of time did that survey of 35,- 000 occur? Dr. Cu~IBEns. I did the first one in New York State, and that oc- curred in 1970. I did the last one in 1975. Senator NELSON. Is that going to all or lust several of the States? Dr. CnnlBBEs. In all, we have done 17 different States, plus the District of Columbia. Senator NasoN. Did you extrapolate from this survey of 35,000 a figure that would indicate from that a percentage of people in the whole population who are involved.in some form of drug abuse? Dr. CHAMBERS. Well, it depends on how you define drug abuse. What we are suggesting, if you control only for the ampheta- mines- Senator NELSoN. If what? Dr. CHAMBERS. If we control only for amphetamine use, and we de- fine &biise as that use which occurs as a result of not getting the drug by your prescription, or that involves extension of that use, or the ex- pansion of that use, and define all of these things as abuse, roughly 65 to 70 percent of all users abuse the drug. Senator NELSON. Sixty-five to 70 percent of all users are abusing the drug? Dr. CIIAMEERS. If you use that kind of definition, yes. I am not sure how many of these are actually disfunctional as a it' suit of that use. Senator Nn.sox. And that figure was 65 percent? Dr. CHA3niEBS. Sixty-five to 70 percent. Senator Nu.so~t. Of all users? Dr. Ctrarnzns. People do not appear to be able to use the stimulant drugs as they are prescribed. Senator Nnsox. Do not appear to what? Dr. CIIAI.rnEns. To be able or willing to use the stimulant drugs as they are prescribed. The vast majority of our eases indicate they extend the time of use or increase the dose. Senator NELSON. And that 65 percent who are abusers, represents what percent of the population? Dr. CHAMBERS. I have no idea. My guess is that you are talking in the neighborhood of 65 percent of roughly 4 or 5 million people. Senator NELsoN. Thank you very much for your very valuable tes- timony. We appreciate your taking the time to come. Dr. CHA3rBERS. Thank you. Senator Nnsow. Our next witness is Dr. Thomas M. Gellert from Huntington, N.Y. I appreciate your taking your time to come here, Dr. Gellert. You may present your testimony however you desire. PAGENO="0129" CO~IPETITIVE PROBLEMS IN THE DRUG iNDUSTRY 14551 STATEMENT OP TBO?ILAS M. GELLERT, M.D., RU1~TINGTON, N.Y. Dr. GELLERT. Thank you, Mr. Chairman. I am here today as a private practitioner, and, therefore, for myself, and as an unofficial representative of 250 physicians who decided to attack this problem of drug abuse, particularly amphetamines, and without waiting for guidelines, prohibition, and coercion, and I also speak as one who has been active in the county medical association of the county and the city of Huntington, and which is made up of 200,- 000 people on the eastern end of Long Island, and also as one who un- derstands somewhat the governmental problems, and as one who has also served on the county board of health. We in Huntington are very proud of our efforts, and are gratified by the results, but now, 5 years after deciding to stick to our princi- ples, we are convinced that some form of Federal regulation is neces- sary if we are really to succeed. Our community is Huntington, N.Y., and just a couple of weeks ago, when "60 Minutes" came on, we were sort of designated the am- phetamine capital of the universe. This is certainly not the case, but I would like to tell you how tins came about. We in Huntington are a township of about 200.000 people, we consider ourselves quite enlightened. We were among the first in the country to set up the youth board, an orgaiuzation responsible for han- dling problems with our youth. I believe you have already heard from some of our representatives who spoke before this subcommittee last week. When heroin became a problem in our community, our hospital do- nated facilities, our hospital-pharmacy donated time and the nurses donated their time, and we set up a free methadone clinic to help con- trol the heroin difficulty, and then when amphetamines appeared on the scene, Huntington physicians decided to stop writing ampheta- mine prescriptions. We hoped that by this volunta~y act that wewbuld remove a sizable number of these drugs from circulation and reduce the number of drugs which could be abused. To accomplish this task we conducted seminars, distributed the lat- est scientific data, held hospital staff meetings, and met with coinmu- nitv agencies. After examining the evidence it was clear to anyone familiar wcth evaluating scientific data that, except for the rare problems of narco- lepsy and the treatment of certain types of hyperactive children, am- phetamines had no bona fide use in the practice of medicine. Specifically, there was more than enough evidence to support the conclusion that amphetamines had no place in the treatment of obesity. Overnight the prescribing habits of Huntington physicians* changed. From several hundred amphetamine prescriptions a year, the average pharmacy found it was dispensing only one or two am- phetamine prescriptions a month. Some pharmacies filled none over periods of several months. Some time after our voluntary amphetamine ban, I recall speaking to a pharmaceutical house representative who observed that contrary 85-569-77----9 PAGENO="0130" 14552 co~rPrrITwE PROBLEMS n~ TEE DRUG INDUSTRY to his expectations the ancphetamine ban extended to all antiobesity drugs and an expected increase in the writing for nonaniphetamine anorectics never materialized. Huntington physicians had apparently decided that drugs in gen- eral had no place in the treatment of overweight patients. `This phi- losophy of therapentics has not changed in the past 5 years. The new physicians in town have been quick to learn of our amphetamine ban and their cooperation has been exemplary. Senator NELSON. Is that number, 250 physicians, the total number in the huntington township? Dr. GELLERT. That is right. If we have become so successful in this effort, why am I here today asking for Federal help to control the production and distribution of amphetamines and related drugs? Despite the honest effort of 99 percent of the practicing physicians in our community, some duly licensed doctors have decided to confine their practices to the drug treatment of obesity in our community. It has been an outrageous situation. They meticulously observe the existing laws, and they hand out a staggering amount of legal amphetamines each day. They are not members of our medical community. They do not prac- tice in our hospitals, nor are they members of our medical society. Thus they escape the censure of their peers and the constraints which might be placed upon them. In the town of Huntington there are two such physicians. The youth board of Huntington township recently conducted an unofficial tally of the number of patients seen by one of these doctors in a typical week. Approximately 800 patients were seen. Over a several week pe. nod, they ranged from 800 to 1,100 patients. Senator Nasoic. Does anyone know what the standard fee for the consultation and prescription is? Dr. GautRT. I do not know what the fee is, but I know that figure is available. Senator NELSoN. That meant somebody could find out what is being charged? Dr. Gattmr. I would imagine $10 or $15. Senator NELSON. That is the only purpose for which these people go to these two doctors? Dr. GELLERT. Yes, sir. Senator NrnoN. All right. Dr. GaLEwr. As a part of his treatment program, this particular doctor distributes amphetamines to all comers. Patients are literally lined up outside of his office. And by no means are all of those in line obese. By a calcnlation, if he sees a patient, he asks the patient to come back even 2 weel~, he probably prescribes 42 tablets, amphetamine tablets, over those 14 days, that is 3 tablets a day. When you multiply that by 42 times 800, and then multiply the num- ber of tablets he is dispensing in a week, and then multiply that by leCs say 50, this figure comes out to over 1½ million amphetamine tablets a year. PAGENO="0131" COMPETITWE PROBLEMS IN THE DRUG. INDUSTRY 14553 Forgetting for a moment those who seek out this man to obtain a supply of "uppers" to get through the day, such doctors have a ready- made parade of victims in any community. They are the tired, overweight housewives; the self-conscious over- weight teenagers; or, for that matter, any ovenveight citizens. These people see in the "diet doctor" an easy solution to their prob- lem and they end up captive to his drugs, needing them just to "keep going.". One such physician can easily prescribe more than a million ampliet- amine tablets in the course of a year. TJndoubtedy, in our community this man's practice is assisted by the unavailability of amphetamines elsewhere. Tins is the outrageous part. This man conies and opens his practice, and lie gets everyone he wants on amphetamines, because they cannot get it anywhere else. . Senator Nasox. Among the physicians in the county, you end tip with some patients then coming to the physicians who do prescribe for treatment for some side effect, as a consequence of their taking the drug? Dr. GELLERT. Yes; I think everyone who practices primary medicine, internal medicine, or family practice, sees patients who of course are certain they have a thyroid problem, because they are overactive, and they have the shakes, and they cannot sleep, or they have lost too much weight, and one of the first questions we ask is, what medicines are you taking, and more times than we would like, we find that they are on amphetamines. Some of our old patients withhold this information from us, because they are embarrassed, that they have gone elsewhere to seek a drug we would normally not prescribe. Senator NELsoN. I see. Dr. GFnERT. And, Senator Nelson, a great deal has been said about why did not the physicians police their ranks. We are asked, why don't we do something about these people. We would like to, we would like to very much. As I mentione.d before, frequently, presently they lie outside the normal channels of control, they are not members of our society, they do not practice with any staff of the local hospitals. Until recently in the State of New York, to discipline the Dhysicians, to take away his license, was almost an unheard of affair. It required getting involved with the department of education, they were the ones who held our licensing permits, and they were the only ones who were able to handle this, and it would appear that indeed, that instead of cooperating with the State medical society, that we were often at odds with our State medical society, but recently our Gov- ernor, Governor Carey, signed into law a change in the procedure, and we now have a disciplinary board, which is set up in the department of health, and do have input, the physicians do have input, they do have input to the board, but the financing is so poor that investigative studies cannot be done, and we are way behind in cases that should be looked into, including people like those men who are pushing pills in our community. PAGENO="0132" 14554 COMDETITIfl PROBLEMS IN flIE DRUG INDUSTRY Now, we have heard a lot of expert testimony this morning. I was more than impressed with Dr. Henderson and Dr. Chambers' testi- mony, and I certainly believe that amphetamine should be barred for the use of obesity. While we certainly have fewer amphetamines in our town than our neighboring communities, how much better it would be for the collec- tive health of our citizens if effective restraints could be placed on the distribution of all amphetamines. If it could be shown that amphetamines and related antiobesity preparations were of value in treating obesity perhaps one could argue that the obvious disadvantages to their use were outweighed by the advantages. The fact is that these drugs are, at best, only briefly effective in the treatment of the overweight patient. Indeed, the preponderance of evidence is that amphetamines have no long-term value other than the placebo effect present when taking any sort of medicine for any sort of condition. If amphetamines were effective and necessary in treating obesity it should follow that during the 5 years since the Huntington amphet- amine ban our community would now have a larger number of over- weight citizens. This is notthe case. Those who advocate the use of currently available "drugs" in the treatment of obesity argue that the supposed appetite suppressant effects of these drugs provide the patient with an initial success in therapy which may spur him on to continue his weight reduction pro- gram drug-free. The extrapolated conclusion, I imagine, would be that to deny the public these drugs would make obesity more difficult to treat. I certainly do not believe the facts support this conclusion. It is like telling an alcoholic that if sometimes we fill you full of tranqui- lizers and get you off alcohol for a week or two weeks, or a month or two, it will solve your problem. We know that that is not the case, when we stop the tranquilizers, he goes right back to the alcohol. Rather the key to treatment of obesity is motivation, and without it, the drug or diet cannot succeed. As a physician whose practice of internal medicine includes large numbers of desperately ill cardiac patients, I have ha.d considerable experience in the successful treatment of large numbers of overweight patients. The key to success is motivation. Without it no drug, no diet, no acupuncture. nothing can succeed. It is the physician's jol) to present to the overweight patient the rea- Sons why he must lose weight. lie must get to know the patient, the patient's family, and the pa- tient's problems. lie must convince him of the necessity for losing weight and the logic of his arguments must be inescapable. Where emotional factors prevent success in a weight reduction pro- gram psychological counseling is in order. When such an emotional impediment to weight reduction exists, th~ last thing a physician should do is to prescribe a habit-forthing drug. It would seem ridiculous to take a patient who has an emotional PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14555 problem, to take this patient and put him on a. drug that would make the patient an addict, that would be ridiculous. I am convinced that drugs have no place in the treatment of obesity. I am convinced that the medical world can practice better medicine without the antiobesity drugs. I am convinced that the overwhelming majority of physicians be- lieve as I do. I am disheartened by the presence of that small number of physicians who capitalize on the habit-brining character of the "diet pill." They threaten the success of the amphetamine-free environment which my colleagues and I are attempting to build. Frankly, they are a public health menace. . I believe there is a method of controlling the injudicious distribu- tion of amphetamines. The solution is straightforward, and it has precedent. Last month a patient of mine with a painful cancer reqwrcd methadone for relief of his agony. Other narcotics had proved meffec- tive or unusable because of his multiple allergies. The drug was pro- vided through normal channels of distribution with the understanding that it was to be used as an analgesic, not for the treatment of drug addiction. I received a telephone call front the pharmacist who filled the pre- scription, and the pharmacist pointed out that I can use this drug only for analgesia, and to use it for any other purpose would be contrary to law. This is a unique situation. The FDA has been reluctant to involve itself in the doctor-patient relationship. Except for regulations per- taining to the use of new drugs or drugs being investigated for efficacy and safety, the FDA has not involved itself in regulating the prescrib- ing habits of physicians. I believe this to be laudable. In the instance of methadone, however, it was determined that the absence of tight control of the distribution of this drug constituted a serious public health hazard. The FDA, therefore, used its authority to prohibit the unrestricted distribution of methadone. The FDA requires that any individual or organization using methadone for the treatment of drug addiction must secure a special license and submit to constant super- vision. To do otherwise is unlawful. I propose that the same regulation with restraints be placed on the use of amphetamines. I propose that a special license be required for the use of amphetamines to control obesity and in the control or treat- ment of drug addiction. I further propose that the existing restric- tions on the use of amphetamines be continued for all other uses. In this way the prescribing of this drug will be limited to a 1-month sup- ply which is not refi]lab]e and which is dispensed in a specially marked container. I also recommend that the continued use of the nonamphet- amine diet drugs be similar]y controlled pending further research into their abuse potential. These changes would effectively eliminate the amphetamines from the "diet doctors' "dispensary. If the deliberations of this committee provide the impetus for the FDA to exercise authority and eliminate the abuse of amphetamines, you will have helped Huntington physicians in their original crusade to ban amphetamines in our community. You will simultaneously aid physicians in communities throughout our country in the control of amphetamine abuse. PAGENO="0134" 14556 com'wrimt flOBLEMS IN THE DRUG INDUSTRY Senator Nasox. Let me ask you a question. If they no longer had the indicated use of obesity at all, then I would assume it would not be difficult to stop the abuse. For example with respect to the two physicians m Huntington, obviously if these drugs are indicated only for narcolepsy, or hyper- kenesis, they would not have 800 patients going through their offices. Is that correct? Dr. GELLEET. Exactly. Senator NELSON. Are you saying that you think there may be some occasion where it is indicated for use of obesity? Dr. GELLEET. No; not for obesity at all. I do not see how one could justify the use of the drugs for obesity. - SeveSl years ago the FDA investigation showed that there was short-term advantage to the use of the drug. It may he indeed that someone some day will find that there is long- term advantage; but as yet that is not so. Senator NELSON; You would take the position if a physician desired that it should not he used for obesity, but that if he wanted to, that physician if he had a justifiable reason, that he would get a special license? - Dr. GELLERT. Yes; and if the controls for such distribution of am- phetamines is similar to the controls and of the distribution of metha- done, I doubt seriously we would be seeing any of these diet clinics in operation. This could not be justified. I also believe there is not enough information today that would indicate that the amphetamines and amphetamine-related drugs, I feel they should be moved up, the amphetamine-related drugs, to where the amphetamines are right now, and that is a class II drug which would require special labeling, a nonrefillable prescription, and no more than 1 month ~`rescribing at any one time. Senator NELSON. Did the lines outside these two obesity doctors' offices get shorter or longer after the "60 Minutes" program? Dr. GEaEIn'. Well, certainly the advertising was there, I would not be surprised if they got longer. Senator NELsoN. The real story in Huntington is that all except two physicians in the whole county have agreed that you should not use amphetamines for the purpose of obesity, but the abuse by the two physicians of this agreement has made it impossible for the other 250 to control it? Dr. GELLERT. In reality we were only able to support one diet iloc- tor before we had the ban. After the ban, the other one joined us. Senator Nasox. Thank you very much for your very valuable testimony, Dr. Gellert. We appreciate you taking the time from your busy practice to come before the subcommittee and to present your testimony. It is very valuable, and we appreciate it. Dr. Gtarup. Thank you. Senator NELSON. Our next witness is Reverend Frank Reynolds, na- tional director of Teen Challenge Youth Centers, of Springfield~ Mo. PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14557 STATEMENT or REVEREND PRANZ REYNOLDS, NATIONAL DIREC- TOR OP TEEN CHALLENGE YOUTH CENTERS, SPRINGFIELD, MO. Reverend REYNOLDS. Thank you, Mr. Chairman.1 * Teen Challenge is a ministry to street people. It began in 1958 as a ministry to street gangs by David Wilkerson.* As the work pro- gressed we began to encounter drug addicts. Many heard the message of hope in Jesus Christ and began to respond in a positive manner. From tins beiinning has grown a ministry that now is in 24 States, the District of ôolumbia, and Puerto Rico, with ministries in 62 cities. Through coffee houses and street workers, Teen Challenge made con- tact with over 380,000 people in 1975. In our various residential facili- ties we have 1,000 people any day. I say this to let you know that we have a broad contact with a lot of young people at the street level where the action is. Our experience has been primarily at the street level, although the past few years we have received more and more people referred by other agencies, both public and private. Our primary thrust has been to what we have called "troubled youth." Tins has resulted in our also working in a preventive-type ministry with drug education programs in schools and commimity youth groups. Through these presentations we had many opportunities to deal with young people in a confidential manner about their own drug in- tolveinent. We were able to get a good reading of what was happen- ing in the drug scene. In the early 1960's we primarily reached the inner city heroin ad- diets. With the "drug explosion" of the mid- and late-sixties we began to reach people with various dependencies on many different drugs: Tranquilizers, barbiturates, amphetamines, hallucinogens, as * well as alcohol, and the opiates. Today, most of the drug dependent persons we work with are so- called polydru~ users. By ~iat we mean they use many different types of drugs and mix them with alcohol. * My personal feeling is to include alcohol with drugs, but we will not get into that. I know this hearing is primarily concertied with the use and abuse of amphetamines. But, I think, ire are going to be remiss if we do not realize that this is part of an overall problem and, perhaps, a phi- losophy of the medical and pharmaceutical business. That philosophy is; that there is a solution to every problem in a pill and its wrong to suffer any discomfort, physical, or emotional. Perhaps, it is a problem of our "cradle to the grave security society." This is promoted in the advertising, on television, and other media. Since I am concerned primarily with our youth 14 to 25, what are we teaching them? "I have an important meeting, I must be up for it, so I eat or drink something to pick me up so I can put my best foot for- ward." Then we get pushed out of shape when our teenagers do the I Reverend Reynolds subsequently submitted the following: "It might be added that * Teen Challenge is a voluntary program. It is also a nonprofit corporation and is privately funded by contributions, we have not received Government grants. One 1-year grant was - received from NIDA for a research study.'~ PAGENO="0136" *145~8 CC)MPETITWE PROBLEMS IN THE DRUG INDUSTRY same thing for their Earth-shattering date, party, or whatever. "l'hat is different, this is a $500,000 deal," we argue. "But," the young person says, "This is the chance of a lifetime to really impress someone that will change my whole future." What have we done? Instead of preparing ourselves spiritually, physically, and emotionally we try to substitute an artificial booster or tranquilizer. We do not deal with the real problem. Let me illustrate. Four weeks ago a young man was released from a certain penal institution. While he was there he got under a lot of tension. So the doctor gave him some Valium. As the tension built so did his intake of Valium, legally. He was released, having coin- pleted his sentence, with a legal prescription and is using 40 to 50 milligrams of Valium per day. He is "free" from jail, but he cannot function in the "straight" 8-to-S society. Let me add he was 8 years in the penitentiary. The 40 to 50 milligrams of Valium does not handle the additional tension, so he has added a little alcohol to he]p out. Now he is in danger of violating the conditions of his release. `SYhat is the problem? Is it tension? Or do we need to dig a little deeper? Then give the individual the coping mechanism to deal with the problem. I have had only 20 mimites with this individual and discovered his tension started when his wife divorced him while in prison. Maybe there was no way to save the marriage, but there is a better way of handling the succeeding emotional problems than a chemical copout. I am not sure this legislative body can solve the problem. but I be- lieve unless we nre willing to see why we get pushed into using diem- ical substitutes we will continue to seek chemical solutions to emotional and spiritual problems. Dr. Blum stated in an article in Look ma~azine, several yean~ ago, `in a discussion of various solutions to tIe drug abuse problem, ~Jf we are looking for a drug to solve the drug problem we will fail. `We will never solve the drug problem until we make up our mmds what our minds are for." Now to speak specifically to our experience with the amphetamine group. By the way, since writing this, I had a man come in, Ins grand- father called me to visit him in jail, and when I got to talking as to what his problem was, I asked him, what can I do to help you. I said. why are you in jail? He said, armed robbery. I said, well, for what? Are you mvolved in drugs? He said, yes, and I said, what kind of drugs? I said, I am not the law, not the court, not the lawyer. What are you taking? He said the truth, I don't even know what happened, but I had taken some speed and some cocaine, and we had some liquor, and the next thing I knew, I was in jail. When I woke up, I was here. I don't know what happened, and he is'charged with armed robbery, but amphetamines is the basis of it. I fonnd out since he was getting them through his mother. We first began to see people coming in with this problem in 1961 and 1968. Not large quantities, but when a person had been involved PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14559 `with heroin and other depressant drugs he would buy "Bennies" to give him a lift to get out and do his "thing" to get the money for the heroin. When the fad of taking drugs hit our high school and college groups, they would have what some called "cocktail parties." Each would bring the medications from their private drugstore, that is, the home medicine cabinet. All the pills would be put in the bowl. Different parties were run different ways. Some would portion a quantity to each one with no regard to what they took. Others would divide them by color or shape and compare notes. What was the main problem? Availability-they discovered that with mom's diet pills they could dance and go and go without stop- ping. iley man, that's terrific. Someone thought we could solve the fat problem without discipline and without pain by taking dexedrine or other amphetamines. The college crew is no different than when I was in school. We did not get our work done until it was due. We did not study until the night before exam. But in the early forties we had to depend upon the coffee pot and cold water in the face to stay awake. Now, thanks to "better living through chemistry" we can swallow a couple of pills, obtainable legally for the diet, the tired feelino, the depressed state, or whatever other excuse-fancy word for lie-i can convince the doctor of. Then suddenly you have people living on this stuff. Then conies controls in the early seventies. By this time we have coming into the program the speed freaks and the spades. They have in their own words "fried their brains." Where did they get the stuff? One student in the program from an Ohio college, who came into the program in 1970, floated a loan, flew to Nexico and brought back amphetamines of various kinds, manufac- tured in the United States, and netted $1,700 for the weekend risk and trouble. The problem arose for him when he became his own best customer. Messed up his mind; could not study, dropped out of school with 1½ semesters to go for graduation. I am amazed that some, as late as last year, discovered an over- production with shipment out of the country to be brought back in illegally. This was common knowledge to us working the streets. We assumed if we knew it, certainly, the professional agencies knew it. Some have told of stealing them off the loading docks by the barrel lull. I do not need to restate the statistics, you have them, undoubtedly, on ifie. The last 3 years I have been in an administrative position and only working as a volunteer with troubled people. It is disturbing and frus- trating to me to start dealing with people and discover the amount of mood.altering medications prescribed to cover up the problem. Yet, no one stops to try to solve the problem or provide a way of handling and dealing with the difficulties. At Teen Challenge our approach to the drug abuser has been that i-our drug takino is not the problem. It is a symptom. We were say- ing tIns when otters said we were foolish to talk like that. PAGENO="0138" 14560 COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY The problem is inside of you. Invariably when we begin to relate to the needy they would speak of the emptiness inside. Nobody wants the "blahs." And when someone offers a chemical, easy solution, you have a good candidate. Our approach is first acceptance of them as a person, regardless of their physical appearance. The speed freak usually comes in skinny and starry eyed, extremely nervous and suspicious. Not trusting anyone. They have been "ripped off" emotionally. Then we share the love of God we have found and the inner peace we have. The next logical step is, "You can have it, too. God so loved you that he gave His best for you." Now, here is where we had to regroup our forces. The heroin addict was quite predictable. After he would withdraw, his head was normal. Not so with the amphetamine user. His attention span is short. 11e is depressed very easily and is just liable to space out on you. Another complication we ran into was that the amphetamine user quite often has used LSD, mescaline, and other hallucinogens. I am not a technical man. So how much of our problems can be attributed to which chemical, is difficult to assess. As I said before, at the street level you do not get someone that does just one drug. After speeding he knows he is going to crash. When he crashes lie knows he is not going to be able to sleep, so he will seek downers- barbiturates. Most can walk into a doctor and give a good con story and get some sleeping pills. If all else fails, he can put on a scene and get rushed to the emergency ward and compassionate people will give him what he wants. Remember, these people know what symptoms to describe in order to get the doctor to give the "right" prescription, and they do. We, just 3 weeks ago, had a policeman call one of the workers, brought a girl in, we do not know what she was taking, tried to get her to three hospitals; they would not admit her. The men drove her to another State hospital, about 40 miles away, they stated their situation, they signed her in, when they got back home, she was there ahead of them with her purse full o~ pills, and that just happened. It takes long patience. About the time you think you are making progress, he flips out. Where with the heroin addict we could put pressure on him and get pretty hardnosed, we find we would have to back off from the amphetamine user, cut down the pressure until he could settle down. I believe it takes the power of God to help and heal some of the scrambled heads we have worked with. We have not won on all of them, but we have as good a record as any. Mr. GoRDoN. As I understand it, it is much more difficult to treat an amphetamine addict than a barbiturate addict; is that correct? Reverend REnor.ns. Well, a heroin addict anyway, and even bar- biturates, when they get down, the barbiturate man will get a lot of trouble physically, once he gets down. Mentally, he is in pretty good shape. These people who are on amphetamines, when we see them, we say, oh, God, give us old-fashioned heroin addicts so we know what they are going to do. PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14561 These are kind of unpredictable. They might flip out on you. We do not know what will happen. Mr. GoimoN. Is it your impression that the original source of amphetamines was generally a doctor? Reverend RErNor.ns. That is a hard one to answer. Those that we work on, there is so much legal and illegal of it that is done. I would hate to put a percentage figure on it. These people are con artists. They can walk into any doctor's office, and convince him of their symptoms. They know what prescriptions he is to prescnbe, so he knows how to get what he wants. Mr. Goimox. And the doctors take his word? Reverend REYNoLDs. And they take his word for it. That is part of their problem, and that is part of our problem. Mr. Gotmow. My mother used to do that. She used to go to the doctor and tell the doctor what was wrong with her. Reverend REncoLns. That is just what they do. Gentlemen, let me recap. lVhat is the problem? One, we are too prone to look for easy, painless solutions to life's problems. Two, chemicals that can alter the mood are available legally and ille~al1y from "legitimate" manufacturers. `three, the knowledge that it is available is well advertised. * Four, the whole health-care field has got to shoulder their responsi- bility in causing the spread of the drug abuse problem. * Five, we can no longer bypass the fact that men have spiritual needs, as well as physical, and social needs. - * Some hopeful signs: One, many of us are redoubling our efforts. Two, medical schools are now requiring medical doctors to take courses in interpersonal relations. Three, many professionals are acknowledging that there are spirit- ual needs that can be met. More cooperation between these two areas is needed. Four, this hearing is being held and we have been able to share from the street level, where the action is. For an idea of the effectiveness of the Teen Challenge program you may refer to a study done under grant No. 1 H81 DA 01505-01. This is the first time we have been able to share some of the things we see from the street side, and we appreciate it. Thank you. Senator NELSON. You state on the first page, that you made contact. with over 380,000 people in 1975. These 380,000 are all individuals who were usinu drugs? Reverend Rtyxoni~s. Probably 85 percent will be drug-related of some kind; Senator NELSoN. You said in some residential facilities you have some thousand people a day? Reverend REYNOLDs. In our total program, we have 1,000 people in. residence. Senator NELSON. When you say in residence, do you have residential facilities for some of your clients? Reverend REYNOLDS. Right. Our program is 1 year long. Senator NELsON. How many? PAGENO="0140" 14562 co!~ETTFflt PROBLEMS ri `rnz DRUG Reverend REYNOLDS. About 2,500 to 2,700 people will complete the program. Senator Nnsox. Two thousand five hundred to 2,~ 00? severend REYNOLDS. Right. &nator NELSON. And will they all live in a residential setting or ~residential situation? Reverend Rinows. During that ye~i. Senator NELSON. And how many cities do you have residential treatment centers in? Reverend REYNOLDS. Sixty-two. Senator NELSON. Sixty-two? Reverend REYNOLDS. Yes. Senator NELSON. And they would average what size! Reverend REYNoLDs. Well, everything from 6 or 8 in some of our facilities, up to 130. Senator Nn.sox. And this program is supervised or managed from where? Reverend REYNOLDS. Well, the program grew like topsy. In the last 3 years, I have been asked to try to coordinate them. I live in Springfield, Mo., or I would say my wife lives there, and I just visit. . Senator NELSON. Well, are all of these facilities under the direction of one national organization? Reverend REYNOLDS. Right. We are just trying to pull an organi- zation together. * Teen Challenge is an incorporated name now, and we are all interrelated. Senator NELSON. And when was the national Teen Challenge organization created? Reverend REYNOLDS. Well, nw office was created 3 years ago. Senator NELSON. Did you ori~inate the program? Reverend REYNOLDS. Well, Dave Wilkerson originated it, but I was with him from the beginning, and I helped organize it. Senator NELSON. Are you expanding the program into other cities? Reverend REYNOLDS. Yes; faster than we would like to. Senator NELSoN. What medical assistance, advice, consultation, psychiatric, or otherwise, have you had? Reverend REYNoLDs. Just on a voluntary basis, we work primarily from the spiritual area, with tile cooperation of medical people at our facilities. Senator Na5ON. So you do have volunteer physicians in some communities? Reverend REYNOLDS. Right. Senator NELSoN. How many communities? Reverend REYNOLDS. Wherever we have a facility, we try to line up a doctor that will work voluntarily. Senator NELSoN. Do you usually find SOmebOdy that will volunteer! Reverend REYNOLDS. Usually. We have had some problems in a couple of areas. Senator NELSON. Thank you very much. We appreciate your taking the time to come to testify. Tomorrow's hearing will resume at 10 a.m. We stand in recess. [Whereupon, the subcommittee was recessed at 12 :35 p.m.] PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) FRIDAY, NOVEMBER 19, 1976 U.S. SENAn, SUBCOMMTrFEE ON MONOPOLY OF TIlE SELECr C0MMfl'IT~ ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 10 a.m., in room 818, Russell Senate Office Building, JIon. Gaylord Nelson, chairman, presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Karen Young, research assistant. Senator Nasox. The subcommittee will please come to order. Today's hearing by the Monopoly Subcommittee of the Senate Small Business Committee constitutes the fifth and perhaps the last day in this series of hearings on the antiobesity drugs. Our witnesses today are: J. Richard Crout, M.D., Director, Bureau of Drugs, Food and Drug Administration, and his associates; Frederick A. Rody, Acting Deputy Administrator, Drag Enforcement Administration, U.S. Department of Justice; and Mr. Isaac McGraw, president of the pharmaceutical division of the Pennwalt Corp. Tn 1972, FDA's Advisors' Committee on antiohesity drugs after con- siderable study, submitted the following conclusions and recommenda- tions to the Food and Drug Administration: One, adult obese subjects on diet plus drug tend to lose more weight than those on diet alone. Two, the amount of weight loss associated with the use of an "anorec- tic" drug varies from triai'to trial. The possible origins of the increased weight loss due to the various drug effects are not established. The increased weight loss appears to be related to variables other than the drug prescribed, such as the physician.investigator, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and nondrug factors on weight loss. Three, the magnitude of increased weight loss of drug treated pa- tients over placebo treated patients was only a fraction of a pound a week. The rate of weight loss was greatest in the first weeks of therapy (14563) PAGENO="0142" 14564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY for both drug and placebo subjects and tended to decrease in succeed- in~ weeks. `t'our, the natural history of obesity is measured in years, whereas the studies cited are restricted to a few weeks duration; thus the total impact of drug-induced weight loss over that of diet alone must be considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors inherent in their use. Five, the amphetamines including niethamphetamine have been widely abused in numerous populations. It is thus in the best interests of the public health to limit the use of amphetamines as far as is compatible with adequate therapy. This is both to minimize the risk of dependence in susceptible patients being treated and to decrease the amount of drugs being distributed, since widespread prescription of a dependence-producing drug inevitably increases the possibility for diversion to nonmedical use and abuse. Six. Evidence presented for newer "anorectic" congeners of His amphetamine family and nonamphetamine drugs do not set them apart as having higher benefit or lower risks than older available drugs. Seven. There was no evidence in the data reviewed winch showed that combination of an antiobesity agent with other drugs increase the benefits or reduce the risk of the antiobesity agent. Eight. Obesity is not an indication for the parenteral use of these agents. The principal recommendations of that committee were: One. That all antiobesity agents reviewed be placed in schedule II on the basis of abuse potential. An exception was made for fenifuramine which was a new drug and about which little was known at that time. Two. That combinations of antiobesity drugs with other drugs be removed from the market. Three. That parenteral amphetamines may not be approved for use in the treatment of obesity. Four. That the single-entity oral antiobesity preparations including the amphetamines be permitted to be labeled for restricted use in obesity provided that they are used in association with a specific weight reduction program and that the clinically trivial contribu- tion of these drugs to the overall weight reduction is properly em- phasized and that the limited usefulness of these agents must be measured against any possible risk factors such as nervousness, in- sofia, and drug habituation that might be inherent in their use. Moreover, these agents can only be recommended for use in the treatment of obesity in a carefully monitored and specified weight re- duction program under the care of a physician. What to do about these drugs has troubled the medical officers of the FDA for quite some time. For example, Drs. Elmer Gardner and Barrett Scoville, Director and Deputy Director, respectively, of FDA's Division of Neuropharmacological Drug Products, stated in 19Th at a symposium: Ultimately, we must au weigh the potential benefits of these drugs tgalnst the risks of the drugs. Here we hope that in giving your opinion, you will con- sider risk In its largest sense-not simply the Innate clinical toxicity of the anoreetics, but the risk to the public health of potential abuse. We do want to bear what these drugs mean in medical practice. But we also must think in PAGENO="0143" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14565 the somewhat less familiar terms of drug abuse. Here Is a problem from which we cannot divorce our thinking In favor of medical considerations. Throughout FDA's records there can be found a depreciation of the usefulness of these drugs for antiobesity purposes: The degree of extra weight loss was small-a few tenths of a pound a week In many cases-and variations were great. - Larger questions of long standing remain unanswered, such as the long-term effect on morbidity and mortality of the use of anorecties. These questions are of basic Importance, since the usefulness of the drugs depends in large part upon the assumption that they somehow help prevent the adverse effects of obesity. The objective of these hearings, therefore, is to ascertain the present views of the Food and Drug Administration on the safety, efficacy, patterns of use and abuse, and the future of these drugs. We are particularly interested in hearing: One. Why the first recommendation of FDA's advisory committee flint all these drugs be placed in schedule II was not accepted. This is especially puzzlthg in view of FD1Vs testimony before this subcom- mittee in 1972 that: Evidence presented for newer anorectie congeners of the amphetamine family and nonamphetamine drugs do not set them apart as having higher benefit or lower risks than older available drugs. (Hearings: Advertising of Proprietary Medicines, pt. S.) Two. Why some combination antiobesity drugs are still on the mar- ket. On February 12, 1973, the FDA took steps to remove Eskatrol from the market, but the drug is still being sold-$5.4 million worth at manufacturer's prices. The saks of another combination, Dexamyl, for 1975 amounted to $2.6 million. In other words, the sales of these two Smith Kline & French drugs, which should have been removed from the market years ago. amounted to $8 million in 1975. The February 12, 1973 Federal Register also noted that the FDA is aware of a study conducted for Smith Kline & French relating to abuse potential of Eskatrol and which was not submitted to the FDA as required by law. What action was taken by FDA against this violation of the law? In the March 30, 1973 Federal Register it was announced that Smith ICline & French had requested a hearing with respect to Eskatrol. The FDA allowed the drug to continue to be marketed pending a ruling on the request for a hearing. It is now 3% years later, and the hearing has not been yet held. Why? We would like to have an explanation of why it was not. The principal problem, however, is justifying the continued exist- ence of these drugs on the market. Given a utility which is "clinically trivial," to use FDA's own term, and given the very extensive list of serious risks to individuals and society including the potential and actual abuse, questions have been raised whether their availability for antiobesity purposes constitute a hazard tothe public. Dr. Thaddeus Prout, Chairman of FDA's advisory panel on these dnlszs, told our committee last Tuesday that he now favors that in addition to placing all these drugs in schedule II, obesity be with- drawn as an indication for the therapeutic use of these drugs. PAGENO="0144" 14566 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We look forward to hearing the views of today's witnesses on this subject. Our first witness is Dr. J. Richard Crout, Director, Bureau of Drugs, of the Food and Drug Administration. We welcome you here this morning. Dr. Crout. If you would identify your associates for the reporter, and for the record, so we will have all statements appropriately and properly printed, I would appreciate It.' STATEMENT OP J. RICHARD CROUT, M.D., DIRECTOR, BUREAU OF DRUGS, FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY RICHARD A. MERRILL, CHIEF COUNSEL, FDA, AND WILLIAM W. VODRA, ASSOCIATE CHIEF COUNSEL, FDA Dr. Cnorrr. Thank you very much, Mr. Chairman. On my left is Isir. Richard A. Merrill. Chief Counsel of the Food and Drug Administration, and on my right is Mr. William W. Vodra, Associate Chief Counsel for Drugs of the Food and Drug Administra- tion. We welcome this opportunity to appear here today to discuss the activities of the Food and Drug Administration with respect to anti- obesity drugs. Previous actions by both the FDA and PEA have had an important impact on the availability, labeling, and use of these drugs. In spite of tIns, abuse of amphetamines in particular, appears to be a continuing problem in our society. It is appropriate that additional action in regard to amphetamines be considered at this time. The story I will emphasize in this testimony is that the available data, while preliminary and incomplete, indicate that the ampheta- mines remain, among the anorectic drugs, the major offenders as drugs of abuse. This problem cannot be solved by invoking additional controls under the Controlled Substances Act since these drugs are already in schedule II, the most tightly controlled category for marketed drugs. The only meaningful next step which can be taken is to remove the indication for obesity from the labeling for amphetamines or to re- move them from the market. FDA is working with the Drug Enforcement Agency and NIDA, the Federal agencies with detailed information regarding drug abuse, to develop the necessary documentation for such a position. Abuse of amphetamines continues to occur, with deleterious and often devastating effects on the individual who abuses or becomes de- pendent upon them. lYe must move ahead vigorously in addressing this iniportant prob- lem in drug safety. Senator NasoN. May I ask a question. I read your statement this morning rather quickly. Do you know what additional documentation is required? I recall from your statement, if I am wrong. please say so, I believe there is not any further necessity for large controlled, double-blind studies beyond what has already been done, cml correct? `See prepared statement and appendixes of Dr. crout beginning at p. 14610. PAGENO="0145" COMPETITIVE PROBLEMS IN TEE DRUG flThUSTRY 14567 Dr.~ Citotrr. That is correct. Senator Nasoy. Then what additional documentation do you refer to? Dr. Cnou'r. We would have a legal burden of making a safety case using the drug abuse data that are anticipated from our sister agencies to make the case that under the Federal Food, Drug, and Cosmetic Act, those drugs are no longer safe for their labeled use. That is a decision which is coiitestable, a position which is contestable in a hear- ing and later in court, so one has to have his legal ducks in a row, so to speak. Furthermore, an accompanying regulatory action would be a move- ment of those drugs from schedule II to schedule I. Senator NELSON. Would be what? Dr. CROUT. An accompanying action in any removal from the market would be a change from schedule II to schedule I of the Con- trolled Substances Act, and that too requires appropriate documenta- tion and can be challen'ed in court. Senator NELSON. W~en you say removal from the market, are you saying removal from the market for any indicated uses? Dr. CliouT. Were that to occur, yes, those drugs would be changed from schedule II to I. Senator NELSON. How does the legal situation change if the FDA decided to remove treatment of obesity from its indicated use? Dr. Cnotrr. The legal situation does not change. We would have to go through the legal process of issuing a notice of opportunity of hearing, and perhaps having a hearing, for that indication. Senator NELSON. Are you saying that you have the same legal ques- tion and the seine problem of removing the drug from the market as you do of changing the indicated use of the drug? Mr. MERRIlL. If I can, Mr. Chairman, let me respond to that. Because there are some proven indications of these drugs for medical treatment, if we were to take the more drastic action of taking the drugs off the market altogether, it is possible our burden would have to be higher because we might have to show that the risks of abuse in connection with the treatment of obesity outweighed any use including legitimate use of the drug. If we simply removed obesity as an indication, we would make a case based on balance of the risks and benefits for this purpose. We would also have to decide whether that action would be sufficient, because it would mean that the dosage form was still available in the pharmacy, and still legally available for a physician to prescribe. Dr. Crout reminds me that there is no misunderstanding, that the legal process through which we must go is precisely the same. The amount of evidence required to sustain our case might be greater. Senator NELSON. Let me see now. With respect to those drugs that are under the 196~ Kefanver amend- ment, the Food and Drug Administration set up a procedure, and that procedure using the National Academy of Sciences, established panels of experts on each class of drug; right? Dr. flour. Yes. PAGENO="0146" 14508 COMPETITIVE PROBLEMS IN~ TB~E DRUG INDUSTRY Senator NasoN. And then the druns were classed as effective, prob- ably effective, possibly effective, not el~ective; is that correct? Dr. (Inour. That is correct. Senator NELSON. And for those that were classified less than -effec- tive, you were required to produce evidence of effectiveness; is that correct? Dr. Citoti'r. The manufacturer was required to provide evidence of effectiveness; yes. Senator NELSON. Yes. - And then if they could not prove evidence of effectiveness, they removed it from the market, which was the consequences of all fixed combinations of anti-infect.ives? Dr. Cnour. Yes. Mr. MEnnrLr4. As you know, it took some time, because the manu- facturers disputed whether or not the evidence they submitted satis- fled the statutory standard. Senator NasoN. How does this situation differ Certainly you could not make a finding of effectiveness based upon the studies. It is seri- ously questionable by the experts we have heard testify that you could say probably effective. The best you could say is possibly effective, it would seem to me any- way. Dr. Cnour. That is not correct. - - The anorectic review of 1972 reevaluated these drugs, and they are all effective and on the market at the present time, fully evaluated by that process. Senator NELSON. Well, the language in that report was that the effect was "clinically trivial," so when you proceed under the 1938 act for proof of safety, and under the 1962 act for efficacy, are you saying you really think the evidence supports the conclusion that they would rank higher than "possibly effective"? Dr. CROIJT. That they are "possibly effective" was the judgment of the panels. Senator NELSON. Possibly? Dr. Cnou'r. Possibly. We have been through the process of evaluat- ing the National Academy's reports, however. That is what was done in 1972. and the committee report you read from in your opening testimony, your opening statement, referred to the process that occurred at that time. We followed the advisory group's recommendations and our own anorectic review in upgrading all of those drugs to a classification of effectiveness. - They do beat a placebo in causing increased weight loss in patients who are on a diet, and this has been demonstrated for each drug for a period of approximately 3 months in controlled trails. That was the standard of effectiveness adopted at that time and the standard of. effectiveness that is currently described in the labeling for those drugs. Senator NELSON. But yon do conclude now in your own statement today that you have got a whole lot more knowledge about the question of abuse and safety than you had in 1972? Dr. Cnour. Yes; there is now new information to lead us to reap- praise the issue of safety. PAGENO="0147" COMPETITiVE PROBLEMS IN THE DRUG nmusnrr 14569 The question raised today relates to continuing abuse, even in spite of control of the amphetamines as scheduled. Senator NasoN. 1-low would you compare your judgment on am- phetamines used for treatment of obesity, against your judgment in re- moving a drug from the market, as the drug which was a combination of tetracycline and novobiocin, which would be called effective in the sense that tetracycline was effective against the target organism prop- erly prcscribecl. Your conclusion was that in combination the two drugs were antagonistic, not additive, so you removed that combina- t.ion from the market. There was no Que~ion, I believe, about the fact that that combina- tion would affect the appropriate target organism. The problem was the side effects as a consequence of using novobio- cm and tetracycline in combination, which exposed the patient to the side effects of the two drugs, but only tetracycline was needed. You, as a doctor, would concede that if you were in some remote part of the world, and if Panalba would affect the target organism, even though the patient might get some side effects, you would use the lnig? What argument is there for leaving the amphetamines in the market for the treatment of obesity, when there are other ways to do it, and when the results are clinically trivial? * That is what puzzles Inc. Dr; Cuout. The issues in the two cases are slightly different. In the Panalba situation, the lack of safety applied to the patient for whom it was prescribed. That particular patient would get a safer drug and just as effective if he took the tetracycline component of Panalba, rather than if he took the combined agents, so that decision involved was a straight benefit-risk judgment about Panalba under the Federal Food, Drug, and Cosmetic Act, where one is thinking of effectiveness versus the safety to the patient. Now, when we originally determined in 1972 that amphetamines were effective under the Federal Food, Drug, and Cosmetic Act, that same benefit-risk approach taking into account what was said by the experts, led to the conclusion that amphetamines, when used as labeled and as directed over the short term and in the proper dose, met ap- propriate standards of safety to the particular patient taking the drug. A new issue arises, however, when patients begin to take amphet- amines in excess, or they divert it to drug abusers. Now there is no longer a safety-effectiveness tradeoff in the individual patient. Rather, it is a tradeoff in relntion to societal abuse of a drug which would not be considered unsafe if it were, in fact, used only as labeled under the Federal Food, Drug, and Cosmetic Act. It is this latter question that we have to address at this time. Mr. MERRILL. There is one other matter relating to the question, and that is what is our legal posture. That difference is that with Panalba. we had a recommendation from an expert panel that there were not the kind of studies to show the effectiveness that the law required, and we initiated action to re- move that drug at that time. With amphetamines, we had a recommendation in 1070; the agency *i~sked for additional data; some 200 studies were submitted; and, PAGENO="0148" 14570 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY whether rightly or wrongly, tile Agency's experts concluded on the basis of the data then in hand that it was indeed effective. Not greatly so perhaps, but nonetheless effective, so the agency is now on record as stating the firm effectiveness of these drugs, as Dr. Crout suggested, is there, but the issue we are now concerned about is whether or not that small effectiveness is substantially outweighed by the kind of abuse and safety problems we are seeing. Senator Nasox. Well, there are two questions about safety: One is the widespread abuse of the drug by the users who have no weight problem, and did not get it prescribed for a weight problem; the other is the risks to the individual for whom it is prescribed, who then be- comes dependent upon it. There is no supporting evidence that it has any long-term effect at all. Consider this question: If a new drug application were filed with the FDA. under the safety requirements of the 1938 act and the efficacy requirements of the 1962 act, would you approve these drugs for mar- keting? Would you not be asking for the effect of their use on obesity over a long term, a year or two at least? Would not you demand of the proposed marketer that he give you controlled studies to show the long-term effect as to obesity, to say nothing now of the possible side effects front the ingestion of the drug? Dr. CR0L-'r. Let us set aside the drug abuse issue. The answer to your question regarding long-term effectiveness is that that issue was debated in the 1971-72 era, and we reached the conclusion that the effectiveness of this class of drugs should not be evaluated in terms of long-tern effectiveness. The reason for that is that obesity can be considered, if I can make an analogy, as one of several illnesses where dietary therapy is para- mount, and the use of a drug is adjunctive. That is true for the management of ulcer disease, that is trim for obesity, that is true for the dietary management of diabetes in patients who are not insulin.dependent. We have not required that drugs for these various conditions have a perfectly demonstrated effect, a com- pletely unequivocal demonstrated effect, on the natural history of those (liseases. They should be considered as an adjunctive therapy to diet for the management of those diseases. Now, one can argue with that standard. All I can say is that the pit- vailing practice of medicine has been to support that standard and the prevailing opinion of experts has been to support that standard. In some respects we liaye to face up to the fact that, while these adjunc- tire dnigs may be clinically trivial over the long term, on the average. they uiav also be useful, es-en dramatically useful, in some patients. In a sense they are also tl~e only game in town. I think if you have a long-term problem, and dietary management is the key to it, drugs that are of consistent help in any way are welcome to patients and the medical profession, providing there is not an overriding safety issue involved. Now, our view is today, as you well know. that the above issue mar well have, become an overriding safety problem for the ampheta- mines. We w-ill look at whether it is an overriding problem for the non- amphetamine anorectics also, but I suspect that a strong safety case PAGENO="0149" COMPETITiVE PROBLEMS r~ THE PLUTO INDIYSTRY 14571 against the nonamphetamhie anorectics cannot be made at the present time. Senator NasoN. When you say non-amphetamine anorectics, are you referring to the so-called congeners ~ Dr. Cuour. Yes. The ones that are in schedules III and IV today. Senator Nztsox. I think the testimony of some of our expert wit- nesses is that a number of those are also addictive, highly stimulative, and subject to abuse too. Dr. Cnout. But I think, as we will see from the graphs here, the evidence is that their degree of abuse is much less than with the drugs in schedule IT. Senator NELSON. Well, all right. On that point, let me say there is nothing in the statute that I know of that is specific about the long-term, short-term, trivial, clinically trivial, and so forth, so one could come to the conclusion as a result of what we know, it is clinically trivial. As a matter of fact, it seems to me more logical that it is clinically trivial. It is obviously subject to abuse, and it would be logical for the FDA to tell the producer of that drug to come in and show the long-tenn effect, not only from the standpoint of the safety to the individual, but the proof of its efficacy in reducing obesity. Dr. Cuour. Again, I simply have to go back to the analogy with many other drugs. I think your comment applies to many agents that are intermediate between truly symptomatic remedies and those that are truly known to be effective in the cure of diseases. We have got a lot of remedies in the drug area that are useful on occasion, in individual patients for purposes of helping them alter their own dietary habits, for p urposes of treating transient problems. I think that the lack of evidence of long-term effectiveness does not mean we should draw the conclusion they are known to be ineffective over the long term. It simply means a lack of knowledge. Senator NELSON. That is not what the law says. The law says you have to have substantial evidence based upon well- controlled studies, and to say that there is no proof- Dr. CitouT. Such proof is there for the short term. `rhere is no requirement in the law that a drug must alter the natural history of disease over the long term. Now, that can be put in the. law and drastically alter the number of drugs we have, but I think one should discuss at length the ramifica- tions-I think first we should consider the consequences of such a change. We must recognize that the bulk of drugs are adjunctive to the natural processes of healing. Senator NELSoN. Well, yes. but we are here dealing with a particular class of drugs-for obesity. What other drugs is there on the market- place that is addictive, widely abused, in which its effect may be very specialized in individual cases, or short tenn-what other ones? Dr. Caour. Set aside the drug-abuse problem, and- Senator NELSON. Well, no, you have to include that, because the fact it is addictive and widely abused increases the risk factor, making the benefit-to-risk ratio unfavorable. Dr. CRouT. I agree with that, and our testimony is that we are pre- pared to take action assuming a well-documented case for the abuse PAGENO="0150" 14572 COMPETITIVE PROBLEMS IN THI DRUG ~INDUSTRY problem is shown, which we anticipate to be there. There is no question about that. Senator NELSON. You anticipate that there will be strong evidence of abuse? Dr. CRour. Yes; for amphetamines. I think for the class as a whole, you will find when the facts are all in, that a distinction can be drawn in the abuse area between those drugs on schedule II and those in III and IV. Senator NELSON. As you probably know, Dr. Henderson, from Ot- tawa, Canada, who was chainuan in Canada of the committee that.! recommended removal of the indication of amphetamines for the treatment of obesity appeared before this subcommittee. lie has now concluded that it should apply to the congeners, also, I believe he said~ except for fenfluramine. . ! - I do not know whether he said that. Dr. Cuout We will be interested in what Canada does. We are in touch with Canada on this. Senator NELSON. I think the record shows that Dr. Edwards, when he was Commissioner, said that most studies of these preparations showed efficacy for short periods. The panel suggested that long-term studies should be conducted. This was in 1970. Have long-term studies been initiated on weight reduction, or have producers of the drugs been requested to produce studies?. Dr. Edwards suggested long-term studies of the effects of these drugs 6 years ago. Dr. CItOUT. Jam not familiar with that request. Mr. Mznnra. There are two parts of the question, I think, Mr. Chair- man. One is whether or not there should be data from well-controlled studies. Senator NELSON. Pardon? Mr. MERRILL. I think there are two parts of the question. One is whether or not there should be data from adequate and well-controlled studies, covering long periods, versus very short periods. Such data covering short periods of use were submitted and evalu- ated. Senator NELSON. Such studies were what? Mr. MERRILL. Such studies were submitted to the agency. Senator NELSON. Long-term? Mr. MERRILL. No; I think it is true the manufacturers have not done that so far as we know. I think they may now be doing it, but to span the length of a lifetime- Senator NELSON. Tam not even talking about lifetime. Jam talking of 1 year, 2 years. Dr. GROUT. Why is that different from 5 years, 10 years, 20 years? Senator NasoN. Well, if something is good for only 20 seconds, you ought to remove it from the market. If you are talking about an impact of a half-pound a week, treated for 12 or 13 weeks and then the patient ends up in the same posftrnn 19 months later- - . - Dr. CROUT. How do you know that he ends up in the same position 12 months later? - Senator NELSON. We do not know. - PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14573 Dr. Onotrr. That is an unknown. - Senator NasoN. That is right, but your own panel says that the effectiveness is clinically trivial. You seem to be taking the position that the burden is on the public to prove that the drug does not work, rather than on the company to prove it is effective. Dr. Cnout No; I am takmg the position that we adopted a stand- ard of effectiveness urged on us by our advisers, and which represents as far as we can tell the prevailing opinion of experts in the manage- ment of obesity, namely that a reasonable standard for effectiveness of drugs in the anorectic class is that they be shown to be effective over the short time, and that is a reasonable standard in our opinion. That was a ground rule of the 1972 review with Dr. Prout, and it was Dr. Prout's committee's opinion at that time. That was the stand- ard adopted when these drugs were upgraded to effective. The labeling states clearly this limitation in the labeling. Senator NELSON. What I read from was the report of the NAS/NRC panel itself, which stated that most studies of these preparations are- for short periods, and the panel suggested controlled studies for the longrterm facts. What I am asking is, las the FDA requested such studies? Dr. Cuout That was the NAS/NItO panel's opinion, and it was silent on who should do that. Senator NELSON. It was what? Dr. OnouT. That report is silent as to who should do such long-terra. studies. Senator NasoN. You mean to say if they are silent, the FDA is.. disabled from proceeding? Dr. Cnon. No; I am saying we reviewed it with care, our panel of experts and Dr. Prout reviewed it, and they did not support that rec- ommendation. A- reaonable standard for marketing of a different typo. was adopted, and that is a standard which is appropriate in our judg-.. ment for a variety of drugs that are adjunctive therapy to diets- exactly the same standard that applies to the ulcer field and the dia- betes field. Senator NELSON. Well, as you are aware, Dr. Prout who did head up a panel in 1072, this week in his testimony said-I quote in party and I ask the other appropriate parts be printed in the record at this point-"Second, it has been demonstrated that the amphetamines and their related compounds have such trivial indications for the treatment of obesity that we should look at questions of whether or not obesity should be withdrawn as indication for their use," and then later on, he said: "I would therefore recommend that obesity be with- drawn as an indication of therapeutic use of these drugs." [The information follows:] The second one, of course, is predictable and that sales of amphetamines like compounds which were not placed on Schedule ii bad a marked increase in use, but not completely unexpected rise In sales. One of these was cited on television for its particularly aggressive promo- tional techniques, of one company, that Is for its rather high Increase In sales. These drugs are now known to be subject to abuse, and it is on the list of the recommendations If you look back, of the Ad Hoc Committee. That would be my first recommendation, that the scheduling of all of these drugs with abuse potential be placed on ~ PAGENO="0152" 14574 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY Secondly, it has been demonstrated that the amphetamines and their related compounds have such trivial indications for the treatment of obesity, that we should look at questions of whether or not obesity should be withdrawn as an indication for their use. This Is the major medical excuse for the manufacture of amphetamines, and the risk of overproduction far exceeds the benefits that might be cited through anecdote of a few patients who, in association with rigid dieting, have believed that the so-called anorectlcs were the causative agent in their particular weight reduction. I would, therefore, recommend that obesity be withdrawn as an indication for the therapeutic use of these drugs. This action has in fact been taken by Canada and other countries, and my own State of Maryland, this action was taken there, and I think it is a model law that might be Indicated in Federal statute, that It be duplicated in Federal statute. Dr. Cxtotrr. May I comment on that? Senator NElsoN. Surely. Dr. Cnotrr. Dr. Prout is the valued chairman of our indocrinology and metabolism advisory committee. He is also a personal friend. We are in touch. I have not had a chance to talk with him on the phone since that testimony, but let me assure you that his opinions will be taken into account by us. I suspect, though, if he has changed his mind since 1972, he is chang- ing his mind for the same reason I am testifying. It relates to the safety problems in spite of control under schedule IT, and not to any change in the degree of effectiveness of these agents through the years. Senator NElsoN. Of course, effcctiveness under the statute, as you are well aware, in vague situations such as this one is a judgmental factor. There is not a very good test such as one would get with an antibiotic versus a particular target organism which could be demonstrated con- clusively in the lab and in the treatment of the diseases of the particu- lar patient. I agree and think myself personally that the Food and Drug Ad- ministration should have asked for some more evidence of its long-term effect, because I doubt that you can justify massively dosing people with a highly stimulating central nervous system drug without some really substantial benefits, and the substantial benefits have never been proven. Are you saying that even if it is highly stimulative to the cen- tral nervous system. is addictive. and has trivial clinical results, we think it meets the standards of safety? Dr. Cnon. I am not saying that. Senator NELSON. That is where we are at. Dr. Cuou'r. I am saying that the standard of effectiveness adopted is one relating to short-term use. *The standard of safety is that the benefits justify the risks to the in- dividual. Were there no issue of abuse, then one would, I thlnlc, have little concern about the safety of these drugs for that use. Today's issue is whether the degree of abuse continuing with drugs that are under schedule II of the Controlled Substances Act is reason *to take away that indication, or take them off the market. Senator NELSoN. Would you not agree, though, that tins is a seman- tic question, you cannot separate safety from efficacy? They are together. It is one ball of wax. There is no way to separate them. The benefit-to-risk ratio is based upon safety and efficacy, and it is all one question. PAGENO="0153" cOMPrrrrivE PROBLEMS IN THE DRUG INDUSTRY 14575 Dr. Cnou'r. They are intimately related, but different, and there are different standards that appropriately apply, depending on the kind of evidence you want in the two areas. The issue of adequate well-controlled trials is paramount to a determination of effectiveness. The issue of adequate well-controlled trials is not paramount to a determination of safety. We will take information related to safety anywhere we get it. It does not have to come out of well-controlled trials. In looking at the two together, I agree with you the benefit-risk decision involves safety and effectiveness together. Senator NELsoN. It seems to me that we have got to be looking at it together. Dr. CROUT. The benefit-risk decision requires they be looked at together. Senator NELSON. But then you have to look at safety and efficacy. Everybody would agree that chioramphenicol is a very potent drug, very dangerous drug; however, according to the NAS/NilO study, it is indicated only when the patient is seriously ill, his life is threat- ened with disease, and no other antibiotic will work, so you have a case in which a drug, that everybody will say on its face is unsafe, but it is not unsafe in relationship to this patient, because the disease is a greater threat to his life. The incidence of aplastic anemia that may result from its use, in the one in 20,000, so you do have to look at both together, you agree with that? Dr. Cnorr. Absolutely. Mr. MERRILL. I think what Dr. Crout is saying is just where we begin to work with DEA to build up our case, and the focus will be on the safety side of the equation, because it is that side of the balance which seems to have shifted since 1972. Senator NELsoN. All right. It seems to me, with something as trivial as this class of drags that you ought to be requiring some better evidence of efficacy over the long period. I should imagine that widespread street use would raise questions of safety. Let me ask you another question. Dr. Henderson from Ottawa, who was on the Canadian panel that I mentioned before, testified that his panel recommended that the indication of obesity for this class of drugs be removed, and this was done. He also said that only in very limited eases, in treatment of obesity-I think that is a fair paraphrasing-would he give fenfluramine, benuse it was not ad- dictive; that, in fact, lots of patients rejected it because they got upset stomachs or something else unpleasant; that there was no way that it would be abused; and in limited situations, he did use fenfiuramine. Have there been any studies done to compare the effectiveness of fenfluramine vis-a-vis the amphetamine congeners to see how effective fenfluramine is? Dr. Cnour. There are studies comparing a variety of anorectics,. one with the other. Senator NELSON. They are underway now? Dr. CR0U'r. No, they are done. One of the purposes of the anoreetic review in 1972 was to look at all of those studies simultaneously, and when you put them all PAGENO="0154" 14576 COMPETITIVE PROBLEMS IN TIITE DRUG INDUSTRY together, our judgment is that from an effectiveness standpoint, all drugs in the whole class are roughly comparable. The effectiveness of fenfluramine in reducing weight is roughly com- parable to any other drug in the class. Senator Nasox. Do these studies show any indication of addictive- ness of the fenfluramine? Dr. GROUT. Fenfiuramine went on the market for the first time at that time so the studies we have relating to abuse potential for fenfiuramine were animal studies only at that time. Senator NELSON. Did the animals help to self-ingest themselves? Dr. Cr.ocT. I believe they did not with fenfluramine. The pharma- cology of fenfluramine is more like that of a depressant than a stimu- lent drug. Now, an important question right now is whether in street use, after *3 years of experience, fenfluramine is turning out to be abused, for whatever reason. Senator NELSON. Is there any indication that it is? .Dr. GROUT. I would have to defer to DEA on that. The prominent safety issue with these drugs relates to their abuse. The intent of the Federal Food, Drug, and Cosmetic Act has predomi- .nantly been considered historically to protect the individual receiving drugs. The intent of the Controlled Substance Act is to control the abuse problem. What we are trying to say at this point is that the Con- trol led Substances Act is not totally successful in controlling the abuse problem, certainly with amphetamines, and perhaps with others in this * class. Therefore, we should now go back under the Federal Food, Drug, ~tnd Cosmetic Act and consider abuse to society as part of the benefit- risk equation. Now, that is a proper use of these two laws in our judgment. But if abuse per so is a reason for taking drugs off the market, you do not need a Controlled Substances Act. The Controlled Substances Act is for the purpose of controlling the * abuse of useful drugs, and while you may consider this usefulness to be minimal, they are useful in the treatment of obesity. Senator Nasox What is the tool under the act for enforcing the law respecting abuse of legally marketed drugs? * Mr. MERRILL. Tinder the statute? * Mr. Goimox. Yes Mr. MERRILL. The statute permits FDA to change the labeling to omit an indication. The other remedy the statute provides is to remove the drug from the channels of commerce. - We do not now have a useful mechanism for restricting availability of marketed drugs. Mr. Gonoox. Nor any mechanism for proceeding against somebody who is using the drug far nonindicated use? Mr. MERRILL. We, generally speaking, have said the Federal Food, and Drug Act does not prohibit an individual physician from pit- scribing a drug for an unapproved use. We have one case now pending in which we are proceeding against a clinic in the South that has ordered the shipment, for imapproved uses, of a series of drugs for a continuing kind of therapy. We have taken a position in court-it has not yet been adjuthcated-that that * kind of trafficking in unapproved use of the drug is tantamount to PAGENO="0155" COMPETITWE PROBLEMS r* THE DRUG INDUSTRY 14577 causing the drug to be misbranded, in other words, that it is illegal ~nder the Federal Food, Drug, and Cosmetic Act. . - Mr. GCRDON. I assume, then, that most of the problem respecting the misuse of drugs is left up to State medical societies, is that correct? Mr. VODKA. And the civil law, malpractice law. Senator NELSON. The reason we raise this is the testimony of Dr. (lellert from Suffolk Coimty, the Town of huntington, N.Y., popula- tionof 200,000, 250 doctors in a remarkable agreement of unanimity respected the wish that they would not prescribe amphetamines for `obesity, and none of them do so. There are two doctors who do not belong to the medical society in -the town. There was one fat pill doctor before, and now thet have two, and they average 800 to 1,200 patients per week. I asked him what the fee charge was, he said he did riot know. I tlunk it would be worth finding out, bitt a certain percent of these patients are of course ending up in the other physicians' offices with Troblems. The lineup outside the clinic consists of all kinds of very thin peo- ple. Obviously you cannot have 800 a week who, if they are not obese, * neither are they narcoleptic adults or hyperkinetic kids. Now, what is the mechanism, or is there not any for dealing with a case in which I liese two doctors in -that place are abusing the drugs? Their patients just come in, get a prescription, and go out. Is there any mechanism for stopping that? Mr. MERRILL. I read Dr. Gellert's testimony, and he suggested that the FDA consider doing what it attempted to do with methadone. We fried to restrict its availability, and we were sued by the Amen- -can Pharmaceutical Association, the association of pharmacists who viewed that as a threat to their access in drugs generally. The district court and the court of appeals here in Washington struck down those regulations, so I guess my answer is the same answer I gave you before, the mechanism available to the FDA under the Federal Food, Drug, and Cosmetic Act is to eliminate the indication or the use of drugs altogether. Mr. VODKA. I might add that I used to be at DEA, and while I was there and I am sure to this day, they do work on cases of physicians selling prescriptions or drues to nontona fide patients, where there is no doctor-patient relationstip whatsoever. That is an exceedhigly costly approach to use. DEA does not have the resources to police all of the physicians in this country, with all of the various drugs, not only the amphetamines, but narcotics, and so forth. Senator NELsoN. But in these two cases, I would gather from the testimony, that it is pretty clear they are in the business of making a lot of money prescribing addictive drugs to people who do not need them at all for obesity. Mr. VODKA. If they can establish there is not a bona fide relationship, it is a criminal offense, a felony offense of the Controlled Substance Act, and they can obtain a conviction in the Federal courts. The Supreme Court has upheld the conviction of a physician traffick- ing methadone, who in 1 day wrote 240 prescriptions for methadone. The Supreme Court said the physician was subject to the act. It is basically a resource question, not a legal one. PAGENO="0156" 14578 COMPETITIVE PROBLEMS IN TIlE DRUG mDUSTRY Dr. CR0U'r. I am told there are several States that have innovative new laws in which the State medical society is asked ~n occasion to make judgments about professional practice of individual doctors, whether or not they belong to the State medical society, and based upon. the recommendations of that committee, the State will take action in revoking a license. So there are some innovative State laws taking place. You might want to look ~nth that. What we are saying is that under the Controlled Substances i%ct, when the Government has the facts, it can move against a physician, but this is relatively difficult. Senator NEI.soN. All right. You may proceed. Dr. thorn. Fine. OBESITY AS A hEALTh PROBLEM Before turning to the anorectic drugs, it is important that we recog- nize the public health significance of obesity. Although some may believe that excess weight is merely of cosmetic significance, the fact is that obesity is America's No. 1 nutritional problem. Obesity sig- nificantly increases the risk of a number of diseases and complicates many other conditions. It is usually chronic and is difficult to treat. Successful therapy depends upon vigilance and effort throughout the patient's I ifetinie. In testimony before the Senate Conirnittee on Nutrit~on and human Needs, on July 27, 1976, the Assistant Secretary for Health. Depart- ment of Health, Education, and Welfare (D11EW), Dr. Theodore Cooper stated: In recent years obesity has become a public health problem of considerable importance in the United States. Approxi- mately 20 percent of all adults are overweight to a degree that may interfere with optimal health and longevity. Obesity aggravates cardiovascular disease and osteoarthritis and increases the liability to hypertension, atherosclerosis, hernia, and gallbladder disease. Over. weight also may facilitate the emergence of latent diabetes in pre- disposed individuals as they approach an advanced age and adds to the hazards of surgery; it makes for postural derangement, and in ex- treme cases, it is the cause of obesity dyspnea with pulmonary insuf- ficiency. It is also of interest that the mortality from cirrhosis of the liver in obese males is 249 percent of the expected. Medicoactuarial statistics make it quite clear that the obese do not live as long as the lean. The chief causes of death amoiig overweight individuals are cardiovascular.renal diseases, diabetes, and disorders of the liver and biliary tract. The burden of obesity is not borne equally among all segments of society. In the United States, it is more likely to be found in the lower socio-economic strata; this association is particularly marked in poor women and to a lesser extent in middle class males. Again, I would emphasize the statistical importance of obesity iu our population and the strong need for and potential benefits of sys- tematic preventive action beginning in early childhood. PAGENO="0157" COMPETITWE PROBLEMS IN TIlE DRUG INDUSThY 14579 ANORECTIC DRUGS The successful treatment of obesity requires only one essential ther- apeutic measure-that the patient take in fewer calories than he or she needs for a given level of exercise so that the stored fat in the body is graduallylost as it is burned as body fuel. All supportive meas- ures for the management of obesity-including group therapy-e.g., weight.watchers-special diets, jogging, and drugs-have as their sole purpose assisting the patient to eat less or to increase his or her level of exercise or both. The pharmacological action of drugs in the anorectic class is to produce anorexia, that is, loss of appetite, and thereby to assist the patient in restructuring his or her dietary habits. There are currently 12 drug entities approved for prescription use in the United States for the treatment of obesity. Three of these, d,l.amphetamine, dextroamphetamine, and methamphetamine have been in clinical use since the 1930's. Six additional anorectic drugs were introduced in the period between 1935 and 1962 before the Kefauver-Ilarris Amendments: Benzphetamine, phenmetrazine, phen- (limetrazme, phentermine, chlorphentermine, and diethylpropion. The remaining three-fenfiuramine, chortermine and mazindol-were ap- proved for marketing by FDA in 1973. All of these, except mazindol, are related in chemical structure, all have central nervous system ef- fects, and, today, all are scheduled under the Controlled Substances Act. BEGULATION OF ANORECTIC DRUGS Before highlighting the major past actions of the FDA, it is worth emphasizing that the powers and responsibilities of the Federal Government to regulate anorectie drugs are shared by the Drug En- forcement Administration-DEA--and FDA. In addition, individual States have passed laws and regulations governing abusable drugs. TheFDA controls the approval of new drugs for marketing, regulates initial and revised labeling, and recommends to the DEA the selection of an appropriate schedule for a drug under the Controlled Sub- stances Act-CSA. In addition; the FDA provides to DEA informa- flon on legitimate medical usage of schedule II drugs which DEAL uses in setting production quotas. While the placing of a drug into a particular category under the CSA is the ultimate responsibility of PEA, it is done only on recommendation from FDA after careful re- view by the FDA scientific staff, consultants and the Controlled Sub- stances Advisory Committee. The DEAL has the ultimate authority to schedule drugs under the CSA. to establish quotas on those drugs in schedules I and II, to monitor the domestic production and distribution of controlled drugs, to regulate their importation and exportation, and to enforce the provisions of the CSA. In selected eases, PEA can act against the prescribing and dispensing of controlled drugs by physicians by in- voking penalties against those who are acting outside the legitimate practice of medicine. The National Institute on Drug Abuse-NIDA-and, in some areas, PEA fund programs to study the potential and actual abuse of drugs, including anorectics. NIDA also funds programs to treat and prevent PAGENO="0158" 14580 COMPETFTIVE PROBLEMS ~N TIlE DRUG INDUSTRY drug dependence. At the State level, licensing boards for physicians, pharmacists and pharmacies, hospitals, and other health care units~ also can influence the prescribing and dispensing practices of health professionals. Furthermore State and local law enforcement agencies, many of which are actively supported by DEA and the Law Enforce- ment Assistance Administration, police the diversion and illicit traflic of controlled drugs. Communication among these Federal and State agencies is main- tained by regular meetings of the involved officials at both the staff and policy levels. The Interagency Committee on Drug Control, as am example, is a working group which includes membership from FDA, NIDA, and DEA. An FDA/DEA liaison staff group also meets~ regularly. In addition, the Commissioner of Food and Drugs, the Ad- ministrator of PEA, and the Director of NIDA meet personally to discuss policy issues. There is also extensive communication between the field forces of FDA and PEA and their counterparts in State law enforcement and health agencies. FDA ACTIONS FROM 1060 ThROUGh 1071 The Food and Drug Administration has for many years supported stringent controls on the amphetamines. In the early 1960's, prior to any clear Congressional mandate, the FDA undertook investigation and prosecution of traffickers in amphetamines. The 1905 Dnig Abuse Control amendments to the Federal Food, Drug, and Cosmetic Act provided stronger regulation over the manufacture and distribution of dangerous drugs, including certain stimulant drugs, and in February 1966 FDA established a separate Bureau of Drug Abuse Control to carry out these amendments. In the first 2 years of the program, FDA carried out over 2,000 criminal investigations, made more than 1,300 arrests, and handled about 300 criminal cases. The FDA made, in addition, approximately 1,100 accountability investigations result- ing in 108 civil seizures of depressant and stimulant drugs. Nearly 60& million dosage units of these drugs were removed from the market- place because no accurate records, as required by the law, were kept by manufacturers. In April 1968, the Bureau of Drug Abuse Control was merged with the Bureau of Narcotics of the Treasury Department to create the Bureau of Narcotics and Dangerous Drugs-BNDD-of the Depart- ment of Justice. In 1973, BNDD became the Drug Enforcement Agency. In October 1970 the Controlled Substances Act~-CSA-wa 9 enacted and added an important new dimension to the control of abusable drugs. The CSA originally scheduled only four anorectic drugs (amphet- amine, dextroamphetamine, metha.mplietamine, and phenmetrazine), and these were listed in schedule III. Injectable methamphetamine was controlled in schedule II. In 1971, in response to proposals by BNDD, FDA recommended that these anorectic drugs all be trans- ferred to schedule IL Prompt action by BNDD in making these con- trols effective resulted in (a) eliminating refills on prescriptions, (b) requiring all prescriptions to be in writing, (c) subjecting manufac- turers, distributors, and dispensers to more stringent security requirements for storing these drugs, (d) limiting production to PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 145811 Government-established quotas, (e) having all shipnients among man- ufacturers, wholesalers, and retailers be done on special BNDD order forms, copies of which were to be immediately provided to BNDD. (f) prohibiting import and export of the drugs without prior BNDD permission, and (g) requiring that reports of inventories and all transactions be sent to BNDD. Concurrent with these actions. FDA has carried out an active pro- gram of surveillance over the advertising of these drugs. Since ~\fay 1966,38 legal, regulatory, and advisory actions related to their promo- tion have occurred. Of these actions, 27 have beeti initiated in the last 4 years. These have included two product seizures, three remedial "Dear Doctor" letters; and one remedial advertisement. Common causes of actions by FDA in regard to the advertising of these drugs have been inadequate prescribing information; unwarranted extension of the indications to special groups of patients such as hypertensives, dia- betics, and teenagers; implied claims of usefulness beyond the indi- cated short-term use of a few weeks; and misleading promotion which attempts to understate the potential for abuse. The FDA advertising rules require that all promotional labeling and advertisements for these drugs meet the usual requirements for prescription drugs and, in addition, display the appropriate CSA control symbol. FDA ACTIONS FROM 1972 TO THE PREsENT: THE ANORECrIC REVIEW Mr. Chairman, as you know, the Kefauver-Harris amendments re- quired t.hat FDA review for effectiveness all drugs previously ap- proved on the basis of safety between 1988 and 1962. For the anorectie drugs the Agency elected to review the whole class at one time so that- the same standards would be applied to each druac The amphetamines were included in the review even though they had been marketed prior to 1038. The overall review included not only a detailed statistical analysis of all of the controlled studies in our files relating to the effectiveness of these drugs in obesity, but also meetings with consultants and ad- visory groups. An obviously important consideration in reviewing this class of drugs was the general standard to be applied in determining effective. ness. It was well recognized then, as it is today, that permanent weight Joss over the long term is the desired goal of any treatment program for obesity and tha.t proof of such long-term eftectiveness is lacking for any of the adjunetive measures used in treating patients with obesity. This does not imply that all adjunctire measures are neces- sarily ineffective-only that proof of long-term effectiveness is not available from adequate and well-controlled trials. In the case of anorectic drugs. long-tenn trials would be very expensive and difficult to perform in view of the many other factors relating to patient moti- vation which would have to be controlled, or at least measured and accounted for in the statistical analysis of the results. The problem of the standard of effectiveness to be required for marketing has been discussed repeatedly within the FDA and with our consultants. The standard we have adopted is that a demonstra- tion of effectiveness should depend upon a finding in adequate and PAGENO="0160" 14582 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY well-controlled trials that patients taking the drug sustain a statis- tically significant greater degree of weight loss than patients taking a placebo. While it would obviously be of Value to know with certainty the effect of the drug on the natural history of the disease, we have considered this to be a public health question which an individual drug firm cannot reasonably be expected to answer in the context of eval- uating its particular product. The approach taken in conducting the anorectic review was dis- cussed by Dr. henry E. Simmons, the former Director of the Bureau of Drugs. in his testimony before tins subcommittee on December 13, 1972, and I would like to restate his description of its magnitude: The scope of the program was ambitious, and involved over 1,000 volumes of data concerned with twelve single entities. The drug products in which these entities were present, eitber alone or in combination, were marketed by 40 firms. Over 200 double-blind and controlled studies of efficacy which bad been carried out en almost 10.000 subjects were included in the review. Individual patient data sheets were coded and key punched to facilitate com- puter analysis. This produced over 70,000 computer cards, representing over 70000 patient visits of the 10.000 subjects. Each card included certain patient characteristics as well as changes In weight, blood pressure, pulse, and other possible adverse effects from visit to visit. The cards contained over 4 million units of information. Programs were then written to permit automatic statistical analysis in order to determine what effect the active drug had when compared with the placebo under "double-blind" controlled conditions. These studies were then evaluated by our medical staff to determine whether there was, for each drug entity, substantial evidence that patients taking the drug sustained on the average a greater degree of weight loss over a 12-week period than patients on a placebo. The 12-week period was selected because it was the longest period for which there was reasonably comparable data on all of the drug entities in the review. The results of this review were presented to FDA consultants dur- ing two meetings in 1972, This group was chaired by Dr. Thaddeus E. Prout, professor of medicine at Johns I{opkins University School of Medicine. Their recommendations were, among others, as follows: 1. The single-entity anorectic drugs including the ampheta- mines should "be permitted to be labeled for restricted use in obesity provided that they are used in association with a specific weight reduction program and that the clinically trivIal contri- bution of these drugs to the overall weight reduction is properly elnphasized." 2. The future approval of anorectic drugs should be "based on demonstration of efficacy or measured by statistical superiority of the drug over placebo in trials using FDA recommended pro- tocols." The group did not recommend that demonstration of a long-term effect on the natural history of obesity be necessary for marketing. 3. All ~rugs in tile anorectic class except fe.nflurarnine should "be placed in schedule II on the basis of abuse potential." - As a result of this review, the following actions were taken by FDA in 1972-73: 1. FDA required that the anorectic drugs be relabeled to empha- size necessary warning information about their potentIal for abuse, and also to reflect accurately the indications for which they PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14583 were judged to be effective and to have an acceptable benefit-to- risk ratio, that is, narcolepsy, minimal brain dysfunction, and short-term adjunctive therapy in obesity. These conclusions were published in the December 1972 issue of the FDA Drug Bulletin which was distributed to some 600,000 health professionals. 2. We determined there was no place for parenteral ampheta- mines in medical practice and these products were removed from the market in 1973. 3. We took the position that preparations containing ampheta. mines in combination with other drugs-.-such as barbiturates, vitamins, and tranquilizers-failed to meet FDA's combination drug policy and were, therefore, ineffective as fixed combinations. Beginning in March 1973. procedures were begun to remove these from the market. A group of small manufacturers brought legal action to contest this action, but on December 28, 1973. the U.S. Court of Appeals for the Eighth Circuit upheld FDA's order. (North Anierican. Pkarrnaeal v. Department of Health, Edvca- Lion, and We//are; 491 F2d 540.) At the same time, several other manufacturers sought formal hearings on the withdrawal of their products from the market. Two products in this category remain unresolved at the present time. The agency has denied a hearing on one of them, Dexamyl, but this denial is stayed pending judi- cial review. The hearing request on the other product, Eskatrol, is still under review. 4. We recommended to PEA in 1973 that all of the. drugs in the anorectic class be scheduled under the CSA. Previous to this recommendation, only the amphetamines and phenmetrazine were under the CSA; these were in schedule IT. The advisory group headed by Dr. Prout had recommended, as I mentioned, that all of the, ~q.norectics, with the exception of fenfiuramine, also be controlled in schedule IT. After reviewing all of the information, however, we felt that the medical and scientific facts available a.t that time could not support this position since evidence of significant street abuse was not available for all drugs in the anorectic class. Consequently, the agency recommended that seven of the anorectics be controlled in schedule III on the basis of abuse potential even in the absence of clear evidence of significant abuse. These drugs were chlorphentamine, benzplietamine. plien- dimetrazine, chiortermine, mazindol, diethylpropion, and phen- termine. Ultimately, the latter two drugs were placed by PEA along with fenfiuiramine in schedule TV. Given the nature of the data available at that time, we believe our scheduling recoin- mendations were medically proper and responsible. Additional information has, of course, been steadily accruing since that time, some of winch, for example, Dr. Jasinski's studies at NIDA's Addiction Research Center, have been discussed in recent testi- mony before this subcommittee. PEA is in the process of analyz- ing this new information on the anoreetics and we look forward to their report. Since 1973, the FDA has developed a mechanism-through the use of the. National Prescription Audit and National Disease and Therapeutic Index-for monitoring the utilization of certain drugs 83-569-t7---il PAGENO="0162" 14584 COMPETITIVE PROBLEMS E~ TIlE DRUG INDUSTRY at the retail pharmacy level and in the offices of selected physicians. The trend analyses reports from this system are used for making pro- duction quota recommendations on schedule II drugs and for follow- ing prescribing patterns. In addition, we follow the data from the Drug Abuse Warning Network-DAWN-which is operated under joint contract from PEA and NIDA. FDA depends on PEA for special reports to identify abuse problems with specific drugs. Such problems may be recognized by PEA agents in the field or through their regional laboratory analyses or through monitoring the output of the DAWN system. Furthermore, NIDA has a substantial program to monitor licit and illicit drug use through general household surveys and through surveys of special populations-for example, high school students-monitoring hepatitis rates, and compiling drug use data on patients in treatment programs. Special demonstration projects or indepth reviews are also the. subject of studies at various times. In- formation from all of these sources can be extremely useful in evalu- ating the extent of abuse associated with any given drug. CURRENT STATUS OF ANOJtECFIO DRUGS Mr. Chairman, 5 years have passed since the amphetamines and pheimwtrazine were placed in schedule II, arid 3 years have passed since the FDA's anoi-ectic review and the placing of the remainder of these drugs in schedules III or IV. It is appropiiate that we review at this time the effect of these important Federal actions on the use and abuse of these drugs and ask ourselves whether progress has been made, whether that progress is sufficient, and, if not, what further rnightbe (lone in the future. I would first like to discuss the effect of these actions on the pie- scribing of anorectic drugs as measured by the nun ber of prescrip- tions filled in pharmacies. Appendix I shows the prescribing trends for anorectic drugs from 1964 to 1976. During the period from 1971 through 173 there was a particularly dramatic decline in the pre- scribing of amphetamines. Senator Nnsoi~. Let me interrupt you for 1 minute. Did we settle the fenflurainine question? Dr. Cuout Its effectiveness is essentially equal to all of the other tlru~s in the class. Senator Nn.sox. You said that you would rely on the DELV to deter- mine whether it is addictive, or whether it is being used in the streets? Dr. Cnon'r. Ys This was a major period of Federal action. The number of manu- facturers of these drugs also dropped considerably during that period. Since 1973 the usage of amphetamines has remained fairly constant at a rate of about one-fifth that of the peak year in 1005. The non- amphetamine unorectie drugs have increased in popularity since 1971 and are now prescribed roughly twice as often as the amphetamines. `Die rate of prescribing of the wholeS class of anorectic drugs is today approximately 60 percent of the peak rate in the mid-1960's. Senator NELSON. Are not a number of those anorectics in schedules III anti IV just as addictive as the amphetamines? Pr. Cium~i'. Potentially so, although perhaps not so much. PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14585 I tlnnk when on get to schedules ITT and IV, you will see some ]ntercsting data on that point. Senator Nnsox. All right. Dr. GROUT. I think the answer is that we are hopeful over the long term it will turn out to be true that there are members of this class that are substantially less addictive, and less attractive to abusers than amphetamines. Senator Ntrsox. have sonic stitdiesbeen doneon that? Dr. Cnotn. Yes; that was the philosophy behind putting them in schedules III and flT instead of in II originally. Senator NELSON. It had been my impression from some of the testi- mony that there were serious questions about these drugs being addictive. Are they all central nervous system stimulants? Dr. GRoUT. All potentially, yes, but drug abuse is a funny business, where von frequently have to find out what happens in the street to know the answer to the question. It turns out there are consumer preferences, if you will, among those who abuse drugs, and in a real sense that test is more useful than some of the labor~atory data we get in smaller studies. Again, these are among the issues we are discussing with DEA. Senator Nr.rsox. But there are seine differences between some drugs, perhaps like fenflurainine, which may not be addictive and which is a depressant. According to the physician front Canada, patients did not like it, and when you have two drugs that are competing, or three or four in the street. and one is highly preferred, it is just a difference between one ordinary brand and another that. has more appeal. And then if (he other three are no longer on (lie street, what hap- pens about this one that has the less appeal? i\fr. Vonn.~. There are side effects that make them more or less attrac- tive. When we surveyed in 1073 about anoreetic control, we talked to street users, and they termed one of the congeners "raunchy ~ppp~,'~ "stuff you use only when you run out of good stuff," and "it is really the dregs." They do not like some of these things. They will use them only if nothing else is availal,le. Senator NELsON. That is the point I am asking. You are impressed by the figures that amphetamine. use has gone down, and the congeners have gone up. i'\Ey question is not whether amphetamines are prefer- able to the use of congeners, hut whether or not they are addictive. If, in fact, that is the only one, that is the question that has to be answered, because if that is the only one available, and it is addictive, it will be used. Dr. GRoUT. Yes; let's go on perhaps to the next paragraph, which I tliinlc will he of interest to this question. I would now like to turn to the issue of abuse of the anorectie lri gs. Before doing so, however, I must emphasize the limitations of the data currently available for uresentation. As I previously noted, an analysis of the abuse potential and actual abuse of the anorectics is underway by DEA, and we look forward to receiving their findings. My comments today are, therefore, based only on gross data from the DAWN system. By the way of background, the DAWN system PAGENO="0164" 14586 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lists "mentions" of a drug during the contact of an individual at cer- tain crisis centers-including "hot Lines"-emergency rooms, and medical examiners or coroners offices throughout the country. The "mention" of a drug can thus range from a telephone call to an overdose death. It should also be noted that "mentions" of drugs fre- quently occur in combination. A specific drug is not necessarily the cause of the episode. For example, if amphetamine is mentioned in an emergency room contact, the person may have, as his primary prob- lem, an overdose of heroin hut may also have taken an amphetamine. More sophisticated analysis is thus necessary before a full picture is available of the societal problems associated with anorectic abuse. With these limitations in mind, I would like to refer to appendixes Hand III to make two basic points. Appendix TI is a bar graph which shows the ratio of total mentions of anorectic drugs in the DAWN system from July 1973 to December 1975, divided by the number of prescriptions for these drugs during this period. Senator Nasox. What are the years? Dr. CEOUT. That is the total. We took all yeats lumped together, 1973 to 1975. The bar graph for amphetamines is the total number of DAWN mentions during the years 1973, 1974, 1975, all lumped to- gether, divided by the number of prescriptions for these drugs during this 3-year period. You can see the left bar graph relates to amphetamines, the next one to Preludin, and then at the bottom, the other drugs in the class. This ratio can he considered as a crude index of the degree of abuse, that is, total DASYN mentions, per given amount of drug dispensed through legitimate sales at the pharmacy level. Mr. GoRDoN. Dr. Crout, DAWN includes only the people who appear in clinics or emergency rooms, and that does not necessarily reflect who is abusing the drug; that is, how many people are abusing the drug. Many people who abuse drugs do not go to these places. `l'he abuse them in their homes, and they do not go to clinics afterward. Dr. CROUT. This is again the ony quantitative index of drug abuse going on in the country today on a national basis. It is not. meant to in- clude all episodes, but it ought to he a reasonable index of the amount of drug abuse activity going on. Mr. VonmtA. I think there is another point about DAWN data. I you look at the population of abusers and users of the central stimulant nervous system drugs, and assume that only a portion will go to points that will get them into DAWN collecting network, this is no reason to suspect a higher proportion of amphetamine users over other stimulant drug users will go into the DAWTN system. Thus, if a proportionate number of people who are abusing each of the anorectics are coming in, then at least DAWN does give, you from among that sample, a relative difference of levels of abuse among the various preparations which is shown in bar graph 2. Mr. GoRDON. It only tells us about those who get sick enough to go to clinics? \Ir. Vonmu. That is right, but this is no reason to suspect an anipheta- mine user will get more sick than a user ?~ diethyipropion or any other anoreetic, if the pharmacology is fairly similar. PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14587 Dr. Cnou'r. There are other sensing systems in our society that pro- vide estimates of the degree of drug abuse. - The National Institute on Drug Abuse has information on data from household surveys, and surveys in schools, and that is among the infor- mation we want to gather. 1 cannot present those data today. In any event, I think it is fair to say, having pointed out the limitations, that the total number of DAWN mentions is an index of abuse, street abuse in our society. Senator NELSON. Just one second. What do the ratios mean on that chart? Dr. Cnou'r. These are total mentions of abuse divided by total dis. ribution of drugs during that period. Senator Nasox. Total distribution? Dr. CROUT. Total DAWN mentions, total incidence related to abuse, divided by sales of drugs during that period, so a tall bar means for any given amount of sales, more drug abuse. Senator NELSON. I see, but that ~~`ould not tell you anything about one, if there were one, that was smuggled into the country from Mex- ho, you would not k-now, would you? 1),. Cnout No; that is one of the variables not reflected in this figure. I believe DFA will tell you, how-ever, that today most of the do- mestic amphetamines do not conic from across our borders. It is legally manufactured and prescribed. Senator NElsoN. OK. Dr. Crtot'r. Both the numerator anc denonunator of this index are sul)Ject to considerable error, as I mentioncd. Ncvertl eless, even this rough approach is revealing. Appendix IL clearly shows that the amphetamines, including meth- amphetamines, and, to a lesser extent, phenmetrazine, are associated with more contacts with the DAWN system per amount of sales than are other anorectics. Here you can see all of the other drugs clustered together. This graph in appendix III illustrates the second point I wish to mako. The graph again shows tim ratio of total DAWN mentions, this time. by quarter years, divided by the number of prescriptions for these drugs in the comparable quarter. The anorectic drugs in this appendix have been grouped somewhat differently-that is, by their schedules under the Controlled Sub~ stances Act. I point out along the bottom line, this isa time trend during 1973 through 1975. Tli~ main conclusion suggested by this graph is that abuse problems are greater with the schedule II drugs than with the other anorectics, as shown by the line at the top, and that the rate of such problems ap- pears relatively unchanged over the past 3 years. Senator NELsoN. And you are saying at the same tine that the studies indicate that the nonamphetamine anorectics and the ampheta- nine anorectics are about equally efficacious? Dr. Cr~ou'r. Yes. Senator Nrr.sox. Roughly as trivially efficacious, I will put it, and that the abuser- Dr. CR0UT. Fair enough, sir. PAGENO="0166" 14588 coi~wETITwE PROBLEMS IN THE DRUG INDUSTRY Senator NnsoN. All right. We will leave itin the record. We have got to win one once in a while, and so your chart shows there is a mitch higher abuse-potential of the amphetamines used for the sante purpose? Dr. CuouT. Yes, sir. Senator Nursox. This is a very convincing case. If they are roughly equivalent in terms of their trivial effectiveness, then it would appear that something ought to be done about the amphetamines? Dr. CR0UT. Yes, sir. Mr. Vomtt. It also indicates, Senator, that there is, for whatever reason, a significant difference in the response of the "abuse coin- nuinity." Senator Nasox. Roughly what? i\Ir. V0DRA. A major difference in response of abusers to the sched- tile II anorectics, that is amphetamines and phendimetrazine, over tire other drugs. This is the point I was suggesting earlier: For sonic reason we have not determined, the abusers prefer amphetamines by a wide margin. They have stated this preference in the illicit market for the scheduled anorectics. Amphetamines remain the problem area. Dr. Cram'. [Reading.] CONCluSIONS AND PLANNED ACTIONS i'c Er. Chairman. I would like now to state our present regulatory position in regard to the anorectics and to indicate our plans -for future actions regarding these drugs. The anorectic review' of 1972 demonstrated that all these currently marketed drigs meet appropriate standards of e1Tectiven~ss under the Federal Food, Drug, and Cosmetic Act. On the basis of the informa- tion available at that time, FDA also determined that this class of drugs meets the safety requirements of the act and are, on a benefit- risk basis, appropriate for marketing for the indication of obesity on a short-term basis as adjunctive therapy. The most stringent controls possible under Federal law have been in place for 5 years on those drugs which demonstrate greater abuse risk than the others, and the remainder of the class of anorectic drugs lies been controlled under other schedules oft] ie CSA for 3 years. Recent information indicates, however, that the schedule II an- orectics-amphetamine, dextroaniphetamine, methamphetamine, and perhaps phenmetrazine-have continued to be abused at a relatively unchanging rate over the past 3 years. While there is considerable opinion that the current rate of abuse of amphetamines is well below that of the late 1960's, there is also evidence that the regulatory inca- sures taken in the 1971-73 period may lìave accomplished as much as they are going to accomplish. It also appears that the major residual problems of abuse and misuse involving anoreetic drugs lie with those already in schedule II and not those in schedules 111 and IV. If the information currently being developed by DEA clearly in- (lieates, as we anticipate it will, that amphetamines remain a major cause of abuse in spite of being in seliednle II of the CSA, FDA will move ahead vigorously to withdraw the indication for obesity from implietanimnes. We need to be sensitive to the other indications for which these drugs arc used-narcolepsy and minimal brain dysfnnc- PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG iNDUSTRY 14589 tion in chuldren-but we must also recognize there are alternative drugs for these indications. I cannot predict at the present time wlie- ther any new regulatory action in regard to amphetamines would involve simply removal of the indication for obesity or complete with- drawal of the drugs from the market. Neither can 1 predict whether phenmetrazine might be involved in any such action. Answers to these questions will depend on the extent of documented diversion and abuse with these agents found by PEA and the judgments of those on our sd- entihc staff and advisory committees who will review the data. I would again emphasize that a report from DEA and additional data. from the National Institute on Drug Abuse are necessary for FDA to take a strong legal position, and our staffs are working to- gether on this matter. The withdrawal from the market of a previously approved drug on the basis of its risk to society, as well as to the patient, is an innova- five position on which there is little legal precedent. But we believe such a position is legal and are prepared to defend it. While the preliminary data available to us do not appear to indicate an important public health problem with the schedule III and IV anorectics, we will, as part of our review consider these drugs also. Again, on the basis of careful consideration of data from our sister Federal agencies and the medical research community, we will take whatever action on these drugs is indicated. Such action might range from recommendations for rescheduling to improvements in the label- i ig. I do not anticipate at the present time, however, any new review for effectiveness comparable to the anorectic review of 1072. In view of the importance of obesity as a national nutritional problem and the lack of any widely accepted, universally effective alternative therapy, we do not think it medically appropriate to question at this time the marketing status of those anorectic drugs now in schedules III or IV. I would also point out that the Food and Drug Administration has underwa two major programs which will ultimately affect many prescription drugs including the anorect-ic drugs: The prescription drug labeling review and the patient package insert proposal. In the ver near future, we will issue final regulations on the format and context of package inserts for the physician and, over the next several rears, all prescription drug labeling will come into compliance with these regulations. Various drug categories will be taken on a priority basis imder this program, and we consider anorectic drugs as properly among the priority drugs. We also anticipate issuing in 1977 proposed regulations relating to patient package inserts for prescription drugs. This proposal will un- doubtedly stimulate- extensive public comment and may ~veIl require another year or more for development of a final order. It is our intent to develop patient package in~erts for specific drugs only in the context of this general statenwnt on policy and procedure. In specific cases in which the public health requires a patient package insert on a prescrip- hon drug, for important safety reasons, we will take such action on an ad hoc basis as we have for oral contraceptives and estrogens. For most drugs, however, we believe- it is wiser to develop general policy ahead of specific patient labeling. WTe, therefore, anticipate at the present time that specific patient labeling for anorectic drugs will not be devel- oped hi (lie near tern. PAGENO="0168" 14590 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Finally, I would comment that whatever future action we in FDA might take in regard to this class of drugs, some degree of abuse may well continue. Clandestine manufacture and smuggling across inter- national borders will remain a problem. Even if amphetamines are removed from the market, other stimulant drugs will remain available and abuse of these agents may grow. The abitseof stimulant drugs willl thus remain a matter of continuing concern, and its control will require sustained vigilance from all of us. Drugs of this type are intrinsically attractive to a segment of our population and, at least for the foresee- able future, will remain so. Control of the abuse problem in our society will require the con- tinuing effort of many patties, as these hearings have made clear- physicians, pharmacists, the drug industry, education, and law en- forcement agencies. FDA is proud of its record in the past in handling the anorectic drugs, and we look forward to maintaining that record in the future. Thianlc you. Mr. Chairman; this concludes my formal statement. My staff and I would be most willing to answer any questions you may have. Senator ~\ELsox. rillaul you very macli. What does the FDA plan to do about these drugs; whether to leave the amphetamines on the market as they are, whether to remove them entirely; or change the labeling so the indicated use may itot include obesity? Dr. Cron'. I think we will have to lie imprecise on that. The PEA is helping us, and we are dependent on that information. I think we will have to review with our advisory committees, or at least with our consultants, tile two indications of narcolepsy and hyper- kinesis due to minimal brain dysfunction in children, because much depends on whether amphetamines are. needed for those uses. I think we can get our opinions in order on that within a number of weeks certainly. We expect it will be several weeks before we hear from PEA, and I am sure it will be a number of weeks after that before we go through tin advisory committee procedure on those issues. How soon an action can be taken would depend on the industry response and the legal processes, what hearings are required, whether there is court review, and so on. That is simply impossible to predict. Senator NnsoN. The court review would not occur until sometime after a ruling has been made. My question. is in regard to the time when a conclusion is expected to be reached. Dr. CROUT. I think with this, we can reach a conclusion within a matter of some weeks, as I mentioned. I think a regulatory action is impossible to predict. Whether hear- ings are required or not 1(10 not know. Senator Nnrso~c. Chart 8. shows the much higher incidence of drug abuse of amphetamines than the anorectic congeners. Given the conclu- sion which, I understand to have been reached by Dr. Crout's testi- mony, that they have about the same amount of effectiveness, what is the legal problem in saying that since in the marketplace there are available a number of nonainphetamine congeners which are as effec- tire for purposes of controlling obesity, and which are not as addictive, PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14591 what is the legal problem in saying that we will remove the indication for obesity? What is the legal question? Mr. MEIUULL. If we assume the state of facts as you assume them,I tiunk we would remove that indication of the drug on the ground it is not shown to be safe in relation to its benefits. I would suspect when we proceed to do that, the manufacturers will probably begin to cross-examine in somewhat the same way Mr. Gor- don did a moment ago. We want to have in hand the backup evidence that makes the facts real. In terms of legal authority we should have no problem; the problem is the procedure. Senator NELSON. I will submit for the record some letters, two from Delco Chemical Co. to doctors. It is pretty clear to see that the promotion is very strong. I would just like to read these: The enigma confronting the practitioner today Is his Inability to substantially increase his income from a level which Is determined by the number of hours in a dny and his physical stamina. Extend himself as be will, the added monetary rewards are discouragingly small. There is a means of coping with this seemingly hopeless situation which has been instrumental in doubling, tripling and quadrupling many practices formerly bogged down In lethargy. The products offered by Delco Chemical Company have made of many phy- sicians key men in the anti-obesity field. Their practices have been built rapidly and either have augmented or supplanted entirely former specialties. The rise In Income Is almost unbelievable and the added effort minimal. The most important factor responsible for this is a therapeutically efficacious product which has been used successfully Ia combatting obesity, a growing prob- lem In our affluent society. If you are Interested in a substantial increase of income may we suggest that you return the self-addressed stamped post card to us and our representative will be happy to call upon you at your convenience. We are the prime suppliers of obesity products which have been proven highly successful to the key men in your area as well as throughout the entire country from New York to hollywood. These physicians enjoy Incomes of $100,000.00 to $300,000.00 yearly. Also, we supply Obstetricians, Gynecologists, Internists and General Practi- tioners who have incorporated weight control into their practices and have added $23,000.00 to $100,000.00 to their incomes yearly. The products offered by Delco Chemical Company have made of many phy- sicians key men In the anti-obesity field. The most important factor responsible for this is a therapeutically efficacious product which has been used successfully in combatting obesity, a growing problem In our affluent society. If you are interested In a substantial increase of income, may we suggest that you return the self-addressed no postage required post card to us and our repre- sentative will be happy to call upon you at your convenience. We have a number of other letters along this line which we will put in the rccord.1 Thank you, Dr. Crout, for taking your time. Dr. CE0UT. I should like to share your nausea listening to those letters. Seiiator NELSON. Thank you. Mr. Gordon, please proceed. Mr. GoRDoN. Doctor Crout, with respect to Eskatrol and Deramyl, why are they still on the market? Eskatrol should have been taken off the market a long time ago. What is the problem? Dr. Cnou'r. Those two drugs are part of our whole DESI review, and the issues with those two drugs relate to their effectiveness. 1 see materials supplied for the record by Senator Nelson beginning at p. 14075. 85-569 O-77-----12 PAGENO="0170" 14592 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY We have more than a hundred hearing requests on drugs like that, and these are two of them. Perhaps the hardest job we have to do from the standpoint of just plain slow work is to handle hearing requests, and particularly when safety issues are not at stake, we treat them with a low priority. That is the reason for the delays. These two drugs are not delayed any longer than any others in that whole group. Senator NELSON. When do you estimate you will be acting on these? Dr. CRotrr. On Dexamyl we have denied a hearing, but have stayed the final order pending judicial review. Perhaps Mr. Merrill can com- ment on that, I think a final order on Eskatrol, we are hopeful of get- ting out reasonably soon. I think I would rather put our work on the amphetamines in gen- eral. Obviously, if amphetamines, in general are removed from the market, that would overtake these two actions. Mr. GORDON. Thank you. Senator NELSON. Thank you very much. We appreciate your taking time to come. Dr. CROU'r. Thank you. Senator NELSON. I have a long-distance telephone call that I have to make before noon. Since I am on a diet myself, we will adjourn for 10 minutes and resiune the hearings. We will recess for 10 minutes. { Whereupon, the subcommittee was in short recess.] AETER RECESS Senator NELSON. The subcommittee will resume its hearings. Our next witness is Mr. Frederick A. Rody, Acting Deputy Direc- (or, Drug Enforcement Administration, Department of Justice, Wash- ington, D.C. Mr. Rody, you are welcome here, and I appreciate your taking time to come. Your statement will be printed in f till in the record. You may present it however you desire, please identify for the re- porter your associates. so that whatever comments they have to make will be accurately attributed in the record. STATEMENT OF FREDERICK A. RODY, JR., ACTING DEPUTY DIREC- TOR, U.S. DEPARTMENT OF JUSTICE, WASHINGTON, D.C., ACCOM- PANIED BY ROBERT I. ROSTHAL, DEPUTY CHIEF COUNSEL; KENNETH A. DURRIN, ACTING DIRECTOR, OFFICE OF COMPLI- ANCE AND REGULATORY AFFAIRS; ERNEST A. CARABILLO, YR., CHIEF, REGULATOItY SUPPORT DIVISION; AND GERALD VOYLES, SPECIAL AGENT IN CHARGE, LUBBOCK, TEL Mr. Rent. Thank you very much. Mr. Chairman. Mr. Chairman and distinguished members of the subcommittee, my name is Frederick A. Rody, Jr., and I am the Acting Deputy Adminis- trator of the Drug Enforcement Administration within the Depart- ment of Justice. PAGENO="0171" COMPETITWE PROBLEMS IN TEE DRUG INDUSTRY 14593 Today, I am appearing before you on behalf of Mr. Peter B. Ben- singer, our Administrator, who `is presently out of the country on official travel. Appearing with me are Mr. Robert J. Rosthal, Deputy Chief Coun- sel; Mr. Kenneth A. Durrin, Acting Director of our Office of Com- pliance and Regulatory Affairs; and Mr. Ernest A. Carabillo, Jr., Chief of our Regulatory Support. Division. The Controlled Substances Act creates a partnership between the Attorney General and the Secretary of Health, Education, and Welfare. The Attorney General is empowered to place a drug tinder control of the act, to remove a drug from control or to move a drug from one schedule to another schedule. To exercise tins power, however, the At- torney General must have the concurrence of the Secretary that the contemplated action is medically and scientifically correct. The law states that the recommendations of the Secretary on medical and scientific matters are "binding" on the Attorney General and if the Secretary recommends that a drug not be controlled, the Attorney General cannot control it. As the. subcommittee has requested, I will briefly outline how that partnership has worked in the area of stimulant drugs. The Controlled Substances Act, as it related to the stimulants, rep- resented a congressional compromise under wInch Congress originally placed liquid injectable metliamphetamine "speed" in schedule II and the amphetamine and nethamphetamine in schedule III. How- ever, it was clearly understood by the managers of the legislation for the House and the Senate that "proceedings will be initiated-by the Attorney General-involving a number of drugs containing amphet- amines after the legislation has become law." DEA's predecessor agency began a study of the abuse potential and actual abuse of the amphetamines and methamphetamine then in schedule III and in February 1971, forward the results of its study to hEW7. In April, IIEW~ agreed that the amphetamines and metham- phetamine belong in schedule II and on May 25, 1971, we proposed in the Federal Register that the rescheduling take place. Thirty days were given for objections by interested parties. Three major manufacturers filed objections: (1) Smith, Kline & French Laboratories requested a hearing on the transfer of its product, Eskatrol; (2) Mission Pharmacal Co. requested a hearing on the transfer of its product, Fetamin; (3) Pennwalt Corp. requested a hearing on the transfer of its product, Biplietamine. On July 7, 1971. all amphetamines and mnethamphetamine, with the exception of the.three dnmgs for which hearings had been requested, were ordered transferred from schedule HI to schedule TI. As to these three, application of the order was reserved pending a review of each drug and subsequent administrative hearings. Our review began with service of a subpena on Smith, Kline & French which in effect cailed for every piece of relevant information the company possessed on Eskatrol. Subsequent to that service, SKF, Mission, and Pennwalt withdrew their objections and requests for hearin~s and by Federal Register notice of August 19, 1971. their drugs joined the other am- phetamines in schedule II. PAGENO="0172" 14594 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY Mr. Chairman, let me digress for a moment to note a fact important to the purposes of this subcommittee. In our efforts at that time to place the most rigorous controls on the amphetamines we received the support of the American Medical Association. Through its house of delegates, the AMA expressed approval of the rescheduling and urged "all physicians to linut their use of amphetamines and other stimulant drugs to specific, well-recoanized medical indications." It was early recognized &at if our efforts to place the amphetamines in schedule II succeeded, a new danger to the public niight arise. Two drugs-phennietrazine-Prelndin-and niethylphenidate-Ritalin- had been placed in schedule III by the Congress. These drugs, while not true amphetamines, have been described as "amphetamine-like." It was considered highly possible that should amphetamines be moved to schedule II with its stringent controls, there could be a movement by drug abusers from the amphetamines to R.italin and Preludin. Ac- cordingly in April 1971, we sought the position of HEW on whether we could properly place these drugs in schedule II. On July 29, 1911, HEW approved that rescheduling and negotia- tions began with representatives of tlìe Ciba-Geigy Corp., then manu- facturer of both products, and Boehringer-Ingelheini Ltd., owner of the U.S. patent on Preludin. It was the purpose of these negotiations to reach an agreement on placement of Ritalin and Preludin in sched- ule II without the need for lengthy liearings The companies ultimately agreed and, on October 28, 1971, Ritalin and Preludin were placed in schedule II. Turning now to the nonamphetamine anorectics-on February 15, 1973, HEW recommended tha.t seven of these drugs he placed iii sched- ule III of the Controlled Substances Act and one, fenfluramine, be placed in schedule IV. In Federal Register notices on May 9 and May 10, 1973, we proposed the precise scheduling recommended by HEW. Mr. G0RDoI'. What constraints resulted from placing the drug in schedule III and schedule IV? Mr. Bony. Basically there is little difference in the constraints be- tween schedules III and IV. There are some criminal sanctions as to trafficking that are greater in schedule III; however, the significant difference is that schedule IV drugs are considered to be less dangerous than schedule III, and there- fore this type of subtle difference certainly dictates to a certain degree the prescription and dispensing practices of doctors. Mr. GORDON. Dr. Crout, not in today's testimony, but in a document we are going to put in the record, says that schedules III and IV have little but psychological impact on the practice of medicine, requiring only a special symbol on the labels and labeling and a practitioner's BNDD number on the prescription. Do you agree with Dr. Crout that it does not have much effect on medcal practice? Mr. BODY. Certainly not as much as those drugs in schedule II. How- ever. PEA believes that NIDA and the medical associations should establish guidelines on prescriptions and dispensing practices. Senator NElsoN. What does that mean? Mr. BODY. Well, I think it would be to our advantage, in the enforce- ment of the Controlled Substances Act, to have established guidelines for use of doctors who dispense and prescribe drugs in their practices. PAGENO="0173" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14595 This would provide a peer influence within the rtrofessional com- munity, and also it would serve as a reasonable base for PEA's en- forcement efforts to be initiated wherever doctors fail to comply with recognized dispensing and prescription guidelines of the medical pro- fession. It would serve as a basis to prove abusive drug dispensing and prescribing practices. Senator NELsoN. Is it not the responsibility of the FDA to establish the indicated uses of the drugs, and does it not have the authority to approve or disapprove them? Whom are you talking about other than the FDA? `Mr. BODY. I am not referring to the FDA regulatory responsibili- ties. FDA determines the medical and science value and safety of drugs, not dispensing and prescription practices. I am referring to the practices of doctors and the suggested need for guidelines by the pro- fession as to what are medically recognized standards of application and how much or amount of drugs the patient should he given, and in what drug category. Senator Nasow. I guess I do not follow that. You are saying the medical associations establish these guidelines? Mr. BoDy. I am suggesting that guidelines be established by NIDA in cooperation with the medical associations. They have the profes- sional and medical experts, while PEA certainly has no regulatory authority on medical practice. We are suggesting self-discipline standards among those profes- sions. Senator NEr.sox. That is what I am trying to identify precisely. The indicated uses of the drug have to be demonstrated under the law. The FDA approves indicated usage of the drug. The indicated use of the amphetamine now is narcolepsy and the hyperkinetic syndrome, and control of obesity. The principal use of these drugs is for obesity. As I understand it what you are saying is that the doctors who are using it more extensively than the approved indications warrant or are using it for none of the indicated uses, are practicing bad medicine, or violating the law, or doing something. I am trying to get clear in my mind, what are you saying in addi- tion to that? Mr. Bony. I am having difficulty making myself understood. What we are suggesting is a professional forum, both in NIDA and in the. medical associations, that they establish the type of stand- ards that are acceptable to those people that practice medicine, as to tha degree of dispensin~ the drugs, and what type of drugs are to be used for those types of illnesses. Senator NELSON. Are you talking only about addictive or abused drugs? Mr. Bony. I think it would be applicable, in all drugs, that have any bad side effects. It would he certainly for those that are addictive or habit forming. Senator Nrtsox. But all the prescription drugs have side effects of snrne kind or other. I suppose. What I am trying to ~et clear in my mmd. are you suggesting that something beyond the Food and Drug Administration now has authority to do these things, that this be done by the National Institute of Drug Abuse. Mr. Bony. Yes, I am. PAGENO="0174" 14596 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Senator NasoN. Why, if the Food and Drug Administration is performing its function in approving the indicated uses of that drug, what in addition are you suggesting to that? Mr. Ro~y. Sir, I am not an attorney, and if I may, could I refer this question to Mr. Durrin? Senator NELSoN. Certainly. Mr. BritaIN. Senator, doctors have a fairly wide discretion and latitude with regard to indications for use on labeling for a particular drug. What the Drug Enforcement Administration is intending to do with regard to controlled substances, controlled substances only- Senator NELSON. You are only talking of controlled substances? Mr. Duxtaix. That is correct. It is to get the leadership in the medical community, and in the medical associations to set firm guidelines, per'haps analogous to `what is done in Suffolk County to set guidelines with regard to the discre- tionary uses for controlled substances among physicians, and we feel this kind of cautionary guideline from their peers will have a decided influence upon the prescribing practices of the vast majority of physi- cians in the country who want to do the right thing, who want to pre- scribe in the best interest of the public. Senator NELSON. All of that is within the authority of the FDA now, is it not? Mr. Dmuux. The Food and Drug Administration of course estab- lishes indications for use, but even beyond that in terms of the number of doses prescribed in given cases, in terms of whether or not the con~ dition of the patient in a particular situation necessitates the use of the drug, there are many discretionary areas that go far beyond in- dications of the use on the labeling of the drug, this is the kind of thing we have asked the medical community to give priority to in terms of guidelines. Senator NELSON. Why wouldn't they work that out with the FDA, and then the State societies, the medical associations, and all of the rest of them would help enforce it? Mr. DURRIN. Of course, we cannot dictate FDA's role, but it is our hope that all of these groups you are speaking of will engage in devel- oping these kinds of guidelines. Senator NELSON. Go ahead. Mr. BoDY. All right. No objections were received from such major manufactures of the anorectws proposed for schedule TIT as the TJ'piohn Co.-Didrex-. Warner/Chilcott-pre-State--TJSv Phannaceutical-Voranil-San- doz Pharmaceuticals-Sanorex-or Ayerst Laboratories-Plegine. No objection to the proposed scheduling of fenfluramine-Pondimin- in schedule IV was received from the A. II. Robins Co. Two major manufacturers filed objections: 1. Merrell-National Laboratories requested a hearing on the sched- uling of its product, Teniiate, in schedule III. 2. Pennwalt Corp., on the scheduling of its product, lonamin, in schedule ITT. The Merrell and Pennwalt hearing requests presented a grave policy issue involving fundamental fairness. All but these two companies had agreed to the ILEW-DEA scheduling proposals. If the products PAGENO="0175" COMPETITIVE PROBLEMS fl~ THE DRUG rxDUS'rRY 14597 of the cooperatin~ companies were scheduled by PEA while the Mer- rell and Pennw~it products remained uncontrolled during lengthy hearings, the economic inequity to the cooperating manufacturers and the danger that Tenuate and Tonamin would become abuse drugs of choice was obvious. Further, three of the anorectics, Voranil, Sanorex, and Pondimin, had never been on the U.S. market and had no domestic history of efficacy or abuse upon which scheduling comparisons with the Merrell or Pennwalt products could be made. Merrell and Pennwalt finally agreed to placement of Tenuate and lonamin in schedule IV pending the outcome of their hearings. This enabled us, on June 10, 1973, to place five of the anorectics in schedule III and fenfiuramine in schedule IV as originally recommended by IIEW. On July 6, 1973, Tenuate and Ionaniin were added to schedule IV. Clearly the resolution of the immediate problem did not resolve the permanent problem. We needed to know more about all the nonamphetarnine anorectics and recognized we could find less than satisfactory answers in isolated, fragmented hearings concerned with Tenuate and Jonamin. It was decided, therefore, to monitor the manu- facture, distribution, and use in the United States of all anorectics con- trolled in June and July 1973, paying special attention to indications of diversion and to chemical research on the abusability and depend- ence-forming characteristics of these substances. Senator NELSON. You mentioned the anorectics controlled ~n June and July 1973. Do you mean all of them that were under some schedule of control including III and IV, or those that were placed on a sched- ule in June and July of 1073? Mr. BoDY. All those that are under schedules III and IV, sir. Senator NELsoN. Go ahead. Mr. BoDY. DEA, after discussions with the National Institute on Drug Abuse and the Food and Drug Administration, began its re- review as scheduled. In addition to employing our own resources on. the monitoring pro- gram, PEA contracted in March 1975 with the Stanford Research Institute to assist in the development of a method to schedule drugs objectively. That study concentrated on the anorectics as models. W"e received the results of the Stanford study in April of this year. We have also received, under contract with the Research Planning Corp., the results of a study devoted in major part to identifying and quanti- tating abuse levels of the drugs in question. On May 13, 1975, PEA forwarded a letter to each major manufac- turer of a nonamphetamine anorectie drug asking information con- cerning the abuse potential of its particular product. On December 9, 1075 another letter to these companies requested manufacturing and distribution data. This massive amount of information has been re- ceived and is under review. Thus, the hearings of this subcommittee have come at a fortuitous time. The testimony given by the witnesses who have appeared here and the conclusions the subcommittee draws from that testimony, to- gether with the information we have been reviewing, will be closely considered by PEA in reaclung our judgments on the drugs in ques- tion. Then, as contemplated by the Controlled Substances Act, those PAGENO="0176" 14598 COMPETITIVE PROBLEMS IN TUE DRUG TNT)USTRY judgments and the supporting data will be forwarded to HEW through the Food and Drug Administration for the definitive medical and scientific evaluation. Mr. Chairman, it should be said at this point that HEW and FDA have always cooperated fully with DEA in those areas in which our responsibilities are joined. We could not ask for better partners. Mr. GolmoN. When are you going to make that judgment you just mentioned? Mr. Root. The judgment would be made by HEW. We cannot give you a firm date at this time. Hopefully by mid-De- cember we will be able to provide FDA with information on diversion and (1mg abuse. Mr. Goiwox. When will that be? Mr. RODY. 1-lopefully by mid-December, and we would also like to have benefit of the hearings, and if we may ask for an expeditious copy of the hearings. Senator NELSON. The hearings will not be printed. Mr. R0DY. Certainly that is what we seek. Senator NELSON. But the transcripts are available, if your depart- ment can afford it. Now, let me get your role straight. You will supply to the FDA all of the information that your Agency has gathered respecting abuse of these drugs, is that roughly it? Mr. R0DY. Diversion and abuse, yes, sir. Senator NELSON. Diversion refers to what? Mr. Pony. Well, that would be diversion of legally produced drugs, where they are either stolen. or otherwise illegally acquired from man- ubeturers. wholesalers or procurement. Senator NELSoN. We have had testimony by a witness who was him- self a drug abuser at one time, and he stated that without having been involved directly, or having firsthand knowledge, drugs were stolen by employees at the manufacturing level, and brought out in the mar- ket. In other cases employees in a physician's office diverted drugs. Does your agency have any information about how extensive diversion might be, for example, out of the manufacturing plant by employees, or from physician's offices! Mr. Pony. Yes, sir, we maintain data, both from our investigative actions and from the diversion investigatory units we have estab- lished. Diversion and abuse information is referred to the State regu- latory agencies in that State to take action whenever it seems to be appropriate. We also conduct an audit as to accountability at the manufacturing level, and wholesale distributor, and at the dispensing level. Senator NELSoN. How good are those controls? Do all of the manu- facturers make their own basic compound, the active ingredients, or do they buy it from a supplier, from other manufacturers? lYhat kind of controls do you have right from the source of production of the ac- tual compound itself? Mr. Pont. We have more accountability in schedule ir. the controls are more restrictive, hut if you would like more detail, Senator may we refer this question to Mr. Thirrin? Mr. Dumnx. We register the material down to the prescribing phy- sician, we have about 535,000 annual registrants on our computerized system at this time. PAGENO="0177" COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY 14599 In addition to the computer system, we maintain an investigative program whereby we inspect each manufacturer and distributor at least once every 3 years. If we find violations, we take action up to and including removal of registration, and we also take appropriate civil or criminal prose- cution. We have seen over a period of time since the effective date of the controlled substances act in May 1971, a very significant tightening up at the manufacturer-distributor level of the handling of drugs. .1 am not saying there is no employee dicersion, but it is a. much lesser factor in the total diversion picture than for example at the re- tail level at this point. Senator NELSON. As I recollect, Dr. Crout said that he would be re- lying upon your agency to supply evidence respecting abuse of the amphetamines, the anorectic congeners, is that correct? Mr. DuIRIUN. That is correct. Mr. Rout. That is correct, and the next portion of my testimony goes right into that. Senator NELSON. All right. Go ahead. Mr. Root. This subcommittee has requested information on the cur- rent patterns of abuse and diversion of antiobesity drugs. Three sources have been employed to gather the information I will sum- marize: First. The druff abuse warning network-DAWN--jointly spon- sored by DEA ana the National Institute on Drug Abuse, receives all drug mentions from selected emergency rooms, crisis centers, and medi- cal examiners throughout the Nation and publishes this information on monthly basis. Second. The system to retrieve information from ditg evidence- STRIDE-constitutes a compilation of reports on all drugs received for examination by all DEA domestic. and fereign laboratories. Third. A recent telephone survey of DEA's domestic regions, which includes information on audits, sales, and so forth. Mr. Chairman, there has been a 28 percent increase in DAWN mentions of amphetamines in the. last 12 months. The increase of chronic effects as the reason for seeking emergency help strongly sug- gests that ever greater numbers of abusers have access to a continu- ing supply of amphetamines. At the same time, our laboratories report the appearance of less illicitly manufactured amphetamines a.nd tl1ere are fewer reports of amphetamines being diverted from legal distri- bution systems. Accordingly, it must be concluded that increasing amounts of abused amphetamines come from home supplies and that these supplies are created largely by prescriptions and direct dispens- ing by physicians. The suggestion is implicit that significant numbers of physicians are prescribing and dispensing well over their patients' actual medical needs. Phenmetrazine-Preludin-has become a serions problem as a street drug in areas of the. Tjnite.d States ranging from Pennsylvania in the east to Nebraska in the. west. Pockets of heavy abuse appear in Texas. The District of Columbia and surrounding States have been pa.rt.icu- lady hard hit. In the District, for example, we find Preludin traf- ficked under the street name "Bam" at $10 for a single 75 milligram PAGENO="0178" 14600 COMPEfl'TIVE PROBLEMS IN TEE DRUG INDUSTRY dosage unit. Since Preludin is water-soluable it is frequently injected mtravenously and used in conjunction with heroin. Senator N aso~i. Is that one tablet? Mr. Bont. That is one tablet, sir, and right now I believe the price is about 19 cents. Senator NELSON. From the pharmacy on prescription, wholesale or retail? Mr. BODY. The 19 cents figure is the wholesale figu.re, but it is being trafficked on the street at $10 a unit.. Senator NasoN. What is the price of a 75 milligram tablet, average price on a prescription from the pharmacy? Mr. Itont About 25 cents, so I am told. Senator NELSoN. About 25 cents a tablet in the pharmacy, and in the streetit is$1O? Mr. R0DL That is correct. Senator NELSON. Where, hero in the District of Columbia? Mr. BODY. That is the indication we have from our investigation in the District. Senator NELSON. Is it similarly priced elsewhere in the country? Mr. BODY. We do not have that much indication of this particular drug being available in all of the other areas of the country; it has been confined to Pennsylvania, westerly out to Nebraska, but particularly here in the District we have had a large indication of usage. Mr. DmUUN. We have seen a price of as high as $15 for the 75 milli- gram dosage. Senator Nasox. That is one of the congeners, one of the ampheta- mine-related tablets? Mr. Bont That is correct, sir. Senator NELSoN. Is this one especially expensive, or is it the same price prevaiin~ for the amphetamines on the street? Mr. Bony. Sir, I would have to defer the question to Mr. Durrin. Mr. Dmuux. Let me just say it is a drug of choice among abusers. They particularly like this. It helps increase the effect of the heroin, and it is more popular than some of the other amphetamine-type drugs by comparison. Pricewise, it is certainly one of the higher priced, legitimate street products. Senator Nasox. Now, Preludin is in schedule II? Mr. Ront That is correct Senator Nrisox. Why did that go to schedule II, since it is one of the congeners? Mr. RODY. That was the result of our previous studies on diversion and abuse, and the data that we submitted to FDA. They in turn made that medical and scientific determination that Preludin should be placed in schedule II. Senator Nasox. Do you somewhere in your testimony, or do some of your associates have any statistics on the cost in the street of the amphetamines? Mr. BODY. We could certainly provide that to this committee. I am not sure if we have it with us at this time. Mr. RosniAt. We will make it available, sir. [Subsequent information was received and follows:] PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14601 STREET PRICES FOR AMPHETAMINE TABLETS The following is a breakdown of amphetamine tablet prices oti the illicit narket. Each listing is a range of prices for varying tablet sizes broken down by Domestic Regions. Region 1 Boston .30 - 1.00/3-iS mg. tablet Region 2 New York .50 - 3.00/3-20 rag. tablet Region 3 Philadelphia .75 - 1.50/3-15 rag. tablet Region ~ Baltimore .25 - 1.50/3-25 rag. tablet Region 5 Miami .50 - 2.00/5-25 rag. tablet Region 6 Detroit .25 - 2.00/5-25 mg. tablet Region 7 Chicago ..25- - 3.00/3.~25 rag. tablet Region 8 New Orleans .50 - 3.00/5-25 rag, tablet Region 10 Kansas City .20 - .50/3-10 rag, tablet Region U Dallas .30 - 3.00/5-25 rag. tablet Region 12 Denver .25 - 2.00/5-25 rag, tablet Region 13 Seattle .25 - .60/3-10 rag. tablet Region 1't San Francisco .25 - 1.00/5-15 rag, tablet PAGENO="0180" 14602 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY Senator NEr..soN. Please proceed. Mr. RuDY. The U.S. attorney for the District of Columbia has focused public attention on the Preludin problem here by highly suc- cessful criminal and civil cases involving physicians and pharmacies. Continuing investigations by DEA indicate the existence of sophisti- cated criminal enterprises employing prescriptions obtained from doc- tors and forged prescriptions to build street supplies. Thefts from pharmacies also play a part in supplying the illicit traffic in Preludm. In 1975 Western Fehr Laboratories, manufacturers of the. basic ingredient in Preludin, Ciba-Geigy Corp., the sole manufacturer of Preludin in dosage form, and Boehringer-Ingelheim Ltd., the sole distributors of Preludin to wholesalers, petitioned DEA for an increase in the 1975 manufacturing and procurement quotas for Preludin previ- ously set by DEA. That petition was rejected by DEA and it was again rejected by an administrative law judge following a lengthy hearing demanded by the companies. This resulted in an appeal by the companies to the U.S. Court of Appeals for the First Circuit which, on January 28, 1976, issued the final rejection. In a unanimous opinion, the court. found in part that, "PEA had the obligation when it found substantial evidence of broadscale diver- sion to achieve a more Spartan pipeline, even though this might cause inconveniences to manufacturer and distributor." Mr. Chairman, just 3 weeks ago, on October 29, 1976, attorneys for Western Fehr Laboratories and I3oehrinEer-Iugelheim Ltd.. filed with Administrator Bensinger objections to PEA's proposed 1977 produc. tion quota for Preludin. Once again an administrative hearing has been demanded by the companies. Mr. Goimox. On what basis are they demanding higher production quota? Did they come tip with evidence to show the medical need for these hi&ier quotas? Mr. RODY. Sir, I believe. tha.t question would have to be answered by those companies. Mr. Gomox. Don't they have to give a reason when they ask for higher quotas? Mr. DrRRIN. The request is based on projected sales, and, of course, we have our own yardstick in terms of measuring legitimate medical need, and sometimes we feel that the firms are a little bit optimistic in terms of projected sales of their product. Mr. GORDON. Projected sales, as we saw, do not necessarily equal medical needs? Mr. DURRIN. That is correct, and that is why we have a different opinion. Mr. RosnTAL. May I speak to that? I conducted the hearing and the argument in the court of appeals. The significant thing I found at the hearing was that the company in projecting its sales for the future years at no time ever considered how much diversion there was. They told us how- much they sold to doctors, and how much was presorihed. When they were asked on appeal, "Well. wbat about the diversion you know about, it is in the streets," they said diversion is DEA's business. PAGENO="0181" cO~ETITIVE PROBLEMS iN ~E DRUG INDUSTRY 14603 Making the drugs is ours they said. Now, that is a paraphrase, but very close. Mr. ROUI-. Methyiphenidate-Ritairn-differs from the other sub- stances tinder consideration here today. It is not indicated as an antiobesity drug. Rit.ahn is described as "effective" in the treatment of minimal brain dysfunction in children and in the treatment of narcolepsy, a form of sleeping sickness. It is considered "possibly effective" for mild depression. It is ironic that under the heading "Adverse Reactions" in the Physicians' Desk Reference the manufacturer of Ritalin warns against loss of appetite in children leading to "weight loss during prolonged therapy." Between July 1, 1973, and July 31, 1976, there were more Ritalin related abuse episodes reported in DAWN than any one of the 10 brandname amphetamines or nonamphetamine antiobesity products surveyed. The profile of Ritalin abuse is unlike the others. The great majority of die amphetamine and nonamphetamine anorectic reports conic from crisis centers, the usual haven for street abusers in various phases of iflness. Two-thirds of the Ritalin episodes were reported from hospital emergency rooms to which the more seriously ill are most often taken. Illicit sources such as street buys, forged prescrip- tions, stolen dosage units or gifts were listed in over half the episodes. 1~fr. Chairman, before summarizing the information on the non- amphetamine anorectics, let me say that one of them, fenfluraniine- Pondimin-may possibly be improperly described as a stimulant. Since coming on the market in 1973 fenllurainine has been reported as showing the indicia of a depressant causing sonic of the responses of an hallucinogen such as PCP. The nonamphetamine, antiobesity products have received far fewer mentions in DAWN than the amphetamines, Ititaliri, or Prehiidin. The anorectics are reported primarily from crisis centers as opposed to emergency rooms or medical examiners. Over 75 percent of the incidents involve legal prescriptions as the source. As with the amphet- amines, the suggestion is implicit that significant numbers of physi- cians are prescribing and dispensing well over their patients' actual medical needs. Mr. Chairman, Benjamin Gordon of the subcommittee staff has asked I)EA for a more detailed report on one nonamphetamine anorectic. lonamin. I have been told that Mr. Gordon's concern with this substance is not based on any known significant differences be- tween lonamin and most of the other nonamphetamine anorectics. Rather, Mr. Gorden's concern is predicated on the past history of the Pennwalt Corp., manufacturer and distributor of lonamin. In May 1971, as earlier noted, Pennwalt reqnested a hearing on the proposed transfer of its amphetamine product, Biphetainine, from schedule III to schedule II. That request was subsequently withdrawn and on August 19, 1971, the drug became subject to the Attorney General's power to limit manufacture by setting production quotas. Mr. Chairman, the dates in this matter are most important. Until some time in June 1971, Pennwalt exported to Mexico City large quantities of the resin complex from which Biphetamine is inanufac- tured. In Mexico City at a Pennwalt subsidiary, the resin complex was encapsulated and sold under the Mexican trade name Bifetamina. PAGENO="0182" 14604 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Within months, Bifetamina appeared on the illicit market in the United States. A special task force working tinder the code name "Operation Blackjack" established that the southeastern and south. western States were being flooded with Bifetatnina and that the drug was being smuggled into the United States at six principal points along the Texas-Mexico border. Pennwalt was ordered to show cause why its registration to export amphetamine products should not be revoked. The company chose not to contest the order and is now barred from exporting its amphetamine products to any part of the world. Mr. Chairman, the order to show cause in that case said in part, "the illicit importation of Bifetamina from Mexico and the sub- sequent illegal sale of Bifetamina in the United States substantially subverts the purpose of placing all amphetamines in schedule II." Senator NELSON. Who are the manufacturers in Mexico? Mr. Rent. Strasenburg, which is Peimwalt's subsidiary in Mexico. Senator NasoN. So Pennwalt was under court order? Mr. R05TILAL. We served them with an order to show cause as to why their registration with us to export amphetamine products should not be revoked, and why the total quota for all amphetamines should not be reduced by the amount of what we would take from them. We conferred with them, I think they knew we had the evidence, because they withdrew, so the order to show cause was withdrawn, and the company, as Mr. Rody has said cannot ship amphetamines from the United States to any part of the world. Senator NELSON. What was the legal basis of the Government in attacking the question of exportation. Mr. R0STIIAL. There was a myriad of enminal eases made all over the South and the Southwest. This stuff showed up at truck stops, and many criminal cases were made. The basis for the order to show cause was, Mr. Body had said in citing from the order, that they were subverting the entire purpose of the Controlled SubstancesAct. What they were doing in effect, Mr. Chairman, was conducting an end run. They had quotas in the United States, bitt they could make as much as they wanted in Mexico City. Senator NELsoN. But the quota in the United States at that time prior to the court order did not apply to exports? Mr. Bosnia. No; the quotas applied, I should have gone back on that. The quotas applied to what they could manufacture for everything, but what they had done in the. 2 years previous to our placing amphet. aminesin schedule II, a move which everyone in the industry knew was going to happen, was to ship large quantities, large quantities of the basic resin complex from their plant ia Rochester, N.Y. to their plant in Mexico City. Senator NELSON. Was the product made at that time in Mexico City, too? Mr. ROSTRa. No, the basic product, the complex was made in New York State. and shipped to Mexico City. As Mr. Body's testimony will develop, this was incapsulated, and they changed the name in Mexico to Biphetamina. PAGENO="0183" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14605 Senator NELSON. Although they may not export, are they manu- facturing the compound? Mr. BOSTIIAL. I do not think so, because I think the only thing that they are making now in Mexico City, or encapsulating in Mexico City is Jonamin, with the name of lonaminas. Mr. Chairman, I think Mr. Body's testimony does develop this. Senator Nn~soN. Fine. Go ahead. I did not get a chance to read it in advance. Mr. Bony. The history of Pennwalt and Tonamin has a similar be- ginning. In May 1973, as earlier noted, Pennwalt requested a hearing on the proposed placement of its anorectic product, lonamin, in sched- ule III. SYhetlier that hearing takes place will depend in large part on the results of REA's comprehensive review of all the anorectics which will include the report of this subcommittee. Meanwhile, lonamin remains in schedule IV. In 1975, Pennwalt exported to Mexico City 300 kilograms of the bulk powder from which lonamin is manufactured. Mr. Goimox. May I interrupt for just a second? You said 300 kilograms. As I understand it, Tonamin is made in two strengths, 30 and 15 milligrams; is that correct? Mr. Bony. That is correct. Mr. GORDON. If these 300 milligrams are manufactured in, say 30 milligram tablets, which is the strongest strength, that comes out to about 10 million pills, does it not? Mr. DURRIN. That is correct. Mr. GORDON. And if they manufacture it in 15 milligram grain tablets, it would come out to 20 million tablets? Mr. BODY. That is correct. Mr. GORDON. Are those pills for the obese people of Mexico? Mr. Bont. We would have to speculate on that. We do know from some of our investigative activities, it is a bit more than that. Thus faD in 1976, another 300 kilograms of that same bulk powder has been exported to Mexico City. In Mexico City, at the same Pennwalt subsidiary where Bifetamina was once produced the bulk powder is encapsulated and sold under the Mexican trade name, lonamina. Mr. Chairman, a report on the most recent survey of illicit sales of lonamin and lonamina will be forwarded to the subcommittee. [Subsequent information was received and follows:] PAGENO="0184" 14606 COMPETITIVE PROBLEMS ~ THE DRUG Th'DUSTRY INTRODUCTION lonanin is the brand nane of ~ generic drug known as phentermine. which is manufactured and marketed by Pennwalt Prescription Products, a Division of the Pennwalt Corporation, Rochester. New York. Cm February 15, 1973, HEW originally recomnended to BNDD that phentenain~ should be made a controlled substance in Schedule III. BNDD published such a recommendation in the Federal Register on Nay 9. 1973. However, in view of evidence which was presented in the resulting comments, PEA announced on July 6, 1973 that phentermine would be controlled in Schedule IV (not XII) effective on July 6, 1973. lonanin is marketed in capsule form, in strengths of either 15 lag. or 30 mg. Cumulative Supplement 2 of the 1976 Red Book indicates that the wholesale prices of the different product sales units are as follows: 15 mg. Capsules Bottles of 100 $13.19 Bottles of 400 $48.01 30 mg. Capsules Bottles of 100 $14.55 Bottles of 400 $52.71 tonamin has a pharmacologic activity similar to that of the prototype drug of this class used in obesity, anphetanine (both d and 1 ampheta- mine). Actions include central nervous system stinulation and elevation of blood pressure. Tackyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. Drugs of this class used in obesity are commonly known as "anorectics' or `anorexigenics". It has not been established, however, that the action of such drugs in treating obesity is primarily one of appetite suppression. Other central nervous system actions, or metabolic effects may be involved. - Whereas the natural history of obesity is measured in years, the available studies involving anorectic drugs are restricted to a few weeks.or months in duration. Thus, the total impact of drug- induced weight loss over that of diet alone must be considered clinically limited. PAGENO="0185" COMPE'TITIVE PROBLEMS r~ mE DRUG WDUSTRY 14607 Page two tonamin is indicated in the management of exogenous obesity as a short-term (a few weeks) adjunct in a reginen of weight reduction based on caloric restriction. The limited usefulness of agents of this class should be measured against possible risk factors inherent in their use. The following contraindications should be locked for before prescribing tonamin, - Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthy- roidism, known hypersensitivity or idiosyncrasy to the sympathonimetic anines, glucoma. Agitated states. Patients with a history of drug abuse. If tolerance to the anorectic effect develops, the recorrLnended dose should not be exceeded in an attempt to increase the effect, rather, the drug should be discontinued. lonamin nay impair the ability of an individual to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle. The 1976 edition of the "Physicians' Desk Reference" (PDR) warns that lonamin is related chemically and pharmacologically to amphetamines and other stimulant drugs which have been extensively abused. The possibility of abuse of lonamin should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. Manifestations of chronic intoxication with anorectic drugs include severe dernatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe nanifestation of chronic intoxica- tion is psychosis, often clinically indistinguishable from schizophrenia. STREET AVAIUSILITY In an attempt to determine whether or not tonamin is available on the street, ECI has collected information from the following sources; telephone survey of the Domestic Regions, STRIDE, DAWN, DRY's, the Import/Export Unit, and the Statistical and Data Services Section. 85-569 O-77-----13 PAGENO="0186" 14608 COMPETI7rVE PROBLEMS IN TUE. DRUG INDUSTRY Page Three TELEPHONE SURVEY The Compliance Program Manager at each of the Domestic Regional Offices was contacted on Wednesday, October 6. 1976, and he was recjuested to supply Ed with any available information concerning th~ Street avail- ability of Ionainin (or of the product lonamina, the brand name for the same product marketed in Mexico by Laboratorios Strasenburgh de Mexico). This data was to be collected from such sources as in-depth conpliance investigations, theft reports, seizures, street intelligence, and local enforcement agencies. - During the past twenty months, the total number of dosage units of both strengths of lonanin which have been reported to DEl as having been stolen or lost intransit is about 153,000 (or about 7.650 d.u. per month). This figure does not include the intransit losses reported by Pennwalt before January 1976. In reviewing the audit portions of those in-depth compliance investigations which included Zonanin as one of the drugs which were selected for audit, only five Regions reported any cases in which there was a deviation of more than ~ The largest single deviation was reported in a case in Region 6 (115-74-0043. dated February 18, 1975) in which. a shortage of 36,300 d.u. of lonanin (30 mg.) was uncovered. The total number of such investigations was twenty-seven. The most significant Compliance case to date is an ongoing investigation in Region 5 (G3-76-2020) in which a pharmacist in a small town in Georgia is believed to have diverted approxinately 96,000 dosage units of Ionamin since January 1975 (all of which were the 30 mg. strength). In their conversations with the criminal groups within each Region, the Compliande Program Managers found that there is little demand for lonamin on the street. Indications are that current street prices range fron a low of twenty cents a capsule in Georgia, to a high of seventy cents and $1.10 per capsule in Texas. The only significant seizures involving lonamin (or lonanina) occurred in Texas where approximately 90% of the 104,155 dosage units of anorectic drugs seized between July1973 and September 1976 were the Pennwalt products. PAGENO="0187" COMPETITIVE PROBLEMS IN Tilt DRUG INDUSTRY 14609 Page Four STRIDE/Ballistics During Fiscal Year 1976, DEA Laboratories analyzed a total of 68 e,thThits of phenterutine that could be identified to presumptive manufacturers or distributors, Of this total 85% (or 58 exhibits) were presumed to have been manufactured by Pennwalt. DAWN Of'the five anorectics analyzed (Preludin, Tenuate,' Ionamin, Tepanil and Pondamin), tonainin ranks third in frequency, Of the 110 episodes purported to have involved lonamin talcen for psychic effect or dependence, during July 1973 to July 1976, 70% of the reports showed' legal prescri~t*ions as the, source. - DIVERSION INVESTIGATIVE UNITS On October 6, 7, and 8, 1976, a limited survey of abuse of Ionaxnin and its generic equivalents was conducted by contacting each of the nine operating Diversion Investigative Units. The following comments reflect the recent experience of each of the nine DIG states. New Jersey DIG reports general, if somewhat United abuse of lonainin, Phentercot, and Fastin, in that order, but far less than the problem with Phennetrazine (Preludin) and Phendinetrazine. Massachusetts DIG reports very limited minor abuse, probably because Massachusetts' law classified phentermine as "an isomer.of Methanphetanine" (leaving out the word "optical" in the definition); and so lonamin is already classified by the state in Schedule "B", the highest available schedule for legitimately nanufactured 4rugs for penalty purposes. Michigan DIG reports no instances of lonainin use or availability in the state. This of course also applies to generic equivalents of Ionaznin/ phenterinine as well. DIG officials report heavy abuse of similar drugs, Phennetrazine and Phendinetrazine. Illincis DIG reports very limited minor abuse and availability of Ionamin; however Preludin (Phenmetrazine) and Ritalin (Methylphenidate) are heavily abused there and readily available. PAGENO="0188" 14610 COMPETiTIVE PROBLEMS IN TIlE DRUG INDUSTRY Page Five California 010 reports a complete absence of traffic in Ionarnin and in lonamina (the Mexican version of the same product) in both Northern and Southern California. The stimulant drugs of choice in that state are Desoxyn, Preludin and Eskatrol, in that order. North Carolina DIU reports moderate abuse of both lonastin and Fastin (a generic). DIU cases related to these drugs tend to be confined to prescription writing doctors "who feel more comfortable' writing for these rather than for more well known stimulants. Pennsylvania DILl reports heavy abuse of both lonamin and Fastin, probably because phenternine was not controlled under state law until August 21, 1976. DILl officials predict a gradual falling off in the popularity of these two drugs since they are now controlled. Texas DILl reports heavy trafficking and abuse of lonamina, the Mexican equivalent of lonanin, in all areas of the state adjacent to the Mexican border, and relatively cornon abuse elsewhere in the state. Except in the border areas, other stimulant drugs still lead in terms of abuse. Since July, 1973 and through at least April 1976, over 25 cases have been made involving tonanina, with seizures and purchases totaling over 104,000 dosage units. Alabama DIU reports exceptionally heavy trafficking and abuse in both lonanin of U.S. manufacture and Fastin. In calendar year 1975, 99% of all drugs purchased or seized by the 010 were lonanin. This phenomenal figure can be traced to a single 0~A cooperation case (J4-75-0016) where 500,000 dosage units were seized. In a related case (same source) the Georgia Bureau of Investigation seized 100,000 more. The responsible distributor (in Miami) surrendered his registration in lieu of prosecution. When the above case is renoved from the figures. lonamin still accounts for 35% of the total drugs obtained by the 010 that year. During calendar year 1976 (to date), 22% of the drugs obtained by the 010 were phenternine, which broke down further to 73% lonarnin and 27% Fastin (a generic). The Alabama 010 considers phenternine to be readily available and heavily abused, although amphetamine (when available) is still the drug of choice for abusers. PAGENO="0189" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14611 Page Six D~'0RT/EXP0RT The following data reflects the volume of tonamin (in its various forms) which has been exported by Pennwalt during calendar year 1975, and thusfar during calendar year 1976: 1975 Dosage Form Destination Total Quantity 15 mg. Capsules El Salvador, 214;810 Guatemala, Panama, - Costa Rica, Nicaragua 30 mg. Capsules About the same 508,800 countries Bulk Powder flexico 300 kilograms 1976 15mg. capsules El Salvador, 161,010 Guatemala, - Panama, Costa Rica, Nicaragua 30 ,og. Capsules About the same 353,870 countries Bulk Powder Mexico 300 kilograms Argentina 250 kilograms Mexico shipments to: Laboratorios Strasenburgh ae Mexico, S.A. de C.'?. Division del Norte 3442 Mexico 21, D.F. Mexico PAGENO="0190" 14612 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY Mr. boy. For the purposes of today's hearing, I will say that Jona- mm is a relatively minor problem in most of the United States. ilowever, in Texas we find heavy trafficking and abuse of lonamina in all areas of the State adjacent to the Mexican border. Since July 1973 through April 1976, some 25 cases have been made involving Jonamina, with seizures and purchases totaling over 104,000 dosage units. Mr. Chairman, that concludes my formal testimony; how-ever, I have with me Mr. Gerry Voyles, our special agent in charge, of Lubbock, Tex., who can provide an update on the status of lonamina. Senator NasoN. One question first. Concerning these 25 cases between July 1973 and April 1976, involv- ing 104,000 doses or units of Ionamina-you are saying that thcse drugs came illegally into the country? Mr. Root. That is correct, smuggled into the country. lonamina as opposed to Tonamin, which is domestically manufac- tured, that is correct. Senator NELSON. Now, in 1972, the FDA testified before this com- mittee that there was no difference between lonamin and the ampheta- mines with respect to benefit, risks and addiction. Is that correct? Mr. BODY. Sir, I do not have benefit of that testimony. Mr. BO5TIIAL. Yes, sir, that is correct. Senator NELSON. All right. Go ahead. Mr. GoimoN. I want to ask one question. Since lonamin is now being illegally imported from Mexico, and illegally sold in the United States as in the case of the amphetamines, why not do for Tonamina what you did for the amphetamines? Mr. BODY. Sir, we have had discussions with Pennwalt, and as recent as October 0, the president of Pennwalt communicated with DEA, and he offered full cooperation, even to the extent, if necessary of removing lonamina from the market in Mexico, and today we would be pleased to accept that offer. Mr. GORDON. That they will no longer ship to Mexico? Mr. Bont. That was the offer that was made, and we would be pleased to accept it. Senator NELSON. Do go ahead. Do you have another witness? Mr. Bony. Special agent Gerry Voyles. He is from Lubbock, Tex., office, and he adds significant insight due to his experience during Operation Blackjack, which I mentioned in my earlier testimony. Senator NELSON. Could you give the reporter your full name? Mr. VOYLES. Yes, sir. Gerald Voyles. Mr. Chairman, I was the field supervisor during Operation Black- jack during the years, part of the year 1971 and 1972. During that time we were making cases. criminal cases against illicit traffickers in Bifetamina, which is a product manufactured by Penn- walt. During that time, and during that investigation of Operation Black- jack as previous testimony has brought out, Pennwalt manufactured in the United States, and exported the bulk material to Mexico. It was then encapsulated in Mexico City, in Strassenburg, a subsi- diary of Pennwalt. PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14613 It was then sold, presumably through legitimate channels to phar- maclas on the Mexican side of the Mexican border. At that time, it was sold in the i]licit traffic, smuggled into the United States through the South, the Southeast, and Southwest, pri- marily, it appeared at tnick stops. The pharmacias were identified during Operation Blackjack, the tnick stops were identified, and many of the traffickers that were not apprehended were identified. It is at this point with lonamina, that we see a very deadly parallel. Tonamina is manufactured in the United States, it is exported to Isfexico, it is encapusulated in their plant in ~\texico. recent investiga- tions show that it has gone to the same pharmacias which we identified in 1971 and 1972, being brought into the United States, through the Southeast, the Southwest, and, again, we have very, very similar cir- cumstances, as we had with Biphetamina in regards to Tonamina, and at this time, we also brought with us Mr. John Myer, from our Chicago laboratory. Mr. Myer has brought an exhibit which he must maintain custody of due to the fact that this is still a criminal investigation, so at this time, we would like to show the chairman one exhibit from one case made in the Midwest Tjnited States, which is still under investigation. lYe have a suspected source identified, so if we could at this time- Senator NELSON. And these are all Mexican manufactured? Mr. V0nES. Mexican manufactured, yes. Senator NEnSON. It is all Jonamina? Mr. VOYLES. Yes, sir, and if you would like to have some comparison between domestic manufacture and 15.5. manufacture- Senator NELSON. They look identical. Mr. VOYLES. The only difference that we have on the Mexican manu- facture, on the capsule, it has RJS. On the U.S. manufacture, it has the Pennwalt logo. Senator NElsoN. How many tablets are involved? Mr. VonEs. This is one exhibit in a case. It is not the only exhibit. Senator NELSON. But this came in what way into the country? Mr. VonEs. This is a criminal investigation that was conducted by our office in Indiana. Senator NELSON. And this is all picked up in one batch? Mr. Von~s. Yes, sir. Senator NELSON. What is the street value of these? Mr. Vows. Sir, the street value runs approximately $1 to $1.50. Senator NEI.soN. A tablet? Mr. VonEs. Yes, sir, and we have roughly 20,000 dosage units here. Senator NELSON. And how much of this product has been picked up moving illicitly in this country in a particular period? Mr. VoyLEs. I cannot give you a definite answer on that. We have several exhibits, which have come into our laboratories of this product. I just cannot give you a figure. Senator NELSON. You do not have a total? Mr. VOYLES. No, sir, Senator NELSON. And this is all Jonamina? Mr. VonF~s. Yes, sir. Senator NELSON. Where does the compound start out? PAGENO="0192" 14614 COMPETITIVE PROBLEMS IN TifE DRUG INDUSTRY Mr. Vonzs. In the United States. Senator NasoN. And then it is sent in bulk? I'ifr. VOYLES. In bulk, and in Mr. Rody's testimony, he said I believe there were 300 kilos shipped this year. Senator NELSoN. And that is about 600 some pounds, I think a kilo is 2.2 pounds. Mr. VOYLES. A kilo is 2.2 pounds; yes. Senator NELsON. And that is how many, 300 kilos is how many tablets? Mr. VanEs. Approximately 10 million dosage units. Senator NELSON. You would make about 10 million? Mr. VOYLES. Yes, sir. Also, there is a couple of other points I would like to make. Where I come from. I have seen an example of lonarnina in Lub- bock. A very well-to-do, very respected woman was arrested in the latter part of September with 60 dosage units of lonamina. I cannot give you the details of the case other than I know it is still pending, the charges she was arrested on by the local police, but the point is this, that it is being abused. She would never think of going out into the street and buying a drug, yet she would go through the trouble to get a prescription. Senator NELSON. She had used it? Mr. VOYLES. Yes, sir. Thank you. Senator NELSON. Thank you very much. Mr. Vonr.s. We would like to seal this up now if we could. Senator NELSON. Certainly. Mr. Von~s. This exhibit in Operation Blackjack, we identified a pharmacia in Mexico. . Our intelligence information in the case is that this exhibit here of lonamina came from the same pharmacia as many of the exhibits we got of Biphetamina during Operation Blackjack. Senator NELSON. The same pharmacia? Mr. Vants. The same pharmacia. Mr. GoimoN. Would you care to guess how it gets from Pennwalt up to Indiana? Mr. VoyLEs. As far as getting from Pennwalt up to Indiana, it is manufactured in bulk in the United States, sent forward to Mexico City, encapsulated, sold ostensibly in the legitimate chain in Mexico. I do not have that information. I do not know, but at that point it is diverted from the legitimate chain. Mr. GoRDoN. Don't you think it is rather suspicious for so many tablets to be used in Mexico? Mr. VOYLES. I would think so. Senator NELSON. Thank you very much. Mr. buY. Yes, sir. Thank you. Senator NELSON. Anybody on the panel have anything to add to the testimony? Mr. bony. No, sir, Mr. Chairman, that concludes our testimony. Senator NELSON. Thank you very much. Mr. GORDON. Mr. Rosthal, did you want to s'iy something? Mr. RosniAL. No, sir. PAGENO="0193" cOMPE'rITWE PROBLEMS IN THE DRUG INDUSTRY 14615 Well, all I ask is, I understand that Mr. McGraw of Pennwalt is going to testify. I do not suppose that there is any objection if I re- mained to hear it? Senator NELsoN. You are free to remain and can comment on the testimony of Pennwalt's testimony, and if they have any rebuttal to your comment, we are willing to accept that. We will give everybody a chance for a full presentation, and full response in the record. Somebody better take those amphetamines away from in front of us. Mr. RosruAL. Simple possession, Mr. Chairman. It is only a mis- demeanor. [Laughter.] Mr. Gonoox. Mr. Rosthal, will you remain in the room? Mr. RosTiiAL. Yes, sir. Senator NELSON. One more question. For clarification-you do have a substantial amount of testimony or evidence as to diversion and abuse of amphetamines and the con- geners; is that correct? Mr. BODY-. That is correct, Mr. Chairman. Senator Nasox. And that will be presented at some early stage to the FDA? Mr. BoDY. That is correct. Senator NELSON. And you say sometime in December? Mr. BODY. Hopefully, I cannot give you an exact date, hopefully in December. We certainly would like to review, of course, some of the testimony that has occurred here. Senator NELsoN. Yes; and how would you describe the evidence you have, substantial, not substantial, overwhelming? Do you have a dese ipt.ion of the evidence of the abuse, of the use of amphetamines, and the congeners that are on the marketplace? Mr. Ront. Sir, I think it would have to be described as very sub- stantial. Senator NELsoN. Does that apply to those amphetamines and con- geners which arc being "legally prescribed" in this country through legal channels? Mr. BODY. That is correct. Senator NELSON. As well as diversion or illicit introduction into this country, is that evidence substantial too? Mr. Root. Yes, sir. Not to the same degree as it is on the ampheta- mines. Senator NELSON. And do you have evidence showing widespread use and abuse? Mr. BODY. Yes; we have data from our DAWN system which would reflect the number of episodes reported over the last 3 years in various categories of drugs. Senator Narsox. And you consider that to be substantial? Mr. Bony. It is reflective as being substantial, yes, sir. Senator NELsoN. Thank you very much. Mr. Root. Thank you. Senator NELSON. Our next witness is Mr. Isaac McGraw, president of the pharmaceutical division of the Pennwalt Corp. Mr. McGraw, could you please identify your associate for the record? PAGENO="0194" 14616 COMPETITWE PROBLEMS IN TIlE DRUG INDUSTRY Mr. McGaAw. Yes, sir. I have with me Mr. Matthew Broderick. Senator MisoN. All right. Go ahead, Mr. McGraw. You may present your testimony however you desire. STATEMENT OF ISAAC B. McGRAW, PRESIDENT, PHARMACEUTI- CAL DIVISION OF PEN~WALT CORP., ACCOMPANIED BY MAT- THEW BRODERICK Mr. BR0DERICIc. Mr. Chairman, I would like to state at the start that Mr. McGraw will be Pennwalt's witness. Mr. Head will not testily. I think I have so advised Mr. Gordon. Senator NELSON. All right. Mr. McGiuw. Mr. Chairman, at the request of your committee, I am appearing on behalf of Pennwalt Corp. pharmaceutical division in order to provide the committee with our comments on the subject of antiobesity drugs. As an introduction, in my appearance today on behalf of Pennwalt and its pharmaceutical division, I will review those major considera- tions which we believe to be responsive to this committee's invitation. In order that you may readily comprehend our views, I should like to summarize, them at the outset and then deal with them more fully by major cateanry. As part of Pen.nwalt Corp., a 126.year.old firm founded and still headquartered in Philadelphia, Pa., with annual sales of approxi- mately $750 million, we share its pride in our collective integrity. I should note that our division represents less than 10 percent of the company's total sales, and that our antiobestiy products represent less than 3 percent of total sales, with less than 1 percent in anorectic am- phetamine products. Senator NEr~sox. Gross sales? Mr. Moflnw. Net sales. Senator NELsoN. How do you define net sales? Mr. McGItAw. Sale less cash discount and shipping cost to the customer. Antiobesity prescription medicine is the only federally recognized effective medicinal aid available in a course of medically supervised `.nfobesity treatment available to tIme 30 to 40 million Americans who are obese, namely, those who are at. least 20 percent overweight. Obesity is a recognized illness, in medical terms, as well as an emo- tional burden. It also complicates other quite serious medical problems. Our pharmaceutical division clearly recocrnmzes that its anorectic products should not be used unless prescribed by a physician. We firmly believe that our marketing program fully reflects this recogni- tion and conta.ins no suggestion that we seek to sell the patient any use of our anorectic products. As this committee is aware, the Food and Unur Administration has found our anorectic products to he safe and effective and, in our judg- ment, we have continued to achieve very satisfactory compliance with the re~ulatorv standards and programs which are the responsibility of the Drug Enforcement Administration. PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14617 We believe that you should find the factual evidence on the prescrip- tion dosage units of our products, per patient, to be consistent with their use as a short-term aid to the medically supervised obese patient. We do not believe there is any probative evidence that our anti- obesity products show any meaningful statistical or other factual evi- dence of abuse. We recognize that in a population of 215 million Americans there is a very small but lughly visible segment who are troubled and who may be determined to misuse or abuse legitimate products. lYe believe, however, that the safety, effectiveness, and judicious pre- scription of antiobesity products cannot reasonably be condemned by the very limited factual evidence of their statistically quite infrequent misuse. The Congress and 42 State legislatures have created, and the FDA, DEA, and State agencies administer, monitor, and enforce sophisti- cated and effective programs designed to insure proper medically supervised use of anorectic products. We fully support these programs and cooperate readily with these agencies. We believe that a scientific, technical or legal analysis fully and fairly considered, on the basis of factual rather than hearsay evidence, will continue to require the conclusion that our anorectic products serve a very worthwhile medical and human need-assistance to the physician who finds that his patient requires this medication. I shall now turn to a more detailed review of the bases for the views I have just summarized. CORPORATE HISTORY Pennwalt Corp. was founded in 1850, in Philadelphia, where it con- tinues to maintain its corporate headquarters. Pennwalt has more than 14,000 employees w-ho are engaged in manufacture, sale, and distribu- tion of its products in the United States, Europe, and elsewhere in the free world. Pennwalt's total annual sales are expected to exceed $750 million in 1916, derived from its operations in chemicals-approxi- mately 50 percent_specialized equipment-approximately 25 per- cent-and health-including both dental and pharmaceutical opera- tions-approximately 25 percent. The pharmaceutical division has annual sales of approximately $70 million and employs approximately 1,100 people. PENNWALT's rIIAnMscnrrIcAL DIVISION The pharmaceutical division manufactures and makes available to the medical profession a variety of therapeutic agents including anti- hypertensives. diuretics, antianxiety drugs, local anesthetics, anti- fungals, antispasmodics, antitussives, and antihistaminics as well as anorectics. The total sales of Pennwalt's only amphetamine product. Bipheta- mine, are less than 1 percent of Pennwalt's annual sales, and the total sales of both Biphetamine and Pennwalt's nonamphetamine anorectic, lonamin, are less than 3 percent of Pennwalt's annual sales. PAGENO="0196" 14618 COMPE'rl'rIvE PROBLEMS IN T~ DRUG INDUSTRY Mr. GORDON. Mr. McGraw, according to the national prescription audit, the 1975 manufacture of sales of Biphetamines was $5,847,000, and lonamine was $11,712,000. These two drugs then account for about 26 percent of the annual sales of your pharmaceutical division, is not that correct? Mr. McGu.~w. Yes, sir. Mr. GORDON. In other words, these two drugs are very, very impor- tant to the total sales of your pharmaceutical division, and when you talk in tenns of 1,2, or 3 percent, it sounds small, hut to the pharma- ceutical division, these two drugs are very important; I want to bring that out. Mr. McGm&w. Yes, sir. Our pharmaceutical division is headquartered in Rochester, N.Y., where it maintains its production, research, and marketing organiza- tions. Our business was founded by the Strasenburgh family in Rochester, and was privately owned until 1900, at which time it was acquired by Wallace & Tiern~n, Inc.. headquartered in East Orange, N.J., with plants located in several areas of the TJnited States and abroad. On March 31, 1909, we became part of the Pennwalt Corp., by virtue of its acquisition of Wallace & Tiernan on that date. Biphetamine ~s scheduled by the Drug Enforcement Administra- tion-DEA-.--as a controlled substance under schedule II. As such, the manufacture of this product is specifically limited in terms of quantity and is strictly regulated at every stage in its chain of distribution by the DEA, as I will discuss more fully later. Tonamin is scheduled by the DEA as a schedule IV substance. It, too, is strictly controlled and regulated at each level of distribution. l3oth products have been ap- proved by the Food and Drug Administration-FDA-as safe and effective, as recently as 1974. Senator Nnsox. You heard the testimony of Mr. Rody, in which he said your company had offered to stop exporting Tonamine to Mex- ico: is that correct? Mr. McGRAw. I had a conversation with Mr. Durrin along those lines; yes. Senator NELSON. Well~ Mr. McGRAw. I will be more specific, Senator. I called Mr. Durrin when- Senator NELSON. Mr. Dnrrin? Mr. McGRAw. Mr. Ken Durrin. I first wrote a letter to the Administrator, Mr. Bensinger, calling his attention to information I had become aw-are of concerning an alleged confiscation of 250,000 capsules of Jonamine on the Southwest border of the United States. This was not factual evidence. I called his attention to the report, and said I would he very happy to discuss it with him. The letter was written on Friday, I have forgotten the exact date. It was in October. In the letter I said I would call him Monday. Unfortunately, Mr. Bensinger was out of the office on Monday. I was in a meeting, that I was unable, to get free on Tuesday, I talked to Mr. Durrin on Wednesday, and asked him if he had any in- formation about this unsubstantiated evidence which I was aware of. Mr. Durrin said he knew there had been one confiscation on the PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14619 border. Tie did not know what the size was, as he was not working in that area, bitt he had heard that a number of capsules contained in one box had been sugared. I offered my cooperation to come down to discuss the situation with him. I went over the controls that we had put in effect voluntarily on the drug in Mexico City. There are no such controls in Mexico as we have in the United States. In Mexico City, as you know, there are no such controls. We had put in our own quota system, and I said I would offer 100- percent cooperation, and if it need be, I will take the product off the market. That was my conversation. Senator NELSON. What was the last sentence? Mr. McGitAw. If need be, I will take it off the market down there- Mexico. That is not a quote, Senator. I was not expecting to hear tins infor- mation this morning, because this is the first time I had any knowledge of it. Senator Nasoy. Mr. Rody said testimony-well, his testimony ivill speak for itself. Of course, we do have the recorded record, but as I listened to it, I thought it was unequivocal that Mr. Rody in testifying said that Pennwalt had offered to stop shipping lonainine to Mexico, and that he said we accept that offer, is that correct or not? Mr. MCGRAW. That was not the offer made, sir. I offered to take the product off the market in Mexico if we could not control it there. I offered to cooperate with the PEA in anyway possible, offered to come to Washington at their convenience. Senator NELsoN. All of the lonamine that your company sells in Mexico is shipped from the United States, or is so fabricated else- where? Mr. McGiww. No, sir, we ship. It is a resin compound of phentermine. \Ve ship the resin from Rochester, N.Y., to Mexico City, where it is mixed with other ingredients, and it is encapsulated, bottled, and distributed through legal channels in Mexico. Senator NELSON. Just so I have it clear in my mind, so far us your company is concerned, is all of the material sold in Mexico the same sort of compound sold here in the United States? Mr. McGRAw. That is correct, Senator. Senator NELSON. What did you exactly mean when you said a few moments ago that you had this conversation, and that you would take it off the market, if necessary, what does that mean. Mr. McGRAw. Well, at that time, Senator, we had no factual evi- dence. I was working without factual evidence. I was offering to cooperate. I was asking if it was fact. Mr. Purrin said he had heard, the figures he gave me of the number of capsules, were in line with the figures I had seen, and the article I had read, and thus I offered to come down to Washington at his convenience to check into the matter with him. PAGENO="0198" 14620 COMPETITiVE PROBLEMS IN TITE DRUG INDUSTRY I told him of the controls we had in Mexico, if it was stolen, there was a possibility of tracing it, sir. Senator NELSON. I still do not understand what you meant by saying you would take it off. You would stop shipping it to Mexico if neces- sary? Mr. McGit~w. Senator, I think I made myself very clear. If we could not control it, if I had factual evidence that the product was being diverted, which we did not have at that time, and if that diversion could not be stopped, and depending upon the size of such diversion, offered to, if it came to that, to Mr. Durrin, if it came to that, I would take it off the market. Senator NELSON. Do you have in your own mind any judgment about whether a substantial amount has been diverted? You saw the evidence in this one case, involving just in Indiana 20,000 tablets. Would evidence repeated of that size batch several times consti- tute- Mr. McGit&w. I would have to see, Senator. I think it is unfair for you to ask me to quantify. Senator NELSON. You intend to talk to the representatives of DEA? Mr. McGRAw. I certainly do. Senator NELSON. On this precise question? Mr. McGRAw. I certainly do. Senator NELSON. All right. Go ahead. Mr. McGRAw. In our pharmaceutical operations at Rochester, we maintain a research and development facility, maimed with qualified professionals including four doctors of medicine, 23 doctors of pharma- cology and doctors of chemistry, and other related disciplines. This staff and our administrative staff-quality control, govern- mental compliance, finance, personnel, and so forth-perform the various functions which these titles suggest. TIlE PROBLEM OF OBESITY AND TIlE USE OF ANonEcrIcs Internationally known medical and nutritional experts in the United States are generally agreed that there are approximately 30 to 40 inil- lion Americans between the ages of 21 and 65 who are at least 20 per- cent overweight. To be 20 percent overweight is to be "obese," a condition that seri- ously affects the individual's well-being and life expectancy. Obesity also compounds other diseases. I%Iedically, obesity is correlated with considerable increase in cardiovascular diseases, diabetes, liver and kidney diseases, and even accidents. Indeed, to be obese is to be ill. The problem was defined by one reputable physician, Dr. Halberstam, as follows: Fatness may be the single most hnportant iuness in America. It Is certainly the most important form of mainutrition. Fat peopie have higher incidence of stroke, of high blood pressure, and, to a less marked degree, heart attacks. On all life Insurance tables fat people live shorter lives than normals. [Emphasis supplied.] In addition to physical disability. the obese frequently carry an additional burden, which Dr. Ilalberstam has described in these terms: `Dr. Michael Baiberstam, "The Pifis In Your Life," Ace Books, 1972, pp. 141-142. PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14621 Worse, the fat middle-class person lives not only with a physical burden, but with a psychologic stigma. The sociologist, David Riesnian, has said that America isa `physionomic democracy." That is, we Increasingly will accept Into our social circles and business lives people of any race, creed, or color-so long as they are attractive. The other side of this is that we shun the ugly, the crippled, the fat. The next time you are at a gathering of strangers or getting on a bus or sitting down at a lunch counter, check your own reluctance to sit down alongside a fat person. In discussing the proper role of anorectics in the treatment of obes- Ity, wc. are confident that while this committee will considcr the testi- mony of the experts, the layman, and others who have their respective and differing views, tile committee will continue to be most interested in that which can be established factually. lye are equally cohfjdent this committee will examine the question of antiobesity medication in the context in which it arises-a population contaIning 30 to 40 million obese citizens who are entitled to medical and other therapeutic assistance in obtaining relief from their physIcal and emotional disabilities. These disabilities cannot be dismissed with the notion that "will- power" or "self-discipline" or "counseling" are all that are needed. We can tell the sinners, the alcoholics, the chain smokers or the obese how to behave and turn our backs on them if they do not. But quite clearly preachment is not the cure for any serious disability. We think it noteworthy that despite great medical progress in this country, the treatment of obesity is one of the few areas of preventive medicine being practiced today. Most other medical practice today remains remedia or post-traumatic. Medical attention is available to help the obese patient in his efforts to attain a more satisfactory level of physical condition by supervised weight loss. Jndced. there seems to be general agreement in the technical as well as popular literature that the obese Bhould seek a doctor's advice before undertaking any serious program of individual dieting. - If we has-c approximately 30 to 40 million obese indlvlduals in the United States, and if we and they recognize that wishing "won't make it so," what remedies are appropriate? Our pharmaceutical division believes that the obese individual has a medical problem which is best treated by a physician and aided by counseling and supportive techniques which will motivate the patient to attain his goals. Pennwalt has acted on this belief in educational programs directed to both physicia.n and patient. We believe that prescription of anorectic medication-ours or that supplied by other reputable pharmaceutical companies-is entirely the prerogative of the physician. Senator NELSON. Do you really stick to that unqualifiably? We had testimony this week from Suffolk County in ilunting- ton Townslup of two doctors avenging 800 to 1,200 patients a week. Observation of the lines of people indicated that most of them did not bave any obesity problem at all. Is it your view that it is solely the responsibility of the physicians in that kind of case, to issue prescrip- tions of the anorectic medication, that it is entirely the prerogative of the physicians? Mr. McGn~w. The physician is the only one, Senator, who can pre- scribe, yes. PAGENO="0200" 14622 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator Nra.soic. You are not endorsing the widespread illegal use? Mr. Mcthtaw. I am not. Senator Nasox. Go ahead. Mr. McGit&w. For more than 15 years, we have provided the patient, through his doctor, with literature intended to educate the patient- not sell him our products. Indeed, our products are not mentioned in this literature. More than 10 million copies of our long-established and free book- let "Are You Really Serious About Losing Weight?", have been dis- tributed. It contains over 70 pages of highly useful information for the patient and no reference to Pennwalt products. The educational value of our booklet was described by the interna- tionally renowned Dr. Jean Mayer of the Harvard University School of Public Health, who said: There have been so many popular books and articles on obesity which make the most unreasonable promises to patients that it is pleasant to see a booklet taking the reasonable and truthful position that weight reduction Is dependent on maintaining a negative energy balance-preferably based both on decreasing food Intake and increasing energy expenditure. It Is even more gratifying to see that the booklet is sponsored by an enlight- ened pharmaceutical company which realizes that while anorexigenie drugs can, in the bands of competent and well-informed physicians, make an important con- tribution to treatment during the Initial period of weight reduction, they cannot substitute for reeducation of the patient as regards eating and living habits. They can gain time and make it easier for the obese individual to become used to smaller food portions. But a great deal of Information and motivation also need to be given to the patient. Because the doctor's time is not unlimited, he needs teaching material, which this booklet quite adequately conveys. Reading the booklet should give the pa- tient the chance for a more informed dialogue with his doctor, In this same booklet, the patient is advised to "Count your facts be- fore you count your calories" and then asked to take a True-False quiz on basic propositions alleged to relate to dieting, with 28 questions and answers. I call your attention specifically to question No. 26 and our answer to it-at pages 3 and 5 of the booklet: Proposition: 26. A diet "pill" is an easier way of losing weight than dieting. Answer: 26. False. No pill can take the place of dieting. A diet pill Is only a "training" aid to help cut down appetite for food while learning to adjust to eat- ing less. It takes time to correct faulty eating habits-the real cause of over~ weight. Do not use any dieting drug unless it is prescribed by your physician for you. In summary, our educational program is specifically addressed to a four-part theme: (1) Dietary counseling by the physician; (2) indi- vidualized dietary control addressed to the specific patient: (3) pre- scribed exercise; and (4) if hecessary, antiobesity prescription. THE REGULATORY SYSTEM As this committee is fully aware, amphetamines and nonampheta- mine anorectics are scheduled drugs which are regulated and con- trolled by the Food and Drug Administration, the Drug Enforcement Administration, and State authorities. In 1970, the Congress passed the Drug Abuse Prevention and Con- trol Act,-"Control led Substances Act"-at which time the Food and Drug Administration Bureau of Drug Abuse Control and the Depart- PAGENO="0201" COMPETITIVE PROBLEMS IN THE DM10 INDUSTRY 14623 ment of Narcotics within the U.S. Treasury Department were assigned to the Department of Justice. This Justice Department enforcement agency is now known as the Drug Enforcement Administration. * The 1970 Controlled Substances Act established categories of drugs in five schedules of gradation, and the FDA and DEA cooperate with respect to specific scheduling thereunder. The FDA's role under the Federal statutory and regulatory scheme is to make a determination of the benefit-risk status and the effectiveness of particular drugs. The FDA has determined that Pennwalt's Biphetamine is safe and effective as an a~junct in the short-term management of obesity, As you know, the DEA has assigned it to schedule II. Similarly, the FDA has detennined that Pennwalt's lonamin is safe and effective. The DEA has assigned it to schedule IV. The 1970 law also imposes stringent accounting, reporting and pro- duction requirements, extensive labeling requirements, registration of manufacturers, distributors and dispensing entities, elaborate it- quirements for safekeeping of controlled substances, and establishes other procedures for the control and supervision of controlled substances. With respect to the manufacture of our schedule II product, Biphet- amine, we must receive a quota allocation from the DEA, annually. That quota establishes the amount of amphetamine base (our raw material) which will be available to us for the relevant calendar year. In this process, Pennwalt: 1. Must have submitted before the close of each year a formal quota application for the forthcoming year, setting forth our raw material utilization for the preceding 3 years. 2. Upon receipt from the DEA, early in the new year, of a quota allocation-which generally does not afford a full calendar year of supply-we operate thereunder. 3. Several months late}, as our inventory diminishes, we must make a further formal request for an additional quota allocation. 4. That request must contain: (1 a statement of current total plant inventory; (2 projected utilization to yearend at our current usage rate; (3 a resultant computation of the additional allocation we require; and (4) such other infonnation as is appropriate to aid the DEA in its evaluation, including, for example, the following: (a) Com- parisons of our distribution, stated in tenns of kilos; (b) Inter- national Marketing Service-IMS-audits of drugstore purchases and prescription utilization; and (c) Wholesale distribution inventory level analysis. As a result of the quota process I have described, we are supplied with a raw material base generally sufficient to meet our actual annual demand. However, we do not receive a quota allocation adequate to guarantee us that in fact we will be able to complete production for that calendar year. As is evident, this rigorous quota control program is an essential part of the regulatory design to insure that the product originates and remains in legitimate channels of manufacture and distribution. The proper scheduling of Ionamin-phentermine-.-has been under review by the DEA since early 1973. At that time, Pennwalt advised 85-509 O-TT-14 PAGENO="0202" 14624 COMPETI'TIVE PROBLEMS TN TEE DRUG INDUSTRY the PEA that it would not oppose schedule III classification for Tonamin if related, competitive products were similarly scheduled. Pennwalt took this position in a spirit of cooperation, although Penn- wait remains unaware of any evidence that would support the schedule III classification proposed by the PEA. The matter remains pend- inn, with Jonamin in schedule IV awaiting further action by the PEA, foI~owing its receipt of Pennwalt's lengthy documentation of the sci- entific and other facts we deemed relevant to the question. In this connection, it should be noted that Pennwalt advised the PEA on November 17,1975, that: Phentermine, that is Pennwalt's lonamin, has been marketed in the United States since approximately 1959. During the 16 (110w 17) years since then, approximately 500 million dosage units of lonamin have been prescribed by physicians for use by a diverse patient population, ranging from young adults to the aging, a population necessarily including a broad spectrum of emotional, mental and physical characteristics. In all of those 16 years, Pennwalt has learned of no deaths or any serious physical or mental injury- or damage attributable to the drug. In addition, Penn- walt is not aware of any significant instances of phentermine abuse, and its product liability experience with the drug lonamin reflects but One payment, in the amount of $3,500, to settle one suit brought by a patient who alleged she had used lonamin (on prescription) as well as several other drugs manufactured by other defendants in her ease. TIlE PEA MONITORS AND AUDITS TIlE DISTRiBUTION OF ANTIOEESrrY DRUGS The Drug Enforcement Administration plays a very active role in monitoring and auditing our scheduled substances. It requires that all manufacturers of all schedule II products submit monthly PEA- 222-C forms. These reports require Pennwalt; for example, to list each purchase or sales transaction involving Biphetamine. as a sched- ule II substance, by date, amount, and identity and location of purchase. The DEA also requires the quarterly filing of ARCOS computer tapes recording each controlled substance transaction under schedule II and all transactions involving narcotic drugs in any schedule exclusive of those on schedule V. These computer tapes show the move- ment of the drug both within the plant and in distribution, again showing date, amount, and recipient. For Ionamin~ a schedule IV product, the DEA requires that we record the name and location of each purchaser, its registration num- ber, and the quantity, identity, and strength of the product by package unit. These same standards apply to our purchase of lonamin's raw material, phentermine. tn addition, the DEA requires a separate listing of all controlled substance transactions, segregated from all other company records, to facilitate ready inspection by PEA representatives. Separate reports of any suspected loss in transit, whether or not confirmed, and any other significant loss of any scheduled drug, are reported to the PEA immediately. If any suspected loss is not ac- counted for, followup reports are made. The PEA also conducts periodic. formal audit inspections of Penn- walt's entire system of accountability for all schedules of controlled substances. Apart from these audits, PEA representatives are on our premises on a regular basis in the routine performance of their duties, PAGENO="0203" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14625 including monitoring, distribution, and reviewing our securitj pro- grams for scheduled products. In addition to Federal regulation, 42 States, including New York, Oahfornia, Pennsylvania, Tllinois, and Florida, have adopted the Uniform Controlled Substances Act, which contains controls similar to the Federal act. EFFECT OF CONTROLS ON I)RESCIIYPION EXPERIENCE: 1971 COMPARE)) TO 1975 Since the passage of the Controlled Substances Act of 1970, there has been a marked change in the prescription experience for anorectie products. These changes may be summarized as follows: £911 1975 1. lotat patientyisitsforobe,ity 23,665000 20,601,000 2. Prescription usage: - Medical prescriptions ofanorecticsOnitial) IS, 773,000 12,413,000 Total 2d or subsequent prescriptions -- 7,707, 000 7,213, 000 Iota? enorectioprescription, 26,080,000 19,626,000 3. Total anorectic prescription,: (I) Amphetamines - 16,232,000 5,504,000 (Initial prescriptions) (13, 201, 000) (2, 745, 000) (2) Honamphetamines 9, 848, 000 14, 122, 000 (Initial prescription,) (5,172,000) (9, 668, COO) Total anorectic prescriptions 26,080,000 19,626,000 4. Reduction in total aniorectic prescriptions from 1971 to 1975 -6, 454,000 These figures demonstrate that the Controlled Substances Act has accomplished a dramatic reduction in the prescription of amphetamine anorectic products, but that a continuing medical requirement for those products remains. The figures also demonstrate that while there has been an overall reduction in the total prescriptions of anorectic products, there also remains a very sizable patient population, consisting of millions of Americans, among the 30 to 40 million obese, who are receiving medi- cally supervised treatment for their condition. FENNWALT'S MANUFACTURE, DISTRIBUTION, AND SALES All of the Federal regulations I described previously are complied with by Pennwalt in its manufacture, distribution, and sales. In addi- tion, at the plant, production and shipping are monitored closely by management to assure the absence of loss and the detection of any attempted theft. As noted earlier, detailed records and monthly and quarterly reports to the DEA show each transaction both intraplant and to customers, its size and the identity of the customer. At the present time, Peni-i-walt sells its prescription products, mclud- ing Biphetamine and lonamin, only to nonprofit hospitals and to approximately 450 wholesale distributors. These wholesalers handle the complete line of Pennwalt products and all of them are also registered and regulated in their handling of scheduled drugs by the Drug Enforcement Administration. In addi- I These data are based titian the National Disease and Therapeutic Drug Index (Non- Endocrine Obesity) and its National Prescription Audit. PAGENO="0204" 14626 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY tion to registration, the wholesalers are subject to the same stringent reporting requirements by the DEA as is required of manufacturers; Using 1973 as a base, Pennwalt's direct sales of both Biphetamine and Jonamin to physicians have decreased. By 1075, approximately 7 percent of Pennwalt's sales of Bipheta- mine, and approximately 4 percent of Perniwalt's sales of Jonamin, were made directly to physicians. Effective in the fall of this year, Pennwalt ceased all such sales. Pennwalt has not promoted or advertised Biphetamine since 1971. Since that date, we have not detailed or sampled Biphetamine to physicians. Pennwalt advertises lonamin, but only in journals ad. dressed to the medical profession. It also samples Jonamin in accordance with prevailing competitive practices and existing law. Senator NELSON. You said your firm advertises only in journals ad- dressed to the medical professIon. Is there any prescription drug advertised in this country to the general public? Mr. McGttw. Not that I know of, sir. Senator NELsoN. Please proceed. Mr. MCGRAW. In August 1076, the DEA proposed that sampling of all controlled products be prohibited. In that same month, Pennwalt wrote to the DEA to express our agreement with their proposal, and will comply immediately should this proposal become applicable to all competitors. Senator NELsoN. This occurred in August of this year, and concerns the supplying of free samples to physicians? Mr. McGRAW. That is correct. Senator NnsoN. Did you agree to comply as soon as all other com- petitors agreed? Mr. McGRAW. We agreed it should be prohibited, and we would cooperate with such a decision. Senator NELsoN. Has that decision been made yet? Mr. llosTnAL. No, sir. Senator NELSON. Go ahead. Mr. MCGRAW. Pennwalt's 1975 promotional expenditures for lona- mm were approximately 0 percent of total Jonamin sales. Otherwise stated, our total promotional expenditures were approximately 4 per- cent of our total antiobesity drug sales. As noted, we have no pro- motional expenditures for Biphetamine. These figures may be compared to the promotional expenditures for the most popular over-the-counter antiobesity product, which has an estimated 60 percent of the market. The total promotional expendi- tures for that product for the last available year have been reported to be more than 20 percent of its sales, on a sales volume of approximately $15 million. PHARMACY SALES OF PRESCRIBED ANORECTIC PRoDucTs Before turning to the subject of alleged abuse of anorectics, we be- lieve it useful to review briefly the total market for prescribed anorectics at the pharmacy level.' `The data cited are based upon iMS reports of pbarmacy purchases for the years 1971 and 1975. PAGENO="0205" OOMLPETrTJVE PROBLEMS IN THE DRUG INDUSTRY 14627 The sales figures just reviewed are in current dollars. If expressed in constant dollars, you would note a significant decrease in dollar volume for the sale of all prescription anorectic products. PURCHASES BY RETAIL PHARMACIES: 1971 COMPARED TO 1975 1971 1975 Amount Percent Amount Percent Total pharmacy purchase, $78, 636, 000 $83, 247, 000 Amphetamine anorectics 46, 670, 000 59. 0 23, 237, 000 21.0 (Penowalt sales) (8, 394,000) 19,0 (6, 761, 000) 29.0 Nonamphetamine anorectics 3!, 966, 000 41.0 60, 010, 000 73.0 (Pennwalt sales) (3, 244, 000 10.0 (11,920,000) 20.0 Total Penowalt anorectic sale, 01,638,000 14.8 18, 68!, 000 22.4 Total anorectic sales of: (I) Other 2 major manufacturers 34, 203,000 28, 380, 000 (2)Pennwalt 11,638,000 18,681,000 (3)Allother 32,785,000 36,I85~00O Total pharmacy purchases 78,636,000 83,247,000 ALLEGED ABUSE OF PENNWALT's ANflOBE5ITY PRODUCTS - The IMS analysis of the relevant data on individual prescription size, for the most recent complete calendar year, 1975, shows that: As-es-age number of capsules per physician's prescription: Copeutes Tonamin 31.1 fllphetamine 335 We believe it appropriate to conclude that the average obese patient therefore receives a prescription for enough lIiphetamine or Ionamm capsules to provide one-per-day treatment up to a maximum of but 4 to 5 weeks, for short-term support. We therefore continue to believe that the IMS analysis demonstrates that pharmacies and the medical profession are providing a necessary service and that the patients are not afforded, by that process, the opportunity for any meaningful abuse. Thus, regardless of anecdotes relating to the alleged high vol- ume of capsules per prescription, in actuality the prescription data reported by IllS is consistent with judicious prescription by the medi- cal profession. We should also note that Pennwalt regularly compares its actual fac- tory shipments of both amphetamine-Biphetamine--and phenter- mine-Ionamin---containing products with IMS audits of drugstore purchases. In addition, our actual factory shipments and the drugstore purchases can be correlated with the quantity of either Biphetamine or Jonamin prescribed and dispensed, as shown by the TMS National Prescription Audit for the same period. Pennwalt regularly under- takes such analyses and remains satisfied that its products are pre- scribed within legitimate medical channels. In short, our products are moving through the distribution chain in a proper fashion. Pennwalt is not aware of any significant illegal use of its antiobesity products. During the period January 1, 1972, to the present time, we have received from the PEA and other enforcement agencies but nine rcport.s of alleged diversion from all sources-five for Biphetamme and four for Jonamin. lYhen claims of either attempted or actual il- legal use or diversion have been brought to our attention, Pennwalt has PAGENO="0206" 14628 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cooperated fully with the enforcement authorities in the investigation, apprehension, and prosecution of those responsible. Our experience also confirms an observation of Mr. Peter Bensinger, Administrator of the DEA, at the annual meeting of the top executives belonging to the Pharmaceutical Manufacturers Association, held in May of 1976. He noted that there is no reason to believe that industry is responsible for illegal trafficking in amphetamine. Pennwalt knows of no evidence to the contrary. As this committee may know, allegations were made in January of 1972 that Pennwalt's antiobesity drug product Bifetaniina-Bipheta. mine-in Mexico, was being illegally diverted by purchasers of that drug. Pennwalt was never given evidence of where and how this diver- sion occurred, nor has Pennwalt been advised of any prosecution with respect to those alleged diversions. Nevertheless, in January of 1972, Pennwalt ceased production and sale of amphetamine products in Mexico and at the same time decided to cease any further export of amphetamine products. These decisions were made to limit our Bi- phetamine sales to the United States and Canada, in reliance on strict regulatory practices which exist in those two countries. As tins com- mittee knows, in 1973 Canada withdrew its approval of amphetamine products. Senator NELSON. For obesity ll'1 - Mn McGRAw. That is correct, sir. Mr. BRonEBIcK. If I may interject, we indicate that we continue to export to Canada, that is wrong. We should have referred to the fact that we continue to sell to Canada. We did not export to Canada. Senator NELSON. All right. The record will stand corrected. Mr. McGmtw. [Reading:] COMBINATION A3IPIIETA3UNE ANORECTICS - In February of 1973, the FDA published in the Federal Register a finding that all fixed combination amphetamine products were in- effective and unsafe. As a fixed combination, this finding included Biphetamine-T. Although the initial National Academy of Science- National Research Council-"NAS/NRC"-flnding with respect to Biphetamine-T was that it was "possible effective", Pennwalt elected not to exercise its right to contest the FDA's 1973 redetermination. Pennwalt therefore discontinued further manufacture of the product and recalled all stocks from the distribution chain, at a cost of approxi- mately $1 million. CONCLUSION On the basis of the evidence which we have summarized today,. Pennwalt believes that there is an established medical and social need for its antiobesity products. . We think it important that this committee differentiate between hearsay testimony, utterly unsubstantiated by factual support, and the testimony and documentary evidence available from sources which are recognized to be technically qualified to deal with a complex scientific, social, and medical queshon. There remains a population, estimated to be between 30 and 40 mil- lion obese Americans, many of whom wish to avail themselves of PAGENO="0207" COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY 14629 medical treatment in order to alleviate or eliminate this unfortunate condition. Our antiobesity products, and those of other responsible manufacturers, remain recognized as the oniy effective prescription medicinal aid available in a course of antiobesity treatment. Moreover, as we have discussed today, the manufacture and dis- tribution of those products is closely regulated by competent Federal agencies, which have the requisite expertise to evaluate the quality of our products and the legitimacy of their use. The regulatory processes established by the Congress, over the years, have created a framework within which the serious questions which concern this committee have long been the subject of professional con- cern, both within the regulatory agencies and within the pharmaceuti- cal industry. That process affords all of its participants due process, from investigatory, scientific, and legal perspectives. Pennwalt appreciates the opportunity to appear before this commit- tee in order to state the bases upon which its products are manufac- tured and distributed. Pennwalt remains confident that it can continue its 126-year-old reputation for integrity while engaged in this part of its enterprise. I am ready to answer any questions you may have. Senator NasoN. Thank you very much. Do you have any well-controlled studies of your own, or are you aware of any well-controlled studies that would produce substantial evidence to refute the conclusion of the report to the Director of the Bureau of Drugs by the panel of consultants on anorectics headed by Dr. Prout in 1972, when that panel in its conclusions stated that the natural history of obesity is iiieasnred in years, whereas the studies cited are restricted to a few weeks duration, thus the total impact of drug-induced weight loss over that of diet alone must be considered clinically trivial? DQ you have any studies, or any evidence that would refute that conclusion, that this impact is clinkally trivial? Mr. McGRAw. I can show in the studies we submitted to the FDA, they were done over a 10-week period of time. Senator NELSON. Were these studies submitted to the consultants on anorectic drugs? Mr. McGit~w. No, sir. Senator NasoN. When were they submitted? Mr. MCGRAw. They were submitted in 1971 to the FDA. Senator NELSON. The report I am referring to is dated 1972. Mr. McGRAw. As a result of the report of NAS/NRC, these prod- ucts were ruled possibly effective, and we had to submit efficacy studies to the FDA. Senator Nasox. The NAS/NRC panel was concluded in 1972. I was wondering if your studies were well-controlled and if they pro- duced substantial evidence to refute the conclusions of the panel that the effects of these drugs were "clinically trivial." IVe would like to have those. Mr. MCGRAW. As I was saying, Senator, the studies we submitted for our efficacy studies were done over a 18-week period of time, and on a week-to-week basis, there was a fractional difference in weight loss, let us say a half a pound. At the end of the 16 weeks, that was sometimes double as compared to a placebo, and I think that is significant as a statistical evaluation. PAGENO="0208" 14630 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELsoN. Sixteen weeks, half a pound a week, it would be 8 pounds, and twice that of placebo, that would be 4 pounds dif- ferential? Mr. McGa&w. You could go 4 to 10 to 10, any multiples. I was going to further say these studies were submitted to the FDA for their evaluation, all of the raw data, and so forth. Senator Nasox. Thank you very much for taking the time to come to testify today. Did Mr. Rosthal have anything to add? Mr. BR0DEBICK. If I may, it was not until today, when I read Mr. Rody's statement, and I am particularly referring to the bottom of page 17 and the top of page 18, that we were aware that the PEA had evidence as the DEA put it, of the seizure of 104,000 capsules. I know that Mr. Rody has offered to submit to this subcommittee the most recent survey relating to lonamine on the Southwest border, and I would request. sir, with your permission, that such surveys be submitted to Pennwalt, so that we may review it, and cooperate with the PEA, sir. Senator Nasox. I am assuming, based upon the testimony of Mr. McGraw, and Mr. Rody, that you are going to be discussing this question anyway, and whatever they submit to this committee would be a matter of public record, so it will be available to everyone. Mr. BRonERicic. Iwould hope they would submit it. Senator NELSON. Mr. Rosthal? Mr. ROSTJTAL. I will be very brief. The statement says Pennwalt was never given evidence of where and how this evidence came about, it- ferring to Blackjack. That insults me. I have pride of authorship to show cause, and I cite the cases. If you have not read it since 1971, I will read it to you now. Mr. BR0DERIcK. I would like to say in response, I do not want to get involved in a dispute with Mr. Rosthal, as I have great respect for him, but, as you know, in 1972, I believe, we appeared, Pennwalt ap- peared before Rogers' committee, when the Mexican situation was discussed. At that time we were requested to submit supplemental information to the Rogers' committee, which we did. One of the items of information which the Rogers' committee re- quested was the sales from the Mexican facility to pharmacies along the Mexican border. We advised Congressman Rogers we had not be told by the DEA the names and locations of those pharmacies. The Congressman said he would ask the DEA to submit them to us. They never did. Senator NzrsoN. Do you have anything further? Mr. ROSTiTAL. I do not remember that. I was at the hearing, and there is difficulty in supplying information to some people. I do not say it directly about these two witnesses here today, but where we do have a case which might in the opinion of the Criminal Division, or a criminal lawyer, amount to a conspiracy, you usually do not tell it to the people who might possibly be conspiring. Mr. Bnonnuczc. Please do not let my silence be an indication of any agreement. Senator NELSON. All right. Thank you very much. The subcommittee stands adjourned. [Whereupon, the subcommittee was adjourned at 2:15 p.m.] PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14631 APPENDIX PREPARED SnnMncn STATfl*NT BY Carl D. Chambers, Ph.D. President Personal Development Institute and Professor and Director Institute for Public Health Research Antioch College at Columbia 17345 S.W. 112th. Avenue Miami, Florida 33157 (305) 233-4900 Presented Before Monopoly Subco,mnittee Senate Select Conaittee on Snail Business Thursday November 18. 1976 PAGENO="0210" 14632 COMPEVITFIVE PROBLEMS ~N THE DRUG INDUSTRY 1. Mr. Chairman, I am extremely grateful for your invitation to appear before your Subcommittee to share with you my research on the patterns of use of amphetamines and related drugs. With your permission, I would like to share two types of research experiences with the Subcommittee. First, I would like to share the experiences derived from conducting some 35,000 face-to-face interviews with persons in 17 States and the District of Columbia. Second, I would like to share the experiences derived from conducting 935 interviews with known drug abusers in nine cities from throughout the country. After a brief prepared statement of these experiences, I will be happy to answer any questions the Subcorranittee may have regarding these studies. Between 1970 and 1976, 1 was the senior investigator responsible for conducting substance use surveys within the statewide general populations of Arizona, Delaware, Florida, Indiana, Iowa, Minnesota, Mississippi, New Jersey, New York, North Dakota, North Carolina, South Carolina, South Dakota, Utah and Wyoming. I have also been responsible for conducting the same surveys among the citizens residing throughout the District of Columbia and the citizens residing in selected multiple county areas of Arkansas and Pennsylvania. These surveys have resulted in some 35.000 interviews with persons carefully selected to represent the total, populations age 14 and above who resided in these areas. Each person was interviewed in private by trained interviewers concerning their use of prescription psychoactive drugs, non-prescription psychoactive drugs sold "over-the-counter," alcoholic beverages and illicit drugs. Viewing these data in the aggregate has brought us to the following conclusions; PAGENO="0211" COMPFI'ITrVE PROBLEMS IN THE DRUG INDUSTRY 14633 2. * The use of amphetamines to diminish fatigue or for their energizing effects is significantly related to both sex and age. For example, our projections indicate some 63% of everyone who uses amphetamines as "pep pills" are males even though males represent only 46% of our population above the age of 13. correspondingly, persons age 14 through 24 represent only about 26% of our total population but contribute sone 55% of all prescription "pep pill" users. * Although there has been considerable discussion about the use of prescription "pep pills" among certain occupational groups such as truck drivers and students, our data suggests the highest rate of use of the prescription "pep pills" is probably among sales workers. Unfortunately, neither other investigators nor I have been able.to look closely at the relationship between one's work and the use of these prescription energizers. For example, I have some information that- the use of these drugs among service and protective workers, migrant workers and those in conpetitive sports is considerably greater than empirical data would suggest. * The use of the amphetamines and amphetamine-containing diet pills ostensibly for their hunger suppressant effect is also significantly related to both sex and age. If I was called upon to characterize the primary consumers of prescription "diet pills," unquestionably I would project then to be women between the ages of 18 and 34. I would PAGENO="0212" 14634 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. further characterize them as housewives who are not employed outside the home or women who are working in sales or clerical jobs. * Our data indicate that the vast majority of these women obtain these drugs through legal prescriptions but that they do not take them as they were prescribed. Substudies of these women show that regardless of why they begin to use these drugs, most ultimately begin to increase the prescribed dose or extend their use and take them because of the drugs production of a "sense of well being." * The use of amphetamines as "pep pills" and as "diet pills" appears to be proportionately distributed throughout the race/ethnic groups. * I believe some brief nention of the use of the non- prescription stimulants sold over-the-counter should be made as there is some evidence that the use and abuse of these drugs is increasing and any controls placed on the prescription stimulants will probably compound these increases. The consumption of over-the-counter stimulants occur more among men than women and more among younger persons. The use of non-prescription stimulants appears to be proportionately distributed throughout all of the socioeconomic and ethnic groups. Of significant concern to my colleagues and me, is our projection that the majority of the regular consumers of these drugs are workers who operate or are around machinery and motor vehicles. Unfortunately, the extended use of these stimulants only PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14635 4. masks the fatigued state of the body and cannot fully restore the sensory perception and reflex action which has been lost through fatigue. I am sure the Subcommittee is most interested in the precise number of people in this country who habitually use these drugs. Unfortunately, neither I nor any investigator I know can give you preciae numbers. All any of us can give you will be projected numbers based upon various surveyed populations. With such a qualifier clearly understood, let me give you the numbers our research would suggest. Assuming our some 35,000 people are representative of everyone in the country, we would project the following: * Some 6.000,000 people above the age of 13 have used amphetamine `pep pills" with some 1,500,000 having done so recently and some 750.000 being current regular users of these drugs. * Some 12,000,000 people above the age of 13 have used amphetamine "diet pills" with some 3,000.000 having dome so recently and some 1,500,000 being current regular users of these drugs. * Some 16,000,000 people above the age of 13 have used non-prescription stimulants of whom as many as 3,000,000 having done so recently. Probably as many as 500,000 people use one of the non-prescription stimulants every week. As I indicated in my introductory remarks, I would also like to ahare with the Subcommittee my recent experiences in interviewing known PAGENO="0214" 14636 COMPETYTWE PROBLEMS IN THE DRUG INDUSTRY 5. drug abusers concerning their use of amphetamines and related drugs. I believe the Subcommittee should be aware of these users and the implications of this use as these users are normally excluded during even carefully desired general population surveys. If they are identified they are less likely to respond honestly to interviewers who are not known to them. Cf equal importance, these types of users make no pretense to claims of use to diminish fatigue or to lose weight. They choose drugs to use solely for their potential for producing euphoria. During last year. Leon Hunt, a mathematical epidemiologist, and I were asked by the Drug Enforcement Administration's office of Science and Technology to conduct a study among known drug abusers relative to the potential for abuse or non-medical use of various legally manufactured psychoactive drugs including the amphetamines and related drugs. As the final report of this total research effort is available to the Subcoffer,ittee from the Drug Enforcement Administration, I won't take up your valuable time in a full elaboration of the study. I will abstract from the study those findings which I believe are most relevant to your current inquiry. In brief, the study called for us to review the drug history records and to interview random samples of narcotic abusers and abusers of non- narcotic drugs who were undergoing treatment for this abuse in nine cities. Records were reviewed and drug abusers were interviewsd in the following cities: Miami, Florida Greensboro, North Carolina Washington, D. C. Atlantic City, New Jersey PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG flThUSTRY 14637 6. New York City, New York Des Moines, Iowa Kansas City, Kansas Phoenix, Arizona San Prantisco, California A total of 3,598 records were reviewed and 935 drug abusers were interviewed. Our analytic technique was first developed to describe the epidemic nature and spread of heroin in a cosmunity. The technique collects the year of first use of a drug and groups these experiences to determine if the event is occurring randomly or is the result of contagious transmission from one user to another. The following results and generalizations should be of special relevance to your current inquiry. * 62% of all the drug abusers we interviewed had histories of abusing amphetamines. However, among drug abusers whose primary drug of abuse was not heroin, the prevalence of amphetamine abuse was as high as 85%. Of interest, 63% of all abusers of amphetamines had been introduced to the drugs by their friends or peers and only 23% had been introduced to amphetamines by a drug dealer. * 15% of all the drug abusers we interviewed had histories of abusing phenmetrazine (Preludin). Not unexpectedly those who abuse phennetrazine were most frequently introduced to the drug by their friends or peers. * Amphetamine abuse in Miami has shown the epidemic characteristics since 1968. There is some evidence that the abuse of phennetrazine (Preludin) and phentermine (lomamim and Fastin) say be becoming popular substitutes PAGENO="0216" 14638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7. for the amphetamines. * Amphetamine abuse in Greensboro is an endemic or stable problem with drug dealers more frequently introducing new users than in any other city we studied. Phennetrazine (Preludin) abuse has become a popular drug of abuse and appears to be primarily imported from the Washington area. * The amphetamine epidemics Washington has experienced in the past may have been replaced by the abuse of phenmetrazine (Preludin). * Amphetamine abuse in New York City is an endemic or stable problem when viewed in its totality with microepidemics occurring within neighborhoods. Our data are too sparse, however, to identify these neighborhoods in time and place. * Amphetamine abuse in Atlantic City is an endemic or stable problem. Phenmetrazine (Preludin) abuse may also have become endemic. * Anphetamioe abuse in Des Moines was probably epidemic during the 1966-1971 period when it probably became endemic. Phenmetrazine (Preludin) abuse has become epidemic. Des Moines was one of the few cities we studied which reflected considerable experimentation with a wide range of amphetamine related drugs. * Amphetamine abuse in Kansas City is an endemic or stable problem. Phenmetrazine (Preludin) abuse has, however, shown the charscteristics of contagious transmission. * Amphetamine abuse in Phoenix can be viewed as epidemic and probably has been since 1968. Phenmetrazine (Preludin) PAGENO="0217" COMPWrITWE PROBLEMS IN THE DRUG INDUSTRY 14639 8. abuse is probably endemic or stable. * Msphetamine abuse in San Franciaco can be viewed as epidemic and probably has been since 1%6. Phenmetrazine (Preludin) abuse is probably endemic or stable. In sineary, our study among known drug abusers indicates the continued popularity of the amphetamines as drugs of abuse. In addition, the abuse of pbenmetrazine (Preludin) has become epidemic in some cities and appears to be spreading into others. 85-569 O-7T----15 PAGENO="0218" 14640 COMPETYrIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT OF ~; RICHARD CROUT, M.D. DIRECTOR, BUREAU OF DRUGS FOOD AND DRUG ADMINISTRATION BEFORE THE SUBCOMMITTEE ON MONOPOLY SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES.SENATE NOVEMBER 19, 1976 PAGENO="0219" COMPET~~1VE PROBLEMS IN THE DRUG INDUSTRY 14641 Mr. Chairman and Members of the Subconnittee; I appreciate the opportunity to appear here today to discuss the activities of the Food and Drug Administration (FDA) with respect to anti-obesity drugs. Previous actions by both the FDA and DEA have had an important impact on the availability, labeling, and use of these drugs. In spite of this, abuse of amphetamines in particular, appears to be a continuing problem in our society. It is appropriate that additional action in regard to amphetamines be considered at this time. The story I will emphasize in this testimony is that the available data, while preliminary and Incomplete, indicate that the amphetamines remain, among the anorectic drugs, the major offenders as drugs of abuse. This problem cannot be solved by invoking additional controls under the Controlled Substances Act since these drugs are already in Schedule II, the most tightly controlled category for marketed drugs. The only meaningful next step which can be taken is to remove the indication for obesity from the labeling for amphetamines or to remove them from the market. FDA Is working with DEA and NIDA, the Federal agencies with detailed information regarding drug abuse, to develop the necessary documentation for such a position. Abuse of amphetamines continues to occur, with deleterious and often devastating effects on the individual who abuses or becomes dependent upon them. We must move ahead vigorously in addressing this important problem in drug safety. PAGENO="0220" 14642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY OBESITY AS A HEALTH PROBLEM Before turning to the anorectic drugs, It is important that we recognize the public health significance of obesity. Although some may believe that excess weight is merely of cosmetic significance, the fact is that obesity is Mierica's number one nutritional problem. Obesity significantly increases the risk of a number of diseases and complicates many other conditions. It is usually chronic and is difficult to treat. Successful therapy depends upon vigilance and effort throughout the patient's lifetime. In testimony before the Senate Cormiittee on Nutrition and Human Needs, on July 27. 1976, the Assistant Secretary for Health, Department of Health. Education, and Welfare WHEW). Dr. Theodore Cooper stated: In recent years obesity has become a public health problem of considerable importance in the United States. Approximately 20 percent of all adults are overweight to a degree that may interfere with optimal health and longevity. Obesity aggravates cardiovascular disease and osteoarthritis and increases the liability to hypertension, atherosclerosis. hernia, and gallbladder disease. Overweight also may facilitate the emergence of latent diabetes in predisposed individuals as they approach an advanced age and adds to the hazards of surgery; it makes for postural derangement, and in extreme cases, it is the c,uce of ohe-.ity rtycpiiea PAGENO="0221" COMPDTITIVE PROBLEMS IN THE DRUG INDUSTRY 14643 with pulmonary insufficiency. It is also of interest that the mortality from cirrhosis of the liver in obese males Is 249 percent of the expected. Fiedicoactuarial statistics make it quite clear that the obese do not live as long as the lean. The chief causes of death among overweight individuals are cardiovascular-renal diseases, diabetes, and disorders of the liver and billary tract. The burden of obesity is not borne equally among all segments of society. In the United States, it is more likely to be found In the lower socio-econornic strata; this association is particularly marked in poor women and to a lesser extent in middle class males. Again, I would emphasize the statistical importance of obesity in our population and the strong need for and potential benefits of systematic preventive action beginning in early childhood. ANORICTIC DRIJCS The successful treatment of obesity requires only one essential therapeutic measure -- that the patient take in fewer calories than he or she needs for a oiven level of exercise Sn that the stored fat in the body is oradually lost as it is burned as body fuel. All supnortive PAGENO="0222" 14644 co~.rPETYrIvE PROBLEMS E~ THE DRUG INDUSTRY measures for the manaqement of obesity -- includino qroun therany (e.q. , Weight-Watchers), special diets, jooqinq, and druos -- have as their sole purpose assisting the patient to eat less or to increase his or her level of exercise or both. The pharmacological action of drugs in the anorectic class is to produce anorexia, i.e. * loss of appetite, and thereby to assist the patient in restructuring his or her dietary habits. There are currently twelve drug entities approved for prescription use In the United States for the treatment of obesity. Three of these, d,l-amphetamlne. dextroamphetamine, and methamphetamine, have been in clinical use since the 1930's. Six additional anorectic drugs were introduced in the period between 1935 and 1962 before the Kefauver-Harris Amendments: benzphetamine, phenmetrazine. phendimetrazine, phentermine, chlorphentertnine, and diethylpropion. The remaining three -- fenfluramine, clortermine and mazindol -- were approved for marketing by FDA in 1973. All of thes?, except mazindol , are related in chernica1J structure) all have central nervous system effects, and, today, all are scheduled under the Controlled Substances Act. REGULATION OF N4ORECTIC DRUGS Before highlighting the major past actions of the FDA, it is wnrth emphasizing that the powers and responsibilities of the lederal Government to regulate anorectic drugs are shared by the Drug Enforcement Administration (DEA) and FDA. In addition, PAGENO="0223" COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY 14645 individual States have passed laws and regulations governing abusable drugs. The FDA controls the approval of new drugs for marketing. regUlates initial ar~d revised labeling, and recoranends to the DEA the selection of an appropriate schedule for a drug under the Controlled Substances Act (GSA). In addition, the FDA provides to DEA Infomation on legitimate medical usage of Schedule II drugs which DEA uses in settion production quotas. tihile the placing of a drup into a particular category under the CSA Is the ultimate resoonsibility of DEA. it is done only on recornendation from FDA after careful review by the FDA scientific staff, consultants and the Controlled Substances Advisory Comittee. The DEA has the ultimate authority to schedule drugs under the GSA. to establish cjuotas on those drugs in Schedules I and II, to monitor the domestic production and distribution of controlled drugs, to regulate their importation and exportation, and to enforce the provisions of the CSA. In selected cases, DEA can act against the prescribing and dispensing of controlled drugs by physicians by invoking penalties against those who are acting outside the legitimate practice of medicine. The National Institute on Drug Abuse (HIDA) and, in some areas PEA fund programs to study the potential and actual abuse of drugs, including anorectics. NIDA also funds programs to treat jind prevent drug dependence. At the State level, licensing boards for physicians, pharmacists and PAGENO="0224" 14646 cor~BTVrWE PROBLEMS IN THE DRUG INDUSTRY pharmacies, hospitals, and other health care units also can influence the prescribing and dispensing practices of health professionals. lurthern'ore. State and local law enforcement agencies, many of which are actively supported by DEA and the Law Enforcement Assistance Administration. police the diversion and illicit traffic of controlled drugs. Coimiunication among these Federal and State agencies is maintained by regular meetings of the involved officials at both the staff and policy levels. The Interagency Coanittee on Drug Control, as an example, Is a working group which includes membership from FDA, NIDA, and DEA. An FDA/DEA Liaison Staff group also meets regularly. In addition, the Coniiissioner of Food and Drugs, the Administrator of DEA, and the Director of NIDA meet personally to discuss policy issues. There is also extensive cormiunication between the field forces of FDA and DEA and their counterparts in State law enforcsnent and health agencies. FDA ACTIONS FROM 1960 THROUGH 1971 The Food and Drug Administration has for many years supported stringent controls on the amphetamines. In thH early 1960's, prior to any clear Congressional mandate, the FDA undertook investigation and prosecution of traffickers In amphetamines. The 1965 Drug Abuse Control Miendments to the Federal Food, Drug, and Cosmetic Act provided stronger regulation over the manufacture and distribution of dangerous drugs, including certain stimulant drugs, and In February 1966 FDA established a separate Bureau of Drug Abuse Control to carry out these Mienthnents. In the first two years of the program, FDA carried out over 2,000 criminal investigations, made more than 1,300 arrests, and handled about 300 criminal cases. The FDA made, in addition, approximately 1,100 accountability PAGENO="0225" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 14647 investigations resulting in 108 civil seizures of depressant and stirmilant drugs. Nearly 600 million dosage units of these drugs were removed from the marketplace because no accurate records, as required by the law, were kept by manufacturers. In April 1968. the Bureau of Drug Abuse Control was merged with the Bureau of Narcotics of the Treasury Department to create the Bureau of Narcotics and Dangerous Drugs (BNDD) of the Department of Justice. In 1973, BNDD became the Drug Enforcement Agency. In October 1970 the Controlled Substances Act (CSA) was enacted and added an important new dimension to the control of abusable drugs. The CSA originally scheduled only four anorectic drugs (amphetamine, dextroarnphetamine, methamphetamine, and phenmetrazine), and these were listed in Schedule III. Injectable methamphetamine was controlled In Schedule II. In 1971, in response to proposals by BNDD, ~DA reconmiended that these anorectic drugs all be transferred to Schedule II. Prompt action by BNDD In making these controls effective resulted in (a) eliminating refills on prescriptions, (b) requiring all prescriptions to be in writing, Cc) subjecting manufacturers, distributors, and dlcprnsers to more stringent security requirements for storing these `Irug'.. (ri) limiting production to Government-established quotas, (e) having all shipments among manufacturers, wholesalers * and retailers hr. qIc,nr (jfl special BNDD order for,uis, copies of which were to be irmnerl 1,1 ~nI y prov `lid to RMDD, (f) prohibiting Import and export of the drugs without prior BNDD permission, and (g) requiring that reports of inventories and all transactions be sent to BNDD. PAGENO="0226" 14648 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY Concurrent with these actions, FDA has carried out an active program of surveillance over the advertising of these drugs. Since May 1966, thirty-eight legal, regulatory, and advisory actions related to their promotion have occurred. Of these actions, twenty-seven have been initiated In the last four years. These have included two product seizures, three remedial "Dear Doctor" letters; and one remedial advertisement. Corrinon causes of actions by FDA in regard to the advertising of these drugs have been inadequate prescribing information; unwarrantedextension of the indications to special groups of patients such as hypertensives. diabetics and teenagers; implied claims of usefulness beyond the indicated short-term use of a few weeks; and misleading promotion which attempts to understate the potential for abuse. The FDA advertising rules require that all promotional labeling and advertisements for these drugs meet the usual requirements for prescription drugs and, in addition, display the appropriate CSA control symbol. FDA ACTIONS FROM 1972 TO THE PRESENT: THE ANORECTIC REVIEW Mr. Chairman, as you know, the Kefauver-Harris Amendments required that FDA review for effectiveness all drugs previously approved on the basis of safety between 1938 and 1962. For the anorectic drugs the Agency elected to review the whole class at one time so that the same standards would be applied to each drug. The amphetamines were included in the review even though they had been marketed prior to 19311. PAGENO="0227" COMPETFflYE PROBLEMS IN PIlE DRUG INDUSTRY 14649 The overall review included not only a detailed statistical analysis of all of the controlled studies in our files relating to the effectiveness of these drugs in obesity but also meetings with consultants and advisory groups. An obviously important consideration in reviewing this class of drugs was the general standard to be applied In determining effectiveness. It was well recognized then, as It is today, that permanent weight loss over the long term is the desired goal of any treatment program for obesity and that proof of such long-term effectiveness is lacking for any of the adjunctive measures used in treating patients with obesity. This does not imply that all adjunctive measures are necessarily ineffective -- only that proof of long-term effectiveness is not available from adequate and well-controlled trials. In the case of anorectic drugs, long-term trials would be very expensive and difficult to perform In view of the many other factors relating to patient motivation which would have to be controlled, or at least measured and accounted for in the statistical analysis of the results. The problem of the standard of effectiveness to be required fur marketing has been discussed repeatedly within the I un ari~I wi Iii consultants. The standard we have adopted Is that ., ;ItIiKUI.I ni of effectiveness should depend upon a finding in adequate an' well-controlled tr1~ls that patients taking the drug sustain a statistically significant greater degree of weight loss than j;at4'rt, PAGENO="0228" 14650 COMPETI'TflTE PROBLEMS TN THE DRUG INDUSTRY taking a placebo. While it would obviously be of value to know with certainty the effect of the drug on the natural history of the disease. we have considered this to be a public health question which an individual drug firm cannot reasonably be expected to answer in the context of evaluating its particular product. The approach taken in conducting the anorectic review was discussed by Dr. Henry E. Sicwnons, the former Director of the Bureau of Drugs, in his testimony before this Subcoimnittee on December 13, 1972, and I would like to restate his description of its magnitude. `The scope of the program was ambitious,and involved over 1,100 volumes of data concerned with twelve single entities. The drug products in which these entities were present, either alone or In cOmbination, were marketed by 40 firms. Over 200 double-blind and controlled studies of efficacy which had been carried out on almost 10,000 subjects were included in the review. Individual patient data sheets were coded and key punched to facilitate computer analysis. This produced over 70,000 comDuter cards, representino over 70,000 patient visits of the 10,000 subjects. Each card included certain patient characteristics as well as changes in welqht, blood pressure, pulse, and other possible adverse effects from vicil to vi',it.. The cards contained over 4 million units of information. I'roqrdnr. were then written to permit automatic statistical analysis in order tn determine what effect the active drug had when comnared with the placebo under `double-blind' controlled conditions." PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14651 These studies were then evaluated by our medical staff to determine whether there was, for each drug entity, substantial evidence that patients taking the drug sustained on the average a greater degree of weight loss over a twelve-week period than patients on a placebo. The twelve-week period was selected because It was the longest period for which there was reasonably comparable data on all of the drug entities in the review. The results of this review were presented to FDA consultants during two meetings In 1972. This group was chaired by Dr. Thaddeus E. Prout, Professor of Medicine at Johns Hopkins University School of Medicine. Their reconynendations were, among others, as follows: I. The single-entity anorectic drugs including the amphetamines should "be permitted to be labeled for restricted use in obesity provided that they are used In association with a specific weight reduction program and that the clinically trivial contribution of these drugs to the overall weight reduction Is properly emphasized." 2. The future approval of anorectic drugs should be `ha~ed on demonstration of efficacy or measured by stati';ticaI superiority of the drug over placebo in trials usinq lilA recomended protoco]s~" The group did not recorrinend that demonstration of a long-term effect on the natural history of obesity be necessary for marketing. PAGENO="0230" 14652 cor~w~rrrrn PRoBLEMS IN TIlE DRUG INDUSTRY 3. All drugs In the anorectic class except fenfluramine should be placed in Schedule 1! on the basis of abuse potential As a result of this review, the following actions were taken by FDA in 1972-1973: 1. FDA required that the anorectic drugs be relabeled to emphasize necessary warning information about their potential for abuse, and also to reflect accurately the indications for which they were judged to be effective and to have an acceptable benefit-to-risk ratio, i.e., narcolepsy, minimal brain dysfunction, and short-term adjunctive therapy In obesity. These conclusions were published in the December 1972 Issue of the FDA Drug Bulletin which was distributed to some SOD,DDO health professionals. 2. We determined there was no place for parenteral amphetamines in medical practice and these products were removed from the market in 1973. 3. We took the position that preparations containing amphetamine' in combination with other drugs (such as barbituratos, vitarimin,, and tranquilizers) failed to meet FDAs coTtination druq policy and ~`iere. therefore, ineffective as fixed combinations. Beginning in March 1973, procedures were begun to remove these from the market. A group of small manufacturers brouqht !``Iil PAGENO="0231" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 14653 !ction to contest this action, but on December 28, 1973. thr United States Court of Appeals for the Eighth Circuit upheld FDA's order. (North American Pharnacal v. Department of Health, Education, and Welfare; 491 F2d 546.) At the same time, several other manufacturers sought formal hearings on the withdrawal of their products from the market. Two products in this category remain unresolved at the present time. The Agency has denied a hearino on one of them, Dexaryl, but this denial is stayed pending judicial review. The hearing request on the other product, Eskatrol, is still under review. 4. We recomended to DEA in 1973 that all of the drugs in the anorectic class be scheduled under the CM. Previous to this recormiendatlon, only the amphetamines and pherfmetrazine were under the CM; these were in Schedule II. The advisory group headed by Dr. Prout had reconriended, as I mentioned, that all of the anorectics, with the exception of fenflurarnine, also be controlled in Schedule II. After reviewing all of the information, however, we felt that the medical and scientific facts available at that time could not support this nsitio!r evidence of signif4camt street abuse was not available for all drugs in the anorectic class. Consequently, the Agency reconnended that seven of the anorectics be controlled in Schedule III on the basis of abuse potential even in the PAGENO="0232" 14654 col.LPETCWE PROBLEMS IN THE DRUG INDUSTRY Sbsence of clear evidence of significant abuse. These drugs were chlorphentarnine. benzphetamine, phendimetrazine, clorternine, mazindol, diethylpropion, and phentermine. Intimately, the latter two drugs were placed by DEA along with fenfluramine in Schedule IV. Given the nature of the data available at that time, we believe our scheduling recomendatlons were medically proper and responsible. Additional information has, of course, been steadily accruing since that time, some of which, e.g.. Dr. Jasinskls studies at NIDA's Addiction Research Center, have been discussed in recent testimony before this Subconinittee. DEA is in the process of analyzing this new information on the anorectics and we look forward to their report. Since 1973, the FDA has developed a mechanism (through the use of the National Prescription Audit and National Disease and Therapeutic Index) for monitoring the utilization of certain drugs at the retail pharmacy level and in the offices of selected physicians. The trend analyses reports from this system are used for making production quota recormnendations on Schedule II drugs and for following prescribing patterns. In addition, we follow the data from the Drug Abuse Warning Network (DAWN), which is operated under joint contract from flEA and lUDA. PAGENO="0233" COMP.rrITIVE PROBLEMS IN THE DRUG INDUSTRY 14655 FDA depends on DEA for special reports to identify abuse problems with specific drugs. Such problems may be recognized by flEA aqentc in the field or through their regional laboratory analyses or through monitoring the output of the DAWN system. Furthermore, NIDA has a substantial program to monitor licit and illicit drug use through general household surveys and through surveys of special populations (e.g., high school students), monitoring hepatitis rates, and compiling drug use data on patients In treatment programs. Special demonstration projects or in-depth reviews a~e also the subject of studies at various times. Information from all of these sources can be extremely useful in evaluating the extent of abuse associated with any given drug. CURRENT STATUS OF ANDRECTIC DRUGS Mr. Chairman, five years have passed since the amphetamines and phenmetrazine were placed in Schedule II, and three years have passed since the FDA's anorectic review and the placing of the remainder of these drugs In schedules III or IV. It Is appropriate that we review at this time the effect of these important Federal actions on the use and abuse of these drugs and ask ourselves whether progress has been made, whether that progress is sufficient, and, if not, what further might be done in the future. I would first like to discuss the effect of these actions on the prescribing of anorectic drugstas measured by the number of prescriptions filled in pharmacies. Appendix I shows the prescrihjnrj trends for anorectic drugs from 1964 to 1976. During the period Iroi,i S5-569 O-7T----i~ PAGENO="0234" 14656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1971 through 1973 there was a particularly dramatic decline in the prescribing of amphetamines. The number of manufacturers of these drugs also dropped considerably during that period. Since 1973 the usage of amphetamines has remained fairly constant at a rate about one-fifth that of the peak year in 1965. The non-amphetamine anorectic drugs have increased in popularity since 1971 and are now prescribed roughly twice as often as the amphetamines. The rate of prescribing of the whole class of anorectic drugs is today approximately 60 percent of the peak rate in the mid-l960's. I would now like to turn to the issue of abuse of the anorectic drugs. Before doing so, however, I must emphasize the limitations of the data currently available for presentation. As I previously noted, an analysis of the abuse potential and actual abuse of the anorectics is underway by DEA, and we look forward to receiving their findings. My conrients today are, therefore, based only on gross data from the DAWN system. By way of background, the DAWN system lists "mentions" of a drug during the contact of an individual at certain crisis centers (including Hot Lines'), emergency rooms, and medical examiners or coroners offices throughout the country. The "mention" of a drug can thus range from a telephone call to an overdose death. It should also be noted that "mentions" of drugs frequently occur in combination. A specific drug is not necessarily the cause of the episode. For example, if amphetamine is mentioned in an emer~ncy room contact, the person may have, as his primary problem, an overdose of heroin but may also have taken an amphetamine. More sophisticated analysis is thus necessary before a full picture is available of the societal problems associated with anorectic abuse. PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14657 With these limitations in mind, I would like to refer to Appendixes II and Ill to make two basic points. Appendix 11 is a bar graph which shows the ratio of total mentions of anorectic drugs in the DAWN system from July 1q73 to December 1975, divided by the number of prescriptions for these drugs during this period. This ratio can be considered as a crude index of the degree of abuse (i.e., total DAWN mentions) per given amount of drug dispensed (i.e., through legitimate sales at the pharmacy level). Both the numerator and denominator of this index are subject to considerable error. as I mentioned. Nevertheless, even this rough approach is revealing. Appendix II clearly shows that the amphetamines (including methamphetarnines) and, to a lesser extent, phenmetrazine, are associated with more contacts with the DAWN system per amount of sales than are other anorectics. The graph in Appendix III illustrates the second point I wish to make. The graph again shows the ratio of total DAWN mentions, this time by quarter years, divided by the number of prescriptions for these drugs in the comparable quarter. The anorectic druqs In this Appendix have been grouped somewhat differently -- that is, by their schedules under the Controlled Substances Act. The main conclusion suggested by this graph Is that abuse problems are greater with the Schedule II rJr'iq~ that with the other anorectics, and that the rate of such prriblon'. appears relatively unchanged over the past three years, PAGENO="0236" 14658 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY CONCLUSIONS AND PLANNED ACTIONS Mr. Chairman, I would like now to state our present regulatory position in regard to the anorectics and to indicate our plans for future actions regarding these drugs. The anorectic review of 1972 demonstrated that all these currently marketed drugs meet appropriate standards of effectiveness under the Federal Food, Drug, and Cosmetic Act. On the basis of the information available at that time, FDA also determined that this class of drugs meets the safety requirements of the Act and are, on a benefit-risk basis, appropriate for marketing for the indication of obesity on a short-tern basis as adjunctive therapy. The most stringent controls possible under Federal law have been in place for five years on those drugs which demonstrate qreater abuse risk than the others, and the remainder of the class of anorectic drugs has been controlled under other schedules of the CSA for three years. Recent information indicates, however, that the Schedule II anorectics (amphetamine, dextroamphetamine, methamohetamine, and perhaps phenmetrazine). have continued to be abused at a relatively unchanging rate over the past three years. While there Is considerable opinion that the current rate of abuse of amphetamines Is well below that of the late 1960's, there is also evidence that the regulatory measures taken in the 1971-1973 period may have accomplished as much as they are going to accomplish. It also appears that the major residual problems of abuse and misuse involving anorectic drugs lie with those already in Schedule II and not those in Schedules III and IV. PAGENO="0237" CGMJ'ETftIVE PROBLEMS IN THE DRUG IflDUSTRY 14659 If the Information currently being developed by DEA clearly indicates, as we anticipate it will, that amphetamines remain a major cause of abuse in spite of being in Schedule II of the CSA, FDA will move ahead vigorously to withdraw the indication for obesity from amphetamines. We need to be sensitive to the other indications for which these drugs are used -- narcolepsy and minimal brain dysfunction in children -- but we must also recognize there are alternative drugs for these indications. I cannot predict at the present time whether any new regulatory action in regard to amphetamines would involve simply removal of the indication for obesity or complete withdrawal of the drugs from the market. Neither can I predict whether phenmetra;ine might be involved in any such action. Answers to these questions will depend on the extent of documented diversion and abuse with these agents found hy DEA and the judgments of those on our scientific staff and advisory cormnittees who will review the data. I would again emphasize that a report from DEA and additional data from the National Institute on Drug Abuse are necessary for FDA to take a strong legal position, and our staffs are working together on this matter. PAGENO="0238" 14660 COMPETITWE PROBLEMS XN fltE DRUG UcDUSTRY The withdrawal from the market of a previously approved drug on the basis of its risk to society, as well as to the patient, is an innovative position on which there is little legal precedent. But we believe such a position is legal and are prepared to defend it. While the preliminary data available to us do not appear to indicate an important public health problem with the Schedule III and IV anorectics, we will, as part of our review consider these drugs also. Again, on the basis of careful consideration of data from our sister Federal agencies and the medical research community, we will take whatever action on these drugs is indicated. Such action might range from recommendations for re-scheduling to improvements in the labeling. I do not anticipate at the present time, however, any new review for effectiveness comparable to the anorectic review of 1972. In view of the importance of obesity as a national nutritional problem and the lack of any widely accepted, universally effective alternative therapy, we do not think it medically appropriate to question at this time the marketing status of those anorectic drugs now in Schedules III or IV. I would also point out that the Food and Drug Administration has under way two major programs which will ultimately affect many prescription drugs including the anorectic drugs: the prescription drug labeling review and the patient package insert proposal. In the very near future. we will issue final regulations on the format and context of package PAGENO="0239" COMPETITWE PROBLEMS C TEE DRUG INDUSTRY 14661 inserts for the physcian and, over the next several years, all prescription drug labeling will come into compliance with these reoulations. Various drug categories will be taken on a priority basis under this program, and we consider anorectic drugs as properly among the priority drugs. We also anticipate issuing in 1977 proposed regulations relating to patient package inserts far prescription drugs. This proposal will undoubtedly stimulate extensive public conmient and may well require another year or more for development of a final order. It is our intent to develop patient package inserts for specific drugs only in the context of this general statement on policy and procedure. In specific cases in which the public health requires a patient package insert on a prescription drug, for important safety reasons, we will take such action on an ad hoc basis as we have for oral contraceptives and estrogens. For most drugs, however, we believe it is wiser to develop general policy ahead of specific patient labeling. We, therefore, anticipate at the present time that specific patient labeling for anorectic drugs will not be developed in the near term. Finally, I would coment that whatever future action we in FDA might take in regard to this class of drugs, some degree of abuse may well continue. Clandestine manufacture and smuggling across international borders will remain a problem. Even if amphetamines are removed from the market, other stimulant drugs will remain available and abuse of these agents may grow. The abuse of stimulant drugs will thus remain a matter of continuing concern, and its control will require PAGENO="0240" 14662 co~pETITIvE PROBLEMS IN THE DRUG INDUSTRY sustained vigilance from all of us. Drugs of this type are intrinsical1y attractive to a segment of our population and, at least for the forseeable future, will remain so. Control of the abuse problem in our society will require the continuing effort of many parties, as these hearings have made clear -- physicians. pharmacists, the drug industry, education, and law enforcement agencies. FDA is proud of its record in the past In handling the anorectic drugs. and we look forward to maintaining that record in the future. Thank you, Mr. Chairman; this concludes my statement. My staff and I would be most willing to answer any questions you may have. PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14863 APPENOIX Figure 1 VIAL IILLIUER OF Rx S FOR ANORECTIC AGENtS, 1964-1976 L;~-n~, -~;~ TOTAL ANADrrT!CS ~PHETN1IfltS AMPHETNII ~s `H ~t: ~ 40 30 I- w -a ~ 20 C - a - -s 10 a projec ted YEAR PAGENO="0242" Milo Ca S. I I I r F Arr,etaire Preps F a _______________________ iherretrarFrfl 1* LLi..i H tLit±It F~yivrCpFfl F F F - _________ Fenfluramne I F ___- - Pherternine F - - .* . ~ I- F-- . .- ccnzptetanlne I F j. .:. I --.. .11:11:1 I~I.I.. -a ~TFI~TTh~T CMorPhen~er~~ ---~ HI I~I~ L I HH- . HI : ~Toreemire F L F - t _- TT V~TI~. I7T~ -- TT.:T 7±tT7n. Lu F'ezind0) .1 It' .1 . . I. I I I ,I4II~~ .1 1 F . ... . ., . a __ F ~pMi~ujne . .., . . . . a, ~.. :.... ~. I ~ . . . ~~HI:IH~. L . I~ .1-Il-. . . .sL~_~,L_tL~ 11.1.. 1.III.i -... ~.i ~. .. .t III IH±I±.H~i1iiH±H.H1h±I-.hTh, IL.: 1.i:. - `±IIII.IH-:.:..H.:IIL-li~i.±i H. ±:J PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14865 APPENDIX III L. .,F ... I .~ .: . I I 11L~: ii I: JICI~ - Ratirtotalfl,wn Tot.! K s(l A) - - - AU. DAWN FACZLITLES -. By Quarter. 07 - - - -- Septl9llthr Dec1975 06~ - - 1 *. 05 - - I .1 ~..: ~. - - I 0,4 t--- ---- ~- . -.. 1 F I [ :I..:I.HH I~ `HI.- .~ Hi 03 01 f H ~ :~` J 1173 1974 1975 Ouutr PAGENO="0244" 14666 CO~ETITlVE PROBLEMS ~i THE DRUG INDUSTRY STATEMENT FOR SENATE SMALL BUSINESS SUBCO~&MITTEE ON MONOPOLY Everett H. Ellinwood, Jr., N. P. ST~M1JLANT AND ANORECTIC DRUGS Introduction In considering the anorectic drugs currently in use, it is important to distinguish between the central stimulant effects and anorectic properties. The amphetamines are perhaps the best prototype of anorectic drugs, havimg strong central nervous sys- tem stimulant activity as well as anorectic properties (See Table I for a listing of anorectic and stimulant drugs). Methylphenidate and phenmetrazine also have strong stimulating properties similar to the amphetamines. In considering the usefulness of these stim- ulant properties, there are two specific medical uses on which a concensus among physicians is held: 1) their use in hypericinetic children; and 2) their use for narcolepsy. In both these conditions, one is Laced with deficiencies in arousal and attention mechanisms. 1-lyperkinetic children demonstrate a remarkable inability to focus their attention on specific tasks or interests before them. They are especially distractable and susceptible to extraneous stimuli from the enviromraent. In a school situation, they are incapable of handling the repititious tasks requiring focused attention, such as reading and writing. Stimulants have also been generally accepted as a specific treatment for narcolepsy, an uncommon con- dition which is characterized by sudden attacks of sleep and weak- ness during normal waking hours, and unusual periodic sleep patterns at night. Stimulants, and especially amphetamine, have been found to change what is at tines an incapacitating condition to an ability PAGENO="0245" COMPETFrIVE PROBLEMS IN TIlE DRUG INDUSTRY 14667 TABLE I DEA SCHEDULE, GENERIC EQUIVALENTS, AND TRADE NA~'1ES OP PRESENTLY MARKETED STIMULANT DRUGS IN THE UNITED STATES DEA SCHEDULE GENERIC ~WTE TRADE N~IE II Amohetamines d amphetamine Dexedrine, Obotan d,1 amphetamine isomers Benzedrine, Biphetanhine, Deicotese, Obetrol methamphetamine Desoxyn, Fetamin d amphetamine + macbarbital . . . ,Dexaniyl d, 1 amphetamine + prochiorperazine . .Eskatrol Other Stimulant Drugs II methyiphenidate Ritalin II phennietrazine Preludin III benzphmtamine Didrex III chiorphentermine Sate III clortermine Voranil III mazindol Sanorex III phendimetrazine Bontril, Melfiat, Obe-Nil, Stratebex, Bacarate IV diethyipropion Tenuate, Tepanii IV fenfluramine Pondirnin IV phentermine Ionan,in, Fastin PAGENO="0246" 14668 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY -2- to return to work, to drive a car and, to carry out in a relatively normal fashion, tasks requiring vigilance and attention. Without the stimulants, the individual would periodically fall asleep as many as six to twenty times a day, and at times and conditions that would be compromising and dangerous. There is disagreement over the use of anorectics having pro- nounced stimulant properties in weight reduction regimes. This disagreement arises primarily because many individuals who have originally taken the stimulants for weight reduction appreciate the energizing and euphoric effects and continue to take the drugs for reasons other than weight reduction. In my opinion, general long- term use of amphetamines or other stimulants for weight control should be discouraged strongly. The current practice of using the more potent stimulants for weight reduction during a two- to three- week start-up period to allow the individual to gradually cut down his food intake patterns then discontinue the medication, needs also to be questioned. Several authors (Penick, 1969; Feinblatt, 1961; Fine~erg, 1967) have specifically recommended this regime as being effective in a weight-control protocol. The Federal Drug Administration has previously reviewed the drug trial data on the effectiveness of the whole gamut of anorectic drugs in weight re- duction regimes and it would appear that they are, indeed, effec- tive- In this unpublished study (Scoville, 1972), using 206 anor- ectic drug trials which had been submitted to the FDA, the FDA re- searchers placed the raw data in a common format and subjected it to a total analysis; they indeed demonstrated that there was a significant effect (at least out to 16 weeks) of these anorectic drugs on weight loss PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14669 -3- Usually, the weight loss amounted to one pound per week nore than a simple diet alone with placebo. For the most part, the researchers at the FDA felt that the majority of the studies were well done, especially those accomplished on the basis of three- and six-week studies. The one-year studies were not well-controlled and did not have good follow-up. A word of caution is needed in that these studies are based on the short-term effects of weight reduction, and if one follows any type of treatment program for obesity for any length of time, the task of keeping weight down in these imdividuals is extremely discouraging. Most researchers (Stunkard and McLaren- huine, 1959; Penick, 1969) report that only a small percentage of patients maintain their weight loss at the emd of a year. Others (Penick, 1969) have cautiomed against the total pessimistic view, in that treatments may have been effective in helping overweight patients from gaining even more weight. There is mo hard data to support the issue one way or the other, and one could certainly conceive of nnorectic drugs being used on a short~'tern basis in order to help the patient establish habit patterns, or become involved in behavioral programs which would foster long-tern weight reduction. Therapeutic Effects Weighed Against Abuse Potential The maim question in evaluating anorectic drugs is not just their therapeutic effectiveness, but also the trade-off against the abuse potential of these compounds. In a later section of this statenent, we will discuss the point that the toxic inpact of amphet- amine-like stinulants on the individual, and indeed on society, is PAGENO="0248" 14670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -4- significant. We should strongly encourage attempts to reduce the use of compounds with potent stimulant properties. Another major question is whether there are amorectic drugs which have less of the stimulant abuse potential but which are still effective anor- ectics. At this point it should be stated that none of the anor- ectics have been proven to be absolutely free of sone forn of abuse potential, yet there may be a new group of relatively non-abused anorectics emerging; that is, the ring-substituted amphetamine ana- logues. To date, the side-chain substituted amphetamine analogues, when tested in self-administration animal models, and in other tests for stimulant properties, all appear to have some stimulant potency. Although weaker than dextroamphetamine and methamphetamine, as well as phenmetrazine, these conpounds would appear to have sufficient stimulant properties to be abused by some individuals. Conversely, the major dependent abuse cycles have not been estab- lished with most of these compounds as has been noted with the above primary stimulants. The ring-substituted anphetanine analogues, fenfluramine and chlorphentermine, are amphetamine congeners which have anorectic effects apparently without major psychostimulant or sympathomimetic effects (for example, cardiovascular stimulant effects) . When tested in man, these drugs instead of producing a stimulant effect, appear to have more sedative properties. Studies using drug abusers to test for euphoric and arousal effects indicate that they do not perceive fenfluramine or chlorphenternine as having the euphoric and arousal effects in the same way as most CNS stimulants. A word of caution is needed for fenfluramine, in that high doses imduced psychotomimetic effects (Griffith, 1976; Gotestam and PAGENO="0249" COMPETITIVE PROBLEMS IN TEE DBVG INDUSTRY 14671 -5- Gunne, 1972); that is, visual and olfactory hallucinations (Griffith, Nutt and Jasinski, 1975), rapid mood swings, distorted time sense, and fleeting paranoia. The psychotominetic effects of fenfluramine should be evaluated carefully since there is one report in the literature (Levin, 1973) indicating that a South African group of drug abusers had used this compound for its hallu- cinogenic properties. There have not been similar reports, to my knowledge, in the United States. With chlorphentermine, one needs to consider that there have been isolated reports of pulmonary hypertension, again which have not been reported, to my lmowledge, in the United States. Thus, these two ring-substituted compounds should be carefully examined, both in the basic research laboratories as well as clinically. Basic research with these two compounds has demonstrated a narked attenuation of stimulant properties as well as the indicators of abuse potential. In the case of fenfluramine, it is 1/20 as potent as amphetamine in elevating blood pressure im rats, and has no effect on body temperature (Blat!, et al. * 1970). Fenfluramine, as well as chlorphenternime, suppress feeding in rats without the induction of locomotor stinulation (van Rossum and Simons, 1969). In the self-administratiom technique for assessment of abuse poten- tial, fenfluraniine has been demonstrated to be a compound for which neither rats (Baxter, et al. * 1973) nor monkeys (Griffith, 1976; Woods and Tessel, 1974) will self-administer. Self-adminis- tration data for chlorphenternine is more equivocal, in that rats have been demonstrated to self-inject this compound as they do amphetamine, phenmetraaine, and diethylpropion (Baxter, et al., 85-569 O-T7-17 PAGENO="0250" 14672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -6- 1973); however, monkeys show little evidence of self-administration (Yanagita, unpublished results). To continue the example with fenfluramine further, in actual practice as an anorectic, fenfluramine has been demonstrated to decrease food intake in many species, including man (see Stuhkard, et al., 1973). Those studies have demonstrated more of a sedative effect chronically with fenflurarnine than for either placebo or amphetamine when administered for weight reduction. Finally, al- though there is a report of the use of fenfluramine for its hallu- cinogenic properties, there have been no published reports of dependence patterns following several million presciptions in the United States. Recomniendat ions In the light of these differences among anorectic compounds, a more rational approach to the abuse potential problem of anor- ectics would be to encourage discriminating basic research and preclinical evaluation of these compounds for the trade-off for their anorectic properties and potential stimulant abuse properties. Furthermore, rescheduling the anorectics with stimulant properties could encourage physicians to be more careful in their prescribing criteria. This observer would consider moving phentermine (tonanine~ and FastinR) and diethylpropion (TenuateR and TepanilR) at least `into Schedule III. In addition, based on basic research in self-adninistration models or evidence of euphoriant effects in nan, conpounds such as beniphetamine, clortermine, nazindol, and phendinetrazine as well as diethylpropion and phentermine, might be considered for Schedule It. Placing these compounds in PAGENO="0251" COMPETITIVE PROBLEMS ZN TEE DRUG TNDUSTRY 14678 -7-.- Schedule IL ~.tould re;uire that the physician explicitly write these prescriptions without refills. This would place considerably more emphasis on re-evaluation for subsequent prescription writing. The more potent stimulants such as dextroamphetamine, methamphet- amine and phenmetrazine currently under Schedule II should be con- sidered for possible discontinuance of their use as anorectics. Certainly these compounds have been denonstrated to have considerable abuse potential. Use of potent stimulants for hyperactivity in children and narcolepsy should be maintained. Finally, physicians might be encouraged to consider prescribing one of the ring-sub- stituted compounds dependent on their evaluation of the patient for an initial weight reduction regime, at least before the more euphoriant and stimulating compounds are considered. Obviously, education of both physicians and the public is a najor means of facilitating this process. Impact of Stimulant Abuse on the Individual and Society In determining the impact of stimulant drugs on the individual and society, one can coasider a host of potential changes including the morbidity and mortality rate among amphetamine abusers; the potential for emotionally apathetic state following chronic abuse and withdrawal which has been described both in this country as well as Japan (Tatetsu, 1963; Utena, 1966; Ellinwood, 1973). In addition, there is evidence from chronic intoxication animal studies that nerve cell death takes place in brain areas which in part mediate alerting and emotional arousal (Escalante and Ellinwood, 1970) Studies in monkeys have demonstrated a long-term, perhaps permanent, depletion of an important neurotransnitter - dopanine -` which lasts PAGENO="0252" 14674 co~.rpr~n'rrv~ PROBLEMS IN THE DRUG INDUSTRY -8- for at least 3 to 6 months following high dose amphetamine main- tenance (Seiden, et al., 1976). Thus, there are clinical descriptions as well as basic research indicating that there nay be long-term changes following chromic amphetamine intoxication. Perhaps the major issue relating to impact on society is that of criminal activity. Obviously, the drug marketplace is an un- stable arena in which crimes against property can become a part of the stimulant abuse pattern (Smith, 1972) One crucial question is whether stinulamts specifically induce violence in abusers. In order to obtain a perspective of the effects of amphetamine on aggressive and violent behavior, one should compare them with the effects of other drugs. The concensus among those who work closely with problems of abuse is that opiates do mot induce unwarranted violence and, in fact, are likely to inhibit tendencies toward violence, even though addicts are frequently involved in potentially explosive criminal situations (Kolb, 1925). On the other hand, for years alcohol and sedatives have been associated with an increase in violence which is thought to be secondary to a lowering of inpulse control (Guize, et al. * 1962). Reports from law enforcement per- sonnel and psychiatrists, as well as from drug users themselves, have indicated that high dose amphetamine use nay also be related. to aggressive behavior - - perhaps more specifically than some of the other groups of drugs. That is. such high dose use may actually facilitate aggression rather than just lowering impulse control (Ellinwood, 1969, 197la; Kramer, 1969; Smith, 1972). Chronic high- dose use of amphetamines, which leads to behavioral aberrations including psychosis, is considered by clinical observers to be a PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14675 -9. volatile state and is the one not infrequently implicated in violent or assualtive behavior. In contrast, several survey studies, where arrestees are interviewed concerning their drug use ( that is, the spectrum of low-dose and high-dose use) indicate that amphetamine use se is not specifically related to violent crines (Blum, 1969; Ecicerman, et al., 1971; Greene, et aL, 1973; Tinklenberg, et al., 1974). Thus, it appears that the violent activity most frequently appears not with low or moderate doses of amphetamine, but with the chronic high dose stage of unstable and/or psychotic behavior. Often the amphetamine-induced paranoid ideation or emotional lability leads to the violent act or even overt homicide (Ellinwood, 1971b). Not infrequently, the amphetamine abuser committing homicide is attacking an imaginary assailant or persecutor created in his paranoid delu- sional thinking. The violent act may take place in a state of terror or panic, often secondary to misinterpretation of events or delusions, Perhaps equally important is the influence of amphetamines in creating: 1) impulsiveness or reactivemess, and 2) a lability of nood in which the user abruptly vacillates from a warn congeniality to fierely hostile moods for the most trivial of reasons (Kramer, 1969; Ellin- wood, 1971a). The drug subculture of amphetamine abuser, of course, is involved frequently in criminal activity in order to support drug use. The anphetanine abuser may suddenly panic and react violently while involved in an armed robbery. At times, this reaction is touched off by a bizarre feeling such as being suddenly and furiously angry because the storekeeper "smiled at me." In the study of amphetamine abusers committing homicide - which I carried out (Ellin- wood, 1971a) seven of the thirteen subjects were acutely psychotic PAGENO="0254" 14676 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - 10 - and delusional at the time, and this disturbance of thought appeared to be di~ctly related to the homicide. Four persons were primarily in an amphetamine induced emotionally labile state. Paranoid ideation nay have been involved in these cases, but it was tot the most salient feature. Two persons with low impulse control had also been drinking at the time the homicide occurred. In two cases, homicide was assoc- iated with armed robbery and this appeared to be the primary contri- buting condition. Although the killers were high on amphetamines at the tine, it is difficult to assess the relative importance of this and other factors since by far the most important factor was the flow of events associated with the armed robbery. Both of these men stated that they were obtaining money to buy drugs. Twelve of thirteen per- sons committing homicide were carrying concealed weapons at the time. Many speed users carry weapons, ostensibly for a variety of reasons including: 1) for use in armed robbery; 2) because of their suspi- ciousness and fears (often he has "heard soneone breaking in at night" or he becomes increasingly fearful of his persecutors and begins carrying a gun) * and 3) there is a certain amount of "cowboy and Indian" braggadocio involved in carrying guns by speed users. Anyone working with amphetamine addicts will hear stories of individ- uals sitting all night with a loaded gun waiting for fantacized in- truders to enter. Under these conditions, speed freaks have been known to shoot at hallucinated noises or images. Amphetamine facilitated violence is not peculiar to the United States; similar reports of bizarre aggression as well as homicide come from Sweden, Japan, and England. Noda (1950) reported that during the Japanese epidemic of amphetamine abuse, in a two-month PAGENO="0255" COMPETITXVE PROBLEMS IN THE DRUG INDUSTRY 14677 - 11 - period 31 of 60 convicted murderers had some connection with the misuse of amphetamines; Rylander (1969) reports that there had been three murders, one manslaughter, and 21 assault and battery crimes committed by the 146 stimulant addicts admitted to his Swedish Forensic Psychiatry Clinic. There had been 109 crimes co,maitted against property; some of these crines were associated with aggression. In his original monograph on amphetamine psychosis, Connell (1958) states that hostile aggressive behavior was observed in 22% of the subjects included in his series from England. In a recent study by the Kalants (1976) examining deaths re- ported by the Coroner in the Province of Ontario in 1972 and 1973 which were related to amphetamine use, they found that 17 of 26 were deaths of a violent nature. Seven were due to accidental violence (usually, due to poor judgment); 7 to suicide; and 3 to homicide. Among the suicides, there was a high incidence of self- inflicted fatal gunshot wounds. Two suicides followed the killing of a police officer with subsectuent impending capture by the police. One male was shot by a policeman after attacking him with a knife. From perusal of both the reported homicide cases and those of assault, it is apparent that many drug -users move through three fairly distinct phases leading to the violent act. The three phases consist of: I) chronic amphetamine abuse, 2) an acute change in the individual's state of emotional arousal, 3) a situation that triggers the specific events leading to the act of violence (Ellinwood, 197la) The phase of chronic abuse often sets the stage; it includes changes in the individual's frame of mind involving suspiciousness, paraaoid thinking, and fearful regard of his environment. It is auring this period that he obtains and begins to carry a concealed PAGENO="0256" 14678 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - 12 - weapon. Armed robbery as a means of supporting the drug habit and conflicts o~ver drug dealing also are segments of the setting that derives from chronic drug use. The second phase, involving a sudden change in emotional arousal and/or a loss of intellectual control, is often secondary to a variety of factors, including a sudden increase in the dosage level (or acute use in a person with low tolerance), chronic loss of sleep, and the use of other drugs, especially sedatives and alcohol. In this emotional and cognitive framework, the person often nisimterprets his environment and becomes increasingly fearful. The emotional misinterpretation nay be quite subtle; for instance. a sudden and overwhelming interpretation of a minor "clue" that fits into the person's delusional system. On the other hand, it nay be a very gross misinterpretation of the entire environment; strangers suddenly become sources of persecution. Often the person mistakes a stranger for a persecutor or, alternately, for a friend (Ellinwood, 1967; 1969). This phase of sudden misinterpretation of the environ- ment is associated with an intense sense of reality. Within this framework, a minor incident can trigger the violent act. Often the threatening incident is half real and half misinter- preted. In nine of the cases in this study, the murder was committed on the basis of an instant decision or impulse secondary to a perceive danger. There were, however, four other cases in which some fore- thought was involv~d in the intent. (One man `tracked down" his victim). Even within this context of pursuit of the victim, there is often a singular event that triggers the violence. In fact in Smith's 1972 descriptions, nonfatal pursuits are not uncommon; Kramer and others (1967) have stated that these games are often only -j PAGENO="0257" COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY 14679 - 13 - half serious. Thus, although chronic amphetamine abuse may set the stage for violence, it is the phase of acute changes in sensibilities that is actually associated with misinterpretation arid the violent - act. At this point, a note of caution is indicated. Homicides related to amphetamine abuse certainly pale in significance when one considers the incidence relative to alcohol related violence. This does not mean that the fewer episodes of stimulant facilitated homicides are not critically important, but we should maintain a perspective with respect to alcohol. Finally, the question can be asked whether there are residual psychological changes that remain after one Kas developed the am- phetamine psychosis. The amphetamine paranoia psychosis is a well- knowm phenomena associated with chronic amphetamine use (Connell, 1958; Kalant, 1966). Although single large doses of amphetamine can produce a toxic hallucinatory paranoid panic state, amphetanine psychosis most often results from chronic abuse and develops gradually; when seem by the examining physician, the process often has extended to the point where a picture of paranoid schizophrenic- like psychosis is present (Ellinwood, 1969). Im fact, many patients have not infrequently been wrongly diagnosed as such. The paranoid syndrome usually does not begin until after the initial few eeeks, or even months of amphetamine abuse. It tends to wax and wane depending on the drug cycle and dosage level. Hallucinations tend to dissipate two to three days after cessation of amphetamine use, yet delusions continue up to two weeks and have been noted in some patients for as long as a year or more. The amphetamine psychosis PAGENO="0258" 14680 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - 14 - usually is a distinct syndrome characterized by delusions of per- secution, ideas of reference, visual and auditory hallucinations, changes in body image, hyperactivity, and excitation (Connell, l958;Kalant, 1966; Ellinwood, 1967; 1969). Whereas the amphetamine psychotic process usually takes a reasonable period of time to develop into its more organized form, once established, moderately high doses can re-trigger the psychosis rather rapidly in indi- viduals who may have been abstinent fron amphetamines for over a period of a year (Kramer, 1969; Bell, 1973; Ehlinwood, 1973). The Japanese (tftena, 1966) also described a tendency for the psychotic symptoms to recur not only with subsequent amphet- amine administration, but also under stress. Since the nore aberrant behavior induced in animal models of chronic intoxication can also be triggered by single moderately high doses (Ehlinwood, 197lb) , the clinical data needs to be taken seriously and examined further. This evidence, plus the observation of chronic delusions in some ampheta- mine addicts seriously raises the issue of chronic persistent behav- ioral effects. PAGENO="0259" COMPETITIVE PROBLEMS rN THE DRUG INDUSTRY 14681 - 15 - CCNCLtJSICNS AND RECO~ThIENDATIONS Obesity is known to contribute to a decreased longevity; thus, it is important for clinicians to have means of establishing weight reduction regimes. Many consider the development of an anorectic without stimulant abuse potential as a goal not only worthy, but obtainable. There is a considerable body of knowledge on the neuro- pharmacology and neurophysiology of eating behaviors. In addition, there are assessment techniques currently available for determining in the laboratory relative stimulant abuse potential for po- tential anorectic drugs. The total abolition of anorectic drugs would reduce the pharmaceutical industry's search for the sion-abused anorectic. There are examples of compounds currently on the market that appear to point in the right direction. Proper use of our cur- rent knowledge base and further research will contribute to the goal of developing better non-abused anorectics. I would suggest establish- ing an independent FDA review comnittee that would provide guidelines for the basic and preclinical research needed to establish the thera- peutic efficacy and abuse potential of new compounds. Use of our current knowledge could very accurately discriminate the compounds that will demonstrate abuse potential and those that will not. In the interim, I would recommend additional rescheduling of the anorectics with stimulant properties to encourage physicians to be more careful in their prescribing criteria. This rescheduling would exclude at this tine the ring-substituted anorectics until there is sufficient data to indicate that these compounds have an abuse potential. The more potent stimulanls, such as dextroamphetamine, methamphetamine, and phenmetrazine, currently under Schedule It should be considered for possible discontinuance of their use as anorectics. PAGENO="0260" 1468Z-co~rPnrrIvE PROBLEMS IN ThE DRUG INDUSTRY - 16 - Finally, it would be helpful to have some means of monitoring and restricting physicians and/or obesity clinics that overprescribe the stimulant anorectics. PAGENO="0261" COMPETItVE PROBLEMS IN THE DRUG INDUSTRY 14683 - 17 - REFERENCES Bell, D. S.: The experimental reproduction of amphetamine psychosis. Arch. Gem. Psychiatry, 29:35, 1973. Bizzi, A., Bonaccorsi, A., Jespersen, S., et al. : Pharmacological studies on amphetamine and fenfluraruine. In: Amphetamines and Related Compounds, B. Costa and S. Garattini (Eqs.), pp. 577596. New York: Raven Press, 1970. Blun, IL H.: Drugs and violence. In: Crimes of Violence, a staff report to the National Commission on Causes and Prevention of Violence, Vol. 32. washington, DC: U.S. Government Printing Office, 1969. Connell, P. II.: Amphetamine Psychosis. London: Chapman Hall, 1958. Eckernan, W. C. * Bates, .7. D., Rachel, 3. V., and Poole, W. K.: Drug Usage and Arrest Charges, a study of drug usage and arrest charges among arrestees in six metropolitan areas of the United States. Bureau of Narcotic and Dangerous Drugs, U. S. Depart- ment of Justice. washington, DC: U.S. Government Printing Office, 1971. Ellinwood, E. H. Jr.: Amphetamine psychosis: A description of the individuals and process. 3. Nerv. Ment. Dis. 144:273-283, 1967. Ellinwood, E. H. Jr.: Amphetamine psychosis: A multidimensional process. Seminars in Psychiatry, 1:208-226, 1969. Ellinwood, B. H. Jr.: Assault and homicide associated with amphet- amine abuse. Am 3. Psychiatry, 127(9):1170-1175, 197la. Ellinwood, E. H. Jr.: Accidental conditioning with chronic metham- phetanime intoxication: Implications for a theory of drug hab- ituation. Psychopharmacologia, 21(2):13l-138, l971b. Ellinwood, B. H. Jr.: Amphetamine and stimulant drugs. In: Dru Use in America: Problem in Perspective, Vol. I. (Second eport of the National Commission on Marihuana and Drug Abuse, pp.140- 157. washington, DC: U. S. Government Printing Office, 1973. Escalante, 0. D. and Ellinwood, B. II. Jr.: Central nervous system cytopathological changes in cats with chronic methedrine intox- ication. Brain Res., 21:555, 1970. Feinblatt, T. H.: Current concepts of therapy in anorexic agents. New Eng. 3. Med., 264:501-503, 1961. Fineberg, S. IL: Obesity and diabetes: A re-evaluation. Annals Intern. Med., 52:750-760, 1967. Gotestam, K. G. and Gunne, L. : subjective effects of two anorexi- genic agents, femfluranine and An 448, in amphetamine-dependent subjects. Br. 3. Addictions, 67:39-44, 1972. PAGENO="0262" 14684 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - 18 - Greene, N. H., DuPont, R. L., and Rubenstein, R. N.: Amphetamines in the District of Columbia: II. Patterns of abuse in an ar- restee population. Arch. Gen. Psychiatry, 29(6):773-776. 1973. Griffith, J. D. : Structure-activity relationships of several am- phetanine drugs in man. In: Cocaine and Other Stimulants, S. H. Ellinwood and N. N. Kilbey (Eds.), pp. 705-715. New York: Plenum Press, 1976 (in press). Griffith, 3. D., Nutt, J. C., and Jasinski, D. H.: A comparison of fenfluramine and amphetamine in man. Clin. Pharmacol. Therap. 18:563-570, 1975. Guize, S. S., Taulson, V., and Catfield, P.: Psychiatric illness in crime with particular reference to alcohol; a study of 223 crim- inals. J. Nerv. Ment. Ills., 134:512-521, 1962. Kalant, 0. .5.: The Amphetamines - Toxicity and Addiction, 2nd Ed. Springfield, IL: C. C. Thonas, 1966. Kalant, 0. .5. and Kalant, H.: Death in amphetamime users: Causes and estimates of mortality. In: Research Advances in Alcohol and Drug Problems, Vol. III, R. 3. Gibbins et al. (Eds), pp. 317-357. New York: John Wiley 6 Sons, 1976. Kolb, L. : Drug addiction in relation to crime. Mental Hygiene, 9:74-89, 1925. Kramer, 3. C.: Introduction to amphetamine abuse. J. Psychedelic PfliS!. 2:1-16, 1969. Kramer, J. C. * Eischmam, V. C., and Littlefield, D. C.: Amphetamine abuse-pattern and effects of high doses taken intravenously. JANA, 201:305-309, 1967. Levin, A.: Abuse of femfluramine. Br. Med. 3. April 7, p.49, 1973. Noda, H.: Concerning wake-amine intoxication. Kurume Igakkai Zasshi 13:294-298, 1950. Penick, S. P.: Amphetamine and obesity. Seminars in Psychiatry, 1:144, 1969. Ruedy, 3.: Drug therapy in obesity. Nod. Treatment, 4:1138-1145, 1967. Rylander, C: Clinical and medical criminal aspects of addiction to central stimulating drugs. Abuse of Central Stimulants, 251-274, 1969. Scoville, B.: Personal communication, 1972. Seiden, L. S., Pischman, N. W. * and Schuster, C. H.: Changes in brain catecholamines induced by long-term methanphetamine ad- ministration in rhesus monkeys. In: Cocaine and other Stimulants, S. H. Ellinwood and N. N. Kilbey (Eds.) , pp. 179-186. New York: Plenum Press, 1976 Cia press). PAGENO="0263" CO3OETITWE PROBLEMS IN THE DRVO INDUSTRY 14685 - 19 - Smith, R. C.: Compulsive methamphetamine abuse and violence in the Maight-Asbury District. In: Current Concepts on Amphetamine Abuse, E. H. Ellinwood and S. Cohen (Eds.), pp. 20S-216. Icashington, DC: U.S.Government Printing Office, 1972. Stunkard, A. and McLaren-hume, M. : The results of treatment for obesity. Arch. intern. Med., 103:79-85, 1959. Stunkard, A., Rickels, K. and Hesbacher, P.: Fenfluranine in the treatment of obesity. Lancet, i:503-SOS, 1973. Tatetsu, S.: Methanphetanine psychosis. Folia Psychiat. Neurol. Jap. Suppi., 7:337-380, 1963. Tinklenberg, J., Murphy, P. L., Murphy, P., et al. Drug involvement in criminal assaults by adolescents. Arch. Gem. Psychiatry, 30(S):68S-689, 1974. Utena, H.: Behavioral aberrations in nethamphetamine intoxicated animals and chemical correlates in the brain. Pro. Brain. Res. 218:1902, 1966. van Rossum, J. N. and Sinons, F.: Locomotor activity and anorexi- genic action. Psychopharmacologia, 14:248-254, 1969. Woods, J. H. and Tessel, R. U.: Fenfluranine: Amphetanine congener that fails to maintain drug-taking behavior in rhesus monkey. Science, 185:1067-1069, 1974. PAGENO="0264" 14686 COMPEPITIVE PROBLEMS IN THE Ditto I1~DUSTRY I t7o ,tssa tilt ian ci Horn icitle Assoc' ;~ ted ~vi ii Atnplactarn' ic Aintse BY EVER Err II. EI.t.i Nw 0(H), 3 It., `1.0. 7he our/nor r/e'seribes (lie lii.storie.s of /3 per- sons Rho cot,,," il/ed ho in it' lt/t ti/I i/c ir,Ioxi- cored sail/a eanr,phe-rant lots. In trios! of rhese roses ihcevc/eodlng,os/ie7ionucielo/ort were direddy ru/ote'd to es"iphcrant Inc in- der~aro,ioid !~ ink lag pta.tic. emotional loU/lily gi-mr,-,-~ I t/ll) tl C control ilk inmost in pont_-nt sot lois/es (j.ssoc lured tilt/I these Cases inc/in/ed p eec/nc/va, lug personal- try, en vi, 0/h/i en teal C freon, I lances, and the use ofa, her drugs. Read at the 123rd annual nientins ol the A mcrican Pochisinic A s5s~cia lion, San Francisco. Calif. May lI-I). 1970. Or. Cl linirood is A sInclair Professor or Pa ycitia try. Duke I) nisers ity Medical Center. Durham. N C. 277~. Thin work wat oupporred in part by Public Hcaltti Service grant MI]- `5907 from the National Institute of Menial Health. The author wishes to en press his appreciation to Dci. Charlru Vernon. Arthur Carlongt. I high Clementn. Ben Briti. Andrew lacako, John Callensore. and Rena Pautu ah. rrhapsmor~~pi'cjflcTl.L,than any otheil groin 0 ~Ll P recent y exa ill used fort r persons who Coin Iii tied murder a fler liking large doses of atisphetamines. The interviews were held after the court proceedings were over.! have out lined below si ree ol these ~ascs to it us. irate )he direct rIled of 3 nolrrlain,inc.in_ duced s;rrsanioid icle;iiion or emotiurtat lalail- ny leading to I he si ` -1 ic `hcse three eases see Fe own hccalasè of tire absence of other variables that often play a pant in the violence associated asisit drttg abuse. The first c:tse illustrates the rapid evolu- tion of paranoid thiti king alter acute Is [gh dose usc Ii ep~s(~ diug usc over several hours of ai11si~ctaruincs a art elton to corn- nat I C r II cets of Ice p ilepa vation. Cane I. This 27je.ur-oId truck driver shot hit boss in the brick of the tread because he thoi,eht the boss was It~ rig to release poison gas into the hack seat or the car in sshich he was riding. `1 hnu,hr they h iii gassed me. My boss ept reach- in g dost n beside hi ml rod puiinng on something. I rolled the si indoss don n to let she gaS Out. I goh nauseated anrl passed out due to the gas; I hen cot tip on fly ctbosr stud shot my boss. "ho was tiriving." Over the prcs'ious 20 hours, in order to make a nonotop 1.600-tuile trip, Mr. A had ingested ISO tag, of amphetamine; he had not slept or 48 hours. Mr. A usually used less than 40 ntg. of ampher amine on long trips. Six to eight hours before she riaurder, he had become increasingly suspicious that someone had planted drugs on his truck. At shis poinh Mr. A called a highway patrol nan. relaled his suspicions in a bizarre manner, and was taken to the local jail for safe- keeping. ~Ahite at the jail, he kept seeing a nan hiding and watchine hun irons across the street. *`Then there were muffled voices in the next room and ahry tried to gut nle. I could heat the hissing. I got down and looked under the door; I saw feet there! I slill remember thetis, Both the jailer and P ISCF.NT STORIES ill tile news itiedia have linked the use of drugs with a Case It ~1i'ar Is series of bizarre murders. Often it is not clearly staled what type of drug is in ques- tion, and in ninny cases several types of drugs have been used. lucre is a need to dis- tinguish as clearly as possible the spcciflc types of drugs associated with aogression and violence. The consensus among those svho work closely with problems or drug abuse is that the opiates do not tend so induce un war- ranted violence (I). [`or years, alcohol and sedatives have been associated by most in- vestigators ss ith an increased incidence ol violence that is thought to be secotadary to a lowering of inspulse control (2L Reports from law-enforcement hscrsolinel and s - - . * - ions ru * a users them- Se yes, ave iii teal e t sat nay nsa be laded b5Th~gfrssWg'bchay~o_s 190) Airier.), Psychic,. 127:9. March /97/ PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14687 the Irrick-stop people acid peculiar: I thought thc~ "crc Out to get inc.' Soon ;iftci";ir d. It is moss arrive d to take him ho rise and hi r. A's delusions about bc boss gradually evolved. "I tried to tell the boss thai hose men wete ssaitinr on us rind vsituld kill us. lie said somethin j~,aSd I knew then he was in on it." When Mr. A artivcd at the car, there were bottles on the floor and he attributed a sin- itter siritifiuance 10 them. Because of this clue. he Ii ness that his boss and the other rider were going to hat in him. Mr. A checked his handbag for the pistol he cart icd with hitn when trucking. Alter several titittittes he panicked when he again smelter1 the "poison gas." An interview IS months alter the shooting re' vealed that Mr. A still believed that mans of the above events hid taken place. `1 `m convinced that those lungs happened; I did see the "art hiding. - . It was just too real rot to he ttue. I knosv it noitnils erniy and I wouldn't believe in if to carouse CISC told nc." There `*~ no other evidence of psychotic thinking or delusions. In fact, I seas struck by Me. A's clarity of thought and jirda utuent in other spheres. Mr. A had pre- viously been judged to be sane by two other psy- chico I ists. II is past history indicated lb at he was ia puts ice i nih vidu a! with strong. dcpen dent fa naily at ac h ments. There was no previous his' tory of psychiatric *tifrceulty or treat ment. More o ftcn chr6nic ataaplccl a mine utsers barn to take paranoid thoughts in thcir stride. They only part ally bcl ieve their thotcczhts and do trot act on them; they appear to be phi) ing games with the "persecutor- victi n'" A factor that nnay contribute to the loss of this awareness of the paranoid nature of their lIt inking is the solitary life-style of some drug users, vshich does not give them an opporttcnity to cross-validate their ideas ssith othert. Case 2 illustrates the gradual development of paranoid delusions in a man "ho lived an isolated life and was a clsronic airphelanaine abuser. Cane 2. Mr. B was a ~6-ycar.old man who had used aaaphrl a in ines for more than two years and had ci actually increased his dose so 500 800 mc. per day Often he used barbiturates or alcohol to calm him dousn but he had had neither prior to the homicide, Althouinh he obtained ampheta- nines Irons people in the drug subeultutre and ob- tained mone) fur drugs illecally. Mc. B was not c~t ensivelv involved in the drug. auhctrlture. Es- sentially he was a loner who spent nost of his time in his apart ment. Durinn the last three mjanths. I got more and more feat `uI and uuspieiousj" At first he knew he vs as "thinkinc crazy Then it becante real, and Astir'. J. P,rt-rlmiui. 127:9. March 197! is at ill feels so at times. I thought m yneigtabor `sat plotting ssith the reds to get me.' I te took hit apurttaent arart. imtcluding his futniture. try. ircg to find tic icroplcone sand I, ok ing dcv ices." Duu ing the last th rcr cur four days before the homicide. Mr. B did not sl~e p at all, lIe described a panic mate over hit ill-defined tortnentort. who were sortie Ii net thought to be federal agents and sometimes a gang than was afire hint because he had stolen drugs from one of its me tubers. Think' big that his neighbor was one of "thena" he waited and watched one cvcnittg until his neigh. her returned. ``I went to hit door to listen. He heard inc and opcncd the door, attd I shot him." At the ti ne of his inierview, three years slier the hotnki~de, Mv. B was a vrry hostile, sullen nan vs ith lilt Ic evidence of any close personal contacts, lie `cad an early history of remarkable uleprivatirurt, aerial as `sPell as emotional. In adulil on to Ca usin n paranoid dcha~j~jc ?E~pheta1cmneS also appear to facilitate act' tn on aggressive iutapolseS. Case 3 illustrates Ic tO ten Sc ,onbis a knee cu osbine with C 510' tional lability to which the individual may be reacting, while appearing to others to be bizarrely unconcerned about site violent act. Cast 3. Dating an argument with her paramour, this 32.year-old woman pulled a pistol out of her waistband, stuck it in his stomach, and calmly fired. 5\'hen the s irtini rot out of the car, she fat- loss ed him and `tat ed, "You wanted to die; I shosved ou" She then chot the victim twice Store. She turned lo a hvtl ander and said, "rut him over and take a picture of his pretty fare," Mrs. C felt that the niust have been crazy, be- cause she later got in the back scat of the patral ear, propped her feet tsp, and tickled the sheriff out the ear, ask ins him if it felt nod. A Ocr inter- rogation at police headquarters, Mrs. C got up sat ins, ``Well, I've got to go; I've got a hair ap- pointment." Originally, a mpheta mine, "crc preneribed for M'is. ci'lset-p her los e vs-ri t'ht. Is osseve r, site "~~"~cseoveecd that they relieved her lonelinert and depression; gradually. over a period of 18 months, she increased the dose to 400 400 mg. per day. i tattueinations were not iolrequucttt. She became suclsieious. ``Even the people who were helping me a eec acainst me." Six ttaonths before the shooting, she bought a pistol to protect her- self and her children at night. "Someone would cotuse itt the vs indow at night; I almost shot E times, it seas to real," "I hated the people I loved the most." Mrs. C became very involved with another man while her husband was away in Viet Nam. At the time for her husband's return drew near, she became patcie-atriek en over how to end their affair. "Yet L91 3 85-569 O-'77----18 PAGENO="0266" 14688 COMPEPI'rrvE PROBLEMS ZN THE DRZJG INDUSTRY I 72 u'iit.tuI_ A-Sc 27 Anne 76 Ch,outc 32 Ct, own/acute 72 Chicauc 27 Ch,oc,c/acu. 30 Chonc 25 Acute 42 AnnIe 20 Ct,,u,,ic 21 C5,ontc 1 9 Ce,,ouic/asute 22 CIsionic 23 Ch,on,r I was fatitastiralty j':zlnhis if be cren nc ntioncd ar,niiicr onions First I snoe'd tril bitt, tic bad to le-,sc me alone; titus I would pity gatnet by feltuuiit0 bitt, to see if he scan uceting router 5505579 I wtrt, Id rifle his uaflet nad err fur let- ten or cities 1_lien I would try to `rotate hiti~ or flirt ssith ethers to titike hint jcalous'' Mis. C was in this I) pe of euueoIion:, fly labile `late -ut the trite of tire shooting. ``I lreuslit'i slcj,t for fr-or clays, WiIS cOnsla]iIly active, rind seat taking ~ili5 like a chicken csi:h its head cut oIl." (She "as taking 600 200 tng per day.) last bela e the incident, she told her paramour that site nit guir.g to lose for ~oerd. Teas innty, he said th:rt he ssoc id Ut inn hi stse w girl fri.d by. `1 nuts wild iac:de the a c.±r'sl animal bitt calm- ly told hun tint Inc nrvcrs-nnuld lie asteti howl would stop hint nd I told bins IsI kill him uttid did" ast the tune of the interview, 13 months after the shouting, bins. C was coanplctely reid, siith- out anty ps)chs',ie nCnu:trst-stions. Both the inter. viescanimi ps),~innloo,cal ieslmmg rcve:clm:d ntw~aitoa ssith low impulse comnt~~j~ espenatly in regard to 1 here a is a p CS~ eupalion and wit in con- tern about her fiuttily and children. Mrs. C had been described by most interviewers as an out' noing, reca ri ous woman whon as rat her enrag- itt her curversation. Fact ors J.c:atdi ng to Violence t3eeause amphelannine abuse in the four cases I examined appeared to be diteetly related to the induction of violence, I sent letters to six lot ensie psyeluiatn isis asking if they had castisiused people stub sitstil:tr his- tories. It Pt osed difficult to find such cases. Only nine addil ional cases were reported by these six psychiatrists (see table I). The rest of this report is based on histories from these 3 cases hut it is complemented by a larger background of in format ion Itoni None June ratr,nd Ncr, lmnoieranrs I.t.t. E'tatsn'rs,,,i~cars, Panielt-a,.,ysmntmeryl A cobol I, rm'cmse Alcohol Alcohol P. a c Id ISO Paranoid tso Panic l*da toht.c'yl SO mpotcio,r/5aaumd Pan a no rSo Pa'an.a,d sittsilnr cases insolsitsg assault, rape, kid. a rpi~g uttetri ptcd ho mieinle, and ``near Bliss Cs.'' A i cview of the histories of these 13 per- Sons who cons stilled hotsi icide after taking anspltct:,tirines niakesjt tthjapiJy_cvudgnj Ibis tticny 9!Tl~T variables nvcre involved in she evol s]tics n or huh ac ion Ic rid ing to the yb fcntattl'nnhahiy,ihctiostinspnrtuuit of these arc: I) yicdispeisirtg pcrscnnahity,2) cnviroiVtnt~umra1 eonnWiio:is, niud ~) the use of !_.~ttU~ Theiiitst p onounecd environ. tent al fact ors lead iitg to 5 iolenee were found in those \sito sset e sells ely involved ins the tuna subculture. the eortcotitilant tine of oilier cli it's, especially sedatives xutnd at- cobol, a ith their known tap:neily to tower ins pulse eo,tt rot, was indeed pertinent. l'ct ha pa the roost ito ci est bog vat iahlc, but the one that is most d tt'scu Itt o as sess, is per- sonalily pectfispositisn, rspeeially in cases lie re the indieid it a! i~s jti dged to be psychotic alter withdrawal of annphetanaines. In the three eases described above, neither involve. nnent in the drug subculture nor concomitant use of other drugs was a factor. These three were not judged to he psychotic after the a ithidrassal of atntnhnetatnines, bitt prcdis- osing personalil was ` en pieta y `a t e secuisd and third eascs~ Roth Mr 13 and Mrs. C svere quite impulsive and aggrcssise, even after the withdrawal of 2m- ph eta "nines. Two others among Ihe 13 included in this review were noted to have si nnil a r in' pulsive personalities. Five of the 13 were judged, by the original exansining psyehiatt ist, to be schiiophrcnie alter complete withdrawal of a napitctansines. In three ofihese live persons, it ssas evident Irotss rite Inistot cs that am- TA~~t I Sor,.eet.,,octr,tnIues ota3A,ct'tnuirefttc.u,s SVS,msCnn,nii,rdltouci4. ustoF romwsn,co..numossro,aon.ntstc 55. vii 2 a 4 S 6 6 a 10 II I, 13 No No No No No No No No Vet Yes Vt:, Ye, Yet (92] Astir,. J. Pajsiiitai. /27:9, Atone!, 1971 PAGENO="0267" CO~OETItIVE PROBLEMS IN THE DEVO INDUSTRY 14689 t',rLtr ii. Li n ,.-siuo, JR. I IS phctattiing:i!ttc$ttad.gquittnt~tP1!~.P~T ~TflTciit ~r,To',irie ada itatiunt ,riOr cue of amphetamines bitt after inhttaton ufdrugtiset:icydcterior*..ttcdr~.tptctly~l-,our flocave 1ttO~ crc Tfl ign one as sch ti 0- pl,rettic repeatedly used ISO in conjunctIOn with am slid -ant ines ~a factor that fut titer complicates the picture. In general, the live diagnosed to be schizophrenic wet e younger (avcra~e rae: 2!) than the other eight persons, sshose average age was 29. Sonar, Other Factors In addition to the pt cdisposing personal- ity. several other recut rent factors were :tp- parent in these hint ones, these factors in- cluded: I) an acute (repeated drug use over several hours) large dose of a I is phet a it ines or a dramatic increase in the amount used; 2) loss of nt ellectual awareness of the delu- sional nature of thought, precipitated either by sleep dcprivaton or by alcohol and seda. tives --in sonic eases, psychotic thinking ap- peared to be potentiated by LSI) and other psych oto ni ntctics; 3) a mjtheta mine- md need sus pcin,Isness. delusions, fear, at,d panic, its well as ensothnal hibitity and tiuptilsive. ness; 4) a solitat y life-style with little chat,ce for cross-va idat ion of dclii siottal thinking; 5) nI usual crib a,,ce,nent of s nspiriett sness and paranoid ideas with other "speed freaks'' (often, however, India iduttts in a "crash grit]" ,n-ill act as a cheek on cite an-- other, puint ing out to an mdiv id al that he is 1,-co fling too paranoid); 6) carrying a concealed weapon; 7) armed robbery as a cleans of supporting drug use; and 8) con- fi met over drug dealings, The acute nature of the amphetamine abuse was a signifleant factor in six eases, Three persons with low tolerance took lame ~on s o a ~T eta v ri ad o f a ew ours~ all three developed paranoid _ggnj~snatss~wo other persons who had be n chroncatly abusing amphetamines dri; natirally increased the dosage for the two to three dnys prior to he homicide, (Thus absolute amphrta mine intake was level of tolerance.) It was noted that in i)TT" states of acute panic the individual often attached his paranoid thought to almost anyone, More s ~ceihieally, she aniphetatnine abuser might attack a tota stranger, ss o jg~Ih~~ppcncd to be passlig by ult the sii~t, Ui:, l~i~c*t~, itrhinal In the cases of anna u It, robhcry, and at- Ic 01 pIed ho titieide, a save II as those of horn- ieidr, the use of alcohol or sedatives a ppeared to he a significant factor in at least a third of the individuals, The main problem ala re't to be a loss ~ f ito elect ual a nv-a rcn~z otthcn:tt,ire i_il the slttte-it,'ittcrd :0 pnr'tsI thtittt)mtgatinl-a loweriiigofitsiptilse control, corn- tuitted quite serious assaults indicat~t sshc,i ,.i,ntti:nntn it:itshlct,ututtessaihi c'thicr inc a met nts ot atcultol s,r si-latis's can often be cotisitinect. Without the a tsph':t;irmiite u~CTie tititis-idual would, rT~e1iasncd our. In contrast th - ~sual~ phu'tattiite use, most of these high-dose eo ` thin ation users have little, if any, niem- or)' of the cvr-tlls asss,ciated ssitli the assault. Sleep deprivation was also a tnajor factor leading to decreased intellectual awareness. In several eases, there was a gradual evolu- ion of a paranoid syste n involving the vic- tim; then, following a period of alcohol intos cut ion or chronic loss of sleep, the, a titphn'tatt'ine abuser acted on Isis delusions. Failure to `a ainta in intellectual awareness oflhe nature sit the drug.utslueed pat anota ts a euttinse utcnoittnator unots-cd In rtsa,ty OF it' e factors I ist'd For i'sssa nrc, several oTTh~Tcstthjects nppearcd to have lost in- tellect a al a is areness licca,tte they lived alone and had litrle chance to cross-cheek their delusional thinking. A horns-term solitary pIe been tic - feaifu( a ttd hallucinatory at night. Many of theta were actually loners and otutsiders, even though they were ac- tively involved in the drug scene. Seape- goating of these outsiders is not unusual, One 21-year-old Caucasian man who used large doses of speed intravenously, along with LSD, developed an acute state of para- noid panic, which was potentiated by his group of Negro companions, Although he overinlerpreted the gestures and behavior of those around him, it was a fact that the group of `speed freaks'' he was running wills did trear him as an outsider and often threat-, Ante,. J. Parch/cr. /27:9, ,Afarc/, /971 (93) PAGENO="0268" 14690 COMPETITIVE PROBLEMS TN THE DRUG TNDUS'PRY 5' KI.1 I II IIIt~s55 11013. JR. pa `a noid think na, and fear lot regard of his environlnenl, It is during this period That heobi',iins and begins so carry a concealed ~scapon, Ar ned robbery as a vu an s of sup' porting the drug habit and conflicts over drug dealing also ate segments of the setting that derives from chronic drug use. The second phase. invols ing a sudden citi nge in cnlot ions I arousal and/or a loss of intellectual control, is o lien sceon dary to a variety of facT ors, including a sudden tie re:lse in tire dosage level (or acute use in a person with low toler:tnee), chronic lost of sleep, and the use of other d rIgs, espe- cially sedatives ~td alcohol. In this emotion- si attd eogttilive fr:tistcsuork- the person oflen misinterprets his unvironrttcnt and becomes increasingly fearful. The emotional t'sisinter- prelalion may lie qs.tc stibtle; for instance; a sudden and overc.itclttiittg interpretation of a ni nor "clue" That flts into the person's dehtsional systetn. (this happened to Mr. A several lines.) On the other hand, it tiny be a vet y gross Itlisinterpretation of the en~ lit e etiviro,l tnent; strangers sutldenly hcco,ne sources of persecution. Often the person list a k esa st r attiter fnr a persecutor or, at- let n~'tcIy, for a friend (II, 32). This pita se of sadden misinterpretation of the enviroti tatent is associated ss ith an intense settse of reality. Within this Ira titework, a nI moe incident can trigger the violent set, Often the threat- ening incident is ltalf real and half micinler. pre'cd. In nine of the cases itt titis study, the 4cr was con, tttisted on the lx' sis of an instant decision or impulse sceond:t ry to a petceived danner, There were, however, four other eases in sshich sotne forethought "as involved in the intent, (One man ``tracked down'' his vktini) Even within this contest of pttrsuit of the victim, there is often a sin- gu ar evc nI that triggers the violence. In fact in S nih's descriptions (4), non fatal pursuits are not uncotnitson; Krattter and others (9) have stated that these games are often only Itaif serious hos, although elit onic amphet- amine ahuse may set the stage for violence, it is the phase of acute charge in setisibitities that is actually associated with In is interpre- tation and the violent act. Cone? tision Until there are figures avail-able for com- paring the incidence of homicide associated 1175 `sith atnphetanrincs tnd that ascoci;tted s'ith such drugs as harbit orates a id narcotics, the tisost rlcfi,titivc ,nssrer to qtiestionsa?sout the relat ionslt ip hut ween violence attd a to- Theta mine usage slay cotne frotts such case reports as the three reported here. In these eases, ho itticide was clearly relitcil toan ~`flspieTh~ n tie-i hiliked etc lasso ial process ~or stateoT ensottottal l.thitity. I recently rcvtewcd several cases of atssptttittitiifffli~t trGad tss Its tn sslttch Its, ha tory_of am,,,, ~,t,chtnLoe abitse svas tot cyen considered us th~ ThirFal evaittation, One wonders si1t~tl Cñhe FCju:t,d trtctdttss,c of ttttplts.ta tit~t~e-in,ttced t,ss,'iult titid IoiniejdJ"1~?uld tiöI hiS' tii'titSh ltighcr ii phy~ieiStiis s'creniore fully'iasi ate of tite j31ôhletW'Ihs ke d"~t have un daIS 5hossingiItenttOthef'of-acs~sjtt~Thd liotniciIR~ ctitiitititted by 3~S'6'pIE~~twer,;~ lit hi is ttt,L ol till l~tctatts t cs °L°~" drtts Rout Inc ttrtnc I sltttin ttons to dctccljh,g kesencc ofdr'tgs itt the system of evcty per.,, scan `iiflstt,sflhlfZfloftnt cii sic_a ould_bs_of,, g:eat'heT~5tnevalu.tingtheineirtcnceofthjs problem, K t; ill IS t NC Cs I, Roth C: frog addict is rctstion tu rrinte. Mc,t Ils-g 9.71 69. 925 2. (`ante S. Tsu,on V. C,tthictd P,et at: Ps' rhisirir itt' remand esinse stith rartirnlar rcfcrcns'e to otrohot- is's-, a siriiy of 223 rnintirats. J Nay Mcnt list 131:5t2-52t. 962 3. K ranier JO: lrt ad retina to atr,tntsrl.i iii or Ps)rhc'!rtle Dew's 2 t -6, 969 4. Smith R: The Siam Set place or `peck skI crier and ronrrstsseincttirdo,,c slime (in press) 5. Coirrlt P14.5mph elasuine t'sshs'sis. London. Cb.spins:in & hall. 958. p54 6 Ontijib 1 A stud5 of illicit ails~lirtat,tinc drug traf- nr in 01, labor's Civ. Anre r .3 Pc)rhia I 113.560. 569. 9(6 7. Angi ci It SI. Gershon S'.;S stilieta nine thuce in New York Cite. 1956-965. Seminars in Pry- chianra 1:195-loS. 969 S Rarirn ,JhV: Street let-el shine or a mpheta mines. in Atuphs'raminc Abuse, Edited by Russo JR. prinf tetd, tlt. Charten C Tlsonsat, 9(8. p~ 51-65 9, K railer iC Fisrhman SC, tinticteld tiC: A isiptsel- amine abuse- paltern and streets of hich drsrs tat, en intrare `musty. 3.' MA t t :305-309. 967 0. Nods H: C onrerns'r,g Si akeamine in tosication, Kuirinc Ig-at.kai jan61 13294-298. 950 It. Etttou nod tIFl,v'A m~t'vtaminr psichosis: a desrrip- tion of the itdi,'idnats aid process .1 N err Men' Oh 44:273-233. 1967 12- Etlttursood F HAm phetamine pn ehosis: a mutti. dimrnsionat procesv Seminars in Pssrhiatr5 1:208. 226. 1969 ,4nrne'r. J. Patch/a,. /27:9, at/on'!, 197/ [95) PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14691 StA~i~MO(~ BY THOMAS N. GELIEMT, M. I). * 150 MAIN STEHET, H1NtINGTON, NEW YORK rnFORE SUmOH~UTJEE ON MONOPOLY SENATE SMALL HJSINESS COM~UTIEE NOYENmR 18, 1976 lfr. Chairman, distinguished membars of the Committee, I appear today as a representative of some 250 physician~ who decided to attack a problem of drug abase among their patients without waiting for governmental guidelines, prohibitions, or coercion. We are proud of our efforts and we are gratified by the results. That now, five years after deciding to "stick to our princi- ples, we are convinced that some form of federal regulation is neoessary. if we are really to succeed. Cur community i5 Huntington, New York, a township of some 200,000 people on the Eastern end of Long Island. The drug we have atteepted to control is the amphetamine, Its immediate fanily, and its cousins the anti-ohesity me&i- cations. Five years ago, in the face of a rapidly increasing problem of drug abase, Huntington physicians decided to stop writing amphetamine prescriptions. We hoped that by this voluntary act we would remove a siseable numbsr of these drugs from circulation and reduce the nusbar of drugs which could in abased. To accomplish this task we conducted seminars, distribated the latest scien- tific data, held hospital staff meetings, and met with community agencies. After exaaT&ining the evidence it was clear to anyone familiar with evaluating scientific data that, except for the rare problems of narcolepsy and the treatment of certain types of hyperactive children, amphetamines had no bona fide use in the practice of medicine. Specifically, there was more than enough evidence to thipport the conclusion that amphetamines had no place in the treatment of obesity. Overnight the prescribing habits of Huntington physicians changed. Prom several hundred amphetamine prescriptions a year~ the average pharmacy found it was dispensing only one or two amphetamine prescriptions a month, PAGENO="0270" 14692 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Some pharmacies filled none Over periods of several months. Some time after our voluntary amphetamine bin, I recall speaking to a pharmaceutical house representative who observed that contrary to his expoc.. tations the amphetamine ban extended to all anti-obssity drugs and an expected increase in the writing for non-amphetamine anorectics hever eaterializod. Huntington physietana had apparently decided that drugs in general had no place in the treatment of ovorweight patients. This philosophy of therapeutics has not changed in the past five years. The newphysicians in town have boen quick to learn of our amphetamine ban and their cooperation has boen exemplary. If we've b,come so successful in this effort why an I here today asking for fodoral help to control tho production and distribstion of amphetamines and related drugs? Despite the honcat effort of 99% of the jraoticing physi- cians in our enmaunity, some duly licensed doctors have decided to confine their practices to the drug treatment of obosity. They meticulously observe the existing laws and they hand out a staggering amount of local amphetamines each day. They art not mosbors ef our medical community. They do not prac- tice in our hospitals, nor are they seabors of our aedical society. Thus they escape the censure of their psers and the constraints which might bo placed upon them. In the town of Huntington there are two such physicians. The Youth Board of Huntington Township recently conducted an unofficial tally of the nu.ebjr of patients seen by one of these doctors in a typical week. Approximately 8C0 patients were seen. As a part of his treatment program, this particular doctor distrilmates amphetamines to all corners. Patients are literally lined up outside of his office. And by no means are all of those in line olmose, Forgetting for a moment those who seek out this man to obtain a supply of "uppers~ to get through the day, such doctors have a readymade parade of victims in any community. They are the tired, overweight housewives; the self-conscious overweight teenagers; or, for that matter, any obose citizens. PAGENO="0271" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14693 These people see in the "diet doctor" an easy solution to their problem and they end up captive to his drugs, needing thorn just to "keep going." One nuch physician can easily prescribe more than a million amphetamine tablets in the course of a year. Undoubtodly, in our cemnunify his practice is assisted by the unavailability of amphetaminoi elsewhere. Therefore, while we certainly have fewer amphetamines in our town than our neighboring communities, how much better it would be for the collective health of our citizens if effective restraints could Ic placed on the distribetion of all amphetamines. if it could be shown that amphetamines and related anti-obesity propara-. tions were of value in treating obesity perhaps one could argue that the dbvious disedvantagea to their use were outweighed by the advantages. The fact is that these drugs are, at best, enly briefly effective in the treat- gent of the overweight patient. Indeed, the prependersnce of evidence is long-term that amphetamines have nq/value other than the placebo effect present when taking any sort of medicine for any sort of condition. If aaphetaieines were effective and necessary in treating obesity it should follow that during the five years since the Huntington amphetamine ban our coissunity would now have a larger number of overceight citizens. This is not the case, Those who advocate the use of currently available "drugs" in the treat- ment of obesity argue that the ,gupposodjepetite suppr.~ant effects of these drugs provide the patient with an initial success in therapy which may spur hia, on to continue his weight reduction program drug-from. The extrapolated conclusion, I imagine, would be that to deny the public these drugs would make obesity more diflicult to treat, The facts do not support this conclu- sion, As a physician whose practice of internal medicine includes large rum-' ters of desperately ill cardiac patients, I hate had considerable experience PAGENO="0272" 14694 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The key to success is motivation. Without it no drug, no diet, no acupuncture, nothing can succeed. It is the physician's job to prese,it to the Overweight patient the reasons why he sust lose weight. He must get to know the patient, the patient's faintly, and the patient's problems. He must convince him of the necessity for losing weight and the logic of his arguments must be inescapable, Where emotional factors prevent success in a weight reduction programs psycho- logical counseling is in order. When such an omotional ispedlisent to weight reduction exists, the last thing a physician should do is fo prescribe a habit~-forming drug. I an convinced that drugs have no place is the treatsent of obesity, I sin convinced that the medical world can practice better aelicjne without the anti-obesity drugs, I sin convinced that the overwhelming eajority of physi- cians believe as I do. I am disheartened by the presence af that small nun- bnr of physicians who capitalize on the habit.forming character of the "diet pill." They threaten the success of the amphetamine-free environment which my colleagues and I are attempting to haild. Frankly, they are a public health menace. I believe thcre is a nnethei of controlling the injuditious distribition of amphetamines. The solution is straightforward and it hn.s precedent. Last month a patient of mine with a painful cancer required aetThdone for relief of his agony. Other narcotics had proved ineffective or u:usable because of his multiple allergies. The drug was provided through nornal channels of distribution with the understanding that it was to be used as an analgesic, not for the treatment of drug addiction. It was pointed ott that a special permit was necessary to use sethazlone for any purpose other than anal- gesia. This is a unique situation. Apparently, the FDA has been re- luctant to involve itself in the doctor-patient relationsh~p, PAGENO="0273" COMPETITIVE PROBLEMS fl~ THE DRUG IZWUBTET 14695 Except for rc~ulations pertaining to the use of new drugs or drugs being invosticatod for efficicy and safetj, the FDA has not involved itself in regulating the prescribing habits of physicians. I believe this to ha laudable: In the instance of methadone, however; it was determined that the absence of tight control of the distribution of this drug constituted a serious public health hazard. The nA~ therefore, used its authority to prnhibit the unrestricted distribution of methadone. The FDA requires that any individual or organization using methadone for the treatment of drug addiction must secure a special license and submit to constant supervision. To do otherwise is unlawful. I propose that the same regulation with restraints be placed on the use of amphetamines, I propose that a special license be required for the use of amphetamines to control obesity and in the control or treatment of drug Mdiction, I further propdse that the existing restrictions on the use of amphetamines be continued for all other uses. In this way the pm-. scribing of this drug will ha limited to a ons-rnonth supply which is not refillable and which is dispensed in a specially.inarked container. I also rocoarmend that the continued use of the non~e2sphets~jne diet drugs be similarly controlled pending further reeearch into their abuse po. tential. Those changes would effectively eliminate the amphetamines from the "diet doctors'." dispensary. If the deliberations of this Committee provide the impetus for the FDA to exercise authority and eliminate the abuse of amphetamines, you will have helped Huntington physicians in their original crusade to beat amphetamines in our community, You will simultaneously aid physicians in coseaunities throughout our country in the control of amphetamine ahise, PAGENO="0274" 14696 COMPETtTTVE PROBLEMS ~ THE DRUG INDUSTRY Statement by: .;llen S. Goldman, M.D. Director The Teratology Center The Children's Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, Pennsylvania. 19104 Before Monopoly Subcommittee of the Senate Small Business Committee November 9, 1976 Distinguished Senators, Ladies, and Gentlemen: I an glad to learn that the Subcommittee is studying various prob- lens of prescription drugs, and I an particularly glad that the com- mittee has asked me to give my views on the possible teratogenicity of the anti-obesity drugs, since the opportunity allows me to act in ,Jtat I consider a most important role as an advocate for the unborn child. Before I discuss the possible teratogenicity of the anti-obes- ity drugs specifically, I would like to give a brief overview of the problem of drugs and teratogenicity in general. Teratogenicity is the capacity of an agent to maIlers the eabryo and the agent is called a teratogen. The thalidomide tragedy has focused attention on the effects of drugs in early pregnancy. Currently, according to the March of Dimes, 250,000 American babies are born each year with mental or physical defects. 500,000 defective fetuses are lost each year in spontaneous abortions and stillbirths. Birth defects cause ndditionally about 560,000 deaths annisolly. The survivors are afflicted with blindness, hearing imp:'irments, heart or circulatory defects, mental retardation, PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14697 bone or muscle disease, digestive, endocrine or urinary impairments. Mthough few drugs have been definitely linked to human birth defects, many are under suspicion. Even aspirin, readily available and massive- ly consumed, has been associated with congenital malformation in exper- imental animals and with an increased stillbirth rate and a significant- ly reduced birth weight in hunans. Several alarming studies of the use of drugs by pregnant women suggest that the problem is that drug~taking is our cultural pattern, According to two prospective studies published in 1963 and 1964 preg- nant Mierican women took on the average of four different drugs per woman during the first trimester of pregnancy. In a more recent Scot- tish survey of 911 pregnant women, 65% took over-the-counter drugs, 2,2 on the average per woman. Eighty-two per cent took drugs prescribed by their physicians, each woman taking an average of four different drugs including iron, analgesics, vitamins, barbiturates, diuretics, antiemetics, antibiotics, sulfonamides, cough medicines, antihistanines, horntones, tranquilizers, bronchodilators, hypnotics and appetite sup- pressants. Unfortunately, the situation with American women has wor- sened in the last decade. A recent study of middle and upper class Texas women indicated that they took from 3 to 29 different drugs `dth the mean increased to 10.3 drugs per woman. Pediatricians used to be terribly concerned that the child was to be delivered into a sea of bacteria. I am concerned that the fetus is being incubated in a sea of drugs. Since most of these drugs were not prescribed to support or save the pregnancy or to save the mother's life and since the effects of 30 many drugs on tbe fetus are poorly understood, administration of 2 PAGENO="0276" 14698 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY any drug to the mother during pregnancy should be greatly justified and) at least, an agonizing decision made in each case. The physician is confronted with two medical imperatives: alleviating suffering and doing no harm. I think that it is time in considering pregnant women that the balance be shifted to doing no harm. It is here that I feel that I an an advocate of the unborn child when I say that the use of drugs should be extremely limited during pregnancy, and then only when the medical indication is compelling. There should be a clear advantage of benefit over risk in each case. The first principle that applies to human fetal malformation which I would like to mention is that the kind of fetal effect an agent produces is dependent upon the tine of its action during devel- opment. Fertilization of the egg by the father's sperm occurs within 24 to 36 hours after ovulation. Implantation of the early embryo in the uterus occurs in the human around the 9th day of pregnancy. The differentiation of the embryo proceeds in this site until the 8th or 9th week of pregnancy at which time almost all organs are fully formed. From the end of the 3rd month when differentiation is virtually com- plete, the embryo becomes a fetus whose main function thereafter is growth. The critical period for nalformations then is during the first 3 months of pregnancy. Thus, the most severe damage caused by a drug in the embryo can occur before the woman in many cases is even aware that she is pregnant. The drugs known to cause human malformation fall into four main categories: The first group of drugs consists of the anticancer agents consisting primarily of folio acid antagonists and antinitot- ics. These drugs are highly toxic to the embryo and produce malfor- PAGENO="0277" CO~ETITIVE PROBI~MS fl~ ThE DRUG fl~DUSTRY 14699 nations in a high percentage of exposed fetuses. The typos of malfor- nations observed in these infants are varied and multiple with no basic ~iattern of syndrome recognizable. The second group of known human teratogens are the steroidal sex hormones, androgems, estrogens, and progestins. It is heartening to note that recent prospective studies of drugs taken by pregnant women suggest that the use of steroids in the first trimester of human preg- nancy has been virtually eliminated. The decline in the use of steroids during pregnancy probably came about as the result of physician educa- tion that androgens and progestins masculinized females, while estrogens and progestins feminize males. Moreover, the primary use of progestins and estrogens to maintain pregnancies in threatened abortions has not proved to be effective. Thus, the benefits to risk ratio of these drugs for this purpose is quite low. The anomalies of sex differentiation caused by the sex hormones occur in a large per cent of fetuses exposed to these agents in the uterus. The third teratogen known to affect the human is maternal alcohol- ism *which produces malformations of a variety of organ systems in ex- posed fetuses. The risk of the fetal alcohol syndroae in exposed fetus- es is only about 30%. The last drug known to malform the fetus and perhaps the best known one is thalidoaide. This drug illustrates the second principle of mal- formations applicable to humans. This principle is that a drug which is virtually harmless to the mother can be devastating to the develop- nent of the fetus. Thaiidoaide again is an exa~ple of a drug that is~ a very strong teratogen affecting nearly 80 to 9O~ of exposed fetuses. It causes a specific syndrome of absence of various joints and bones PAGENO="0278" 14700 CO~'ETY~t~E PROBLEMS IN THE DRUG TRDUSTRY called phocomelia. I think because of the widespread publicity con- cerning thalidomide, I need not daell on the lessons learned from the use of this drug in humans. The thalidomide experience has led to the establishnent of four criteria for the detection of a new teratogenic agent in man. The criteria for detection require: (1) an abrupt increase in the inci- dence of a particular defect or association of defects or symdrorne,. (2) coincidence of this increase with a known environmental change, for example, widespread use of a new drug, (3) known exposure to the environmental change early in pregnancy at the critical period yield- ing characteristically defective infants, and (4) absence of other factors common to all pregnancies yielding infants with the character- istic defect. It cam be seen that these criteria for detection of new teratogenic agents will be useful only if the teratogen is effec- tive in a majority of exposed fetuses. In this case any of the above mentioned drugs already known to be effective human teratogens would have fulfilled these criteria. I call a teratogen which has the ca- pacity to affect above 30% of exposed fetuses a hard" teratogen. However, most of the other drugs suspected to play a teratogenic role in nan are not of the hard variety but are soft" teratogens. A soft teratogen has a low level of effectiveness that is, it has the capacity to raise the incidence of a defect by a factor of 2 to 4 tises over background level. I believe that the data on the anti-obesity drugs, which Dr. Nora probably will present in greater detail, suggest that these drugs fall into the category of soft teratogens. The history of the studies suggesting possible teratogenicity of anti-obesity drugs is typical of that of detection of soft teratogens. PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14701 In 1965 Dr. Norm and his associates had noted that 3 mothers of children born with the congenital heart defect of transposition of the great vessels had taken an anti-obesity drug, dexamphetamine sulphate, during the early weeks of pregnancy. They then determined whether dexamphet. acme sulphate could produce in pregnant mice congenital malfornations especially congenital heart defects. They administered the drug in approximately 20 to 50 times the human dose to the mice in order to maximize the chances of detecting malformations. They found that in addition to cleft lip and eye abnormalities cardiac malformations were produced in the experimental animals and not in the controls. Thus, a single very large dose of dexamphetamine sulphate can produce con- genital cardiac and other malformations in mice. ~1oreover, another appetite suppressant, phenmetrazine, has also heen shown to produce congenital defects in animals. In 1961 Dr. Norm's group in a retro- spective analysis of 219 cases and a prospective study of 52 cases involving use of dexarnphetmmine sulphate during human pregnancy yield- ed no teratogenic effects. The question was reconsidered in 1970 however, when a subsequent study of 184 mothers of-infants with heart malformations showed a higher incidence of amphetamine ingestion than a controlled group. Another study has found an elevated incidence of biliary tract atresia among offspring of mothers taking amphetamines. Some confirmation of these suspicions comes from the retrospective survey of Scottish mothers which showed a higher proportion of chil- dren with various malformations including congenital heart defects fren mothors who had taken dexnmphetamine for suppression of appetite during the early part of pregnancy than the control sothers of nornal :nfants. Two studies also show that phennetrazine was associated with PAGENO="0280" 14702 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the birth of defective children, hut it was not confirmed by a third report. These studies cannot be considered at the moment to be more than tentative evidence * s thee the numbers of cases in all of the surveys of congenital heart disease associated with exposure to anti-obesity drugs are too small to be able to detect a three to four fold increase over the background level of congenital heart defects. The background incidence of congenital heart defects in humans is approximately S per !000. To detect a teratogen which sufficiently raises this background level one would need a minimum of 18 cases of congenital heart disease occurring per 1000 exposed fetuses to demonstrate significant soft teratogenicity. However, I think the fact that these associations consistently turn up in a variety of studies makes the anti-obesity drugs a highly suspect drug for producing defects in humans at a low level. We have been talking to this point about the teratogenicity of an agent which is only manifest as anatomic malformation recognizable at birth. I wouid like to raise the possibility that the anti-obesity drugs when administered in the critical period Day be able to produce functional malformations not observable at birth but only at later stages. These so-called latent effects raise another hazard of pre- natal drugs. Work published this year has shown that the administra- tion of dexamtphetanine sulphate to rats at the critical period in the same dosage as given to humans did not produce recognizable anatomic defects in the rat pups at birth. However, it was found that the experimental offspring showed a marked reduction in the ability to accommodate to new surroundings and this effect persisted for at least PAGENO="0281" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14703 S months after birth. The effect was associated with a persistent depression of brain autononic nervous system transmitters. This i\ xv 0 0 0 0 0 0 0 2 `0 `. PAGENO="0327" COI'flETITIVE PROBLEMS IN TEE DRUG INDUSThY 14749 DEPARTMENT OF HEALTH, COUCATION. AND WELFARE STATEMENT BY DR. DONALD R. JASINSKI Chief, Clinical Phaniiacology Section NATIONAL INSTITUTE ON DRUG ABUSE ADDICTION RESEARCH CENTER Lexington, Kentucky ON COMPARATIVE CLINICAL PHARMACOLOGY OF THE AI4TI-OBESITY DRUGS BEFORE THE SUBCOWIITTEE ON MONOPOLY OF THE SENATE SELECT CO~VIITTEE ON SMALL BUSINESS NOVEMBER 10. 1976 PAGENO="0328" 14750 COMPETITIVE PROBLEMS 1K THE DRUG INDUSTRY TESTIMONY BEFORE U. S. SENATE SMALL BUSINESS COMMITTEE November 10, 1976 on Drug Abuse Mr. Chairman and members of the Subcorimittee, my name is Donald R. Jasinski. I am a physician who is a Comissioned Officer in the United States Public Health. Service. I hold the position of Chief, Clinical Pharmacology Section, of the National Institute Addiction Research Center, Lexington. Kentucky. For over forty years. the Addiction Research Center has conducted studies in volunteer prisoner addicts to assess the abuse potential of psychoactive drugs proposed for introduction into therapeutics. Such studies with narcotic analgesics have proven to be a valid means of protecting the public health. In the last six years, the comparative pharmacology of stimulant drugs has been studied in order to assess the abuse potential of these drugs relative to dextroamphetamine and to provide a basis for scheduling decisions under the Comprehensive Drug Abuse Prevention and Control Act of 1970. * The principal underlying assessment for abuse potential is the identification of a prototypic drug which has been abused and is judged to be a danger to the public health. All drugs having a similar mode of action and sharing the same profile of pharmacologic effects are viewed as having a potential for abuse. Nnphetamine, the prototypic drug for anti-obesity agents, produces characteristic and reproducible alterations In mood, feeling states and perception in our addict population. Volunteers can distinguish these PAGENO="0329" COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY 14751 Page 2 amphetamine-induced subjective states from those produced by agents such as morphine or pentobarbital. One type of change Is "euphoria" or feelings of well-being and elation which are felt to be related to the ability of amphetamine to initiate and maintain drug-taking. In addition, amphetamine produces other characteristic effects including increases in blood pressure, decreases In pulse rate, increases in body temperature, decreases In the amount of food eaten, and a slight Increase In pupil size. From our studies, d-methaniphetamine, methylphenidate, phenmetrazine, !-ephedrine, diethylpropion, phentennine and benzphetamine all produce typical amphetamine-like effects. These drugs differ from one another In milligram for milligram potencies (see attached table), In sufficient doses, however, all can produce the same degree of effects. - In contrast, our studies also indicate that the appetite suppressants fenfluramine and chlorphentermine are not typical amphetamine-like agents. Fenfluramine in low doses can produce feelings of well-being or elation. Large doses more characteristically produce unpleasant subjective states, Subjects clearly distinguish the effects of amphetamine from fenfluramine and more frequently identifiedfenfluramine as ISO or barbiturate-like substances. A further difference is that fenfluramine has little effect on blood pressure and body temperature, but produces a marked increase in pupil size. Three subjects had visual and olfactory hallucinations, distorted time sense, fleeting paranoia and sexual hallucinations. Chlorphentermlne markedly increases pupil size, produces sedation which Is regarded as unpleasant rather than euphoric, decreases appetite without 85-ZOO O-TT-----22 PAGENO="0330" 14752 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 3 producing Increases in blood pressure or body temperature. Some subjects were grossly sedated by chlorphenteniilne, but no hallucinatory syndromes were observed. Abuse potential judgments from pharmacological studies can only be validated by comparison with actual incidences of abuse of available drugs. In this regard, methamphetamine, phenmetrazine and methylpheni- date are three of the drugs pharmacologically equivalent to amphetamine. At times all have had a high incidence of abuse equalling that of amphetamine, On the other hand, three anti-obesity drugs, diethylpropion, benzphetamine and phentermine are also amphetamine-like drugs which are abused. The incidence of abuse of these drugs is much less than that of amphetamine. One source of information on abuse incidence is the Drug Abuse Warning Network (Project DAWN), which is a program co-sponsored by the National Institute on Drug Abuse and the Drug Enforcement Adminis- tration. This program tabulatesdrug mentions associated with drug- related deaths from medical examiners and drug-related medical or psychological emergencies from hospital emergency rooms and crisis centers. In calendar year 1975. the number of mentions in Project DAWN for diethylpropion and phentennine were only 5 to 8% of those for ampheta- mine. According to the National Prescription Audit for this same period, the number of new prescriptions written for these drugs were 40 to 50% of those for amphetamine, suggesting that the lower incidence of abuse cannot be accounted for simply by differences in the relative amounts prescribed by physicians. Similarly, the number of mentions for benz- phetamine is only lt of those for amphetamine, while the number of new PAGENO="0331" COMPETITIVE PROBLEMS IN ~XE DRUG INDUSTRY 14753 Page 4 prescriptions are 6% of those for amphetamine. An additional NrDA- sponsored survey conducted from October 1974 to May 1975 supports these conclusions from DAWN. in this study, 2,510 men representative of all men in the general population who were 20 to 30 years old in 1974, were surveyed for their non-medical use of stimulant drugs. The specific stimulant drugs reported were amphetamine. methamphetamine, methylphenidate, phenmetrazine and biphetamine. There were no mentions of diethyipropion, benzphetamine. or phentermine. Similar considerations also indicate a relatively low incidence of abuse of both fenfluramine and clorphentermine, two agents which are not pharmacologically equiva- lent to amphetamine. The assessment studies in prisoner addicts are valid measures of abuse potential; however, it must also be concluded that factors other than pharmacological equivalence determine the incidence of abuse of a drug. In the case of drugs marketed as appetite suppressants, these factors are not known but experience suggests that at any point In time the incidence of abuse of a drug is determined by customs, fads, attitudes, type of pharmaceutical preparation and knowledge of the drug's actions. In addition, certain properties of the drugs themselves may limit attractiveness to the drug abuser. For example, drugs which cannot easily be dissolved in water are less attractive to the addict who Injects drugs. In retrospect, the comparative pharmacology and the incidence of abuse support the scheduling decisions made under the Comprehensive Drug Abuse Prevention and Control Act of 1970 concerning the anti-obesity PAGENO="0332" 14754 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 5 drugs. On the one hand, amphetamine, metharnphetamine, phenmetrazine, and methyiphenidate are recognized as having similar abuse potential and as such have been placed in Schedule II. On the other hand, a number of other appetite suppressants have not been extensively abused to date. These drugs have been placed in Schedules III or IV. Some would argue that all drugs which have pharmacological equivalence to amphetamine should be placed in Schedule II in order to protect the public health. My own opinion is that this action would in certain instances be detrimental to the public health. The group most directly affected would be those patients using the drugs In a therapeutic situation since restrictive controls make them less available to the consumer. This situation is most clearly illustrated with ephedrine. In contrast to amphetamine, ephedrine is not used as an anti-obesity drug but Is used mainly in the treatment of asthma to relieve spasms of the bronchioles in the lungs. An amphetamine-like spectrum of pharmacologic effects, including euphoria, indicates that ephedrine has an abuse potential. Ephedrine is available in small amounts in a number of over-the-counter preparations and can be purchased without a prescription. The incidence of abuse of ephedrine is quite low and there is no evidence of danger to the public health. Under the present circumstances, the control of ephedrine is unwarranted, especially since the major consequence would be to decrease the availability and increase the cost to patients with chronic asthma. In conclusion, the utility and need for assessment studies to protect the public health is self-evident, especially in those instances PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14755 Page 6 where new agents are being introduced into therapeutics. It is in the interest of public health that we make rational scheduling decisions to forewarn the therapist of the dangers of the drugs he may prescribe and to assist him in their rational use. At the same time, Inappropriate controls must be avoided since this would place unnecessary burdens on the patient. Our studies with stimulants have demonstrated that drugs which are structurally dissimilar to amphetamine can produce amphetamine- like effects and have abuse potential. A similar situation exists with substitutes for narcotics where a large number of synthetic and structur- ally unrealted drugs produce effects similar to morphine and heroin. Further, drugs which are structurally similar to amphetamine do not necessarily produce amphetamine-like effects. In this regard, we have only preliminary data on two recently introduced anti-obesity agents, cloreteniiine and mazindol. We have not studied phendimetrazine. Unfortunately, further data on these agents will.not be obtained. Mr. Chairman, this concludes my formal testimony. I will be pleased to answer any questions you and other members of the Subconmilttee may have. PAGENO="0334" 14758 COMPETITIVE PROBLEMS IN THE DRUG INDUSTItY EQUIVALENT EUPHOROGENIC DOSES Subcutaneous Studies 4-amphetamine 10 my 4-methamphetamine 10 my Methylphenidate 20 my Phennietrazine 40 mg Ephedrine 50 mg Diethyipropion 140 mg d-amphetamine (oral) 10 mg Oral Studies 4-amphetamine 10 my Phentermine 20 my Benzphetamine 50 my 1-Ephedrine 50 my Diethyipropion 70 my PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14757 PIflTSIOLOGIC, SUBJECTIVE, AND BEIIAVIOI{AL EFFECTS OF AMPIIETAMINE, 3IETHAMPIIETAMJNE, EPIJEDRINE, PHKNMETRAZINE. AND METIIVLPIIENIDATE IN MAN W. it. MARTIN, Md). J. W. SLOAN, 11.5. .1. U. SAPIRA, M.D. and P. R. JASINSKI, MD. Lexington, Ky. The National Institute of Mental Health. Addic- tIon Research Center, United States Depart- ment of Health, Education, and Welfare, Public health Service, Health Services anti Mental Health Administration Reprinted from CLINiCAL PhARMACOLOGY AND THERAPEUTICS St. Louis Vol. 12, No. 2, Part 1, Pages 245-258, March-April, 1971 (Copyright © 1971 by The C, V. Mosb~ Company) (Printed In the U. S. A.) PAGENO="0336" 14758 cOMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY Physiologic, subjecflve, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methyiphenidate in man Five centrally acting sympathosnimetic .,mines, d-.amphetamine, d-onet barn phetarnine, ephedrine, phenmetrazine, and methylphenldate, were studied in man. All of these agents increased blood pressure and respiratory rate, produced similar types of subjective changes, and increased the excretion of epinephrine. Wish regard to these parameters, there was a high concordance between estimates of their relative pot encies. The concordance between the potency estimates for the different parameters suggests, but does not prove, that these jive agents share a common mode of central actton. Further, if the peripheral modes of action as elucidated by animal studies are true for man, this study suggests that it is unlikely that their central actions in man are a consequence of the release of norepiuephriue in the brain. W. R. Martin, M.D., J. W. Sloan, 6.5., .1. D. Sapira, M.D., and D. R. Jasinskl, M.D. Lexington, Ky. The National Institute of Mental Health, Addiction Research Center, United States Department of health, Education, and Welfare, Public Health Service, Health Sensices and Mental Health Administration Several central nervous system stimu- Jants, including d-amphetaniine, d-meth- amphetamine, mcthylphenidate, and phen' metrazine, have been increasingly abused and their abuse seems to share many features in common. Patients taking these drugs to obtain feelings of well-being and euphoria frequently escalate the dose to the extent that a toxic psychosis is pro- duced. On the basis of animal expcri- Received Cur p,,blicatian sept. 4. 1970. Accepted toe p,sblieatisn Nov. 6, 1970. ~P,nent add,,',,: Depann,e,'t of Medicine, Univenity of Pittsbusth school at Medicine, Pittsburgh. Pa. ments, these drugs have several known modes of action including release of cat- echolamines, blockade of uptake of cate- cholamines, inhibition of monoamine oxi- dase, a serotonergic action, and cocaine- like effects. Our experiments were con- ducted in man comparing the effects of d- amphetamine, d-methamphetamine, plien- metrazine, methylphenidate, and ephcdrine (Fig. 1) on several physiologic, behavioral, and neurochemical measures to delineate their mode or modes of action in pro- ducing subjective effects. Closely related to this end was the goal of validating meth. 245 PAGENO="0337" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14759 246 Martin at al. CUScgI Pharmacology ad Therapeutic, CH2-CH-NH2 CH5 AMPHEtAMINE /~~-CHr. CH-NH-CH3 CH3 E I HAM PHE TAM IN E QOH CH3 CHCHNH CH, EPHEDRINE OH~ - C- C / % - 0 NH ,` / c-C H2 Ha PHENMETRAZINE 0 O C-O--CH3 CH~c_ - CH2 NH I I H2 `12 METHYLPHENIDATE Fig. 1, Chemical structures of amphetamine-like thugs. ods for assessing amphetamine-like sub- jective effects which are related to their abuse and abuse potentiality. Methods Phyaiologieal and behavioral measures. Subjects participating in these studies were male prisoners serving scntences at the Clinical Research Center, Lexington, Ken- tucky, for Federal crimes committed in connection with narcotic use. All subjects volunteered for the study and were exam- ined to ensure their mental and physical suitability. Studies were conducted on the wards of the Addiction Research Center, At weekly intervals the subjccts were ad- mitted to the Addiction Research Center ward the evening prior to the test day. All were interviewed, and blood pressure, pulse rate, and body temperature were determined ia order to detect intercurrent minor illnesses. After dinner was served, the patients engaged in various ward ac- tivities (table games, television, reading) until they retired. The patients ,were awakened at 0600, and breakfast was served on the ward. Base-line physiologic observations were obtained at 0700 and 0730. Medication was administered sub- cutaneously in a 2 ml. volume at 0800 on a double-blind basis, and physiologic ob- servations were made and questionnaires completed by both subjects and observers at 0830, 0900, 1000, 1100, 1200, 1300, and 2000. The following physiological observations were made: (1) indirect blood pressure (always determined on the same arm by the same observer with the patient supine: mean blood pressure calculated as the diastolic pressure plus one third of the pulse pressure: blood pressure determina- tions repeated until 3 consecutive mean pressures fell within a 5 mm. sange); (2) pulse rate; (3) respiratory rate; (4) rectal temperature; and (5) pupil diameter (determined photographically in 30 foot candles of light with an accommodation distance of 26 inches). The food chosen by the patients at lunch, which was served at 1130, was weighed and the caloric con- tent calculated from standard tables, The caloric content of uneaten food was not measured. This measure then is an in- dex of the appetite of the patient at the time that he went through the food line. The questionnaires completed include the single dose questionnaire for both sub- jects and observers' and a psychological test completed by the subjects which con- sisted of questions from the following scales PAGENO="0338" 14760 COMPEtITIVE PROBLEMS C~ TEE DRUG fl~DUSTRT Effects of amphetamines 247 VcJ.ane 12 Nu...hev2.Partl I 0 30 00 isO SO LOG DOSE .,o/7055 PLACEBO AMPHETAMINE 0-0 METHAMPHETAMINE E PHE DR IN S fr-A PHENMETRAZFNE ME THYL ID AT E 7 0 50 100 ISO LOG DOSE ~`q/70kQ of the Addiction Research Center Inven- Way°: 1'CAG (pentobarbital, chlorproma- zinc, alcohol group scale), which is a measure of sedation; MUG (morphine- benzedrine group scale), a measure of euphoria; LSD (lysergic acid dicthvlamide group scale), which esti,nates dvsphoric and psychotomimetic changes; and 13G (benzedrine group scale), an empiric nmphctaniine scale. In addition, a new 11 ite,n amphetamine (A) scale was coIl- structed for those items for which there was a significant regression of response against dose for the 3 doses of d-amphet- amine and a nonsignificant deviation from linearity. The items of the various scales are presented in Appendix 1. On the morning following the test day, subjects were asked to estimate, to the nearest ½ hour, the a,nount of time they had slept the previous night. No attempt was made to verify this subjective estimate. Dose levels of the drugs to be compared "crc selected on the basis of results ob- tained in the preliminary dose run-up study. The comparison was done in two parts. In the first part, cl-amphetamine (7.5, 15, and 30 mg. per 70 Kg.), d-meth- 250 200 50 r `00 C 0-4 50 a `-50 7 `0 30 00 `00 TEMPERATURE I `0 40 ~3~3 100150 100 = so. C "~0 30 DIASTOLIC B P A 2 0 a- 1-4 to 2 0 a- `-I U, 2 0 & I-I 20 10 A SCALE SUBJECT LIKING ~ ,boi~o OBSERVER LIKING ib 30 00 `50 -8 ;~-~---`---,~~ .94 ,~, io ibodo BGSCALE / 40 30 A `000 20 ~t00 £00 -S U D. F 400 7 `0 30 00 150 IX 30 E 20 C 10 10 C 5-5 0 `-4 Rrsp'RAIION I 0 40 7 `0 ao~ S CALORIES 15 2 0 a. 0-4 200 20 50 MDC SCALE S 4 `I, = 0 I Ix i lb 30 ~I2O SLEEP Fig. 2. A summary of dose-response relationships obtained for several physiologic and sob- jevtive paraneters with amphetamine-like drugs, these data provided the hasis on which rela- tive potency data presented in Table I were calculated. jib 30 LOG OOSE ~s~ITOIq PAGENO="0339" CO~tQETITXVE PROBLEMS IN THE DRUG INDUSTRY 14761 248 Martin et at Clinical Phan,saeoIog'd and 3hcrapeiasica Table L Potencies of methamphetamine, phenmetrazine, methylplzenidate, and ephedrine relative excretion Drags Systo/ic blood pressure Diastolic blood pressure Mean blood pressure Hespirntory Tale Amphelernine scale d-Mothaniphetaniine 0,92' (0.76-1.13) 1.491 (0.98-256) 0.99' (0.78-1.25) 0.923 (0.52-1.59) 0.93+ (0.67-1.26) Phonmetrazine 0.26) (0.22-032) 0.41' (0.31-0.53) 0.31) (0.25-0.38) 0.32' (0.21-0.42) 0.21' (0.12-0.38) Mctlsylplsenidate 0.31' (0.2-4-0.43) 0.571 (0.41-0.82) 0.441 (0.34-0.5S) 0.48' (0.33-0.67) l-Ephedrine 0.27' (0.22-0.31) 0.111 (0.08-0.16) 0.l9~ (0.15-0.2-I) 0,24' (0.15-0.45) 0.17' (0.11-0.24) Potency e,tos,ates seer .prmued as number S milligram, S d-un,phelan,sne equisal,'ot to' mg of the drug, Figures in least our of the c-eiteña foesvalid bioassay was not fulfilled. `Based on a 5 point sIssy. Based on `6 point sass y. *Ba,edona4 point assay. amphetamine (15 and 30 sng. per 70 Kg.), and a placebo condition were compared. Twelve subjects participated and were as- signed to one of two 6 x 6 latin square blocks for which dose ordering was ran- domized. The second part of the study was initially planned to compare ephedrinc (75 and 150 mg. per 70 Kg.), plienmetra- zinc (35 and 70 mg. per 70 Kg.), and methylphenidate (15 and 30 mg. per 70 Kg.) also using a 6 x 6 latin square design. Eleven subjects participated in both cx- perirnents. Because one subject who had participated in Part 1 could not participate in Part 2, a placebo condition and the three amphetamine doses were added for the twelfth subject in Part 2. In addition, because some of the bioassays were not completely satisfactory, a 7.5 mg. per 70 Kg. dose of methamphetamine and 60 mg. per 70 Kg. dose of mcthylphenidate were administered at weekly intervals at the end of the second part of the experiment to the 12 subjects participating in Part 2. Analysis of variance was done to deter- mine if there were any significant across- weeks effects which could indicate the development of tolerance or arlaptation for the first part of the experiment, as well as to segregate the variance due to regres- sion (dose effect), between-preparations differences, linearity, and parallelism for both parts. Depending on the particular experiment ant) the particular parameter, either a 4, 5, or 6 point assay was used. A valid bioassay was one in which there was a significant regression, no significant devia- tion from linearity, no significant difference in prepiorations, and a significant treatment effect. Relative potency and confidence limits were calculated according to the method of Cox and Ruhl.~ Urinary catechotarnine methods and pro- cedt,res. Patients voided immediately be- fore receiving medication or a placebo at 0800 and then drank 500 ml. of water. Urine samples were collected from 0800 to 1100 in bottles containing 10 ml- of fiN HCI. During this time, the patients re- mained in bed, except when physiologic ohservations were made, to minimize van- ability in catecholaminc excretion by par- tially controlling for the influence of exer- cise. The urine specimens were frozen and stored at -18° C. until analyzed. Sped- mens whose volume was less than 500 ml. were diluted to this volume prior to being frozen. Urinary epincphrine nor- epinephrine, and dopamine were analyzed using a modification of the method of \Veil- Malherbe.~° Duplicate samples were used PAGENO="0340" 14762 co?~ETITIvE PROBLEMS IN THE DRUG INDUSTRY Vol antiS Number 2. F~fl I Effects of amphetamines 249 to amphetamine for physiologic and sub/active measures as well as enhanced epinephrine BC scale Subjects' liking Observers liking Caloric intake Sleep time Unrsary epinephrine 1.68° (1.14-2.30) 1.161 (0.71-1.82) 1.22f (0.89-1.12) 1.191 (0.80-1.83) 1.451 (0.93-2.58) 2.341 (0,99-54.8 0.31° (0.21-0.42) 0.22° (0.08-0.65) 0,33° (0.26-0.41) 0.43° (0.23-0.81) 0.251 (0.12-0.44) 0.21t (0.04- 046) 0.58' (0.45-0.80) 0.59° (0.46-0.82) 0.5Sf (0.42-0.80) 1.05° (0.64-1.83) 0.52° (0.22-1.39) 0.751 (0.38- 2-16) 0.11° (0.11-0.24) 0.2P (0.15-0.33) 0.21° (0,15-0.29) 0.19' (0.12-0.29) 0.07' 0.221 parentheses axe the 95 per tent conade,ace limits of the estimot a, The omission of 95 Pr,- cent confidence timsu mdscstes that st for determining endogenous catecholaniine content. Determinations on duplicate sam- pies to which a mixed standard of epinepil- tine, norepinephrine, and dopamine were added prior to the hydrolysis were made to determine the efficiency of recovery of the method and to permit values to be corrected for standard recovery. Centrifu- gation of the specimens which is frequently necessary before the urine is applied to the alumina column was omitted in this experi- ment because a heavy precipitate was not produced in the dilute specimen; hence, there was no impediment to flow through the column due to this factor. Urinary ereatinine was estimated according to the method of Peters.2' R.su Ifs Physiological changes. All drugs pro- duced a dose-related increase in blood pressure (Fig. 2), and as can be seen from Table I thcre is good concordance between the potency estimates for systolic, diastolic, and mean blood pressures for all drugs. With one exception, the potency estimates were not significantly different from one another. The effects of ephedrine on diastolic blood pressure and systolic blood pressure were relatively less and greater, respectively, than the effects of amphetamine on these same parameters (Table land Fig. 2). Amphetamine, methamphetamine, ephe' drine, and phenmetrnzine had about the same relative potency in increasing respira- tory rate as they bad in elevating mean blood pressures. Although niethylphenidate also produced a signiBcant increase in respiratory rate, the slope of the dose- response relationship over the dose range studied was not statistically significant. The maximum increase in respiratory rate was significantly less than that seen following the highest doses of amphet- amine, methamphetamine, and ephed- rine. All drugs produced signi&ant increases in body temperature. The relative potencies and 95 per cent confidence limits for the three drugs in comparison to amphetamine in which the criteria for a valid assay were met are: ephedrine, 0.06 (0.00 to 0.11); phenmetrazine, 0.33 (0.01 to 0.51); and methylphcnidate, 0.41 (0.20 to 0.65). As can be seen from Fig. 2, ephedrine was less potent in increasing body temperature than in increasing mean blood pressure and respiratory rate and in producing sub- jective changes. Although methampheta- mine was quite effective at all dose levels studied in elevating body temperature. PAGENO="0341" COMPETITIVE PROBLEMS ~ THE DRUG nqDUsTRy 14763 250 Martin et al. the slope of the regression line was not statistically significant (Fig. 2). All drugs except ephedrine produced a significant degree of pupillary dilation; however, a valid assay was obtained only when amphetamine was compared with methamphetamine (0.92 [0.05 to 6.62]). The effects of all drugs on pulse rate were quite complex. All drugs produced tachyeardia; however, for amphetamine, methamphetamine, ephedrine, and phen- mefrazine there was an over-all negative correlation between pulse rate and blood pressure (Table II). The time-action curves of amphetamine on blood pressure and pulse rate am presented in Fig. 3 and illustrate typical relationships between these variables that have also been seen with methamphctamine, ephedrine, and phenmetrazine. Both the 7.5 mg. per 70 Kg. and 15 mg. per 70 Kg. doses pro- duced a modest increase in blood pres- sure and a tachycardia during the first 5 hours after administration. In contrast, the 30 mg. per 70 Kg. dose level pro- duced a greater increase in blood pres- sure, and, during the time when blood pressure was maximally elevated, the mean pulse rate was not significantly different from placebo value. However, 5 hours after administration of the high dose of amphetamine, when the pressor response was decreasing, a marked tachycardia was observed. The relative bradycardia seen Clinical Pharw.acalogy end rh.eape,aica with the greater pressor responses was un- doubtedly reflex in origin and accounts for the negative correlation between blood pressure and pulse rate. In contrast to these drugs, as can be seen from Fig. 3, all doses of methylphenidate produced a marked tnchycardia, and a positive cor- relation was found between blood pres- sure and pulse rate for methylphenidate (Table II). All drugs reduced appetite as assessed by the calorie value of food selected from the serving cart, and valid assays were ob- tained for all drugs. Potency estimates were not significantly different from potency estimates obtained using blood pressure for methamphetamine, phenmetra- zine, and ephedrine. Methylphenidate was somewhat more potent in suppressing caloric intake than it was in elevating blood pressure but not in producing am- phetamine-like subjective effects (Table I). All drugs decreased the patients' esti- mates of sleep time, and valid assays were obtained for this measure for all drugs except ephedrinc. The potency estimates were in good agreement with the potency estimates obtained with the physiologic measures and subjective rating scales (Table I). Subjective effects. All drugs increased in a dose-related manner the scores on A. BC, and MBC scales (Fig. 2); however, the usefulness of these scales in calculating Table 11. Analysis of correlation coefficients between blood pressure and pulse rate for the five centrally acting drugs Drugs Correlation between ce11s Correlation within cells Correlation between subjects Total correlation Amphetamine -0.702' (20) -0,134 (231) -0.223' (11) -0.28i * (251) Methamphetamine -0.585' (20) -0.144 (231) -0.370' (11) -0.278' (251) Ephedrlac -0.734' (13) -0.136 (154) -0.003 (11) -0.277' (167) Fhemnetrazine -O.147 (13) -0.485 (154) -0.612' (11) -0.367' (167) Methylphenidate 0.679' (20) 0.111 (231) 0.179' (11) 0.238' (251) Betweem.cells correlation represents that altdbo,t,ble to oh, different observation periods (1) and the done (0) as wru as I x 0. Within.cell, cororlationt include between-subjects and the frslerssction, involving subjects (5. 5 x I, 0. and S ,c I x 0). The £g,re. in parentheses repre,e,l lhe degree, of freedom. The between-cell, correlation coeffi- cient, were tll* significant when they were tested with the S x I 0 interaction term, thus drenoosaeati.g conclusively that these correlation, we,. due to drug effect, and not to a relationship between puls, rate,,, blood preso,ue that coc,ld have existed in the population.~ p `C 0.01. PAGENO="0342" 14764 COMPETITIVE PROBLEMS fl~ THE DRUG ~cDXYSTRY Effects of amphetamines 251 5:1 HOURS relative poteneies differed for different drug comparisons. Valid potency estimates were obtained for all drugs except ephedrine when using the A scale and for all drugs except phenmetrazine when using the BC scale. None of the assays were valid using the MBC scale. All drugs decreased PCAC scale scores below placebo levels. The largest doses of all drugs increased LSD scale scores above the placebo level. By and large, relative potencies ob- tained using the A and BC scales were in good agreement with each other, as well as potency estimates obtained for blood pressure. Subjeets indicated that they liked the effects of all drugs, and the observers felt that the patients liked all drugs. The "ilk- inC scores were dose related (Fig 2). and potency estimates for all agents showed a good agreement with potency estimates obtained using the A and BG scales (Table I). Patients' and observers' identifications of the various drugs and doses are presented in Table III. The frequency that drugs were identified as "benzedrine" increased with dose levels for all drugs; however, even at the highest levels less than 30 per cent of the identifications made by patients were that of henzedr'me for any of the drugs studied. It is particularly interesting, especially in view of the similarities of the subjective effects of these drugs to morphine,' that not a single patient iden- tified any dose of any drug as an opiate. The identifications by the observers were quite similar to those of the patients, ex- cept that the percentage of benzedrine or ephedrine identifications for the high doses of amphetamine and methamphetamine a PC d - AM P HE TAMt~E MET HYLPHENIDATE MEAN BLOOD PROSSURE 10 05 o.-o I3~;7O4 tOO 95 F PULSE RATE Volume 22 Number2,Pa61 = z a = 0. C C a lx Fig. 3. Mean blood pretsure and phenidate. and a saline placebo. `5. HOURS 5 2 pulse rate time-action runes for d-amphetamirse, methyl- PAGENO="0343" COMPETITIn PEOBLE?ZS IN THE DRUG INDUSTRY 14765 252 Martin at a?. Clinics! Phanneaertogy and There penatics Table UI. Drug identification by sub fects and observers (single dose questionnaires) d-Arnphcfa- d-Methampheta- di-Phena- Via- nsine mine i-Ephedrine met razine Methylp)nenidate Drugs ceho7S~15I30 7515 30 75 150 35]70 15 30 60 Subjects Benzedrine - - 7 29 4 15 20 II 15 - 22 17 13 21 Cocaine __~_ 4 7- - 6 4 - - 6 10 12 Falarihuana - 1-- 5 5 4 - 8 6 6 - 5 8 Coolballs --~ 2- - - 4 6 -` - 4 1 - barbiturate) Other 7 13 38 46 21 41 43 49 54 6 35 15 24 42 Blank 93 86 51 16 70 39 33 30 13 88 37 58 45 14 Observers Benzedrine - - 15 57 - 27 57 13 20 - 25 11 7 22 Cocaine 5 - - - Ephedrinc - 2 13 - - 11 7 - 7 - - 7 2 7 Coolballo 4 1 1 2 (barbiturate) Other 4 37 31 34 56 43 17 53 59 32 50 30 54 58 Blank 92 61 41 9 44 19 18 34 14 68 14 52 -36 11 Foe each hvar'neno there sssere seven opportunities (times) for each subject to idssatify the drug. The nomttero in each column are percentage identifications and were natcoatated taring tIle total possible responses (84). Some ohaenvca itteuti' Led the agent as "ephednime" on several occasions. Table IV. Summary of symptoms and signs (single dose questionnaires) d-Amplaeta- d-Methamephota- di-P hen- Symptoms Via- "`less mine i-Epheeiriiae met razine Met laylphenidcste andeigsas cebol.5115I30 ~*~l 15130 75150 35170 15130160 Symptoma Bc-taxed 7 13 24 40 18 36 31 45 38 18 2t 20 18 23 Nervous -- 22010 27 29 15 29 - 30 18 5 36 _Driven - - 2 12 - 4 15 5 11 - 2 5 14 21 Castriesensa- 1 - 2 4 - 4 12 2 4 - 10 1 5 17 tlttn 4 8 8 12 26 - 21 14 33 23 2 2 2 19 32 4 35 69 83 55 65 63 52 69 32 76 40 543 75 Nenous - - 2 8- 12 14 15 21 - II 7 6 7 °Drive -~ --12- 10 18 4 14 - 7 4 6 29 Sleepy 11 Nauceaand 4 2 2 vomiting - 4 Other 4 5 7 2 1 5 7 11 13 1 5 - 4 10 Percentages were calculated tea the tame manner as that for TahIe lit, escept that the sssssptemo listed were not asutualtyeneios,ve. For purposes of tabulation, ~NenpooC also tncludes the response "initabit"; `Drive" includes the response "noted"; "Canine sensation" indudr, the responses nausea, "pleasonsn o,ck,""nensosas stomach," and turning cat the flossed,, PAGENO="0344" 14766 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Effects of amphetamines 253 In z 0 0. Ix ii ~ ~ :1 Ia TIME IN HOURS Fig. 4. The time-action curves for approximately equipotent doses of the amphetamine-like drugs. was much greater than that for ephedrine, methylphenidate, and phenmetrazine. Table IV summarizes the frequency with which various signs and symptoms were reported on the single dose questionnaires by both patients and observers. "Relaxed" was the most commonly reported sign and symptom. The incidence of feelings of nervousness increased with dose of the drugs, and nervousness was more com- monly reported by subjects than observers. Time course. Fig. 4 shows the time- action course of approximately equipotent doses of all drugs for mean blood pressure and subjective changes as assessed by the amphetamine scale (A). The duration of action of ephedrine on mean blood pres- sure seemed to be shorter than that of the other drugs; however, the subjective ef- fects of all drugs persisted for 12 bours, being above placebo level at this time. Catecholamine excretion. Tab!es I and V summarize the effects of the drugs on urinary catecholamine excretion. As can be seen, none of the drugs significantly af- fected the quantity of creatinine excreted. Only the 30 mg. dose level of methamphet- amine significantly increased the volume of urine excreted. All drugs increased the excretion of epinephrine in a dose-related manner, and valid potency estimates were obtained for all agents except ephedrine. As can be seen from Table I, the potency estimates for all drugs based on epineph- rine excretion were not significantly differ- ent from those obtained for the other Volume 12 Number 2, Part I lb 100 I C C Ix 90 82 MEAN BLOOD PRESSURE 3' 2 5 TIME IN HOURS `a 5 4 3 2 AMPHETAMINE SCALE PAGENO="0345" COMPETITIVE PROBLEMS Ui THE DRUG INDtSThY 14767 254 Martin a at. Clinical Phansacology gad Therspratca Table V. The effects of single doses of d-amphetamlne, d-met ham phetamine, ephedrine, mesh ylphenidate, and phenmetrazirie ott urinary epinephrine, norepinephrine, dopamine, are atinine, and urine volume during the first 3 hours after the drugs were administered Treatment No. Subjects Norepi- Dopo- Creati- Urine Epinephrine nephrine mine nine volume (~g per (Pg per (~g per (nag. per (ml. pet 3 hr.) 3 hr.) 3 hr.) 3 hr.) 3 hr.) Placebo 13 1.90±0.26 9.1± 1.4 96± 25 262±53 539 ± 48 d-Amphetamine. 7.5 mg. per 70 Kg. d-Amphetamine, 15.0 nag. per 70 Kg. d-Aniphetamine, 30.0 nag. per 70Kg. 13 13 13 3,01 ± 0.39 12.9 ± 2.9 346 ± 282 283 ± 22 553 ± 88 3.66 ± 0.44° 12.2 ± 1.7 180 ± 113 251*24 699 ± 72 3.85 ± 0.42f 10.6 ± 1.4 74 ± 12 221 ± 20 679 ± 86 Placebo 12 1.95± 0.28 9.4 ± 1.5 101 ± 26 274 ± 56 563 ± 45 d-Methamphetamine, 7.5 mg. per 70Kg. d-Methamphelsmine. 15.0 nag. per 70Kg. d-Methamplaetamlne, 30.0 nag. per 70Kg. 12 12 12 3.41 ± 0.37f 13.3 ± 2.3 153 ± 45 242 ± 28 647 ± 83 3.80 ± 0.461 8.8 ± 0.6 94 ± 20 225 ± 13 730 ± 113 4.35 ± 0.671 10.2 ± 1.2 75 ± 11 225 ± 28 767 ± IOU Placebo 12 1.70±0.18 9.0± 1.5 99± 27 267±57 538± 53 Ephedrlne, 75mg. per 70 Kg. Ephedrine. 150 mg. per 70Kg. 12 12 3.03 ± 1.01 8.8 ± 0.6 79 ± 15 246 ± 16 489 ± 83 3.94 ± 0.481 13.3 ± 1.5 103 ± 17 249 ± 17 559 ± 82 Placebo 12 1.70± 0.18 9.0 ± 1.5 99 ± 57 267±57 528± 53 Methylphenidate, 15mg. per 70Kg. Methylphenidate, 30mg. per 70Kg. Methylphenidate. 60mg. per 70Kg. 12 12 12 2.99 ± 0.421 10.7 ± 1.0 139 ± 45 256 ± 29 542 ± 69 3.50 ± 0.431 12.3 ± 0.2 77 ± 6 231 ± 17 572 ± 84 4.62 ± 0.57f 10.9 ±0.8 88 ± 5 252 ± 13 487 ± 66 Placebo 12 1.70 ± 0.18 9.0 ± 1.5 99 ± 27 267 ± 57 528 ± 53 Phenmetrazine 35mg. per 70Kg. Phenmetrazine, 70 nag. per 70Kg. 12 12 2.55 ± 0.40t 9.7 ± 1.0 76 ± 10 245 ± 19 450 ± 55 3.57 ± 0.431 8.4 ± 1.0 12 ± 10 244 ± 19 507 ± 70 The results Er. expressed as the mean pit., or minus one .tandard error. p <0.005: Different from placebo by a paired comparison t lest. ~p <0.001: Different from placebo by a p,ired comparison t teat. lv < 0.05; Different from placebo byapaired comparison I teat. parameters. The quantity of norepinephrine excreted under all drug conditions was not significantly different from the placebo condition, although the slope of the dose- response line for ephedrine was statistically significant. Dopamine excretion was not altered by any of the drug conditions when compared to the placebo condition; however, the regression coefficients for the dopamine dose-response relationship for methamphetamine and methyiphenidate had a significant negative slope. Discussiøn The mode of action of amphetamine- like drugs in producing central nervous system effects is not known; therefore, at this time classifications of these drugs must be based on similarities of drug syndromes. On the basis of physiologic responses as well as subjective changes, amphetamine and methamphetamine were equipotent with respect to most parameters, and no evidence was obtained that supported the view that the central stimulatory actions of methamphetamine relative to its periph- eral effects are greater than those of am- phetamine in man when the two drugs are administered subcutaneously. Aside from the fact that phenmetrazine was ½ to ¼ as potent as either ampheta- mine or methamphetamine, it seemed to be qualitatively similar to amphetamine and methamphetamine. Methylphenidate differed from amphet- 85-569 O-77----23 PAGENO="0346" 14768 COMPE~FITWE PROBLEMS IN THE DRUG INDUSTRY Volume 12 Number 2, Pod I Effects of amphetamines 255 amine, methamphetamine, ephedrine, and phenmetrazine in that pulse. rate was positively correlated with blood pressure; whereas, a negative correlation was seen with other drugs. The negative correlation between heart rate and blood pressure was probably a consequence of reflex in- hibition of heart rate caused by hyper- tension. !sfethylphenidate has been shown to abolish reflex hypertension produced by carotid occlusion," and analysis has shown that the locus of this action is probably iii the central nervous system." It is pos- sible that methylplienidate also antagonizes centrally the baroreceptive reflex respon- sible for bradycardia. The subjective effects of ephedrine were quite commensurate ~s-ith its effects on mean blood pressure and (lid not support the commonly held position that its central effects are less marked than those of am- phetamine. Ephedrine was disproportion- ately weaker than amphetamine in elevat- ing diastolic blood pressure than in elevat- ing systolic blood pressure. It is also note- worthy that ephedrinc was the only drug that did not produce a significant degree of mydriasis and was the least effective agent in increasing body temperature. Several drug effects that may reflect in- creased activity of central autonomic eon- ten should he mentioned. Although the dose-response relationship for methylpheni- date in increasing respiratoxy rate and rectal temperature and the dose response of mcthamphetamino in increasing body temperature were quite flat, both drugs in- duced significant increases of these vari- ables. As previously mentioned, ephedrino did not cause mydriasis and was less ef- fective than the other drugs in elevating body temperature. Interpretation of these disparities is difficult. If taken at face value, they would indicate that metb- amphetamine, ephedrine, and methylphcn- idate do differ from amphetamine and phenmetrazine, at least with regard to certain central actions, On the other hand, these discordant results stand by and large in contrast to an over-all concordance of the potency estimates and may be attribut- able to sampling, despite the fact that these differences were statistically significant. These discordant results do deserve further investigation to determine if they are due to differences in selectivity of action, dii fcrences in intrinsic activity, or differences in modes of action of the drugs. With regard to the subjective effects, the drugs were similar. Differences between potency estimates derived from the A, BC, and MBC scales should not be overly interpreted, since the items of all three scales assess affective states characterized by happiness, contentment, pleasantness, and feelings of proficiency. The predomi- nant effect at low and iatermediate dose levels was the production of feelings of relaxation, well-being, and contentment. Although these feelings were intensified by the largest doses, the largest doses also produQed signs and symptoms of nervous- ness, as well as elevation of LSD scale scores. It is paradoxical that these drugs, which are classified as stimulants, produce symptoms and associated signs of content- ment and relaxation; however, this is the most important aspect of their euphoriant actions. In defining the abuse potentiality of a drug, a variety of factors are of importance including its ability to induce compulsive drug-seeking behavior, its organ and psychotoxicity, and its social toxicity.'6' IT As has been previously discussed, the five drugs studied produce simflar types of sub- jective effects and peripheral effects, and because of these similarities it is probable that they have a similar mode of action in producing central changes that cause theft abuse. Dependence of the ampheta- mine type is characterized by the produc- tion of compulsive drug use and by a toxic psychosis that is a consequence of intoxi- cation.3 ~ " The abuse of amphetamine, methamphetamine, mcthylphenidate, and phenmetrazine is well recognized. Further, severe intoxication with methamphetamine, ~ phenmetrazine,"' and methylpheni- date" produces toxic psychoses that are in- PAGENO="0347" COMPETITIVE PROBLEMS IN THE DRUG INDUSTItY 14769 256 Mactin et at distinguishable from that produced by amphetamine. Ephedrine was selected for this study because it is a widely uscd sympathomirnetic amine which, we thought. had not been abused and could therefore serve as a negative control in validating the methods. Review of the literature revealed several case reports of the abuse of ephe- drine. Fanse" in his review cites two cases of ephedrine abuse reported by Croene- wald in his dissertation in medicine (Dus- seldorf, 1960). Subsequently, Herridge and A'Brook" reported two cases and I'rokop" one case of ephedrine abuse. In these cases there was not only evidence of compulsive drug-seeking behavior, but all patients de- veloped a toxic schizophrenia-like psycho- sis. It would thus appear that the constel- lation of suhiective and physiological re- sponses herein described provides a valid measure of the abuse potentiality of am- phetamine-like drugs. Epinephrine was the only catecholamine whose excretion was enhanced by the five sympathomirnetie agents studied. The blood pressure changes are more character- istic of those produced by norepinephrine than epinephrine. These findings would be consistent with Vane's" observation and conclusions that the pressor effect of tyra- mine and amphetamine is caused by a local tissue release of norepinephrine which is not accompanied by an increase in circula- tosy norepinephrine. The observations in man are difficult to reconcile with the ob- servations of harvey and associates" who found that amphetamine increased blood norepinephrine levels in the anesthesized pithed cat with or without adrenal glands. Jt is possible that dose level and route of administration may be important differ- ences between the experiments. In Harvey's and associates' study, all doses were ad- ministered intravenously, while in our study they were administered subcutaneously. Further, the lowest dose of amphetamine that they studied `vas 0.5 mg. per kilo- gram whereas, in the study in man it `vas 30 mg. per 70 Kg. it is quite certain that the peak levels of amphetamine obtained COnical Phi nnacoiogt, and Thnape,'lica in this study would be less than those obtained in Jlarvey's and associates' study. Of course, species differences may also be of importance. Studies of Thoma nnd Wick2a indicate that phenmetrazine is a directly acting synipatliomimetie amine since its pressor effect and effect on the nietitating mem- brane were enhanced rather than antago- nized by cocaine. The fact that phenmetra- zine enhanced epinephrine excretion in man would therefore suggest that increased activity of the adrenal gland was due to the central activation of efferent sympa- thetic fibers. There is little evidence that methylphenidate causes the release of either epinephrine or norepinephrine from peripheral sympathetic neurons or that it has a significant direct sympathomimetic action" "; therefore, it must be assumed that the peripheral autonomie changes must be a consequenco of a central action of methylphenidate. One must further as- sume on the basis of methylphenidate's peripheral effects that either the central norepinephrine receptors differ from those in the peripheiy or that methylphenidate interacts with another type of receptor. If this line of reasoning is correct, and it is based on the assumption that the pharmacology of these agents elucidated in animals is applicable to man, and one further assumes that the similarity of the syndromes of the five amines indicates that they have a similar mode of action, then one must conclude that the euphorogenic and psyehotogenie effects of these agents must be due to activation of a receptor other than a noradrcnergie receptor; how- ever, these data do not completely rule out the noradrenergie hypothesis because niethylphenidate may inhibit the uptake of centrally released norepinephrine since it has other cocaine-like activityah ~ and therefore could increase the amount of norepinephrine available at central post- synaptic receptors. The authora wish to thank Dc,. C. A. !-iaert,eo and B. Hoeldtke for their help in the statistical analysis of the data. PAGENO="0348" 14770 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Effects of amphetamines 257 Vdum. 12 NumberS, Pa's! References 1. Bethell, M. F.: Toxic psychosis caused by "Prelodiss," Brit. Med. J. 1:30-31, 1951. 2. Clein. L.: Toxic psychosis caused by `Trelu- dos," Brit. Med. J. 1:282, 1951. 3. Connell, P. H.: Amphetamine psychosis, Maudsley Monograph No. 5, London, 1958, Institute of Psychiatry. 4. Cox, C. P., and RuhI, D. J.: Simplified computation of confidenca intervala for rela- tive potencies using Fieller's theorem, J. Phannaceut. Sri. 55:368-371, 1966. 5. Edwarda, A. L.: Experimentat design in psychological research, revised edition, New York, 1960, Rinehart & Company. Inc. 6. Fraser, H. F., Van Horn, C. D., Martin, W. B., Wolbach, A. B., and Isbell, H.: Meth- ods for evaluating addiction liability. (A) "Attitude" of opiate addicts toward opiate- like drugs; (B) A short-tenn "direct" addic- lion test. J. Phannacol. Eap. Ther. 133:371- 387, 1961. 7. Clatt, M. M.: Abuse of metlsylassspbetamine. Lancet 2:215-218, 1968. 8. Griffith, J. fl: Cavanaugh, J. H., Held, J., and Oates, J. A.: Experimental psychosis in- duced by the adminiatration of d-ampheta- mine, in Costs, E., and Garattini, S., editors: International synsposium on amphetamines and related compounds. Proceedings of the Mario Negif Institute for Pharmacological Research, Milan, Italy, New York, 1970, Raven Press, pp. 897-904. 9. Haertzen, C. A.: Development of scales based on patterns of drug effects, using the Addic- lion Research Center Inventory (ARCfl, Psy- chol. Rep. 18:163-194, 1966. 10. Harvey, S. C., Solkowski, T. S., and Weenig, D. J.: Effect of amphetamines on plasma catecholamines, Arch, mt. Pharrnacodyn. 172: 301322, 1968. 11. Hawks, D., Mitcheson, M., Oghorne, A., and Edwards, C.: Abuse of methylamphetamine, Brit. Med. J. 2:715-721, 1969. 12. Herridge, C. F., and A'Brook, M. F.: Ephe. drino psychosis, Brit. Med. J. 2:160, 1968. 13. Himmelsbach, C. K., Cleek, D. M., and floyd, B. J., Jr.: Studies on the addiction liability of benzedrine sulfate. Unpublished data, 14. James, I, P.: A metlsylamphetamine epidemic? Lancet 1:916, 1968. 15. Jorgensen. F., and lcodahl, T.: Om Ritalin- misburg (On misuse of Ritalin), Ugeskr. Laeg. 123:1275-1219, 1961. 16. Martin, W. B.: Drug dependence, fss Di Palma, J. B., editor: Drill's phanssacology in medicine, ad. 4, New York, McCraw-Hill Book Co., Inc. In press. 17. Martin, W. R.: Drug abuse-the need for a rational pharmacologic approach, in Brill, L., and Harms, E., editors: Yearbook of drug abuse, New York, Libra Publishers. In press. 18. Maiwell, R. A., Flummer, A. J., Ross, S. D., Paytas, J. J., and Dennis, A. D.: Anti- hypertensive effect of the central nervous stionulant, methylphenidate. Arch. mt. Phar- macodyn. 112:26-35, 1957. 19. Maxwell, R. A., Plummet, A. J., Ross, S. D., and Daniel, A. 1.: Studies concerning Use cardiovascular actions of the central nervous stimulant, methylphenidate, 5. Pharmacol. Exp. Thee. 123:22.27, 1958. 20. Pause, F.: Psychiatrische krankheitabdder, Os Lauhenthal, F., editor: Sucht ussd miasbrauch, Stuttgart, 1964, Ceorg Thieme Verlag, pp. 169.202. 21. Peters, 5. H.: The determination of creatin and creatinine In blood and mine with the photoelectric colorimeter, 5, fbI. Chens. 146: 179-186, 1942. 22, Prokop, H.: Halluzinose bet ephedriusoclst (Hallucincais in ephedrine addiction), Nerve- narzt 39:71-75, 1988. 23. ThomI, 0., and Wick, H.: Uber einige tetra- bydro-1,4.osazine mit sysnpathicominsetischen eigenschaftess (On some tetrahydro-1,4-osa- zines with syssspathomimetic properties). Naunyn Schmiedeberg Arch. Fl,arm. Exp. Path. 222:540-554, 1954. 24. Vane, 5. B.: The actions of sympathomimetic amines on tryptamino receptors, Os Vane, 5. B., Wolatenholme, C. E. W., and O'Connor, K!., editors: Adrenergic mechanisms, Ciba Foundation Symposium, Boston, 1960, Little, Brown & Company, pp. 356.312. 25. Weil.Malherbe, H.: The estimation of total (free + coniugated) catecholamines and some catecholamine metsbolites in human urine, Meth. Biochem. Anal. 16:293.326, 1968. Appendix My speeds is slurred (PCAG). lam not as active as usual (PCAG). I have a feeling of just dragging along rather than coasting (PCAG). I feel sluggish (PCAG). My head feels heavy (PCAC). I feel like avoiding people alehough I usually do not feel this way (PCAG). I feel dizzy (PCAC). It seems harder than usual to move around (PCACI. lam moody (PCAC). People might say that I am a litsle dull today (PCAC, negative BC). I feel drowsy (PCAC, negative LSD), I arts full of energy (negative PCAG). PAGENO="0349" COMPETITWE PROBLEMS ~N THE DRUG INDUSTRY 14771 258 Martin et al. Today I say things in the easiest possible way (MEG). Things around me seen, more pleasing than usual (MEG). I have a pleasant feeling in my stomach (MEG). I feel I will lose the contentment that I have now (MEG). I feel in complete harmony with the world end those about me (MEG). I can completely appreciate what others are saying when I am in this mood (MEG). I would be happy all the time If I felt as I feel now (MEG). I feel so good that I know other people can tell it (MEG). I feel as if something pleasant had just happened to me (MEG). I would be happy all the time if I felt as I do now (MEG. negative LED). I feel more clear beaded than dreamy (MBC, BC. negative PCAG). I feel as if I would be more popular with people today (MEG, A). I feel a very pleasant emptiness (MEG, A). My thoughts come more easily than usual (MEG, A, BG). 1 feel less discouraged than usual (MEG, A). I am In the mood to talk about the feelings I have (MEG, BC). I feel more excited than dreamy (A, negative PCAG). CUsdaJ Phcsw,cooleg~, cad fl.,eps.dies Answering these questions was very easy today (A, BC). My memory seems sharper to me than usual (A, BC). I feel as if I could write for hours (A, BC). I feel very patient (A, negative LSD). Some parts of my body are tingling (A, BC. ISO). I haves weird feeling (A, LED). My movements seem faster than usual (BC). I have better control over myself tlsan usual (SC). My movements seen, slower than usual (negative BC). I find it hard to keep my mind on a task or job (negative BC). I don't feel like reading anything right now (negative BG). It seems I em spending longer than I should on each of these questions (LSD). My hand feels clumsy (LED). I notice my hand shakes when I write (LED). I have a disturbance in my stomach (LSD). I have an increasing awareness of bodily sensa- tions (LED). I feel anxious end upset (LSD). I have unusual wealmess of my muscles (LED). A thrill has gone through me one or snore times since I started this test (LSD, negative ECAG). My movements are free, relaxed, and pleasurable (negative LED). PAGENO="0350" 14772 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Reprinted trotn CLINICAL PnsItsIAc,,L,,or AM' THCISM'tt'Tics, St. b,uis Vol. 16, No, 4. Pages 645-6)2. October. 1974 (Printe,i in the L'. S. A.) (Copyright D 1974 by The C. V. Mosby Co,npitny) Effects of diethyipropion and d-amphetamine after subcutaneous and oral administration The effects of die'thylpropion were determined and compared wit), those of d-amphetamine irs 9 sids/ects osit~g a crouover design. Diethylpropion produccd effeet.s qnalitatively similar to those of d-amphetamine. but significondy len potent. Orally diethylpropion Wa, ~ to 1,~, at potent as d-amphctaninc while aishcutoneotasly dietliylpropion wae ~ to ½'~ as potent at d-arnphetaniitte. A striking difference between dictllylpropion and d-anphetotnine was the relatively greater oral efficacy of dir'thrjlpropion. Diet hylpropion wee twice as patent orally as sul,cutancously while oral and subcutarleou.e d-amphetamine were equipotent. Donald R. Josinski, M.D., John C. NutS, M.D.,5 ond John D. Griffith, M.D. Lexington, Ky., and Seattle, Wash. National institute on Drug Abuse, Addiction Research Center, United States Department of Health, Education and We'lf are, Public Health Service, Alcohol. Drug Abuse, and Mental health Administration, Lexington The phenethylamine, diethvlpropion (Tenuate, Tepanil), differs structurally from amphetamine (Fig. 1) and is claimed to be a more selective anorexiant than d-amphetaminc.' The incidence of abuse of diethvlpropion is reported to he rela- tively low." This study characterizes the actions of diethylpropion in man and compares these actions with those of d-amphetamine. It was undertaken to further validate methods established for measuring centrally active sympathonsimetic amines in man" as well Rectiv,'tt for p,,hh rati,sn Jan. 26, 1974. Accepted to, publication M~r 3. 1974. Itepeiti req"estt to~ Donald S. Jasintki, M.D., Addicti,,n Research Ce,,tr,, P0. Bat `2300, Leo,agton, Kr. 40511. `Present addrenv Division of Ne,,rotogy, Uoiveoaiiy of `va,hingoon School `f Medicine, Seattle, WaA. Methods the modes of action of amphetamine-like stim- Subjects were 9 federal prisoners ~vith documented histories of narcotic abuse. All admitted prior abuse of amphetamine-like agents. Each was judged to be in good health. Drugs were administered under double- blind conditions with at least 7 day inter- vals between drugs. Each of the 9 subjects received the following 13 treatments in random order: placebo condition; d-am- phetatnine 7.5, 15, and 30 mg administered subcutaneously; il-amphetamine 10, 20, and 40 mg administered orally; diethylpropion 150, 300, and 600 mg administered subcu- as to elucidate anorexiants and ulaots. 645 PAGENO="0351" COMPETITIVE PROBLEMS ~N THE DRUG INDUSTRY 14773 blood pressure (obtained in duplicate), respiratory rate, pulse rate, and rectal temperature "etc recorded after subiects had been in a supine position for 10 mm- rites. Pupils were photographed after each set of observations. At 8:00 AM., medica- tions were administered both subcutane- ously and orally to maintain double-blind conditions, Placebo condition consisted of "blanks" by both routes of administration. At 3:30, 9:00, 10:00, 11:00, and 12:00 AM., and 1:00, 2:00, and 8:00 i'.st., physiologic observations and subjective effects were measured. Anorexic effects were measured by esti- mates of tIme caloric value of food con- sumed at the noon and evening meals of the test day. Except for nonealorie bever- ages, subjects fasted from midnight until the noon meal (11:00 As!,) and then again until the evening meal (5:00 ass,) - At each meal the portion of food chosen was weighed; after eating, the residual food was weighed and this weight was subtracted from the weights of the food chosen. Caloric "aloe "as determined from stan- dard charts, Total calorie intake "as the sum of the calorie intake for the two meals, On the morning following the test day, subjects `vere asked to estimate to the nearest half hour the amount of time they lsad slept the previous night. From 6:00 Psi, of the test day until 6:00 AM, the mnrning followiisg the test day, observers would observe the subject and judge if he "as sleeping. For each ohservation of sleeping, a half hour of sleep time was awarded. The hydrochloride of dieth~lpropion and the sulfate of d-amphetammue ~vere used, For subcutaneous injection. drugs `vere dis- solved in normal saline. For oral admin- ist ration, drugs "crc added to 30 ml of cherry syrup. Normal saline "as the sub- cutaneous blank and 30 ml of chermy syrup was the oral Islank, Results (`Ii,,ieol P',armaco?ogm, arni The,~peutir, 646 Jasinski, Nutt, and Griffith a ETH YLPROPION C H2 -CH - N H2 d-AMPHETAMINE Fig. I. Structure of diethrIpropi~,n and d-amphc'ta- mine. taneouslv; and diethvlpropion 100, 200, and 400 mg administered orally. The methods used in stodying these drugs, with some modifications as de- scribed below, have been previously re- ported.' Subjective effects and euphoria were measured with drug identifications and "liking scores" from the sub feet's and ob- server's single-dose opiate questioiinaircs~ and scores on three scales administered as a subjective drug-effect questionnaire. These scales were the "Benzedrine Crosip" (BC), the "Morphine-Benzedrine Group" (MBC), and the "Amphetamine Scale," The \tl3G, containing euphoric items, and the BC, containing items relating to intel- lectual efficiency', were determined with factor-analytic techniques from items in the Addiction Research Center Inventory')" The "Amphetamine Scale" is an 11 item subset from the MBC and BC scales demonstrated by Martin and his col- leagues'' to sho~v a significant regression of response against dose for subcutaneously administered d-amphetammne. Physiologic effects measured were sys- tolic aod diastolic blood pressures, rectal temperature, poIse rate, and pupil size. Pupillarv diameter was determined photo- graphically with the eye 11 inches from a hack-illuminated opal glass screen deliver- ing 300 footlamberts of luminance, The following protocol was followed each test day- At 7:00 and 7:30 AS!., con- trol observations of systolic and diastolic The four drug conditionsuljeutane- ously administered diethylpropion, orally PAGENO="0352" 14774 COMPETITIVE PROBLEMS TN THE DRUG IYDtTSTRT g 0 0 administered diethvlpropion, subcutane- ously administered d-amphetamine, and orally administered d-amphetamine-pro- duced qualitatively similar subjective effects and euphoria as evidenced by sig- niBeant dose-related scores on the "Am- phetamine Group,"Benzedrine Group," `Morphine-Bcnzedrine Group," and liking" scales (Fig. 2). Furthermore, both subjects and observers predominantly identified the four drug conditions as "amphetamine" or "cocaine" (Table I). By both routes diethylpropion and d-amphetamiaie increased systolic and di- astolic blood pressure, increased rectal temperature, and decreased calorie intake (Fig. 2). As reported by observers (Fig. 2), subcutaneously administered diethyl- propion and el-amphetamine did not pro- duce significant sleep decreases, whereas whets administered orally, both drugs de- creased sleep. As reported by subjects (Fig. 2), the largest dose of each four drug con- ditions significantly decreased sleep. Significant pupillary dilation was oh- st-rved only with the 300 and 6~ mg sub- cutaneous closes and the 400 mg oral doses of diethvlpropion. Tachycardia occurred with all four drug conditions with a trend for pulse rate to be negatively correlated with blood pressure. Although dieth~lpropion and d-ampheta- mine produced qualitatively similar syn- dromes, diethylpropion was less potent Vosirnw is Diet/i ylpropiori and d-amplietamine N.aaher4 0 647 40 stNzEOR'Pst GROUP SCALE Ti 5 30 00200400 0 2040 100300G00 005E "5% * 4.M~*PeTAM['dE 5 * 4-AMPHE `AMINE ORAL aLTPnPq0T'ON ORAL * OIET4StPROPOR -PLACESO - - Rfl COSEIOENCE 04115 MEAN PLACE ~ RESPONSE 75 3 30 00200400 75 5 30 `00200400 55 5 30 ~20O4C0 `0 20 40 50500 AX 0 20 40 00350200 `0 20 40 50 300 AX DOSE P5, DOSE Psi DOSE 5155 Fig. 2. Dose-response curves for placebo condition, and subcutaneously (s.c.) and orally admin- istered diethylprupion and d-amphet&smine. Each point represents the mean response of 9 sub- jecta. Responses for subjective scales represent the sum of the scores for the first 7 nhservatioi,s (total 6 hour scores). For blood presi.ors- and temperature, responses are calculated as the sum ,sf the ehangea from the mean of the predrtig controls fstr the first 7 observations (total 6 ho,,r change). Total calorie intake and total sleep time calculations are described in the test. All subjects gave zero scores on the `amphetamine' sod subject's liking scales for placebo administration. PAGENO="0353" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14775 648 Iasinski, Nutt, and Griffith Clinical Pharmacology and Theispesdic. Table I. Drug identification from the single-dose opiate questionnaire for the compartcon of placebo condition, with il-amphetamine and diet/nj! jsropion d-Amphctarnisse d-Aanphetarnine Die-fit ylpro plan Diethrjlpropion Pie- subcutaneous oral subcutaneous oral celia 7-51 15130 10! 20140 1501300f600 1~~l2L~I400 Subjects!: Blank 63 41 43 29 63 42 31 41 30 22 51 31 11 Benzedrine (am- phetamine) 0 14 15 25 0 19 .16 10 17 21 12 23 33 Cocaine 0 2 5 8 0 0 7 0 0 7 0 7 10 Marijuana 0 0 0 0 0 0 0 0 0 0 0 0 7 AIrohol 0 0 0 0 0 0 0 0 0 0 0 0 2 Thorazine 0 0 0 1 .0 0 0 0 Ii 0 0 0 0 Miltown or Librium 0 0 0 0 0 0 0 0 2 0 0 0 0 Other 0 0 0 0 0 0 9 0 0 7 0 0 0 Observers): Blank 58 33 28 10 56 25 13 46 21 9 36 22 2 Benzedrine (am- phetamine) 5 29 22 52 6 36 50 11 42 48 26 41 61 Barbiturates 0 0 13 0 0 0 0 0 0 0 0 0 0 Dope(oplates) 0 0 0 1 1 0 0 0 0 0 1 0 0 Thorazine 0 0 0 0 0 0 0 1 0 0 0 0 0 Other 0 0 0 0 0 0 0 1 0 0 0 1 0 Numbrr, "present total responses by all ss,hjecu lass the first 7 olswnutioos. Maximum responses si any category are 63. tmere were usa subject identification,, of lsaolsitstr,teo, dope (opiates), so LSD. Itherewen-no observer identifications of maoliuana. alcohol. LSO, Millaiwo, or Lihoicin, Table II. Relative potencies and 95% con fidence limits from the dose-response curves in Fig. 2 for the comparison of diethyipropion and d-amphetamine° d-Anaphetanoina oral Diet/s ylpropion oral equivalent to I tog Dietlsylpropion oral equiealent to I tog of of d-eusspluetaroine equivalent to I rug of dietliyipropion solscuta,,eous n-Amphetamine oral s,ibcutar,eous Parameter! (rug) (sag) (sag) Amphetasnine Scale 1.1 (0.2-3.1)) 6.6 (3.0- 75.9)~ 0.49 (0.20-0.83)) Benzedrine Croslp Scale 1.4 (0.8-4.4)) 5.5 (2.6- 43.9)~ 0.53 (0.19-0.90)]] Morphine-Benzedrine Group Scale 1-3 (0.1-3.9)) 6.3 (2.9- 68.5)~ 0.48 (0.16-0.85)) Subjects liking 1.4 (0.8-3.1)]] 6.4 (3.2- 35.8)ç 0,58 (0.31-0.90)]] Obterver's liking 1.4 (0.8-8.8)11 11.3 ~G.6- 26.4)] 0.50 (0.28-0.74)!] Systolic blood pressure 1.1 (0.9-1.5)) 10.9 (3.8-573.1)) 0.54 (0.34-0.74)) Diastolic blood pressure 1.0 (0.2-6.9)~ 7.7 (3.0-244.9)j 0.55 (0.26-0.99)]] Temperatssre 1.2 (0.6-3.0)ç 7.3 (3.0-110.7)'] 0.68 (0.33-0,94)) Caloric intake 0.9 (0.1-3.4)) 8.0 (3.5_ 14.8)~ 0.56 (0.13-1.2)]] Sleep-eshoerver 0.8 (0.0-3.9)]] -~ -~ Sleep-subject 1.0 (0.6-1.8)1] 11.7 (5.2- 65.9)]] 0.85 (0.451.48)) ntatistscal requii-ems-sstn were mns-t Ow s'alidily of pisoallel line bioassaya from a `Assays wise calculated such that the randssmizrd black analysis of vaoiance. tCmsfideoce limits in pareslhe~a. 14 point bioassay. 43 point bioassay. (B point bioassay. ¶Issvalid assays. PAGENO="0354" 14776 COMPETITIVE PROBLEMS IN THE DittO I?4DVSTRY Diethyipropion and d-amphetamine 649 AJ z C I LA I E O~ C'AYL °R0P'ON ScL'USEcts QLETrvL PROPIOS ORaL ~ ~ ~ ~ :~1~ 2345 2 I 345 2 ~40URS P05' OSLO HOURS POSt OPLIG Fig. 3. Time-action curves for changes in systolic blood pressure from the mean of predrug controls following placebo condition and the administration of il-amphetamine subcutaneously (A), and orally (B), and dietisylpropion subcutaneously (C), and orally (D). Each point repre- sents the mean change from 9 subjects. thass d-amphetamine, as indicatcd by rela- tive potencies (Table II) calculated from the dose-response curves shown in Fig. 2. Oral diethylpropion was ¼ to %a as potent as oral d-amphetamine. A striking contrast between diethyipropion and il-ampheta- mine was the potency difference between routes of administration for each drug. Oral d-asnphetamine was cqtnpotent to or slightly less potent than subcutaneous ct-arnphetaniine whereas, in contrast, oral dicthylpropion was twice as potent as sub- cutaneous diethylpropion. Subcutaneous dietli~lpropiots can then be estimated to he to ~ as potent as subcutaneous il-amphetamine. Time-action curves for changes in sys- tolic blood pressure (Fig. 3) indicated trends for differences in the ossset of action of the four drug conditions. Subcutaneous d.amphetamine (Fig. 3, A) had a prompt onset of action with maximum effects at the half hour postdrug observation while sub- cutaneous diethylpropion (Fig. 3, C) had a slower onset of action. Relative to the subcutaneous route, the onset of effects with oral il-amphetamine (Fig. 3, B) was slower with peak effects at 1 to 2 hours. Oral dicthylpropion (Fig. 3, D) produced effects more promptly than subcutaneous dietlsylpropion (Fig. 3, C) and possibly more rapidly than oral a-amphetamine (Fig. 3, 13). Discussion Diethyipropion produces a syndrome qualitatively similar to that of il-ampheta- mine as evidenced by identifications as am- phetamine' and "cocaine" responses on scales for subjective effects and euphoria, increases in blood pressure and body tem- perature, and decreases in caloric intake and sleep. On the other haisd, relative potency calculations for these measures in- dicate that diethylpropioa is ¼ to %~ as potesit as d-amphetamine when both are administered orally bttt 1/~ to as potent when both are administered suhcotanc- ously. Furthermore, relative poteneies for concurrent measures indicate no significant Volume 16 Nunba4 +40 SMPHtTASRIN t ORAL 1-30 A20 * PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14777 650 Jasin.cki, Nutt, and Griffith Clinical Phan,,acologv and Thn,opcidic, dissociation among acute anorexiant activ- itv, vasoprcssor activity, or suhjcctive effects. A significant contrast between di- ethvlpropion and d-arnphetamine is the oral-to-parenteral potency ratios where di- ethvlpropion is twice as potent orally as subcutaneously, while, in contrast, oral and so heuta nt'ous d- amphetai ``inc were nearly equipotent. The relative potency estimates in these studies correspond to those determined by other investigators. The relative potency of ;~ (dietlsvlpropion as d-amphetamine in man for decreases in caloric intake (Table II) corresponds to the acute ann- rexia,st potency estimates of Gylys and his colleagues" of ½ in rats and % in dogs for oral diethylpropion and (i-amphetamine. Iloxill and his colleagites2 estimated di- ethvlpropinn ,, as potent as d-amphcta- nline as a vasopressor in anesthetized dogs; they', too, observed differences in potency estimates for routes of administration in that diethv Ipropion may have been rela- tively- more potent by' iistraduodenal ad- mimustration than by intravenous ad,uin- istration. In man, Jonsson and colleagues estimated 50 mg of oral diethylpropion equal to 10 tug of oral d-amphetaniine as a euplinriant. Existing data suggest that the greater oral effectiveness of diethylpropion may be attributable to greater conversion of di- ethylpropion to an active metaholite. In mam, orally administered diethylpropion is metabolized through sequential N-deethyl- ation, reduction of the ketone, paraliydrox- ylation of the henzene ring, oxidative cleavage of the nitrogen, and conjugate fom'mation resulting in 21 identified and 2 unidentified mnetalsolites,'" \tetabnlites formed by N-deethvlation or reduction of the ketone have been synthesized and demonstrated to have anorectic, stimulant, antI vasopressor activity in animals,' Blood samples taken ½, 2, and 4 hours after oral *cnpullsbcd data, Fmjcvt 8,-poe 0-84-05 0mg Memabolism Dr-padm,-nm, The WOrse, S. Merre]l Co., sin,, of Hirhardso,,-Mrnrll, Inc., Cinri,inati, Ohio, administration of 400 mg. of diethylpropion and subcutaneous administration of 600 nag of dicthvlprop ion in one subject not in the crt,sso'-cr study indicated that -at these times the levels of dietlmylpropion were higher following subcutaneous than follow'- ing oral adrninistrati,,n.° Demonstration of amphetamine-like sub- ~ective effects, euphoria, and physiologic effects cnmmplesl with reportsR 4 II. 4. 0. 21 of compulsive drug-seeking behavior and psychoses indicate that dieth~lpropion is appropriately cl.tssified as an amphetamine. like drug. Relating the abuse potential of dietlivlpropion to ansplietarnine-lik-e agents held to have hi gli aim Se potent al is d iffi- cult since diethylpropion has been mar- keted for a decade and a half with ex- tremely' few' reports of abuse. Relating the abuse potential nf diethylpr,,pion to cen- trally' active svmpatlioniimetie amines with little or 110 recognized abuse potential is even Inert' difficult. Eplsedririe, a centrally' active svmpathoniimetic amine widely' available with almost no abuse, clearly pro- duces amphetamine-like subjective effects, eupl cria, and pl nsio logic eli eets,'" at least ss-hen administered subcutaneously. Diethylpropion is available only as a 23 ~sag tablet or 73 mg Dospan (a niueilagi- nous gel in aqueous solution designed to retard release). As a paremiteral t-uphoriant. the 25 mg tablet would be equivalent to 1 to 2 tug of (1-amphetamine. It would be necessary to dissolve a large, if not impos- sible, nuniber of tablets to achieve doses equieuphoric to doses of amphetamine re- ported br intravenous abuse. Compara- tively, the standard 25 mg tablet of ephe- (lrine administered parenterall~ would be equiemipliorie to 5 mg of parenterally administered d-amplietamine.°° Similar con- sitlerations of the 75 mg Dospaa prepara- tion leads to a ennclusion of low likelihood of parcuteral ahuse. This estimate of low parcnteral abuse potcutial is supported by 9'Ia,mana,nplci anal,zed by On,. C. Wright and j. Lang, Onig M,-,aholism Department, William 5. Meccelt Co. PAGENO="0356" 14778 COMPETItIVE PROBLEMS TN TIlE DRUG INDUSTRY Diethyipropion and d-amphctarnine 651 Vr4umc 18 Kumbcr4 lack of reports of sustained intravenous abuse of diethylpropion. Diethylpropion could more easily be used as an oral euphoriant. The 25 mg di- ethylpropion tablet would then he equiva- lent to 2 to 4 mg of d-aniphetamine. The euphorigenic potential of the 75 mg Dos- pan preparation cannot be estimated since plasma studies in man following admin- istration (If diethvlpropioss in this prepara- tion indicate delayed absorption! The ah- scenee of data on the euphorigenie proper- ties following oral administration of other centrally active svnipathonsimetic nmines, especially those of low abuse potential, such as ephedrine, prevent relative coin- parisons. Consequently, judging relative abuse potential of oral diethyipropion on the basis of relative euphoric properties re- mains moot. The low incidence of oral abuse may indicate a relatively lower abuse potential than c/-amphetamine. This estimate is consistent with general experi~ ence with other psychoactive drugs phar- macologically equivalent to standard drugs of high abuse potential that are widely available with relatively low levels of abuse. This is especially true of narcotic anal- gesics with, drugs such as codeine," d-propox~phenc," " and diplsennxvlate.' The low abuse potential of these narcotic analgesics is generally held to be related to their availability exclusively or predom' inantlv as oral preparations in low dosage units and to their plsysiochemical prop' erties, wl,iels make intravenous abuse of the agent of preparation difficult (Sr impossible. Oss the basis of these studies, diethvl- propion appears to be qualitatively similar to d-arnpltctanaine in its action with a parenteral potency half that of eplsedrine. References 1. Birl, J. Ii.: Structure-activity relationships of amphetamine and derivatives, in Costa, E,, and Carattini, S., editors: International nm- posiuns on amphetamines and related com- pounds, New York, 1970, Raven Press, pp. 3-19. 2- BoxilI, C, C., Be,,, M., Hillyard, 1. WS and Warren, M. 11.: The cardiovascular smooth muscle aetio,s of clslnrphentermaine hydrochlo- ride (p.chioro.a,a-diniethy!p!senethiylamine )- a new an~srexigenic agent, J. Pharniacol. Eap. Ther. 137,198-205, 1Q02. 3. Caplan, J.: I tabituation to dicthy!pnpion (Tenoate), Can. sled. Assoc. J. 88~943.944. 19433. 4, Clein, L. J., and nenady, D, B. Case of di' ethvlpn'p:on addiction, Br, Med. J. 2:456. 1902. 5. Finney, D. J.: Statistical method in biological assay, ed, 2, New York, 1964, Hafner Publish- ing Cu, 6. Fraser, II. F,, and IsIs-li, II.: Pharanacologv and addiction liability ot dl- and d-propoxy- phs'mse, Bull. Narc. 12:9-It 1960. 7. Fraser, II. F., and Lsl,eIl, II.: human phar marulogy and addictivencss of etisyl 1-ta- cyano-3,3-phenylpropyl ) ..4.phenvl~4~piperiditte carboxylate hydrochloride (R-1 132, Diphenosy' late), Bull. Narc. 13:29-42, 1961. 8. Fraser, II. F., van lion, C. C.. Martin, W, R., Wolbach, A. B., and lsbcll, H.: Methods for evaluating addiction liability: (A) "Attitude" of opiate addicts toward opiate-like dnags, (B) a short term "direct" addiction test, J. Phar- macol. Eap. Thur. 133:371-387, 1961. 9. Cylys, J. A.. Hart, J, J. I)., and Warren, M. R.: Chiorpheotennine. a new anurectic agent, J. l5haro,acol, Exp. Ther. 137~365-373, 1962. 10. Ilaertzen, C. A.: Development of scales based on pattcnss of drug effects, using the Addiction Research Center inventoru.' MaCI), Paychol. Rep. 18:163-194, 1966. 11. Jasinaki, D. H,, Martin, W. 8., and Hueldtke, R.: Studies of the dependeitce-producing prop- erties 01 CPA'1657, profadol, and propiram in man, CLot. Pitanasacoa. THEa, 12:613-649, 1971. .12. Jones, H. S.: Diethvlpropion dependence. Med. J. Auat. 1 207, 1968. 13. Jonsson, C. 0., and S;dberg, L.: Studies in the psychological effects of a new drug di- ethylpropion, Scand. J. Psychol. 8:39-46, 1967. 14. Kay. H. C., Corodrtzky, C. \Y., and Martin, ~V, H,: &)otparative ellecta of codeine and morphine in man, J. Phannaco]. Exp. Thur. 156:101-196, 1967. 15. Koenssberg, E. V.: Diethylpropion, Br, Med. vol. 2, pp. 729-730, 1962. 16. Martin, 55'. H,, Sloan, J. iN., Sapira, J. H., and Jasinski, D. R.: I'hyaiologic, subjective, and behavioral effects of amaplsetamaine. methaua' phetamine, ephedrine, phiennsetrazioe. and tatthylphenidate in man, Ca.ts. PHARMAcOL. THEa. 12:245-258, 1971. 17. Medical letter: Diethylpro1sion, an appetite suppressant, vu1, 13, no. 25, issue 337, 1971. PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14779 * 652 Jasfrtski, Nuti, and Griffith 18. Rylander, C.: Clinical and medico-eTiminologl- cat aspects of addiction to central stimulating drugs, In Sjoqviat, F.. and Tottie, N., editors, Abuse of central stimulants, Stockholm, 1969, Almqvist & Wiksell, pp. 251-273. 19. Schreiber, K C., Mm. B. H., Zeiger, A. V., and Lang, J. F.: Metabolism of diethylpropion-l- C" hydrochloride by the human, J. l'hannacol. Exp. They. 159:372.378, 1967. Ctmarel fl.ann.cologV and Then pestle, 20. Schreiber, E. C., Bozian, R. C., Evert, C. F., Bunde, C. A., and Kuhn, W. L.: Dynamics of diethylprnpion in the human, J. New Drugs 5: 261.262, 1965. 21. Whitlock, F. A..: Diethylpropion and psychosis. Med. J. Mist. 2:1097, 1970. PAGENO="0358" 14780 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Reprinted from CLINICAL PHARMACOLOGY AND THERAI'EtJTtCS, St. Ijaoti Vol. Ii. No. 5. Pan 1, Pages 553-570. November. 1975 (PrInted In the I'. S A.) (Copyright ~ 1975 by Thee. V. Mosby Company) A comparison of fenfluramine and amphetamine in man dl-Fenfluramitre hydrochloride (60. 120. 240 mgI, d.amphetomine sulfate (20, 40 ing). and placebo were compared in 8 postaddkr volanteers, each dose given oral/v in random sequence at weekly intervals using a double-blind crossover design. Fenfluramine had little effect on blood pressure and temperature, but caused a marked dilation of pupils, whereas amphetamine was a potent vasopressor and a weak mydriatic. While fenflurarnine produced euphoria in some subjects, its ot~rall effects were unpleasant. sedot,ve, and qualitatively different from amphetamine. Three subjects given 240mg of fenflitramzne experienced bnef but vivid hallucinogenic episodes characterized kv olfactory, visual, and somattc hallucinations. abtupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenflurannne is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like. John 0. Griffith, M.D., John C. Nutt, M.D., and Donald R. Jasinskl, M.D. Lexington, Ky. Natiolmal institute on Drug Abuse. Division of Research. Addictton Research Center Human subjects given the anorexigenic drug. fenfluramine (N.ethyl.ni-trifluoronlethyl phe- nylisopmpylatnine. Pondimin), often report a sense of unpleasant lethargy front the drug rather than a euphoric "high."8 and concomi- tant electroencephalographic patterns can be more characteristic of sedative agents than drugs of the amphetamine class,2"5 Moreover, with animal paradigms of human drug-seeking be- havior, fenfiuramine is not reinforcing22 and relatively devoid of amphetamine-like sympa- thomimetic properties.' From these and other studies, one might con- clude that fenfiuramine is unique and not likely to lead to amphetamine-like psychotoxicity or Received toe publication AjniI 0. lOSS. Accepied foe publicat,on scpi. 5. 975. io: t,sitn 0. Griffith. M Add,~,ioa R.Mearch (`enter. P0. Son I2390. Leai,ngsnsn. Ky- 40511 Preseti address: Depanmeni of Neuntloty, Untserstty of Wushtegn" Sch'e>I of Medicine. Seattle. Wash. OttO. abuse-an estimate corroborated by the very few reports of fenfioramine abuse in Europe where the drug has been available clinically for some years." 20 On the othcr hand. Levin has reported descriptions of 60 young men from South Africa (where the drug could be obtained without prescription) who self-administered fenfluramine in doses of 80 to 400 mg on one or more occasions to obtain a euphoric ef- fect."' `~ The constellation of symptoms re- rnembered by these men included hallucino- genic, sedative, and amphetamine-like effects. Of possible concern are still other reports of dysphoria and sleep disturbance after chronic fenfluramine use and abrupt withdrawal," " a like sequence also following amphetamine. There is therefore the possibility that fen- fluramine may have reinforcing properties (amphetamine-like or otherwise) not previously identified in controlled clinical studies. To explore this issue, the subjective and physio- 563 PAGENO="0359" COMPETITIVE PROBLEMS IN tHE DRUG INDUSTRY 14781 564 Griffith. Nun, and Just nski (t,,~uil :,idlhen.peuncs logic effects of fenlluramine and amphetamine were compared by using methods previously described by Martin and associatest~ and .lasin- ski. Nutt, and Griffith. Methods Participants were S men detained for federal crimes committed in connection with their narcotic use. They ranged in age from 31 1044 and were in good health, as evidenced by medi- cal history, physical examination, and appro- priate laboratory studies, and exhibited no psychiatric impairment beyond drug abuse and concomitant antisocial behavior. All had used narcotics for an average of IS yr before in- carceration; in addition, 7 had also used am- phetamine or cocaine, and 4, LSD-like hat- lucinogens. Participation was voluntary. The doses of dl-fenfluramine hydrochloride (60, 120. 240 mg) and d-amphetamine (2040 mQ) were selected following a dose mn-up and on the basis of prior studies,° respectively, During dose run-up. I subject given 270 mg of fenfiuramine reported transient, paranoid thoughts just prior to a euphoric episode. For this reason, and because a demonstration of psychotomimetic effects was not a purpose of this study, the largest dose of fenfluramine used in the crossover was 240 mg. an amount also well tolerated in toxicity studies done elsewhere. A cherry syrup with a trace of qui- nine added served as both the vehicle for the drugs and as a placebo. Each treatment was administered orally in random sequence at weekty intervals under double.blind conditions, Subjects were admitted to the ward the eve- fling before their test day and examined to rule out intercurrent illnesses. On the test day, they were awakened at 6:30 AM., and baseline physiologic observations were made at 7:00 and 7:30 AM. Treatments were given at 8:00 AM. Physiologic observations would then be repeated at 0.5, I, 2,3,4.5.6, 12, and 24 hr postdrug. These were: (I) duplicate tO-mm supine blood pressures as determined by cali- brated sphygmonsanometer and auscultasion; (2) pulse rate; (3) respiratory rate; (4) rectal temperature; and(S) pupil diameter (determined photographically; eye II inches from a back- illuminated opal glass screen and target trans- illuminated to 300 ft-lamberns). Two-rain stand- ing blood pressures and pulse rates were ob- tained at 3 and 24 hr and compared to the im- mediately preceding supine values. Urine pl-l was not controlled in this acute study. At these posidrug intervals, subjective ef- fects were measured by a group of question- naires completed by both subjects and obser- yen. These were the Single Dose Opiate Qucs- tionnaire for subjects and observers° and a special questionnaire for subjects that consisted of items from the following scales of the Ad- diction Research Center lnventotybo; MRG (Morphine-Benzedrine Group Scale), a general measure of drug-induced ettphoria; LSD (Ly- sergic Acid Diethylamide Group Scale), a measure of dysphorie and somatic symptoms elicited by graded doses of LSD and certain narcotic antagonists"- 7. and an Il-item Am- phetamine Scale a measure specific for the dose-related effects of d-amphetamine.Th The Amphetamine Scale contains items that relate mainly to concepts of self-confidence and per- sonal assertiveness. The effects of drugs on food intake were estimated by calculating the caloric value of food actually eaten at the noon. evening, and breakfast meals (using weighed portions and standard tables). Except for noncatorie bev- erages. including coffee, subjects fasted from midnight until the noon meal and then again until the evening meal (5:00 P.M.). The morning following the test day, subjects estimated their time asleep to the nearest half- hour. Sleep time was also estimated by ob- servers who insFeted subjects at half-hour intervals during the evening and night (6:00 P.M. to 6:00 AM.). Dose.effect relationships were determined by partitioning the treatment sums of squares from the analysis of variance for a randomized block design into components to test the sig- nificance of the regression mean square of measured total 6-hr response on each measure against dose of amphetamine and fenfluramine. In addition. mean placebo responses and 95% confidence limits of mean placebo response were calculated for each measure to allow dif- PAGENO="0360" 14782 co~n'ETITIvE PROBLEMS IN TUE DRUG INDUSTRY Fenflurarnine 565 50 AMPHETAMINE SCALE 40 30 -~ 20r7 `0 - P: ACE SO 0 -. `225 BLOOD *t95 PRESSURE I, / SYSTOLIC Ii P155 (SUPINE) ``35 + 75 4 45 ~, `n:-__t~ ~-I5 ferentiation of fenfiuramine and amphetamine effects from placebo. Results To compare the effects of fenfiuramine and amphetamine during the first few hours after administration, the responses with each mea- sure for the first 7 observations (total 6-hr scores) were summed and the mean total 6-hr scores were used to construct dose-response as illustrated in Fig. I. However, some effects persisted as long as 12.24 hr. Fhytiolngicol effects. The most prominent physiologic effect of fenfluramine was a dose- Volume IS Numher SPort! `a a 0 en x ID I 10 Ir 0 U 5, "I a 0 en I ID -I 4 P 0 z 4 Ut a 6 r ID 4 SUBJECTS LIKING -C' -I 2 4 `a a 2 0 0 2 4 I U 1' I ID -J I 5, a 0 0 I 5 SYSTOLIC BLOOD PRESSURE, POSTURAL CHANGE 0 * I---~ A Pt ACE*0 ~: -~-------- -~5 ~-3nI ,0570006 - - at.A05T-O$IJS 20 4060 120 240 20 40 60 20 240 DOSE mm DOSE mm PLACEBO REP0NSE .-&.MPHETAMINE ._FENFLURAMINE 20 40 60 20 24O DOSE mm - - - 95% CONFIDENCE LIMITS *6 SUBJECTS MEAN Fig. I. Dose-rcsponse plots for placebo condition and orally administered d!-fenfiuramlne and d-amphetamine. Each point represents the mean group response of 8 sobjects (6 subjects. 240 mg fenfiuranline condition). Responses for subjective scales represent the sum of the scores for the first 7 observations (total 6-hr scores). BlOOd pressure and temperature responses are calculated as the sum of the changes from the mean of the prednig contml for the first 7 observatiotis (total 6-hr change). Caloric intake, sleep time, and postural blood pressure change are dcscnbed in the text. PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14783 Griffith, Nut:, and Jasinski CThi,roj Pkurmoeorogy sod Thempetu cx related increase in pupil diameter; the effect of amphetamine by this measure during the first 6 hr was, by comparison, relatively slight (Fig. I). Fenfiuramine also elevated systolic and diastolic blood pressures, but less than did amphetamine. Although not statistically sig- nificant, there was a trend for pulse rate to increase with fenfiuramine and to decrease with the larger dose of amphetamine. The larger dose of amphetamine caused hyperpyrexia and differences in standing and supine blood pres- sure, the latter being manifested 24 hr later (Fig. I). As may be seen in Fig. 2, the pressor effects of amphetamine and fenfiuramine gen- erally assumed a time-course paralleled by the duration of euphorogenic effects (Amphetamine Scale). The mydriatic and LSD Scale responses were of much longer duration. Appetite and sleep. Amphetamine, 40 mg, and fenfiuramine. 120 and 240 mg, reduced caloric intake at the three meals following drug administration, but because of a large variability, only the effects on the noon meal were statistically significant. Valid relative potency calculations for this effect indicate 4.2 mg of fenfiuramine equivalent to I mg of amphetamine as an anorexiant, but with ad- mittedly wide 95% confidence limits (2-412). Both fenfluramine and amphetamine caused significant reduction in self-estimated sleep time (Fig. I); only amphetamine, however, reduced observed sleep time. Subjective effects. Significant degrees of euphoria were produced by amphetamine as indicated by elevated Amphetamine, MBG, and Subjects' Liking Scale scores (Fig. 2). This euphoric response tended to change gradually in a stepwise fashion during the 6-hr interval. The dysphoric items (LSD Scale) elicited by amphetamine were not significantly different from placebo in this small series. Seven of 8 subjects rated the larger dose of amphetamine as more euphorogenic than the 20-mg dose, and a significant dose relationship could be shown AMPHETAMINE SCALE *d-iMPMCTSI&1NC40*i *FCNFLUflMIN C 20 ~o DCC'*FLUiiMIPE C SO ~os *PLACCD0 LYSERGIC ACiD SCALE 7- S 5 4 UI 0 U U) UI 4 U ~0 z 4 UI UI 0 U U) UI -I 4 U U) a 0 UI 0 z 4 t I t S z 4 UI a *20 0 O I 2 3 4 5 6 12 24 SYSTOLIC BLOOD PRESSURE IS LI P IN I U20\ o I 2 3 4 5 6 2 24 HOURS UI a C 0 UI I) a 4 I U a C a 5 tID tO.5 0 03 PUPIL DIFFERENCE 23456 12 24 HOURS FIg. 2. Time-action curves for amphetamine and fenfluramine. Each point represents the mean change from S subjects. Euphoric effects (amphetamine scale) were paralleled by elevation of supine blood pitssurc white dysphoric effects (1.50 scale) were accompanied by mydriasis, 85-~89 0-77-24 PAGENO="0362" 14784 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Fenfluramine 557 Volume JR Number 5. Port I Table 1. Drug identifications (single dose quest ionnaire)for comparison of placebo condition with d-ampheramine and fenfluranaine Subjects Placebo d-ampheta'nine Fenflurantine 20 40 60 120 240± Blank Dope Cocaine Marijuana Barbiturate Alcohol Benradrine (amphetamine) LSD Thorazine Libtium Others 45 0 0 0 0 0 3 0 0 0 I 25 0 2 0 0 0 29 0 0 0 0 l9 0 0 0 0 0 36 0 0 0 4 42 0 0 0 0 0 0 6 0 0 6 23 0 3 0 0 0 5 tO 0 0 I II 0 0 0 12 0 8 5 0 0 9 S Sir sub orts - among these 7 by Amphetamine, MBG, and Liking Scale measures. One subject, however. denied both euphorogenic and dysphorogenic effects after the 40-mg dose (but not at 20mg), which flattened the dose-response curve. These effects of amphetamine were generally cate- gorized by subjects as "amphetamine" (Table t). Although subjective effects were accom- panied by obvious behavioral changes, no relationship between behavioral change and dnag condition or dose condition could be demonstrated. The response 10 the 60 mg dose of fen- fluramine was modest. Only 3 subjects identi- fled this dose as psychoactive (subjects' liking. Fig. I; Table t). The effect with the larger doses of fenfluramine was more definite; however, subjects varied considerably in thcir response to the same dose of fenflur.amine and to different doses, and in terms of the manifestation of a particular effect over time. In contrast to amphetamine, the euphoric mood states elicited were of shorter duration, epi- sodic, and accompanied by degrees of per- sonal grandiosity. These euphoric changes would alternate (sometimes in a matter of min- utes) with even more striking dysphoric epi- sodes that eventually became the more pre- vailing and predominant effect. These polar opposites of mood and early psychotomimetic effects were reflected in simultaneous eleva- tions of Amphetamine. Liking, and LSD Scale measures during the first 6 hr. The comhtned 6-hr MBG Scale response, a more general measure of dnig-induced euphoria, was not different from placebo. However, a randomized block analysis of variance of peak MBO scores indicated significant dose-related increases with fenfiuramine. These MBG Scale peaks were of short duration (I-? hr) and associated with peak Amphetamine Scale and blood pressure elevations. Five of the 8 subjects receiving the 240-mg dose of fenfluramine eventually were sedated and categorized the response as "barbiturate"- ]ike (Table I). although their appearance more resembled that seen following a large dose of phenothiazines. Hallucinogenic phenomena were not observed in these 5. Three other sub- jects, however, experienced frank hallucino- genic episodes of sudden onset, but without sedative effects. Halltwinogenic effects. Three subjects sus- tained clear-cut hallucinogenic syndromes during the crossover assay. This response was not expected and, except as noted, promptly antidoted with diazepam. Only mild changes were noticed in I sub- ject. Approximately 1½ hr postdrug, he be- came angty and demanded a conference to learn "why people were looking at his tele' vision set"-an inappropriate concern because the receiver was locked and secure in his room in another part of the building. In a matter of minutes, however, he experienced a "mellow high." denied being angry, and explained PAGENO="0363" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14785 5U Griffith. Nun, and Jasinski that his preoccupation was without foundation. He thereafter continued with tesdng and iden- tified other changes such as time compression and alterations of body image, which came in `waves" for about 5 hr. Because the patient was comfortable, in good contact with staff. and willing to continue, no attempts were made to terminate these symptoms. With 2 other subjects, hallucinogenic effects were more pronounced. One man ~sith con- siderable LSI) experience became niute some 45 mm after taking fenfluramine, and for the next half-hour communicated by making ani- mal-like noises and gestures. Upon recovering his voice, he explained that he had been on a "beautiful trip," which began with his noticing that the shadows cast by the Venetian blinds reminded him of a reptilian underbelly. Sub- jectively, he was very quickly transformed into a large and fearsome dinosaur, searching. during what seemed like a period of years. for his dinosaur wife and child-an experience that culminated in an eestaey of reunion and closeness with his family group. The subject later explained that he was at all times aware that his experiences were drug-induced and unreal, but his decision to remain mute was to prolong the state as long as possible. The the- matic content of his hallucinogenic state was connected by the subject to a troubled domestic relationship. A second subject also experienced derealiza- tion, rapid. and polar alterations of mood, visual hallucinations, distortions of perspective, changes in body image, vivid sexual hallucina- tions and ideas, and transient paranoia. In con- trast to the episodes described above, this sub- ject evaluated his experience as mostly un- pleasant, except for the sexual hallucinations. He and the above subject experienced infre- quent, short-lived episodes of unreality for 3 days postdrug. Discussion Previous studies from the Addiction Re- search Center have shown the relationship between amphetamine stnicture and amphet- amine activity in man or, more specifically, the phatmacologic profiles obtained by modifi- cations of the isopropylamine side chain (meth- (Ir,uai Pharrn,tco(,~g~ and Therapeun,-s amphetamine. phenmetrazine, nsethylpheni- date, ephedrine, diethylpropion. benzphct- amine). These structural configurations were observed to have a profound effect on weight potencies but pharmacologic profiles were essentially unchanged. In other words, for a given effect on appetite, all drugs produced equal degrees of euphoria and vasopressor change despite differences in physical potency ranging from I I to 1:20°' it was significant to learn whether a different type of structural modification (ring substi- tution), as exemplified by fenfluramine, would give qualitative alterations in pharmacologic responses and not merely qualitative differences in overall potencies. Our study indicates that the most conspicuous similarity between the effects of amphetamine and fenfiuramioe is an aoorexigenic effect, fenfiuramine being aht,ut 1/4 as potent as amphetamine-an estimate in keeping with olher efficacy studies in man23 and inhibition of food intake by oral fenfiur- amine in the dog.' In rat assays, fenfiuramine is relatively more potent,1 perhaps because this animal can parahydroxylate the reference drug, amphetamine, more rapidly. This is a minor pathway in man. There is also good evidence that fenfluramine and aoiphetamine-induced anorexia may involve different pharmacologic mechanisms.a II 21 In most other respects, the effects of feo- fiuramioe were quite different. `Fenfluramine, unlike amphetamine, caused substantial and generally dote-related subjective expressions of lethargy, sedation, dysphoria. and unplea.saot somatic symptomatology. While feofluramine was to some degree euphorogenic, as evidenced by elevated Amphetamine and Subjects Lik- ing Scale scores, this response could be dif- ferentiated from amphetamine by the transitory MBG response, subjects' drug identifications, and clinical manifestations. The physiologic profiles were also different. Fenfluramioe was a weak vasopressor and a potent mydriatic, whereas amphetamine caused substantial in- creases in blood pressure and mild pyo»=xia, but effects on pupils had a rather long latency. Only amphetamine induced significant pos- tural differences in blood pressure. These data indicate that fenfiuramioe is not amphetamine- PAGENO="0364" 14786 COMPETITIVE PEOBLEMS IN THE DRUG ILNDUSTRY Fenfluramine 569 Val,a,e /8 N,,.,bqr 5. Pan / like and probably would not substitute in am- phetamine-like patterns of abuse. In support of Levin's studies,aa n~ fenflur- amine was observed to have hallucinogenic activity in 3 of 5 subjects who experienced syndromes characterized by visual hallucina- tions, sensory distortion, fleeting paranoia, derealization. depersonalized awareness, so- matic symptomatology, labile mood, a modest increase in pulse rate and blood pressure, my- driasis, and hyperactive tendon reflexes-the last not measured systematically. This con- figuration resembles that produced by a number of hallucinogens. including LSD and certain ring-substituted amphetamines. This similarity, plus the cases cited by Levin, suggests that LSD-like, rather than an amphetamine-like, abuse potential should be considered. This issue aside, hallucinogenic and dysphoric symptoms may well limit the therapeutic utility of fenfluramine as an anorexiant. While 3 subjects experienced hallucinogenic phenomena (without sedation), 5 others were moderately sedated following the largest dose of fenfluramine and denied psychotomimetic symptoms. No reasons can be given for these differences. Preliminary data suggest that the hallucinatory response may result from a rapid absorption of oral fenfluramine or its conver- sion to norfentiuramine. The similarity between the effects of fen- fluramine and endogenous emotional depres- sion, both characterized by symptoms of dys- phoria, hypochondriasis. insomnia, emotional lability, and anorexia, is of interest, suggesting that ring-substituted phenethylamines may be used as tools to investigate these functional states. The authors thank Mr. Robert Eads for his tech- nical assistance- References I. Alphin, R. S.. and Ward. J. W.: Anorexigenic effects of fenfluramine hydrochloride in rats, guinea pigs, and dogs. Toxicol. AppI. Pharusa- enl. 14:182-191. 969. 2. Cox. R. H.. and Maickel. R. P.: Comparison of anorexigenic and behavioral potency of some phenethylamines, 3. Pharmacol. Exp. Ther, 181:1-9, 1972. 3. Fink. M., Shapiro, 0. M.. and ltil, T. M.: EEC profiles of fenfluramine. amobarbitat and des- troamphetamine in normal volunteers, Psycho- pharmacologia 22:369-383. 1971. 4. Firth, H.. Lewis. S. A.. Ogunremi. 0.0., and Oswatd, 1,: The effect of acute administration of (mete trifluoro methyl-phenyt)- I -(henroyl oxy) ethyl amino-2-propane (780 SE) and fentlur- amine on human steep, Br. J. Pharmacol. 39: 462-453, 1970. 5. Fnxwelt, M. H., Funderhurk, W. H., and Ward, J. W.: Studies on the site of action of a new anorectic agent. fenfluramine, J. Pharmacot. Exp. Ther. 165:60-70, 1969. 6. Fraser, H. F., Van Horn, C. 0.. Martin, W. R., Wolbach, A. B., and l.cbell, H.: Methods for evaluating addiction liability. (A) "Attitude'' of opiate addicts toward opiate-like drugs: (B) A short-tent "direct'' addiction test. .5. Pharma- cot, Esp. Titer. 133:371-387. 1961. 7. Gauttier, M.. Efthymiou. M. L.. and Cottereau, C.: Intoxications aiguës par es anorexigênes rCcents (amphetamines exctues). Eur. 3. Toxicot, 1:55-73, 1968. 8, Cotestarts, K. C.. and Cunne. L. NI.: Subjec- tive effects of two anore,cigenic agents fenfiur- amine and AN448 in amphetamine-dependent subjects, Br. 3. Addict, 67:39-44, 1972. 9. Groppetti, A., Zambotti, F., Biazzi. A.. and Mantegazza, P.: Amphetamine and cocaine on amine turnover, in Usdin, E., and Snyder, S. A.. editors: Frontiers in catechotamine research, New York. 973. Perganion Press, pp.9i7-925. tO. Haertzen, C. A.: Development of scales based on paoerns of drug effects, using the Addiction Research Center Inventory (ARC). Psychol. Rep. 18:163-194, 1966. II. Haertzen, C. A.: Subjective effects of narcotic antagonists cyctazocine and nalorphine on the Addiction Research Center Inventory (ARCI). Psychopharmacologia 18:366-377. 1970. 12. Harding. T.: Fenfiuramine dependence. Br. Med. 3. 3:305, 1971. 13. Jasinski. 0. R., Null, 3. C., and Griffllh,J. D.: Effects of diethylpropion and d-amphetamine after subcutaneous and oral administration, Ct.tN. PHARMACOL. THER. 16:645-652, 1974. 4. Jespersen, S.. and Scheel-Kroger, I.: Evidence for a difference in mechanism of action be- tween fenflurarnine- and amphetamine-induced anorexia. J. Pharm. Pharmacol, 25:49-54. 1973. IS. Levin, A.: Abuse of lenfiuramine, Br. Med. 3. 2:49, 1973. 6. Levin, A.: The non-medical misuse of fen- fluramine by drug-dependent young South Africans. Postgrad. Med. 3. 51 (Suppl. I): 183-185. 1975. 17. Martin, W. R.: Assessment of the abuse poten- tiality of amphetamines and LSD-tike hallu- cinogens in man and its relationship to basic PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14787 870 Grjffith, Nut:, and Jasinski animal assessment programs, in Goldberg. L., and Hoffmeister. F., editors: Bayer Symposium IV, Psychic dependence, New York, 973, Springer-Verlag, pp. 146-155. 18. Marlin, W. It,, Sloan,J. W., Sapira. 3. D., and .Iasinski, 0. R.: Physiologic, subjective, and behavioral effects of amphetamine, metham- phetarnine, ephedrine, phenmetrazine. MId methylphenidate in man, Curs. PHARMACOL. THER. 12:245-258, 1970. (This reference in- cludes verbatim wording cf the questionnaires employed.) 19. Oswald, F., Lewis, S. A., Dunleavy, 0. L. F., Brezinova, V., and Briggs, M.: Drugs of depen- dence though not of abuse: Fenfluramine and imipramine. Br. Med. J. 3:70-73, 97!. C'inicaI Piarnwcologv md Theiapeu'ks 20. Oswald, I.. Jones, H. S., and Mannerheim, 3. E.: Effects of two slimming drags on sleep. Br. Med. 5. 1:796-799, 1968. 2!. Shoulson, I.. and Chase. T. N.: Fenliuramine in man: Hypophagia associated with diminished aerotonin turnover. Curt. PHARMACOL. THER. 17:616-621, 1975. 22. Woods, 5. H.. and Tessel, It. E.: Fenfluramine: Amphetamine congener that fails to maintain drug-taking behavior in (he Rhesus monkcy, Science 185: 1067-1069, 1974. 23. Woodward. E., Jr.: Clinical experience with fenfluramine in the United States, in Cost, F., and Garattini. S., editors: Amphetamine and re' tated compounds., New `York. 1970, Raven Press, pp. 685-691. PAGENO="0366" 14788 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PROGRESS REPORT ON STUDIES FROM THE CLINICAL PHARNtACOLOGY SECTION OF THE ADDICTION RESEARCH CENTER Donald R. Jasinski, M.D. John 0, GrIffith, M.D. Jeffrey S. Pevnlck, M.D. and Stewart C. Clark, M.D., Ph.D. From tne National Inflitute on Drug Abuse Division of Research Addiction Research Center Lexington, Kentucky U. S. DEPARTMENT OF HEALTH, EDUCATION AND WELFARE Public Health Service Alcohol, Drug Abuse, and Mental Health Administration PAGENO="0367" COMPETiTIVE PROBLEMS IN THE DRUG INDUSTRY 14789 This report presents findings relative to the morphine-like properties of three drugs. d-propoxyphene napsylate. azidomorphine, and butorphanol and to the assessment of three amphetamine congeners, d-benzphetanhlne. dl-fenfluramine, and chlorphentermine. Brief reference will be made to a peculiar effect of amphetamine on blood pressure. SECTION j: MORPHINE-LIKE DRUGS d-Propoxyphene This drug (Darvon® ) is a morphine-like analgesic. In recent years. the napsylate salt of thi~ ~ ~as been utilized to maintain or detoxify heroin dependent patients~''' where It was felt that the drug had certain advantages over methadone, i.e. * 1) a lower abuse liability; 2) milder degree of physical dependence producgd; and 3) greater acceptance by sore patient categories. Fraser and Isbell demonstrated some years ago that the hydrochloride salt of d-propoxyphene had morphine-like effects in man, since the drug produced both miosis and morphine-like subjective effects and suppressed morphine abstinence. Moreover. In direct addiction studies, the hydrochloride produced morphine-like physical dependence. Although d-propoxyphene was less potent than morphine, It was relatively more toxic. Oral doses of 800-1600 mg of d-propoxyphene napsylate have been recom- mended for detoxification and/or maintenance of heroin addicts. Larger doses produce untoward manifestations such as convulsions and a toxic psychosis. It is of interest, therefore, to determine the degree of morphine- like activity produced by d-propoxyphene napsyl ate in this dose range and to determine if this activity is sufficient to suppress abstinence in subjects physically dependent upon 60 mg of morphine/day: Nine non-dependent subjects were a~ninistered the following conditions in random order at weekly Intervals: morphine sulfate (10. 20mg subcutane- ously); d-propoxyphene hydrochloride (210, 420, and 600 mg, orally); d-propoxyphene napsylate ç3lO, 620, and 700 mg orally); and placebo (oral capsule and saline, s.q.). To maintain double blind conditions, subjects received both the oral and subcutaneous conditions simultaneously with appropriate substitution of active drug. One and one-half mg of d-propoxyphene napsyl ate and 1.0mg of the hydrochloride contains equal amounts of d-propoxyphene base. Prior studies have shown that d-propoxyphene. 600 mg, orally, produces effects equivalent to a 20 mg subcutaneous injection of morphine sulfate; and this dose of d-propoxyphene hydrochloride is not convulsive in man. Therefore. 900 mg of the napsyl ate salt was presuiied to be the maximimi dose that should be studied. However, during a preliminary dose run-up, 750 mg of d-propoxyphene napsylate produced nervousness, anxiety, apprehension and hyperreflexia (effectively antagonized by naloxone In one subject). For this reason, the PAGENO="0368" 14790 cOi\WETITISt PROBLEMS IN THE DRUG INDUSTRY Page 3 Jasinskl maximum dose of d-propoxyphene napsyl ate was chosen as molar equivalents to d-propoxyphene hydrochloride (210 and 420 rig). Drug e~fects were measured by change In pupil size (measured photo- graphically ) and scores ~n scales froni the Subjects and Observers Single Dose Opiate 9~estionnaire ~ and items frm the Morphine-Benzedrine Group (1130) Scale. Subcutaneous morphine and oral d-propoxyphene hydrochloride produced a dose-related miosis and morphine-like subjective effects. d-Propoxyphene was 1/30 to 1/40 as potent as morphine but d-propoxyphene hydrochloride, 600 mg orally, and morphine, 20 rig subcutaneously, produced equivalent effects (Fig. 1). These flndings7wlth the hydrochloride are similar to observations reported previously. M S C :: OPIATE SYMPTOMS E 15 10 / (IA-ILl) / : ~ 2 /~;;~ (Is_hal ) 0 20 Ig 210 420 200 - 0 20 mq 20 420 700 10 20 ,,` 2104700 MORPHINE 50.11(1 _- 4.PROPOXYPHENE HCL(PH) h- d-PROPOXYPHENE NAPSYLATE (PIll - PLACESO - -- 95%C0NFIDENCE LIMITS OF MEAN PLACESO RESPONSE Figure 1. Dose response curves utilizing total 5 hour scores for the com- parison of orally administered d-propoxyphene napsylate, orally administered d-propoxyphene hydrochloride an? subcutaneously administered placebo. Potency istimates with 95% confIdence limits in parentheses are expressed as mg of d-propoxyphene napsylate orally equivalent to I rngmorphine sulfate subcutane- ously (PH:M) and rig of d-propoxyphene napsylate orally equivalent to 1 rig d-propoxyphene hydrochloride orally (PN:PH); PUPILS 30 25 20 Is (0 S OPIATE SIGNS +2 0 S 0 0 I, 4 0 S 4 2 OSSERVER3 LIKING 10- S 6 4 2 10 S 6 4 2 0 SuBJECTS LIKING / lllI~flI PEP- LI z: PAGENO="0369" COMPETITIVE PROBLEMS IN THE DRUG INDVSTRY 14791 Page 4 Jasinski No response to orally administered d-propoxyphene napsylate was greater than that observed with 10 mg of subcutaneous morphine (Hg. 1). For this reason, valid relative potencies could not be obtained using morphine (10 and 20 mg) as a reference drug. Potency estimates were then calculated between the d-propoxyphene napsyl ate and 4-propoxyphene hydrochloride using the responses to the two lower doses of the d-propoxyphene hydrochloride as a standard. A valid relative potency estimate on pupils of 1.5 was obtained which would be expected for the two salts on the basis of equal base content. A tendency for the salt of the napsylate to be less potent was indicated by the various scale scores (FIg. 1); however, because of the wide confidence limits, these differences in potencies were not statistically significant. The data was further analyzed to determine if there is any difference in the onset of action between d-propoxyphene napsylate and the hydrochloride since plasma concentration studies in dogs administered large toxj5 doses of d-propoxyphene indicate delayed absorption of the napsylate salt. Time action curves for d-propoxyphene napsyl ate, 620 mg, and d-propoxyphene hydro- chloride, 420 m; (containing equal amounts of base) were compared and also to the response to d-propoxyphene napsylate, 700 mg orally, and placebo (Fig. 2). The naps~ate, at these dose levels, appears to have a longer latency to onset. The second group of experiments was conducted using subjects dependent upon 60 mg of morphine administered subcutaneously (15 mg q.i.d.). This level of dependence has been shown to be amociated with a discomforting abstinence syndrome upon abrupt withdrawal and with sufficient dependence to conduct substitution and preclpitatj2n tests. The first series of expert ments were 24 hour substitution tests, each subject being given, in place of regular doses of morphine, the following drugs: placebo (oral capsule plus subcutaneous injection); morphine 3 and 6 mg subcutaneously, d-propoxy- phene hydrochloride 110 and 220 mg orally, and d-propoxyphene naps7late 165 and 330 mg orally. Each of these doses was administered double blind at weekly Intervals 3 times for 3 consecutive 15 mg maintenance doses of morphine. Double blind conditions were maintained by administration of appropriate blank medications so that subjects received an oral capsule and an Injection each time. From the 14th through the 24th hour after the last stabilization dose of morphine observations were made hourly for with- drawal sickness as Qa not sick; 1 slightly sick; 2 = moderately sick; 3 = severely sick. PAGENO="0370" 14792 COMPETITIVE PROBLEMS IN THE DRUG flThUSTRY Figure 2. Time action curves from the comparison of orally administered d-propoxyphene napsylate. orally administered 4-propoxyphene hydrochloride. and subcutaneously administered morphine sulfate. The 420 mg dose of d-propoxyphene hydrochloride and the 620 mg dose of d-propoxyphene napsyl ate represent approximately equal amounts of d-propoxyphene base. Subcutaneous morphine, oral d-propoxyphene napsylate. and oral d-propoxyphene hydrochloride suppressed abstinence scores significantly as shown In Figure 3. In addition, all diminished sickness scores relative to the placebo condition. These results Indicate that both d-propoxyphene napsylate and the hydrochloride salt are capable of suppressing abstinence signs and symptoms. Valid relative potencies were not obtained In these PUPILS CS HOOPS POST DRUG 4 2 -I 25 -J 00 -075 -0.50 *.22 0 +025 20 IS 1.0 0-5 0 Page 5 Jaslnskl SIGNS HOURS POST DRUG O-O PSOPOXYPHFPSR HCL 420H5 PS0P0SS~*NR PtAPSYLAT( S2OH~ * PR~0SYPIOdt NAPSTLATt SWRS ~ PLACERO OPIATE SYMPTOMS * 2345 HOURS POST SINUS 12 PAGENO="0371" COMPETITIVE PROBLEMS IN THE DRUG ITTh~STRY 14793 Page 6 Jasinski studies because the statistical criteria were not met. However, it was estimated that d-propoxyphene hydrochloride is approximately 1/24 as potent as subcutaneous morphine in suppressing abstinence and d-propoxyphene napsylate Is roughly about 1/49 as potent as morphine. 210 PLACEBO 200 I 90 UJ 170 PLACEBO LESS LEAST SIGNIFICANT DIFFERENCE 60 -- z ~I50 ~ \ PftM24 140 \PN:PH 2 g ~ 130 `U I 20 110 3 5 110 220 mg 65 330 *o MORPHINE SULFATE (MI so. * *PROPOXYPHENE ICL (PH) oral £ d-PROPOXYPHENE NAPSYLAlE (PNI oral Figure 3. Total abstinence scores from 24 hour substitution studies in subjects dependent upon 60 mg morphine per day with morphine subcutaneously, d-propoxyphene napsylate orally, and d-propoxyphene hydrochloride orally. The least significant difference was ifetermined fran randomized blocks analysis of variance. The open circle for the morphine, 3 mg, represents a replication of that treatment one week following the completion of the other substitutions. PAGENO="0372" 14794 COMPETITIVE PROBLEMS ~ THE DRUG INDUSTRY Page 7 Jasinskl Following this, 2 of the 4 subjects participated in an additional experiment In which oral d-propoxyphene napsylate (300mg q.l.d.) was completely substituted for chronic morphine. For 2 weeks subjects received a double blind injection of 15 mg morphine subcutaneously and a blank capsule (lactose). Daily observations were made which included observations for abstinence sc~ges (daily Hirmielsbach scores) as..well as completion of a questionnaire designed to measure the chronic effects of opiates and the effects of abstinence. Capsules containing d-propoxyphene napsylate were gradually substituted for the morphine until after a period of 9 days subjects were maintained on 1200 mg/day of orally administered d-propoxyphene napsylate (Table 1). For the next 10 days this dose of d-propoxyphene napsylate was maintained as were all observations. During the transition phase, when the subjects were receiving both morphine and d-propoxyphene napsylate, there were significant Himelsbach scores Indicating mild abstin- ence with subjects reporting `kicking' (Table 1). However, the transition from morphine to d-propoxyphene was purposefully slav to minimize these abstinence symptoms so that subjects felt comfortable. During the period of maintenance on d-propoxyphene napsylate alone the demonstration of Himmeisbach scores suggested mild abstinence was present (Table 1). A number of symptoms were reported during this maintenance on d-propoxyphene napsylate which included feelings of persistent tiredness, weakness, lethargy; additionally there were initially, episodic feelings of elation, euphoria, palpitations and restlessness described by the subjects as effects most closely resembling those following amphetamine and cocaine. During this period of maintenance on d-propoxyphene, caloric intake was suppressed and the subjects lost body weight. The major source of points in the abstin- ence scores during this period of maintenance on d-propoxyphene were due to this decrease In caloric intake and contlnulnj'loss of body weight, an the 21st day of the experiment placebo capsules were substituted for the daily maintenance dose of d-propoxyphene napsylate (Table 1). Both subjects Immediately perceived the substitution and reported withdrawal sickness (Table 1). During the next few days abstinence scores Increased reaching a peak on the second or third days of substitution, Both subjects additionally identified this as mild abstinence and reported that the drug made them feel bad and were uncomfortable. On the eighth day a 2,5 mg dose of morphine was administered because of these feelings of uncomfortableness. PAGENO="0373" - Page a - .iasinsKi Table 1. Responses by subjects and observers to chronic opiate questionnaires, daily drug doses and daily Hlmmelsbach scores for the substitution of ~ for morphine. SUBJECT #2 d-Propoxyphene Hia.oelsbach Kickint Feels4 Hlmelsbach Klck1n~3 Feeli~ Day Morphine liapsylate Score Sub. Obs. Sub. Obs. Score Sub. Cbs, Sub. abs. 1 45 250 6 N N -1 0 16 V V -3 -1 2 30 500 5 V V -3 6 1 V V -3 -1 ~ 3 30 600 11 N V 0 0 9 V V -1 -1 m 4 32.5 600 12 N V -1 0 10 V V -3 -1 5 25 900 12 N V -1 -1 13 - V V -2 -1 ~ 6 15 900 7 N V 0 -1 16 V V -2 0 ~ 7 20 900 14 N V 0 -l 12 V V -2 -1 ~ 8 5 1200 7 N V 0 -1 12 V V -1 -1 `t 9 7.5 1200 13 N N 0 +1 9 V N 0 +2 ~ 10 0 1200 8 N V -2 -1 8 N V -l -1 11 0 1200 10 N N -1 +1 13 V N -1 +1 r 12 0 1200 12 N V 0 -1. 16 N V -l -1 ~ 13 0 1200 15 N N 0 0 10 N N 0 0 ~ 14 0 1200 14 N N 0 0 11 N N -l -1 15 0 1200 11 N N 0 0 16 N N 0. 0 ~ 16 0 1200 18 N N 0 0 11 N N 0 -1 17 0 1200 20 N N 0 0 16 . N V 0 0 18 0 1200 18 N V 0 -1 12 N N 0 0 19 0- 1200 17 N N -1 0 15 N N -1 ~1 20 0 1200 11 N N -1 -3 16 N N -1 -1 ~ 21 0 0 12 V V -1 -1 15 V V -1 -1 ~ 22 0 0 21 V V -1 -1 16 V V -2 -1 ~ 23 ~0 0 22 V V -1 -1 33 V V -1 -l 24 0 0 24 V V -1 -l 14 N N 0 0 ~ 25 0 0 22 V V -1 -2 20 N V 0 -1 ~ 26 0 0 21 V V -1 -2 12 N V 0 -1 27 0 0 24 V V -1 -1 12 . N V 0 -1 e 28 2.5 0 22 V N -1 0 10 N N .0 0 ~ 29 5 0 26 V N -1 0 11 N N 0 0 30 0 0 22 N N 0 -1 7 N N 0 0 -f Responses (yes or no) to question. `Are you (is patient) kicking?" cc tHow do you (does patient) feel? Very good +2; Good +1; Average 0; Slightly bad -1; loderately bad -2; bad -3; Very bad -4. PAGENO="0374" 14796 COMPETITIVE PROBLEMS fl~ TBE DRUG UThVSTRY Page 9 Jasinski On the basis of these studies the following conclusions are made: 1) Single oral doses of d-propoxyphene napsylate can produce morphine- * like activity equal to 10 mg of morphine subcutaneously 2) d-Propoxyphene napsylate orally can suppress the signs and symptoms of abstinence in subjects dependent upon 60 mg of morphine per day administered subcutaneously 3) Abrupt withdrawal of chronically administered d-propoxyphene napsylate, 1200 mg orally/day, is associated with a morphine-like abstinence syndrome 4) Daily oral doses of d-propoxyphene napsylate, 1200 mg, would be equivalent in morphine-like activity to 20 mg of subcutaneously administered morphine daily. By extrapolation, this level of morphine-like activity would be equivalent to that of 10 mg of heroin parenterally or 10 mg of methadone orally. Evaluation of Azidomorphine for Morphine-like Effects Azidmiorphine (Fig. 4), a morphine derivative, Is 40 to 300 times more potent than morphine as an analgesic In man and animals but In equianalgesic doses is reported to be l~3s1~o~c and to produce lesser degrees of physical dependence than morphine. The miotic and morphine-like subjective effects of azidomorphine as well as its ability to suppress abstinence was assessed. Miosis and Subjective Effects Seven, non-dependent subjects received the following drugs at weekly intervals: azidomorphine bitartrate, 0.35 mg. 0.70 mg, 1.40mg and 1.80mg; morphine sulfate 15 and 30 mg; and placebo (normal saline). All drugs were administered subcutaneously in random order under double-blind procedures. Drug ef~ects were measured by changes in pupil size, measured photog~a~- ically; Subjects' and Observers' Single Dose Opiate Questionnaires; and from the Morp~jne~Benzedrine Group Scale (MOO) of the Addiction Research Center Inventory. - Control photographs were obtained at 0700 and 0730. Drugs were admin- istered at 0800 subcutaneously under double blind conditions and at 0830. 0900, 1000. 1100, 1200 and 1300 pupil photographs were repeated and question- naires were completed. PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSPRY 14797 Page 10 Jas Ins ki N-C H3 HO AZIDOMORPHINE N3 N-CH3 HO MORPHINE 01-i Figure 4. Structure di agranis of azidomorphine (6-deoxj-6-azido-di hydra- isomorphine) and morphine. PAGENO="0376" 14798 COMPETITIVE PROBLEMS IN THE DM10 INDUSTRY Page 11 Jasinski Azidomorphine produced dose-related morphine-like subjective effects and miosis, as shown by the decreases in pupil size and elevated MBG Scale scores, Opiate Signs and Symptoms scores and Subjects' and Observers' liking scores (Hg. 5). Both azidomorphine and morphine had similar profiles (Table 2) and azidomorphine was consistently identified as an opiate (Table 3). Relative potency calculations, meeting the statistical criteria for valid bloassays, Indicate that azidanorphine bltartrate is 10 to 50 times more potent than morphine sulfate (Table 4). Comparison of the time action curves for the effects of azidomorphine 1.8 mg; morphine 30 mg; and placebo on these same measures indicates that azidomorphine may have a more rapid onset and a shorter duration of action than morphine (Fig. S -c S C I C z a ________________________ S o 50 40 C 3° 20 0 r 10 C 6 oesERvEps LIK$NG i/I M 90 OPI4TE SYMPTOMS - OY IS SuBJEcTS LIKING l0~ Ca, ,. Is 0.? I.. 30 BAZOOMORPNINE ...MORPHINE -pLAcEBo Ba' CLOT MEAN PLACEBO RESPONSE Cas A 30 - 0.? i.e Figure 5. Dose-response curves utilizing total 5 hour sums from the compari- son of azidomorphine, morphine and placebo. PAGENO="0377" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14799 Page 12 Jasinskl Table 2. Opiate signs and symptoms: Responses to morphine and azidamorphine on the single dose opiate questionnaires. Response Placebo Morphine Azi domorphine 15 mg 30 rig 0.35mg 0.7 mg 1.4mg 1.8mg Opiate Signs Normal 38 9 0 20 7 2 3 Scratching 1 22 34 16 27 35 29 Red-eyed 3 12 19 0 12 20 15 Relaxed 4 33 42 20 36 39 39 Coasting 0 10 19 18 4 10 24 16 Soapboxing 1 16 9 13 19 19 Vomiting 0 0 7 0 0 2 1 Nodding 0 0 1 0 1 0 1 * Sleepy 3 2 5 4 9 8 8 Nervous 0 2 15 1 1 8 14 Drunken 0 0 1 0 0 1 0 Other 1 5 11 1 9 27 5 Opiate Symptoms Normal 42 20 6 39 24 16 13 Turning of stomach 0 6 15 0 6 8 6 Skin itchy 0 2 14 2 7 16 23 Relaxed 0 6 17 3 14 18 15 Coasting 0 4 11 0 4 7 9 Soapboxing 0 0 7 2 4 7 9 Pleasant sick 0 11 11 0 5 5 7 Drive 0 0 1 0 0 2 5 Sleepy 0 2 6 0 0 2 2 Nervous- 0 0 5 0 1 3 0 Orunken 0 0 . 0 0 0 0 6 Other 0 0 0 0 0 0 0 Each value represents the total nunber of responses obtained in the total 5 hour observation period for all patients. Maximtmi ntrber of responses for any one category Is 42. -. - 85-569 O-7T-~5 PAGENO="0378" 14800 COMPETITIVE PROBLEMS ~c THE DRUG INDUSTRY Page 13 - Jasinskl - Table 3. Drug identification patterns on the single dose opiate questionnaires. Identification placebo Morphine Azidomorphine 15 mg 30 mg 0.35mg 0.7mg 1.4mg 1.8 mg By Observers Blank 38 9 0 20 8 2 3 Dope 4 33 42 22 35 40 39 By Subjects Blank 42 22 8 39 25 16 13 Dope 0 20 32 3 17 26 29 Barbiturate 0 0 1 0 0 0 0 Other 0 0 1 0 0 0 0 Each value represents the total number of responses obtained in the total 5 hour observation period for all patients. Maximtm, nianber of responses any one cate~op' is 42. Co~3ne. marihuana, alcohol, benzedrine, L.S.D., Thorazine * and Miltown or Librium Identifications were not reported by observers or subjects. PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14801 Page 14 - Jaslnskl Table 4. RelatIve potencies of azidomorphine bitartrate and morphine sulfate.4 Total 5 Hour Peak Response Parameter Response Pupils 0.09(0.000 to 0.246)~'~ 0.07(0.002 to O.185)~ Qpiate Signs 0.04(0.009 to0.092)5 0.04(0.006 to o.i05)~ Observers' Liking 0.05(0.015 to 0.O98)~ 0.04(0.008 to 0.097)~ M.S.G. 0.04(0.004 to 0.109)6 0.02(0.000 to 0.099)4.+ Opiate Symptoms 0.05(0.007 to 0.112)6 0.03(0.002 to 0.096)~ Subjects Liking 0.06(0.011 to 0.131)6 0.04(0.009 to 0.ioi)~ +Potencies expressed as rig azidomorphine bitartrate equivalent to 1 rig morphine sulfate with 95Z confidence limits in parenthesis. Suprascripts following parenthesis Indicate number of points used in parallel line bloassays. `Values for confidence limits 0.0004 and lower are shown as 0.000. PAGENO="0380" 14802 CO~ETtTWE PROBLEMS ~ THE DRUG ~DUSTRY Page IS ,Jasinski PUPILS I OPIATE SIGNS OBSERVERS LIKING 0 I OTT - . OTT_i'., I II B S OPIATC SYMPTOMS SUBJECTS LIRING 012345 2 012345 2 012345 - 2 HOURS POST DRUG HO&S POST ORIJO 10MG POST 001.10 O'.OAZIOOMORPHINE .8mg .-aIORPHINE 3OR9 S-PLACEBO Figure 6. Time action curves for placebo, azidarlorphine, 1.8 mg, and morphine, 30 mg. Brackets represent the standard error of the mean placebo response. Substitution Studies The ability of azidomorphine to substitute for morphine and suppress morphine abstinence was determined in 5 subjects dependent upon 60 mg of morphine administered ~b1~taneously daily (15 mg q.i.d.). The 24 hour substitution procedure was used in which each subject received 3 double blind medications in place of 3 consecutive doses o,f morphine and from the 14th to the 24th hour of substitution observations were made hourly for abstinence signs. At these same times subjects rated their degree of withdrawal sickness as 0 = not sick; 1+ slightly sick; 2+ = moderately sick; and 3+ = very sick. Control responses to placebo, morphIne. 3 mg, and morphine, 6 mg. were obtained Initially. Each subject then received a dose of 1.8mg of azid~norphine in the 24 hour substitution procedure (total dose 5.4 mg). In these studiesazidomorphine effectively substituted for morphine and suppressed abstinence (Table 5). PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14803 Page 16 Jasinski Table S. Total abstinence and sickness scores during the 24 hour substitution test.' Drug Abstinence Store Sickness Score Placebo 189.6 ± 24.9 10.6 ± 2.2 Morphine 3 rig 154.2 ± 24.4 10.0 ± 0.8 Morphine 6 rig Azidomorphine 1.8 rig 130.2 ± 20.O~' 106.4 ± lS.4~' . 4.6 ± 1.8 ± 2.0k 1.1+ `Total scores represent the means and standard errors for 11 observations in 5 subjects in which placebo, morphine and azidomorphine were substituted for 3 consecutive 15 rig doses of morphine. ~Significantly different from placebo as calculated using 2-way analysis of the variance and the method of least significant differences. These present studies indicate that azidomorphine has morphine-like activity in man as indicated by its ability to produce morphine-like subjective effects, miosis and to suppress morphine abstinence. AzidorTorphine is 10 to 50 times more potent than morphine and may have a somewhat more rapid onset and shorter duration of action. Evaluation of Butorphanol for Morphine-like Effects The morphinan derivative, butorphanol, (z-BC-2627) ~gig. 7) Isa morphine antagonist having analgesic activity in man and animals. Butorphanol does not sub~3itute for morphine nor suppress abstinence in the morphine-dependent monkey. Butorphanol is currently being evaluated for the ability to produce dependence of the morphine type in man. PAGENO="0382" 14804 cOMPETITivE PROBLEMS IN THE DRUG INDUSTRY Page 17 HO .1.c4ncki CH2-() Figure 7. Structure diagrams 3, 14 s-dihydroxymorphinan). Miosis and Subjective Effects of butorphanol (t-BC-26»=l, t-N-cyclobutylmethyl- Initially, single doses of butorphanol, morphine and placebo were com- pared to determine the ability of butorphanol to produce morphine-like subjective effects and miosis. Ten subjects received at weekly intervals, placebo (normal saline), morphine sulfate. 7.5, 15 and 30mg; and butorphanol tartrate, 2, 4, and 8 mg. Drug effects were measured by change in pupil size, measured graphically; Subjects' and Observers Single Dose Opiate Questionnaires and Items on the Morphine-Benzedrine Group (MBG) Scale, a general measure of drug induced euphoria; the LSD Scale, a measure of early psychotomimetic and dyspharic effects; and the Pentobarbjtal.Chlorpromazine_Alcohol Group (PCAG). a measure of apathetic sedation, control pupil observations were taken each day at 0800 and 0830. Drugs were administered subcutaneously under double-blind conditions at 0800. At 0830. 0900, 1000, 1100, 1200. 1300, 1400 and 2000 pupils were again photographed and questionnaires were PAGENO="0383" COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY 14805 Page 18 Jasinski completed. Time action curves on changes In pupil size and the various scale scores indicate that the duration of action of butorphanol appears to be similar to that of n~rphine through the 12 hours (Fig. 8). Dose response curves (Fig. 9) were constructed on these same measures using the mean total 5 hour responses (sum of the first 6 responses). Compared to morphine (Fig. 9; Table 6, 7), butorphanol produced certain effects similar to morphine, including pupillary constriction, significant dose- related scores on Symptoms and Signs Scales, `Li~ing" Scales, and identi- fication as an opiate by subjects and observers. Butorphanol, however, did not produce significant scores on the MBG Scale (a measure of drug-induced euphoria), but did produce significant ISO and PCAG Scales elevations (Fig. 9). Butorphanol was also identified as a barbiturate more frequently than morphine and produced nervousness" and `drunkenness' more frequently than morphine (Table 6. 7). Thus, the overall profiles of butorphanol appear to reseritle those produced by agents such as nalorphine and cyclazocine. Potency estimates meeting statistical criteria for validity were obtained on certain of the measures (Fig. 9) indicating butorphanol tartrate was 1/3 to 1/5 as potent as rerphine sulfate. I- 23401 4 `31154'S S~3't34Sl S It 1t3421 4 lIOURS $OURS WOUSS 400SS *~-S I -Sc-2627,R,.II 4_S M0RP~flR t 3044) 0-0 .t.*ct.0 + 37450450 15404 0~ 4044 41.40140 415405,0 Figure 8. Time action curves for changes in pupil size ~nd scores on scales for placebo, morphine, 30 mg. and butorphanol (t-BC-260), 8mg. PAGENO="0384" 14806 COMPETITIVE PROBLEMS IN THE DRUG ~DDSTRY 0 Figure 9. Dose response curves utilizing total 5 comparison of butorphanol. morphine and placebo.- ally valid relative potencies with 95% confIdence expressed as mg of butorphanol equivalent to I mg assay, five point assay**, six point assay***. hour responses from the Nunbers represent statistic- limits in parentheses n~rphine. Four point 0 C Page 19 JasInski 2 4 4 4 30 2 4 I IS 50 0 4 I IS 2 0020 (US) 0021 (143 0021 ISP - A_Ut1527 M0S~ISt PL*CU0 ---S3%CL 09 5145 LACCUOIESP0521 PAGENO="0385" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14807 Page 20 Jasinski Table 6. Cumulative responses to symptans and signs frecu the Single Dose Opiate Questionnaires. Maximian response in any category is 70. Symptoms Placebo Bqtorphanol Morphine 2.0 4.0 8.0 7.5 15 30 Normal 63 44 20 6 55 32 18 Turning of Stomach --- 5 3 4 5 1 18 Skin Itchy --- 4 4 15 --- 6 23 Relaxed 5 `7 24 23 9 24 37 Coasting Soap Box 2 10 15 9 9 5 20 10 Pleasant Sick --- 1 4 2 4 Drive --- 1 Sleepy --- 1 10 16 --- 3 4 Drunken --- 4 7 30 Nervous --- 10 4 16 --- 1 1 Other --- 2 2 9 4 2 5 Signs Normal Scratching 40 8 29 9 6 23 3 22 31 12 15 28 8 49 Red Eyes 46 726 13 2 20 42 Relaxed 28 3460 56 37 18 62 Coasting 8 11 16 34 12 18 20 SoapBox 11 2926 45 25 41 43 Vomiting 1 --- 1 --- --- --- 3 Nodding --- 3 10 2 *-- 1 3 Sleepy Nervous 10 5 5 15 16 104 17 2 1 1 1 9 --- Drunken --- 1 9 17 --- 6 6 Other 2 6 16 13 9 12 17 S PAGENO="0386" 14808 CO)OETIPIVE PROBLEMS ~ TBE DRUG UThUSTBY Page 21 Jasinskl Table 7. Cumulative identifications by subjects and observers from the comparison of butorphanol, morphine and placebo. Maxim,.r responses in any category is 70. Subjects Placebo Butorphanol Morphine 2.0 4.0 8.0 7.5 15 30 *rdentified as: Blank 63 44 l~ 6 53 33 19 Dope 3 3 24 30 11 26 47 BarbIturate 2 14 24 22 --- 6 1 Alcohol 7 Other 2 9 3 12 6 5 7 Observers - *Identlfied as: Blank 40 29 9 5 31 15 8 Dope 21 34 14 50 39 48 62 Barbiturate --- 4 4 10 Alcohol --- 5 --- 6 --- Amphetamine --- 1 7 1 Other 7 15 20 27 9~ 1 6 as identifications: N *The following choices were listed but were not chosen cocaine, marihuana (pot), LSD (acid). Thorazine, Miltown or Librlwn. PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14809 Page 22 Jasi nskl Despite the unpleasant side-effects noted, subjects also evidenced `liking' scores which equalled those produced by 30 mg of morphine (FIg. 9)~ One interpretation of these "liking" scores is that butorphanol Is pore reliably euphorogenic than agents such as nalorphine or cyclazocine and suggests that there may be a difference in the profiles of subjective effects produced by agents such as pentazocine, cyclazocine and butorphanol. An additional study was conducted to compare the subjective effects of pentazocine, butorphanol, cyclazocine and morphine. The same expert- mental procedures and methods were utilized as described above except that the last observation time was omitted. Nine subjects participated. Each received In random order at weekly intervals the following medication; placebo (normal saline); cyclazocine (base), 0.5 and 1.0 Tog; pentazocine (base). 40 and 80 mg; butorphanol (salt). 2 and 4 mg; and morphine sulfate (salt), 10 and 20 Tog. One subject did not complete the 1 mg cyclazocine treatment because he found this dose to be extremely disturbing. Conse- quently. the responses to cyclazocine. I mg, are based on 8 subjects. The effects of butorphanol, cyclazocine and pentazocine could be differentiated from morphine by elevated PCAG and LSD Scale scores; greater responses on the symptoms and signs categories, "sleepy," "drunken," "nervous"; and a tendency to identify these effects as barbiturate-like (Fig. 10; Tables 8. 9). Relative potencies (Table 10) wer13similar to those22 obtained previously for butorphanol (Fig. 9). pentazocine. and cyclazocine relative to morphine. A second set of relative potencies calculated for comparison of cyclazocine with pentazocine and butorphanol with pentazocine (Table 10) indicate that butorphanol is approximately 15 to 25 times more potent than pentazocine and that cyclazocine is approximately 25 to 100 times more potent than pentazocine. Of interest was the observation that statistically valid relative potencies were not obtained with all measures for these comparisons with pentazocine because of significant "F' ratios for non-parallelism and preparation mean squares. in the analysis of variance suggesting differences in the profile of subjective effects among these agents. Precipitation Studies The first studies conducted in 5 subjects dependent upon 60 mg of morphine per day (15 mg q.i.~2 subcutaneously) Involved precipitation tests using our standard procedure in which each subject received placebo; 1.5 and 3 eg of nalorphine; and 4, 6 and 8mg of butorphanol. Butorphanol, 4 Tog, precipitated mild abstinence with abstinence scores equivalent to that produced by nalorphine 1.5mg (Table 11). However, increased doses, 6 and 8 mg, did not increase abstinence scores. The precipitated abstinence scores for butorphanol were not significantly different from those produced by placebo, Larger d~ses of butorphanol were not given because the 8 Pg of butorphanol produced nervousness, apprehension, and irritability, along with a mild degree of abstinence as would be expected from the single dose studies. PAGENO="0388" 14810 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY * GPJATE STMPTOMS ..w~ OPIATE SIGNS ~H: SUBJECTS LIKING OSSENVEfl LIKING : // :z/ZZ Figure 10. Dose response curves (total 5 hour responses) of butorphanol , pentazocine, cyclazocine. morphine and placebo Page 23 Jaslnskl PUPILS ~ /// PcAo / 7 MEG LSO / -1 `a S0 Q 0 0 02503 It SO ~O 0 ~ SO Gfl GB là SO *0 .0 GOJOBO SQ - .4 CYCLAZOCISE *._4 I-aC-555? 0_S 505.4151 S__S P~tAz~IA5 - PLBCESO --.50% CO. SF MEAN P5.4515055550504 from the comparison PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14811 Page 24 Table 8 Jasinshi Identi fication of drugs by subjects and observers from the cowarison of butorphanol, pentazocine, cyclazocine and morphine. Maximum responses In any category Is 54. Subjects Placebo 8utorphanol -- Pentazocine Cyclazocine ~r 0.5 1.0 Morphine 2.0 4.0 40 80 10 20 BLANK 52 33 22 17 18 21 11 25 16 DOPE 0 10 12 14 18 13 8 6 14 Cocaine 0 0 0 0 0 0 0 0 0 Marlhuana 0 0 0 0 8 5 2 0 0 Barbiturate 0 0 4 14 5 3 5 4 0 Alcohol 0 0 3 1 0 0 5 4 5 Miphetamine 0 1 0 0 4 6 0 4 6 LSD 0 0 0 0 2 0 9 0 0 ThorazIne 0 0 0 2 0 0 1 0 0 Llbrlirni 0 0 2 0 0 0 0 0 0 Other 2 13 13 11 11 12 17 14 13 Observers - 23 - 6 8 20 - 5 Blank 38 -_- 6 11 - 5 Dope 6 23 47 38 47 15 27 48 49 Cocaine 0 0 0 0 0 0 0 0 0 Merihuana 0 0 0 0 *O 0 0 0 0 Barbiturate 0 1 1 5 1 8 5 0 0 Alcohol 0 0 0 0 0 0 0 0 0 knphetamine 1 0 0 0 0 0 0 1 0 LSO 0 0 2 0 1 0 0 0 0 Thorazine 0 0 0 0 0 0 0 0 0 Libritan a Th 0 0 0 0 0 Other 10 8 3 3 5 13 6 0 1 * Responses from 8 subjects PAGENO="0390" 14812 CoMPETITIVE PROBLEMS U~ THE DRUG INDUSTRY Page 25 Jasinski Table Cumulated nw~ber of responses by subjects and observers to signs and symptoms of the Sir.gle Cose Opiate Questionnaires for the comparison of butorphanol pentazocine, - cyclazocine. morphine and placebo. Maximum responses In any category Is 54. Opiate Symptoms Placebo 8utorphanol Pentazocine Cyclazocine Morphine 2.0 4.0 40 80 0.5 1.0* 10 -20 Turning of Stomach 2 0 4 4 13 8 5 11 7 Skin Itchy 0 1 5 7 7 0 5 4 14 Relaxed 0 6 8 11 18 10 9 8 14 Coasting 0 6 5 9 14 4 10 1 1 Soap-BoxIng 0 0 0 3 0 0 4 4 5 PleasantSlck 0 0 1 0 8 0 2 0 0 Drive 0 0 2 0 3 0 2 1 5 Sleeny 0 5 7 5 11 6 3 4 2 Nervous 2 0 0 5 9 0 3 0 2 Drunken 0 0 9 13 10 3 18 5 5 Other 0 3 8 8 4 5 12 9 10 Opiate Signs Scratching 4 9 23 12 27 5 21* 15 38 Red-Eye 4 4 15 14 23 13 15 21 17 Relaxed 15 32 47 43 47 33 37 48 47 Coasting 2 13 25 20 21 11 19 10 20 Soap-Boxing 6 13 18 23 21 6 17 21 22 VomitIng 0 0 1 0 3 .0 0 1 0 Nodding 0 0 1 0 6 0 4 0 1 Sleepy 7 13 19 9 23 18 18 9 10 Nervous 6 1 5 20 6 6 5 5 8 Drunken 0 sO 0 5 10 4 9 0 4 Other 2 10 16 9 8 17 3 6 17 * Responses from 8 subjects PAGENO="0391" COMPETITWE PROBLEMS IN TUE DRUG INDUSTRY 14813 Page 26 Jasinski Table 10 Potencles of butorphanol, cyclazocine and pentazocine relative to morphine (1 mg). Butorphanol Pentazocine Cyclazocine Pupils 0.32(0.21-0.85)~ 4.23(2.96-6.22) + Symptoms 0.35( )~ 2.24( )~ 0.04(0.02-0.07) Signs 0.24(0.13-0.89) 3.0l( )~ 0.07(0.03-54.78) S. Liking 0.18( )* 2.44(0.40-4.12) 0.04( )4 0. Liking 0.25(0.17-0.45) 3.62(1.33-7.38) 0.08( MBG 4.05(1.30-13.53) 0.04( P040 t 0.005( )+.$ LSD -~ + $ Potencles of butorphanol and cyclazocine relative to pentazocine (1 mg). Butorphanol Cycl azocine Pupils 0.07(0.05-0.l5)~ 0.04(0.02_5S6.66)~tt Symptoms 0.15( )`t* 0.01( Signs 0.07(0.04-0.25) 0.01(0.01-0.11) S. Liking 0.09( )+ Q,Q)( )t 0. Liking 0.06(0.04-0.12) 0.02(0.01-0.14)~ MOO 0.07( )+ 0.01( PCAG 0.15( )# 0.01( LSD 0.04(0.007-0.21) 0.01(0.007-0.01 )* + SIgnificant preparation difference + Nonsignificant regression coefficient ~ Significant nonparallelism PAGENO="0392" 14814 COMPETITIVE PROBLEMS uc ThE DRUG INDUSTRY Page 27 Jasinski Table 11. Means and standard errors for total modified Hinnelsbach score obtained in precipitation tests. Total precipitation scores are the sums of scores from five observations. DRUG PRECIPITATION SCORE Placebo 52.2 ± 11.8 !ialorphine 1.5 mg 64.0 ± 12.2 Nalorphlne 3.0 mg 102.6 ± 21.39*025 Butorphanol 4.0 eq 65.6 ± 21.8 Butorphanol 6.0 mg 59.8 ± 22.3 Butorphanol 8.0 mg 69.6 ± 10.3 The superscript is the level of significance for the difference from placebo as calculated using 2-way analysis of the variance (subjects X treatments) and the method of least significant differences. PAGENO="0393" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 14815 Page 28 Jaslnskl Substitution Studies Following pre~pitation tests, subjects also participated In 24 hour substitution tests to determine if butorphanol could substitute for morphine and suppress abstinence. On separateweeks, subjects were given, In lieu of regular doses of morphine, three consecutive doses of each of the following: saline placebo; morphine 3 and 6 rig; and butorphanol, 0,6 and 1.2 mg. Abstinence scores were assessed hourly from the 14th through the 24th hour of substitution. At these same times the degree of sickness was assessed as 0 not sick; 1+ = slightly sick; 2+ mildly sick; a~d 3+ very sick. Partial maintenance doses of morphine suppressed both the symptoms and signs of abstinence (Table 12). Butorphanol, 0.6 and 1.2 mg, both suppressed the abstinence but this effect was slight and no significant dose relationship was found. On the basis of preliminary studies it appears the pharmacologic profile produced by butorphanol is not morphine-like but more closely resembles that produced by agents such as nalorphine, cyclazocine and pentazocine. Morphine antagonist activity was not clearly demonstrated. SECTION II: N4PHETNIINE-LIKE DRUGS Side-Chain Modified Amphetamine Congeners In 1971, Martin et al.23 reported on the subjective and physiological effects of d-amphetamThiind several related congeners (Fig. 11, #1-5). While these agents differed in terms of mg potencies. none seemed to have a sele~5ive effect on euphoria, blood pressure or appetite (Table 13). Martin proposed that this profile of subjective and physiologic effects be used to classify agents as amphetamine-like in man for the purpose of assessing abuse potential. Since then, several more drugs have been assessed by these same methods. This program is directed by Dr. John Griffith. The 5 agents originally studied by Martin et al.23 were various side chain modified amphetamine congeners (Fig. 1l).'t~ further examples of this class have been since studied, diethylpro9ion and benaphetamine (Fig. 11, #6, 7). Diethylpropion was reported last year as being `amphetamine- like." It is a relatively weak compound, however, as indicated by the potency estimates in Table 13. Senzphetamlne This compound, also a side-chain modified derivative, was assessed more recently. Its profile o,_f subjective and physical effects resenbles that of amphetamine but its oral potency is of the sane order as diethylpropion or subcutaneously adminfttered a-ephedrlne (Table 13). 55-469 O-77----26 PAGENO="0394" 14816 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 29 Jaslnski Table 12. Means and standard errors for total abstinence scores and total sickness scores obtained in 24 hour substitution tests In 4 subjects where morphine, placebo and butorphanol were substituted for 3 consecutIve 15 fIg doses of morphine. Total abstinence or total sickness scores are the sum of scores from all 11 observations. DRUG ABSTINENCE SCORE SICKNESS SCORE Placebo 189.6 ± 25.0 10.4 ± 2.2 Morphine 3 mg 154.2 ± 24.4 10.0 ± 0.8 Morphine 6 mg 130.2 ± 19.0.025 4.6 ± 2.0.025 Butorphanol 0.6 rng 154.4 ± 8.2 6.2 ± 1.8.05 Butorphanol 1.2 mg 163.2 ± 35.6 6.8 ± 2.0.1 Superscripts are levels of significance for the difference from placebo as calculated using 2-way analysis of the variance (subjects X treatments) and the method of least significant differences. PAGENO="0395" COMPE~1'ITIVE PROBLEMS IN THE DRUG INDUSTRY 14817 Page 30 .lacinckl SIDE-CHAIN MODIFIED AMPHETAMINE CONGENERS SIDE CHAIN GENERIC NAME I. (O>--CH2_CHNH2 d-AMPHETAMINE Cl-I3 2. -CH2--CH-NH-CH3 d-METHAMPHETAMINE Cl-I3 3 II -CH--CH-NH-CH3 1-EPHEDRINE OH CM3 ¶H3 4. " -CH~-CH PHENMETRAZINE / `S ~NH CM2 -CM2 0 `~C-O-CH3 METHYL.PHENIDATE -CM-C CHzNH CM2 CH2 CM2 -CrCHN DIETMYL.PROPION * `I ~ru - CH 25 3 7 -CH3-CH-N-CH2 - i P6506*04. CR2006 ,~ /`~ \ ~\eL~*~ ~a;: *S20~ \ \ `-oo] \ rT'." - 4-*1491CT46151 L' w4. `s~ 20.] \-.`541E !__!.500I ..~.25 **S000E010 20 4060 20 240 20 4060 20 20 20 40*0 20 240 Inc mc 059 Figure 13. Dose response curves from the comparison of chlorphentermlne. d-arnphetamlne and placebo. PAGENO="0400" 14822 COMPETITIVE PROBLEMS W THE DRUG INDUS7RY Page 35 Jas ins ki Chlorphentermine Chlorphentermine was assessed in a manner similar to that described for fenfi urarni me excepting that the Pentobarbital -Chi orpronazi ne-Alcohol GroupScale (PCAG) (apathetic sedation) was included as an additional measure. Nine subjects received chlorphentennine (50. 100, 200 mg); d-arnphetamine (20, 40 mg) and placebo, each condition athninistered orally at weekly intervals. Chlorphenteni~ine produced a profile of effects distinct from that of d-amphetamlne but similar to that of fenfluramine (Fig. 14). Chlorphenter- mine Is mydriatic, dysphorogenic (LW Scale). anorexigenic, and sedative while relatively devoid of vasopressor effects. Although some subjects were grossly sedated by chlorphenternnnine, no hallucinatory syndromes were observed. AG~wtTAM4~0 SCALE SO NZEDNSKGNOIJP ~PIISd-ttcC0SOI( SuSaCTS LIKING * ~0 SCAI.t *~ 05050 SCALE :1~-t~L :::-cL ~-.-~=~--~ ~. SO SCALE PC AS SCALE SYSTOLIC El ASOOLIC _40 40 200 *t000 pflSSUEE *OiSL000P POESSON I * I IS5PISEI I sup+. LI ~i: ~ ::~6 40 40 EIOSPHINE 240m~/0AY FE AK 36 8± 2 .7 ~ 30 30 AREA.l9e.l ±16.3 S fl8 40 PENTAZOCINF ~ 40 pi.~toqpHNe 2C0~,/OAY PEA4. 3.5 21.7 30 AREA: ~50± 53 30 AREA: 345 ± 12 0 2 3 4 5 6 7 6 9 10 0 I 2 4 4 3 6 7 6 9 10 0422 OF WIThDRAWAL ODYS OF WITHOR±WAL Figure 4. Mean daily Ilioneisbach scores for the withdrawal of butorphanol in 6 subjects and compa~ison with wi~hdrawal 6 lti±rnnelshach ,eores for cyclazygine, nalbuphine, morphine, pentarocine, and nalorphine. N represents the number of subjects. Alno shown are the means and standard errors for the peak and total area hirmeisbacli scores. On the basis of these and previously reported studies,1 butorphanol appears to produce effects ~hich most c1o~ely reserbie th~se produced by agents such as peutazocine, cyctazocine, and nnhirphine rather than norphins-like agents. Unlike these agents, butorph~nol did not precipitate abstinence in morphine-dependent subjects. EJUTORPHAFIOL 451110/OAY PEAI( 24.3 ±3.7 AREA .1441±132 N6 30' 20 10 r±2LBUPHIIRE 203112/OAY PEAK. 244±1.5 MEA~l36 ± 6.4 N 5 PAGENO="0413" Table 4. C~sporison of scan sources of points in the }U~e1sbach scares for butorphanol5 sorphine,6 nalorphins,t pentazocine.7 nalbuphine5 and the 10 days fol1owin~ abrupt withdrsvd. Source of Points Morphine (H) ffaiorp?oino (WI) Pcnto.nooina (P) Nalbuphin. (Nb) Cojaiaaooine (C) Thatorpkanol S Total Points amok Total Points Rank Total Points Rook S Total Points Rook Total Points Rank Total Points Rank +Sians 4.4 6 11.0 3 9.4 4 17.3 3 12.8 4 11.1 6 ++Signe 9.3 5 3.8 7 - 29.2 1 26.2 1 16.7 2 18.3 2 Caloric ictake 1.9 8 6.7 6 3.2 8 4.8 7 5.3 6 13.0 5 Itcstlcs.oncoe 0.8 9 1.1 8 0.0 9 0.8 8.5 0 9 0.5 9 taosis 2.8 7 0.0 9 4.6 6 0.8 8.5 0.7 8 5.4 7 Fever 17.1 1 15.8 1%.5 1 12.9 6 3h9 1 18.6 1 llypnrpnos 31.1 1 10.8 4 26.2 2 20.2 2 11.1 5 4.6 Systolic blood prcasure 25.5 2 9.5 5 3.5 7 8.8 5 3.1 7 13.8 4 Iei8ht loss 11.5 4 20.9 2 8.4 5 8.2 6 15.8 3 15.0 3 Ta MXNIO.60 r NXN1-0.27 ~ MXPO.60 NJ. X P - 0.40 MXP-0.47 N1XP-0.18 MXNb-O.64 Ni I Nb - 0.44 PXNb.0.88** MXNb-0.44 N1XNb-0.19 PXNbaO.90** MXCeO.47 Nl X C 0.72* PXCO.78* Nb I C a 0.71* NXC-0.16 N1XCeO.87** PXC..0.54 Nb I C . 0.53 MXB-0.37 Ml II -0.52 PXZO.43 Nb Xl -0.40 C I B * 0.80* MXB-0.03 19118.0.57 P18-0.33 Nb I 8 - 0.45 011.0.69* - * ~ correlation coefficients (re) and produc t moaant correlation coefficients Cr). Comparisons are made mith Spearman rank order ~Op <0.01 *p<005 cyclazocine abstinence for 2 a tel C C) C a çri PAGENO="0414" 14838 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 10 Jasinski Assossnent of Oxi~~pi~gn Oxilorphan is a narcotic antagonist proposed as a §ossible therapeutic agent in the treatment of opiate addiction. Previously we had obsen'ed that subcutaneously administered oxilorphan is approximately equipotent to dt-cyclazocine in precLpitating abstinence in morphine-dependent subjects. On the other hand, subcutaneous oxilorphan was only 1/4 as potent as subcutaneous dt-cyclazocine in producing increases on the LSD and PCAG Scale scores in non-tolerant. non-dependent subjects. Further, at 24 hours after administration of single doses, there were persistent LSD Scale scores, PCAG Scale scores and niosis with both oxilorphan and cyclazocine. Thus, oxilorplian appeared to have the duration of action of dt-cyclasocine with equal antagonist potency but a lesser ability to produce agonist effects. Two additional studies have been completed. First was a comparison of single doses of orally and subcutaneously administered oxilorphan in non-tolerant, non-dependent subjects, and second, at, assessment of the duration of action of oxilorpham in blocking the effects of morphine in non-tolerant, non-dependent subjects. In the first study o-xilorphan, 1.5 ng and 3.0 rg, was administered both orally and subcucaneously to 8 subjects at weekly intervals under double blind conditions. Drug effects we~e measured with subjects' and nbservers~3single dose questionnaires and a subtective drug effects questionnaire containing items from the LSD, PCAC ar.d NaG Scoles of the Addiction Research Centor Inventory, as well as with photographs measuring change in pupillary size. Drug effects ware assessed at 1/2, 1, 2, 3, 4, 5, and 6 hours after drug administration. In these doses, orally sdministered oxilorphan did produce some effects which were distinguished from placebo; however, the onset of effects with orally administered oxilorphan were rarkodly slower than those with subcutaneously administered oxilorphan. Consequently, the responses at the 3rd, 4th, 5th and 6th hours which to e:t extent represents the neon peak response of both orally and subcutaneously administered oxilorphan were utilized to construct dose response curves (Fig. 5). Measures where valid bioassays vere obtained indicated that orally adninistered oxilorphan was 1 to 1/2 times as potent as subcutaneously administered oxilorphan (Fig. 5). PAGENO="0415" COMPETITIVE PROBLEMS tN THE DRUG iinrns'rwr 14837 Page 11 Jas inski ___ 21 ~ i ~ ~: ~ 211J Dolt -.---p~~:Ew --91% CllFOF.*~CI*1$%t!Ts s:l~,~\n.scA,L.;.~t.Pt~cceo t'021 Figure 5. Dose response curves utilizing responses at 3rd, 6th, 5th and 6th hours for orally and subrutanecualy administered oxilorphan. In the second study, the blocking effects of subcutaneously adrein- istered oxilorphan, 0.6 og/70 kg, en the effects of subcutaneously administered morphine sulfate, 25 mg/iD kg, was assessed in 6 subjects. Each subject received in random order at veekly intervals the following 5 treatments; 1) rnnrphine alone; 2) oxilorphsn alone; 3) morphine preceded by oxilorphan at 12 hoLirs; and 5) morphine preceded by oxilorphan at 24-hours. The Ioperinentsl design was siollar to thnt used by Nartin and his colleagues to estimate the duration of blocking action of cyclazocine, 0.6 og, on morphine, 25 rig/70 kg. PAGENO="0416" 14838 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 12 Jasioski Oxilorphan administered 4 and 12 hours before morphine clearly btocked the niocic effects of morphine. At 24 hours there was still a blockade but to a lesser degree (Fig. 6). Similar results were obtained on the measures of subjective effects. Comparison of the data obtained with oxily5'jhan with that for cyclazocine obtained by Nartin and his colleagues suggests that even though oxilorphan has some degree of blocking activity at 24 hours, its blocking activity nay decrease more rapidly than cyclazocine's from the 4th to the 24th hour. Figure 6. Blocking ability of oxilorphan (0.6 rig subcutaneously) on the niotic effects of morphine (25 r.g/70 kg subcutaneously). )unhers represent the "t" values calculated for the comparison of the iziotic response to that of morphine alone. 12 9 6 3 0 E E c~Z In ft Ca I~0 >- Ccx Lii -j 0~ 1.79 120; 0 6 12 IS 24 HOURS 7.15 MORPHINE ~ ALONE OXILORPHAN ALONE MORPHINE AFTER PRETREATMENT 0 WITH OX IL OR PH AN PAGENO="0417" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14839 Page 13 Jasiaski Assess..ent of Vv-16,225 for ~lorphine-t1ke Subjective Effecrs and Niosis Wy-16,225 is a bridged aminotetralin (Fig. 7) t;hLch is an effective analgesifibut does not appear to be a morphine-like drug in studies in r.onkeys. In morphine-dependent monkeys Wy-16,225 precipitated abstin- ence in non-withdrawn monkeys end did not suppress abstinence in with- drawn morphine-dependent monkeys. Further chronic administration of Ly-16,225 did nec induce physical dependence. C H3 Wy- 16,225 OH Figure 7. Structure of Wy-16,225 ((-)-133-amino-5,6,7,g,9,lO, ll,l2-octahydro-5 e-methYl-5.ll-methanobenzocYclodecefl_31_ol) *H Br A single dose study was conducted in which each of 10 subjects recoived Wy-16,225, 15, 30 and 60 ag; morphine. 15 and 30 ng; and placebo at weekly intervals under double blind conditions. Drug effects were assessed at 0.5, 1, 2, 3, 4, 5, 6, and 12 hours after drug adninistration with change in ~u~illgry19ierteter, subjects' and observers' single dose13 opiate questionnaires ` - and a subjective drug effects questionnaire. PAGENO="0418" 14840 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Pr~e U. Ja~inoh1 Exanination of tine action curves su';~ost that Yy-16 ,225 tins a so~te;;har note rapid onset than c.orphino and shorter duration of action (Fig. 8). Wy-l6,225 usa identified predontnantly as an opiate (Table 5), pniluced a typical pattern of opiate-like synprons and signs (Table 6) and produced dose-related increases on the various scales noasuring morphine-like effects (Fig. 9). Relative potencies iron these dose response curves indicated that Wy-l&,225 was approxinately equipotent to morphine (Fig. 9). 2'. 30 75° 24 20 Is 0S 04 £2, 65 LLLLLL_~- 0 `-`~`-. .-`--l-- 0 0I N0425 04]416 SI0~s 0 2 0 IS WrIS 22060 .,,I 0-.-~ 6,22 5530131 *3C P1 4C600 ~ 5t'.,or,'.oqoF~o3p'.6csoo P!i'0356 Figure 8. Time action curves for the conparison of l?y-16,223, morphine and placebo. Each point represents the neon response. The response to morphine, 15 rig, sod Wy-i6.225, 15 tog, doses wore omittod. PAGENO="0419" signs and Symptoms 26 5 20 22 7 28 Relaxed 20 32 Coasttng 11 28 Soap Ccx 1 Ploasant Sick 0 8 Drivo 0 0 Sleepy 3 5 Drunken 0 Nervous 9 9 0 0 1 2 0 11. 60 97 138 63 136 162 9jnteSi~ns Norw:iI. 39 5 Scratching 9 27 Cod Cyas - 3 27 Rciaxcd 20 55 Coasting 9 9 Soap Ccx 1 30 Voalting 0 3 Noddin9 - 0 1 Sleepy 8 2 Nervous 0 9 Drunken 1 1 Othor 4 72 Totals 94 191 *Each value represents the total numbor of rospoi,nos Table C'. cusulativo responses on ~adividuAl Rem a once Opiai.e 9vo-ptoms Placebo Normal 54 Tomb2 of Stomach 0 Skin Itchy 0 6 0 0 0 0 0 0 0 Cmos, the Single Dose Opbsv-a Ornr,tiaar.sirc.* ~ 15 8 3 3 10 15 9 26 21 19 40 31 7 29 31 o 6 0 4 2 11 0 1 2 1 3 0 0 0 0 3 11 11 Other lot ala 2 0 w t.4 t~j 02 -I a a 2 3 0 2 48 37 39 t5 30 12 19 38 57 57 60 56 24 12 21 27 33 27 22 30 4 1 2 11 0 2 0 2 5 5 8 5 13 6 10 8 3 1 1 7 17 19 11 76 PAGENO="0420" 14842 coi~w~~n'ivE PROBLEMS t& THE DRUG INDUSTRY Page 17 -I .425 0 ~100 .5 I- 7_s Figure 9. Dose response curves utilizing total 5 hour scores for the comparison of Wy-16,225, morphine and placebo. Numbers represent relative poLencies and 95% confidence limits expressed as ng of ~Cy-16,225 equivalent to 1 eg of morphine. Jasinaki 65 PUPILS 50 40 .1 I0.61 30 2 6 4 0 .4 OPTATE SYMPTOMS 20 LI 4 0 U 6, S 0 0 I MBG 20 10 .3 1.1061 5I~ 50 25 0 IS I? (07-2Of 2 MORPHINE 0-C "r15.225 PLACEBO 0. 5 30 60 O0SE(mg~ ---95% CI. OF MEAN PLACEBO REsPONsE PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14843 Page 13 Jasioski ~vnlnatton of P'r.snterriine and i-Enhedrine for ~`r.,hetonfn~-liko Effects ~-Ltenternine (a,n-dimethyl phenethylat~ine, Ionani~) and Z-ephedrtne were ovaluated for their relative ability to produce a~phetanine-lika subJective and physiologic effects in man. Each of 10 subjects received at weekly intervals oral phentermine, 25, 50 and 100 rtg; oral ~-ephedrine, 75 and 150 rng; oral d-amphetanine, 15 and 30 mg; and placebo utilizing a double blind crossover design. ~9u~4ective and physiologic effects utilizing our standard procedures ` were assessed at 0.5, 1, 2, 3, 6, 5, 12 and 24 hours after drug administration. Both phentermine and !-ephedrine produced typical anphetanine-like subjective and physiologic effects. Potency estimates indicated that oral phentermine is 1/2 as potent and oral ephedrine is 1/3 to 117 as potent as oral d-aophetarnina (Table 7). The potency of these two drugs in producing euphoria relative to previously studied drugs is shown in Table 8. table 7. F~nlntivc potoncies and 93% confidence limtts from the conparison of phenternine, !-ephedrine. d-anphetanine, end placebo. Potencies expressed as m~ of phententine or d-ornphetamine equivalent to 1 in; d-anphecaaine. Subjectiva flees,tres Phent ermine Z-Ephedrine Morphine-Benzedrine Group Scale 2.5(1.7-3.6) 6.7(3.6-41.2) Amphetanine Scale 2.5(1.8-3.6) 5.2(3.2-3.5) Physiologic t~easurcs Systolic blood pressure 2,4(2.0-2.9) 3.4(2.6-4.1) Diastolic blood pressure 1.8(1.0-2.9) 6.3(4.4-16.0) Pulse decrease 3.5(0.1-7.1) Temperature increase 2.4(2.0-2.9) PAGENO="0422" 14844 COMPETITWE PROBLEMS TN THE DRUG INDUSTRY Page i~ Jasinski Table S. Sut~2ary of estinatDs of relative potcr.cies of various amphetanine-like dnigs in producing Subcutaneous Studies Reference d-Mtphetenine 1 d-Nethasiphetarnine 1 14 }tethylphenidate 2 14 Phorretrazine 4 14 !_Eplledrine 5 16 DiethylpropiOfl 14 15 d-Anphetanine (Oral) 1 15 Oral Studios d-tnphotznine 1 Phenternine 2 Eenzphetarnine 5 1 !_Ephedrine 5 Piethylpropion 7 15 PAGENO="0423" CO~OETITXVE PROBLEMS IN THE DRUG I2ThVSTRT 14845 Page 2fl Jasin,ki Assn~srenr_of }~unrotornhine for Nor2j~ne-Likacffpctsi~'~drvolu_l~ as a ~:n tutensnce Drur in the Treat,~nt of ~nrcotjc Addiction Buprenorphtne is an oripavine derivative (Fig. 10) which is an effectiva analgesic in man and animals. In monkeys, buprenorphine did not exacerbate or suPpress morphine abstinence and did not produce ~hvgical dependence in direct addiction tests. In the chronic spinal dog,1 buprenorohine 1) produced a profile of morphine-like effecS in the non- dependent animals, 2) precipitated and suppressed abstinence in dependent anicals, and 3) produced physical dependence with chronic adninistration, It was concluded from these studies that bupronorphime was a partIal agonist of morphine. CH3 CH3 ---C--- C-CH3 OH CH3 0 C H3 SUP RE NOR PH I N E Figure 10. Structure of bupronorphine (N-cycloprcpylnethyl-7 ~ l'i-tetre--hydronororipavino). HO 0' PAGENO="0424" 14846 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Fe;e 21 Je~inski The present studies were initiated to assess t~a abuse potential of huprennrphine in nan. During the course of these studies, however, it became zt?parent that huprenorphine was a potent, long acting drug whIch suggested its possible utility as a maintenance drug in the treatment of opiate addiction and the studies were codified accordingly. It was thought that buprenorphl-V-e as a partial agonist of morphine with perhaps a greater affinity for the morphine receptor and a long duration of action would 1) be an effective blocker of norphine through the mechanism of cross tolerance and the mechanism of conpetitive dualism, 2) have some reinforcing effects, and 3) would produce only ninimal physical dependence. Three single dose studies were conducted. In each, drug effects were measured with change in puflflary diameter, subjects' and observers' single dose 1~iate questionnaires ` and the subjective drug effects question- naire containing items from the NBC Scale and PCAC Scale and the LSD Specific Scale. In the first study, subcutaneous buprenorphine, 0.2, 0.6 and 0.8 rg; subcutaneous morphine, 15 and 30 mg; and placebo were compared in 9 subjects utilizing the double blind crossover destgn. In these studies ob:~srvationS were cads at 0.5, 1, 2, 3, 6, 5, 12, and 24 hours after d,v~ administration. Buprcnorphine produced typical nnrphina-like sch)ective effects and Tainsis but its effects were of slower onset than morphine and were longer lasting. There was a greater effect at 24 hours with all doses of buprenorphine than wIth the 30 dose of norphine. Subjects and observsrs identified buprenorphine predominantly as an opiate with a pattern of signs and symptoms similar to those for r.nrphine. Because of the disparity in time nction curves, dose response curves were constructed utilizing peak responsas for each drug rather than total 5 hour scores. BuprenorPhine produced dose-related increases in mean peak scores on niosis and all measures of morphine-like subjective effects and was estimated to be approximately 30 to 50 tines more potent than morphine (Fig. 11). There is no evidence that bu~renerphine produced elevations on the PCAG or LSD Scale scores greater than those produced by morphine (Figure 11). In these studies buprenorphine. like norphina, had mactic action but this emetic effect of bupronnrphine would persist 8 to 12 hours after buprenorphine and was found disturbing by some of the subjects. In the second study subcutaneous huprenorphine, 0.6 and 1,2 mg, and subcutaneous morphine. 20 and 40 rg, were compared to determine if the e±fects a buprenorphine plateaued on these measures as it did ~ certain measures in the non-tolerant, non-dep~ndent chronic spinal dog. Onail measures the responses to 1.2 mg were 3ess than responses to 40 trg of~ morphine. flelattve potencies vera obtained only on the niotic effects indicat tng again that buprenorphina was 1/25 to 1/30 as potent as PAGENO="0425" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14847 Page 22 Jasiflski morphine (Fig. 12). The responses to the 1.2 rg dosa of buprenorphine as measured by the }~C Scale scores and the opiate s}~nptoms scores were less than that produced by 0.6 ng of huprenorphine. Again, buprenorphine did not produce significantly greater PCAC or LSD Scale scores than morphin;:. These results suggest that 1.0 og of beprenorphine may produce maximum effects with these effects in the range of 30 mg of morphine. flAG 7,, ~=_ 00 04 09 `3 30 005! 99) - *LAC! 90 -- ,.~c ..,,.9c...,~t. eA, PLACEbO b!SPOOSE 0009 per .n.n * peon bloAssAst &~~E0eop)oof a2o~. 9 90)9o5 StOASSAY Figure 11. Dose response curves for the conparison of buprenorphine, morphine and placebo utilizir.g mean peak responses. Numbers represent relative potencics and 95% confidence limits expressed as ng of morphine equivalent to 1 mg of huprenorphine. `.3 I? It pupils 49.5 iii 5-119 / 0_S 05 -0-. 0U9J0C93 115190 7 ~ / :: 1490 0.9 54 4. 4.0 36 30 a 0050590NS 1)4*90 29.2 ,., r Zn I_s 075 00 `9 to OPIATE 2*003 07.11 900! CiP~I 0- 02 04 00 II 30 00,5 Ippot 85-569 O-17-----2$ PAGENO="0426" 14848 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Nge 23 `75 *75 Jasf nski Figure 12. Dose response curves for the comparison of buprenorphine, morphine and placebo utilizing total 5 hour scores. Relative potencies expressed as Irg or morphine equivalent to 1 mg of bupre- morphine. In the third single duse study buprenorphine, 1.0 mg; morphine, 30 irg; methadone, 30 mg; and placebo were administered intramuscularly at weekly intervals to 14 subjects utilizing a randomized crossover double blind design. Observations were made at 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after drug administration. Norphine produced significant miosis through the first 24 bourn of drug administration (Fig. 13). P~iprenorphine and rnethadono, hovevur, produced persistent niosis which lasted through the observation at 72 hours (Fig. 13). t-lo?phine produced subjective effects lasting through the second day while buprenorptt~ne ond rethadone produced some degree of subjective effects which lasted at 1oa~t 72 hours (Fig. 13 and 14). All three drug conditions 06 `3 ze 40 0000 fr,37 see /1 2C5 /1 flUP5E~OkP**IS! 6 C__C MO0P.S 7;! DOSE `]7~37 PAGENO="0427" COMPETITIVE PROBLEMS D( THE DRUG rwDus'rwr 14849 Page 24 Jasinaki - ?d a characteristic tiuc action of sebjsct.tve effects. DurinG the fiL:~t 6 hours there were sigTtiiicant MEG elovaticus but concurrently reasured PCAG scores were not elevated. Fron the 12th hour on, however, the ECAC scores becare significantly elevated while the previously elevated tC~G scores returned to control levels. LI 5 2c,:os 4S5460 `2 Figure 13. Corparison of the duration of action of buprenorphine, morphine, rethadone and placebo in constricting pupils, proiuoing FCAC nnd ~ir; Scnle scores. & 75~, a Peac `34 "I 06 74 33 36 46 ~4 60 `2 .3053 600 00 ME ~~06D03E SEE 60 PAGENO="0428" 14850 COMPETITWE PROBLEMS IN ~E DRUG INDUSTRY `° it" Z4O \ 30 5201: oLoi, `,.rL:°_S:~CtTLRLz 39 24 3~ 34, 495460 22 Figure 14. Comparison of the duration of action of buprenorphine, morphine, methadone and placebo in producing scores on the symptom, sign and liking scales. The single dose studies indicate that buprenorphine produces typical morphine-like subjeL'tive effects and euphoria in nan and is 25 to 50 times more potent than :~hine. Further, there nay be a plateau of maximum activity with 1.0 of buprenorphine. A direct addiction study was conducted with subcutaneous buprenorphine to determine if 1) buprenorphine produced significant physical dependence, and 2) to determine if chronically administered buprenorphine would block the effects of morphine. Once daily at 8:30 a.m. five subjects received 35-I s~.~::~s- 2 .4 2 2 25 20 30 -2 243) 34 2) 324,3 £0 S 3)33 j !`)~ ~ 33~. - - . .~ ,_-~~,_-,_-~_-.-.-.--, 24 2 343334 495400 73 LIV. N 0 0 S~ ,,~ 30 I? 243030 405400 72 H3j33 21.33 0300 PAGENO="0429" COMPETITIVE PROBLEMS IN THE DRUG TNDUSmY 14851 Page 26 Jasineki a single subcuta:nous injection. For 2 weeks this injection was sauna. Then hupre:iorphi:~e, 0.5 ng, was substituted for the saline injection. The dose of buprenorphine was progressively doubled until the 15th day when a dose of bunrenorphine, 8.0 mg, was administered. This dose, which would be equivalent to approximately 240 ng of morphine, was then admin- istered once daily through the remainder of the study. During the period of chronic administration, 2 sets of experiments were performed. Single doses of morphine and placebo were administered under,douhle blind conditions and their effects compared with the effects of single doses of placebo; morphine, 15 eg; and morphine, 30 mg, adninistered during the control phase when subjects were receiving saline. These experiments were to determine if buprenorphine exerted a significant blocking action. The second set of experiments during chronic administration consisted of the adminfetration of naloxone to precipitate morphine-like abstinence. During chronic administration of buprenorphine, analysis of responses on the chronic questionnaire administered once daily indicated that subjects identified the drug predoninaittly as an opiate (dope) and liked the effects of buprenorphine (Fig. 15). The pattern of symptoms from the chronic opiate quastionnaire were sirilar to those observed with morphine in other studies. During chronic administration, pupils constricted and diastolic blood pressure decreased slightly (Table 9). There were no changes in pulse rate, systolic blood pressure, respiratory rate, body weight or significant decrease in caloric intake. between the 18th through the 25th day of chronic administration of buprenorphine, each subject received single test doses of placebo; morphine, 15 trg, and morphine, 30 mg, subcutaneously. To correct for the effects of bupro- morphine, the response to norphine, 15 and 30 m~~,was corrected by subtracting out the responses for placebo. Comparison of the placebo- drug differences for morphine, 15 snd 3D ng, during chronic buprenorphine administration with effects of norphine, 15 and 3D mg, administered to the same subj tcts durIng the control period indicates that these effects were significantly decreased (Fig. 16). Subsequently, single doses of morphine to 120 ag were administered without any significant effects (Fig. 16). In an additional experiment, a placebo was substituted for the 8:30 a.rn. buprenorphine in~action under double blind conditions and a tnst dose of norphine, 30 mg, administered at 10 a.m. The morphine effects were blocked to the same degree as they were in the condition when buprenorpirina had been administered 1 1/2 hours before morphine administration (Fig. 16) indicating that the blocking effects of buprenorphine persist undiminished for at least 25 to 30 hours after drug administration. - PAGENO="0430" 14852 CO~ETITWE PROBLEMS fl~ THE DRUG INDUSTRY Page 27 Jouinski At ICY SUYJECTr LJKINO eLJP9E1;oCY~l*!%r SJSJECTS 1. x"~a MaCrHINE 130194/DAYI arC/carl N. I stoja LIKIN OMOYYPHF'.E 24 0C,o/OAYI "°~ SueJECtS L;~IN0 `.10 YPHINE l'?or~eaaYl 2 ..I'N...PoP'_~..\wac~~r 2 L'rE AREA~N7t3O L~E p PEaK. 21005 ~ IPSO AL bOYS ON OCUG INITIAL DAYS ON 051)6 Figure 15. Mean liking scores during the period of chronic buprenorohino administration compared with liking scores obtained iron 3 ocher groups of subjects during chrunic rorphine admin- istration (unpublished). PAGENO="0431" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14853 Page 23 Jasioski T.:ble 9. i.oen and stardard errors for 5 subjects over all observations ti:ring the pre-drug control period (14 days) and the period of chronic tuprectorphine adr.inistratioi Pro-Drug Chronic Control Buprenorohine t Pupils 3.9 ± 0.3 3.3 ± 0.1 3.25 <.05 Temperature 36.7 ± 0.1 36.9 ± 0.1 1.97 Pulse rate 70.0 ! 1.6 73.1 ± 1.6 1.18 Systolic EP 116.3 ± &.6 114.3 3.3 0.81 Diastolic 5? 72.7 ± 2.9 67.9 ± 1.5 2.95 <.05 Rmspiratory rate 17.1 ± 0.7 16.9 ± 0.4 0.23 Body weight 79.3 ± 3.9 78.0 ± 3.6 0.63 Caloric intake 1978 ± 154 1747 ± 67 1.30 Two of the Rye subjects withdrew frcm the study prematurely. One subject vithdrcw after completing the tests of the blocking ability of buprenorphine (42 days of chronic administration). During these tests, he reported nervousness and irritability. His reasons for withdrawing were that the effects of the drug had become somewhat disturbing especi*ally at night such that when in had he would close his eyes and have episodes of seeing his thoughts. He would becore frightened, short of breath, feel his heart beating raptdly, have tingling in his arms and logs, and feel the ron:r closing in on him. These syrptoms occurred only when he was alone end could be inhibited by talking to people. tie second suh~oct vithdruw after completing three precipitation tests with naloxcne. He had reported persistent nausea from the drug usually for 3 to 4 hours after drug adoinistration. On the 47th day of drug adam- is tration lie had an episode of nausea and vomiting occurring approxic.ately 2 to 3 hours after drug administration. tie re~uosted to withdrnw fron the study because the nausea and voaiting were interfering with his job assignrnen t. PAGENO="0432" 14854 COMPETI'TWE PROBLEMS IN THE DRUG INDUSTRY +10 +9 +4 +7 +4 ~ +3 2 +3 +2 +1 o -l o 0 hi 0 C 0. 44 4. 2 +7 ft +4 o +5 44 +3 Isi +2 +4 0 -3 42 +1 *19 4, 44 +3 +2 +4 0 -l -3 -4 Page 29 Jasins'~t flgure 16. Responses to morphine 1) administered 1 1/2 hours after saline placebo (solid circles) during ths pre-dru; control period. 2) adiztinistered 1 1/2 hours after buprenorphine, 8 mg, (open circles), during chronic buprenorphine administration, and 3) 1 1/2 hours after saline (triangle) `ras substituted for the 8 irg dose of chronic buprenorphine. PUPILS * 20 SIo~Is +15 ~--+ +40 OBSERVERS LIKING MBG I, SYMPTOMS a 7 S 5 4 3 2 0 0 o SUBJECTS' LIKING I' 30 50 45 20 (SQ MORP14INt Is 30 6'O S'S ISO a; MORPHIME - 5 30 40 45 120 mQ (AORPPIINt PAGENO="0433" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14855 Page 30 3 as in ski Ldninistration of naloxone to doses of 4 zag subcutaneously did not procipitote any dIscernible abstinence as r~easured by the abstinence score or by subjects' reports of withdrawal illness (Fig. 17). These sane doses will precipitate abs tinence in subj eats dependent upon zag of morphine daily (7.5 zag q.i.d.) and in subjects receiving chronic pentazocine or chronic butorphanol (Fig. 17). After completion of the precipitation tests, the 3 subjects vho did not withdraw were stabilized on buprenorphine for B nero days and then saline placebo was substituted under double blind conditions. 40 Is p00 0 * Go M[5.PLACnO SCOPe Pp ~UPRDC~tptN! ~.vosTp OSOUP 0070 00 030 060 050 Pr 40 005! 0! Gat000s S OPt' *-* Mos;.,pIt~_ lsops,esyp * P!NtflOCIO$ COOS OPPIIOAYI 0 5U;OZSORPHPS S~t'0~i 0 5510! SOC IOSppp DAVI Figure 17. Abstinence scores following the adninistration of placebo and naloxone to subjects dependent upon corphine, 30 tog daIly (7.5 zag q.i.d.), bunrenorphine, 8 org. butorphanol, 48 ng daily (12 ag q.i.d.), and pentazocino, 580mg daily. PAGENO="0434" 14856 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY V,trn 31 S taloski During the 2 days after dtscontir.-ir~ huprennr~iiina none of the S s.f ~cts reported any withdrawal syrprore. In t'osa 3 subjects who un r~nt the withdrawal double blind, c~e substitutica of placebo was no i:..:ndiately discerned (Fig. 18). :eginning on the third day of withdrawal subjects began reporting fn~ernictent episodes of hot flashes, chills and skin sensitivity. These ware mild and subjects found then only mildly discomforting end did not seek relief from these symptoms with additional drug administration. They denied being sick (Fig. 18) or withdrawing. These symptoms persiste.d and did not increase markedly in intensity for the next 10 days. $ F CT HIMMEL$BAt~I SCORE -~ FEEL THE DRUG? I ____ AREA. 613±251 r~s 20j PEAK. 11.0± 2.~ 2 1L *~0 -----a---~-----a-----*- - - -a---. 0] ,..~_ I -----~----.------ i. ~ __________ ~ 0 -f- T-1---r--,-rIr-~' rrrI~r-, , 0 I 2 3 4 5 6 7 A 9 0 0 I 2 3 4 5 6 7 a 9 0 VERY +2 HOS no you FEEL P GOOD 0000 + I KICK MC 2 avrpaoe 0 SL.{CHTLY_1 - . `AD MOOERATLC. - 2 {YES ~ {YES :s_: E ~ AAO 0 I 2 3 4 5 6 7 a 9 10 0 I 2 3 4 5 e 7 0 9 `0 WITHDRAWaL DAYS WITHDRAWaL DflS Figure 18 ..Mean daily lururelabach scores and responses on the chronic questionnaire in the 10 days following ahrupt withdrawal of htlpreElnrph Lne. PAGENO="0435" COMPETITIVE PROBLEMS ~N TEE DREG ThWt7SDRT 14857 Pa's 32 Jasinski During the first 10 days of withdrawal }licrelsbach scores indicated tha presence of raild abstinence (Fig. 18). Tho abstinence syndrome was balow the level of clinical significance for morphine withdrawal. Comparison of the peak and total area scores for the first 10 days of withdrawal fron hw~ranorphtne is less than observed with other drugs which have produced mild abstinence syndromes in direct addiction tests (Table 10). In the 2 subjects who withdrow, a test dose of 30 mg of nnrphine was administored en the 11th day of withdrawal and a placebo was administered on the 13th day of withdrawal to deternine if buprenorphine was still present in significant sraounts to block the effects of morphine. The lack of a clear abstinence syndrose suggested the possibility that buprenorphine was stilt present in large amounts. The responses to morphine were compar- able to those obtained in the pre-drug conttcl period. These 2 subjects reportod increased withdrawal symptoms following these tests (14th - 17th day of withdrawal). The other 3 subjects who were withdrawn double blind continued on observations and continued to show }iitnnelsbach scores in the range of approximately 10 paints through the 13th day of withdrawal. On the 14th day of withdrawal, there was a marked increase in withdrawal signs and Himmelnbact~ scores increasing frost a moan of 9 points on the 13th day to a mean of 23 points on the 14th day. Subjects reported feeling bad, were deprossed and demanded relief of their synptotas with morphine. icausea, vomitiag, restlessness, insomnia and diarrhea ware present for the first time indicating more severe withdrawal. These and other studies indicate that buprenorphino 1) is a morphine- like agent in man which may be a partial agonist, 2) is relatively non- toxic in chronic adninistration; 3) has an extremely long duration of action, and 4) effectively blocks the effects of large dnsss of norphine during chronic adainistration. These findings suggest that bupre~iorphine mey hawe utility as a maintenance drug in the treatment of narcotic addicts. Buprenntphime has the duration of methadone, is en effective blocker of narcotics, has a losser abuse potential than nothademo, and is loss toxtc than methadone or d-propaxyphene. ¶tive ~!ctaholism of d-Propoxypiterie }icl and d-Pro,oxvnhene Napsytate in tina Five of eleven subjects participating in a double blind cros~ever - experiment to evaluate the morphine-like effects of propoxypliene agreed to participate sintiltsneously in this study to explore poaoible phareaco- kitintic dtffcrrnces between prnpoxypliane EC1 and propoxyphann napsylate. PAGENO="0436" -4 a 00 C,' 00 Page33 8 Jasin~ki L's Table 10. Comparison of peak and total area Ilimmeisbach scores for the first 10 days of withdrawal of bupranorphine and other agents. Daily Morphine Peak Dose N Poten~y E~u1valenee TAS Score ttafcrence o MorphIne 240 ~ 8 1 240 ~ 198.1 ± 16.3 36.8 ± 2.7 6 Cyclazocine 13.2 i~ 6 20 260 ag 103.6 ± 13.2 18.8 ± 2.9 4 .Nalorphine 240 mg 7 1 240 ag 129.6 t 10.6 18.2 ± 1.8 8 Malbuphine 203 rig 5 5/4 243 r.g 136.0 ± 6.4 24.4 ± 1.5 5 L,r~ Pontazocine 580 rig 6 1/4 145 ag 106.0 t 9.3 15.8 ± 1.8 7 d Butorphanol 48 rig 6 5 240 rig 164.1 ± 15.2 26.3 t 3.7 Propiran, 1786 rig 3 1/8 222 rig 129.5 ± 32.0 21.3 ± 3.4 17 Profadol 510 rig 4 1/2 255 rig 188.0 ± 21.3 33.7 ± 4.3 17 Buprenorphine B rig 5 30 240 rig 61.3 ± 4.2 11.0 ± 2.6 PAGENO="0437" COMPETITIVE PROBLEMS IN THE DRUG nmus'ray 14859 Ps~-~i, Jas tuu-:d. In t:.ts 9 weak crossover study each subject receivad 3 oral doses of ?-*~- 2oxyphene Ed (210, 420 and 600 rig), 3 oral doses of d-propoxyphene na,uyiate (310, 620 and 700 rg), 2 subcutaneous doses of morphine, and a placebo in random order at weekly intervals. Blood savples of S or 10 ni were drawn by venipuncture into heparinized tubes 1/2 hour before drug adatnistration and after drug at 1/2 hour, 1, 2, 3, 5, 12 and 24 hours. Plasris was irndiatel.y separated and frozen until analyzed. Plasna senpies were also collected from one subject approximately every other day (at 2 hours post oral drug) during substitution of propoxyphene napsylate, 300mg p.o. q.i.d., for morphine, 15 rg subcutaneously q.i.d. The substitution period was 21 days followed by 10 days of abrupt withdrawal (under blind conditions). Saoples were analyzed for plasma concentrations of propoxyphene, norpropoxyphene and c~lic dinorpropoxyphene by the gas chroiratographic method of Nash etat. who assisted in setting up the procedure. Nean plasma propoxyphene concentrations are shown in Fig. 19. There was a significant positive correlation of these values (and also mean norpropoxyphane levels) with mean decrease in pupillary diameter, with correlat±on coefficient equal to 0.85. Propoxyphene lid was somewhat more rapidly absorbed than propoxypltene napsylate, giving significantly greater propoxypilene concentrations in the first 2 hours after drug administration and showing peak mean levels at 2 hours compared to 3 hours fur the napsylate. Peak mean plasma propoxyohane levels were sltghtly greater for the HC1 than the napsylate in the low and middle pairs of doses, which were approximately equinoler in propoxyphene for the 2 preparations. liowevor, in the high doses mean propoxyphene levels were approxfmately equal for the 2 salts, even though the napsylate dose was lower than the Ildi dose in this pair. Propoxyphene napsytate showed a linear dose response relationship in peak mean propoxyphene levels. However, propoxypliane hydrochloride also showed a significant quadratic relationship with peak mean propoxyphene levels anproxinately the sante for the niddle and high doses. After 2 hours post-drug only a linear dose response relationship was seen in nean propoxyphene levels. This could indicate a dose-related difference in absorption of propoxyphene hydrochiorido or, with a small n of 5, it could be a random statistical anomaly. Neon plasna propoxyphene values found after the largest propoxypuens doses of both salts were in the range of 400-500 ng/nl, which nay represent near reaxiriun non-toxic plasma lecals in non-tolerant sub j cc t 5. Peak norpropoxyphene levals were 10 to 752 greater than propoxyphene levats and occurred 2 to 6 hours later. ma dose response relationships were not .,s clearly defined as for the prunoxyphene levels. Norpropoxy- phene values in the nrdor of 50 mg/nil were scen consistently 7 days after PAGENO="0438" 14860 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 300 400 200 400 300 200 l0~, 0 Sot, - PfrOGoO /1 _ _ $123 2 7 HOURS flgure 19. Plasma propoxyphene concentrations in 5 subjects following single oral doxes of cZ-propoxynhene hydrochloride (I'M) and c!-propoxyphone napsylate (ON) During substitution of oral propoxynhane napsylate in one morphine- dopenden~ subject plasca propoxyphene 3oveis reached approximately constant values of 800 to 1000 ag/al 7 days after inItiation of propoxyphone Mats- istration. Norpropoxyphene plasea levels increased tepidly to 3300 ag/cl by]4 days after beginning propoxypheno, and risen increased to about 3500 rg/nl ovcr the last 7 days of chronic adoinistration. Dtnorpropoxr phone plasma levels increaund gradually and continuosi:;ly during the entire Page 35 Jasins~ci the large single oral doses of both saltn. Very small ar.nunts of door- propoxyphene t~ere found in a few sor.pks. PLASMA PR0POXYP~tNE CONcENIRATIOR ing/mO 200 - PH'420 / \. -- PN.e?0 300 200 `00 PH(=~) (pPsPcs(Y ClIENt SS44~SELAOt 24 24 HOURS PAGENO="0439" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14861 Page 35 ins ir~ski 3 week; of propoxyphone adicinistration, reaching a peak value of Ill Pg 1. Following abrupt withdrawal, propoxyphane was detectable In th ~lasna for 8 days and nor- mid dinorpropoxyphora wore detected on the 10th day at levels of 87. and 19 ng/ml respectively. 1. .Jasinaki, D. It., Griffith, .1. 3.' Pevaick, J. S. & Clark, S. C. Progress report on studies from the Clinical Pharmacology Section of the Addiction Research Center. Presented at 37th Ifoeting, CPDD (1975). 2. Martin, W. It., Jaainski, D. R. & Mansky, P. A. h7altrexoae, an antagonist for the treatrent of heroin dependence. Arch. gen. I'sychiac. (1973) 28:784-791. 3. Jasinski, U. It., Martin, U. It. & Haertzen, C. A. The huron pharma- colo~y and abuse potential of }h-allylnoroxynorphone (naloxone). J. Pharxacol. oxp. Ther. (1967) 157:420-426. 4. Martin, U. Ii. * Fraser, II. F., Corodotzky, C. V. & Rosenberg, D. F. Studies of the dependence-producing potential of the narcotic antagonist 2-cycloprepyloethyl-2'-I,ydroxy-5,9_dimethyl_5,7 benzonorphnn (cyclazocine, Win 20,740; ARC II-C-3). 3. Pharmacol. exp. Thor. (1965) 150:426-436. 5. Jastnski, U. R. & Manaky, P. A. Evaluation of nalbuphthe for abuse potential. Clin. Pharinacol. Thier. (1972) 33:73-90. 6. Fraser, II. F. * Van Horn, C. 3., Martin, U. It., t'olhach, A. hi. & Isbell, H. Methods for evaluating addiction liability. (A) "Attitude" of opIate addicts toward opiate-like drugs, (8) a short tern "direct" addiction test. .1. Pharrnacol. exp. Thor. (1961) 133:371-387, 7. Jasinski, 0. It., Martin, U. It. & Iloeldtko, It. U. Effects of short- and long-term adritnistratiort of pentarocine in man. Clin. Pharmacol. Ther. (1970) 11:335-403. 8. Martin, U. It. & Corodetzky, C. U. Denonatration of tolerance to end physical dependence on N-ailylnorrnorphine (nalorphfne). .3. Pharnacol. exp. They. (1965) 150:437-442. PAGENO="0440" 14862 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY Page 37 Jasiaski 9. Jasinskt, I). K. & Nutt, S. C. Progress report en the clinical assessment program of the Addiction Research Center. Presented at tha 35th meeting, CPDD, Chapel Hill, N. C. (1973). 10. Martin, V. K., Corodetaky, C. V. & McClane, 1. }C.An experimental study in the treatment of narcotic addicts tcith cyclazocine. Ciin. Pharmacoi. TIter. (1966) 7:455-465. 11. Nails, 3. L.,Rosenthalo, N. E. & Cluckman, N. I. Animal phaiacology of t4y-1G,225, a new analgesic agent. 3. Pharmacol. exp. met. (1975) 194:488-49 8. 12. Martin, V. K. 6 Fraser, H. F. A comparative study of physiological and subjective effects of heroin and morphine administered intra- venously in post-addicts. 3. Pharrincol. exp. Ther. (1961) 133:388-399. 13. Jasinski, B. K., t{artin, V. K. & Sapira, 3. B. Antagonism of the subjective, behavioral, pupillary and respiratory depressant effects of cyclazonine by naloxone. Clin. Pharmacol. Thor. (1968) 2:215-222. 14. Martin, V. K. * Sloan, 3. ¶7. * Sopira, 3. 3. 5. Jasinski, 3. K. Physiologic, subjective and behavioral effects of amphetamine, nethanphetamine, ephedrine, phenmetraaine and nethyinhenidate in man. Clin. Pharraacol. Thor. (1971) 12:245-253. 15. Jasiuski, D. K., Mutt, 3. C., S Griffith, 3. 3. Effects of diethyl- propion and d-aaphetamine after subcutanaous and oral edministration. din. Pharmacol. Ther. (1974) 16:665-652. 16. Martin, V. K., Eades, C. C. * Thompson, 3 .uppler, K. 3. & Gilbert, P. E. The effects of morphine- and nalorohinc-like drugs in the nondependent and morphine-dependent chronic spinal dog. In press. 17. Jasinski, I). K. * Martin, V. K. & Hoeldtke, K. 3. Studies of the dependence-producing properties of CPA-1657, profadol and propiram in teen. dim. Pharmecol. Ther. (1971) 12:613-649. 18. Nash, 3. F., Bennett, I. F., Bopp, K. 3., Erunson, N. K. & Sullivan, H. I Quantitation of propoxyphena and its major ratabolites in heroin addict plsssa after large dose adainistration of propoxyphone napsylate. S. Pharn. Sci. (1975) 64:429-433. PAGENO="0441" COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 14863 STATEMENT BY EUGENE R. JOLLY, M.D., Ph.D.. PRESIDENT BIOMETRIC TESTING INC., 661 PALISADE AVENUE/PO BOX 1383 ENGLEWOOD CLIFFS, NEW JERSEY 01632 BEFORE THE rnNOPOLY SUBCOI'NITrEE OF THE SENATE SMALL BUSINESS COH~1IflEE ON WEDNESDAY NOVEMBER 10, 1976 AT 10:00 A.M. Senator Nelson, nembers of the subconunittee, it is a privilege to be here with you today to provide a summary of my findings resulting fron clinical investigations of amphetamine and related drugs used as adjuncts in the treatnent of obesity and in>' thoughts in regard to the applicability of these drugs in clinical nedicine. It is a particular honor to discuss these matters with you, Senator Nelson, one of the truly distinguished citizens of ny hone state. By way of introduction, Biometric Testing Inc. is an independent testing laboratory, engaged in clinical research performed for the food, drug, cosmetic and chemical industries on a contract basis. As a recognized clinical pharmacologist with over 20 years of experience in drug research and development, my technical function is to design appropriate studies on test products, closely monitor their progress, evaluate responses to the test products and provide a comprehensive interpretation of the data obtained. I should emphasize that I an a researcher and do not practice medicine. 85-SO O-77------29 PAGENO="0442" 14864 COMPETITIVE PROBLEMS ~ THE DRUG U~DUSTRY Our list of sponsors includes a wide spectrum of large, intermediate and small firms, Of particular interest is our work for the small drug manufacturers. It is probable that we have conducted more bioavailability comparisons with generic drugs than any other research group in the world. We are well known by both the industry and the Food and Drug Administration for our work in this field. The amphetamine-like drugs fall into the general category of sympathominetic agents. That is, they mimic a part or all of the responses seen from activation of the sympathetic nervous system, the so-called fight or flight mechanism of the body. Those responses include: an increase in blood flow to the heart, lungs, skeletal muscle and brain; stimulation of the heart with an increase in cardiac output; dilatation of the bronchi and bronchioles of the lungs to allow more efficient oxygenation of the blood; and, central nervous system stimulation counteracting fatigue and increasing mental alertness. Metabolic effects include elevation in blood glucose and fatty acids and an increase in metabolism mainly through breakdown of fatty acids. It is important to recognize that there are numerous drugs in this category which produce sympathomimetic actions in various degrees. Therefore were amphetamine products, for example, to be removed from the market, other coirmercially available drugs could be substituted for them. PAGENO="0443" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14865 This question will he considered in our discussion as will the possibility of imposing further restrictions on the distribution of some or all of these products. Of the series, eethamphetamine and amphetamine are the most powerful central nervous system stimulants. The stimulant actions of one of these, amphetamine, were first described by Alles in 1933. In 1935 Prinzmetal and Sloomberg initiated clinical use of amphetamine for the treatment of narcolepsy, a disease characterized by inability to stay awake. Since that time, amphetamine products have been employed for a variety of conditions including chronic fatigue, parkinsonism, epilepsy, childhood hyperkinesis and poisoning by CNS depressants. Of course, the most popular use of amphetamine products today is in the treatment of obesity. Of the various clinical applications, experts still consider amphetamine as valuable in the treatment of patients with narcolepsy and for children with hyperkimesis in selected cases. This condition is very prevalent - experts estimating that some 5% of our children are affected to some degree. One of my children, for example, exhibited sufficient hyperactivity, lack of attention span, and associated behavioral problems to require therapy. Similar symptoms were exhibited by some of my other children and drug therapy night have been useful. In retrospect, I probably also presented similar symptoms during childhood. Hyperkinesis in children PAGENO="0444" 14866 CO)OETITXVE PROBLEMS U~ mE DRVG fl~DUSTRT requires more intensive study and greater recognition. It is frequently associated with leaning, speech and other perceptual deficits. My own son suffered severe emotional problems related to the disease which one psychologist felt represented a borderline psychosis. The mental and emotional scars that are unavoidable sequellae represent the most damaging hazards associated with this disorder. Fortunately, the symptons usually moderate with age and are seldom apparent in young adults. Obesity of course is the most prevalent disease in our society. Just from the cosmetic standpoint, the disease cam represent a serious threat to well-being, and we all appreciate the importance of the quality of life as opposed to its duration. The contribution of obesity to the incidence and severity of other diseases; particularly those involving the lungs, heart and blood vessels are considered by most experts to be significant. However, epidemiological surveys suggest that remarkable imfluences on longevity are only seen with early onset obesity; dating back to the teen-ages, twenties and early thirties. Conversely, moderate obesity does not appear to significantly change morbidity and nortality associated with pulmonary and cardiovascular disease when weight gains start in later-years (after 40). Of course, severe obesity at any age represents a serious disease state which can adversely effect the function of all organ systems. There should be no question that amphetamine and related drugs are effective adjuncts in a therapeutic program for obesity. Their actions are clear-cut and reproduceable. PAGENO="0445" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14867 My evaluation of the research work accomplished with amphetamine-like drugs has been requested. With the disclaimer that specific projects cannot be evaluated with precision unless they are monitored and the data thoroughly reviewed, my general opinion is that the background of animal and clinical work on these drugs is both extensive and adequate to make a judgement of effectiveness under conditions of use- The actions of these drugs are clear-cut and even under relatively lax experimental conditions, should be reproduceable. Controlled studies to demonstrate effectiveness in comparison to placebos require hard work but no unusual skills. Study administrators may frequently be tempted to guess which patients are being treated with active drugs because of the side effects exhibited. This is a research problem common with the study of most pharmacologically active drugs. Experienced researchers discourage such speculation by the technical personnel. Those who do engage in guessing gaines will often find out that they were wrong. The actions of a placebo will often match and sometines exceed those of an active naterial. conversely, a very potent drug may not elicit any renarkable signs or symptoms in some individuals. Regardless, when objective endpoints are available, such as actual weight loss, assessments are simplified and data are nore concrete. Moreover, when results obtained from a number of research sites prove essentially equivalent, it can be concluded that the findings are valid. On this basis, the effectiveness of amphetamine-like products as adjuncts in the PAGENO="0446" 14868 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY treatment of obesity has been generally accepted by experts qualified by training and experience to make these judgements. Our data, confirmed by other investigators and resulting from separate investigations of amphetamine formulations and two related drugs can be sumliarized as follows: 1. Patients treated with amphetamines who complete the study requirements (weekly clinical visits, maintenance of the prescribed dosage intake, continued diligence during study periods ranging from 8 to 16 weeks) on the average will lose more weight than patients who are naintained on placebo medication during equivalent periods of time. 2. Weight loss in both placebo and treated groups are more notable when dietary plans are detailed and maximum caloric intakes are calculated for each patient on the basis of height and body build, in contrast to weight losses associated with less rigid programs involving non-specific dietary restrictions. - 3. Fewer patients treated with placebo can maintain the personal motivation required to complete a weight reduction program, in comparison to patients treated with an amphetamine formulation or related product. There will be significantly more drop-outs in the placebo group prior to completion of the study requirements. PAGENO="0447" CO~OET!TIVE PROBLEMS IN THE DRUG IZWVSTRY 14869 4. The most important aspect in a weight reduction program is personal motivation. Unless highly motivated an individual cannot stay on a diet and no program will be successful. S. Patients do not appear to become resistant to the effects of amphetanine, rather they gradually lose motivation. 6. Very obese patieiits have great difficulty in reducing caloric intake and losing significant amounts of weight with or without an amphetamine crutch. Such individuals are often called compulsive eaters or food addicts. 7. The amount of attention paid to the trials and tribulations of obese subjects is directly proportional to the success attained. Reviewing progress, counseling, gentle persuasion and strong encouragement are important facets of a weight reduction program. A rather dramatic illustration of the profound influence of the human psyche pa eating habits is afforded by reviewing results of administration of sympathomimetic drugs to experimental animals. In the so-called lower forms these drugs are truly anorexigenic - appetite reducing - drugs. Most of us regard our canine friends as the most hedonistic of all creatures when it comes to food. Yet dogs given amphetamine will PAGENO="0448" 14870 COMPETITIVE PROBLEMS 1K THE DRUG INDUSTRY frequently stop eating entirely and literally starve themselves to death. The effects in rats and monkeys are a little less extreme but still remarkable. None require diet programs, motivation, tender loving care or any of the other forms of psychological bolstering so important for humans. Clearly, if we resembled our animal predecessors just a little more closely, amphetamines might be fine, reasonably safe drugs for treatment of obesity. True, they may produce numerous side effects such as anxiety. tenseness, restlessness, throbbing headaches, tremors, weakness, dizziness, and palpatations and, most important, difficulty in sleeping. But the - side effects are usually controllable by dose reductions and tend to abate with continued use. Surprisingly, the stress which amphetamines induce on the system does not appear to produce any appreciable harm with moderate doses during short periods, except possibly to individuals with advanced cardiovascular disease. Rather the problem with the amphetamines as with many other drugs which affect the central nervous system relates to that intricate, mysterious, perverse tissue mass, the human brain; responsible for the indefinable human psyche. During a relatively short span of availability, amphetamines have emerged as major drugs of abuse. PAGENO="0449" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14871 In consideration of the number of very unpleasant side effects a reasonable question is why? Like most drugs subject to abuse, amphetamines produce desirable responses that for some individuals outweigh any associated discomfort or, in gross overdosage, physical distress. Compulsive users of amphetamines fall into roughly two categories. Individuals who consume therapeutic doses or doses only slightly in excess of therapeutic doses routinely, but not necessarily daily, fall into the first category. Such individuals have learned to rely on the drug to help then cope with the demands of their social environment. knphetamines produce an elevation in mood and increased alertness. They counteract fatigue and improve the ability to concentrate. Physical performance may be enhanced considerably at times. Perhaps the most insidious perceived benefit is an increase of initiative and self- confidence. Even though, on occasions, paradoxical responses occur, it is easy to understand how the student, the athlete, truck drivers and other individuals who receive rewards for either intense or prolonged efforts can be hooked. Consider also the overworked or harassed executive who finds that amphetamines improve the quality and quantity of his work output, while increasing self-confidence and the housewife who may use the drug simply to counteract boredom. PAGENO="0450" 14872 COMPETTTTVE PROBLEMS IN THE DRUG U~'DUSTRY Some of these mildly addicted individuals use the drug for years and don't present any remarkable social problem except occasional distressing loquaciousness. With moderation, amphetamine effects Sound good and have a definite appeal. Unfortunately all is not as rosy as it sounds. Users have difficulty sleeping and tend to either become exhausted or to use sedatives starting the classical "upper-downer" cycle. Some find alcohol an effective antidote for the stimulant side effects. Alcohol and sedatives as a whole are really more pleasant drugs and can become a far greater problem than the amphetamines. Actually people don't become physically dependent on amphetamines. They can stop use without any terribly unpleasant responses. But they can and do become physically dependent on alcohol and some even to the sedative hypnotic drugs. Other problems associated with chronic use are less well defined; however, mental depression and gastrointestinal diseases appear to be frequent concomitants of routine amphetamine intake. The most important side effect of weight reduction programs in which amphetamine is employed as an adjunct, is therefore chronic compulsive use of moderate doses. Experts regard even this form as abuse as more often a result of experimentatio and subsequent reinforcement of a sensation of need for the drug in order to function, rather than as an iatrogonic problem. This pathway appears to be characteristic of all drugs of abuse. However, susceptibility to moderate abuse seems widespread and the risks involved even with adequately supervised short term use are undoubtedty real. PAGENO="0451" COJ~fPETITIVt PROBLEMS IN THE DRUG INDUSTRY 14873 Self-administration of gross overdoses of amphetamine-like products either orally, by inhalation or by intravenous injection represent a second and extremely hazardous form of abuse. Such activities are restricted preponderantly to members of our drug culture'. Individuals who employ large doses of amphetamine, methanphetainine or similar drugs usually abuse other central nervous system drugs including alcohol, opiates, barbiturates and narihuana. It seens that any mechanism that can provide them with a means of escape from the expectations and inpingecaents of society, their conscience and evem consciousness, is subject to adaption by these individuals. Amphetamines are valued because of a "rush" sensation produced particularly when injected. The exhilaration experienced reportedly resembles a sexual release. Cardiovascular and CNS side effects are of course magnified and it is difficult to understand how any degree of pleasure can conpensate for the associated unpleasantness. I've only seen the results of acute amphetamine abuse on one occasion during a day long visit at the home of a university professor, a psychologist by training. On arrival in the morning, his wife appeared to be floating on air. She remained that way until shortly before our departure in the evening, when she collapsed into a deep sleep. During the day she would not or could not maintain a givem conversation or sit for any length of time. She was inordinately garralous and obviously edgy. This response was purportedly the result of sniffimg a quantity of dextro-amphetamine. PAGENO="0452" 14S74 CO?,~~ETITflt PROBLEMS ~N THE DRUG INDUSTRY Most of us have seen the results of chronic, gross amphetamine abuse on TV, or at least read descriptions in the lay press. The anorexic actions of the drugs are illustrated by the fact that chronic users generally appear emaciated. But signs of mental disturbances are also obvious during periods of prolonged and repeated use. Diminished intelligence level can be appreciated particularly in previously highly intelligent individuals. Delusions and frank hallucinations are coimnon. Feelings of persecution, suicidal urges and even homocidal responses are characteristi of this category of amphetamine addiction. Deaths resulting from amphetamine overdoaage can occur, but most often are a result of administration of companion drugs. Actually, it is amazing how resistant the cardiovascular system of the human being is to this form of grievous assault; particularly when one considers that the death rate fron cardiovascular disease remains our leading killer. Fortunately, when an amphetamine addict is "dried out" mental and physical pathology usually prove reversible. Nor do chronic, high dose, amphetamine abusers suffer withdrawal symptoms seen with addiction to depressant drugs; unless they happen to be addicted to any of these materials at the same tine. Also, gross amphetamine abuse is usually episodic rather than continual as with classical opiate, sedative addiction. However, the property of tolerance to high doses is shared by this group. A dose of amphetamine which night prove fatal to a normal person may be employed PAGENO="0453" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14875 routinely by some. Finally, it should be emphasized that this form of addiction to ai-nphetanine is regarded by nany experts to present the greatest potential for social aberramcies of a hazardous nature among the whole group of drug abuse problems. These individuals can be mutilators of children as well as adults, rapists and cold blooded killers. One wonders for example, if the Hanson Cult were amphetamine freaks. The issue remains whether the risk to benefit ratio associated with the therapeutic use of amphetamine for obesity or any other disease, is sufficiently low to justify their continued conmiercial availability. At present straight amphetamine and methamphetanines are included in Schedule II of the Controlled Substances Act along with norphine, cocaine and other drugs of abuse. Should these two drugs in particular be relegated to Category I, thereby prohibiting any form of cornnerciai distribution? Should their use be restricted to cases of narcolepsy or childhood hyperkinesis in which they may well represent drugs of choice? Those who hold that an elevation to the Category I status would be overkill point out that initial results obtained through imposing the Category II restrictions have been moderately effective iii diminishing the low-dose amphetamine abuse problem and that with improved surveillance this form of moderate abuse will be effectively retarded. Many have doubts that a Category I status would have any appreciable effect on PAGENO="0454" 14876 COMPETITIVE PROBLEMS D THE DRUG ~ThuSTRY severe abuse incidence in spite of increased effectiveness of our enforcement officials. The Street price of amphetamines which rumor tells us is presently about $3.00 per dose would certainly increase which may afford some deterrant action; but, more likely, such an increase would prove of greater efficacy in supporting the ventures of organized crime. speaking to the pro-Category I question, the therapeutic merit of amphetamine products are probably not sufficiently remarkable to dictate that they remain available even with further labeling restrictions. It seems unlikely that clinicians on the whole would strenuously object if the amphetamine products were completely banned; particularly if they could be assured that deletion of thess occasionally very useful drugs would not be an exercise in futility. An investigative reporter, with whom I've become friendly recently disclosed to me that reliable information exists suggesting that other synpathomimetic drugs are presently achieving the wide-spread abuse category. He specifically designated the drug, phenteramine as a popular amphetamine substitute. This drug is presently listed among the drugs with low abuse potential in Category IV. Our work at Biometric Testing Inc. indicates that at effective therapeutic doses some of the synpathoninetic side effects may occur (dry mouth, palpitations, nervousness) but that the mood-elevating, anti-fatigue actions associated with amphetamine and methamphetamine are minimal. PAGENO="0455" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14877 Although not as extensively studied as amphetamine, phenteramine and other drugs with similar activity have been well characterized pharmacologically. Jerome Jaffe in the standard test, Goodman and Gilman cites the work of Martin and his associates (din. Pharmacol. Thor. 12:24S, 1971) which suggest that some representatives of the series can produce central nervous system stimulation in experimental animals comparable to that of amphetamine depending upon the dose administered. Since human investigations have been restricted to recommended doses, the relevancy of these data in humans cannot be defined. However, as a response to the invitation to discuss this problem with you I have explored this possibility further, A former classmate and expert in the pharmacology of drug addiction, Dr. Gerald Deneau, provided me with data showing that primates under given conditions will self-administer some of these presumably less stimulant sympathomimetics. These data support the work of Martin et al and suggest that the appreciated amphetamine responses might be obtainable with elevated doses. Most investigators would discount a significant abuse potential for phenteramine and similar drugs on the basis of the data available in the literature. The drugs have just not proven to elicit sufficiently rewarding responses in comparison to associated discomfort. Yet, we cannot sell the human animal short. A lesser crutch will frequently be acceptable if the parent is not available, even though it is reasonable to assume that unwanted side-effects will be proportionately amplified with higher doses. PAGENO="0456" 14878 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Any evidence suggesting a significant abuse potential requires critical evaluation before conclusions are warranted. To achieve a conclusion that a given amphetamine-related product possesses abuse potential of an order to dictate added sanctions, it should be possible to document an increasing incidence of abuse. In contradiction to my reporter friend, another close observer has failed to note any remarkable or alarming upsurge in recreational, non-nedical use of the amphetamine-related drugs. He states that fenfluramine, a newer introductior more likely to produce drowsiness than stimulation, appears to present as many problems as some of the older products. Yet, on the basis of limited data, it seems that baboons, at least, do not enjoy fenfluranine and will not self-administer the drug abnormally. Perhaps baboons are more discriminating than humans. Undoubtedly our flEA, regulatory officials will be able to provide us with more definitive information in regard to the current incidence of cases of confirmed abuse of amphetamine-related drugs; particularly the incidence associated with the inhalation and intravenous routes of administration. If indeed the related drugs prove to possess an abuse potential approaching that of amphetamine, then clearly they should be placed in Category II. PAGENO="0457" co:ETIT: PROBLEMS fl~ ~E DRUG ~U~Y 14879 If new findings illustrate that a drug is favored by the drug culture" as an agent of gross abuse, it may well merit Category I status. Under any circumstances, we should remain diligent in defining degrees and hazards of abuse associated with those drugs retained on the market, and any potential substitutes should they be withdrawn. 85-~569 O-71----30 PAGENO="0458" 14880 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY STATEMENT BY EDWARD A. KING JR., A.C.S.W., DEPUTY DIRECTOR TOWN OF HUNTINGTON YOUTH BUREAU 1328 NEW YORK AVENUE, HUNTINGTON STATION, NEW YORK 11Th6 BEFORE THE SUBCOMMITTEE ON MONOPOLY SENATE SP~LL BUSINESS COMMITTEE NOVEMBER 11, 1976 PAGENO="0459" COMPETITIVE PROBLEMS IN `I'RE DRUG INDUSTRY 14881 MR. CHAIRMAN, MEMBERS OF THE COMMITTEE, MY NAME IS ED KING. I AM DEPUTY DIRECTOR OF THE TOWN OF HUNTINGTON YOUTH BUREAU, AND PROGRAM DIRECTOR OF THC TOWN'S COM1IUNITY-BASED DRUG PROGRAM. MY TESTIMONY TODAY IS BASED ON OVER SEVEN YEARS OF EXPERIENCE IN MY PRESENT POSITION WITH HUNTINGTON TOWNSHIP, WHICH IS A LARGE LONG ISLAND SUBURB OF NEW YORK CITY, WITH A POPULATION OF 220,000 PEOPLE. IN 1968, THE TOWN OF HUNTINGTON ESTABLISHED THE FIRST TOWN LEVEL YOUTH BUREAU IN NEW YORK STATE FUNDED BY THE NEW YORK STATE DIVISION FOR YOUTH, AND OUR YOUTH BUREAU WAS AMONG THE VERY FIRST AGENCIES TO RECEIVE STATE FUNDS TO OPERATE A COMMUNITY-BASED PROGRAM FOR THE PREVENTION AND CONTROL OF YOUTHFUL DRUG ABUSE IN 1970. IN 1971, THE TOWN OF HUNTINGTON INSTITUTED THE FIRST VOLUNTARY AMPHETAMINE BAN IN THE UNITED STATES. THE TOWN'S COMPREHENSIVE YOUTH PLAN INCLUDES EIGHT PRIVATE, NON-PROFIT CORPORATIONS KNOWN AS YOUTH DEVELOPMENT ASSOCIATIONS SERVING LOCAL NEIGHBORHOODS WITHIN THE TOWNSHIP, AND SEVERAL SUPPORT PROGRAMS IN THE AREAS OF JOB DEVELOPMENT, SUMMER CAMPS, RUNAWAY PLACEMENTS, FAMILY ADVOCACY, AND COURT DIVERSION, AS WELL AS THE DRUG PROGRAM WHICH CO~SISTS OF A HOTLINE, COUNSELLING CENTER, AND OUTREACH WORKERS ASSIGNED TO THE LOCAL YOUTH DEVELOPMENT ASSOCIATIONS, WE FEEL THAT OUR EIGHT YOUTH DEVELOPMENT ASSOCIATIONS ON CONTRACT WITH THE YOUTI3 BUREAU PROVIDE THE KEY TO THE DEVELOPMENT OF *PROGRAM STRATEGIES SPECIFIC TO REDUCING DRUG ABUSE. THEY ARE OPERATED BY LOCAL BOARDS OF COMMUNITY CITIZENS (ADULTS AND YOUTHS), AND ARE IN THE BEST POSITION TO RECOGNIZE LOCAL PROBLEMS AND THEIR PAGENO="0460" 14882 coMrEPITwI PROBLEMS LW THE DRUG INDUSTRY SOLUTIONS IN COOPERATION AND COORDINATION WITH OUR YOUTH BUREAU PROFESSIONAL STAFF, THIS ELABORATE SYSTEM OF CITIZEN INVOLVEMENT IN LOCAL GOVERNMENT INCLUDES, (IN ADDITION TO LOCAL NEIGHBORHOOD BOARDS), CENTER COUNCILS, TASK FORCES, SPECIAL COMMITTEES AND PROGRAM VOLUNTEERS, WORKING WITH THE UNDERSTANDING AND SUPPORT OF THE APPOINTED MEMBERS OF THE YOUTH BOARD AND THE ELECTED OFFICIALS OF THE TOWN COUNCIL. WE DESCRIBE THIS GRASS-ROOTS VOLUNTEER EFFORT WITH OBVIOUS PRIDE, MR. CHAIRMAN, TO ILLUSTRATE THE IMPORTANCE OF THE WORK OF THIS COMMITTEE. WITH ALL OF THIS LOCAL COMMUNITY CONCERN AND EFFORT TRANSLATED INTO QUALITY PROGRAMS AND PROFESSIONAL SERVICES, WE WILL ULTIMATELY FAIL TO FREE OURSELVES OF DRUG ABUSE UNLESS INSTITUTIONALIZED FORMS OF DRUG ABUSE *ARE ADDRESSED AT THE FEDERAL LEVEL. I WOULD LIKE TO OFFER A VERY SPECIFIC ILLUSTRATION AT THIS TIME. IN FEBRUARY OF 1972, THE TOWN OF HUNTINGTON PROVIDED EXPERT TESTIMONY IN THE PERSON OF EDWARD M. GUROWITZ, PH. D., THEN DIRECTOR OF CLINICA SERVICES OF THE TOWN'S NARCOTIC GuIDANCE COUNCIL, BEFORE A SENATE SUBCOPITTEE CHAIRED BY THE HONORABLE PAUL G. ROGERS, DEALING WITH THE VERY SAME CONCERNS OVERAMPHETAMINE ABUSE WHICH WE ARE ADDRESSING HERE TODAY. IN THAT TESTIMONY, DR. GUROWITZ REFERRED TO A DOCTOR WITH A "DIET PRACTICE' WITH OFFICES IN THE SAME BUILDING AS OUR TOWN'S COUNSELLING CENTER, AND ALSO HOUSING THE SUFFOLK COUNTY METHADONE MAINTENANCE CLINIC. HE SPOKE OF HIS DIFFICULTY IN EXPLAINING THIS PAGENO="0461" COMPETrI'IVE PROBLEMS IN THE DRUG INDUSTRY 14883 TO YOUNG CLIENTS WHO SAW LONG LINES OF PEOPLE, MANY OF THEM YOUNG FEW OF THEM OBESE1 WAITING TO OBTAIN DRUGS FOR WEIGHT CONTROL. THE SITUATION WAS AGGRAVATED BY THE FACT THAT MANY OF THESE CLIENTS WERE COURT REMANDED FOR TREATMENT AFTER ARREST AND CONVICTION FOR THEIR ILLICIT DRUG ABUSE4 AND HAD REAL FEELINGS ABOUT THE DAILY PARADE OF "LEGITIMIZED" DRUG TRAFFIC WHICH THEY WERE WITNESS TO. THE FOLLOWING STEPS WERE TAKEN ON THE LOCAL LEVEL: THE SUFFOLK COUNTY DISTRICT ATTORNEY'S OFFICE WAS ALERTED TO THE SITUATION) THE SUFFOLK COUNTY MEDICAL SOCIETY WAS INFORMED (BUT THE DOCTOR WAS NOT A MEMBER, AND THEY COULD IMPOSE NO EFFECTIVE SANCTION)) THE TOWN'S COUNSELLING CENTER WAS MOVED TO A NEW LOCATION) AND, SOON AFTER, THE COUNTY'S METHADONE CLINIC MOVED AWAY ALSO. AS OF THIS WRITING, THIS SAME DOCTOR REMAINS UNDER INVESTIGATION OF THE DRUG ENFORCEMENT ADMINISTRATION, AND IN ACTIVE PRACTICE IN THE SAME LOCATION WITH AN ESTIMATED WEEKLY CASELOAD OF OVER 800 PATIENTS. IN JANUARY OF THIS YEAR, ONE OF THOSE PATIENTS, A TWENTY YEAR OLD FEMALE, CAME TO OUR COUNSELLING CENTER WITH THE HOPE OF BREAKING A ONE YEAR ADDICTION TO AMPHETAMINES. THE PILLS WERE GIVEN TO THIS CLIENT ON A REGULAR AND UNREGULATED BASIS. SHE STATED THAT SHE WAS GIVEN THE PILLS DIRECTLY BY THE DOCTOR, AND THAT SHE WAS ABLE TO GET MORE THAN THE USUAL WEEKLY ALLOTMENT OF TWENTY-ONE PILLS WITH EASE. SHE FURTHER STATED THAT, AFTER THE FIRST VISIT, NO SIGNIFICANT EXAMINATION WAS MADE OF HER PHYSICAL OR EMOTIONAL CONDITION. DURING THAT YEAR, BEFORE SHE CAME TO US, SHE WAS OFTEN DEEPLY DEPRESSED, HAD VISUAL HALLUCINATIONS, WAS DELUSIONAL IN HER THINKING, AND ATTEMPTED SUICIDE ON THREE SEPARATE OCCASIONS. SHE WAS HOSPITALIZED EACH TIME, PAGENO="0462" 14884 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY ON FEBRUARY 2ND oF THIS YEAR) WE REFERRED HER TO A LOCAL DETOX UNIT, AND THEY REFERRED HER TO A LOCAL RESIDENTIAL TREATMENT PROGRAII. SHE WITHDREW AFTER TWO DAYS, BUT OUR FOLLOW-UP DETERMINED THAT SHE REMAINED DETOXIFIED FOR TWO MONTHS BEFORE SHE RETURNED TO THE DOCTOR'S OFFICE FOR MORE PILLS WHICH SHE RECEIVED. ON MAY 4TH, IN THE PRESENCE OF ONE OF OUR WORKERS, SHE WROTE A LETTER TO THE DOCTOR, AND TOLD HIM OF HER ADDICTIVE HISTORY WITH THE PILLS HE HAD BEEN GIVING HER, AND PLEADED WITH HIM TO NEVER GIVE HER PILLS AGAIN, EVEN IF SHE BEGGED HIM. I WISH THAT I COULD SAY THAT THIS IS AN ATYPICAL AND OVERLY DRAMATIC CASE, MR. CHAIRMAN, BUT THIS SAD STORY IS UNUSUAL ONLY IN THE SENSE TUAT TUIS YOUNG WOMAN CAME FOR HELP. WHEN AMPHETAMINES ARE INVOLVED IN AN ESTABLISHED PATTERNOF DRUG ABUSE, DEEP DEPRESSIONS, AGGRESSIVE ACTING OUT, PARANOIA, SUICIDAL TENDENCIES AND RESISTIVENESS TO CHANGE ARE THE COMMON TRAITS. JUST AS THESE HEARINGS ON ANTI-OBESITY DRUGS ARE FART OF A LARGER STUDY OF THE DEVELOPMENT, MARKETING, AND DISTRIBUTION OF PRESCRIPTION DRUGS IN GENERAL, THE ABUSE OF AMPHETAMINES IS USUALLY COMBINED WITH THE ABUSE OF TRANQUILIZERS, SEDATIVES, AND BARBITUATES OBTAINED. FAR TOO OFTEN, FROM OTHER DOCTORS. MANY ADULTS IN TOWN, AS WELL AS YOUNG PEOPLE, FIND THEMSELVES ON A CHEMICAL ROLLER-COASTER OF "UPS" AND "DOWNS." THE SUBURBAN HOUSEWIFE SEEMS TO BE A PARTICULARLY HIGH-RISK POPULATION FOR THIS KIND OF DRUG ABUSE. SOME START WITH DEPRESSANT DRUGS, DEVELOP TOLERANCES, AND THEN GO TO A "WEIGHT DOCTOR" FOR AMPHETAMINES TO HELP THEM GET UP IN THE MORNING. OTHERS GET "STRUNG OUT" ON THEIR PAGENO="0463" COMPETITIVE PROBLEMS IN nIE DRUG INDUSTRY 14885 INCREASED TOLERANCE FOR AMPHETAMINES AND GO TO ANOTHER DOCTOR WHERE THEY PRESENT THE SYMPTOMS OF EXTREME FATIGUE, ANXIETY, AND TENSION, AND TRANQUILIZERS OR SEDATIVES ARE PRESCRIBED. WE HAVE FOUND VERY FEW AMPHETAMINE ABUSERS IN OUR TOWNSHIP WHO HAVE OBTAINED THEIRDRUGS FROM THE STREET IN RECENT YEARS. THIS IS NOT THE CASE WITH TRANQUILIZERS, SEDATIVES AND BARBITUATES, WHICH ARE MORE COMMON IN GENERAL AND MORE AVAILABLE IN THE ILLICIT DRUG TRAFFIC. IF WE COULD SOMEHOW CONTROL THE PRODUCTION OF TRANQUILIZERS, SEDATIVES, AND BARBITUATES SO THAT TOMORROW THEY WOULD BE AVAILABLE FOR ONLY THE APPROPRIATE MEDICAL USES, I WOULD THINK TWICE BEFORE DOING IT. I CERTAINLY WOULD NOT WANT fo DRIVE IN HEAVY TRAFFIC THE NEXT DAY! THE KIND OF HUMAN SERVICES NECESSARY TO ENABLE LESS FORTUNATE MEMBERS OF OUR SOCIETY TO COPE IN A HEALTHY AND RESPONSIBLE WAY WITH THE STRESSES AND ANXIETIES OF MODERN DAY LIFE ARE SIMPLY NOT IN PLACE. THIS IS NOT TO SAY THAT DEPRESSANT DRUGS ARE NOT GROSSLY OVER-PRODUCED AND OVER-PRESCRIBED. THEY MOST CERTAINLY ARE, AND FEDERAL CONTROLS ARE URGENTLY NEEDED. HOWEVER, THESE CONTROLS SHOULD BE DEVELOPED CAREFULLY AND INSTITUTED WITH CAUTION. A PHASE-IN PERIOD OF SEVERAL YEARS IN WHICH PRODUCTION LIMITS WOULD TIGHTEN IN SET STEPS WOULD ALLOW FOR THE NECESSARY ONGOING EVALUATION WHICH THIS EFFORT WOULD REQUIRE. PAGENO="0464" 14886 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMPHETAMINES ARE A DIFFERENT STORY. THE TESTIMONY OF DR. GUROWITZ FIVE YEARS AGO CAREFULLY ESTABLISHED 1,200 KILOS AS A REASONABLE NATIONAL PRODUCTION LIMIT FOR AMPHETAMINES. THIS WOULD PROVIDE AN ADEQUATE SUPPLY TO SUPPLEMENT THE NON-AMPHETAMINE DRUG OF CHOICE (RITALIN) FOR THE TREATMENT OF THE RARE CONDITIONS OF NARCOLEPSY AND HYPERKINESIS. THE LATTER CONDITION IS PRESENTLY THOUGHT BY MANY TO BE CAUSED BY ALLERGIC REACTIONS TO DYES AND PRESERVATIYES IN FOODS; YET ANOTHER FORM OF INSTITUTIONALIZED SUBSTANCE ABUSE. IT SEEMS TO ME, MR. CHAIRMAN, THAT AMPHETAMINES ARE THE PLACE TO START WITH STRICT CONTROLS ON PRODUCTION. WHILE THE ABUSERS OF DEPRESSANT DRUGS ARE OFTEN SELF-MEDICATING TO CONTROL THE SYMPTOMS OF UNDERLYING EMOTIONAL TURMOIL, AMPHETAMINES ONLY AGGRAVATE AND INTENSIFY THOSE VERY SAME SYMPTOMS. THE PERSON WITH UNDERLYING HOSTILITY BECOMES MORE HOSTILE. THE PERSON WITH UNDERLYING DEPRESSION BECOMES MORE DEPRESSED, THE PERSON WITH UNDERLYING PSYCHOSIS BREAKS MORE COMPLETELY WITH THE REALITIES AROUND HIM. THE OVERALL IMPACT OF THIS AGGRAVATED AND INTENSIFIED CONFLICT ON FAMILY LIFE ES BEYOND CALCULATION, BUT MOST CERTAINLY WIDE SPREAD AND TRAGIC IN ITS EFFECT. WE, IN THE TOWN OF HUNTINGTON, ARE PLEASED AND GRATEFUL THAT THIS COttIITTEE IS ONCE AGAIN FOCUSING ATTENTION ON THE CRITICAL NEED TO CURTAIL THE OVER-PRODUCTION OF COMMONLY ABUSED PRESCRIPTION DRUGS BY BIG INDUSTRIES THROUGHOUT OUR NATION. BY BROADENING THE FOCUS OF OUR PUBLIC CONCERN OVER DRUG ABUSE IN THIS WAY, WE CAN PAGENO="0465" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14887 TAKE REAL STEPS TO DEMONSTRATE INTEGRITY IN OUR NATIONAL EFFORT. YOUNG PEOPLE ABUSING DRUGS OBTAINED ON THE STREET HAVE BEEN SCAPEGOATED FOR TOO LONG IN OUR SO-CALLED `WAR ON DRUG ABUSE." YOUNG PEOPLE IN GENERAL ARE EXTREMELY SENSITIVE TO HYPROCRACYJ AND WOULD BE QUICK TO RECOGNIZE ANY REAL STEPS TO DEAL FAIRLY AND SQUAftELY WITH INSTITUTIONALIZED DRUG ABUSE AS ALSO BEING STEPS TO REDUCE SIGNIFICANTLY THE ALIENATION YOUNG PEOPLE FEEL FROM THIS NATIONAL EFFORT AT THE PRESENT TIME. YOUR LEADERSHIP WILL GO A LONG WAY TOWARD UNITING YOUNG AND OLD ALIKE IN A NATIONAL EFFORT TO FIND HEALTHY AND RESPONSIBLE WAYS TO LIMIT AND CONTROL DRUG ABUSE AND THE CLOSELY RELATED HUMAN ABUSES OF ALL KINDS. WE THANK YOU FOR THE OPPORTUNITY TO BE A PART OF THAT PROCESS, AND STAND READY TO ASSIST IN ANY WAY POSSIBLE. THANK YOU. PAGENO="0466" 14888 COMPETITIVE PROBLEMS IN ~E DRUG INDUSTRY Statement of Isaac R. McGraw, President Pharmaceutical Division nf Pennwalt Corporation Submitted to Senate Monopoly Subcommittee November 19, 3916 PAGENO="0467" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14889 INDEX Page Introduction I Corporate History 3 Pennwalt' s Pharmaceutical Division 3 The Problem of Obesity and the Use of Anorectics S The Re~u1atory System 9 The DEA Monitors the Distribution of Anti-Obesity 12 Effect of Controls on Prescription Experience~ 1971 Compared to 1975 14 Pennwalt's Manufacture, Distribution and Sales 15 Pharmacy Sales of Prescribed Anorectic Products 17 Alleged Abuse of Pennwait's Anti-Obesity Products 17 Combination Amphetamine Products 20 Conclusion 21 PAGENO="0468" 14890 COMPETITIVE PROELEMS IN THE DRUG INDUSTRY At the request of your Committee, lam appearing on behalf of Pennwa3.t Corporation's Pharmaceutical Division in order to provide the Committee with our comments on the sub- ject of anti-obesity drugs. PAGENO="0469" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14891 Introduction In my appearance today on behalf of Pennwalt and its Pharmaceutical Division, I will review those major considerations which we believe to be responsive to this Committee's invitation. in order that you may readily comprehend our views, I should like to summarize them at the outset and then deal with them more fully by major category. As part of Pennwalt Corporation, a 126.year old firm founded and still headquartered in Philadelphia, Pennsylvania, with annual sales of approximately $750 million, we share its pride in our collective integrity. (I should note that our divisior represents less than ten percent of the Company's total sales, and that our anti-obesity products represent less than three percent of total sales, with lees than one percent in anorectic amphetamine products.) Anti-obesity prescription medicine is the only federally recognized effective medicinal aid available in a course of medically supervised anti- obesity treatment available to the 30 to 40 million Americane who are obese, namely, those who are at least 20 percent overweight. Obesity is a recognized illness, in medical terms, as well as an emo- tional burden, it also complicates other quite serious medical problems. Our Pharmaceutical Division clearly recognizes that its anorectic products should not be used unless prescribed by a physician. We firmly believe that our marketing program fully reflects this recognition and contains no suggestion that we seek to sell the patient~~y use of our anorectic products. PAGENO="0470" 14892 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY As this Committee is aware, the Food and Drug Administration has found our aoorectic products to be safe and effective and, in our judgment, we have continued to achieve very satisfactory compliance with the regulatory standards and programs which are the responsibility of the Drug Enforcement Administration. We believe that you should find the factual evidence on the prescription dosage units of our products, per patient, to be consistent with their use as a short-term aid to the medicafly supervised obese patient. We do not believe there is any probative evidence that our anti-obesity products show any meaningful statistical or other factual evidence of abuse. We recognize that in a population of 215 million Americans there is a very small but highly visible segment who are troubled and who may be determined to misuse or abuse legitimate products. We believe, however, that the safety, effectiveness and judicious prescription of anti-obesity products cannot reasonably be condemned by the very limited factual evidence of their statistically quite infrequent misuse. The Congress and 42 state legislatures have created, and the FDA, DEA and State agencies administer, monitor and enforce sophisticated and effective programs designed to ensure proper medically supervised use of anorectic products. We fully support these programs and cooperate readily with these agencies. We believe that a scientific, technical or legal analysis fully and fairly considered, on the basis of factual rather than hearsay evidence, -2- PAGENO="0471" COMPEtTITIVE PROBLEMS IN THE DRUG INDUSTRY 14893 will continue to require the conclusion that our anorectic products serve a very worthwhile medical and human need- -assistance to the physician who finds that his patient requires this medication. I shall now turn to a more detailed review of the bases for the views I have just summarized. Corporate History Pennwalt Corporation was Iounded in 1850, in Philadelphia where it continues to maintain its corporate headquarters. Pennwalt has more than 14, 000 employees who are engaged in manufacture, sale arid distribu- tion of its products in the United States, Europe and elsewhere in the free world. Pennwalt' s total annual sales are expected to exceed $750 million in 1976. derived from its operations in Chemicals (approximately 50%), Specialized Equipment (approximately 25%), and Health--including both Dental and Pharmaceutical operations (approximately 25%). The Pharma- ceutical Division has annual sales of approximately $70 million and employs approximately 1,100 people. Pennwalt' s Pharmaceutical Division The Pharmaceutical Division manufactures and makes available to the medical profession a variety of therapeutic agents including anti- hypertensives, diuretics, anti-anxiety drugs, local anesthetics, antifungals, antispasmodics antitussives and antihietaminics as well as anorectics. The total sales of Pennwalt'a only amphetamine product, Biphetamine, are less than one percent of Pennwalt' s annual sales, and the total sales of both Biphetarnine and Pennwalt's non-amphetamine anorectic, lonamin, are less than three percent of Pennwalt's annual sales. -3- PAGENO="0472" 14894 COMPEPITWE PROBLEMS IN THE DRUG INDUSThY Our Pharmaceutical Division is headquartered in Rochester, New York, where it maintains its production, research and marketing nrganlza- tinns. Our business was founded by the Strasenburgh family in Rochester, and was privately owned until 1960. at which time it was acquired by Wallace t~ Tiernan, Inc., headquartered in East Orange. New Jersey with plants located in several areas of the United States and abroad. On March 31, 1969, we became part of the l'ennwalt Corporation, by virtue of its acquisition of Wallace ~ Tiernan on that date. Biphctamine is scheduled by the Drug Enforcement Administration (DEA') as a controlled substance under Schedule II. As such, the manu- facture of this product is specifically limited in terms of quantity and is strictly regulated at every stage in its chain of distribution by the PEA, as I will discuss more fully later. lonamin is scheduled by the PEA as a Schedule IV substance. It, too, is strictly controlled and regulated at each level of distribution. Both products have been apprnved by he Food and Drug Administration (IFDAF~) as safe and effective, as recently as 1)74. - In our pharmaceutical ope rations at Rochester, we maintain a research and development facility, manned with qualified professionals in- cluding 4 doctors of medicine, 13 doctors of pharmacology and doctors of chemistry, and other related disciplines. This staff and our administra- tive staff (quality control, governmental rompliance, finance, personnel. etc.) perform t',0 various functions which these titles suggest. -4- PAGENO="0473" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14895 The Problem of Obesity and the Use of Anorectics Internationally known medical and nutritional experts in the United States are generally agreed that there are approximately 30 to 40 million Americans between the ages of 21 and 65 who are at least 20 percent over- weight. To be 20 percent overweight Is to be "obese", a condition that seriously affects the individual's well-being and life expectancy. Obesity also compounds other diseases. Medically, obesity is correlated with considerable inciease in cardio-vascular diseases, diabetes, liver and kidney diseases and even accidents. Indeed, to be obese is to be ill. The problem was defined by one if reputable physician, Dr. Lalberstam as follows: "Fatness may be the single most !mportant illness in America. it is certainly the most important form of malnutrition. Fat people have higher incidence of stroke, of high blnod pressure. and, to a less marked degree, heart attacks. On all life in- surance tables fat people live shorter lives than normals. (Emphasis aipplied) in addition to physical disahility, the obese frequently carry ~n additional emotional burden, which Dr. Halberstam has described in these terms: "Worse, the fat middle-class person lives not only with a physical burden, but with a psychologic stigma. The sociolo~ist. David Rlesman, has said that America is a "physionomic democracy," That is. we increasingly will accept into our social circles and business lives people of any race, creed, or color--so long as they are attractive. The other side of thi, is that we shun the ugly, the crippled, the fat. The next time you are at a gathering of strangers or getting on a bus or sitting down at a lunch cou&er, check your own reluctance to sit down alongside a fat person. 1/ Dr. Michael Halberstam, The Pills in Your Life, Ace Books. 1912, pp. 141-142. -5- 5 85-~569 O__'iT---41 PAGENO="0474" 14896 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY Fatness has become a stigma--we associate it with poverty. ignorance, bad smell,, sour lives. To a large extent this is correct--and the fat person knows it.' In discussing the proper role, of anorectics in the treatment of obesity, we are confident that while this Committee wilt consider the testimony of the experts, the layman, and others who have their respective and differing views, the Committee wilt continue to be most interested in that which csn be established factually. We are equally confident this Committee wilt examine the question of antiobesity medication in the context in which it arises--a population contain- ing 30 to 40 million obese citizens who are entitled to medical and other therapeutic assistance in obtaining relief from their physical arid emotional disabilities, These disabilities cannot be dismissed with the notion that `wilt-power" or "self-discipline" or `counseling" are all that are needed. We can tell the sinners, the alcoholics, the chain-smokers or the obese how to behave and turn our backs on them if they do not. But quite clearly preachment is not the cure for any serious disability. We think it noteworthy that despite great medical progress in this country, the treatment of obesity is one of the few areas of preventive medicine being practiced today. Most other medical practice today remains remedial or post-traumatic. Medical attention is availahle to help the obese patient in his efforts to attain a more satisfactory level of physical condition by supervised weight loss. -6- PAGENO="0475" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14897 indeed, there seems tn be general agreement in the technical as well as popular literature that the ob'se should seek s doctor's advice before undertaking any serious program of individual dieting. If we have approximately 30 to 40 million obese individuals in the United States, and if we and they recognize that wishing `won't make it Sn!!, what remedies are appropriate? Our Pharmaceutical Divisinn believes that the obese individual has a medical problem which is best treated by a physician and aided by counseling and supportive techniques which will motivate the patient to attain his goals. Pennwalt has acted on this belief in educational programs directed to both physician and patient. We believe that prescription of anorectic medication--ours or that supplied by other reputable pharn'~ceutical companies--is entirely the prerogative of the physician. For more than fifteen years, we have provided the patient, through his doctor, with literature intended to educate the patient--not sell him our products. Indeed, our products are not mentioned in this literature. More than ID million copies of our long-established and free booklet. "Are You Really Serious About Losing Weight?", have been distributed. It contains over 70 pages of highly useful information for the patient and no reference to Pennwalt products. The educational value of our booklet was described by the intereationally renowned Dr. Jean Mayer of the Harvard University School of Public Health, 2f who said: "There have been so many popular books and articles on obesity which make the most unreasonable promises to patients that It is 2/ See Preface to "Are You Really Serious About Losing Weight? ", copies of which have been supplied to the Committee. -7- PAGENO="0476" 14898 COMPETITIVE PROBLEMS IN ThE DRUG INDUSTRY pleasant to see a booklet taking the reasonable and truthful position that weight reduction is dependent on maintaining a negative energy balance--preferably based both on decreasing food intake and increasing energy expenditure. `11t is even more gratifying to see that the booklet is sponsored by an enlightened pharmaceutical company which realizes that while anorexigenic drugs can, in the hands of competent and well-informed physicians, make an important contribution to treatment during the initial period of weight reduction, they cannot substitute for reeducation of the patient as regards - eating and living habits. They can gain time and make it easier for the obese individual to become used to smaller food portions, but a great deal of information and motivation also need to be given to the patient. "Because the doct&r's time is not unlimited, he needs teaching material, which this booklet quite adequately conveys. Reading the booklet should give the patient the chance for a more informed dialogue with his doctor." In this same booklet, the patient is advised to "Count your facts before you count your calories" and then asked to take a True-False quiz on basic propositions alleged to relate to dieting, with 28 questions and answers. I call your attention specifically to question No. 26 and our answer to it (at pages 3 and S of the booklet): Proposition: 26. A diet "pill" is an easier way of losing weight than dieting. Answer: 26. False. No pill can take the place of dieting. A diet pill is only a "training" aid to help cut down appetite for food while learning to adjust to oating less. It takes time to correct faulty eating habits--the real cause of overweight. Do not use any dieting drug unless it is prescribed by your physician for you." In summary, our educational program is specifically addressed to a four-part theme: (I) dietary counselling by the physician; (2) individualized dietary control addressed to the specific patient; (3) prescribed exercise: and (4) if necessary, anti-obesity prescription. -8- PAGENO="0477" COMFEtTITIVE PROBLEMS IN THE DRUG INDUSTRY 14899 The Regulatory System As this committee is fully aware, amphetamines and non-amphetamine anorectics are scheduled drugs which are regulated and controlled by the Food and Drug Administration, the Drug Enforcement Administration, and state authorities. In 1970, the Cong±ess passed the Drug Abuse Prevention and Control Act (Controlled Substances Act') at which time the Food and Drug Administra- tion Bureau of Drug Abuse Control and the Department of Narcotics within the United States T~easury Department were assigned to the Department of Justice. This Justice Department enrorcement agency is now known as the Drug Enforce- ment Administration. The 1)70 Controlled Substances Act established categories of drugs in five schedules of gradation,and the FDA and DEA cooperate with respect to specific scheduling thereunder. The FDA's role under the Federal statutory and regulatory scheme is to make a determination of the benefit- risk status and the effectiveness of particular drugs. The FDA has determined that Pennwalt' a Biphetamine is safe and offective as an adjunct in the short-term management ef obesity. As you know, the DEA has assigned it to Schedule Ii. Similarly, the FDA has determined that Pennwalt's lonamin is safe and effective. The flEA has assigned it to Schedule IV. I The 1970 law also imposes stringent accounting, reporting and production requis'ement~. extensive labeling requirements, registration of manufacturers, distributors and dispensing entities, elaborate s'equirements for sa?e-keeping of controlled substances, and establishes other procedures (or the control and sopervision of controlled substances. -9- PAGENO="0478" 14900 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY With respect to the manufacture of our Schedule II product, Biphetamine, we must receive a quota allocation from the DEA, annually. That quota estab- lishes the amount of amphetamine base our raw material) which will be available to us for the relevant calendar year. In this process, Pennwalt: I. Mist have submitted before the close of each year a formal quota application for the forthcoming year, setting forth our raw material utilization for the preceding three years. 2. Upon receipt from the flEA, early in the new year, of a quota allocation--which generally does not afford a full calendar year of supply--we operate thereunder. 3. several months later, as our inventory diminishes, we must make a further formal request for an additional quota allocation. 4. That request must contain: (I) A statement of current total plant inventory. (2) Projected utilization to year-end at our current usage rate. (3) A resultant computation of the additional allocation we require. (4) Such other information as is appropriate to aid the flEA in its evaluation, including, for example, the following: a. Comparisons of our distribution, stated in terms of kilos. b. International Marketing Service (IMS) audits of drug store purchases and prescription utilization. c. Wholesale distribution inventory level analysis. -10- PAGENO="0479" COMPDTITWE PROBLEMS IN THE DRUG INDtJSThY 14901 As a result of the quota process I have described, we are supplied with a raw material base generally sufficient to meet our actual annual demand. However, we do not receive a quota allocation adequate to guarantee us that in fact we will be able to complete production for that calendar year. As is evident, this rigorous quota control program is an essential part of the regulatory design to ensure that the product originates and re- mains in legitimate channels of manufacture and distribution. The proper scheduling of lonamin (phentermine) has been under review by the flEA since early 1973. At that time, Peonwalt advised the flEA that it would not oppose Schedule III classification for lonamin if related, competitive products were similarly scheduled. Pennwalt took this position in a spirit of cooperation, although Pennwalt remains unaware of any evidence that would support the Schedule UI classification pro2osed by the flEA. The matter remains pending, with lonamin in Schedule IV awaiting further action by the flEA, following its receipt of Pennwalt's lengthy documentation of the scientific and other facts we deemed relevant to the question. In this connection, it should be noted that Pennwalt advised the flEA on November 17. 1975. that: "Phentermine (i.e. Pennwalt's Jonarnio) has been marketed in the United States since approximately 1959. During the sixteen (now seventeen) years since then, approximately five hundred million (500, 000. 000) dosage units of Iooamin have been prescribed by physicians for use by a diverse patient population, ranging from young adults to the aging, a popula- tion necessarily including a broad spectrum of emotional, mental and physical characteristics. -11- PAGENO="0480" 14902 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "In all of those sixteen years, Pennwalt has learned of no deaths or anyserious physical or mental injury or damage attributable to the drug. In addition, Pennwalt is not aware of any significant instances of phentermine abuse, and its product liability experience with the drug lonamin reflects but one payment, in the amount of $3, 500. * to settle one suit brought by a patient who alleged she had used lonamin (on prescription) as welt as several other drugs inanulact ured by other defendants in her case." The DEA Monitors and Audits the Distribution of Anti-Obesity Dr~ The Drug Enforcement Administration pjays a very active role in monitoring and auditing our scheduled substances. It requires that all manufacturers 0f all Schedule II products submit monthly DEA-ZZZ-C forms. These reports require Pennwalt, for example, to list each pur- chase or sales transaction involving Biphetamine, as a Schedule II substance, by date, amount, and identity and location of purchase. The DEA also requires the quarterly filing of ARCOS computer tapes recording each controlled substance transaction under Schedule II and all transactions involving narcotic drugs in any schedule exclusive of those on Schedule V. These computer tapes show the movement of the drug both within the plant and in distribution, again showing date, amount and recipient. For lonamin, a Schedule IV product, the DFA requires that we record the name and location of each purchaser, its registration number, and the quantity, identity, and strength of the product by package unit. These same standards apply to our purchase of lonamin' s raw material, phente rmine. -12- PAGENO="0481" COMPE'TITIVE PROBLEMS IN TilE DRUG INDUSTRY 14903 In addition, the DEA requires a separate listing of all controlled substance ti ansactions. segregated from all other company records, to facilitate ready inspection by IDEA representatives. Separate reports of any suspected loss in transit, whether or not confirmed, and any other significant loss of any scheduled drug, are reported to the IDEA immediately. If any suspected loss is not accounted for, follow-up reports are made. The IDEA also conducts periodic, formal audit inspections of ~ entire system of accountability for all schedules of controlled substances. Apart from these audits, IDEA representatives are on our premises on a regular basis in the routine performance of their duties, including monitoring distribution and reviewing our security programs for scheduled products. In addition to federal regulation, forty-two states, including New York, California, Pennsylvania, Illinois, and Florida, have adopted the Uniform Controlled Substances Act, which contains controls similar to the Federal Act, .43- PAGENO="0482" 14904 com'ETITrvE PROBLEMS IN THE DRUG INDUSTRY Effect of Controls on Prescription Experience: 1911 Compared to 1975 Since the passage of the Controlled Substances Act in 1970, there has been a marked change in the prtscription experience for anorectic products. 3' These changes may be summarized as follows: - 1971 1975 I. Total patient visits for obesity: 23, 668, 000 20, 601, 000 2. Prescription Usage: Medical prescriptions of anorectics (initial) 18,373.000 12,413,000 Total second or subsequent prescriptions 7,707,000 7,213,000 Total anorectic prescriptions: 26, 080, 000 19. 626, 000 3, Total anorectic prescriptions (I) Amphetamines: 16,232,000 5,504,000 (Initial prescriptions) (13, 201. 000) (2,745,000) (2) Non-amphetamines: 9, 848, 000 14,122,000 (Subsequent prescriptions) ( 5,172,000) ( 9,668,000) Tots! anorectic prescriptions: 26,080,000 19,626,000 4, Reduction in total anorectic prescriptions from 1971 to 1975 -6,454,000 3/ These data are based upon the National Disease and Therapeutic Drug Index (Non-Endocrine Obesity) and its National Prescription Audit. -14- PAGENO="0483" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14905 These figures demonstrate that the Controlled Substances Act has accomplished a dramatic reduction in the prescription of amphetamine anorectic products, but that a continuing medical rcquirement for those products remains. The figures also demonstrate that while there has been an overall reduction in the total prescriptions of anorectic products, there also re- mains a very sizable patient population, consisting of millions of Americans. among the 30 to 40 million obese, who are receiving medically supervised treatment for their condition. Pennwalt's Manufacture, Distribution and Sates - All ~f the federal regulations I de~eribed previously are complied Mth by Pcnnwalt in its manufacture, distribution and sales. In addition, at the plant, production and shipping are monitored closely by management to assure the absence of loss and the detection of any attempted theft. As noted carlie r, detailed records and monthly and quarterly reports to the DEA show each transaction both intra-plant and to customers, its size and the identity of the customer. At the present time, Pennwalt sells its prescription products, including Biphetamine and lonan,in, only to non-profit hospitals and to approximately 450 wholesale distributors, These wholesalers handle the complete Line of Peonwalt products and all, of them are also registered and regulated in their handling of scheduled drugs by the Drug Enforcement Administration. In addition to registration, the wholesalers are subject to the ssme stringent reporting requirements by the flEA as is required of manufacturers. -15- PAGENO="0484" 14906 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY Using 1973 as a base, Pennwalt's direct sales of both Biphetamine and Lonamin to physicians have decreased. By 1975, approximately seven percent of Pennwalt's sales of Biphetamine, and approximately four percent of Pennwalt's sales of lonarnin, were made directly to physicians. Effective in the fall of this year, Penowalt ceased all such sales. Pennwalt has not promoted or advertised Biphetamine since 1971. Since that date, we have not detailed or sampled Biphetamine to physicians. Pennwalt advertises lonamin, but only in journals addressed to the medical profession. It also samples Ionamin in accordance with prevailing com- petitive practices and existing law. In August, 1976. the IDEA proposed that sampling of all controlled products be prohibited. In that same month. Pennwalt wrote to the IDEA to express our agreement with their proposal, and will comply immediately should this proposal become applicable to all competitors. Pennwalt's 19Th promotional expenditures for lonamin were approxi- mately 6 percent of total lonamin sales. Otherwise stated, our total pro- motional expenditures were approximately 4 percent of our total anti- obesity drug sales. (A, noted, we have no promotional expenditures for Biphetamine. These figures may be compared to the promotional expenditures for the most popular over-the-counter anti-obesity product, which has an esti- mated 60 percent of the market. The total promotional expenditures for that product for the last available year have been reported to be more than 20 percent of its sales, on a sales volume of approximately $15 million. -16- PAGENO="0485" COMPETITIVE PROBLEMS r~ THE DRUG INDUSTRY 14907 Pharmacy Sales of Prescribed Anorectic Products Before turning to the subject of alleged abuse of anorectics, we believe it useful to review briefly the total market for prescribed anorectics at the pharmacy level. Purchases By Retail Pharmacies, 1971 Compared to 1975 1971 1975 1. Total pharmacy purchases: $78,636,000 $83,247,000 Z. Total pharmacy purchases Amphetamine anorectics: 46,670,000 59%) 23, 237. 000 (27%) (Peonwalt sales) 1 8,394,000 (19%) ( 6,761,000 (29%) Non-amphetamine anorectics: 31, 966,000 (41%) 60, 010, 000 (73%) (Pennwalt sales) ( 3,244,000 (10%) 111,920.000 (20%) 3. Total Pennwalt anorectic sales: $11,638,000 114. 8%) $18,681,000 (22. 4%) 4. Total anorectic sales of: (1) Other two major manu- facturers: $34,213,000 $28, 381.000 (2) Pennwalt: 11,638,000 18,681,000 (3) All other:* 32, 785,000 36, 185. 000 Total pharmacy purchases: $78,636, 000 $83, 247, 000 The sales figures just reviewed are in current dollars. If expressed in constant dollars, you would note a significant decrease in dollar volume for the sale of all prescriptionanorectic products. 4/ The data cited are based upon (MS reports of pharmacy purchases for the years 1971 and 1975. -17- PAGENO="0486" 14908 COMPETJTIVE PROBLEMS IN THE DRUG INDUSTRY Alleged Abuse of Pennwalt' a Anti -Obesity Products Thu IMS analysis of the relevant data on individual prescription size, for the most recent complete calendar year, 1975, shows that: Average Number of»=Qsules, Per Physician's Prescription lonarnin 31.1 Capsules Biphetamine 33,5 Capsules We believe it appropriate to conclule that the average obese patient therefore receives a prescription for enough Iliphetarnine or lunamin capsules to provide one-per-day treatment up to a maximum of hut 4 to 5 weuks, for short-term support. We therefore continue to believe that the IMS analysis demonstrates that pharmacies and the medical profession are providing a necessary service and that the patients are not afforded, by that process, the opportunity for any meaningful abuse. Thus, regardless of anecdotes relating to the alleged high volume or capsules per prescription, in actuality the prescription data reported by IMS is consistent with judicious prescription by the medical profession. - Ill - PAGENO="0487" COMPETIPWE PROBLEMS TN THE DRUG TNDUSTRY 14909 We should also note that Pennwalt regularly compares its actual factory shipments of both amphetamine (Biphetamine) and phentermine (lonamin) containing products with IMS Audits of drugstore purchases. In addition, our actual factory shipments and the drugstore purchases can be correlated with the quantity of either Biphctarnine or lonamin prescribed and dispensed, as shown by the IMS National Prescription Audit for the same period. Pennwalt regularly undertakes such analyses and remains satisfied that its products are prescribed within legitimate medical channels. In short, our products are moving through tho distribution chain in a proper fashion. Pennwalt is not aware of any significant illegal usc' of its anti-obesity products. During the period January 1, I 972, to the present time, we have received from the DEA and other enforcement agencies hut nine reports of alleged diversion (mm all sources (five for Biphetamine and four for Jonarnin). When claims of either attempted or actual illegal use or diversion have been brought to our attention, Pennwalt has cooperated fully with the enforcement authorities in the investigation, apprehension and prosecution 0f those responsible. Our experience also confirms an observation of Mr. Peter Bensinger, Administrator nf the DEA. at the annual meeting of the top executives belong- ing to the Pharmaceutical Manufacturers Association, held in May of 1976. He noted that there is no reason to believe that industry is responsible for illegal trafflcking in amphetamine. Pennwalt knows of no evidence to the contrary. -19- PAGENO="0488" 14910 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY As this committee may know, allegations were made in January of 1973 that Pennwalt'santi-obesity drug product Bi fetarnina (Biphetamine), in Mexico,was being illegally diverted by purchasers of that drug. Pennwalt was never given evidence of where and how this diversion occurred, nor has Pennwalt been advised of any prosecution with respect to those alieged diversions. Nevertheless, in January of 1972, Pennwalt ceased production and sale of amphetamine products in Mexico and at the same time decided to cease any further export of amphetamine products, except for Canada, These decisions were made to limit our hiphetarnine sales to the United States and Canada, in reliance on strict regulatory practices which exist in those two countries. (As this committee knows, in 1973 Canada with- drew its approval of amphetamine products.) Combination Amphetamine Anorectice In February of 1973, the FDA published in The Federal Register a finding that all fixed combination amphetamine products were ineffective and unsafe. As a fixed combination, this finding included Biphetamine-T. Although the initial National Academy of Science - National Research Cpuncil ("NAS/NRC") finding with respect to Biphetamine-T was that it was "possible effective", Pennwalt elected not to exercise its right to contest the ~ 1973 re-determination. Pennwalt therefore discontinued further manu- facture of the product and recalled all stocks from the distribution chain, at a cost of approximately one million doliars -20- PAGENO="0489" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14911 Conclusion: On the basis of the evidence which we have summarized today. Pennwalt believes that there is an established medical and social need for its anti-obesity products. We think it important that this committee differentiate between hearsay testimony, utterly unsubstantiated by factual support, and the testimony and documentary evidence available from sources which are recognized to be technically qualified to deal with a complex scientific, social, and medical question. Pennwalt is aware that the notoriety of amphetamine commenced in the 1960's, when some troubled individuals received, or administered to themselves, either injections or inhalations of methamphetamine, known commonly as "Speed". Pennwalt is also aware of the fact that the aberrant will seek bizarre - experiences by a variety of means. We deeply regret those instances of actual tragedy which befall those unfortunate people. We do not conclude, however, that these alleged cases narrated by those who appear in public to report their reformation, or their counselling association with alleged abusers, amounts to the kind of factual evidence which would permit a meaningful conclusion with respect to the actuality of those alleged experi. ences or the lessons that should be drawn therefrom. There remains a population, estimated to be between 30 and 40 million obese Americans, many of whom wish to avail themselves of medical treat- ment in order to alleviate or eliminate this unfortunate condition. Our anti- obesity products, and those of other responsible manufacturers, remain recognized as the only effective prescription medicinal aid available in a -21. 85-469 O-71-----32 PAGENO="0490" 14912 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY course of anti-obesity treatment. Moreover, as we have discussed today, the manufacture and distribu- tion of those products is closely regulated by competent federal agencies, which have the requisite expertise to evaluate the quality of our products and the legitimacy of their use. The regulatory processes established by the Congress, over the years. have created a framework within which the serious questions which concern this cormnittee have long been the sub.~ct of professional concern, both within the regulatory agencies and within the pharmaceutical industry. That process affords all of its participants due process, from investigatory, scientific, and legal perspectives. Pennwalt appreciates the opportunity to appear before this committee in order to state the bases upon which its products are manufactured and distributed. Pennwalt remains confident that it can continue its I 26-year- old reputation for integrity while engaged in this part of its enterprise. I am ready to answer any questions you may have. -22- PAGENO="0491" COMPETITIVE PROBLEMS 1K THE DRUG INDUSTRY 14913 (STATEMENT BY (DR. JAMES J. NORA, PROFESSOR OF PEDIATRICS. DIRECTOR OF PEDIATRIC CARDIOLOGY, UNIVERSITY OF COLORADO MEDICAL CENTER, DENVER (BEFORE SUBCOMMITTEE ON AIITI-OBESITY DRUGS (SENATE SMALL BUSINESS COMMITTEE (NOVEMBER 9. 1976 Certain Central Nervous System Stimulants and Birth Defects Ny charge, as I understand it, is to speak to the possible role that amphetamines and related drugs ray play in the production of birth defects, if there is exposure at a vulnerable period of embryonic or fetal development, and if there are both a genetic predisposition to react adversely to these drugs and a genetic predisposition to sonic form of inaldevelopeent. All of the qualifications of the previous sentence must be applied to amphetamines and to most potential teratogens, Fortunately there are few agents in our environment that possess the disastrous teratogenic potential of thalidomide or rubella virus. And, conversely, und9r the right combination of genetic predIsposition ~ exposure at a vulnerable period of development, one could project that almost any agent that has pharmacologic activity could be teratogenic. Between these extremes, I believe there exists a number of agents causing birth defects in enough susceptible individuals to constitute a significant health hazard. It is in this latter category that I believe dextroamphe- tamine may belong. Sore of my co-workers and I have devoted a not inconsequential portion of our research activity to Investigating such teratogens, which are difficult to identify in the epidemiologic sense. To give an example: Thalidomide causes malformations, including a rare sentinel anomaly, phocorelia, in 5O-COZ of infants who have had a maternal exposure during the vulnerable pried of embryogenesis. With those factors in favor of PAGENO="0492" 14914 COMPETITIVE PROBLEMS IN ~E DRUG INDUSTRY 2 prompt detection of the teratogen. thalidomide was on the market for over two years before the first suspicions about its safety were voiced. How much more difficult is it to Implicate a `low risk agent that causes maldevelopment in only 1% of exposures? Yet. if the exposures are frequent, say, in 10% of pregnancies then 3000 malformed Infants would be delivered in the United States each year as a result of taking such a `low risk agent.' - The pitfalls in conducting epidemiologic studies that will yield a confident answer as to whether or not an agent Is teratocenic are many. in brief, precise verification Is essential in both retrospective and prospective studies, But, even with careful verification, the possibili- ties for systematic bias and the limitation in the type of data obtained (no population frequency rates) make retrospective studies less conclusive than prospective ones. The published studies of the potential terato- genicity of amphetamines are retrospective. Prospective studies, in which one could be mere confident, have not been done. The reason is simply this: prospective studies require many more patients and no one to date has accumulated a large enough series to address this question prospectively. We have considered that amphetamine provides a good model to illustrate the obstacles in the way of reaching confident conclusions about the presence or absence of teratogenic effect of a given agent.1 Cur own experience with this drug may be summarized briefly. in 1962, the mother of an Infant born with transposition of the great vessels (a complex and frequently fatal congenital malformation of the heart) expressed more than the usual concern about the cause of the heart defect In her infant son. PAGENO="0493" COMP~~ITWE PRORLEMS IN THE DRUG INDUSTRY 14915 3 She volunteered that she had taken amphetamine diet pills during her pregnancy and asked directly if the amphetamine could have caused the problem. We were unable to find any evidence in the literature of such an association and so reassured the mother. But within two weeks we encountered two more such cases of transposotion and first trimester exposure to amphetamines. These three cases represented a very provoca- tive epidemiologic cluster. At this point we began three studies: I. a retrospective study to coirpare histories of maternal exposures to amphetamines in congenital heart patients and in normal children; 2. an animal homology study to see if we could produce transposition of the great vessels giving amphetamines to mice and chicks; and 3. a prospective study, starting with mothers prior to delivery who had documented amphetamine exposure In the first trimester and were awaiting the outcome of their pregnancies. We reported the results of the animal studies in mouse first,2 and in mouse, chick and drosophila later.3 k,phetamine produced malformations in all three models. But this doesn't mean It produces malformations in humans. The fact that three phyla were affected, and that two strains of one species were also affected was suggestive of the teratogenic potential of the drug. An unexpected finding that greatly Influenced our thinking about the etiology of congenital heart diseases in general was that in one species of mouse we caused ventricular septal defect and in another species we caused atrial septal defect.4 We were unable to produce trans- position. It appeared that amphetamines brought out the malformation to which the strain was predisposed. And it was this observation that led us PAGENO="0494" 14916 coMPETrrnT PROBLEMS ~N THE DRUG UcDUSTItY 4 to the belief that there must be a predisposition to a given malformation together with a predisposition to react adversely to an agent given at the vulnerable period of development as the three essentials of teratogenesis. The first retrosnective study of congenital heart patients was inconclusive.5 We did not find a statistical difference at the .05 level. After publishing these findings we redesigned our protocol, admitted younger patients into the study (to reduce maternal memory bias) and tightened our verificat~cn procedures. After two more years we analyzed our new data, found a statistically significant difference between the congenital heart and control groups, and were forced to retract our previous report that there was no significant amphetamine influence In congenital heart disease.6 Thus two studios by the same investigators led to opposite conclusions. We believe the second study to be the more reliable one. It has already been pointed out that retrospective studies are less conclusive than prospective ones, so we put our eggs in the basket of a large obstetrical practice that used amphetamines liberally. I carefully avoided telling the obstetricians which of the many drugs on our questionnaire we were most Interested In, but a medical student working with me spilled the beans and the obstetricians immediately stopped using amphetamines--and lost interest in our project. That was at a time when malpractice insurance was $60 per year. You can imagine what a threat such studies are now. We did publish a small prospective study of 240 patients, eight of whom delivered Infants with malformations, three of which were associated with maternal exposure to amphetamines.7 The loss of a prospective study of sufficient size was probably of positive benefit to the patients, but It has obviated~ our reaching the confident conclusions we desired. PAGENO="0495" OOMPE'rrnvE PROBLEMS IN THE DRUG INDUSTRY 14917 S Since I have brought up the subject of malpractice suits, I would like to call attention to a trend which I consider to be indefensible. From the number of coimnunications I receive from legal firms all over the country regarding the role of maternal drug exposure in birth defects, it appears that some of our legal colleagues believe that the way to demonstrate that a drug isa teratogen is through passionate litigation rather than through dispassionate investigation. The Idea has been fostered that one need only to demonstrate the possibility that a given agent could have caused a malformation in an individual. But as I have said (and I believe that most teratologists would agree) under the the right conditions almost any drug can be teratogenic. However, the cuestion we are addressing here is whether or not amphe- tamines cause birth defects to the extent that they reoresent a significant health hazard. From our retrospective data and the peripheral evidence from experimental studies of mechanisms of action in animal models, I would give a qualified yes to the guestion. There have been a number of retrosoective studies published by other investigators of teratogenic affects attributed to amphetamines and related sympathomimetic drugs, such as phenmetrazine. Levin8 found a significant Increase in biliary atresla following maternal exposure to amphetamines, and we have some confirmation of this in our study. Matera and co-workers9 reported an infant with exencephaly, which Is one of the prominent mohforma- tions we found in our mouse studies. Nelson and Forfar10 in a retrospective study of 1369 patients found an excess of infants with maternal exposure to appetite suppressants among those with abnormalities. Lenz11 found a case of diaphragmatic hernia and Powell and Johnston22 two cases, following maternal phenmetrazine administration. Moss13 found limb anomalies In the PAGENO="0496" 14918 COMPETrFWE PROBLEMS IN mr~ DRUG INDUSTRY 6 the infant of a mother who had taken phenmetrazine. It shoüFd be noted that all of these studies are retrospective and some are merely case reports, but they contribute to a sizable volume of evidence which supports the possibility that these drugs are teratogenic. despite the fact that the definitive prospective study has not been performed. If appetite suppressants (which is just a polite tern for Puppersu) had a useful function in the medical arnamentarium, one could not accept the present retrospective data as sufficient evidence to abrogate the use of these drugs. We are currently trying to resolve the problem of con- flicting retrospective data regarding birth defects and the Pill" and various progestogens and estrogens through a prospective study. The point is:the world needs the "Pill" or some agent that can perform its function equally well. I am unable to identify a similar need for amphetamines and related drugs. PAGENO="0497" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14919 References 1. Nora, 3.3. and Fraser, F.C.: Medical Genetics: Principles and Practice, Lea & Febiger, PhIladelphia. 1974. 2. Nora, 3.3., Trasler, D.G. and Fraser, F.C.: Malformations in mice Induced by dexamphetamine sulphate. Lancet 2: 1021-1022. 1965. 3. Nora, .3.3. and Vargo, T,A.: Congenital malformations in four animal species following maternal exposure to dextroamphetamine. Presented before the Southern Society for Pediatric Research, 10th Annual meeting, Richmond, Virginia, November 22, 1969, by Dr. Vargo. (Abs.) Southern Med. 3. 4. Nora, 3.3., Sormierville, k.], and Fraser, F,C. : Homologies for congenital heart diseases: rourine models, influenced by dextroamphe- tamine, Teratology 1: 413-416, 1968. 5. Nora, 3.3., McNamara, 0.0. and Fraser, F.C.: Dexamphetamine sulfate and human malformations. Lancet 1: 570-571, 1967. 6. Nora, 3.3., Vargo, l.A., Nora, A.H. et alt Dexamphetamine, a possible environmental trigger In cardiovascular malformations. Lancet 1: 1290-1291, 1970. 7. Nora, 3.3., Nora, A.H., Somerville, R,J, et all Maternal exoosure to potential teratogens. 3.A.M.A. 202: 1065-1069, 1967. 8. Levln, J.N.: Amphetamine ingestion with biliary atresia, 3 Pediatr. 130-131, 1971. 9. Matera, R.F., Zabola, H., and Jinienez, A.P.: flifid exencephalia. Teratogen action of amphetamine. mt. Surg. 50: 79-85, 1968. PAGENO="0498" 14920 coMPETITIVE PROBLEMS IN TIlE DRUG rNDUS'PRY 10. Nelson, N.M. and Forfar, .3.0.: Associations between drugs admini- stered during pregnancy and congenital abnormalities of the fetus. Brit. Med. J. L: 523-527, 1971. 11. Lenn cited in Nishimura, H.: Clinical Aspects of the Teratogenicity of Drugs. 1976. 12. Powell and Johnstone: cited In Nishimura, H.: Clinical Aspects of the Teratogenicity of Drugs. 1976. 13. Moss, P.D.: Phenmetrazine and foetal abnormalities. Brit. Med. .3. 5319: 1610. 1972. PAGENO="0499" CO~\WETITWE PROBLEMS ~ THE DRUG rNrnJSTRY 14921 STATEMENT BY THADDEUS E. flOUT, M.D. ASSOCIATE PROFESSOR OF MEDICINE THE JOHNS HOPKINS UNIVERSITY AND CHIEF OF MEDICINE GREATER BALTIMORE MEDICAL CENTER BEFORE THE SUB-CO~4TflEE ON MONOPOLY SENATE SMALL BUSINESS CO?NITTEE NOVEMBER 9, 1976 PAGENO="0500" 14922 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. Chairman, Members of the Committee: I have been asked to come before you today to discuss the use of amphetamines and related compounds in the treatment of obesity. I have had the privilege of appearing before this Committee on previous occasions and realize only too well the seriousness of this Committee's work. In my remarks today, I would like to discuss first the trivial effect of these drugs on the lifetime condition of obesity and to draw conclusions based on the present knowledge of the use of these agents and the attitude of the pharmaceutical companies in their promotion. You will recall that as chairman of a board of evaluation of prescription drugs proposed for the purpo~e.of weight reduction, the following conclusions and recommendations were sent to the Commissioner of the Food and Drug Administration after careful study of available information: CONCLUSIONS 1. Adult obese subjects instructed in dietary management and treated with "anorectic" drugs on the average tend to lose more weight than those treated with placebo and diet in relatively short-term trials. 2. The amount of weight loss associated with the use of an "anorectic" drug varies from trial to trial. The possible origins of the increased weight loss due to the various drug effects are not established. The increased weight loss appears to be related to variables other than the drug prescribed, such PAGENO="0501" COMPETITIVE PROBLEMS EDi THE DRUG INDUSTRY 14923 as the physician investigator, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss. 3. The magnitude of increased weight loss of drug treated patients over placebo treated patients was only a fraction of a pound a week. The rate of weight loss was greatest in the first weeks of therapy for both drug pnd placebo subjects and tended to decrease in succeeding weeks. 4. The natural history of obesity is measured in years, whereas the studies cited are restricted to a few weeks' duration; thus, the total impact of drug-induced weight loss over than of diet alone must be considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors inherent in their use. 5. The amphetamines including methamphetamine have been widely abused in numerous populations. It is thus in the best interests of the public health to limit the use of amphetamines as far as is compatible with adequate therapy. This is both to minimize the risk of dependence in susceptible patients being treated and to decrease the amount of drugs being distributed, since widespread prescription of a dependence- producing drug inevitably increases the possibility for diversion to non-medical use and abuse. PAGENO="0502" 14924 COMPETITWE PROBLEMS IN THE DRUG LNDUSTRY 6. Evidence presented for newer "anorectic' congeners of the amphetamine family and non-amphetamine drugs do not set then apart as having higher benefit or lower risks than older available drugs. The risk potential of Fenfluramine may be an exception to this general statement. 7. There was no evidence in the data reviewed which showed that combination of an `anorectic" agent with other drugs increase the benefits or reduce the risk of the "anorectic" agent. S. There are no clinical data which support the parenteral use of these drugs in the treatment of obesity. Obesity is not an indication for the parenteral use of these agents. RECOMMENDATIONS On the basis of the data reviewed and from all evidence at hand, the following actions are therefore recommended: 1. That all "anorectics" reviewed (dl-amphetamine, d-amphetamine, methamphetamine, benzphetamine, phentermine, chlorphentermine, clortermine, phenmetrazine, phendimetrazine. fenfluramine, mazindol, and diethylpropion) with the exception of fenfluramine, be placed on Schedule 2 on the basis of abuse potential. 2. That combinations of "anorectics" with other drugs be evaluated in accordance with the policy of the FDA on combination drugs, that each constituent of the drug combination contribute to the total effect claimed for the combined drugs, and that the present available and proposed drug combinations be handled in this manner in view of the lack of demonstrated efficacy for each of the constituents of the drug combinations reviewed. PAGENO="0503" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14925 3. That amphetamines prepared for or in a form suitable for parenteral use not be approved for use in the treatment of obesity. 4. That single-entity oral "anorectic" preparations including the amphetamines be permitted to be labeled for restricted use in obesity provided that they are used in association with a specific weight reduction program and that the clinically trivial contribution of these drugs to the overall weight reduction is properly emphasized. To carry out the latter recommendation, a statement such as that made in the conclusions drawn from this review must be included in all labeling and promotional products. This statement should include the following points: Studies of the effect of "anorectic" drugs in the treatment of obesity when compared with the effects on patients treated in a similar manner without the use of the drugs demonstrate that the magnitude of weight loss of drug treated patients over non-drug treated patients was only a fraction of a pound a week. The rate of weight loss was greatest in the first weeks of study for both the drug and the non-drug treated subjects and tended to decrease in succeeding weeks. The natural history of obesity is measured in years whereas the studies offered for review are restricted to a few weeks duration. Thus, the total impact of "drug induced" weight loss over that of diet alone must be considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors such as nervousness. insomnia and drug habituation that might be inherent in their use. Moreover, these agents can only be recommended for use PAGENO="0504" 14926 COMPETITrVE PROBLEMS IN THE DRUG INDUSTRY in the treatment of obesity in a carefully monitored and specified weight reduction program under the care of a physician. 5. That future approval of all "anorectic" drugs prepared for future use be based on demonstration of efficacy as measured by statistical superiority of the drug over placebo in trial using FDA recommended protocols. These protocols should include provisions, among others, for the testing of a specific target population, specification of a minimum duration trial to assure clinical relevance of the study and give consideration to the handling of patient drop-out. 6. Further, that appropriate summary data derived from efficacy studies be presented in labeling and in all promotional material to indicate the degree of weight loss that was found. For this purpose the guidelines noted in (4) above should be supplemented by the addition of the specific facts found for the specific drug under consideration. Only part of these recommendations have been put into effect. The amphetamines and some, but not all, of the related drugs reviewed were placed in Schedule 2. For those in Schedule 2, quotas for production were established as required by law. The remaining drugs were placed on Schedule 3 or 4 without production quotas. As predicted, there was a shift from the schedule 2 to the drugs in Schedule 3 and 4 which require very little change in the prescribing habits of the physician. Extraordinary production and sales have been realized by certain companies to meet this increased usage. Pennwalt, producers of lonamin. a resinated preparation of phentermine. has been cited as one of those companies with unusual sales. We must express serious concern that the PAGENO="0505" COMPETITIVE PROBLEMS IN `FIlE DRUG INDUSTRY 14927 pharmaceutical companies continue to produce amounts of these chemicals that appear to be far in excess of any potential medical need. If this be the case, it clearly demonstrates the wisdom of the prior recommendation, it exceeds the tolerance of society to allow them to continue, it certainly belies the statement made in an open meeting of the then Medical Director of the Pharmaceutical Division of Penuwalt Company who said, "1 assure you that the drug manufacturer wants his drug to be used as well and as *accurately as it can possibly be', and it begs for curtailment of the rapacious attitude of some pharmaceutical companies toward society. In 1972 the Canadian government, led by the medical profession of Canada, withdrew the acceptance of amphetamine and related compounds for the treatment of obesity. I know of no information which suggests that this has caused any hardship or that Canadians today are fatter than they were four years ago. A similar move in the country would save our citizens something over $85 million per year in prescription sales alone for these agents. Experience in Sweden and Japan, to cite two of the countries on which we have some information as well as in the United States, suggests that the use of amphetamines in the street represents on the one hand the interface between legitimate and illegitimate drug usage and, on the other hand, the start of the trail that leads deeper and deeper into the wilderness of the drug cult. For these reasons we must recognize that production of these agents which is clearly in excess of present 8~-5i39 0-41-33 PAGENO="0506" 14928 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY medical usage is unquestionably finding its way into non-medical and, hence, non-legitimate usage. It also reminds us that we are a principal proveyer and consumer of drugs in the world today, and if Sweden's attempt to limit drug traffic through legislation has been somewhat less successful than they and the world had wished for, it may well be that we and other nations as members of the world society must all tackle this problem simultaneously. Today, however, we must get our own house in order, and it is therefore my recommendation that the recommendations of the Committee that I have just laid before you be activated and extended as follows; 1. It has been demonstrated that the amphetamines and related compounds have trivial indications for therapeutic use in obesity, yet this remains the major medical excuse for the large quotas of these pharmaceuticals now being manufactured. From the point of view of society, the risk of overproduction far exceeds the benefit that might be cited through anecdote of a few patients who, in association with rigid dieting, have believed that the so-called anorectics were the causative agent in their particular weight reduction. I would, therefore, recommend that obesity be withdrawn as an indication for the therapeutic use of these drugs. 2. The increasing traffic in the amphetamine related medications indicates that the previous recommendations to place in Schedule 2 all d~~g~j4th abuse potential should be followed. This measure has been effective in limiting the use of those placed in Schedule 2 three years ago. PAGENO="0507" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 14929 3. It is also recomended that ~ of productioh be sharply curtailed to at least less than 10 percent of present production for those pharmaceuticals that are recommended for use in some condition other than obesity. Drugs marketed only for use in obesity that have abuse potential may well be forced to withdraw from the market. 4. Eliminate the manufacture of combinations of pharmaceuticals involving this class of drug and of all intravenous preparations. 5. Enforce the efficacy and safety regulations for drugs and ~g~4re that all agents proposed for the treatment of obesity in the future pass the test of efficacy and safety before acceptance by the FDA based on an FDA regulated protocol designed to eliminate trivial products. 6. Eliminate the over-the-counter pharmaceuticals since they have been found to be entirely worthless in the treatment of obesity. It is much too costly for the government to tackle these one by one under trade name when the company need only change its name and the name of the product and be out from under the law again. All such preparations should be eliminated as worthless unless they can pass the standards set by FDA for new products. Although this would, in effect, impliment the concerns of the Committee in relation to its single-minded pursuit of the relation of these compounds to the treatment of obesity. it would not take care of other very real problems. The bigger question that needs to be reviewed is the rapacious attitude of PAGENO="0508" 14930 COMPETITrVE PROBLEMS IN THE DRUG INDUSTRY some of the pharmaceutical companies. To do this, legislation should establish other requirements: 1. Review the practice of bulk shipment of drugs to individuals and to clinics for direct dispensing and, if necessary, eliminate it. Shipments in bulk to facilities of 100.000 dose units can no longer be justified, even if obesity continues to be an indication for these medicines and will certainly not be justifiable if obesity is withdrawn as an indication. The pharmaceutical houses are aware of this, but they are unfortunately in business to sell drugs and not to serve society. 2. Require the pharmaceutical houses to show the cash flow to physicians and medical institutions for support of "research" * "consultation", "teaching". "goodwill" or any other word that might be used for the favor that they curry with their largess. We will speak to the problem of physician education in a later section. 3. Expose the ownership of the "throwaway journals" that bombard physicians daily and limit the use of funds for this and other types of promotion by pharmaceutical houses so that the savings on drug cost can be passed back to the consumer. These institutions should be singled out and made to pay the true cost of distribution of this literature and not be virtually subsidized by the taxpayer by having this material transported at less than cost by the overtaxed facilities of the U.S. mail. In addition, we need to strengthen the process by which drugs are reviewed for use by the general public and are accepted for purchase by the medical installations of the U.S. government. PAGENO="0509" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14931 Whether this is done by the FDA under the present structure or by some other system will require study. A suggestion that was made in 1972 before this Committee bears repetition. Congress should establish a committee of "blue-ribbon untouchables" similar to the Council on Pharmacy and Chemistry previously active in the American Medical Association. This possibility deserves further thought and discussion, especially since it drew the fire of no less a spokesman than the later Morris Fishbein. Such a connuittee, in association with the FDA, could: 1. Become the responsible authorizing agent for drug procurement by all agents of thet.S. government. Billions of dollars are spent on worthless products by medical facilities of the U.S. government at this very time. This must be eliminated if the taxpayer is to look to the federal government for help in medical expense. 2. Begin a more thorough study of the ways in which new drugs can reach the market. This could perhaps implement and speed up the process of review as well as work out the very difficult problem of requiring so-called Phase 4 studies. These studies would require that surveillance of drug products be continued after they are placed on the open market in order to retrieve long-term answers to the question of efficacy and safety. 3. Make available to the consumer relevant information about drugs and drug usage and work out details for the production of a consumer package insert. The task of this committee would be to design a drug description understandable by patients and available to them if not contraindicated by PAGENO="0510" 14932 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY their condition. In December 1972 1 asked that this connittee become seriously committed to the problem of consumer education. The people expect and need it, and it is not difficult to provide. It should not wait for other more far reaching legislation in the health insurance field. Finally, Mr. Chairman, but not least, we must think of the educational process of the physician himself. It is a disgrace to our country that most of the postgraduate education of physicians takes place in their offices by the representatives of the pharmaceutical companies. Continuing medical education must not be neglected in the future, and any plan to deliver health care to the American public nust recognize and formulate a plan for dealing with this problem. The pharmaceutical houses have stepped into a void that is not being completely met by the society primarily because they do not always perceive the dangers of accepting the benefits of pharmaceutical gifts. A large proportion of the physician courses are subsidized by industry and are designed to downgrade scientific work that is not promotional and upgrade that which is. Attitudes toward the oral hypoglycemic agents in contrast to those on the hypotensive agents are excellent examples of this process. In the former, only physicians known to be complimentary to the pharmaceutical industries are accepted on programs of continuing medical education to discuss the oral hypoglycemic agents. Every effort is made to downgrade and to cast suspicion on scientific work that threatens an industry worth at least $100 million a year in gross sales and twice that amount in retail sales. In contrast to this, the hypotensive agents found on the basis of one study to be highly efficacious even at PAGENO="0511" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14933 levels of pressure not ordinarily treated by the practicing physician is being given wide exposure and support by the companies who make these products. If we do not rescue postgraduate and continuing medical education of our physicians from the pharmaceutical houses, our citizens will be even more medicated and undertreated than is true today. The method by which this should be done needs further study. The creation of traineeships in clinical pharmacology in programs involving medical schools and community hospitals has many virtues. In brief summary then, Mr. Chairman, I would recommend: 1. That the former recomendations of the committee be implemented. 2. That obesity be eliminated as a medical indication for the use of the agents under description in which the so-called anorectic property goes hand in hand with abuse potential. 3. Eliminate over-the-counter nostrums advertised for the purpose of reducing obesity. 4. curtail the activities of the pharmaceutical industries and in particular make certain that they pay their way from their swollen profits for all of their promotional efforts. 5. Establish an authority or strengthen the existing authority to study a) the problem of drug selection for the medical agents of the U.S. government, b) plan Phase 4 studies ofof new drugs, and c) address the probme of consumer education. 6. Review the question of continuing medical education of the medical profession and replace the pharmaceutical manufacturers as the principal proveyer of postgraduate training through the evolution of a federal plan for this purpose. PAGENO="0512" 14934 coMrEtn'rvE PROBLEMS IN THE DRUG INDUSTRY Statement by- Frank N. Reynolds, National Teen Challenge nepresentative, before Monopoly Subconunittee of Senate Small Business Committee, November 18, 1976. teen Challenge is a ministry to street people. It began in 1958 as a ministry to street gangs by David Wilkerson. As the work progressed we began to encounter drug addicts. Many heard the message of hope in Jesus Christ and began to respond in a positive manner. From this beginning has grown a ministry that now is in 24 states, the District of Columbia, and Puerto Rico, with ministries in 62 cities. Through coffee houses, and street workers, Teen Challenge made contact with over 380,000 people in 1975. In our various residential facilites we have 1000 people any day. I say this to let you know that we have a broad contact with a lot of young people at the street level where the action is. - Our experience has been primarily at the street level, although the past few years we have received more and nore people referred by other agencies, both public and private. Our primary thrust has been to what we have called "troubled youth'.. This has resulted in our also working in a preventive type ministry with drug education programs in schools and coimnun- ity youth groups. Through these presentations we had many opportunities to deal with young people in a confidential manner about their own drug involvement, We were able to get a good reading of what was hap- pening in the drug scone. -1- PAGENO="0513" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14935 In the early 1960's we primarily reached the inner city heroIn addicts. With the drug explosion' of the mid and late sixties we bagan to reach people with various dependencies on many different drugs: tranquilizers, barbiturates, amphetamines, hallucinogens, as well as alcohol and the opiates. Today, most of the drug dependent persons we work with are so-called poly-drug users. sy that we mean they use many differ- ent types of drugs and mix them with alcohol. I know this hearing is primarily concerned with the use and abuse of amphetamines. Dut,I think, we are going to be remiss if we do not realize that this is part of an overall problem and, per- haps, a philosophy of the medical and phannaceutical business. That philosophy is; that there is a solution to every pro- blem in a pill and its wrong to suffer any discomfort, physical or emotional. Perhaps, it is a problem of our "cradle to the grave security society". This is promoted in the advertising, on television and other media. Since I am concerned primarily with our youth 14-25, what are we teaching them? I have an important meeting, I must be up for it, so I oat or drink something to pick me up so I can put my best foot forward. Then we get pushed out of shape when our teen- agers do the same thing for their earth shattering date, party, or whatever. "That is different, this is a $500,000. deal," we argue. "But," the young person says, "This is the chance of a lifetime to really impress someone that will change my whole future," What have we done? Instead of preparing ourselves spiritually, physically, and emotionally we try to substitute an artificial booster -2- PAGENO="0514" 14936 COMPETPTI1T PROBLEMS IN THE DREG LNDL'STRY or tranquilizer. We do not deal with the real problem. Let me illustrate. Four weeks ago a young man was released from a certain penal institution. While he was there he got under a lot of tension. So the doctor gave him some Valium. As the tension built so did his intake of Valium, legally. He was released, having completed his sentence, with a legal prescription and is using 40-50 ng, of Valium per day. He is "free' from jail, but he cannot function in the `straight' 8-5 society. The 40-50 mg. of Valium does not handle the additional tension so he has added a little alcohol to help out. Now he is in danger of violating the conditions of his release. What is the problem? Is it tension? Or do we need to dig a little deeper? Then give the individual the coping mechanism to deal with the problem. I have had only 20 minutes with this indi- vidual and discovered his tension started when his wife divoriced him while in prison. Maybe there was no way to save the marriage, but there is a better way of handling the succeeding emotional problems than a chomical cop out. I em not sure this legislative body can solve the problem, but I believe unless we are willing to see why we get pushed into using chemical substitutes we will continue to seek chemical solu- tions to emotional and spiritual problems Dr. Blum stated in an article in Look magazine, several years ago, in a discussion of various solutions to the drug abuse problem, "If we are looking for a drug to solve the drug problem we will fail. We will never solve the drug problem until we make up our minds what our minds are for." Now to speak specifically to our experience with the amphet- -3- PAGENO="0515" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14937 amine group. We first began to see people coming in with this problem in 1967 and 19GB. Not large quanities, but when a person had been involved with heroin and other depressant drugs he would buy "Bennies" to give him a lift to get out and do his `thing" to get the money for the heroin. When the fad of taking drugs hit our high school and college groups, they would have what some called "cocktail parties". Each would bring the medications from their private drug store, i.e. the home medicine cabinet. All the pills would be put in the bowl. Different parties were run different ways. Some would portion a guanity to each one with no regard to what they took. Others would divide then by color or shape and compare notes. What was the main problem? Availability-they discovered that with Mom's diet pills they could dance and go and go without stopping. Hey man, that's terrific. Someone thought we could solve the fat problem without discipline and without pain by taking dexedrine. The college crew is no different than when I was in school. We did not get our work done until it was due. We did not study until the night before exam. Hut in the early forties we had to depend upon the coffee pot and cold water in the face to stay awake, Now, thanks to "better living through chemistry" we can swal- low a couple of pills, obtainable legally for the diet, the tired feeling, the depressed state or whatever other excuse (fancy word for lie) I can convince the doctor of, Then suddenly you have people living on this stuff. Then comes -4- PAGENO="0516" 14938 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY controls in the early seventies. By this tine we have coming into the program the Speed Freaks and the spacies. They have in their own words "fried their brains". Where did they get the stuff? One student in the program from an Ohio college, who came into the program in 1970, floated a loan, flew to Mexico and brought back amphetamines of various kinds, manufactured in the U.S.A.1 and netted $7000. for the weekend risk and trouble. The problem arose for hin when he became his own best customer. Messed up his mind; could not study, dropped out of school with 1½ semesters to go for graduation. I am amazed that some, as late as last year, discovered an over production with shipiiemt out of the country to be brought back in illegally. This was coomlon knowledge to us working the streets. We assumed if we knew it, certainly, the professional agencies knew it. Some have told of stealing them off the loading docks by the barrel full. I do not need to restate the statistics, you have them, undoubt- edly, on file. The last three years I have been in an administrative posi- tion and only working as a volunteer with troubled people. It is disturbing and frustrating to me to start dealing with people and discover the amount of mood altering medications prescribed to cover up the problem. Yet, no one stops to try to Lolve the pro- blem or provide a way of handling and dealing with the difficulties. At Teen Challenge our approach to the drug abuser has been -5- PAGENO="0517" COMPETITIVE PROBLEMS fl~ THE DRUG INDuSTRY 14939 that your drug taking is not the problem. It is a syTaptc!n. We were saying this when others said we were foolish to talk like that. The problem is inside of you. Invariably when we begin to relate to the needy they would speak of the emptiness inside. Nobody wants the blahs. And when someone offers a chemical, easy solution, you have a good candidate. Our approach is first acceptance of then as a person, regard- less of their physical appearance. The speed freak usually canes in skinny and starry eyed, extremely nervous and suspicious. Not trusting anyone. They have been ripped off emotionally. Then we share the love of Cod we have found and the inner peace we have. The next logical step is, "You can have it too. Cod so loved you that he gave His best for you." Now, here is where we had to regroup our forces. The heroin addict was quite predictable. After he would withdraw, his head was normal. - Not so with the amphetamine user. His attention span is short. He is depressed very easily and is just liable to space out on you. Another complication we ran into was that the amphetamine user quite often has used L.S.D., mescaline, and other hallucin- ogens. I am not a technical man. So how nuch of our problems can be attributed to which chemical, is difficult to assess. As I said before, at the street level you do not get saneone that does -6- PAGENO="0518" 14940 COMPEIITIVE PROBLEMS IN THE DRUG INDUSTRY just one drug. After speeding he knows he is going to crashes he knows he is not going to be able so he will seek downers-barbiturates. Most can walk into a doctor and give a good con story and get sane sleeping pills. If all else fails, h~ can put on a scene and get rushed to the emergency ward and compassionate people will give him what he wants. Remember these people know what symptarts to describe in order to get the doctor to give the "right" prescription, and they do. It takes long patience. About the time you think you are making progress, he flips out. Where with the heroin addict we could put pressure on him and get pretty hard nosed, we find we would have to back off fran the amphetamine user. Cut down the pressure imtil he could settle down. I believe it takes the power of Cod to help and heal sane of the scrambled heads we have worked with. We have not won on all of them, but we have as good a record as any. Gentlenen, let me recap. What is 1. the problem? We are too prone to look for easy, painless solutions to lifeb problems. 2. Chemicals that can alter the mood are available legally and illegally from "legitimate" manufactures. 3. The knowledge that it is available is well adver- tised. 4. The whole health-care field has got to shoulder their responsibility in causing the spread of the drug abuse problem. crash. When he to steep, -7- PAGENO="0519" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14941 5. we can no longer bypass the fact that men have spiritual needs, as well, as physical and social needs. Some hopeful signs. 1. Many of us are redoubling our efforts. 2. Medical schools are now requiring medical doctors to take courses in interpersonal relations. 3. Many professionals are acknowledging that there are spiritual needs that can be net. More cooperation between these two areas. 4. This hearing is being held and we have been able to share from the street level, where the action is. For an idea of the effectiveness of the Teen challenge pro- grain you may refer to a study done under grant # 1 1181 PA 01505-01 - B- PAGENO="0520" 14942 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY STATEMENT OF Frederick A. Rody, Jr. Acting Deputy Administrator Drug Enforcement Administration U.S. Department of Justice before the Subconinittee on Monopoly (Gaylord Nelson, Chairman) Senate Committee on Small Susiness November 19, 1976 PAGENO="0521" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14943 Hr. Chairman and distinguished Members of the Subcommittee: My name is Frederick A. Rody, Jr. and I am the Acting Deputy Administrator of the Drug Enforcement Administration within the Department of Justice. Today, I am appearing before you on behalf of Mr. Peter B. Bensinger, our Administrator, who is presently out of the country on official travel. Appearing with me are Mr. Robert 3. Rosthal, Deputy Chief Counsel; Mr. Kenneth A. Durrin, Acting Director of our Office of Compliance and Regulatory Affairs; and Mr. Ernest A. Carabillo, Jr. * Chief of our Regulatory Support Division. The Controlled Substances Act creates a partnership between the Attorney General and the Secretary of Health, Education, and Welfare. The Attorney General is empowered to place a drug under control of the Act, to remove a drug from control or to move a drug from one schedule to another schedule. 85-569 O-77---34 PAGENO="0522" 14944 coMPE'rrnvE PROBLEMS IN THE DRUG INDUSTRY To exercise this power, however, the Attorney General must have the concurrence of the Secretary that the contemplated action is medically and scientifically correct. The law states that the recojmnendations of the Secretary on medical and scientific matters are "binding" on the Attorney General and if the Secretary recommends that a drug not be controlled the Attorney General cannot control it. As the subcommittee has requested, I will briefly outline how that partnership has worked in the area of stimulant drugs. The Controlled Substances Act, as it related to the stimulants, represented a Congressional compromise under which Congress originally placed liquid injectable methamphetamine ("speed") in Schedule II and the amphetamines and methamphetamine in Schedule III. However, it was clearly understood by the managers of the legislation for the House and the Senate that "proceedings will be initiated (by the Attorney General) involving a number of drugs contain- ing amphetamines after the legislation has become law." -2- PAGENO="0523" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14945 DEA's predecessor agency began a study of the abuse potential and actual abuse of the amphetamines and methamphetamine then in Schedule III and in February of 1971 forwarded the results of its study to HEW. In April, HEW agreed that the amphetamines and methamphetamine belonged in Schedule II and on May 25, 1971 we proposed in the Federal Register that the rescheduling take place. Thirty days were given for objections by interested parties. Three major manufacturers filed objections: 1. Smith, Kline & French Laboratories requested a hearing on the transfer of its product, Eskatrol. 2. Mission Pharmacal Company requested a hearing on the transfer of its product, Fetamin. 3. Pennwalt Corporation requested a hearing on the transfer of its product, Biphetamine. On July 7, 1971, all amphetamines and methamphetamine, with the exception of the three drugs for which hearings had been requested, were ordered transferred from Schedule III to Schedule II. As to these three, application of the order was reserved pending a review of each drug and subsequent admin- istrative hearings. Our review began with service of -3- PAGENO="0524" 14946 co~rEPITrvE PROBLEMS TN THE DRUG INDUSTRY a subpoena on Smith, Kline & French which in effect called for every piece of rehrant information the company possessed on Eskatrol. Subsequent to that service, SKF, Mission, and Pennwalt withdrew their objections and requests for hearings and by Federal Register notice of August 19, 1971, their drugs joined the other amphetamines in Schedule II. Mr. Chairman, let me digress for a moment to note a fact important to the purposes of this sub- committee. In our efforts at that time to place the most rigorous controls on the amphetamines we received the support of the American Medical Association. Through its House of Delegates, the AMA expressed approval of the rescheduling and urged "all physicians to limit their use of amphetamines and other stimulant drugs to specific, well-recognized medical indications." It was early recognized that if our efforts to place the amphetamines in Schedule II succeeded, a new danger to the public might arise. Two drugs - phenmetrazine (Freludin) and methyiphenidate (Ritalin) - had been placed in Schedule III by the Congress. -4- PAGENO="0525" COMPETITIVE PROBLEMS E~ TEE DRUG INDUSTRY 14947 These drugs, while not true amphetamines, have been described as "amphetamine-like". It was considered highly possible that should amphetamines be moved to Schedule II with its stringent controls, there could be a movement by drug abusers from the amphetanines to Ritalin and Preludin. Accordingly in April, 1971 we sought the position of HEW on whether we could properly place these drugs in Schedule II. On July 29, 1971, HEW approved that re- scheduling and negotiations began with representatives of the Ciba-Geigy Corporation, then manufacturer of both products, and Boehringer-Ingelheim Limited, owner of the United States patent on Preludin. It was the purpose of these negotiations to reach an agreement on placement of Ritalin and Preludin in Schedule II without the need for lengthy hearings. The companies ultimately agreed and, on October 28, 1971, Ritalin and Preludin were placed in Schedule II. Tuning now to the non-amphetamine anorectics - on February 15, 1973, HEW recommended that seven of these drugs be placed in Schedule III of the Controlled Substances Act and one, fenfluramine, be -5- PAGENO="0526" 14948 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY placed in Schedule IV. In Federal Register notices on May 9 and May 10, 1973, we proposed the precise scheduling recommended by HEW. No objections were received from such major manufacturers of the anorectics proposed for Schedule III as the Upjohn Company (Didrex), Warner! Chilcott (Pre-Sate), USV Pharmaceutical (Voranil) Sandoz Pharmaceuticals (Sanorex) , or Ayerst Laboratories (Plegine). No objection to the proposed scheduling of fenfluramine (Pondimin) in Schedule IV was received. from the A. H. Robins Company; Two major manufacturers filed objections: 1. Merrell-National Laboratories requested a hearing on the scheduling of its product, Tenuate, in Schedule III. 2. Pennwalt Corporation, on the scheduling of its product, Ionamin,in Schedule III. The Merrell and Pennwalt hearing requests presented a grave policy issue involving fundamental fairness. All but these two companies had agreed to the HEW-flEA scheduling proposals. If the products -6- PAGENO="0527" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14949 of the cooperating companies were scheduled by DEA while the Merrell and Pennwalt products remained uncontrolled during lengthy hearings, the economic inequity to the cooperating manufacturers and the danger that Tenuate and lonamin would become abuse drugs of choice was obvious. Further, three of the anorectics, Voranil, Sanorex, and Pondimin, had never been on the U.S. market and had no domestic history of efficacy or abuse upon which scheduling comparisons with the Merrell or Pennwalt products could be made. ?lerrell and Pennwalt finally agreed to place- ment of Tenuate and lonanin in Schedule IV pending the outcome of their hearings. This enabled us, on June 10, 1973, to place five of the anorectics in Schedule III and fenfluramine in Schedule IV as originally recommended by HEW. On July 6, 1973 Tenuate and lonamin were added to Schedule IV. Clearly the resolution of the immediate problem did not resolve the permanent problem. We needed to know more about all the non-amphetamine anorectics and recognized we could find less than satisfactory answers in isolated, fragmented hearings concerned with Tenuate and lonamin. It was decided, therefore, to monitor the manufacture, distribution, and use in the United States of all anorectics -7- PAGENO="0528" 14950 COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY controlled in June and July, 1973, paying special attention to indications of diversion and to chemical research on the abusability and dependence forming characteristics of these substances. It was further decided that eighteen months under control should provide sufficient information upon which our review could then be based. DEA, after discussions with the National Institute on Drug Abuse and the Food and Drug Administration, began its review as scheduled. In addition to employing our own resources on the monitoring program, DEA contracted in March 1975 with the Stanford Research Institute to assist in the development of a method to schedule drugs objectively. That study concentrated on the anorectics as models. We received the results of the Stanford study in April of this year. We have also received, under contract with the Research Planning Corporation, the results of a study devoted in major part to identifying and quantitating abuse levels of the drugs in question. On May 13, 1975, DEA forwarded a letter to each major manufacturer of a non-amphetamine anorectic -8- PAGENO="0529" COMPETITIVE PROBLEMS ~r THE DRUG £NDUSTRY 14951 drug asking information concerning the abuse potential of its particular product. On December 9, 1975 another letter to these companies requested manu- facturing and distribution data. This massive amount of information has been received and is under review. Thus, the hearings of this subcommittee have come at a fortuitous time. The testimony given by the witnesses who have appeared here and the conclusions the subcommittee draws from that testimony, together with the information we have been reviewing, will be closely considered by DEA in reaching our judgments on the drugs in question. Then, as contemplated by the Controlled Substances Act, those judgments and the supporting data will be forwarded to HEW through the Food and Drug Administration for the definitive medical and scientific evaluation. Mr. Chairman, it should be said at this point that HEW and FDA have always cooperated fully with DEA in those areas in which our responsibilities are joined. We could not ask for better partners. This subcommittee has requested information on the current patterns of abuse and diversion of -9- PAGENO="0530" 14952 COMPETITIVE PROBLEMS IN TIlE DRUG I1~DUSTRY anti-obesity drugs. Three sources have been employed to gather the information I will summarize: 1. The Drug Abuse Waning Network (DAWN), jointly sponsored by DEA and the National Institute on Drug Abuse, receives all drug mentions from selected emergency rooms, crisis centers, and medical examiners throughout the nation and publishes this information on a monthly basis. 2. The System to Retrieve Information from Drug Evidence (STRIDE) constitutes a compilation of reports on all drugs received for examination by all flEA domestic and foreign laboratories. 3. A recent telephone survey of flEA's domestic regions. Hr. Chairman, there has been a 287, increase in DAWN mentions of amphetamines in the last twelve months. The increase of chronic effects as the reason for seeking emergency help strongly suggests that ever greater numbers of abusers have access to a continuing supply of amphetamines. At the same time, our laboratories report the appearance of less illicitly manufactured amphetamines and there are - 10 - PAGENO="0531" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14953 fewer reports of amphetamines being diverted from legal distribution systems. Accordingly, it must be concluded that increasing amounts of abused amphetamines come from home supplies and that these supplies are created largely by prescriptions and direct dispensing by physicians. The suggestion is implicit that significant numbers of physicians are prescribing and dispensing well over their patients' actual medical needs. Phenmetrazine (Preludin) has become a serious problem as a street drug in areas of the United States ranging from Pennsylvania in the east to Nebraska in the west.. Pockets of heavy abuse appear in Texas. The District of Columbia and surrounding states have been particularly hard hit. In the District, for example, we find Preludin trafficked under the street name "8am" at $10.00 for a single 75 mg. dosage unit. Since Preludin is water-soluable it is frequently injected intravenously and used in conjunction with heroin. The United States Attorney for the District of Columbia has focused public attention on the - 11 - PAGENO="0532" 14954 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Preludin problem here by highly successful criminal and civil cases involving physicians and pharmacies. Continuing investigations by DEA indicate the existence of sophisticated criminal enterprises employing prescriptions obtained from doctors and forged prescriptions to build street supplies. Thefts from pharmacies also play a part in supplying the illicit traffic in Preludin. In 1975 Western Fehr Laboratories, manu- facturers of the basic ingredient in Preludin, Ciba- Geigy Corporation, the sole manufacturer of Preludin in dosage form, and Boehringer-Ingelheim Limited, the sole distributors of Preludin to wholesalers, petitioned flEA for an increase in the 1975 manu- facturing and procurement quotas for Preludin previously set by flEA. That petition was rejected by flEA and it was again rejected by an Administrative Law Judge following a lengthy hearing demanded by the companies. This resulted in an appeal by the companies to the United States Court of Appeals forthe First Circuit which, on January 28, 1976, - 12 - PAGENO="0533" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14955 issued the final rejection. In a unanimous opinion the court found in part that, "DEA had the obligation when it found substantial evidence of broad scale diversion to achieve a more Spartan pipeline, even though this might cause inconveniences to manu- facturer and distributor." Mr. Chairman, just three weeks ago, on October 29, 1976, attorneys for Western Fehr Laboratories and Boebringer-Ingeiheim Limited filed with Administrator Bensinger objections to flEA's proposed 1977 production quota for Preludin. Once again an administrative hearing has been demanded by the companies. Methylphenidate (Ritalin) differs from the other substances under consideration here today. It is not indicated as an anti-obesity drug. Ritalin is described as "effective" in the treatment of minimal brain dysfunction in children and in the treatment of narcolepsy (a form of sleeping sickness). It is considered "possibly effective" for mild depression. It is ironic that under the heading "Adverse Reactions" in the Physicians' Desk Reference - 13 - PAGENO="0534" 14956 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY the manufacturer of Ritalin warns against loss of appetite in children leading to "weight loss during prolonged therapy.t' Between July 1, 1973, and July 31, 1976, there were more Ritalin related abuse episodes reported in DAWN than any one of the ten brand name amphetamines or non-amphetamine anti-obesity products surveyed. The profile of Ritalin abuse is unlike the others. The great majority of the amphetamine and non-amphetamine anorectic reports come from crisis centers, the usual haven for street abusers in various phases of illness. Two thirds of the Ritalin episodes were reported from hospital emergency rooms to which the more seriously ill are most often taken. Illicit sources such as street buys, forged prescriptions, stolen dosage units or gifts were listed in over half the episodes. Mr. Chairman, before summarizing the information on the non-amphetamine anorectics let me say that one of them, fenfluramine (Pondimin) , may possibly be improperly described as a stimulant. Since coming on the market in 1973 fenfluramine has been reported as showing the indicia of a depressant causing some of the responses of an hallucinogen such as PCP. - 14 - PAGENO="0535" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14957 The non-amphetamine, anti-obesity products have received far fewer mentions in DAWN than the amphetamines, Ritalin, or Preludin. The anorectics are reported primarily from crisis centers as opposed to emergency rooms or medical examiners. Over 757~ of the incidents involve legal prescriptions as the source. As with the amphetamines, the suggestion is inplicit that significant numbers of physicians are prescribing and dispensing well over their patients' actual medical needs. Mr. Chairman, Benjamin Gordon of the sub- committee staff has asked DEA for a more detailed report on one non-amphetamine anorectic, lonamin. I have been told that Mr. Gordon's concern with this substance is not based on any known significant differences between lonamin and most of the other non-amphetamine anorectics. Rather Hr. Gordon's concern is predicated on the past history of the Pennwalt Corporation, manufacturer and distributor of lonamin. In May 1971, as earlier noted, Pennwalt requested a hearing on the proposed transfer of its amphetamine product. Biphetamine, from Scheduje III -- 15 - PAGENO="0536" 14958 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to Schedule II. That request was subsequently with- drawn and in August 19, 1971, the drug became subject to the Attorney General's power to limit manufacture by setting production quotas. Mr. Chairman, the dates in this matter are most important. Until some time in June, 1971, Pennwalt exported to Mexico City large quantities of the resin complex from which Biphetamine is manufactured. In Mexico City at a Pennwalt subsidiary, the resin complex was encapsulated and sold under the Mexican trade name Bifetamina. Within months, Bifetamina appeared on the illicit market in the United States. A special task force working under the code name "Operation Blackjack" established that the southeastern and southwestern states were being flooded with Bifetamina and that the drug was being smuggled into the United States at six principal points along the Texas-Mexico border. Pennwalt was ordered to show cause why its registration to export amphetamine products should not be revoked. The company chose not to contest the order and is now barred from exporting its amphetamine products to any part of the world. - 16 - PAGENO="0537" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14959 Mr. Chairman, the Order to Show Cause in that case said in part, "the illicit importation of Bifetamina from Mexico and the subsequent illegal sale of Bifetamina in the United States substantially subverts the purpose of placing all amphetamines in Schedule II." The history of Fennwalt and tonamin has a similar beginning. In May, 1973, as earlier noted, Pennwalt requested a hearing on the proposed place- ment of its anorectic product, lonamin, in Schedule III. Whether that hearing takes place will depend in large part on the results of DEA's comprehensive review of all the anorectics which will include the report of this subcommittee. Meanwhile, lonamin remains in Schedule IV. In 1975, Pennwalt exported to Mexico City 300 kilograms of the bulk powder from which lonamin is manufactured. Thus far in 1976, another 300 kilograms of that same bulk powder has been exported to Mexico City. In Mexico City, at the same Pennwalt subsidiary where Bifetamina was once produced the bulk powder is encapsulated and sold under the Mexican trade name, lonamina. Mr. Chairman, a report on the most recent survey of illicit sales of lonamin and lonamina will - 17 - 85-569 O-77---35 PAGENO="0538" 14960 cOMprrxTrvE PROBLEMS IN THE DRUG INDUSTRY be forwarded to the subcommittee. For the purposes of today's hearing, I will say that lonamin is a relatively minor problem in most of the United States. However, in Texas we find heavy trafficking and abuse of lonamina in all! areas of the state adjacent to the Mexican border. Since July 1973 through April 1976, some 25 cases have been made involving lonamina, with seizures and purchases totaling over 104,000 dosage units. - 18 - PAGENO="0539" COMPETITIVE PROBLEMS IN TUE DRUG IIThUSTRY 14961 STATEICNT BY BARIJ2T SCOVILL~., M.D. BEFORE SUBCOMMITTEE ON MONOPOLY Sa~ATi SMALL BUSIN~S~ COMMITTEE Novuca? 10, 1976 PAGENO="0540" 14962 CO~ETflWE PROBLEMS iN THE DRUG INDUSTRY Mr. Ch~~rman, members of the Subcommittee, I am here to provtde you and the public with information on the decisions made about anorectic drugs - drugs used in treating obesity - during the time I worked in the Food end Drug Administration, and about my current personal opinions on what modifications of those decisions may be desirable, as well as on any other matters you wish to ask me about. I have testified before this Committee in the past about the FDA review of drugs used in treating obesity. To recapitulate, in 1971 and 1972, the Food and Drug AdmInistration was confronted with decisions on the efficacy and safety of old and new anorectic drugs, some 11 chemical entities in all, over 130 drug products. The questions about efficacy included questions on the amount of weIght loss, if any, associated with the use of anorectic drugs by obese patients, the duration of admin- istration of the drugs, and possible differences in efficacy among the different chemical entities evaluated. The safety questions involved chiefly the public health hazards of a special toxicity, that of the potential of these drugs for producing dependence and for being abused. Data bearing on the efficacy questions included over 200 controlled trial involving almost 10,000 patients, PAGENO="0541" COMPETITIVE PROBLEMS LW THE DRUG INDUSTRY 14963 trials carried out by drug manufacturers and submitted to FDA as part of various applications. The data on safety were a snore heterogeneous assemblage of different sorts of evidence - chemical, animal and human - which might have some bearing on abuse potential and other safety questions. The efficacy review involved an tin- precedented re-examination of all individual patient data sheets, representing 70,000 patIent visits, computerizatIon of the data, and FDA re-analysis of the data, using its own computers and statisticians - who deserve much credit for the massive job. In making the final decis~ons on the drugs, the FDA was advIsed by a consultant panel headed by Dr. Thaddeus Prout. The former Council on Drugs of th~ American M2dical AssocIation, headed by Dr. Harry Shirkey, also gave us its opInIon on the proposed actions. The institutional FDA decisions were embodied in a comprehen- sive memorandum proposing various alternatives with the pros and cons of each, the final decisions being initialed by the Commissioner of Food and Drugs. In carrying out the decisions, the FDA itself Implemented decisions with respect to marketing approval and relabeling. Decisions on controls to be imposed becausa of abuse potential were and are the primary responsibility of the Bureau of -2- PAGENO="0542" 14964 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Narcotics and Dangerous Drugs, now the Drug Enforcement Administration, although the FDA does have major statutory responsibilities in this area, too. Recommenda- tions were forward to the BNDD and controls were imposed by that agency. The results of our review, which ended in the latter half of 1972 with implementation of the decisions in early 1973, were as follows. First, a consistent policy and set of regulatory actions for all anorectics, based on a better characterization of their limited but unequivocal superiority to nondrug therapy and including recommendations that they be used only for short-tcrrn use as adjuncts to diet. Second, the elimination of a large number of combination drug products. Only two major combtnation products remain on the market, with litigation ongoin2. The position of the manufacturer of these drugs, Smith, Kline and French, appears ethically and legally weakened by their faLlure to report important adverse information on the abuse potential of one of their products. Third, controls bearing on abuse potential were imposed on eight of these drugs for the first time, in a precedent setting class action. Fourth, all injectable anorectics were eliminated from the market. You may wish to know what I think of these decisions -3- PAGENO="0543" CO~ETITWE PROBLEMS TN THE DRUG INDUSTRY 14965 with the benefit of hindsight, over three years after the fact. I believe that the basic efficacy decision remains a good one. Obesity remains a chronic disease, extremely difficult to treat, and even the limited efficacy of anorectic drugs is better then nothing. The safety decisions appear in need of revision. It is my under- standing that you will hear Government data suggesting or showing that amphetamines remain the leading stimulant drug of abuse - with the possible exception of cocaine - in spite of the most restricted measurer. If so, it would seem reasonable to withdraw approval of amphetamines for use in obesity, for which safer drugs are available. In a parallel fashion, the use of any other Schedule II drugs in obesity should be exeriined to see if there may be a similar abuse problem. The other anorectics were quite diffIcult to evaluate for abuse or abuse potential in 1972. Data were scanty, and none had been subject to epidemic abuse. We nonetheless recommended control on grounds of abuse potential. It is my understanding that in the interval, some of these drugs have been better tested, with confirmation of their abuse potential, and that observers of patterns of abuse have seen abuse potential turn into actual abuse in the street for some of these drugs. You -.4- PAGENO="0544" 14966 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY have or will have obtained testimony on this problem from more expert witnesses than me. if the data are as I suggest, they will support greater controls for some of the drugs currently In Schedules III and IV. BS:ck S -5-. PAGENO="0545" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14967 Sumner J. Yaffe, M.D. Div. of Clinical pharmacology C'L.,IA "n's l-lo~o~tal ii uL ~, `, A~FPBl.~ldrl~rn I ,`dwlrws. \oI. 51, No. 2 34th St. & CIVIC Cent I~II:lrv, 1173 Philadelphia, PcnnSY~Van13 19Lu~*tgtsr,'s,'r~.,~i USE OF d-AMPHETAMINE AND RELATED CENTRAL NERVOUS SYSTEM STIMULANTS IN CHILDREN TIlE abuse of amphetamines has become properties, side effects, and abuse liability a problem of international significance. of dextro-amphetamine, methamphetamine, Japan was the first country to recognize this methylphenidate, and phenmetrazine. Since problem, and by 1954 there were an esti- the latter two drugs are available only mated 500,000 to 600,000 abusers in Japan. through a single company as a trademarked More than ten years ago Japan banned the product, control has been strict and large use of amphetamines. The United Kingdom scale diversion to illicit channels has not restricted distribution of amphetamines to been a problem in the United States. hospital pharmacies in 1968. Sweden eate- The FDA also has limited the amount of gorized amphetamine as a narcotic in 1944 amphetamine which can be manufactured. hecasise of abuse; and in 1965 phenmetra. In 1972 procurement of niethylphenidate zine (Preludin) and in 1965 methylpheni- was cut in half (from 2,854 kg produced in date (Ilitalin) were removed from the mar- 1971). and that of phenmetrazine was re- ket. Patients now requiring amphetamines dIRt'd from 4,638 kg to 2,672 kg. are registered with the government. Swe- In addition, amphetamine, phenmetra. den has about 10,000 drug addicts (almost zinc, methamphetamine, and methyipheni. all between 15 and 30 years of age) using date were elevated to Schednie II sub- central stimulants intravenously; this is stances, the same category as opium. about the same percentage of their popula- codeine, and morphine. Schedule II drugs tion as the estimated percentage of heroin nrc those considered to have a high potential addicts in New York City.' In contrast, the for abuse, and such abuse may lead to Se- number of heroin and opiate addicts in yore psychologic or physical dependence. Sweden is estimated to be less than 500. The Health Protection Branch of the De- In 1970, the Food and Drug Adnsinistra- partment of National Health and Wel- tion (FDA) responded to the problem of fare of Canada, with the endorsement of amphetamine abuse in the United States by the Canadian Medical Association and limiting the package insert labeling for am- l'Association des médecThs de langue fran- phetamines to three indications: narco- çaise du Canada, has moved to prohibit lepsy, hyperkinesis in children, and the the use of amphetamines and related corn- short1erm treatment `of ohesity. Currently, pounds for weight reduction purposes as of the Jafter indication is being reviewed and September 1, 1972. may no longer be valid. The actions by governmental agencies Among the related agents there is some prompted this review of the medical indien- specificity in labeling, e.g., methyipheni- tions for the use of amphetamine in the pe- date is approved for use irs adults with mild diatrie age group. The Committee will also depression, narcolepsy at any age, and ehil- consider ways in which these agents be- dren with minimal brain dysfunction hut come diverted to illegal usage. not obesity; phenmetrazine for use only in At present there are only two valid mdi- obesity, etc. However, in the broad view eations for the use of amphetamines in there is a similarity in the pharmacologic childhood: (1) the hyperkinetie syndrome, The statements presented herein do not preclude alternatives which may be more appropriate, taking into account local sit,,ations and all other relevant facts. Executive Board, SAP Psnixr,ucs, Vol. 51, No. 2, February 1973 302 PAGENO="0546" 14968 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and (2) the rare condition of narcolepsy. Although adequate studies are not avail- able, the usefulness of amphetamines for the treatment of obesity appears to have short-term value without a lasting effect on weight gain attained during adulthood. The use of amphetamines for cramming for ex- aminations and improving athletic perfor- mance cannot be condoned. The hyperkinctic syndrome is character- ized by motor restlessness, short attention span, poor impulse control, learning diffi. cultics, and emotional lability.' It affects an estimated 3% of grade school children,~ and apparently resolves spontaneously in most instances by puberty. Carefu~ly Sc-. lected patients respond favorably to long- term medication with d-amphetamine or methylphenidatc in about 65% of patients?-4 The mechanism of drug action is unknown, although certain inhibitory centers in the brain may be activated. Children respond- ing to medication promptly and unequivo- cally exhibit increased attention span and control over spontaneous motor activity. Omission of a single dose may result in re- turn of the hyperactivity. Also, academic and behavioral performance may become more productive because treatment may break the vicious cycle caused by the effects of the disturbing restless, impulsive behavior on the family and on the school situation. in a 12-year follow-up study of 340 by- perkinetic patients.' no major problems re- sulting from drug toxicity were found. Simi- larly, follow-up studies on patients treated during childhood give no indication of in- creased use of amphetamines or other drugs in later years.' In fact, there has been a lack of willful increase in dosage, presumably resulting from the lack ni euphoric effect from amphetamine in these patients. A re- cent paper documents lesser weight gains in nine children on medication Cd-amphet- amine, 10 to 15 mg, or methylphenidate, 30 to 40 mg/day) for two years. Although there was a correlation between depression of weight gain with linear growth, further 303 studies will h0 nes-ded to ascertain if adult height is compromised by long-term ther- apy. Narcolepsy is a lifelong disorder charac- terized by excessive daytime sleep patterns (narcolepsy proper); in some patients it is accompanied by emotion-induced muscular weakness (cataplcxy, 66%), sleep paralysis (20%), and presleep-hypnagogic halluci- nations (30%). The exact incidence of this disease in the pediatric-aged population is unknown, although it is a rare condition. In a report from the Mayo Clinic,' 400 narco- leptic patients were seen in a seven-year period. Sixty percent had onset of symp- toms before the age of 15, although only 16 of the 400 requiring trcat,nent were under age 15. d-Amphetaminc and similar agents provide symptomatic relief of narcolepsy proper and a 50% reduction in cataplexy. The dosage required is in the low range (5 to lOmg, two or three times a day), similar to that used for the hyperkinetic child. Caf- feine is also effective, .~ncl the dose of d- amphetamine can be tapered if caffeine is eoadininistcrcd; caffeine can be given in tablet form, as coffee, or as a cola bcver3ge. Amphetamines are popularly promoted for the treatment of obesity without proof of lasting benefit; therefore, their use in weight reduction programs cannot he en- dorsed, Regardless of initiating cause or causes, obesity results from calorie intake exceeding metabolic expenditure. The problem of obesity in childhood is impor- tant because 80% of these children become even more obese during childhood.' The relatively few double-blind control studies in adolescents treated with various amphet- amines and amphetamine-type drugs have shown that any beneficial effect on weight loss is generally evanescent, lasting four to eight weeks.' Studies purporting to show beneficial effects are almost all of short du- ration. A familiar pattern is that weight loss occurs during the first few weeks of the trial; the patient then becomes refractory, an increase in dosage is necessary, and this increase causes side effects. No `veil con- AMEB1CAr~ ACADEMY OF PEDIATRICS PAGENO="0547" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14969 trolled study has demonstrated a long-term beneficial effect on body weight of obese adolescents. Reports in the literature con- cerning adults who abuse drugs frequently indicate that their firtt exposure to stimu- lant drugs was through a physician pre- scribing amphetamines for weight reduc- tion. Moreover, a fair percentage of ado- lescents are over-weight and this age group is particularly vulnerable to becoming abus- en, in contrast to the young child who re- ceives medication for hypcrkinesis. The availability and use of amphet- amines is commonplace among teenagers. In a study'° of 1.300 students in five San Francisco area colleges, only 8% reported having any difficulty in obtaining a supply of amphetamines. In the 1971 Playboy sur- vey of 3,000 college students, use of am- phetamines while in college was registered at 30% and was exceeded only by use of al- cohol and marijuana. Over 60% of those who used amphetamines denied chronic use; most used them when "cramming" for examinations, attempting to lose weight. or hoping to excel in athletic competition. These patterns of abuse probably should be considered as distinct from the abuse by in- travenous administration of high doses in a chronic manner. A physician prescribing the drug is frequently the initial source of supply; its use can then be continued by its easy availability from peers. The abuse of stimulants is frequently concurrent with se- quential abuse of depressive drugs, particu- larly barbiturates and alcohol. Thus, the signs and symptoms of abuse may range from undetectable to those of paranoid de- lusions and wildly destructive behavior as- sociated with heavy use of intravenous methamphetamine in so-called runs, i.e., the administration every few hours fnr as long as several days. The misuse of these agents frequently can he traced to mistaken ideas ahniit their usefulness as therapeutic agents. Pediatri- cians have had unduly optimistic expecta- tions of thc-raneutie resisonses for the child wit', roor school performance, the over- weight child, or the teen-agcr with mild depression. School and team physicians have allowed or overlooked the use of asnphet- amines and similar agents in athletic con- tests. Pediatricians are also under pressure from educators and parents who are con- cerned regarding children who act out in school or are difficult to manage. Agents such as methylphenidate (Rita- ho). phenmetrazine (Preludin), meth- amphetamine (Desoxyn), and eblorphen- termine (Pre-Sate) have properties similar to d-amphetamine. When tested in a ran- domized, double-blind fashion under care- fully controlled conditions, experienced abusers did not distinguish among intrave- notis amphetamine,.. methamplsetamine, pheninetrazine, and methylphenidate." An estimated S billion amphetamine-con- taining tablets are manufactured annually in the United States; this is enough to give every man, woman, and child in the nation 35 substantial doses. This indicates a wide- spread misuse of an agent having extremely limited therapeutic value. Pediatricians must reflect on their role in introducing pa- tients to these agents; they must not unwit. tingly contribute to the current problem of overuse, misuse, and abuse. Moreover, phy- sicians must be aware of the widespread use of these agents by some of their patients so they can accurately diagnose illnesses ranging from mild problems of insomnia, nervousness, and depression" to such severe conditions as hepatitis. septicemia, and psy- chotic reactions which may result from in- travenous abuse. The Committee on Drugs recommends that: 1. the use of d-amphetamine and similar agents be limited to children with a clearly defined h~perkinetic syndrome or narco- lepsy; 2. d-ainphetamine and related agents should not he used in thi' treatment of obe- sity; 3. pediatricians become familiar with the wide variety of signs and symptoms that may resu't from use and abuse of amphet- amine-like drugs; 304 USE OF d-AMP}IETAMINE PAGENO="0548" 14970 COMPE~iTI\~ PROBLEMS IN THE DRUG INDUSTRY 4. the use of central nervous system stim- ulants in athletics be condemned. COMMITTEE ON Unucs SUMNER J. Y.&m, M.D., Chairman CHARLES Vt BIERMAN, M.D. hOWARD M. CANN, M.D. ARNOLD P. Gou,, M.D. FREDERIC M. KENNY, M.D. HAPnI5 D. RILEY, Ja., M.D. JRWIN ScHAFER, M.D. LEO STERN, M.D. CHARLES F. WEiss, M.D. Consultants: CRECORY CHUDZJE, Pharm. D. H~anv C. SHIRKEY, M.D. Litsnn F. SOYKA, M.D. Liatson: JOHN C. BALUN, PaD. ALAN IC. DONE, M.D. LOUIS FARcIJIONE, M.D. JACcuF.s LECER, M.D. JEAN D. LOCKHART, M.D. STEVEN SAWCHUK, M.D. APTEMIS P. SIMOPOUI.OS. M.D. REFERENCES 1. Penman, E. S.: Speed in Sweden. New Eng. J. Med., 283:760, 1970. 2. Eisenberg. L.: Symposium: Behavior modifica- tion by drugs. fill. The clinical use of stimu- 305 - lust drugs in children. PEnsATlucs. 49:709, 1972. 3, Report of the Conference on the Use of Sti,nu- lust Drugs in the Trcatn.cnt of Behaviorally Disturbed Young School Children. Office of Child Development and Office ~f the Assis- tant Secretary for Health and Scientific Af. lairs, Department of HEW, January 11-12, 1971. 4. Oettinger, L., Jr.: Learning dicorden, hyps'rld- neds, and the use of drugs in children. Re. hahilitation Literature, 32:162, 1911. 5. ~ C.: Benzedrine and dizedrine in the treatment of children's bel,avior disorders. FEDIATI'SCS, 5:24, 1950. 6. Safer, D.. Allen, B., and Ban', E.: Dcpreccion of growth in hyperactive children on stimu- lant drugs. New Eng. J. Med., 287:217, 1972, 7. Yost, B. E., and Daly, D. 0.: Narcolepsy in children. PSaSIATRICS, 25:1023, 1960. 8. Wolff, 0. H.: Obesity in childhood and Its effects. Postgrad. Med. J., 38:629, i962. 9. Lorber, J.: Obesity in childhood: A controlled trial of anoreetic drugs. Arch. Dii. Child., 41: 309, 1966. 10. Blum, B. H., ed.: Students and Drugs, vol. 2. College and High School Observations. San Francisco, Jossey-Bass Publications, 1969. II. Martin, W. B., Sloan, J. W., Sapira. J. 0., and Jasincki. D. B.: Physiologic, subjective and behavioral effects of amphetamine, meth- amphetamine, epl.edrine. pluennietrazim. and methylphenidate in man. Clin, Thann. Ther., 12:245, 1971. 12. Kosman, M. E., and Unna K. B.: Effecta of chronic administration of the amphetamines and other stimulants on behavior. Clin. Phann. They., 9:240, 1988. AMERICAN ACADEMY OF PEDIATRICS PAGENO="0549" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14971 STAT ENTS PRL~ENTED BY REVEREND R~INALD TAKE, ~CUTIVE DIRECTOR, TEEN CBALLEI~E TRAIND~ CENTER, EE}{REBZBUTC, PA. The doctor's office, at all times, would be packed with young people ranging in age from 19 to 35 or 40. From their conversatioms I could tell what their motive was for seeing the -doctor. All of them were after prescriptions for speeo, of which this one was phendhnetrizthe. The people there were from different cities, Boston, Pall River, Brockton, etc. They traveled from all over to this doctor. How did they find out about this particular doctor? News in the street travels fast. The other doctor who gave out Bipheta.mines also had an office packed with patients, but he also had some older folk that were there for reasons ether then to obtain speed. The people there for prescriptions for speed greatly out.numbered the older patients. I learned from being in this con game with doctors that there were various other ways to get other prescription drugs from doctors. For example, in order to get a certain drug, you would have to have a certain story for the doctor to believe, hut not everybody knew these stories. I am talking about Borbituates and Delsda now. These stories would cost money along with certain ~ names. I am just trying to show how easily it is for someone that is a good con to be able to get what he wants from certain lenient doctors. Also all of these doctors kept records of these visits for the goverement or the Medical Association to inspect if ever necessary, so I see that it isn't only the doctors that are lenient but the people that are over them also. Most people using speed in the street don't see themselves as drug users because they are usually house mothers, college students studying for exams or just the good people in society that are very social. This speed, which they don't call it, is just something to pick them up; it doesn't make them silly or incapable of doing work but in fact helps them. They don't realize it's potency and effect on their lives until it is too late. Then they find they can't function without it and when they are deathly sick because of the lack of nutrition that they deprive their bodies of when they take these so called diet pills, and then they find out they are a nervous wreck because of the abnormal effect of the drug, such as being able to stay awake for maybe 24 hours, 49 hours or even 72 hours at a time. Diet pills are being used for everything bit dieting. Oh yeah, it is popular around heavy drinkers; speed allows the drinker to drink in excess without felling all over the piece. I have nothing against the medical profession or the laws of this country, but there is always one bad apole in every bunch, and the odor of this rotten apple i $ smelled by everyone and takes away the sweet fresh fragrance of the other good apples. PAGENO="0550" 14972 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY flovember 10, 1976 "On or about the early part of' 1970 myself and sev- eral friends were involved in the purchase of Methodone in the southwestern part of Washington 0. C. We were able to purchase as much Methadone, (which on some days ranged up to the hundreds of dollars' worth,)"--as we were able to pay for. "The doctor was completely aware of what was going on, and made no effort to hide it. Not too far from this same location was another doctor who was doing the same exact thing. The drugs which were purchased were taken to Belt- more where they were sold on the streets for higher prices. From about the middle of 1973, up till the later part of 1975 I was involved in the buying of pills through doc- tors in the Baltimore area. This was set up so that I had medical assistance, and could go to various doctors during the day. I was able to purchase various types of drugs, including valium, parest, nebutal, seconal, tutinals, pla- cidyalls, and many others, including class A narcotics. PAGENO="0551" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14973 These doctors were aware that I was on a drug program, and still would prescribe drugs. The doctors, (some, not all) were careful of how they dispensed the drugs. They would prescribe only enough for one month's supply, but would prescribe several different types of medication, Other doctors would insist that several different people would cone so they could prescribe to (then), but I would receive the drug after we left (the office.) Some, though, would prescribe a large amount and tell you not to come back. On one occasion I can recall, 1 told a doctor I was strung out on valium, and needed to be detoxed off of them, I was told I could handle it myself if he could prescribe a large amount, He did so willingly. This I did on several different occasions, to the same doctor. On another occasion in the Baltimore area, ray girl- friend was approached while in a doctor's office and asked if she would exchange sex for an assorted amount of drugs. There are many, many instances I could give you of how doctors have sold drugs to myself and many of my friends, knowing they were being used illegally. -2- PAGENO="0552" 14974 COI~1PETITIVE PROBLEMS IN THE DRUG INDUSTRY November 10, 1976 I am here to inform you that I had the distasteful confrontation In meeting and dealing with the so-called doctors of this day and time. I am not referring to all doctors, but specifically some who should have their license tenninated for a period of tine. These particular doctors offer you any kind of drugs for a price, knowing that they are very dangerous to withdraw from; they offer you barbituates In quantities, for cash money. I believe they should be under strict control in terms of dispensing these drugs. I was getting it free, five different doctors while under the influence of alcohol and Methadone, this mixture will kill any creature on earth. Today there are many young people that are turning to drugs because they are very sinpie to get their hands on. I pray to Cod that there would be something done about this, We are dealing with precious lives. God bless you. PAGENO="0553" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MATERIAL Svnun you THE RECoRD BY SENATOR GAYLORD NELSON ACTIONS BY THE bOB AND DRUG ADMINISTRATION AND DRUG ENFORCEMENT AGENCY SINCE TEEMINAnON OF HEARINGS DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE PUBLIC HEALTN SERVICE FOOD AND DRUG ADMINISTRATION ROCKVILL£ MARY LAND 20S52 20857 Honorable Gaylord Nelson Chairman, Subcommittee on Monopoly Select Committee on Small Business United States Senate FEB Washington, D.C. 20510 - Dear Senator Nelson: In response to a request from Mr. Benjamin Gordon of your staff, I am writing to outline our currentthinking in Itegard to amphetamines. We presented the issue of the need for amphetamines in the treatment of narcolepsy and minimal brain dysfunction to our Neurologic Drugs Advisory Comittee on February 3. 1977. It was the view of this group that there are alternate safe and effective, but not fully equivalent, treatments for minimal brain dysfunction. Therefore, the withdrawal of amphetamines from the market would have a deleterious effect on the treatment of patients with minimal brain dysfunction. They further stated that there are alternatives to the amphetamines for the therapy of narcolepsy, but these are not equivalent, let alone superior to the amphetamines. Thus, the Committee concluded that the withdrawal of amphetamines from the market would have a deleterious effect on patients with narcolepsy. Additionally, the Committee considered that, although there may be safe and effective alternatives to the use of amphetamines in certain forms of epilepsy and in alleviating the sedative effects of anticonvulsants, withdrawal of the amphetamines from the market would have a deleterious effect on the treatment of some patients with seizure disorders. Given the above advice from our Neurologic Drugs Advisory Committee, it seems unlikely that total removal of the amphetamines from the market would be in the interest of good medical care for patients with these serious conditions. Our current plan is to present our overall approach for relabeling amphetamines and promoting their proper use in medical care at a public meeting in April or May. At that meeting, we would present the final data received from the Drug Enforcement Administration (DEA) and the National Institute on Drug Abuse (NbA) and solicit testimony by experts in the field of drug abuse. We would also invite members of medical professional associations, State Boards of Medicine, and the interested public. Regulatory action on our part would then be based on the data submitted as well as expert advice related to those data. We will, of course, include in our deliberations the testimony of the expert witnesses who appeared at your Subcccrrittee meetings last November. 85-069 O-7T-----36 PAGENO="0554" 14976 coI~rrETITwE PROBLEMS IY THE DRUG INDUSTRY Page 2 - Honorable Gaylord Nelson While I cannot be certain at this time, I suspect that our overall approach will include a proposal to withdraw the obesity Indication for amphetamines and to include a patient package insert in all amphetamines emphasizing that their proper use is only in patients with minimal brain dysfunction, narcolepsy, or certain types of convulsive disorders. In addition, we may be in a position by then to recomanend scheduling changes for other anorectic drugs should the data being gathered by DIA support such a position. We would also hope to have gathered the formal support of a number of medical organizations by that time so that any regulatory action on our part has broad support from the medical profession. It has become clear to us that combined Government-professional action is likely to produce the best result in limiting the use of amphetamines to their proper indications. While It will take longer than we originally predicted to develop such a combined program, we believe this will be time well spent in the long run. In addition, we would expect that State level legislation (as in Maryland), vigorous activities of such groups as the Federal-State "Diversion Investigation Units (supported by the Law Enforcement Assistance Administra- tion (LEAA) and acbninistered through DEA) and articles in the FDA Drug Bulletin and professional journals will be influential in keeping inappropriate prescribing of these drugs to a minimum. We will keep you informed as to the outcome of our data review and the upcoming public meeting on this Important issue. Sincerel yours, ~ Richard Crout, M.D. Ulrector, Bureau of Drugs PAGENO="0555" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14977 DEPARTMENT OF HEALTH EDUCATION. AND WELFARE PUBLIC HEALTH SERVICE rooo AND DRUG ADMINISTRATION ROCICVILLC MARYLAND 5S52 January 28, 1977 Mr. Benjamin Gordon Staff Economist Senate Small Business Conmiittee Room 424 Old Senate Office Building Washington, D.C. 20510 Dear Ben: As per our telephone conversation, I would like to keep you abreast of the latest activities in our review of the anorectic drugs. As per Mr. Rody's testimony, the Drug Enforcement Administration transmitted their findings on the current abuse of amphetamines to us on December 20. 1976. The findings include field data on amphetamine diversion, audit reports, and field intelligence as well as DAWN data and recent production figures. I understand from DEA that they have already for- warded you a copy of their report. Following FDA staff review of that material, on January 14, 1977. Mr. Peter Bensinger, Administrator of DEA, Dr. Dupont, Director. NbA, and I met together with our respective staffs to discuss the preliminary DEA data and to discuss FDA data needs. We stated those questions which we felt must be answered prior to our initiating any regulatory proce- dures. We shared our present understanding of the current level of anoreCtic drug abuse and the various data systems that are available to our respective agencies to further expand our knowledge. The data which DEA has transmitted to FDA mostly pertains to the Schedule II anorectics and particularly to the amphetamines. At our meeting, we agreed that action might appropriately be taken on any member of the entire class of anorectic drugs, should the data developed reveal that the most signif- icant drug abuse problem was with that particular drug Dr group of drugs. We need not be constrained by schedule or chemistry of these drugs. I pointed out to the group that for us to take action on any of the drug products, we would need to be able to show that those specific anorectic drugs present a significantly greater drug abuse problem than the others, and that those specific products causing this problem are legitimately produced. The respective agencies understood our position and gener- ously offered their staff assistance to work with FDA personnel on the collection and analysis of further data. An Inter-agency working group was identified and, I am pleased to say, had its first meeting this past Friday, January 21. PAGENO="0556" 14978 COMPE'fl'flVE PROBLEMS IN THE DRUG INDUSTRY Page 2 - Mr. Benjamin Gordon I also Informed Dr. DuPont and Mr. Bensinger that FDA plans to discuss appropriate treatment of hyperkinesis and narcolepsy with our Neurology Advisory Comittee on February 3, 1977. That corrrittee will provide us with expert advice on the current state-of-the-art in this area. I also explained our proposed administrative approach to any regulatory action. In short, for those drugs which are associated with the great- est drug abuse, we will develop a Notice of Opportunity for a Hearing that will be published in the Federal Register. Our current target date for such a Notice is March 1977. We anticipate a hearing would be requested and, If so, this would prolong any final action by a number of months. We also discussed the possibility of rescheduling the anorectics should the data suggest that this is appropriate. DEA has been developing in- formation on the level of abuse of phenmetrazine as well as the Schedule III and IV anorectics for some time and expects to report their findings to us within several months. I am pleased with progress to date and consider the work by our respec- tive staffs to be on schedule. Best wishes for the New Year. Sincer yours, Richard Crout, M.D. irector Bureau of Drugs PAGENO="0557" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 14979 UEC 20 976 Mr. Sherwin Gardner Acting Commissioner of Food and Drugs Food and Drug Administration 5600 Fishers Lane Rockville, Maryland 20052 Dear Mr. Gardner: In accordance with the commitment undertaken during the recently concluded hearings on safety and efficacy of the anti-obesity drugs before the Monopoly Subcommittee of the Senate Snail Business Committee, Senator Gaylord Nelson, Chairman, I am forwarding this agency~s findings reflective of the current abuse of amphetamines. These findings include field data i.e., amphetamine diversion, audit reports and field intelligence as well as DAWN data and recent production figures. Collectively. these findings are indicative of an unaccept- able level of abuse despite recently imposed Schedule II restrictions. The issue remains whether t?t~ risk to benefit ratio associated with the therapeutic use of amphetamines for obesity or any other disease is sufficiently low to justify their continued comercj,o-l availability. Additional updating of field, surveys and analysis of the level of abuse of phenrnetrazine and the Schedule III and IV anorectics is underway. This task will require an addi- tional two to three months and will be forwarded when completed. Sincerely, D,ua1.d MllliY Peter B. Bensinger Administrator PAGENO="0558" 14980 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ANI'IlLIA~I1NL DIVERSION Back round - In the White Paper on Drug Abuse published during September, 1975, the Domestic Counsel Drug Abuse Task Force reported that the use el various dangerous drugs (including harhi turutos tranquilizers, and a~nphetamines) has increased rapidly n the Unitcd States during the inst decade. This report further states that, `These drugs are being prescribed mere frequently and used more often th the general population... Most of this use is under medical direction and controlled by prescription. But uncontrolled non-medical use of these drugs has grown sharply during this period of increasing usage.. Abused amphetamine can be categorized in two broad classes - those originating from legitimate sources (manufacturers, who]esalers, physicians, pharmacies, etc.~and those of clan- destine origin. This paper will attempt to put into perspective the extent of abuse of amphetamine originating from legitisate sources. Auuhet and no S For Human Ijs e On February 12, 1975, the Food and Drug Administration of the Do pnrtiao]1 t of Ito a 1 tli , Education and lie 1 fare put' ii shod in the Federal Register, Volume 38, No. 4249-SO, n stateaent relative to ``,\nnhet2]ejnes for Ilunan Use.'' copy ci this notice is PAGENO="0559" COMPETITIVE PROBLEMS IN THE DRUG rNDUS'rRY 14981 Page Two attached as Attaohme,,t A to this report. This notice served to approve the following indications for the use of amphetamine: (1) Narcolepsy (a condition marked by an uncontroflable desire for sleep or by sudden attacks of sleep occurring at intervals). (2) Minimal brain dysfunction in children (hyperkinetic behavior disorders) as an aid to general management. (3) Management of exogenous obesity as short-term (a few weeks) adjunct in a regimen of weight reduction based on - caloric restriction for patients ,~in whom obesity is refractory to other measures. Analysis of Ar.rhetamina Abuse Trends flEA's Special Programs Division conducted an analysis of amphetamine abuse trends and piecing together data obtained from DAWN, STRIDE, and theft reports concluding the following: (1) We are experiencing a trend of increasing amphetamine abusc. The increase of chronic effects as the reason for seeking emergency PAGENO="0560" 14982 col~1PErrrwE PROBLEMS IN THE DRUG rNDUSTRY Page Three help suggests that increasing numbers of abusers have access to a continuing supply of amphetamines. (2) The decreasing amount of presumed illicitly manufactured amphetamine appearing in STRIDE reports suggests that increasing amounts of legally manufactured amphetamines are con- tributing to the increass in amphetamine abuse. However, the decreasing amount of stolen amphetamine suggests that the diversion from legal distribution systems is becoming less important as a source of abuse of amphetamine. - (3) The above suggests that increasi~g amounts of abused amphetamine come from home supply. This supply provides môt only the increasing `legal prescription" source, but also much of the increasing "street buys" source reported by DAWN. (4) This availability of amphetamines beyond what is needed for immediate medical needs in family medicine chests, to the extent that abusers have sufficient supply to PAGENO="0561" COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY 14983 Page Feur accrue chronic effects from the drug, suggests that significant numbers of physicians may be prescribing well over their patients' actual medical needs. A complete copy of the report leading to the above conclusions can be found as Attachmeat B to this report. Theft Reports (as provided by PEA) In addition to the theft data reviewed as part of analysis of amphetanine abuse trends, the following figures are note- worthy: A. Drug Thefts By Volume: FY'73 FY'74 FY'75 FY'76 Dosage Dosage Dosage Dosage Units Units Units Units V. Amphetamines 15,398,776 7,331,454 8,644,550 5,528,247 B. Volume of Thefts fren Pharmacies: FY'73 FY'74 FY'75 FY'76 Dosage Po5age Dosage Units Units Units Figures Nat 6,626,D95 6,330,696 4,195,313 Available Documented Diversion Each of DEA' s demestic Regions have providud an analysis of the diversion probien of legitimately manufactured amphetamines PAGENO="0562" 14984 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page Five in their respective Regions. The following summarizes the degree of each Region's amphetamine abuse problem. PAGENO="0563" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14985 Page Six Region 1 - BOSTON Legitimately manufactured amphetamine products are readily available on the illicit market in Region One (1). Source of supply for these amphetamines can be broken down into two (2) main areas; (a) Drug Store break-ins/armed robberies, (b) diversion from the retail level (practitioners, pharmacies etc) Information received from cooperating individuals indicates that amphetamines can be obtained iR lots of 100's to 1,000's with the price varying according to the strength of the dosage units and the quantity purchased. Since January 1. 1974, Region One (1) has participated in or initiated more than thirty (30) investigations of practi- tioners involved in the diversion of amphetamines into the illicit market. The majority of those cases were concerned with the indiscriminate prescribing and dispensing of amphe- tamines by physicians. In one case, a New Hampshire physician was responsible for the dispensing of approximately one half of the total amphetamiaes purchased by all of tho registrants in that state. The same physician was also responsible for the dispensing of two thirds of the total moth:inphetam inc purchased by all of the registrants in that state. PAGENO="0564" 14986 COMPETITIVE PROBLEMS IN THE DRUG rNDUSTRY Page Seven In all of the above mentioned cases, each defendant was responsible for the diversion of at least 100,000 dosage units of amphetamines into the illicit market during a period of one (1) year. It should be noted that these violative practitioners are responsible for the purchase of 60% of the amphetamines marketed in Region One (1). A conservative estimate as to the percentage of legitimate amphetamine dosage units encountered on the street in the Region, would be approximately 701. It is impossible to compile exact figures as to the abuse of legitimate manu- factured amphetamines. since none of the states in this Region have the capability of distinguishing or identifying the sources as licit or illicit. One state, however, Rhode Island did advise this office that in excess of 90% of the ariphetamines encountered on the street wer~of legitimate origins. Investigators from the Boston Regional Office and Hartford District Office surveyed the records of two (2) dispensing practitioners, two (2) prescribing practitioners and two (2) retail pharmacies which specialize in filling "weight control" amphetamine prescriptions. Based upon these studies, it can be safely stated that none of these practitioners or pharmacies are adhering to the indications established by the FDA for the use of amphetamine for short term weight control - PAGENO="0565" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14987 Page Eight One of the pharmacies surveyed purchased in excess of 1,100,000 dosage units of amphetamines (mostly Dexedrine and generic Dextro Amphetamine Sulfate) since January 1, 1974. The ampheta- mine prescriptions on file in that same pharmacy account for approximately 93~ of its total Schedule II prescription business. In general, all practitioners throughout Region One (1) who have practices limited to weight control, disregard the FDA and PDR guidelines concerning short term use of amphetamines. PAGENO="0566" 14988 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY Page Nine Redon 2 - New York The diversion of legitimately produced amphetamines appears to occur at the practitioner level in the Region 2 area. Based upon a review of records maintained by practitioners and several on-going investigations, it appears that amphe- tamine products are generally dispensed in violation of current Food and Drug Administration standards for obesity treatment. Amphetamines are readily available to the abuser population through the utilization of fraudulent prescriptions as well as from the sale, by patients, who obstensibly obtained the amphetamine products for weight control. A few individuals, in the legitimate drug industry, who would p.-. not agree to be queted, were of the opinion that availability of amphetamines is attributable,-..to some degree, to the aggressive sales policies pua~sued by several manufacturers and distributors. These individuals further stated that the policies mentioned are in complete disregard of the current accepted medical needs of the country. Therefore, although volune sales hy some manufacturers to pr:ict i honors flay not be classified us outright diversion, such sales contribute significantly to the attitudes professed at the practitioner level relative to ampin e tataa ne p ro~Iuc t PAGENO="0567" cOMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14989 Page Ten Most of the information supplied by informants relates to illicit laboratory operations. Information relating to the diversion of legitimate amphetamines is not commonly encountered. SIGNIFICANT CASES A New York physician was arrested twice by state and local authorities for illegal sales and dispensing of amphetamine capsules (Biphetasine and Delcohese). As a result of theso arrests, this practitioner's license to practice n.edicine in New York State was revoked. This doctor then moved to the state of Florida. This doctor ordered over 330,000 dosage units of Delcobese in the month and and a half before he moved to Florida (prior to his license revocation). Attempts are being made to locate this doctor and effect the seizure of the Belcobese. Undercover purchases of 12,703 dosage units of amphetamine (Delcobese) and 6,235 dosage.units of other anorectics were made fion a pharmacist in Queens, New York. The pharmacists source of supply was identified and an additional undercover purchase of S 000 dosage units of siaphotamines (Delcobese) was made from this source. It was further ascertained that this source of supply was operating in the capacity of a physician in practitioners office, aithnngh lie was not PAGENO="0568" 14990 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page Eleven licensed as a physician and had been twice arrested on charges relating to the unlawful practice of medicine. Investigations at physicians offices have revealed evidence of illegal sales of controlled drugs (Delcobese) diversion by other employees, maintenance of fraudulent records and failure to maintain required records. Evidence has been presented to a Federal grand jury. Three (3) significant burglaries have occurred at this practitioner's offices since February, 1976, in which over 50,000 dosage units (35,000 recovered) were stolen. The doctor is currently ordering over 2,500,000 dosage units of Delcobese per year as well as substantial amounts of Schedule III and IV anorectics. Another physician, who is currently orderirw~ at the rate of approximately 3,000,000 dosage units of amphetamine (Delcobese) per year has been thé'subject of two (2) in- vestigations by state authorities. These investigations have disclosed that (a) the doctor caused to be dispensed large amounts of Delcobese by nan-medical personnel when he was not present in the office, (b) large shortages of Delcobese, and (c) faijure to maintain required records. The doctor is currently the subject ef a state investigation relative to the fraudulent dispensing of controlled drugs PAGENO="0569" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14991 Page Twelve (use of a fictitious name for a patient). In addition, several undercover purchases of amphetamines were made from this doctor by the New York City Pouce Department, Diversion Investigation Unit. No prosecution resulted frori these under- cover purchases. A New York practitioner is currently the subject of a joint DEA/Bronx District Attorney's Drug Squad Investigation. Four (4) undercover purchases of amphetamine (Celcobese) have already been made. This doctor is currently ordering at the rate of approximately 3,000,000 dosage units of Celcobese per year. Videotapes of the doctor's office have revealed an inordinate amount of patient traffic. Another physician was arrested after a series of undercover purchases and an audit identified him as &rnajor source of illicit amphetamine (Delcobese). This doctor was classified as a Class I violator based on i diversion of an estimated 130,000 dosage units of Delaobese. An investigation by the New York State Police resulted in the arrest of a doctor's son and the seizure of a large quantity of anorectic controlled drugs. A follow-up accountability by the Drug Enforccment Administration and state authorities dis- ciosed a shortage of over 58,226 dosage units ol amphetamine 85-469 O-77---37 PAGENO="0570" 14992 COMPETITIVE PROBLEMS D~ mE DRUG LKDUSTRY Page Thirteen (Delcobese and various generic products) as well as a shortage of 277,000 dosage units of Schedules Lit and IV anorectics. Investigation continues. Region 2 is currently conducting active investigations of several large manufacturers and distributors of amphetamine products.. Specific details relative to these cases cannot be revealed at this time as it is felt that the release of even general information could jeopardize these ongoing cases. PAGENO="0571" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14993 Page Fourteen LNF0RNwTro~pgo~I lOCAL LAt~FNFORCF\IFNT AND RECULATORY_A!JT}jflRITtpS The New Jersey Divcfsion Investigation Unit reports that pbs'- sicians continue to present a major problem by issuing illegal prescriptions for amphetamines. The prescriptions are generally for 30 to 60 D.U. `s each. In itself, this is not a significant amount of drugs, however, when multiplied by the hundreds of prescriptions written, it emerges as a significant diversion of licit drugs. The New Jersey State Dcpartnent of Health, Drug Control Program estimates that 30% of the legitimately prescribed amphetamine products eventually find their way into the illicit market. The New York State Department of Health, Bureau of Narcotic Control, advises that practially all amphe.anines en- countered illegally have originated from legal sources, i.e. doctors speciali:ing in the tro1~nent of obesity. PAGENO="0572" 14994 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page Fifteen Pn'ir~' OF RECOPPS OF DISPENSING PPACIITIONPP.s A. As an integral part of this current survey, a sample rnmiber of dis- pensing practitioners were visited in an attempt to verify their adherence to the indications established by the Food and Dnig Administration for the use of amphetamines in cases of obesity (short term use). The results of these visits are as follows: A Brooklyn, New York practitioner has a large practice as a Bariatric Specialist. This doctor dispenses 42 dosage units of Celcobeso bi-weekly to patients at each visit. The strengths of the medication vary with each patient. Cf the selected group of 40 patients records reviewed, the following was revealed: At least 25 patients received amphetamine produc~- for a period of more than 21 days and sone for a period of up to one year. Another group received medication internittentlv for a period of several weeks to more than two or three months. weight loss was achieved in most of the patients whose records were reviewed. The doctor stated that amphetamines wore in many instances used as a maintenance dn~g in on attempt to keep weight from fluctuating. PAGENO="0573" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14995 Page Sixteen A New Jersey practitioner las a large practice primarily limited to family medicine. He indicated that 50 to 75 patients "crc treated by him for obesity. Patients are seen approximately every two (2) weeks and are given 42 dosage tmits of Delcobese of various strengths. The records reviewed at this physician's office indicate that most patients were treated for more than several months, some for more than a year. Some patients were treated for several months, left and returned for additional months of treatment. A Brooklyn, New York general practitioner treats approximately 175 patients for weight co~troi. 24o dispenses either amphetamines (Celcebese) or other anorectic drugs. Ovef Ii period of time, various combinations of'drugs are dispensed. Patients are seen either weekly or bi-weckly depending upon the individual. Eleven (11) patients records ;.ta.-.C.-~-5 S - -- DARGflOUS Oct03 - (Reprinted from Federal Register of ribnary 12, 1972; 38 F.R. 4249) flde2lJo.daodvn OUR! -7000 AND Delia ADMINIS. TWAnON DEPARPAEN-T- OF HLAi2H ZDUCA11ON, AND WtLflAE *jC~en c-oe~, PARr 130-NEW DRUGS Aeiiphebmloeafor Human Use On Aoqost 8.2070. theoiwna o,sbllsned to the Pesnos Rzcesns 23 10. 12652) I 130.45 000emang aawese!smsnes and thdt salle and leveneisrnsne and ii. seittnecton ll48 reciureel the submis- s1000fne. drugaopiicacsous fir ampiset. sadie Or dtrtrtsm;netasmre and their salts as a otoditiso for continued mao- bunj. Tb. new ditg sppithauocs were to contain eeldnire of emracy. Inroad- my encsey In the trealment of tees.... Pennant to ttiaS requtrement `55 new dreg applIcatIons for sncphetanures Or arnphetunuae.contadsino dr.1;s were re- teSted. The enslmle of thi daIs fill- mmcd toneornioc the aniphetanmes and oU~r, nonsosphetnznina ertorectlc dress, generally tis000rten the erfcscy of enorecIlt dru~. Us. of the dr-tie In otese paile~la was *scoclalod with mcne weseht lots than wee diet alone The cern of attt wetzht beau was smnz cal,o tenths - a ecoud a wet 50. many cases). oasis- toot were real, arid Ire ear. of wesnul lose dec,eaneei after the first weeks od therapy. On the basis of the clt-rer.t!y available salIence, the Cnntmissloueeeor.cludse thaI oral dotere form: to arnnitetanune sad/or destroornohetirithe are etiectite In the osoreentit of exilceuctus olosit, as a abort lazes Sa foci wets) adjunct In a retlasen of alight reducuon booed to alone restrtctton frr `,allenta a wh~ obesity Is refractory to other mnanr~. Approorlat. notices concern- log ~ch dnie, wiush stave teen renewed In the These Ertcacy Stucy wilt be out-. labed In It-. Fives;,. Rzcutrrs. ft U55 0' aol Ol'asstsmlrtes for loro p.- of urns at bend Ia dna 0 e~erd- I~a. and at-ate. At-tie of the tmnrat- Iteesina loss been ecu atot Per'tsrence iJed aSiase pride, conditIons of roarcs:i.-g 7d~csibed heroin nay tend the C~ari,rus- eloter to take further ftrps to restrict the O.eof these data Me data have teen received proesdlno uisbatantlaf solder. of elfeUvj~ess of l.eaaafetarnln. and its silts. Aczeetrc!s~ these preparatofti c0n5.atu. to - 0e- tasted as new 4na rrouinng tppIo,ed Sun new ages applicetlons. On seotslerl. ill!, a trur ~eacy Studr ,00zretieiltatl*ti itt-u, wee cub-' Itahed 10 lie lilIan. Rmina 38 155 litf,~ ~~III tins eliiaciofle'snhin bsorocttortte laotian Urnencra `or otter than aflorettit tndkasrtnss was rewarded as effective ftc Sims mica- tons and less than effective 100' oatzrs. rio Commissioner his now fur cv- sienod the evideurn on the sa,ty and effectIveness 00 this driiç. son tnnj con- CliiOied thai the wehl-dnclinlietirod history 01 abuse of ~ann'erai ni,tr_maor.rt- article. brother seth the sevr, mix of dependence ar.i Lie araslattitIr of frr and elviad, soeCre si1 .rc dr-sirs. creates ao sflnerob!e b,iarr, or rtsk to benell. A prnrsnl to r.thdi-,w ep. ~nvsi or tacos new drug applications as letting evIdence of saietr Is pptalshed elsemhert irs this bite ci the Frinia. trirm. The Cocun-smlor,r alec ron~ chides that. for lIe Sante `esacus. Pr- rster,i rrerentlons contahr.thz e.-nuuet- Srnthe. destroantohetounte, or ieeantseI~ amine or their sails are uscasog esifence Of `amy. On Aural I. 5970. a Drar E~cacy ehld7 Imphrmeeution notice was pals- hasted in the Fenetot Rarustu 525 FR 126i51 stating that vasious cnrnbthacon t'-ssicottainlts an artorecin diii. ten reesoded as sow-, Ca--Moe esCztd ecserect: affects and lactic lutiatnual credence or effettavenor.. Soc thetr other indurstoni. Data were It- cowed s,crernizte those dates and ties costusnalson anal) what Were sti alerts *0 new droag I satUrations Subleiltied as retuared hr I 135.46. the 0000lbthatioihl conaaisd of Coerce tic scents aisocaare4 with. Sir example. aedatire.. trauqeasus- nor,. rautolOs derivaxares. or vitamins. The data were reviewed arid found niL in fulfill tha cntena set sortas In ti4 Slatemcnt of General Policy ot In- teroretalcon 13.05 FL7ed-cereobjtbtion prescr.ptrtn dnjc, nor humans. palmed in the FrIrsaL scorn, of October 15. lan os 055 :55371. list-tier. In view on the isc~ of tuoafantiai evidence of circe- tas-ences Cl 41 druta As ffneu comets- tons, the roctruadet potential or Lists, of one omrhetarunz. dl,' flbsnrr.ela- noIre. iseiitl.nnaietacsoe. sired omen- rtruiitetomoosien:a and the a'roaabbd- cry ot alternative there ocutic mesatirco eAch are infer ted effective tinting- tltfls cnntcuteurlt such eomronenia also - lack eric! of 511.17. ?rocretirts to aim- draw approval of tout-h nopilcitsens are Stirs Instearec. and an enort'ortzte notIce Is tutlasttel elsewhere in this lassie 0' the incus. Retinae. Zn a forthcomusg Issue or the Prerpos Rainru, the Cortesniss,orier will set for'rh his poalcy `sIn respect to anorectic agrnt. In &enezui. On the basis of eli of Lie data and In- lorrisatlo nsubmittsd pesnuant to 0 13041. punelant to DrovIa5000 of tote Federal Food. lOcus. and Cosmetic Act tier,. 505 Ifs. II). 555. ar Ins - 52 5taL 10514] as amended. 1055: fl C-SC. 352ff), tIe. 355. mb) I. and under the aisthotity deieeated to bins 21 COst 2.2201, the Cc,nrussianer or Food and Dreis here by reelzes C 130.46 tO Part 100. Subpart A to end as follows: 120.46 Amphel.e,hses (as.pheiae-,lee, .Oosi,oa.epheisov'e.e, sod joel, nit. sod leea,.s(einowe and is salts) foe' (as 5n.p!setnneir.e and dixtrosnunheta- mine and their oaSis, 15 Fusitiant to the drtz eacec, requlreneents of the Federal fled. Drut. and Cosmetic Act, the Na- third Asnoeres' on .Srleucea-Natonai Re- seaSta Council. nra Zolcicy btudr Group. )e.,s evalsstcd cer'.ain dnsaoe forms of amohetartiflea end o:hrr Inn- patiiorr.imealz slirnslr.nt L-san thter.Ced dsr use In the treatment of obesity and for other uses. rho Academy round that cues flnits as a tins nave been snoovis to Save a renersllr snort-term snorect:c attica. ncr fu.-ther commented that chutes eotnlon Ca the csnaruuuois of the sutpathoitetso stImulants an a weight reduction prtqnrn Vanes widely, the antorectit elect of there dross ellen pItteslis or diminishes efter a let wee~s. most Studies of theet are for short flttds, :0 tradable evidence shows that rue of anorec:io alie, the natural hiutore of obesity. some evidence Indicates that Snorer tic effects nm, to atstnslp Iniffuencod be the Zen- mtbrnty of the ;a7bett. and fleeces- toils cant about the sActuac,' of ills contoiath.ometitheesinaiaiomuuss. Their siasisteant eaoo.nual jar dr-us anute was also cloth :5 In addition to tunic dnaaqa fonr.s that were rev'.ewed for entacy ty lice Msd.my. outer isolate forms 0' asnp:tet- tootle dnan are on .io mart-i rhist were not oaesre'.i tltroeieh the new-otis protedasres. While cer°ain amploetantislos acre ear-heeled prior to eflalitlIlalil Os trio Fpderai Food. Dress, and Ccrntettc Act Sn 1531. amelia of the conditIons of se s..bitqueotly prescrIbed. rertmrneudcl. or slat ersto 4 in their abelias e tier e- aneple, Soc tIme treacmm.oa oacsitvl us:- let from toes clause-i lot tat eambucta- mines bofore salts ensctniena. mica atm Attachment A PAGENO="0610" 15032 COMPETI'I'IVE PROBLEMS IN THE DRUG INDUSTRY (page 2 of 2 p~oe°) bay, not been cleared through the ef- fectivenao provisions of tile Drug Amendments of 1062 (PublIc ta. 17-701 allah amended the Federal Food. Drug. and Cosmetic Act). These dross art very extensIvely used Isa the treatment of O~eslty. The estest of use for turn poor- posea as nareole~ay and mamma brain dnfimctlon in chaidren Is bruce ed to be minor as compared with the total togge of thesedrugs. Because of tlseirsti moolant effect on the central nervous system, tiler bay. a potential for misuse by those to wbono they are available through a ploy. ~ctana prescription, and their abuse by the,, who obtain them throith ittlcit channels Is well documented. Porductron data Indurate that anspnetsrmnea have been produced and prose ford a osianti- toes greatly In excess of demonstrated medical needs. (3) Pursuant Is a notice publIshed In then cccii Rcorsrca of August I, `010 (35 fl 02652). wlach r010red the cub. missIon of new fru gasplucallona as a onnditlon for continued maoge tine or amphetamines, 109 pew dnic apytoca. lions for amphetamor,es or arnrne:a. alizle-contslmnr droog products were received. The data submrte.ed intho.. applIcations. and data obtained from other sources conrerninq anor ectro dstgs, generally soppo rted the effIcacy of ausrectic dnigs. (be Qua the basis of currently available evidence derived from sfinrt-rarnvotuooe, the CommissIoner cinctudes that single dnog entity Oral dotage forms of am met- amine or dtxtrtamphevanune Ire ci- fective In the managemeot of evttvnous obesity as a short-term (a rev wrap) adjunct in a regimen of weight reduc- lioss, based ora Calonc r~troctlonl. frr peilent, In whom obesity as retractors to other ooeasusws. roe purposes of this regulation, a mlsture of deatroalnyheta- ovine and ampnetwoine Is ordinarIly re- garded as a ainole drug ene ti. Cc) The Food and Snag Adsnlniatrntion Is not aware of oath proeloing luostan- t al enttgnre of cute electiveness of leoasiietss,sofl rand ifs salts and retains these rreporatlcns as re. Cruvs req air- ing approval liii now-drug an priratidns. (dl in view of the woll-docolnlested hoslory of abuse of parentc -al amphe ta- mlnosthesevere rut of drug det,en defoe. arid the availability of paretteras drugs which are equally effective br recco'naicd non-anorectuc tr.dlntitfl'- tho Food said Drug Adnslrj- aIrs isn reform parrnteralarnpneta. mines as lacking evidence of safety. tel .tnyttmblnatlon drue conta mine amrbetamlne or deotrosm pneta tine Is regaxted as a new dais gretoJrln an ap, proved full ne v-drug applIcatIon as a eorartlon formarcetrng DIscs in new, drag a psligatior,aeercooaieedtugtthll the rnler.a let forth in igia goverr.ing r,xedrombmaucn presefortoon drues for hwn ens. (f) toe. drug applications have been receIved from persons marketing orally admovilotered single entity pinyhelazolne or destroamptvetansire dosage forms. Arty usher person who intends to market such drug Is repaired to submit to the Food and Drug Adfntn strati on ana 0- brev'stcd new drug application (11504 e~i except that in addition, the applI- cation thati contain flail information required under Itema 7 and I ecomposf. alan slid methods. farilt tics, and con- trtisl of the new dnig apptfration form PD-latH (EtSO.4tc)l_ eta The labelIng conditions for single entity oral dosala forms at anapiaeta- mine and dextrosnsphelaaajna and their salt. are as follows: (I) `the label shall bear the statement Caution: Federal law prohibits dam- pensing without prescription". (Is `floe drug shall be labeled to romply wIth all reqolgemeols of the act and fee' ulatluns. The labelme ahaji bear ade- quIte Iniorusation for sage and effective use of the drug. The liodicltaons for use are: )-`aeeelop,y. btlsievsi lean d,,f'soetloa lv children (bivveetioetle aabasloe als000efll. 5'5 aid aeoeeeaeiaeai050st. alasageroersi or eaogeareo aoe,lty Meson' term aioweeeoaladlsocu.aaee(l005se selthi redscsloaaaas0000aiaelaeeuirie- ales, for paileus. is elsie sieusap Is reload- seep to ether aeslsaes. (Si Complete labeling guldctinos are avaliabte from the Food and Drug Ad' nuniatratlon. in Rectilatos, proceedings soIl hi Initiated with regard to arir auth drug wattjn tne Jurndtctlon of the act which Is nt', maccard with sOils reevalaton. £ffectlre daft. This regulation shall Is cilective on March 14. 1911. rOatSt Fobrisan 7. 0975. Wmnae F. Rgvootp,o. ArdieaoMiociofe Cosvvussalseser - far Ca,sspiiaha'c(. PAGENO="0611" COMPETITIVE PROBLEMS IN THE DRUG rNDUSTRY 15033 OCT Qu ~75 * Mr. Ernest A. Carabillo, Jr. Chief, Special Programs Division FROM Chief, Special Studies Section - there are indications that the amphetamine abuse proble has changed direction and is now worsening. This paper analyzes the amphetamine abuse treads in tens of the nature of abuee and the sources of the abused drugs. k~ examination of D~LD~ data on a quarterly basis for the three year period endin5 in June 1976, indicates that a trend of dinirtishing aaptmta-mine mentions from a peak early in 1974, started to reverse itself during the last sit quartets with a Zfl inf~uase in DAt~ mentions during the past year. the emergency room data and the crisis center data did reflect the reversal of the downward trend (Pig. l).* The major reasons given for seeking help in emergency rooms are shoim in Pigura 2. The number of nentions due to overdoses and chronic effects of amphetnz~ne have boon constantly rising since the third quartor of 1973. °icdical e,ma;;incr data acceuntcd for only about one and onethird percant of DAm~: anpl;ctamine zmont±ons. They were too snorc~ and too variable ovor tthe to asses.; trends in amphetamine related duaths. .-., ~ UNITED STATES Co';ERNI'IENt A4enz 0 T61 77(11/)72 &TT~CPIt~E~T S sUBJEcT: AnalysIs of Anmphetazina Abuse Trends PAGENO="0612" 15034 COMPETrFWE PROBLEMS IN THE DRUG INDUSTRY -2- Unexpected reactions showed a transient rise early in 1974, dropped to a low early in 1975 after which it too bcgan a steady upward climb. When these raw data are converted to percent of each quarter's total, as in figure 3, it may be seen that while relative changes in overdose and unexpected results portions coaplecienc each other, there has been a small but steady increase in the relative frequency of chronic effects as a cause--indications that an increasing portion of amphetamine abuse is accounted for by individuals with access to a continuing supply of the drug. The major motive for taking amphetamine is its psychic effect as shown in Figure 4, and since the first quarter of 1974, this motive has been increasing in terms of beth absolute number of mentions and its share of all other identified motives. Although dependency and self-destruction have continuously increased in number during this period, efter the first quarter of 1975, they slowlrbut steadily diminished in relative importance. Street buys are consiscently the majar source of aphetanines leading to er.ergency room mentions (Figure 5), end a peak in both abso- lute and relative importance occurred early in 1974, coincident with the peak in unexpected reactions to the drug. This diminished by the beginning of 1975, at which tIme the nuabor of strec t buy nunrions increased, although its relative L'epettance renainad constant. Thu omly other significant source of amphetamine was from legal proscrip- tiens. Its importance, boty absolutely and relatively, betremed uut during the middle of 1914, after which it has been continuously PAGENO="0613" a - COMPETITIVE PROBLEMS N THE DRUG INDUSTRY 15035 -3- increasing in Lortas of absolute numbers (an increase of about 407,), and in its share of all sources. As street buys as well as legal prescriptions abuse sourcos can originate from prescribed drugs taken from home aedicine chest supplies, an attempt was made to estimate sehab portion of street available amphetamine is of illicit origin, what portion was stolen or diverted from legal distribution systems, and what portion can be assured to come from legally dispensed home supplies. The data available in DEA's STRIDE sysr~a can be useful in determining the sources of abused amphetamines. Rocause the d-isomer of amphetamine is pharmacologically three to four tires as patent a stimulant as the 1-ironer, coamercial manufacturers tend to separate the two isosers and market thea separately. On the ether hand, the manufacturers of illicit anphotaminos do not do so, and their product is usually a 50-50 mixture (dl-arphetaminc) Thus, `~ comparison of the relative amounts of d-amphotonine and of dl-smphetamine exhibits processed by DEA laboratories and entered iota the STRIDE system can serve as a cruda indicator of changes in the pardon of legally manufactured and illicitly manufactured aaphatanincs made available to street abuse.* An earliar analynis of ouch darn for the 18-iso,, til period from July 1971 to Doce~bor 1973, detarninod that SIR ac rha euhihits were *flinichio]jo L.t'. , Lawson, J, 9,, Ourduor, (.A. , Seoknnp, t,.N. The Suon lv, Pictrilmti,~-~ md r0 PatLrr.q rf I'r,rc of A1~ISC. Drt,~ EnfercL:ront Adstni~rrasiea, Sn-fR-li, October l~ 4. . PAGENO="0614" 15038 COMPETYrTVE PROBLEMS IN THE DRUG INDUSTRY C C C 1500 0 - 1~ 2U:. 1. :-u, * / ._.-~__-___---__---__-,-__-------------~-----_.------------- I ,- I ~J a~ 2~j0 2:: _ __ 1250 -- - - 1' 1000 1-- .~ ~:~rocnCyoocms~ o 1~ 7, *___***_% - * - **.--------r'-- - 30 S PAGENO="0615" COMPETITIVE PBOBLEMS fl~ THE DRUG INDUSTRy 15039 r~. ~- _-_*_*~\ / 2 / 0,roaic Effacia 50\~ _____ ___- 85-560 0 -77 - 40 r. 450 400 350 V\ /7 Ri 2 z~on for Cart ic 7<> 300 7) ,/ Cncxpec ted Reaction 250 - ~-r~'- -__-;~ -- z 200 -- 150 / 100 ~ I PAGENO="0616" 15042 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY bO 53 40 0 V 20 I - 70 2__IN ) /~ 1.5 So~rcc ni ~ t~rr-~ S~rcct Buy - .4 - / / - . ,- L.~ga1 ?r.25cr1?tLon 1 ~ T *~-~ ¼. .~` . . * ! . N>~ ~ ~*\ :/ Ci1ITh~~ / ~\-!~ 0 / PAGENO="0617" I COMPETITIVE PROBLEMS IN THE DRUG INDUS'PRY 15043 / ~: // - - ~ = `C I - ri I i__lI 1-J I - I o ~- I L -~ PAGENO="0618" I r o C I IC S *j%I - S tO ~ I .S0~ S ~ a ~rUI~t~ so-a. 0 0 - S I S S.. C I S - SU~ 55.. 4 S *U20 III 2 - S OC~ S I I t I 42~~~S S~Ss*.~S 2: -. I S I I 00 - * I S S - SC - S S I SZ o I_U I S -J S 5-. .r~r = I I C I I - S lot IL ~ Ib~.~tI ~. Cr I S~~4~S - r-S-. I S I 50 0 o SO I IC~ 5= - *~!- SO~ I_U!!= II - - 5, 00.05 02.-C S S 0U54 Z O,s StO_USLS5~ o_JoStflfl.5CS~i0J'5'&0 0.4 0 Ct * I S I fl-I S S S - S I S I 7 CC o C S I S 00 Il-C S S O*0 S - 0,2= I. Sr 00 I - II S 5 00 I 555 oc*~~SUtO°S S0~4 50 00.01 0~~1US S S S (52 0 Is.- I I5o0 IX S S tOSS - S I S S r S I I SW - - S S S 57 -. *55 500 5.00 (`2 * U, O 0sISi2_U'CS~5~ 5100 IS'S cc_S Th~.JSflSSU~U I C5*fr10 0 S a 05 50S*IS- 005 S I I I * S I I - S S S ItT * 0 S S ICC 5 00 5 Usc -.o icr -4 00105=_U - - I S I SC 0 IS* S 55.2 I 00 15 ~ ~ `5t0 . 00 o~ -t- -* S S I IC - . sr S C hr 0=05 *20tI*~*_U I .Itstt 552 0005 (Os.0I~ SIs*I_.UIfi S 7 s-u - OS S~2t55 0,435 S52~ I fir., 0 `2 0. NI swaqaoua aAJatadnOO 9fQ~J I PAGENO="0619" COMPETZTIVE PROBLEMS ~r THE DRUG INDUSTRY 15047 U I.J - o~-. I- z *t a - -1 - at Cu C -. I. - a', a, a. r. a C U x.,u ~..,, .t.~t -, p-o~, to', - -S a.- PAGENO="0620" 15050 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - -I Zn - 0~ - 0 0 .-sxJ sat, itt, S~t~ 00 x a. z.x1taSar~Z(X - I_i to 0S tan a-, - o~-,0~,0o- 00 000 Ui 0 * - 0~~ 0 9- - .4-iC-"-.-. i-ia I I 00 I -~I S r .a ..~ So-c a ..n.nCS 1._. ,,c.-.P-~ C = an - a IS i-I an. I .05 OI S I 5 0 I ~op_II-It *nr_.SaIan-tSan4OI"~tO -C ~ PAGENO="0621" - It-., I * fvc - C _J I I I I 0 I 0 ,-* ~JIPI o*c - I C I * * I I fl I I - * *.flefl * v,.. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15051 t `I" I M _) p0c-÷I $ -. itg~h ~ 2-0 doaa.a,.aa xs ax-I a axaza 01 _0~n 0~,- 000 000 ac~ - I. * - 0 0 = 2- PAGENO="0622" 15052 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY AN'nOnESITY DiiL~G5-GENERAL 3IE~ionAxouu FrnntLAa-r 5, 1964. To Ralph C. Smith, M.D., Acting Medical Director, From: Robert 0. Knox, M.D., Medical Officer. Subject: Drugs or classes of drugs in which there isa particular question of salary or lack (if efficacy. 1. There is serious doubt us to the efficacy of the anorexigenic drugs in general ii the treatment of obesity. (Ref:JAIA July 9, 194W, Vol. 175. pp. 1131-1135). According to one report, only 2% a ccocnpllsh a long-term reduction in weight. Most of the reports cliii ming efficacy are based on short-tern, studies, and demon- strate only a few pounds of weight loss. 2. There is also serious doubt as to the efficacy of tire peripheral vaso-dilator drugs in the treatment of intermittent cia udication. Most workrs feel that they are of little benefit, and there are reports of an actual decrease of blood flow to the muscle, coupled with the danger of liypetension due to cutaneous vaso-dilation. 3IEM0RANOUM Jnx 28, 1907. To: Merle L. Gibson, M.D., Acting Director, Division of Neuropharmacological Drugs. From Robert 0. Knox, M.D.. Medical Officer, Division of Nellropharmacologicat Drugs. Subject The need to improve the present packnge inserts for the `Anorexigenie" drugs. 1. Despite much evidence attesting to the relative Ineffectiveness of these. or any other compounds, in the treatment of obesity. aumerous preparations are widely distributed and represented to lie effective agents. 2. it a ppen rs advisable at this time to revise the present package inserts (arid thereby the ndvertising) fur these drugs Including those already on the market to reflect more a ecu ratelv the true situation. 3. Attached is a rough draft of a tentative packa go insert which may serve as a ha sis for further discussion. It would seem advi sable to invite rej resentatives from Drug Surveillance to discuss this matter with us so that we may arrive at a consensus. Several a tteinpts have already been mdc to occoarplish this, hut frequent changes in stat! have prevented any definitive step being taken. 3tmronAxolnr MAY 19, 1969. To: Merle I,. Gil son, M.D.. Director. Division of Nenro~ihariaaculogical Drugs. From Robert 0. Knox. M.D.. Division of Neuropharam:rcologieal Drugs. Subject : E~tnld I shiment of all FDA policy regarilirig anorexigenucs. 1. Du ring 196Th the NAS/NRC pa riels have evaluated various synipathonnimetlc am ines used in the treatment of obesity. For exo nude. pluenternrine a ml a irben- mnetra zinc prelu ration were evalimat ed as "Effective, but by the panel on Psyelua trie Drugs. A minority of two of the panel muemliers evaluated the syni- pat ho mimetic stiniiml in ts as ``p rol a 1 y effective.'' Thu e d oclun en ta Ii on a I per] (led to tlu,'i r opinions consist of four references : (a) TIre first by J. F. Fa zekas whi rIm discusses vo rioiis concepts in thera pv using ammorexigeumic a gents, hint Ii as ]uo aetna I clInical data. (Ii) The second is a 19-IT article in the AMA by Harris. Ivy. and Searle using Dexedrine. however, there were only sevelu tuluesi' subjects used In two sopa rate four-week i eriods dli ring wh icim tIm e lose of the 1 rug `~`as progres- sively Increased, The second experi nients concerned ten volmniteer imuedii'a I stu- dents of mmonm] I weight. (e) Time third article liv Kinard et al. has to do with the use of ri-a mphetamim'e in patients on resernine therapy. (d) TIre foum'tlu refereoce is to lJ~rrison's text irook of Internal 3tedlciue which of (`nurse commtains no actual raw data. 2. On November 20. 1968. the Council of the British Medical Association for- ~varded a report to the Interdepartmental Standing Advisory Committee on drug dependence which contained the following recommendations: PAGENO="0623" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15053 `That amphetamines and amphetamine-like compounds should only be pre- scribed for those conditions for which no re~isonah,le alternative exists, or as part of the therapy of those patients already dependent on those drugs; more specifi- cally - (1) These drugs should be avoided so far as possible in the treatment of obesity, but if in individual cases the doctor feels they must be used they should be prescribed for a limited period only The report further recommended tha manufacturers, pharmacists, nurses, and doctors should voluntarily take the so me preca utioiis. and keel) the sanie records, as they already do for those drugs covered by Part I of the Schedule of the tin ngerous I )rugs Act, 196~5.'' and that if the voluntary measures of control recommended do not succeed than restrictive legislation seems inevitable 3. According to the Report of the 23rd Session of the Commission on Narcotic Drugs of the United Notions Economics and Social Council, doted February 24. 1909. the Government of ~w'e{ien asked that nnip]ietamine. (ioxanhlillet:t mine. I net ha mi Ii eta In inc met hylphteni di te, ph came tra xi lie a ad pip rail ul I a' t'OII troll ed ii' terms of Article 3 of the 1961 Convention which has to do with narcotics. "While there were different opinions in the Commission as to the applicability of the 1961 Convention to the amphetamine-like or ally other psychotropic sub- stance. there was eonmplete unanimity that the problem of the abuse of the am- phetamine-like substances raised by Sweden was indeed a most serious problem." `The amphetamine-like substances, especially plieninetrazine to which lie had referred were taken by some 5,($M) to 10,000 lx'rsons. especially youths by in- travenoiis injections The Swedish representative "wished to record that this experience of intrave- IIOUS abuse of certain amphetalnine.like substances thus created physical de- pendence with an abstinence syndrome contrary to the description of other de- pendence of n mplietanune-like substances described by the WI 10 Committee in their 13th Report." The unanimously approved resolution of the 24-Nation body declared that abuse of amphetamine-type drugs presents a grave danger both to individuals and to society and that immediate action is necessary to combat this threat to the health of mankind. According to the Hospital Tribune of March 10. 190i), "Supporting Sweden's appeal for urgent action. D. 1'. Anand. representing India, salt! lie believed the world was confronting a greater danger through psychotropic drugs than it had with regard to traditional narcotics, lie observed that many agriculturni coun- tries have accepted controls over such crops as opium, hashish, and coca, making eeononiic sacrifices to do so. `Is it too much,' lie asked, `to expect that the manufacturing countries will show the same magnanimity as the opium-producing countries, wInch have risen above their own narrow interests by accepting controls?' 4. As regards the efficacy of the sympathomimetic ambies in the treatment of ohestiy, It should he noted that contrary to numerous articles appearing iii the literature, the efficacy of these compounds is of a very small order. For example, in the case of NDA 16-BIS, for fenfluraniine, the sponsor chooses to indicate the results iii tcriiis of average weight loss per week. Tins is merely a device for observing the fact that the actual poitiuls of weight loss by patients on fen tiara- amine averaged in most studies less than five pounds. It should he noted that most studies submitted to the FDA for anorexigenit' compounds ma for only a month or two. It is well established that the initial ent hitisia sni plus the initial ioipact of a sym~ m tlinmimel ic a mine may result in a weight loss daring the first few weeks of therapy, hut that shortly thereafter tolerance develops, entliusiasia wanes, and weight loss ceases. Indeed, in a large percentage of cases, the u-eight retnnis to the previous pre-treatinent weight. In view of the above. It may prove worthwhile: (a) To request the NAS/NUC panels to define their criteria of effectiveness. (b) To consider banning these substances entirely as Sweden has already done. (e) Alternatively, to insist on a package insert and advertising which reveals the actual total pounds of weight lost and the duration of therapy, in tabulated fashion. RonnatO. lCxox, M.D. Division of Yeuropharmacoiogicaj Drugs. PAGENO="0624" 15054 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY MEMORANDUM NOVEMBER 18, 1069. To: John Tennings. M.D., Acting Director, Bureau of Medicine. From: RobertO. Knox, M.D., DND/OND/MED. Subject: Pending class labeling for anorexigenies. I would like to draw your attention to the fact that there is now pending a class labeling for anorexigenics. This class labeling is tinder consideration for publication in the Federal Register iii the near future. Tins labeling may lead the physician to erroneously conclude that anorexigenics are more effective than they actually are. The labeling of these dregs in the liast has been misleading as far as efficacy is concerned. Would it not lie desirable to iaclude in the class label- ing a factual statement as to the actual amount of weight loss achieved iii the studies submitted in support of any given NDA? The promotion of Pro-Sate is typical in that it gives resuts in terms of the amount of weight loss pcr v-eric without giviug any idea of the total number of pounds lost or the duration of treatment. Most of the studies submitted in behalf of nnorexigeaics rim from one to two month,4 or less. The dissenting mhiority opinion of the NRC/NAS panel evaluated the sympalho-ahinietic slhiaulants as "probably effective" as anorexiants. Their reasoning for the "probably effective" evaluation was that: (a) Most studies of the preparations have been for short periods; (b) There is no available evidence that the use of these anorexiant prepara- tions alters the natural history of obesity; (e) There is some evidence that anoh-ectic effects may he strongly influenced by the suggestibility of the patient, and (d) There are reservations about the adequacy of the controls in some of the clinical studies. The minority suggested that controlled studies on the long-term anorectic efficacy of the synipatlio-minietie stimulants lie conducted. Although there may be no precedent for this type of package insert, these drugs fall into a special category as far as efficacy and abuse are concerned. Enclosed is a copy of my memorandum dated May 19, 1041.9 coacernlng the establishment of aa FDA policy regarding anerexigenics. MEMORANDUM FEBRuARY 17, 1070. To: John Jennings, M.D., Acting Director, Bureau of Medicine. From: Robert 0. Knox, M.D.. DND/ONJ), 311) 120. Subject: Position paper on FDA policy concerning the labeling of amphetamines and amphetamine-like compounds. References-fl) 3Ev memo to Dr. Gibson dated May 10, 1960. (2) My memo to Dr. Jennings dated November 18,1960. 1. I discussed labeling for the amphetamines with representatives of the Office of Marketed Drugs; however, we were unable to agree on the proper wording for the package Inserts for these drugs. 2. Therefore, I am summarizing my thoughts on this matter as follows: A. It is generally agreed that there is a definite danger of abuse connected with the use of these drugs. B. While there is no unanimity of opinion as to the efficacy of these drugs, the following opinions merit careful consideration: (a) The British Medical Association has concluded that "These drugs should lie avoided so far as possible in the treatment of obesity (h) Arthur C i-oilman has stated that"... There is no evidence to indi- cate that these agents suppress appetite as has been claimed, which is the basis usually for advocating their use. The only rationale for their use is the hope that by counteracting the depression induced by hunger the patient is better able to abstain froui overeating. However. the anorexigeuic agents have proven of little efficacy in actual Practice ..." (Pharmacology & Therapeutics. Lea and Feblger, 1065.) (c) Feinstein, A. R., J. dir. Dis, 11:349-389, No. 4, April 1960. ". . - The results obtained with anorexiant agents therefore (1) are in many instances inferior to those obtained with unsupplemeated diets, (2) show the same marked variations present in the tabulated results of diet alone, and (3) PAGENO="0625" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15055 indicate that the newer agents often compared poorly with the older ones whose deficiencies they presumably were intended to correct." "... The variety and inconsistency of these results indicate that ninny nutritional. pharmaceutical, and other theories of weight reduction have not been clini- cally verified and appear to be the result of fallacious reasoning. In the absence of cinitirniatory controlled studies and `vith Inadequate techniques for measuring accomplishment. ~suecessful' performances in weight reduc- tion have been attributed only to features of the diet or dietary adjuncts. Whenever cottiplete results have been given for dietary programs the data have shown that niore patients fail then succeed," Cd) Nutrition Reviews, Vol. 20, No. 2, p. 38, Febninry 1952. "The point which seems to have been almost forgotten in these reviews and reports is that people become and remain obese for a reason. The balance between ap- petite and requirement is upset by something else, perhaps frustration, bore- dent or disappolntnient. This is the reason why diets, drugs, and exercises are relatively ineffective in so many obese persons. Why then should physi- cians attempt to correct obesity? If not for cosmetic or social reasons, should they do so because obesity shortens life expectancy, hastens the onset of cardiovascular disease, and favors the development of diabetes? Snece'~s can be achieved only is-lien the condition for which weight reduction is advised is more serious than the urge which causes the obesity. it seems illogical for physicians to prescribe sympatliominietic dnigs which may in themselves cause as much `stress' in the long run as does the obesity itself - Ce) Edison. George R., M.D.. iii a letter to Congressman Claude Pepper. dated November 3. lOGO. ". . . I stand with a majority of physicians in feel- ing that these drugs no longer have any place in the practice of medicine. with one or two rare exceptions. I made this proposal In a letter published in the Journal of the American Medical Association over a year ago, a copy of which I am enclosing for your interest. "I understand that one or two other countries have actually banned the use of these highly dangerous drugs. There is no justificatIon for our con- tinuing their `legal' use. To continue It would be simply to perpetuate one more massive inconsistency in our standards of morality." (f) Wolff. Frederick-, Research Director at the Washington Hospital Center and Iload of George Washington University Clinical Pharmacology Division. testified at a drug price hearing on September 18. 1007. The follow- ing statement was quoted in FDC Report of September 18, 1967: "In the only questioning about specific drugs and drug classes, Wolff said that on the whole appetite suppressants which he described as a $100 million a year market, are `totally unnecessary.' They are grossly over-prescribed. have a very limited use, and on the whole, probably do more harm than good he said." C. The majority opinion of the National Research Council panel which acted upon the amphetamines declared them to be effective. The NRC has not set forth their criteria for efficacy, hut they have given certain bibliographic refer- ences, I have previously discussed in paragraph I of my memo of May 19, 1960 the inadequacies of these references. r~o Cass was also cited by them as an authority despite the fact that FDA had previously deelared Dr. Cass to be an unacceptable investigator. 3. According to MiX 16-618 (fenfiuramine) the weight loss averaged in most studies less than 5 lbs. 4. According to NDA 16-&~0 (chiortermine), the weight loss ranged from: 0.5 lbs. less than to 4.5 lbs. more than with placebo. The average difference in weight loss in these studies was 25 his, more with chilortermine than with placebo. for the 4 to S weeks for which these studies were run. (These figures represent the total amount of weight loss, not the w'eek-ly rate of loss.) In four Phase II studies, the average difference between Pre-Sate and clilortermine was 0.6 lbs., in favor of I're-Sate. 5. In addition to the fact that the above amounts of weight loss the of dubious clinical significance, there are numerous discrepancies in many of the laboratory values and the case report forms of the NDAs which I have reviewed, CONCLUSIONS 1. The present labeling fails to give the physician any idea of the degree of efficacy which has been demonstrated in the NDAs for these compounds, It is unlikely that anyone reading the present labeling would suspect that the support- 05-500 a - - 41 PAGENO="0626" 15056 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY lug data in the NDAs revealed such a limited degree of efficacy. Although we customarily do not include such information iii package inserts, the ampheta- mines constitute a special case and must he dealt with accordingly. 2. I urge that the labeling of these compounds be revised to include, in ens-li case, a factual tabulation of the actual a mounts of weight loss which have been reported by the various investigators, to iicliide the du ration of therapy, so that the physician will lie in a hotter position to decide as to whether or not use of a Syiilpthon]inrietic amine is warranted. The c"ininoii practice of expressing re- suits in terms of rate of weight loss per week is particularly objectionable and should be discontinued. 3. The duration of therapy to he recommended in the package insert is very lmportaat Various recomruendal-ions have been made, e.g.: a. Use short-term therapy as initial treatment sirily, with the purpose of re- educating the patient's eating liabits,etc. h. Use Jong-term therapy in spite of the fnct that tolerance is known to develop to the sympathominuetic amines. c. Use Intermittent therapy so as to allow the patient ii,' opportunity to regain sensitivity to the drug. Only limited results have been demonstrated with the first two methods, and the third method is merely a variation of tile second. I suggest that unless long- terni therapy can he demonstrated in controlled trials to he significantly effective, only short-term therapy be allowed. The development of tolerance figures prominently in this decision. 4. NDAs which are now under review ii' the OND pertaining to antiobesity drugs should not be approved unless: (1) a clinically significant amount of weight loss is shown by controlled trials, and (2) the package insert conforms to the above suggestions. MEMORANDUM Arnrt 8, 1970. To: John J. Jennings, MD., Acting Director, Bureau of Drugs, From: Robert 0. Knox, M.D. Subject: A suggested tabulation of therapeutic results to he Incorporated into the package insert of a sympathomimetric amine. 1. In accordance with your request of March 24. 1070, for an example of a tabulation that could be incorporated into the pack-age insert of a synipatho- mimetic a mine in order to present the physician with some plant itative results which had been demonstrated by the investigators, the attached model is sub- nutted for preliminan- consideration. 2. Some of the points shown by this tabulation are (a) the almost total lack of a dose-response relationship. (b ) the fact that most of the studies reveal less thin a 5 lbs. of tot:, I net weight loss. (c) Dr. Ilolhingsworth reports greater weight loss follow-big pliieebo than most of the other investigators reported with fentluranuae-pven using the high dose of 120 ing. 11cr clay. His results largely depended on whether feii- fluramine or placebo was given first. 3. Some relevant excerpts from `Drugs of Choice by Walter Modell. MI).. The CV. Mosliy Co., 1970, are appended: `The long-term results of anorexiant therapy are very poor at present an anorectic- a gent is likely to have as little effect ``mm I lie overall prohilein, of obesity as disulfiram ( Antabmise) has had on tine overall control of alcoholism none of the anorexiants are effective unless food intake is controlled as well hence, it Is obvious they really are not very effective against this force." `...even when the double-blind I ec-h nique is used to start, after 30 nil nutes some patients know wI, kIn is medic: it ion a i id wh ic-li is placebo, and only the physician rema his Id lad. All the lsyclne impact of the knowledge that an effective drug is being taken is thus exerted iii favor of the drug being tested. From this point of view, therefore, a difference between the effects of the pInes-ho a nd the drug in these studies may well result from the detection of this difference by the patient as well as from the action of the drug Itself." it is by no means definite that these drugs have any primary effect en appetite at nh." PAGENO="0627" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15037 NDA 16-618, PONDEREX, A. H. ROBINS CO. INC. Average total weight lass, pounds . fentlorarnine Net weight Fenflura- loss, Investigator mine Placebo pounds Duration, weeks Dose, patients milligram completing pea day the study Adult: I. Itol!ingsworth 13.8 2.9 15.9 2. Roginnky 14.1 4.4 9.7 3. Roginsky 11.2 4.4 6.8 4. Hollinngsworth 7.6 12.8 +3.2 5. Roginnsky 7.0 4.0 4.0 6. Hurts 4.8 .3 4.5 8 12 12 8 12 4 220 24 60 28 40 27 120 10 80 30 60 15 7. Rosenberg 4.7 `.7 3.0 8. Rosenberg 3.6 1.7 1.9 1-12 4-8 120 29 0 9. Stern 3.0 .4 2.6 10. Each 2.6 .3 2.3 8 4 80 20 120 04 10. 0 `en lneft~tive 2 40 12 Pediat,ic: 12. Andersen 5.7 -F. 7 3 90 20 13. Baco 4.8 -i-.7 ~.5 4 20-60 14. Bacona 2.2 +.7 2.9 4 20-60 20 a Crossover, giving fent9urarniise first. 2 C ronsocer, gic a ng placebo first MEMORANDUM APRIL 0, 1071. To: Barrett Scoville, M.D., Deputy Director. Frosas: Robert Knox, 31.1). Subject: Notes oxi the panel discussion on anorexic drugs held April 6, 1071. SUMMARY Dr. Prout, Chairman Dr Reidenberg Dr. Goldberg Dr. Rogers Dr. (`rowell Dr. liollingswortlu Dr. Ciuristalcis Dr. Hertirig, Abbott Labs Dr. Bray Dr. Scoville Dr. Front reviewed the agenda which had been previously distributed by tine FDA, and then called on Dr. Ilerting to present the indust~'s view of the matter. Dr. Herting discus~rl the pliarasuacology of the aniphetaminoes arid their clinical uses, He stated that there does seem to be some detinnite evidence for the fact that the value of an appetite suppressant is tlsat it gives you about two times the rate of weight loss that diet alone does. That seems to hold up whether you give pla- cebo or not. The duration of these studies was 12 weeks up to 20 weeks; 24 weeks was about the longest hut it didn't have placebo. Intermittent and cr,nstinssoiss treatment were compared with Tessuate 1)ospaou being used. The actual total weight loss on intermittent was a little greater-but tin' continuous therapy ac- tually did a little better (sic). RegaiNling tolerance, lie said that there is some evidence that at least it is riot a 2-3 week effect. mu the literature, a really good program reaches 55 percent of target weight in females in a 12-week period, and 37 percent of the piacelx, groups arrived at a-desired weight loss at the end of the 12 weeks. Males r~-S5 percent with drugs 25 Percent with, placebo. (When flues- tioused by Dr. Pronit as to what constituted "target ~veighut," Dr. Ilerting replied that in general the target weight was the ``Ideal weight as listed in the Metro- politan Tables.) There Is little or nothing to prove tine hong-term efficacy of these dngs. The suspicion is Gnat most of the patients are fat again. The question is whether they would have been fatter without the drugs. Dr. Ilerting went on to compare tine situation to that of the anti-eoagulants----dises tine drnsg have to be proven to do any real good? Dr. i'rout stated that yoni obviously c~n't ask the drug ot do anything In tIne long ranre. lie asked Pr. Ilerting to sent a copy of his laiblingraidoy to Dr. Seo- voIle (this was In relation to Dr. Ilerting's claim that 55 percent of ideal weight had been achieved using those drugs for 12 week). Dr. Reidenberg poonted out the importance of reali'ing the obese patients, are terribly hetro geneous as to their characteristics and said we should define the groups in which PAGENO="0628" 15058 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY it works. lie asked how important is the euphoric effect; and went on to say that a certain number are depressed and therefore an anti-depressant drug would be better. Dr. Hollingsworth seconded Dr. Reidenberg's comment and said that Itis vital we know more about CNS effects, nor.epiuelillriae, growth hormone, in- sulin . . we ought to start with animal models. ~he then said that a large group of obese are never hungry-how then call you evaluate an anorxigenic in these patients? . . . polydipsia Is very common on the other hand ... I have not beet, able to rationalize placing fat children on drugs. Dr. Prout then stated that we accept the potential value of these drugs. He next said that It is very important to avoid bias on the part of the person who analyzes the data (this remark seemed to tie directed at the statistics). The panel agreed that patients should he at least 20 percent over the Metro- politan ideal weights to be included in a study. Dr. Goldberg said that we must exclude hypertensives if Phase 1 data sug- gest that the drug he contralndlcatcd. Dr. Prey voiced the opinion that of course there are standard reference drugs which are effective. Dr. Reidenberg replied that Dr. lenry Simmons had just Indicated that efficacy had not been conclusively demonstrated for any of these drugs. Dr. Christakis made a plea for caution and responsibility on the part of the profession-the burden is on Industry-in vielv of the great potential for harni from these drugs. Dr. Prout felt that 12 weeks was the minimum duration of therapy with these drugs that would provide meaningful data. Dr. Bray felt that C-S week-s was enough. Dr. Ilolllngsworth pointed out that obesity was a life-long disease. Dr. Goldberg said that the number of weeks should be put in the package Insert. Dr. Knox then asked Dr. Prout how efficacy conk-I he defined. The reply was that the Federal Register contained the statement that these drugs have short- term efficacy and therefore the Panel could not consider the question as to whether there was a medical significance involved, In other words we must ac eept any statistically significant difference as acceptable evidence of efficacy. (Dr. Prout followed up by saying that in his opinion none of these drugs were of any value and that he would not use them). Mat.roaArqnuM Arait 12, 1971. To: Henry Fl. Simmons, Director, Bureau of Drugs, PD-i. From: Barrett Seoville, M.D., Deputy Director, DNDI', BD-120. Subject: Brief abstract of meeting of advisory group on the drug treatment of of iesity, April 6, 1971. A group of consultants with a special interest or experience in the drug treat- ment of obesity convened on April 6 for a one-day discussion of the questions in the attached agenda. The conclusions of the group as expressed by the chairman, Dr. Prout appeared to lie essentially the following: 1. Anorectlc agents are potentially of value. 2. Long-term follow-up in respect to drug efficacy of patients who have lost weight on a regimen involving Anorectic drugs is not the responsihility of drug manufacturing finns. A short term follow-up of a few week-s could reasonably he asked of drug manufactures. 3. Efficacy of anorectic agents should depend on the demonstration of statisti- cal superiority of drug to placebo. The group, through its chairman, explicitly declined to require "biological" superiority, e.g., some minimum loss in terms of percentage of excess weight. 4. A minimum duration for efficacy trials of 12 weeks was proposed, Labeling claims sholih-l reflect the duration of trials. 5. A number of changes in details of the PMA version of second-draft guide- lines were proposed. The long "philosophical" discussion of various criteria of efficacy on pp. 11-17 was excluded from discussion. Norn,-Tn view of the long-range implications of the group's conclusions for trials of anoreetic agents, particularly insofar as they may relax efficacy criteria, PAGENO="0629" COMPETITIVE PROBLEMS ~ THE DRUG INDUSTRY 15059 I believe the conclusions should be discussed within FDA before any possible uncritical release of them to the public. DARREll SCOVILLE, M.D., Dcput~ Director, Division of Neuropharmacological Drug Products, Office of Scientific Evaluation, Bureau of Drugs. Those present at meeting: George 3. Christakis, MI).; Edward I'. Crowell, D.C.; Leon I. Goldberg, Ph. D., M.D.; Dorothy Hollingsworth, M.D.; Daniel M. Rogers, M.D.; Thaddeus E. Prout, M.D., Marcus Reidenberg, M.D.; George Bray, M.D.; Robert Ilcrting, M.D., Ph. D.; and Barrett Scoville, M.D. 3lncoRANDmf APRIL 10, 1971. To; Dr. Marion Finkel, Department Director, Bureau of Drugs. From: Leszek Ochota, M.D., I). Sc., DNPDP. Subject: IND 420 for Stimsen (thozalinone) Lederle Labs. Dr. Finkel's `lierno of April 8, 1071. SUMMARY Dr. Finkel; Since you may have been possibly misinformed about the discussion of the guidelines for antiohesity agents by the Committee that met at the FDA on April (1, 1971, I would like to call your attention to the following facts: The Chairman of the Committee, Dr. Thaddeus Front rather forcefully proposed a minimum of 12 wecks for the study of the anorexigenic agents, with additional 2 weeks for "followup". While other members of the Committee did not comment on this problem, I did amplify Dr. Bray's position by citing several unpublished, well controlled studies which showed that adequate (leeisioll as to the effectiveness may be made after 4 to 8 weeks of study. NB: I personally believe that there is no scientific rational for the 12-week studies of the antiohesity agents, and agree with Dr. Bray that 4 to S weeks studies are entirely satisfactory. LE5ZMC OcHoTA, M.D., D. Sc., Supervisor, Jfcdicat Office, Division of Ncuropharmacologicai Drug Products. MEMORANDUM SaprEMBER 22, 1011. To: The Commissioner. From: Henry K Simmons, M.D., M.P.H.. Director, Bureau of Drugs. Subject: Neuropharmacology Advisory Committee MeetIng, September 13-14, 1971. PURPOSE The following Is an abstract of the issues considered and the recommenda- tions made by the Nei,ropharrnncology Advisory Committee at their meeting on Septernher 13-14, 1911. TEXT OF THE INFORMATION A. Parafon Forte I and Parc flex 1. The firms can make only these claims for which they have shown sufficient data. It was generally agreed that Parafon showed statistical superiority over placebo with respect to low-hack pain; however, there was lack of evidence that the improvement, was due tn a specific niuscie relaxant effect. 2. Other suggestions to he communicated to the finn Include: - a. Eva'nation of these drugs with standard treatments (sedatives and analgesics). h. Testing of other specific syndromes (cervical psin. etc.). c. Ontimization of dosage sehodulec and correlat%o,i with blood levels. d. There should he continued efforts for definition of criteria for improvement. e. Relationships between statistical significance and clinical significance should be clearly defined. PAGENO="0630" 15060 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY B. Navunc 1,NDA's need to be more adequately organized awl the data better documented. 2. It was suggested that Dr. Mitchell Baiter (NIMII) be invited to the next consideri ug efficacy based on the material available to the coammittee members, 3. All medical officers reviews should he standardized. A sample is to be presented to I lie Committee prior to the next meeting. C'. Class labcling I. Committee members were not ii' total agreement that psychomicti ye drugs should not he used for stresses of eyerydimv life in mion-diagnosis patients. Data at tins time, however, Is not available. It was the opinion of some of the Coiimiaitte*' inemliliers that advertising for a psychoactive drug should promote time drug emily for svmptonmatic relief of anxiety In medically or psychiatrically diagnosed dis- orders. Mr. Jerome Levine (NIMI!) is to investigate possibilities for implement- ing research in time area of psychotronic drugs used for the relief of iymnptoms produced by everyday stresses. 2. It was suggested that Dr. Mitchell Walter (NJMH) be invited to the next Coummnittee meeting for discussions of his findings concerning the patterns of use of psychoactive drugs. 1). ltyderginc 1. The Com mnittee did not vote as to whether or not the submission would be considered acceptable since they had not reviewed the actual data. 2. It was suggested that definite benefits could he derived from appointing a Task Force ~vliiclm would consider the development of geriatric scales (standard) and in establishing criteria for the evaluation of studies in the geriatric population. F. Anorejqge,,ie agmmtg 1. The length of time for testing such agents should lie at least 12 weeks. 2. Criteria have been proposed by a previous committee with expertise in the use of such agents. Jf data show that, such agents are effective in obesity, the Neuropharinncology Advisory Committee will become involved In discussions regarding possible abuse potential. F. Con flirt of in terest 1. The Members of the Committee expressed a concern in this area since most, if not all, ha ye been or are involved in consulti ~mg ~vi tim or conducting trials for various drug firms. They wish to the appraised (if the legal responsibilities and lnq lien lions. 2. This topic is to lie placed on the next Agenda and specific standards for procedure will he proposed. 0. Rci'icu' of `possibly effective" drugs The Committee was generally in favor of Dr. Finkel's discussion of the proposal that Committee members (or Junior Staff) be actively involved In the evaluation of such drugs. Tun FDA Raviaw OF Axogrcnc DRTrc,s: EAcKc.Rovyo. CURnENT .STA'rjrs.Arcn Pa0nLEM AREAS (Presented by llarrett Scoville. M.D.. Deputy Director and Elmer A. Gardner, * M.D.. Director, Division of Neuronharmacologleal Drug Products, Food and Drug Administration, as part of the synmimsium "Dru~s nnd the Control of Overweirht: Medical Considerations and Public Policy ," June 12. 1972. Wash- ington Bilton flotel. Washington, D.C.) The Food and Drug Administration Is Intensely interested In the discussions of this symposium and appreciates lioth the efforts that have gone into it and the opportunity to exchange ideas with other discussants, This is a time at which policy in respect to the use of nnorectic drugs Is hehmg formulated, and we are seeking as much Input as possible. The title of tie symposium summarizes time issue, which is one not iust of a medical decision hut one of public policy. It is a narticularlv difficult area, In which facts and value judrments are often unwittingly confused. Obesity. nI. most alone among the nathologieni conditions, remains a moral Issue in many people's eyes., as Jean Mayer regretfully noted. It is regarded with the severity PAGENO="0631" COMPETITIVE PROBLEMS Th~ THE DRUG ~ThUSTRY 15061 of a sin, rather than with the humility which would be appropriate to a condi- tion the causes of which are poorly known and the treatment of which is diffi- cult. As if that weren't enough. the drugs proposed for treatnient almost all involve a set of moral issues of their ow-li, I hose a 550cm ted with drug abuse. In preparing broad policy on tile use of anorectic drugs we have been review- iiig quest loris 9550cm ted with them quite intensively since late last fall, through a project of which have been the manager and Dr. Gardner the chief adviser, and of which I will tell you niore later. The questions underlying the discussions here are not new, and you may won- der what leads FDA to review the question of auorectic-s at tins time. Broad national concern for drug abase, including CNS stimulant drug abuse, lies be- lurid many of the questions, but there are four relatively recent elements which have made more a cute the need for broad policy. The first factor was the Drug Efficacy Study, In this study the National Academy of Science/Nntio,ml Research Council and FDA reviewed the status of all drugs-approxiniuteiy $01$)-~vhich were first ritarketed between 1035 and tile passage of the Kefairver-Harris amendments to the Food Drug and Cos- inetie Act in 10432. These 3000 drugs included all marketed anorectic agents ex- cept one (Pre-Sate or chiorphentermino). The NAS/NRC Panels expressed qual- itications as to efficacy of anorectics so that the FDA publications on allorectics to date have indicated them to lie less than effective, requiring more evidence in the form of clinical trials. Such evidence has been submitted, and I'll come to that later. As a corollary of the NAS/NRC review, FDA also reviewed tile status of the amphetanmines and concluded that they, too, were affected. Amphetamine manu- facturers responded in 1071 and 1072 to an FDA announcement to this effect with applications to continue nmark-eting lOG amphetamine drug products. The need to review tile 1043 amphetamine applications and other material sub- mitted in the context of tile Drug Efficacy Study was the first element leading to our project. A second Involved applications for drugs net yet on the market. Within the last year and a half. 3 major manufacturers have requested ap- riroval for marketing of anorectic agents which they had been investigating, and of course decisions are required here consistent with any policy relevant to anorectics subject to the Drug Efficacy Study. The third and fourth elements requiring policy towards anorectics involve drug abuse, with its ninny medical, social, and legislative implications. The prob- louis of drug abuse led hi October, 1070 to the ~massage of the comprehensive Drug Abuse Prevention and Control Act. This Act, also known as the Controlled Substances Act, vests a number of responsibilities in the Department of Health, Education and Welfare; two are of particular concern to FDA in respect to anoreetics. One is the need to determine the degree of control under tIme various schedules of the Act appropriate to any drugs with abuse potential or which mire abused. More control has been considered necessary for oral mnethnnipheta- nmlne, the other amphetamines, and pheametrazine, for example, and they have now been placed under time restrictions of Schedule II. The remaining anorectics nrc not controlled under any schedule, and it has been proposed by some that amphetamine conzeners like diofh"hiropion and benzmihetamine have abuse potential, too, so that their use should also lie restricted. The Secretary of HEW hears fundamental responsibilities in respect to scheduling drugs, and within 1IE\\'. FDA plays a leading role in advising the Secretary. The last major element which has led to the current review' of anorectic efficacy is another new responsibility stemming from the Comprehensive Drug Abuse Act, Thig is the Secretary of HEW's new responsibility to report to the Department of Justice on the legitimate medical and scientific needs In the ITS. for drugs controlled in Schedule IT. Tins means specifically how much amnhcta- mine. metllarnlihetamine, and phenmetrazine is needed each year in the legiti- mute treatment of obesity. Witlun the Department of Justice, the Bureau of Narcotics and Dangerous Drugs relies heavily on HEW estimates of medical riced In establishing quotas for the amounts of these drugs which may he manufactured each year. Sn, to summarize, the efficacy review of older onorectic drugs, the review of arimilications to murket new entities, the responsibility to determine appropri- ate control schedules for abusable drugs, and the resnonsihility to estimate med- ical needs for anorpeticq hove been the four major immediate elements lending to our present work to define more clearly and consistently the place of anti- ohmesity drugs. PAGENO="0632" 15062 COMPETITIvE PROBLEMS IN THE DRUG LNDTJSTRY In reviewing the place of anorectic agents In the treatment of obesity, we decided to review the entire therapeutic class. here are the drugs Involved, by generic name (Slide). The list begins with the various amphetamines anti l'reludin, goes through marketed congeners of the amphetamines of which many practitioners are una~vare-l'legine, Didrex, lonarnin, `l'enuate, and l're-Sote-, includes three non-marketed compounds, some of which may be different from the amphetamines-and ends with a drug at one time marketed over-the-counter for weight control, ~henyipropanoiamine, We have looked at the class as a whole for several reasons, One reason might he cal led intellectual and administrative consistency, that is. that coin- parable drugs be evaluated in a similar way. But tile most important reason involves abuse of these drugs, The abuse potential of the amphetamine and phenmetrazine has been relatively well definer]. particularly by events here, in Sweden and Japan. The ahuse potential of the lesser known compounds is much more poorly defined. But we believe it should be considered carefully across the board, lest an action decreasing the availability of certain drugs merely lead to the abuse of others, in the way that restrictions on the anipheta- mines In Sweden appeared to lead to abuse of pheametrazine nnd inethylpheni- date (Slide 2). Here are the prescriptions written for antiobesity agents. Tile profound drop in amphetamine prescribing represents the impact of the placing of these drugs in Schedule II of the Comprehensive Drug Abuse Act, with its requirements that prescriptions be non-refillable and that separate records he kept. We are watching the prescribing rates for amphetamine cogeners, which are here combined. Wilt some of them merely replace the amphetamines In the legitimate treatment of the oliese-or will their use become characterized by the excesses associated with the abuse of amphetamines? There appear to us to he a number of options for action in respect to anorectie drugs, They involve removal of drugs, relabeling drugs, rescheduling them, recommending quotas, and requesting further tests. In more detail, the options are as follows: 1, It Is conceivable that the amphetamines or other anorectlcs might he re- moved totally from the market. The practitioner would then he obligated to use alternative drugs or diet alone in treating the obese. In this respect we see little place for the use of parenteral amphetamines, and at this moment have some doubt about the oral amphetamines when suitable alternatives appear available. 2. Tile amphetamines ond other nnorecties might he relabeled in a consistent fashion indicating use only in certaia patients, for example those refractory to other regiinen.s or otherwise characterized, or only under certain conditions, for examnple, only after a brief trial Ia which the patient is ohscn-ed to lose weight. The amount of weight loss to be expected and a reasonable duration of therapy might also he indicated. 3. The congeners of amphetamines might be placed in Schedule III or Sched. ue II of the Drug Abuse Act. Schedule III serves chiefly to alert prescribers to abuse potential; drugs in Schedule II are under fairly severe restrictions re- ferred to previously. 4. Quotas might be imposed on the production of anorectic drugs to decrease their availability for abuse and diversion. At In-esent quotas may only be set for drugs in Schedule II. 5. Further testing, both for clinical efficacy and for potential to Induce de- pendence, might be required for some or all anoretic agents. In respect to abuse potential, drugs might be scheduled in Schedule III or II pending results of studies. A prominent problem here is the imncertnin predictive value of even the most promising tests, the self-administration studies in primates. As you all know, data on which to base a rational choice among these options or against them vary also in quality and quantity for different drugs. For some of the most important questions they may be almost lacking, In particulor, there are unanswered questions as to clinical efficacy and as to abuse potential, and we have concentrated our efforts on these questions. in re- spect to efficacy, the most important is that of how the pharmacologic effect of anorectic drugs is translated into clinical terms. Weight loss is the chief de- sideratum. But bow much. expressed in what terms, at what rate, for how long? And in what percentage of obese subjects, and u-bat are the characteristics of those who lose? For bow long should the drugs be tried before the drug Is con- sideied a failure? Given answers to some of those questions, can the different drugs be distinguished oae from another, or ranked in terms of efficiency? Are PAGENO="0633" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15063 amphetamines more effective in more people titan newer congeners-or could they be replaced by these cogeaters? The FlU. has i a the form of new drug applications and notices of invest iga- tons a at uaisi railed respository of (I ata, supplied by itianufacturing finns, in- eluding in most cases the individual patient data sheets from patients iii clinical trials, These exist both for the newest sul,niissions and for those pertaiiii ug to inasit of the older drugs. (Slide). These are the tuinibers of applications on file with FDA for anorectics. They constitute over 1100 volumes of materIal. We believe they contain data which if analyzed will clarify the answers to at number of the questions just referred to. `oat veittiojial ha aid-retrieval and scholarly review of this mass of material is lie- yotid our resources of bitt Ii ste if anti time. We thus chose to screen material relevant to efficacy. 1111(1 sulunit coiitniliod. double-blind studies to analysis by computer rather than by medical officers. Characteristics of each subject, as well as eat-li study, and ft dlow-up data at each vlsi t were coded and key lunched nit stands rd data cards. Tite citrUs are then interrogated in different programs, and tia ta tititulal ed or aim lvzed lii various ways. Here are some of the b,i ck- ground facts and flmliiigs obtained so far. (Slide) There are now 206 studies available for analysis tot aitort-etic agents. Of these about 143 are Isirallel studies. The great inaji,ritv of the studies deal with dextroamphetamine. niethampheta- mine, diethylpropiort. pheaterniine, phtenmetrazine, chlorphenterin me, fenflura- mine, clortermine, and mazindole. The duration of the studies ranges from S weeks to B months, although few, if any studies retain a significant number of subjects for longer than 16 weeks. I had hoped to present a comprehensive overview of all studhe~. Although those working on the computer end of the project have achieved a great deal, programs are still not fully debugged, so that we nfl- running behind, and I an, most re- gretfully unable to talk on the basis of knowledge of 204i thoroughly analyzed studies. What we do have is satisfying but not startling. In those infrequent studies with relatively low drop-out rates in which obese subjects were treated for eight or twelve weeks with drugs such as dextroainphetamine, phenmetra- line. diethyipropion, fenfluramine and chiorphentermine or with placebo, those treated with active medication do show a weight loss of almost a pound a week iaore than those on placebo, or about 1 to 2 munds per week total weight loss. Preliminary analyses in terms of percent of initial weight lost, or percent of excess u-eight lost appear to confirm the differences. The role of the investigator is important, but even investigators who achieved maxImal weight loss on pla- cebo induced even more with active drug. Comparisons between drugs are gen- erally only possible indirectly and so are imperfect at present; but the weight loss induced through the use of different drugs appears to be of the same order of magnitude-no one drug has appeared superior. We now believe that the project will be finally completed by August 1, Instead of July 1, as originally projected. In respect to the question of relative abuse potential of amphetamine cogeners, the data remain meager, as you know. Similar toxicologic and pharmacologic profiles suggest that the drugs differ chiefly in potency. Monkey self-administra- tion data and human "liking" scores are present only for a few drugs and are of uncertain value. Are amphetamine cogeners relatively little abused for intrinsic reasons-or merely because of the easy availability of the cheaper prototype compound? Confronted w-lth incomplete data, do we attempt to predict abuse potential-or do we wait until there Is a full-blown epidemic of abuse of a given drug? This is one of the questions we ask your comments and advice on in discussion today and tomorrow. Ultimately, we must all weigh the potential benefits of these drugs against the risks of the drugs. Here we hope that In giving your opinion, you will consider risk in its largest sense--not simply the innate clinical toxicity of the anorcetics, but the risk to the public health of potential abuse. We do want to hear what these drugs mean in medical practice. But we also must think in the somew-hat less familiar terms of drug abuse. Here is a problem from which we cannot divorce our thinking in favor of medical considerations. It is here that tIme in- formation gaps are greatest, and where we need the hroadest, best informed, and most open discussion of tile questions on which reasonable and consistent national regulatory policy and medical attitudes towards anorectics must he based, The questions which must be asked regarding the balance between the benefits to be gained by the use of appetite suppressants in weight reduction and the PAGENO="0634" 15064 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY risk to society from the abuse of some of these drugs do not present all-or-nothing alternatives; the questions do not simply Involve questions such as-is It benefi- cial for the obese to lose weight and do drugs hell) in weight reduction for a size- able proportion of any population group than would diet, exercise, counseling, and so forth without medico ti.,n. The other questions which must be asked are 1. Do some of the drugs represent a public health risk and, if so, are there alternative drugs with equal efficiency and less or no public health risk? 2. Are the anoreetics being used largely in weight reduction programs for populations with medical disability or increased risk of morbidity and mortality, or is time great bulk of utilization for esthetic purposes-for example in women with mild to moderate obesity. 3. If there is a public health risk due to medical misuse and due to illicit di- version with street abuse", are we talking about reasonahle and legitimate Ire- scriptloa and utilization of these drugs or are we, in fact, dealing with an abund- ance of drugs which are mm]anufactured in amounts well heyond that needed for any treatment of obesity-with overprescription and loose or careless utiliza- tion? Let me in this respect give you figures on amphetamines and methampheta- mine production. Regardless of whether the anorectics are misused by medical uscr.s of these drugs or abused by non-medical users-psychopathic or otherwIse-is there a public health risk and, If so. do overlYrescription, careless prescription, Over-pro- duction, and the use of drugs with greater abuse potential than others contribute to such a risk, what can be done? W'ijl more intensive medical education cam- ~igns help? Would greater peer review and/or control through medienl societies be beneficial? Must sonic drugs be lilacS under prescription and record keeping control-as in Schedule II? Must production controls or quotas be maintained for sonic drugs? When there is a public health risk, these questions can't be ignored and the best information and opinion curren fly available is needed to make what are obviously complex, multifaceted social as well as scientific judgments and decisions. FINAL REPORT TO TIlE DIREcToR, BI~nEALt OF DRUGS. BY TITADnEL'S E. Pgom', M.D., CHAIR\IAN, CONsULTANTS ON AxoREcTrc Dgt'Gs On June 27 and July 25, 1972, a group of clhiicians amid statisticians met under my chairmanship to review data compiled by FDA Staff on the safety and efficacy of anorectic drugs. After careful review of clinical trials and of pharmacologic data the following conclusions were reached and recomendatiomis made: CONCLLSTON5 1. Adult obese subjects instructed In dietary management and treated wit:, "ammorectic" drugs on the average tend to lose muore weight than those treated with placel mo and diet in rel:mti vely short-term trials. 2. The amount of weight loss associated with the use of an "nuorec-tic" drug varies from trial to trial. The possible origins of the increased weight loss due to the various drug effects are not established. The increased weight loss appears to he related to variables other than the drug prescribed, such as the physician- investigator, the population treated, and the diet prescrihed Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss. 3. The magnitude of increased weight loss of drug treated patients over placebo treated patients was (only a fraction of a pound it week). The rate of weight loss was greatest in the first week-s of therapy for both drug and placebo subjects and tended to decrease in succeeding weeks. 4. The natural history of obesity is measured in years, whereas the studies cited are restricted to a few weeks duration : thus, the total Impact of drug- induced weight loss os-er that of diet alone must he considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors Inherent in their use. 5. The amphetamines including methamphetnmine have been n-idly ahusd in numerous populations. It Is thus in the best interests of the public health PAGENO="0635" CO~ETITWE PROBLEMS fl~ THE DRUG iNDUSTRY 15065 to limit the use of amphetamines as far as is compatible with adequate therapy. This is both to minimize the risk of dependence in susceptible iiatleiits being treated and to deerease the amount of drugs being distributed, since widespread prescription of a dependence-producing drug inevitably increases the posstblhity for diversion to non-medical use and abuse. 6. Evidence presented for newer "anorectic" congeilers of the amphetamine family and non-amphetamine drugs di, not set them apart as having higher bene- fit or lower risks than older available drugs. The risk potential of Fearfiuramine may be an excepilon to this general statement. 7 There was no evidence in the data review-ed which showed that combina- tion of all "anorectic" agent with other drugs increase the benefits or reduce the risk of the "anorectic" agent. K There are no clinical data w-hich support the parenteral use of these drugs in the treatment of obesity. Obesity Is not on Indication for the parenteral use of these agents. REcoM MnnATroNs 1. That all "anorectics" reviewed, (dI-amphetamine, d-amphetamine. metham- pitetamine, benzphetamine, phentermine, chlorphentermine. clorterinine, pLea- metrazine, pliend imet razine, fentlurami,ie. mazindol and diethylpropion ) with the exception of feyitluramine, be placed on Schedule II oil the basis of abuse potential. 2. That combinations of "anoreetics" with other drugs he evaluated in accord- ance with the policy of the El )A on combination drugs, that cacti constituent of the drug coinhii,iatlon contribute to the total effect cmi med for the combined drugs, and that the present available and proposed drug combinations he handled in this manner in view of the Lick of demonstrated efficacy for each of the con- stituents of the drug combinations reviewed. 3. That amphetamines prepared for or in a form suitable for parenteral use not lie approved for use in the treatment of obesity. 4. The single-entity oral "anoreetlc" preparations including the amphetamines be permitted to he labeled for restricted use In obesity provided that they are used in association with a specific weight, reduction program and that the din- ically trivial contribution of these drugs to the overall weight reduction is prop- erly emphasized. To carry out the latter recommendation of a statement such as that made In the conclusions drawn from this review must lie included in all labeling and promotional products. This statement should include the follow-lag points: Studies of the effect of "anoreetic" drugs in the treatment of obesity when compared with the effects on patients treated in a similar manner without the use of the drugs demonstrate that the magnitude of weight loss of drug treated patients over non-drug treated patients was only a fractioa of a pound a week. The rate of weight loss was greatest in the first weeks of study for both the drug and the non-drug treated subjects and tended to decrease in succeeding weeks. The natural history of obesity is measured in years whereas the studies offered for review are restricted to a few weeks duration. `l'hns, the total impact of ``drug induced" weight loss over that of diet alone must lie considered clin- ically trivial. The limited usefulness of these agents must he measured against any possible risk factors such as nervousness, insomnia and drug habituation that might be inherent in their use. Moreover, these agents can only be recom- mended for use in the treatment of obesity in a carefully monitored and speci- fied weight redaction program under the care of a physician. 5. That future approval of all `anorectie" drugs prepared for future use he based on demonstration of efficacy as measured by statistical superiority of the drug over placebo in trial using FDA recommended protocols. These protocols should include provisioas, among others, for the testing of a specific target population, specification of a minimum duration trial to assure clinical relevance of the study and give consideration to the handling of patient dropout. 6. }`urther, that appropriate summary data derived from efficacy studies be presented in labeling and in all promotional material to indicate the degree of weight loss that was found. For this purpose guidelines noted in (4) above should be supplemented by the addition of the specific facts found for the -specific drug under consideration, PAGENO="0636" 15066 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMOEANIWM OCTOBER 6, 1972. To: The Commissioner. From: henry E. Simmons, MI)., MPh., I )ircctor, Bureau of Drugs. Subject : Amphetamines and other Anorectics-.4etion Memorandum. ISSuE The use of ampheta mines and other anoreetic drugs iii treating obesity has raised questions with respect Itoth to efficacy and to abuse potential of these drugs. FDA must act upoti a large number of New )rug Applications for many of these drugs. In addition, Fl )A must reconinlelni to BNI )T) whether those a norectic drugs as yet unscheduled under the Controlled Sul stailces Act possess sufficient abuse potential to require rescheduling. FACTS By a Statement of I'olicy and InteriretatiOll (August 8, 1970), FDA required the submission of New Drug Applications for amphetamines. One hundred and six applications were submitted and 55 are awaiting action, 51 having been withdrawn lit the interi `a been use ma rk-etitig ceased. In addition to the a inphetamines. phenmetrazine. pliendimetra zine. benzphet- am] ne, phentermine, oh lorphientern~ine. and diet liylpropion are also marketed as anorectics. All hut chiorplientermine require action under the Drug Efficacy study, since they were first marketed prior to 1962. The initial publication on these drugs as single entities under the DESI study las not yet occurred. New Drug Ap~dications for three previously unmarketed drugs (clortermine (Voraitil ) fcnliuramine (I'ondiinia ) . niazindole ( Sanorex ) ) have been sub- mUted and also require action. The amphetamines and phenmetrazine are in Schedule II of the Controlled Substances Act. As such, the Bureau of Narcotics anti Dangerous I)rugs sets manufactu ring quotas for them, based in large part upon estirna tee of medical need for these substances provided by FDA. Our estimates for 1073 are overdue. All of the anorectic drugs appear to possess at least some degree of abuse potential, but on)y the amphetamines and phenmetrazine are currently scheduled under the Controlled Substances Act. The scheduling of all drugs in this class thus appears in need of revision. DISCUSSION The attached action tnenora,ulnnt from Dr. Cront to me outlines in depth the problems, alternative solutions, and potential Impact of various solutions to this complex question. There are numerous drugs involved, the medical condition for which they are used Is widespread, and a number of value judgments are involved none of the solutions is free of controversy. Staff within the Bureau have studied these problems intensively and compiled all available data over the past seven months, utilizing consultant advice where possible. I believe that the attached memorandum describes a coherent and reasonable set of actions on these problems. I also believe that action should he take,, now on each of the items listed, but we should be explicitly prepared to re-evaluate our position in a year, particularly with respect to the use, or overuse, of the amphetamines and to the possi hip increased abuse of alternative agents, ItEOOMMENImATION That under the set of Dcri8ions below, those alternatives nnmbered ``1'' be approved under sections "A" throng]. "11' and all actions except "ES" be approved under "E" and "F". DEcISIoNs A. With respect to the approval of anorectics Ia general: (These alternatives are mutually exclusive.) I. Base judgments on the efficacy of anorec'tic drugs on the currently avail- able substam tial evidence derived from short-term studies (up to 8 months). We recommend that this be coupled with a requirement for further testing wIth re- spect to abuse potential. (See 1)-i below) Approved Disapproved PAGENO="0637" COi~fPETITWE PROBLEMS iN THE DRUG INDUSTRY 15067 2. Require that the efficocy of .qnorectics be based on substantial evidence that the use of these drugs results in achievement and maintenance of weight loss, with improved morbidity or mortality. Approved Disapproved 3. Approve anorectics based on short-tern trials, but simultaneously require itmg-term studies. Approved Disapproved B. with respect to amphetamines, including oral inethamphetamine: (These alternatives are nuitually exclusive.) 1. Label amphetamines to exclude use in obesity. Approved Disapproved 2. Label aniithetauiiites for restricted use in obesity, e.g., for patients refractory to other dnig therapy. Approved Disapproved 3. ContInue current labeling for amphetamines, i.e., for narcolepsy, for minimal brain dysfunction, and for short-term adjunctive use in obesity. Approved Disapproved C. With respect to abuse potential: (These alternatives nre mutually exclu- sive.) 1. Recommend that all anorectic~ execØ fenfiuramine be placed in Schedule 11 of the Comprehensive Drug Abuse Act, fenfiuramine to be placed in Schedule IV. Approved Disapproved 2. Recommend that all anorectics including fenfluramine he placed in Schedule II of the Comprehensive Dnig Abuse Act. Approved Disapproved 3. Recommend that some or all the currently unscheduled anorectics be placed In Schedule III and/or iV, (the amphetamines anti phenmetrstzine remaining in II). Approved Disapproved 4. Recommend no changes in the current scheduling of these drugs. Approved Disapproved D. With respect to possible further testing: (These alternatives are not mutually exclusive; only #1 is recommended. 1. Require further testing of some or all nnorectics with respect to abuse potential. Approved Disapproved 2. Require further testing of ame or all anorectics in long-term prospective trials. Approved Disapproved 3. Require epidemiologic surveys relevant to how anorectic drugs are used or abused. Approved Disapproved Ii. Other requirements (All hut #~ are recommended) 1. Eliminate parenteral amphetamines. Approved Disapproved 2. Withdraw approval for all currently marketed combination drugs contain- ing amphetamines. Approved I)isapproved 3. Require anorectic drug labeling describing the reservations many experts have w-ith regard to use of anorectic drugs. Draft wording Is attached (Tab "C" of attached memo.) Approved Disapproved 4. Require fenfluramine labeling to include reference to the possibility of unusual adverse effects. Approved Disapproved 5. Require anorectic drug labeling for the consumer. Approved Disapproved F. Certain ancillary or implementing actions (These are all recommended.) 1. Publish en article on anorectics In the Drug fleltet in. (See draft, Tab "A" of attached memo.) Approved Disapproved -. 2. Publish a Slaicmcnt of Policy and Interpretation on anoreetics (See draft preamble to Sfl. Tab "B" of attached memo.) Approved Disapproved . - PAGENO="0638" 15068 COMPETITIVE PROBLEMS ~ THE DRUG INDUSTRY 3. Publish a Bt.atenic,,t of Policy and interpretation on amphetamines. Approved Disapproved 4. Publish follow-up efficacy notices on DESI drugs for which data have been submitted in response to a previous Notice. Approved Disapproved FOOD AND DRUG APMINISTRATI0N, Rockritlc, if d., March 26, 1973. DELCO ChEMICAL Co., lac. 7 JlacQnrstcn Parkway North Mt. Vernon, New Yorl: GErcTLnIEN: This letter Is being Issued under the combined sposorsbip of the Fosl and Drug Administration (FDA) and the Bureau of Narcotics and Danger- oils Drugs (BNDD) and is in reference to the product(s) you manufacture, dis- tribute, or repack, containing amphetamine, dextroamphetamine or levamfeta- mine drugs alone or In combination with other drugs. On February 12. 1973, Regulation 21 CFR 130.46, `Amphetamines (a,nplieta- mines, dextroamplietarnine and their suIts and levamfetaufines and its salts) for Human Use", copy enclosed, was published in the Federal Register (38 FR 4249) setting forth the Food and Drug Administration's position regarding: 1. ~2oinbinntlon drugs containing amphetninine or dextroamphetanilne and their salts in combination with other drugs (for example-sedatives, tranquilizers, rauwoifia derivatives, vitamins, etc.) 2. Parenteral amphetamines; 3. Levamfetainine and its salts; and 4. Specifies certain conditions for marketing of single entity oral dosage forms of amphetamine or dextroamphetamine. (For purposes of the regulation, a mix- ture of dextroaniphetamine and amphetamine is ordinarily regarded as a single drug entity). The Food and Drug Administration has concluded, In part, that: 1. combinations of anorectic and other drugs were not found to differ either in efficacy or in the incidence of adverse side effects from the anoreetie drugs alone (please see the enclosed Federal Register announcement of October 15, 1971, "Fixed Combination Drugs for Humans") 2. That the benefit-to-risk ratio is unfavorable for parenternl injections of am- phetamnines, therefore, amphetamines may he marketed in the future only for oral use; and 3. FDA has not received substantial evidence of effectiveness nor is there a general recognition among qualified experts that levamfetanmiue preparations currently on the market are snfe and effective for the treatment of obesity. If any drug contains an amphetamine or dextroamphetamine or their salts in combination with other drugs such as sedatives, tranquilizers, rauwolfin deriva- tives, vitamins, etc., or is a parenteral amphetamine preparation, or is or contains levamfetamimme, it is subject to the February 12, 1973 announcement, and is ihere- fore a new drug for which an approved new drug application is not in effect and is misbranded tinder the appropriate provisions of the Federal Food, Drug and Cosmetic Act. The purpose of this letter is to advise you that Regulation 130.46, which became effective March 14. 1973. makes Illegal tIme continued marketing in Interstate commerce of products which fall under the scope of that portion of the announce- ment which deals with combinations. injectables. or levamfetamino and its salts without an approved new drug a pplieutiomm. The continued marketing of such drugs is in violation of the new drug and misbranding provisions of the Act and outstanding stock-s of the articles in trade channels are subject to regulatory proceedings under the appropriate provisions of the Act. Consequently, the mar- keting of such drugs must cease immediately upon receipt of this letter. The Bureau of Narcotics and Dangerous Drugs tvill no longer allow procure- ment quotas for drugs deemed violative under this regulation. With respect to that portion of the announcement which deals with ampheta- mines and/or dextroamnphetamines and their salts, the announcement also speci- fies certain conditions for the marketing of single entity oral dosage forms. Any marketing of such drugs must be under an approved new drug application and appropriate labeling as indicated in the regulation. Failure to comply with these provisions will result In regulatory proceedings. PAGENO="0639" COMPETXTIVE PROBLEMS ~ THE DRUG ~WUSTRY 15009 We request your reply within 15 days aver receipt of this letter stating your intentions with respect tt your,products, if any, which are not In compliance with the rnnouncement, and the Immediate removal of all outstanding stocks from trade channels down to the retail level. The F1)A district office will contact you shortly to work out the details of the recall. We are enclosing for your convenience, a model recall letter which you may put into immediate use to facilitate your recall efforts, aitd a representative of BNDI) will contact you to inform you of required accounting and disposition procedures for your inventory and returned goods. In the event you have already discontinued marketing, FDA would appreciate particulars on the following for each product: (1) the date discontinued; (2) flu estimate of size and frequency of previous shipments for the past year; (3) to whom shipped; and (4) an estimate of outstanding stocks on the market and in your posseSsion. This program is being carried out with the full cooperation of BNDD. Because of the required record keeping under the regulations administered by ENUD (21 (`FR 307.21), any destruction of your inventories innst be BNDD authorized. Completion of BND-41, (Voluntary Destruction) is required as well as a witness to the destruction. A list of BXDD offices is attached to assist you in notifying ENIID once you are ready to destroy drugs returned to your firm. For purpose of this recall oul3, IINDD has waived the need to use order form (BXD-2220) until June 30, 1973. In lieu of order forms a complete and accurate record must be retained by both your firm and your customer, identifying hoth parties, date of transaction, and the kind and quantity of each drug that is re- turned. Any Schedule II controlled substance returned after that (late will re- quire the use of order forms. Alt responses or inquiries to this letter should he directed to the Food and Drug Administration, Bureau of Drugs, Office of Compliance (BD-317), 5600 Fishers Lane, Rockville, Maryland 20832. Sincerely yours, SHERWIN GARDNER, Acting Conim4ssiotrer, Food and Drug Administration, JOHN IL INOERSOLI~ Director, Bureau of Narcotics and Dangerous Drugs. S Foon AND DRUG ADMINISTnATTOrc, Ilockrille, Md., September 2-8, 1974. Dr. ALEXANDER 1%!. SdHMID'r, Commissioner of the Food and Drug Administration, Parklau'n Building, lioelcvilic, Md. DEAR Din SCHMIDT: We are in receipt of your September 18th letter, and wish to comply with the need of an investigating committee for accurate, complete, and specific Information concerning our testimony of August 13. 1974. We cannot fulfill this request immediately, because of the time and care we deem necessary for resnnnse and because we feel that final response to you at this time would jeopardize attempts to obtain a reliable account of the agency's work. We continue to lie deeply concenmed about your plan to issue a separate report on the issues at hand. We feel that one independent group should do the investi- gating, and that we should not he subjected to multiple Information demands and judgments. Should you Issue a report in the near future, the Secretary's com- mittee might find it difficult to override you. If you desire to make an investiga- tion anti report. we ask you to do so on the basis of documents and testimony of the Secretary's committee, and issue the report only after that committee has completed and released its work. We want to publicly present the facts underlying our testimony, so that the American people will be informed. Any investigation must be open. The potential for serious abuses is inherent in the promise that material will he held confidential. The term "trade secrets" has not be defined. Therefore, we request that any investigating committee refrain from keeping any information confidential, and provide a straightforward, tin- ambiguous deflaition of "trade secrets," PAGENO="0640" 15070 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We are pleased that full access to all agency records has been offered, as we requested in our September 13th letter to you. I have reijuested through Divi- sional channels all volumes of NDA 10-618; to date, only six volumes have been delivered. We appreciate your assurance that we ~viil have an "adequate opportualty to prepare and present ...views and supporting materials" I shall supply an accurate, complete, and specific report as soon as possible. The following are examples of matters I am reviewing and intend to report upon: The evaluation and handling of NIL~ 16-618 and NDA 1G-S80. Attached is a condensed summary concerning NDA 16-618. Sincerely yours, ROBERT 0. KNox, M.D. MEMORANDUM JuLy 0, 1076. To: Ed Melton, OLS. From: Bill Crabhs, IIFD-120. Subject. Tonanun, Biphetamine, your memo of June 23, 1970. Steve Kennedy has spoken to Mr. Gordon on the plmne and referred him to PEA for drug abuse information on the drugs. I understand that Mr. Gordon is primarily Interested in lonamin. therefore I've concentrated Ca this drug In gathering tlieattachaients. The attached material about the Task Force review of anorectics applies to both lonamin and Biplietanilne. The original NDA for lonamine Includes studies by Burton M, Cohen. M.D. and S. Charles Freed, M.D.; the XDA was allowed to become "effective" on May 14. 19i1). Tue Cass study of Jonamin, Biphetamine and Biplietamlne-T was included with the firm's annual report on Ionamin submitted on June 24, 1060 and was, as far as I can tell, not requested by FDA. Apparently no medical review- of the study was done and the study had no impact on the status of the drug which had previously been allowed to be marketed on the basis of other data. lonamin and l3iphetamine w-ere originally published as "possibly effective" on August 8, 1070. Two clinical efficacy studies on lonamin were done as a follow-up to the DESI notice and were reviewed as a part of the Anorectic Task Force. These were done by Eugene Jolly, M.D. and Robin Shearer, M.D. and showed statistically significant efficacy. Similarly, 3 studies were done on Biphetninine, two by Albert Cohen. M.D. and one by Eugene Jolly, M.D. As a result of the Task Force review and evaluation, both lonamin and Biphetamine were upgraded to "effective" (see .Tuly 19, 1974 FIt statement). The NDA for Biphetamine-T was withdrawn oa March 30. 1973 since the data submitted did not show efficacy of the drug as a fixed combination. I've nttaclied pertinent reviews, including the Task Force review and a copy of the Cass study. I don't know if there is any problem with respect to releasing any of the information since some is confidential, lint I'll leave that up to you. MEMORANDUM To: Director, Bureau of Drugs through the Deputy Director. From: 1 Richard Crout. M.D.. Acting Director, Office of Scientific Evaluation. Subject: Amphetamines and Other Anorectic Drugs-Action Memorandum. OBJEcTIVE This memorandum Is aimed at providing discussion of issues, data, and alter- native actions necessary for a comprehensive policy with respect to drugs used as anorecties in the treatment of obesity. Policy and implementing actions will he discussed with respect to both the therapeutic usefulness and the abuse potential of the drugs. ISSUES In simplest terms, the major Issues are as follows: 1. Some or all drugs used therapeutically as anorectics have marked potential for abuse. PAGENO="0641" COMPETITIVE PROBLEMS ~r THE DRUG nWUSTRY 15071 2. The therapeutic usefulness of nnorectie drugs has been poorly and variably defined, and the definitions disputed. 3. Regulatory decisions regarding anorectic dnigs appear to have been made in the past largely piecemeal; a hroad explicit policy with consistent implemen- tation has been lacking. FACTS Relevant to the issues above are a niunher of more concrete facts, old and new, scientific and administrative. The major hack-ground facts are listed below. It Is suggesteiL however, that the material attached nuder Tahs "A" and `13" he read first, as easy and more extensive descriptions of the complex background. .%DMINISTRATI~t ACTIONS WIT!! RESPECT TO ANoaEcTIc naves 1. Suh,nis.sions of NDA's for Currently Jfarlceted Amphetamines required by the Statrmen t of Policy and Interpretation of 8-8-70 Of the nnorectics, the most prominent group, the amphetamines. were con- sidered "granufathered" until August 8, 1970. At that time the FDA published a "Statement of Policy and Interpretation" (see Tab 11) which essentially re- voked grandfather status and required among other things the submission within a year of New Drug Applications for amphetamines. NOAs were sub. mitted by sponsors, and are the principal documents on which formal action will he taken in implementation of future amphetamine policy. A few NDA's had been submitted a number of years ago for special amphetamine formulations or combinations and will also he acted upon. The indications for which the amphetnailnes might be provisionally labeled were set forth in the announcement of August 8, 1970. The indications were: as an adjunct in the treatment of obesity: as a adjunct in the treatment of mini- mnal brain dysfunction in children: narcolepsy. The first indication is the subject of this memorandum, the efficacy of amphetamines in the latter two being Some- what less controversial. 2. Review of currently marketed non-a,aplmetarnines by the Drug Efficacy Stud', (PEST) All hut one of the other, non-amphetamine anoreetic drugs currently marketed in the United States are subject to review by the Drng Efficacy Study. so *that decisions are pending on these drugs, The only anorectic DESI Notice published to date, (Tab I) on special formulations and combinations, lisle*l the drugs effects as "possibly effective". Efficacy data have been submitted in response to the Notice, and these `E" supplements mnst be acted upoa in implementing this policy on anorectics. 3. S,,hnmi.~sions of NDA's for onorectic drugs not prcviousty marketed New Drug Applications have been submitted for three anarectic drugs not yet marketed: fenfluramine (Pondinmin). mazindale (Sanorex), and clorter- mine (Voranil) - These have purposely been held up in their processing with the agreement of the manufacturer, pending development of overall policy. These must be acted upon. .3. Revision of scheduling of anorcctie drugs wider the Corn prcben&rc Drug Ab,i.te .4et The Comprehensive Drug Abuse Prevention and Control Act (controlled Sill)- stances Act: CSA). passed in October 1070, is designed to impose restrictions on use appropriate to the abuse potential of drugs. Schedule 11 of the CSA, the most restrictive for marketed drugs, requires non-refillable prescriptions. special records, and manufacturing quotas, anmag other things; Schedule III and IV have little hut psychological impact on the practice of medicine. requiring only a specIal symliol on the labels and labeling and a practitioner's BNDD number on the prescription. The Schedules of the Act include three anorectics-mcth- amphetamine, the amphetamines themselves, and phenmetrazine. Other anorec- tics, e.g.. diethylpropioa, are not included, although they nrc labeled as having abuse potential, (and almost certainly possess abuse poteatial). The Schedules also exhibit other inconsistencies and omissions, and they requlr~ revision. Along these lines, the amphetamines and oral methnmphetamine were moved from their oririnal place in Schedule III to the more restrictive Schedule TIm July 1971, following FDA recommendations, Phenmetrazine was moved from III to II In January 1972, again following FDA recommendations, 85-559 0- 77 - 42 PAGENO="0642" 15072 COMPETITIVE PROBLEMS IN THE DRUG LNDUSTRY No fonnal move has been made to schedule other anorectics, but their absence from the Schedules appears to be one of the significant omissions of the Act. ImW, and by extension FDA, are obligated both scientifically and by the Act, to advise the Justice Department with respect to drugs with abuse potential. Formal recommendations with respect to the abuse potential of marketed and unmarketed anorectics appear overdue. 5. Deadlines Deadlines and commitments of various kinds exist with respect to the actions liuplied above. The NDA's both for amphetamines and new entities have now exceeded the statutory review time limit of 180 days. The DESI Notices iniple- meating 8 NAS/NRC recommendations await publication. Efficacy supplements submitted in response to the "possibly effective" Notice for other anorectics have exceeded the 180-day period. An estimate of medical nerd for aaiphetamines and phenmetrazine depends upon our conclusions as to efficacy, and is also over- due: npoa It will depend inonufacturing quotas and industry plans for 1973. In this regard, we were questioned in February 1972. before the House Subcom- mittee on Public health and Environment and the Senate Subeommittee on Juvenile Delinquency as to our conclusions on the use of amphetamines in treat- ing obesity, and we projected an answer for July. SCIENTIFIC BACKGROUNI) WITH REsPECT TO ANOEECTIc DREGS 1. Efficacy studies Repeatedly in discussions with consultants and outside experts the question of the results of anorectic trials in generai was raised. FDA staff therefore carried out n unique computer-supported review of all controlled anorectic studies on file in FDA. 206 studies with 11 anorectic drugs were analyzed after screen- ing by physician-medical officers. Individual patient data on 9.800 subjects were recorded on 72,000 IBM cards; and programs for tabulation and analyses of the data w-ere developed and applied. The resulting library of data and analyses provides an unparalleled review of the class of drugs, The analyses generally supported the efficacy of anorectic drugs. Use of the drugs Ia obese subjects was associated with more weight loss than was diet alone. The degree of extra weight loss was small-a few' tenths of a pound a week in many eases-and variations were great. In trials which continued for 12 or 16 weeks, those subjects who remained in the trials lost a significant nmount of weight e.g., 25-40% of excess weight, both in the control groups and when on drugs, but they consistently lost more weight on drugs. 2. 3forhidity-mortality data Larger questions of long standing remain unanswered, such as the long-term effect on morbidity and mortality of the use of nnorcctlcs. These questions are of basic importance, since the usefulness of the drugs depends in large part npon the assumption that they somehow help prevent the adverse effects of obesity. 3, Evidence of abese Evidence of various sorts of abuse is most abundant for the amphetamines. This is particularly so for use in the "street" and in student populations but also was found In a large sample of people of fixed residence in the conventional occupations. It is reasonably assumed that abuse Is also associated with prescriptions for obesity, but there are only minimal studies of this association. In addition to evidence of abuse of amphetamines, evidence also exists in fair quantity for abuse of phenmetrozine and diethyiproplon. Far other anorectics evidence of abuse Is scanty or lacking. Experience with other abm'able drugs has shown. however, that documentation of abuse lags markedly behind abuse, and, when It appears. Is only the tip of the iceberg. 4. Animal and other studies on the conzparahiiit;~ of fINE effects Pharmacologic data in animals which would permit detailed comparisons of auorectic agents are imperfect or incomplete. Insofar as they exist, they indi- cate that tbe drugs are far more similar than dissimilar. The one exception to this statement is fentluramine, which appears to possess depressant rather than stimulant qualities. This pharmacologic contrast Is based on observations in both animals and humans. I PAGENO="0643" COMPETITIVE PROBLEMS ~ TEE DRUG ~DUSTRY 15073 Animals given fenfluramine in appropriate doses differ from those given amphetamine by exhibiting decreased motor activity. supprcoed conditioned avoidance responding, increased total sleep time, cad EEG changes of increased slow-wave sleep time, slowed elcetrocortic-al activity, and depressed reticular- foramtion activity. In humans, sedation is the most prominent side effect of fenfiurnmine, in contrast to amphetamines. EFO changes correlating with sedation were ob- served. Amphetamine addicts could not distinguish between fenfluramine and placebo, and rated fenfluramine as less eu:phorlant than placebo. These observations generally suggest strongly that fenfiurmnjine should not be considered equivalent to other anorelics with respect to dependence poten- tial of this class of agents. 5. Pulmonary hyperten-siom 0 A European anoreetic drug aminorex (Menocil), pharmacologically related ~ to amphetamines but structurally somewhat different, has been associated with potentially fatal pulmonary hypertension. Congeners have been neither con- victed nor exonerated of similar effects although recent German reviews have publicized tire possibility of similar effects. Gennan regulatory authorities have just required wnrning labeling in this regard, which we are *to receive nnd review. ASSUMPTIONS Following this section are the alternative courses of action which we believe may reasonably he considered with respect to anorectic drug policy. Before discussing them, ceitun assumptions should be made explicit. (As is appro- priate to the format of a memo like this, these assumptions are discussed in the DISCUSSION section on page 17, to which the reader may wish to turn before proceeding.) The assumptions are: 1. Actions are `best tab-en with respect to the whole class of anorectics. 2. Actions should not be tab-ca with respect to pharmacologically related agents of different theraputic classes, but should be restricted to anoreetics. 3, Actions should not be deferred. 4. The two indications for amphetamines other than obesity are basically accepted (minimal brain dysfunction in children; imreolepoy). 5 Efficacy demonstrated for some amphetamines can be extended to all amphetamines generically. ALTERNATIVE COUtSES OF ACtION In Implementing policy for en entire class of drugs, indicated in en extremely widespread condition, actions will be numerous, and alternative choices corre- spondingly mimnerous. In the interests of clarity, we present here only the major decisions, as we see them, with viable alternative courses of action. A. With respect to the approval of anorceties in gcnerel The first major area in which alternative courses of action should be distin- guished is the area of criteria for demonstration efficacy of anorectic drugs in general. The three aliternativos are considered mutually exclusive. 1. Base judgments on the efficacy of anorectie drugs on the currently avail- able substantial evidence derived from short-term studies (up to 3 months). This would be coupled with a requirement for further testing with respect to abuse Potential (see D.1 below). PRO: This Is `the recommendation of FDA consultants. (See Tab C) Severni past `attempts to gain support from experts for longer-term trials or for a more "clinical" definition of efficacy (eg., loss of 50% of excess weight) have failed. Trials of this sort reflect the current state of the art To increase requirements now would mean that all NI)A anorectics are non-approvable for an indefinite period of time. No better alternative drags exist. CON: Approval based on shor-titerm trials leaves unanswered questions as to the long-term effect of drug therapy on the natural history of obesity, as well as on morhidity and mortality associated with obesity. 2. RequIre that the efficacy of anorectics be based en substantial evidence that the use of these drugs results in achievement `and maintenance of weight loss and in improved morbidity or mortality. PRO: Fulfillment of criteria along these lines would provide evidence that these drugs are medically useful in undeniably important ways. PAGENO="0644" 15074 CQ~.EPETXTIVE PROBLEMS ~ THE DRUG INDUSTRY CON: No drugs currently marketed or proposed for marketing have been tested in a fashion adequate to fulfill such criteria. It is not certain that appro- priate testing could lie practically carried out. Many Investigators, as well as drug firms, feel such critena are unreasonable. I )rugs in other classes are considered useful even if they *pniduce only minor or te,ripornry improvement. Nor is it clear that anorectics are not useful as adjunctive them I ly for obesity over the long-term : the data are simply not available. 3, Approve anorectics based oil short-term trials, hut. simultaneously require long-term studies. PRO: More data might be obtained on the course of obesity treated with and without drugs. The FDA would maintala more control over the drugs than it unqualified approval were given. CON: The type of data to he obtained has not been established. Even if long- term administration of drugs were to lie tested, it is deliata ide whether anorec- tic drugs should lie given chronically. Even If long-terra trials revealed no dif- ference between drug-treated and placebo-treated groups, `the fact remains that more subjeets lose more weight over the short term on active drugs.A collabor- ative study of the magnitude and thoroughness necessary for meaningful results would represent Investment of research effort on the scale of the I'GJ)P study. Nettlier FDA nor, probably, the research community nppeaiu able or willing to design and carry out a definitive. unequivocal trial of the necessary scope. The methodology and results of any single study would be disputed, and it appears somewhat unlikely that a satisfactory study is possible. B. With respect to amphet',niines, inctuding oral ,nethanuphetaniine The second major area in which alternative courses of action should be dis- tinguished is with regards to the amphetamines (assuming that other anoreetics are considered effective.) These three alternatives lire consIdered mutually exclusive. I. J,nbel amphetamines to exclude use In obesity. PRO: This would eliminate the major indication for amphetamines, and so would decrease the amount distributed and susceptible to misuse. Manu- facturing quotas woidd lie lowered accordingly, thus restricting the amounts produced. The action would eliminate ii controyersial Indication. It would lie tacitly approved by many laymen and physicians, probably `the majority. Effec- tive alternative drugs are available. 1~limination of the use of amphetamines in obesity would be a dramatic action against abusable drugs which the public would easily understand and approve. Both laymen and some experts have advocated that amphetamines not be pre- scribed or labeled for obesity. This is because of the abuse of the drugs, and the belief that widespread use increases the opportunity for abuse and, fur- thermore, may "inoculate" susceptible subjects in weight-reduction programs who might othenvi.se not have been exposed to the drugs. It is almost certain that pressure to eliminate `the use of amphetamines in treating obesity will continue. Alternative agents nre available, Abuse of the amphetamines has been far more extensive in the United States than abuse of alternative agents. If nniphetamines lire labeled only for use in patients refractory to other anorec- tics this would be an indication for which the drugs in a strict sense have not been tested. CON: The action would be contrary to the explicit recommendations of FDA eousifitant.s and the nmjority of academic figures who have been heard from. It would restrict nmcdjcul use because of non-medical abuse, and data are skimpy with respect to any relationship between the two, Alternative drugs appear to possess abuse potential, too. Decreasing the supply of legally manufactured amphetamines would increase the price of amphetamines on the street, and illicit labs would increase In response to the demand. As no'ted In the PRO section of recommendation Ri, It would he more appropriate to use the Con- trolled Substances Act to reduce the drug abuse lirobleni associated with the widespread use of these drugs in the treatment of obesity. 2. Label the amphetamines for restricted use in obesity, e.g., for patients ref raePwy to other drug therapy. PRO : This is consistent with the recommendations of the consultants. It would take account of the now well-documented action of amphetamines in producing weight loss. The selection of a restricted group of potient.s would work further to restrict use of the drugs; although not explicitly recommended by consultants, it would be in line with their discussions. The action would PAGENO="0645" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15075 nonetheless leave the oldest and best known anoreetics available for tile prac- titioners who believe they possess special efficacy. It would pt-event din rges of overreacting ~vhidh have been voiced in advance I y ~vel I-known acaileiiiic (`liii- ical l.Iiarmucoiovists when the possiliilitv was suggested thnt amphetamines might no brnger be avai Lqbie. This action might be coupled ~fl h a eonmiiaitnient to review time sUtummtion again at sonic fiitu re period. e.g. in a year. This action. together with furl her reductions in the quota when indicated, continues to make appropriate use of the Controlled Substances Act as a response to the safety problem of drug a lmuse. Eliminating the use of a mnplieta mines for the treatment of obesity as a media- `usia for controlling drug ahmu~ze would reliresemut mmtiliza twa of the Food. I )rug and Cosmetic Act. to control the type of safety problem for which the Controlled Smi hstauces Act was pro,uuuhgated. CON I )ata are anecdotal or lacking that a amphetamines (To in fact work in mu tient.s refr'aeto to other drug therapy. The labeling would imply relative efficacy and/or risk without clear-cut evidemuct- to back up the i niphiea dons. The labeling would be a somewhuat unsatisfactory comnproause which would net cliii controversy on the use of aniphuetamines in obesity. s. continue current labeling for anuphetamines, Le.. for narcolepsy for anal- mal brain dysfunction and for short term, adjuacitive use in obesity. PRO: Amphetamine labeling is already restrictive. Evidence does not exist for efficacy in patients refractory to other drugs. If other dnigs are placed in Schedule II, this assumes equal abuse potential, and labeling should not be discriminatory. CON: The history of amphetamine abuse is so distinctive that amphetamines should receive special labeling. Maintaining the status quo appears completely to underestimate the problem. C. With respect to abuse potcmutiqt The third major in which alternative courses of action should be distinguished concerns abuse potential of anorectic drugs. The four alteratives are considered nmutuallt exclusive. 1. Recommend -that all anorectic crcept fentluramine lie placed In Schedule TI of the Comprehensive Drug Abuse Act, fenlluramuiae to lie placed in Schedule IV. (see Tabs B, F and G for draft labeling with respect to Drug Dependence.) PRO: All CNS stimulant anorectics would he treated consistently and restric- tively. Physicians, patients, and addicts would not lie led to seek out previously unabuscd drugs simply because they are not on Schedule II. Pharmacologic and chemical data would be extensively relied on to predict ubuse before it occurs. Abuse of these drugs would he prevented, so far as is possible under current law. FDA and the Eurcau of Narcotics arid Dangerous Drugs have agreed in gen- eral that it is desirahle to use predictive data. Since fenfiuramnine hasa different pliarniacologie profile and appears to possess less abuse potentIal in animal tests, it would lie distinguished from amphetamines. CON: Since predictive data are imperfect, sonic drugs with little or no abuse potential may be scheduled. In the past, scheduling of non-opiate drugs has often depended upon evidence of actual abuse. Placing all anorectics In Schedule II will he viewed by some as overcrowding this Schedule and rendering the less re- strictive Schedules almost meaningless. To act only upon the anorectics is to ignore the abuse potential of synmptuthomiinetic auuines in other therapeutic classes, e.g., mephentermine. It Is not certain flint IINDD will formally concur with our recommendations. 2. Recommend that all anoreetics including fenfluramine be placed in Schedule H. PRO: This would eliminate the competitive advantage which mumight accrue to fenfiuramine If all other anoredics are placed in Schedule II. Past claims that other lieu- drugs. e.g.. l.lienmctra zinc. nueperidi ne. do not possess the abuse hmoten- tial of older congeners have been invalidated with the passage of time. CON: Fenfiuramine appears to rossess pharmacologic actions qunhitatively distinct from other anoreeties. winch suggests that its abuse potential is sit least quantitatively and probably qualitatively, different from other nnorectics. Experts consulted have all been of the opinion that fenlluramlne should not be lumped with other anorectics. PAGENO="0646" 15076 COMPETITIvE PROBLEMS IN THE DRUG INDUSTRY 3. Recommend that some or all the currently unscheduled anorectics be placed in Schedules III and/or IV, (the amphetamines and phennietrazine remaining in II.) PRO: This would take account of. the lack of documented abuse of unscheduled flhlorectics relative to amphetamines. it would expose us to less criticisiii of over- reacting. It would not represent the severe competitive differential of alternative #1 between fenfiuramine and other anorectics. CON: Schedule Ill and IV have little practical effect In preventing Overpre- Senption or diversion. Addicts would thus preferentially turn to drugs not pre- viously abused for "administrative" reasons. 4. Reconiniend no changes In the current selieduli rig of these drugs. PRO : This would avoid stigmatizing possibly inrnx'ent drugs as possessing abuse potential. I would avoid controversy as to the admittedly imperfect pre- dictive value of pharmacologic data. It would not prematurely advertise the abuse potential of drugs of which addicts may not yet he awn Fe by pT acing previously unscheduled drugs on display In the Schedules. The Bureau of Narcotics and Dangerous Drugs should monitor the vital thformation on street abuse of the drugs, and move when abuse becomes important. CON This would not deal with the inconsistencies in the Controlled Sub- stances Act and would permit considerable abuse of at least, some of these drugs before any action would be taken. D. With respect to f urthcr testinq A fourth area in which actions may he taken is that of requirements for further testing of various sorts. The three requirements are not mutually exclusive; we recommend only the first at present. I. Require further testing of seine or all anorectics with respect to abuse potential. PRO: Data would be obtained on tile most disputed safety question assosiated with these drugs, their abuse potential. The Lexington Addiction Research Center of the NIMFI Is beginning testing of this sort. CON Testing methodology has not been standardized. Results of tesb4 done so far are of uncertain predictive value with respect to subsequent abuse under actual marketing conditions. 2. Require further testing of some or all anorectics in long-term prospective trials. PRO and CON: This is a recapitulation of parts of altenintives A2 and AS, and the argiinients presented there apply here. 3. Require eqidemiologic surveys relevant to the use and abuse of drugs. PRO : TIns requl rernent should produce drug-use data. Surveys might also reveal abuse earlier thu ii does the present fortuitously received izifonnatloji. i'his requirement would be an innovative, positive response to long-felt needs for data. CON: Methodology Is imperfect. FDA is not familiar with evaluating data of this sort. Firms would resist a new requirement of this sort. B. Other rcqnirerneuts Certain further options can he distinguished with respect to the amphetamines, Independent of the two major alternatives above nuder B. In addition action must he taken on PEST drugs, and labeling changes appear desirable. All but #5 are recommended. 1. Eliminate the marketing of parenteral amphetamines for obesity. PRO: This is a recommendation of FDA consultants. Amphetamines pnsluce a more intense euphoria and rush" by parenteral routes; parenteral administra- tion has been associated with the most destructive forms of abuse. No indication for amphetamines exists which cannot he adequately treated by the oral route. (This last argument does not hold for the use parenteral nietliamphetamine as a pres~nr agent, but alteniative ond helter pressor agents exist). CO N Certain I iracti ti oners cl:ii iii that I y gi viii a nq theta nil nes by Inject tori they maintain better control over the drug, since the patient does not administer the drug to hiraself but receives it under supervision. 2. Withdrawn approval for all currently marketed combination drugs contain- ing amphetamines. PRO: This has been recommend by FDA consultants. Combinations are gen- i-rally with a sedative or transquilizer, the rationale being to decrease the stim- ulant action of the amphetamine component. PAGENO="0647" COMPETITIVE PROBLEMS TN TEE DRUG ENVVSTRY 15077 Data submitted In general fall to demonstrate that the sedative constituents of anorectic combinations contribute to the total effect claimed for the drug (with the possible exception of Eska t rol) , so tim t continued lila rketlng would not be consistent with the FDA combination policy. Elimination of combinations would permit substantial decrease in manufacturing quotas. It would also eliminate certain drtigs, (e.g., Dexaniyl) which appear to possess qualities attractive to special subpopuia tions of addicts. The sedative or tranquilizer components pro- duce adverse effects of their own. Phenothiazines, e.g., as In Eskatrol, have never been clearly shown to produce anti-anxiety effects as single entities, let alone in combination. The trials carried out with Eskatrol exhibit technicel deficiencies. CON: Small studies of one combination contrast with other studies in suggest- ing that proehiorperazine (in Eslcatrol) reduces the adverse effects associated with d-amphetamine. (however, prochlorperazine. a phenothiazine. may produce serious adverse effects of its own under certain eond tlons). The manufacturers of Eskatrol especially have expressed the Importance of this product to the finn and may be assumed ready to contest an adverse decision. 3. Require labeling descrihing the reservations many experts have with regard to use of anorectic drugs. A draft wording is attached (Tab D). PRO: This is a strong recommendation of FDA consultants. Omitting such labeling appears somewhat inconsistent with principles of full disclosure. Re- quIring it will prevent unjustified promotional claims front being made. These labeling statement may mollify the critics of anorectic drugs. CON: The reservation are serious enough to raise questions as to the wisdom of using these drugs at all: for some people they may raise questions as to FDA's wisdom in permitting the drugs to be marketed. Certain practitioners, e.g., ban- atricians, will disagree with the statements. 4. Require fentluramine labeling to include reference to the possibility of till. usual adverse effects. (See Tab J for draft wording.) PRO: It would slightly offset the promotional advantage given fentluramine by the proposed less restrictive scheduling. This balance is particularly desirable, since with fenfluramine an advantage (Schedule IV) which is basically unial- portant for the majority of patients may lead physicians to ignore nspcets of fenfluramine's pllaramcologlc profile which may for many patients be less de- sirable e.g., Potential for producing diarrhea, sedation, or aIiM post-treatment depression. CON: This action appears not to have adverse implications. 5. Require anorectic drug labeling for consumer. PRO: Information would lIe provided to the patient so that be may participate in a controversial decision. lIe will he more fully informed on the benefits and risks of anoreetic drugs. This would be consistent with the general movement toward more complete informing of the consumer. CON: Guidelines for determining drugs requiring consumer-oriented labelIng have not been established Anoreetic drugs do not, appear to he more hazardous than many other drug classes which do not have consumer-oriented labeling. F. Certain ancillary or irnpletnentin actions Tile fifth area In which alternative courses of action may he distinguished con- sists of ancillary or implementing actions. (These are all recommended.) I. Publish an article on anoreet ics in the Drug Bulletin. (see draft, Tab A). PRO: This is desirable no matter what we (10, since physicians will learn of our actions Conner or later. The FDA Drug Bulletin has been established for such purposes. CON: Publication may retard our action. We are nader pressure to act as soon as possible. 2. Publish a Statement of Policy and Interpretation in the Federal Register with respect to anorecties. (See draft preamble to SPI, Tab B). PRO: This will establish explicitly and officially our policy towards those drugs. Even as a proposal It would e4ablisht many points for the record. CON: This would commit us to a firm policy, whereas we may wish to revise policy after assessing the impact of our initial actions. 3. Publish a Statement of Policy and Interpretation for amphetamines. PRO: This would be an appropriate fallow-up to the August 8, i970, SF1 on amphetamine, which led to the current amphetamine submissions. It would enables us to make desirable distinctions between amphetamines and other anorectics. CON: This should not be allowed to prevent speedy action on individual am- phetamine NBA's. PAGENO="0648" 15078 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4. I'uhlisli follow--up efficacy notices on DESI drugs for which data have been SIII ui itt i'd in relq louse to a lirevi 0U5 I oLive. VItO: `This appears inescapably logical from all administrative point of view. (`ON Nothing. oIscUs-sIox 1. .1 IlSlOil/IfiOfla - Time a 551110 jit ions ii oted (Ill II. Ii of tins i 11(1110 all pea r Ia rgels- self-ox pt a riiitory. rut cii ii lIe d sin ted. We I a'li eve. Ii rs t, tilt I ``(hISS ml ctioi i' is fairer iii all lIrlai 11- istrative semIsi', aiid more valid scielitiljcilllv. Tile last is Particularly true with respect LI, drugs with abuse liotelitial. for unless-action is taken cilia broad front. addicts milay a liaudon the restricted drug merely to begin to abuse sinhihar drugs iiot yet scimeil imled.] Piecemeal action muiglitaji~Iear ``consers-ative''' but we believe It fails to take account of such (`otisitlerittions IS the great lag bi'tweeii abuse iral III CI `111011 til tii iii (if 111)1150. The second a 5511111 p t i (III III' V ii}'~ (`ii r lIar Ii ally ii IcOmisisfen t \vi Lb the first, iii that "-e suggest Ii mi ti ng act ion to alioreci ics ra tlier than extending them, for example, tO all sylIIlIatllon,iinetie lilililleS. WI `iii' thus laity neglect for tlt e 111(1111511 t sucl :11 usa Ide drugs as III e1lhe,I te rmu no, it is a valid assulillitioli ~vi UI respect to efficacy a ml to the way in which the drugs are used, i.e.. orally and sImi acul ely. Moreover it Ii ants our actions to a mlmammagealile size and to ilrimgs sharing a collIlnori ilidictltiOll. In addition. dcci- si°n~ OIl etfica (3' ill trea tiiig (I )t'sl ty ill vi (1 VI' :1 1111111 her of jiol icy (I i'ei 10115. in (1 -- lie II deli t of Lii e sd ed u Ii ng q uesti Oils. The t lii rd assllnilltiom,. tlja t actions should not he dcferred, appears far prefer- able to aiy (`olnpronhise or delaying action. New- Drug Applications has-c hee,i suliitiitted 1111(1 will continue to lIe sIlhmnitt('(l. and they should Is' acted (Iii. Early decisions are also required with respect to deteriiiii,n tions tif `umedica 1 need" foi' Iliorectics nail 111811 ufa ctnritig quotas of scheduled suhistances, e fall rtIl assilni tILl Oil, ti lemi \`e its do iii Sen ssi (Ills cit in i iii nia I bra iii (13's fu ac- tion (MB B) 011(1 11:1 rcoiepsy. is a logical deternii nat loll ill I erins of the scope of the 1001110. Ii we wish, wi' will ha ye the ojqlortnhiity to FO\i 50 our jiosi tiomi on \flhI) later since I tore is ongoing discussion if t lie idace of CNS st inmulant dnmgs ii, treat i hg 31BD a cu trout com,sulta nt to sk force should help us here if llecessar3'. The fifth a ad last assuniptiomi is that a decision (`an he made generically for all a in ph eta n~ inc drug prl slu ct 5. I'll Is nii~ieai's a sound a i pfl In cli. I leca use cliii ical experience and cI illical trials ha ye used "a rloims drug products \vi tliout results suggesting differences. 2. Reco ma: r,mdcd cello Its a It 0 a,gu at en ts in ia ppm-f of f/i em Briefly we reconi mend the following actions, discussed at greater length above. together with their alterna ti yes (`Fhie letters a 1111 mililIlhiers in parantliesis refer to alternatives discussed above-in the ALTERNATIVE COURSES OF ACTION SECTION.) (Al.) Base appm'oval of aimorectics for wInch NDA's fire currently imiider review on demoust rat cii superiority to ldacello imi relatively short-term (e.g.. 1-l~ weeks , trials of weight reduction. Further testi 11~ of soniC sort, e.g., for allnse isitetitial, would lie mi desirable coralla rv. (El.) Label amnldleta In nes to exclude use iii obesity. Cl.) Place all aria rectics except feimfl ii rann me in Schedule Ii. amol fenfiur:i- maine iii Schedule IV. l).1 . I Bequire further testing of auom'ect ics with respect to it liuse poteiiti al. (El.) Prohibit maarketitig of parcmiteral fIIr,Iiulitio,is of anorectic drugs for' (diesity. (E.2. ) Reject NDA's receitlv suhitil tterl for a lilpimeta m,iie-sedat lye coiiili la- tio as a ad w itlid I'a w iIppFOi~il I from ol her J)E Si's ` nib ill a i I m NI IA `s for wh i cli efficacy supplements were subnntted. E.3. ) Require a liorectic drug lahchilig to detail more exldi citly tIe I in ita tions and hazards of use. E.4. ) Require fenfiurn mine ml eli ng wInch, hala nces decreased abuse potentmai ags inst other possi Ide ilicrea sod adverse elicits. (P.1-4.) Make the actions public tlirourhm the Ffl.4 flreg Gene/in and two SPI's as svell as through app]'opria to DESI notices and follmv-iip notices. In sumni a ry, arguinen ts in support of those rerornmemided act ions are as fol- lows : The act ions are consistent with tile best a vol Ia I Ic dii ta. They estalmlisli and implement a comprehensive policy for a difficult class of drugs. They pro. PAGENO="0649" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15079 vide a reasonable basis for approving drugs, the approva.hility of which in the past has depended upon rat her ant rary value judgments. The most eontn versial use of flie itiost controversial dnigs, the am1ilietnnuines,- is elinitnated. The actions restri,t the `iso of other d rugs with respect to abuse so far as current statutes permit, lint niaii.taii. the availahili ty of drugs fir those i.ract itioners who depend upon them. They infonu the practitioner of the limitations of use and of the risks assis'iated with these drugs. Most praeti('aIly, they are coil- sistent with the closest nplroxim at `ott to a COil5~flS1i5 of experts a nil practitioner which we c;tii strike, ~,-itli the exceptioli of the a mpeta mines. and even there we may still expect 11111(11 l,rofessiOna I and ay support. In short, the actions repre~ sent the policy which best balances the limited lint demonstrated efficacy o a norectic d tugs against their potential fit' abnse. 3. Pro Pica is ic it It rcco,i I (fl (`Ii qtcd 0 c (jolts - Ta Ic tin g on an entire ci ass of drugs used ii, t ci old iti on as pie "a 1cm it mis ot s's it y. a ad with a special hazard tif at omse potential. we should expect multiple prid den,s Iii liii pleinemiti rig any pulley It sh ailil lie clear that ni act ion or set of Let ions ~vifl satisfy all sector~. We tail sntic'ipmi te pi'olileuis t lot t will ii linost cert duly - result from the recrimnielided actions and ito doubt others, as vet unforeseen. will arise, But we believe that it clear stand oil the in ajor priihlenis we citil expect which are discussed lielirw will pitt us in an optimal position. ( Minor problems are discussed only above, in the section entitled ALTERNA'I'IVE COUItSES OF ACTION.) a!. The central problem appears to lie that of according formal recognition of efficacy to a disputed class of drugs. Sonic authorities object to culling dnigs effective if they (10 not alter the long-terra Course of obesity. We believe. how- ever, that this is an tin rea sonalile requ irenient iii view' of a demiionst rated effect on weight loss over the short term. and in the a! sence of more effective alter,i,t- tive therapy. b. A second problem will result from elinunatiiig the indication of obesity front amyheta mines labeling. Aca dli~nnc medical tl~ures and many practitioners will criticize us for over.reilctilig or for depriving physicians of a useful druz ~vl Ut which they are font ilia r. We will I ic~ goitig ago inst the advice of our smnll consultant group. ,. !.~ ! c. A third major prohieth will he the recoin nienda tion to schedule in Sclmednie II. We wish to mnak-e it quite clear that a basic is.q,,e iii drug scheduling is hi. vofred.- that is, whether we await evidence that n drng is being abused before scheduling it or a ttenipt to predict al use potential. Data hem'e are Imperfect and spotty, as they so often are. and we coil lie challenged on itidividital dnigs. But the overall picture Is one of rirnirs thijit are more alike than dissiiniln r. They all possess CNN stimulant aethit auil appear wer likely to lie attractive to addicts. particularly if previhushy preferred drugs were in Schedule II. In addition there are scattered reports of act ual abuse for almost all t lie non.sclie.lulesh drugs. Of nil the currently non-sr'hed tied drugs dietliylpm'opi on is the one for which evidenèe of abuse; its a-elI as of aimse poteiithmi, Is best documented. d. A fourth problem is that of quotas. Quotas must lie established for ahnost all a norectics In the tien r future, if they are put iii ! Schedule! TT. am! we are mincerta it how to estalil isli them. This however, appears only one inure muani- fosta tion of a problem which should rentain secondary to the primary eonsideru- (ion of restricting abuse. We are developing techniques for projecting medical needs and quotas. - ~ - ! - ! e. The fifth major pie! 1cm is that of len fiuira a' inc. Feitfi ura nnae cviii receive a, marked competitive advnnta ge if.as iimp sed, It is the otiiv lii orectid' drug not placed in Scited nle I. It seems unre:i soiialile lio~veker to fly iii the face of pharmacologic data for reasons if market lug. `I'lie proposed In lieling will help slightly to p1 ace the probable decreased abuse potential in perspective. - Political ,uuplieo (ion Congressman Pepper. Senator ]layli. and Oongress,nai, Rogers have all been interested as Congressional Snli-coinmi ttee chairmen in the misc of CNN stimulant drugs to treat obesity. rJiie stand of Congressman- Pepper has been formally to oppose such use; ! the latter two tend towards such a stand hut until now have been cont~it to await FD.t policy... . . . These: Sub-commIttee chairmen. quite -certaialt represent the- opinion of a suhstantiul portion of time electorate~. which vaguely disapproves of "diet pills", considered obesity to stem from lack of will power, and of course is extremely PAGENO="0650" 15080 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY concerned about drugs with abuse potential. A vocal c,,nsir,ner group, 2/ic Huntington (Long Island) Narcotics Council. has publicly decried using CNS stimulant drugs to treat obesity, and cm this basis has twice petitioned EN! II) to reduce manufacturing quotas, once for amphetamine and once for plien- metrazine. RECOM MEN nATION That the attached memoramiuia slunmarizing rer'oriimended actions lie signed and forwarded to the Commissioner for concurrence. nisposITiox After concurrence or revisions have been indicated by the Commissioner, the package should be returned to this office for preparation of iiniilemnenti rig docu- ments. DESI should I.e infonaed of the recommendations whirl. t hey should implement. TAll A-DRAFT ARTIclE FOR Disco BULLETIN AMPHETAMINES This PaTter \vihl serve as technical background for Possible discussion on the control and distribution of amphetamines and other central nervous system stimulant drugs \vi tim abuse potential. It refers briefly to the history of ampheta- mine use and abuse, describes in some detail time recent control actions taken by i-JEW and the Department of Justice in the context of the Controlled Substances Act and refers to recent educational netions of FDA. Raceinic amphetamine and dextroamphetamine were introduced into clinical medicine iii the early 1930's; their rapacity for being abused was recognized within the so me decade. The drugs `Tore quite widely used for their stimulant effects by both sides during World War II; Perhans as a consequence more wide- spread abuse began to occur In the post-war years, with a particularly extensive and well documented epidemic of amphetamine abuse occurring ía Japan. In the post-war years, clinical use of amphetamines also grew extensively, as the drugs became widely used in the treatment of obesity, and other conditions. The abuse potential of amphetamines was not Initially fully acknowledged by the general medical community. As it I,er'nmne so, the availability and distribution of amphetamines was progressively restricted. Benzedrine inhalers and other amplietanune products were place.! on prescription ; controls were applied under the Drug Abuse Control Amenilments of the Food, Drug and Cosmetic' Act in 1i$35, More recently, further controls were applied under time Controlled Substances Act, The Controlled Substances Act, passed in October of 1970, as Title IT of the Comprehensive Drug Ahuse Prevention and Control Act, includes five "schedules" Into which drugs with abuse potential are to be pta ced, each schedule differing somewhat in the degree of abuse potential cif the drugs which it contains and in the degree of control which is applied to the drugs within it. The most stringent is Schedule I, restricted to investigational drugs. For marketed drugs. Schedule II applies tIme most severe controls and presumably contains drugs with the most severe abuse potential, while Schedule V applies minimal controls and penalties. The Act when first passed included injectable methamphetamine in Schedule II. Oral mnetliamphetamine as well as oral and injectable amphetamines were in- cluded in Schedule III. together with methylphenidnte (Ritalin) and plien- mnetrazine (Preludin) two related stimulant drugs. Other anorectic drugs used in the treatment of obesity were not controlled at nil, although possessing central nervous system stimulant activity. Many people Interested in the control of ahusalde substances both inside and outside government felt that the controls of Schedule III were Inadequate for the abuse potential which the amphetamines had demonstrated in the past. Thus, relatively early in 1971, the Food and Drug AdministratIon together with other units within the Department of Health, Education, and Welfare recommended that the oral amphetamines arid methamphetamines lie moved from Schedule III Into the mnore stringent Schedule II. This was accomplished with the accord of the Department of Justice through Its agency, the Bureau of Narcotics and Dangerous Drugs (now the Drug Enforcement Administration). Later in the same year, niethylphenidate and phenmetrazine were also moved up into Sched- ule II. PAGENO="0651" COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY 15081 In 1972 the Food and Drug Administration carried out an overall review of all drugs used in the treatment of obesity. The FDA concluded that all drugs used in treating obesity or proposed for treating obesity did indeed possess some abuse potential; the control of the remaining drugs was finally achieved in 1973. (The drugs placed under control were as follows: phendlinetrazine (Plegine), benz- phetamine (Didrex), chlorphentermine (l're-Sate), maziadole (Sanorex), clor- tennine (Voranil), alt in Schedule III and fenfiuramine (Pondimin), diethylpre- pioa (Tenuate), and phentermine (Ionnmin), into Schedule IV, the latter two in IV only because the manufacturer petitioned for a hearing-they had been recoin- mended for Schedule III). The changes in scheduling have had an interesting, differential effect. Schedule IJ prohibits refilling of prescriptions, and allows the Justice Department to impose production quotas that are based in large part on HEW estimates of medical and scientific needs. Schedules III and IV allow five refills of prescrip- tious In six months time, and (10 not impose production quotas. The impact of imposing Schedule II cofitrols resulted in a drastic decrease in the distribution of amphetamines following the transfer of these drugs from Schedule III into ScliNlule II. Monthly pharmacy prescriptions dropped from hetween one and a half million to two million per month to approximately six hundred and fifty thousand prescripdons per month. There has been an additional continuing down- ward trend; on the basis of the downward trend together with the elimination of certain combination and injectable amphetami lie products, the Bureau of Nar- cotics and Dangerous Drugs, utilizing FDA recommeadations, has now imposed quotas permitting only approximately 8% of the amphetamines production which existed prior to rescheduling. The rescheduling of drugs into Schedules JIl and IV has not so far produced a decrease in prescriptions for these drugs. TAD hJ-DRAFr l'n,WIBLE To Psorosa AyoREc'rlc SPI The Food and Drug Administration has reviewed extensive data on `anorectie" dnigs used in obesity and concludes that the drugs have a limited place in obesity trea tinent regimens. The Agency concluded that all of the drugs investiga ted possess sonic potential for abuse and so should he used with particular care. The most controversitd members of the therapeutic class, the amphetanunes, produce weight loss, too, and so will continue to he In beled for use in obesIty. The Agency will continue to check all evidence of non-therapeutic use and diversion through preseriptiqo abuse; if present control measures prove inadequate during time ne~~t year, further restrictions will be necessary. These decisions were made following a review of seven months time of the over 200 controlled, double-blind studies submitted to the Agency in the last 12 years by manufacturers of anorectic drugs. These include a number of a niplietamine preparations such is I )exedrine, Biphetamine, and Obotun. and closely related congeners, such as phenmnetrazine (Preludin). methiamphietanline Syndrox. Desoxyn ) , benzphetamine (Didrcx ) . phendimetrazine ( I'legiae) diethytpropi on ( Tenuate, Tepanil ) , phentermine ( Tonani in, Wilpo) . and chlorphenterinine (Pre-Sate) - In oddition, studies carried out with three as yet unamarketed drugs were also reviewed and Indicated that these drugs are basically comparable with older ngents. They will thus probably be approved for marketing after technical details are ironed out. Tile FDA relied in part on the advice of a task force of outside consultants. chaired by Dr. Thaddeus 11 Prout of .Johns Hopkins. Consultants and FDA agreed that the risks of pmirenteral injections of amphetamines outweighed any possible advantages associated with these routes of administration, so that anorectic" drugs `viii be marketed only for use by the oral route. Data were also reviewed on the efficacy of combination drugs, chiefly on the possible role of barbiturates or tranquilizers in counteracting the adverse effects of the principal active agents. The combinations generally were found not to differ in a statistically significant way either In efficacy or in the Incidence of adverse side effects. The review project made unique use of the massive files of data in FDA to obtain a computerized overview of the whole therapeutic cia ss. After initial screening and review by six physician-medical officers, records of 206 drug trials were found adequate for in-depth analysis. Individual patient records including patient characteristics, treatments, serial weights, dates of all visits, and any PAGENO="0652" 15082 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY adverse effects were abstracted and key punched onto IBM cards. The resulting 73,000 cards contained over 4,000.000 pieces of informal jolt on 9.900 patients tested with various drugs or pl:rcelio for periods ranging from 3 weeks to 1 year. After tabulating data a rid ann ly-zing them for significance, it could he seen that adult obese subjects instructed in dietary management and treated with `at' orectic'' drugs on the average tend to lose more weight than those treated with placebo auddiet in relatively short-tern, trials. Further conclusions were: The an,ount of weight loss associated wi tic the use of art ``anorectic'' drug varies from trial to trial. The possible origins of the increased weight loss due to the various drug effects are not established. The increased weight loss ap~wnrs to lie related In part to variables other than tire drug prescribed. such, as the physician.investigatior, the population treated, and tile diet prescribed. Studies do not permit conclusions as to the relative linliortalice of the drug and iron-drug factors oil weight loss. The magnitude of increased weight loss of drug-treated patients over placebo- tn'nted patients was only a fraction of a pound a week. Tire rate of weight loss was greatest In the first weeks of therapy for 10th drug and placelicu subjects and tended to decrease In succeeding weeks. The no rural history of obesity is measured in years. whereas tire studies cited are restricted to a low weeks or months (hrratioir ; thus, the total impact of d rug-induced weight loss over that of diet nlone must he considered clinica lix small. The limited usefulness of these agents must lie measured against any possible risk factors inherent in their use. Evidence presented for newer congeners of tile amphetamine family and non- amphetannne drugs do not set them apart as having higher benefit or lower risks tlran older avail:, tile drugs. The addiction risk potential of fenflurainine riray he an exception to this general statenrent, but it nray have some depression inducing capability. Consultants also noted that the amplietarn ines, including methanrlrlietarnille. have heeir widely abused In numerous populations. ] t is thus in the liest interests of the public lrealth to ii mit tire use of a ruplietamines as far as Is con' lxi table with adeqnate tirern py. Tins is ijoth to mininuze tire risks of dependence hi susceptilrle lraticrits being treated and to decrease I lie a inocuit of d rugs being distributed. since widespread prescription of a dependence-producing drug inevitably iircreases the possibility for diversion to r,oir-niedical irse and alrrise. The FDA us'ilI thus recommend that `anoreitim"' drugs be placed under the rccordkeepimig and other requirements of the Controlled Substances Act. State- irieirts will lie required i a the lalreling of all anorectic drrrgs advising the practi- tioner of tire limited nature of benefits ire may expect with rise of ci rugs arid diet rather titan diet alone. Labeling will also I ncirnle stateri,ents alerting lam to the lsrterrtial of these drugs for induci mrg drug dependence aird for being abused. The a mphetamnines uvill carry a special warning in view (if their i mast history and they will be recommended only for trials in obese liatients who have not responded to alternative drugs. The total effect of the FDA actions will thus ire to leave nnorectic drugs available for practitioirers wlii Ic imifornntrg then, more fully of the lincita tions and risks associated with use of the drugs. The individual physician prescribing or dispensing "nirorectic" drugs will titus decide whether in his judgment individual patients require a given drug in addition to tire basic essentials of a calorically restricted diet, supportive therapy, and clinical follow-up. TAB C-CONSULTANT STATEMENTS CONSULTANTS ON AN0RECTIC DRUGS MEETINOS, coNcLUsroxs. AND nEcoMMExruTIorcs FDA Iras consulted with a number of experts on anorectic drugs in tIre past inchiding a large coirsultant group under the Chairmanship of Dr. P. E. Prout in early 1971. Dr. l'ront is Associate Professor of Medicine at Johns hopkins and (mdii July 1, 1072) niernirer of the FDA Advisory Committee on Metalrolic and Endocrine Drugs. For tire present review, a small working group was Invited, again under the Chairmanship of Dr. Tlraddeus Prout. The otirer clinicians in the group were the Chairman of the Metabolic-Endocrine Committee, Dr. T. S. PAGENO="0653" COMflT!TIVE PROBLEMS IN THE DRUG ~DUSTRY 150S3 Danowski. Professor of Medicine at the University of I'ittsluirg, Dr. Jay Tepperinan, Professor of Medicine at the State University of New York at Syracuse, also a menibpr of the Metabolic-Endocrine Committee, anti Dr. 11. J. Levin, a general practitioner, valued for Ills colnnlou-sense comments and careful opinions from the point of view of the day-to-day practice of medicine, in addition to the clinici ails, one or both of two statistical (-onsu ltaitts were present at each meeting: Dr. Samuel Greenhouse and Mr. Jerome Cornfield, of the FDA Bionietry Advisory Committee, I )r. C reeiihouse being the Cila irlllan of that Committee. The statisticians advised an interllretat ioa of data, but did not make clinical recoin Inelldations. `l'he Consultalits met twice. on .Tune 21 and .Tuly 25 At the first meeting they si inlied the first results of the Fl lÀ revie'v, ;leciuai nted themselves ~vi th I pack- ground, format, and major decisions to he made and commented in preparation for the second meeting. Ill the latter meeting. ct pimsnltants pored over cia ta. drug I ty drug, and tilell drafted (ollchlsions. RecolOIllelIda tioas were dra ftecl by the Chairman and l)r. Scoville ii' line with tile eotiehiisioiis anti discussion of the liieeti mig. These draft conclusions a mid reconimeuda tions were then mailed to time citmisulta nts for revision a lid concurrence. We have received letters frola all four clinicians indicating concurrence (except for minimal editorial changes TAB D-Dmnyr ANORECrIC DR~-G LABELING: AcrIoNs AND INDICATioNs CLASS "ACTIONS" AND "INOiCATIONS" LABELING SECTIONS FOIl ANORECTIC DRUGS .4efion.t.-Is a sympathomimetic amine with ~ihamacologic activity similar to the prototype drugs of this class, time amphetaniilles Actions include central nervous system stimulation and elevatioll of blood pressure. TaclIy~Illylaxis and tolerance have been demonstrated with all drugs of this class la which these phenomena have been looked for. Drugs of this class are commonly known as "anorectics" or "anorexigenus". It has not been established, however, tlla t the ItetiOli of such drugs in treating obesity is primarily one of appetite suppression. Other central nervous system actions, or metabolic effects may be involved, for exa ample. Adult obese sulljects instructed in dietary Inn nagement a ad tn'ateci svl th "anoretetic" drugs lose more weight on the average than those treated with placebo and diet, as determined in relatively shor-term clinical trials. The magnitude of increased weight loss ctf drug-treated patients over placebo- trea ted patients is only a fraction of a pound a week. The rate of weight loss Is greatest Ia the first weeks of therapy for 110th drug and placebo subjects and tends to decrease ill succeeding weeks. Tile possible origins of the increased weight loss (Inc to the various drug effccts are not established. The amount of weight loss associated with the use of an "anorectic" drug varies front trial to trial, and the increased weight loss appears to be related [In part] to variables other tha mm the drug prescribed, such as the physician-investigator, the population treated, and the diet prescribed. St udies do not permit conclusions as to the relative importance of the drug and mion-drug factors on weight loss. The natural history of obesity is measured in years, whereas tile studies cited are restricted to a few weeks duration thus, the total impact of drug-induced weight loss over that of diet alone must he considered clinically trivial. In.dtraiion-Is indicated ill the Ilianagenment of exogenous obesity as a short term (a few' weeks) adjunct in a regimen of weight reduction based oa calorie restriction, The limited usefulness of agents of this class (see ACTIONS) should he measured against possible risk factors inherent in their use such as those described below. TAB E-Tlauo DEPENDENCE WARNING FOR Al.!. NON-AMPHETAMINE AxoREcncs ExcrrT FENFLURAMINE Is related chemically and pllarnlacologicahly to the amphetamines, Amphet- amines and re1ated stimul-int drugs have been extensively abused. and tile possibility of abuse should he kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. Abuse of amphetamines PAGENO="0654" 15084 COMPETITIVE PROBLEMS IX THE DRUG INDUSTRY and related drugs may be associated with intense psychological dependence and severe social dysfunction. These are reports of patients who have increased the dosage to ala fly times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and aieiititl depression clia ages are list> noted on the sleep EEG. Manifestations of chronic intoxication with anorictic drugs include severe tlerniatoses, marked insominia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic Imitoxications Is psychosis, often clinically indistinguishable from schizophrenia. TAR F-Dour. Drrrynnxrr Box WARNING FOR AMI'IIFTAMINF.S Proposed wording if a mphetamnines are l:sl eled for restricted use in obesity.) Amphetamines have ii high potential for abuse. They should thus lie tried (ally In weight reduction programs for Patients in whom a] ternative agents have been ii ,effect iv pAd ml n i stai in of a in p betammi i lies for i iroloziged len sis of time in oliesi I y ma v lead to drug deli ende, lee and iii ust lie a vo i deil. Pa rti ciil a r at tei it lou should lie paid to the possilolitv of subjects tilitaiiiing amphetamines for non- ii erapeutic mist' or distribution to others, and tile drugs should be lireseril jet! or ilispemised sparingly. (In addition, the current I Irug Dependence WAR N INC for am phetamnines would lie retal ied in the body of the package in sort. See Ta Ii ``1 1'' for elm rreuit labeling.) TAB G-DBLTG DEPENDENcE WAENING FOR FENFLURAMINE Pondim in (fenflura mine) is related chemically to the nmpheta nones, although it differs somewhat pharmacologically. The amphetamines and related drugs have lieeui extensive]y abused and can produce tolerance nnd severe psychologie dependence, as well as other adverse organic nail mental changes. In tins regard, after cessation of prolonged adma inistra t ion of fejithura anne in liu nia as. (lepres- sivo mood changes and "reliomimid" sleep EEC changes have occurred. Fentlura- a `iii i' diii itt it produce signs of psych il ogic del lendeiice in `unit keys. Ii o~s-ever, in contrast to amphetamines, a ad a p~iea rs to produce uliore seO atlon tim n CYS sti- niulatiouu. suggesting that It's abuse potential may lit' less than tim t of the am- phetamines. Since negative I diii riuacohogie dal a n re of uncertain predictive value lvi th respect to the it bust' potential of a raplietantine-relat ed drugs, the pos- a] liii i tv thi at fea fi miram i ue nay I ndui `e ii epeiidenee sI ii iii d lie kel it iii nm i nd in evaluating the ilesirn hiilitv of mel i,ihinr it iii a weight reduction progra In. (Tab TI-Amplietannne SPI of S-S--TO unavailable.) Tsn I-PEST NoncE OF CERTAIN Axoitrc-ric Daros or Ato. S. 1970 00, Ba-I PEST Aunouncentpnt-Certa in Oral Anoreetfe Preparations (PEST 5375). Cli aries C'. Ed~,-,m rds, M.D. Coatnassi 00cr of Food a ad Drugs. OC-1 1. We recommend publication in the FEDERAL REGISTER of the enclosed draft Implementing 23 reports of the National Acadeniy of Sciences-National Re- search Council on the subject drugs. Twenty-nine rein rn ti Oils (23 NDA's) are covered by the announcement. The drugs are: Ama milieta nil u e wi th dex troll mi ih eta nil lie its sufona teti I oh ~sty rene en au ilexes (prolonged re'ease). Amupheta mine with dextroa mnphieta mine and iiietliaqun houe as sulfomu ated poly- styrene t-oaiplexes (prolonged release 1. I )extroa mnpheta in ii me Sulfa te wit Ii 3feu i rot a ala te. Dextroa amphii'ta "line Sulfate with I'rochlorperazine Maleate (sustained re- lease). Dextrolmmnpiieta anile Sulfate with Reserpine. Diethylpropion Ilydroehloridle (continuous release). Methuarnphetanune III drochtlonide. Methma ampheta mhue Ilyil rochiori tie with Reserpine (long acting). tlh-3fethuaiupheta miulne Ilvdroehmloride tll-Methaunphctanune hydrochloride with Amoharhutal (sustained release). PAGENO="0655" COMPETITIVE PROBLEMS IN THE DRUG ThThUSTRT 15085 Methamplieta illine Saccitarate and Hydrochloride wit II A,nlillctamine Sulfate 811(1 l)extroaniplretantine Sulfate. Pliennietrazine Ilydroililoride with Vitam us and Minerals. l'henterniine as the sulfanateil polystyrene complex I prolonged release). UI of the ~urepa ra tunis were evaluated by the I'a twl on l'sychia tHe drugs. (It her in nels 815,) part tell a ted ill II e oval, lilt oils. TI e Acad eli ys evalu~t Ii rins for the ancireetie (lainls for these drugs ranged from etlective, but" through inef- feet i to. We (s 11(111(10 that a Ith ougi I some at t lie all o rectic a gell tsa re effective in other i ri *1 mt 5. tue Ii igirest tin ssi uII*:, t ion Icr t hose particular ii red jilts sinai ld be teissi liv effect iv~. The enclosed evaluat iii,! sheets set forth tie ilidicat lot's for whirl, the reviewed drugs are rega nied as possibly effective 8,111 ineffective by the F I )A 1111(1 OX 1)111118 ti (Ills (If tl iffeni ices in the F1)A eva I un huts Iroill I hose of tile A i~a deiny. 3. A liltIjOrity of tue uu,,iiil,ers of the Panel on l'syclci:itric l)rugs concluded tii;it SV 1111 )fl t 110111111 et k' st jill alIt lits as a (`Iii SS II ave I I~C11 slio \Vll to have it generally sir art- Thriii lIll( Irelt Ic ft et loll. `.t I lOYl re II (It a tre~ t tnt en t (If ol ess ty ill th eniselves a ml sl,oiild lie used its all adjunct, to a total program of weight reduction. Further, the a iiorettit effect oft eli Idatea us or di Illinislies after a few weeks. Clinical opinion as to t lie con t ri In ti on of tile sy 101111 I homi III eli c at in iu In nts in a weight-reduction progralil varies widely. Most studies of these preparations are for short periods. The panel suggested that controlled studies of tire long-term effects of syllipathO- llliinetic stimulants in a weight-reduction program be conducted. 4. The Panels' reasoning for their possildy effective classifications for the ilnorectic indications of these drugs falls into fonr broad categories: a. Sustained- or prolonged-release preparations. Documentation stated to be available to the Panel regrit-ding blood levels of these drugs following tile use of the sustained-re] ease form w-as in~lderiuate to allow a ny superiority of such form. (Ace. Nos. 1290,1295. 1296. 1302. 1303. 1306, 1308. 1318. 1321) b. Corn binations containing reserpi ne. The Panel questioned tile effect of re- serpimie in tile crllllllination and the aiuiount (If reserpine ill a usual dose. (Ace. Nos. 1291, 1311) e Methiampiuetanuine as an ingredient. On the basis of a presumed pharma- cologic similarity to amphetamine. muethaluphetamine umlay have a similar auoree- tic effect. However, sujijlorting evidence is inadequate. (Ace. Nos. 1292, 1208, 1290, 1309, 1310, 1312,1313, 1318, 1321. 1321, 132.5) d. Conau,in a tlon prepa rations. The utility of the conubinatioii in the treatment of the conditions claimed for each ingredient has not been determilined there is a tntal absence of positive coptrolled studies. (Sec. No. 1291, 129.5. 1300. 1303, 1804, 1306, 1308, 1311, 1321) 5. The proposed announcement provides for deletion of ineffective indications within lid days and 6 months to submit effective data, and for sustained-release forms, data showing that the drug is available at a safe and effective rate. 6. Other phennietrazine products (Geigy's l'reludin Tablets and Preludin En- durets) are being covered In another announcement (DES! 11752). 7. Other diethy]propion products (Merrehl's Tenuate Tablets and National Drug's Tepani] Tablets) and another phentermiae product (Dorsey's Wilpo Tablets) are being covered in PEST 11673, as are other effective anorectlcs, benz- plieta aline and phendimetrazi ne. 8. l'a renteral iuietliainpheta mine reports `viii be announced later. 9.Nu,iuerous other nnoreetic preparations, not subjects of NDA's, are on the market. 10. Marketing of two of the products listed in the announcement (ND_% 6390 Anlrd,erlroxyn Hydrochloride Tablets, Lilly, and NDA 12-371. l'reiu-Vlte Cap- stiles, Geigy) hits been discontinued. 11. The holders of NDt's for products reviewed by NAS will be sent a copy of hue ~t A S-NRC report prior to put,] icntioa of tiuis anltounceinelit. Subsequent to publication tire holders of NDA's for similar drugs not reviewed by NAS (see enclosed list) wIll he advised that their products will also Ire affected. liExay K SrMMoxs. M.D., Director, Fierce it of Drugs. Tan J-Si'ncian LAnELING FOE PENFLURAMINE tnder ACTIONS: Most of the statements from the class ACTIONS section for anorectics (Tab D) are applicalde. In addition, a statement along the followIng lines should be u ad tided. PAGENO="0656" 16086 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Fen flu ra ~l inc (1 ocs not npi `ear to i ,oss ess liii' d egret' of a husk' I Ut euti al ~f such lii used 1110 rect h-s as the i,iijii icta `Ui lies, when tested ill 11Th! 1 5 and ii ii `,,a,as see I el ow ``rider 1) tug 1) rpm -len cc ) - Under l'ItECAJ'TIONS Fen flu rat aine iii frers it I its pu a ml a vol ogle p n file fri iril other mi tiorect iC' drugs with wine!, the prescribing practitioner may lie familiar. (`orres~wnnlingly. there are liossi ide risks not associated with other anorectics'' ; such risks include those of diarrhea. sedation, - and post therapeutic depression. The possibility of these hazards shr,til,I I,e weighed a ga Inst the possible n,Iva ritage if decreased cen- tral Ilervolis systet,, stinnil;i tion and/or a liuse jw'tential. In addition the consultants reviewed and a pu'roved the d raft hiren mile to a policy stat ement which fornts the attactia,en t nuder Ta, Ii. The conclusions and recol,,,,iend:tt ions were ~ts follows CONC1.I'SIONS 1. Ad flit obese subjects instructed In diet,i ry lI,alIa genlen t and treated with anoreetic'' drugs on the average torah to los, more weight thu a those t rented with placebo atig.l diet iii mel:, tively short-tern, trials. 2. The amouli t of weight hiss associa ted with the use of all i,tioreetic' drug varies froir, trial to trial. Tue Possible origins of tl,e increased weight loss due to the various drug effects lire not established. Tile increased ~veiglit loss a ppea rs to be melt, ted to variables other than tue drug prescribed such flS tile physician- investigator, the lopu] a tion treated, a rid the diet prescribed. Studies iii iiot permit toniclusions as to tile relative iniportarice of the drug a ad non-drug factors or, weight loss. 3. The ii,agnit ude of imicrea scsi weight loss of drug trea ted patients over placebo treatcd patients. WI, only ii fraction of a piiuiTlri a week. The rate of weight loss, was grea test in the ft rst weeks ergrfcTlvEyeEss IN ,.vtt.o nepsEsatYC Pt SCCIONS Depresatva reactions inttuds a variety of s~os- dromes svith a wide range of severity and a slrong natural tendency toward spontaneous remission. Their very diversity makes evaluation of any treat- ment extraordinarily difficult. Yet, common to msny depressed pemons are conflicts around oral-depend- ent noeds, which suggests that drugs such as alcohol, barbiturates, and amphetamines he used with caution because of their ability to produce dependence. In- deed, depression is the undectying osood in many, if not moat, high-dose srnpbrssmine abusers or "speed freaks" (8). But many doctors ask if amphetamines, although theoretically dangesous, are nonetheless a useful and practical measure for treating mild depressions. Tra- dition grants them a position of aorta in the treatment of mild cases, although recommendations for their ave are becoming incrtasingly rare (for example, the 1968 edition of Nopes' Modern CIi,tfceal Paycltiaeey sg:sores titem). Occasionatty one finds a favorable mention, as in hlcsdctson's article (9) in Freedsnan and Kaplan's textbook of psychiatry: The amphetamines are often useful and sometimes gras, fssise Ic elflcacios,s in Ii (sing tie api rituin mild depression. Whcta anode peessive medication is re- soated to, the aniphetami ses should probably be tried before prescribing the newer sntide pressive chaos. Virtaintly no astihorisy, hosvever, sstpports their site for nsore tints sn immediate euphoriant lift, asd most hel,evc that they' have no ptacc at all in tie treatmsnt of depression. Aeeordittg to Jarvik, `so Goodman and Oilman's text, (tO), no wetl-cootrotted long-teon study has hero able to dtmonssrase their effective- ness. The sympathomimetie amine; naich aa amphetamine s,sd phcnnse erazins, and similarly acting cc astral neevossu system stimulant,, such ss mcihytphenidate and papradrot. were tried in the treataascnt of de- peessionas d found wanting except in certain mild cases in which a detsg-iadaced acute euphoric state would sort rho report of an AMA cotsmittce states (3): Published studies have indicated that, in goneral, dextroamphetamine ia osiy slightly more effective that a placebo in amelioratisg depressive syeas ptomn. Cole and Davis (11), also writing in Freedman and Kaplan's textbook, review the evidence thus: Amphetamire was found to fast teas effective than piaceho in the treatment of depressed outpatients by British gcnerat practisioneru. ... In still another British study, smphetamine also proved teas effective than pheselzioc. and no beater than placebo, in the treatment of depression. to Veterana Admin- iateation study, dextroamphetamine was no more eftecsiee than placebo in treating hospitaliaed dc- pressed patisnss. to a recent review of the pharmacologic treatment of depressions Schitdkraut (12) arases: The psychomotor stimutaats (for example. amphet- enlint, methansptaesamine and methylphenidate) cause mood elesat,on. increased alertsess and en- hanced pert ormance in normal astbjecls. These dmgs may alleviate some of the symptoms of de- pression in certain depressed patients. but such beneficial eeeeta act often transient and may be accompanied by a number of unwanted side-egeces. It is furl5' gener alt far reed that the psycho- rnotnc sti ms,l attts h iran ret.- tive :y I `tale to offer in %Ite ttea5meut of maior depressive disorders. NoNvs-FnerlveNrss IN CONTROLLINO OSEStTY Obesity is usually regarded as a complex, long- 606 Ap,Stault.Aesats ut leaeaestusd,siee' Vsiaisi. 74.Nse,se,4 PAGENO="0669" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15099 `xs'm problem with major social and psychological determinants. Frequently recognized psychological tsatssr 5 are chronic tencion and depression, unusually strong oral dependent needs, nubility 10 tolerate ftts- ~ssion, and substitution of food for ocher forms of patification These psychological characteristics may had to dependence on many kinds of drugs as `sell as on fond. As in the case of depressive reactions, it ray be illogical to include in the trealittent °f such a condition drum that have a strong potential for cast- jag dependence. "In fact, the use of aniphetamise- Is-pc drugs is contraindicslcd for alcoholic persons and other dependence-prone persons" (3). Short-Term Effect: it in granted by most that am- phetamines can induce a period of appelite auppres- uioo and increased weight lost for a few weeka. Whether this is of lasting value in questionable, how- ever, since in most cases obesity continues to be a -problem over a period of years. Very few short-term pins in ftestmrnt of obesity have been translated into long-term successes. Iselore importantly, it is likely that shoet-eerm effeceivtncss is caused more by a stimulant effect than by any direct effect on the ap- petite control center of the brain. Thom aod Bondy (13), in their textbook article, state: As a rmule of stimulation, or a `lift,' the pstient't drive toward oveecating may be sipnificsntly modi- fied and as far as he is concerned, the over-all effect of the drug is `appetite-dc pressing' Obvi- oust>', drugs `s-bitt, create mets a state of euphoria nsay lead to habituation in censin individuals. Modell (14) pointed out in hi, 1960 report: Central atitssslstion, not a specific ceetral depressant tifect ott appetite, is then the common mretianians theougta which these drugs act; it is ctear. there- fore, why undesirable ceo teal aein,ulant effects. which have constituted their chic I clinics I limitation, have thus far appeared to be indivisible from asorextgesic action. lo other words, obese patients may use the drugs in the same way the `eperd freak" does-to obtain a "high." There is also some doubt ss-lsrther amphetamines are effective in the shore term. Again from ?slodctl'a report (14): The emphesasnises present special peohtemn in the evaluation of their effectiveness. Patients often promptly recegnice the dr,'g ba one or asothrr of she central stinsul an I effects (usually the `Ii ft') - Thus, they can distinguish between drug and placebo `shea lb ese are used in what theoretically appears to beawe Il-designed clinical tvuluaston wish a double-blind control. !n patients with emotional disturbances pursiculaety, st-ho inet'tdt moss cotnpulsis-e os treaters, she ability to distin' guists medication from placebo by any effect other than she one under evansination fit this case weight loss) makes it eaeeedisgly difficult to prevent bias and psychological faders from shaping the apparent rffecls of the dnig- Loss g-Term Effect: Thom and Boody (13) evaluate pharsnacological treatment of obesity as fotlnvva; Depression of appetite by a pharmacologic agent cat facilitate weight loss, although it is apparent lbs las soon as she pharnsseologic effect wears oft. or the medication is disconeinued. appcstle `sill resurn and weight gain will recur unless the pattent's inherent capacity to costrot hit food intake has been altered fundamentally. That the pltartaeaeologic ogese used for cheat ptarpoues be det-oid of serious toxic side effects is axioms/ic temphasis added]. tinforlunaletv there is so pharmcamene `n~la~~flspdmar~ In her sexebook article Aibrinic (15) devotes 3,600 words to the treatment of obesity. Thin is her discus- sion of amphesantines; Doags. Appetite-nuppresssnt drugs cf she amphet- amine group are effective for only a few weeks. Dependence on their stimutalory effect occasionally makes withdrawal a problem. Such doegi have no demonstrated role in the beg-tee-in caaaaieaneut of obesity. Reinforcing this opinion it the report o~ the AMA Cotnmitlee on Alcoholism and Addic;ictt and Coun- cil on Mental Health (3); In long-tees, (more than a few weeks ~-arams of v-eight reduction, the supe rort vnaese tsb- stances to placebo has not bees demon `t:tkd. In 1959 Slunkard and lstcLaren-Hutnae (16) re- viewed the lileratuee on the Ireasmert cf obesity. Theic Summary ttatet: A review of the literature on outpaeient t,-eaunent for obesity reveals that the asnbiust reported eesults has obscueed the relative in of such treatment- When the per cent of patients losint 20 asd 40 pounds is used as a criterion of success, she reports of the lest etterey `ears show remarkably similar results. Although the subjects of shese reports see frossly ovens-eight persons, only 25% were able eo lost as much as 20 pounds and only 5% loss 40 pounds. Tn 1966 Clennon (17) reported a follow-up; Review of the literature stnee 1958 did not reseat a successful tong-term study using a diet regimen by itself or in combination wish drugs. psychotoglc ereatmcett, or an eserciat proeram. Anlssood (18) is even more negative in his evalu- ation of all methods of taeatmenl, ieeluding the phar- macotogie. rst.ss.A.spheta'sts.. 607 PAGENO="0670" 15100 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Ar' of us know that we can't get fat people to become, lint by suggesting a diet, so we conclude, for the time being as least, that obesity j sincurahie. )itodetl (14) reemphasizes the point in site sum- mazy of his repost: New and togleat phannacothecapy for persons who overeat wilt more likely come with tsnderstanding of the procesne unsolved than through the c,trrrn practice of devetuping more variassont on oti thenicess tsi.h hate atre aify been weet esploi'cd and have not satisfied tt,e need. Tb ccc is rca Ily nothing new on the scene. There act no `snore siants" to fir specific disturbances ~O Ca sing patterns. arid here are tea useful depressants of the appetite ante c, w Isecevec it may be Cs, -rent phamsacotherapy for persons who overeat has limited ssse. Insofar as dusts are concerned, as the very best their potential t n secondary to she clint a ation of the cause of the hyperphsgia. Drttgs which give assist- ance along the Is nes now ava `table provtde short- lised sa mytomatic relief only. Despite 20 rears of extensive use rtser,jlse lace of aFphe ~y,~es in cli caljsracdce is ar rUm estab- lished. They represent the earasrncnt of_.ghpicefqf only a smali catcher of those patients for svhom they are presc b~ed_Tneir effectisenese its treating obesity `iisd depressi'.e rePdtions ft thinimat and conkoversiat. -. ln:eres:.nz:y. the phana aceutical industry tctts us indirectly hat Lie annphetamittcs and related drugs offer oc:v a iow order of effectiveness by constantly intrcduci-'arevv fongeners and combinaciona. For cx- annie, in i270 Physicfssnf Desk Ref crencf eight eomprtics ha. a listed nine `new' amphetamine prod- ucts no: :h::d in the 1968 edition, The industry nends the came messase in another more encouraging way; within the taat 2 yearn four companies have voluntar- ily discontinued their production of amphesamitses (MethedrincT, Burroughs Welicome; Phetobeset, Cole; T.V,D. Formula', Lambda; Ad~Ndt, Medics). Hatards of Amphetamines The irony of the amphetamine situation is that whereas we have been slow so admit the negligible utitity of these agents, we have also been nlow so rec- ognize slant daneers, Their illegal and casual use aa stimulants of the central nervous syntctn lsas grown tremendously. They have becom,pjpgh~pg the most serious dnsgpf abuse in the United States (as in sev- eral other countries), except in the large cities, where heroin addiction is widespread. Most physicians are not yet sufficiently familiar with tlsese ha,ards, which are well documented else" here (I, 3, 8. 19-22). Briefly, they fall into all three major areas of concern in psychoactive drugs. I. Amphetamines are astociated with tolerance and with an intense p,syclsealogicol deperudeoce, which makes it difficult to svithdraw front the drug without help. High-dose use nsay begin in a pastern of illegal cxpcrinttntation, but it may also heetrs with a physi_ class's well-intended prescription. The nature of else drug's effects leads easily to progressively increasing dosage in suseeptilslc persons. Prediction of "susrtp- tihlen" e:snnot hr ntadc with contidcnce, ttut patients for whom aisspheiaminen are prescribed are probably, by else .c ry nature of their tlnest,en, casting thom moss likely to increase lIne dose and become dependent. mess becies a prolonged at, uggle to discontinue drug use, an effort usually attended by intense letharey and depressive nymptoms. The perind 0f depression dur- ing the withdrawal (or `crash") is frequently asnoci- seed with suicidal feelings and actions, The absence of physical dependence in atnphctaneine abuse may give the impression that it is easier to withdraw from than heroin. This baa nest generally been thc case; in fact, else reverse may be arut, although data on this point are lacking. 2. Tine behavioral fo.rieiey of high doses is usually such that the uaer cannot maintain work, school, or family relationships. With high doses a typical pny- ehosis often develops, characterized by hyperactivity, distortions of realits', inspsirrd judgment, paranoid ideation, and hallucinations. Despise this disturbance, the sensorium is clear, and the individual may appear sugnerfcialty normal (19). 3. The physical toxic effects on the sutonovnic nervous system and cardiovascular system include sympathetic gastrointearinal and urinary symptoms, occasional systolic and diastolic hypertension, some- times cardiac arrhythmias (8, 21), sand possible nec- rotizing angiitis (22), to addition, malnureition, hep- atitis, and other serious iefcetions are associated with the innrssenous use or thrne drugs, These are she major loxic nanifcxtationa of illegal, high-dose amphetamine use. But damage also results from she lena apectarular adverse reactions to small, legally prescribed amounts and may cause disability for greater numbers of people. These cave examples are familiar 10 moss practicing physicians: Cast 1: A 23-year-old mate test-year medical student asked his physician foe stimulants to help him overcome clausroons drown mess. dsfticutty in studying, and mild da- pveauson, He did nol have n:sreotepsv, Dextroamphet- amine. 5 mg daily. was prenerilsed, LIe was ask-nd to resum bus dsd not. When next seen. he had flunked out of school. Althoesgh not the sole factor in this patseas" taiture, she ampstes.smsne obviously eltd not help h's studying and may have been a critical determinant in his avoidsng early, appropriate coun acting. Case 2: To control her appetite a 47-vear,ld woman had sassd various amphetamines almost daily for 50 608 Ap'it 5 a7a.Ae,,.ss as tet,,,,.5 M.dislei Vesa,,,. PAGENO="0671" COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY 15101 stats. Despite this, she was grossly obese. She eea!iaed that she had continued to take ihe medication largely to avoid lethargy and to get llsroush each day- She v-as now attempting to wiihdraw but was finding herself dc pressed, gaining weight, unable to mobilize enough en- ergr to keep her house clean. fiahting with her husband, and hiamiag herself for all her children's personal prob- ems because she had worked while they were growing up. H crust of amphetamines had allowed her to manage her personal and family problems in ways she no longer considered appropetate and had provided a comfortable alternative to counseling (which she had tried sa irsuecess- fully). \Vtth lIre children grown, menopause reachrd, and husband alienated, she was now steeompensati ng without the drug. Case 3: A 20-year' old female ntodent was well- adiusted hue occasionally depressed in the face of reli- grous confitets between strict parents and a mure related faneg. With marriage and a job 6 months away, she felt the need so lose some weight cern though she was not obese. She sppcoaehed her physician for diet pills. He reluctantly prescribed 30 Desbstral Cradttmet® teblees, each eontainiee JO ing of methamphetamine hydrochloride and 60 mg sodium pentnbarhital. Site lost 7 lb in she nest 30 days. She also etsgeged in her first coitus during this period, experiencing deep guilt. After finishieg the prescribed amount she felt tethargic and depressed. Four days after taking the last tablet she had tights with her fiancé and her stster, became very upset and de peeved, and impulsively ingested 30 tablett of sedati',e-analgesic (Ftoeinat~), each containing SO mg of anintee sned.ate-acting barbiturate (butathital). She "as heaspilalized mod erase ly intoxicated, and recovered. For this girl the combination of major emoticnal con- flicts and the depress-i on caused by amphetanrine with. drawal led to a suicide altentpc. It is important to recognize that these patients were giving their physicians a common message: they nee~ded help with an emotional problem. The physi- cian's response to the overt request for a pill pre- vented bra, from providing help for the real problem. Why Are Amphetamines Stitt Being Peeser',btd? Why are drues of tuch dangerous potential and ao littt objective advantage still in wide use? Amphet- amines are, after all, sot life-saving agents. Stvrral explanations are possible: I. Most phyxiciasss have noc had an opportunity to observe a seriously affected high-dote amphet- ammo abuser or `speed freak," 2. Most physicians feel a need to offer aomething to the patient trying to lose weight, both physician and patient often tensing, but not verbalizing, that they are dealing with a problem nearly untreatable in traditional terms. 3. The econontic value of amphetamine tales is substantIal, judging from the industry's enthusiastic promotion of these agents denpite the serious ques- tions about their utility. 4. Tens of thousande of respectable adstlts are no some extent dependent on them and exert auation on their physicians to continue prescribing tlsem. 5. Physicians themselves use and abttne psycho- active drugs more often than the general population (23). This suggests that aotaseeimea they may also have dilliesalty objectively evaluating the use og these drugs (or their patientt. 6, it it possible that amphetamine popularity cc' fleets American culture. As Fiddle (24) has observed, the amphetamine user is a caricature of many widely admired American traits: intense actisiry, efficiency, persistence and drive, and the desire to excel, to break recorda, and so move with ever greater speed. These ace admirable behavior patterns that are not easily relinquished, even when a drug may be re- quired to achieve them. The result it the perpetuation of the legal ute of dangerous agents of little therapeutic advantage. This is not the first description of the hazards or of the minimal effectiveness of these drugs, nor in it the first effort to suggett that their medical use be curtailed (25-27). But the problem grosvs. To tome extent the current drug-abuse epidemic may relate to the way ste as physicians hose handled the amphetamine problem. Our use of the t-seg may be providing a poor model for ehiidrez a~d adults- cents to emulate. By creating with dr4;s a condition stteh as obetiny, which probably moss vitro, has its roots in social custom and psyehulogi:a~ eon~ict, arc we giving license by example to ozn:~t:os who would treat their own social and ps'ehcio&cal dis- comforts pharmacologically? The time to face the unpleasant facts En long over- due. Amphetamines are fascinating substonces with a wide range of effects-some good. some tad. Their use represents a sincere effort to treat maCor causes of human suffering. Au present, how-ever, see art not to a potitioa to handle them safety. The situation raises uacotnfortsb!e quettiotta: If snnphetamiue use of all types-legal and illegai-'-wrre to cease completely tomorrow, would we be better or worst off with re- gard to health than we are today? Do we realty need these drugs? We must begin taking steps now to end the epi- demic overuse and misuse of amphetamines. Few of us wotttd sselcnme more restrictise legislation in the drug field or more extensive activity by the Food and Drug Administration. Yet this is the prospect if we avoid taking immediate remedial action. This action should begin with the phyaician's vol- untary cessation or sharp reduction of prescriptions for ampltetamines and their eongeners. Eneeption might be granted in individual cases for the treatment tds.as'As, thet.sstse' -609 PAGENO="0672" 15102 COMPETITrVE PROBLEMS IN THE DRUG INDUSTRY of narcolepsy and hyperkinctic reactions of children but rarely in other conditions. Ii is difficult, if not im- possible, to justify their continued use in obesity and depression. Physicians may need a buffer against pressures for continued prescriptions from some pa- tients- If so, a medical eonttnittee or board could be established to authorize these exceptions, as in Swe- den (28). To circumvent the weariness most of sit feel toward more committee ssock and the allspicion that an endless list of drugs may later come t,tder such scrutiny, let me suggest that it is no more than we would do if heroin were n,cde legal. Ampheta- mines cut no less a menace. Severe curtailment of production is essentiaL Less than 1% of the current volume would probably be an adequate supply for the exeeptiorsr.l ease. No more than two pharmaceutical houses are needed to pro- side this amount. The indu:~y's voluntary adion tosvsrd this coal would proside cefreshing es idetce that it puts the public welfare first and that legislation is not required on everY urgent health matter- FinaUy. advertising of these peoducts in medical journals is inappeopritte. We need rot delude oueselves that these measures svitl end 3c.. phetamine abuse they will not. It is not certain that sill as en reduce if measurably for several years, Black- norket production `sill doubtlessly cx- pacath l'be d::zovis of narcolepsy may suddenly be- com ensoe.z portlier- These measures am, bosses cc, a step in the th;e::.o n of removing one major inconsist- ency in nc: aperoach to dons and of establishing a climate thnt does not so sigorousty promote drug abuse. AeaoecovsL:oCt-lENTS: R,eeisnd at Nsvecmhar 197a; stsOst>_o.saer 1971, c~15.41105'5 tee e,pvirtssh,,ald be eddeetsed to Ounige B. Edtnors, M.D. S_Cit Staid. Send,, Us!'~m~ity of Utah, Silt Lake City. Utah s.slta. References a. Cos,tt.t PH: Clinical aspen. of amphetamine dependesa., as The Ilsa..atvacnlstwnl and Lptala,,oc,lasw.al .4spenla `/ c4doteaeeet Da.ag Oopeo'ieaice. ed:ted by WILtS,, CWM. O,levd. Pa, east's Pans., 1965, pp. .s.ss 2. Php-svta,ea Desk Reje,enco as Phap,esceaticat Sppoistt,e, and Bttnlneieals. 24th ad. Ors.J,i, PS.!., Medical Ecoaas'ce.. Is:., `970 3. A.sarsircs MosleM, Assoelagioti Cv,sisniseta ox Is'. can AnuicintsN Asia Cnu.ae,L Os Mr.5751. stcaLTh: rae. pe,td,oceoanatph.cantatea ass canoe stin,iilast dosas. JAMA 197:tsa)-5u27, sash 4 Nu,io'tar l7.snerTtoe Sterna, Ff50-IN, U.S. Dee,cxs,,s, or 545,5Th!. Fl,castsys, usa 5V,,.,anc: TI,, Up sea! Dave, Pits Pabtcrslien No. tao. svashsaaglon DC, us, Osc,ensiest Print:,5 Otsee. 569 SHins,'. 3. iy,usssta K.Ss,rnuS.etat:Acntebaehit,sa,eis. nscccaiaou. 1.4 5CA am a95.9scs 1969 6. Pius,, B: Slvep anti is,, disside's, is Cncit-!.snh Tea,hccka; fl-itt',,:,. tat', ed.. ,dtt,d by sirse,,, Pn, Isle Dr,s,srr sv. Philsct'lph i.e. 55 If .iusssl,es Cs.. 1967, p. 1432 7. 0 sUed ttOt~5ii5t it `palm,,, ease-reds, tsp,iUseticcbittav,s `claus. JA.tqA 759.t(t3.113t4. 19b9 S. Ss,ro, 01 sp,,J tss,ks ss. acid hi,),. Clan Pedtat tPhiial s:lci.loy. 3~5 9. Mv ssr,.s,,x St N'ro:atic O'pv,nsi an teacliss. it Comp,,. haetLr Te,t5,,,ci. e/ /``,et:iaut, rutted 5' PurteMus AM Kul't.sv itt. Sui':ec:,e, Sic, uvstt:ons \5,ts,s. Ca, lax; p. 936 IS Jsvstu Mr fatty: `sell is ,t:a i,ey'mgsrl It ysychianrie it rip I'I:a,maroy:.gsxtl arise 0/ Zhersyr:c:cr,. 5:4 a4, edited by 000assas ta, Otissas A. New Ysrt, Ti. Mcescctias Cs.. 965. p. 191 II. Coin des. Occn 555: An,td,pce'.ssss dna,,., Tanhc,,k e,t /`,1eSa.t,,. edt,cd by raxtasna'. AM, K-pta-a 111 SslLlrmcs', mc WithIn' & Witk,sc Ca.. Sb'. p. Ira 57. Sets'! scans v 3 Nasa ypsschyyha,s,acstaoy cad thu a dtsa'dcs (Sea, ct threa pacts). .\~` F5~ I Pined 25t:197- 2113, t9(9 as. Toes 055', Isa-aug Pu: Obesity, in Pcmcia/es at !utreuat stodtrvan. 3:5 a,!, `450455 Hapoisos Ta, Ascot 50, lesson IL, ~t,5. New York, McO,a,.H,ll FloeS Car, 1965, 3,. 390 14.Mssrit.W:t:staaaedprauyoctsfdesasfsraus-eeeatiaio Report so ASIA Council as Degas). /4.504 173:11314135, 960 IS. ALnuast MI. Obesiiy, is Cecst.Loph flcaback `1 .5! piscine lashed. es(is,d b~ Bess'. PB, Ste Drns,o'r I/i, Phcladelpho, `S.D Ssssctata c,., 1567, p 5170 16. Sarssasa A, McI..usrra'Hustr SI: Thet,stut,,sfectaloens leo obesisp. A `oh Shop,, diet5 (Climaagal 505' 79.83 1939 at (iiessc,s IA: W,ieost eede:assan-auensxasu. AceS Sc,.,, Mod (LOairc:yl tl6:l~2. 956 II. Asawasa BA: alto har,tsca at coopclesea. Eedttro&:,s1c~a 71:531 341, lIsa t9. Cos'tvLl rid: ,Sa,ph,a,ao,a'sa Psoehath SIc,d)ny Mc,n,agcnph Na 5. Landsa, Osfa,d Unicaesisy Press, 930 20 fC,snrs IC, ti,ekssu s VS. Lit's,, rpttia DC: Amphetamine sb,asm. JAVA 201:105-5159. 5947 21. Loan, DB-Steslhslsampl,casisn,otpteaaare.giaiugdrsgs. Arch 1,,,,,,, Med (ChIcago) 123:12.17, 969 21. CtvenN RB. 54 aIprax `S MaCautos- M, et at: Noatnunot aut,tis as,w,c,ted math drug ntame. Np's Fe.: I `ICed ala: 1033-tOll. ISIs 13. V sill *51' GE, Ii cuaros IS, MeAsassue C: Physicians' ass ul maod-sitenng Sian,,. Rem Eeg I Piled 29t3s3.a70, 930 24. Bionic 5: C,cc',s b,:osd 0,e cteusulcepsce: son's hunaSm ebsuta,,phetanai,eah'.te, in Apnpltetasnise A6,ca. ed,aed by Russo JR. Sae,ocaald, Itt , Charles C macsax, Pablsahet. 1968, pp. Sf09 29. Kit-on LO. Bess-sos 5: sachiasasion nasa aclajicuon Is e,,,phannesinos. 0:0 vied) 1.40-43, 1952 26. 5111,555 CalM (aCtors- The S'hap,nacs/agiss! and Epld.snl- obtains! Aspen,, at A,tttt,aecus Dec Drpeud,'re. Oclaid, Press. lilfcI. pp. 236.757 27. Esoss OR: Abase of umphrtaethnes (lester). 1,41514 255: soc-ams. 967 25. Psesasa as. Steed is Sissies (ctli.eniai). Net, fftsg I Med 253. 36)751, rib 610 PAGENO="0673" COMPETITIVE PROBLEMS IN THE DET5G INDUSTRY 15103 ffron the Medical Letter, ll4:91.~6, Dee. 6, l97~7 DRt~S IN PR~NANCY Since the thalidomide tragedy11l~Ti has been increased concern about the ef- fects of drugs on the unborn child; testing of new drugs in pregnant experimental animals has been required in the United States since I 962. In one study, more than 99 per cent of 3,072 pregnant women tnok at least one drug and four per cent took 10 or more; the average number of different drugs taken during pregnancy was four (C.. 1-I. Pecicham sod II, W, King, Am. .1. Obstet. Gynecol,, 87:609. 1Q63). A more recent survey of 1,369 women found that 97 per cent took at least one drug during pregnancy IM. M. Nelson and 3. 0. Forfar. Br. Med. J., 1:523, 19711. CYT0TOX(C DRUGS - Most cytotoxic agents used in cancer chemotherapy and imnIunosuppression have teratogenic potential. Aminupterin given during the first trimester in 52 pregnancies was associated with 34 abortions; malformations were noted in 10 of 12 fetuses that were examined (II. 0. Nicholson, 1. Obstst. Gynsecol. Br. Cornmonw,, 75:30?, 1968). Methotrexate administered during the first trimes- ter has been reported to have caused malformations of the skull, face and extrem- ities (A. Miiunsky etal.. 3. Pediatr., 72:790, 1968; 1!. R. Powell and H. Ekert, Med. 3. Aust., 2:1076, 1971). Mercaptopurioe (Purinethol), azathioprine (Imuran). and cyclophospharnide (Cytoxsn) taken in the first trimester have been associated with a high iocidsnce of abortion, but not with an increase in major malformations in the small number of pregnancies that ended in live births. CENTRAL-NERVOUS-SYSTEM DEPRESSANTS - Barbiturates, opioids and other central-nervous -aystem depressants may cause neonatal respiratory de- pression when administered in high dosage during labor. Reserpirie adrniniatered at term produces nasal congestion that can lead to serious respiratory obstruction in the oewborn - Narcotic abuse by a pregnant woman often produces withdrawal symptoms in the newborn infant; these can be lethal if they are not recognized and treated. With- drawal symptoms appear to be especially prolonged in infants born to women tak- ing methadone, as compared with heroin (B. K. Rajegowda et al., 3. Pediatr., 81: 532, September 1972). There is some evidence that LSD taken io early pregnancy may produce malformations in the, fetus (S. R. Assemany et al., Lancet, l;1290, 1970; 5. L. flIer and 3. M. Morton, N. Engl. 3. Med., 283:395, 1970). 85-569 077 44 PAGENO="0674" 15104 CO~WZTITnt PROBLEMS 1W TEE DRUG INDUSTRY ANTICONVULSANTS Drugs used for the treatment of convulsive disorders include a number with pharmacologic properties that pose a potential threat to the fetus. Daphenyihydantoin (Dilantin; and other brands) for example can interfere with folic acid metabolism. A recent survey of the outcome of 427 pregnancies in 186 women boing treated for seizure disorders found twice the usual frequency of major congenital malformations. The most common deformities were cleft lip with or without cleft palate and microcephaly (II. 0. Speidel and S. it. Meadow, Lan cet. 2:839. October 21, 1972). ANTICOAcJULANTS - Oral anticoagulants can produce hemorrhage during la- bor. leading to fetal death. If coumarin-type drugs are usedin pregnancy, they shouid be stopped about one week before labor is expected to begin. If anticoagu- lation is required in a pregnant woman at term, heparin is the drug of choice. ANTIBIOTICS AND ANTIMALARIALS -Sulfonamides taken near term can in- crease the risk of kernicterus in the infant. Streptornycin administered at any time in pregnancy and quinine near term have caused deafneas of the newborn. Tet racyclinea chelate with calcium and are deposited in bones and teeth: these drugs cross the placenta, collect in fetal calcified tissue and remain as stains in deciduous teeth. The penicillins are gene rslly considered safe for administration during pregnancy. One of the earliest reported d rug-induced P~iii~ian malformations was mascu. linization of female fetuses by maternal progestational therapy. Many synthiti, progeetins. as ~vel1 as metliyltesliisiernne. have been implicated. Recent studies report that vaginal adenocarcinomos occurred in adolescent girls whose mothers took dietliylstiltic-strol (DES) during pregnancy, The numle of cases reported recently in young women exceeds the total number found hcfr,ri the drug was used in pregoancy (A. L. llerbst eta)., N. Engi. J. Med., 284:878. 1971; P. C reenwa Id et sI.. N. Engi. J . Med., 285:390, 1971). Whether other d rugs can produce such long-delayed effects is not known. PAGENO="0675" COMPETITII'X PROBLEMS IN THE DM73 INDVSTRY 15105 ANTIHISTAMINF.S - Some piperazine antihistamines were once frequently uteri as antiemetics in early pregnancy. Animal studies have shown that three common- ly used drugs - meclizine (l3onioe), cyclizine (Marezine). and chlorcyclizine - are teratogenic in the rat (C, 1. C. King ci al., J. Pharrnacol. Exp. TIter., 141:391, l965~. The severity of these deformities and their frequency, approximating 100 per cent, led to concern about their use in man. Although retrospective studies, including thousands of infants whose,mothers had taken these drugs, found no in- creased incidence of abnormalities, most Medical Letter consultants consider it prudent to avoid them during the first three months of pregnancy. Nausea of preg- nancy is more safely managed with small, frequent feedinga. VITAMINS - Excessive quantities of vitamins may harm the fetus. Very large amounts of ascorbic acid are now widely used to prevent and treat colds and other acute respiratory infections. Such high doses taken during pregnancy may cause scurvy in infants when birth abruptly removes them from the high ascorbic acid environment 1W, A. Cochrane, Can. Med. Assoc. L, 93:893, 1965). Synthetic vita- mm K given in large doses near term can raise serum bilirubin concentration and increase the possibility of kemnicterus. 111gb maternal doses of pyridoxine have been implicated in withdrawal seizures in infants (W. A. Cochrane, cited above). CONCLUSION - Many drugs taken during the first three months of pregnancy are teratogegic. An even greater number produce fetal injury when taken after the first three months or at term, The 1962 Amendment to the Food. Drus and Cos metic Act requires testing of new drugs in oregnant animals before testing in man, but there is often a difference between teratogenic effects in animals and humans. Drugs that do not produce these effects in several soeciea of animals might still be teratogenic in humans; careful clinical observation over many years is eaten ~tial to exclude injurious effects. Unleas a drug is urgently needed, it should not be administered during pregnancy, especially during the first trimester or close to the time of delivery. PAGENO="0676" 15106 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Science, vol. 194, pp. 1027-28, Dcc. 3, 1976] AMPHETAMINES: TIGHTER CONTROLS Oy TIlE HORIZON (By Constance I lolden The abuse of the central nervous system stimulants know-u as amphetamines tins dropped since "speed" had its liey-d:iy iii the 1960's. lint amphetamine abuse is still a in ajar pail 1cm iii terms of piiysiei I (Ia ma ge a,' (I emoti iiiial Ii' ix~n ii ellc'y. Atid des pi to (lie fact t Ii at mann factu re a lId di st r it ut jolt of ti, e `itost danger' us varieties of the drug have tieeil inider strict federal controls since 1971, it still seems to lie a vol table to anyone who wants it. Thats what Senator Gaylord Nelson ( D-Wis. ) , chiairm~i,i of the tnoiiopolv sub- commit tee of the Senare ~inaIl ]li,sint'ss Ci ,ninijt tee, heard in 5 days of hetirriigs lie 0011(1 lUlled last lilontli Oh the Sn t'ety and efiic,iey of antiobesity drugs. `Flip mnaj or condition 1, ir whi tell a ~n ph eta in ines a rid a 1111W t tml ne-I ike drugs amphi'taiaiie eoiigeners I are legally prescribed Is obesity. But the evidence is stroll g Ill at Ii Ir most of lie 2.25 inillic iii A Inc rica 115 est i In a ted regularly to t like prescri lied a in phleta in iDes-il 01' to mention 1111 Coil nt oil ilsel'5 ~i'h ii I }il~' t heni Oil lie si reet-t lie drugs are not primarily I icing used for legit ima to medical purposes. It has been 6 years si ice ClIng less fi~isseil the Controlled 5111151 lIllC~5 Act. which en aided I he goverlin wiit t a put res trio lions iii, the produel 1(111 and di st ri tIn- tioti of licit drugs that tire subject to abuse. Anlhllietamilos ainl their coligeners ire co, it a died undo r the law, n I, ic-hi I ins sI `a rpl y redu coil preseri pt ions of the formulat iOlis t honglit to lie most dangerous. But the act seems to ha ye reached the limits of its effectiveness, because the level of airiplietainine coustlmlitioil, according to Food and Drug Administration (Ft IA) statistics, has reaiai ned constant over the' past 3 years. Furthermore, coiisuniption of anllihetanilile- like drugs Ills goii 0 up an (1 there are nm II y lx 9+' rt S wI to I iet ie ye the i r pot eli Hal for abuse is at most its great as it Is for an] phet~minines. TIns phenomenon, combined with aecumulatillg evidence to the effect that diet pil Is are tif marginal use in coml ltting f~t t. tins led Nelson to conclude t hat, aceordiiig to an aide, "the time is ripe" for amldietamines to lie wiped off the market a Itogetlier. and for stricter controls to lie lint oil other sy inpathomimetic diet drugs. There reilinill t `vu respectable apjdicat ions for at least one omplu'ta- ill no ~`oi mgen e i-Hi tat in (in ethyl phien id ate) -wIne!, ire n a rr'olepsy a lId ch 11(1! ioi id liyperkinesis. Itital iii is not used as a diet drug hut It and l'reludia ( whose only indication is for obesity) are said to be the most heavily abused drugs in the a in pbeta ni Inc family. It Juts been 4 years Si nec nil FDA advisi,rv panel colk'lmhed that ampheta- mine-type diet drugs were "olin icnhly trivial," The prep. ndernnee of testinlony from noligovernment witnesses at the hearings w-as to tile effect that the drugs a Ic neit tier safe nor efficacious. They curb appetite for a short time, hilt toter' alice is quickly hu ilt. a lid If the pills a i'e withdrawn the appetite returns in full force. Tentative evidence \\`as a Iso presented that I liese 1ii [is to Icon In the early weeks of pregnancy Inay cause fetal heart. defects and (itller inalfarmnations. Now, judd ng from what government witnesses si hI at I lie lIen riilgs, It npjw;i rs that the FDA and time Drug Eiiforcernent Adlnilnstratioli (flEA) are getting ready ti agree that the alilise Ilotential of 1110 liy of I tiese (1 rugs outweighs what- ever sillirt-terla benefits they have in lielpillg obese People ella age their en tiug habits. As J. ltichnrd Crout, director of the FDA's Bureau of Drugs, testified, in view of the failure of the Controlled Substonces Act to minimize abuse, "the only pica o In gful next step \i-Il i eh cat' lie to Ice ii is to reni ave the i rid ``at ion for oh `esi ti from the lahuehi itir for anipt,eta lIlt nes or to remove them from the market.'' Since obesity Is the only indication for some, changing the label wmuld lie tantamount to outlawing them nitogether. It huts heen more thaI) a dozen veqrs since various groups. including members of Congress, have ice,, attempting to curb or eveil hail entirely t lie marketing (If nnoreetic (appetite-siipprt'ssing) d rugs. hut the success hi as been I nil ted in the face of dedicntesl resistance Ill tile part of pharnmaceiltieah manufaeturers~ amphetamines and their relatives are the backbone of the diet 11111 business-and undiscriminating preceription practices on the part of same pliysieiaris-all enter- ing to vo"aeions public demand far fast-acting moans to thinness and ilappiness. The 1070 act sharply reduced production of diet pills-which reached an alt' PAGENO="0677" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15107 time high of 12 billion in 1971-by 1aitting the most dangerous substances, am- plietainiie. met hainphetaflfllle, and plielIlilet razine (otherwise known as l'reludiil oil schedule II of tile Control led Substances Act. This is the most restrictive category for licit drugs. It lilvs down product ion riuotas. requires detailed mob- I onng and rec~ rd-keeping, and forbids renewals of a prescription without a pl,ysiciaii's approvaL Other amphetamine-like drugs were put on Schedules III anti IV, a move that reel gli'iZeS their abuse potential hut doestit restrict distri- I intl on other than through proscription req ii remeb its. The regulatory problem has become increasingly complex in recent years as colapa `lies have come out with new drugs that are amphetamine-like in varying degrees. Some of these have been put on Schedule III or IV even though their abase poteiitial would seem to warrant tighter restrictions~. For example, Penn- walt (`orlioration, tile country's biggest manufacturer of diet pills. rechin naehed its energies to marketing a drug called lonaniin after its big seller, Biphetanline. was pitt on Schedule II. I'ennwalt cia ims that joxiamin is not an amphetamine and does not have the associated side effects. I*ster Grinspoon. ~ ehiatrist at iSlassa- ehusetts Mental health Center and the lead-off witness at the Nelson hearings. says, however, that the chemical structure is similar to aiaplietamnine, and any minor chemical change is unlikely to change the drug's action much. [There is a class of amphetamine-like compounds that exert effects that are more sedative lila ii stimulant, and soinetinlcs hallucinogenic. Fe,iflura mine (lIla rketed as Pondi- mm) is an example. These are not subject to much abuse, but neither is their anorectic value dearly established.] The fact is, say Grinspoon and others, the search for a drug that reduces appetite without producing the side effects char- acteristic of amphetauiine has met with failure. (lie says the situation is anal- ogous to what happened when researchers tried to synthesize a nonaddictiag opiate analgesic. The "hero" drug they came lip with in 1805 was named heroin.) There Is a distinct division of opinion on this matter. Government officials believe sonic congeners are reasonably safe and Crout said, "I suspect n strong safety case against the imonamphetaniiiies can't be made at this time." The best supporting data for their addiction potential are government statistics showing thin t, indeed, Schedule II drugs are much, more widely and heavily abused than those subjected to more lenient controls. The popularity of amphetamines and their syinpathomi ajetic relatives has been phenonmenni since they first hiecit me available in pill form in the 1950's. And, says 0 rinspoon, "there's been nothing like this ii. the way it's been erallraced by tile medical profession anti pushed by industry.'' According to testimony of Frederick A. Itody, sr., of the PEA, some pharma- ceutical companies have raised strenuous resistance to having their drugs more tightly controlled, even in the face of massive abuse of their product. Some have asked for an expansion of their production quotas to meet expected demand, said Rody, even though the demand projections were considerably higher than I IDA estium ates of legitimate nledica I need. Itody related how nile company, Pcnnwalt Corporation, responded to forth- coming restrictions on its a n,i'hetamlne drug Biphetamine Just before It was put into Schedule II. the cciainuany exported large quantities of the raw materials to its subsidiary in Mexico City. There the stuff was encapsulated. under the name Ilifetamlna. presumably for sale in Mexico. So much of the substance was smug- gled back into the United States and sold on the black market that PEA hind to mount a special operation. "Oi'erution Illoekjaek" to clamp dow-n on the traffic. Subsequently, under pressure from PEA. Pennwalt agreed to get out of the an,phetaniine export business. But then, in what a PEA agent called a "deadly parallel" to tile Biphetnmine episode, Pennuvalt has exported over the past 2 years CiIX) kilograms of the bulk powder from which Tonamio (a Schedule TV drug) is manufactured-enough, for 20 to 40 million pills. There has recently been found to lie heavy trafficking and abuse of "lonamina" in states adjacent to the Mexican border. "Discussions" with PEA have recently been held, and Penn- wait bus now arreed to stop shipments of lananmia powder to Mexico. The president of I'ennwalt's pharmaceutical division. Isaac II. McGraw. de- fended his comapany. saying It had always scrupulously obeyed the law a ml can-nv cooperated with the government. "SVe (10 not believe there is any proba- tive evidence that our anti-obesity products show meaningful statistical or other factual evidence of abuse." testified McGraw. And. "Pcnnwalt is not aware of any significant illegal use of its anti-obesity products." Other witnesses, including those deuling w-ith street level nddicts. in fact agreed that most "uppers" are obtained through legal channels. lady said illicit PAGENO="0678" 15108 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY itianltfacture anti diversion of the drugs is oil the decrease, so the increasing availability of supplies art created "largely by lI'eserilltilns Intl dire't dis- IelIsiwr by pliysieiuiis,'' who are apparently `prescribing and (lisjleIlsing well over the 1uttiellts' actual medical needs.' Siii'lt lflIctiti~ilt'r5 include thi,' small lint not or bitS Ii a ad Liii of "fat d dorM'' in T,o tig 1 si; 111(1 who. ~v Iti lesses sit iii, tid a iste r to the needs of 800 ft 1200 people a week, very few' Of ~vboi,i are fat. The Anu'rbean )ltslicttl Association has not tried very hard It, i-un, such practices. an'ortli,ig to (h'inspoon. AMA s]uOkesniail Frank (`liapjile says its ma ii nil i. .1_i!.! J)r,, 1/ Eu' alit,, t ions, l'econi mends against .r,'seril it ig at d iota it iii's and like suhtstatu'es for weight control, loft that otherwise the organization is not p rei cii, piet I wit] t t I,.' p rolilen,. TI ii' A MA di sI ii, ailed its (`tutu, il on I )rngs in 1971 after that hod" issued a strong warning about ttnilhletaiilixles, and (iriusiston ,idt's that it hitis gi'tiirally I ned to avoid offending the drug industry, which, In' i'stinitites. is supplying over hi;ilf tIre AMA budget `viii $15 utilliout ~vi,rtIr of drug advertising a year. (Iritispoon believes a total hat, Oil ;intplietaniine-like suiliStllTlces-5fl1'hl as has los-n enacted iii Sw-eden mid japan-is iunfeasihtle. The stuff is too easy I, nialin- f;ietui'e illicitly and, as with l'roliiltitioi,. it just wouldn't work. Frank Reynolds. direct, IF of Teen CI, all cage Yttur ti Centers a nil an ill icr wit ness a t t Ito Nets, ml hearings, dials with drug llroldi'flls at the street level. From his vantage point neither prolilition ilor tighter restrictiuois ni, drugs are going to ,nnke niuchi of a dent on I lie i ri hi eta so lot i g as the I el ief .revai Is f ro `a l'a nc A~- out no to t I e gli et to t hut t if yon Ii a ye a l ln blein vi) ii simi ye it w itt, , pill. TIe techinolotri cal a p~ Iron cli to sob-big Ian a in ~i jo] items was iii 1iIi cit I y con Ii ri aed I y ot tier wit tiesses u-li.) persisted in referring to (Imesity as a ``disease." Obesity is a condition. antI for most Pet title it Is nIt more a "di seas." thin a is loneliness or any of the other emotional factors t hat cause Itetitile to overeo t. [Front the Federal Register, vol. 11, No. 154. Aug. 8, 1970. pp. 12075-79) No'rlcrs DEi'ARTtrEN-r 01' IIF,ALT1[. EDUCATiON, AN~ WELFAnE Food anti flrnq .1 thu ii, ,,strat,on [DEST 53781 CERTAIN aNonEci-ic incus - Drugs for Ilunta ii Use Drug Etliemi c Study Iniphenient ati on The Food nit d I) rug Adin in is t rat ion 1 `as eva lu a ted rej ii its n'eci veil front t lie National Actidi-tir of Sciences-National Research (`4 uneil. Drug Eflicm,ey Study G `~ii Ii, on t lie fol I tw-i hg ant trect ii - drugs 1. Itiplietamine `7%" Capsules, Biphetaniine ``12¾'' Capsules, mind P,ililiela- mine "21)' Capsules. respecti~-ely. containing 375 milligrams. 6.25 nulligramns, ,rnd 10 milligrams each of dextroamnphetanune anti ainjdietamnin' per emilisule, till as cation exchange resin clIh,illlexes of sulfonatetl lsdvstvrene Strasei,liimrgli Laboratories Division of Wallace and Tienitin Tue.. Post Office itt ix 1710. Rochester, N.Y. 141103 (NDA 10-00%). 2. B i1 1, etanli ,,e-T ``121/.'' (`a I `suIt's a nil TI ipi iet a ii, ine~T ``20' (`il]us jilt's. resl cc- tivel,contninitig 62.5 milligrams each of dextrotinIlaletamuimle and omnplietamaine. and 40 niilligran,s nieth;,qualone per capsule, anti 10 niilligrt,n,s tacit of dex- troanipietatoine and ainplatam,,iii' and 10 ntitligrants niethaqualtine I~('I capsule, nil as c;ttioii exchange resin complexes of sumifontited iitilvstyt'ene St risenlairgh, Laboratories Division of Wallace and Tiertian Inc. (NI1A 11-135) 3. Ton am iii ~J 5~ 4 psules a tid Ton a miii ii ``30'' (`mu suIts. resps'cti veI~, eontai liii] 15 milligrams phentermine and 30 milligrams ldlentermoimie per capsule. 1,0th as cat] 0!) cxcii a 11g.' resi ii c' ni pie xcii of su 1 ft `iti t i'd itol 1st vreute St rtI si'il am rgli Laboratories Division of Wallace and Tiernati inc. (NDA 11-4113) 4. Du-Oria Tablets containing 10 tuilhigranis nielliatnpliet;,n,ine l,vdroclilo- ride, and 025 mill zn, mu reserpi no per s,mstai nod rehen so tablet P.. 1". Asciter and Co.. Inc.. 5100 East 19th Street. Kansas City. Mo. 6-1130. (NDA fl-fl-ltD. PAGENO="0679" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15109 5, Obotrol-lO and OI,etriil-20 Ta! lets, resliecti vol). containing 2.5 milligrams or 5 ni liii gr~ ii s Ca cli of met Ii a in! detain i at sa eel in rate, met! `am jiliet a in me lrvdrocliIoride.aii~pbet:,iiiiito sulfate. (!extroairllllietaluhrii' sulfate per tablet: 0! ret rid l'lm rm a i'ei Heals. 1)1 vi si 0,r of Rex jr I'I'a r,ini cal C op 2 ~eIiot Ic Ic Avenue, Brooklyn, N.Y. 11207. (NDA 11-522). U. l'rela-Viti' (`:rpsiiles conlajaing 25 nrilligran,s Idlenirletrazilie Iiydroel,loride. 2.000 I'S!' mats vitaiaii, A, 200 USI' units vitnniiii 1). 2 ulilligrairls Iltininine !llolloIiitrate, 2 nrililgrairis riboflavin. 20 rnilligraias iiiaiiiiiiiiiiile. 3 inilligrarris i'oleiiir,i palitotheliate, 1 inilligrari, i~vridoxirie hydrochloride. 0.5 iair'rogralri eolial~uniii conei'tit,'a!i'. 17.5 iiiilhgrains ascorbic :it'icl. 5 milligrams inn. 140 roil- ligrairis (rilcillIll. 103 inilligrarris iliospliorlls, 0.1 niilligrani iodine and I inilli- gram clipper per capsule: Geigy Clreancat Corp.. Ardslev. N.Y. 10502 (NIIA 12-371). 7. ~teth~dd~ Tablets coataitrii,g S niilligr,,iirs lrotbaiiilllietalirii,e Iiyiirx-hilori,le per tablet : B ii rn a, ghs We] Rum p & Co. ( U. S. A. ) . Inc.. 1 Sea rsd ale 1t lad. `l'r Ic Ic; t - Iris', N.Y. 10107 (NIIA 55(11). S. AIiI I hitI ro xy a Ilyd roclilo ri di' Ta hI c1s (0! it a iii I ~ig S ni ill ig rams ni et lr;i,ii - jl,et,taiine livdros'liloride per tablet: Eli Lilly and Co., l'ost Office Box IflS, Jlldiairarsilis, md. 162011 (NI1)A 6390), I Ic! to ta-sen S ted)- talns coat a i niri g 20 n ill i grail's dl-i netli a mplieta lii ill 0 Ii yd ro- eli In ri lIe and 120 irill ligra iiis in in lIar! ii tal l~'r 511 stall] cr1-re! eli so t a! det Eastern Research Laboratories liii',, 302 Smith Central Avenue, Ilaltirnore, Md. 21202 (NI1A 12-415). 10. Del to ta ml no S tedyt a! is con ta mg nO nil II igra I~5 sil-met Ii a mph e hi an lire Ii y. droi'liloride I er slista lied-release tablet Eastern Itosearch Laboratories Inc. (NI)A 12-410). ii. I )esoxyn Tablets eo'i ta lull] g 2.5 m'rI Ii grains or 5 in ill i gra nis ni et liar, ~l iot- a In no Ii yd roehilo ride i er tablet, I )esoxy a Grad U,,, el Tat lets (lint ala I rig 5. 10. or 5 inilligr,inis met ha niplieta ni me hydroeiilorii]o per tablet, and Pesm ixyn El lxi r con- Hi inhrig 20 milligrams inotha aijilietamino hydroehilori di' per 30 mliii lit ers : Abbott Laboratories, 11th and Sheridan Road. North Chicago. Ill. 0004M (NI)A 5375). 12. Drinalfq Tablets containing 5 nii!ligranis lnetlia,Iiplietanairie Iiydroelilorirlo per to tilet K R. Sin 11Th arid Sons, Inc., Georges Ito:i d, New Brunswick N.J. 05903 (NDA 5750). 13. Bamadex Ta blots containing 5 ninTh igrains slex t roanrpliota mine sulfate amid 400 In illigrainis ilielirobanra to Icr tablet Lerlerle Labora tories Dii'isian. A ,neriea n Cyana,riid Co., Post Office Box 500. Pearl River. N.Y. 10065 (N1)A 11-250). 14. Ba nun dcx Sequels cor,tainil.g 15 in illigrams dextro;i iaplieta maine snrl fate and 300 imiihligranis melirohamato per sustainer! release capsule; Lerlerlo Laboratories Division, American Cvanainjil Co. iNDA 12-570). 15, Tenuate Dospan Tablets containing 75 rnilligratns dietliylpropion hydro- elilori di' ~`er coat innliiis release tablet TIne William S. \forrell Co., Dlvi 5km of Rici~ordson-Merrell Tue.. 110 East Amity Ttoad, Cinei,inati, Ohio 45215 (NDA 12-540). 16. Aiipetrol Tablets containing S mill i zr,i ins dext roaniplieta inline sal fate and 400 iiiil]igrains rneprohani'rte per tablet : Wallace I'lia rniacoutieals. Division of Carter-Wallace, Inc.. Half Acre Road, Craahiirv, N.J. (1~.912 (Nfl.t 12-127). 17. Aj wet rol-S. It. Ca lisp los con t a liii ng 15 trill Ii rra las (I ext roa nil di eta in imie sul - ía to and 300 inrillirrarns inenirolia mate per sustained release capsules : W'allaco I'ln:irmn;neemmtjc,ils (NDA 12-024). 1 S. Esk-a t rol Span sit ho cm nit a liii ag 15 Ia lb grams (lox troa in lilieta miii no snil f;i to ~u,d 7,5 Imniligramas lmroclmlirperazi,,e (mis the iiialcate) per sustained release cap- sule ; Snilth Kline and French La lOratories. 1500 Spring Garden Street, Pliila- delnhia. Pa. 19101 (N'DA 12-442) 19. Ito corn ic 1 )esoxvephcdrine Ilyd roclihorjde Tablets containing 5 mi II gm ins siT-met ha to liliet,) maine hydrochloride per toll ot : 111gb Chemical Co.. 1160 North lTow'ard Street. Phil-mdelm,Iiia, Pa. 19122 (NDA s-non). 20. ,3hiller'Drine TalnleLs eontaimnng 10 niilligranis tll-mnetliarn;ilietaa,ine Imydro- chloride per tablet Smith. Miller a rid I `a tel,. Inc.. 401 Joyce iCilnier Avenue. New Brunswick, N.J. 05902 (NDA (1-003), 21. Dexserpiao 4i5'~ Tablets containing S nifllirra,ixs dextroomplietamnmne sulfate and 0.1 milligniin reserpine per tahtmet : Nysco Laboratories, Inc.. 31-24 Vernon Boulevard, Long Island City. N.Y. 11100 (NDA 10-207), 22. Norodin Tablets containing 5 milligrams methamphietamine hydrochloride per tablet: Endo Laboratories, 1000 Steward Avenue, Garden City, Long Island. N.Y. 11533 (NDA 5-0)2). PAGENO="0680" 15110 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 23. D-O-E- Tablets containing 5 milligrams lmiethamphetami,,e hydrochloride i*r tablet; Tilden-Yates Laboratories, Inc., 295 Lafayette Street, New York N.Y. 10012 (NDA 5-603). A. Effectiveness classification.. I. The Food and Drug Administration 11115 con- sidered the reports of tile Academy, as `veil as Other evidence and concludes thu there is a Jack of substantial evidence (if effectiveness of the lnethamiilletamine- containing preparations for: use as an adjunct in some cases In ~vl,ich nervous- ness, tension, and irritability are combined with feelings of depression, anxiety, and lassitude; use iii the management of a Icoll, 0115,11 (acute a ad chronic) cnuresis ; nausea and vomiting of pregnancy use its a mild analeptic in barbitu- rate overdosage restoration of optimism acid mental alertness In the ease of depressive state of mind ; and temporary or enlergencv use as a cerebral stinnihint to decrease fatigue and increase the urge to work 2. All the above-listed drugs are regarded as possibly effective for their claimed anorectic effects ; for their claims for prolonged, continuous, (IT sustai tied release and for all other labeled indications not listed in paragraph Al. B. Marketing stat us. l.a. Within 60 days from tile date of publication of this announcement in the Federal Register, tile labeling of methamphetann,ie- containing drugs should he revised as needed to delete those imldicmitions described in paragraph Al for which substantial evidence of effectiveness is lacking. ii. Tile holder of any previously approved new-d nig application for such (I rug Is requested to submit a supplement within (ID days after publication hereof to pro- vide for such revised labeling. Tue supplement should lie submitted under the provisions of § 130.9 (d) and (e) of the new-drug regulations (21 (TR 130.9 (d) and (e) ) , which permit certain changes to lIe put into effect at tile earliest p~s~- sible time. Failure to put such labeling Into use ntav result in a proposal to with,. draw approval of tile new-drug application. 2.a. holders of previously approved new-drug allldications for the drugs listed above and persons nlark-etilig any of these drugs without approval `viii lie allowed 6 months from the date of publication of this ai,nounceinent in the Federal Register to obtain and to submit in a supplemental or original new-drug applica- tion data to provide substantial evidence of effectiveness for tilose indications for which these drugs have been classified as possibly effective. h. For preparations claiming sustained-action, timed-release. or other delayed Or prolonged effect, such data should be adequa te to assure tile biologic avail- ability of tile drug in the farnlnlatioll which Is rila rkoted a rid should show that the drug is available at a rate of release which will lie safe anti effective anti that It has the prolonged effect claimed. 3. At the end of the 6-month period, any such data will lie eva I uo ted to deter- mine whether there is substantial evidence of tile effectiveness for such uses. After tile evaluation, the conclusions concerning the drug ~vill lIe puldished in the Federal Register. If no studies have been undertak-en or If tile studies do not provide substantial evidence of effectiveness, procedures will lIe initiated to with- draw approval of the new-drug applications for tllese drugs, pursuant to the i ro- visions of section 505(e) of tile Federal Food. Drug, and Cosmetic Act. With- drawal of approval of the applications will cause any such drugs on the market to be new drugs for which an approval is not in effect. The above-named holders of tIle new-drug applications for these drugs have been mailed a copy of the NAS--NRC reports. Any interested person may obtain a copy of a report by writing to the office named below. Communications forwarded in response to tills announcement Silonid refer to PEST 5378 which identities this announcement and should lie directed to the attention of the following appropriate office and addressed. unless otherwise specified, to the Food and Drug Administration, 5600 Fishers Lane, Rock-yule. Md. 20S52: Supplemeats (identify with new-drug application number) : Office of Marketed Drugs (IID-200), Bureau of Drugs, Original new-drug applicntlons: Office of New Drugs (BD-l00), Bureau of ~~:,~ments on this announcement: Special Assistant for Drng Efficacy Study Implementation (BD-201), Bureau of Drugs. Requests for NAS-NRC reports: Press Relations Staff (CE-200). Food and Drug Administration, 200 C Street SW., Washington. P.C. 20204. PAGENO="0681" COMPETITWE PROBLEMS IN ~E DRUG INDUSTRY 15111 This notice is issued pursuant to provisions of the Federal Food. Dnig and Cosmetic Act (sees. 502. 505, 52 Stat. 1050-53, as amended 21 USC. 352. 355) arni under authority delegated to the Commissioner of Food and 1)rug,s (21 CFIt 2.120). Dated: July 30. 1Q70. CHARLES C. EDwARDs, (`on,uii~sjoncr of Food and Drugs. [Fit. Doe. 70-10354; FIled, Aug. 7.1970; 8:47a.m.) [Frani the Federsi Register, vol. 35, No. 154, Aug. 8, 1970. pp. 12652-id] RULEs AND REOT-LATIONS TITLE 21-Foon AND 1)gr'c,s flhseptcr I-Food and Drug .4dininistration, Department of H cult/i, Education, and Weif are SUBCHAPTER c-DRUGS I'ART 130-NEW DRUGS Subpart A-Procedural and Interpretative Regulations A\EpIIETAMINES (AMPHETAMINE, DEXTROAMPIIETAMINE. AND PliErs SALTS, AND LEVAMFETAMINE AND ITS MALTS) Fox HUMAN USE; STATEMENT OF I'oi.icv Pursuant to provisions of the Federal Food, Drug, am) (`osmotic Act (sees. 502(f), (j), 505, 701(a), 52 Stat. 1051-53, as omended, ]055; 21 U.S.C.352(f), (j), 355. 371(a)) nnd under authority delegated to the Commissioner of Food and Drugs (21 CFR 2.120), I'art ]30 is amended by adding to Subpart A the following new section § 130.46 Amphetamines (amphetnmjne, dextroamphetamine, aad their salts nRc! levamfetamine and its salts) for humaa use; statement of policy. (a) Amphetamine and dcwtroamphctaniinc and their salts. (1) Pursuant to the tiotial Academy of Sciences.-Natii,na~ Research Council. Drug Efficacy Study Group, has evaluated cert~in dosage forms of amphetamines and other sym- pathomimetic stimulant drugs intended for use in the treatment of obesity and for other uses. The Academy found that such drugs as a (`lass have been shown to have a generally short-tern, anorectic aetior,. They further commented that clinical opinion on the contribution of the syinpatbomiinetic stin,nlants in a weight reduction program varies widely, the anorectic effect of these drugs often pleateaus or diminishes after a few weeks, most studies of them are for short periods, no available evidence shows that use of anorectics alters the natural history of obesity, some evidence Indicates that imnoreetic effects may he strongly influenced by the suggestibility of the patient, and reservations exist about the adequacy of the controls In sonie of the clinical studies. Their significant potentinl for drug abuse was also cited. * * * * * * * PREcAUTIONS Caution is to he exercised in prescribing amphetamines for patients with even mild hypertension. Insulin requirements in diabetes mellitus may be altered in association with the use of amphetamines and the concomitant dietary regimen. Amphetamines may decrease the hypotensive effect of guanetludine. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. PAGENO="0682" 15112 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ADVERSE REACrIONS Cardlo iaseular: I'alpitatlon, tacliy(a rd in. elevation of blood pressure. (`en (pal ,ierro (Is sjjsf cm: Overstiitiula tion, test less,iess. dizziness. i risoiiinin, euphoria, dysphoria, tremor, lieridaclie rarely, psycliol Ic episodes :i t rei'Ohii- mended iloses. Castro! ntcx( in a?: Dryness of the mouth. uuipleas~i ut taste, diii rrlieri, other gastrointestinal dist urliances. Anorexia and weigh t loss niay occlirr as unde rsi I'- aide effects when amphetamines are used for other than the a not-vet Ic effect. Allergic: Tjrtirrrta Endocnne: Impotence, changes In libido. D05A0E AXE) AOMLNISIRATIOX Regardless of indication. anipheta `nines should ire adini nistererl at tl ie lowest effective dosage and dosage should he individually adjusted. Trite evening medica- tion sli ovid Ire avoided heca use of t lie resulting i ns( nit tin I. Narcolepsy Usual (lose 5 lo Cl) milligrams per day ii divided doses. 2. 31 initnal I rn in dysfunction a .N ot recoinnieuulr'd for children under 8 years of age. h. Child rca fri rn 3 to 5 years of age 2.5 no I ligranis daily, rated iii increments of 2.5 milligrams at weekly intervals until ollti,nal response Is ol itai ned. e. Cli ildren (1 years of age arid older: 5 milligrams once or twice daily. increased In increments of 5 milligrams at weekly intervals. Only in rn re cases will It lie necessary to exceed a total of 40 milligrams per day. 3. Obesity: Usual adult (lose 5 to 30 milligrams per day in divided (loses. 0 van nos A (1 E Manifestations of acute overdosage wIth aniphietaniines include restlessness, confusion, assaultiveness, hallucinations, panic states. Fatigue ond depression usually follow the central stimulation. Cardiovascular effects include arryth- lain, hypertension or hypotension, and circulatory collapse. Gastrointestinal sytnptotns include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma. Management of acute nmphetnmine intoxication is largely symptomatic and Includes Invage and sedation with a barbiturate. Experience ~~4th heniodialysis or peritoncal dialysis in inndequate to permit recommendations In tins regard. (5) Distribution of any such preparation currently on the market without an approved new-drug application may he continued provided that all the following conditions are met i ) Within 60 (lays following the (late of publication of this section in the Federal Register, the labeling of any such jirep:t ration shipped witlil ii the juris- diction of the act is In accord with the labeling conditions described Iii tIns sec- tion. After said 60 days any such prepn ration labeled or advertised contrary to this section will lie rega riled as misbranded withhi the Ineani a g of section 502(f) (1) and (2) and (ii of the act and will lie subject to regulatory proceed- ings. New drug charges will he included in ap~ iroliria te cascs. (ii) The manufacturer, packer, or dist ru iutor of such drug subunits to the Food and Drug Administration, within 1 year after the date of pulilication of this section in the Federal Register, mi new-drug a phihication providing substnntial evidence derived from adequate and ~vell-controlled clinical I ovestiga thins tha the drug is effective for each of its labeled Indications. Since the treatment of obesity necessarily requires a prolonged period of time. sin tim in support of the drug's long-range effectiveness in this condition must lie based on studies con- ducted over periods exceeding a few weeks; intertuu i ttent adni ml stra tioui of the drug may l,e required. Such studies should also include data on long-term tox- icity for example, cardiovascular and ceatral nervous system. Such information Is essential for an evaluation of the benefit-to-risk ratio. (iii) The applIcant submits within a reasonable time additional Infornia lion required for the approval of the application as specified hi a written counniuni- cation from the Food and Drug Administration or in a notice published in the Federal Register. (iv) The application has not been ruled incomplete or unmipprovable. (v) The Food and I )rng Administration has not, by publication In the FammAL flaorsrra, announced further conclusions concrening amphetamines based upon information submitted in new-drug applications or other Information available. PAGENO="0683" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15113 (0) The labeling of any eoinl,i,iation drug containing amphetamine or dcx- troit injihetamine or their salts which includes any of the san',~ indications for use as are listed in the labeling in this section should be revised lo reflect the substance of those huirts of the labeling set forth in I his section that Ore applicable to the amphetamine component. Combinit tion products labeled as reiiui red by tins section are regarded as Den- drugs *aud must be subjects of approved new-drug applications. (I) Levanifetunnnc and its salts. (1) Levamfetamine preparations currently on the market are represented to lie useful iii the treatment of ol,esitv. `l'he Food and Drug Administration linds there is neither substantial evidence of effective- ness nor a general recogiiitiott among qualified experts that lhese drugs are safe and effective for such use, ~ these preparations are regarded as 110w drugs requiring ap~,roved new-drug applications. (2) Regula tory proceedings bused on section 5(15 of the act may lie initiated with regard to any such drug shipped wilhia the junsihiettiju of the act for which an approved new-drug application is not in effect. Those products eiainiiiig cx- eniptioii from the efficacy provisioas of the Drug Anaei.tliaents of 10(12 (Public Law 57-781; 76 Stat. ISO et seq.) under the ~grandfathier'' provisions (see. 107(e) (4) of that act; 76 Stat, 75'.)) will lie considered oi, tin individual basis. (Sees. 502 U). 1)), 505, 701(a), 52 Stat. 1051-53, as amended, 1055; 21 U.S.C. 352 (f) ii), 355, 371(a)) Dated: July 30, 1070. CILABI-Es C. EDWARDS, Con,,s,issio,,er of Food and Drugs. (FR. Doe. 70-10353; Filed, Aug. 7,1970; 847 n.m.] IFrom the Federal Register, vol. 38.No, 28, Feb. 12,1973, pp. 4249-501 RULES AND REGuLATIONS Title 21-Fo'jd on'l Dregs chAPTER 1fl)Ol) AND likEn Ao\iINLsThrATrox, DEPARTSIENT OF JIFALTIr, LOUCATI0N, AND WELFAaE SUBCHAPTER C-DRUGS PART 130-NEW DRUGS Amphetamines for Human Use On August ~, 1970, there was published in the Federal Register (35 FR 12652) § 130.46 concerning a inphetamines and their sails and levamfetamine arid its salts. Section 130.46 required the submission (if new drug apiihie;t lions for am- 1)11 eta ml Ire or d e xtroa a: ph eta nil tie a iid their salts as a (`011(1 ition for c iii lii `tied marketing. The new dnig aphicatiotis were to contain evidience iii efficacy, iii- chiding efficacy in the treatment of oh i-si ty. Pursuant to thin I requirement 105 new drug applications for auiiihet:nn ines or aniphetanaine-containing U rugs Were received. The analysis of the U a ta suhimitteil concerning the amphetamines and other. nonampliet .ini inc anorectic U rugs gen- erally supported the efficacy of anoreetic drugs. Use of the drug in obese patients was ii ssoria ted with more weight loss thai. was U iet alone. The degree of extra weight loss was small (a few tenths of a wmnd a iveek iii many cases), variations were great, and the r:l I e of weight loss ilecrea sed after the first weeks of I herapy. On the basis of the currently ava hIM he evidence, the Comiimissii 111cr e()1,chuides thin t oral dosage forms of aini ,hetamines and/or dextroalillihetaliuines are effective In the managenle,it of exogenous obesity as a short term (a few weeks) adjunct In a reginlen of weight reduction l,as,'d on calorie restriction for hiatients ill whom obesity as refractory to other measures. Appropriate notices concerning such U rugs whi ida have been reviewed if. the Dnig Efficacy Study ~vihl be pub- lisiteil in the Federal Register. Use of amphetamines for long periods of time may lead to drug dependence and abuse. Abuse of the aaiphietainhries has been svehl known. Persistence of abuse PAGENO="0684" 15114 CO~ET1T1VE PROBLEMS IN THE DRUG INDUSTRY under conditions of marketing described herein may lead the Comntissioner to take further steps to restrict the use of these drugs. No data have been received providing substantial evidence of effectiveness of levamfetamine and its salts. Accordingly these prel)aratl()Ims continue to be re- garded as new drugs requiring approved full new drug applications. On September 3, 1971, a Drug Efficacy Study lm1deioentation notice was pub- lished in time Federal Register (33 FIt 17069) stating that methamplmetnnuiae hydrochloride injection (intended for other than anoretic indications) was re- garded as effective for some indications and less than effective for others. The Commissioner has now fully reviewed the evidence on the safety and effective- ness of this drug, and has concluded that the well-doeuineiited history of abuse of parenteral methaniphetanline, together with the severe risk of dependence and the availability of safer and equally effective alternative drugs, creates an un- favorable balance of risk to benefit. A proposal to withdraw approval of those new drug applications as lack-lug evidence of safety is published elsewhere in tills issue of the Federal Register. The Commissioner also concludes that, for the same reasons, lmrenteral preparations containing arnldietamine, dextroam- phetatnine, or levajafetamine or their salts are lacking evidence of safety. On August 8, 1970, a Drug Efficacy Study Inlllleineiltatioli notice `v,is pllblislled in the Federal Register (35 FR 12015) stating that various combination drugs containing an anoreetic drug were regarded as possibly effective for their claimed nneorectic effects and lacking substantint evidence of effectiveness for their other indications. I lata \vere received concerning those t1 rugs mid also combination drugs which were subjects of new drug applications suimnutted as re- quired by § 130.4C The conmlmmnatioiis consisted of anoret ic agents associated with, for example, sedatives, tranquilizers, rauwolfia derivatives, or vItamins. The data were reviewed and found not to fulfill the criteria set forth in the Statement of C enerat l'oliey or Interpretation 3.80 Fixed-conibimiatiomi pro- scription drugs for humans, published in the Federnl Register of October 15, 1971 (36 FIt 2(X)37) . Further, in view of the lack of substantial evidence of effcctiveness of the drugs as fixed coinhinations, the recognized potential for abuse of the amphetamine dextroaniphetamitie. niethamplietamnine, and phen- metrazine components, and the availability of alternative therapeutic measures which are safer and effective, comliinatioims coitaiiiing such coinponent~, nlso lack proof of safety. Proceedings to withdraw approval of such applications are being initiated and an appropriate notice is published elsewhere in this Issue of the Federal Register. In a forthcoming issue of the Federal Register, the Commissioner ~vill set forth his policy with respect to anorectic agents iii general. On the basis of all of the dmm ta and inforimmation subinitteti pursuant to § 130.46 pursuant to lirovisions of the Federal Food, Drug, and Cosmetic Act (sec. 502 (f), (1), 505, 701(a), 52 Stat, 1051-53; as amended. 1053; 21 1T.S.C. 352(f). (j), 355, 371(a)), and under the authority delegated to him (21 CFR 2.120), the Commissioner of Food and Drugs hereby revises § 130.46 of I'art 130, Subpart A to read as follows: § 130.46 Amphetamines (amphetamine, dextroamphetamine, and their salts and levamfetamine and its salts) for human use. (a) Amphetamine and dextroamphetamine and their salts. (1) Pursuant ~i the drug efficacy requirements of time Federal Food. Drug, and Cosmetic Act, the National Academy of Sciences-National Researcll Council. Drug Efficacy Study Group, has evaluated certain dosage fornms of amphetamines and other sym- pathomaituetic stimulant drugs intended for use in the treatment of obesity and for other uses. The Academy found that such drugs as a clmis have been shosvn to hnve a generally short-term anorectic action. They further commented that clinical opinion On the contribution of the synipathomimetic stimulants in a weight reduction program varies widely, the nnorvctic effect of these drugs often plateaus or diminishes after a few weeks, most studies of them are for short periods, no available evidence shows that use of atlorectie alters the natural history of obesity, some evidence indicates that anorectic effects ii]av lie stronmrlv Influenced by the suggestibility of the patient, and reservations exist about the adequacy of the controls in some of the clinical studies. Their significant potential for drug abuse was also cited. (2) In addition to those dosage fonns that were reviewed for efficacy hy the Academy. other dosage forms of amphetamine drugs are on the market that were PAGENO="0685" COMPETITIVE PROBLEMS iN TUE DRUG INDUSTRY 15115 not cleared through the new-drug procedures. While certain. anllinetaliiines \` eYe marKeted prior to enactment of the Federal t ood, Drug, and t~osmetic Act in suaa, some or the conditions ot use subsequelltIy prescribed, recommended, ol) suggested in their labeling (for example, br Inc treatment or ooesity) utifer horn uses claimed tor the anipiletamines before said enactment. bucli uses nave not beea cleared through tIle eflectivelie.s5 l~rov~~~s or the Drug Amend- belts or s~,02 (lublic Law si-mi which amended tile Federal kood, Drug, and Cosmetic Act). These drugs are ~ery extensively used in the treatment of Ooesity. Tne extent or the use for such purposes as narcolepsy and minimal brain dysfunction in children is believed to tie minor as compared with the total usage of these drugs. Because of their stimulant effect on the central nervous system, they have a potential for misuse by those to whom they are available tnrougti a physicians prescription, and their abuse by those who obtain then. turougli illicit channels is svell documented. Production data indicate that am- phetamines have been produced and prescribed in quantities greatly in excess of demonstrated medical needs. (3) Pursuant to a notice published hi the F'EoEu~~L REGISTER of August 8, 1970 (35 kIt 12652), which required the submission of blew drug applications as a condil ion for continued marketing of amphetamines, 106 new drug applications for amphetamines or amphetamine-containing drug products were received. The data submitted in those applica thins, and data obtained from other sources con- cerning anorectic drugs, generally supported the efficacy of anorectic drugs. (b) On the basis of currently available evidence derived from short-tern. studies, the Commissioner concludes that single drug entity oral dosage forms of amphetamine or dextroaniphetamine are effective in the management of ex- ogenous obesity as a short-term (a few weeks) adjunct in a regimen of weight reduction, based on caloric restrictions, for patients in whom obesity Is refractory to other measures. For purposes of this regulation, a mixture of dextroampheta- mine and amphetamine is ordinarily regarded as a single drug entity. (c) The Food and Drug Adnnnistration is not aware of data providing sub- stanti:il evidence of the effectiveness of levamfetamine and its salts and regards these preparations as new drugs requiring approval full new-drug applications. (d) In view of the well-documented history of abuse of parenteral anipheta- mines the severe risk of drug dependence, and the availability of safer alternative pareiiteral drugs which are equally effective for recogiiized jion-anorectic Indi- cations, the Food and Drug Administration regards pirenteral ninphetaniine.s as lacking evidence of safety. (e) Any combination drug containing aniplietamlne or dextronmphetamhae is regarded as a new drug requiring an approved full new-drug application as a condition for marketing. Data in new-drug applications are required to fulfill the criteria set forth in § 3$6 governing fixed cornblnntion prescription drugs for humans. (f) New drug applications have been received from persons marketing orally administered single entity amphetamine or dextroaniphetamlne dosage forms. Any other person who intends to market such drug is required to submit to the Food and Drug Administration nfl abbreviated new drug application (§ 130.4 ~f)) except that in addition, the application shall contain full information re- quired under items 7 and S (composition and methods, facilities, and controls) of the new drug application form }`D-3561T (I 130.4 Ic) ). (g) The labeling conditions for single entity oral dosage forms of ampheta- mine and dextroamphetamine and their salts fire as follows: (1) The label shall hear the statement "Caution: Federal law prohibits dis- pensing without prescription." (2) The drug shall lie labeled to comply with all requirements of the act and regulations. The labeling shall bear adequate information for safe and effec- tive use of the drug. The indications for use are: Narcolepsy. - Minimal brain dysfunction in children (hyperldnetic behavior disorders), as an aid to general management. Management of exorenons obesity as short-term (a few weeks) adjunct ia a regimen of weight reduction based on caloric restriction, for patients In whom obesity is refractory to other measures. (3) Complete labeling guidelines are available ti-nm the Food and Drug Ad- ministration. PAGENO="0686" 15116 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY (Ia) Regulatory proceedings will tat' initia ted with regard to any such elrnag with in the jurisdiction (of the act which is not ill accord with this regain finn. Effective date. This regulation slonll be effective oil ~t:ircl, 14. 1973. Dated Fel mary 7, 1973. Woo,o.x.-~ Pd F'. lOAN flOf.Plt. A cling .1 .qsoe / (lie COW Pal (08/oil (`r for (`one JiI/O nIec. [Fit Doe. 73-2717 FlIed 2-9-73; 843 Cml Fnuoo the Feelers I Register, vol. IS, No. 25, Feb. 12. 1171. pp. 4279-821 NOTICES DE5'ARTS(ENT OF FIEA5.Tsr. ElaVc'.tlloN. AN!) WELFARE FOOl' ANU DRUG .&OM!N1S'FRATJON [DES! 5378; Dorket No. FDC-D-5.S2; NI1A No. 9-PIn etc.] (`EguTAly (`o~ranNAT!orc ANoas}:cTIc Dituos OPPORTUNITY FOR hEARING ON IIOOPOSAL TO \VITIIDRAW APPROVAL or NEW DRUG APPLICATIONS In a notice (1)ESI 5378) liulolisliesl in the FF:UERAL REGIsTER of August 8. 1970 (35 FR 12678), the Commissioner of Fond and Drugs aoiauouuced his conclusions pu rsnnant to the evaluation of a report reeei s'ed from the National Academy of Sciences-National Bescarch Cnuneil. Drug Efficacy Study Group, on the drugs deycerit,ed l,elovw sth ti ng that the drugs were regarded as possibly effective and lacking substantial evidence of effectiveness for the Various labeled indications. NDA No. Drug tWA Holder 9-946 Ou.Onia tablets containing 10 mg methamphetammne hydrochloride, and 0.25 mg reserpi n e per s asta t nod release ta blot. 10-207 Denserpirie `5' tablets containing 5 mg deutcoaniphelamine sulfate and 0.1 mg reserpine per tablet. 11-280 Bamades tablets containing 5 mg deutroamnpbetammne sulfate and 400 mg meprobarnato per tablet. 11-522 Obetrol-lO and ObetroI-20 tablets, respectively, containing 2.5mg each or 5 mgeach of mntharnphetamine uaccharale, methamphotamimse hydra- chloride, an phetami Ce sulfale, deutroa mph vIa mice sulfate per tablet. 11-538 Biphetarnine.T q2y4' capsules and Biphetamioe-I 20'' captaIns, respectively, containing 6.25 erg each of dostroarniphetamine and amphetamne, and 40mg methaqualone per capsule, and Ii mg each of deetroamphetammnie and amphetamine cad 40 nag methaqualore per ca pa We, all an cat' on e ocha ege rca in com p Icons of sulfa sated potysly- re a e. 12-042 Esliatool Spanaules containing 15 mg destreamphetanimne sulfate end 7.5 m g p rochlarpeo aol re (an the malcale) per sustained re Inane Capsule. 12-127 Apyetrol tablets containing 5 mg destroamphetansine sulfate and 400 rug meprobamnate per tablet. 12-371 Prelo-Vite capsulen contaieing 25 nag phemamelcazine hydrochloride, 2,000 USP units v,tamin A, 200 USP units vitamin D, 2 org thiamine mon000tonte, 2 rug riboflavin, 20 mg eoacmnam,de, 3 rung calcium panto- thenale, I mg pyomdoomne hydrochcloo ide. 05. mg cobalaer, n concen- trate, 37.5 mg ascorbic acid, 5 mg iron, 140 mg calciam, 108 nag phos- phorus, 0.1 mg iodine and I mg copper per capsule. 12-415 Delteata-sed Stedytobs containing 30 org dI.rnetharnrphetarrine hydro- chloride and 120 mg amobarhital per sustoined-releaoe tablet. 12-570 Bamades Sequels containing IS mg dentroamphetamint sulfate and 300 mg mep rsba mane per sustained-release capsule. 12-624 Appetrot.S.R. capsules containing 15 slog deatroamphatarmaine sulfate arid 300 rung meprobamaoe per auotoired-released capsule. Formerly marketed by B. F. Ancher & Co., Inc., Post 010cc Bos 127, Kansas city. Mo. 64130. Formerly marketed by Nysco Laboratories, Inc., 34-24 Ver- non Blvd., Long Island City, N.Y. 11106. - Ledorle Laboraloroes Oieis,on, American Cyanamud Ca., Pont Office Box 500, Pearl River, N.Y. 10965. Cbetrol Phormaceuticsls, Diei- sb n of Rosar P harm acol Corp., 382 Scheeck Ave., Brooklyn, N.Y. 11207. Slraneeburgh Pharmaceutical, Di- visioa Penowalt Corp.. 755 Jefferson Rd., Rochester N.Y. 11623. Smith Kline & French [abonn- tories, I 500 Spring Garden St., Philadelphia, Pa. 1910!. Wallace Pb an maceutica In, Div. smon of Carter- Wa I lace, Inc., Halt Acre Rd., Coanbuny, N.J. 01512. Formerly marketed by Geigy Pharmaceuticals, Division of Ciba Geigy Co., Saw Mill Ricer Rd., Ardoley, N.Y. 1i502. Eastern Research Laboratories Inc., 302 South Central Ave., Baltimore, Md. 21202. Ledenle Laboratories Division, Aniericao Cyanuiaaid. Wallace Pharmaceuticals. PAGENO="0687" COMPETITIVE PROBLEMS IN fl-rE DRUG INDUSTRY 15117 Data submitted pursuant to the iiotiee have been reviewed and found not to provide substantial evidence that tile drugs are effective as fixed coinhiiittt toils for their claimed uses. II) view of the lack of substantial evidence of effectiveness of tli e d nigs as ft xcii (`01111)1 nit ti on s, t lie recognized po tell ti~d for abuse of t lie it In iliC t:tnij lie. (Icr- roa nil ii ieta nil tie, nietli ttin~ ih eta `nine, and pile ii met rim z I lie coil, line) t s, ii] d the availability of alternative therapeutic lileasures which ale safe,' and effective, the coiiibi,iatioi j rodtiets are also regarded as licking h iroof of safety. I )ata subniitted in response to the notice of A Imgust 5, 1970. do not support a contention tli;i t the coniliinat ion Products decrease the ieidence or severity of side effects associated with the si ogle ingredient or flint the addti ma I (-oaiponent (s) lessens the tihu se l otto liii as co ill iii red to I hi at of I lie sill gle eli ti I V a lior.ctic d rug. Al so. I he hut `VII ad Verse elicit s a ssoi ia teil `vi tli ph cii ot Ii ia zi tie dru ~s raises an a (Id i- tional question of safety of use of Eskatrol which contains ihoxti'oaotphietauane sulfate ~ii (-omlit)i na ti oIl \vi t hi I m'och to rhienl 7.1 lie. With further respect to Eskat rol, the Foot! a ,id Drug Adni I Inst rat ion is aware of a study conducted by Dr. Cart (`hanibers "elating to the abuse potential of lie prod tic I, an (1 for which no repu irt I as tieen Si ib ni itt i'd by theN DA hi older pursuant to section 505t-i) of the act alit! 11130.13 and 130,35 of the regulations (21 C FIt 130,13 antI 130.35). Therefore, notice is gi yen to the holder Cs) of the new- (I rug application (a a nil to any' other Iliterested erson tlta t the Conu Inissioner proposes to issue a a order under section 505(e) of the Fedi'rtrl Food, DI'IIg a nil Cosmetic Act (21 U.S.C. 355(e) ) withdrawing apitrova I (if the I isted new drug apphica tiori (s 1 and all a men (110 cii t 5 a lid 5091 ilenien t a t I teret 0 on time grim rids tli it 11 ew Info l'ni iti on before hilii with respect to the dnig( s ) , evaluated together with the evidence available to him at the ti lao of approval of the appi icatioii (s I, shows that (1) There is a lack of sulistaiitial evidence thu t the drug(s) will h,u ye all the effects they purport or are leprcsen ted to have; and (2) the drugs ore not shown to be safe for use under the conditions of use prescribed, reconllne,uiierl, or suggested in the labeling; and (3) further, in the case of Eska trol tablets, tin applicant has deliberately failed to make required reports in accorda, ice with sect ion 5115(j) of the act (21 U.S.C. 355(j) ) and 130.13 and § 130.35 of the new drug regaIn. tions (21 CER 130.13 and 130.35). Alt identical, related. or si nubi r products, not time subject of an approved new drug application, lire covered b-v the new drug ipplie,t thou(s) reviewed. See 21 CFR 130.40 (37 FIt 2318.9, October 31, 1972). Any manufacturer or distributor of auth all identical. rela ted, or silni Ia r product is all interested person who may iii response to tills notice smihnm it data arid I ,iforma t ion, request tlia t the ne~v drug application(s) not be withdrawn, request a hearing, and tin rtieipa te as a party In any hearing. Any person who wishes to deterniiiie whether a specific product is covered by Hi is not ice should write to the Food and Drug Adniinis- tration. Bureau of Drugs, Office of Comnpliance (BD-300) , 5600 Fishers Lane, Rockville, MD 20552. In accordance with the provisions of section 505 of the act (21 U.S.C. 255) and the regulations ~iroinu1gateiI thereunder (21 CFR Part 130), the (`orn,nissioner hereby gives the a pjilit'a nt(s) and any of her interested person an opportunity for a lien ring to show why approval of the new drug apj li cation (5) should not he witlidra ~ The applicant(s) and any other interested person Is required to file with the hearing Clerk. Department of health, Education, and Welfare, 1100111 0-85, 5600 Fishers Lane. Rockville, MD 20552, on or hiefore March 14. 1973. a written appear- anr'e electing whether or net to avail lnniself of the opportunity for a hearing. Failure of an applicant or ,iliv other interested person to file a written appear- alice of electi on in' March 14. 1973. will constitute an election by hini not to avail hiniself of the opportunity for a hearing. If no person elects to avail himself of the opportunity for a hearimig. the Coin- missioner without further notice will enter a final order withdrawing approval of the application (a) If in applicant or any other interested person elects to avail himself of the opportunity for a hearing, lie must file, on or before March 14, 1973. a written appearance requesting the hearing, giving the reasons why approval of the new drug application(s) should not he withdrawn. together with a well-organized and full-factual analysis of the clinical and other investigational data he is PAGENO="0688" 15118 COI~WETITIVE PROBLEMS IN THE DRUG INDUSTRY prepared to prove in support of his opposition. A request for a hearing may not rest upon mere allegations Or denials, but must set forth specific facts showing that a genii tie and substo ntial issue of fact requires a hearing (21 CFR 130.14(h)). If review of the (Ta ta sul,t,iitteil by an a liplicant or any other interested person warrants the conclusion that there exists substantial evidence demonstrating the effectiveness of tire product(s) and evidence that the drug ( ) is (are) safe for use for the labeling cIa in's involved (and. Ii I lie ease of N DA 12-042, that there has been iii, violation of seci ion 505 ( j ) of t lie aft ) t lie Ci an `iii ssi I lie r wi IL rescind this notice of opportunity for liea ring. If review of the data in the a ~ipIication (s ) and cia tn submitted by the a ppli- cant(s) or any ot her Interested person in a rei nest for a hen ring. ti getlier `vi Ut the reasoning and factual analysis in a request for a hearing, warrants the con- clusion that no genuine and substantial Issue of fact precludes the withdrawal of ap~ Font I of the a ppl Wa ti on ( s ) t lie Coinnu ssi olier will ci it er an order (if with - diii Iva I in ak-it g findings and c' md usli ins on such dli (a. If, upon the request of the new drug applicant(s) or any other interested per- son, a hearing is justified, the issues wit I lie defined, a hen, ring examiner wil I lie named, and he shall Issue, as soon as practicable after March 14, 1973. a writ- tot, ii or ice t f the hitti e and place at which t Ii 0 I lea ri rig will con, mcii cc. All persons interested in identical. reIn ted, (iF sinut;i r Products covered 113' the new drug ap- plication (5) will lie afforded an (11115 rtu nity ti appear at the liea ring, file briefs, Present evidence, cl'iis~-e xantine witnesses, sutitnit suggested findings of fact, and otlier~vl Sc participate nsa party. TIme lien ring cotiteinplated by this notice n-ill be open to the pul ii ic except t I tat any port jot' of the lien ring tIm t concert is a method or process the Comnussioner finds entitled to protection as a trade secret will not lie open to t lie public, unless the respondent specifies otIier~viso iii his appearance. - Requests for a hearing and/or elections not to request a Itearitig n1a3 lie seen in the Office of the Hearing Clerk (address given nbove) during regular business hours, Monday through Friday. Tins not ice Is issued pursit ant to provisions of the Ferlera I Food. Drug, and Cosmetic Act (sec. 505, 52 Stat. 1052-53. as nmended; 21 U.S.C. 355), and the Administrative Proceilure Act (5 U. S.C. 554). and iuider authority delegated to the Commissioner (21 CFR 2.120). Dated: February?. 1073. WILLIAM F. ItANooLpir. A eting A sfloriaft, (`oiii at i,~siou cr br Compliance. [FR Doe. 73-2710 FIled 2-9-73; 8:45 mm] [DES! 116731 CERTAIN ORAL ANonEcrIc PREPARATIONS: PIIE,cTEnMINE ITYDR0CIILORTDE Puny- oIMETtrAzrxr TAnTRATE; BENZPIH7rAMINE IlvonociTnonton; DTETJEYLPR0PI0N Ilyonoci: roRIoE DRUGS FOR HUMAN USE: DRUG }~`FICACY STUDY IMPLEMENTATION The Food and Drug Administration has evaluated reperts received from the National Academy of Sciences-National Research Council. Drug Efficacy Study Group. on the following anorectic drugs: I. W'il no ta lilets, containing S iug. phienternihie hydrochloride her tablet Dorsey Laliorntories. Division of Sandoz-Wander Inc., Northeast. 1'.~.6 and In- terstotoSO, Lincoln. Nelir. 65501 (NIJA 12-737). 2. Didrex tablets, containing 25 rng. and r.o ing. hienzpetamine hydrochlo- ride per tablet: The Upjohn Cii.. 7171 Portage Road. Kalamazoo, MI 49C~1 (NDA 12-427). 3. Plegine tablets. containing 35 lag. pliendimetrazine tartrate tier taldet Ayerst Laboratories, Rouses Point, N.Y. 121)70 (NDA 12-245). 4. `l'epanil tablets, containing 25 mz. diethyipropion hydrochloride per tablet: The Morrel I-Na ti otto I Priur Co. Division of P i eha rdsnit-Merrell, Inc.. Ill) East AmitvRoad. Cinoinmnti. OtT 45215 (ND-k 11-673). ~. Tentiate tflhbatc. containing 23 m~. diothvlnrnnion hrdrnohlo-b-lo per tab. let: The Merrell-National Drug Co., Division of Rlchardson-Merrell, Inc. (NDA 11-722). PAGENO="0689" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15119 6. Preludin Endurets (prolonged-action tablets), containing phenruetrazine hydrochloride; Geigy Pharmaceuticals, Division of Ciba-Geigy Corp., Ardsley, N.Y. 10502 (NDA 11-752). Although not specifically referred to the Academy for review, Preludin tablets. a conventional oral dosage form coritahiing phenmetrazine hydrochloride ( NDA I0-4610, Geigy Pharmaceuticals) was approved on the basis of safety prior to 19(12, was evaluated by the Academy, and is appropriately included herein. Such drugs are regarded as new drugs (21 U.S.C. 321 (N). Supplemental new drug applications are required to revise the labeling in a nd to update previously approved applications providing for such drugs. A new drug application is re- (lulled from any person marketing such drug without approval. I. Sustained-action, time-n-ieasc, or oilier delayed or prolonged effect forms of P/i enmctra~ine ifydrochloridc The Fo.,.1 and Drug Admin istrati oil has considered the Academys report, as u-eli as other available evidence, and concludes that pbenrnetrazine hydrochlo- ride in prolonged-action tablet form is less than effective ( possibly effective) with respect to any special cia im for prolonged action when offered for the mail- ageineut of exogenous obesity as a short-term adjunct (a few weeks) in a regimen of weight reduction based on calorie reotriction. Any data snhini (ted iii resls,nse to this notice to support claims for which the drug is classified as other than effective must he previously unsubmitted and in- clude cia hi from adequate and well-controlled clinici I investigations (identified for ready review) as described in § 130.12(a) (5) of the regulations published In the Federal Register of May 8. 1070 (35 P.R. 7250). Carefully conducted and doc- iimented clinical studies obtained under imeontrolled or partially controlled sit- uations are not acceptable as a sole basis for approval of claims of effectiveness. but snch studies may be considered on their merits for corroborative support of efficacy and evidence of safety. It. Conventional tablet forms of Phcnmetraz(ne Hydrochloride; Pl,en-tcuiiae .ifydroehloridc; Jlcnzplietamine hydrochloride; Phcndimetra:inc Tar- tretc; or Die/i ylpropion Ibydrochioridc A. Effect/i-en ess clqss/flcqt/on.-The Food and Drug Administration has con- sidered the Academy's reports, as well as other available evidence, and con- eludes that these drugs, administered In cou~-entiona I oral closa ge form. are effective in the management of exogenous obesity as a short-term ndjuuct (a few weeks) in a regimen of weight reduction based on caloric restriction. II, Conditions for approval and marketing-The Food and Drug Adnminls- tration is prepared to approve abbreviated new drug applications and ahlirevi- ated supplements to previously approved neiv drug applications under conditions described herein. 1. Form of drug. Such preparations are in tablet dosage form suitable for oral administration. 2. Labeling eondition.q. The label hears the statement. "Caution : Federal law prohibits dispensing without prescription." The drugs are labeled to comply with all requirements of the Act find regula- tions, and the labeling be-irs adequate Information for safe and effective use of the drng ( s). The "Indications" section Is as follow's: INDICATIONS (Name of dn,q) is indicated in the management of exogenous obesity as a short term ii diunet (a few weeks) in n regimen of weight reduction based on caloric restriction. TIme limited usefulness of agents of this class (see Actions) shouhd he measured against possible risk factors inherent in their use such as those described bolow. In addition, the labeling contains the followIng "Actions" section and drug dependence warning the "Warnings" section Acriorcs (:venic of drug) Is a sympnthomlmetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions Include central nervous system stimulation and elevation find blood pressure. Taehn-phvlaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. 85-569 0 -77 _45 PAGENO="0690" 15120 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY Drugs of this class used in obesity are coinnioiily known as' anorectics" or "anorexigeiiics'', it has not I ccii esta dished, ho ivever, that the action of such drugs iii treat lug obesity is primarily one of appetite sappresshm. Other cdii rat nor yin is 53 stein ac-tic ins, or mclii liii Ic effects, ii ly be involved, for ex:i in pie. A ditl t 01 esi' S iii joe t s instructed in dietary ala iiage men t a nil treat etl Wi Ui `a ito rect ic' drugs, i is,' in ore wei gut oil tIle a vera go ti ia ii t h se treat cii wi Ut placebo and diet, as determined in relatively short-term ci aical trials, The in ag it ude of iii l're~i sed weight I oss of d ru g-t tea ted patients over jila eel co- tI-dated I ,at i eli t s is only a fra cti liii of a i flu ilil a week. TI ie rate of we i gi t I is 5 is greatest in U', Ii rs t weeks `if then ~iv for lit it Ii ii ri i g aixl lila It' 0 siil ii ects and tends to decrease iii siicv'eeiling weeks. The possible i irigi us of the i iicreaseil weight loss due to the various drug effects are not established. The amount of weight loss associated with I lie use of all ``a' free tic' drug 1-aries from trial to tn ii, a liii t lie in ere:i sod weight loss appears t I Ic rd `ted lii i art t (I Va ri a Ides other t lion the drug lirescriheil. snob as the physician -investigator, t lie population treated, III tI t lie diet i' reset i bed - Studies do in d peru ut c-i I ic-I as mis its tt I t lie relative i inliortanee of the drug and non-drug factors on weight loss. The ii;itiiral history of obesity is measured in years, whereas the st tidies cited are restricted to a few weeks du r:i tic in : thus, the I otal impact of drug-i nil uced weight loss over that of diet alone must lie considered clinically limited. WARNINGS Drug dependence: (Name of drug) is related chemically and pharmacologically to the aliililietaniin,-s. Arniilietoinines anti related st nulant drugs have leon extensively abuseti. and the possibility of abuse of (000w of drug) should ice kept in mimi ssheii evaluating the desirability of Including a drug as part of a weight reiluetioii program. Muse of aniplietmiaiines and related drugs may lie associa ted with intense psvehoiogica I dependence and severe social rlysfunction. There art' reports of patients wIll) have increased the ,hicsage to many times that recoin ii lel 1(1 id. Ab ruilt (`eSsii ti on flil I ow lug i roli iii ged lii gli tiosa ge :,tIni iii strati iii results in extreme fatigue and mental depression: changes are also noted on the sleep EEG. Manifesto tions of chronic intoxication with aiiorectic drugs include severe di' mi a toses, n Ia rked in soion i a. i rn ta l,i lit y. Ii y pe ra et i vi ty, a ii ti I icr sf1 Ia lit y changes. `l'hie most severe manifestation of chronic intoxicatious is psychosis, often ci in i ca 113- intl i stin gui sh a I Ic fro mu semi i zoph roll it. 3. iTo rh-cf lug sto tit.t. Marketing of such drugs may lie continued under the con- ditions described iii the notice entitled Conditions for Marketing New Drugs Eva Inn ted iii I )rug Efficacy Study, pnl1li shed in the Fedora I Register ,luly 14, 1970 (85 FR 11273). is follows: a- For holders of `deemed approved" flew' drug applications (he.. nn appliea- I ion which became effective on the I a sis of safety prior to Octol er 10. 19412 the sul ia is si, in of a suppl clii emit for revi soil ha heli ug 0 ad a su Pl)lO~ oil t fo i ill mtl a ti hg iii fill-lIla t i on, ii id u dii ig full man ii fa ct u ring i mufoi-n Ia t OIL lvi th re s~s-ct to i te ills 7 and S of Form FD-250H (1130.4(c)). as described hi poragrapli (a) (1)iij antI (ii U of the notice of July 14, 1970. 1. For any person who does not hold an approved or effective hew drug ali- ph icf ti on, ti.' mm I cmi ssi oil of an a lilt revia ted ri -\v drug ap~ lit-a tic in a .~ d `sen I ed Iii paragraph (a) (3) (i) of that notice, except that full rnarnmfaoturing inforina- tioii with, respect to Items 7 and S of Form Fl )-3W,l1 (1139.4(c)) is regnired. c. For any distrihici I or of flip drug, the use of liii el log in a i-cord w-i thi t ho 5 all- nounceinent for any such drug sbipperl witln,i the jurisdiction of the Act as tie- scrod in paragraph (Ii) of that notice. T-:achi of the above-na nied holders of tue new dnmg ap1ilic-ati ons for these drugs 11 as I let `n lila l 1111 a col ty ot the Ac-a deni y S repo it. Co Ui ni 1110 cat ions farwa nied iii respon so to this a nm~ on ii c-eliuen t sli oi il d be i ilel it if, il lvi Iii lhit' refer, -nec m inn i tier I lEST IIGTh, di rooted to tile at tell tion of the foil owing ahiprolinia to office, and an- dressed to the Food and Drug Admi ast ration 56(10 Fishers Lane. Roekville. Ml) 20552: Supplements (identify with NDA number) Office of Scientific Evol nat ion (El 1-100), Bureau of Drugs. Original a hiI)revia torI new' drug applications (identify as such) : Drug Efficacy Sturly Implementation Project Offioe (ED-GO), Bureau of Drugs. Requests for the Academy's report: Drug Efficacy Study Implementation In- formation Control (BD-~6). flurcaim of Drugs. PAGENO="0691" COMPETITIVE PROBLEMS IN TILE DRUG INDUSTRY 15121 All other communications regarding this announcement: Drug Efficacy Study Implementation Project Office ( BD-410) . Bureau o Drugs. All identical, related, or Sini liar products, not the subject of an alipi'ived new drug ii pplica non. are covered I ty the now drug ii pp1 ications reviewed and are sub- jeet to this notice. See 21 (`FR 130.40 (37 FIt 23155. October .31, 1972) Any per- son who wishes to determine whether a specific product is covered by tins notice should write to tile Food and I 1mg Ad in iii istra tion. flu rena of 1 )rilgs, Office of Compliance (I1D--300) , 5600 Fishers Lane, Itoclivilie, MD 20S52. `l'his iiotiee is issui'cl plirsun itt to the Federal Fond. Drug, anti (`osinetic Act (sees. 502. 505, 52 Stat. 1050-53. as amended 21 U.S.C. 352. 355) and the Admia- ist rative Procedure Act (5 U.S.C. 55.1 ) , anti under the a tithority delegated to tire Commissioner of Food and Drugs (21 (`FR 2.120). D:i ted : Felt run 13 7, It 173, WJLLLtM F. RANnoiI'n, Acting .Issociatc Conin,iss(oncr fe, Co ai p/to .1cc. [FR Doe. 73-2715 Filed 2-9-73 S :45 ami [DESI 12101] CoxrnlNAnnN Dime. CoNrArNINc, Synosixcorrym AND Hrnnociiaonoruuziai*: liRijc.s FOR HUMAN 1T5E PErle EEFICA~Y STUDY IMFLnIFNTATI0N The Food and Drug Administration has evaluated reports received from the National Academy of Sciences-National Research Council, Drug Efficney Study Group on tue following drug Si ngoser~.-Esidrix Tti lilets (2 strengths) containing syrosingopine a id liyd ro- chlori,tliiazide Ciba I'ha rniaeent ical Compa ay, I livision of Ciga-Ceigy Corp., 55G Morris Avenue, Summit, NJ 07901 (NDA 12-101). Such drugs are regarded as flew drugs (21 U. S.C. 321 (p) ) . The effeetiveneas cia ssiflca tion is described below. A. Effcctii'c-ncrs dossiflcqiion.-Ti.e Food and Drug Administration has coil- sidered tire Academy's reports, as well as other ova liable cvi deuce, and con- eludes that the drug is less thai. effective (possibly effective) for its iabeied indications. B. k514 tim js.~jon, of data-Any data submitted in response to this notice ti) ~UI~ port indications for which the drug is classified as less than effective must be previously iinsui.mit ted a ad include data front adequate 111(1 well~'oatrolled clinical investigations (identified for ready review) as described in § 130.12(a) (5) of the regulations puidislied in the Federal Register of May 8, 1970 (35 FR 7250). Carefully conducted and docinnented clinical studies obtained under un- ctintrolied or pa rtia fly controlled situations are not acceptable as a sole basis for approval of via i ins of effectiveness, but such studies may lii' considered on their merits for corroborative support of efficacy and evidence of safety. A copy of the Academy's report has been furnished to the firm referred to al `nyc. Coin inn n lea t i oils forwarded in response to this all n On neon) ci it sli ould he identified with the reference iiiiinlier nEST 12101. directed to the attention of I lint appropriate office fisted below and addressed to the Food and Drug Adinin- istr:iti,.n,5IiO0 Fishers Lane Ttockvilhe, MD 20552. Supplements (identify with N PA nun] her) Office of Scientific Evai nation (ED-lOll), Bureau of Drugs. Requests for the Academy's report: Drug Efficacy Study Information Control (RD-CC), Bureau of Drugs. A ii tither comm unica lions regarding tins announcement : 1 irug Efficacy Study Impienientation Project Office (BD--CO) . Bureau of Drugs. All iclelitica I. rein ted, or similar products, not the suhj.'ct of an approved new drug applicat Lou, are covered by the new drug application(s) reviewed a ad are subject to this notice. See 21 (`FR 130.40 (37 FR 23155. October 31. 1972). Any person who wishes to ileterini lie whether a specitic product is covered by this no- tice should write to the both a rid Drug Ada. i nistrat ion, Bureau of Drugs. Office of (`onipliance (BD-300). 56(~ Fishers Lane. Roekvllle. MD 20852. Tins notice is issued pursuant to provisions of the Federal Food, Drug, and Cos- metic Act (sees. 502, 5(15. 52 Stat. 1050-52, as amended: 21 U.S.C. 352. 355) and PAGENO="0692" 15122 COMPETITWE PROBLEMS IN fIR DRUG INDUSTRY the Administrative Procedure Act (5 U.S.C. 554) and under the authority del- egated to the Coinniissloiier of Food and Drugs (21 C}'R 2.120). Dated: February 7, 1973. Wjr&J,ni F. IIANDOLPII, .4cting .4nsociate Comniigsio,,cr for Compliance. [FR Doe. 73-2714 Filed 2-9-73; S :45 am] [DESI 5504; Docket No. FDC-D-587; NDAs 5-674; 5-757] MFTIIAMPHETAM1NE lIYDRocHLoaroE (I'ARENTERAL) OPPORTUNITY FOR hEARING ON PROPOSAL TO WITHDRAW APPROVAL OF NEW DRUG APPLICATIONS The Food and Drug Administration published a notice (DESI 5504) In the Federal Register of February 23, 1971 (36 FR 3387), regnrding tile efficacy of the following drugs containing ]nethainplletamine hydrochloride for parenteral use and classifying them as effective, probably effective, or lacking substantial evidence of effectiveness for certain indications. NDA 5-674 (incorrectly listed as 5-504) Methedrine Injection; formerly marketed by Burroughs Welicorne & Co., inc., 3030 Cormvallis Road, Research Triangle Park, NC 27709. NDA 5-757; Drinalfa Injection: a R. Squibb & Sons, Georges Road, New Brunswick, N.J. 08903. Subsequent to that notice, a publication In the Federal Register of August 8, 1972 (37 FR 15046), further ruled on those indications that had Initially been classified as probably effective. The Food and Drug Administration has recently reviewed the entire class of drugs offered for use as anorectic agents and the available evidence pertaining to their safe and effective use, including their potential misuse and abuse. On the basis of this recent survey, the Commissioner of Food and Drugs concludes that the well-documented history of abuse of parenteral Incthamphetnmine, together with the severe risk of dependence and the presence of effective alternative drugs, creates an unfavorable balance of Fisk to benefit. Therefore, notice is hereby given to the holders of the new drug applications listed above and to any interested lerson who may be adversely affected, that the Commissioner of Food and Drugs proposes to Issue an order under section 505(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(e)) with- drawing approval of the above new drug applications and all amendments and supplements thereto. It Is proposed to withdraw approval of these applications on the grounds that new evidence, not contained in the new drug applications or not available to the Commissioner until nfter the applications were approved, evaluated together with the evidence available to him when the applications were approved, show that methamphetarnine hydrochloride for parenteral adminis- tration is not shown to be safe for use under the conditions of use upon the basis of which the application `vas approved. All identical, related, or similar products, not the subject of an approved new drug applications, are covered by the new drug applications reviewed. See 21 CFR 130.40 (37 FR 23185, October 31, 1072). Any manufacturer or distrihutor of such an identical, related or similar product is an interested person who nay in re- sponse to tills notice submit data and Information, request that the new drug applications not lie withdrawn, request a bearing, and participate as a party in any hearing. Any person who wishes to determine whether a specific product is covered by this notice should write to the Food arid Drug Admiaistration, Bureau of Drugs, Office of Compliance (Br)- 300), 5600 Fishers Lane, Rockville, MD 20852. In accordance with the provisions of section 505 of the Act (21 U.S.C. 855) and the regulations promulgated thereunder (21 CFR Part 130), the Comnris- sioncr hereby gives the applicant(s) and any other interested person an oppor- tllnity for a hearing to show why approval of the new drug application(s) shollid not he withdrawn. The applicant(s) and any other interested person is required to file with the Hearing Clerk. Department of Realth, Education, and Welfare, Room &-8~, 5000 Fishers Lane, Rockville, MI) 20852, on or before March 14, 1973. a written appear- ance electing whether or not to avail himself of the opportunity for a hearing. Failure of an applicant or any other interested person to file a written appear- A PAGENO="0693" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15123 alice of election before March 14, 1973, will constitute an election by him not to avail himself of the opportunity for a hearing. If no person elects to avail lumseif of the opportunity for a hearing, the Com- missioner without further notice ~vlll eater a final order withdrawing approval of the application(s). If an applicant or any other interested person elects to avail himself of the opportunity for a hearing, lie iiiust file, on or before March 14, 10Th, written sip- pearance requesting the lieariiig, giving the reasons why approval of the new drug application(s) should not be withdrawn, together with a well-organized and full-factual analysis of the clinical and other investigational data he is prepared to prove iii support of his oppo ition. A request for a hearing may not rest upon mere allegations or eleruals, hut must set forth specific facts showing that a genuine and substantial issue of fact requires a hearing (21 CFR 120.14 (b)). If review of the data submitted by the applicant or any other interested persoil warrants the conclusion that the drug is safe for use under the conditions of use prescribed. recommended, or suggested in its labeling. the Coinnnssiiiner will r~cind this notice of opportunity for hearing. If review of the data In the application(s) and data submitted by the appli- cant(s) or any other interested person in a request for a hearing, together with the reasoning and factual analysis in a request for a hearing, warrants the con- clusion that no genuine and substantial issue of fact precludes the withdrawal of approval of the application(s), the (2onimissioner will enter an order of with- drawal making findings and conclusions on such data. If, upon the request of the new drug applicant(s) or any other interested per- son, a hearing is justified, the issues will be defined, a hearing examiner will he named, and lie shall Issue, as soon as practicable after March 14, 1973. written notice of the time and place at which the hearing will commence. All persons interested In identical, related. or similar prtiduets covered by the new drug application(s) will be afforded an opportunity to ii ppear at the hearing, file briefs, present evidence, cross-examine witnesses, submit suggested findings of fact, and othenvise participate as a party. The hearing contemplated by this notice will be open to the public except that any portion of the hearing that con- cersis a method or process the Commissioner finds entitled to protection as a trade secret ~vill not be open to the public, unless the respondent specifies otherwise in his appearance. Requests for a hearing ai$/or elections not to request a hearing may be seen In the Office of the hearing Clerk (address given above) during regular business hours, Monday through Friday. This notice is issued pursuant to provisions of the Federal Food, Drug and Cosmetic Act (sec. 505. 52 Stat. 1052-53, as amended; 21 U.S.C. 355), and the Administrative Procedure Act (5 U.S.C. 554), and under authority delegated to the CommIssioner (21 CF'R2.120). Dated: February 7, 1973, WII.LLAM F. RAn0LPH, Acting Assoei ate Consmisxioncr for Cornphia,we. [FR Doe. 73-2715 Filed 2-9-73; 8 :4~ nm] [Frosa tbe Federal Register, vol. 38, No. 61, Mar. 30, 1973, pp. 8240-411 NOTICES DEPARTMENT OF HEALTH, EnUcATroN, AND WELFARE FOOD AND DRUG ADMINISTRATION [DESI's 5378, 5504; Dockets Nos. FDC-D-582, FDC-~587; NDA's 0-946. etc., 5-674, 5-757' AMPHETAMINES FOR IIUxAN UsE NoTIcE or WIThDRAWAL OF APPROVAL OF NEW DRUG APPI,TcATIONS lathe Federal Register of February 12, 197.3 (3.4 FR 4240), the CommissIoner of Food and Drugs revised § 130.48 of Part 130, Subpart A concerning amphet- ansines (amphetamine, dextroamphetamine, and their salts, and levamphetAmine and its salts) for human use. That revision became effective March 14, 1973. PAGENO="0694" 15124 cOMPETITIVE PROBLEMS IN THE DRUG INDUSTRY When published in the Federal Register oil August 5, 19W (35 FR 12652), § 130.46 perieuil ted continued marketing of t liese a nulilieta lilines I cased upoar receipt of a new drug application. In response to that regu a finn, 106 new drug appi lea - titans were receiveil arid continued nail rRet i rig of those proilucts was permitted pending fuel r cloth lied review iii conjunction with a review of all anoreetic drugs anti consideration of any Issues they presented. Also published in the Federal Register on February 12, 11)73 were notices of opportunity for a hen ring to withd raw approval of 1111 Previously 0 pproved slow drug applications providing for a noreet Ic drugs in eoml iilnrition with other i ngredi- cuts siancli as sedatives, tranquilizers. rauw'olfia derivatives, or vitamins (3M Fit 4270) and for parenteral nietlianiphetamine hydrochloride (35 FR 4252). Tlurty days were allowed far holders of the new drug applications or any interested per. son who manufactures or distributes a drug sian liar, related, or ideutica I to a drug provided for in the approved new drug apolieatis ins to tile a written appear- ance requesting a Isea ring a rid giving the reasons svhay new drug app1 icn finn approval slioul el not lie svitlsdra wn, together with a svell-organized and full- factual analysis of the clinical and other investigational data t hey were prepa red to pros-c in support of their opposition. in accordance with the decision announced wit h the revision of § 130.16 pub- lished in the Federal Register of February 12. 1973 (33 FR 4249). each of the the new' drug applications providing for a coneslu nation a norectic drug for oral administration or for parenteral metharnplsetamine hydrochloride, whether sub- naitted pursuant to § 130.46 or the subject of a previous approval. has been the subject of a notice of opportunity for hearing, either in a letter anal led to the ti flu or through notice in the Federal Register, or both. Pursuant to those notices, requests for hearings have been received with respect to the following corabinalion drugs: NDA No. Drug NDA holder 1-522..... Obetrol-lO and Obetrol-20 tablets, containing methamnphetasnine sac- Obetrol Pharmaceuticals, Division ctsarate. mntharasphetanaine hydrochloride, amphetamine sulfate, and of Recur Ptmarn,nral Corp., 382 deetsosnaphetamine sultate. Schermek Ave., Brooklyn, N.Y. 11207. 2-042 Eskatrol Spanssrlea (sustained release capsules), containing destro- Smith Kline & French Laboratona. amphetamine sulfate and prochlorperarine (as the naaleale). tories, 1500 Sorieg Garden St., Philadelphia, Pa, l9l~. 12-570 Bamadex Seqaels (sustained release capsules), cootainisg deetroamphet- Ledenie Laboratories Divinion, amine sulfate and mepnobamaee. American Cynoamid, Post Office Boa 500, Pearl River, N.Y. 10965, Deeassyl Tablets, Desamyl Elixir, Desamyl Spansules (No. I) (nusiained Smith Kline & French Labora- release capon les), and De us myl S panss len (No. 2) (sustained release tories. caps slos), cones a rig asnscha rbrtal and dentroa mph eta m inn sun rate. Delcobese Tablets, Delcobese Sustained Release Tablets, Delcobese Delco Chemrcal Cs., Inc., 7 Mac. Capsules, and Dolcobese Sustained Release Capsules, conlainrng Queslenm Parkway North,Mount dexenoamphetamine sultate, methamptsetamioe hydrochloride, meth- Vernon, N.Y. 10550. amphetamine adipute, and amphetamine sulfate. The products specifically nanaaed above may conti,aue to be aaarketed pending a ruling conk the reqnsests for hearing. Also, psmrsuant to the notice of opportunity for hearing for pareurteral meth- amphetansine hydrochloride proposinsg to withdraw approval on the gronanids tlaat the drug is not slacawn to lie safe. a request for luea ring was recci veil frosar \terle flimeat, i%f.D. pertaining to all such products. insclnded in I lie reelnsest were the writer's opinion, concerasi ng time effectiveness of p~tremiteral ~manpbet~i naaiaaes isa I maaproving the mental status nuad well being of patients in their tolerationa of. a id recovery frones, a nsestbetie procedures, and Ins staitr'nnenst.s taking except ion to the (`oanamissin nor's conclusion tlua t the well-does, mnenmted hi story rif alsoase of this dosage form, tlae severe risk on depenudenc-e, aaad the a vail:e hility of effective. alternative drugs constitute lack cif proof of safety. `l'hie ceinstesa tionas of lye'. I )ianeaat have been considered and the Conasnissioner of Food and Drugs ceinclsades tIm there is no genuine and substantial 1550°c of fact requiring a heotrineg. No c'hnrge was made Ia the niotice of opportunity fiar he'arinag that pa renteral aatetlua nailihel a- rnhue hydrochloride lacks substantial evidence ol' effectiveness; rmather, the notice stated that snach products were considere'il effective, ilo~vt'ver, the use for which Dr. Dirnent recommends continued a vailalailitv of the drngs has snot beena ap- proved in the ne'v drug applications, and no substantial evidence to support suc'he PAGENO="0695" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15125 nYc accompanied the request. Ills comments conrr'rning safety of the drug and es~ioussng a principle that allows continued availability notsvitlsstaridirng tile Is flown Isltential for ml suse and it I nYc. are testimonial at lest asid do lint ((iluipt'lsO adequate proof of 511 fet).T bus. based oso the infonna kiwi before him a rid a review of the sta te,nent.s made by I )r. Di mont to support Isis contention flint approval of the new drug a pplleatioaus sluora Ed not p withdrawn, the 6 `onimissioner finds tim lucre has been a failure to present ad equate evidence of safety for pareanteral nuet ha mphet annin le hydrorhioride a nil the request for a lien ring is denied. (`moments were receivrd fri ml two physicians. I )r. Williams K. ha laiR, in. Pro. aessor and Chairman, Department of Anesthesia. School of Medicine, University of (`alifonna, San Francisco. and Dr. Jack )loyors, (`met of Anesthesia. l'rofessor 811(1 1 lead of Do1 in rtnient (if Aliestliesia. T'nnversity of Iowa. both ohject ing to lie rein ovol cit a ii seful (1 nn g fm in t lue~ iii a rIce t In ca ii so of its on so ann d a boise for 11011 thorn bet it ic pa r~ ,oses. Xci cia ta aecon II id nied tli e re9 oases. In respoilse to the satires (If ojiporti]ni ty for licaring pa hlished hi tile Federal Register of February 12. 1973 (33 FR 4279 and 42S2) none eif the holders enf the following new (In] g ri lip] lea tionu s ha In ed 1mm t hose no! ices Ii ave Ill ed a ss cit ten a]i- I lea ra lice of elect tori as I irovi dod liv said notic p. The fa thin re to tile sinchi au a P tiearaace constitutes an electit in by snub personos not to avail thmninselves of the opportunity for a hearing: TIDA No. Drug NDA holder 6-946 Du-Oria tabletn containing metbarniphetamine hydrochloride and reseipine. 10-207 Dexserpine 5'' tablets containing destroamphetamine siltateand reserpine. 11-280 Barnadem tablets, containing destrone amphetamine sulfate and emtprolamate. 11-538 Biphetamine-T `]2h' capsules and Bipheta,nine-T `20'' capsules, containing - dextroarnptietamine, ampheta- mine, and methaqualone, all as cation eucharge resin complens of suitonaied polystyrene. 12-127 Appetrol tablets, cottaining destroannnphetamine sulfate and iseprobamate. 12-371 Prelu-Vite capsules, containing pheninetrazine hydro- chloride. Vitamin. A, Vitamin 0. thiamine en000nitrnte, riboflavin, niucinamide, calcium pantothenate. pyiidonne hydrochloride, cobalarnin concentrate, ascorbic acid, iron, calcium, phosphorus, iodine, and copper. 12-415 Detteta-sed Stedylabs (sustained release tablets), contain- ing di-methamphetamine hydrochloride and amobarbital. 12-624 Appetrol-S.R. (nastained release capsules), containing deatroamphetamine suldate and meprobamate. - 5-674 Methedrine injection, containing methamphetamimse hy- drochloride. 5-757 Drinnlla, tnjection, containing methamphetamine hydro- chloride. Formerly marketed by B. F, Anber 8 Co., Inc., Pont Office Bus 827, Kansas City, Mo. 64130, Formerly marketed by Nysco Laboratories, Inc., 34-24 Vernon Blvd., Long Island City, N.Y. 11106. Lederie Laboratories Divinion, Amesican Cynamamid Co.. Post Office Son 500, Pearl River, N.Y. 10165. Strasenbirgh Pharmaceutics!, Division Penn' walt Corp., 755 Jefferson Rd., Rochester, N.Y. 14523. Wallace Pharmaceuticals, Division of Carter. Wallace, Inc., Halt Acre Rd., Cranbury, N.J. 08512. Formerly marketed by Geigy Pharmaceuticals, Division of Ciba Geigy Co., Saw Will River Rd., Ardoley, N.Y. 50502. Eastern Research Laboratories Inc., 302 South Central Ave., Baltimore, Md. 21202. Wallace Pharmaceuticals. Formerly marketed by Burroughs Wellcome & Co., tnc., 3030 Cornwuilis Rd., Reoearch Triangle Park, N.C.27709. 6. R. Squibb & Sons, Georges Rd., New Bruns. wick, N.J. 01903. All identical, related, or similar products, not the ssslsject of all approved new drug application, are covered by the new drug applications reviewed and are subject to this notice. See 21 (`FIt 130.40 (37 FR 23185, Oct. 31, 1972). Any person who wishes to (leternsirie w]nether a specific product is covered by this aaotlce should write te tile 1-'ouid a nd I 5mg Adnuisustrationi, Borea Is vaf I )rugs. Office of Ceiniphiansce (B])-300). 56(X) Fisiuer,s Lstrae, Rnckvilht, 311) 20552. The (`osumission r of Food and Drugs, lila rsua lit to the provisions of the Fed- eral Food, I )rug. and (`osmotic Act (sec. 505. 52 Stat. 10.53, as a mended 21 U.S.C. .S55 ) , a nid the Admlnistra five Procedna re Act (5 I `S.C I). and nnniier authority delegated to him (21 CFR 2.120) finds on the basis of new information before hi rut evahnated together ovi fli the evidence stvai lalde to hi ni at time of approval of the applications that, with re.9sct to the aliove-listed comlanation prepsiratious for which no hearing was requested: (1) there is a lack of substantial evidence that the drugs will have all the effects they purpart Or are represented to have; ann (2) the drugs are not shown to lie safe for use sander the conaihitlons of use lire-scribes], reconnmended. or suggested inn their labeling: and witis respect to the parenteral drug products containing methamphaetansine hydrochloride, snicha prod- ucts are not shown to be safe for use under tile conditions of use prescribed. ree- ommendeci, or suggested in their labeling. PAGENO="0696" 15126 col%n'ETITivE PROBLEMS IN THE DRUG INDUSTRY - Therefore, pursuant to foregoing findings, approval of the above new drug ap- plications (except for those for which a request for hearing was received), and nil amendments and supplements applying thereto is withdrawn effective on March 30, 1973. Shipment in interstate commerce of any combijiatloll drug prod- net other than those few listed above that may continue to be marketed pending a ruling on the request for a hearing, or of any parenteral amphetamine product (e.g., amphetamine, dextroamphetatnine, levamphetamine, or methamphetamine) is henceforth unlawful. Dated: March 28, 1073 WILLIAM F. RArthoLT, -4cting Ansociate toni missioner for Compliance. [FR for. 73-6230 FlIed 3-29-73 S :45 am] [From the Federal Register, vol. 38, No. 155, Sept. 25, 19731 NOTICES (DES! 5378; Docket No. FDC-D-582 ; NDA 11-522j CERTAIN COMBINATION AN0REU'rrc DRUGS ~1flL ORDER ON OBJECTIONS AND REQUEST FOR A HEARING REGARDING WITIIDRAWAt OF APPROVAL OF NEW DRUG AFI'LICATIONS In the Federal Register of August 8, 1970 (35 FR 12652) the Commissioner of Food and Drugs published a statement of policy (21 CFI4 130.40) concerning amphetamines for human use. The statement contained the findings of the Food and Drug Administrntion based upon reports received from the National Acade- my of Sciences-National Research Council (NAS-NRC) Drug Efficacy Study Group. Also published in the Federal Register of August 8, 1970 (35 FIt 12678) was a notice (DESI 5378) on drugs containing amphetamines and their salts, stating that the drugs `vere regarded as possibly effective for their claimed anorectic effect and lacked substantial evidence of effectiveness for their other labeled Indications. The statement of policy also contained the findings of the Commissioner that because of the extensive use of the drugs in the treatment of obesity, and their stimulant effect on the nervous system, they have a potential for misure and actual abuse, and production data indicated that amphetamines are produced and prescribed in quantities greatly in excess of demonstrated medical needs. As a condition for continued i~sarketing of amphetamlne~, the statement of policy required relabeling as specified and the submission of a flew drug application (NDA) within One year for all such drugs not then the subject of NDA approval. Holders of approved NDAs were required to submit additional evidence of safety and substantial evidence of efficacy in the forni of adequnte and well-controlled clinical investigations. On February 12, 1973, the Commissioner published in the Federal Register (38 FR 42-19) a final order stating that there was a lack of substantial evi- dence of effectiveness for,- and a recognized potentinI for the abuse of, fixed comhlnntioa drugs for anorectic use which contained, among other ingredients. amphetamine. methamphietnmine, Or dextronmplietamine. In ndditlon, the Coin- missioner found that alternative therapeutic measures which are safe and effective are availab'e for use. The Commissioner also stated in the finnl order that a mixture of dextroamphetamine and amphetamine i.s ordinarily regarded as a single drug entit3. A similar conclusion as to a mixture of dextroarnpheta- mine and niethamphetamine. and/or amphetamine and methamphetamine, was not made. In § 3.88 (21 CFR 3.80) the Food and Drug Administration set forth a policy on fixed-combination drugs for prescription use requiring that ench drug In a fixed-combination drug contribute to the (`Inimed effect of the drug; section IV, infra. Therefore, drugs containing combinations of amnplieta- mine and methamphetamine and/or dextroamphetamine and mcthamnphetamine, are fixed combination drugs. The final order :sise stated that a proposal to withdraw approval of such combination drugs for anorectic use was puhlished elsewhere in the same issue of the Federal Register. In a notice In the Federal Register of February 12. 1973 (38 FIt 4279). the Commissioner announced an opportunity for hearing on his proposal to withdraw approval of new drug applications for the combination amphetamine or other PAGENO="0697" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15127 anorectic drugs. This notice was based en evaluation of data submitted pur- suant to the Federal Register notice of August 8, 1070 (35 FIt 12678). This data was found, after review, not to provide substantial evidence that the drugs named in the Federal Register notice of February 12, 1973, were effective as fixed combination for their claimed anorectie uses. Based on this lack of substantial evidence of effectiveness of the drugs as fixed combinations, the recognized po- tential for abuse of these combination drugs, and the availability of alternative therapeutic measures which are safe and effective, the named drugs were also round to be lacking In proof of safety. The Commissioner further found that the data submitted in response to the Federal Register notice of August 8, 1970, did not support a contention that the combination products decrease the incidence or severity of side effects associated with the abuse potential of the single entity anorectic drug. Notice was therefore given to holders of the named new drug applications and all other interested persons, including those mar- keting similar, identical or related drugs (~ 130.40 (21 CFR 130.40) that the Commissioner proposed to withdraw approval of these new drug applications based on a lac& of substantial evidence of effectiveness and a lack of proof of safety. All holders of the NDA's and persons marketing similar, identical or related drugs, nnd other Interested persons were invited to request a hearing on the Proposed withdrawals and to submit with such request a well organized and full-factual analysis of the clinical and other investigational data they were prepared to prove in support of their opposition to the withdrawal of the named NDA's and any such similar, identical or related drugs. The notice stated that if substantial evidence of effectiveness and evidence if snfety was received for any of the named drugs, or for sImilar, identical and related drugs, the notice would be rescinded as to such drugs. Ia response to the notice in the Federal Register of February 12, 1973, re- quests for a bearing were received from four persons for five drugs. The persons and the drugs were named in the Federal Register notice of March 30, 1973 (35 FR 8290). The subject final order concerns only two of those persons rN~uestlng hearings. Rexnr Pharmacal Co., 396 Rockawny Ave., Valley Stream, NY 11582, requested a hearing for the drugs Ohetrol-lO and Obetrol-20 Tablets (NDA 11-522). These drugs are the subject of an NDA which was made conditionally effective on .iuly 24, 1959. and fully effective on February 23, 1960. The Ohetrol drugs had been reviewed by the NAS-NIIC and found to be possibly effective as an ad- jnni't in the management of some forms of obesity in which an appetite depres- sant is indicated. The NAS-NRC finding was incorporated into the August 8, 1970 Federal Register notice discussed above (35 Fit 12678). Delco Chemical Co., 7 McQuesten Parkway North, Mount Vernon NY 10550, requested a hearing for the drugs Delcobese Sustainted Release Tablets and Capsules and Delcobese Tablets and Capsules. Pursuant to the August .8. 1970 Federal Register order, the Commissioner received from Earrows Pharmacal Inc.. 34$) Prospect St., Inwood, NY 11696, four new drug applications on the fol- lowing dates for the following drugs: March 15, 1071, ND_k 17-162, Delcohese Tablets, S mg., 10 rng., 15 mg., and 20 mg.; March 15, 1971, NDA 17-161, J)elcobese Capsules, 5 tog,, 10 tog., 15 mg., and 20 mg.; March 20, 1971, NDA 17- 160. Deleobese Sustained Release Capsules, 5 mg., 10 mg., 15 mg., and 20 mg., and June 24, 1971, NDA 17-15.9. Delcohese Sustained Release Double-bayer Tab- lets, 5 Ing., 10 tog.. 15 lug., and 20 mg. All four of the drugs consist of a conibina- tion of a nipheta mines and niethiampheta min~. No data wi's submitted in support of the efficacy of these combination drugs: the sponsor merely paraphrased the conclusions stated in the August S. 1970 Federal Register notice in support of the stnfety and efficacy of the drugs for use as anorecties and in treating narcolepsy a nil minimal brain dysfunction in children. Due to the large number of new drug applications received pursuant to the August 8. 1070 Fed'~ral 1tegi~ter order, a review and evaluation of the ncw drug applications submitted by narrows was delayed, narrows was notified of this delay by a letter from the Food and Drug AdministratIon on February 25, 1972. On January 15, 1973, a letter ~vas sent to narrows from J. Richard Crout, M.D., Acting Director, Office of Scientific Evaluation. Bureau of Drugs, stating the conclusion of the Food and Drug Administration that the four new drug appli- cations submitted by Barrows could not be approved bemuse the submissions PAGENO="0698" 15128 CO1I~ETITIVE PROBLEMS IN THE DRUG INDUSTRY IProin the Federal Register, vol. 39, No. 140, July 19. 1971, pp. 26439-62] NOTICES (DES! 5378; Docket No. FDC-D-6S7; NDA 5-3m, etc.] FOR IIUSFAN USE-DREG EFFICACY STUDY IMPLEMENTATION CERTAIN Six- OLE ENTITY ORAL ANORECTIC Ducos IN CONVENTIONAL OR CONTROLLED RELEASE D05AGF; FoaMs FOLi.O~V-Ui' NOTICE AND OPPORTUNITY FOR HEARING l'lw Food anti Drug Administration published an announcement in the Fei. eral Register of August 8. 1970 (35 FIt 12678) regarding the effic~icy of the fol. lowing si ~igle entity oral anorectic drugs 1. Biphetamine "~1A" Capsules, Rij lietamino ``1 21/,'' Capsules, and Biphetanline `20'' (`alisules. respectively, contal fling &75 milligrams, 6.25 milhigraitis, and 10 inil ligra ins each of dextroamphetaniine aild a IIIPIICtO nilne per capsule, all as ealiois exclionge resin complexes of sulfonated polystyrene; Strasentiurghs Labo- ratifies, Division of Wallace and Tiernan Inc., Post Office Box 1710, Rochester, NY 14603 (NbA 10-003). 2. lonamin "15' Capsules and lonamin `20" Capsnle.s, containing, respectively, 15 lililligralils phellterm inc and 30 milligrams phentermine per capsule, both as cation exchange resin complexes of sulfonated polystyrene; Strasenburgi. Labo- ratories Division of Wallace and Tiernan Inc. (NDA 11-4113). - 3. 3lethed rifle Tat,] ets colitainilig S lull ligrams niet hamhihetalnille liydr4i- chloride Tier tablet forllserly marketed by Burroughs Welleolne & Co., Inc .,3030 Coruwallis Road, Itesearell Triangle Park, NC 27709 (NDA 5-504), 4. A rnhilledroxn I lydrochloriile Tablets (tollta ill ing 5 inhlligra ins lilethalilplleta. mine hydrochloride per tablet; Eli Lilly and Co., Post Office Box 618, I~sdianap- eshis, lad. 40206 (NI hA 6-390). 5. Delfeta mine Steursuant to 21 Cl'R 310.6 elects to a'n ii Ii imself of the opportunity for a hearing, he shall file (1) on or before August 19,1974, a written notice of alipeara nce and request for lien ring. and (2) on or before September 17. 1974, the data, information, and analyses oil which lie relies to justify a henring, as specified In 21 CFIt 314.200. Any other interested i ierson may also submit cotuinents on this proposal to withdraw ap- proval. The procedures and requirements governing this notice of opportunity for bearing, a notice of alipearanee and request for hearing, a s,ilrnission of data. information. am-I analyses to justify n hearing, other comments, and a grant or denial of hearing, are contaIned in 21 CFR 130.14 as uhilishied and discussed In detail in the Federal Register of March 13, 1074 (39 FR 975tfl, recoditied as 21 CFR 314.200 oji March 29. 1974 (39 FR IWO). The failure tif art applicant or a nv other person subject to this notice pur- suant to 21 (IFR 810.6 to file timely written appearance and reqlie'zt for hearing as reouired liv 21 CFR ,114.200 constitutes an election liv such person not to avail himself of the opportunity for a hearing concerning tile action pronosed with respect to such drur product and a waiver of nay contentions concerning the legal status of such drur product, Any such drug jirod,ict labeled far the Indira. Hon (s) lacking substantial evidence of effectiveness referred to in parngranh £8 of this notice mmiv not thereafter lawfully be marketed, and the Food nnd Drug Administration will initiate anprOnrlttte rerulatory action to remove such drug products from the market. Any pew drug product marketed without tin apprnvecl YDA is snhject to regulatory action any time. PAGENO="0703" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15135 side effects attributable to the dextroamphetamine component. Lederle also argues that P,amadex Sequels must be found effective because meprobamate and dextroarnphetamine have each been found by the FDA to be effective as single entities, and that Its product must be found safe because Bamadex Sequels were approved on the basis of safety in August lOGO and there has been no clinical experience to the contrary since that time. Lederie contends that the addition of Ineprohamate, a schedule TV controlled substance under the Controlled Sub- stances Act (21 U.S.C. 501 et seq.) to dextroamphetamine, a schedule II sub- stance under tile same act, results in a combination with significantly lower potential for abuse than dextroamplietninine alone, within the meaning of 21 CFR &S6(aH2). Finally, Lederle claims that the FDA interpreted certain data in its investiga- tions in a manner contrary to the observations and reports of the investigators who conducted the studies. The Commissioner has considered all of the material submitted by Lederie and has concluded that there lsno genuine Issue of material fact requiring a hearing and that the legal objections offered are insubstantial. A full discussion follows: I. The drug Bamadex Sequels contahm (each capsule) a fixed combination of milligrams dextroamphetamine sulfate and 300 mIlligrams meprobamate. If. Recrnnnrended uses and dosage; rationale for the ec,nbinatio,r The labeling reviewed by the NAS/NRC, Drug Efficacy Study Group, claimed that Barnadex Sequels was useful in the management of obesity, curbed appetite with minimal overstimulatior, of the central nervous system, and provided a sustained release of active ingredients,~ Lederle's present labeling retains the claims with respect to sustained release and minimal overstimuiation of the central nervous system, hut incorporates the changes required by 21 CFR 310.504 and recommends Bamadex only for use In exogenous obesity as a short terra (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction. The usual adult dosage of Bamadex Sequels is one capsule daily in the morning. Lederle's rationale for the combination is twofold: (1) The dextroaxnpheta- `nine results in a drug with a lower abuse potentinl than dextrosuphetamine counteracts the overstimuiation which frequently accompanies the use of dextro- amphetamine sulfate, and (2) the addition of meprobarnate to dextroampheta- mine results in a drug with a lower abuse potential than dextroemphetamine alone. III. Data. aubnzittcvi to support cla/ms of effectiveness A. Ilarnadex Sequels at e4es.-Lederie submitted three clinical studies in sur~ port of the claimed effe~tlveness of Bamadex Sequels. These studies, with the exceptions noted below, followed substantially identical protocols; they are evaluated as follows: 1.Noble, Rudolph E., `A Comparison of Bamadex Sequels (15 mg dextroam- phetamine and 300 mg meprobamate). Bamadex Sequels Minus Meprobamate (15 mg dextroamphetamine) and Placebo on Weight Loss and Side Effects Ia 90 Overweight Patients," unpublished study. 1071. In an attempt to establish, inter alia, that patients on Bamadex Sequels experience fewer adverse reactions than those who receive dextroamphetamine alone (i.e.. that meproiramate reduces the side effects attributable to dextroamphetamine), t?'e investigator selected 00 patients who were 20 percent overweight according to Metropolitan Life Insur- ance Company standards. These were divided into three equal groups and ran- domly assigned to one of three treatment regimens of Bamadex Sequels. dextro- amphetamine, or placebo. The first group received liamadex Sequels for 21 days. placebo for 21 days, and then Bamadex Sequels for the final 21 days: the second received dextroamphetamiae for 21 days, placebo for 21 days, and dextroam- phetamine for 21 days; tile third received a placebo for the entire 9-week period. Each patient was instructed to take one capsule each day at. least 1 hour before breakfast. Male patients were placed on a 1,500 calorie daily diet: females on a 1,200 calorie daily diet. Prior to entrance in the study and at 3. 6, and 9 weeks after entry into the study, patients' height, weight, pulse, and blood pressure were recorded and compared. This study is not adequate and well-controlled within the meaning of 21 CFR 314.111(a) (5) (ii) (a) (2) (iii) in that it falls to assure that test and control groups were comparable with respect to the use of drugs other than the test drug. Thus, although the Investigator undertook statistical analysis to assure the 05-569 0-77-45 PAGENO="0704" 15136 COMPETITIVE PROBLEMS uN THE DRUG INDUSTRY groups were comparable with respect to age, sex, percent overweight distribution, and the mean dosage duration, no such analysis was performed with respect to the use of concomitant medication. This is always a pertinent variable and liartic- ularlv so in this study where patients were taking diuretics (which could inter- fore with tire effect of test medication on weight loss) and major tranquilizers, analgesics, and antihistomines with sedative effects (which could interfere with adverse reactions related to the central nervous system). The study fails to explain the methods of observation and recording of results with respect toalde effects (21 (`F11314.111(a) (5) (ii) (a) (3)). Thus. nodetails are given as to whether subjects were questioned as to whether they experienced side effects or whether only the investigator's Observations were counted. If t lie subjects were questioned regarding side effects, no details are given as to tire nature of the questions asked. Were the questions only designed to elicit dextro- amphetaminedike side effects or were they also directed at uncovering inc-pro- bamate-type side effects? Obviously, it makes no sense to claim that the side effects of dextroainphetamine are reduced if the other component, nreproharnate, Is responsible for equally serious side effects of its own. Without details as to how adverse reaction data were elicited, it is Impossible to dctenuine if the investiga- tors took such a possibility Into account, Indeed, without any knowledge as to how data were observed and/or recorded, it is impossible to make any meaningful evaluation as to the realiahility of the study's findings. Even If it could be shown that the groups were comparable and that the data had been assembled and recorded in a proper manner, the results do not support Lederle's contention that the addition of Ineprobarnate to the conililuation tie- creases the incidence or severity of side effects associated ~vith the primary Ingre- client, dextroamphetamine sulfate. Thus. although the raw data showed that there were numerically slightly fewer side effects associated with patients on Bainadex Sequels (10) than there were with patients who used dextroampheta- mine alone (13), Lederle's own statistical analysis demonstrated that this dif- ference was not statistically significant since Lederle stated that the proportion of subjects reporting side effects was not significantly different for the three groups. In other words, there was no assurance that the observed difference ~vas not due to chance, Lederle has failed to show that mel}robamate significantly reduces the number of side effects attributable to (lextroamphetamine and consequently has failed to demonstrate that meprobamate enhances tire safety of the principal ingredient, dextroomphetamine, within the meaning of, and as required by. 21 CFR 3.86(a) (1), and as claimed In its labeling. The study is incapable of scientifically demonstrating the anorectic effective- ness, or lack thereof, of flamadex Sequels because, as shown above, the investi- gator failed to assure group comparability with respect to the use of concurrent medications (21 CFR 314.111(a) (5) (ii) (a) (2) (III)). The study also fails to explain the methisls of observation and recording of weight loss data (21 CFR 314111 (a) (5) (ii) (a) (3)). Thus the author does not explain whether patients were always weighed at the same time of day, whether the menstrual cycles of female subjects was taken into account and, more Ira- porthatly, whether any analysis was done to determine which patients, if any, followed their diets. `l'hese factors cannot be overlooked in a study designed to measure weight loss. Using Lederle's criterion for satisfactory weight loss (5 or more pounds In both active drag phases), Jederle's statistical nnnlysls showed that Baaiadex Sequels patients did not lose significantly more weight than patients who took the placebo. Lederle also conducted a statistical analysis of the difference iii mean weight losses. Tire difference between the Bamadex and placebo groups were stahsticaliy significant only at the end of 3 weeks; there was no statistieollv significant dif- ference either for the second on-drug period (7 to 9 weeks) or overall (1 to 0 weeks). Thus. Lederle's own findings are inconclusive, and even If they weren't, they would he scientifically meaningless because of the defects pointed out. 2. Schein. 31.. "A Comparison of Bamadex Sequels. Dextroamplietamiae arid Placebo on Weight Loss and Number and Types of Side Effects in 90 Overweight Patients," unpublished study, 1071. To exclude climatic conditions as a factor, this investigator had all 90 patients begin the study during the same week. Otherwise. this study followed the same protocol as the just-reviewed Noble study. Accord- ingly, it too failed to assure comparability with respect to the use of other drugs (21 CFR 314,111(a) (5) (ii) (a) (2) (iii)). Thus. 13 of the 30 patients in the Eamadcx group were receiving concomitant medication, while 6 iii the ampheta- mine and 8 in the placebo groups were concurrently using other drugs. As In the PAGENO="0705" CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY 15133 A request for a lieu ring niay iiot rest upon lucre allegations or denials, but must set forth slwcific facts showing that there is a genuine and substantial issue of fact that requires a hearing. If it conclusively appears from the face of the data, iiiforinatiou, a iii! factual aria lyses iii the request for the flea ring that there is iii; genuine and substantial issue of fact which precludes the withdrawal of approval of the application, or when a request for lieu rilig Is not made In the re- qi i red fornia t or with the required analyses, the (2omn,issioner ~vilI enter sun,- mary judgnient gaiust the person(s) who requests the hearing, making findings and conclusions, denying a hearing. All submissions pursuant to this notice of opportunity for hearing shall be filed iii qni ntuplicate. Such submissions, except for data nail information prohibited frin,i public disclosure pursuant to 21 U.S.C. 331 U) or IS U.S.C. 1905, may he seca iii the office of the Hearing Clerk (address given below) during regula loisi `less hours, Monday thu ugh Friday. Ci innn un cii t ii ais forwi~ riled lii rest onse to t los a ii noun cernen t should be id en ti- fled with the reference nnn,l er DES I 5375. directed to the attention of the appro- p ri ate iiffi I.e listed I eli) W'. and a rid ressed to the Food a a nl I 1mg Ad miii is trot i or'. 5600 Fishers Lane. Itockvillt', Mi) 20s,~i2 Supplements (identify with NDX number) : Office of Scientific Evaluation UFI 1-101)), Bureau of J)rngs. Original abbreviated 1mw drug applications (Identify as such) : Generic )rug Sta fT (I IFD-107 ) , Office of Scientific Evaluation, Bureau of Drugs. Sulini issions hiursoa nt to the notice of oppiirtun I ty for lieu ring (identify wit!, docket nn,nl er) : lieu ring Clerk, F'ood nnd I)rog Adnnnlstratjoi, (HFC-20) lii or,, 6-SO. Parklawn Eu i liii ng. Requests for the Academy's report: Drug Efficacy laformation Activity (1!l'D- S. Bureau of Drugs. All other coin iunnicn tions regarding this announcement Drug Efficacy `~ * Implementation Project Manager (H lffl-101 ) . Bureau of Drugs. Tins notice is issued pursuant to provisions of tim Fedenul Fond. *~ig, and Cosmetic Act (sees. 502, 505. 52 Stat. 1050-5.3, as amended; 21 U.ft 350 355) nod under the authority delegated to the Director. Bureau of Dr igs (21 CFR 2.121). Dated: July 3, 1fl74. S. Iti HARD C.ROUT. Director, Rureau of Drugs. IFli Doe. 74-16522 Filed 7-18-74: 5:45 n~u. [From the Federal Register, vol. 40, No. 101, May 23,t~) 5, pp. 22570-75] NOTICES tDESI 5378; Docket No. FDC-D-552 NDA i2-570j B.&~cAnEx SEQUELS PF.NI.~L OF ItF.ARIxo AND \vITiTnRA\vAL OF APPROvAL OF NEW DRUG APPLICATION The Commissioner of Food rind Drugs denies hearing and withdraws approval of new drug application for Bamarlex Sequels, effective Jane 2, 1975. In a notice published ii' the FEDERAL Itromsvrn of August 8, 1970 (35 FR 1267$), the Food and Drug Administration (FDA) announced its evaluation of 23 ano- reetie drugs, including Barundex Sequels and Baniadex Tablets, NDAs 12-570 and 11-280. held by Lederle Laboratories, Division of American Cynnainid Co., Pearl River, NY 100115, hereafter Lederle, The announcement stated that tile FDA had considered the reports of the National Academy of Sciences-National Research Council (NAS/NRC), Drug Efficacy Study Group, together with other evidence and concluded that there was a lack of snbstantial evidence for several claims but that the listed drugs were regarded as possibly effective for their anoreetic (appetite-suppressant) claims arid for their prolonged, continuous or sustained release claims. Manufacturers were given 60 (lays to revise their labeling to delete those Indications for which no substantial evidence of effectiveness had been found and (1 months to provide substantial evidence of effiectiveness for the anorectic and sustained release claims. Finally, the notice advised that at the end of the 6-month, period, the data PAGENO="0706" 15134 COMPETITIVE PROBLEMS JN THE DRUG INDUSTRY would lie evaluated to determine whether or not the existence of substantial evidence of effectiveness had been demonstrated, and if it had not, procedures would be initiated to withdraw approval of the new drug applications pursira it to section 505(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355 (e) ). In the same issue of the FEDERAr. ItFoisTEa of August 8, 1970 (35 FR 12052), the Commissioner of Footi and Drugs issued a 5th teinent of Policy (21 Cl ft 310.504, formerly 21 CPU 130.46) regarding amphetamine containing drugs. including dextroamplietamine, The order stated that the NAS/NRC had found, inter alia, that this class of drugs had a generally short term (a few weeks) nuorectic effect, that there was no evidence that they altered the natural history of obesity, a rid that they had a signifle~i nt potential for abuse. The FDA con- curred with the NAS/NR(.) report and, Ia addition, noted that production data indica ted that a .nphetainines were manufactured and used in quantities greatly in excess of demonstrated medical needs. Accordingly, the order required that such drugs be relabeled to reflect the present state of knowledge concerning amphetamines, their potential for misuse and abuse, and their limited medical usefulness. The order was made specifically applicable to combination drugs which contained dextroamphetanune. In response to the notice (DESI 5378) of August 8, 1970, Lederle submitted three clinical studies for flamadex Sequels (Noble. Miller, and Schein) and three clinicaL studies for Bamadex Tablets (Trodella, Parsons. and Bowlan), together with a list of side effects and combined statistical analysis for all six studies and a combined statistical analysis for the three clinical studies of Barna- dcx Sequels. Subsequently, the Commissioner issued a notice of opportunity for hearing, published in the Fedcral Register of February 12. 1973 (38 FR 4279), covering orectic combinations including Bamnadex Tablets and Bamadex Sequels. lie ii tic.' stated that the submitted data had been reviewed and found not to provide substantial evidence that the drugs were effective as fixed combinations for their `laimed uses. Neither, the notice continued, did the submitted data support the ontention that the t,oiri bination products decrease the incidence or - severity of sh effects or lessen tire abuse potential associated with the single anorectic Ingret `ent. Accordingly, the Commissioner proposed to withdraw approval of the m amed new drug applications a mid invited holder(s) of new drug applications and other interested persons, Including manufacturers and distributors of ide itical, related, or similar products, to submit on or before March 14, 1973, a vrittea notice requesting an opportunity for hearing. Those requesting a hmeatin~ were Instructed to state the reasons why approval of the new drug application ~hould not lie withdrawn and to provide a well-organized and f till factual aualysi~ of the clinical and other investigational data that they were prepared to prove in ~upport of the requested hearinir. In the same issue of tht~ Federal Register of February 12, 1973 (3,3 FR 4249), the Statement of Policy regarding amphetamines for human use (21 CPU 310.504, formerly 21 CPU 130.40) was revised to reflect that while sufficient data had been submitted (in response to tIme previous Statement of Policy) to generally support the anorectic efficacy of single entity amphetamine drugs, tIme degree of extra weight loss was small) a few tenths of a pound a week in many cases), variations were great, arid the rate of weight loss decreased after the first weeks of therapy. Accordingly, time commissioner concluded that single entity oral dosage forms of amphetamine ~or dextroanilihetamnine were effective In the management of exogenous obesity as a short term (a few weeks) adjunct in a regimen of weight reduction based on calorie restriction for patients in whom obesity Is refractory to other measures. The notice advised that anarectic combinations containing sedatives or tranquilizers were regarded as new drugs requiring approved new drug applications and that the data in such applications must meet the require- ments of 21 (`FR 3.86, fixed combination prescription drugs for human use. On March 9, 1973. Lederle requested a hearing for NDA 12-570 covering Boama- dex Sequels. Letlerle did not request a hearing for Bamadex Tablets, and the Commissioner withdrew the approval of the NDA for Baniadex Tablets (NDA 11-280), notice of which was published In the Federal Register of March 30, 1973 (38 FR 5290). In Its hearing request. Lederle contends that its submissions demonstrate (a) that, with respect to weight loss. Bamadex Sequels are significantly better than placebo and not significantly inferior to dextroamphetamine alone, and (b) that the meprobamate component significantly reduces the central nervous system PAGENO="0707" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15137 Noble study, there were patients receiving anti-inflammatory agents with anal- gesic properties, antihlstantines with sedative properties, and major tranquilizers, any of which could interfere with central nervous system side effects. Similarly, patients in the Bamadex group also used thyroid and diuretic drags ~vhich could also influence weight reduction. This study also fails to explain the methods of observation and/or recording of results as required by 21 CFIt 314.111(a) (5) (ii) (a) (3). No details are given as to whether subjects were questioned ns to whether they experienced side ef- fects or whether only the investigator's observations were counted. Thus, as be- fore, there is 110 way to determine the accuracy or quality of the data relating to adverse reactions, and hence there is no way to scientifically assess the result. Al- though the investigator reported only one side effect for the Ilamadex group, a check of the patient reports show-ed that an additional patient. No. 222, experi- enced depression and had to be switched to other medicntions.This indicates that the investigator had not accurately observed and/or recorded the results (21 CFR 314.111(a) (5) (ii) (a) (3)). There were 6 patients In the dextroainpheta- mine group who experienced side effects. Even if these deficiencies are ignored, Lederle's own statistical analyst admits that there was no statistically significant difference found in the side effects re- ported for the three groups. This study, therefore, fails to provide evidence that meprobamate contributes to the clnimed effects within the meaning of and as re- quired by 21 CFIt 3.86(a) (1). With respect to the claimed anorectie effect, tins study shares the identical defects as the just-review-ed Noble study, i.e., the author failed to assure group comparability with respect to the use of concomitant medication (21 CPU 311.111 (a) (5) (ii) (a) (2) (iii)) and failed to explain the methods of observation and recording of results (21 CFR3II.111(a) (5) (ii) (a) (3)). The investigator initially defined a `satisfactory" response as a loss of at least 9 pounds for the 9-week period. Under this definition, he found no statistically significant difference between the three groups, I.e., the placebo group did as well as the I3amadex group. Accordingly, a second, less stringent, standard was adopted which defined "satisfactory" response to be a loss of at least 6 pounds for the first and last 3-week periods. Using this criterion, the results of tire Bamodex and dextroamphetamine groups were found to be satistically significant when compared to the placebo group, and tue differences between the Bamadex and dextroaniphetamine groups were not statistically significant. Lederles statistical analysis of the mean weight losses claimed statistically significant differences for the Bamadex and dextroamphetamine groups over the placebo group for the end of both active treatment periods (1 to Sand 7 to ii weeks) and overall (weeks 1 to 0). However, since the study was not adequate nnd well-controlled, as dis- cussed above, these reported results are not reliable Or scientitically evaluable. 3. Miller, Jerome, "A Comparison of Bamadex Sequels, Iiextroarnphetannne. and Placebo on Weight Loss and Side Effects in 90 l'atlents'', unpublished study, 1971. ThIs study aL~ followed the bosic protocol used in the N~ble and Schein studies with only one exception: To assure more reliphie it-eight-loss data, followup weiglungs %vere done in circumstances similar to the original weighings w-lth respect to time of day, seales, and clothing. As with the previous studies, this study failed to assure group compara- bility with respect to the concurrent use of other drugs which could have inter- ferrerl with the central nervous system side effects and the claimed anoreetic effects (21 CFR 314.111(a) (5) (ii) (a) (2) (iii)). Although the author did explain that lie conducted t.he weighings at the same time of (lay and under similar conditions with regard to scales and clothing. lie t:.iled to explain whether or not, and if so how, he took into nc,mnt such variables as ~lorie Intake and menstrual cycles (2! CPU 314.111(a) (5) (Ii) (a) (3)). For the third consecutive time, Lederle's statistical analysis showed that there wits no statistically significant difference between the three groups with respect to the lncidenc~ of side effects. Therefore, this study, too, fails to pro- vide evidence that ineproltanrate contributes to the cIa i rued effects within tire meaning of and as required by 21 CPU 3.86 (a) (1). With respect to anorectic effects, the investigator's own clinical evaluation showed that tire number of Baniadex-tre'ated patients with an overnll satisfac- tory clinical (w-eight loss) respense was strikingly similar to the nunther for tire placebo group and smaller than the dextroomphetamine group (Bamader Sequels, 12; dextrx~amphetniuine. 20: placebo, 10). Since the placebo and Ram- adex groups were nearly identical with respect to this vnrinble, if anything, the PAGENO="0708" 15138 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY evidence suggests that lianiadex is no better than a placebo with respect to the claimed anorectie effect. While the statistical analysis of junta weight losses based ott averaging total weight loss over all subjects shows that t lie difference - between Ba niadex and placebo `s-as statistically significant, tins result is at odds wit ii t lie investigators evaluation of the Overall clii neal response I instil on nunil er of subjects who lost weight anti, in any event. Is rendered scientifi- Ca Ily unreliable by the study's Li ilure to meet the regulatory criteria for alt adequate and well-cirni rolled clinical investigation (21 C1'R 314.111 (a) (5) (H) Leslerles owli investigations and analyses of the lianuidex Sequels studies not ott] v fail to sulista ritia te its rationale for I lie oouih,i,iati. in, bit affirmatively deraoristra te that itis-prohaniale si es not reduce the incidence of side effects attributable to the pri liellial ingredient, dext roaruphieta mine. Moreover, using the clinical res~it.use data, only one study ( Schiein ) shows that the difference in anorectic effect between Banmdex and plaeqlio was statistically significant, and ii' that case the Investigator snis forced to lower his initial criterurn of `satisfactory'' to find a statistically significant difference. B. Ho macfez Ta bicts 8t it rIjcg-1 ederie also conducted three clinical studies with l3arnadet Tablets (5 rag dextroa rnpbeta,nine and 400 mg ineprohiamate Si lice both Bainadex Tablets and Ba rnadex Sequels contain :t lie Sn me neil ye ingredients and are reanuniended by t hiei r respective Ia lids for the ,czj rae Indi- cation, i.e., as a short term adjunct iii the treatiiien t of exogenous obesity, and since Lederle in its request for hearing dated March 9, 1973, relied upon a list- big of side effects and a combined statistical analysis sit data fnnn the three Barnadex Sequels studies arid three studies of Barnailex Tai lets, the thief? Barnadex Tablets studies are relevant to 1-ederles request for a hearing. With the exception of the dosage schedule (one tahil ct three times daily), these stud- ies followed the pittocol used In the Jiamadex Sequels studies. The results are sirinma rized as follows 1. Parsons, W. B., Comparative Efficacy of Bamadex Tablets (400 rag ineprobaniate and 5 rag dextroamphetamlne), Bamndex Minus Meprohtainate, arid Placebo in the Control s.f Obesity and Measurement of Side Effects.' unpuli- lishesi study, 1971. This study Is not adequnte and well-controlled within the meaning of 21 CFJ1 314.111(a) (5) (ii) (a) (2) (iii) in that it failed to assure that tire test and control groups were comparable with respect to the use of d rugs other tItan I lie test drug. Seventeen of 25 patients In the Baniadex group, 15 of 27 patients in the dextron rnphetami tie group, and 15 of 29 patleats in the lilacelni group were concurrently using drugs other tItan t.he test drag. Concur- rent riiedieation included diuretics arid transqui hizers which could affect the results of a study designed to measure the anorectic effect and the incidence of adverse reactions related to the central nervous system. Tile investigators failed to erplain the Irietl,iids of observation and recording of results with respect to side effects (21 CFR 314.111(a) (5) (ii) (a) (fl). No details are given us `to whether subjects were questioned, as to xvhiethier they experienced side effects, or whether only the investigators observations were counted. Thus study also fails to provide aily statistical analysis of the anorectic Ilairt and tItus does not comply with 21 CF11314.l1i(a) (5) (ii) (a) (5). Even if the defects al love, which render the study mit adequate and well - controlled within the meaning of 21 CIt 311.111(a) (5~ (ii), are ignored, the results do not support Lederle's contention that the addition of nieproharnate to the co,nhiintioii decreases the incidence or severity of side effects associated wit I, the primary ingredient, dextroa mplietn ml lie sulfate. The results of this study showed a markedly higher occurrence of side effecis with Bamadex than w-ith either dextroamplietaaune alone or placebo. Of the patients who tcok Bainadcx Tablet?, 10 repou'ted side effects while only one in the dextroaraplietamine and 4 in the placebo group showed adverse reactions. Since the Bamadex Tablets contain more nieprobainate anti less dextroamphieta- mine than the Bornadex Sequels (300 rag meprobaniate ansi 15 mg dextroam- phetanrine) , these results directly contradict lederle's rationale for the inclu- slot) of meproha mate with dextron mphetamine. If. as the sponsor claims, iaeproiiam~ite decreases the incidence of adverse effects associated with dex- troamphetarnine, this dec-reuse should lie more evident in the tablet formulation which utilizes a higher ration of meprol,an,a te to dextroainplietanrine. As shown above, however, this was not the case. Since there were 10 tImes as many side effeets associated with, the use of Baniadex, there is no support whatever for PAGENO="0709" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15139 the contention that meprobamate enhances the safety of the primary ingredient, dextreanhlihetanhllie (21 CEll 3.56(a) (1)). 2. Trodella. 0. P., "Comparative Efficacy of Barnadex Tablets, flamadex Minus Meprol,aniate, and Placebo in the Control of UI esity and Measurement "1 Side Eltiects.'' unpublished study, 1971. The results of this study with respect to side effects were very simila r to those In tile I'arsons' study. The investigator reported three side effects in the Bamadex group, one in the dextro.iniplietamine group. 1111(1 t~vo in the placebo group. Since Lederle's own statistical analysis concluded that the differences in the incidence of side effects for the three groups were not statistically significant, the results of this study do not support I .ederles contention that rne-proha roat e signifies ntly decreases the adverse reac- `oils ussotiated ~vithi dextroiinpheta lame, as required by 21 CYR .9.86 (a) (1). This study shares tIre same dcfect as t lie Pa rsoris' study previously described in that the investigator failed to explain the methods of observation and record- ing of results with respect to side effects, 21 CEll 311.111(a) (5) (ii) (a) (3). No details are giver! as to whether siil jects were questioned as to wixeth er they experienced side effects, or whether only the investigators observations were counted. With respect to weight loss (both overall clinical response and average weight loss), Leslerle admitted that at the end of the second 21-day period, Bamadex was inferior (bath overall clinically and in average weight loss) to the placebo. and at the end of the first 21-day period Baaiarlex was ordy equal to a placebo in average weight loss. 3. Bowlan, W. L., "Comparative Efficacy of Bamadex Tablets, Bnrnndex Minus Me-prol~nrnate a rid Placebo in the Control of 01 esity and Measurement of Side Effects," unpublished study. 1971. In this study the incidence of side effects was low for all three groups (one on Bamadex, two on dextroanlphetainine, and four on placebo). Statistical analysis failed to demonstrate any statistically significant differences between the active medication with respect to side effects. Censequently, this study fails to support Lederles contention that ineprobamate decreas.. tIre side effect.s associated with dextroarnplietamine and therefore, fails to provide evidence that meprobamate enhances the safety- of the principal aetive component of Ilamadex as required by 21 CFR 3.56(a) (1). Lederle did not attempt to perform any statistical analysis on the anorectic data (21 CEll 314.111 (a) (5) (ii) (a) (5)). No details are given as to whether the subjects were questioned as to whether they experienced side effeets or whether only the investigrttors observations were counted. Therefore, this study fails to explain the methods of observations and recording of result as is required by 21 CIt 314.111(a) (5) (ii) (a) (3). The three tablet studies, whether taken individually or together, failed to show a signifIcant decrease in side effects for Bamadex patients when compared to patients u-ho used dextreainplretam Ic alone. In fact, the combined results for the tablet studies show more side effects for Bainadex patIents (14) than for the dextroampheitanilne patients (4). C. (7onrbined statixf teal a-nalyscs.-Lederle submitted a combined s-tatlsticnl analysis of the side effects and mean weight loss for the Bamade~c dextro- amph famine, and placebo groups in the six studies reviewed above and a coin- bined statistical annlysis of the three sequel studies alone. Since these analyses are depeudcnt upon the data obtained front the ipdivilnal studies, and since the individual studies have been shown to be not adequate, and well-controlled within the meaning of 21 CEll 31-1.111(a) (5) (ii), any analysis of such data can only yield results that have no scientific validity. The tabulation for the sequel studies shows discrepancies between the number of side effects recorded by Lederhe and the number disclosed by examination of the individual case reports. In the Schein study. Leilerle noted only one side effect for the Bamadex group while the ease reports reveal that patient No. 222 experienced depression. in the Miller study, Lederhe noted only three side effects for the Bamadex gronp. whereas both Lederle's initial analysis and tIre case reports show four side effects. Any statistical analysis which is based upon inaccurate reporting of data cannot provide substantial evidence to support drug effectiveness (21 CEll 314.111 (a) (5) (ii) (a) (~) (ilL). Lcslerlo has failed to show that it was justified In pooling the results of the three sequel studies. Thus no details were provided as to whether or not the groups in each study were comparable with respect to coucurrent drug use and whether each investigator observed and recorded his data In the same manner. The scanty information that was provided shows that theer were differences in - C. - - -- PAGENO="0710" 15140 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY study methodology thus, while Dr Miller was careful to conduct followup weighings at t lie same time as the initial weighings, neither Dr. Scheia nor Dr. Noble did so. Dr. Scliein had all his sulijects begin t lie study during the same week it does not appear that either Dr. Noble or Dr. Miller followed this pro. cedure. it is, therefore, not at all clear that the did a from tile three studies are suflicisatly lionmogeneous to `Va rraiit pooling. With respect to the combined statisticaL analysis for all studies, the tiiscrep- ancies in the tablet studies are even Inure striking. In t lie Bowlan study, Letlerle reported only one side effeet for the Baniadix group whereas I lie case reports showed seven patients had side effects (No. 401-''ner~ mis,' No. 419-no en- ergy," No. 427-"dry niouth," No. 130-irritable." No. 4-I2--"increa~ed void- ing,'' No. 449-emotionally upset,'' and No. 4(j$ onstipated" ) . Similarly, while Lederle included only 21 patients in the dextroaniplietainine group and 20 patients in each of the Baniadex and placebo groups, FDA's cheek of the case reports showed that the following patients returned Li ir at least one visit after the I ititial interview arid should have been included in the calculation the Ba made_v group, 30 patients the dextromi tnphietamiiie group, 2$ patients a id the placebo group, 25 patients. In studying side effects, it is essential to use all data available. To exclude patients who hm:icl only one follow-up and/or who were dropped from the study is to eliminate front ci nsideratii in the very patients who tiiay have discontinued bcea use of side effects. In the Trodella study, Lederle reparted t hiree, one and t `vo side effects respec- tively for the Ilaniadex, rlextroanil,heiianunc and l~laeeb groups while the rem irt forms simhitu itted 1w the Investigator showed the lianiadex group had i~eve,m side effects (Nos. 505, 510, 522. and 5:lR-"fatigue,'' No. 545-"irritalile," No. 50$- ~`rash and swelling," and No. 576-"marked increase ii' blood pressure and head- aches") the dextroaniphetainine group, four (No. 507-constipation," No. 521- "swelling of feet." No. 529-"fahls asleep.'' No. 59 l-"trouhile sleeping if took all three lulls' and the placebo, four (No. 525-'hieadaches," No, 533-nausea ted and upset," No. 540-"very tired," and No. o90-"sleepy"). I"inalty, in the I'arsons study JA~lcrle based its ca Iculatiotis on 20 patients iii the Bamadex and dextrouniphetamiae gm-ups and 25 patients in the placebo group. A check of the patient report f' mis, however, shows that 27 patients should have been evaluated ii' the Bainadex group ( only No 010 failed to show up after initial visit), 2$ in the dc_vt roa nihihietani me group (all ~ia ients evalu- ated through at least first ph:ise ) . a iid 25 In the pt icebo group (only No. 6-IS failed to show up after initial visit). Using Lederie's I nterpreni tion In the patient report foritis, the results for all six studies show that the identical intuit or (if side effects (2-S) occurred for both the Bamnadex and dextroanipheta anne groups. There is iii, basis for the coii- teutlon that iueprobaniate significantly reduces the number of side effects asso- ciated with dextroa ruphetni imie. In addition, Lederle's statistical a ni lysi 5 (if the reduction in the total number of side effects of Br madex wIie,r coinpa red to t lie total number of side effects for dextroa nitihietamine only" approached significance." These data pj~~~j de no evidence that inep nil ii lila te co i tn liii tes ti i the ci `in ho - nation's claimed effect. Lederle has clearly failed to conic forwo nI with any evidence derived from adequmi te and well-control led si tulips showing that mETro- baniate reduces the no oilier of side effects attrihiiita lile to slextroanipheta mine within the ineailing of, amiti as required by. 21 CEll 3.56 (it) (1). It is also nmurtant to note that with respect to the -laitned anorectic effect, the rirna ry indication for Baniadex. all mdi vidoal studies fa led to sho~v that the differences between the lianiadex and placebo groups for the 9-week study were stntistitall~- significant. Similarly, two of the three tablet studies also failed to show that Banadex `vats any better I ha a a placebo. Since, as shown above, the studies upon which hioth of the analyses are based are twit adoqmnte and ~vell~ontrnlled within the meaning of 21 CFR 314.llI(a) (5) (ii), and since the analyses thensel yes incorrectly and macdin teiy report results from the studies, ally data from the eiunbtned statistical analyses would be scientifically meaningless. IV. ~nnlmary - For the foregoing reasons, the medical evidence submitted by Lederle fails to meet either the statutory standard, section 505(d) of the act (21 1J.S.C. 355(d)). for "adequate arid well-controlled investigations" as set forth by 21 CFR 314.111 (a) (5) (ii) or the requirements established iii 21 (`FR 3.56 for a fixed corahinu- tlon prescription drug for human use. PAGENO="0711" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15141 All three of the clinical studies submitted by Le~erle in support of the effec- tiveness of the sequels shared the same basic defects: They each fail to assure that the test and control groups were coiiiparable with respect to the colic urrent use of other drugs, a requirement of 21 (`FR 314.111(a) (5) (ii) (ci) (2) (cii) and they each failed to explain the method of observation and recording of results (21 (`FR 314.111(a) (5) (ii) (a) (3)). These defects conclusively render these subanssions inadequate and not well-controlled on their face. As pointed out above, eve!' when those critical defects are Ignored, the results, as rnter- preted by Lederle. of each of the sequel studios tnkci, separately failed to support the conteuti on that nieprobamate significantly reduces the incidence of side effects attributable to dextroainPhetamine. The combined statistical analyses submitted by 1.ederle furl her support this conclusion since I.ederle .s analysts were unable to conclude that ineprolianiate reduced the number of side effects in a statistically significant manner (21 (`FR 386(a) (1)). None of Lederle's initial statistical analyses for the three sequel studies showed B~iynndex to he a significantly better anorectic (overall clinical response) than placebo. Only in tile Sehein study, when a second analysis was perfonned and the standard for `satisfactory" clinical response was lowered, did the results show Bamadex Sequels to he significantly better than a placebo. Iloivever, these results are not scientifically evaluohile since the Schein study is not adequate and well-controlled. Similarly, two of the tablet studies (l'arsons and Trodella also failed to show that Bam;idex was significantly better than placebo as an anorectic. While the Bow-land stmly suggests that Baniaciex is a significantly better anorectic than placebo Lederle (lid not sulnait any statistical analysis on the anorectie data. Lederlie's statistical analyst. when ecuifron ted with the combined data for all three sequel studies concluded that "Bamadex Scsiuels may have slightly less efficacy ia terms of weight loss than (lextroaniphetamine". Thiu~, the clinical studies suggest that ineprobainate reduces the anorectic effect of dextroam- phetanilne. Lederle failed to submit any evidence to support its claim under 21 (`FR 3.86 (a) (2) in its March 9. 1973 request for hearing that the additioa of meprobaniate enhances the safety of the principal active Ingredient, dextroainphetami no, by lowering its abuse potentIal. Finally, although Ledcrle's current labeling does not cia in! that Bamadex is safe nnd effective for the treatment of exogenous obesity ivitli concomitant anxiety and tension, the nrgianent is raised in Lederle's March 9. 1973 request for a hearing and, as stated above, the claim was made in J.ederle's earlier Bamadex labeling. However. Lederle has not submitted any evidence to deaion- strate the existence of a significant population which fits this description and which requires the dosage of both dextroamphetamine find nieprolcamate coil- tamed in 1(rnuidex for a comparable period of time, as is required by 21 (`FR 3.56. To show that such a patient population does exist, it would have been necessary for Investigators trained in the use of evaluation of standardized psychological rating scales to have applied the scales to the patient population being studied. Neither investigators with the requisite qualitications nor the rating scales were present in any of these studies. 1'. Lcgot argitnirnf.i In its March 9. 1973 request for a hearing, Lederle argues that the three sequels studies demonstrate a statistic-a fly siglu fleant anorect ic superiority of Bama dcx Sequels over the placebo and no sigili ticant difference from dcxtroani- ph etamine. ma siauch as llama dcx Sequels conta ills dcxtroa mph otami lie, a recOg- muzed a norcetic, it would not lie at all surprising if the (Iota did demonstrate significant superiority for this Indication when compared to a placebo, As shown above, however, this is not the case. Le~lerle's major argument is that the sequel studies, the list of side effects and the combined statistical analysis, dcmo,istrate that a satistically significant re- ductioa In the central nervous system side effects is achieved by mcprobaniate, i.e., that nieprolcamate enhances the 5:1 fety of the principal active ingredient ~vithin the meaning of 21 (`i'll 3.S6(a) (1). As shown above, this contention Is not supported by Lederle's evidence. In the first place, none of the submitted studies are adequate and well-controlled clinical investigatIons within the mean- lug of section 505(d) of the act (21 V.S.C. 355(d)) and 21 (`FR 314.111 (a) (5) (Ii). Next, even assuming, a rgnendo. that the studies `vere adequate and well- controlled, Lederle inaecurntely recorded the data from its own patient report PAGENO="0712" 15142 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY forms so that the analysis is based on utirelialile data. I'D_Us interpretation and flu tistu,'al a, ialysis of the patient report foruis shows there was Ito statistically significant reduction In side effects wit Ii Bainadex. It slti mId lIe empimsized, however, that FIU. does not rely eli its analysis for its action but rather 0'' the failure of Lederle's data to meet the statutory and regulatory (`Lit cria for ade- quite and ~v4Il-ciilitroIled studies (section 505(d) if the act (21 U.S.C. 355 (di and (21 CEll 314.111(a) (5) (ii))). Finally, even if all these discrepancies are ignored, Lederle's statistical analy- si 5 I Ia sed oil Leder I es Interpret it ii iii of t lie ii:, lit', it reiN irt forms fails, wit Ii C~il tI conclusivel less, to deni oust tate a 113' Si gi 1 lien o t red hit ii ii in side effects for Ham a- dcx. `rh is judgment holds true whether the I hiree seq id studies are jiiilged ii- dividually in' collectively, whether I lie three ta hilet studies are judged individually or collectively, and whether all six studies are combined. It is obvious that the unanalyzed list of side effects, I y itself, is of no e' identiary value. Since this d:i ta is I nco rpora ted in to Lederle's (`On! bin ed st a (is t lea I analysis, its sigl illici, lice sth mis or falls with the evallia tim, of that report. With l'esls-ct to the interpretatioii of the pat ku t rejsirt forms, Lederle con- tends that FDA incorrectly characterized tli,' iiir'ideiice of side effei't~. T tilts is simply not t lie case. Lederle's carelessness i a tabulating its Owl' d,i ta is clearly S v id ci we.l lix two instil ices ( 1 ) Led erie's t a I he, svhi it'l, simm ma rises t lie cii! tlii ned ii umber of side effects (and upon wInch Lederle bases its overall statistical analysis), does not even square with its own' earlier reported findings for each individual study ; Lederle lists Iii ree side effects in its summary table for the Baniadex group in the Miller study, and Dr. Miller's summary lists four side effects; and (2) iii the Parson tablet study, no side effect was recorded by Lederle for patient No. 632 despite the investigator's eon) nient, ``Didn't find medication very helpful. Too much of a tranquilizer-a Ii iidrance in his work. Didn't alter appetite. Also seemed to en use impotence (no previous trouble) There were many sitniia r itistauices flip ughiout the studies where the investi' ga tor's comuient regardiiig adverse rca it ions \veat iitinotie,'d by Lederle. The issue of correctness of interpretation of lultient report forms need never be reached since Lederle's own analysis fai Is to ilemonst rate any statistically sig- nificant reduction of side effects for Bamadex compared to dextroaniphetamine. Lederl e a Iso coil ten, Is that since ineprcI a in it e I Ia $ beet i found effec Ii ye for the relief of anxiety atitl tensiiui 1111(1 Iii I lie treatment of ilisea ses in wIt ich anxiety and tension are manifest, arid since dext roauhlilietamine has been found effective in the management of weight reduction, that Bamndex Sequels, which contains both of these ingredients. must be reeogiiized as effective for its claimed effect: the management of obesity with minimal overstimulatioi, of the central nervous system, This reasoning is fallacious because (1) that meprohaniate is effective for anxiety n ,id tension or in the treatment of diseases accoinpa nied by anxiety and tension is Irrelevant to the issue of its effectiveness, or lack thereof, for its claimed effect in llama dcx since there is no proof tli:i t central nervous system side effects are related to the conditions of :,nxietv a ad tension and (2) Lederle's nrgumeat is, as a matter of law, i i,suffieieiit since although each of the com- ponents of a drug may lie safe and effective, It dis's not necessarily follow that a combination of the same ingredients will be effective. (See 21 (`FIt 310,3(h) United States v. Au article of drug * * * P'crcstrol, 204 F. Supp. 1307 (ND. Ga,, 1068), aff'd 41.5 F. 2d 390 (CA. 5. 1069) ; United States v. 41 Cases * * * 4oØ }~ 2d 1)26 (CA. 5, 1070) ; United States v. * * .ierae Alcohol Acne Gel, CCII F.D. Oosm. IL Rep. ¶40,836 (ND. II!., 1971) : United States v. Au article of drug * * * Jiqfr~;( 1'. Medicated. 362 F. Supp. 424 (SD. Cal., 1973): United States v. An article of drug * 0 * `Atykocert", 345 F. Supp. 571 (ND. III., 19721 ; United States v. * * * ".4sper Sleep", CCII ED. Cosm. L, Rep. ¶40.832 (ND. III., 1971). The reasoning behind these cases is particularly cogent where, as here, one of the in g redi eli ts, n ieprol I ama te. Is tee `mmii ended by the I a hell rig for tim, com bina- ion fo" a use different fri in limit for wIn cli it hi as lice,' fi iii nil effect i ye. In such a case, there can lie tin liti sis for a cIa ml that the effectiveness of ineprohamate is established for its role in time cornionati on. Thins. time il inical evidence must lie the determinant of whether meprohiatna te coii tributes to the effect of Ba madex or makes the principal ingredient safer. Ilowever, as shown above, the cihiuca I evidence submitted by Lederle not only fails to demonstrate that meprohiamnte makes a contribution to the claimed effect. but suggests that it reduces the ef- fectiveness of the principal ingredient, dextroatnphetamine. Lederie next argues that Barnadex Sequels must lie found safe because the product was approved on the basis of safety in 1960, and there has been no clint' PAGENO="0713" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15143 cal experience to the contrary since that time. Tins argument is irrelevant in the absence of e' idence showing that the drug is effective as a fixed conihihuatioli. .Ls has been shown, Lederie has totally failed to provide such evidence. No drug earl be considered safe if it is not effective. Moreover, It Is now clear that the marketing history of a product, standing alone, cannot meet the standards of sub- stantial evidence. Upjohn v. Finch, 422 F. 2d 944, 954 (CA. 6, 1970). Lederles last argument is that by coin bining meprobamate, a Schedule IV con- trolled substance (under the Drug Abuse Prevention and Control Act, 21 U.S.C. 501 et seq.), with dextron mphetaniine. it Schedule Ii controlled sul stance under the same act, the abuse potential of the Latter drug is reduced. and therefore, the safety of the principal ingredient is enh a iced within the Inca ning of 21 (`Fit 3.86(a) (2). It is significant to note that the Attorney General placed Brimadex drug products under Schedule TI. the sonic as for dextroamplietamine, rather than in the less restrictive Schedule IV in which meprobamate is placed A claim of decreased abuse poten tia I. like other claims, must be supported by evidence, not speculation No such evidence is offered In' l~ederle. Leilerle does not support its contention that the abuse lx)teltiai of a drug is lowered by comhin lag it with another drug with air intrinsic abuse potent l,il of its own. VI. FiNo,Nc,s On the basis of the foregoing review of Lederle's evidence and legal arguments, the Commissioner finds that (1) There is a lack of substantial evidence that this drug has the effects it is represented to have under the conditions of use recom- mended, suggested, or prescribed in its labeling and (2) new evidence of clinical experience, not contained in the application and not available to the (1ommis- sioner until after the application was approved, evaluated together with tile evidence available to tile Commissioner when the application was approved, shows that Bamadex Sequels have not been shown to he safe for use under the conditions of use upon tile basis of which the application was approved. The evi- dence fails to show either that each component of the coinbirution contributes to the total effects claimed or that meprohamate enhances the safety or minimizes tile abuse potential of the principal active ingredient, dextroamphetnmine. There- fore, Enmadex fails to meet the requirements of 21 CFR 3.86. Furthermore, Lederle has not submitted any evidence to show thllt there exists a significant patient population requiring the concurrent therapy for exogenous obesity to- gether with anxiety and tension or that Bamadex is effective for that indication as required by 21 CFR 3.86. Lederio has failed to offer a substantial legal argument or to set forth facts showing there is a genuine and substantial issue of fact requiring a hearing. Therefore, pursuant to provisions of the Federal Food, Drug and Cosmetic Act (sec. 505(e), 52 Stat. 1052, as amended (21 U.S.C. 355(e))) and under author- ity delegated to the ~ommnissioner (21 CFR 2.120), the request for a hearing is denied, and tile approval of the new drllg application (NDA 12-570) for Bamadex Sequels, including all amendments and supplements thereto, Is withdrawn, ef- fective June 2, 1975. Dated: May 15. 1975. A. M. ScuMint, Cornrn(snioner 0/Food anti Drugs. IFR Doe. 75-13548 Filed 5-22-75; 8:45 am] MEMORANDUM FEBRUARY 20, 1973. To: Deputy Director, Division of Neuropharmacologicnl Drug Products. From: Acting Director, Office of Scientific Evaluation. (Through: Director, Division of Neuropharrnaeologicai Drug Products.) Subject: Sustained Release Formulations of Anorectic Drugs-Action Memo- randum. ISSUE Decisions are required on claims for sustained-release formulations of anorec- tic drugs for Federal Register follow-up publications. These decisions will also be applicable to amphetamine products being handled on a case-by-ease basis. PAGENO="0714" 15144 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FACTS The decision memo on a rnpheta;nines a rid other anorect ics initialed I y the Commissioner took a staml to the efficacy of the various drugs marketed or pr~ posed for marketing as aaorec-ties. It did not go into most special dm015 for specific drag products, e.g.. claims for individual formulat ions. A group of spiMia I cia i ins req ui ring fu rt her d ecisi on is tim t of the "sits! a i ned-aeti, ii'' foriti `hat ions. A number of anorect it drugs are in formulations associated wit!, claims for sustained action or soruetlii ilg Si olin r. Exam! los are 1 ) I) let Iiyipropioit ii, `Di ,spi! its'' or `Te il-Ta! is". I he form Cr 1w i zig ii Itydriphilic matrix. carboxv~ioIynietiivleiie (2) Phentermine or am pheta mi lie (lonanun Or Biplietanaine, respectively as a resin complex~ (3 ) Ani pliet a in i ne or d ext romi iii pheta nil no nsa' Spa ii sule' (4) Phe,imetrmtzi,ie as an ``Eaduret', containing aluminum tristerarate and silica gel to slow dissolution ; and (5) Metlianiplietantine as a "Gradurnet', it,, insolnaitle plastic matrix front \vhicli the dnig is leached. A brief survey of NDA's for these products yields the attached blood level curves. (Attachmeuts-Tal, ~\, i)exedrine -Tab B, Tenuate) It appears tliitt. with the possible exception of pheumetrazine the ``sustained-action" formulation does not itrodme blood levels which differ snbstn ntiallv Iron, thom' lro~l need liv the same (lose of drug in a non- "sustained-action'' formulation. Other di ffereni'es exist for plienmetrazine, so that in each ease examined, any practical diffirerice or special thorn peutie benefit of the sustai ,,ed-aetion' formulation appears un- likely, and is not supported by these studies. Efficacy trials have by and large been done with the "sustained-action" formu- lations, `vi th a demonstrated drug-placebo difference, so t lint general efficacy is not a question. Therapeutic (as opposed to blood-level) eonipn risons of the special formulations with conventional tablets or capsules have not leca done; the slow- ness of weight loss, i.e., days to weeks. and the large inter-subject variations makes it appear irnpracticnl to do such trials. ( Short-term trials of food con- sumption by rnealtiroes might be practical. lio~vevi'r.) T lie 51(1' studies suggest less jitteriness with tile ``Spansule'' which would he consistent with the lower, slower peak. Administrative deadlines for decisions of two sorts exists. First, a number of New Drug Applications Include claims for "sustained action" for single-entity drugs, and our conclusions on these claims sI 01,1(1 lie communicated to the spon- sors our reservations may he indicated in a general way for now, and a final conclusion left until later. Second, follow-up DESI notices' are due on Tenuate Dospen, Diphetainiiie, lonamin, flesoxyn. nnd sonic lcs.s known amphetamines. These Notices should include our definitive conclusions. DiscussioN rt apj-~ars that claims for "sustained action' for current formulations of anorectics are not justified. On this basis we have incorporated the following form paragraph in letters to sponsors of NDA's. We have serIous reserva lions as to any labeling claims for sustained action. We request that you either delete such claims or stale in niore precise language any possible therapeutic difference of the sustained release formulations from all equal dose of tablets. We hope you concur with tli is if you have reservations, the language of the pa ragra ph will permit future revision of our stand. Assuming that `sustaIned-action'' claims are colisi tIered Inn deqitately su~ ported, further questions arise, for example, what future studies and results might the firms attempt to achieve. Two pressing arid visible decisions are required now however. The first involves publishing follow-up notices for sustained-action nnors'tus, for whit!, "possibly effective" notices were published over two years ago. \%e believe we can go ahead oil these they would require deletion of cli, in's for sustained action, so placing the 1w rden oil the firms to support ally special claim other than general efficacy. The second involves formulation hrand names. The proprietary names. "Dospau" and "Euduret" imply prolonged action, and we suggest these names be deleted or replaced by a neutral linine such as "matrix formulations" or PAGENO="0715" COMPETITITE PROBLEMS IN THE DRUG INDUSTRY 15145 delayed-onset formulations". Alternatively. the name might lie allowed to remain wit!] a qualifying statement in the insert I hat the formulation 1)0 S not been shown to preduie results superior to tile same dose In conventional fonnula thus. The question of dosage reconi,oeiida tions may arise. We see 110 iiiije~'tiori to giving dos-age regimens fi ft ea cli forninlatioa-a t.i.I, regimen and a q.d. regimen. e.g., 25 mg t.i.d. standard forinulat ion or 75 mg, q.d.. matrix formulation, in the DO~AGfl AND ADMiNISTRATION section of the inserts. Other issues might be raised, lint these Seem the main ones. Decision options are listed below. We've (liseussed the ml tue Ilnestion with Mary MeEniry ard Ted Byers. who favor deleting the no urns. They recalled ill) preceden Is. RECO M MEN I) ATIO N That option 1 of cacti Decision group below he approved. BARRETT Sc0vILLE, M.D. DECISIONS A. With respect to data on "sustained-action" of anoreetics (1) Consider tile data (10 not snplsirt such claims. e.g.. publish follow-up DESI Notices. Approved Not~~~ppr0ve(1 (2) Defer decisioli to est aldislimeit t of Committee criteria Approved . Not Approved B. With respect to drug naliles (1) Delete iia'iies which may imply special formula tioti claims e.g., `En- (IlIret", ``U raduniet", "Dospii n, Stedy-Tab'', ``Spansitle' ( tills also would iii' elude disclaimers in insert). Approved Not Approved (2) Leave names, but label with a diseln liner. Approved . Not Approved PAGENO="0716" 15146 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DEPARTMENT or JUSTICE, DRUG ENFORCEMENT AGENCY Tu ~r. RnhCrt J. ~ - tct1i~; Chief Cov~:~~.-i ?.o} Ron :u-H A. flu-cnn, Ciii,-' Conp15 ance Investicat ~-,. - , U,.inC 1107111, 0? Rc-'t-c'nh't i'1~ ti,u Ii,, SCi-;u~cr''..i 7; he" `;orit nteJ ] irci;CC ~!i fn,',,,atinn obt:'t ;e;i he'.' Pc ci:- 8 11ci;OcBhic-t:ciIifl (an [; ,hc,ta;1170l'V,Cili'r1 `--or -` Lnh'rrnL(,r ins hI:ra :-huni:; tIc R'-,---~ i-c ~A. ch f' L cc 21 `~-c 1:~.;:~;'hc',t1 ..; c. ~ ?`nri-o. `rc-xns Ccl:,~'c';:r' 1fl;'~sin - fljc Cflcl5 rn h-cleary. F~'tch,, -ri (o]c;':ch, . rUarl: tic1) ~c;:. ```I;-.-, 7'd'r'u:c,'' ,-a-C'' Ce,';t d'waAr-cuccir- ,;,`C'c'fl,':-;c~');fcEg ut:'- ~Vn ijijet;; linac L: `c)UCiiLll, tiicrc `4 1'- tn :UIi--;c'';-e server `/ . d,ct~r7Lr1~C;: r~ InrIl - ~ iNiiD'- I'll''; at'- [cr1) o-.-c'r'17Pt4',. a. CII iroc t~u l:r'~ - ,-`~`` ~, -~ ortr. -- is ~t'nr'hoci, fl:r i--:Jc,i:i-: ;~` Icr- -, [l:'-l.-'~ct ° nt ;,i1-n"i: 3 i-rI, s,7rHtler'_'lC:C'C-L t -vie:'- -rliL trc 1Jiir:)_i district' IjIc rt i:r' Ii---. `ti-Dr. 1.'; docitc'entt: an 11] Ic It c';~ty'il --:t-.cri a, -II~' I-. ,-:,`,Lhkv, Ifi-gion -`s crap, ci -eccr'-d' - var -r the jItic-tt distrilittice; ci Cctsc c-, Ih'; r-rc.n ~e~-o;1'nr y a ystan (ICC- ur''rr't' civ t- v','r- Cfl ~1 nh~(Y P (;, U. Yr 1'~ nh-ave ir-e'tt(:°.' 5-kr' tn_'n talc -Iht'',o ¶`DL'eI C aptil'C~ ins hc::i, CcLcD'n:;t-' -~ Ic `c ,-,5.-r'rin-c a ncrrr'i-a U. - Li-'' co hodec', Tl;ro-~ app-It- I-a bc-.I irl ~-` ~tr :--~cc;'1 v: - 01 Ri ~c:i:rr' 7;;: in Mexico. i1~c rarsc'lcc sr-i- otto,') i;r Untied Ptctecr through Iii Pnso, Dc') fin, I's-fIr L:e'~, I `ado-, ?ehileti rind I,x'w:nsv 1111 - ` 07.: Tar ,lifclnr' Pt? peYcI:.lSC'4.r--:~;Ed `-~ 4 ,c''~': 1. 1''-- ,cont 1, hnr~r, tnni'i" Len? fcc t~-r:neee :1) Iafl~ ncii& 110l :1:1 -cx ru Cii:'. PAGENO="0717" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15147 -2- he reqLCat Or L~FA i.tae lINDa) Laboratory DivisLo~a queried dv State Foriis to Lalaera tories * The ,`osuits of that (cv\'fl~P nitacord, In ir,i.,rt dna eI,tained leer. Strascmh,i rgt' , floch.I,~ter, New York, k I toe r'trrn of `,rr hot am ne re via C oej~1ex Ii ave been ;tc;d iroui (lie ,ilai,L at fleches ci, New York, to the plant in ?:exlco (`liv saner, Maid, l~7O. This amoent or r,'si n ~:V~h_tQ P1 nICCO "SI PO~ ~OOO d *J)t.. of ll~ na ~rase'ahirgh y one of a !`t]':)~)i'i'' `I 1~' X1 (`0 a?' ILd iv pr2~juctn~ `J'herniaot,nt of A,a ,tartnria' ,~``: `0 - ft eia--)ou 0 ~.ex;.o.Ti~_~: COu~ Z'C :1 t tt,c(,xtentordivore,onnt pro'--! `N; 1 ci; a,--;.d,rocl by I h;,n 11Cr; In Mexico Cdv expose'; a flIer ]!rndu',t; on. :rins ode production ;`r;,'hLe;';~';;1; d~ccrsioix te r,-rc'ai i;i'~ a sittir~t:tOr1 ahiehira ~Oic. Act i 05110!! `_t~Jl1%i*'~ tei-c br~ taken fli. deny reno; at of ..e,port. a; 1ti1~a! o ~ r,Po Iacsi 1~J?~- ~ dr-;iç repae~vnJ emit, In be taicca before that date. PAGENO="0718" 15148 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SE~TD lflDER CIRCUiF 1C-S--71 J~tnes B. x TO ALL r~:stxc no:.:: JOHN It. ENRICH?, Cl-UHF OF C:~ll2!tncN2 SL'BJ! SL'~ARY OF DA~O}lHOUS INtLO TRAFFIC FROM ~`HXICO INTO THE n;xnn ST;t:s TilE OCCURRENCE OF A~jPltETPiIIN2S ~PPEPHING IN TRE DONYISTIC REEN OCCURRING AT A CCYSTfNT LVZL C'.~F. ?. LCIG PFTIOD, IT 13 ESASCNATI2 TO Lsli':lR Ti:AT THE DI'.~SICN fiNn s:WOCLING 0? IT2U~ES FRCNM::.IcO :;ILL I~ tT~SI `ICE TO TEE CF AEflIETIMflES TO SCbLDCLE II. THIS CilAN3~ OF SC1FC&'LL WITH TEll CCINt2ZPCNDI:lG RlsTltrcTIc:;s CC~ ECIMEETIC fiV.AILPDILIT?, !~`) TIlE DIEIJ~ND FOR t'.!pi1FT~MIN:S IN TICS ILLICIT fl~' FF10 TIlL 32 it LECICO IN I::CflEA~jED AcTlvxrz IN TEE ;Ml'EETClIfl ST"IEGLING TRO'! IIEXICO. INFOIIEATION GAI'!CSTtEfl TO 3~TE SEOJS TI! IS FItOELEM EEANATITG FECE THREE 3CURCTIS WHICH, ThOUGH INC'IPWHDENT, CCEPLIM~Pr EA~! OZCH IN CFZEATIITG TIlE ABUSE SITUATION. BRIEFLY THESE SOUIICES ARE: 1 7 PAGENO="0719" COMPETITIVE PROBLflIS IN TUE DRUG INDUSTRY 15149 p UIJL't! SEND UNDER N«=CfliE POJITDD/ENIA CIRCUIT 10-3-71 - 4217 I) LABORATORIES STRASENDURGU DY MEXICO S. A. WEXICO DF ~!flIcO - INTflLIGENcZ I.VtREATION O3TMNFD FROM REGIONS 5, 6, e, 11 MiD 12 5110W BIPW~T.&~!INA 20 (AN AEflUTflSTNE PRODU~2 PRODUCED BY LADORATORIES STEASLNrnmGR RE MEXICO FOR DISTRI- BUTION IN MEXICO) IS ItL'.DTLY AV~ILAELE AT TRUCK STOPS TURO3m:CUT ICIXICO, TEXAC, C:~Ln:0:1A, LCUISII.IFA, tLASi'M4', ~.. TENNESSEE, CECEQIA, KrrJCEY, FLORIflA PND COLORA!X). A PRZLIMIN4SRY INTElLIGENCE SURVEY CONDUCTED DY ENFA SEWS Tiil.T BEflEEN APRIL 1 - SEPT2-C2It 30, 1971, EXDD hAS MADI~ PUR~1ASE2 ANT) SEIZURES 0? DIPHETAMINA 20 To'FAaING OVER 177,000 DOSAGE flUtE. TERSE PURC1t~EES ANT) SEIZL'RES RAVE RE1 MPD IN j3 SEPARATE CASES. REGION `3 hAS SUDNITTED A SECONDARY SYSTEM CONSISTING OF TUE ILLICIT DISTRIBUTION OF BIPIIETAMINA. Th13 SECONDARY SYSTEM DOCUMENTS AN ILLICIT DISTRIDUTICT CF 240,000 DOSAGE UNITS S~ONDU.Y. n~oi'~u PROPOSED SECONDARY SYSTEM SULMIrTED BY REGION 5 DOCUMENTS A MONThLY DIVERSION 0? 160,000 DOSAGE UNITS OF BIPHETANINA. ThESE TWO PROPOSED SYSTEMS, EOWEVER, REPRESENT ONLY A SLIALL PORTION 07 TIlE rr'ru 2 ~ PAGENO="0720" 15150 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~UU SEND U?TDER StCEr CIRCUIT 10-8-71 3. Beclcner 4217 OVERALL AVAILABILITY 0? ThIS PRODUCT IN TUE ILLICIT TRAFFIC. INFORMATION OBTAINED FRC~I U. S. Ct'STVMS MEXICAN BORDER STATIONS INDICATES AN ADDITIONAL 157,000 BIPHETAMINA CAPSULES !~IRE SEIZED FROM APRIL 1, 1971 - SEPTEMBER 30, 1971. TIlE TOTAL PURCHASES AND SEIZURES FOR TIT SIX L~ONTh PERIOD IS APPROXIDATELY 334,000 ~tITU AN ADDITIONAL <00,000 ~&B.AGE UNITS BEING DI\TRTED pUR MONTE. IN MOST OF FIIE ABOVE ~~TIONE1) CASES THE SOURCE OF THESE BIPUETAMIN.4 CAPSULES HAS BEEN DETERMINED TO BE PHAfl3~ACIFS ACROSS TEE UNITED STATES - MEXICPN BORDER. THE CAPSULES ARE ENTEP.ING THE UNITED STATES THROUGH EL PASO, DEL RIO, EAGLE PASS, BRO;YNSVILLE, EtCALLEN AND LAREDO, TEXAS AND DOUCLAS, ARIZONA. TEE BIPHETAMINA PURCHASED AND SEIZED TO DATE HAVE FOR tIE MOST PART BEfl IN ORIGINAL FORTY-CAPSULE BOTTLES WITH THE LABEL SHOWING PRODUCTION IN EEXICO CITY, THE BULK RAW MATERIAL (ii AND dl AMPHET&EINE RESIN COMPLEX) FOR DIPIZETAMINA IS MANWP.CflIRED BY STRAENEmtG!!-R0CHESTn, N. `1. FOR PP.OCESSING INTO TIlE FINISHED CAPSULE 2OtM UUUU 3 7 PAGENO="0721" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15151 UUVU s~:m UNDER SECC~t CIRCUIt 4217 x At STRASENELRGS-MEXI~O. INFORMATION OBTAINED FROM STRASENI3URGH-EOCHESTLR, N. Y. SHOWS 900 I:ILGCRAtXS OF TIlE RESIN COMPLEX HAVE SEEN EXPORTED TO STRASENEURGH-MEXICO FROM DIE ROCHESTER PLANT SINCE MARCH 1970. ThIS AMOUNT OF RESIN IS EN0USM TO PRODUCE 45,000,000 DOSAGE UNITS OF RIPIIETAMINA. STRASENBURGU IS ONLY ONE OFA liI3LDER OF FIRMS MEXICO ~IIICH ARE pr~Or~ucING AMPUETAHflZE PRQQIiflt TEE POPULATION 0? MEXICO Is 35 MIflION. RECENT INTELLICENCE INDICATES THAT BIPHETAMINA IS AVAILABLE IN ALMOST UNLIMITED QUANTITIES IN REGION 11 BOMDE~1 LREAS. A CURSORY INTELLIGENCE PROSE BY REGION 11 INDICATES THAT THERE ARE 200,000 HIPLTETAMINA READY FOR IMMEDIATE DELIVERY IN TEE EL PASO AREA. AT TEE PRESENT TIME APPROXILIATEtY 1,000,000 DOSAGE UNITS PER MONTH ARE MOVING THROUGH REGION 11. INTELLIGENCE FROM AN INDEPENDENT SOURCE IN GEORGIA INDICATES THAT BIPHETAMINA IS AVAILABLE IN 10,000 DOSAGE UNIT QOANTI- TILS FROM NUMEROUS TRUCX STOPS. ttt.t-3 CII~C12LT 4 7 85.569 0-77 - 47 PAGENO="0722" 15152 COMPETITIVE PROBLEMS INT TIlE DRUG INDUSTRY ~SAGE __________________ P.LCLOENO MCUIlfl C~$~~UOT.* UUUU P SEND UNDER SECURE 1NDD/ENFA ~øo CIRCUIT C(,,SITICAOON FO~ INfOWTAAl~ ON CAEL Of SSSSGL o o MthTWSI.AOOPlSS ro~ OST OP ~aspMwac4Iao~4 C5.IT - MTSSAOE TO !T TR5~1SAk[TTW (Vod~sb4 ~s~.sd .11 ~.p,& /.o.,., 2) SMITH, KLINE AND FRENCH S. A. MEXICO, DF MEXICO - REGION 11 REPORTS LARGE QUANTITIES OF DEXEDR~NA AND - BENZEDRINA PRODUCED BY THIS FIRM TO BE READILY AVAILABLE IN THE ILI1CIT TRAFFIC IN THAT REGION. REGION B ALSO REPORTS AN AVAILABILITE OF THESE PRODUCTS. 3) *!MINI_A\n)I1ETt%:,iINES~~ - TO DATE OVER FIVE MILLION `MINI- AMPHETAMINE" TABLETS HAVE BEEN PURCHASED OP SEIZED BY AUTHORITIES IN REGIONS 3, 5, 7, 8, 10, fl, 12, 13 MD 14. BNDD BALLISTICS REPORTS CONFIRM THESE "MINI-AMPHETAMINES `It BE COMING FROM TWO COMMON TABLETING MACHINES. THE LOCATION OF TIlE SOURCE OF TIIESE "MINI-AMPHETAMINES" HAS NOT YET BEEN DETERMINED. INFORMATION RECEIVED, }IOWEVEH, LEADS TO THE CONCLL'STON THAT THESE TABLETS ARE COMING FROM A SOURCE IN BAJA, CALIFORNIA. $TTVIjfl Ctas3,nc.'~oN UUIJIJ P*ot SO !~O Cl P05 SEND UNIX~R SLCy:' 5 ~ CIRCUIT -______ PAGENO="0723" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15153 qAPHIC MESSAGE - *IICWINC I / UUUU ACflO~ SEND UNDER SECLtE / pOJ/DNDD/ENFA CIRCUIT Tin O~~ESLAGI 10-5-71 FOE INFOEMATEON CALL 0 lINGO ______________________________ -~ ~OlINL~NTI *001 4217 MUITLTII.ALSkISS THIS SPACE FOX £51 OP COMSILNHATIO.' UNIT MIS SAOF 10 II IIANS5r110,c. d,-bLi _____________________________________ ______________________ TO: THIS Tfl IS BEING FURNISHED FOR INFORMATION TO ALL REGIONS A2~D AS A FOLLOW-UP TO MY lYE TO REPRESENTATIVES OF REGION 5; 6, 8, 11, 12 & 14 NOTIFYING THEM OF THEIR DIRECT INVOLVE- 4-, MENT IN TcIE PLANNING AND IMPLEMENTATION OF fl ANPIIETAMINE TASK FoRCE. TEllS TASK FORCE WILL SERVE TIlE PUAL PURPOSE OF DEVELOPING ARRITIONAL INTELLIGENCE INFOUMATTON WITH PRIMARY FMP1TASJS ON THE DIPIIETAMINA SITUATION AND ALSO IDENTIFYING AND IMMOBILIZING MAJOR BIPIIETAMINA DISTRIBUTORS IN TIC UNITED STATES. THE TASK FORCE SHOULD REMAIN IN OPERATION UNTIL APPROXIMATELY JANUARY 15, 1972. * * * * * * PAGENO="0724" 15154 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY John U. Jiiaf of Cpera tions Le:~ota A. ~)urr ie.1.ief cost~1i~cee iz~vC~tt~3L&ct; 1vI~ic~n Su'rnry of trnn~erons Uru-: ?n~ffic XZOQ Ilexico into the Lnttc~ Ztnta The occurrence of atphet*mtreta optxI)rtnf in the dateitta illicit traffic, rL~ich ap~,arcnt1y on ;lr.nted in text~o has bnu occurrin, at it ccnstaist level over a io~~ Portoc. At Is roeso,aole ¶-" assist that the Civar,,iue pi~r1 unuirc1in~ of tin~,et~ntnes (rota ~ c~r~2~j~1 ~, to5c'~edt le, 10fl can tic ~ illicit tr,fflc Yill 0 ~ ~t the iccre,sedactivitnth 0 amphotautre ulvcrneu a~1 ¶nrL ;Un; :ro~, zxtcn. Znionation nthered to date shovs this prcbloa ewannting rrc~ t~ree sourr~n whtt,h, thcn~t, ini'e--~'rf'nt, cc-r'ltz~er2t earh et~ter in creating tao abuse i;ituatioa. £riofly thos3 oourccs are: 1) Laboratories Stra,,enburzh Co ~1atico S. A. t~extco D? :~xico - 1utolli~enco tnIorraatioc obtatn~,d (tori i-~e~ions 5, ~, 3, 11 aa.-~ 1 s~iO. Uip~otnntha ?~) (an ~n tO~firzitQ `~rodu,t ~r~,duced by Lat~orfltC,- its Str.senburz~ do !.[ezico ~cr dt3tributtc~ in kexico) 1, readily avoilaule at trm,k sta',s throu.hout t~ew I~extco, (CZ'!~i, Oflx~ioria, Louisiana, Ala,r~a, fennerce, Goor~ia, ~onttery, i'Ic~rt'!fi ~,ci colorado. i~. preliain;ry thte11izen~e survey conducted by fl~'A sho~tri that ~:ettcen Mril I - L.oritca-or 33, 1371, [XC:) his wade plnchases and notzure3 of Ci~etzntra ~O totnllir.tr over 117,t~3 do,are units. Lease ,n,rcnpses end seiruros have teen rate in 13 separate ensos. flo~ion 6~s sutz'ttted a ~ecotWar~ ,jyatn eoc~~i3tin.I or Li., illicit Cthtrl5.tttou 0! Biph',tzinina. T2l~ occondary snt~n ?oeunsnt~ ?n illt,Lt diutri':ution of 2~O,'i~O dosaze units monthly. ~nother proeo2ed seconth'ry ~ysten sucaitted by aortae s docuarants a ro,t~lv dtvor,ion of 1CO,003 dosre units of Dichetanir.,. T,euo t-,o -`ro,oqocl n7sten~, to'cever, re~ro~rot only a snail eortthr of tnt overall availability of this procuet in the illicit traffic. In~orc,t1on o~tainod fr~ U. S. `Y.ntoaa i~czican E~~rCsr .?Cationi in~: eato3 Y'fl p~Jit1cnaL 1r7,CDO tI'YioLaclnz capsules ten seized trc~ ~Spri1 1, l$1l - .$.ptrsber 3'), lull. tie -. `2: - ``,..L.I.t Pr. PAGENO="0725" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15155 total purcbs~es and c'etzu.res for the six month period is a',,roxt- sately 3~4,Ofl0 with on additional 400,000 doea~e units bein; diverted per month. In most of the above c,nt1,z~fl cases the ,ource of thens Bi-'t~eta- nina capsulen ~aas boen nai:~ed to be paanacies across trio United ~tntes - .~exicn~t ~ Tao can-:ulcs are entering t:e Caited 3tatc; to~i~i ,.t ..~, T~l 2to, T ~;1a `asl, Erc~nviI1O, McAllen and Laretio, Texas tad ~roug1ts, ;rizona. The fliphetflnitn purt~nsc~ j~rd cetzec~ to :.~vo f3r t~o nrt nsrt been in eriginal forty-capsule bottles wiUi the label Eiowizg producticu in ~exico ~ity. The bulk raw material (.3 and dl amphetamine resin complex) I or Biphotamina is manufactured by Jtrasonuurgh-Rocbester, N. Y. I or processin; into the finished czpstrlo fern at Strasenburgh-teZiCO. Information outained from otrasonourgh-~ZQcQSstCr, N. 7. shot~ 900 kilc;rnns o~ the resin cooplex have Leon exported to Strasen- burgh-~icxico fro, the liocae,ter Plant since March 1970. This amount of resin in enou;h to produce 45,030,000 dosave units of Biphotanian. itrnven~urzh is only one a niaber of fins in kexiso which rrcciuclng zmphettmine products. The population of iinxico is 35 nillion. Recent intelli~rence indicates that l3inhetaina is svailnblo in almost uslinited qunntitie9 in fleflon 11 border areas. A cursory inte1li,~enco probe by 1;etion 11 indicates that thore are 2C0,CC0 Bi,betnaina ready for mediate delivery in the El ~so arcs. At the present time anprozinatoly 1,000,000 dosazo units per montfl are moving through Legion 11. Intoili~Ience from an independent source in Georgia indicates that Biphetamina is available in 10,000 dosage unit quantities frau n~erous truck stops. 2) Smith, Kline. and French S. A. Mexico, 0? toxieo - !to;ion 11 ronorts lotte quantities of Doxedrina and BenzedrlnaproducOd by tbis firm to be readIly available in the illicit traffic in that rezion. RoIion B also reports an availability of these products. 3) `Jlini-amphetaminea' - To date onr five million `mini- amphetamine' tnblets ban been purchased or seized by authorities in Re:tions 3. 5, 7. 8, 10, 11, 1?, 13 and 14, ENDD Ballistics retorts confirm these `jni-an-,hetamine. to be ccnin~ Iron t~o co~aon tabletint nachines. The location of the source of those `aini-amphetnaines' has not yet been detormin~d. Information recotved, ~ovcvor, lead, to th.3 conelni ion that those tablot3 are coning from a source in flaja, 3lifornia. L PAGENO="0726" 15156 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1-~ -3- It ts rce~rn'',i tnt t~i ~ "Icr e;irtt~~ of tha et,-~r,e4 re~tor~ji Le rotI:.i'. i., .~`~t'.'rtc, pn~ n ~ held to mtno t::~r~e'.~ t i~'',n1 r:-~-r, :~,t rn;1 ~unCs to tn'~t,t i~~t :l'~cv::t~s: ti.o `:rç:~,. I: Is tccom~~tc~ed they ho si, :~n~ ...g:~r r.n~; on .~t ~ I~ 0 .A:zor t~,e r~t~ .ZZ cmi £ C2tert±c- .>. :.,~ r~i nnn-~o r,d z~~11snt!tty c~ fun;s,itt;~; ...a.jL.:a...';eo~ointhofio1diu eperati~n to in.'~? .~ ~o :,±~r ., 1)11. ThiB ta~,h ic:~o ~±il ~rta ~ Ln~iI rU:20IO of dnvo1c~in~~ atti~r~1 tfltOIli.tZI_j ~ .t~ -~.,r-: r:;j~t Ga b1x~ eitt:~txo~ z~t.J aluo :., :t1E~13; ttsjor £1,r,t,n1:;3 distri~utors in the Ustt"-~ - t~to~. C.~o task Three ~~iou1d rr~.y,tC in operation i~att1 ~:reoxIt.ste17 .lamicry 15, 1972 at ~aicLi flue any c~-o, iuiti,t~~1 -~,tii4~) con~I'r'oJ. T'e!e co,oe. cc~bin~J with the intollt;ence ~4t.ared, nIl he utilized as t~e basia for i~ttin~ a .;~1ryy ~ CTYOT to -! trazeDaur~ th;oratories- Rochester, ~. V. C~nv±n;; th,ir ro-ro;tttration ~ nn ar,cvter The Ehos ause ~r~3? rvnt be t~3ued prior to february 1972. Inte1fl;~'sn is'trzst.nn ,o~,tntr3d c~sccrttr~t the ~int-3c~n .3 u:~!r-'r Luturo ,ro;rtos c~oitç~c:~ to gli~That, ~ .1 -~ sXtu~ltAuas. ENFA Chron. fl~FA iubJ. ENFA/flW/ml/4217/lO-7-71 PAGENO="0727" COMPETITIVE PROBLEMS IN THE DRUG ffiDUSTRY 15157 cr;::SITI'c-1; NOV 2 ~ 1!ono~tblo .I~it~i 1. Mitchell Attor~iay G;~a':ra 1 - Jc!n E. Tn~cr~n1l, Director Durc~u~~- :cet' .:.1 .. - ~`t't)r `` Cper~ttion Biac:çjrtck In anticiration thnt the inposition of Schedule XI controls on araphctnntnc ttititt generite increased smt~tling activity we initi~t~d a nrolininary intoll1;c1~ce ~urvoy in Augunt 1971 to determine the co-~rccs and extent of ~uq,~ietnnins smuggling and traffic frc'n Mexico into the United States. Thin survey discloaed pnttnrnn of diverefon fro~n the Pepublic of !exico into tha United States enanating fr~ three principal sourcen, Two or th~se ecJrces are lagiti- nate fIn-s I'~ ~t~-tieo City; L'bonteric3 Strascnburgh do Mosico A .:ico, Ln.ico iid d:aith, Zliin ~nd rrcuch S.A. MexIco, 3)2 L'exlco. The third source is believed to bo a cl~ndoatine m,sufacturln'r creratica lecated in the area of Laja, California, ~cpublic of 3)exico. An overall plan was devele~ed to in'nobtlire these sources and R. .1. Strasenbur~rh was selected for the first phase of this plan. Strssnhtr~ was s~lccted for the fol1c.wIn~ reasons: 1) this is a denestic firm with diract control over their subsidiary in ?.e::ico, 2) the tin is regis- terod with E~T3) to espart cantrollod su~:tancca and docs export to their Mexican piRat the anmhetnmine powder used to prodi:cc their anchetanine product, i3ifet~ntha, which has bean pnpoarin~ in aignificnnt quantities in the do~te~tic illicit traffic, and 3) their proJuct, Bifetnatina, is the drw~ of choice amoag a substantial number of abusers in the southeastern and soutbweatern sections of the United States. During Novc,ber W71 a ~tnbt1e Tatak Force was formed to operate in the 7) ~llas, Penver, Z~aw Orleans, fliani and Detroit ilegions to develop further intelligence on the st:cttxYS-fl CC~71~23C2 PAGENO="0728" 15158 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY c:t21rns-m CC~FIDENCE -2- patterns of ~n'tgling nrd traffic involving Bifetanino. The Tas'c Force is also oc~~rnti!,~ in conjunction with the respOn- siblo F.cr~iOrS to c~'vo1on cauos ?gaia4t per5ona involved in this traffic. The re~ulcant ca5cs aud intelligence ~vill be used in support of zia.ittlen to ~ay the re-reglutratien of a. 3. Strasen~urg 053 rn e~~orter of controlled substances. The t.r:~c dnto for cc~1~tir1 of this T~'~ Force pro~cct is January 15, 1972, at whtch time an order to Show Cause will be is~ued. Tho firo's present registration expires on February 29, 1972. Investigation to date has documented approximately five hundred thousand co3aw units of Strasonburg'S Mexican encapsulated Bifetarnina in the domestic illicit traffic. Upon completion of the 1omestic investigation, our Mexico City Office has been instructod to work closely with the Govorrnaent of Uexico in taking action against the points of diversion in Mexico, principally drug stores along the border who cre illegally selling in ~vho1enale quantity. s:r:~3ITx77~-I:t ccTxiy:;ct. PAGENO="0729" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15159 U'-. ArOrc;) C. Tarta~!k1,~o rc~p~ity Dirccto~ fcr fl1~cn'ttLons Kr~m~th A * flcrrira A~s~ :trrnt Dh,ector £o: The overall objecLivc~ of tiij~ro,cvat.toI1 \pa.3 to_c1ocu:~Cnt~tQ_ ~ ~Ts 7~eUDiU in the divc,r~;ion ~oi ~ tbc. u~titcci Statci. 13~oru ~&et1on could ho teken to ci Taieatu thie divcR5siOfl 1X3 !C:e~, ty,o iaetc,r~i !:oci to be dctcna1'~ci, Ci) wii~i2Or the djv.~x :~jw1 ;:as occ~irrigc; freA Conas~:iC or ~or~i~fl sc~:eo5 ~tid, (2) the J c:vc,i or extci?~ oZ dIversion. Pa jntelli:0s00 surycy rovioti of ~iX just ~ ~,a~'re t:ois psrticn1~r Coo: ~t £uo~' of ~a:miu \;aa jcro~~i to Livo r:-~)cr~d in ~bo illicit tvztiTic. ~Ahisinc2t~od :::.DJ C02o:-, i~aificoiit Cl1OtC'r~3 ure: no C procxascs C a! sei:~urcs reoerted to Ei a5 toe; D~vti~io;~ for ane);sJ.o by state end locel euthoritit:~. At U' oo;:1o titnj a roqacot tas sent to 7io~si'n ~2 to ob~a1aa frc:~ thc GtrnrscnV.~r~h Ircoeviption Ps'ofuotca Divthioii, flocI~cs tot', Now j:2o;-nt~t1oe relative to or~autzat5.onal stroctuoc , a.tethodo 02 000CUCt:LOXi and sh3~,acut. of 1~ul~t and uinishcd orocicets, locatIons c'f fc,L01g11 facilities, c)~foronco in Lovouletlon oZ Y!i'otrrtinaCao~'d lii the !Y. r,. ccoporc~ te that proCucecl outsIde the U. U., etc. Aertlyzat!on of dc intelligenco i,ifor rat:ic.i coliretod sho,ed the fo].ioid-ng: (a) All tnlir anphotan:i `ic renth pcdr!ev fo:c niphetemino ttari producoC n t Stro enburgLi ` n ~Pci lit1 at ;:oehnstcr , New Yoth. (U) The fin had subsidiary faciliidco ou:dc the U. S. that c,c,ro receiving this hill: j~o;:T'r for encat:sulatJ.Jis at their i'~o;~~ectivo boat ion~ , (Coluchi a, Lane Ca, /. cnt)Sfl, P~;n~, ned the :to,uhlic of dox:iCo) froa thIs loed.~tc'u. PAGENO="0730" 15160 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - (c) Tue fir4 h~id ~hIp~,c~* ap o~i~atoIy 030 ki!or~, or cr:phct:rdno fos~n c~i~c, J;:uary 1J70, (enoulh to 1~rchiea ~::,opo,cco c~s~c ti.nIts of fl1phetan~ino) to th~ subsidiary in LL~xico City, Lexico. (C) That there \vnre d1~t±nct ~iffercs~ce~ in filled vei.;htc;, cnp~u3o u~rhin~s, etc. * bet~:oeii Biplicta- nIne prc~ucod :Cor ec~cGtic dif. triiution U; the plant in floc:~cster, 2~t' Icr!: ,aid Dhfc*ta~Ina produced by the cuh~1 di~ry firrt L7.horatoricn do Cts~ah:rzh ,~-.~;;ico City, Mccico. Ce) M~iny dtd~~o vt.tts ivhich hnd Utca ~;cizcd by nu-. thoritic:n ~~ore In eri:i~11 on ita~.ncrs indicating production by thc, flni Li hoxiec. City. (1) Flovy p~tLcrnn of itiI~it GintriLutlon th~~hou~ the .iot ~.;c~iThiid .~`JJL ~tcn~JdLt~:a Z~ates sheyed ~ThTscYeflji~into h~ c~7crai Locntionr3 alci~ the U3/1iczieo borccr. (g) Iliis pr~et hnd hcreo:~o the drZZJ Of ChoIce in the flTTixoijrc~'~nci , Th3 jfl ~t rd ~ .-,~ 4 (h) ¶Ch(' tern `Pit~ck :!oili~:;,""i3lack )~eutic;j 11r!° `" and ``iti:~c~h ~dots" yore cc~1!1oa strec t tenw for t1~. prcdi~ct, ~nd ovc~r 173,C~) des:~c, u;iits of Blfota-tn h.td bccri pi~rcha;~cd md seirod bcttecLt April 3, .1071, and Cctc~:ir i, t~7i. ino rhot'c £~\etor~ c!c~ct:ciy poj.ntcet! out a ~;1tun~ ~2hcro a Ii. ~. LV ~ ~ ~r..sJThi1j1±c1 ~ cc,uTcecd a1on~c ti;iii'G7Tealco border and ~ the f:nuthern portion J~e_jQ3~t~cF It \vaO decided at thIs tIne to t~hcaTnzh Force eporoach to the problc.n. The ohjcctiveo of th~ Tanh rorce ivero: (a) To docv:trnt fnily a; rec::!blc the extent of diver- sion of ::et~,~im~ by a e- ep.trntel pre~r?r~ of prc1~n:ez.ani Eciyurcs o.C oviC~;::o. PAGENO="0731" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15161 Ct;) To C~;r,~!~ t:~ iet;?f~; 0! EXtfl~jtjy~t 1O~i of thO jJZCC~U3~ \;~ ~.hin Lac* U~i:. n 3~E~t2:3, ~t~(I (c) To ~t~entiZv ~ :r~c~~ ~*rir~ lo.i:i~.o~~; r"c t C - I 7 )s1( of M2r;icn fea- i1lici~ c!i~tri5.~i~a:t J~.tcc1 2r~ca. ~haT:s!. ro~re, t;.~ichc.~stctcOe2 t:' E::c~t~~EsitedT 10 to 15 n;c~tc !~ o flosic;fl C, C z~i~U IC;. o~: ;TcJ-tt_~ brt~ai~ bc,ca-ic, o~,cun.tionnl ~ I:e~ho~ C, IEY:i. `/1 orccr divicIe~ ~o to Ic, chic t~ cpci~t~, ~r.j~';c;':!t ~~ru~h$c~1 ~o~at±ots si:u1tcrcc~'s). ~ a~2~.3 lCC2tiClt of the l'oa'ce \?Cre ri): fC); * :i~:t~, fitirTita, &:q;ia, t~i El `aso, Tca:c~. , t'i~la Y::.': c~ I );n~ iocctc;.i in ~~aii~;, Tc~:::~a. Tc: ?; :.::`.>tzx. alct~ i:cLe!.~r, - C~I ~ 1.1 n:oa rhc.'o the activit: I t~;:~t~j~ ~Ioc3. a c-:o~irccs. utin t!rc, :~~1~icd c,Z Ec~v~:,C;~ S, ~ t~TcJva.:~ 5., l072~ (the L rcJn~t:~o:i (Ito o Iho h;~at. ~2 tIc o;c,ratio:i) `~.,o 1cjf~ _.`CC''_Ct . C1 Di )t' (_~t d £~ ~:ei:r p ~c: cji~ or ~c:~d. Thcna `:;;E~ t';;e~~ty-±2vI C:ICCi i;s~ti:tcd :n'z'; this ptrtod t;hieh ic,iul~.c~ i.i SLO0~D/i (of ;hich ~7,0D ;;o:o rcc~.v~~r2 CE) ~XiiaC01tic:~, thr~c, crc ~~;nt:~ fe:' 10 (of':~ts. A tC,tr1 L';::ce:31 of t:i:cr~ t'ithi:-t thc tion t~ttrchcd to t~a1s rcEz'rt. - I:,t~cs of Illicit cJ1z~t:iLution tc tr~'cId to F-.~,t1oj~l courc:a ct Li ~ nnd E2tiic;:,, Te::as, L~s l;cEiCu. !.lL~o an acrha,na,:;cl t;:c' nou~'ccc Ia the fl;p;;hl~ c of LE-~-ico t'cre iccntftficj. ~uhEcq~:Dnt to the conplction of the Te:atz iorcc r2:zt~c of the oporatic;n a r:z,c- tiiaj t,nc held \1~t7s tIc, D~'-'ihr tt~:c'~ec-y C-n~oi'al lrnncn i:ochC;j~ez o1 thc E~ibtic of 2Ec~ice in vi'~c:h the tion ¶.1a o:;:It~:in~ to )tir~ it, dctail. fl~.ct~' floc!r5Eitez Plc~:cci tho)LlL.~ 0t.cltbn 4~tC3~_ ~ ~j ii) in the ctin1:actie~ of this prohlca. Tic, Attorac, C ~rnirs office hera moo crinounced ~hct laho:'a- torica Utrzt~j~hua'~ia do Eca:ico till no lon~o~ to rti1os~o~ to prc~~rco e:~;Lactanincn. - On Jr.m~cx-y 13, 2072, cn cr~or to c,ho: cct.t~-~ thy the license to c::'acrt cat act ti'5; oi:c'.t] cot Ic, ac:vc,I:a-d :o~1 the 1c~72 produeLlon c:uota £t:cQ t:dea E~oc of the L~tro3lo.d PAGENO="0732" 15162 COMPETITIVE PROBLEMS fl~ T~ DRUG INDUSTRY S't~strmccs Act should not be reOucc-d by the anount previously allocated for caport pnr;csos van served on the Str~scnhurgh Prescription Products ~iivi.~;1on of the Poenwait Corjeeatien. On January 25, 1972, the Peatnalt corporation requested that their expert license be attended to Cejote the cxport~t±on o~ anpheteuinca. The fIrs a~zo rcqu~stcd that their 1fl72 pro- duction esota be rcduaed hy the anount ~flsct.tcd for export purposes. T3NDJ) accepted this reT~ost. This reduction \vill cause a rcduotion of 10~, of the overall 1972 anphctanine production quota. At the present tine a 2oi~'t Strike rorco consistIng of flrDD agents fron Regions 11 and 15 ned Mesica,.i Federal ogonto is being nsscr~bleC. This [tniho Force v;±hl concentrate its e~forts on olininating sources along the U3/~axico border which ~vero identified as scvurcc,s of il]ic~tt drugs during Operation i3tachJaek. The 9trit:e Force till be utIlizing ifl~ foruants developed during Operation fl!ac-hjack. Tiic payrc~nt of i;d'or7rnts as wall as pert~al funding o. o~~erationai costs will also be taken from funLo allocated to the operation. iThen this final phase of the oporrrt iOfl is coanleteci action will have been taken naainet the fir~to inpochuster, Nov `~crk, and Uo:-dco City, L~cz±co, to well to ngI~rm:t illicit ~istri;.'u- tion in bath the Unitc:ii Stats: and ~o;zico. results of these actarns will clininate a sa~n source o~ dangunous drugs in the illicit traffIc in the United Etutes. To date, a total of $31,000 has been enpended in the operotion for P7/mi. Operational conto to date e::cuat to $40,000. The anticipatcd cost of the partIal lundint the Striho Force Is ~7,5C0. The total of those three f)f;uwc-o areou:;it to $103,520 _4.~t. 4 ~ (fl rrfl ~ ~ - operation. Attachnent PAGENO="0733" C7'tVfTTCCT ~JJ~CTrJAC~ AprU i~ 1071 1~ovc~t~cf 3~ 1371 to to 2 2ifctc~!ia ~izcd (Dcc~::o Ux~tr;) 551,032 7~i,C~7 !3I~o~szint trtL~z~J (~oja~Q tThits) 3!1,OM ~o3,z41 200,24: C~? !~c.v~r~cd 7,0CC .7,0CC * 25 ~ 24 24 Ctti~ Zru~a t,1 teroin £3 Cocair.Q 2C Other Attpttz~iu~ 103,C02 103,602 ~flci) jr ibs, 1.5 1b3. ltcbiturt.tos 7,153 7,133 23 CC -a C) to b~i .~rreatc-j PAGENO="0734" 15164 COMPETITIVE PROBLEMS IN THE DRUG iNDUSTRY UNITED STATES DEPARTMENT OF JUSTICE BUREAU OF NARCOTICS AND DANGEROUS DRUGS ~. WASHINGTON. D.C. 20537 & 0~ IN TIlE MATTER OF Strasenburgh Proscription Products Division of Penawalt Corporation 755 Jefferson Road Rochester, New York ORDER TO SHOW CAUSE Pursuant to section 1003 of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (21 U.S.C. 953), NOTICE is hereby given to affon~ you an opportunity to Show Cause ac to why the flurcau of Narcotics and Dangerous Drugs should not deny your application, dated December 27, 1071, for a Certificate nf Registration to export aeighetaiaiiie, its Sn ts, optical isomers and salts ~ Hg op~;ica1 isomers and rcsi~ complexes of amphetamine and dcxtroar.phctamine (ho r'oC fter "schedule II , 1100'') and as to why I ho 1072 production quota for Schedule II, 1)00 tixod under Section 306 of the Comprehcns iwo Drug Abuse Proven H on aid Control Act or 1071) (21 U.S.C. Si C) should not be reduced by the ameun now allocated by you lot export purposes, for the reason that the Director of the Bureau of Narcotics and Dangerous Drugs (hereafter "Director") is unable PAGENO="0735" COMPETITIVE PROBLEMS IN THE DRUG mDUSTRY 15165 -2- to determine that your application for registration to export Schedule II, 1100 is consistent with the public interest. More particularly, the Director in applying the factors of Section 303 (a) of the Comprehensive Drug Abuse Prevention and Control Act (21 U.S.C. 823(a)), notes that you have not maintained effective controls against diversion into other than legitimate medical, scientific, research, or industrial channels, of - Schedule II, 1100 shipped by you into the Republic of Mexico under authority granted under your prescn~_plipfl_ registration (No. PS 0003183). The Director further notes that information has been furnished to him indicating: 1. That Schedule II, 1100 is shipped by you to - Laboratorios Strascnhurgh do Mexico S.A. do C.V. (a subsidiary of Penawalt Corporation) at Mexico City, Mexico, where it is used in making an amphetamine product under the trade mane "Bifetamina"; 2. That a substantial percentage of this Bifctanina is then snuggled into the United States and is then sold illegally ln the United States. For example: PAGENO="0736" 15166 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -3- (a) On November 5, 1971, special Agents of the Bureau of Narcotics and Dangerous Drugs arrested two individuals at Atlanta, Georgia, and seized 20,000 dosage units of Difetamina in the original bottles; (b) On November 13, 1971, special Agents of the Bureau of Narcotics and Dangerous Drugs arrested two individuals at Glendale, Kentucky, and seized 40,000 dosage units of Bifetamina in the original bottles; on November 14, 1971, a third individual was arrested in conneeti)n with this case; (c) On December 10, 1971, special Agents of the Bureau of Narcotics and Dangerous Drugs arrested two individuals at lrattiesburg, Mississippi, and seized 72,000 dosa~e units of Bifetanina in the original bottles; (d) On December 16, 1971, special Agents of the Bureau of Nr.rcotics and Dangerous Drugs arrested two individuals at San Antonio, Texas, and seized 30,000 dosage units of Difetamina which were not in bottles used by Laboratorio~ Strasenhurgh do Mexico S.A. do on December 17, 1971, two additional individuals were arrested in connection with this case; PAGENO="0737" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15167 -4- Ce) On January 6, 1972, special Agents of the Bureau of Narcotics and Dangerous Drugs arrested an individual at Birmingham, Alabama, and seized 24,000 dosage units of Bifetamina in the original bottles; (f) On January 11, 1912, special Agents of the Bureau of Narcotics and Dangerous Drugs concluded investigations into two entirely unrelated cases. In one case, two individuals were arrested at El Paso, Texas, and 60,000 dosage units of Bifetamina in the original bottles were seized. Xn the other case, also at El Paso; Texas, one individual was arrested and 62,000 dosage units of Bifotamina in the original bottles were seized; (g) Beginning on November 8, 1971, and ending on January 15, 1972, a special BNDD project designated "Operation Blackjack" was in effect. Information developed by Special Agents assigned to Operation Blackjack indicates that Bifetamina enters the United States at six principal points along the Mexico-Texas border -- El Paso, Del Rio, Eagle Pass, Laredo, McAllen and Brownsville. Across the border from each of these Texas locations there exists in Mexico a "farmacia" from which the Bifetamina begins its journey into the 85-569 0 - 77 - 48 PAGENO="0738" 15170 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -7- to the Bureau of Narcotics and Dangerous Drugs, 1405 Eye Street, LW., Washington, D.C. 20537, Attention: Robert J. Rosthal, Deputy Chief Counsel. (Telephone: 202-382-3411) (John ~E. In~erso1l Dircotor, 8ure~Cu of Narchtics and Dangerous Drugs January 14, 1972 PAGENO="0739" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15171 ~flrpar1incni øj~ ~fu~Iice FOR IMMEDIATE RZLEASE January 27, 1972 The country's largest amphetamine products exporter, whose Mexican stimulant drug capsules have been showing up in large quantities in the illicit United States market, has decided nd to seek renewal of its export license, Attorney General John N. Mitchell announced today. Mr. Mitchell said the action will result in an additional 10% rollback In the 1972 amphetamine production qunta set by the U.S. Department of Justice. Mr. Mitchell said that the Strasenburgh Prescription Products Divisin of the Penawalt Corporation has agreed to withdraw its December 27, 1971, application to the Bureau of Narcotics and Dangerous Drugs (BNDD; for a license to continue extorting amphetamines. BNDD Director John E. Ingersoll said that the company's action came in response to an order to show cause which was served on the Strasenhurgh Division on January 18, 1972. The order, based on Information developed by a special BNDD investigative task force designated Operation Blackjack, showed that a substantial percentage of amphetamine exported to Mexico by Strasenburgh had been smuggled back into the Unfted States for illegal sale here. Mr. Ingersoll said that BNDD will move immediately to reduce tho 1972 prtulu~ lion quota for all U.S. manu racture rs. PAGENO="0740" 15172 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 2 On December 2. 1971. the Bureau proposed 5,870 kilograms of amphetamine as the total which could be produced in this country. This figure will now be reduced by 1,190 kilograms resulting in a new, lower total o14, 680 kilograms. The December 2 quota proposal represented a 40 per cent rollback from 1971 amphetamine production. Today's action means that the rollback will be increased to SO per cent of 1971 production. Mr. Ingersoll said that "since every objective sought by BNDD's order to show cause has now been achieved, the public hearing set for February 23, 1972, will he unnecessary." - The most recent report to stockholders by the Pennwalt Corporation shows approximately $8.3 million in sales of amphetamine for 1970. Of this amount, approximately $4 million resulted from amphetamine exports. Until today the Strasenburgh bulk amphetamine powder had been shipped to customers in Canada, Argentina, Peru, Colombia and Mexico. Dosage units of amphetamine have been shipped by the firm to Alaska, Puerto Rico, Panama, Guatemala, Nicaragua, Honduras, El Salvador, Ecuador, Uruguay, Chili, Belgium, Italy, Lebsnon, Switzerland, Guam, the Philippines, Dominican Republic, the Netherland Antilles and Hawaii. Pending applications for shipments from the firm's Rochester, New York, location to Switzerland, Italy and the Philippines amounting to almost two million dosage units hsvo been denied by the Bureau of Narcotics and Dangerous Drugs. -30-. PAGENO="0741" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15173 D~ .0 (Li. UNITED STATES COVERNMSNT DEPARTMENT OF JUSf{CE A~Iemorandum TO ; Mr. Kenneth A. Durrln DATE; ¶O~/ 2 igi~ Assistant Dir~ctoi**for Compliance /2 ____ C?!tt~~ (`(`-( FROM Larry Kç4ness, Chief Regulatory Enforcement Division suBJEcrr, Proposal for Development of Information to Enable Denial of B..!. Strasonburgh's Domestic Registration Reference is made to memorandum dated September 21, 1972, from Jerry N. Jenson, Associate Regional Director, New York, New York, to you requesting that a show cause order be issued to Strasenburgh Prescription Products, Rochester, New York for denial of re-registration as a Schedule II amphetamine manufacturer. Before issuance of this show cause order we should dIscuss' this situation in detail with Chief Counsel's Office. I think the basic approach we should take is to develop suffici~tt infornitT~iFtrsow thactrMlow Strasenburgh to continue in biiflii~js would not be in the best interest of the nub14c~ t~fl~i~te re-regtstr1TtThTtif?~Uon that fact as omoosed to denyiñ~fl-thrtpecxiic violation of CSA. The facts to be considered in developing this information are as follows: - 1) Operation Blackjack - All information obtained during this operation can be presented at the hearing to establish a backgroundthat the firm does not have adequate safeguards for distribution of amphetanines to foreign customers, 2) Quotas - The firm's amphetamine procurement quota fof1972-wzrz-ttTtrflnriW' my~~retrutu~eiaenqU~trto be the amount of a substance they may purchase within a given year. The firm has already produced and sold more than its procurement quota would permit for 1972. As of June 19, 1972, the firm had sold 541 kilos. and Dr. Head stated that he anticipated production and sales of 900 kilograms during 1972. Our interpretation is that the procurenent quota PAGENO="0742" 15174 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -2- is that amount needed for legitimate consumption during the year. Therefore, the firm is in effect Sn in that they do not care what is needed for legitimate ca ~1onu__wifliell *fi~tever the demand i~2~res_ 3) Security - Minor security violations were detected during the current audit. The firm has been advised in writing during previous audits that their security was inadequate but their security remains inadequate. 4) Statements before Rogers Committee - Shortly after Operation Blackjack Dr. Read appeared before Senator Rogers regarding the situation. Re made certain statements which were false. He stated that the firm voLmtarily closed their Mexican operation once the show cause order on their export registration was issued. jQ2~S~ bvjexican puthorities ijcttetthaithe._nn was in full operation when they entered the plant after the issuance of the show cause order arTW~CThe authorities ciosvathrptant as br. Head also stated to the Rogers Committee that the Strasenburg in Mexico City had no intention of producing bifetamina in Mexico again. However t I at Ion in Mexico show&SflatkMrfly tter the plant closing the firnflproached the Mexican Government requestii~~Th re-open thrjlmt. 5) Possibility of Be-exportation of bulk amphetamine from Argentina or other countries. All foreign exports are being obtained from the firm since 1970 and follow-ups in these countries may show re-exportation. 6) Setting up Mexican Operation to Subvert CSA - This fact will be hard to prove but we do have some possibilities. A history of the firm should show that for a number of years the firm in Rochester shipped bulk to Mexico to be encapsulated there. It will also show that as of the effective date of CSA they suddenly ceased this practice since the firm in Mexico was at that time able to completely nanufacture the product. It is also PAGENO="0743" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15175 -3- possible that interviews of fired employees, nanely Irwin Rahn and Mr. Fritzner could shed light on this situation. 7) Any written communications (cables, etc.) sent by the firm could be subpoenaed. This could show current transactions with foreign countries. 8) Review of Export Permits for the eriod mmediately prior to CSA Sc e U e II requirements for an hetamine shows that the firm was attempting - o ship large quantities of bi e amine ou 0 e Oountry. This was probably in anticipation of the quota system. - 9) Statement by Deputy Chief of Missions (DCM), U. S. Embassy, Mexico City. During Mr. Voyles recent visit to Mcxico he conferred unofficially with the DCM who stated that a Philadelphia banking official and a vice-president of Pennwalt were recently In Mexico City. The DCM had a neal with these individuals and they told the ~M that it would be good for U.S.-Mexican relations if the firm was allowed to go back in business in Mexico. We should attempt to get a written statenent from the ~M regarding these conversations. 10) The records of Senator Rogers hearings should be obtained to extract any pertinent information from then. it) An intelligence probe in accordance with N-GO should be conducted In the Regional and District Office cities to determine availability of the firm's products in the illicit market. 12) The firm's total distribution of anphetamines for the year just prior to the quota system and mowing of amphetamines into Schedule II should be compared to their total distribution during the year immediately after this to see if sales have increased or remained the same. Other major firms have noted 25% - 40" decr~a~g. uring he a er per o . We may be able to show t~n1~enurgrnRflyiserm~~vsrff and in effect canceieo the intcndcd purpose ofTff~ quota system. inese Ilgures shouid be conpar&~ tSI~~lcsselnuive y. PAGENO="0744" 15176 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY -4- 13) An audit of the fins Los Angeles distribution warehouse should be conducted to determine any possible diversion or security violations and also supply pot3ntial leads which could be investigated. 14) An operator of the illicit black amphetamine capsule and secobarbital laboratory in Mexico City was a former employee of Laboratorios Strasenburgh, Mexico City. We should determine the possibility of interviewing this individual relative to any knowledge he nay have regarding Strasenburgh's previous activities. 15) A complete print-out of the firms domestic distribution for a one year period should be obtained frcm the urn and analyzed relative to distribution patterns and leads which could be followed-up with audits and/or criminal investigations if indicated. 16) A recent Dunn and Bradstreet Statement should be obtained on the firm. 17) DIU Units in Texas and Michigan should be alerted and any intelligence obtained should be supplied to ENA. To prepare this case for the show cause hearing an Attorney from Chief Counsels Office should be assigned. Field personnel and ENA personnel will be available to assist the Attorney in obtaining the information necessary. If you agree with these recommendations a neeting will be arranged with Mr. Rosthal as soon as possible to implement the above and get their recommendations. PAGENO="0745" COMPETITWE PROBLEMS TN THE DRTJG INDUSTRY 15177 !lr. Fred',rlrl: !. r-rr±c,ld Assistant rirector IOV scientific Support ier:sth A. i~:rit ~* Assisttnt :i:-rctor for Corpliance St:'.: ~.tu. - ENA ha: rc.~cntly becca: cc. ~Lz:flt t:~~ product tesamin manufactured by R. .1. Strase~thur~h, Eocbester, New York, appearing in the illicit traffic. During Operation Blackjack a truckstop Owner in S lacara a ~uoa ``a un zl ted çuantit OS 0 .1 U sor Sa1-O S a n~ that it vas as ~oo as c amine, easier to ret hod èould ,;oll tahe the pf~EoofB±fetam~r tn a C. .i j~ as a so cen purchased by D~DD recently !ff7t~on 1. A lecal ,hntuclst acvi~ed that a t~i~" -, ~traconburzn a~V SO - U flU onanin would be replacin~ PT?iiaine as a ~,oi-ht ro~vction dn-. ~Thic ~,ta!lnan furf,er aunted tuat u~ibJ h-rn otitered in~E~eEent ~ffii~Th. j. Strasofltrf'h st±nulati,rt that if StrasC,-~-urr-" allo-xed ~±1otazine to be placed in Sc~ieduie II that ENDD roulu not placo lonarain uAd~Tttnt~uL. In view of the ahcta it ~p~ears that lonazin has the potential of bccoa~n; a drut of abure. ~?ould you please 1:000 me aclvtc.cd as to an7 ~nfcrnt~o: rh±ch tay co::a to your attention on lonanin appearing in the illicit traffic in any dosa~a form. .1'.?) - £NAE/OHendrix/ksp/4217/3914-72 cc: ENA Chron ENA Subject PAGENO="0746" 15178 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY P. 3225 f~derc1 (e3~3~er ArIa C440 202 flaea ~3-4a40 DEPARTMENT OF JUSTiCE Drug Eol,rceeeeo I Adininistro lion CONTROLLED SUBSTANCES IN SCHEDULES I AND II 0915 real Ag5regate Production Quotas BecLion 306 or the Comprehensive .`rao Abuse Praeiea !u'n and C000eoi Art 0970 2' U.s c. iobi reultIrt s the At- enter General to eviablisOt aggrerste ``roduction quotas foe nil roniroileol tint- Lances in Schedules I sod U roth year. his rrsesl.Iecillee rico von ol'.Oa:iilril 00 110 Adilioniob seoi 01 ito Lii il co;o,ce- ,irnt Adlaunit tnition eurstiitnt too Otto :0 Title 20 001st Coder I Federal RetaIn- inns. On December 19. 974, a notice of the ,ropoaed aggregate prodstctltct .eetqtaa or these aubstoutoces Was published in tote. 7naIeaL RELiant 29 FE 2411. All po arette d parlor., tee-ieinoited tocooisotritt 0 Or oio,ect to bite pi005edirttretate roust Lion qililtito thor Oriole Jilts- try `3. 0073 Ee~cept coitit relerenre to \tethylpheiiidntr. no requests tsr hoar- `oos hare been receloed by tire Admiels- `align relating to the pruli0100 glirtos. on,mnnta anti ehirceiriso rel.itltr to lie proposed ncoieoaie prod Itoh sins hare been receited train West- rio toter Lubqrstnries relative to `tienotetrorirt. ti-ens }tiilrotsn-La Recite 0. eels tire In Aielqaprndior. from Lilly sno Cotta to trio Live to `mobarbihat and Serortrb,iot. and -sm Rtchaittean-MrrtoIl inc. erlatiee that Ptiiinii 00 hits Ijeoosy ei.i,e,i,-ine clots allots tell l,ae rite Pt 0 dechon of o-Drrnsve olird!ipe for toe itt the tiufe.ctiireoi'niian-rooi rel2r,i sun. `Dcc. Sega-Ion actors eel alive In these `insrtents `iii be outi~nnd ha £ 144cc LatEOd. RactaTta notate. - Osie to Else tact thsata request roe a hearing hot teen received by Ste Ad- mintotritton nil. hrerercnre to the pro. pticd aggregate proctor lion quota fur Metoylotenjditte. the argreiate prober- lien quota for Methrlp isenidate does not appear In this order. Raced upon rer.o,deretlnn of Ite fac- tors net forth in 39 FR Oil, tIle Adnim- tar p0 the Drug Eniorrcinent Atminui tension, under rIse authority tea ted in the Attorney General tyIng- Lion 306 ei the Comprehrnsiee Drug .unttoa Prrnention and Coilliol At ol 1170 71 Lisp. gaol pod delrliard to tile AdmirstatratOr be 10 ItO to Title 20 to the Code of betienal Reosilietinlis orders that tot eaggreiate tarodhlcitoit qnttas iur I 075 our cn,otrelled susotittores, esprevuod In grams in Itrn7S or their resnec use *nhsdguaa babes, tao Estabiiahtd as bib Wa Rdeesrsa a Eiioieoi000l I-ti pita-are tpissrthitdtir - teteahpdeatinuoleutli oe..a.ee.an Ba3s dave-Coo Orates tare, t_tirpslat icon .alei 000.010 MoepOloeiioenaoin~i~l -. 43. 102.1010 020. Opium Iltaittlee.. eta e,00eeao in Wet. of - apiami l.(04.itle. (mao 10cc. lire ooiei Os00040e.ilae eshoselolant.. 7.tlai Oeriroepiitr.e . atoll rriiil3-oeoitul 0R,tta,01r. Pvliiloii,,e 17.057.ail victor 2.74l.7rJ ie,420.eal-' Tli,e'..aote il-ic noel 4.700.0- Ilt000ilie it-c tOtteitio,i -- 1.720.50.,? - 1750.100 teals. foe not prod ,eiiaa 01 to. etde.sonvepOeaetioe ion see trotted pe0000l, tog Ostntn lee peso cccvii Pursuant to Title Ii Code or 5°eder.sl Reguiatieaa. 50303 23e go the Aiiniieitu_ teatnr of rho Proof F.esrorceroent Aoeei,i- Cr00010 ivtroiiau 5th lilearir i97a edia,ar- hoot dioiaieaimoioolovtoriogeaalysaiicciivo for 0070 based upon 1074 rod no he reninry ligoren soomiitt d by uneSco 111 of noel ir el a no us len ii:r reqiilremer.tln an be provided by ole Food end tori.? Admlnlttrahion. A irvrveiou who niotositled an station- for 01011cr an inijis-oduai macafar- toeing quilts Or trot arement Stout icr 1010 till be noti fled hr mail Pa to thgi: reot)oroive 1170 ymca esoablielir d by the ionic Esiroerement Adalmotraitan. This order in elEilcUhe on January21. lola. Dated January IS. IbiS. Jolla R. Ri 03 Eat, 3 r.. Ad nile inlet tar, Drag Eofarcce.ie.if A Omiqiafrat on. ret Dae.?a-flM net a-17-tn.i:.a Aiehaeetdito Aeasooarb,eai Osisheinesiar Asilinitlite Apoitolyth'. - Coeqitc codn:oo toe aalet........... cod ritie toe ettiemios 0010,50eieteoelte P ii,7deee000tcio Dtpbesonylsee ers01000 H000000000e a000eoee,oe piloil. Motqedqiqe Mriha0000 bst.emedlsee 4. nones-a dleoOttni_tmtetn, 4.dipt.tet battle I Meted Albnanid. at Opines 14. 500 02. Ciba. 504 2.151. 300 -aa. baa a-coo tOO. QUO 40,27], 000 1,100.004 I. ~ 204 ale. on 44.000 a 000 ego. 0(0 70. 200 2 000 2.241-ito ago, too 19,000.135 000.231 01Oct55 ormntEi.. COt. 40. enD. I a..iooNooe. jaNlasy ao. bra PAGENO="0747" Co am Wa cnc, cD(D H C, 3(0 (A 3- CD (00 S CD (A) 0 C -I 0 ttJ I-, (0 0 z Co Mi 0~ a 3 a /7 Cl -*1 (0 PAGENO="0748" 15180 C01%IPETITIVE PROBLEMS IN THE DRUG INDUSTRY Central Tactical Unit Four by Douglas Chandler Supct~isnr CENTAC 4 Ut A Office 01 Enforcettseii EdUrs Nole, ff551. ills cppsry psi (`(Ni 45' .i. pcsif (`sip lips `puck 4, sir' irpip pip hauls. Spcu.ii ,`ipPPi ~ (`issuer Sr,psp' firi'pc'ipsp,rari',.i's' p' lisp' pp pkprf ,iL''rpI~' iiiuiclip'; ```jr/ii's lisp' jiirPiCAP is, his lilAc C psi','! Isp pp ii l./ppuc f's" pep', hi' sip', (,,,rfp,p, is, Pip,' spell! rips' PAGENO="0749" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15181 We JLJSI ditril line entiugli lien here Our pe-scinnel re'lng is Xbui we have only Y on corer lvotiinrc ire sicti king o s-eri,me now ciniply iii hanr lie hi pnohl -iii iii / Jtlis's the learli Iris Lilt In Pro sil1ieriinr noire, ii ri.citgni~e the genuine note cii anuiltig tIlerhIlitis siltiluly reluorlillir bLisiruess IS USLI al Ailiile hi'', note is pint rate iii nip, priilrscion ii p elhitrils is nil psI riPe,, iii iis~iPPn,sr* lii a iriippp,iI ol il ic-iginitirinlc the chtliciiiir,Iii,ir iiiIi~I I `p `ie1rarecl elite, lion dciii, ti hi' hil.rtuitii, slagesni air sslirrlrsvrll liii, rosa -rita' spiluuivi', tills, N none 55 elcomes a utran, it,, Anohlrerrtrti,ie nut so ollen heard by sulpeiltirs, ttttes stiroellirni; hike liii `here is PeeriLteil lii mu ttresti~'. I `urn IV, whir-lu ripe spout, to lhipitk isj big dcl Tlu,'viip,ilil 1p~ see our pollen 01 As ii ippriuihp sse runt,'; p.o-p ermori ill lit clii' The nd result's ihai lie `or-al rrith!enp is goi'ug Ii, hirrir p urInal (hianges `1 ii'liry 1 `tutu ii itt-n. Iirtltrii Ilpu' or' Luests ltpe assistance or lnlltiwpirt will prig clown svillr esaslieraling lrerliierlly lIre lit's! rich plan' rpi Ilit' lleadildrarlers still In, lIre big iilleratintisvp hIred ``I,,, ccl The d pstn,pk,p, ii, creases .15 lii' `spIn k ri'rlui ed ii tI iesrtiiatl I ui-encsl sc 11,0 u.n -ii `liii C sasllrpstic'.tttuiI The clptipi-tilppec .lrJs,npg hi",u Itiese ía, lit' thislanice sepiaraling r,ll'ces. and they lnicntiie 21 PAGENO="0750" 15182 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Ischetenrps',aotlisc-ri s,eiOi,'ge (,_rs.rcIci,pci~iscis C(samiler ,s-t,,sar'ccssh tr-e\al(ss.is.glscicsrsup crws,olflEAs\,,i nseenry,cr,,cc oil's,' iras,cg,esp karsd(ecari a it1 `its Lost cresicart dr a rhtiri c oral liii lie I would like to cnntni end Adminis- trator John R. Bartels, Jr. and Isis follow agents at D(A as well as the many state and local law enforce- in tnt agenctes in this country, Met- ro, and Canada, whose hard work and cooperation resutted in one of the most signi lie ant law enlor remiss endeavors in the history of our country. Senator Birth Barb Chairman, Subcommittee to tnsesi'gate Juvenile Detinquestry (Cong rescLLsrs a( teen rd, SepremlLer 12, 1 974( P ` - . t'j H ; ~ -~ - -- kc ``Cs - 5'_'cifl [1(1 c-LIicsIr,in ,sgr',rlsl s~FLiscc'' lcd', sire-c s.,\ s_cs,- .uls li-SILT iv,,, k cliltic . (is ``cmi C Ito Lois IV tic- (sigcit-i c_Icc'S thus tile Is,, cl ccr'nc-, iso lie sill-c rocisiLer. il's hess to,rcinal invecsis(al,ce cs,srk s(s-cccansl' .5 sic,',,. 55(5cc1 1:151' Inc l( s, ii i'll ,s-,cllcss-r el ciccsscisesc,cT!v rice crc hc.ccsrll.csgccrich'~c(e lIeu-rd ant uric ~,t,csrc sir coccus I en,c,sscji wr irs .11 re ilsc,r tnhiil) (en ilrL'c,ccc' tIn- lion' I_i tr(Lcs Is- 1550cc Ii err (sac, 1,1 loire. in Iris ,Lirlgcruc-rsr is I whirl' (s,:,(c (0 IrslTnsr. il,, isecI snort is done by dls,csen,slcc,cliilerint he dc-u-dive ol pcs,stcl,ir Icrinsci, makisrg icrl,uccicc' cin-igsri(cc,rirsiL-'irc'- . is,, rsicscecsscstserc trail a `qcsl Icn'lscsg asr.cllc.s ((iri-(ic cii, csczlst idea, hid `ely skinusssc-sl slit' ccc ocr-lcd lIsp cer,sssccscssr k. :5 rs-ric,scct,scs . ccsec!r_criic.cl I(C_iiildccri cii cfl,,'cti(i.i lIce 11cc he (ccl) set li,'rs, ic (cc ac,ric irk,' l's ((sick (lost -s clrar~s( ysvsssc (ec( r,risr,sc,scrc liii's's (re.stlciussd,-sc tsic'ci-ssicrks.irsccciiicriorn tip arrs'Ihisrg Icc. In pt-inning bun irnportantcnv,-ssig,itrs',n. will invcslve several cvicle(y cca(lecerl stc(rc(Ls'cvinns, it's' gocol rnan,i51iLr eannisi p11,1cc arry ii lssrc cic,rtslv hee,ccsss' cores sh cccl iv un-lecsrals(r clanpow or's has cU-cnspssncasidrcssscirceuctcal(y discusccd icr ,ii,iiliematit_ri term-. `mIss cccmplis arid ISV f:p scsrpssrrc(eo.isIsc ii cccics-rcc e ,ciiire. The- ms-s placois-r diii,, Id,1 `iesi,sins- cs cli,' - cdicLcc(_ Tic blow sidci ( cili5il(5cc5~ Cr ``req curer I siibdivi'_rsrn ic's ((Sc (I cmv ter,sri,c (c'sic (I (I' isssiniiu&'ohcccrss a ``liii are!1 ci' cola Tics ,sri,sdiliinis ((hi- cc riecv sqicr ,i(idln ()~ies lb s- ctciceccrosrt Linc Ic-ictanul Sirs isriscrc bc-v P his trrne car, heclt'vccied is, Isp era I is Sn ~`cIccc shno(i( Sue in charge cii he ``coral! rrprradcussit If not clue (iai(icu'ca scs1ierciscc(, (hp's' wIred is (In role, and what is his relaliccrschi(c Is, cite lisle Lrcclracg& PAGENO="0751" COMPETITIVE PROBLEMS IN THE DRUG rNDUSTRY 15183 TI itit-iririsir lr'rt iiiitrsssill apply ri argo ulirl ci rrririiiii-iarts-rir1-ogr.i1tlirr-aIly. II re neg .0 e c'lii'ctsgriisv hr irs5 rhiriririr It, IF ii' sr,,'ii I tIre triatfil as well. A `hiatt rstitiiertt.t,artrn,'nt, where everyone <`hines hiserysirit. else `IruuI'l h_tsr trnn aerilrlem al all. Ntany larger departments base lreadc1u,ri cr5 detective stall which call cross ini'rrnct litres at will to pitrsueacace. travel wititin a errs is tliereFoteeotacon',ictr-ration this ihnay seirhi ii. lii' hr p'lli'cltoiLil-rem ice 11171. line groups seni it tr-ic r-iuiiriern tin liar'' I II.! torn Fitting Ntmng via Paris iii Aintci,'eii,mtnt. (`in inn a ry 21, 1974, a scmztire ii of A si.nninog ill in k utrininenvan nn.nuie ai (~IIv, ~rliitmt I. `trim I) iiiuil:i nit' litn1ni'riuiuit `I! Ii I c' ,tm,'i,!n,ir mIll ns'-i'ii' tluiu,in-i'r,'m i. `ci- dt'intiy io imnllninit ad clot tin iiy to i,icate lit ec'en p mimI is ii Nut I t,ero,n nsinich liii! lti','tn ni'creied Is l!,r'ncmiicace's lilting. T.isitcrrt,nier', `sort' arueslc'u!. (),ie,nf i!ni',nI h,tti pie- vii,uclysini I `it N, irway, i) t'nnrnar k. arid Aminsterdam. the pit-cia! p,,tnt `al thin traffic. Since I u!y 11172 fit ro,nt' an notice dint1 customs euuuctaln base arrestc'u 6] Cininnest' mt flit ken anne1 `el/cd final 01 1711 pouitm!s ni Asian h ermnin - ccv years heroin ariuilcuin,n inns i ncreanert in tto pit ncuinat ci! ies ot Net !nerianiric, Fraince, Gent, - ``iv, aol! Italy. As N mw York its rink i nm'elt line urInals diitni!m,i `iii) cn''riee (inn I reroin hire. A irish- has h er-lrn'.e lbe oral Inc mt lilt mm traiimccn- tnic!n iitcrs far hIs int'etn ide' quatclv coin tinner! w,i!nnin F cptcmpe in tin ecrlint ing tlnrrntins DEA unit icreign officials cs-ill cinnti ntii' Inn anti! yresources "sIr ike at him trait ii or cotniain ii at a leo'i n-herr' it lnlisi will 0''! ut' chic 1° cilreari:r'' wardi Nrnrt!n America- oicg(tnmnimrm,,nn cni.,iI,.nnins ta PAGENO="0761" COMPETITIVE PROBLEMS 1K TilE DRUG INDUSTRY 15193 Narcotics in the Mail Stream liv Willian, I. Collur Chiel Potlal liispeclr.r Li. S. Posl~l Service liii' liiifli'ilifll ç,,*( li1~nt'r'tlitriil;f' iiritdjtlioii itl lirillil', liii C' I an h;sl,nxr err. Nil(riiIiJlic ``rely Jelled Willileil lIit'cnriJi'i,iri't'qiiiil p1(11/000 `tic !dIt'flIltneItIL',tl ~A flrt'n iS. Diii,,' I, rrei'rr'ril .`i/iirr,,r'lr,rlrt',ro,,.. V V esralrli..lreclrrn bin, 1)7.1, iii srle:i'; `nina Int'l', ~el II,, Little ai,'ar,i' I 111111 flricelii..Iraii;, in lii, Ii uric I Slale... I/ore, or liii' ti'. `I i*tiri',iilit Ia utah, Iv, - ``h',Illil,i,,~Ii'; I lii ill ilIfl,I'iiii) ,i'ii Ii'r ii It'll'; li'i,il cirlI'4 li,riIitLili;l I A, wirl, oilier slgrrieriit rl ii.,. lire `rural lru..;,i'vlii;ii Si',, lie apiul.iriclecI Ihe Cre,;li.,o Di DEr\ irlr;elillrliarl'cil,all,lir Ii,,'. holy.. xcii aIiiiipi'r,l ph i..ecule Lu err lai;,it'.,..v'tlirii ii i,'rr ,;i..Ir ur,u'i_'r.lr g,rlivc li;nc;livlir,n A/il otto/i ho yeatl i' uteri ii'. iii 0 .liCr./ r~ `liii I tl,tr~~ ciii'. ff111 St.'' I iIr',''.i,r, 1111.11.. 111,1. ill 0111'. ii.', `:p;u'uiralb pc',;.', li/clip.. are ,`.rr,,iir', her.. Tlri.ilependr.rrle,inclrL,hrs lie uirr:Li,ircI;'ci SIne Ii,'.., c''~iei i,illy ii, lair prIori riiii.l',, 11,1 I. iri~i' Iloll rc'liiirrprl ali,i ppiiitiu lii.. irk/ri lii, hi 11,1 l,ii;lrec I, `in,1 i,,ii,c~ liii, I', ii ,;`.,u,ti, it ill'1' liar ..Irorl finn. p1111 `rh,1 pI,iriu~r'vnrcr.. rltiro in','.. lois in. riced lnrrrui'iur I ``rid; - S inn' nor' iii II ii' `ii,,; I.. ri nirllarviul ci liuili'is,il-,'. i),irr, (rri(iiIl',iil'i,I.ti'.-irlrer PAGENO="0762" -P.., mover') to iltr' 051,11 Inspection Service, wi have cooperated with other IecI,'ral and local .i,,ttrotplt in ii tI rote ,-rli,rls ii' c,,ni hat IF p peril dons prohietri of t-,rFiic tn drugs. In tIre lasI, willi ike liii' rouliri,'i eFi'rs.ils cii itiIeIl,,reriie to other ,igeJr' id-s havEn,: nun,' ``plicil `iatuio,v iesi,insn Irilicy iii (sir I o,c,'s,onal case t,'Irrrr the `flails well' the cirtigs. Itui during lie lasi li'sr' eats, when lire flow ilrisi'inuntryr,'ar'liedl floocitlilt' ,ri,rr'inrtsi,icreasecl prolitoiiirialely. ~V,lee'c tIne tad ira! ri I'ihicseinv,'st'g,ltetl 42 chug c,tses-i,i,oht,nlr,,rah,,,,rsn,iir otii,'ratn'n,ies and macIc out,' (rh arrests in p,us:,tl-relalecl dive' hly contrail, ,n lie last iroal year, ``Fir n,tr,oiics ,,`eslrgatrons totaled 3,201. res,,!t,ng in 92 arrests arrrl B4't,',,,in'iel,on. this ii,.rrpar,urnirc'11r,'cernr'aidrilrt'rrr htr,,s increase in Ii,' P bLurs 55 Inn I tutu niispi'i'lots us,,' `los-in,', 1k) l,'trh.ipps;ln ti' .11 `0101 IIL'a tint' lie rr,ihlent its Ireconi,- in ott,' society tOday. I st-tnt lii tiLe f rrn,'iIs' Ii' nil nit' I rio,' it iii `intl,, 11)11 Ii'' `Lit ais,,,,ro1n,'r .1 k'~0't Flu `it! ii')''', hi-rat law i'lilord'eIiieli ,hrrni es in,., Fruit, F ,`-idiianc'' ri mint on.nijo,t and ftuirarirvlL,,'s (`tI huh, il ~i'i' pitniip tIe_i leniririr's' ill n,'enn,ni,,',in'niri I p04 nt, ``rain rf(eclr'ralsia rut,'' lIre iirsi'si,val,itri arid aptnrehens'ooof trig erihtii"r ,nga,rish tIre Prislal 5001cc. TIns activity oc,,',,Fries over (41 our time. ins,, d,rlat,i,l,,i,lsVi,nin ii.; 2.11 te rrr,iL'ili''ri o I itad, ins I_ti F ilIril' ill, II rim gin a `vu! (`t,ir,i'Lv iii plus sri it `t'cIFuIh,' l,r,,r,n, nuts ancltliepnri'sr,n,ei,iaintit,i,,,,i'L FSI',iri,tF' Finn,'. .1. lIt,' `mIcro ,iF a,,nlnr ri all i'c,s ti Si's,' cc' f,ri.,ur, inl Simm urn' ~p~, is',,, uI,',uFali',I it iii' ,,`,`,r' ,,`Int `Irk' thin Fin, ,,o'i-'or,ii-i'i ,tni', ks a' `rn,' ,ri.,FF,'l.iir'sv.hliss.'c 11.11 t Srqrp. slit 0 CPa l9"ll Esirlence tisat the defenrtan I had SI gfassine hackers con sitting 32 grants cit herrsrn, i liar be was nut a riser of her,sin, that ihe hetcsio was packaged in tile m aibner csincsoonly used in Icc' illegal `crept disitihrrtirs,c of drugs and that he was armed was uu foci ent 0 esiahi icli lseyond a reacrsna bIn buIlt lila t lice defenria ct intended 10 ist rihu Ix the heroin in his plassession. 39 85-569 0 - 77 - so PAGENO="0768" 51200 CO3~ETITIVE PROBLEMS IN TIlE DRUG INDUSTRY What Makes Kenneth Run? - -. - - ViIrerp Keirrrptir Cappr'tt is_is 14 years old he cprpiie lii Deirini svitlp wild cIvic liii ways ct pital~e _i jr-_I Uric k april a yell (or Unty ran. In lips ii hpippl years Ire nariagp'rl -p `iring dli pnsltt.i ti-s alIrtig lire harc itral line (ass Ctiprjtlptr a lyIrilal piiii er-city area pp hal tilt-i I liv lltiice ciii l.a, Iprirci incnntp, and at ni1thii ry mm drinks gprrilrli-rs_ Tire Ccviii .rc iva' Cirpe II, is pe Ii ~iaie and over tip- tear' up- ki-1ip it ic a lip'e of rip.ratir,ns itttrilri iii? icing ir.1orc lie niriveil I.. a iris- `Pry *itsalirrtc-nt lit - pIp ipIrIrir-Init trIp' riacrrl-p clritilpi ripipi I R p-liiitii-t liv. ire a liaiikriill cr1 Slylini by irtckiiry a cliii lois- \Viiirrn len `-c-pr' or iii-. It, aIIi-rrr-ii In rare rid Iii sips,, Ii P'rprtpi pti-tptIttrttipn nit grInding Sir rlrillirpri 1 %l.al~ Tin' I) nit Lid pii-rp-ttn cr11 Api cliii'- Piri-_Itriectipt ,itipi,p pill.. (i.prri- Its - ppiictliv-_ `chip ii I pi-t~ppp it. `c-ppp~ lip-I p-spelt, liii it icprptgtp ii piioii ti's nfilrl All ICings coilca I rip lii vca' a lipckv year bin Canrcln_ `VIII. c-tlelsitriiilciiiypn-_ipilenI a \Ve-rt- ern-ci~ln ~liipppInlil ccrili Iellrtn- Iraf- ii,iii-r' tt ru. a tiaptirri-url ncr Ppiis~ - cirpice ililve in Siputlrlip-Ipi R rtuurnriir g lip Pr k pup supinre p hIpPies -i pci pr liii- `p, I iil~p-l ipu ruin-ru lrc-rpiirr_ .iru.prdiip g Ipi ui- lIiiii7Ptire nviirlrls_ tic-wa- larryirrit Siat!nrl in cash. A ciii irnrpwaitirig Inc Ituin Ii. epic-rye (ruin lire cic-v.ric,p. Diii ire cipriitt-cl cu c-ilk Pipe `lain'- Iii lire linre llrey liii.. lie It-nI lid lull -P null. 11-clip, I II pipcvrtiri aninirnpu alir NVl,v-n iii' apietrts arrivpri piji lire sIc-tIp lIrc-y cntppstrcl 14 1)1111,-I liiptt-s ti tire isa11' aflil ninny ri hue haD- N ii-arpir liii i-a' eaeuh carrun I I ti~i-ii i~(l~tiliC( I lii Dr A - nhinr-rs iic-rpiiiiairil irane' rn inprppnnl ill iil.istiv lag' nfl lire iPrefliPres iiipl lpncep evidence is-a' ncp-plr-ri Carp-it in. up er.p Ii- not nil -i tip in rite Ca', C (urn lipir. hap N c-cs-i' I ii' Mliii Ill `i iii Pr-ioin-.tp p rlnpill alrly 2 rip-ri ciii frLIip~--ipir $11141 In darpa, nippon iii pipanhp' cleinverie~ crib pllic,uu;-_ll Iris Irprrpipissas raIn l.i'pri'ilipi ire.ir-sr_rii-pI ipip,'.. .1111 `i ruararl lee liii- drug' if a rca' Irnipiren ipr ii rn- Ca' I third piP N nip-iiilrl-i 27 rite Ipnai ncniintlpipr lick rlare. in pile Ibcl Prig Din. Caop-pI. now 25 his liripliter is'rippalrl_ 24 his np Ui-up- I (ic-ui (iuu',uvis_ 4 lisp. kuuprnini n_it111 ii) pIt a,pd i-mini pill Si c-Pd' ,muie'uiti_ l~iA agulpis `I haif-pnpind rn hinnin. lscrp riiiiaes of cptuaiple_ sir ittiirs_ SIDE plp~tiarc in rash aprrl lIter ci Cae- inldresdiclnc___irvn 1973 (ui pities unit i 1 1174 M erpaudes-il ,,r~ - [Ire round lii. av rnrrin it g ii, I )EA Repicinial D,rrrrplpir Tirpnriilre t Ver i Ike ic_arts-pin I. pul li--lilt I hipai agrirlirs: (IS Di~raitripp-iri,pl inspire Sinike Force At In tnt_v tjiijcentie U i_en; pill. is. Tle_rqlrys hIll-all III All rpinn,l. Tri- ll, irliP .rnpl I icl~plrrti' - lip inntihhiste.rrc P ni.psipipr pt lire Mu ipigan lli'irii lIter cr1 it evPnppl'; .InI I) p-troll Prihir-i' i)ip_rtmeiit Hank Drip il epi IPpi in-p ii-ip t_ pipp pp a- - liii. I Illir - iru~irP PAGENO="0769" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15201 lii~i~iIl,'iIiin,lii 111.0 kIl!IIieiiIIaIIe l,,k,i ~ c-kr, For Distinguished Service L5~ `1': -` 1 ~ ,,,i' amen P. HuM, Assinlani fbi or ``1 he New 0",ik Regional OIi're xi he )lLlg f,,iiorcerxx,',,, ArIn,in,nl,,iiion was recenhly awarded one of lie txighi'ni ill hr 11.5- l)i'par minI., I nice ---i he Al lorney General's Aw,i I I) `li,xgu'nliecl S ern'iri' llierrleranrrjrxi,,,al irivi'xlig.-,t,xr sylin lots lion' luau 23 y'','rsu,t enlein leder,xldrug lass' enl',rrenxcnl in'annnlninal,',l or the award an 01 ``lcaclershipnvl,irh has inclairech Inn division (a riiliale an t'olr,ioriipnan' number of high-level r,is~," In an award u_crenxnhlv (In Deremln'r 12 Aclnxjniclraior R,irlrlc r,o'rt tic linitsacresponsuhf.' for hi' arreor iii ionic major viiilatoeu lxiii any r,lher (lIn~liiili'n liii' Crilire Ditig fniilrieilil'nlAzlm,r,inl,n,ui,n (iii he game day anuinlxer iii I,llui'u'n'eie'verl lie PEA Anarul iii Auiini,g hem u-ac k'u'geht,i Cii'i'raia, Sperual A,'rnl (`I'm lie Ii's Au,~elen Regional Office, wI `o svac arnl,us lied hxy 20 Mexican Ira flickers and soot ),acly wounded while on duty wilh "Operation SEAM," a oct LJ.S'Mexir,,n lack force In conl, of rho l,anchnrder drug Ira iiic. lShonlly alter Chrici man, Gueva nt relived a Los Angeles hospilal for surgery on his right eye, which nuflered impaired viuion as a resull of a butte Iwoli nd in she head.l loho Monelev, Direrlor 01 the Miami Regional Office, ,rrcepied an Award 01 Honor on heharl of his entire s raiL whoce artionni n he wake ol he dit- asiroun collapse of their office building on Auguct 5, 1974, "exemplified Ihe highect tradition of prolessionalium and exhibited councless acts or valor." The accident resulted in the dealh of eight DEA employees and in'ury to 14 .rlhers.l For its superior leailer"hip at lie `one of the denIer in naiI'gLuarlling the lines in fill iii' r'nllillln-i','n thu lxxiii I, `alit4' Ilie s,'rLiui In',, I lie ,iie,i, ih,' `Omant of II ``or on in In,',, huh IC' oil Aru'irl lnn1I,', l''r Ink,' I'. l1lAsliigl,,.oi ```nil' tb,, net, Is' I,,,' nit,, ls',s,u hIlt' Ni's, SoiL I wit Tack "cr C. New 0 "`k Cits Del cruises ``liii C,lrnI'l,,n,l `nit K ovum Pal ywer'' t,,,iou cii luigellrer will, lIlA Star ial Ari,'ix in l.al,n I C,,iriland l','k'r C. Nil's, and I l,ir,,ld A Ri "I'll ``Out Nos'enilari It, 1974'' n,u.l Mr. hinds ``wi,d,' `"annliicli,Ig a narr,plirn sl,rvi'ill,uxre lIar's,' nun nline,o','ul all ,a,,,,i'il oihli~'iv iii pn,.l',nI.sn in New Y,,rk `xi ```as firi,,1'ari'n-,,ln,'r i'll', Is' Ir,,u,i u-in,Ii,w 0 I arc'' Ii in isv" ,i i'r,u,,1,l RI'S load i,,nuIn 11111 r'i',,'il in a lIliI,rxob,ilo' l,liki'tl at il,, curl, it it' ,l,,n'i'r .11 I'LiI'ln'nl I. cli,' tue, eolal urn' `xiii' clin,iir,u't I intl pl'ti,',l unilt', uris `-million ils'seohl,rernilisi Itinrung llaciu,o'v,,lnje,','' 41 PAGENO="0770" CONTrOLLED SUBSTANCES Final 1975 Revised Ar,srg.,te Predostion Quotas in Ssheduies land Ii Section 2010! the Corn p,~hcissive Or,'e Abuse Pee ~v,tti Oil otid Colitlol Act of 1070 121 USC. 120 8 cr11111 coo the At- tonic 01 C eneryl ho cots b l,sh,s?rre:rate produrtlarl q,iotits for all contra led ~sliecs in Sel,c,l'ilcs land U civil year. This respohss, Witty boo been tielegated to the Ad 15111 laIr:, toe of the Psilli En- lorrrioent AdminIstration pursuant to 10.100 of Title rOof tile Code of Federal Rerulitt Ions. On MaY 27. `975. 5 flourS of the pro- lost d revisril egerecate production ,ots's for I lull wlca pu ii shed In the )p,ttrAL ruro,s' 0 110 Fit I02~. All Ill- terosted parties were Invited toconirnent or obseet to Chic ti-oposed acerreate pro- Suction quolas on Or before June 30. 5075. No eornllienls or objectIons were received, Cli erefo: r, under the wothori I yvested in tho Attorney General by SectIon 300 volItion or.d Control Act of 1950 St U.S.C. fIll, siid elelcoated to tile Ad- silnustretor oh the Drug E uif',rrernen AdlnhiilslratlOII by 10.100 of Title 25 of the Coele of l°rdrrrh Itertlif lions and Ia, thee. lsnsi se beets city ete;.i,',,sted as Arcing Adnsih,lstrstor by Order No, to?- 15 0! tue At tacitly U rise: I. ei;utl.el May II). 10175. In 5l:eOrtlilltCe wills U Ic hi', I hodI slated thuerci is. em! Illllsu:lll I to t :050- O iioz-i ty delegal cii to the fsrtlhu: All oslit- istuator be if_IS' il I 5,tle :5 of the Code of letlec ii hSeurIuI., tunas, :11551 Wised upon colic tuceati iii of (list fat' toes set forth In 40 FR. 102. the Acting A dn,ln- lotrator of the Drug Ehlforrelslellt Ad- o, Ililotration hereby orders this t the ageless to hsrod,urt:on 15110105 for the con- traIled substances his led below, exisressed In Cr1015 in Icons of their respectivo anhsyclrotis bases, be established an follows: snoeeeuo-o llsl.tl'iltd ee'iad Cci Isle 555 `still, .tlrl.seosd 38,550 C.lIll +17,151 C's-iso Stsol 710,0, +11185 I, bUrl I tOot. 535 4351. lOS esk-Sa._. rotas vlvao -b/two sl,iS,a.una Is.',.. It', ,.s.g, lltThu.l5 0-1.515555 I.55slI.l l,.tll,tl5 _ts'i,ul_l II. dish 21.711. IsiS `itico.othl rope-soil olett,,ele,',,,,i,,e,r,l,,-'h,,n,sl',o,. `l,ltl.l..I.l"s.'uus-.,.l.,le.s..lSoit,.-l,.,,.',s.'ll.e, - dl `o,seise-l,,to' I.e,... I,, I.e ,`.,,,,,i., i,,tl Ills Lalils,-p.,.1u,,.tii,,,I.li'l:sl',.i'.t..,. Thit order is effective August 10 3075. Dated; Aueusti. 1970. Jo;loy N. Juissow. cOtflOO A'Olt'O' lslrrfor, Drag Es tOerc,,tcl,t sSeb,sI,s,tere' (loll. li//t 1)ee.75-2lIj0 1511511 5-5 8-73; 84 P 36152-53 15202 COMPETITrVE PROBLEMS 1K TIlE DRUG INDUSTRY icclti'cd (@9~Z~S( Ann Cede 202 55.0. 513-5240 0050SAt RrGhiTrt, SOt. 40. 040. 1el-10i505'O, AUGuST I', 0975 PAGENO="0771" COMPETITIVE PROBLEMS IN THE DRUG rNDUSTRY 15203 METI 1YLPI-tIZN1DATE rinal 1975 Ag~regale Production Quota Section 305 of (lie Conspre},cnstve Drug Abisco Prevention and Control Act or 1070 (21 U.S.C. 820) rerpllres VIse At- torney General to establish aggregate production quotas for all controlled aid,- stances In Seisecluies I and II en cli year. This responsll,illty hiss been (Ieiega.i ed to the Adininistra or or the Drii;r Fis - fort ciii en t Achisi us tin tion jsii las a St to 0100 of Title 28 of the Code of Fcc!- i~ectdat. On August. 19. 1975. a notice of (lie proposed agerconte production quota for 1975 for Metiiylplseiddate was puui~ihi~scC In the Fr.ar.a,z. flEGIFTER UQ FIt 161). All Interested parties ssi~c IIivI ted to ecnsnicnt or object to the proposed ills - gregitte production quota on or before Scisteniber 26, 1075. No coinoieuts or ob- jectIons were received. Therefore, under the authority vested In Use Attorney General by Section ~06 of (lie Cos ii prel leusive Dii' Aba. Prevention and Control Act or i 970 Cii U.S.C. 826) * and delrateel to (lie Au- In iuutstrator of (lie Drug Enforren'.cnt Aduninistrat.ton by 7 0.100 of Title 28 or tiio Code of Federal Regulations and fur- ther, having been (icily designated as Act- ing Adunliul.ctrator by Order No. 607-75 of the Attorney General. dated May 30. 1975. iii accordance with the authority - stated therein, and pursuant to the au- tlionty delegated to tile Acting Aclunin- Istrator by § 0.112(d) or Title 28 of (lie Code of Federal flegt,latio:ss, anti bared ujlon consiclerabois or (iso factors set forth in 40 lIt. 102. (tie Acting Arinsiss- istrator of the Ursuis Enforreinen t Ad- ministration hereby orders (.bat Usc ag- gregate production quota for t.ise con- tiolled substance listed below. expressed In grams in terms of anhydrous base, be established as follows: NOTICI3 SCIEETSULS it Grant crt-1975 Basic doss: Motiwlpllcnldata 1,241.000 This order Is effectIve October 14, 1075. Dated: October?. 1975. heNRY S. DaMN, Acting Admiof.strotor, Drug Enforcement Ac/ni tsltsti-ation. (Pa Doc.2'7566 Flied 1e~i0-75;8:4S soil FEDERAL REGiSTL~. vol.. 40, NO. 199.. IUISDAY, OC I 0811 14. 197S PAGENO="0772" 15204 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 50547 notices ThJt cuon - th~ FIDEAAL IECISIrA etetaifli dtctsn.eb elks, Its' `sits pespesad ivies Qiat an soglkabI. It Bit p.i65Ic e(elicn J at lsaad,sn I'd ast.ifatises. ct.sa.in.s m.sl.e.s. .ssscy d.eis,ew ted sakes.. datwetees .6 aaiis.e.te. aPi..a of p.bOioaa ails aecseafelait i and taoist, au.ttee.at. of 00alintifa .ad fissaicas a,. twsplet .6 dfc*aeis.nti lege.51il5 Ii, IsiS baths. CONTROLLED SUBSTANCES IN SCHEDULES I AND II fInal 1976 Aggregate Production Quotas Seotloit 308 or the Comprehensive Drug Abuse Preventions nd Control Act of 0910 (21 U.s c, 1261 requires tilt At- torney General to eatsolish segregate production quotas for all controlled nib- atalices in Scheduiel tand II each year. This responsibility hilt been doleguted to the Administrator ci the tonic Kisiurre- ment Adnl~n~s.t~t(on pursuant to 0.100 of Title 280' tile Code of Fedrat Regtle- tioni and has been rurtlier delegated tO the Acting AdmInistrator by virtue of hIs desitnation as stich by Oader.toumber 601-15 of the Attorney General, dated May 30. 1915 and pursuant to theau- thority delegated to thin by 60.1321 di of Title 28 of the Code of Federal Regula- tions. On Auflust 21. tOIS. notice of the proposed segregate ptoduction quotas tot' ll'ljwnl published in the Fosant ReGIsTER 40 FR 312411. All Interested parties were invited to conlmell t or ob- ject to the proposed agerega to produc- tion quotas with these commen Li or oh- Jeetiona to be received by September II. 1555. scud submitte deomomefeil ta relative to the proposed areregato prod urtion quota for Thebaine for said. tlailinckrodt com- mented that the proposed tmuota does not pennit the ronvers ion ol oil T heiaair.e derived from the recessing or rita'g onmuni to a stable form. As result of in lsvslua- bie qpantines of Tliebalne would be last si'hiehconid be rsmmaertett to medicinal sordrocod000 or Osyrodone. if the The- baine were prnces.sftl `0 is stable corn, Endo Laboratories. Inc. of Gardell City. New York also corn niented that tue proposed aggregate proelurtlon quota tue T hebaine I roe said w ill not pennit mime full recovery ot Thehainc from rum opium and amnily striuse which is nor- eased In tic United states. Western Flier Laboratories or Ponce, Puerto Rico throui~li their round Klein- feitt. Kaplan. ansi Peels yr ot Wss!ii ntinn. D.C. have cornineiste d 0mM tile proposed aggregate prod sirliun tilloln for P mess- Isietrafineis imlisdeoisis IC to provudo `for U me esti mated nmcmiicuit neetis of she United Si-alt'.s (tsr flIt. Wintheoii Labor.' tories. Dines en lie S lyrlimic Dm1151 I lie. ot Rein vetoes'. Ni's' York his atloiseti that it is tiieit op lilioul that tue i,roposrd aff legate protlur ibis quota roe 1~rthld i ic is mmlii in ent for 1070. The film fur I her advised that the fur theIr opniioll nsa be related to the fart that their 1975111111 0010 prodllcti~ oil cycles have been re- cemitly chanced. Pennwalt Corporution of Rochester. New York has commented that the DrlIf ICOIRAL ItOm1118, VOL MO. NO. 2I0-OIOUItOAY, 000151 20. 5971 PAGENO="0773" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15205 sods Enforcement Administration should con- sider building into the aggregate produc- tion quotas an amount to he available to manufacturer, later In the quota year. which would allow the Drug Enforce- ment Administration more flexibility than It cusrentiy has and would obviate the administrative time delay which we-lId be encountered by both the 0mg Enforcement Adinlnlstrailon and mdl- vtdual companim by having to repub- lish In the Fuagaet Rgomstga revised ag- gregate production quotas, when in- creases of the aggregate production quota are warranted. CIba-Geigy Corporation (Ciba) through their Attorney William Ragoila, Jr. flied a comment relative to the pro- posed aggregate production quota for Methylphenidate for 1018. Ciba request- 14 that the Acting Adminiatcator decer establishing the 1916 aggregate quota foc Methylphezuldate pending the outcome of Administrative locating, with refer- ence to the registration of Importer, of basic class Methylphgnldate Osee 40 FE 3706042. August 25 IllS). It is Cflsa's opinion That as. result of these hearings the ageregate production quota as pro- posed for 5971 may prove to be lnadc- quate. None of the above mentioned corn- manes specifically requests a formal hearing on the aggregate quotas los pro- posed for 1076. Pursuanl too 1303.llicl, the Acting Adnsinlutrator cc ths Drolg Enforcement Administration has deemed. In his solo discretion, tint hear- Ingu relatise to any of the above men- tioned comments are not slecessary Rep- eesentatlveu of the Drug Enforcement Admonistralion viii loss-ct wutls repro- aPaLaeivs.u er (ho .;cz llu~.-s~ to review the conmscnts submitted. Therefore, under IOu authority vested In the Attorney General by section 300 of the Compreliessaive Drug Abuse Pre- veostion end Control Act of 1970 (21 U.S.C. 82C1, and delegated to the Ad- mlnlatcator of the Drug Enforccment Aclminiatrs tion by `0 ItO of Title 20 of tese Code of Federal Regulations and sur- thee, having been duly designated as Act- ~ng Aeionlsulstrator by Order No. 601-75 of the Attorney General, dated May 30. 1075, in accordance sith the authority stated therein, and potrau ant to theau- thority delegated to the `Acting Admin- Istrator by 10.132(0) of Title 26 of the Code of Federal Regulation, the Acting Administrator of the Drug flafottement Administration hereby orders that the aggregate prodoctioss quotes for the con- trolled substances listed below, expressed In grams In terms of their respective an- hydrous bases, be gstabllshed as follows: ecietaut. It Qoals 5,1st- ltehrd- aa&e closE 1970 Aipisapeodlesa 47.860 Amelseott.i 11.079 080 Ampoueus,aooa 5.580.800 Antieciduue 30,000 ApopsOephie. ,_~ I, 786 Cocaine 1,111.000 Cedeise (foe sale) 11.411,000 NO11CES -ft glee.- loesle eisa,: . sale Codeine (foe bonveeelsqL..,_ e04, 000 Dseotgspliddtlse - laas,'OoO Dlhydr~d.lae 105, 000 Dlpmseaoavleee 1.041.000 gL091suselsoIn. - 55. 100 ?,uianpu 2. 500 Kydeseedee. Tie. 000 ltydoomeer.iseTh. ,,.., 00.100 taesei,hesol 9.700 Methadone t 405.000 Methedee. lesteemedlata 04- erase-s dinsetlspI-.sulsa- 4.4-diphenyl butsee) 759,000 ateghesssialeaa 14.001.000 Methyipheeldat. ~, -- 1,007,000 killed Alkaloids of OpIum..., 44,000 Morphine eeoc sale) ass. 005 Msrphloe (fee eoeoeesiou) -- 40,716.000 slorpetlsldi Oe 700.800 Optasees ettfleturea, estesess. Cu eet.ea, tepreesed In eeee,s of oplomi I, 801.000 Osyeseaas (rot sale) -- 2,475. tOO Oayeadsna ef'sr eeaseesiou) - 7.000 OessaOrpbss. 4.000 Pentobaebltal 13.807.000 petIlielse 0,414.800 Pheqeiseteaslssa 1.312.000 Oseebeebital 50, 186.000 Theo.lsse foe sale) 1,2.00,000 Tlieh.lea tree eaeseeaiee) -- 1.010.000 2.205.000 g foe the production cc ieee- eeeeayephedrlee goes,, Il I ,55eoears)ied. IsSaioee'aei pablo peoduet. nod 331,086 tee the pradaetlae of nsethas,phetemille. Pursuant to TItle 25 of the Code of Federal Peg titstions. I 1303.23'cS. silo Acting Administcutor of the Drug Li,' Oorceneng AdministratIon will In too-Ic 1016 adjust individual mtnufactllnltg quotnl allocated for 1076 for the ebovc ;,slsuia,bcea based upon 1975 end of year inventories and a re- view of 1975 disposition data as suhmittcd by quota opplicantt. All suenons who submitted an ,pist)t-n- tion for either an indivIdual mis noifoc' turing quota or a prociarernent qttutn fur 1558 slU be nolified by mail Is to their respectIve 1970 quotas established by thc Do',i~ Enforccment AdminIstration. lists order is effective upon the date of Its lasumisce, Dsted: October 21. 1075. RIver S. Doris,, Acflno Adsesesistr.ufor Dreg Fntee'ceeeleesf .4deesfedsfro fist. 518 1)08.75-19137 nIce l0-l9-7a;a:ee ,eoea*t P1005159. VOt. 40, 40, 250-TH1JIIIAY. 0c20109 30, 5075 PAGENO="0774" 15206 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY - IIOTICES DEPARTMENT OF JUSTiCE Drug Ersfor.-emrni AdmInistration CONTROIJ.rD S005TANCES IN SCHEDULES I AND II final 1976 ReviLed Aggrogale Production Quotas Section 320 or the Comprehornh-e Druog Abuse Prevention and ctntrol Act of t071 421 U.S.C. 020) reouI~s the At- torney C enora to cstablEhnxrgregate production quotaa for all controlled sub- glances In Soheolulee I and U each for. Thiagosiooiosllotl)ty tm been delegated to the Admlo,ls trotter of the Drug Enforce- ment A~1minlsttaLlon purotlant to 60000 of Title -20 of the Code of Federal Regu- lations. On May 14. 1070, notIce of the pro- tImed revised oseregatg proottlctlon quota ror 19)8 for varlota Seheolule U con- tmlced stthtt7ners Woos published In Use FEDERaL err.clsrrt (II tfl 19991-21 - All Interested paroles acre InvIted to com- ment or object to the Proliosed ogcreeat,t proelurUon quota.. on or before June 31, 1976. No colnments or objections were r00elved. Therefore. toiler use authority vested In the Attorney C.ettrrtsl by sectIon 300 of the Comprehensive Onig A bine Pre- ver.tion and Control Art of 1970 (21 U.S.C. 820) * sod delegsted ~ the Ad- Ialnlstrltoe of the Detg Enforce non A dllslilIstrettoIO by 60.100 of TtUe 20 or the Code of Federal Reesllntloobs, the Ad- nintsenvtor of the Proc Enforcrment Adeoololblmtloo hereby orders that Uoc 5974 segregate prcdttcttoro otsntve for the controlled $)l~Slances . listc~ below. eB- pressed In erisroco ot enhydroots base, be cotabtlohed sa follows: 0576 pro docile.' qolti It Amobsrblfoi II. 315,00° Pity,Iesr000lne 400,000 sort e.sdooIe lot seemedlole -- - 2. 040.000 000(151050 00+, 030,500 too cossee.lo,,.._, 15.000. 000 Norpothidltte Potoeobset,lU.j 31.002. DOtI 11.000 000 2.000.000 Seesbarblto I 21.000,0(0 Throats. for eotot.rutoa I. It I. 000 77:0.' ordgr Is ctfeetlve upon date of Ito losotatsee. Dated: July 01970. Peers B. Bee.ooste,rs. A dulls. to rotor. CIt OsgooD 0725 PIlot 7-7-70;It:49 .505! 0000SAL 850111(5. VOl. 4L NO. 113-00000DOAY. JULY 8, 0974 PAGENO="0775" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15207 Form P ANNUAL STATISTICS OF PSYCIIOTROPJC SUBSTANCES A SINGLE COPY of these stati%ties should be sent to the INTERNATEONAL, NARCOTICS CONTROL BOARD, l'alaie des Nations, Geneva (Switzerland), as snon as possible, but not Inter Chain 30 June, after the end ni tie year to sshich they relate. JUL 1 4 1976 COUNTRY OR REGION: ..... tNITCfl..STJ,~tS. eTh..flQpJC\ DATa- COMPETENT DBPABTMENT: ..HJJG...ECsLL~1T..&o~casnisx~N (SsynM) ._..__. .U..~< t.* TIfl~ OR }~ONcTIO~~s~ Ath,iniotrator t' `i'ecer B. Buasin~ar . . . .- These statistics retfle to the catendar year 19.75.. RRMARKS This report includes American Samoa, Guam, ?ata~aCz,at Zo,.e1 ,.~ ti~ VLrg~ I~l,.aj terrLt.,~Lao of the United States. Please note: The drug schedules listed in this report filed with the International Narcotics Control floard do not correspond with the drug schedules utilized by DEA in controlling substances in the United States. PAGENO="0776" Iai detail Imported horn: SUBSTANCES LISTED IN SCHEDULE II - . Son Ittstrae,lons - . 2 . Arnphctaxi"ne 2 Dnampeiamlaja 2 - . P'Intharnphclamiaa 4 . MeIhyIphenud~te 5 . Phencyclidine 6 Phenmctrazlne I. Quaotityrnanufoctured.. IOU 209 deg,oo~,ua - ..................~3i09 X,Ior,oo..e,: 369 litlara..,ep. ~ Auo~ernn Nil Ad~g,o~ou; 2741 II. Quantity utiliocd for the manufacture of prepa- rationsetempt.dundcrart.3.paraa25nd3*, * .. bill lilt Nil lU). Ni). itt. III. Quantity Ltitized for the manufacture of ttc.n- psychotropic tubatar.ces or praduc Nil. . . bit Nil lIlt. Nil. tILL IV. Manufacturcrostccksan3lflccernbcrt 7_a 94 17.5 949 Nil 2117 V. Imporls -s Ca 0 cc (3 0 tel 0 1-~ Co C 0 -4 C d Total Nil Nit Nil NL.I Spool!, Qsa.s~Iao ~-l . Co~$,,y.,,,,,a4 4 Australia .. PAGENO="0777" COMPETITIVE PROBLEMS XN~ THE DRUG ThWU&PRY 15209 2. 42965 F: C; :ri:~.u ~ Csds 205 Phi.. 123-0200 Drug Enloecesiret tdoiisistratioa CONTROLIXO SOJI3TANCES Prepased Actrezite Psodsclion Quotas Poe IOfl Section 3t6 no b.c Cci: trotled Sub- stances Act 2! U.S.C. 07 II eeouiees taint Cite Attorney General establish resteetale prodisetico otlotos for nil csr.trgticd sub- Stances ruled in Schcd.lIrt. I sood 30. Till, reonotooibiiitr has been delegated to aloe Adsllnlolrssior to the De'otg Cr. `treossent Adrntnintrot,on by SlOt 0! TItle 29 of the Code of Feders] Ooertli'atitbi. Tile quotas are to preclde adequate supplies or each verb substonce br It) The estimated nieooecal. aeicna hoe, re- search. agod lndilstrla met do of the Unit- ed 8taocs. 12 law Cue eytort require- menlo. and 53) the estaslishnest and maIn teToan Ca cc reserve stocks. in establishing the below tilted pro- posed 007 lserregt Ce erodlctlos 120105. the A dmlnlslratgr consIdered 7siryusnt to SectIon 502 subsection a I If i.e P.11,- lie Health Screices Act 41 U.S.C. 242 (a)) the `3 esults of atte.jlgo and laces- tigutlono of the quantIties of osmotIc drugs or other dregs subject to control under ouch Arts, togetloer with reserves of such drugs, that ore necessary to sow- yin the norneal end ersiercenay eoedlelnal and wien tine regulrero snto of the UnItes! States" whIch were supplied by the Ge- partenent of plesith Fduca lIon. slid We!- tare, In addltlun, hoe proposed aeeeeeate quotes were el1090ls bed eonssdering the following factors: (Ii Total lottol 1075 and estimated 1970 and lot? net disposals of each pub- atance b3s Ill osaniafacturers, g21 Projected trends me, the nations] roteofnet ~L'~' suloot eochsutstonce. III F.,ttlma'rsor,nvenl,lrlrv 01 each substance and p2 one slCetoa,ce oars- ftc nil-ed trg.so Is. 2nd tltnele lets rcurseu- boats of 011th Intrete'rsre. 4.11 Prolrtted detilosid 25 inellraled by peoclsremelt Stint's op200ctI.og., sohich were 111cC punsi ant 00 0207.0? or Title 21 ef the Cools no redernl Perdlel allots. rursuustt to `ntis its Cs,to of Cyst-.rnl fleepiotions. 02)1 23 Ic). trotor of the Drop Enforcement .-~deosn- frtpaviotl silil in early :921 odiete mdl- vIola: mantel orIon ne quests allocated for 5017 aasrd onoet I Ore reid of 3-ear Inventory Scores and ortlugi tote dispo- sstlsn fitures SI curt SusIe clasp of Srhed'ute 1 end elena erected nubotanres which wf! be pravitic d by quota appli- canto. Based tee en eonsiderwtjon or the above factors, the A dlnllll,troior of ejie Dfllf ~fleermest Ad tibia traitor. herebr Dna- Isosci that aecrenuir product-ash tuotIs for 1)17 for 1l'.g Ce: twine c onsr:ltiru nib- stances, enpretoedlse(ea015lostersslo? their respective an hydrous base, bees- tabaLshed as fellows; Salle clone: Pee3saoed ZIP? qsolo Se~tedasa I 2-1 iisoeetetsyswis!,essssssse... 41,000,000 tysts-gis acid dLnOlsyJOsside.. laruaiioe .. 200 ScTaeitaIeiZ Alpbapeediiae 41.00* .iassbseaisai 05,41,000 Amphetamtoa ________ ~ersa,° Asilneldise 270.00) easels. __~ 2.24). 000 C000lso One 00101 42.000. 0053 Codeine (foe 0000ers leap 1,243,000 De00spepheaelss 50,41)0000 Ste the pewsogulan or lose- de.otyephednae toe sat is a Oooeeetes!led. soepsewnp- tins petasset p04 393,000 g Ste lbs oeodasstoo at sooth. awpts550mimsei I. 502,000 005p005000eLst ens. 000 tnspsooasyluts 5.272. 000 Zthpieoseisles. 31.1000 70502571 2.000 Bsdroe040se 721000 Mpdeeesoeptste. 78.400 teesephaeol a. ceo Mebhuaoea 1.433.000 sdet00400e leseewedisat (4-00- ant-I dTet.tayl,ias100-4.4- alyhearm 000tasel 2, 211. twO Od,05equuieee 17,010, eta Lset1501esheeid a.,,,, oo~ wise, 502000100 oe sploss.. 40,530 Moss slots foe 551° I 400,000 Macpolo. (top nsssenlest... 44,017, e0* Qplssse tussnosoo, etc.) (eoprnooed Is tore, of pesdtwed 5 0. COt. 000 0s~eudose (etc sutet.,,..__._ I,at~s00 Osjeodoes `Or cso.'aeclon(... 3.000 000005ep5005 1.500 P.ssohaealtai 20, 144,000 Pethitiss _._ 03.428.1000 pleeooeenesaltse 1.123.100 Oevobeeblssi 17.000.cdo Tis.hiisa (toe at.) 1.500.000 21155410. leap 000aersloS} 7210.000 Tine proposed afergeale production quota for AmphrthlIoiiO'7 brIne reserved pen'2Ing tile c,u,n::l,::t:, 01 t retire ass ti:osdrrtoIiselrL.'t5.tllla..t055t5. It is ontlnipated that GstA tout arts':; 1~0 a tsropesad agerefsle prodsoctapu booth tot levi far Oh lo sot sEance in the meoac At- bite rrsted persolis are invIted to stohusi ethel rcc,s:slietlts and ohjeotloso~;) v-rlti',,treeordjno thou proposal. `ltese comments or sated! 00usd said slate stills piortictutueiiy Ohm issues conrenolet g sib er. bbs person desires to be heard. A per:;als shop obJect or comment Oct (no pnopooals rets:tinr to soy foe or more of the above althsut~lin g c000ments or ob)cetlooo regarding he othees. Coessoiteit ts and ,bjsctionositotdd be submilted in qslintupileate to eats Ad- enlnlstrttor. Droll Etifoncein rot Ads) its- he estion. thoted Stifles Departinclit of Jttstice. hvathine toil. D.C. 20531. Atten- tiset t GSA 5c~rrai Rep leer Rep re'entl- tier. Oil dtstust be reeeovgd by October 2:4. t070. If a person bellevel that one more bases raurd by hi mwarrtnt a fult adeerso ny-type heaciet e, he should 00 state end asoruenanize the reasons for isis belief. In the cent thnt comments or oblee- tloeta to thia propoosi rune one or sass-a issues odeelt the Aol,nlflitteatto' itnds. ill Ills sole dii,rrr'i)nt. sierra sits .5 full loS' vetaary-troe hearlnt. the Adlolinmrtratos' shall oruterapslbhle ilearieset lea the l°ro- Is-at 0005.5155 nummaritir,e the Lesisto to be belied piud eettenf the tlsc,e for roe hearing ewhleh shall nit be less thin 20 dayo after September10, 10Cm. Dated: September 21. one. Psoga B. messoysea. .otdwioigorOtoo'. Dreg Enforcement A udeiisioirofiow. IFS oee.74-flsan Feed O'.21-10,0t44 asic erooaee. 15010.51, VOL 41. NO. 0 9!-'WbDNt5000, sIPittedle 20, i 554 PAGENO="0778" 15210 COMPETIflVE PROBLEMS IN PIlE DRUG INDUSTRY DEPART:~ENT CE JUCT:'CE -/-~Drug Enkncerr.ent Admh'.istration AM PH 8 TAM 24 E Aggregate Production Quota for 1974 Section 3&G of tl:e Controfled Sub- staa:ces Act (21 U.S.C. 826' rcc'uires that the A ttbrney Genera! era abtish ererate product ion c,u(das for p.11 cort rotted sub- clatter's listed in ScI,rduln 1 and 15 L'~ July 1 of cacti year. Titis responoibility laits been cteie':n ted to the Adn:intztrator of the btut' E:.torcencni Administration by t 0.100 of T:t!e 23 of the Codo of led- eral forum in::s. The cuotas are to pro- nut' atle rtu:,le r.:tt)t;tie: of each such rub- stoulce her (a I the estimated unedieni. seteni ifie. retard,, end industz-ial ateds of the Untiru Stn: cc. (2) hc~vfu1 export tcqtuirenient a. and fI the establishnuent and :i,,~tntet:u:tre of reserve stc:ics, th: Jut'.' 3. 1f73, tite ijrur F,siorccroent Ad:n:ni. :r:,:.c ,t j:::'i:,.shnd in I ftc a s:.~,,ze of "rn"-:e,t 1~~4 A"- rrrretr l'uc ctt:tinn (~,:`fla for Ampncta- trifle .3 1;: jut ord", to ntsot the rnituior,' require- fir c Ut used for setht:c the 1i~4 Q'Jute on uuty 2. 1373 ZC FR 11m73). C:: -`,. .~ Adai:,,.r:t,,c. 1:uL,,s,,od csi~ II lum.t!clun aNrtir~ of Propr,.rd 1374 Am- j,ict:t,:,',c t.r!tit;em l'r,uciucI:nui Qt:cta ,c~L~1:t;' mao ,`:`t 2, lltr' 5'tcpOrCU n~- ri ``ii. `vi! mu'. were lr,SIVO to flit c-c r-:. ~ a he 1'rc''rcst'd r'rodtmc:o:: qun:fl (`nor bv:e're 14. c'fo rowit'-t,tc Or (`Otf"tiOflS it: I'~,,:l a cce':vcai by C it Ad:niniscra - u lurrofoum., the Ariuninistrat or of'\~mc Urt:: h::ft.r,-r:nua:t A (:~tnu.rtrattn:) ur,cem :t:o','ity V.., ``iit',h stir At toruaca Ch:;e:ui b, rcct:~': hijC of site Compre- Dri'" Am;'::~' Vd'Vcntmon cnd t'cuu,.,IA't of 1273 (21 U.S.C. 826 `atarI med to tnt Ada:nnis:,'al or, Drug F:. ft ~ ti. en t Artin tie S rot ton by 5cr don Ojc-~ or 7ule 22 m..~ tho Code el Federcti Vcrt;in Loti' . orders tI:~ ,haiflZj,'mvgre- r.rr ti rn on qta u a (er en,: pise tatrire a's T'rc' `cci in grunt' ml teams of its C C - its bone, be c:,b. b2iuned us lotlowa: Jtt,'si t' r.t,:f_~~ t,cttcmine, Omitted. 3.C37,133. Aim prrsons who submitted an appli- cation for either an individual manu- facturit'g quota or procurement quota lot' 1274 wifIl be nottflrd by mail as to their u fsuicctive 1974 quota c sttblh!ied by the Attministm'ation, This order Is cftcctive on Juno It Er::ç, Enforccmcr.t J,cntct.sni,rcfron, sic Dec.75-] 37(0 h'ed C-14--t4:t PAGENO="0779" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15211 MATERIAL ON PENWALT CORP. FROM FILES OF DRUG ENFORCEMENT AGENCY, DEPARTMENT OF JUSTICE VTtvd,2I ON PHOOUO~S F55 Jc~rtnsoN ,,oao. O'JC'~~T! U. N.Y. I4~~I P.O. 005 ruc,ccT~c V. 4505 (JlC~z75-~c-j A'~gnst 13, 1970 ALL FIELD SILtS FEtSOfINEL You undoubtedly have read in your newsPapers that the Food and Ct-u, Aduinistratjon has officially published a general policy state-mont for anoretic drugs, As we have experienced in ~he past, Icy press reporting of such information is pot always an accurate interPretation of the Food and Dr-so ~ pi:Uiications, In this bulletin we ~:il attempt to pass alnoig co ynu, (2), the fccts Concernin? Our pirticular cruructs - B~:Jhet.ami:,c, jonas-in and Biphetemine-T, and (2), infornation concerning all other scv.phet- a;ninns. 1. Bip~otanine, lontrein ccl 6iphetamjne-T TI's drrg c-'~mendments of 1962 requirs that any ,acrketed drug uith an h111. nporoved during the period. 1933-1962 had to sub;.sit data rogarding efficacy. The reason fnr this was that prier to thc drug regulations of 1952, thu For'd and Drug Adt~inis- tratio;s was 001)' concerned with the safety of the drug and no~ the efficacy of the drug. Since %iphatarine, Icnamin and Piriheta- irine-T were "?DA'd drugs", we subni tted efficacy data in Septcm~er of 196~. The Food and Drug Administration did not have ssfficient personnel to review this data aid contracted with the National Academy of Srier:ces and the Pstjcnal Research Council to review the ofricocy data. The Food and Drug Adrinistration has just made public the evaluation of the aca-lemies with regard to Liphotasnine, lonamin and Dirnetarsine-T. All, three products were ruled "onssibly effective" for the treatnent of obesity. The reoutations state the ~ PAGENO="0780" 15212 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY For your inforn~tion, of the volume of data submitted to the Food and Drug Administration to establish efficacy of DiphetatiLne, lonamin arid Cipl~etamine-T only a few specific points were questioned. We are cenfid cat that we will be able to supply tire Food and Drug Administration with the data requested and establish the efficacy of thesa products to their satisfaction. 2. Amphetamines The National Academy of Sciences and the National Research Council evaluated amphetamines as generally effective for short- tere anoretic actioi. The Food and Drug Administration is thus requiring alJ manufacturers of amphetamine preparations to change their labeling to conform with the findings of the academy. As soon as the new labeling is available, it will be forwarded to you. As far as we are concerned, there is nothing objectionable in the labeling suggested by the Food and Drug Administration for these products. The above information is not the best news we could have received nor is it the worst. For the past three yearr many of the so-called experts have declared amphetamines worthless for the treatment of obesity. We now have reccgnition from the National Academy of Sciences and the National Research Council that amphetamines are generally effective, in the treatment of obesity for a limited period of time. We certainly can not disagree with these findings. In fact, the Nationsl Acadeny of Sciences and the National Research Council endorse our "four essentials' fcr treating obesity with the following statement which appears in their report - "Ahoretic agents supress appetite. They are not a treatment of obesity in theoselves and shculd be used as an adjunct to a total program of weight reduction for obese patients that includes patient education, motivation, caloric restrictions and exercise. Thqanoretic effect of anoretir. agents often plattaus or diminishes &~ter four to six weeks. The~~e or tnc orug must be 1nd1v1duallfit~ated Thus, our complete program of "Are You Really Serious" and Siphetamnine, lanamin and Biphetamine-T fulfills the overall treatment design of the National Academy of Sciences and the National Research Council for the treatment of obesity. ~ loLl HAVE SL2~'ETEINC 2V SELL? Cordially yours, - f~))~cG/iiw, II Vice Prcsidq~mL I ld.i/ sw - - PAGENO="0781" COMPETITIVE PROBLEMS IN ~E DRUO INDUSTRY 15213 ~4~L~T YOU CAN SLY t.t0~Y lt1Pl~ETANlflLS, nr'ETt:~rNt$-T BiphetaminP is a sympachemimetic amine with CNS stintilant actIvity. The anoretic effect dininishe.s after a few weeks. t$phetscineC is indicated in exogenous obesity as a short term (a ftw weeks) adjuac in a regit~en of weight reduction based en caloric restriction. Dosage of BipheLa'eine~ is one, capsule daily, 10 14 hours before retiring which way be adjusted to individual requirecr.nts. tiphotaraine0 Is available in three strengths: Eiphetarnind~''7'f, Biphetaair.a© `12½' and Biphetanind~ `20'. Biphetantr.e@"-T is a sye,athorjlmetic arn~.e with CNS stImulant: activite The aceret~c effect di'ainishes after a fa~*; weeks. Patients on Biphetamine©-t may experience lass irritability than those en rmphetceiae alone. Eiphetaeinaat is indicated in exogenous obesity as a short: tern (a few weeks) adjunct in a reginen of waight redtctiun based on caloric restriction. Dosage of EiphetamIne~-T is one capsule daily upon arising. Blphetanina-T is available in twa strengths; Biphetamine~-T ~ and Biphetaminc0-T `20'. PAGENO="0782" 15214 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY S..LJ~ r U Pedree 3 5 e~e L~ ccc -- ictHex,. & fl?reeOfl:I 3 20, 3 /10 re. `illir F. Head - - -- Fr. Lidu P. truaua Flaqoorl t. (scaler fl urety Tn - coass,e ~Iicreflnwin~ te a suveary or tb Aou ar0 respcnsThtlity gitiGelines harrerec'. rut ce1c3 our roceluretlcn on the shine 3 a FOeise((Or Wbdccaia frs~uzt 11, 1970. LI so preesret oral psrttalpat irg Vile Vincent IStainfeld, eta, counoel on F L DA 3c":3. and ~c~:ulretory rttcrs, ted Dr. Oars Fayer frees Fanard, well knowil authority in the fieLo of uctritin;. en) seat rcecntly Specie). Assaahtal to the freslC't of the tLhrrrd Gtates for 1:tritiQnal Affairs end the can cci rpaeaaironeultenu to sin in rmtterr Of charity act I. Retired Lcttoa fl: -- 1T3~ October ~. 1970 tao 13'ortooaut4eal Div sio;s nuot revise the 3.abciing of it, earn; adrtoi;aereed :crebet'u. i've reid Oe,cteo~ p-nhet-uetiee eratri r) `a prosucts to cosfo.a;. wit~.s the receorrera-at:. sat fuet)i ox `e5:e; ltn7) sect al tee Procedural tact ii; yitcLlvs Reruin- ccc puali:ceai dc t:u Federal }ee~-.tc Err, Vol. 35, Do. 15'r -- x~aLurd:y, Lstciet 8, 1970. ResDonsihility for earryina out thin requIred actIon is nested to Dr. Pillion F. dead. 1. Sc.ecific predicts to be re-labeled are~ a. Biphetzeoion `7~-, `l2~', ant `20' b. fliphetaiaine-T `12~', Bijdiotssntr.e-T `20' 2. IndIcatioc 0nd dose ~ae infoneation contained in the raricad labe1ii~ shell be restricted to exo~eno"n oheritv end shell cyclude narcolepsy and hyperktiieAi;a behaviour d5scedors. 3. Our preroutOy itsod do~.c~e statorcent in labels end 1abelin~ shall be ratuixed. !+. b'o-lnoellrexa rerni roe `slaviob adherence' to the F & leA nester that lila; or orally edanictered ceç;'otacrl' cud slexu eejrn3: cIt Jeer and their salts should ho au'.,xt~tnt,stXs ccc aublieled th the August P, 3970 Federal Pagtster. PAGENO="0783" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15215 Iv. WI' tte V. 11usd Os. h2.ao 7. Tr~urt 2. ~ 197~ 5. 9iope~ition of other items: a. Dc ~ord !.,.rr~ta..,i!I~ rs to rcpJ.aco the dl-anphetssia.e decipsatier in ,:ew labels and :tabol&na in line wiih the nornonclaturo ssced in the Federal Rs~pictor notices. b. `fliMsatacel' centainir,g amphetamine ml dextroasipbstar*5td as phorphatos is to be deleted cc of October 3, l~7O or as na~h be:fore that dale p.c stocks rvcy be cxht.ustrd. Sales p_nd sales sotential 0f the t,radoct use too insicnificent to x-orrant retention in the line. c. Injootitle Raphetarine Ihosphate 1% is ret an osafly ada_s istc-rsd asohetascine product sal therefore not subject to ths Aupast 8, 1970 order. a. )r. EcOrew and The. ~Tsad are to make an izrtcdiate dott"- ation and recoavcendaticn ~.rflh respect to the c1iencaitior o~ methcrhetetiflO-cOntadnirc prud;ots in the line,.i.c., `hifran, `Edroxine. If retaihad on the ssarke1~, the labels and lnbclino for these products oust be brought into conformity ~r1th the provision of 1.1. round on Page 12679 of the Federal Register notice of.kuwast 6, 1970. The oniy cuestiOlt to be resolved by the determination and receendat!On of Pr. ?.bGratr and Dr. 1{ea~! is ~thsthar to delete these products ss of October 0, 1970 or as of February 6, 1971. II. Pequiret Action t2: -- fly February 8, 1971 the Pharmaceutical fli'iision ernst submit in response to the implementation notice of August 8 cow, rrevioosly uneubrsdtted data including that "from adequate end well controlled clinical inc'estigatiore". In su~,ort of effectiveness claims for `Pipheteminc', fliphetnnine-T' , and `Ioncnio' now ruled as Possibly Effective by the F & BA. flesponsibility for Action 52 -- Dr. &ido P. ~t~cnt and staff. 55-569 0~ 77-51 PAGENO="0784" 15216 CO~.TPETITr%E PROBLEMS iN TUE DRUG INDUSTRY F. Y',.iUa ". TriLanO 3. JLLnust 20)570 l.OThceifie products 1cr Action ~2 are: FL. Eio~Letacine `7~ B1p~v Cosine `12' `20. b. Pipi:otanne-T'l2~ nod Lip'votacrl.no~T `20. c. leoandn `l5~ ant Icnzurjn 33'. 2. Panning detc~rnnac,c no that eLLa he rteh$.evecl ocJjinccn~c:cnce~-.it1c F 5 Di officials, objoettvoa of protocols ohz].J. ir.c.iudu the a. `Biohet,jsir.e' -- (i) Short tons, Lnoractdc eticctivancss in `exogenous c5ws~t, as e short. ~en (a fcr.n wea-sLa) adjunct n a regs.zen of o,eigtt reduttlon Laced en caloric rostniotios,. (2). Contribution of reo.iratiou in ton-s 0- (a) Flood brain. (`a) Icngor onration of effect. (c) Fesror adversn rcacticnc v:i less "1,eakinL-' effect. b. `Biphetrsir.e-T' -- (i) Short tern. anorectic eff.-sctivoness in "exogenous obesity", as a short tons (a few o,eei~s) adju:sct in a rogtinen of .et5ht reduction based on cslce to restrIction. (2) Contribution of rcsixcstion in tenos of (a) Blood levels. (b) Longer duration of offset. (c) Fewer odverne reactions and less "renkihi' effect. - (a) Contribution of Tharobo to 53 iplics tnsni .rs-T PAGENO="0785" COMPETITIVE PROBLEMS IN ~E DRUG INDUsTRY 15217 fly. 7 Dr. `~ld, P. ~nwct .&~i~ys~ 1), }(;7(I C. `Icrisnin' (a.) Short tint anorectic tffectivoii.2o5. (2) Contrioution of rcsinuticrt in. tents uf: (a) Eiooi lords bioavailabi]ity. (b) Dcc,;or duration of effect. Cc) Admzotages. III. Coos Ferti.~ent Cosentilore 3.. Virceat Kieinfsici accurutuly confirnoc? the distinction. between the `~r,ossibly effective" rulin~ for our drc'~e as containod its thc ~u,icse-ctation notice of August 8 trots the "effective, but observation contained in the X&S/aT~L reports. As Vincont. pointee~ out, tie ~kz/::Rc `effective, hut cbosrvati,n os o-,asrel to the "possibly effootive" ruling by the F & LA could be ci value ~u a court but was otherwiso meaningless to ass since we have no choice but to ooroly with the ";oasib1~' effective' F & LA ruling. 2. In the new label nor') for `Biohetarcine-T' ~dcr "ittions" Jean Dayer laid thu fejndat±nns foe a statt'ment with respect to the contribution of Psazole to flirhetaie.c-T' e,~re,sed alon~ these lines "Fitl.ctc.:inu-f traduens an otloreciio effect which itni_ini sites ric,~r a few weeks. p..rpnie.,e,. laYs irrttabiltrMt]lz;i with `wruheteni ne alone. 3. The sitadots of caution and the critical irportanoe of slavish wihorenoe" to the kegust 8, 1970 inolernentation order rublisbad by the F & PA were heavily underscored by 1/inocot hleinfeld. 14. rt yes ocnsludei that eaoh'strergth of bar products be included to studies. 5. It van unanincously agreed that every effort should be made in lice with Aid.: Trunr.t' thirJ:ing to 5et the thinking of the arneotniate F & Pt offi c~ ole with respect to satisfactory objectives ond tho protocols theesulves. ticnthatt the such as oursdves thu benefit 0f iheirv,,t .`ntinn Vittrtn..oo~)pnotoeolowiiibc pursued. hut we er.:sU have to eaSy pnlcarriy Ufi on iaos~7FiT~n , Giovositi Costa, to glenn some guidclines frcn F & PA officials. PAGENO="0786" 15218 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Pr, T.i*ii Ii L'I 2 Pr. APi'. P. treauL 5, `(~te ftcsi !rtr'e, Iii n con cilici: th. Jr xi 11 ~y:er ~fl 1 lade Sj':I air I; eli.'. liav~, `1: Is .~r: tory 1, the D'j'UL Ccn ion I C20O. 1:, hept' that Fr Cs-ar, t ri `1 F,: ubioto?e]pF't1oticy;r.al j,rc:cY:'t-pl" ttr~ reaLS the t he cnn i-c of hula in. lIejar: en a cenftri-o,ce ln.th tFene Pa Dl oifici.ni. eta hre,o nininific ecancos- ihil&t.y tar h:rn,ti.i,r Li r.:.-. Aces in qeuretto::. stione:rateti'z.titrdc'..tbewefltr-,-rjtc to the Foci &tai: J.Psin:e':rctten with COP- to the .Loca). preen. to ,:ero 9 c,j000r:rnen end Senators, arre000siog CrC sr-na thy e:ath their ooj .`c piece ruit otto::, trac Vent era have doI.etoi certoin of cer aa~t~e Lr.eYno nrA r.etbnr."tarone dnp;:.. FF11-c this i&:; ri~' deserve sour colaicluration, the co.aeral tepli.nt of 4.he çreut, Its to the c-fPeat that this vonAri bonn illadvict.d. 03 .`L'~ that are should prnrroed lea a ha-ri `rar-lilr v-p.'; that cur- n-aar:-r':r,'rnt of CUT drclri.oa to witS drn.n feat the aarhat sr-rh :cn'uG:ctr BSphaLacvl . `Efroxino `triJr:r P0,02.0tc the ocro.Son far tr, etr~dtretr. COaCS VOL. F to Dl preesinp ~ ~ vnlarrt,vy eniihdrra;p_L iron irate chroujeLs all. inveitorir: ci these itar.s. COO cOncord :1 orrn7an~ out 55cr an ardor eJ One flP.' ate:1 the n:na. 7. lea thc orrtrcicrt of Vie'.ront ~2eirrfaU it ~iU ta':e F Ei PA par-s rauntho ether frortracrv 3 to rrvalautc trio Febranry 3, l9~1 sb ee'eanc. It is our jud~çrant that we, 025 this cart stoic, sail be ebo.c to contiera.j nrhatl.eC those protects erithout int.arrutttco thrce;h toe grcalor part of 1971. 8. !Llthnuih Vincent Kiclatolt ceehasizsd the fact Vest Urn P & Is is datin~tei" boa tile torerd. mnphotari~n.a rxi-i- seniletrrrins-cant000i.ng coebirrations, art that, oiftniabo renot atroragly to political ar'ee.Lu-'os led by the n-jrie.i~ of teen l'tayerti:ere in picrivof soon fAr opti.r.c tea that ercient cevaltr.nce art psereantuison of dat,a will ron aporovol. 9. ~1rccnt fleinfeid Snot the fo7'o~.Arjsto `TflP is a a a a . ~.rrj'~p OS' fl `221.'. "7LT:-vL:i.lar:L;rtroarrrcia;u~flcflL.:.Lr,I1TThh so thirty tree cc Is:. reject' car.oi.rce. .1: tie e'.---juu. 1. ,ttr.c:ac.er,e~v,esrin diliFt. At. ~ err.? tile tL2lo the renizot Thro puhiis hen.1' i Lie, di.taa-'.oyr ainee:: rat n-i. a 3:0 or air30. :r:1;c the F IDi. :2 a' a,,''], i. Shi ecerite. P. per Afaru viaiicll..c!..a,,oa,iipj..a_uuar.:.UIsy.,.pic PAGENO="0787" COMPETITIVE PROBLE!v!S IN THE DRUG rYDUSPRY 15219 Pr. Vi]3Jne P. fl'sd Dr. Aido P. TrLtant C. 4,t~ss~. 2G, l~j7G -t iso to oat rnaf.tcnlj, sta~jssT~thdrs',aJ nf the ereduc the, eni~_~J~j'tto~- can hr s'esc,lved. It js isaor.sijiic to cite the nurbr~ uf nonth:; or years a0c1 its he'. Or-' yard PS] .t oJ Via ours ~ Os bore was to dotonailie by isp, ;r,s'anr, .-:a'iy. Wa, could I ~ co~ 2''° ~ ~" that carsOn irr,r'-,ao. It rieseass teat the 110's cool' `is 5 5 5 jeutioriop~Th~r_,~zCsfl of yeouestin~; a h:ariuz raid1 a possible suocecucat court test would have to ho E~e!jsll' tO~OlOiflUI'25s 10. Uoqucstionabl3, aribmianiuris by firm, rtric-h failed to 5up513 a~oauate supportong, tridence of safety usd effective- ness for claims udfl be rcjrct,2d and s'abjeot to xdthrrrrsral `nrocesdirgs. It i.e coruelvoblu tast thir; could resale in some firrs socuriag as'rrovai nor] otors'.s not. And sooe srnpliers could f'C2. tIc ~rtiu. To. mc' judgment, sre feel it very idluly t~'r'.t sO-I dood su'sztsslcns will either to approved or `Wejecte.i. h-sjc'stiori in the case of good suhoissior.e would hero to be saute on technicalities. Sub.risstcns which are c.:trigTst dofietont to Osliove will be rejected in any case. fl; Sha.c~ng the tosSing pruotictrlorly of Jests Xt~'rr we have evory roarcn to pmccoc.t tribe brord-hoodel optiralure in ouooeseiuiiy' disohorging the horrendous burdno laid, eel cur shoulders. Elwoo't A. Garner /b1 PAGENO="0788" 15220 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY C PRESCRIPTION PRODUCtS 755 JEFFEASON ~OA0. 6OCNEXTEN. Id. V. *4621. 1.0. 005 *74*. SOCHESTEP. N. t `4675 - (716* 271-leeS November 2, 1970 TO: All Division and District Managers FROM: J. Marion Meason SUBJECT: ACTIOW NEEVEV NOW~ I have just completed a spot check of your salesmen's daily reports. Ex- cluding those districts on our new Call Planning System, your salesmen are averaging about six H, 0, calls per day including those seen at hospital displays. Is it merely coincidence that names like Gobar, Gallop, Bridges, Brannon, Farrar and Gayley popped out on the list with 40 or more calls for the week? Too many men are making as few as 25 to 30 calls per week. Is it merely coincidence that these same Then are waking little, if any, sales progress? Ethical anti-obesity preparations, according to 0K&l(, climbed to l4.S% in August. Strasenburgh claimed only a 12.7% Share of Market for the lowest share of market we have held in a very long time. Any way you slice it, we are being outsold by our conpetitorsI Mcneil is up; Abbott is up; Semed is up; National is up; Lederle is up with a new entry. Too few physician calls, I am sure, are only partly responsible for this state of our business, Very closely tied to this must be the fact that our men are less than effective on the calls which are made. iThy? Let me pose a few questions to you. Is it possible that, having been blasted by some physician who said in effect, "Miphetaaines are no damn good and should be taken off the market", your salesman is afraid to bring an anorectic out of his bag in front of the next physician? Is this same fear of being "put down" the reason for making fewer calls? Is it possible that this same fear stampedes your salesman when a normal question or objection arises in an interview? Is this responsible for the actions of a salesman who Is swinging strongly to IONNIIN because it is non-amphetamine? Are you teaching salesmen to ask why when a physician says, "I have quit prescribing anorectics"? Are you teaching him to pursue this with the physician in terms of giving the doctor adequate justification PAGENO="0789" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15221 All Div. - 2 - November 2, 1970 [list. Mgrs. to prescribe SIPHETAMINE, BIPHETA'IINE-T or IONANIN and Me You Really Seft.Lou4 Abowt LosLnd WcAg~ii? rather than refer them to "Weight Watchers or "TOPS"? tthat do your salesmen do when the doctor says, "I don't prescribe amphetamines anymore"? Have you taught them to ask why? Remember that amphetamines, both plain and combos, still held 69.1% of the $7,696,000 market for August. Are our competitors better equipped to sell their products? Are they really better salesmen and managers? Enclosed is a structured" presentation for BIPHETN4INE, BIPHETM4INE-T and IONANIN that suggests a way to utilize the strongest support we have had for our 4 E6aentLaZ8 SyUei. Not a single one of our competitors has as much to sell! This presentation will be forwarded to all salesmen and should be implemented to your satisfaction immediately. Selling today requires guts~ Timorous "detailing" won't quite get the job done. CAN WE MEASURE UP? Cordially, .1, anon P'lmasom National Sales Manager J)44/mr Enclosure PAGENO="0790" 15222 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BIPUETA'AINE - BIPKETAMIIJE-T - 10t44M!N "STRUCTUREV" PRESENTATION `Doctor __________, - "We, at Strasenburgh, have for sometime advocated a program or system of successful weight loss and:control that incorporates certain essentials: (1) patient education and motivation; (2) caloric restriction; (3) exercise; and (4) medication, when indicated, as an adjunct to a weight reduction program. "It is quite gratifying for Strasenburgh, and especially for me, Doctor to learn that our ideas are in line with the National Academy of Sciences and the National Research Council. "The National Academy of Sciences and the National Research Council, in their review of anorectic agents, stated that `they are not a treatment of obesity in themselves and should be used as an adjunct to a total program of weight reduction that includes patient education, motivation, caloric restriction and exercise.' "In theory, how does this apprpach sound?" (Let him answer - listen.) `This approach is feasible in actual practice with Me You ReaLty Se.tLou4 About to4ing Weight? "Me You ReaLty Senioa8 About Losing WeA~kt? provides you with the educa- tional eaterial and helps you coranunicate quickly with the overweight patient (1st Part - show) `About Their Problem' and (2nd Part) `IThat to Do About the Problem'. For example -- True - False Quiz -- you don't have to correct. "The three alternatives to rigid dieting (Substitution Diet section, 100 Calorie Portion section and the Portion Control section) help you provide your patient with a diet that isn't dull and give you a way to tailor-make a diet to the ethnic background and economic status of the patient. (Show how.) "Your patient will better understand the role of exercise after studying pages 19 and 20. Many physicians are now prescribing a daily activity schedule for their overweight patients. "Doctor __________, do you think that you could use Me You Redly Sextou.s About Lo4ozg lQeeght? with your overweight patients?" (Let him answer - listen.) "The National Academy of Sciences and the National Research Council states further that `dosage of anorectic drugs should be individually titrated.' PAGENO="0791" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15223 `Doctor _________, when you prescribe an appetite suppressant, have you found that one certain medication fulfills the requirements of most of your overweight patients or do you vary the formulation and dosage strength to the individual patient? "Strasenburgh is the only company offering you the flexibility of dosage strength and formulation in the three types of medication to curb appetite. (Show BIPHETA}IINE starter.) "BIPHETM4INE is amphetamine resin. BIPHETA24INE provides appetite control on one capsule daily. BIP}IET.ANTNE is available in three dosage strengths: SIPHETMIINE `7 1/2', BIPHETA~1INE `12 1/2' and BIPH5TM4INE `20'. (Show BIPHETANINE-T starter.) "SIPHETANINE-T is amphetamine resin with Tuazole (methaqualone resin). BIPHETM4INE-T provides appetite control on one capsule daily. Patients taking BIPHETM4TNE-T may experience less irritability on BIPHETAMINE-? than bn plain amphetamine. BIPHETANINE-T is available in two strengths: BIPHETANINE-T `12 1/2' and BIPHETANINE-T `20'. (Show IONANIN starter.) "Should you prefer to prescribe medication which has less of an energizing effect, IONA14IN (phentermine resin), a non-amphetamine, will provide appetite control on a single daily capsule dose -- IONMIIN 15 or IONM1IN 30 mg. "Doctor _________, how many overweight patients would you see in six weeks that would benefit from Ant You ReaLLy Stn.Louh Abowt Los/_ng O)eLgkt? "Would you like starters of BIPHETM~INE, BIPHETA4MINE-T or IONflIIN to give to your patients with each book? What strengths? CLOSE.~"So that we can continue to provide this service and expand it, we ask that when you use Ate Voa ReaLty SexLou4 About Lo4ALng WeAgkt? and in your judgment the patient needs an appetite suppressant, would you prescribe (doctor's choice of BIPHETAMINE-BIPHETA14INE-T - IONAIIIN)?" (Get his commitment.) "SIPHETA14INE, BIPHETN1INE-T and IONkMIN are available at every drug- store and I will be happy to supply you with additional copies of Ate You Rttthj Sc4L0u6 About L04J.flg WeLgkt? when I call on you in six weeks." PAGENO="0792" 15224 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY suc.rc. Uru linac (ci Nov tn,.bcr `1, 1970 IC' W.F.. }J"ati,t_..l'.'fruant.I.ii.IlcGrz,'r,E.jhthr-, ~OQiA ]i. A. Cantor IN OO~'LV W - coPthS 10 Attached you trill find a cepp of \`ira-cnt Klei:'felci's letter to no refardina ito `Cc-;rchc-nsiv: J)rir; Ahuno ~t'evnntirn end Con-trot let of 3970" Dr. Ui] lit F. florid, V. P. Technical 0o~:nat5 one, shall be cur chief compaianco office-i ~ritt réc oct to the -owovisi one of this Act that ace port~e.cnt to our ore-rations. Fill `Eiid.otarsimo' that tDi]~iot_~i.~oTI , ftillin~ into Sehtr]ulc III under t!zc Ant, to rrnnufnrrc-± i-n ceheidule II? The f-ito_ray cosara]. hts the tnnn'crr to ihitiat: PrOCOCdirrS ri'fccttn~ n-ithie a tronsfer, hut rocordiar no /1 nce:tt -an I nfctd an.!] rue Yn.i;- rn n.n :t~-;it h~h and `noncayrenec ci the 1' PA. After talinine `tIn-i tecmle at the Justice D-vi,nrt'nen t,. ~f t!;e Attorney Cernenral scnishad to re-v-c a drug or scout:,.- a saL of a. aetna onan-d cnnta y, .acenid:.c.t Co so i.'it]ecut tb-c c-onc~nrrunce of the Un. !Jti,ouh the lc;n:ac:o of the law is not.too ecnnlicit a~nd thoro do still soars confusion about the point, his r;rcnJc::tld' felt tL~n~ ito crane rostrintiarn ::onnlcr annn3~to a subctru.-.n, Leo-, on: se'n.ntu a to c-redraw. 7ne stoat scent Cs thc,t in and Birli,;ir ,ine-T' were roved into Scn":cctul o II, these dn;re wnnilni hecon'o suhjrrt to pn'cd'aztioo cunannc. Pro,Lnnctiort oniotso in tOwn world to cotabe. fiat by the I icr v Cn'tna:'nl `die, seen--hog to the Jo-.-,, "shall detce-cioc the total qrtutity anti establish production quotes for each brute class ad .oor,trollod substance in Sehodnn].cs I ant] II to ho renutautuneni each ealendnr year to pn'ovid-n for the estimated medical, seionti lie, research, ant industrial needs ci the United Statcs, for lawful e:rport re-prfr_uicnts, and for the entnrbiiohr.errt an-i raintenance of rnsnrva stoeho. Pranhctis-o qnutns shell ha established in term: of qi'ant tile of' catch britain c less of con traIled sirbnrtunc e ant1 not in terms of irmii-ridtral it canaan's anti deenOt for,,-m na-crc rod ft-one or eontatnin~ such a control] ed eubatnatso''. bets it crrrrh dnn!,l~ ira.c--r-. ties [h-it our Feliruatf 8, 1971 s'ibnr.i ~ to the ioon A Jirtic Amnain.i oti-atir:tdlitrtniv ru-macac anti s'e-eetei,liclm the i,t-tu ,-rlaual -neil tar `jncchcin-'uu .-,..`Lv.a:i. tflhisil-T' as nanoicatien to ovoiti platte Lion (nioSrit it-i m; ,unt.eblti alied mie-roly on thr' tints its of otrrl.c-nntnr on-; -a- r 1 C-f'' Eli iitoil A. /`l PAGENO="0793" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15225 J~ij:i-:i'i:,a,a-n, 1:_\. [a:' U C ((`030 Mr. 1.100(1 1'. Corner Pacoutive Vice Prcs*d.rnt Penriualt Cor.,eratir,:i P. 0. 2cr 1710 Rochester, Row York 14003 Doer Pieced: - We are cnclosinq, for your infornation, a copy of the ::coau)rohensivc brue J'bunc and Prevention e:nd Control Act of 1970. "The Act which connolidatdg, modifies and CXDOOdS UUQrr nineteen sorrrato njecs:c of .1eoislation~ providrr,- a com~,:'c-* Jiensite and connie:: 5CjI(Iryc to dual with the n]otlorrs of drug thu a o~ 11 ,-cca ~o'-~ 0: 0 ~Ct mis o'~ a ssec ti v ix :1c'.d:s fe .j caine i be ores :pue a (eta, of Do tehor 2 7, It 70.. `f()C Act - as-tr'.?~tehes fiVe scheriulox Cf. ceatrolj cr7. suostances and ijSt.( t.[L)SC srh.; tcyccs ~:AiC. ara :i.r~.tiuiir i.nelut:rd ii, each of t:,o:i~-u sehoctuj.ea (-202).!'-. nro:.~, is n:-u-,.at'--rco'- ttho. A homey Caner; I, uoo:' ;nct: i no a!;; ronri. ate ii a di ocj S , Is `.17 P rn - ntrin;t:- ::y'e'l:tiyt: e~'tvr:yy't' r~: rai::c'~s~'-'.c: te c:-o cC the, ft'. 1 1; Ci:-:- (jules, renaming (~< (``C c::lcr SUt :1:22 C.; Ii. free tao schedule.:, ortrer :r::!nr a cr5: or other subaLr:nco -:2:':: c.s-hc,lr;le::. :efor,i::i-.-a:incr t:nnn ore:::-: urar, t':o At- torn-v grarral i:: r::uirm-J Lu uciCast iron tho flAW `ti sc~ .-~~`1fj~, coot radical evuluattea, and his raco:..nond.a- tions , :sto whct.mrr such d. i- or oL;ar C hence should to or braved as a controlled. nuentanco. " it r000:-:rn'n- dattoni,v the Secretory that a drug or other substance should ho controlleo in hincl.~ nc,~ on the Attorney General, anti ho cannot s'oajact suon drug or other su:-,::tctncc to control under the Act.. A:-:cer,tions to those procecluren arc provided ~-,here 1) con- trol is required under the treaty ebliqatjons of tho Unitod States, 2) the Actorney Gc»=a:'ra~. deci(:-c to control on i;-.unciiato prccur:-:or of a controlled su[:rtonca, t:rcl 3) a final doternrina- flon to control a drug in r.r:do :~urst~on:; to adreinistrativo pro- ccclii r:r mit i at ed pm! or to t~ is en a tm: a L: cia to of the Act. ilLatru ,,i;U iairt.',.u r.n(urs `i,it:i Pie- r'xr,-rtioii nt- the.liq uici;ijcctr able ;iruh un',ircrtomi nra; era nuhjc ct-ho Sehed ci', III class]. ii cation PAGENO="0794" 15226. COMPETITIVE PROBLEMS IN mc DRUG INDUSTRY Jrs-,e~ri:rp ,-~-:;-, lr -2- k-he liquid in joe Lob ic- me Lb a-c-~ in t. amine: re alas r: tie ci as S C~ ted sin TI COn troll Pd drucs: ) omeve r, ii: 1:. leo art ant to p a to th:tJob:t irce-r::olJ, .nis P etc-a ~-1T-2r), 5.i a ic:htc-r ad- dressed to Conqrr:ssna cir~r, indicz,L ad that tie fluroac, c;-ill initiate procaduros r- :-sua::t to Section 201 of the ?\ct to tran-;fer certain Of I h, cop otacaines froc schc:'lulcr III to Sct.edule II classifin;t1 on. `rho efloeL ~hnt such a transfer - wc''ald Ii ave cm the r::nuf act'ar1 ci aid dis brii;nti on of tho trans- ferred nmahc-t;enires will be discussed I or itt th~ s 2etter. Except as othere i:e provided in rc'--ufationn eromulgo trd by -the Attorney Gener:~l, every pvrson ~rho rannufactures, dix-- tributes or dispenses new controlled sube-tance (0302), or who imports into the UniI:cd States any conLaclind substance, or exports from the U0J tcal S-~otee any control tcd substance in Schedules I, II, III, or TV (01037), is :eoccuirsd to, obtain an-- nually .a registration issued by tho Attorney General. - -A separate regist-ration is required to- ch principal. place of business. Unlike Section 510 of the FE'OCA, registration uncles the Act is not automatic, rather, Section 303 and Sectiot 100! set fort!: the reruirernonts er criter~ a for ils issvonrr, or denial of a registraticn ?rc'visicns crc mrdn for oro~d sionnl registration mending registration or denial vndtr the Act. - Finally, a orocodern, $ ::cluc7incr the ric:ht td an itdminis&rdtive henries rn-f J'i~C~ C1 rovsow. Se: `:roviC I for the daniol, roaoa cation or s'aspensicn of regisI:~aLion (531f) kegistrants, with carts*n excejt.e:s, arc required by Section 307 to keep end make a:'ailah'.o for inspection the fol- lowing records or reports: - fl On the effective date of Section 307 and every second. year th c.: face, nconalete and recerauc record of all stocks ef controlled su :;Lanc-es en hand, 2) a current, comoleteztnd accurate record of each controlled sub- stance ~ranufactured, received, sold, delivered, or othcrn-:iso disposed of by hin. In addition, registered manufacturers are required, upon request of tha Attorney General, to `make periodic reports to the Attorney General of every sale, deli.va~' or othor disposal" of any controlled substance end distributors are re-- guirod to make such reports with respect to norcotic controlled sit s ton ccc The Jahol and lahaling of controlled substances must ren- tzii: an identifying symbol in :ccerdinnce with regulations of the At to racy Ce: oral. Tb 0:e 1 of d r or s Ii 0 ted in feb edu las II, III or TV asint lce;rr wnrnincs at: to the core.equr-ncnn of ii legnl din tn but ion `---hi c:n are `sos cnihad by the Socre tory o )fld-1 pursuant to Section 503 (1:) of the o'eDCic. Also, controlled PAGENO="0795" COMPETITIVE PROBLEMS iN THE DRUG INDUSTRY 15227 1~ss:T')~s::u hA I -3- subs tonc(s iii Sche'lulcs I or Ill ,rc:oi:ic drugs in Sr:hednlLs III or It? i's I be trfl,t'':'d ii, cnn'ai `sm securely ceded asrcc~ttircd by rcquiat:cs: of ALtersy Osnerel. In addition to the resinirerentl nj-s ci fled 0)0cc, which ore genera]ly opelicahac to all heroonu who esnufacture, distribute or di spon se control led subs t Z!fl C , the Sian uf act ux or of S ch a du los 1 or-lI controlled su'os~unces arc E;ujnrt to mesufecturing quotas based on r:cdi ccl and cci cr. U. Lie' rends (0306) and these substances cannot ha distributed "e::c'.npt in pursuance of a written order (shich nut be preserved inn a period of tie years) of the person to whom such substance is distributed, made on a fon~t to he issued by the Attorney General" (5306) further, prescriptions for controlled drugs in Schedule II nay not be refilled (5300). The .limitations and restrictions on the importation and exportation of controlled substances which arc set forth in Title III of the Act are even more restrictive then those pre- viously discussed. Except under specified circurstances and parsuant to regulations prontulgnted ha the Attorney General, Section 1002(a) provid:s for or, ot:Lric~t prohibition on the ilnport.etion of an" controlled subs tense in Schcd,,les I or II and any rz,reotjcd,-ur, in Schedules III, IV or V. The ime~,rto- tien of any ne~nnrcc,'ic cjntrellna :;~`;3t?ncos xr, Schodslcs fli, IV or V is pro:nibibn ttnl em it is "it7ortcd for medical, scient~f~c or other legitiriat:e uses" and `pursuant to such notifies::ion or c:rcl.aratica r u12-cs:ots as the ;.ttereey General may by regulation jose-scribe." Unless ot)tc-runsecut-ho"jzec~, tt;a e:-:~ortatie~ of any Schedules I or II controlled substances anti ccv narcotic des' in Schedules HI or IV is prohib5 ted unless certain specified reqttires-onts era sint and `a Per:sit to escort tho controlled substance in each instance has been 5 ssued by the Attorney General." The exportation of any nonnarcotic controlled sub- stance in Schedules III or IV or any controlled substance in Schcdule V is prohibited unless: 1) `there is furnished (be- fore export) to the Attorney General docurentary proof that importation is not contra~' to the laws or ,:eriule.tions of the count*r~' of desfination;" 2) "a special controlled substance invoice, in triplicate, occor:p,-inies the shipment setting forth such Information as the Attorney General nay Prescribe and 3) "j~'o oddition.l conies of the invoice crc fon:arded to tl,c Attorney Cthnrrcl bolero the cor,trollcd substance is exported from the United States. PAGENO="0796" 15228 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AN!' In this letter, we have summarized those provisions ofT-Lire Act which we felt ~-:o~, id ha of part cult con sara - r:m'ocli(o I tire Act are other provisionc, such as those dcralin~ with :.drtin- istrative inspections and warrants, oonal~:ies,fc;rfciia,re-; (seizures) , and injunctions which we have not discussed Let which are pertinent to the manufacture, clistrjhut$on, importa- tion, and exportation of control] ed substances. If you have any questions, p~ecse let us know. Sincerely, 7/. A. Fleinfeld -VAX/abc cc: Dr. U. F. Heal, Jr. PAGENO="0797" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15229 L~l:~1~L It-ce, t~s eL,.fl,s(,,; tots. rp;,s!-~..;.. in-'... Cr, ne V. t~,c'].t7tO Sn `C' Yt~nrurtry 5, 1 111 ADL FfECD&~f::2 Toe re r.w,.re of t.he ~.` the Foe" serf: On,- Adt1nf at,'.- teen it. t:hith PLnhetaH .&e, 1~~.-v: ~ ecre s-tI "possIble effective" t of t~'fo v'tit'e V te subei t, :tshi us sy net ccci' znh,ez' * Deer tcct~e at, to sucoceefull:- achieve th~se cb~ectivos von: L to ccaroh out the he"' clinic~n, In the U:'it d States Tn eor't., the clieloni e'tucect, 2. to ~~`~`~ro "rotouoj.e and lete-atere or ,,neirt ehich for IDA £r~cro'efs 3. tocrr',';olt t4t,'nth'7E[ I-pert of, cf o .e', er'51 cC. tOed when poe nu]e the te ice c ;n cc the c~u±:ity of: the work thret oro.e: bolos' (,cro Cf th~ ttzo rertod it, which to subeit the data. Th~J, reore:-on-'0n the cc acooratoiy estC,],ash the therapeutic value of these :-~asts. The ce't,t,,n time civeo by the FDA was not an extension of thi dordilno to phi con reed but eoecitica1I~r to Strasenbur~h_ This inforratior, is suspiled to you so you rUt know the etatun of Bir'ert Iojrtin"), end illrhetanir,-t'l) as of February 8, 1971 and should nut be usaC in any we)' in the protcotion of these products. Cordiefly yours, Isp.ao iL,2.2~Jaw4 II Vies ~side~/ PAGENO="0798" 15230 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PRCFE'Il c-i pnoru:: loaJ.:ree.';-n!, IOAU. ~OC Stii. N V. u~2I, 0. POx ,z~x e.DcH~'rxR U. - (1Is} O7l-ICPt- Parch Ii. 1071 TO: All Dlvi Sin! DJ.s lr~ Ca ~an2gtrs FROM: .1. Mrrion Weasc'n su3Jaa: £,TAYUS OF .&`J~R5CT10S It is apparent that rany of our wholesale cijata-ners have grave deu',ts varying ~eizro;s of atpveF.onsion rh~at th, status of ae,h~ tnrine products today. This rçfl'~:r. ;;hy the mv sitori cc of our products, Birhatrr,nzC, ciphotr-nincr.-Tn:'-i sorirLi ru, cr cii as ox, rvr,ta:o vs are beinç elm-cd cc duirdle to nothing. Proorts of cu-~ c~ s~ocio and EoJ~ Ckc'ths err nor? frvrzer.t thcr crc,. Those wholesalers ae~d your reassurancn The rctsiler is a victin of the Sara thi'kirg too racy li-stances. Your saloa:ea err affected in direct pranorti on to the nurber of exp:ti:nr to such negative thoughts. Therefore, consider the follos-'ing actions mandatory on your part every dCiv yoa are in tho field. 1. Take your salesman to his wholesaler. Reassure the wholesale buyer, sales manazer, etc. * that: A. Uiphetazsine. Biphetaeine-T and lonae.irs ore still ~Q.Lr9 prod-acts. lice Isaac McGraw's letter of February 5, 1971, regarding the status of Diphetarine, Biphetamine-T and lonamin. B. Show then what our prnnotion schedule is, C. Show them "Are You Poally Serious About I.esing Weight?" and .hat we are doing in the physician's office. D. Got ihot invontorf 5,cL upto adcquate levels for doing i'usiness PAGENO="0799" COMPE'I'ITEVE PROBLEMS IN THE DRUG INDUSTRY 15231 sV. ~ 2. Every whD en!e, Pr r to Cfl~ led Ca by your sOlCS!PiI~ at least once a 7011.1 to 1 ~c>,,ra wad totivato thc buyer and sales 3. Ar 1cw~t five sor:. c-,! ~a'~ ha rrda óy every aalesoan e,kch e~v. Show tho s~iewa h. t o rcaaauac the phnraitcin In the Sante way ycu 711 ~ tha ,r.clctut~cr. 4. Your visit with ccc ~ilor.aai rho inn),.!. hc.l~ttoring his own belieS in what is dob~-,. Prohe an~ listen, You coy prevent disastrr b,fc:ø i~ c.. nzcirnnd n~n t:ve customer reaction can dest ray sat elan * a worn' and effect iveneas Fe, you or we cannot afford to ~ct this hanpen. Let's do the job rightl Cordially, ¶í . :~arion x-raso-, Nat icont Sot esfla.iaeca tr.closures (2) cc: I. IL F:Graw1 Ii 85569 0-77 -52 PAGENO="0800" 15232 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY yJ i. ti' ci!,, ii~'~i Jr;r~'ciri I.'., rrtars'r', r/',,:.: i~v3r'o:.rs'icr i's~'''.nr, !r:V Y(Y% i~COa'~75i:'?i .101 hay 2.0, lOll Dr. Barrett Scoville 01' Fi cc, ci Sci on tifi c EV;LIUatiOI ~ of Drugs Fred end Drug Adsinis ~rarion Rockville, Maryland 20352 gDA JJ.-533 /5-004 ijear Dr. Scoville: We litre tareully re~iew.ed your letter ~f April 29,' l271rcgardi~g proposed changes 1n the labeling for our product Bir'iintarino-TC.. We. are in genera3 agreemont with the basic theme of your revisien to incorporate full di2el050re inforr.atiort for. the ir.ethnquaiono conponent. as it relates specifically to Btphetsoinc-T. Prior to adonting this coDy for final' revision in printing we have several CO:t!etILs whirl': von tray wish to consider. `On pcte two of watt ] cttc r, oarogrn'.h; 3 en~ Ovnpr:;ent a al.:nr dcportnwc from recent FDA policy oug~caring the elitinution of results arid data oh rained crea studS vs nt lahomntnrv en s. On pege three, parn3rcoh 7 regarding rtethacuslcnw r,etebolisa in rho 1iver~ we stigges I the following sentence. Sioce B,tnhctanine-T con' dna retl,nc'ual ens which is w~--tsholi .:nd in the liver, it should be used `ti th caotien in these with irpaired hrpnric function." lhr physician is not adc~inhstrring r2tha,,unlonz as a single entity, ;n~ it 53 not possible for him, the phareacist or the patient te reduce the ::othsqualena desege in a unit dose of Biphn taeine-T. rho unit dote of Rinietsniae-T already con- tains a substantially reduced dose of nothaqualene, /.3 ng. as conç'ercd to ~a `300 mg. sedative ieee. On page three, paragraph 8, me disagree that the adverse reactions listed hzrse positively occurred with the cur,hinatioe. It is sugges ted that a mote accurate phrasing would be, " .. . have occurred with the individual drug ccvpenents and which asty possibly occur with tie r,or,hinaden." a PAGENO="0801" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15233 lit. ikirrelt Srovilla Pope Iwo liz:y 20, 1971 On pegs four, parnhrcph land 6, s~ uco l.:nny of the, adverrn re;:rt ions are needl ossly repel: ted we' out-nest CO:11)lOJ07 these paran raplis .15 foIl ows. ,-r 1 icr" oUe eva tcni Ovcrs t iretI :li:inn, tee LI essneos * di iiiess I nersija, eu-e!eoria, deseohoria, tremor, toroc'r, Iseadeecho, rengover, atigue, ansi eLy, trsosi ent pares tIersi:,, of the cs:trca.L tic::; rarely, p:;vehotic epi nodes at rocersce,de,I dusts.'' On page four, nnroprnnh 2, for better word fit:, wo suggest el, following. `Gas:tioioeest-inni., Dryness of tho touSle, uciplensent taste, diarrhea, enoroxia, nausea, eoesis, epigastric diseosafort and other hIs trointsstius,l dis turbasces.'' Our cost serious conepria is in the section under OVd!tDOSAc,g eccoarin; on pages: four sod five. The first two paragraples in this section represent regulntory copy applIcable to ai~heta:eines. `the remaining paragraphs appear to be a direct lift leo,, ec-thequclene labeling as applied to a sinpia entity drug. believe this nay he confusing and sisleading. It wou~d he possible to include tb, subhead:i ng ~ Ovetdntur,e'' prior to the first- two par~1grephs ansi the subh ondiug `tiethscualc,ne Ovcrdcsnge'' tic the hr-gInning of tho third psrogre:sh. to cur ogi `:100, this is aol: satisfactory since the r-ajcr sertias, OVEItptVfll:, should relate to a specific product, nrraly 7U ~°e~ taePas--T. t?a rasues t that you rcce:is-ic'cr tb.' entIre sectIon endur O\ EheJPSZ,CE with regard to ~eutc ovardosag:: wi ti, tnett-sgi'alene. Us do mt gues Li or, the basic accarocy of (hi informatiu,, lu t rather its appli canility in the Inbeling for thIs specific product. - in exasple of the rt'cmmltin" iuconsistencv is seen in the seceod para- graph reenrrcnding sedatie:, auth a barbiturate and in the fifth peragreph reca::eeaonding supportive r:easures for the uncunscio,,s patient. We offer the folle:'ing suggasted copy for h\'FPOOSAGE which covers' ,be sfgnifiernt points in re).i tionship to bipleats:tno-T. OVERDOSACE, )Ianifeststions of acute ovordosoge with arsphotseaines include restlessness, confusion, assaultiveness, hallucinations, panIc states. Fatigue and deprrns-ion usually follus the central tinulati on. Cardi cvasru] Cr effec to mc) tide arrhy thnias , hypor- tens ten or hypotoneicn and circulatory collapse. Gastroi,-testinal syrptoess include nausea, vormiti ng , dmarrheti and nbdentnot craros. In I:al pal coning uneelly terminu l:es in consul stone and coma. The syiepto:1:atology 7.istcd shove `may be aggravated by the neetitaqualene coIspoelant of Bipheiacsino-T. PAGENO="0802" 15234 COMPETITIVE PROBLEMS IN TIlE DRUG rNDTJSTRY Pr. tail cit 5_ovi 1 Ic Page lie wee flay 7(1, 1971 HonngeflenL of nciire arpbetntaLnr intoxication is ]argely syirpie- lone and inct~,e(cs 1avs'~o and a cdi Lion :ith a banlitturat a, if applicable. Exacrience id iii heandi rrlysis or peritoneal dialysis is inadni1uatc to perrrit recUr aonnd itions in th r rc~ard. Analoptics are contra-i odiretod. For prolon~cd convulsioiio, the litre of - - surgi cal rustle roii axents acceapari red by eechzjiically controlled or a:a~ sLed ventilation, by practi Lioncra akil led in monte thesis end resuscitatina, lens been proposed. Your comments on these suggestiona will Ic-appreciated. Very sincerely, srrJesE::BuRdH i.AFCJRATORTES IL! Id. F. Pearl, Jr., FleD. \iice President Tcrirniciel Oporoticeea Ipif/vina PAGENO="0803" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15235 ~itJ.~ DLPAid;.'LNf OF AL1F!. Lr~tic:Arici;~, A:~D v.'l.Lr,;ilE PLflhI IC IICALTII r~OVI( C II0cIZVIIII:. sIAI'YLAF,L) 3 FDA ii-5~8Is-0O4 APII aS 1971 Stran~cnburgh Loborn tortes Division of Ponun) I Cczpnny Attention: `7. F. heat', Jr. , lhD. P.0.Do,: 1710 nodes t or, Pd;? tent l~G03 Con Ilernon: Re formic o is cii sic to yuur coop I eLn"r. to 1 `ic, ding on]. Ic at ion of October 7 * 1~70 suinaittod ptircuaot to section i05 (b) or rho Fcdcral Food, Drug, end Cotootlo Act for fllphetaminc-T. (d-aapho- tomino, dl-ar.p'i~t:ar.iine and saethiaqua lone) capr,ilos Tho supploetantel applicntid:i providar far labeling revised .11 accord vtth the Federal Fhgjstcr_Senrerend of ii;utt d, 1970. We have concluded our revicu of the s:ih;.~ittuc lsbei 1r~'; and find it I r.adoquate to provicic for so fe tiac of t;': drug. Accordingly, no recommend that tint Label ithl ho roviznod sibFtantiOl IF as represont ad I,y thc Colloning :u~:ge;tcd ~abclisg: Diphet1amttZ:-P:eir5~ Lniie11*~g: ;pimm;wilhs PAVE A SIGNIFICANT POTENTIAL FOR ALUSN. :1U~ VIEU o~ TI7EJnLr;]'r::f) S :r-r~2.s; t;iaa~ciic trF;ur /.;:n RAPID Drd';:Log:::~:T e:'co~.yC.::C;:, x::::i Lc:fi) t,gEo CAUTIOP AND OtLY FiNd LIt~lTED FEF.I01IS OF TIFfS ~ fl~fl~ ni;DUCTIO:; r~:olLr::s. DPSCRIPTION: Ihiphotanino- Biplietonina- T-12% 120 Each capsule contains cationic Each capsule contains cationic ;csi a cnn;,ioxcs cciii iva Font to rosin corp lcxea enuivo lc-nt to, :rer~,hioLitcine 6.25 513 .`*;f:..- e~/)ipI'ctariine 10 ing. Tulizolo Tna::nlc (methiaqualono) 40 tag. (mc tbnqua I ono) 1,0 mg. The Empirical !-`oniuia of r.,cthiaquolonn is 7 nicthiyl-3-0-tol.yl- 4 (311)-quanaroline. PAGENO="0804" 15236 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -2- / C £ IONS Ac'cçchecnccci.ues are rc7raIlo::rcr:cc I cosines tic CNS cticccc I ant activity. ierijhcr:ci neticci'; ic:::]cc;ia oftvnti eno f nysiol an:' din stu lie I' land p cc s surer an'] van I: brouclicid ii at or and r esp Ira Lacy stiraulaut action. lice ncnreasic effect dic:cinIslcac; after a fec, wee~~. l's U cots on E~ picet o:oinel' nay cx en ence jess irritability rIcan those on ns::hcrnniue alone. lice exccrt rode of sedat lye-hypnotic actS nc ci rcelhac1ua lone is not icncr.nc. - idothaqualene has ccciii' ssive arc] anrispa snrudi c activity in oxporinenta I nov75! s. It is cisiolco tired in the liver and excreted in the on oe;cccd feces. INDICATiON: Exogenous obesity, as short tc-rrn (a few weeks) ad tLnct in ci rcgimcn of weight rc'duction unsed on en tone rest notion. CONTRIcINDICATIONS: Advanced 5cr terioaelcrosir , zycrptoc..at~ c card ;ovnscu lot cliserse roderate to revere Ig'pcrtcorfc::, hyertl.i~re±dircn, ircec'n typer s.cnsitivity or ticcccyucrrsy to c::e syc:;~tIcfl3clc:7tic r.nfncs and/or rasthagna Lo:icc. Agitated states. Patients with a his tory of drug those. Daring or within 14 days foilocciccg the ad:aiuintra Li en e intact - mine oxidase inhibitors , hypds ttnsiva cr1 an's ray resul Women irico are or boecro ~roynOnL. P,et'roduction studies t~~ethaçna nun n rice rat revel Ic.] nir~r tat c tear-cr tifflorac. nec,nn-.a rrfTFtJ cc t Icc' yru;cy. ncc1nc.Jc' t~OoSt1'ctO5_21 4~PhCt~tnie 1 a.s,.t ci' ` i at. WARNINGS: Toicra nec to the /oot: Ca' tic effect utica liv dove lot, ui tic in a few weeks. When ttci.c; octets, tic recorrcrnclrd dote shotild uot be excooJad in in at, ccvi t to increase ri.' effect:; rather, the drug thou ld be ti i scent i cued PAGENO="0805" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15237 -3- itils dciii; I".;) I irist) the ebility of lie patient In engage in - patent is 1 I)' liar a rd;., s net ir it; es stiel; as op cia ii ~ rinciti nery or ci ri' in-; a its (or velti ci c c pat onE should ti ore fore he ecu U cc~:d ;ic:card trigly ~ /;mplieea,ninos hive a s goificani: potential. for abuse. Toici tirice and cx tre-ne psycitolegico 1. dependence have occurred. Tiere are reports at pr t ients s.ho have increased the dnscge to cony titsos that reenteirende-il, Abrupt ccsi-o tine inti owIng pro longed i; I gi dosage adam t st rat ion resu its s-n cx': rear: La t igu e and rent a]. P op rest; Sc;, cbs egos arc' al so tin Lcd in tb; r let;, EgG. lianifcrtarior;s of chronic irtonicatfo,, with amphir t ,ssi not inc 1. uric soy ore durras u;: cc, rhed in ;:omnic 5rrjtr.hjj icy, I;yporaetivity, and petseno iuty changes, Inc tncst severe r;.sni feats tie;, of r,ron it inronica U on is psy- chosis, often clinics!] y indistinguisliable free schi zophrenmo in ciii lc~ren This drt:g is not recour:icndcd for use in child rcn under XX years of ccc. Care should be used durcng adninistra tien with other sedative, analgec Ic, or psycl;etrep ft drugs er with alc~,hol bscotiso or pond bin additive (fleets. PREcAUiXONS, Crwtien ft to be .exrreised is j;rcccrihing actpl'nta,i;,cs for patirnts with even mild hyocrtens:ion. lou] in oc;uirerscts in diabetes r,al titus coy be altered fn association with the u so of nr.:pl;ecs ties and the concomitant dietary regirser. Airpliotamines i-ray dccrease the hypote-asive effect of girinseihidin6: Thu least crrounb fe~sih1e- ~hna1d h& prcrcrihnd or dispe;ised at or.e tir.e in order to mininize the poss~bilsty of o~erdoange. Since mothaqus Irne is metabolized in the liver, it should he given In reduced doses, if at all, to those with impaireo liepatte function. ADVERSE REICTIONS: Tli~ following listing includes adverse reactionr.uhiciil,'ve occr;rredt~ççlj_tlie individual drug componentsC~ well asisi.tli the cs-J.~uIi `;r..., `~ Cardiuvnccular: Palpitatien, tachyesrdia, elevation of blood pretr.ute. PAGENO="0806" 15238 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - `I - CruIral flare -a. rgg~ca.~ Ov:csti,,,l nI.ir.n, restlessness, diz:-:inc:rs, icata., t:~a. i d:~:inc~, [`car':, headache; rarely, p_yeas. e c:1Ssv: a at of ti: sri 1 ,iitiicntP at taste, diarrhea, our :asrrc.:t-) r:tinJt cia.r:_-5s,ces. It:inrc;:ts; `lusts, es:asi'nnicpi:sLricdi.:;coui-ort. J:it~Q!1!BSJ. It'.70t snee changes in liJido. ion~eve:, fatihee, dizziness, torpor, C raass.c:,t pates Lhc s~ 50 of Cc ext arauitic As orcnsiorua 1 p; ajar baa e:cxrirne ed :c:t 1 cssne,s or ansi ery. P-rs,tniea.ic: ,ipi sat: Oafs potatisly cc Letod Lu raetlsnus lone las been very rats iy ] s,,or Liii. Jii!~tgi2ric! Disphrroses, breshi ci roels cxont'umma. Uktic;iris les to cii pa ci i.cu lca:iy tell docursant ed, 1i9 eli [ho rue Lbs L1ia lint: C 0: up 0:: out IIUSCE APP 1 ~lPI srhiTxo:: Regardless cC inziicatin::, aa.-,!scts:ainer slits-id Is arualniscered at the lot-cat offset isa dcr:::s a.:- ci sc cia.: ii be ind-~ vici_ally adjusted. La to evening aedicati on ui:OLII d be avoided because of the macicing inrrra.in. Obesity: 1 capsule daily upon arising. b\'EILDOSACE t-isni Cestoti or-a of acute overdoscugo with cni:c,taaises foe lude restlessness, confusion , assst~ ILi/enoas, halluc faction:, panic states. Fat iguc one; depression r,tuali y follow the cc-stun 1 sLits-ala tics. Cordiouc scu lee effects Inc hide arrhyth.tias, hypertension or hypoticnsion, earl circu la Lory collapse. Castro- jutes t inc I syrap t eras inc hue non sea, vcrsi S iirs, ci jars bee, a ad aldoacina 1 craa.g,s. Fatal poisoning use: 1v icn:icuotes in convulsions anti corn. Mcna~enent of acute at pluetnauine intoxication it a rgely ryrpto- tactic sod i.hc hides I ruva~ae a::! ardoti en usitlu a ba.vbitnrn to, Experience niL!: lcearslia.lysis cc peritonoal dialysis is iitadoucce to petal t sec or-sends Lions in this reuard. Acute ovorduisago with :cctliaqtin lone insy recu It in deliri jo and o:na , vi cli r as t less nCr s end Ii) pie Ionic, proj~ros I rrg to cnn vui - sinus. PAGENO="0807" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15239 SpOntaneous ~`oiflitinfr and increased secretions ore crisson and rr-ny It-rd to osp~ rtt jr-n print-rnaitlN or- ~-cn~5ntory abettor- thin. La:-1;o overlores in-c bairn accic;:nit.d by ce triricor-re edosri, pul nancy edoso, liopa a icdnn;trn, renil into I ficianry, and 1,1or-dinr-. Ovnrdorcs of sr-tliac;reniiinc rFp1rrnr to ho less often as icinbed `-ii iii card ice or reep irir cry depression than are o~ordoscs of Liic avail barti rita' toe, but sI,cc.k arid rer-piratnry nrrcs' occasionally cc-cur * Coast has occurred vi tb rico L C- OCr doenres of rtt115t!un lone a ~cregi n~ 2.4 r~ a. tan tli a occur,- rd to I l.or:$ ,r' in~ oat ic-as of S ~;aar . In ethos ant psticnta~ have survivc-d the ii~rr-tio:s of up to 22 grams, of rrsthsqualone. I-lost fatal cc ses have Id 1o~:od ingestion of everdoros occonrnni ad by a lenhol. gcccr-t~ondcd rinnar-cainist Intl udc-s 1,roarsc c-vacua t~ on of ga s trio contents, esintenanc a of adoquc to vanU lotion, su,aport of blond pros:] re if nec easary, and the usual supportive aaeasurcs for the unconscious patient. tialysis may be helpful. Anzrleptics are contxn-jndicaled. Use of succinylcirolino sccCr--snniec i-f car-). S C e0 icautro tion hem been proposed for prolonged ceituleiorio. 1111W SUPPLlEo: (to be arnnlied oyfnn~ Tire cbs-i' should h' c~ ar-sr-eon a' pn.ifl,L~ cad in an, cisc, within 3(5 clays of receipt of this lettor. Please lc~us boor, a:itlrin 15 dnysof rcrcipt, of this lotter your pro1r-otn 1 its regard to the ahcvo - ret's-rn nala lion. Sincerely yours, it tersest Sroville, 1',D, Deputy Director Division of heurophsrmacolotlicol Drug Produces Office of Scie,,ti tic Evoluatiers Bureau of Dregs PAGENO="0808" 15240 COMPETITIVE PROBLEMS ~N TIlE DRUG INDUSTRY no~. tacra.~u :;rUfle:VflU:: ~ tn: ..S~; nf.cc~LpsnIee in this iniusLvl! is bn~d o~' their ability to - edjust ta zuc~ cban~e St~~ib-~' a nvth pet~or,, vjfl b~accelar~tC.~ ane to thin auie Withlo t~o years: IonezJ.rf~ wiU be the f'J xr rr~b~d e,-&,~±~in~ Bithatanlnc<) will be tb.~; Pt tirhctz~ne-~YO vill be the :1 rrazorfl~~ cct~ati on :;ca -fl-ill be tho cnVy e the ~str;. CordIally ~uu~i, c~k~<7 Y 1t5M7-iC' NcrcA~I, It vi IRH,'ew cc; Mr. 3. Mtrlon Meason PAGENO="0814" 15246 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY i: 19 7~ fl'ff. W. I'. lica&, Jr - t'5ructor Con;:co'. - Pru.~4: Cc2t 3r~t~r~ on P. U. 2o>. J)JC Roti~.cstur ~rio2o~oJ ri a co~,' oi objcchic:tr;;e lad toJ~y w.~ :± t~ro 2u:~2aT.r cJ Na: :sr-ud 2Cnc-c,rc~:r~ Drum; ~!t~s ~uocUf) iiir~r.Lr:rrjna anc. Ni ._-T. ~ahe ccnt-~-~t is :uaj. No yr eo:o:. on Juno 24 Lc~tltt ~ you as Sam; or W*2 `s~c-'1.'e any war'. East rr.qrcdo. SincCr.aiy, * -J AX~nE. inI~r, HE C El V Atflc/~~3c I ILt I End. cc: I-r, Liwnod A. Crtsner (~,er,ci) icr. I .Nr.croo: (t-r/'rr*o:t) Dr. Mdc D. Truant (w/c'rsci) PAGENO="0815" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15247 LA%1 O~ I :\~s;u<,Jx)) n:':') ~ zr, ~ a7,, :.t,I ,, .nnnc.;c,N.L~.c. 2oC,ThC TI~OM~I 0. Juan 25, 1971 Di teats,:, 2t:r$auc,fSs ccti CS' and Drznrsrotis Druris Pep.' tztzvt Jitatice Waz~hingten, U. C. 2u337 Dear Sir: - Pursuant to Section 201 (a) or the Controlled Substai;css Act (Act] and in accordance with the procedures spraified in 21 CFR J03.45 and 316.47, the undersigned, on behalf of the ?hcrrmacr'stical Division Of Peonwalt Cs.rporaton [Pejinwalti whose : ~it:Lng tzd'ivoss i~ Post Offics ?.r:-:171 0, Ptctctntar, rzn~ York 14605, horehy reqne3ts a haarinq in t~t-~ matter entit'iacl "Prc~zosed Transfer of J\motetszainu and atbs:.zphez:a:Ine and Their Salts, OFtical Xsoners, and Salts cf Their Cptic.nl Isomers T'rce Schedule Sli to Schedule It, Uith Certain Exceptions." The pro~ posal was pubtished in the Federal Register of Nay 26, 1971 (36 F.P,. 9563). - (A) dii June 17, .1971. representativos of Pennwalt net with repr'dsentatives of the Eurccu of Narcotics and Dengerous Drugtt [Bureau] to explain that two Pennwait drug preparations cozitainincz reoin coaploxes of amphetamine and dczxtrocm',hotaminc, and matteL-- under the t:rade names I4ipho-Ez.anine and ~i5phnteni.nc--T, were nnt should us La nut: act to the so;, tIc.l ttc-:t-,i-, end by rae ,-~ V .: proposal - Pe'nntcalt tainted OtiL that titcn;c resin czcznple:ccsa: 65-509 0.77 - 53 PAGENO="0816" 15248 COMPETItIVE PROBLEMS IN THE DRUG INDUSTRY `-`) A::1, J.i_LL't' - not clossifxsblc :~.j~-L~e5 n-2 or ;e~hcL~inct salts ~~jtLinM~e reasonable an~ prclps,: cH' ::e:~ir:g of those terr.s and th~i. other tern uazd in t~iu proposal was arplicable to either of the Biphotasine :yroducts. - - Ca June 21, i~7i, a ,-c7ro-.-:atjjiiva of the Bureau notitirt Ponuwalt that, contrary to ~oaittcn taken by Penewalt, it was the Bureau's conclusion that the scope of the term °arnphota- mine salts" did in fact an~Orf'/n3s the rc~in corepleses contai:lecI in the LiohetPJrine preparations cal accordingly, that Biphetainias and Bipilota4tine-'f ware presently subject to Srh~c1ule III class!- ficatirn and, unr2ev the ~n~' 26 pvape:-:nl, Di er-u~ize and Biphetesiite-T peuld hecone subject: to Schedule It classifica~c'~ if the proposed transfer wuro to beaccoisplishod. As a consequence of the neLoro of the controls inpo~ed ~:c~ Schedule XI controlled coboL-auras,- thu cisnufneture ref d sta~r tion of Biphatantine end fliphetamine~T would be severely and unnecessarily restrIcted were the proposal, as interpreted by Boreau, to Jr-s zr-ado into a final regulation. Such restricL-ior~ would be to the substantial detriment of I'ennwalt, medical practitioners, an-f patients who are presently, being henefi.ttud by these safe and effective a':oractic drugs. - It is respectfully subnittcd that a hearing on the record as provided for in Section 201 (a) of the Act and Sections 4 7 of 1-he Adninistrativa Procedure Act (nrA) (5 U.S.C. §5553 cud PAGENO="0817" COMPEnTrVE PROBLEMS IN THE DRUG INDUSTRY 15249 ]Cr.:~n~i:~ s&, is rec~u1red Sn e::tc,re-.:01 ``c, :heh;-sros raised h-' t~.-e e')jec-~: - so for U~ `:-~ c' 2- -- ~+c-1. t'nc~t ow i S t~ Y LI~ WI. C: prchativn, and sti': ni C. a 523 5225 ppo:: t of subj c-c fling mine cccl *h-'_tartre--? to SUVfl-fli : £ z.I.eaa&ttc:rbion. Usrlor §7 of thaarI~, the, suaccu, -c t'.t_-prof-onarLt of the rule, has th burden of establi~hin; at a :s.ariSw c-. 1 tho rcscrd the vnJ 141 t.y of the factual allcgatioas °r°~ ~:hicW I he rule is requirc-d to based and Pennualt, as the oepcnent, - ss catitled to prnso~it itfis case, "to subatit rebuttal evidence, and to conduct such cross- examination as mecy he required for a full and trun disclosure of the faces." (~) ~ e cbjeot~ ens as they ann-tsr heR-., - issue5 for a hearing and prn:srnt reewe ebb grounds in ~fl?nfcrh of Pennwelt' a oj~position to the proposed rule, as it is S a bar- preted by the Bureau: -- - 1. shore is not sufficient reliable, orobc~2ivn, ~ substan ihi crvtcence to suar;ofl-C the :oci-ual dTl:ersination sade by th:- Eure.a' shet a:; -- maine resin coroloxes arcs nelurlafli ~~ich~n - or wihiiin the cac'aninq 01: any o~ the other Lerns used in_prorowd section 303.12(3) (1). Peanwalt, in rebuttal of testirauny that may be Offered b~' the Bureau, is prepared to present scientific and factual evidence, including the testimony of highly qualified chenists and other scientists, that, due to the distinct differences in PAGENO="0818" 15250 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JTT.I:r:. `~,,-.ne:' chc i.iC~ I a ~n cc a: rh: :. 1, hi oc~-. eacic ci ~a~u a.:. acj ia: charactc.risLtCS anta.fl. C:7:-..'- ..71 :1.. a3:d aaphataa4ifle~.0c exchange ~c'r:~ a cc:'.C::ra, i.s~:e atual and acicnhificall'J incorrect, Lea. rana..1 .:c. an-I ~ i~ ao clansify atphca:.:Z~.. ream cczajnl~::e5 j:s ha.: :.aLt_: cc a-: cay of th: ci ~h~:r substances included with: a the tanca used in :~ro~osed Cactien 20S.12(d)(l) c-f the rcquiat*c:1s. 2. Thnre ~n net ~tffIefcat rc1jab~c, prc~ve,rt Cia:: :.c;:t tan u of ~j.th.e~~ah..c n:: : :a::.r.:' in c:;-.:a,'ie The- Director, in ;:be Ma1' 2C 14:cha:al ~agirLar p: onoc'. 1, :- . - a blanket an serticni tl:t :r hotanLanes an: : -..aa.hI~c-.f..ta a:. their salts, optical is~anvs and salts of their op~uca- on-.a., all meet the criteria for Schedule II cor.trol. henn,:aJ.t clen:.er the truth of this assertion as it may. be sought to be appiiPd to the preparaLiofla )3iohehanifle eeC, Liphctcnina-T. renewal;: 1:- prepared to rebut by adcc:uate factual and scientific at idena en:. testimony that the Director may offer which might seek to cs.~I~ -. - - that Diphetarnine and Biphetaminet are salts of arnphetanino cc. even if they are such salts, that they meet the Schedule II criteria (1) of having a `high potential for abuse' and (2) Ca: their abuse may lead to severe caychological dependence. The Pemmwalt rebuttal evidence includes scientific data thich draflact:: : - that the abuse potential ol nael:aunc.Lr.e ras.1r I. suasten..xaliy less than that of j?ataraiACS,anihctrtiflC PAGENO="0819" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15251 ~-v'~ `N and any substa,:ou c~ r~.n. :j in Sohc~d'zlo II. At m9st. rolativoly m,nir~?. rich o psycho2oc~cct dependence would h~ associated with thn ahun~vo uan of enph~tmaixe resin ccmciL~:.r;. In addition, at the ~`~arinq I'en -al~: uifl, it r.ecessary, ShG:~ that tho history and pattern of nbase of )3iphetanine end Din~c- tnxaine-T done not suoport a Schcdule II classification. Under Section 202(b) of tho Act, in order to subject a or other substance to Schedule II controt. the Director of Bureau must find that the substance meets the criteria. f~r inc].usion specified in Section 202(b) (2) (A) Cr) and (C). flndi.gs may he mnde on2y after. the Director has received scientific and r~sdical evaluation and recornmendatien from Secretary of Health, Education and Welfare. Dy letter datoc 3, l~7l, the Direc~or formally requested the Secretary to provide his evaluations and recoam'endaticrs - on moth r.nhet~t the amphetamInes, and on Ciba's Ritalin and c.eiçy's PreluctLk. a letter dated Xay 13, 1971, from the Secretary of ?icalth, Education,and Welfare to the Attorney Genoral,.the Secretary tot forth certain naked findings and recommendations t'hich related solely to the amphetamines and nethamphetanine. These findi~;s and recommendations in no manner dealt with amphetamine resin complexes. Consequently, no proper foundation prescntly exis;s to initiate prcccadir.gs to subjeel: such complexes to Sohedn'e II controls. PAGENO="0820" 15252 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lCtLr:nrtrn *~xn IC ~PLAO (C) In conclusion, l'canwait rocruests a hearing in order to determine the legal and factual bases, if any, of the Bureau fl assertion that Biphetenino and Biphebamine-T may appropriately be subjected to Schedule II conaroc and, if necessary, present its evidence rebutting thu assertion. Included among the factual issues for determination at such a hearing are:. 1. Whether a-nphetztnine resin corapluxes as present in fliphetaraine and Eiphotarnine-T are salts of amphetenine; . 2. Whether Biphetarline an~ Piphetamine-T specifically were the subject of a scientific and medical evaluatien end recommendation by the Secretary of Eealth, Education and Welfare as to vhether they should be controlled; 3. Whcthor ... . - (a) Biphetamine and Oiphetamine-T have a high potential for.abuse; and (b) Abuse of Bipheta~nifle and Biphetamine-T may lead to severe psychological dependence. All notices to be sent pursuant to the proceeding should be addressed to: - Eleinfeld and Kaplan 1320 19th Street N. W. Washington, B. C. 20036 Respectfully yours, KLEINFELD 0 KAPLAN By_j~~d <~t~; ~ /1 k, I PAGENO="0821" COMPETiTIVE PROBLEMS IN THE DRUG INDUSTRY 15253 0* PRESCAIPrION PRO~JUCTS SUBJECT ~EPO2T ON DIVISION ?WJAOEME~JT CONFERENCES - 9/74 - 77, 1911 DATE September 20, 1971 TO Isaac B. McGraw, II FROM J. Marion Neason SITUATION ANALYSIS; A more opportune time for holding such brief meetings could not possibly have been selected Nary of cur field magers were in need of reassurance and reinforcenent. This was particularly true in those areas were Biphetanined and BiphetanineS-T have taken a real tunbie due to actions of local. Medical Societies. The probless were identified readily and were as foflows: 1. Fear of sales losses of some magnitude due to conditions beyond their control. 2. Protective attitudes toward Biphetesine and Biphetesine and Biphetamine-T spawned mostly by fear of loss. 3. Dilution of Iomasin® promotional. effectiveness end effort throu~ trying to salvage all possible writers of Biphetamine and Biphetssioe-T, 1.. Fear of losing good salesmen because of the sales losses on Biphetanine and Biphetamine-T. CORRECtIVE ACtIONS TAflM: 1. Managers were told there was no alternative to sefling lonemin. 2. Managers were convinced that this was not a disaster but rather a ~eat opportunity. Those successful in getting a lion's abate of the good prescribers switched to I9nsmin would actually hit a new sales high in the anorectic area. PAGENO="0822" 15254 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I.R.McGraw, II - 2 - September 20, 1971 3. Plans for increasing both call averages and quintile calls were implemented. s. Plans for more closely managing call activity by prime specialty were implemented. 5. Plans for more thorough coverage of the "reasons ~ so that all salesmen are properly motivated and effective were implemented. A positive opportunity vs a negative reaction is the objective of every manager~ discussions with salesmen. 6. A new lonamin presentation is being prepared. lot!: Complete coverage, although by necessity brief, was given to the following additional subjects: 1. Green & Cold & Tussionex promotion. 2. Kais~m - Hospital & Private Physicians 3. Expense control - Managers and Medical Sales Representatives ¼. Manpower turnover 5. Vacant territory priorities J~*Vmr Attachment PAGENO="0823" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15255 MEPICAL SOCIETIES RESTRICTEP ftJJPUrAMINE P~ESCRIVflO~S Charlotte, North Caa~olioa (Mackleoburg County) Louisiana State Medical. Society Tasvefl County Illinois (Peoria) Savannah (so.) County - Chatb.as, Georgia Valdosta, Georgia (tovudes County) Marion County - Van&arberg County, Indiana (Indianapolis, Evansvifle) Pulton - DeKaib (Atlanta) Harris County (Moustoo) Texas Medical. Association Montgomery County (Texas) Brazoria County (Texas) Walker County (Texas) Ilueces County (Texas) Tarrant County (Texas) Firs County (Arizona) Maricopa County (Arizona) Utah Medical. Society Beno, Nevada (Storey County) Dallas County (Texas) Okiahosa State Medical. Association Greene County (Missouri) Fort Wayne, Indiana CAlico & Whitley) St. Joseph County (Michigan) Huntiogton, Long Island, New York (Suffolk) Eaverhill, Massachusetts PAGENO="0824" 15256 COMPETITIVE PROBLEMS IN THE DRUG LNDUSTRY DELCO CHEMICAL Co., Mount Vernon, N.Y. DEAR DOCTOR: The enigma confronting the practitioner today in his inability to substantially increase his income from a level which is determined by the number of hours in a day and his physical stannna. Extend himself as he will, the added monetary rewards are discouragingly small. There Is a means of coping with tIns seemingly hopeless. .situation which has been instrumental in doubling, tripling and quadrupling many practices formerly bogged down In lethargy. The products offered by Delco Chemical Company have made of many physi- cians key men in the anti-obesity field. Their practices have been built rapidly and either have augmented or supplanted entirely former specialties. The rise In income is almost unbelievable and the added effort minimal. The most important factor responsible for this Is a therapeutically efficacious product which has been used successfuily in combatting obesity, a growing prob- lem in our affluent society. If you are interested In a substantial increase of Income may we suggest that you return the self-addressed stamped post card to us and our representative will be happy to call upon you atyourconvenience. Very truly yours, Louis Conax. DELCO ChEMIcAL Co., 3fount Vernon, N.Y. DEAR DOCTOR: We are the prime suppliers of obesity products which have been proveo highly successful to the key men in your area as well as throughout the entire country from Xciv York to Hollywood. These physicians enjoy incomes of $100,000 to $300,000 yearly. Also, we supply Obstetricians, Gynecologists, Internists and General Prac- titioners who have incorporated weight control Into their practices and have added $25000 to $l00.000to their incomes yearly. The products offered by Delco Chemical Company have made of many physi- cians key men in the anti-obesity field. The most Important factor responsible for this Is a therapeutically efficacious product which has been used successfully in combatting obesity, a growing problem in our affluent society. If you are interested In a successful increase of income, may we suggest that you return the self-addressed no postage required post card to us and our repre- sentative will be happy to cull upon you at your convenience. Very truly yours, Louis CoHEN. [From the Times-Union, Jan. 18, 1972] STRA5ENRURGR Qnzzrn ON AMPHETAMINES Strasenbargh Laboratories of Henrietta is threatened with the loss of its amphetamine export license as the result of a lengthy investigation in 12 states and Mexico which has resulted in the arrest of 39 pcrsons and seizure of about a million amphetamine tablets with a `street value" of about $1.5 million. John B. Ingersoll. director of the Bureau of Narcotics and Dangerous Drugs, announced the investigation and actions In Washington today. Elwood A. Garner, president of Strasonburgh Laboratories, denied the com- pany was involved In any way in illicit trade. - Ingersoll said Strasenhurgh has been ordered to show cause wily its license for exporting amphetamines shouldn't he lifted and why tl~e country's ampheta- mine export quota shouldn't lie reduced by the amount heing exported by Strasenburgh. A hearing on the show cause order will lie held here Feb. 23. Ingersoll said the action against Strasenhurgli is not a criminal charge and the hearing is an administration action. - Ingersoll said the Strasenhurgh Prescrintion Products Division, 75o Jefferson Road, Henrietta, a subsidiary of Pennwolt Corp. of Philadelphia, was manufac- turing its patented amphetamine product and shipping it to a Pennwalt subsidi- ary In Mexico City, Lahatorios .Strasenhurgh de Mexico. There they were packed as "Bifetamina" capsules, Ingersoll said. They found their way back across the border at six principal points and also by other PAGENO="0825" COMPETITIVE PROBLEMS rw THE DRUG INDUSTRY 15257 methods, such as light aircraft landing at remote airstrips, Ingersoll said. After that they found their way into illicit drug trade channels In southeast and southwest states. Garner said the Strasenburgh product, Bifetamine, has not been shipped to the Mexico company for at least six months. He said the Mexico company has been making Bifetamina since 1906. In this country and Mexico, he said, the production of amphetamines is strictly controlled to the point of delivery to the pharmacies. "We operate strictly under the law," he said. "We have these charges under very serious study." Amphetamines are supposed to he used only when prescribed by a doctor. In illegal use they're known as "speed" or "uppers" and give the user a feeling of exhilaration. Irrom the Daily News, Jan. 19, 1972j SnzE $L5M ftp Pats (By Jeffrey Antevil) WashIngton, Jan. 18 (News Bureau)-Federal officials announced today the seizure of $1.5 million worth of amphetamines manufactured by a Rochester, N.Y., firm which the government charged was the principal source of fliegal `speed" in the southern United States. Announcing the end of an investigation called Operation Blackjack, the Bureau of Narcotics, and Dangerous Drugs said the firm, Strasenburgh Prescription Products, exported bulk amphetamine to a Mexican affiliate, which placed it in black capsules and smuggled them back into the U.S. The pep pills acquired such street names as Black Beauties, Black Mollies anti Black Widows in the Southern states, where they were w-idely distributed, ac- cording to Andrew C. Tartaglino, the bureau's deputy director for operations. lie told reporters that the 10-month Investigation ended in 84) arrests and the seizure of 1.2 million capsules, 22 vehicles and 15 weapons by bureau agents. The Justice Department ordered the Rochester company to show why its license to export amphetamines should not be revoked. [Press Release, Jan. 21, 1972] PENNWALT CORP. In view of the Department of Justice's action on January 18, 1972, challenging the company's right to export amphetamine-containing products out of its Stra- senburgh Prescription Products Division at Rochester, N.Y., William P. Drake, President and Chairman of l'ennwalt Corporation, stated today that the com- pany is conducting a complete review' of its marketIng of those Products by our Mexican pharmaceutical operation, Laboratorios Straseaburgh de Mexico, S.A. do C. V. Mr. Drake said that on the basis of the results of this study thus far, the following conclusions appear to be warranted: (1) The company's sales of Biphetamine (our amphetamine-containing prod- uct) in Mexico were made only through channels of distribution licensed by the Mexican government. No Biphetamine, in any form, was exported by the com- pany's Mexican operations to the United States. (2) The company has no knowledge, nor is it aware that any of its employees have been charged with having knowledge that its products were being sold into illicit channels of distribution in Mexico or the United States. (3) Although the company has manufactured Biphetamine capsules in Mexico since 1907 and has not exported any capsules to Mexico since 1907, it did continue to export to Mexico the resin complexes from which capsules are manufactured untIl June. 1071. (Our initial understanding that we exported nothing was clearly erroncous.) Since that time, there have been no exports of Biphetamine In any form to Mexico. (4) The company learned on January 20, 1072 that the Mexican government had served notice on that date to all producers (8) of amphetamine-containing products In Mexico that (1) as of January 14, 1972, such products and other specified pharmaceuticals became subject to even more stringent regulatory PAGENO="0826" 15258 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY controls, and (2) amphetamines (including the company's Biphetamine prod- ucts) are required to he phased out of production by the end of a 180-day period, commencing as of January 14, 1972. These two developments were anticipated by the company's Mexican operations when budgeting, last November, Blphetamine sales for 1972 of only $100,000. (5) In November, 1971, the company's United States operations budgeted l3lphetamine sales in the U.S. in 1972 based on the domestic regulations then (and still) in effect, at a level substantially lower than the company's 1971 sales of ]3iphetamine products. (6) The budgeted export of Biphetamine (either resin or finished capsule) from the United States in 1972 did not include any projected export to Mexico. As to all other existing or anticipated exports of Biphetamine products from the United States in 1972, the total amounts Involved are and `vere not signifi- cant in dollars, units of weight, or numbers of capsules. Mr. Drake stated, further, that the continuing study will review specifically the amount and distribution of Biphetamine product sales In Mexico during the past several years, in order to ascertaia whether there has been any failure on the company's part, through any of its representatives at any level, to maintain effective internal controls against diversion of the company's products Into other than legitimate channels, Mr. Drake stated that it is the company's intention to cooperate fully with the United States government in order to make certain that all appropriate ac- tions by the company and any of lt~ rek)resnt.tvo ..y 1:-kerr to further our common interest in proper regulation and control of Biphetamine. He added that its use as a prescription pharmaceutical ruts neen e,1a;isira-d for' inatty years in the United States as well asia many foreign countries, including Mexico. TELEPHONE CoMMuNIcATIoN JANUARY 27, 1972. To: FDA Memo File. From: W. F. Head, Jr. On January 26, 1972, a return telephone call was placed to a Dr. Alvin Gardner of the Division of Neuropharmacology, FDA. lie had previously contacted Dr. Truant requesting amphetamine quota information. In his absence Dr. Barrett Scoville of FDA received the call nnd requested the Information following. Dr. Scoviille was given the general provisions including the complete list of drugs covered by the new Mexican law, lie was informed that amphetamines were not outlawed by this act hut rather were placed in a narcotic category. lie was also Informed that we had stopped shipping Biphetamina and Bipheta- mlna-T until such time as we could clarify the exact narcotic requirements (forms, etc.) with the proper authorities in Mexico. He did not question nor was information volunteered concerning specific letters directed to us by the Mexican government concerning Biphetamine and Biphetamine-T. Dr. Scoville questioned how we knew that our shipments were intended for legitimate medical and scientific purposes. He was Informed that all of the regulatory requirements were met by our firm and that we dealt through whole- salers only for 95 percent plus of our business. It was Indicated that we knew most, if not all, of our wholesale customers personally and that their BNDD number was on file for the proper schedule of drug ordered. This BNDD number Is in the eomputer with programming to prevent the writing of any order if the BNDD number and proper schedule is not available. Furthermore, a proper BNDD order blank is required for filling orders for Biphetamine and Bipheta- mine-'!'. To his further inquiries concerning our knowledge of legitimate move- ment at the physician level, he was Informed that in an extra-regulatory manner we do perform prescription audits using DKK (DIS) and comnare these mdc- pendent figures to our own sales figures. lie was informed thnt these independent audits check very closely with our sales figures. Finally, it was indicated to Dr. Scovillie that we also utilize a data processing physicians call report system whereby physicians profile information including prescribing habits can be obtained. Dr. Scoville wanted to know how we had arrived at our quota renuest and what the present needs are for amphetamine. The procedure we followed in making our request on October 15, 1971. was covered In detail with him including the 50 percent inventory allowance stated in the regulations. PAGENO="0827" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15259 It was pointed out to Dr~ Scoville that the request was far in excess of our known needs at that time, but that the procedure had been spelled out in the regulations and on the application form itself. The amounts used in manufac- turing as stated on the form included both units sold, as well as work in process. It was further pointed out that when the application was made it was baaed upon 1970 performance figures and that transfer of Biphetamine and Bipheta- mine-P to Schedule II was so recent that valid marketing information was not yet available. Therefore, not knowing what sales performance to expect, figures were based upon the only reliable information then available. Briefly, we re- quested 2,100 kilos amphetamine for domestic use and 400 kilos for export. To this total figure of 3,100 kilos we added 1,550 kilos as a regulatory 50 percent inventory allowance. Our current forecasts were stated briefly to Dr. Scoville and It was indicated that these figures were probably more reliable since we now have approximately four additional months of marketing experience with Schedule II. It was Indi- cated that approximately 900 kilograms of amphetamine are needed In 1972 to cover sales requirements in the U.S.A. If 450 kilos as a working inventory is added to this figure a total of 1,350 kilos quota can be calculated. This is exactly 50 percent of the amount requested for domestic use. Dr. Scoville indicated that other manufacturers were indicating a 50 percent decline in business. It was also indicated to Dr. Scoville that an additional 50 kilos of amphetamine would be necessary for export to Canada. It was further pointed out that this was presently being negotiated between our Corporate Offices and tbe BNDD. Dr. Seoville was informed that sampling amphetamine products is not iillegai but that a proper order blank is necessary for the transfer. As a practical result, sampling Is discouraged and most manufacturers have ceased sampling amphetamine products. lIe was informed that we do not synthesize our own amphetamine base but that this material is purchased, He was also iuformed that we do not know If we are the only exporter of amphetamine but that to our belief there are other exporters of this material. It was indicated that we do not import any quantity of amphetamine. A brief historial review of amphetamines was given to Dr. Scoville including its introduction in approximately 1%8 as a prescription drug. In 1965, the DACA regulations placed amphetamines in a C-Rx category and in 1970 amphetamine became subject to the Controlled Substances Act. Dr. Seoville questioned our lonamin gales performance. He indicated that other non-amphetamine anorectics has shown some increases. Dr. Scoville was Informed that sales of lonamin had increased but not to the same extent that Biphetamine and Biphetamine-T had decreased. It was indicated that this was probably due to some physicians prescribing other non-amphetamine anorectics while others chose to prescribe no medication at all. The purpose for requesting this information was stated to be that FDA must appear before Representative Rogers' Subcommittee next week to answer certain questions in this general area. He seemed very appreciative of the data and cooperation given. [From the Washington Post, San. 28, 19r2] Dnu& Exponita To Quit TaAnE The nation's largest amphetamine exporter has notified the Justice Department that it will not seek renewal of its export license, Attorney General John N. Mitchell said yesterday. The action by the Strasenburgh prescrij)tion products division of the Peunwalt Corp. came after the company was ordered to show cause why its export license should not he revoked. A special investigation by the Bureau of Narcotics and Dangerous Drugs dis- closed that a substantiql amount of the amphetamines shipped to Mexiëo was returned through illicit channels to the United States. The Pennwnlt Corn, said in its 1970 report to stockholders that its sales of amphetamines totaled about $8.3 million. About $4 million worth of amphetamines were exported. The Straqenburgh action will result in a 10 percent reduction of the 1972 amphetamine production quota set by the Justice Department. Mitchell said. PAGENO="0828" 15260 COMPETITrVE PROBLEMS IN TIlE DRUG INDUSTRY [From the New York Times, Jan. 10, 1972] NEW DRUG AGENCY To FIGHT PUSHERS ON LOWER LEvas NIXON TO ANNOUNCE PROJECT, HEADED BY CUSTOMS CHIEF, IN JUSTICE DEPARTMENT- AREA CALLED NEGLECTED-NEW YORK AMONG 24 INITAL TARGETS-CITIES THAT AID WILL GEY FEDERAL FUNDS (By Robert M. Smith) WASHINGTON, January 18.-The Administration Is preparing a new program to Cope with traffickers on the intermediate level and in the street retail trade In narcotic drugs, according to Government sources. It will be bead by Myles J. Ambrose, flow the Commissioner of Customs. - The program, which will be centered in a new Office of Dnig Enforcement In the Justice Department, will be announced by l'resident Nixon Thursday in his State of the Union Message, with the details to be provided next weekend, the Government informants say. The aim of the program, according to the sources, Is to focus sharply on an area of the drug problem that the Administration believes has been neglected- the lower levels of suppliers. The tools that will be used are investigations and grand juries, with close links among the Federal, state, and local authorities. 24 Target Areas Initially at least, Mr. Ambrose will have 24 target areas In his program. These Include New York City, Los Angeles, San Francisco, Chicago and Washington. The Informants Indicate that funds will be made available to the cities by the Law Enforcement Assistance Administration to cooperate in the program. Meanwhile, in an effort to curb the heavy return flow of amphetamines from Mexico Into this country, the Bureau of Narcotics and Dangerous Drugs took action against the largest exporter of the drug. It ordered Strasenhurgh Prescrip- tion Products of Rochester, a division of the Pennwalt Corporation of Phila- delphia, to show why its export license should not be revoked. The legal action was the first step toward revoking the license. Some Fvnd8 Available In the projected drive against the lower levels of narcotIc suppliers. It was not known how much money would be spent on the program. Some of the money, according to Government sources, will come from funds alrendy appropriated for the Justice Department-for the Criminal Division, for example. No Congres- sional action is believed necessary to set up the new office. But the Administration may have to ask Congress for more money for this specific project. In a sense, to those familiar with the program report, it is an outgrowth of a cooperative effort already under way In New York City, were agents of the Bureau of Narcotics and Dangerous Drugs, the New York Police Department and the United States Attorney's office have been working together on the narcotics problem. The program also parallels the strike forces that bring the resources of several Federal agencies to bear on organized Crime, Some of those close to the project say that one of the motives leading to It has been a glaring lack of cooperation between the Customs Bureau, charged with keeping narcotics out of the country, and the Bureau of Narcotics nnd Dangerous Drugs, headed by John E. Ingersoll, charged with policing drugs within the country. Mr. Ingersoll, who wos reached todsy by letephone in Paris, where he has been meeting with French police officials, would make no comment. Democratic sources in Congress suggested that the program itnght be part of an Increased effort by the Adnilnistration. in an election year, to put teeth Ia its drive against crime and particularly to help communities move against street crime. The restoration of "law and order" was part of the AdministratIon's platform Ia 1068. As described by Government sources, the proJect represents an effort against a neglected link In the chain of narcotics distribution and a neglected element In the system of narcotics supply and demand. They explained that, on the demand side, the Administration was trythg to educate peop1e not to use drugs and to rehabilitate those who do. On the supply side, It is attempting to work with foreign governments to keep narcotics from PAGENO="0829" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15261 being grown and processed, to try to keep them out of the Untied States through efficient customs enforcement and to drive large wholesalers out of business through prosecution of organized crime. Under the 45-year-old Mr. Ambrose, the new program would subject suspected dealers to the close scrutiny of special units operating out of the Justice Depart- ment. These units would draw men from the department, from the narcotics bureau and from the offices of United States attorneys. In announcing the program, the President is expected to say that Mr. Ambrose will have the strong support of the White Rouse and will coordinate his `york with the White house staff, although his office will be In the Justice Department and he will be responsible to Attorney General John N. Mitchell. Accorifing to Government sources, those running the program will go to state and local officials in target areas" and ask for their help. They may offer them some funding and will try to enlist them in a cooperative program against street pushers and the second, third and fourth level suppliers between the pushers and the large-scale suppliers. Mr. Ambrose was named Commissioner of Customs In June, 1969. Prior to that, be was a lawyer In New York and, from 1957 to 1060, special assistant to the Secretary of the Treasury in charge of enforcement. In that post he had general supervision of the Secret Service, the Bureau of Narcotics and the Bureau of Customs. He also served as executive director of the Waterfront Commission for New York Harbor. [From the New York Times, lan. 19, 1972] UnITED STATES ACTS To BLOCK AMPHETAMINES FSOM Msxico (By Harold M. Schmeck Jr.) Wssuixumx, January 18.-The Bureau of Narcotics and Dangerous Drugs took action today against what It called the largest exporter of amphetamines in an effort to curb the heavy illicit return flow of the drug from Mexico into this country. The bureau ordered the concern to show why Its export license for amphet- amines should not lie revoked. The bureau said that a 10-month investigation showed that much of the com- pany's exported amphetamine was returning to the United States illegally across the Mexican border. More than a million of the pills, estimated to be worth $1.5-million in street sales, have reportedly been seized. The legal action, the first step toward revocation of the export license, was taken against Strasenburgh Prescription Products of Rochester, a division of the I'ennwalt Corporation of Philadelphia. MOVE CALLED BASELESS Later, William P. Drake, president of Pennwalt, termed the bureau's order baseless, The Associated Press reported. In a statement, he said that although Penuwalt's division in Rochester has a license to export amphetamines, it does not now export any such drugs to Mexico, the news agency reported. lie asserted that since 1960 Pennw-alt has manufac- lured in Mexico its amphetamine products that are sold in that country, the news agency said. But an official of the narcotics bureau, responding to Mr. Drake's reported statement, said that over the last 18 months the Pennwalt subsidiary continued to ship the amphetamines to Mexico. lie said that the drug was shipped in bulk and was oaly capsuled In Mexico. Officials of the bureau said that halting the Illegal return flow from Mexico to the United States would plug a big hole in efforts to curb the illegal traffic in amphetamines. The so-called "pep pills" are used by drug abusers for the "high" they produce and by others, notably truck drivers, who want to stay awake for long periods. On the illegal market, the black capsules from Strasenburg'h's Mexico affiliate are called "black beauties~ ," "black Moilies," "black widows' and "ItJ.S's." At a news conference today, officials of the bureau said that the company ex- ported bulk amphetamine resin to Laboratories Strasenburgh de Mexico City. There the drug is produced in 25-milligram capsules to be sold under the trade name Bifetamina. PAGENO="0830" 15262 COMPn'ITrVE PROBLEMS TN THE DRUG INDUSTRY The officials said it appeared that large quantities of the capsules were sold tc a few "farmacias" near the Texas border. Some of these retail outlets appear to be standing almost in open fields in places where there is little population, they said. From the size and number of seizures of the product in this country, It appears that most of the capsules are then smuggled into the United States, officials of the bureau said. In the Investigation, called Operation Blackjack, there have been 80 arrests in connection with the massive drug seizures. flifeta.mlna from Mexico was described as the "drug of choice" among users of Illicit amphetamine in the Southeast and Southwest. The stimulant drug may be purchased only on prescription In this country. One of the persons arrested In this country was a Mexican citizen who was found to be carrying more than 100,000 amphetamine pills and $82,000 in small bills at the time of his arrest. Andrew C. Tartaglino, the bureau's deputy director for operations, said that there appeared to he a big Illicit distribution network in the South for the drug from Mexico. Spokesmen for the bureau said that the action against the American drug concern was being taken because there seemed to he so much diversion of the drug into illicit channels. MUsT PRODUCE RECORDS The Rochester company was served with a subpoena requiring it to provide all records pertaining to exports of amphetamine products from 1069 through 1971, including the proofs given by foreign receivers that the drugs ~vere to be for legitimate medical, scientific, research or industrial purposes. In late December the company asked for permits to export 800,000 domestically produced amphetamine pills to Italy, 85,000 to the Philippines and 840,000 to Switzerland. An official of the bureau said that the permits would be held up pending a hearing on the order to show why the license should not be revoked. At the news conference today, Mr. Tartaglino said that the company's bulk exports to Mexico in the last 18 months totaled approximately four-fifths of a ton of amphetamine, enough to fill 45 million Bifetamina capsules. He estimated that at least 60 to 70 per cent of it is later smuggled back into tbe United States. No one knows how many amphetamine pills are sold Illicitly in the United States In a year. Estimates have ranged from 29 to 50 per cent of domestic production. At the news conference today, Robert J. Rosthal, deputy chief counsel for the bureau, said that the drug abuse control law that went into effect last May made It difficult for amphetamines to be diverted from legitimate domestic supplies to the illicit market. A drug produced Ia another country is not subject to the same controls at its source. The bureau has proposed 1072 production quotas for amphetamines that would be about 40 per cent below the actual production in 1071. An official said that 10 per cent more could be trimmed from the total if Strasenburgh's export license was revoked and Its production quota was reduced accordingly. U5ED IN RARE AILMENT It is widely believed tbat legitimate medical uses of amphetamines could be supplied by a relatively small fraction of the amounts produced in recent years. The drugs are recommended for treatment of a rare disorder called narcolepsy, in which the patient has an overwhelming desire to sleep, and for a type of hyper- activity among children. The pills are more widely used as a short-term aid to obesity control because they tend to suppress appetite, but specialists have seriously questioned their use- fulness for this purpose. [From the Wall Street Journal, Jan. 19, 1972] PRNNwALT DIvIsioN's LICENsE To ExpoRT AMPURTAMINE CHALLENGED BT JUsTICE UNIT WAsHINGTON-the Justice Department ordered a division of Pennwalt Corp. to show cause why Its license to export amphetamines shouldn't be revoked. The department said the order ~vas a result of a 10-month Investigation in which it allegedly was found that a patented amphetamine product manufactured PAGENO="0831" CO~ETITWE PROBLEMS fl~ TIlE DRUG 2ThUSTRY 1 by Pennwalt's Strasenburgh Prescription Products division at Rochester, N.Y., was shipped to Mexico City and then smuggled-back into the U.S. for sale in the Illicit drug market. The department didn't charge that Pennwalt or the division was involved In the alleged illicit sales. In Philadelphia, a Pennwalt official said the company exports resins from the U.S. *that are used to manufacture amphetamine products. But, he said, "the whole implication that we have done anything by design is upsetting." The department's Bureau of Narcotics and Dangerous Drugs, which headed the Investigation known as "Operation Blackjack," said the Strasenburgh division made shipments of the amphetamine product in bulk to Mexico City, where another Pennwalt affiliate, Laboratorios Strasenburgh de Mexico, markets It under the trade name Bifetamina. The show-cause order said Elf etamina is "similar in contents and effects" to Blphetamine and Biphetan'inc-T, amphetamine drugs produced by the Strasen- burgh division for sale only by prescription within the U.S. Amphetamines are stimulant drugs, normally prescribed for weight control and other medical uses, The Bureau of Narcotics charged that the amphetamine product shipped to Mexico was smuggled back into the U.S. In the form of Bifetamina tablets and sold In the Illicit market. The bureau said that since last April the tablets have been found In the Illicit market in New Mexico, Texas, Oklahoma, Louisiana. Alabama, Tennessee, Georgia, Kentucky, Florda, Colorado, Mississippi aud Arkansas. The investigation, the bureau said, found that Blfetarnlna was entering the U.S. at a half-dozen points along the Mexico-Texas border. Most of it, the bureau said, was concealed across the border and then distributed along regular truck routes through Southeastern and Southwestern states. Some of the pills, however, were flown over the border by light aircraft, which landed at remote air strips In mountainous border areas, the agency added. The bureau announced yesterday that about 40 persons had been arrested In connection with the alleged smuggling and that about one million amphetamine tablets, with an Illicit street value of about $1.5 million, had been seized. Most of the seizures were of unopened 40-capsule bottles, packaged at Mexico City and hearing the Laboratorios Strasenburgh de Mexico label, the bureau said. The black Bifetamina capsules are sold illegally In the XIS. under the srteet name "Black Beauties," "Black ~1oll~eq. ," "Black Widows" and "RJSs," the bureau added. They said the price of a single Bifetamina capsule on the illicit market in the U.S. is about $1.5, compared with between 9 cents and 13 cents In the illicit market in Mexico. In announcing the order requiring Pennwalt's Strasenhurgh division to show cause why its export license shouldn't be revoked, the Justice Department said the concern also was ordered to show cause why the 1972 industry-wide quota for U.S. amphetamine production shouldn't be reduced by the Pennwalt division's export allocation. A hearing on the order tentatively was set for Feb.23 in Washington. The action against the Strasenburgh divisIon was the first of its kind taken under the Dnig Abuse Prevention and Control Act, which took effect last May. The law requires the bulk amphetamine powder produced in the 17.5. for export be used in the country to which it's shipped exculsive~y for medical and scientific use. It also Imposes strict controls on the manufacture and sale of amphetamines in the U.S. The Bureau of Narcotics said that, after these strict controls went Into effect In the U.S. last July, the amount of domestic amphetamines available for diver- sion Into illicit channels In this country fell sharply. Czrcnz Emtopzzy lIE REcHERCHEs TLIERAPEUTIQVE5 APPLIQUEES BA. 1040 Bruxdfles, May 15, 1972. Mr. Isaac U. McGraw, II, Vice President, Pennwalt Corp., Pla-annaceutieal Division, Rochester, N.Y. Duaji IKE: I wish to reiterate my wholehearted thanks for your kind invi- tation to the international Symposium In London-"Modern Diuretic Therapy In B5489 0 ` 77 ~ PAGENO="0832" 15264 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the Treatment of Cardiovascular and Renal Disease-as well as for all the cour- testes and the fine hospitality extended to me during my stay in London. I also thank you very much for the breakfast meeting of Wednesday, May 10, during which we have had the opportunity to review some questions of mutual Interest. During my stay in London, I greatly enjoyed the privilege of making the acquaintance of Ms. McGraw and of meeting Mr. George McCoy. Certaa equipment Under separate cover, I am sending you a second copy of the list and description sheets of the equipment used by Certa In the manufacture of the resin compounds and in the preparation and packaging of Biphetamine-T, Ionaniin and Tussionex (liquid and tablets). This equipment forms part of the manufacturing facilities of Certa, located at Noville-sur-Mehaigne, with 1,600 square meters of floor space (one square meter corresponds to approximately 10 square feet). The administration as well as the promotion and sales office are located in )3rus- sels (floor space: 470 square meters, together with `Certa International MA."). Certa's packages I hope that you bave already received, in good condition the specimen packages of the `Strasenburgh" products, sent by aig-parcel post on May 5, 1072. Regarding the two red stripes on the labels and boxes of Biphetomine, Bipheta- mine-P and Tussionex, please note that they are compulsory by law: they are the Identification mark of preparations containing narcotics and of such products as amphetamines submitted in Belgium to the same restrictions and controls. Blphetamiiie Please communicate to us, at your earliest convenience, your decision concern- ing the possible supply by Certa to some of your licensees and distributors, of Biphetamine capsules, to he manufactured by us in Belgium according to your specifications and under the very strict control of the Belgian Authorities. Zaroxolyn agreement I am awaiting with great interest, the text of the new Zaroxolyn agreement, which-as you told me during our break-fast meeting-Is being prepared by your Legal Department. Furthermore, I was happy to bear that the registration and approval formali- ties of Zaroxolyn in Great Britain, are being completed according to schedule and that, by June/July, you expect to obtain the approval of the hypotensive claims of Zaroxolyn. It is noted that Zaroxolyn has already been approved as a diuretic, In the U.K. As agreed, the application for registration In Belgium will be submitted as soon as you obtain the U.K. registration. Zaroxolyn re gi at ration in Belgium As a first step, the monography on Metolazone substance has already been approved by the Ministry of Health, Brussels, under reference N° G/S43/3/71, on March 12, 1971. A copy of this monography had been sent, In due time, to Strasenburgh Inter- national. - In compliance with your request, during my stay in Rochester (March 1972), two copies of the monography and two copies of its approval have been seat to you by Mr. Maurice Renard (his letter of March 23,1972). The registration "dossier" of Zaroxolyn for Belgium Is ready, on the basis of the data and papers received from your end. We suggest and will be happy to sub- mit to you, for approval, a full photostatic copy of this file. I will welcome your comments. Sales of diuretics etc. in Belgium Regarding the sales of diuretics in Belgium, as well as those of hypotensive agents, I handed over to you the statistics of the 4th quarter of 1971, with recap!- tulative totals for the whole year and a comparison (±%) with 1970. The quantities (units) and the values mentioned in these statistics must be multiplied by 100. PAGENO="0833" COMPETITIVE PROBLEMS IN THE DRUG rNDUSTRY 15265 For example: "LASIX" 615.7 = 6i5,700 units; 48472.8 = 48,472,800 Belgian francs. The present rate of exchange is, approximately, 44 B.francs for one dollar. Ionamin I am enclosing a copy of a telex message sent to-day by us to Dr. Aldo Truant, re: the new study on "lonamin", published in the U.S.A. on May 10, 1972. Troponwerke, Kotn-iIüZheim I recommended to your attention this major German drng producer, as a p05- sible supplier of Phentermine, Methaqualone and other fine chemicals. This Company was acquired, at the start of 1969, by Farhenfabriken Bayer, A.G., and Is now a member of this giant German group. Codeine Resin Complex Further to our talks in Rochester (last March), regarding Codeine Resin Coin- plex, Dr. William F. 1-lead, Jr., wrote to me on April 4, 1972. I thought that Dr. Head was attending the Symposium in London. I had, there- fore, brought with ale some data concerning "Netux" of Roussel (France) and "Codipront" of Mack (Germany), with the hope to have, first, the pleasure of meeting Dr. Head in London and, second, if time and circumstances permitted, to submit these data to his kind attention and have his opinion. Unfortunately, Dr. 1-lead did not come to London and, for this reason, I availed myself of the opportunity offered by our breakfast meeting, in order to communi- cate to you these data. I thank you very much for your kindness to transmit these data to Dr. Head, in Rochester. Awaiting with great Interest your good news, I remain with kindest regards, Cordially yours, CERTA, S.A. JOHN S. CANAVIS. [Telegram] MAY 15, 1972. PENNwALT CORP. Pharmaceutical Dlvl-eion, Rochester, N.Y. (Attention of Dr. Aldo Truant). Kindly airmail soonest possible copy of recent paper on "lonamin" published May 10. Thanks. Regards- JoH N CAnvIs, Certa Brussels. PAGENO="0834" 15266 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY PENNWALT CORP., June 27, 1972. EUPsRMA1 ViaDeiTe Panche, 44 Firenze, Italy. (Attention of Dr. Saverlo Mecca). DEAR DR. MEccA: flank you for your letter of June 0, 1972 and the Informa- tion concerning the new amphetamine regulations In Italy. We have been endeavoring to ship additional Biphetam:ne to you but so far our endeavors have met with failure. We have been granted permission to ship stocks of Biphetamine from Mexico but do require importation papers from the country receiving such merchandise. I believe that as a result of Saul Babbin's and Dr. Head's vIsit early In July we will be able to make some definite decisions concerning the future of Biphetamine in Italy. I believe we will be In a position to guarantee a continuous supply of Biphetamine to Eufarma. The big question In my mind Is what will be the effect of the new regulations on the sales of the product In Italy. If such sales are reduced, we must then take steps to get other products to Eufarma to increase your profits and ours. Based on the excellent Job you have done with Biphetamine, I do believe you could sell lonamin In the Italian market. I recognize the fact that Hem- rich Mack offers competition with Mirapront and Roussel has a plientermine resin on the Italian market. However based on the results of our presently Increasing sales In the United States, I am sure Eufarma could take a good percentage of the Italian market with phentermmne resin. May I have your thoughts on this matter? Corthally yours, IsAAc It. McGRAw, II, Vice Presides t. PAGENO="0835" MATERIAL FROM FOOD AND Duua ADMINISTRATION Fnus ox BIPHETAMINE AND JONAMIN SUMMARY OF NOA 11-613 STRASENBUROII LABs, ROCHESTER, N.Y., Original Appearance Date: December 2, 1957. Name of drug: Trade-lonamin "15", lonamin "30". Generic-Phentermine resin (Phentermine complex on cation exchange resin). Dosage: Oral-i capsule, sustained release, 15 or 30 mg/day. Category: Anorexigenic. Material reviewed: Study 1-Six months "chronic" administration in Rat and Dog. Interna- tional Research and Development Corp. June 22, 1964. Study 2.-Three litter breeding cycle in Rat. International Research and Development Corp. Part 1-2 litter. October 19, 1963, 3rd litter February 14, 1964. Study S.-"Newborn mortality study". Strasenburgh Lab. March 25, 1905 (actually a 1-cycle reproduction study). PIIARMACOLOOIST'S SUMMARY Study 1.-Rats were given 10, 25, and 50 mg/lcgf day phentermine 1101 by garage seven days a week for 26 weeks. There were 20 males, 20 females in con- trol and high dosage groups and 15 males, 15 females in another two. There was less weight gain on drug which was nost evident in males and was dose related. Food consumption was slightly higher on drug. No significant differences in sur- vival, nor were there drug related deaths or pathology. The most frequently observed drug related sympton was hyperactivity which was marked at 50mg/kg. Occasional alopecise occurred at this level (Sat HO). Beagle dogs (2 male, 2 females at each level) were gIven 5, 10, 15 mg/kg/day RC1 phentermine in 2 divided doses, for 26 weeks). An additional 4 dogs received 1 or 2 doses each of 20 or 40 mg/kg Mydriases, tachycardia, and hyperactivity were the principal drug and dose related signs. Lethargy prior to 1st half of daily dose was seen at 10 and 15 mg/kg. One animal at each of these level-s dicd during test period-s. Alter one dose of 20 mg/kg S dogs died within 434-7 hours and the other in less tItan 24 hours. Three dogs died after one 40 mg/kg dose In 4-S hours and the other 1 hour after second dose, Weight gain was normal at 5 mg/kg but weight losses occurred at higher doses. Appetite decreased during Mit kit weeks but returned to normal after 5th week. No apparent drug induced hen,atotogic or pathologic changes were seen. Study 2.-This reproduction rat study included 20 males and 20 feanales given 40 mg/kg/day (70 x HTD) Phentermine resin by gavage thru three breeding cycles. During the third cycle drug administration was stopped 10 days after pairing. The reproductive performances are shown in the following table: Cycle and drug Percent pregnancy Live felines per litter Dead fetuies per litter Birth weight 2! day survival per lifter 21 day weights M I. Control 80 10.0 0.38 6.4 9.8 39.4 3 20.5 1 lonamin (40) 2. Control lonomin (40) 3. Control 79 79 67 93 7.3 9.5 8. 8 8.1 1.00 0.87 0. 80 0.92 5.5 5.9 5. 5 6.3 8.9 2. 4 - 8.1 38.1 3 27.2 2 43.7 4 42.6 4 Ion.min(4l) 80 7.8 1.25 6.1 7.1 (15267) PAGENO="0836" 15268 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In the first two litters there are slightly lower birth weights, considerably lower 21 day weights, (50% deerease-ist litter; 25%-2nd) and a very low 21 day survival of offspring of animals receiving the drug. The third litter study in which drug was stopped 10 days following 3rd pairing is claimed to support the contention that maternal hyperactivity on the drug is an important factor In poor survival and growth in the offspring in the previous two litters. however, it does not rule out the effect of the drug on the fetus and neonates during late pregnancy and lactation. Moreover, 6 of 12 pregnant females had been taken off the drug before they conceived in the third cycle. (INi) 1131 Summary delivery data dated February 16. i964. This table is not Included in final report to Nt)A 11-013.) FIfty percent of females who eventually became pregnant failed to conceive during the ten day period of pairing on the drug as opposed to 23% of controls during this same period. Since only 1 female received the drug for more than 6 days after conception (as calculated from day of littering) this third litter is of little value as a teratology study. While no anomalies have been observed grossly, adequate examinations by clearing and staining or sectioning for skeletal and visceral changes were not carried out. Study 3-Rats dosed 5 days per week, 2 mg or Sing/kg/day (3,3 and 8.3 HTD) prentermine resin complex (day of pairing to 21 days post partum) showed no significant differences in % pregnancies, live or dead fetuses per litter, birth weights or 21 day survivals. Twenty-one day weights were significantly higher at 2 mg/kg than In other groups hut this is probably not drug related since not dose dependent. No anomalies reported. EvALUATION Lack of teratogenielty at doses of 3.3 and 8.3 times HTD in the pregnant rat appears satisfactorily established hut since this drug is specifically recommended for weight control in pregnancy, teratologic studies according to 1066 guIdelines should be run iu another species at higher doses, given only at time of organogenesis. The six month subacute toxicity study was carried out on the piieatermine IIC1 powder (not on the resin) in spite of earlier recommendations and queries as to the possibility of accumulation of the drug suggested by the increased death rate (0 during l3th-27th week) In the chronic S litter reproduction studies on 40 mg'kg as opposed to no deaths in a shorter 5 week study at the same level. L. L. PuILLIP5, Ph. B. MEMORANDUM Foon AND Dave ADaincIsTnATIorr, August13. 1958. To: New Drug~Branch. Attention: Dr. DeFeliee. From: Division of Pharmacology. Subject: Ionamine Resin (R. 5. Strasenhnrgh Co.) The toxicity data submitted in support of this NflA are not sufficient to evaluate the safety of this preparation. We have advised the company by tele- phone that they should complete the toxicity study so that we could properly evaluate the safety of the preparation, They have several groups of rats on the drug for about 8 weeks and plan to carry them for C months. They plan to start dogs on the drug by the end of the month and carry these animals for 3 months. 11. I, GOLDENTITAL. PAGENO="0837" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15269 MEMORANDUM Fooa AND DRUG ADMINISTRATION, February 17, 1959. To: New Drug Branch. Attention: Dr. Deielice. From: Division of PharmacologyL Subject: lonamine Resin (R. J. Strasenburgh Co.) On the basis of the animal toxicity work in rats and dogs, the compound appears to be ~fe at a domge of 30 mg per day. There were a large number of deaths in the rats which were attributed to tubing errors. No evidence of drug toxicity was observed either grossly or historically. Ia my opinion, the clinical studies appear pretty weak especially *ith regard of the duration of drug administration, but that decision is up to you. E. I. GOLDENTIIAL. 3lEMoRAxorM Fool) AND Dauc ADMINISTRATION, January16, 1964. To: Division of New Drugs. Attention: Dr. A. G. Pleron. From: Dr. William D'Aguanna, Division of Pharmacology. Subject: Tonamine Resin (Phentermine Resin Complex), R. J. Strasenburgh Co., Rochester, N.Y. AP 13-460. The culmination of 10-28-63 contains a subacute oral rat study and a 2 litter rat reproduction study. I. Subcute Oral Rat Study: In order to find a sub-toxic dose for a subsequent reproduction study, Ioaauilae Resin Complex was administered once daily for 5 wks to 4 groups of 10 rats each at 20. 40, SO and 100 mg/kg. Results: Drug was well tolerated at 20 and 40 levels but hyperactivity and diminished growth rate occurred at all levels. Alopetla appeared at the 40 level but mortalities (1/10 and 7/10) occurred only at 80 and 100. Except for fact of necrosis in the livers of 1 rat at the 20 pnd 2 at 120 levels, pathology was not remark-able, 40 mg/kg was chosen to%e the subtoxic dose. II. Two litter Reproduction Study: Ionaniine Resine Complex was adminis- * tered at 40 mg/kg to rats in a reproduction study essentially similar to one we are recommending. Results: There was no evidence of teratogenicity and Incidence of pregnancy, fetal development and av. litter size were normal. But the following adverse effects occurred: (1) Parental mortality was increased In treated group (10/40 for treated vs 1/40 for control). Other than 1 death at 7th week, all the other deaths occurred between the `j?tli and 27th weeks of admInistration. This could seem to reflect a cumulative toxic effect which was not observed at thi~i dose level in the 6 wk. subacute study. (2) Parental hody weights of treated were below controls. In the case of males, the av. weight was 40% below control whereas females weighed only 10% less. (3) While the av. weight of newborns was only slightly less, two litters showed marked growth repression. This pattern of growth retardation was much more striking * * - MEMORANDUM FOOD AND DRUG ADMINISTRATION, Octobcr 29, 1965. To: Division of New Drugs/IND Branch Attention: Dr. F. 0. Kelsey From: Dr. S. UsIa. DTE/Drug Review Branch. Subject: IND 1133, (ND.( 11-013) Progress Report, 4/8/65. Name of Sponsor: Strasenburgh Laboratories, Rochester, N.Y., At' 18-400. A. Organization Performing Toxicity Studies (Project Rapid) (1) Reference Sponsor Above PAGENO="0838" 15270 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY This is a report on the rat reproduction study employing low doses as requested earlier in connection with NDA 11-613 (1/16/64). Young adult rats, 26 or 27 each sex per group, were administered daily oral doses of 2 and 5 mg/kg during 5-day mating period. Dosing in females was con- tinued through gestation till weaning The results showed no difference from controls in most reproduction activities. A slight decrease in conception rate was noted. Group (Percent) - Conception rate Control - 55.6 2 mg/kg 37.0 5 mg/kg - 42.3 The effect does not appear dose-related. There were no abnormalities reported in either the parent or the pups. Comments: The above study seems to indicate that the drug is not teratogenic In the pregnant rat at oral doses of 2 and 5 mg/kg/day, equivalent to 3.3 and &3 X human dose of 0.6mg/kg. This is considered adequate to suynmrt its use as proposed In the INn. MEMORANDUM OP TuLupiroris INTERVIEW STRA5ENBuROH LABoRAToRIEs, Rochester, Ny (Al' 13-460) December 8, 1067. Between: It. 0. Rothwetl, M.D., Medical Director, Strasenburgh Laboratories, and Robert M. hodges, M.D. Director, Office of New Drugs. Subject: Bionamin-NDA 10-421. This was a call returned by me at the request of Dr. Rothwell. lie wished to inform me that the Etonamin application had recently been amended by 25 vol- umes of clinical materials and that it had been explained to him that this volume of material constituted grounds for declaring the application withdrawn and * resubmitted. I stated that I had been informed by the reviewing medical officer that Dr. Rothwell made telephone calls at approximately two-week intervals to inquire into the progress of the review of the application and intimated that he was going to continue to call at these intervals presumably with the idea of keeping us on our toes. I stated that I felt that this conduct verged on harassment and was clearly Inconsistent with acceptable procedures stated frequently in public by representatives of the FDA, the last occasion being before the Nelson Committee in August by Dr. Goddard. Dr. Rothwell denied that there was any intent of harassment and said that his statement about calling every few weeks was just a little joke. I said that I hoped it was but that this conversation should certainly clear up any misunderstanding. The application would continue to receive ex- peditious review and if there were any point that required clarification we would be only too pleased to call him. Otherwise, he would hear from us when we had completed our review and the appropriate action had been taken. founT it lioooss, M.D. FOOD AND Dnuo ADMINISTRATION, August 28,1.969. STRASENEtuGH LAnORAtoR~s, Rochester, N.Y. NDA 16-421 Gentlemen: 1. Reference is made to your new drug application dated June 10, 1086 sub- mitted pursuant to section 505(b) of the Federal Food, Drug and Cosmetic Act for the preparation Bionamin (d-amphctamine, dl-amphetnmine and phenter- mine) capsules. 2. We also acknowledge receipt of your additional communication dated Decem. ber 20, 1963 addressed to the Acting Director of Bureau of Medicine; his reply of January 9,1969; and to the meeting held at the FDA on October 2, 1968. 3. On page 2 you state that you were told that what transpired at the May meettng was totally irrelevant. We believe that what was actually stated was that the reviewing medical officer, Dr. Robert Knox, was not present at the May PAGENO="0839" cOMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15271 meeting, and therefore could not speak with first-hand knowledge of what was said. 4. Concerning the contribution of components, it is our position that In order to justify the addition of one or more Ingredients it is first necessary to demonstrate that these additions provide either greater safety or greater efficacy than a single component alone, 5. On page 3 you state that subtle differences can be shown in rigidly controlled animal experiments. At the May 3, 1968 meeting our view was expressed that the transposing of the effects obtained In animals to what might he expected to occur in man is not acceptable as hard data on which to base approval of a new drug application. 6. On page 3 you also state that you cannot obtain clear evidence of supenority and that you do not believe that you are required to. It is our position that although it Is not necessary to demonstrate superiority In either safety or efficacy of single compounds as against previously approved single compounds, a different situation exists in the case of polyphannaceuticals. See paragraph 4 above, 7. On page 5 you state that to show contributions of component you submitted 1310-43 and 1310-47. In 1110-43 Dr. Schmitz used concomitant therapy, Including diuretics. Under date of June 11, 1968, in connection with 1310-15 hy Dr. Evaugelista, you stated "Since both treatment groups received the same concomitant drug It may be argued that this approach would still result In a valid comparison of active nnd non-active medication. However, this argument does not follow since there Is no way of predicting what portion of the drug weight loss was due to diuresis or whether the combined therapy Blonaniln and Diuril produced antagonistic pharmacologic actions." On the other hand, in connection with 1310-44 by Dr. Orehow, submitted under date of February 27, 1968, you stated: ". . - a large number of patients In each treatment group received concomitant drugs. Since in general the type of additional drugs is relatively the same for each group it Is assumed that their use did not greatly Influence the comparative analysis of the study results." These two quotations certainly appear to be contradictory, and raise the question as to whether the results reported by these two investigators influenced the arguments advanced. (Dr. Orehow In 1310-44 found that the average weight loss with Bionamla was 13.1 lbs while that with placebo was 8 lbs., whereas Dr. Evangelista in DIO-45 found that there was essentially no difference between the results achieved with Bionamin and the results achieved with placebo). On page 6 you refer to 1310-17 by Dr. Milton Cahn. This study ran for only 3 days, hut you state that "a contribution for 3 days Is still a contribution." In this connection your submission of July 8, 1968 states on page 00011 that "the average (albeit artificial) value of 5 calories per gram was applied to the difference In total Intake. In this context, subjects treated with Blonamla exhibited a reduction in caloric Intake of over 900 calories per day when compared to volunteers given Phentermine." "The reduced caloric Intake may be one explanation for the significantly greater mean weight loss observed in subjects treated with Bionamin." Applying this same value of 5 eal./Cm. to other figures in Table I on page 00012, we arrive at, for example, an average intake of 7,795 cal. of solid food for the Placebo subjects for flay III. The reported average weight loss for the three days was as follows: Pounds Blonamin ~ 9 Phentermine 2. a Placebo 1.5 It Is most unlikely that even on complete starvation one could lose more than a pound of adipose tissue a day: on the other hand, patients characteris- tically tend to retain fluids for the first week or so of a diet rather than to excrete more than the normal amount of fluid. Even if efficacy were' demon- strated over a 3-day period, this would not be sufficient evidence of efficacy since a drug which was effective for only three days would be of no practical medical value lathe treatment of obesity. We request that you explain the discrepancies noted in your submission dated July 3, 1968. 8. On page 7 with regard to point #1, the fact to which we were drawing attention was that whereas in your submission of July 1, 1967 (page 0000062) the data Indicate that the serum level values have fallen off sharply (in PAGENO="0840" 15272 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY dogs) to close to zero at 12 hours, whereas in 810-39, In humans, the urinary excretion In the first 12 hours was 1.9 mg, in the second 12 hours It was 1.7 lug; for a total of 3.06 mg for the first 24 hours. During the second 24-hour period the excretion was 2.8 ing; and this was following a single dose of medication. Regardless of whether spectropliotofluorometry Is used or whether gas elironiatograjiliy is used, the fact remains that the profile Is very different according to these data. As reganis point #2, we note that in your submission of }`ehruary 6, 1968 you state iris report represents a rapid and specific metlitsl for the determination of aniplieta!nine a rId phenterrniue in human serum levels down to 2 mg/mI." In your submission of May 16, 1968 you state that".., It was necessary to give more than one capsule of Bionamin on the day the blood samples were collected. Only in this way would it be possible to measure blood levels with reasonable accuracy, even using this highly scu~sitive method." Since the serum a niphetamine levels reported in 1110-46 (I )r. Austin Stough following it dosage of 4 capsules were in the neigliliorhootl of 50 to 100 manograms it appears that your letter of May 16. 1969 was Inaccurate. Because the serum levels \vere determined after the four capsule doses, we are essentially examin- ing the results of weekly dosages rather than daily tiosuges. Iligh concentra- tions of drug are not necessarily metabolized in the same manner us low doses. With regard to point #4 we do not believe that you have shown that lower blood levels produced by the slow absorption forms make them less susceptible to abuse, except possibly via the intravenous route. it Is quite clear that abuse of these drugs taken orally will be related to the availability of the various formulations. It has been estimated that approximately 50% of all these drugs are sold illegally. Therefore it would he erroneous to conclude that differences in incidence of ahuse were due solely to pharmacological dif- ferences. As Dr. Kalant states: "Finally, the argument so frequently used, that scarcity of reports indicates absence of abuse has been amply demonstrated throughout this review to he unfounded." With regard to point #7, in reply to our request for specifie dates con- cernhig study 1310-S you merely state that you informed us "as 500" as we could extract Information." The reason for this request was to determine the adequacy of the monitoring of the work done for this NDA, and we are attempting to establish the manner In which these studies were assigned, performed and followed. There are serious questions regarding the following studies: 63-3-K, 6,5-3-I~, 810-8. 1310-13, 810-iS, 810-42. There are contradictory summaries on 1310-44 and 810-45: and 7 studies were cancelled without adequate explanation. We again ask that you answer the questions listed in paragraph 7(a) of our letter of July 19, 1908. As regards side effects, it Is more a matter of safety than Just minor side effects. If less danrer of abuse is substantinted, this would he of greater significance than a reduction in the number of minor side effects. floannu 0. Krcox, M.D.. Medical Officer. NEw Dave, AppLlcATrorc No. 10-093 Test drugfl): Blphetamine (amphetamine and dextroamphetamine) Capsules Code-BIPhI, (0131). Man ufacturer: Pennwalt Corp. Studies reviewed: (3) Eugene Jolly. 3LD. (Study #41098), Albert Cohen, M.D. (Study #4201)3); Albert Cohen, M.D. (Study #43093). The principal objective of these studies was to demonstrate unequivocally that Biphetamlne is truly effective rather than "possibly effective". The three clinical studies we reviewed were studies of effectiveness in producing nnornxia, I.e., weight loss in obese patients. The patients in each of these studies received treat- ment for 10 to 20 weeks on one of three schedules: A. Biphetamine 20 lug., given continuously. B. Blphetarnine, 20 mg.. given in a regimen interrupted at every fourth week by a week of placebo therapy, and C. Placebo medication given con- tinuously. These studies were conducted in 1970 and 1971. The tables sm,,nii,arize the results for this N1)A. Our (`onelucions are base:l on the covarate table. For days our analysis probabilities equal to or less than 5% shall be considered to differ significantly from chance. ICalnat, 0. : The Amphetamines. Charles C. Thomas, 1966, p. 132. PAGENO="0841" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15273 Conclusions 1. Initial weight comparisons indicate that the two treatment groups in each study did not differ substantially. 2. The observed final adjustment difference in favor of Biphetamine differed significantly from chance for 2 of the 3 studies. NEW DRUG APPLICATION No. 11-5S8 Test drug(s): Biphetamlne-T (amphetamine and methoqualone) Code-BIPT. Manufacturer: Pennwalt Corp. Stud,es reviewed: (2) Albert Cohen, M.D. (Study #4&38) Eugene Jolly, M.D. (Study #47538). The first objective of these studies was to demonstrate that Blphetamlne-T is truly effective rather than "possibly effective". In the two studies we reviewed, Biplietaniine-T and plain Biphetamiue are compared as adjunctive therapies. In another submission (NDA 10-093), plain Biphetamine was compared with placebo. A three-week crossover pilot stage (Biphetamlne-T, Biphetamine and placebo), and a week on placebo was followed by a 12-week parallel group trial. These studies were conducted in 1971. The attached tables summarize the results for this NDA. Our conclusions are based on the covariate table. For our analysis, probabilities equal to or less than 5% shall be considered to differ significantly from chance. Conclusion 1. On the basis of Initial weight-comparisons, the groups appear not to differ significantly. 2. No differences greater than those expected by chance were found between the two treatment groups in both studies. NEW Dnuo APPLICATION No. 11-613 Test drug: lonamin (phentermine resin) Capsules, 30mg., Code (0701). Mann feeturer: Pennwait Corp. Studies Reviewed: (2) Eugene Jolly, M.D. (Study #48613) Rabin Shearer, 31.1). (Study #49613). The principal objective of these studies was to demonstrate that lonamin Is tn'!5 effective, rather than "possibly effective'. The subjects of the 2 studies we reviewed were fat adults whose obesity had beeti caused by eating too much. They were randomly allocated to three treatment groups as follows: Group I-Placebo plus diet restrictions, Group IT-Continuous lonamin plus restrictions and Group ITT-Intermittent lonamin plus diet restrictions and Group 111-Intermittent Jonn- mm plus diet restrictions. The treatment phase was for 16 weeks and the studies were conducted In 1971. The tables summarize the results for this NDA. Our conclusions are based on the covariate table. For our analysis probabilities equal to or less than 5% shall he considered to differ significantly from chance. Conclusions 1. Initial weight comparisons indicate that the two treatment groups In each study did not differ substantially. 2. The observed final adjusted difference in favor of lonamia differed sig- nificantly from chance for the two studies. MEMORANDUM Foon AND DRUG ADMncI5TRAn0N, August 30, 1972. To: Barrett Scoville, M.D., BD-120; Division of Neuropharmacological Drug Products. From; Walter Slol,oda, Division of Statistic Evaluation Branch. BD-282. ADDITIONAL WORK ON THE AMPHETAMINEANORECTJC PROJECT 1. As per your request, please find below some possible further analyses which would aid th summarizing the data so that the results may be published in One or more articles. PAGENO="0842" 15274 COMPETrFWE PROBLEMS IN THE DRUG INDUSTRY 2. We have grouped below certain questions and suggested analyses into three general areas; which could be worked on separately or simultaneously. More specifically, we would suggest additional work along the following lines: a. Efficacy: (1) Introduce time as a factor to answer some of the following questions: (a) Does weight loss per week yield the same conclusions as looking at final weight? (b) Is there treatment x time interaction? Sex xtime, etc? (c) Is it true that the patients lose weight at a decreasing rate over time? Is the trend linear? (d) Make tables of lengths of time in study for the treatments and try to describe the patients which continue longest by age, sex, race, ihitial weight, etc. (e) Estimate the missing observations. (f) Do the random fluctuations differ in magnitude over time, and is there a trend? (2) AscertaIn a descriptloa of the population which would best to benefited with amphetamine treatment. (3) Obtain a description of the population which will use or now uses the drug to demonstrate that the applicant has considered a comparable population. (4) Describe the evidence of Importance of accompanying diet. (5) What conclusions can be made about appetite suppression and can a protocol be made to consider it? (6) Make conclusions about diet, exercise, and combinations from the existing data. (7) Detailed comparison of continuous and interrupted therapies and effect of Washout at beginning and/or end. (8) Approach and describe investigators to find who has a better success and/or safety by characteristies. (9) Analyze with treatment, age, severity, sex, and baseline, and lime In the model. (10) What Sn be concluded with a followup. (11) Can It be tested If the double-blind were broken, and what would be the effect if itwere? (12) Is amphetamine weight loss anthropometricaliy equivalent to diet weight loss? b. Safety: (1) Analyze the safety data, like blood pressure, and pulse by the amlysis of variance. (2) Give a summary and describe the dropouts by length of study, age, side renctions, etc. by treatment. (3) Define and describe the effect of chronicity. c. Statistical: (1) Calculate the power of the test or the probability of rejection the hypothesis of equal treatmeut effects for selector alternative hypotheses from the data submitted. (2) Make tables or graphs of the power to help determine the sample sizes and study length to detect specific differences with specified probabilities. (3) DesIgn protocols which will allow adequate study of drug, diet, exercise, and combination drugs. (4) Further consideration of comparability of treatment groups by age, vari- ance, etc. for both baseline and post. (5) Pool studies. (6) Compare the physicians' ideal weights with those of the Metropolitan Life Tables. 3. Please let us know If this proposal Is satisfactory. PAGENO="0843" COMPE'n'TIVE PROBLEMS IN THE DRUG INDUSTRY 15275 MEDICAL SUMMARY OF NDA 11-613-SUPPLEMENT (5-004) AND AN NUAL REPORT R-iO Date summary completed November 28, 1972. Sponsor: l'enwalt Corp., Rochester, N.Y. Name of drug-Trade: lonamin; Generic: Phentermine Resin. Dosage forms: each containing uationlc resin complex equivalent to: Per capsule Phentermine 15 mg; 30 mg flitegory: Anorexigenie agent. Route of administration: oral. Material reviewed: Volume 11.1. Reason for application: In response to DES! #5378, to demonstrate that lonamin is `effective", rather than "possibly effective" as a "short term adjunct hi a regimen of weight reduction based on caloric restriction." Clinical evaluntion-Studies Reviewed: (2) for Efficacy: #48613 by Eugene It. Jolly, M.D., Ph.D.; #49613 by Robin Shearer, M.D. The subjects of the two studies were fat adults whose obesity had been caused by eating too much. They were randomly allocated to Ri groups as follows: Group I-Placebo plus diet restrictions. Group II-Continueus lonamin plus diet restrictions. Group Ill-Intermittent lonamin plus diet restrictions. - The Rx phase was for 16 weeks. Comments: In vitro studies purport to show that phentermine Is released from the resin into the G.I. tract over a period of several hours, thus preducing a release piittern intermediate between that of a classical salt and that exhibited by a "sustained-release" formulation. In the 2 studies reviewed, the observed final adjusted difference in favor of lonamin differed significantly from chance. Recommendation: lonamin (resin complex of phentermine) has been marketed for over a decade as an adjunct In the management of exogenous obesity. Pending declaration of FDA policy on the use of amphetamines in the Rx of obesity, no action need be taken. THERESA 2'. Woo, M.D. MxMORANDIIM Fooo AND DRUG ADMINISmA'noN, Januart) 24, 1973. (Supersedes Briefing Letter of May 14, 1970) To: The Commissioner-Through: The Deputy Commissioner The Associate Commissioner for Compliance From: henry E. Simmons, MI)., MPH., Director, Bureau of Drugs (ED-i). Subject: PEST armouncemeilt: Certain non-amphetamine, oral anoreetic prep- arations- (DESI 11673)-action memorandum Objective - To Implement the Dnig Efficacy Study by publIshing In the Federal Register the enclosed announcement concerning seven reports of the National Academy of Sciences-National Research Council, Drug Efficacy Study Group, on certain non-amphetamine, oral anorectie preparations. Background Rating the drugs as effective, but .., the Academy's Panel for Psychiatric Drugs commented that sympathomimetic stimulants as a class have been shown PAGENO="0844" 15276 c0MPEflTIVE PROBLEMS r mr~ DRUG INDUSTRY to have a generally short-term unorectie action. They fire not a treatment of obesity In themselves and should he used only as an adjunct to a total program of weight reduction. Further, the anorectic effect often plateaus or diminishes after a few weeks. The PEST announcement for these drugs has been delayed pending completion of a comprehensive study of the efficacy and abuse potential of the entire class of drugs used an anorectic agents. The recommendations resulting from that study were forwarded to you in a memorandum dated October 6, 1972, a copy of which is enclosed for background information (Tab B). As that memorandum with its attachments pointed out, our staff carried out a eomnpiiter-su~~ported review of all controlled anorectie studies on file in FDA. Time analyses genenilly supported the efficacy of anorectic drugs in that use of the drugs In obese subjects was associated with more weight loss than was diet alone, although the degree of extra weight Ii~s was small and variations were great. The proposed announcement, therefore, represents our conclusion that these drugs, in conventional dosage fern,, are effective in the management of exogenous obesity as a short terni (a few weeks) adjunct in a regimen of weight reduction based oil caloric resrtictions. The limited usefulness of the drugs nmust be weighed by the physician against possible risk factors. The enclosed announcement covers the following drugs: Phentermine Hydro- chloride; l'bendimetrazine Tartrate; Beazphetamine hydrochloride; methyl- propion Hydrochloride-all in convention, oral dosage form, and I'liennmetrazine Hydrochloride in conventional and prolonged action oral dosage forms. The claim for prolonged action (phenmetrazine hydrochloride) is classified as possibly effective. Geigy mnrket.s this drug as Preludin in a 25 mg. conventional tablet (NDA 10-460) and In a 75 mg. prolonged action tablet (YDA 11-752). The prolonged action pro~uct was the one Geigy submitted for Academy review, claiming that a supplement approval after 1962 for the 25 mg. tablet con- stituted an efficacy determination. However, the Acadernys report deals with the basic drug, not with any prolonged action claims. The PESI announcement pertains to both. Action The announcement classifies the drugs as effective in conventional dosage form for their only Indication and sets forth the lanunge to be used for that Indication, as well as for the `Actions" section of tile Inbeling and for a drug-dependence warning. The prolonged action drug Is rated possibly effective with respect to Its claim for prolonged action. Abbreviated NDAs will be accepted for the effective drugs; however, full manufacturing information Is required. Bioavailabillty data will not be required at the present time. T,npact The subject document Is one of several proposed documents which will impact on the entire class of drugs used for obesity. The others are: A revised policy statement on amphetamines; a proposal to withdraw approval of NDA for parcnteral inethamphetamiae; a PEST follow-up notice proposing to withdraw approval of NDAs providing for anorectic drugs in combination with sedatives or tranquilizers (initially classified as possible effective in PEST 5378, August 5, 1070-Tab C) and a PEST follow-up notice which will elevate certain single-entity drugs previously published as possibly effective (Tab C), to effective (except for sustained-action claims). Other preparations which contain the active constituent of drugs In the subject document are as follows: 1. Phentermine in a resin complex offered for prolonged release (NDA 11-613 lonamin Capsules) is in PEST 5375 (Tab C). 2. Dietbyipro~ion IICI in sustained or prolonged release form. Tenuate Pospon Tablets (ND.t 12-540) are included in PEST .9378 (Tab C). Marketed as Tepanil Ten-Tabs (provided for In a supplement to NDA 11-673 (Tcpanil)), it was not reviewed by the Academy; however, that product will be subject to the follow-up notice applicable to Tenuate Dospan. Diethyipropion I-Id In combination with vitamins (NDA 12-261-Natorexic has been discontinued and NDA approval, withdrawn. 3. Phenmetrazine in combination with minerals and vitamins (Geigy's Prelu- vite, NDA 12-371) has been discontinued. It was handled in DEST 537S (Tab C). Tenuate was among the leading 100 drugs prescribed In 1970 and Preludin was among the leading 150. PAGENO="0845" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15277 Each firm listed In the subject announcement has been furnished a copy of the Academy's report. .Recomnien tic lion That the enclosed Federal Register document (Tab A) be signed. REVIEW OF A BIOAVAILAIIILITY STUDY IONAMIN 15 AND SO CAPSULES RESIN COMPLEX CONTMNING 15 AND 30 MC. OF PHENTERMINE, NRA 11-611, PENNWALT CORP. Al 13-169. SUBMISSION MAY 30, 1913 1. SubmItted are clinical studies to show efficacy of the product, and blo availability studies to demonstrate the availablity of the product. If the clinical studies were done with the present formulation and show satisfactory efficacy, there is no need to consider the bloavailability studies, However, In case the hioavallahility studies are needed, they are briefly reviewed below, 2. EIghteen subjects were used. Eights were crossed over at the 30 mg. and six at the 15 mg. does. The reference products were capsules containing 10, 15, or 30 rng. of phentermine. The 10 mg. pheatermine capsules were given to four subjects at the 10 x 3 mg. dose. It Is not clear if this was given nIl at once or In separate dosages of 10 mg. each. Blood samples were taken at 0.5, 1, 2, 3, 5, 6, 7, 9, 11, 12, 16, 24, 36, 43 and 72 hours. The essay used was a gas earomatographic method as described in volume 1.3 beginning on page ~l36. The phentermine capsules produced an average peak blood level in 5 hours of 51.5 and 190.2 mg/al for the 15 and 30 mg. dosages respectively. The corresponding values for the resinated product were 50.3 and 93.0 nc/my. the peaks being at 9 hours. The 10 x S dose produced peaks of 75.5 ag/my at 11 hours. The average areas under the curve for the 30 mg. dose was 253.75 and 2413.88 ng-ar/ml for the reference and lonarnin products respectively. The blood level enrves for the test and reference products were very similar. Comments and rccomrnciidationg The Idoavailability data for the test and reference products show similar blood levels. Acceptance of the bioavallablllty studies are reCommended provided the company can satisfactorily answer such piestions as 1mw the reference products were prepared. However, if the clinical studies are satisfactory, there Is no need to pureue the bioarailability studies any further. They were done in 1971 and the details of the studies may not still be available. The company should not be allowed to make claims that their resin.complex product produces better or more prolonged blood levels than the nonresinated preparations. hARoLD R. MutoocE, Ph.D.. - Clinical Research Rranch/DCR. MEDICAL OFFIcER's I1F.vlr.w or NDA 11-613 ANNUAL REPORT u-il Date a~lgned tome: June 21, 1973. Date review completed: October?. 1973. Sponsor: Pennwalt Corp., Rochester. N.Y. Name of drug: Trade: lonamin 15' and `30': Generic: phenternilne resin. Dosage forms (per capsule) phentermln&-15 mg; 30mg. Route of administration: Oral. Category: Anoreetic. Adverse reaction reports: 1. A young female taking Jonamin for her obesity became jittery, insomniac and complained of dry mouth. "She had become addicted to it." She had a "nervous breakdown accompanied by a catatonic condition". She was admitted to a State Hospital in N. J. for 3 months. Other details not given. PAGENO="0846" 15278 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2. Patient taking lonamin 30' for obesity, developed a pruritic Maculo-papular rash all over the body and limbs. Comments FDA has considered the NAS/NRC report and concluded that lonamin, a controlled release formulation. Is "possibly effective' in the lix of obesity. The Sponsor has not submitted bloavailability data to evaluate this controlled release preparation. Recoin mendations 1. Consult B. Cabana, Ph.D. (BD-220), regarding hioavallability studies required for lonamin. 2. Send Pennwalt, FDA Labeling Guidelines for anorectics. Present labeling needs complete revision. THERESA T. Woo. M.D. FOOD AND DRUG ADMINISTRATION, February 19, 1974. Pennwalt ~rp., Aldo P. Truant, Ph.D., Rochester, N.Y. NDA 11-4313/5-004, AF 13-460 Gentlemen: We acknowledge the receipt on August 9, l9Ti, of your supple- mental new drug application dated August 8, 1971, submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act for Tonamla (plientermine resin complex) capsules. We also acknowledge receipt of your additional communications dated May 22. 1972, and May 30, 1973. The supplemental application provides for revised labeling and efficacy and bioava liability data in response to the August 8, 1970, Federal Register statement. We have completed our review of this supplemental application. However, before we are able to reach a final conclusion We request that the labeling be revised to conform to the enclosed guideline labeling except that the ACTIONS section should include the following additional paragraph: "The controlled release chancteristlcs of lonamin have been studied In humans in which blood levels of * * formulation has not been shown superior in ef- fectiveness to the * * dosage of the standard, controlled release formulation." Please submit twelve copies of final printed labeling revised in accordance with the above requests. Sincerely yours, BARRETT ScovILLE. M.D. Deputy Director, Division of Pharmaeomgical Drug Products, Office of Scientific Evaluation, Bureau of Drags. MEMORANDUM OF C0NFFRENcE FDA 11-013 October 3, 1974. Present: Pennwait: Dr. William Head; Dr. J. R. McGraw; Dr. Floyd Leaders; Dr. John E. Giering. and FDA: Dr. Barrett Scoville; Dr. Thomas Hayes; Dr. Harold Murdock; Dr. Theresa Woo; Mr. William C. Crabbs. Subject: Revised labeling for lonamin (phentermine resin), an anorectic. On February 19. 1974, Pennwalt was asked to revise Ionaniin labeling to con- form to the guideline labeling; they were also ask-ed to add a statement to the ACTIONS section concerning the sustained release properties of the drug. The finn requested this meeting to discuss their proposal with respect to revising the labeling. A draft labeling proposal was passed out at the meeting which formed the basis for discussions. PAGENO="0847" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15279 Some of the changes proposed by the ljrm were merely editorial and were not the basis of any objection. However, the firm proposed in some Instances to minimize the adverse effects associated with their particular drug. Their proposed "drug dependence" sug- gestion was not satisfactory in this respect. The reference to a study of 16 weeks In duration in the ACTIONS was also objectionable, since labeling for the class of drugs INOTCATES USE FOE "A FEW WEEKS". Some discussion was held about the use of the same labelling for all drugs In a class. The firm contends that individual drugs may have slightly different effects and should therefore have more individualized inserts. The firm was requested to make a formal submission of the labeling and to address the issues to which we objected, since policy decisions at a higher level will have to be made. They were also requested to submit material in advance for discussion at future meetings. WILLIAM CRABBS, Division of Ncurophurmaeologicat Drug Products, Office of Scientific FivaTuatioa, Burcau of Drugs. Foon AND Dzro ADMINIsTRATION, April 10, 1975. PETER K MANN!, Ph. D. Pharmaceutical Division, Pcnnu'alt Corp., Rocivster, N.Y. NDA 11-613/5-096, AF 13-450 GENTLEMEN: We acknowledge the receipt on March 17, 1975, of your communi- cation dated March 14, 1975, enclosing printed labeling pursuant to your sup- plemental new drug application dated November 18, 1974, for lonamin (phenter- mine resin complex) capsules. The supplemental application provides for revised labeling. We have completed the review of this supplemental application, and it is approved. This action approves your application, as supplemented, on the basis of effectiveness of the drug as well as safety. The enclosures summarize the conditions relating to the approval of this application. Sincerely yours, BARJrnT'r Scovu,cn, M.D., Director, Division of Neurophannaeological Drug Products, Bureau of Drugs. SupERvIsoRy EnIEw or RzvxEw DATED Fannuaay 17, 1976 Name of drugs: Trade; lonamin; Generic; Phentermine resin. Sponsor: Pennwalt Corp., Rochester, KY. Subject review notes that an adverse reaction occurred In a nurse who took medication for 7 days and noted palpitation. restlessness, insomnia, and euphoria while receiving the drug and developed severe withdrawal symptoms of tremor, confusion, restlessness and severe depression following discontinuation. The nurse reporting the experience describes herself as a "sober alcoholic" for 1% years. Dr. Woo recommends that alcoholism should be added as a contraindication. It appears to me that there is Insufficient evidence that the reaction In this nurse Was related to her prior history of alcoholism. It appears that there is an insufficient reason to include mention of alcoholism as a contraindication, based on available evidence at this time. THOMAS A. Iflns, M.D. 05-569 0 - 77 -5~ PAGENO="0848" 15280 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IAIIOTZAL Ac,~a:MY or Sc,ENc[S-NAI IONA!. flL5LJ.RCK Cou:;c,L D~4..,, ci M~ëico Sc;e,,cc, DIIUG EFFICACY STUDY F,~,, A To be suh~ittcd io doplicote by opplicoci I /`~I 9 C IhoANoob., Woos TS'f Z.D,,,O.,,,,.fl,,..d._~spi~mrnZ3~_1955 ,,~ o.CD dIc,,dnoe~ BJNLT&MINE `7½', `12½', `20'_ - Strasenburgh Laboratories Div. Wallace Tiernan, Inc. S *pp~oM.Woo 755 Jefferson Road, Rochester, New York 1~623 A dd'.o~ 6. OvoctiIoTic,e Founolo ~,T,bPuT,odIN.,.P...,.!,,yTSo,o..IAd,o~ bc,'.d.AeT. I5.,cdec,h,00 .01,6.11 Aooo.oIIp,,tcb'.T.p.col.1'11 BI1t~ETkl1NE `7½' d-Mphetnnine 3.75 op. di-Ar1jhetnrine - . 3.75 Op. both as Cation exchange rosin complexes of sulfonated polystyrene BlPIiETkIINE `12½' - d-Mphotaniine 6.25 op. d1-ksphet~aiine 6.25 op. I,oth sis cation exchange resin CoOp] oxes of sulfonated polyrtyrono BIItcrA'IINE `20' d-Asphetarninc 10 eg. d]-knphctz,mino 10 mp. both as cotion exchange rosin complexes of sulfonated polystyrene Riphetamino `7½' Biphosaisine `12½' Biphetarsine `20' L Do.o,. A.,,, cob',,. ,,h~ite Capsule, BLack White Capsule, Black Ca,sule S Root. OR Ad,,. 0.-I. el~ Who'. o'~ dc-0 op od.,co,l,pl.o,, o.poloco I,,,.. oheold ho o,od t.Tl.Rc000*occl Clo,,-._A''coI,IOcobcF. ,,dlOpo,o,c,i,,.,l. -t...dloo,,~o',ocro.,ATbLeI p.c,,o,t,.oo.ooioo.io,,Isho.ff.c,oo.ltI..dcclT~ocoh. p,..~poo,~oeoh,oI' `k,p,,'.o,.~',o,'.e,b,o".l'o. App(OALO'I'Ie Ii bey,.I.c.o000 ocd I,opv todool,,,', CohoAlohI.fl Scm reverse sidc. TI.meopp'.,otl,..t-.l.d,.'0000 d.c;..,.I,,,he,, ..,,,,p .oh.do,,pt;oI,l-ct.. p.., ,I,.h...or_ol.000rch,dc_c byIhRAlo4~'c~~ Th,,sop,ioo.tl.'y,oloo'cI,I.eId b.,,lbo,pd o-s~FW..A(.h~k I. h,:~1,,.p, etlIc~oolo'ociTIk,,5oo_lod. `I. ,,,6;o.po,.,p.,,c.b;.I,,dd.oo.ib.h,,.I,,o..pI.o.cI~.,.eooo.ot!k.l.o,ohoiT1Od*Ihfo0Alo01oT. I. (~uhle-b1thd, cI-oss-ovor in mentally retarded obese subjects. 2. Double-blind study in obese subjects. 3. Pools] o-hlind study to dotorcire duration of action. The b_Ill `°`c 0_Id,,.,, ot Op000 II pod PAGENO="0849" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15281 10. LIST OF PERTINEVr LITERATURE REFERENCES 1. cass, L.J.: Ann. lot. Med. 51:1295, 1959. 2. Freed,~ S.C.; Xeating, J.W. * and Hays, E.E. : Ann. lot. MS. 44:1136, 1956. 3. Reich, W.J.; Nechtow, N.J.; Reich, J.B., and Mibaz, A.: Ctie. Med. 69:695, 1962. 4. Cohen, Bit.: Med. Tthe~ 90:1087, 1962. S. Freed, S.C., and Mizel, ML.: Ann. let. Mad. 36:1492 * 1952. 6. Freed, S.C.: OP 7:63, 1953. 7. Cass, L.J., and Frederik, ES.: Ann. let. Med. 49:151, 1958. 8. Jo Riche, W.H., and Van Belle, G.E.: Caned. M,A.J. 85:673, 1961. * Die pI,otoatatic copies of case histories are held in the files of the Research Center. A. P. Truant, Ph.D. PAGENO="0850" 15282 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BIPIIETAHINE 7. 12½, 20 NM 10093 LOG 271 1Q90 Panel on Psychiatric Drugs - INt1C~TI0i~S I. Ziphetamine is useful and effective in weight-control problems requiring safe and predictable appetite appeasement and mild invigoration. EVALUkTION: Effective, but CiPIEHiS The Panel, suggests the deletion from the indication of the phrase: `requiring safe and predictable appetite appeasement sod mild invigoration." A majority of the Panel evaluated the sympathomisetic stimulants as "Effective, but as anorectic agents, with the following comment. Sympathomisetic stimulants as a class have been shown to have a gener. itty snort-term, anorecttc action Anorectic agents suppress appetite. rea ts,ent of ohe s,~yin t7 eWdI i~shou1d be used ~ 1>' as anadiunct to a total program of~T~Tt reduction for obese_, patients that includes atient education motivation calorie restriction, and exerc Se. The anocectic~7Thi~f snoreric ants often plateaus or diminishes after - weeks (1). The dosage of drug must be individ- ually titrated end given at least 1 hr before meals. Clinical opinion as to the contribution of the synpathorimetic stimu- lants in a weight-reduction program varies widely. Nost studies of these preparations are for short periods. The Panel suggests that controlled studie, of the long-tern ~ stimulants in weight-reduction programs be `tlS~i~lve'iiiinificant potential for drug abuse. A minority of two of the Panel membsrs agreed with the above comment of the majority of the Panel, but evalusted the sympathomimetic stimu- lants as `Pcobablyaffectiva!las anorexiants. Their reasoning for the `Probably effective" evaluation van that: (a) most studies of these preparations have been for short periods, (b) there is no available evidence that theuse of these anorexiant prep~r ta ons *g term the - natural history of obesity, (c) there is some evidence that anorectic.. itltrtt-mnytrTtThngyflfl GTh~Ert~ the auggestibi lit, of the gg.gjgnt 1fl'ffflhere a a i~T56but rod a equacy of the controls in some o the clinical studies. The minority suggest.: that controlled iT~Thson the iong-term anorectic efficacy of the syepathoeiimecic stimulants be conducted. DOCWElrrATIow: - I. Harris, S. C., A. C. Ivy, and I. N. Searle. The mechanism of amphetamine~indu~~~ loss of weight; a consideration of the theory of hunger and appetite. J.A.M.A. 134:1468-1475, 1947. PAGENO="0851" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15283 Page 2 of 2 BIPHETMIINE 7, 12¾, 20 tWA 10093 LOG 271 /.290 II. Biphetamine effects: 10-14 hr of appetite appeasement with mild invigoration. EVALUATION: Possibly effective. COSPtNT$: More substantiation in support of this indication is required. DOCLTheEHTATION: Clinical experience and judgment of the Panel. III. Strsaioesic release, originated by Strssenburgh, is best for sustaining therapeutic action. EVALUATION: Possibly effective. CO~G1MTS: More substantiation and caeparative documentation in support of thie indication are required. ~ Clinical experience and Judgment of the Panel. GENERAL CC*VIENTS - The Panel euggeste the deletion fron the package insert of the following statement, because it refers to the possible consequences of weight loss, and not to a direct action of the drug: Biphetsinine is useful and effective in the following diseases or conditions: Arthritis: Weight loss decreaeea the load on diseased jointc. Cardiovascular Disease: Loss of weight relieves the work load on the heart. Hypertension: Loss of weight is followed by decrease in blood pressure. Obstetric,: Weight control decreasee risk at delivery. Cynecology: Weight loss improves surgical risk. Diabetes: Weight loss aids in controlling the disease. Dosage of insulin or oral diabetic therapy should be adjusted to cover decreased caloric intake. Surgery: Preoperative weight loss improves surgical risk, The Panel cited several additional references in support of it_s statement that the annrectic effect of sympathnmimecic stimulants after 4.t, weeks (1-3). DOC1flNIATION: 1. Fesekas, .3. F. Anoraxigenic agents. New Eng. 3. Med. 264:501-503, 1961. 2. Kinard, S., 1.. C. Mills, 3. Terrell, and 3. H. Moyer. Use of d-ampheta,sine to curb the increased appetite and over-eating induced by reserpine therapy. .3. Amer. Ceriat. Soc. 4:1-73-1077. 1956. 3. Thorn, C. W., end P. K. Bondy. Obceity. p. 395. loT. R. Harrison, R. D. Adams, I. L. Bennett. it., W. H. Resnik, C. V. Thorn* and N. N. Wintrobe, Ida,. Principles of Internal Medicine. (5th ed) Ncw York: McGraw-Hill Book Co., 1966. / ~ - PAGENO="0852" 15284 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The Drug Efficacy Study of the National Academy of Sciences National Research Council has requested that the following qualifying addendum be conveyed with their reports to the uitistate recipients of these reports: "Drugs of identical chemical composition (so-caned gennr3r drugs) fo~ulated end marketed by numerous individual firms under Ceneric or trademarked ns~s have been evaluated for efficacy as a group without consideration of `therapeutic equivalence.' In the event that no evidence for pharcecolcgicel availability or therapeutic efficacy in man can be presented for any of the indications claimed for the use of any of the dnsgs in the attached listing, their classifications of effectiveness may need to be modified if regulations of the Food and Drug Administration require such proof.' PAGENO="0853" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15285 Oih of `-`fool ~cience, DRUG O'FICACY STUDY Fern, A To Sr ,.beiti,d n dLp'icot, by cop l~ccffl) p~CAti,nb~ 1161a Cfl/ aD,c.Oo0ecOp App..,S__.~'' 3c.GoTcO 4. !.cdN,,,__j~~ `15' `30' _____________________ _______ - Strasenhuxghj!ahoratories Div. Wallace Tict~fl~Inc. 755 Jefferson Road, Rochester, New York 14623 6. Quonlitolive Formu!o *,tcbI;,k.dcNoc.P,,p,i.,cry'Ncn.,c A,t... lO.\A-SIIN `15' !hcntcroLine 15 lag. as cation exchange resin complex of sulfonated polystyrene IONAMIN `30' Phenteraine 30 mop. as cation exchange resin corplex of sul fonated polystyrene JONAYIN `is' IOfVdIN `30' , ) 7. O,,cc. F,.' ~ .~.S~L~c2S~!_ Yellow capsu3e(<~'- 0- R.cm..IAdn O',. .5. W~....,.cd.o5o,pI5e!on,,,.., Oral ci cd..nc..&cc. ,.pc,.,.Po,r,,I.ccId ...dIOp,.kc~ci..cJc i'o.,dl'cc.chccJte.,Afb~rl ,,dIcnoyccS..pmc..F,.cAld.1 cisc ,tk,r,c'c,.,.ic,.n,..'..u pn,ocn,t,cr..ch..h.c ~ riS,d,..qc.,tN. pc.p,...J,-c.kch,c,, *.p.I.9--,c,,.,,b,ckc.nApp,n,.conS Sc. let. n,¼o,.rc cod I,,,, .cd.pe,.. Foe A lrh.lcl.I See reverse side. I,. To.pppI.,.;.; 54.'.,,,, d.oc..,c,cb,l ,re.np.L-l.,'.S.., ,.IAsS preh.,rp',ts~,I.o4oo,lthp do.q by's. &.,,c-c~Ccos. lh,,.pp5'c.uc,..e...&.b.,Jdb. po,k*qrd,..O. Fc,.,A(,hF.}A,,91.,,py c,ih;.n...'li,,,q.,,Sd. .4 b.bocP..,yp'.'.'lc.,e,y,.l5.pf,bn;4ipd.Fo,.Alch3~l. 1. Double-LUnd co9)arat]ve efficacy study (llumrccnrnn) . .4-. 2. Double-blind corznrative efficacy study (63-5-K). 3. Double-blind coaparati~e duration of action study (53-3-L) ii,. copy, c.;,;.,, Ti. bo,c -, cl., Wh;.pc,p,;. 4_re,,., cirdil sdd.,;, Llpoc PAGENO="0854" 15286 COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY 10. LIST OF FERT]NE~T LITERATURE REFERENCES 1. Cass, L.J. : Ann. let Mad. 51:1295, 1959. 2. Freed, S.C., and Hays, ES.: Mi. J. M. Sc. 3. le fiche, H.: Caned. LA..!. 82:467, 1960. 4. Cohen, Bit.: U. Timea 90:1387, 1962. S. Sands, R.X.: Am. .7. 056t. Gynee. 83:1617, 6. Rider, J.A., and Iteller, H.C.: AppZ. The,t. 7. Sehnert, K.1~.: CLbi. Mad. 70:400, 1963. 8. Hook, C.: Med. ~`aLt. 37:1907, 1961. 9. )hiller, C.: Med. ae&. 2:121, 1965. 10. Sprang]er, 3.: MU,ichen. Med. Wehn6cJtk. 107:1833, 1265. The photostatic copies of case histories aTe held in the files of the Research Center. A. P. Truant, Ph.D. 238:55, 1959. 1962. 5:523, 1963. PAGENO="0855" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15287 Pafle I of 2 ION/faN "15" & "30" NDA 11613 LOG 667 Panel on Psychiatri~_p~g~ Ipr,rcATJors - I. lonanin (phentermine resin) is indicated for obesity. EVALUATION: Effective, but . co;r'rcwIs: The Panel suggests thet the phrase `as an adjunct" be inserted in the indication before "for obesity." A majority of the Panel evaluated the syr'pathonismtic stimulants as "Effective, but as annrectic agents, wit!~ the following cm. eat. Sympathorniactic stimulants as a class have been shown to have a ger.er- elly ahort.tera anorectic action, Anorectic agents suppress appetitc, They are not a treatment of obesity in themselves and should be uaed prirarily as an adjunct to a total program of weight reduction foc obese patients that includes patient education, motivation calocie restriction, and cxercise, The amorectic effect of anorectic agents often plateaus or diminishes after 4-6 weeks (1-4). The dosage of drug mL,st be individ- ually titrated and given at least 1 hr before meals. Chafed opinion as to ti's conttibution of the syrpsthomiaetic stimu- lants in a veight_rcduction program varies wide ly. Mast studies of those preparations are f-or short periods. ~~epa,io1 suggests that controlled studies of the long-term effects of the sympatho~Kinibllc itins'iants in weight-reduction progra~ea be conducted. These prepera tionsh~gaigp~cantpotentj~jf0~ drug abuse, - A minority of two of the Panel s,erabers agreed with the above comment of the majority of the Panel, but evaluated the ayLnpathomimetic stimu- lants as "Probably ~ as enorexiants, Their reasoning for the Pro~~~~y effective'' evaluation was that: (a) mast studies of these preparations have been for short periods, (b) Lhgra_jsn9avajlabi_e evideaco that the use of these anorexiant preparations alters the d&i,c e that a Tre ct 1 effects may be strongl~jnfluen~e~ by the suggestibility of the patient, and (d) fterc_are reservations about the adequacy of the controls in some eL_the clinical studiEa, The mtKoriry sü~ested that controlled studies on tlibIbhtre~i~brectic efficacy of the sympathomir,atfc stimulants be coeducted DOCItIENTATIOIc: I. Fazekas J, F, Anorexigenic agents. Now Eng. 3. Mcd. 264:501-503, 1961. 2. Harris, S. C., A. C. Ivy, and L. >5. Searle, Tl,e mechanism of amphetamine_induced loss of woight; a consideration of the theory of hunger and appetite, J.A.N.A, 134:1468-1475, 1947. PAGENO="0856" 15288 COMPETITWE PROBLEMS IN ~E DRUG INDUSTRY rage 2 of 2 IONANIN "15" & "`0" - NDA 11613 LOG 667 3. Kinard, S. * L. C. Mills, .1. Terrell, and J. H. Moyer. Use of d-aaphctamine to curb the increased appetite and over-eating induced by reserpine therapy. J. saner. Geriat. Soc. 4:1073-1077, 1956. 4. Thorn, C. U., and P. K- sondy. Obesity, p. 398. In T. R. Harrison, R. 0. Adams, I. L. Bennett, Jr., U. H. Resnik, C. U. Thorn, and H. H Wintroba, Eds. Principles of Internal Nedicine. (5th ed.) New York: McGraw-Hilt Book Co., 1966. II. lonamin effects: 10-14 hr of appetite appeasement. E~'ALUATI0N: Possibly effective. CoptMgsrrs: Inadequate docuaeotation regarding blood levels of the prepa- rat on folio tog the u se oUF~Piiifa nmd-r lenrg,lp sulv tsi~ai1ao le to the Panel; the Panel suggests that furthor studies be condudf411 to derion- itrate the superiority of the sustained release form to the usual form of administration. - DOCUNENTATION: Clinical experieoce and judgment of the Panel. GENERAl. C014>IENTS The Panel suggests the deletion from the package insert of the following statement ,~ecause it_refers to the possible consequences of wed ght loss, and not to a direct action of the drug: Ionasii~tphentermine resin) is useful and effective in weight control problems requiring safe end predictable appetite eppeasessent, including: Arthritis: 1-height loss decreases the load on diseased joints. Cardiovascular Di sease~. Loss of weight relieves the work load on the heart. Hypertension: Loss of weight frequently is followed by decrease in blood pressure. Obstetrics: Weight control decreases risk at delivery. cynecology: Weight lose improves surgical risk. Diabetes: Weight loss aid s in controlling the disoase. Dosage of insulin or oral diabetic therapy should be adjusted to covet decreased caioric - intalce. Surgery: Preoperative weight loss improves surgical risk. L7proved by~~ ~< Chalrzta PAGENO="0857" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15289 The Drug Efficacy Study of the National Academy of Sciences - National Research Council has requested that the following qunlifying addendum be conveyed with their reports to the ultimAte recipients of these reports: "Drugs of identical chemical composition (so-called cen~rir 6riic's) forru)ated and marketed by nuaterous individual fins under generic or trademarked names have been evaluated for efficacy as a group without consideration of `therapeutic equivalence.' In the event that no evidence for pharmacological availability or theraocutic efficacy in sian cen be presented for any of the indications claimed for the use of any of the drugs in the attached listing, their classifications of effectiveness may need to be eadified if regulations of the Food and Drug Administration require such PAGENO="0858" 15290 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DRUG EFFICACY S1UDY ten, A (To be wbn,IIvd in duplicete by oppl.conl /-79.6 fleA N.ebn 11538 Co I ~. a,,. oi~;..I'~ s,p,.e._ 25, 1961 1. 5. OTC 0 BTI1!fl.&'ITNt-T 12½', Bifli I1XE-T 20' Appr~..'. ~. ~ras~rc Uboratories Div. Icallace Tie~an Inc. *.4 ~ 755 Jefferson fload, Rochester, New York 1462S - - 6. Q~unhiIctive Fotniela Ieb.I) A~.e.M (F~' f~bto. .Ld,-l BIPUEFAMIKT-T `12½' d.Mphetanine .~ 6.25 mg. dl.Mcho1~arniflC 6.25 sag. NethaqitalOfle 40 sag. all as cation exchange resin coniplexes of sulfonated polystyrene BIflIUFANINE-T'ZO' d-Miphetainine 10 ,,~. dl.Mghetarnine 10 san. }iethaCiUalOfle 40 all as cation exchangc resin coeplexes of sulfonated polystyrene BIflIETP)IINE-T `12½' BIflIETAMIXE-T'20' P.O ,. .k, MackG Creencrnst,le, Black Red Capsule ("2. -Cr.. t.,I. .5 Ad... O~.l. *.s, Win..e.., d'..g ,ppc,.te.,..., Oral - ~ ~ d.) ....d)...;,;,.' fe.nA ~ sua.fI.'...t',."t.""'. ..o.tp..Ii.~"I,. ~ ,4,.,gf.,ik.pc.r..., Ic~..A,,I. 1 h.lt,..d..th. lob,'. .0t p.,i.n. ill,.'. n b~.1ho'. App,~.~l.@toly a I. 10 I.y~~l~l.ltl .?.,.q....l.d,l .l,bl. jAIled, ``nP..' ~o, *1 I .,p ylodnplk~I. boo A `5.3 See reverse side. I.tb..pplke.'is io,c;l,d iIb*~o d. uo,cb,s.cy,,,,bli,Po,den,00;,lth.t. p., i,*t...,etc,,lo,.IIh, 4~oot by~b.A,.~.'a- CO~l~dl. lM~*epPI~oo~ ,v_Ol.,.,5.t.c, b~p Set c.lI. 7.,OA ..h.l.lA,h,ol.,.pTtSth,0,,*tndOl .o1o4co~Iod, 0.5. tb.,.,p..o. p1..,. lie, .e4 d,,,.~b. b..fly lb. .eppk',.'t,'y ,,Io,i'3 b.l ,eI,ei,I.d .1,5 F~'.' A .-bt.I. See reverse side. Tb. 00.0 cli'', I,.. ~ 0. I PAGENO="0859" COMPETITIVE PROBLEMS IN THE DRUG INDUStRY 15291 EDA 11538 - LOC GSG Pnnl on Pr~chiz5,-dc !5rug~ 1ND1C&flO~S I. flipl,etamine.T is indicated for exogenic obesity. EVALUATION: Possibly effective. C~DENTS: The amphetatsines have been evaluated as "Effective, but as snorectic agents in obesity. The Panel evaluates e2etha~ua1ene as "Probably effective" as a daytime sedative, similar to such daytise seda Lives as k~i4turates in the trcots:ent of anxiety. The utility of the combina t[on in the treatment of either condition or both concurrently has not been determined, The drugs night sr.tagonire each other's effccts. In the total absence of positive controlled studies, the combination is evaluated as `Possibly effective." Basic studies, beginning in the animal, of the interaction of the snorcctic and tranquilizing effects of the two drugs in this combination are necessary to begin to clarify the issue.- - A majority of the Panel evaluated the sysipathoainotic stimulants as ~ but ." as snorectic agents, with the followina cerenent. Sympaihoaimctic stimulants ss a class heve been shown to have e Corer- ally short-term snerectic sction. Annrnetic aeents supprero appetite, They are not a treatment of obesity in themselves a0d should ba teod primarily as an sdh',,rr !~ totsl progr:o of toigtt rcdu~t;,,,, ru~ obese patient, that includes patient education, motivstien calorie restricticn, and exercise. The anorectic effect of energetic agents often plateaus or.diminishes after 4-6 weeks (1-4). The dosage of drug must be individ- ually titrated and given at least 1 hr before meals. Clinical opinion as to the contribution of the sy,npsthoainetic stiou- lants in s weight-reduction program varies widely. Nest studies of these preparations are for short periods. - The Panel suggests that controlled st-idles of the long-term effects of the sycipstho:ninetic stimulants in weight-reduction programs be condocted. These prepara- tions have a significant potentisl for drug abuse. - - A minority of two of the Psoel members agreed with the above corrant of the majority of the Vend, but evaluated the syapathontireric stiou- lants as "Probably effective" as anorexiants. rh-air reasoning for the "Probably effective" evaluation was that: (a) east studies of these preparationa have been for sh,orc periods, (b) there is no available evidence that the use of these anorexiant preparations alters the natural history of obesity, (c) there is sor.e evideere that anorectic effects ,say be strongly influenced by the suggestibility of the patient, and (d) there are rescrvatjona about the ade4uacy of the controls in some of the clinical studies. The minority su~ges ted that controlled atudios on the long-ten, anorectic efficacy of the zyapothomiretic stiatulants be conducted, PAGENO="0860" 15292 COMPETITWE PROBLEMS IN T}IE DRUG INDUSTRY nnrnni;r:c-~ ~l2;", "20' lit'S 11538 . nr too 6Sf. 50C'JUEkTAIION: 1. Fazckas, 3. F. Anorcx5gcnic agents. Mew Eng. 3. Mcd. 264:501-503, 1961. - 2. Harris, S. C., A. C. Ivy, and 1,. H. Searlo. The mechanism of ampl,otas,ine-iiiduccd loss of weight; a consideration of the theory of hunger and appetite. 3 .A .M.A, 134: 1668-1475, 1947. 3. Kinard, S., L. C. Mills, J. Terrell, and 3. K. Moyer. Use of d-amp1~ctnoine. to curb tie increased appetite and over-eating induced by reserpine therapy. J ~ner. Ocriat. Soc. 4:1073-1077, 1956. 4. Thorn, C. W., and P. K. Bondy. obesity, P. 398. In T. ~t. flarrison, R. 3. Mains, I. L. Bennett, Jr. * U. U. Resnik, C. W. Thorn, and H. 11. Wintrobe, Eds. Prir.ciples of Internal 1-!Qdicine. (5th ed.) Mew York: Mc0raw-Hill Book Co., 1966. II. Biphetsmtne-T effects: 10-12 hr of appetite anpeasewent with mild invigoration and reduction of aro:iety. EV&LU.6110N: Possibly effective. - C0)9-tfls: Inadequate documentation regarding blood levels of the props- ratioo follouj:,g the use of the sustained-ne) ease capsule is available to the Penol; the Panel suggests that further st,,di en he cond':ctsd to darien- the suporirri ty ni ph5 *`.,,tain-,d rulee:: Sara lathe usual form of adotnistratinn. See also coasnents for Indication 1. DOCJ?ttKTAII0N: Clinical experience and judgment of the Panol. III; Biphotarsino.? utilizes a 1:1 ratio of lcvoaaphctar.ine to dextroamphcteaine. This ratio has been ahoun to have better a,,orectic activity than the dextroforin alono. - LYALUAflOP: Possibly effective. C0~-lB~hTS: Documentation in support of this assertion Is inadequate. DDCIJZNTAT3ON: Clinical experience and judgnent of the Panel. CflcrR1\L C0~tY.KTS The Panel suggests the deletion free the pactiàge insert of tI~efojlowing unsupported statement'. Both the appetite-curbing action of tipiietaniine and the calming action of Tuazole (nietl,aqunloue) Are rcloased simultaneously at a predictnblc rate. PAGENO="0861" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 18293 .1 01 i BpltEt~~ITt~_T"l2?~". "20" E1I\ 11538 r J.0~ 666 I-J'J.J The Panel suggests the dclcti on frost the package insert of the follow- ing statenents, which pertain to tl,c md ividual ingredients of the com- bination and not necessarily to the ceribmnation; there srateents should be so phrased that they do not imply that the ease individual action occurs with the cosbination, unless such action can be demonstrated: Tuazolo (nethiaqualone.) has been shown to be a potent and effective calming sgent with a low order of toxicity. Tuazole (methaqualone) has several qualities of both short- acting barbiturates and meplienesin. As a calming agent, Tuazole (me thaqnalono) is desirable and lends itself ideally to prolongation through ionic release from its resin cosplex. These properties make Tuazoic ideal for decreasing the hyperactivity sssaciated with amphetamine therapy in stain. pstien~s N ~ irprovos b7 PAGENO="0862" 15294 co~.n'ETITWE PROBLEMS IN TIrE DRUG mDUSTRY MEDICAL OFFICER'S REVIEW CF NDA 11-613 (Annual Report: R-13 of 5-28-75 FED 17 1978 Date review completed: 2-12 SPONSOR: Pennwalt Corporation - Rochester. N.Y. NPJIE OF DRUG: 11~DE: lonamin 15 and 30 (CIV) GENERIC: phentermine resin wTERIAL REVIEWED: In volume 12.1 PREVIOUS MEDICAL REVIEWS: 11-28-72; 10-2-73; 3-12-74; 1-15 & 3-26-75. PUBLISHED ARTICLES (translations): / a. Backmann. R. et al: Primary vasoclar pulmonary hypertension (PVPH). Verh.Otsch. Ges. Kreislaufforsch. 38:134-141. 1972. A workshop was held at the fled. Coll . of Hanover in Feb. 1970 to discuss the increased Incidence of PVPH related to the use of aminorex fumarate (AF). The following conclusions were drawn from the evaluations of the convnission of the German Society for circulatory research: (1) In a retrospective study of PVPII patients. and selected controls, there Is a significant relationship (pCO.COl) between AF ingestion and PVPH. (2) with the exception of 9 cases, there is a close chronological relation- ship between AF ingestion and the appearance of PVPH In all the patients. (3) There is an increase in the Incidence of PVPH for 1968 and 1969 and a decrease In the incidence since 1970. The chronological relationship between the Introduction, expanded usage, and decline of AF is given. (4) A dosage dependence of the path risk with respect to PVPH after AF Ingestion could be demonstrated. (5) The fact cannot be excluded that other amphetamine-like anorectics and stimulants may cause PVPH. - (6) Besides AF. no other factors that might be responsible for PVPH could be Identified. The Cormuisslon Is.of the opinion that the use of amphetamine-like anorectics and stimulants, for which PVPH is suspected can no longer be justified. b. parwaresh, N. IL et al: Tissue alterations in exp animals after chronic administration of anorectics. Verh. Dtsch. Ges. KreislauffOrsch. 56: 513- 517, 1972. PAGENO="0863" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15295 NDA 11-613 - Page 2 In rats (Sprague-flawley) chlorphentermiine (50 mg/kg, i.p. for 6 weeks) induced pulmonary hypertension. This was similar to the effects produced by acninorex and phenmetrazine but contrary to the effects of amphetamine, ephedrine and phentemaine, Chlorphentermine was the only drug, which evoked morphological alterations: the alveoli contained a great abundance of macrophages resembling foam cells, Mo alterations could be detected in the vessels. The excessive formation of foam cells was accompanied by a significant accumu- lation of chlorphenterinine in the lungs. The foam cells contain a consider- able amount of phospholipids (mainly lecithine), which are responsible for the increased binding capacity of chlorphentermine in the lungs. In their opinion, the cellular alterations, whiáh are also found in other organs (adrenals, spleen heart, etc.) as well as in different species (mice, g. pigs, rabbits) are to be considered as a chlorphentermine-induced phospholi- poidosis. c. Munro, J. F.: Management of obesity. Brit. J. Hosp. Med. 8-14, July 1973. The sheet-anchor of the medical management of obesity is dietary restriction and re-education in eating habit. The success of dietary control depends upod the ability of the patient to adhere to the prescribed regime. Medical manage- ment cannot be separated from the psychological support that many obese patients need. ~unflarv of 5t~idv 10-6 b'; II. (~ershbero.jL~, on 22 obese (at least l5~ over- weight) maturity-onset diabetics: 11 received lonamin 30 and 11 placebo, for 16 weeks. All were placed on a 1000 calorie diet. Results cannot be evaluated for the 2 groups were not comparable. lonamin group consisted of 7 males and 4 females, whereas 10 females and only 1 male received placebo. Also, no information is available on conconmiitant medication, except that none of the patients received insulin. Comments: A 34 year old RN reported an adverse reaction on 3-15-75 to NDA- T7~S»= (rastin), For 7 days in 3/15, she took one 30 mg capsule of Fastin (phentermine Nd) daily. She noticed palpitation, restlessness, insomnia, euphoria while on Fastin (3/8 - 3-14-75). On 3-15 she developed severe with- drawal Sx: tremor, confusion, restlessness and severe depression. This RN has been a "sober alcoholic" for 1 1/2 years. Recormuendation: as suggested by this RN, the labeling should be revised as follows, under: Contraindication: third sentence should read:6patients with a history of drug abuse "or alcoholism." -7;- ~c 2~ Theresa T. Woo, M.D. HFD-l20/TTI 00/21776 F/T:dmwhitted:2l775 85-569 0- 77 56 PAGENO="0864" 15296 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SOVT~ARY OP REPORTS Date Sunriary Completed: 12/9/69 - NDA &1~613) Company: Strasenburch Labs Rochester, New York ORIGINAL APPROVAL BATE: 5/114/59 NN4E OF DRUG - Trade: lonamin `15' Ionamth `3O~ Generic, phentermine resin DOSAGE fO~4S AND ROUTE OF ADNINISTPATIONI 15 ng. and 30 mg. Capsules, sustained re1e~se, for oral use. CATEGORY OR USE OF DRUG: Anorectic DATE OF REPORTS: February 28, 19~9 - September 15, l~9 REASON FOR REPORTS: Annual Report 2-28-69 (R-Ø7A) Adverse Reaction 9-15-69 and 9-30-69 MATERIAL REVIEWED: Designated Reports CLINICAL EVALUATION: No clinical studies, pre-clinical studies, or animal studies were submitted with this report. Bthlioc~h: Clinical references by author, title, journal and date are submitted on 32 items publi shed 1966-1969. These studies are chiefly with amphetamines, obesity treatments, appetite suppressants, comparisons, adverso results, end various factors relating to anorectics. None deal individually with p'nentermine and their general approach makes them of dubious clinical significance. Reproduced copies of 6 of these references are submitted, but they provide no mew information npplicable to this review. PAGENO="0865" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15297 Pharmacological references by author, title, journal and date are submitted on h6 items published 1966-1968. Prom the titles none deal with reproductive studies or teratology. Most of these involve amphetamine studies. Copies of 10 of these references are submitted. They are of dubious clinical significance. Distribution: January - December 1968: Ionaznin `15': 290,000 .~x's averaging 27 capsules for a total of 7,830,000 capsules. lonamin `30': 545,000 Rx's averaging 30 capsules for a total of 16,350,000 capsules. Adverse Reactions: - 1. May 1, 1968, Dr. H. Grossman, Douglas, Arizona reported experiencing convulsions while taking lonamin personally. He was also taking Lasix. He has not since responded to inquires. Without odditional information, this reaction would not be attributed to the taking of phentermine resin. 2. September 15 and 30, 1969, Dr. A. Guest, London, Ontario reports a 30 year old man developing an inferior myocardial infarction after taking lonamin for 3 weeks. The Drug Experience Report indicates prior minimal angina pectorjs for which he was being trented with Vitanin E. Since the label states that the drug "may be used with coution in hypertension and cardiovascular disease", it is possible that the reaction in this angina patient resulted from use of the drug. Corsaent: This case gives evidence for a need for labeling revision. EVAL1JATIO!~: M.O. reviews of 10/17/66 and 7/17/68 reconm,end labeling revisions. These have not been acted upun. Dr. 3. K. lamar reviewed the pharmacology of phontermine HC1, November 28, i966, and, reports "Studies are inadequate to support safe use in pregnant women by our l~6 guidelines". He suggests that pregnancy warning should be included end that the manufacturer be asked to supply reproctucticn studies according to the 1966 guidelines for teratologieal effects. PAGENO="0866" 15298 COMPETITWE PROBLEMS IN TIlE DRUG INDUSTRY Dr. L. L. Phillips reviewed the pharmacolor~' of phentermine resin, January 17, 1967 and reconmiended teratologic studies according to the 1966 guidelines. CONCWSIONS: 1. Efficacy is under NAS/NBC review. 2. Labeling revision is necessary to provide for safe use. RECa~21ENDATION3: 1. Adequate animal reproduction studies should be performed in accord with our January 1966 guidelines, including adequate teratogenesis (Segment II) studies. 2. Labeling revision to comply with the current. anorectic guideline label as follows: Description This drug is a sympathomimetic amine or chemically and pharmacologically related to the amphetamines. Actions - This drug is a central nervous system stimulant; the precise mode of action is unknown. With respect to its anorectie effect it is generally accepted that this is of short term duration, Indications As an adjunct only in the initial treatment of exogenous obesity in order to facilitate adherence to diet. Ancreetic agents are not a treatment of obesity when used alone. Centrnindicatior.s Advanced arteriosclerosis, cardiovascular disease, moderate to severe hypertension, hyporthyroidism, known hypersensitivity or idiosyncrasy to the sympathcmimetic amines, and agitated states. Patients with a history of drug abuse. During or within 11; days following the administration of monoamine oxidase inhibitors: hypertensive crises may result. PAGENO="0867" COMPETITIVE PROBLEMS Ill TEE DRUG INDUSTRY 15299 Warnings Tolerance usually develops within a few weeks, When this occurs tEiiecofr~~ided pose should not be exceeded in an attempt to increase t he a 1101 CL~LL WI jecu Because of the effect on the central nervous system, anorectic agents may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly, DRUG DEPgMIENCR: Tolerance and extreme psychological dependence have occurred vitflrugs 0' this class. Patients hove been kno~ to increase the desage of drugs of this typo to many times that recomnended~ Abrupt cessation following prolonged high dosage administratiorr~biu1ts in extrene fatigue and mental deorcssion ~rr~mrrncd changes noted on the sleet EEG. Authorities differ as to whether such withdrawal manifestations indicate true physical dependence. Manifestations of chronic intoxication - with agents of this class include severe dermatoses, norked insomnia, irrita~ITtF h' era onalit" chanr.~ e taos severe manifestation of ch"onic intoxication is ps12~2~is äNen clinically indistinguishable from sehiz~p~r~nia., USAGE IN PP.EG~TANCY: Safe use in pregnancy has not been established. Reproducti~i studies in manvnals at high nultiples of the human dose on some anorectic drugs have suggested both an embryotoxic and a teratogenie potential for this type of drug. Therefero, use of anorectic agents by women who are or who may becone pregnont, and especially those in the first trimester of pregnancy, requires that the potential benefit be weighed against the possible hazard to mother and infant. USAGE IN CHILDREN: Not recommended for use in children under 12 years of age. Precautions Caution is to be exercised in patients in whom there is even mild hypertension. Insulin requirements in diabetes inellitus may he altered in association with use of these drugs and the conconitant dietary restrictions. Psychological disturbances have been reported in patients who concomitantly receive an anorectic agent and a restrictive dietary regime. - PAGENO="0868" 15300 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY Adverse Reactions 9verstimu1atj~,_~estlesSneSS, insomnia; gastrointestInal Msturbanees, diarrhea; palpitation, tachycarcia, efdV~tT6n of blood pressure; tremor, sweatinr, headache, dr;tcss ot the mouth or unplea ant taste, ~corie, chonges in libido. Rarely, Dosage and Administration Use above heading; delete statement that Tonmain may be prescribed for patients who are arthritic, diabetic, pregnant, menopausal, and may be used with caution in hypertensive and cardiovascular disease. OVERDOSACE: t.:anifestations of acute overdosage with asphetatnines or other anorectic nger.ts include restlessness, confusion, assaultiveness, hallucinations, panic states. Fatigue and depression usually fellow the central stimulation. cardiovascular effects include arrhythmias, hypertension, or hypetension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Fatal poisoning usually terminates in convulsions and carla. !-lanagenent of acute intorcication is largely symptomatic end includes sedation with a barbiturate. If hypertension is marked the use of a nitrite or rapidly acting alpha receptor blockir~g agent should be considered. Experience with hesodialysis or peritoneal dialysis is inadequate to permit recoreacadatiens in this regard. B. Kinbroufh, M.D. cc: :n(rm~~oO~ . ~` Di~DUU-32O) 7 / ~cimbrough:rjw:l2/lOI69 PAGENO="0869" CO3~ETITWE PROBLEMS IN TEE DRUG INDUSTRY 18301 CC "~°" Barrett SEovIlle, ;&o./oucp DIV ~°` Wal ter 51 oboda /60-233 - ONOP SO Cl CCI, Anorectie Study ~eviews SUMMARY Attached is a draft outline of material to be checked by physicians reviewing anorpctic studies. tet me also list the areas not included, on the assumption that you, your program, and perhaps tech aides will check them. Please correct me if the asstniption Is wrong. Number of subjects in study and in treatment groups. Randomization procedures. Stratlfièat ion. Camparability of treatment and control groups and subgroups. Verification of completeness of data sheets, together with some assessment of importance of incompleteness. Verificatinn that certain `standard' items are recorded, By `standard' I mean such thinos as data of entry into' study, dates * of follow-up visits, dosages employed. Checks for internal consistency. Examples might be: cross- checking patient number randomization against date of entry into çtudy; checking intrasubjeát consistency (e.g., deos subjects weight begin at 202 and go to 150 1 week later); examining age and weight distribution; checking ideal weight' figures against height, age, sex, and frame recorded. Of course we rely on your analyses of finns statistical model and techniques. - - Presentation of conclusions validly supported by the data in quantitative form, e.g., for each study, percent of excess weight lost because of active drug over applicable time intervals. Quantitative prkis of study along these lines: study with 44 subjects, 21 active day, 23 placebo, 33 pts completed study Should any of these areas be amplified? or rephrased? Other areas you expect to analyze? - ~U-MAYUn,: oo<.UM'-n~IlUMoo - 01,0 FPHauji 111/611 PAGENO="0870" 15302 COMPETITIVE PROBtEMS ~ THE DRUG INDUSTRY MATERIAl. FROM FOol) AND Dare Ao~rIxIsTRATxoN FILES ON CLORTERMINE (TRADE NAME: V0RANIL) BENJAMIN SIMEIN, M.D. Los Angeles, Calif., February 1, 1968. \VILUAM S. WESTLIN, M.D., Clinical Research Section, CIBA Pharmaceutical Co., Summit, N.J. DEAR DocToR WESTLIN: I was very disturbed to receive your letter of January 23, 1008, suggesting immediate termination of the SU-10568 study, particularly since it followed hard on the heels of a most extraordinary se~lon that I had with your some two or three weeks ago. I was quite surprised that you made such a recommendation (which, incidentally, was also suggested by during our Interview), without first personally discussing the matter with me. I consider your failure to directly communicate with me, and your formulation of a decision concerning this study based upon a secondhand report by a non- medical monitor without any kind of a report from me, a breach of your pro- fessional responsibillty to your clinical investigators. Furthermore, I would like to assert, that: (1) from my vantage point, the prevailing tone that seems to stem from your group is that of an employer to a paid employee, rather than the mutually respectful professional relationship of a Director of Clinical Research to a carefully chosen clinical Investigator; find (2) from my point of view, Is not a satisfactory project monitor, and cannot take the place of a medically qualified representative of the Clinical Research Section. Allow me to complete these prefatory remarks (before getting down to specif- ics) by re-Informing you that, prior to the present CIBA study, I have success- fully and fully completed 6 anorectic thug evaluations for 4 different pharma- ceutical manufacturers since 1956, the last two conducted during the past two years. Six published papers in established medical journals have emanated from these studies. The average length of time for completion of each of these studies (embracing comparable number of patients as the present CIA study) was 9 months, varying from 6 to 12 months as conditions allowed was given all of this information in our first meeting last spring. Furthermore, I had the honor of having been contacted by the FDA approximately three or four years ago, to testify in their behalf In a Court case in Chicago; they were particularly inter- ested in my presentation of my published placebo data In publications of 1060-el. Unfortunately, I could not oblige them at that time. In view of the preceding, I feel a sense ef insult and consider it a blemish on my past record when you informed me that "it appears that you will be unable to meet your commitment". flow, so? It is particularly disturbing to me, since I have just this month tuned down a request to do a study for the Upjohn Oompany, because I felt that I could not do full justice to my commitment to you by taking on another study at this time. As for your statement that I received drug supplies in July, 1967, true, but I should remind you that I did not receive the fir~ check from you until the end of September, whereupon the study was immediately launched. My records show that I deposited your check for on September 28, 1967. You will note from the case report forms that the first patient entered the study on September 20, 1067. In my past experience, no study has ever been begun prior to receipt of the first installment of the grant, As I have already indicated, I had previously told last spring that three months was not a realistic time for the performance of this study, in view of my past experience of a nine-month average for comparable studies, as well as ~the re- strictions of the present protocol ruling out patients with Ilypothyroidism. Diabetes, and hypertension. If there Is to he an onus for this situation, it will have to be since he apparently did not take sufficient notice last spring of my statement to him that I was an Internist subspeciallzing in Endocrinology which includes ~me obese patients. lam not a barlatric specialist. First of all, as already indicated, he either does not or chooses not to remember things that I have previously told him. Second, in my opinion, he knows very little about the subject of obesity and consequently fails to comprehend much of what PAGENO="0871" COMPETITIVE PROBLEMS Iii THE DRUG INDUSTRY 15303 I discussed with him, resulting In a considerable waste of my time. Third, and most important of all, in our last meeting he passed some unpleasant and Ill- advised remarks, unbecoming to a representative of the Clinical Research Section of a major reputable drug house. After commenting to him that the results of the first 12 patients appeared rather disappointing, and, more importantly, that I had failed to notice any appreciable patient acceptance of SU-10i565, he countered by saying that other investigators were getting good results and suggested that my poor results might be due to the bias of the investigator, namely, me. It was after my vehement denial of such a bias that asked me if I wanted to drop the CIBA project because of my `difficulty" in securing patients. This juxtaposition was most disconcerting to me since it meant throwing out of your clinical evalu- ation of SU-10568, an investigator who was not seemingly obtaining good results. This is akin to throwing out the bad experiments in a laboratory investigation. I was so incensed by this interview that I was sorely tempted to call you. Un- fortunately. I didn't because of my knowledge of recent heart attack and bus request to me to ferget what he said. However, your follow-up letter, released me from any sense of restraint concerning my relations with In summary, I would like to make the followlag points: (1) your office (unlike all others in the past) has not established a good professional relationship with this investigator; (2) I personally cannot relate to for the reasons already given; (3) perusal of the 12 enclosed case report forms, as well as my past record and reputation, should answer the question of bias; (4) in view of the unfavor- able results to date (although more than half may represent only placebo pa- tients), accuracy would not best be served by haste; and (5) 1 personally feel that I have been rather shabbily treated with a consequent sense of Insult. Since there Is no public honor these days in dispensing anti-obesity drugs from the office, and since there is equally no feeling of honor emanating from your office, I, too, think It best to terminate the study, but not until I have provided ynu with the data of the 20 patients covered by the grant installment you have already given me. I will give you data on S more patients and rail it quits. I have at no tIme stated or Indicated that I was unable to fulfill my commitment. Enclosed you will find the completed case report forms of the first 12 patIents. Finally, I would like to request that you append this letter when you transmit my portion of the data to the FDA. Very truly yours, BENJAMIN SIMKIN, M.D., Assistant Clinical Prof essor of 1lfedieinc, University of Sontkera California Medical School; Chief, Endocrine Service, Cedars of Lebanon Hospital. MEMORANnUM OF TELEPHONE CoNvtasA'noy CIBA PHARMACEUTICAL Co., Summit, MJ. Dec. 30, 1969. NDA 16-SSO-AF 20-332 Between Mr. George Ohye, Director of Drug Compilance, Ciba Pharmaceutical Co., Summit, N.J. and William Dworkin, Food and Drug Officer-OND/DND/ Med. Initiated by: Mr. George Ohye. Subject: Voranil. ~Mr. Ohye called regarding the status of his firm's NDA 10-850 for "Voranil". He stated he had received information that all of the reviews were completed and wondered whether I could tell him If we would soon be Issuing a letter on the application. We told Mr. Ohye that we do not know whether or not any of the summaries are completed, but we could tell him that none had reached this office. Therefore, PAGENO="0872" 15304 CO~ETIPWE PROBLEMS IN THE DRUG INDUSTRY we could give bin no idea as to when we might be writing a letter on NDA Mr. bhye would not comment on the source of his Information but said he must have been misinformed, lie apologized for having called unnecessarily. We told him to feel free to call at any time. WILLIAM Dw0RJCIN, Division of NeurophorflIaCOiOVicOl Drugs. ADDENDUM TO MEDiCAL OFFICER REnEW or NBA 16-880 PROPOSED MEDICAL SECTION OF LETTER ON EDA 16-880 JAlcuAnt 19, 1970. Not approval (b) (1). (a) Concomitant therapy Is not covered adequately on the Case Report Forms. Past experience indicates that we cannot assume that if no mention is made of concomitant therapy thea none was given. (b) Serious discrepancies are present with respect to the laboratory data submitted: - (1) Dr. Melvyn Wade (Vol. 1.60). The values listed for hematocrits and hemoglobins are incompatible. (2) Dr. C. Dletz (Vol. 1.79). Many patients have Identical hemoglobins and hematOerlts on 3 successive occasions a month apart. Futher, con- secutive patients have the same Identical hemoglobins and hematocrits. Additional examples may be found in the other laboratory tests reported. (3) The data eonceraing laboratory work submitted for Dr. W. Grater (Vol. 1.27), Dr. J. Sobotka (Vol. 1.29), Dr. P. Saplenza (Vol. 1.45), and Dr. A. Mickal (Vol. 1.81) are also characterized by similar Irregularities. (c) The sponsor's analysis of the clinical laboratory data (Vols. 1.2, and 1.3) is inadequate because: (1) The ranges of normal laboratory values given are too broad to be meaningful. In the ense of the normal ranges for hemoglobin and hematocrit, the difference between the male aad female values Is Ignored. (2) Only laboratory values outside of these broad limits are considered as meriting attention, whereas, in fact, a marked drop in one of the parameters, such as hemoglobin or hematocrit should be Investigated, even if the two values fall within the broad limits of normal which were selected by the sponsor. (d) Bias has been Introduced into the statistical analyses by deleting data from certain investigators In such a manner as to exclude unfavorable ftndings. A high drop-out rate does not necessarily Invalidate a study. With respect to Dr. Simkin's letter of 2-1-68, we request that you submit a copy of your letter to him dated 1-23-68. His letter refers to an additional 8 patients he Intends to forward. We request that these additional S Case Report Forms be submitted to us. (e) The patient populations used are not described adequately enough to permit proper evaluation of case material and experimental design. fliustrative of the type of information required to enable the reviewIng medical officer to make an adequate assessment of the clinical data are the following: (1) The address of the office, clinic, hospital, or Institution where the patients were studied (merely giving the investigator's address or hospital affiliation is insufficient). (2) The identity and location of the laboratory in which all laboratory tests were done. - (3) Source of patients: The circumstances of selection of patients and the criteria for their Induction Into a study should be fully described. If patients are entered consecutively, this shqnld be stated; If not, the manner of selection and entry Into the study should be detailed. (f) Most of the controlled studies are limited to 8 weeks' duration or less. Since obesity is a chronic disorder usually lasting for years, long4erm controlled studies are needed if long-term administration is proposed. (g) Since most of the controlled studies demonstrated only 1 to 4 pounds greater loss than placebo, this limited response would have to be clearly delineated In any package insert and advertising. PAGENO="0873" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15305 (h) We request that you provide us with the names of all monitors involved in the clinical investigation of Voranil, and the dates during which they served in such capacity. (1) There does not seem to be a consistent pattern for the numbering of Case Report Forms, Will you please advise us as to the methods employed- especially in those cases where a chronological order was not observed. RousutO. KNox, MD., Division of NeuropharmaeolOgieal Drugs. MEMORANDUM U.S. G0vEnNMENT, February 12, 1970. To: John Jennings, M.D. From it. Ne~vberry Subject: NDA 16-880 Voranil (Clorterinine lid) tablets. Original NDA-Not approvable letter based on inadequacies in almost all areas. Although the letter does not actually say so, It is apparent that the evidence so far does not show sufficient benefits to justify the risks involved. I am wondering if we should encourage further clinical studies at all. As I read between the lines, this drug appears to be a good candidate for drug abuse. Foon AND DnUG ADMINISThATIOIc, February 19,1970. Ciba Pharmaceutical Co. Summit, NJ. (Attention Joseph S. Harun, M.D.). NDA 16-S80-AF 20-232 Gentlemen: Reference is made to your undated new drug application sub- mitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act for the preparation Vorenil (clortermine hydrochloride) Tablets. The application was received on July 29, 1969. We also acknowledge receipt of your additional communication dated July 31,1969. We have completed our review and find that the Information presented is inadequate and the application is not approvable. The deficiencies may be summarized as follows: The application is Inadequate under section 505(b) (1) and (6) of the Act in the absence of data winch show that the drug Is safe and effective in use under the conditions prescribed, recommended or suggested. Concomitant therapy Is not covered adequately on the same report forms. If none was given, the record should so state. In several studies there are apparent discrepancies with respect to the heniato- logical data submitted; further clarification is required. The bases for the opener's analyses of clinical laboratory data are subject to question because of the bread range and the possibility of sex differences. Bias has been Introduced into the statistical analyses by deleting data from certain investigators in such a manner as to exclude unfavorable findings. With request to Dr. Sinkins' letter of February 1, 1968, we request that you submit a copy of your January 23, 1968 letter to him. His letter refers to an additional eight patients he intends to forward; these additional eight case report forms should be submitted to us. The patient populations used are not described adequately to permit proper evaluation of case material and experiental design. Studies submitted are of insufficient duration to support long term administra- tion. Most of the controlled studies are limited to eight weeks duration or less, whereas the proposed labeling does not Indicate a time limitation. The names of all clinical monitors and the dates during which they served should be provided. The method used for numbering case report forms should be provided, particularly In these cases where a chronological order was not observed. PAGENO="0874" 15306 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The chronic toxicity studies do not support safety of administration to man for unlimited periods because the rate study ran for only twelve months and because Voranil produced signs of tolerance In dogs given 50 mg./hg./day orally after three to four months of treatment. The reproduction and teratology data submitted appear to be equivocal, and raise questions regarding the embryotoxic and terategenic potential of Voranil. Since toxicity data in rats Indicated that this species could tolerate as much as SO mg./kg./day for two months without affecting weight gain significantly, further terntological studies at greater unltiples of the prepared human dose would appear to be feasible. Higher dosages could probably be achieved by utilizing pair fed animals in the study design. The application is also not approvable under section 505(b) (4) or the Act In that it fails to contain a full description of the methods used In, and the facilities and controls used for, the manufacture, processing and packing of the drug. The application is not approvable under section 505(b) (5) of the Act In the absence of some of the required samples and full Information pertaining to them including detailed results of all laboratory tests made to determine the identity, strength, quality and purity of the batch represented by each sample. It is required that each sample consist of four identical, reparately packaged subdivisions, each containing at least three times the amount required to perform the laboratory tests procedures described In the application for identity and essays. Insufficient reference sample of clortermine hydrochloride, lot S-OS-fl, has been submitted to perform the tests for identity and the assays described. Information covering samples submitted: As the Voranil Powder (new drug substance) is identified only with the codes * * , and the analytical results are labeled p.o. Batch no. * *, Control no. 1720, it is not clear whether the ana- lytical results submitted refer to the batch represented by the sample. Also, the analytical data for the batch specify that assay requirements for the batch are 97% minimum. This Is inconsistent with the specifications submitted for control af the new drug substance. For the reference standards represented by batch number 5-68-0, clortermine hydrochloride, and batch number S-GO-?, the major impurity normally encoun- tered In the new drug substance, complete descriptions of their preparation are needed, and for the latetr, come additional evidence, other than elemental analy- sis, for the structure proposed. Although we are withholding final comment on the proposed labeling until above deficiencies are corrected, we call your attentIon to the following at this time: The draft label for market packages of 1000 tablets should be submitted. Carton labels for the market pack-ages, if any, should also be submitted, and the manner in which they accompany the package should be Indicated. Also, the chemical structure pictured in the pack-nge insert is somewhat con- fusing. We suggest revisions to the more conventional geometric format of side chains attached to the ring. This file is now closed. If you wish to reopen it, the submission should be in the fonn of an amendment to this application, adequately organized, which repre- sents the information necessary to remove all deficiencies we have outlined. If you do not agree with our conclusions, the law provides you an opportunity to obtain a hearing, if requested within 30 days from the date of issuance of this letter, on the question of whether the application, as you have presented it, 15 approvable. This may be obtained by a written request for filing over protest, as authorized by section 130.5(d) of the regulations. Notice of opportunity for a hearing will be published in the Federal Register. Sincerely yours, JOHN JENNINGS, M.D., Acting Director, Bureau of 3fedic,ne. PAGENO="0875" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15307 NEW DRUG APPLICATION No. 16-880 Test Drug: Voranil (Clortermine hydrochloride) 50 mg Tablets, Code: CLTM (1000). Manufacturer: CIBA Pharmaceutical Co. Studies reviewed: 54. Because such a large number of studies have been submitted and different protocols and comparison drugs were used In this NDA we shall concentrate on the double-blind studies In which placebo was a control on normal obese subjects. Voranil is indicated for the management of exogenous obesity as a short-term, i.e.. several week-sadjunet in a regimen of weight reduction based on caloric restriction. The planned duration of therapy for all 54 studIes was S weeks. A description of the studies with respect to type of patient, control drug and dietary restrictions is shown in table 1. Each study was analyzed separately as shown in the attached tables. Our con- cluslojis are based on the covarlate table. For our analysis probabilities equal to or less than 5 percent shall be considered to differ significantly from chance. Conclusions Only two protocols covered nonnal patients with a placebo control. As seen in table I there was no dietary control for Protocol 101. and a 1000-calorie dietary control for Protocol 102, 102L. 1. Protocol 101 (a) None of the 8 studies had significant initial weight differences. (b) Three of the eight studies showed a significant drug effect greater than that of placebo. 2. Protocol 102,102L (a) None of the 23 studies showed significant Initial weight differences. 9) Four of the 23 studies showed a significant drug effect greater than that of placebo. 3. Reference to table 1 and the attached tables show that only one other study (Protocol 203-5, Study 161 880, Diabetic patients) showed a significant drug effect greater than that of placebo. MEMORANDUM U.S. GOVERNMENT. To: Dr. Robert Knox. From: Lawrence Jlauptman. Subject: NDA 16-880 Voranil-hernoglobln values. 1. As requested I have examined the hemoglobin values from two studies, Jackson and Sobotka. I have compared both studies to the "normal" values (mean 13-6; standard deviation, 1.2) given. "Normal Ilemotological Values In the Central American Populal. 2. The mean and standard deviation for the Jackson data were 13.1 and 1.47, respectively. The mean and standard deviation for the Sobotka data were 12.4 and 0.73 respectively. 3. It Is unlikely that either the Jackson data (PL. 04) or the Sobotka data (PL. 001) come from a nonnal distribution with mean, 13.6 and standard devia- tion 1.2. 4. The Jackson data could have come from a normal distribution with a mean and standard deviation equal to the observed values, 13.1 and 1.47. 5. It is unlikely (PL. 02) that the Sobotka data came from a Normal (listribu- hon with mean and standard deviation equal to the observed values 12.4 and 0.73 6. Disregarding the form of the distribution, the hypothesis that the Jackson data came from a distribution with mean, 13.6, could not be rejected at the .05 level. However, for the Sobotka data the same hypothesis could be rejected at an extremely small significance level (P-.000002). 7. Of the 45 values from the Sobotka study, 38 ended In an even number while 7 ended in an odd number. Under the hypothesis that even and odd endings are equally likely the probability of the above event or of one mere extreme Is ex- tremely low, P-.000001. PAGENO="0876" 15308 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY MATERIAL FROM Foon AND Dauo ADMINISTRATION FILES ON FENFLUBAMINE (TRADE NAME: PONDIMIN, PONDEaRE) CHRONOLOGY OF NDA 1&-618, PONDERnI, A. II. ROBINS March 3, 1967: NDA. 16-618 submitted. August 29, 1967: Initial Medical Officer Review (MOR) by Dr. Zoppa, Public Health intern, states: ". . . claim that the drug is an appetite sup- pressant. ,. would appear to be supported by the studies submitted." No conclusion section included at end of review. August 31, 1967: Dr. Hodges' "incomplete" letter based only on deficiencies under (b) (4) & (5)-no reservations expressed concerning the cllincal data. June 7, 1968: Memo of Dr. Hodges' phone cal ito sponsor: can't approve NDA because Dr. Colmore's study is the only one which supported safety and efficacy. (At a Division meeting I had expressed my views on the method of evaluation of a drug for weight-reduction). November 4,1968: Vols. 3.1-3.14 submitted by sponsor. November 8, 1968: Vets. 2.1-2.12 and 3.1-3.14 were delivered to my office (at Crystal Plaza, Arlington, Va.) for review. April 25, 1960: Statistician's analysis of 8 studies requested by Dr. Knox: - at best, these studies are suggestive of a drug advantage over placebo." May 6, 1969: Dr. Knox' MOR concludes that sponsor has not provided sub' stantial evidence of efficacy; recommends non-approval. June 17, 1969: NDA withdrawn and resubmitted to avoid a non-approvable letter. October 23, 1969: Dr. Moser's MOR. "Application was considered withdrawn on July 18, 1969, nnd reassigned' for review with respect to safety and efficacy." "Conclusion: The application Is Incomplete and not approvable. "Recommendations "The finn perform two more well-controlled studies The claim that fenfiuramine is less stimulating . . is justified and should be Included in the labeling." November 25, 1969: Amendment to NDA Includes 8 clinical studies. December 29, 1960: Dr. Moser's MOlt reviews snbmlsson of 11-25--SO and states that data is adequate provided protocol is accepted by Div. of Statistics. (Notation at end of p. 7: "MD 120/JMMoser: abe 2-2-70). When Dr. Knox learned that an approvable letter was being sent to Dr. Simmons, he asked Dr. Moser for a copy of his MOE, and after reading It through noted that there was no statement under "Review of Individual Studies" concerning the number of lbs. of weight lost; each of the 8 studies was listed simply as "Favorable" or "Not favorable," without these tenns' being defined. Dr. Knox pointed out this deficiency to several persons in the Bureau of Medicine; since no satisfactory response was received, Dr. Knox wrote a memo to Dr. Simmons expressing his concern re the lack of quantitative data in Dr. Moser's Review dated 12-29-69, Later, Dr. Knox checked the Divisionni files to determine the status of this NDA, and found another version of Dr. Moser's MOE therein; this second one also carried the date, 12-213-SD, on p. 1. The second version was almost identical in wording to the one first shown me, but at the bottom of p. 4, four additional lines were inserted, having to do with the amount of weight lost. (Notation at the bottom of p. 6: "MD 120/fllMoser: che-2--6--70," February 17, 1970: Memo from Dep. Statistics to Dr. Moser expresses a number of reservations concerning the adequacy of the data. March 30, 1970: Dr. Moser's MOE recommends approval of NDA. June 24, 1970: NDA reassigned to Dr. Dobbs who had replaced Dr. Gibson as Div. Dir, of Neuro-pharmacologic Drugs. She estimates It will take 6 wks. to review the NDA. All the volumes of this NDA had been removed from my office witheit prior notification to me. Upon enquiring, I was told by the Div. Dir, that he had to reassign the NDA to Dr. Moser because the sponsor hod accused sac of beThq biased. I pointed out that there was a danger in this type of reassignment, since it might place Improper control of the review pricess in the bands of the sponsor. PAGENO="0877" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15309 July 9, 1970: Sponsor's letter to Dr. Edwards Includes a comment re the "obvious bias" on the part of Dr. Knox. August 6, 1970: Dr. Freeman's Memo to Dr. Dobbs concludes that the results of the 6 studies reviewed are inadequate Individually and collectively to establish anorexigenic officacy for fenfiuramine. - September 11, 1970: Dr. Simmons/Finkel letter-inadequate (b) (fl-in- corporates Dr. Freeman's conclusions. August 31, 1971:68 more volumes of data submitted by sponsor. November 8, 1971: Dr. Knox received phone call from Dr. Leong who told him he was being detailed to Div. of Oncology & Radiopharmaccuticals as of 11-9-71. August 21, 1972: Dr. Knox receives Notice of Personnel Action, dated 341-72, notifying him of his transfer to BD-150. June 14, 1978: NDA 16-618 approved. MEMORANDUM OF TELErIIONE CoxvnsA'noN A. H. RoBINs Co., INC. Richmond, Va., June 7, 1968. Between: ft. William Dent, Jr., M.D., A. H. Robins Co., Inc~ and Robert M. Hodges, M.D., Office of New Drugs. Subject: Ponderex. Dr. Dent was called and told that we had discussed this application with Dr. Ley who agreed with our evaluation and recommendation. Because of a more critical approach to the evaluation of anorexigenic agents we had again reviewed the clinical data available to support the efficacy of this product. They had been subjected to statistical review and It was our conclusion that only one study, that of Dr. Coimore, supported the efficacy of this drug compared with a placebo. It was, therefore, felt that we could not recommend approval of this applicatiolL We would be pieased to discuss with the sponsor the protocol for studies which we felt would demonstrate the efficacy of the product. Pr. Dent said that he would make an appointment with Dr. Gibson for this purpose, and I said that I felt It would be appropriate for their statistician to meet with Mr. Peter James for the same purpose. ROBERT M. HODGES, MD. Fooo AND DRUG ADMINISTRATION, Washington, D.C., .June 20, 1968. Attention: ft. William Dent, Jr. A. H. Rostas Co., INC. Richmond, Va. NDA 16-4318-Al' 16-375 Gentlemen: Reference is made to your new drug application dated March 3, 1967 submitted pursuant to section 505(b) of the Federal Food. Drug, and Cosmetic Act for Ponderex (Fenfiuramine Hydrochloride) Tablets and Capsules 20 mg. We also acknowledge receipt of your additional communication dated Decem- ber 15, 1967. We have completed our review and find that the application is not approvable. The information presented is regarded as Inadequate under section 505(b) (1) of the Act as follows: As I stated in a June 7, 3968 telephone conversation with R. William Dent, Jr. M.D. of your coml~ny and also in a June 11 conference between membera of Office of New Drugs. Bureau of Medicine, and representatives of your firm, four of the control clinical studies with Ponderex subjected to statistical analysis revealed deficiencies In the study designs that placed in question the efficacy of Ponderex as an anorexigenic agent. - - This file is now closed. If you wish to reopen It, the submission should he in the form of an amendment to this application, adequately organized, which repre- sents the information necessary to remove all deficiencies we have outlined. PAGENO="0878" 15310 COMPETITIVE PROBLEMS Ri THE DRUG LNDUSTRY If you do not agree with our conclusions, the law provides you an opportunity to obtain a hearing, if requested within 30 days from the date of issuance of this letter, on the Question of whether the application, as you have presented it, is approvable. This may be obtained by a written request for filing over protest, as authorized by section 130.5(d) of the regulations. Notice of opportunity for a hearing will Is, published in the Federal Register. Sincerely yours, ROBERT 31. }looGEs, Ml)., Director, Office of New Drugs, Bureau of ~tcdicine. MEr,roisArqnuM At-OUST 9, 1968. To: Acting Director, DND/OND/MED. From: Division of .Statistics, Office of Medical Support/MED. Meeting with Mr. Lester W. Preston, Jr., Statistician for A. II, Robins Com- pany and an Evaluation of Data Submitted at this meeting. On June 27, 1968 I met with Mr. Preston for about four hours of Intensive dis- cussion. The possibility and desirability of tins meeting was Indicated at an earlier meeting (June 11, 1968) with a number of A. II. Robins representatives. It was my understanding at that time thfl the purpose of Mr. Preston's visit was to discuss and review new protocols and designs for future studies. These were to incorporate some of our suggestions and criteria for valid clinical and statisti- cal work. When I met with Mr. Preston it was immediately apparent that his visit had two purposes. First. to present to me (or the Bureau) additional tabulations of older studies and data and to discuss these with me. Second, to present and discuss protocols for new studies. The protocol was Introduced after we had spent some time Is discussing the older data. The material and data which he submitted to us at this meeting are listed below (for our in-house consideration and evaluation) 1. Tabular summaries give some "baseline' and weight change information on all "controlled" clinical studies Involving the testing of Fenflurainine (AHR- 3002) under NDA 16-618. 2. Backed~up computer tables listing certain data for Individuals used in these studies. 3. A folder of information which I review'ed with Mr. Preston. This folder, containing a new protocol and my views on its contents, were to be submitted to you after you had an opportunity to evaluate the firm's new tabulations of old data and discuss these with me. The material in this folder was su~equently modified and supplemented by Mr. Preston. Following our meeting, he mailed me a new protocol which incorporated changes Influenced by my additional sug- gestions and criticisms. 4. Some additional material was delivered to me by messenger on July 16, 1068. It showed modifications of the tabular material Included under Items 1 and 2 above. It purports to be a copy of data submitted to the Canadian Directorate of Food and Drug. This was identified as such and placed on your desk the same day. On July 30 I turned over to you and Dr. Robert Knox all of the material listed above. I also infonned you that, according to Mr. Preston, the firm believes that these new tabulations, based on previous studies, demonstrate conclusively that their product is effective. Further, that these tabulations also constitute a re- sponse and rebuttal to the "incomplete" letter issued recently. Mr. Preston asked that I convey these points to you as well as his analyses and discussion points made during the course of my meeting with him. The balance of my memorandum is a detailed analysis and discussion of the material submitted by Mr. Preston. A few of my findings and doubts about these data were made orally at the July 30 meeting with you and Dr. Knox. As background I should point out that my participation In the second meeting represented a back-up for Mrs. Lucille Pog-ue who was attending the Eniversity of Pittsburgh at the time. Since her return I have briefed her on developments and my findingu In the mnterlal submitted by Mr. Preston. She is now in position to resume full responsibility for this NDA and any additional evaluations or discussions which may ensue. PAGENO="0879" COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 15311 ANALYSIS OF DATA SUBMiTTED BY MR. PRESTON Jntrodvction A glance at Summary Tables A through 0 will show certain entries empha- sized with Yellow crayon. Tins color emphasis was provided by Mr. Preston. He wished to demonstrate the following: 1. Table A. That initial starting weights were comparable for the placebo subjects and those In the several drug groups. He was not too happy with the data for the males, but tended to discount the differences because of small sample sizes. 2. Table B. The yellow entries are supposed to show that the average "% overweight" shown at the bottom of each table was comparable for all dosage groups and the placebo. 3. Tables C, D, and K The yellow entries are supposed to show drug superi- ority In average weight loss for specific time periods. 4. Tables F and 0. The yellow entries are supposed to show statistical significance for the drug groups. J)i8cu.ssion You will note that there are many yellow entries. Please be aware, also, that these tabular data represent an Indiscriminate pooling of "controlled" studies. After you and Dr. Knox have had an opportunity to examine more closely the material submitted by Mr. Preston, you may then wish to consider its official status also. Should the manner of submitting it through me be considered unacceptable, either as a procedure or as a rebuttal to the incomplete letter, you may wish to reject this material. You may wish to do this if the material is considered unacceptable clinical evidence or non-pertinent to the contents of the letter. In either or both Instances you may not wish to read the balance of my report. Ilosvever,shoul d you believe that, eventually, we must accept this material, though through proper circumstances, and must also respond to the Implications of efficacy suggested by the data and the yellow entries, then you may wish to react the evaluation and discussion of this material which follows: At first glance the data In these tables suggest that the firm has made Its points on clinical balance and consistent evidence of superiority over placebo. ThIs advantage over placebo is considered to be sufficient evidence of superiority. The premises and assumptions which the firm has Incorporated Into this statistical analysis of pooled data Include the following: 1. Sample sizes will become larger, permitting more and better comparisons between the drugs being tested and between clinical and demographic sub- groups within each of the groups of subjects being given each product under study. 2. That imbalances and differences within and between Individual studies will sort of "wash out" or balance with respect to the following: (a) Diagnostic and demographic baselines (b) Population characteristics. (c) Protocols and study designs. (d) Dosage and treatment regimens. 3. The superiority of the drug will show through this mixture, if not clinically, then statistically, 4. The averages of the pooled data provide valid and unbiased measures of the drug's effectiveness and relative advantage over placebo. 5, Statistical tests of significance may validly be applied to pooled data and, with inflated sample sizes, have a greater chance of demonstrating that differ- ences between the test products may be significant. 6. It is perfectly valid to compare results on placebo with those on four different dosage regimens and to test differences between them despite the fact that some studies In the pool contributed little or no Information th these clinical comparisons and some studies had significant basic differences with respect to design, populations, duration, etc. 7. Consistent evidence (statistical in this Instance) of advantage over placebo in demonstrating some weight loss, no matter what drug dosage or time period was followed, would prove clinical claims that the drug actually depresses appetite. Assumption number 7 appears to be the key one for your consideration and seems to be the foundation for the finn's position. Can we accept, in a sense. i5-5'9 0-71 57 PAGENO="0880" 15312 COI~1PETITWE PROBLEMS Di TIlE DRUG £NDUSTRT extrapolations or generalizations from weight loss data as direct evidence of anorexigenic erects or properties of the drug? The problem is somewhat con- founded by evidence that the placebo also produced small but consistent weight reductions. If this assumption Is considered by your office not to be tenable with medical knowledge and our program requirements, then these data can be rejected and the matter is closed. The remainhig assumptions and the practice of pooling can be challenged on the basis of: 1. Common sense. 2. The requirements of the law with respect to substantial evidence from adequate, well controlled studies. 3. Our statistical paragraphs in the new law on medical advertising. 4. On the basis of generally accepted practices and principles of statistics. Our first approach in responding to these data is to examine them as presented and see what they show and what they may hide. Next, we can apply some common sense and basic rules of experimentation and statistics to determine which studies and clinical (drug/placebo) comparisons are acceptable and pre- sent enough data to he acceptable on an individual study basis. We might even give the finn the benefit of the doubt and permit some pooling of acceptable data. This procedure I have followed. Table A This table shows the "initial' body weight. For the placebo subjects "initial" means exactly that, the first measuromeats taken at the beginning of the study. For the subjects in the various drug groups, the initial measurement can be different. For some it was the very first measurement, for others it could be the second, third, etc. measurement depending on the length of placebo period pre- ceding drug use and the frequency with which mcasurements were taken. This was done deliberately, according to Mr. Preston, in order to counter the erects of placebo which preceded drug use. However, this introduces a potential bIas and some inconsistency in the procedure for handling data since some studies did not use a pre-drug placebo period. It Is an example of the types of problems which can occur when dig-similar data and studies are pooled. Even a cursory glance at Table A will reveal gaps and unequal sample groups. Relatively few male subjects were used. Some investigators used none at all. These factors all tend to detract from the meaning and acceptability of the totals and averages shown at the bottom of the table. For the moment, these doubts can be held in abeyance and the averages examined as presented. There is an upward bias in the average starting weights of each base group that Is related to the size of the dose used. The placebo subjects had the lowest and the 120 mg/day group the highest average. This is also true of the male subjects. This could he due to a numhcr of factors: chance allocation of subjects, the unequal sample sizes in the studies, or an unconscious or conscious allocation of heavier, and perhaps more prone to lose, subjects to the drug groups. - An examination of the subsequent tables suggests that this bias is not fortul- tou,s hut persistent in the data and, as such, appears to place the placebo at a disadvantage, generally. Table B This table, for both females and males, shows a similar trend for the average percent overweight. This also generally increases with dosage level. The placebo group has relatively fewer overweight subjects and the higher dosages, the most. Thus we see in hoth Tables A and B evidence that the study groups may not have been properly balanced at the outset of these studies both with respect to base- lines and numerically. These are factors that must he taken into consideration in interpreting and evaluating the data on weight loss in the subsequent tables. Tables 0, D, and E show weight changes from "initial" body weights. In studying these tables one should he aware of another casualty of pooling-failure to provide concomitant clinical comparisons. The differences In the timing of initial weights, as mentioned earlier, prevents this type of clinical comparison. A change In body weight observed after two week.s on the placebo, for example. means specifically the first two weeks of the study. For subjects in the drug groups, this two week change can also refer to the change between the first and third weeks or between the second and fourth weeks of the study, etc. This factor of noncomparahllity also pervades Tables 1) and E which show- weight changes at four and six week Intervals from "initial" measurements. PAGENO="0881" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15313 Table U Only one table is presented for the two week Interval. The data for males were so skimpy that they were not tabulated. Please note the suggestion of greater weight loss with Increasing dosage. Tables!) and E In addition to failing iii providing chronologically comparable data between placebo and drugs, these tables and weights changes are based on only a few subjects. Please note the small numbers in parentheses. This highlights the fact tbat relatively few subjects have bee,i studied on tills drug. Even with pooling the numbers are often too small. Of even greater concern to me is the fact that the weight changes shown in these tables are based on differences between two numbers. There is very little supporting or intermediate data to indicate that there is actually a trend In decreasing body weights. It can be noted again how body weight loss appears to lie linked with the dosage level trend. Consider, too, the relationship between tills trend and that seen in Tables A and B. Because of these imbalances and other sources of variation It Is difficult to judge the degree of superiority, if any, of the drug groups over the placebo. Is there actually a built-in bias In these data? Is the superiority of drug groups or a single drug group as consistent and marked as It appears to be In these tables? In attempting to assess these questions and others fairly, I have re-assembled tile data In these tables into sub-groups that provide data for all pertinent clin- ical and dosage comparisons, Certain studies and data were rejected since they provided no information for judging relative effectiveness with an acceptable control. This procedure appears justified on the basis of common sense, the requirements of the law and the tenets of valid experimentation. In summary these adjust- ments produced the following actions and sub-groups: 1. All studies without a placebo control were not used; these were stud numbers 1,2, 6, 7, and 9. 2. Study number three was not used since It had a few subjects only on placebo. 3. Study number 10 (}`innerty) was eliminated for the following reasons: (a) Gross differences between the starting weights; the placebo suhjects aver- aged 171 pounds, the drug group averaged 283 pounds. (b) Imbalances in sample size and study groups composition. There were only 10 placebo subjects (males and females) and 18 in the drug group, of these none were females. (c) The percentage of overweight average over twice as much in the drug group. Placebo subjects were only 18 % ovenveight; those on the drug were 39% overweight. (a) The drug dosage used in this study ~vas 80 mg/day. It was an odd dosage regiman since its use was limited to only this study, (e) From the above It appears that the study was not well planned or con- trolled and, very likely, not double bliud. 4. The number of subjects and studies which could provide direct comparison between placebo and one or more drug groups were reduced to only 174 and 7, respectively. Not all of these were comparable to each other. The following dis- tribution of subjects shows the possible comparisons: Drug group Subgroup Plgoebo 40 rig 60 rig 120 rig Tothi 57 23 16 16 174 I, 3-groupcompari000(2studinonly No,.4and5) Il 16 16 48 II. 3-groupcomparjson(4,Ii,diee No,. 11,12, 13,14) 24 23 50 107 Ill. i-groupcomparison(studies4, 5,8, II, 12,13,14) 51 78 135 The above counts Indicate that two studies provide 48 subjects with whIch to evaluate the relative effectiveness of the placebo, the 60 mg/day dosage and the 120 mg/day regime, Only 10 were males. These are maximum counts. Not aJI subjects had data for the 2,4, and 6 week study durations. Pour studies provide 107 subjects to evaluate the placebo, 40 mg and 60 mug dosages. Again these are maximum counts not always represented by data in PAGENO="0882" 15314 COI'flETITWE PROBLEMS U~ THE DRUG INDUSTRY these summary tables. Please note that in these four studies twice as many subjects were given the 60 mg dosage. This suggests a predetermined clinical emphasis or bias In the allocation of study material to the treatments used. Seven studies provided 135 subjects with which to compare placebo and the 60 mg dosage. Again, these are maximum counts and are not always re- presented by data in the tables. The average number of subjects per study is only 8 for placebo and 11 for the drug. I have recomputed all tables (A, B, C, etc) for these three sub-groups. In tables A and B, the bias and trends with increasing dosage of initial body weights and percent overweight appear to persist in all three sub-groups. The averages for each study group are shown below. The numbers in parentheses represent the number of subjects contributing data to these averages. Sexes are combined. TABLE A-AVERAGE INITIAL BODY WEIGHT Subgroup P1 acebo 49mg 6 0mg 120 mg II III 191 175 176 (17) <24) 182 (23) (57) `86 189 186 (15) 208 (16) (50) (78) Study number 12 (Fred), Included In both IT and III, was particularly biased against placebo. Initial weights in the order above were 152, 181, 100. TABLE 8.-AVERAGE INITIAL PERCENT OVERWEIGHT Subgroup Placebo 40 rug 60 nig 120 mg- I II III 56 38 36 (4) (23) 36 (23) (43) 30 50 45 (3) 64 (3) (~0) (62) Only nine females provided data for group I and these counts are too small for judging trends, These data also show a considerable bias against placebo in study 12 for which percent overweights averages were 22, 37 and 53, respectively, for the placebo, 40mg and 60mg groups. Presented below are summary data for sub-group I corresponding to Tables C, fl and 11 The fraction to the right of the average weight changes indicates the ratio of tile numbers of subjects providing data to that in the population studied. For example In the two weeks' data, twelve of seventeen placebo pa- tients had weight measuremests at the two week interval and thus provided data for the averruge-O.66 pounds reduction. The numerators vary considerably for each study Interval and strengthens our concern about small and spotty sample sizes. Table arid study duration Arorage weight change (pounds) Placebo 60 mg 120 m! Subgroup I: C-2 week, -0.66 12117 -2.00 9/iS -2.92 10116 D-4weeks - .93 7/17 -2.91 10/15 -7.12 8/16 6-Swans -2.58 li/Il -3.00 8115 -2.67 3/IS The above averages provide a suggestion of emcaey that appears to be dose related as are the data in Tables A and B. What appeared to be a strong advan- tage for the 120 mg dosage seems to he washed out at the 6th week interval. To emphasize the uncertainties In these avenges, it should be pointed out that a single placebo subject provided a weight loss which was responsible for most of the increase In the placebo average at the 6th week. This patient was not included in the data for the second and fourth week averages. Also, a single subject was responsible for the large 120 rng average at the 4th week-; this sub- ject was not included In the data for the other two averages. PAGENO="0883" OOItOETITZVE PROBLEMS tN TUE DRUG INDUSTRY 15315 Listed below are the average weight changes for sub-group II. Both male and female data are included. SUBGROUP 11.-AVERAGE WEIGHT CHANGES In potJndsi Table Duration (weeku) Placebo 40 rug 69 mg 2 -1.94 24124 -18 23/23 -3.63 49150 0 4 -1.88 19/24 -4.31 22/23 -5.57 44/50 6 -1.67 19/24 -6.52 19/23 -6.37 47/50 Four studies contributed `to these larger study numbers. The data are pre- dooninantly tlaose of females; only seven males provided data. The weight losses again appear to be dosage related and may be affecting some of the bias In `rabies A and B on Initial body weight and percent overweight. The weight losses in the drug group appear to be more consistent and larger than these of subgroup I. Even the placebo managed to provide some "anorer- igenic" effect over the 6 weeks' period. Shown below are the data for sub-group Ill. Mates and females have been combined. Average change is body weight (pounds) Table and duration Placebo 60 rug Subgroup Ill: C-2 weeks 0-4 weeks E-6 weeks -1.10 -1.81 1.52 56/57 42/57 30/57 -3.17 -4.98 -5.88 73/78 66/78 55/78 Seven studies contribnted data to this tabulation. It provides the strongest base for comparing placebo with a drug group-In this Instance, the 64) mg/day doeage. The advantage over placebo appears substantial and seems to increase with study length. However, there are at three factors whkh must be taken into account in judging this relatiw adv~ntage. 1. The placebo has provided some weight loss or anorexigenic" effect in all sub-groups and study periods. Therefore, there is a built-in placebo effect com- ponent in the drug average. 2. The initial baseline imbalances and biases must be contributing to some ex- tent to the weight loss of the drug group. 3. At least four of the studies had twice as many subjects assigned to the 60mg group than to placebo. This suggests that these studies may not have been blind and well controlled and that subjectivity may well have influenced the recording of weight loss data. Just how much the above and other factors contributed to the greater weight loss and just how much was contributed by the drug Ingredients is not known. This puts us in a difficult situation because we see some evidence of effectivene~ but it is based on relatively Insufficient and to some extent questionable evidence. Furthermore, the data submitted suggest a lessening effectiveness with duration of drug use. The data submitted by the firm and also re-tabulated into my sub-groups should be evaluated on a weekly loss basis to be fully meaningful. When this is done for sub-group III data for examp'e, the weekly weight losses do have a trend. SUBGROUP Ill-AVERAGE WEEKLY CHANGE IN BODY WEIGHT tin poundsi Duration Table (weeku) Placebo 60 mg C 2 -0.55 -1.58 D 4 -.28 -1.23 E 6 -.25 -.98 PAGENO="0884" 15316 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The above shows a trend which suggests that the rate of weight loss declines as the drug is used. This trend is also evident in the data for the other sub- groups. Tb!5 possible lessening of effeetiveness, whether It be weight loss or appe- tite depression, appears to be an additional factor for consideration In evaluating the evidence submitted to date and the claims proposed for this product. Finally, there appear to be several miscellaneous items which have a bearing on the validity of the data submitted and appear worthy of consideration. It was noted in Table A that the study number series changed from the 2000's to the 8000's. It may be worth while to learn whether those in one series are cnn- siderably older studies, perhaps not as well controlled, or blind, and perhaps using a range of dosage and protocols more apt to be classified as phase I or phase II studies. There are two additional Tables submitted, F and 0. Table F contains Infor- mation which confirms the several biases mentioned earlier. This table shows the number of subjects in each dreg treatment group falling into specific classes of percent overweight, It will be noted that the placebo group hnd 5 subjects who were the least over- weight, while the 60 mg/day group had only one subject, despite a numerically larger overall sample size. The placebo had only 5 subjects who were In the greatest overweight class, while the 60 mg/day group had 13 subjects. This constitutes adisproportlon in the other direction. Please note this shift in the bar graphs in Fig. N. This disproportion in the distribution of patients in the placebo and 60 mg groups with respect to percent overweight was tested statis- tically and found to be significant, p<2.05. The 60 lug group is represented by relatively more studies and more subjects and appears to be the pivotal drug group for comparison purposes. This table also shows the spottiness hi the number of patients studied on the other dosages and the poor basis for trying to make comparisons with placebo, The other interesting phenomenon revealed by this table is the correlation be- tweea the amount of weight lost and the percent ovenveight. This relationship is quite apparent in the placebo and 60 mg groups. Weight loss Is greatest in the groups that were most overweight. This relationship is also shown In Figure X at the bottom. Even the placebo trend lines have an upwsrd bias. Again this places the placebo at a disadvantage because it contained proportionately fewer of these subjects. Table 0 shows the results of applying two different tests of statistical sig- nificance to the pooled data. The data are the same as these in Tables C, D. E and F with all the gaps, non-comparabilitles and biases mentioned before. These tests require certain conditions or assumptions before they can be applied to data. Among these is the assumption that the groups to be tested are actually com- parable In a clinical and experimental sense and are free from any bias which may distort study balance, group avernges or the variahility of individual results around group averages. These conditions are far from met here: we cannot as- sume that theoretical and practical deficiencies have somehow balanced out or that their effects are minimal. The tests show- strong statistical significance in favor of the drug groups as one would suspect. They reflect the data as presented and calculated; they do not tell how much, actually or on a relative basis, the drug groups are superior. Some suggestion of drug efficacy Is evident in these data, but the statistical evi- dence is not very meaningful under the uncertain circumstances and biases sur- rounding the data. Finally, the data as presented to us in these tables may not he completely cor- red or complete. The Colmore Study (2005), supposedly one of the better clinical efforts, shows data only for placebo. Data for 12 subjects on the 60 mg/day dosage and 12 subjects on the 120 mg/day dosage are not shown. Some of the entries for representing a 2, 4 or 6 week interval from baseline. actually were taken from data ohtained a week prior to or after these indicated Intervals. The table does not show all weight data obtained in these studies. As Mrs. Pogue's Initial report indicated, some weight measurements were taken at variable intervals, others at odd weekly intervals, and some at periods beyond those re- ported in these tables. PAGENO="0885" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15317 MEMORANDUM OF CONFERENCE A. H. Romirs Co., INc., Richmond, Va., September11, 1968. Present: R. Dent, Jr., M.D., K. Woodward, Jr., M.D.-A. H. Robins Company, Inc., R. Murphey, Ph. D., Mr. L. Preston, Jr., and 14. L. Gibson, M.D., Director. DND/OND/Med/FDA, Robert 0. Knox, M.D., Mr. Peter James-SA/DS/Med/ FDA. The visitors came not to discuss the protocoi but to dispute our decision that the data submitted to date was inadequate to demonstrate safety and efficacy. Therefore, Mr. James went through his memo of August 9, 1968 addressed to Acting Director, DND. Our visitors disputed many of the points, including, for example, the statement that In Finnerty's study the drug group averaged 233 pounds initial weight vs. 171 pounds for the placebo subjects and that this would introduce a bias. We were advised that approximately seven or eight hundred more case report forms were shortly to be submitted to provide additional basis for a decision. The question of the package insert was then raised and we pointed out that the package Insert would have to present a well-rounded picture to the physician of just what had been accomplished In the clinical studies. It was suggested that tabulations would be required. The question was then asked whether this in- formation had to be included In that part of the package insert which controlled medical advertising, since they felt that tabulations were difficult to insert in advertisements. We told them that we would contact our advertising department in an attempt to clarify the matter. ROBERTO. KNox, M.D. MEMORANDUM Ama 25, 1969. To: Peter G. James, Acting Chief, Statistical Analysis Branch. From: Jacqueline 14. Tillman, Statistical Assistant. Subject: Statistical Review of NDA 16-018 (Ponderer) (vols. 3.1, 3.2 and 3,3). I have examined the case records and summaries for 8 studies submitted by Dr. Robert Knox. These are listed below: Patient. Study No.-lnvestgators name Dates of study started 2002-JohnA.Owen,lr Aug.i5.i9sstoMar.a.1967 2009-Solomon Fisch, M.D Nov. 1964 to Sun. 1967 201&-Benjarrnn A. Ro,enber~, M.D., F.A.C.P Jan. 1955 to July 1967 2020-Roberts. Anderson, M.D Apr. 1965 to Nov.1957 2025-Dorothy R. Holl,ngsworth, M.D Jan. 1966 to July 1961 2050-B-Martin S. Rogirasky. M.D May 1966 to Apr. 1967 2055-B---Geor3eE. Bacon, M.D Oct. i966toAug. 1967 2060-'SolB.Stern,Jr.,M.D Aug.i967toJan. 1963 12 60 34 20 25 120 20 31 The purpose of this review was to audit summary data submitted by the Firm (A. H. Robins Co.) and to assess generally the characteristics and validity of these studies and their raw data. Despite a search of other NDA volumes and IND sources I have been unable to find a protocol for any of these studies. Thus we are unable to find an Indica- tion of study objectives, designs, data parameters and other factors pertinent to clinical and statistical review and labeling claims. The only semblance of a protocol is the summary sheet(s) In Vol. 3.1 which accompanies the patient records for each of these studies. In Study 2009 the Reference to Raw data sheet stated that it was a double- blind, randomized study. The drugs used were Fenfiuramine capsules. 20 mg. and 40 mg., Dextroamphetamine 10 mg. and Placebo capsules. The results stated were Placebo weight loss per week-O.43 lbs., Fenfiuramine 20 mg. weight loss per week-1.00 lbs., Fenfiuramine 40 mg-weight loss per week-0.54 lbs., and PAGENO="0886" 15318 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dextroainphetamine weight loss per week-O.86 Pu. According to my calc,,lations the average weight loss per week teas- 1.06 for Placebo-I .41 for Fenfluralflifl~ 20mg-I .06 for Ecu fluraniine 40 my. and-0.89 for Deztroaoiphetaflhiflc. My cal- eviations and their calevlation.s agree on the number of dropouts. Without protocols I was not able to do very much in assessing the correctness of these statements. Entries on the case records for sonic studies lead me to believe that the blinds were jeopardized or broken. For example, in Study #2050, there were dosage entries written at the top of the individual case records such as: 40 mg., 20 tng., etc. In another study (2002) the drugs were identified as P+P, p+f, p+m, etc. As shown on the first page of my report these are very old stndies, nearly all were completed in early 1967. Some are still stated to he incomplete. In one study (2009) there was a considerable dropout rate of about 50% in all drug groups. Oaly 30 snbjects finished S weeks of study. The placebo had the smallest dropout rate, 33 percent. I attempted to verify the summary data in #2020. In this study patients were given Fenfiuramine for S weeks, and Placebo for S weeks. The firm reports an average weekly weight loss of: Fenfiuramine-l.70 lbs.; placebo-lAG lbs. There were no placebo body weights listed on the data sheets; therefore, I could not verify this average. I computed an average for Fenfiuramine patients that completed 60 days in this study. It is 0.42 lbs/week loss based on 28 patients. On four of the case records medication is entered as "Caps" 40 mgm. For Study #2016 none of the patients followed protocol which required cross- over on 3 drugs. Some had crossover in two drugs with the identity of the second Rx In doubt. Of the 34 only 21 had some treatment with two drugs. The protocol further states that observations were made every two weeks following the start of medication. Very few subjects satisfied this requirement on both drugs, The treatment and visit regimen is very inconsistent and variable. Only two subjects were observed every two weeks for as long as 4 week-s. Only two subjects were observed every two weeks for as long as 6 weeks. Some patients were observed often irregularly for as long as 12 weeks on one drug. Their comparable duration on the control ranged from 2 to 7 weeks. Some subjects had only 6 weeks on one lIz and only two or less en the cross. over. The durations of treatment both on a single drug and on its counterpart are so variable and spotty that the data cannot be summarized meaningfully. Fur- ther compounding difficulties in working with these data Is duplication of case numbers for different subjects and different case numbers for the same subject. Study #2020 was a double-blind, crossover, randomized. Total length of study was 9 weeks, included 3-3-week periods. Drugs administered were 30 mg. Pen- fiuramine capsules and Placebo capsules. On the reference to raw data sheet the total average weight loss for those subjects receiving Fenfiuramine was 1.4 pounds per week as compared to 0.34 pounds per week on Placebo. My calcula- tions averaged-l.33 pounds per week weight loss on Fcnfiurnmlne which in- cluded nh subjects. Of those that completed the study (n-IT), the average weight loss on the drug was o.so and for the Placebo average weight loss per week was 0.56. MEMORANDUM Apr11 25, flOP. To: Robert 0. Knox. M.D.. MD-l20. From: Peter G. James, MD-460. Subject: Ponderex-lIeview of older studies. Attached Is a report by Mrs. Jacqueline Tillman based on her review of "con- trolled" studies included in the last submission to this NDA and which are the subject of your request of March 3, 1969. Please note that nearly all of these studies were planned and initiated, In some instances, long before the efficacy provisions of the K-Il Amendment was pro- mulrnted. It Is not su1mr'sin~ thou to find an ln,deq.'ate proto"ol arni litt'e in the way of basic information and adequate design to satisfy our current require- ments. PAGENO="0887" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15319 The duration of several studies Is unusually long and the study populations relatively small. It does not appear reasonable that initial study standards, blinds, etc. could be maintained throughout these long periods. The inconsistency in which patients were observed bears this out. Mrs. Tillinan's report Indicates the difficulties in reviewing these studies and In attempting to verify their summaries. These studies do reflect different stand- ards of performance and interest among Investigators. All indicate a spotty and poor picture of getting clinical evidence that has some meaning and reliability. If one must use the information from these studies in considering the effective- ness of this drug and the acceptability of this NDA, he will need to assume that these studies provides valid and substantial evidence and are acceptable pieces of clinical work. This is a considerable assumption; or best, these studies are suggestive of a dnig advantage over placebo. 110w much of aa advantage and for how long a duration it persists cannot be determined from these data. Results state.! were Placebo weight loss per week-0.43 lbs., Fenfiuramine 20 mg. weight loss per week-1.0O lbs., Fenfiuramine 40 mg.-weight loss per week- 0.54 lbs., and Dextroamphetamine weight loss per week-0.86 lbs. According to my calculations the average weight loss icr week was-lOG for Placeho-L41 for Fenfluramine 20 aig.-1.06 for Fenfluramlne 40 mg. and -0.89 for Dextromphet- amiae. My calculations and their calculations agree on the number of dropouts. Without protocols I was not able to do very much In assessing the correctness of these statements. Entries on the case records for some studies lead me to be- lieve that the blind were jeopardize or broken. For example, in Study #2050, there were dosage entries written at the top of the Individual case records such as: 40 mg., 20mg., etc. In another study (2002) the drugs were Identified as p+p, p~f, p+tn, etc. As shown on the first page of my report these are very old studies, nearly all were completed in early 1967. Some are still stated to be incomplete. In one study (2000) there was a considerable dropout rate of about 50% in all drug groups. Only 30 subject finished 5 weeks of the study. The placebo had the sraallest dropout rate, 33 percent. I attempted to verify the summary data in #2025. in this study patients were given Fenfluramine for S weeks, and Placebo for 8 week-s. The firm reports an average weekly weight loss of: Feafluramine-1.70 lbs., Placebo-1.46 lbs. There were no placebo body weights listed on the data sheets; therefore, I could not verify this average. I computed an average for Fenfluramine patients that completed 60 days in this study. It is 0.42 lbs/week loss based on 28 patieats. On four of the case records medication Is entered as "Caps" 40 mgm. For Study #2916 none of the patients followed protocol which requircd cross- over on 3 drugs. Some had crossover in two drugs with the identity of the second Rx in doubt. Of the 34 only 21 had some treatment with two drugs. The protocol further states that observations were made every two weeks following the start of medication. Very few subjects satisfied this requirement on both drugs. The treatment and visit regImen is very inconsistent and variable. Only two subject were observed every two weeks for as long as 4 weeks. Only two subjects were observed every two weeks for a long as 6 weeks. Some patients were observed often irregularly for as long as 12 weeks on one drug. Their comparable duration oa the control ranged from 2 to 7 weeks. Some subjects had only 6 weeks on one Rx and only two or less on the crossover. The durations of treatment both on a single drug and on its counterpart are so variable and spotty that the data cannot he summarized meaningfully. Further compounding difficulties in worktag with these data is duplication of case num- bers for different subjects and different case numbers for the same subject. Study #2020 was a double-blind, cross-over, nindomized. Total length of study was 9 week-s, included 2-3-week peroids. Drug administered were 30 n~g. Fen- fluramine capsules and Placebo capsules. On the reference to raw data sheet the total nvernge weight loss for those subject receiving Fenfluoramine was 1.4 pounds per week as compared ot 0.31 pounds per week on Placebo. My calculation aver- aged-1.33 pounds per week weight loss on Fenfiuramine which included all sub- jects. Of those that completed the study (n=17), the average weight loss on the drug was 0.96 and for the Placebo average weight loss per week was 0.56. PAGENO="0888" 15320 COMPETITIvE PROBLEMS IN ~E DRUG INDUSTRY MEDICAL OFFICER'S REVIEW OF NDA 16-618 ADDENDUM NO. 2 MAY 6, 1909. Sponsor.-A. H. Robins Company Inc., 1407 Cummings Drive Richmond, Va. 23220. Chemist: C. Loekett, Pharmacologist: V. Clocklin, Ph. U. Product.-ponderer Original review-August 29, 1967 by Dr. B. Zoppa (Vol. 1.1) whIch contains no conclusions as such, but on page 17 under Labeling Evaluation states: "The labeling for Ponderex (lenflurarnine hydorehloride) in my opinion gives full dis- closure. The sponsor's claim that the drug is an appetite-suppressant indicated as adjunctive therapy In the medical management of exogenous obesity would ap- pear to be supported by the studies submitted. The statements made in the labeling that fenfiuramine's primary CNS effect appeared to be sedative and that It has little propensity for producing pressor effects compared to fl-Amphetamine seem to be substantiated by the studies." On February 2, 1968 an additional note was made by Dr. Zoppa (Voi. 21) : "The revised labeling (package Insert) submitted on 12/15/67 has all the labeling changes agreed upon in the 0/20/67 conference between sponsor and OND." On June 20, 1968 the FDA sent an `inadequate" letter containing the statement that four of the control clinical studies with Ponderex subjected to statistical analysis revealed deficiencies in the study design that placed in question the efficacy of Ponderex as an anorexigenie agent." On November 5, 1968 we received amendments consisting of 14 addItional volumes of study summaries, raw data and other information, including a revised package Insert. Due date: May 5, 1960. I. Category-Appetite suppressant. II. Structure 1onnula~- Cr, Cli, I Clir~H-NHC,HdUC III. Dosages recomniended.-20 to 40mg t.l.d. IV. Related drugs-The amphetamines. V. Pt.unnaeoiogy.-Pharmacologlst's review dated February 19, 1969 states that the preclinical information in this resubmitted NDA for Ponderex does not change our previous evaluation of August 20, 1967 and January 29, 1968 that the drug appears to present no problem of safety and that the labeling is acceptable. \Tf Conaulat ions with other divj~ions.-None. VII. Ctinieal Studies.- A. Investigators Five Investigators performed special studies. Eight Investigators performed controlled clinical studies. Ten Investigators performed non-controlled clinical studies. Two Investigators performed "other" clinical studies. Ia general, the physicians listed appear technically qualified; however. I have reservations about the validity of work done by Dr. Daneman because of the work submitted by him in connection with a thiazide diuertic several years ago. B. Clinical condition The diagnosis of obesity is frequently not backed up with data as to the height of the patients; therefore, it Is impossible to make a determinati on as to the degree of obesity jresent. PAGENO="0889" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15321 C. Numbers of eases . . Controlled studies: Vol. 3.1 (p.236,et,eq) Feri M fluramine Placebo F MS M F MS Age Total 2002: Owen. J. (DBRX) 2009: usd1, S. (OBR): 20mg 40mg 2016: Rosenberg, B. (I3BRX) 2020: Anderson, It. (DBRX) 2025: Hollingsworlh, 0 20500: Roginsky, M 2055-B: Bacon, C 2060: Sterri,Sul Total 2 12 II 3 3 32 I 2 1 6 2 IC 2 10 Adults 12 2 14 1 Adults 60 0 22 4 5 23 5 Adult, 62 11 3 I? Adults 20 3 1 32 3 1 Adults 36 23 4 1 24 3 Adults 113 22 3 24 5 14 6 14 Children 20 18 0 20 Adults 60 79 155 17 63 112 9 383 D. Dose: Milligrams Investigator: per dat, Owen Finch: (1) 60 (2) 120 Rosenberg: (1) (2) 12(3 Anderson Hollingsworth 120 Itogiusky: (1) 40 (2) (3) SO Bacon: (1) ~.. 20 (2) 40 (3) GO Stern SO 1). Onset of action Probably within an hour. F. Duration of treatment I am unable to locate protocols for the following Investigators: Finch, Rosen- berg, Anderson and Ilollingsworth. It Is very difficult to determine the duration of treatment by looking nt case report forms because of the large number of dropouts and other Irregularities. As best as I can piece it together, the proposed duration of therapy by Investigator was as follows: Number of weeks Roginsky 12 flolllngsworth 8 Stern S Rosenberg Bacon 4 Finch 4 Anderson 13 Owen `2 1 Not sure. PAGENO="0890" 15322 co~ETITfl'E PROBLEMS ~ THE DRUG INDUSTRY G. Effectiveness The analysis supplied by the sponsor consists, as is often the case, of pooled data. Efficacy is expressed in terms of rate of weight loss per week. I do not believe this Is a valid analysis, since dropouts are usually not considered in arriv- ing at averages. In addition, the actual nuniher of pounds lost by the patient Is more important than the rate of weight loss. When efficacy is expressed in tenus of pounds per week lost, there is an Implication that the rate of weight change is constant, but there i.s abundant evidence to indicate that this is far from the case. The weight loss according to the figures compiled by the sponsor are as follows: Rate oi' weight Investigator: lois pounds per week Owen +0.02 Fiseh: 60 mg per day -1. ® 120 mg per day -0. 54 Rosenberg: 60mg per day I -1.12 60 mg per day II -0. 01 120 mg per day I -, -0.75 120 mg per day II -0. 51 Anderson -1. 4 Ilollingsworth -1. 7 Roginsky: 40mg per day -0.54 60 mg per day -0. 02 80mg per4ay -0.68 Bacon: 20mg per day same 40mg per day 4 as 60 mg per day 3 placebo Stern 80 mg per day -0.34 judging from the number of weeks on fenfiuramine and the weight loss as expressed in pounds per week, It would appear that the absolute weight loss was very small, and In the case of Dr. Owen. Dr. Hollingsworth and Dr. Bacon the results were about the same as with placebo. In connoctlon with Dr. Rosenberg's study they make the statement on page 245 of Vol. 3.1 that the number of patients In the study was small and therefore no definite statement may he made regard- ing the results; but there were 34 patients Involved in a crossover design, there- fore I do not believe that their statement is valid. An attempt to evaluate the data submitted is hampered by the fact that I cannot find protocols for Drs. Rosenberg, Fisch, Anderson and Hollingsworth. II. Laboratory studies "Of the total number of laboratory examinations done in 319 patients there were 63 abnormal values. A majority of abnormalities were minor alterations in hematological parameters or changes in the urinalysis. No incidence of agra- nulocytosis or pancytopenia were noted and many of the changes reverted to normal later in the investigation. Whether these changes in laboratory values were drug related was not always clear but when in doubt they were considered probably drug related. The mechanism of reproduction is unclear. "There wore no major changes in the blood chemistry values. Ilepatic and renal function appeared to be unaffected by fenfiuramine even after long periods of administration." I. Adverse reactions Much emphanls has been laid on the fact that fenthiramine is supposedly a central nervous system depressant rather than stimulant in spite of its close relationship to amphetamine. A paper entitled "Fenfiuramino. Study of its Central Action Through Its Effect on Sleep" was presented at the 4th Annual Meeting of the Canadian Society of Chemotherapy by C.aguon. 31-A. et a!. (Vol. 3.1, p. 175). The study wns undertaken to determine whether or not fonfiuramine produces insomnia like nmphetamine does. The subjects consisted of 66 chronic patients, 19 `vomen and 47 men, In a psychiatric hospital. In a double-blind study tw'o doses of fenfluramlne 40 mg and SO mg Were compared with placebo. Medi- cations were given at 8:15 p.m.; a questionnaire was given to the patients the following morning. This questionnaire had previously beea used for the assess- ment of hypnotic agents. ". . the results of the questionnaire had been earre- PAGENO="0891" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15323 lated with objective observations of the patients during sleep. A significant correlation had also been demonstrated for the results obtained with two types of subjects: medical students and psychiatric patients Each subject served as his own control. According to the authors, ". . . fenfiuramine disturbs sleep and therefore a CNS stimulating action appears evident. "It seems that, because of their lack of sleep, the subjects felt dull and dizzy during the mornings following the fenfiuramine test nights..." It is then questionable whether daytime drowsiness is a. manifestation of a truly sedative effect of fenfinramine, or rather a symptom of fatigue follow- lug primary excltation No facilitatica of normal sleep has ever teen reported, although a few eases of Insomnia were." In this connection, an article by Oswald, I. Brit. Med. Jour. 1968 Vol. 1, pages 796-799 states: One may take the example of diethylpropion reported by Seaton et al. (1961) from Edinburgh to be an effective appetite reducer with `no evi- dence of undue central nervous stimulation or insomnia . . - no important side effects'. Time, however, showed that diethyiproprioii like dexamphetamine and phenmetrazine was a pep pill causing elevation of mood and of the pace of thinking The Edinburgh group has since reported on the effective new slimming drug, fenfiuramine, again reporting `no evidence of stimulation of the central nervous system.' Oswald found that diethylproprion caused 1) frequent awakenings; 2) suppression of paradoxical (RAM) sleep. Fenfiuramine caused neither but caused frequent shifts into and increased time in stage 1 sleep, at the expense of stages 3 and 4. S. Evaluation The present submission contains 3 controlled studies; the sponsors summaries of these studies appear on pages 236 to 269. The summaries contain a blank for the protocol number as Item 2; however. this number has been left off, and so far! hate not been able to find protocols in IND 1T03 for }`Isch (Study 2), Rosen- berg. Andersm, or llollingsworth. On only two sets of case report forms, those for Owen and Stem, are heights given, therefore it Is Impossible to determine the degree of obesity present, The results are expressed as average weight change per week. This is an inadequate method of expressing results; a far better and more revealing method is to tabulate the actual number of pounds the patient is considered to he overweight and the actual number of pounds of weight loss. According to the sponsor's summaries their conclusions are as follows: Owen No. 2002-the doses employed In this study are not anorexigenic. Fisch No. 2009: Ponderer 40mg t.i.d -0.54 Ponderer 20mg t.i.d -1.00 Placebo -0. 43 Rosenberg No. 2016: tin pound, per weekj 1st period 2d period Both pedods Fenfiuramine, 40mg, ti.d Ferifluramine 20mg, lid Placebo -iJS -1,12 -.47 -1.51 -.01 +.iB -0.61 -.72 `,20 "The number of patients Ia the study was small and therefore no definitive statement mar is' made regarding the results. Weight loss from fenfiuramine was greater than placebo hut the magnitude of difference was not great." Po~undR Anderson No. 2020: per week Fenfiuramine 1.4 Placebo 0.34 Hollingsworth No. 2025: Ponderer :1. 70 Placebo 1. 46 Roglasky No. 2050-B: Ponderer 40 mg b.i.d 0. 54 Ponderer 30 mg bid 0. 92 Ponderer 20 mgbi.d,,...,_,,. 0.6$ Plaeebo 0.29 PAGENO="0892" 15324 coIsIPETITIvE PROBLEMS IN THE DRUG INDUSTRY Bacon No. 2055-B: No figures given ("data shows fenfiuramine equal to placebo In effectiveness; however, subjects lost more weight In first period of the study regardless of drug (fenfluraznlne or placebo) used. Therefore design of study not good to detect weight loss effect. Also, study periods too short." Pos ads Stern No. 2060: per week Ponderex -0. 34 Placebo +0.20 The actual total weight lost for 3 studIes was as follows: Average tot at cumulative weight ton Flsch: Pounds 40mg 2.6 20mg 4.8 Placebo 0.3 Completions only All patients Roginiky: 40mg 60mg SOng Placebo -11.2 -14.1 -7.0 -4.0 -7.0 -11.0 -5.0 -3.0 Stern: 80mg Placebo -3.0 -.5 -0.5 -.3 Since the duration of these 8 trials varied from about 2 to 12 weeks, more com- monly 4 to 8 weeks, the studies submitted do not provide data for long term therapy. The above $ controlled studies were completed between March 1967 and .Tanu- ary 1968 and were not submitted until November of 1968. They were all deslg~ aated as Phase 2 studies on the summary sheets. In addition, there were 5 "special studies': No. 1001 Fred, H.; No. 1®~ Arson, B.; No. 1006 Till, T.; No. 2051 Cagnon, M.; and No. 2003 Fink, Xi. These studies were not primarily concerned with weight loss but with interac- tion between the fenfluoramine and metbamphetamine; effect of fenfiurauilne on reaction time and BEG; a study of Its central action through Its effect on sleep; and effect on behavior, etc. The paper by Cngnon Is the only one which does not have a summary by the sponsor. It Is slgaifi~nt that Dr. Cagnon concludes that fenfiuramine disturbs sleep and therefore has a ONS stimulating action, He further states that it Is questionable whether daytime drowsiness is a manifestation of a truly seda- tive effect of fenfiuramine or nther a symptom of fatigue following primary excitation. The group of non-controlled clinical trials are all designated as Phase S studies. The duration is from one week to approximately a year. There are no tabula- tIons of the actual weight loss hut only of the rate of weight loss. When the individual results are tabulated, it appears that the patients on 2 months' treat- ment did just about as well as those on 3 months' treatment so that results are not proportional to duration of therapy. Dr. Berman voiced the opinion that the drug was a poor one for general anorexigenic use. Dr. Araujo of Mexico achieved no less than 38.5 lbs average weight loss perperson. The marked variation In results demands an expiation other than merely differences in population. Finally, there are two "Other Clinical Studies", one froni Dr. Danernan. Spon- sor has not included his work in their statistics because no weights were rce- orded. The second study by Dr. Feldman, #3025, was terminated due to his death. VIII. Literature reviewed 1. Faxekas, J. F. Anorexigenic agents. N.E.I.M. 264:501-503, 1961. 2. Harris, S. C. et al. The mechanism of amphetamine-Induced loss of weight. S.A.M.A. 134:1468-75, 1947. 3. Thorn, 0. W. and Bondy, P. K. Obesity, p. 398. In Harrison's Principles of Internal MedicIne (5th ed.) 1966. 1 PAGENO="0893" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15325 IX. Labeling evaluation A. Identity disclosure-Adequate. B. Clinical uses-It Is questionable that the indication for the medical man- agement of obesity has i,een supported by the study. C. Adverse effects should include a discussion of Cagnon's observation on the stages of sleep. IL "Reproduction studies in 5 anImal studies have been carried out (see lie- production and Teratology). However, since studies of the safety of I'onderex In human pregnancy have not been performed, its use In women who are pregnant or who may become pregnant or In lactating mothers Is not recommended at this time." K Technical requirements-Adequately met, aceording to Cthemlst Review of February 24, 1069. X. Consultatlona See statistician's r~jaort of 4/~/69, Vol. 3.1, IND 17~3, which was received April 0, 1964, had not been reviewed by a Medical Officer between March 10, 19(15 and the date it was re-assigned to me, 3/17/t39. It comprises 10 large volumes. XI. Conclusions I recommend that a non-approvable letter be sent to the sponsor for the fol- lowing reasons: Although sponsor claims that efileacy has been demonstrated, he relies on the rate of weight loss per week rather than giving actual amounts of weight loss. An analysts of the S controlled studies yields the following approximate average cumulative weight changes following fenflnramlne or placebo: Investigator and done in Duration in Weight change (milligrams per day) weeks in pounds Investigator and dose in Durattor in Weight change (milligrams per day) weeks In pounds Owen: 40 2 Ineffective Finch: 60 4 -4.8 120 4 -2.6 Placebo 4 -.3 Rosenberg: 60 6-8 -3.6 lao 6-6 -4.7 Placebo 6-8 -1.7 Andersen1 3 Holliogswocth: A. 120 a -ia.s Placebo 8 -2.9 B. Placebo 8 -12.8 120 8 -7.6 Roginsky: 40 12 -11.2 60 12 -14.1 80 12 -1.0 Placebo 12 -4.4 Bacon: A. 20-60 4 -4.8 B. Placebo 4 -2.7 Placebo 4 20-60 4 -2.2 Stern: 80 8 -3.0 Placebo 8 -.5 I Case report forms inadequate as regards date,. Where as the sponsor claims that Owen's dosage was too small, we note that Raginsky using floe same dosage achieved a weight loss better than most of the other Investigators. On the other hand, Ilollingsworth found a greater weight loss with placebo than did most of the other investigators with fenfiuramine. On page 245 sponsor states that the number of patients in Dr. Rosenberg's study was small and therefore no definite statement may lie made regarding the re- sults; however, there were 34 patients In a cr~s-over study, which is more than tile number of patients in the studies done by Owen, Andersen or Bacon and almost the same as the number in Dr. flollingsworth's study. In Dr. Ilollings- worth's study, sponsor states on page 249 that the average weight loss on fen- fluramine was -1.7 Ihs/wk as compared to -1.46 lbs/wk on placebo. On page 256 sponsor states that Dr. Bacon's study shows ". . - fenflurnmiae equal to placebo in effectiveness. 1Io~vever, subjects lost more weight in the first period o the study regardless of drug used. Therefore, design of study not good to detect weight loss effect. Also, study periods too short - The study period was 4 weeks-equal to Dr. Fisch's and more than Dr. Owen's or Dr. Anderson's. The case reports forms submitted for Dr. Hollingsworth and Dr. Rosenberg are partially illegible. The case reports forms for Dr. Anderson are Inadequate In that actual dates are not given above the weights; only elapsed time. The dates that are recorded elsewhere en the Case Report Forms are ambiguous. PAGENO="0894" 15326 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The summary for Dr. Bacon, pages 255 through 266, is obscure; page 262 appears to be totally extraneous. Although the summaries bear a space f-or protocol number unrler Item 2, these have generally not been filled in, and I have yet to locate any protocol for Piseb, Rosenberg, Anderson, or l-lollingsworth. Most of the ease report fonas (10 not have the height or ideal weight recorded, so that the degree of obesity Is unknown. The claim that fenfluramine Is a sedative rather than stimulant is question- able ia "jew of Dr. Cagnon's article. The S controlled studies sulunitted on 11/5/68 are all designated as Phase 2 studies. There are some designated Phase 3 lut -these are uncontrolled studies. The weight losses recorded by Dr. Fisch and by Dr. Roginsky are almost in- versely related to the dose of fenfluramine. Most of the patients listed in this NDA lost too little weight to be considered as successful therapeutic responses. - ROBERT 0. Kxox, M.D. Fooa AND DRUG ADmNI5TRAI-loN, `rvasftington, D.C., Septcrnbcr 8, 1969. To: A. H. Robins Co. NDA 16-618--Ponderex Ponderex remains nonapprovahie under (h) (1) as follows: Lacking is suhstnntlal evidence for efficacy. Efficacy must -be measured In terms of the amount of adiposo tissue lost. The rate of weight loss is not a sufficient criterion unless the duration of treatment is adequately taken Into account. It is further necessary to gain an approximate ide-a of the "ideal weight"; in order to do this the height as u-eli as weight must he measured. On analyzing the con- trolled studies, we find that in C/S of the controlled studies the Investigators re- ported average net weight losses of approximately 2 to 5 pounds, which is not a su~cient achievement to recommend the drug as a treatment for obesity. The duration In these studies varies from 2 to 8 weeks. In 2/8 of the controlled studies where greater weight loss was reported, Boll- ingsworth recorded more weight loss (-12.8 lbs.) with placebo than any other Investigator' following the use of fenfluramine; while Roginslcy reported an average weight loss of -11.2 lbs. with only 40 mg per day dosage-a greater weight loss than any other investigator (except llollingsworth) achieved using fenfluramine In doses up to and including 220 nig per day. Bacon reported a greater average weight loss (-4.8 lbs.). at the 20-80mg level than Rosenberg or Fisch reported at the 120mg level. Dr. Fiseh showed less weight loss (-2.6 lbs.) at 120 mg dosage than any other group-except half of Dr. Bacon's pntients, who are given 20-60 mg per day. Examination of the uncontrolled studies cast further doubt on the validity of the evidence submitted. For example, Dr. Arauj-o In Mexico, Study #3028, reports an average weight loss of 36.5 lbs. Ia 8 weeks using only 50 mg fenfluramine per day whereas Dr. Berkowitz In this country reports only 8 lbs. weight loss in a 12 week study using 120 lug. Dr. Berman voiced the opinion that the drug is poorly suited for general anorexigenic use (page 283). Any attempt to dismiss these discrepancies by claiming population differences runs Into the dificulty that, excepting abnormal pathological conditions, caloric requirement per square meter of body surface Is almost identical from person to person providing the amount of exercise is the same and therefore it would be necessary to show that the groups which achieved greater weight loss also aver- aged much more exercise or ate much less food, No evidence has been presented that would lead us to believe that this is the case. Therefore we must conclude that the data fail to demonstrate a dose-response relationship. The practice of pooling data before analyzing it obscures the conflicting results obtained by the various Investigators, and fails to give an adequate picture of the clinical findings. As regards the claim that fenfluramiue Is not a central nervous system stimu- lant we note on page 186 that Dr. Gaguon statrd: ". . - fenfluramine disturbs sleep and therefore a CYS stimulating action appears evident." * I Except for some of Roglnsky's patients on 80 mg dosage, PAGENO="0895" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15327 "It seems that because of the lack of sleep the subjects fell dull and dizzy dur- ing the mornings following the fenfiuramine test nights..." - It ft then questionable whether day time drowsiness is a manifestation of a truly sedative effect of fenfiuramine, or rather a symptom of fatigue following primary excitatioa. No facilitation of normal sleep has ever been reported, al- though a few cases of insomnia were" (page 188). Any claims as to sedation or tranquilizing effect will have to take Into account Dr. Gagnon's paper. If you dis- agree with Dr. Gagnon's findings we request that you supply clinical evidence to refute them. The case report forms submitted for Dr. Ilollingsworth and Dr. Rosenberg are practically illegible. This should he corrected. The ease report forms for Dr. Anderson give no actual dates, only the elapsed time. The dates that are recorded elsewhere on the case report forms are am- biguous. Actual dates should he supplied for the starting and stopping of medi- cation on all ease report forms. Page 262 is out of context. Please clarify as to its proper location. With regard to Study #3027 (Newman and Weger) in which the greatest number of patients, the' highest dosage of fenfiuramine, and the longest periods of treatments were adopted, we find it difficult to analyze the raw data, since the dosage levels used on any given patient were changed so often and at irregular in- tervals. We request that you tabulate for each patient the duration in weeks that each dosage level and the number of lbs. lost during each such period, as well as the initial and final weight difference. Because of the volumlaous nature of this NDA and associated INDs 1703 and 4402, we request that you submit a tabulation, both alphabetical and chronologi- cal, of all clinical lavestigators 0151 their protocols so that we may more easily locate the protocols for each investigator, On page 245 you state: `The number of patients in the study was small and therefore no definitive statement may be made regarding the results" (Dr. Rosen- berg's Study #2016). A randomized double-blind crossover technique was de- scribed for this study; there were 21) patients on fenfiuramine and 33 patients on placebo for a total of 62 patients, and this number is more than that for any other investigator doing controlled studies, with the sole exception of Roginsky. If Dr. Rosenberg used too few patients, then the rest of the investigators did likewise. On page 256 in connection with Dr. Bacon's study you state ". . . fenfiuramine equal to placebo in effectiveness. llowever, subjects lost more weight in the first period of the study regardless of drug (fenfiuramine or placebo) used. There- fore. design of study not good to detect weight loss effect. Also, study period too short." The design was a double-blind crossover and the study period was the same as that used *by fljt Flsch and Dr. Rosenberg, viz., 4 weeks. What study period do you consider adequate? The submission of June 17, 1969 Is an uncontrolled study by Dr. Lange which does not materially alter the situation concerning evidence for efficacy of fenfiuramine. We are withholding comments concerning the labeling until the NDA is satis- factory In other respects. ROBERT 0. Exox, M.D., Medical Officer. 3innicst Or-rrcan's Ravjaw or NDA 16-618 Oc'rennn 23, 1969. Product: Fenfiuramine Trade name: Ponderer Sponsor: A. H. Robins Co.. Richmond, Va. PnEvio~s REvIEws 1. RIchard Zoppa, M.D., reviewed this application on 8-29-67. His summary has been reviewed and approval is not recommendcd for the following reasons: (1) Control.lcd studies the eapoule formulation did not include a restricted low calorie diet schick is necessary In any weight reducticn program. (2) Controlled studies using the tablet formulation were not well-controlled I.e. they were "open" in design, not "double-blind". (3019, 3020, 3022, and - 3023) (3) The application Is submitted for the tablet formulation only; data from the capsule formulation cannot be applicable in the absence of data equating the biologic availability of the two formulations. 65-560 0- 77-50 PAGENO="0896" 15328 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2. Robert 0. Kno~r, M.D., recommended a na-approt'able letter on May 19, 1969. Application was considered withdrawn en July 18, 1.969, and reassigned for review with respect to safety and efficacy. I. Category: Appetite Suppressant II. Structural formula: CF3 ciii çJ_Cur~1r._Niic2nnHci III. Dosage recommended: 20 to 40 alga. TIP. IV. Related drugs: The amphetamines. %?* Pharmacology: Review dated February 19. 1969, states the drug appears to present no problem of safety and that the present labeling is acceptable. VI. Consultation with other divisions: None. VII Clinical studies: A. Investigators-Five Investigators performed special studies. Eight investi- gators performed controlled clinical studies. Ten Investigators performed non- controlled clinical studies. Two investigators performed "other" clinical studies. The Investigators' curriculum vitae appears adequate nnd they are considered acceptable. B. Clinical conditions-Patients are all said to be overweight; many had as- sociated diabetes and hypertension. Evaluation of the studies-Study No. 2002, Investigator John A. Owen, M.D., Charlottesville, Virginia. Study Design: Compared Ponderex with Methamyhetamine and a placebo In order to determine anorexic properties and side-effects of Ponderex alone, meth- amphetamine alone, and the combination. It was double-blind and crossed-over, two weeks on each of the four treatments with no diet prescribed. Patients used were ten female and two male, of which ten were diahetic, one an arthritic, and one normal Individual. Of the ten diabetics, three were on no medication, one was taking Orinase, one was taking Ilydroton, two were taking Dymalor, and two were taking Insulin. All patients took all four treatments. Po~are sehedtilp.-(1) .Fenfiuramine, 40 mg/day; (2) Methamplietamine, 2.5 mg/day; (3) Placebo; and (4) a combination of }`enfiuramine 40 mgs and Meth- amphetamIne, 2.5 mgs, given once daily. All treatment periods were 14 days. Results showed a slight weight gain with the Fenfiuramine and a slight weight loss with the Placebo. Conclusion-Data does not support efficacy for Ponderex with regard to its anorexic claim. It does support a claim of being less stimulating to CV. system than the amphetamine (slight decrease in blood pressure and pulse rate with test drug compared with Ponderex). Study No. 2009, Investigator Solomon Fisch, M.D., V. A. Hospital, Bronx, New York. Stud,~ design-Comparison of the safety and efficacy of Fenfiuramine, flex- troamphetamine and a placebo. Low calorie diet was not prescribed. The patients were divided into four groups and the results were as follows 1. Dextroamphetamine group; fifteen subjects; five completed the study. There was a weight gain lu two of the subjects and a weight loss in three of 5-10 lbs. 2. Placebo group; fifteen subjects; nine completed the study. There was a weight loss In six of 5-10 lbs. and a weight gain in three. 3. Fenfiuramlne group (20 mg TIP); fifteen subjects; seven completed tIme study. There was a weight loss in all seven subjects, five lost less than 10 lbs. and three lost more than 10 lbs. 4. Fenfiuramine (40 mgs TIP) group; fifteen subjects; eight completed the study. There was a weight loss in five (three lost less than 10 and two lost more than 10 lbs.). Comment and evaluation-Subjects completing the studies were not enough to make a significant evaluation therefore data Is not substantial. It is also noted that the heights are not given for any of the subjects In the study. An accurate diagnosis of overweight should have the height and weight determined for each Individual. The results of this study does not adequately support anorexic claim PAGENO="0897" COMPETITIVE PROBLEMS IN TflE DRUG INDUSTRY 15329 for Fenfiuramlne. Even though the protocol is not specifically supplied as such, It has been determined that the study was double-blind, randomized, and divided into four groups of subjects and it lasted for five weeks. Study No. 2010. Investigator Benjamin A. Rosenberg, M.D., F.A.C.P., Brooklyn, New York. Study Design: Double-Blind, Cross-Over, and Randomized comparing Fenfiura* mine with Placebo (compared the 20 mg TID vs. 40 mg TID dose of Fenfiura- mine). Duration of treatment was six weeks. Results: The Fenliuramine Group, Sub-Group A. (20 mgs TID), 12 completed the study of of fifteen; nine lost weight from 4 to 12 Ibs; two had no change. Sub- Group B, Fenfiuramine (40 mgs TID) ; 14 completed the study out of fifteen; weight loss in eleven and weight gain In three with no change In one; amount of weight loss was from 2 to 11 lbs. (six lost less than 5 lbs.., and five lost more than 5 lbs.), one gained 18 lbs., and one gained 1 lb. Sub-Group C, (Placebo Group) twenty-six completed the study out of thirty-three; thirteen of whom lost weight (more than 5 lbs.), and thirteen of whom had no change or gained weight. Comments.-The firm has totalled up the results and arrived at a pounds/week weight loss. It is more accurate to state the number of pounds each subject lost with each of the medications. The firm's figures as they are presented suggest that the Fenfiuramine dose of 40 mgs TIl) (after all the results were apparently pooled into a pounds/week weight loss) Is five times more effective than a Placebo. In actual fact 41% lost more than 5 lbs. with test drug and 50% lost more than iS lbs. with placebo. Conclusions-Data not adequate because; 1. A low calorie diet was not used, 2. Number of patients losing more than 5 lbs. on drug was not significantly greater than those taking Placebo. CLINIcAL sTtD!ES (coxmoLIn) Study No. 2020: Investigator: Robert S. Anderson, M.D., Nashville, Tennessee Study No. 2025 Double-blind, cross-over, randomized; duratIon, 0 weeks divided Into three 3-week treatment periods; number of subjects, 20; diet varied from patient to patient. Some are on a 1500 calorie diet, others are on a 1800 calorie diet, others, a 1200 calorie diet, 140') calorie diet; all patients seem to be diabetic. Many of them also had hypertension; and again we note the absence of the measurement of the height of each patient. The dose used here was 30 mg of Fenfiuramine 3 times a day, and the actual treatment periods were two-one, placebo, and one drug, each period lasting about 32-88 days. Results The data have been closely analyzed and it can be seen that out of the 20 sub- jects studied, all diabetic, there were 4 patients In which it could be said that the fenfiuramine produced a significantly greater weight loss than the placebo. The other 16 subjects showed that fenfiuramine did not produce any greater weight loss than the placebo, and, in fact, several patients gained weight while on the test drug. Comment and evaluation-This study is poorly designed in that we have no height measurement, and no consistently low caloric diet. Conclusion 1. This Is not considered a well-controlled study. 2. It does not support the claims made for this drug since drug did not Influ- ence weight loss when compared to the placebo. Study No. 2025 Investigator: Dorothy B. Hollings~vorth, M.D., West Haven, Connecticut Study Design: Thirty-six subjects randomly assigned to One of two treatment groups, fenfiur- amlne 40 mg. t.I.d. or placebo. Each group was to proceed through two mxty-day treatment periods. All subjects were placed on a 800 calorie diet. Fourteen of the subjects had diabetes and 11 had hypertension. Study was double-blind. PAGENO="0898" 15330 CQMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Observations Subjects were seen every 2 weeks during each 60-day treatment period, and the blood pressure, pulse, weight and subjective reactions to the drug were all noted. Results Each and every case report has been studied and the results are as follows: 17 patients lost more weight wit!. the test drug than they did with placebo; 10 patients lost as much weight wit]. the placebo as they did with the drug; I) lost more ~ placebo than with test drug. 9 failed to complete the stndy. Comment and evaluation-This study can he considered `veil-controlled in that the dose of fenfluramine that was used was constant, and every patient was put on an 800 calorie diet. However, 10 patients lost the Same amount of weight or more with placebo than with drug (19 vs. 17). Side effects reported were mod- erate diarrhea in 5 patients; overtrnnquilization varying from constant sleeping to lethargy in 4 patIents; total impotence in 2 patients; mild pruritus in 2 pa- tients. We note that there were no changes in the blood pressure or pulse, and no mention of any sleep disturbances during the night. Laboratory flrtd4ngs There were no abnormalities noted in the blood count, urinalysis, BUN, FBS, and SOCT determinations. Conclusion: Not substantial evidence for anorexic claim. Study No. 2050-fl: Investigator: Martin S. Roginsky, M.D., Meadowbrook Hospital, East Meadow, N.Y. Study design One hundred and twenty subject divided into 4 groups of 20 each in which fenliuranune in a dose of 20 mgs, 30 mgs. and 40 mgs, and the placebo were treated for 12 weeks; there were 19 diabetics and 12 hypertensives in the study. Dosage schedule Group 1 took 20 mgs of fenfluramine twice a day; Group 2 took 30 mgs of fenflnran,ine twice a day; GroupS took 40 mgs. of fenfluramine twice a day; and Group 4 took tile placebo twice a day. All patients were put on a 1,000 calorie weight reduction diet. The study was double-blind and randomized, and not crossed over. Results are listed as follows; 1. The 20 mg, twice-a-day group had 11 effectlves; 7 fair; 5 not effective; and 7 dropouts. 2. The 30 mg, bid, group had 16 effectives; 6 faIr; 8 not effective, and 4 drop- outs. 3. 40 mg, hid, group: U effectives; 5 fair; Snot effective; and S dropouts. 4. Placebo group had 5 effectives; 7 fair; 11 not effective, and 7 dropouts. Comment and evaluation-The term "effective" Is applied to all those patients who lost more than 10 pounds during the 12 weeks of treatment. It can be seen that a'! groups talking the drug lost more weight and more patients lost weight than those taking the placebo. It Is Interesting to note that the 30 mg. bid, dose was shown to be a success in more patients than the 20 aug. dose or the 40 mg. dose. This schedule is considerably different than that used by Hollingsworth, and It Is difficult to determine any dose response relationship here. It mu'1 he concluded. however, that this study (Dr. Roglnsky) showed the drug to he more effective than a placebo when given In conjunction with the 1,000 calorie diet over a period of 12 weeks. Study No. 2060 Investigator: Sol B. Stern, Jr., M.D., New Orleans, Louisiana. Study Desiy-n Sixty adult patients divided Into 3 groups. Group A took fenfluramine 20 Ings. 4 times a day: Group B took Tenuate 25 mgs. 4 times a day; Group C took a placebo, 1 capsule 4 tImes a day. Duration of study was 2 months for all 8 groups. All patients were put on a low calorie diet from 1,000 calories to 1,500 calories per day. PAGENO="0899" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 15331 Results 1. The test drug group showed 2 effectlves; 6 fair; 4 not effective; and 8 drop- outs. 2. Teuuate group showed 5 effective; 7 faIr, 5 not effective; and 3 drop-outs. 3. Placebo group showed 1 effective; 4 fair; 9 not effective; and C drop-outs. Comment and evaluation.-It seems to this reviewer that the selection of pa- tloiits could have been a little bit better. Test drug not slgiilficantly better than placebo. Conclusion.-Does not support efficacy. REVIEW OF SUBMISSION DATED JUNE 17, 1969 Investigator-Raymond L. Lange, M.D., Milwaukee, Wisconsin. Study design Nineteen obese patients, with concurrent cardiovascular disorders whose weight was at least 15% above the optional limits defined by the Metropolitan Life Insurance Company. Study was open and all patients were put on a low calorie diet of 1,000 calories a day. The purpose here Is to evaluate the anorexic effects of fenfluramine as well as Its effects on the central and autonomic nervous systems in patients with cardio- vascular disorders. The duration of the study varied from 5 days to 326 days. Fourteen of the patients took the drug for at least 6 weeks, and 5 patients took it. for less than 6 weeks. Results Ten of the 19 patIents lost 10 or more pounds during the period of treatment. The dose used in these 10 patients was 20 mgs. t.i.d. Nine of the patients lost less than 10 pounds and most of these lost less than 5 pounds duriag their period of treatment. One of the subjects took 40 yngs. 3 times a day. Since one patient took 40 mgs. 3 times a day (which Is considered the top dose), this study does not adequately reflect the effects of the top dose given Ia patients with cardiovascular conditions. Tho drug in this study in the dose used did not cause any adverse cardiovascular effects. Since we have no placebo con- trol here along with the 1.000 calorie diet, these results do not demonstrate effi- cacy for fenfluramine with respect to anorexia. SPEcIAt STUDIES Study No. 1001 Investigator-Herbert L. Fred, M.D., houston, Texas Study Objective To determine the nature and extent of interaction between fenfiuramine and methanphetamine administered at different times on the general feeling of well- being, on CNS symptoms, and incideatly, In influencing loss of weight in obese patients. It was double-blind, cross-over, with each subject taking all 4 drug schedules each for 2 weeks. The order of administration was randomized. As it turned out, each subject took fenfluramino for 2 weeks, methanphetamlne for 2 weeks, feafluramine and methanphetamiae for 2 weeks, then the placebo for 2 weeks. Twelve subjects were used and there was no diet restriction. Re-titus The dose used was fenfinramine 40 mgs. twice a day, 5 mgs. of methanpheta- mine, and placebo. 1. 8 out of 11 subjects lost more than 1 pound a week. 2. The placebo group-S out of 11 subjects lost more than one pound a w-eek during the treatment period. Blood pressure effects showed the fenfluramine to produce a slight decrease in blood pressure, as ~vell as a docre,se in pulse rate. It is noted that the com- bination consisting of 40 mgs. of fenflaromine and 5 mgs. of niethanphetamine given twice a day produced a greater loss of weight than the fenfluramine alone. PAGENO="0900" 15332 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Stud y No. 1002 EU Larson, M.D., Miami, florida-Investigator. This investigator conducted the study identical to No. 1001 (Dr. Fred). The results are essentially the same in that the blood pressure and pulse rate tend to decrease with the fenfiuramine, and the weight loss Is greater with fenflura- mine than with placebo. This investigator also makes a statement, "In terms of the effect on sleep, the methanphetamine periods appear to have interfered slightly with sleep, the fenfiuramine period increasing sleep, and the placebo hav- ing little or no effect". Study No. 1006 investigator-P. M. Itil, M.D. Study design To investigate the effect of fenfiuramine on the reaction time and measure LEG changes. 17 adult females took part, study was cross-over in design, and the patients were out-patient in type. The reaction time to an auditory stimulus using fenliuramine and a placebo were compared when given in a single dose. Feafluramine was given in 20 nigs capsules, with the daily dose based on body weight. Subjects le,~s than 140 pounds receIved 3 capsuLes a day, and subjects over 170 pounds received 6 capsules a day. Each subject's reaction time to an auditory stimulus was ascertained during a continuous EEG recording. These reactIon times compared placebo against fenfluramine. The results of 17 patients showed that fenfluramine in daily oral doses of 40 mgs. in female volunteers, Increased tem- porary reaction time performance to an auditory stimulus, but did not effect a discriminative reaction time performance task. The same author has com- pared moprobamate, secobarbital, chtorpromazine, amphetamine, and methyl- phenidate under the same experimental conditions. It has been detennined that CNS sedative drugs produce a slowing of reaction time tasks and CNS stimu- lants either produce no effect or a quickening of the reaction time. In this regard, fenfluramine In the doses used here, may be classsitled among the CNS sedating drugs. Study No. 2051 Investigator: M. A. Gagnon; J. M. Ilorderlfau, and L. Tetrfeault, Montreal, Canada. Study objcctivc Study of fenfluramine's central action through its effects on sleep. Subjects were 66 chronIc patients in a psychiatric hospital who continued to take psychotropic drugs at their usual maintenance dosage during the study. The study was doubledilind, comparing a dose of fenfluramlne, 40 mgs. with a placebo when taken at bedtime in an effort to determine the effects on sleep. (We note that the top recommended dose of fenfluramine is 40 mgs. at bedtime. It is not 80 mgs. as evaluated here in this study.) Rcsults The authors found that both doses-40 mgs. and 80 mgs.-dld not disturb the Induction of sleep. I.e., all patients went to sleep as usual, whether they took the 40 mg. dose, the 80mg. dose or placebo. This is In contrast to amphetamines taken at bedtime where patients have trouble going to sleep. The 80 tug, dose of ten- fluramine had the following results: A few hours after falling asleep normally. the subjects awakened in such a disturbing way that their rest was troubled and the length of time they could sleep was reduced. The following morning they felt dull and were conscious of a short and unsatisfactory night sleep. The effects of the 40 mg. dose of fenfinrantine were not different from those observed following the placebo. fli,qrugsion The 80 ing. dose produces disturbance In sleep, whereas the 40 mg. dose does not, when both are given at hedtlmes. Dr. Gagnon makes the statement that, In animals. fenfluramine does not produce the amphetaminic EEG desynchronlza- tion. and actually denresses the activating retieular formation. In contrast to amphetamine, when Injected before the harbituate, fenfluramine prolongs the sleening time of harhituate narcosis In mice, and even potentiates the action of the barbiturate. So, the Interpretation of the results of Dr. Gagnon's study Is that fenfluramine does not have a stimulating CNS action like the amphetamines; In PAGENO="0901" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15333 fact, it is less stimulating to the CNS. The present recommended dose (maxi- mum) is 40 rngs. 3 times a day. This dose did not disturb sleep in his study pa- tients (Dr. Gagnoa's study population consisted of inmates of a psychiatric institution who were taking a psychotrophic drug along with the fenfiuramine.) Conclusion u,ith respect to labeling The results of the studies thus far presented (fled, Larson, Itt!, and Gagnon) leave 110 doubt iu this reviewer's mind that fenfiuramine is less stimulating to the eNS and the automatic nervous system than the amphetamines. A statement to tins effect in the labeling is adequately substantiated by the data submitted thus far. IilSck'SSlON ANI) COMMENT W~T1I RESPECT TO TIlE EFFICACY OF FENFLURAMINE IN Tills APPLICAUON Guideline criteria for the dcsigm of a weight-reducing study 1. $0 to 100 overweight subjects; divided into 2 groups, one on each me-lien- double-blind, randomized, ushig placebo and drug, non-crossover: subjects sh,.uld ho 15 to 20% overweight according to the Metropolitan Life Insurance tables. 2. A low calories diet that is the same for all individuals In the study; this would lie a maximum of 1200 calories per day. (The following authorities recognize the need for a low calorie diet In any weight-reducing program: Harrison's Medicine, Goodman & Gilirnan. and the J. American Medical Association New Drugs, and British Medical Association. (Report of Working Party, November 1965 on amphetamine preparations) 3. Two-week, pre-medication baseline period with weight measured at the same time during the day at three weekly hnte~als. 4. WeIght should he measured at the same time during the day at weekly Inter- vals during the study, preferably after breakfast every morning. (In this way, the bowel and bladder habits will be accounted for.) 5. DuratIon of drug treatment period should be 4 weeks. J?easona for the above guide7inc 1. The study should be non-crossed-over with everybody on the same low calorie diet: if a subject is crossed over from drug to placebo, he will have had the bene- fit of the low calorie diet duriag the drug period. We know that all patients on reducing diets lose their weight more rapidly early In the study. This would tend to give the Impression that the drug was better than the placebo; conversely If the patient Is crossed over from placebo to drug he will have had the henefit ef the low calorie diet during the placebo perIod, which could show the placebo to be equal or better than the drug. 2. The determination of how much each patient should be overweight in order to be selected for the study could never he decIded unless we arhitarily used a table from Metropolitan Life Insurance Company Information or samething similar. 3. Proper randomization of 2 grouns-~ne on the placebo and one on. the drug- should take care of the possibility or drug and placebo patients cheating on their diets. 4. It would seem to this reviewer that the duration of treatment should not be any longer than 4 weeks in order to establish efficacy for a drug in this category, because In studies lasting longer than 4 weeks, patients tend to lose weight at a slosvar ,nte after the first 4 weeks. \~IIT. Literature reviewed: 1. Goodman and Oilman: Pharmacological Basis of Therapeutics; 1965 2. Ira rrlson's principles of Internal MedIcine (5th Ed.) 1966 3. Report of the Working Party on amphetamine preparations November 1968; British Medical Association Summary of sevn. adult-controlled studies Rub-group A-studies supporting efficacy-I. Martin S. Roginsky, M.D., East Meadow, N.Y. Ruh-eroup fl-Studies not supporting efficary, for this drug-i. .T. A. Owen. M.D.. Charlottesville, Virginia. 2. Solomon Fi~h. M.D.. Bronx, New York. 3. B. A. Rosenberg, M.D.. Brooklyn. New York 4. Robert S. Anderson, M.D., Nashville, Tennessee PAGENO="0902" 15334 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 5. Sot B. Stern, Jr., M.D., New Orleans, Louisiana 6. I). It. Hollingsworth, M.D., \Vest Haven, Connecticut In summary, then, we have Gout ofT well-controlled studies that do not support the efficacy of fenfinramine in this dose when given as an adjunct In a weight- reducing program. The data cannot he considered adequate. Conclusion: The application is incomplete and not approvable. aECOM M ENDATION 5 The firm perform two more well-controlled studies, using the above-suggested guideline criteria, One study would use the dose of 40 mgs 3 times a day. The other study would use 30 mgs 3 times a day. Each (lose regime is to be double- blind, randomized, using a placebo. Tins should mensare the ability of fenfiur' flnii'ie to re(lnce the desire for eating when subjects are placed on a low calorie diet. The claim that feufiuramine is less stimulating to the central nervous system titan the amphetamines is justified and should be Included In the labeling. Perhaps a combination of fenfluramine and amphetamines would be worth studying. lAMES M. Mosra, Jr.. M.D., fli,'jaion of Neuropharnmcolog jest Druqg. MEDICAL OFFIcER'S REvIEw or NDA. 16-618 DECEMnER 20. 1969. Product: Fenfluramine. Trade name: Ponderex. Sponsor: A. H. Robins Co., Richmond. ITa. AnDEIcnUM The firm has submitted an amendment to their new drug application dated November 25, 1969. This mnterial contains the results of clinical studies by eight different investigators, all of whom evaluated the appetite suppressant effect of }`enfiuramine Hydrochloride according to the same study plan. The nmeudment also contains a revised pnclcnge Insert. LIST OF INVESTIGATORS I. Study No. 2536 herbert L. Fred. M.D., Ben Taul) General hospital, Texas Medical Center, houston, Texas. 2. Study No. 2537 Gilbert C. C.remmel, M.D., 7702 LouIs Pasteur Drive, San Antonio, Texas. 3. Study No. 2538 Raymond S. Gutin, M.D., 955 Pennsylvania Street. Denver. Colorado. 4. Study No. 2539 John C. Esposito. M.D.. 226 East Springfield Road, Springfield, Delaware County, Pennsylvnnia. 5. Study No. 2540 Soi B. Stern. M.D., 3600 Prytanla Street, 68 Cushiug Court. New Orleans, Louisiana. C. Study No. 2541 Arthur J. hladler. M.D.. Veterans AdminIstration, 17 Court Street, Boston, Massachusetts. 7. Study No. 2543 Antoine (attereau, M.D., hospital hotel, 3840 St. Urhain, Montreal 38. Quebec, Canada. 8. Study No. 2544 Rudolph E. Noble. M.D.. Director. Ols~sity Clinic. San Fruncisco Eye and Ear hospital, 1801 Bush Street and Octavia, San Francisco, California. PAGENO="0903" COM'PETIflVE PROBLEMS IN THE DRUG INDUSTRY 15335 9. Kiudy No. 2545 Rudolph E. Noble, Ml)., Director. Obesity Clinic. San Francisco Eye and Ear HospItal, 1801 Bush Street and Octavia, San Francisco, California. The above-named investigators used the identical protocol and the same study plan. This is described below: EXPERIMENTAL DEStON Each study consisted of 32 subjects who were grcuped Into one of the four cells indicated below prior to double blind assignment 1,ito one of four dosage schedules. Such random assignment was predicated on a randomization schedule based on appropriate tables selected from -~ and Oakford, Tables of Random Per- mutations. Stanford University Press, 1962. The cells are described as follows; Eight male patients who were 15 to 30 pounds overweight, and S male patients who were 30 to 75 pounds overweight; S female patients who were 15 to 80 rounds overweight, and 8 female patients who were 30 to 75 pounds overweight. The sulijeets were 21 to 65 years of age with mature, non-endocrine obesity as evidenced by being 15 to 75 pounds heavier than the desirable weight. Special inclusion criteria were an expressed desire to lose weight, and an expressed interest in and willingness to participate in this drug trial, on either Pondercx or placebo for a period of 12 weeks. EXCLUSION cRrrEnrA 1. Endocrine or other metabolic canses of obesity. 2. Evidence of abnormal fluid retention. 3. Obesity of childhood onset. 4. History of weight loss regimen in the last 6 months. 5. Inability to reasonably ensure accurate reporting of any deviation from the dosage schedule, side effects, etc. 6. Severe hypertension. 7. Marked coronary artery disease. 8. Severe renal impairment. 9. Severe hepatic Impairment. 10. Pregnancy or apt to become pregnant. 11. Lactation. 12. Overt depression. 13. Have taken in the Inst 2 weeks, or currently taking Or likely to take any of the excluded concomitant drugs (anorexigenics, tranquilizers, sedatives, MAO inhibitors, diuretics, thyroid preparations, and steroids). DOSAGE SCHEDULE One group received Fenfluramine tablets 60 mgs/day (one tablet t.l.d. of a 20 mg strength) ; the next group received an equivalent sized placebo tablet t.i.d.; the next group received Fenfiuramine tablets in a dose range of 60 to 120 mgs/day given in three divided doses, and, the fourth group received a placebo dose that was equivalent to the Fenfluramine high does schedule. So, we have groups of patients properly randomized, two received a low dose schedule of either Fenflura- mine or placebo, and two groups receiving a high dose schedule of Fenfluramino or placebo, The treatment was for 12 weeks continuous, and not crossed.over. The drugs were packaged in appropriat&y lahblc'd bottles (double blind, coded), containing a two-weeks' supply of tablets. The Investigator issued a bottle at the first, third, fifth, seventh, ninth and eleventh visit to each patient und requested the subject to return the unused tablets in two weeks so that the remaIning ones may be counted and recorded. No special diet was recommended. It is felt that a rigid low calorie diet is not necessary to determine appetite suppressant qualities of any drugs. on 5ERvATION S The following observations were made at the Initial visit, and every 7 days for the entire 12-week period: 1. Weight-Every effort was made to ensure accuracy and to minimize the extraneous variations from visit to visit; i.e.. personnel were to be carefully Instructed. The same person, if possible, was to do all the weighing; medIcally A PAGENO="0904" 15336 CO~ETITIVE PROBLEMS EN ThE DRUG INDUSTRY balanced scales were to be utilized; ip1iolntinents were to he inn do at apl)rOXi- niately the same time of day; shoes were to lie removed during the weighing; ordinary clothing would he worn otherwise; arid, weight was to be recorded care- fully to the nearest quarter of a pound. 2. Blood pressure and pulse rate were taken while subjects were at rest and in a sitting position. 3. At the Initial Interview, the subject was told to look for but not to expect the following adverse effects: nausea, vomiting. diarrhea, constipation, tenseness, abdominal discomfort, noeturin, urinary frequency, visual disturbances, daytime drnwsiness, headache, dizziness, insomnia, fatigue. depres4on of mood, irrita- bility, and rash. At each subsequent visit, the investigator would merely ask: `In general, how have you felt this last week `C' 4. Subjects were also questioned as to whether it had been easier or more difficult than usual to control their appetite, whether they had more or less day' time energ~, whether they had been more or less drowsy in the daytime, and *hether their sleep at night had been easier or more difficult. COMMENT ANY) EVALUATION This protocol seems adequate and is acceptable to this reviewer. However, Division of Statistical Analysis wilt be requested to review this protocol and coininerrt on any deficiencies they may find. REVIEW or INnIVIOTJAL STUnIES Study No. 2536 byJi. L. Fred, M.D. Drug-M effective, G not effective, and 4 dropouts. I'lacebo-e effective, 7 not effective, and 3 dropouts. Conclusion-Not favorable. St,tdy No. 2537 by (1. C. Gremniel, M.D. Drug-lO effective, 3 not effective, and 3 dropouts. Plaeebo-5 effectIve, 0 no effective, and 3 dropouts. Co .win gion.-Favorable. Study No. 2538 byE. S. CutE,., M.D. This study is of no value due to lack of sufficient number of patients complet- lag the study. Study No. 2539 by 31 C. Esposito, M.D. Drng-22 effective, I) not effectIve, 1 dropout. Placebo-C effective, S not effective, 2 dropouts. Conciusio,t-Favorable. Study No. 2540 by S. B. Stern, M.D. Drug-C effective, 6 not effective, 4 dropouts. Placebo-S effective, 9 not effective, 4 dropouts. Conc lusio,..-Favorahle. Study No. 254! by A. .1. Ifadler, M.D. Drug-5 effective, 6 not effective, 4 dropouts. Placebo-6 effective, 7 not effective, 3 dropouts. Conclusion-Not favorable. Study No. 2543 by A. Cattereau, M.D. Drug-? effectIve, 2 not effective, 7 dropouts. Placebo-~-3 effective, 2 not effective, 9 dropouts. Conclusion -Favorable. Study No. 2544 by 12. 12. Noble, M.D. Drug-ft effective, 2 not effective, 5 dropouts. Piacebo-3 effectIve, 4 not effective, 9 dropouts. Conclusion -Favorable. Study No. 2545 by 12. PJ.Noble, M.D. Drug-13 effective, 0 not effective, 3 dropouts. Plaeebo-7 effective, 4 not effective, 5 dropouts. Conclusion.-Favorable. PAGENO="0905" COMPETITIVE PROBLEMS IN THE DRUG 1NDU~JTRY 15337 iSumnuiry of the Results of the Double Blind Identiea2 Protocol Studies is as Follows.- Favorable-6 clinical studies with 5 investigators. Not favorable-2 studies. Of no value-i study. CONCLUSION It would seem that the data Is adequate to support an appetite suppressant claims for this drug, }`enfiuramine, provided the protocol is accepted by our Division of Statistical Analysis as adequate. JAMES M. MOSER, Jr., M.D. MEMORANDUM FEBRUARY iT, 1970. To: James M. Moser, M.D., Division of Neuropharmacological Drugs/OND (MD-120). Thru: Acting Assistant Director for Scientific Coordination (MD-401). Acting Dirertor, Division of Statistics (MD-450). From: Peter G. James, M.D., Acting Chief, Statistical Analysis Branch. Subject: Statistical evaluation of NDA 10-018 (Ponderex). 1. We acknowledge receipt of your request of January 5, 1970 for statistical evaluation of summary data contained In Vol. 4.1 of NDA 10-618. A detailed response to your request and a comprehensive analysis of these summary data is now being prepared. 2. Your request implied the existence of FDA criteria (both clinical and sta- tistical) for the demonstration of appetite depressant properties of a drug and also made reference to nine (9) separate (well-controlled) clinical trials. Since neither of these is fully extant a detailed analysis and discussion became neces- sary to clarify these Issues. 3. In the interim since review time has expired, a summary of the statistical findings is now submitted. It Is based on our dlscussion.s and an overall view of the summary data and our findings. It Is emphasized that no original case records of the individual studies were submitted for our examination and be- cause of the limited time remaining when our review began none were requested. The issue of whether a series of studies were well-controlled, properly conducted and adhered to protocol sufficiently is of tea resolved by a close examination of the original clinical records and the clinician's entries. 4. We do not have nIne (9) separate, well-controlled clinical trials in this submission. Four to five may be acceptable since they substantially adhered to the "standard" protocol and were relatively free of gaps in the treatment regimens and of doubts about missing data. 5. Pooling is not acceptable because we must examine enough findings from Independent individual studies to assess a product's general performance on safety and efficacy over a variety of experimental situations, 6. Pooling is further negated because the `standard" protocol was not fully imlemented. A number of clinicians failed to follow the treatment regimens and to obtain the demographic and clinical population balance described in the protocol. 7. The data from the more acceptable studies appear to support a finding that the two drug treated groups data combined) lost more weight than their com- bined placebo counterparts for the first six week-s of medication. The advantage beyond the first six weeks is small. This fact plus the greater loss of patients beyond that point would be deterrents to a claim for a longer period of effec- tiveness, particularly if overweight loss is to be equated to anorexigenic properties and reference to this relationship Is not Included in the iabeling. S. At the sixth week all studies show some advantage of the drugs over the plaeehos. One study failed to hold this advantage and at the 12th week the placebos showed a slightly greater average weight loss. The study to study consistency which we seek appears to be present in this group of studies. The amount of advantage over placebo is not consistent, ranging from an average of 0.06 to 1.37 pounds per week for the six week period. 9. The high, variable dosage drug regimen appears to show greater advantage over its placebo control than the low fixed drug regimen. In makIng this com- parisoa I have counted all full studies, Including the questionable Gattereau and first Noble studies, because the number of patients In each group was small. PAGENO="0906" 15338 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 10. A number of negative features In the NDA data will be reported In my subsequent, detailed report. however, there are two which cause some uneasi- ness. The first concerns the high dosage data for the placebo. The firm presents statistical summaries for each study showing the high dosage Incrementation over the 12 week study period. It fails to show similar data upon which to deter- mine whether the high dosage placebo was incremented in the same manner, The Implications may be minor, but could be mnjor. II. The other negative feature concerns the range of efficacy which may be attributed to the drug products. It is the small number of subjects in each study and In all studies combined upon which to base claims for efficacy. Should these claims be extended to the different dosage regimens and to the male/female sub-groups the supporting study data becomes increasingly sparse, ever, when au studies are combined. One investigator failed to get any males into his study. Others had no more than a sole male ~tient in one or more of the drug or placebo regimen groups. Some studies did not have critical drug to placebo com- parisons for males thus failing to provide support for "well-controlled clinical trials". 12. Of critical Import is the fact that the better results of the studies, overall. w-ere observed In the male groups. However, even should all complete studies be combined the number of males is 10 and 15 in the high and fixed drug dosage groups and 13 and 11 in the respective placebo groups. This paucity of male sub- jects was mentioned to you, orally; however, its significance was discounted because this appeared to be "representative". The concept of "representative- ness" may have been misconstrued. It was not the purpose of these studies to enter patients in such a manner as to represent the proportion of overweight males and females motivated to lose weight. It was the purpose to get enough males to determine the drug regimens' relative effectiveness. 13. At this point the sufficiency of data for males Is borderline if we combine all studies and both regimens. It probably is not sufficient to support claims for either drug dosage regimen. MEDICAL OrncEit's Rgvrgw OF NDA 16-618 Product: "Pondimia". Sponsor: A. H. Robins Co., Richmond, Va. Date of Submission: Mar. 25, 1970. Firm submits draft labeling for package insert for NDA 16-MiS based oa our conference with the firm on March 23, 1970. Labeling review Firm has made all the revisions recommended In our conference with them on March 23, 1970. Clinical references have been reviewed and are considered satIsfactory. The labeling has been compared to the guidelines for "Anorectic Prepara- tions" prepared by OMD and is considered acceptable. Con clnion The applicatIon is complete and approval Is recommended. JAMES M. Mosrs, Jr., M.D., Division of Ncaropharmacological Drugs. A. U. RoBINs Co., Richmond, Va., July 9, 1970. ChARLES E. EDWARDs, M.D., - Commissioner, Food and Drug Administration, Department of Health, Education and Well are, Roekritle. Aid. Dr.AR Couvissroxrx EriwARns: I appreciate your willingness to meet with representatives of Robins and Congressman Satterfield to discuss the Comnany's National Drug Act 16-618 for fenfiurnmine hydrochloride. Mr. Satterfield has advised us that the meeting is scheduled for 2 p.m.. Tuesday, July 14. 1970, at: Federal Office Building #5. 200 "C" Street. Room ~3R19, Washington, ThC. In order to permit a more meaningful exchange. I enclose for your prior review a history of NPA 16-618. Although prepared Internally, objectivity was the goal in the preparation of this history. PAGENO="0907" COMPETITIVE PROBLEMS IN THE DRUG rNDUS'rRr 15339 We look forward to our discussion and thank you for your courtesy In making it possible. Sincerely, B. Camonica Rourns. Enclosure. JANUARY 26, 1970 UPDATED JULY 6, 1910.. Subject: Fenfiuramine Hydrochlogide (NDA 10-618). Fenfiuramine hydrochloride is an appetite suppressant drug designed for use in the medical management of obesity. The A. II. Robins Company has licensed fenfiuramine from Les r~boratoires Servier of France for sale in the United States, Canada and South America. It is presently marketed in France by Les Laboratoires Service and In the United Kingdom by their subsidiary, Seiphanu Laboratories, Ltd. In the United Kingdom it has received outstanding acceptance due to its lack of stimulating effect Ca the central nervous system. As in the United States, the liritish health authorities have been concerned about the stimulatory effect of amphetamines on the central nervous system and their mnsequent potential for abuse. This has resulted in the removal of all antl'obesity agents except fenfiuramine from the list of drugs considered acceptable with re- spect to both safety and effectiveness for use under the National Health Service by the Standing Joint Committee on the Classification of Proprietary Preparn- tions (Macgregor Committee.) Studies In the United States under the auspices of the A. H. Robins Company have confirmed the lack of stimulatory effect on the central nervous system and have demonstrated the effectiveness of this drug as an appetite suppressant. All available European data and the results of animal safety studies con- ducted in the United States were submitted to the Food and Drug AdmilL- istration with our Notice of Claimed Investigational Exemption for a New Drug in April 1964. The drug was then studied as an appetite suppressant In hospitals, clinics, and private practices throughout the country. As the reports from the physician investigators were received by our Medical Department, the data were tabulated and the effect of the drug on the weight of patients par- ticipating in weight reduction programs was analyzed by our medical and sta- tistical departments. These analyses and the results of all studies in laboratory animals and human patients were submitted to the Frod and Drug Administra- tion in our New Drug Application dated March 3, 1967. This application con- tained data on 1,548 patients, over a thousaad of whom received fenfinramiac. The remainder received inert placehos or other available appetite suppressants In order that comparisons rni,ght be made with fenfiuramine with respect to both effectiveness and safety. !Ihe following is. a chronology of the actions that have taken place since the submission of the New Drug Application: March 8, 1967: FDA acknowledged receipt of NDA for fenfiuramine. August 31, 1967: FDA notified us that the application was incomplete in that it failed to contain adequate information concerning the synthesis, extraction, and purification of the new drug substance to determine its identity, strength, quality and purity. No additional animal or clinical data were requested. September 20, 1967: RepresentatIves of the A. H. Robins Company met with a chemist and medical officer of the FDA to discuss the chemical Information requested in the FDA's letter of August 31, 1967 and the proposed labeling for the drug. December 15, 1967: Information about the chemistry of fenfluramine and a revised package insert (labeling) were submitted to the FDA. March 1,1968: FDA chemist contacted to determine status of review, Between this date and June 7, 1968 numerous contacts with the Bureau of Medicine were made in an attempt to determine the reason for the continuing lack of response to our submission. Only vague excuses were offered. June 7, 1968: Received phone call from Dr. Robert Hodges, Director. Office of New Drugs, who informed us that it had now been decided with Dr. Ley's concurrence that the application could not be approved until additional clinical data were submitted. This decision was prompted at least pnrtally because most other drugs of this therapeutic class were then being reviewed for effectiveness by the NAS-NRC panels and reports had not then (and still have not) been un- plemented by FDA. It was felt by the FDA, therefore, that the application for fenfiuramine should uudergo an especially intensive review. This review resulted PAGENO="0908" 15340 COMPETITWE PROBLEMS IN TIlE DRUG INDUSTRY in questions being raised concerning the statistical significance of data submitted. (Additional statistical analyses of our data subsequently convinced us of their significance hut was not agreed to by the FDA.) June 11, 1908: On the invitation of the FDA, representatives of the Company met with the FDA to discuss the design of future controlled clinical studies of fenfiuramine vs. placebo to support the effectiveness of this drug. FDA repre sentatives clearly indicated that these studies were absolutely necessary in order to gain NDA approval. (Planning and implemeatation of these studies was begun immediately. Completion and final analysis of the data would require 17 months.) June 20, 1968: FDA officially notified the Company by letter that the applica- tion was not approvable under Section 5(fl(b) (1) of the act on the basis that the controlled clinical studies revealed deficiencies of the study designs that prevented conclusions concerning the effectiveness of the drug as an appetite sup- pressant. FDA closed the tile. September 10, 1908: Representatives of the Company and FDA had a con- ference to discuss the statistical analysis of the clinical data. At this meeting It was agreed that an amended NDA would he submitted with additional statis- tical treatment of the date in the original NDA and 700 to 800 additional case histories from studies flint were still in progress when the NDA was filed. November 4. 1968: A fourteen volume amendment to the NDA containing over 796 additional case histories was submitted to the FDA. These data in- cluded reports on eight controlled studies winch were conducted In accordance with presently accepted requirements for satisfactory study design. A revised package insert and a re-analysis of previously submitted data were also included in the NDA amendment. May 15, 1969: Representatives of the Company met with representatives of the FDA to discnss the status of the NDA. At that meeting the reviewing officer (Dr. Knox) publicly commented that he did not feel that appetite suppressants of aay kind were effective. This obvious bias on the ~nrt of the reviewing medical officer led to additional discussions with higher officials in the FDA. June 18, 1969: Since the allotted 180 days allowed for review of New Drug Applications or resubmissions had been exhausted nnd the NDA had been assigned to a different (and hopefully less biased) niedical officer who did not have suf- ficient time to review the application, the Company withdrew the applIcation and resubmitted it on the same day. A report on a small clinical study was sub- mitted at that time. In addition to obtaining a less biased review this administrative maneuver had the advantage of keeping the `application open and under active review. The alternative would have been receipt of a nonapprovable letter and closing of the application. In that event, the large volume of data submitted on November 4. 1968 would have remained unreviewed until another substantial submission could have been made. November 25, 1969: The Company submitted an amendment to the application for fenfiuramine tablets containing results of a research project by eight different investigators, all of whom evaluated the appetite suppressant effect of the drug according to the same study plan (so-called "block study"). These data and the accompanying statistical analysis confirmed the previous findings that fen- fiuramine is an effective appetite suppressant and aided patients in weight con- trol programs. December 11, 1969: At the request of a chemist at the FDA the Company sub. mitted revised bottle labels for use in tIme event that expiration dating of drug products becomes a requirement prior to the approval of the application. These proposed labels were accompanied by additional stability data on fenfiuramine capsules and tablets to support the recommended dating period. It was noted that expiration dating was not a requirement and a disclaimer was included in the Companys letter that this was not a commitment on our part to show expiration dates on the labels of this product unless or until the regulations are revised to require such expiration dating. January 10, 1970; FDA contacted to determine status of NDA. Only the non- committal statement that "time medical officer w-as having discussions with the statisticians" could lie obtained. We later learned, however, thot the FDA did not as a result of the submission of November 2~5, 1969. begin another 180-day review period. From this it. wos concluded that the FDA was desirous of com- pleting the review at an early date. January 21, 1970: We received a computer print-out from the FDA notifying us that this NDA has been in process 197 days (17 days overdue). No Indication of proposed action by the FDA accompanied the print-out. PAGENO="0909" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15341 March 23, 1970: Representatives of the Company met with Drs. Gibson, D'Aguanno and Moser of the FDA to discuss the format and presentation of In- formation in the package insert. Additional matters concerning the pharmacology were discussed by phone on March 24. March 25, 1970: The Company submitted revised draft labeling containing all the information and changes agreed upon in the conferences with FDA. A new tradena me, Pondimi ii. was used throughout the labeling. April 27, 1970: Dr. Moser of the FDA called Dr. Dent to request minor changes in the ial:elir]g submitted on March 25. The next day Dr. 3loser was notified by phone that the Company agreed to make the requested labeling changes. May 20, 1970: Dr. Moser called Dr. Dent to inquire about the prevalence of depression among patients taking fenfiuramine. lie reported that Dr. Stanley Yolles, then Director of the~Nati~nal Institute of Mental Health (one of the Nil!), had written an unsolicited letter to the Commissioner of Food and Drugs in which be reported that large numbers of patients In the UK had developed depression while taking feuflurn mine. June 9,1970: In response to Dr. Yoltes' charge concerning depression, the Com- pany submitted a computer print-out of adverse reactions that had been reported to the Dunlop Committee in the UK (The Committee on the Safety of Drugs). This print-out was submitted to the FDA in trip hate and a fourth copy was delivered directly to Dr. ~~()~er. .~ccording to tire Dunlop Committee only 13 cases of depression had been reported from January 1964 through April 1970. We later learned that the Dunlop Committee had also sent `a copy of the print-out directly to the Commissioner. Dr. Thiles, meanwhile, had been relieved of his position at the National Institute of Mental health. June 24, 1970: Mr. Habenicht learned that the NDA for Pondimin had been assigned to Dr. Dorothy Dobbs on june 23 for further review and that Pr, Dobbs hag estimated a review (Il~ six weeks. Dr. Dobbs is the Director of the FDA's Di- vision of Neuropsyehiatrie Drugs in the Office of New Drugs. (Now the Office of Scientific Evaluation). july 6, 1970: The NDA is now in process 383 days since tire (`lock started run- ning after v-c withdrew the application and re-submitted on June 18, 1969 (see page 6). MEMORANDUM FOOD AND Dara ADMINIsTRATION, Aug. 6, 1070. To: Dorothy S. Dobbs, ND., Director, DD 120 From: Martha ~L Freeman. M.D., Division of Neriropharmacological Drug Prod- nets, ED 120 Requested evaluation of C double blind placebo efficacy studies for Foadimine table 20 mg-fenfiuramine hydrochloride. 1- J?cginsky #2050-13~ompared fenlluramine 20, 30, 40 mg bid. (capsule formulation) vs. placebo in 83 patients on 1000 cal- diet x 12 weeks. Since capsules rather than tablets were used, tire data are not ajrplie-al,le to establish efficacy for the table formulation proposed for marketing. Additionally, deficiencies In study design (lack of detail regarding methods used) preclude scientific evaluation of possible drug effects. 2--C These 5 investigations were conducted under Master Protocol #25. Four additional studies in this "block" were previously judged by another reviewer to ire inadequate to establish efficacy, and have not been included in this review'. The protocol provided for 32 subjects per study subdivided into 4 treatment "ce1ls" of S subjects each ("high" and "low" drug-40--60 mg t.i.d. and 20 mg t.l.d.; and "high" and "low" placeebo). Further subdivision within each "cell" specified 2 male antI 2 female subjects per "high" and "low" overweight category (30-75 lbs., and 15-30 lbs., respec- tively)-thereby providing for IC sub-groups in each 32 patient study. Preeau- tions to limit non-drug variables included such measures as weight determina- tions at the same `time of day, on the same scale, by the same observer, and similar amount of clothing at each weighing. Dietary restrictions were purposely omitted in order to demonstrate appetite suppression of sufficient magnitude to result in weight loss from voluntary reduc- tion in calorie intake. PAGENO="0910" 15342 COMPETITIVE PROBLEMS IN ~E DRUG INDUSTRY CBITERIA USED ~DR EVALUATION OF DATA Results of only the first C weeks of the 12 week study were included because of the high drop-out rate In the second 6 weeks and because of the proposed labeling limit for "short term usage". Comparison has been limited simply to drug vs. placebo effects because of the small numbers of subjects in the various subgroups according to dosage levels and patient categories. Only losses of more than 10 lbs. after 6 weeks of treatment have been consid- ered arbitrarily as evidence of possible clinically significant drug effect, since non-drug factors may easily account for ± 5 lbs. "Drop-outs" as tabulated included all patients who failed to have a 6 week weight recorded and one who failed to have a baseline weight. Investigator qualifications have not been reviewed, except to note that 1 (Gram- melt) is a Professor of Medicine, 1 (Gatteroau) lists an Obesity Clinic in a specialty hospital, and 2 (Stem and Esposito) gave street addresses. PAGENO="0911" 0 r P1 03 z 0 JEl subjects initially. - a ~3 subjects initially. * 12 lost II-143-~lb; I lost 31 lb. 0 8 Drug' Placebo2 Range 10 lb. (pounds) Comments Dropout 6 weeks Ru Lost Range loss 10 lb (pounds) Dropout 6 weeks Ru Lost 2-Gremmel No.2537: High 3 Low 2 7 6 3 1 3 3 8 7 0 11-39 dropouts: Relatively few lapses in therapy or intercurrent 0 ilinessee report. 0 0 4-33 dropouts: Irregular treatment administration during holidays 0 and intercurrent flu. 0 0 5-It dropouts: High incidence of intercurrent illness. Frequent 0 lapses of treatment administration. Protocol deviation indicated by investigator on 4 case records. 0 0 12-29 dropouts: Only 17 patients eraluated. Many subjects had 0 jntercurrentillnese. 0 1 8-32 dropouts: This investigator is credited with 2 studies con- I ducted simultaneously. However Ho. 2544 cannot be evaluated due toitlegible records, irregular monitoring, confused identity 2 12, IS of which treatment patment received. Ho. 2545 demonstrated greatest efficacy reported for both drug end placebo. 2 12,18 blat 5 13 4 11-I33~ 6 15 3--Esposito No. 2539: High 3 Low 0 6 8 0 1 I 0 7 8 Total 3 14 1 11 0 15 4-Steri No. 2540: High 1 Low 1 7 7 0 1 1 2 8 4 Totat 2 14 I 14~4 3 12 5-Gottereau No. 2543: High 2 Low 2 6 4 I 0 3 5 2 5 Total 4 10 1 31 I 7 6-Noble No.2: No. 2545: High 1 Low 3 7 5 4 2 2 2 6 6 Total 4 12 6 11-13 4 12 ~- Grand total IS 63 13 (5) 22 61 PAGENO="0912" 15344 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY SUMMARY AND EVALUATION Although more drug-treated than placebo subjects lost weight In each of 5 studies, the significance of the drug-placebo differences cannot be evaluated due to 1. Drop-out rates of 3-40% which eliminated entirely some (if the proposed subgroups. 2. Protocol deviations e.g. too few subjects varying acceptance criteria re- garding amount of overweight, irregular treatment administration variation in return appointment intervals, etc. 3. A high incidence of non-treatment-related weight changes due to intercurrent lllaes~ (Asian flu epidemic) and dietary excesses during the year-eml holiday season. 4. Lack of information regarding comparability of population groups for each study (e.g., private patients vs. clinic). Such inter-study variations preclude reliable conclusions being drawn from pooled data. Further, such `pooling" would fail to reflect results of 4 additional studies which were conducted under Master Protocol No. 25 and which were previously judged not to establish superiority of fenfluramine to placebo. However in order to evaluate roughly the trend favoring drug over placebo In this heterogeneous group of obese subjects we note the combined results from these 5 studies as follows: Studies were Initiated In 81 drug and 83 placebo subjects. Sifly-three drug treated subjects hod 6-week weight determInations. 39/63 (62%) lost more than 5 lbs.; 13/03 (20%) lost more than 10 his. Sia'ty-ouc placebo-treated sub jects had 6-week weight determInations. 14/01 (23%) lost n'ore than 5 lbs. 2/61 (3%) lost more than 10 lbs. Rouge at weight losses Fenfiuramine: 12 patients lost 11-14'/~ his. One patient lost 31 lbs. Placebo: 2 patients lost 12 and 18 his. Although comparative efficacy evaluation favors drug over placebo (20%/3%) the therapeutic merit is questionable for a drug, for which only 1 in 5 subjects is likely to benefit from the recommended course of treatment. "For `proof of efficacy', it is necessary to establish the proportion of patients who can be expected to receive optimal benefit If a new d rug Is intended to provide a cure for a heretofore fatal disease, variability and a rather high rate of failure will be condoned. However, if it is for relief of a symptom such as pain~for which we have a number of analgesica-then its efficacy must lie great. Relief must occur in nearly all patients with pain of similar origin and like severity." (K. C. Kohlstnedt, M.D., Proof of Efficacy-Industry's Point of View, In Pharmacologic Techniques in Drug Evaluation, Vol. 2, ~Iage 18)-Nedine and Sicgler, Ed. 1067. CONCLUsIoNs The results of the 6 studies reviewed fire inadequate individually and col- lectively to establish anorevigenic efficacy for fenfiurarnlne under the conditions of recommended clinical usage. Since fenfiuramine Is to be indicated as adjunctive therapy In the management of obesity, the eurreut study design which specifically excluded dietary restric- tions, may be inherently inadequate to establish efficacy under conditions of recommended clinical usage. "Full disclosure" labelling information for drugs In this category should In- chide the proportion of subjects likely to benefit, as well as the range and rate of weight loss which may be anticipated as a result of the recommended course of treatment, in order to enable a physician to evaluate the potential therapeutic benefit for a particular patient. Finally, this review of circumscribed case data from 6 efficacy studies In no way constitutes an adequate over-all evaluation of the safety and efficacy of fenfluramine for marketing, as required by the Regulations. PAGENO="0913" COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 15345 MEMORANDUM Foon AND DRUG ADMINI5TItATTON, October 8, 1970. To: All medical officers, Bureau of Drugs. From: Marvin Siefe, MI)., Acting Director, Office of Scientific Evaluation, Bureau of Drugs. Subject: "Disqualified" clinical investigators. 1. This updates Dr. Simmons' memo of May 20, 1970 on the same subject. 2. The following physicians are not eligible to receive investigational use drugs. Studies should rn-it lie performed *by these physicians after their date of disqualiticatiin and if such studies are observed in support of IND's NDA's, Form 5's or supplements they should be brought to the attention of the office director and follow-up initiated. In the absence of evidence validating their work', data from these individuals, regardless of date cannot be considered reliable to support safety or efficacy claims in INI)'s, NDA's, supplements, or Form S's. NAME OF INvEsTIGAToR AND DATE OF DISQUALIFICATION `William Abruzzi, M.D., Wappingers Falls, N.Y., August 31, 1906. Sheldon Bender, M.D., Pinladelphia. Pa., February 17, 1909. Leo Cass, Ml)., Cambridge, Mass., December 15, 1905. DUF Research, Inc., New York, N.Y., October 18, 1966. Edwin Dunlop. M.D., Attleboro, Mass.. February 10, 1970. Anthony Lapolla, M.l)., Camarillo, Culif., May 5,1969. Leo Loewe. Brooklyn, N.Y., October 18, 1960. Kathleen Roberts. M.D.. Owego, N.Y., November 24, 196t Bennett It(bin, M.D., Silver spring, ~Id.,,Tune 19, 1964. Wallace Rubin, Ml)., New Orleans, La., March 13, 1970. harry Shubin, MI)., Philadelphia, Pa., March 16, 1970. Joseph 3. Sobotka, M.D., Phoenix, Ariz., September 21, 1970. Samuel Splitter, M.D., ilempstead, N.Y., Jnly 29, 1068. 3. The four physicians listed below have at one time been ineligible to receive Investigational-use drugs bu!t have been reinstated as eligible. Work performed subsequent fo reinstatelnent is acceptable for evaluation. Work performed prior to reinstatement, in absence of validating evidence, cannot ho considered in support of safety or efficacy claims in TND's, NIIA's, supplements, or Form S's. NAME OF TNVE5flGATOR AND PATE OF REINSTATEMENT Cburles Caner, M.D., Orlando, FIn., July 29., 1969. Ilerbeft Copelan, M.D., rinladelphia, Pa.. August 19, 1906. Albert Kligman, M.D.. Philadelphia, Pa,, August 19,1906. Gordon Mcllardy, M.D., New Orleans, La., January 27, 1909. 4. Investigations of the work of clinical investigators are conducted and coor- dinated by the Scientific Investigations Group of the Office of Scientific Evalun' tion. It is requested that all suspicions concerning validity of a physician's work with Investigational drugs be communicated informally to SIG (BD-10S, Room 14B-31, Ext. 31727). fl. Regulations relative to the disqualification" of Investigators may be found in Section 130.3(e) of the New Drug Regulations as found in Title 21 CFR (page 11 in the January 1, 1970. Revision). 0. Disqualification of investigators is one of the most serious actions that we take. For thIs rensoli, we make every effort, as provided in our regulations, to give an investigator an opportunity to explain deficiencies that we encounter In his studies. In addition, an action to disqualify is only disseminated to other sponsors or iu~ilicants who have previously used the services of the investigator and to interested government agencies. When and If a criminal action is filed against an investigator for submitting faLse data, it then becomes public information. PAGENO="0914" 15346 COMPETITIVE VROBLEMS IN THE DEUG LNDTJSTEY BUREAU OF DRUGS, RESEARCH Co~tMInEE FORTY-SEVENTH MEETING, OCTOBER 29, 1970 AT 10:00 A.M., CONFERENCE BOOM C, PARELAWN BUILDING Present: Dr. John T. Litdhhleid, Jr., Chairman Dr. William W. Wright Dr. Charles Anello Mr. Theodore flyers Dr. Marvin Siefe Mr. Richard Terselic Dr. Robert A. Littleford Dr. C. II. Maxwell, Secretary Dr. Edward Kravitz Dr. Edwin Ortiz Dr. Jule K. Lamar Dr. Arthur Ruskia Absent: Dr. John Palmer, Miss Zelda Schiffman. Guests: Dr. Knox, Dr. Milliken, Dr. Johnson, and Dr. Dully. PROCEEDiNGS The meeting was called to order at 10:05 n.m. by Dr. Litchfield, Chairman who presided. lie called attention to the slowness with which some of the material for the Research Committee had been submitted and stated that the material must be in the office of the Division of Extramural and Clinical Research ten (lays prior to the meeting of the Research Committee. The order of the material to be reviewed was' diseussed and the preseat order first, correspondence, commit- tee reviews second, and the protocol third was continued. Seven projects were considered. For all of them the essential material or the complete protocol had been circulated prior to the meeting. The follow-lag were considered: 1. Blood types in. thromboe,nbolie diseases, Stnllcy and Scrt well, Johns Hopkins University This was deferred for a statistical review. 2. Effects of oral contraceptives on cervical cytology, Dr. Spector, Temple University There were considerable discussion as to whether studies of this type should be sponsored by the FDA. Mr. Terselic thought they should not as demograpitic material was not FDA responsibility and projeets of tills nature should be linder tl:e auspices of the NIH. Dr. Litcitfield agreed with this, By a unanimous vote it was recommended that the FDA support tile cytological studies, hut not the demographic part of the study as proposed by Dr. Spector. The priority was 222 for the cytology study. 3. Action of self onylureas in animals and Iman, Foe, Wayne State University The feeling was that support for this type of proposal should come from sources other than the FDA. Preferably, the funds should come from the Drug companies, hilt It `vas not considered the responsibility of the FDA to support such work. The project was rejected by unanimous vote. 4. Anorectie drng8 in obesity control, Knor, FDA Dr. Knox gave a very detailed account of the difficulties in evaluating the efficacy of anorectic drugs. Tolerance develops quickly so that they are used for only a short time. The drug companies will make short-term studies, but will not make long-term studies. The FDA needs the information which could he obtained from long-term studies for guidelines for use of these drugs. The proposal as presented by Dr. Knox did not hnve a cost estimate, except on very general terms. By vote of 5 to 3, the Committee disapproved the proposal as presented, hut suggested that a well developed detailed proposal with realistic cost estimates would receive very sympathetic consideration. PAGENO="0915" COMPETITIVE PROBLEMS ~N THE DRUG INDUSTRY 15347 The Research Committee directed that the problem of obesity control be brought to the Bureau Director for serious consideration and direction as to the steps which should he taken by the Bureau of Drugs. 5. Arterial demage from protein derived parenteral drugs, Murtin, FDA Dr. Martin of the FDA presented Dr. Minick's proposal from Cornell. By a vote of 5 to 4 this proposal was disapproved, but the suggestion was made that with certain changes In the protocol it might receive Committee approval. Dr. Martin promised to canvass the Committee for suggestions and have the proposal resubmitted. 6. Screening of protein derived drugs for antigenicity, Martin, FDA. This was approved unanimously for funding with a priority of 288. 7. The effects of long-term esposure of people wiw are not iran-deficient to s diet containing several times the usual amount of iron, Dr. Crosby, Tufts University This Is exactly the same proposal as submitted and considered in the early part of this year. Again it was turned down by the Research Committee by unanimous vote. November 5th and December 10th were the dates set for the next meeting of the Research Committee. It was suggested by one or more members of a commit- tee that when an individual has a proposal before the Research Committee that lie absent himself when the vote is taken. This was agreed to by the Committee. The Committee adjourned at 11:55 a.m. C. II. MAXwELL, M.D., Secretary. DErnrMENT OF HEALTH, EDUCATION AND WELFARE, FooD AND Dnuo ADMINISTRATION, - Roekvif Fe, Md., Aug. 31,1971. Re: NDA 16-618 GENTLEMEN: Enclosed in triplicate is a revised and updated New Drug Appli- cation for Pondimin (fenfluramine hydrochloride) tablets, 20 mg. The original New Drug Application for this article was submitted on March 3, 1967. The questions in your communication dated August 31, 1967 concerning the chemistry and control portions of the application were answered In our communicntlon dated December 15, 1967. In June 1968 the application was de- clared inadequate due to questions concerning the clinical data, and the file was closed. Subsequently, in November 1968 fourteen additional volumes of sum- maries, data and other information were submitted in support of the effectiveness of this article. On June 17, 1969 we requested that the New Drug Application for this article be withdrawn without prejudice and resubmitted as of that date. Accompanying our submission were a summary evaluation and patient data from clinical study number 1426. On November 25, 1969 we submitted clinical data and an analysis of data from a ivell controlled study by eight different Investigators (Protocol #25) all of whom evaluated the appetite suppressant effect of fenfiuramine hydrochloride according to the same study plan. Included also were other newly available study reports, copies of published papers, manuscripts and translations. The present submission, comprising 66 volumes, is an overall summarization of all available data on fenfiuramine hydrochloride. This includes a resubniisslon of all data and Information contained in previous submissions and all new data available to us since the submission dated November 25, 1969 through an April 1, 1971, "cutoff" date. The new clinical data consists principally of Protocol #30, a well controlled multiclinie study in 307 patients in which fenfiuramine hydro- chloride was compared with placebo on a double blind basis (Volume 4.13 page 6). In addition, the data from a previously-submitted, well controlled multiclinic trial (Protocol #25) have been re-audited to reduce extranecus variables and re-analyzed to eliminate the objections raised by your agency in your letter dated September 11, 1970, and in the subsequent conference concerning this communi- cation on September 30, 1970. PAGENO="0916" 15348 COMPEnTrVE PROBLEMS JIM THE DRUG INDUSTRY A table of contents of the entire submission will be found In volume 4.1 begin- lung on p ige 10. In addition, each imi ividuat volume contains a table of contents to facilitate your review of this Application. W'e trust that this new submission on (enfiuramine \v ill he found to contain data sufficient to permit approval of this New Drug Application by the Food and Drug Administration. We will appreciate being notified as promptly as feasible with respect to any questions concerning the Application. Sincerely, F. A. CLARK, Jr., M.D. DEPARTMENT OF hEALTh, EDUCATION, AND WELFARE, PUBLIC IIEALTIL SERVICE, Foon AND DRUG ADMINISTRATION, Rockuille, 3!d.,3!erch 7, 1,975. Dr. ALEXANDER 31. SchMIDT. Commissioner of the Food end Drug Administration, Poo,i, 14-Si, Parkiawn Building, Rockvifle, 3rd. DEAR DR. SCHMIDT: In compliance with your letter of March 3, 1075, and in accordance with Mr. Allen T. Eaton's February 15, 11P75, letter to you, I am enclosing additional material relevant to the issues raised at the Senate Sub- committee on Administrative Practice and Procedure hearing on August 15, 1074. Sincerely yours, RDnERT 0. K,~ox, M.D., Medical Officer, Division of Oncology end Railioph qrniaceutieals. DOCUMENTATION IN StrronT OF TF.5TIMONY GIVEN BY ROEERT 0. Kcox, M.D. 1. INTRODUCTION I jointed the FDA in August 1963 asa Medical Officer (MO) and was assigned to the review of New Drug Applications (NDAs) for a variety of drugs including "anorexiants." Many of the clinical investigations were of dubious quality and contained questionable laboratory data (I) and sponsors' summaries and analyses were often unreliable (1). Substantial evidence of efficacy was lackIng in the NDAs submitted for "an- orexiants," but since many of tIuc large firms already had their amphetamines on the market, failure to approve new NDA probably had little effect on the scale of manufacture and distribution. (~) In 1058, "The Amphetamiiies-Tlieir Actions and Uses," by Chauncey Leake, Ph.D., advanced the claim that amphetamines were lioth extremely useful in medical practice and free of toxic effects and other untoward consequences such as addiction. Between 1963 and 1973 the only anoretic approved by the FDA was Pre-Sate, NDA. il-COG; it had been assigned to another MO and \vns approved on April 20, 1965. A. brief inspection of the Medical Officer Review (MOlt) indicated that specific efficacy results by each investigator Were not treated separately but, rather, general statements were relied upon-possibly quoted from the sponsor's summary. The average amount of weight loss demonstrated wns less than 5 lbs. In 1966. "The Amphetamines" by Oriaaa Kalant. Ph.D., expressed a very dif- ferent view on the amphetamines and questioned Dr. Leake's claims. (3) A great amount of activity has been manifested by the drug manufacturers In producing amphetamine congeners which have been claimed to have fewer undesirable adverse reactions than the amphetamines, hut with the passage of time evidence has mounted indicating that the amphetamine derivatives share most of the disadvantages at tIme parent compound. In spite of repeated urgIngs (4) over a period of several years that an FDA pa1 icy he established relative to time a mpheta mines, the Bu3ted di il not formulate any policy. Of concern was the doubtful efficacy of these drugs, the potential for al,use, and failure of the package Inserts to present a true picture of the poor efficacy usually achieved. `Numbers In parentheses refer to the Items In the attached Appendix. PAGENO="0917" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15349 When the BuMed was reorganized in 1960, the anorexiants were assigned to the Division of Neurophariiiacologic Drug Products (DND1') and I was transferred at my request to that. l)ivissiiii iii oruer to continue woridug on the same types of NDAs, e.g., anorexiants. 2. ABBREVL&TED RESUME OF NDA 16-618. (FOE FULLER CHRONOLOGY, SEE SECTION 8) March 3, 1967.-NDA lu-UlS, I'oaderex (Po,idinain, fenfluramine) received by FDA. June 20, ISGS.-BuMed issues an "inadequate" (not approvable) letter. Vovcni bet 4, 196a.-14 lilore volumes added to NDA. May 6, 1969.-My Medical Officer Review (MOlt) recommends nonapproval. May11, 19(19.-Sponsor accuses nie Of bias. .Scpton her 9, 1969-I drarted a lIon-approval letter to be sent to the sponsor. This rough draft listed a 1111111 her o~ serious discrepancies. October 2, 1969.-NDA 16-618 was removed from my office without prior notifi- cation or explanation and ri assigned to a third Medical Officer MO October 23, 19(19.-The third MO concludes that the NDA was not approvable. ~~orcniber 25, 1969-9 nlore volumes were submitted containing 9 additional studies. December 29, 1969.-The third MO Concludes in his second 31011 that the data is adequate to support an appetite suppressant claim, He made 110 mention of the amount of weight lost. When I, belatedly, obtained a copy of the December 20, 1969, MOB, I advised tile Division Director, and then the Bureau Director, of my concern regarding the lack of quantitative data ia this MOB. The "approvable" letter svhlch had been drafted for signature by tile Bureau Director (lid not issue. May 2!, 1970.-I found In the Division files a revised MOB, also dated Decem- ber 29, 1969, which had Ileell altered to include a sentence to tile effcct that ii weight loss of 5 his. `vas considered satisfactory evidence of effectiveness. June 24, 11170.-The Director of DNDP is replaced by a second Director who reassigned the NI)A to a fourth, MI). August 6, 1970-MOR concludes that the November 25, 1969 studies are inade- quate Individually and collectively to establish a aorexlgenic efficacy. September 11, 1970.-Alt "Inadequate" letter Issued by BuDrugs. April 6, 1971.-An Advisory Panel took the position that a statistically signifi- cant difference between Placebo and dnig was all that was necessary to justify approval of an anorexiant. I objected to this. Augu.Qt 31, 1971-6? more volumes added to NDA. September .13-14, 1971.-Tile Second Advisory Panel altered its previous posi- tion re statistical sign i (lea lIce. IVOVeIn herS, 1971.-I \s-as transferred on less than 24-hr. notice from the DNDP to tile Division of Oncology a lid Itudi oplia rniaceuticais (DOll) About this time, the BuDriigs arranged for a computer analysis of 206 studies, all of ~vhiich bad been conducted on behalf of various dn,g firms over a period of 12 years. to be carried out by the Statisticnl Division. "The Statisticians advised an interpretation of data. but (lid not make clinical recommendations." After considering this statistical analysis the Panel concluded. iii 1972, that the amount of weight loss induced by anorexiants was `clinically trivial." In spite of this, the Bul.)rugs, in 1973, issued approval letters for several anorexiants. The pack- age insert did not contain any tabulation of the amount of weight loss achieved, but merely stated that weight loss was "clinically limited." 3. EXPANOEn CHRONOLOGY OF XDA 16-618 (Volume LI) March 3, 1967.-A. H. Robins submits NDA 16-618, consisting of 22 volumes, for fcnfluranline. which was claimed to have a mark-ed advantage over ampheta- mine in that it was non-stimulating anti therefore unlikely to cause abuse. The NDA is assigned for review to a Public Health Intern (a)'in DNDP. July 28, 1967.-I write a memo to the Division Director, DNDP (5) recom- mending revision of the package insert for "anorexigenlcs." August 29, 1967.-MOB, written by a PITS Intern, states: ". - . the claim that drug is an anorexic indicated an adjuactive therapy would appear to be sup- ported." (6) `Letters In parentheses refer to names of persons referred to in the text. See Key In Section a. PAGENO="0918" 15350 CO~'vDET1TIVE PROBLEMS IN THE DRUG INDUSTRY August 31, 1967.-"Incomplete" letter Issues. No mention of clinical deficieri- des. (7) March 4, 1968.-I voice the opinion in a Division meeting that substantial evi- dence of efficacy was lackiag for NDA 16-618; following this, the NDA was reassigned to me. (Volume 2.1) June 7, 1968.-The Director of Office of New Drugs phoned A. II. Robins and told them that"... Because of a more critical approach to the evaluation of nnorexigenic agents we had again reviewed the clinical data available to support the efficacy of this produèt. They had been subjected to statistical review' and it was our conclusion that only one study, . . . supported the efficacy of this drug compared with a placebo. It was, therefore, felt that we could not recommend approval (8) June 20, 1968.-An "Inadequate" letter Issues along the above lines. (9) August 9, 1968.-Tbe statistician wrote a 13-page memo pointing out numerous inadequacies in the data and its analysis. (10) Septem her 11, 1968.-In a conference with the sponsor I recommended that the package insert should contain a tabulation of the amounts of weight lost by the patients studIed. (11) (Volume 3.1) November 4, 1968.-14 more volumes submitted.' April 25, 1969.-The statistician's analysis of S controlled studies, submitted 11-4-68, states: `. . . at best, these studies are suggestive of a drug advantage over placebo." (13) May 6, 1969.-My MOlt of the November 4, 1968 submission recommends non- approval on the grounds that substant'al evidence of efficacy Is still lacking. (14) May 15,1969.-Sponsor accuses Dr. Knox of bias. (15; page 5) May 19, 19ti9.-My meulo to Director (b) of DNDP re FDA policy on ampheta- mines Includes a recommendation that the package insert and advertising con- tain tabulations of tile actual total pounds of weight lost and the duration of therapy. (4) June 17, 1969.-Sponsor requests that NDA be "withdrawn and resubmitted"- In order to avoid a non-approvable letter. (16) September 9, 1969.-I submit a proposed `medical section" of letter (17) to sponsor which detailed many serious deficiencies In the NDA. October 2, 1969.-I discover that all the volumes of NDA 16-018 have been re- moved from my office without any prior notification or discussion with me. Upon enquiring as to their whereabouts, I am told by the Division Director (b) that lie had hud to reassign the NDA to another (the third) Reviewing MO because the sponsor had accused me of bias. I dispute the charge and point out that there Is a danger in this type of reassignment, since it might place improper control of the review process in the hands of th3 sponsor. Nevertheless, the third 310 (c) continues to review this NDA. October 23 ,1969.-The third MO concludes in his MOlt that the NDA was not approvable because 6 of the 7 controlled studies did not support the efficacy of fenfiuramire. (IS) November 18, 1969.-My memo to the Acting Director (d), BuMed, includes a recommendation that the labeling for anorexigenics contain a factual statement as to the actual amount of weight loss achieved in the studies submitted In sup- port of any given NBA. (4) (Volume 4.1) November 25, 1969.-fl more volumes submitted containing 9 additIonal studies (all following Protocal #25) by 8 different investigators. December 29, 1969.-The third MO reviews the 11-25-69 submission and states that the data Is now adequate to support an appetite suppressant claim provided the protocol is accepted by the Division of Statistics. (19) Sj have been unable to find a written record of this review. `A common practice of drug firms has been to respond to a disapproval letter with a deluge of additional volumes, which raises a question as to whether this is one of several forms of harassment. (12) The argument that the voluminous amendments were merely an sttempt to provide more and hetter information must be examined in light of the nature of the material submitted and the circumstances surrounding each ease. `These recommendations were never incorporated into a letter to the sponsor; instead, the ro,lrh draft was returned to me 8 months later, without comment, by the Food & Drug Officer. (17) PAGENO="0919" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15351 On learning, later, by chance, that an approvable letter was being forwarded to the Bureau Director (e) for signature, 1 asked to see the third 310's MOB.. The original version (10) of this 31011 whIch was shown to me contained no state- ment under "Review of Individual Studies" concerning the number of lbs. of weight lost. I discussed the matter with the Division Director (b) and finally sent a memos directly to the Bureau Director expressing concern about the lack of quantitative data in the MOB of December 20, 1060. There was no acknow- ledgement or reply to my memo; but the letter did not issue. February 17, 1970.-Memo from statistician (20) expresses a number of res- ervations concerning the adequacy of the data submitted on 11-25--GO. February 17, 1970.-My menlo to Acting Director (d), BuMed, re "position paper" on FDA policy on amphetamine labelIng. (4) April 8, 1970.-My memo to Acting Director, Bu3Ied, giving a proposed tabula- tion of weight loss for inclusion in a package Insert. (3) April 10, 1970.-My 0-8-6,9 rough draft of proposed "medical section" of letter is returned without comment. (17) April 21, 1970.-Deputy, Director for Scientific Activities (f) advises me that lie has taken up tile matter of the anorexiants with the Deputy Director (g), BuMed. May 17, 1970.-Deputy Director, BuMed, OK's "approvable" letter for the Bu- reau Director to sign-but the letter does not issue. May 21, 1970.-Oa checking the DNDP files, I find a second version (21) of the MOB, also dated December 20, 1061, whIch was almost identical In wording to the one first shown me except that, at the bottom of page 4, four additional lines have been added. Exnmiuation of the duplicate (red Jacket) copy reveals the fact that the last four lines were a separate addition-the letters are darker, sharper, and not exactly parallel to the preceding lines; the bottom margin of this page is much narrower than on the other pages. The last two lines on page 4 state that a weight loss of 5 lbs. or more is considered satisfactory evidence of effectiveness. June 24, 1970.-The Director of DNDI' (b) Is replaced by a second Director (h) who reassigns NDA 16-618 to a fourth MO (I) for review. July 9,1970.-Sponsor's letter (15) to FDA Commissioner (j) states, referring to me, ". . . This obvious bias on the part of tile reviewing medical officer led to additional discussions with higher officials in the FDA." The letter confirms that the Commissioner has agreed to meet with Robins' representatives In Fed- eral Office Building #8 to discuss NDA 16-615. July 22, 1970.-In respoase to a request for suggestions of worthwhile projects to be funded by FDA, I recommend that studies of weight-reducing drugs be carried out to determine their efficacy because, after several years of reviewing JNDs and NDAs I conclu~ed tlat It was necessary to have such studies per- formed free of any drug industry influence. My proposal as presented is rejected, 5 to 3, by the reviewing committee. (22) August 6, 1970.-The fourth reviewing MO concludes (23) that the studies submitted 11-25-01) are ". - . inadequate individually and collectively to estab- lish anorexigenic efficacy . - August 8, 1970.-Federal Register statement: * * * The Academy found that such drugs as a class have been shown to have a generally short-term anorectic action. * * * Since the treatment of obe- sity necessarily requires a prolonged period of time, data in support of the drug's periods exceeding a few weeks (21) It should he noted that the above statement does not say that these drugs cause long-range effectiveness In this condition must be based on studies conducted over weight loss-only that they are anorectie. September11, 1970.-A "not approvable" letter issues. (23) Sept cm ber 30, 1970.-Menlo of conference with sponsor includes: * * * It was pointed out repeatedly that criteria of cignificant weight loss should be based on a weight ions which Is of medical or cosmetic importance. (26) Nevertheless, in 1073 three anorexiants were approved despite the conclu- sion of the consultants on Anoreetic Drugs that " . . - the total impact of drug- induced weight loss over that of diet alone must be considered clinically trivial (80) December, 1970.-The second Director of DNDP is replaced by a "Consultant" (k) who acted as Director. * The Buprugs has been unable to furnish a copy of this memo. PAGENO="0920" 15352 CO~ETITIVE PROBLEMS IN TilE DRUG INDUSTRY April 6, 1971.-Panel on Anorexgenlc Drugs. The Chairman (1) takes the posi- tion that: (a) alt that was needed was a elenionstration of a statistically significant dif- ference between placebo and active drug. 1 object that this Is an inadequate method of determining efficacy because the amount of weight loss needed to dem- onstrate a statistically significant difference becomes smaller as the number of patients entered into the study Increases. (b) 12 weeks was the minjnlunl duration of therapy that would provide mean- ingfuL data. (27-A, 27-B) Apsil 19, 1971.-Supervisory MO (rn), DNDP, memo (27-D) to Deputy Direc- tor, BuDrugs, states that in his opinion 4-S weeks is entirely satisfactory for anti-obesity studies and that there Is no scientific rationale for 12-week studies. (Cf. Federal Register statement of S-S-TO above) - (Volume 5.1) A',yi~st 81, j971.-Sponsor submits GO more volumes. (12) September 13-14, 1971--Second AdvIsory Panel Meeting on Anorexigenics. (27-F) The previous position, that only a statistically significant difference Was needed to show efficacy, is relinquished! November 8, 1971-The Deputy Director for Scientific Activities phones me to tell sue to report on "detail' the following morning to the Division of Oncology and Radtopharmaceutic'als (nOR). No "~otice of Personnel Action" was received by me. On reporting to Dolt, 11-9-71, I find that office space is not immediately available for me, hence I return to DNDP and continue to work there until an office becomes available, a week or so later.5 March 12, 1972.-T~eiter from Director (k) DNDP ta sponsor advises that: In view of unusual l'uI,Iic Health prob]ems as welt as considerations re- lating to che efficacy of anorectic agents we have found it necessary to develop special criteria and procedures for the review nnd evalnation of the safety and efficacy of anorectic agents~." (20) June 12-13, 1972.-A meeting was held in Washington, D.C. to "discuss the medical and social issues of amphetamines and related compounds in managing obesity (See Section 9) June 27 c~ ,Thly 25, 1972,-Consultants on Anorectic Drugs meet "to review data just compiled by FDA staff on the safety and efficacy of aporectie drugs." One of their recommendations is that approval of "anorectic" drugs be based on demonstration of efficacy as measured by statistical superiority of the drug over placebo. (30; para. 5) Efficacy Is not defined; the duration of the trials is not specified. October 6,1072-Memo (32) from Bureau Director (e) to Commissioner recom- mends that Judgments dn the efficacy of anorectic drugs he based "on the cur- rently available substantial evidence derived from short-teriii studies January 10, 1073,-Grounds for Approvabie Letter (33), based on the "Am- phetamine-Anorectic Review Project" (AARI'), prepared by Deputy Director (u), DNDI'. Febrvary 15, 1973.-FDA issues "approvahile" letter. (34) (Volume 6.1) May 1, 107&-FDA letter requests revision of Drug Dependence section to in- clude reports of abuse (54) to 400 mg) associated with euphoria, derealization and perreptual changes. (33) June 14, 1073,-FDA issues approval letter. (30) The package i-sert does not contain any tabulations of the amount of weight loss; the wording of the Con- snltants' Statement, ". . . the total impact of drug-induced weight loss over that of diet alone must he considered clinically trivial ..," has been altered to read: ". . . clinically limited." (37) June 18, 1973-Competitor claims fenfiuramine has been suggested to cause risk of serious abuse in Scotland. S. Africa, and Jamaica. (See BNDD statement, Federal Register 38, No. 89, &-t~-73) - (38) `Minutes of this meeting are unavailable. On August 21, 1972. a "Icotideatlon of Personnel Action" dated 03-31-72 is delivered to my office notifying me that! had been transferred to nOR. (23) `This Is an attachment ("TAB C") to an undated, 21-page, memo from Acting Director (0), OSE, to Director, BuDrugs. A PAGENO="0921" - COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 15353 ADDENDUM The AARP referred to above consisted of a computerized statistical evaluation, said to have cost $50,000, which was initiated at about the time of my sudden transfer from DNDP to 1)011. According to a 21-page memo wfth attachments, from Acting Director/OSE to Director of EuDrugs (30A; 3DB), decIsions concerning anti-obesity drugs were made following a review of seven months time of the over 2(~ controlled, double- blind studies submitted to the Agency in the last 12 years by manufacturers of anoreetic. - "Tue review project made unique use of the massive files of data In FDA to obtain a computerized oven'iew of the whole therapeutic class. After Initial screening and review by sir physician-medical officers, records of 206 drug trials were found adequate for in-depth analysis...~" One of the main purposes of this AARP was to determine the efficacy of "anor- exigenic" agents; hut, included in these 200 drug trials were the following studies from ND.%. 16-880: #115, Sobotka (1); #131, Sapienza (1) ; and #135, Melvyn Wade (1). These three studies are cited as examples of data about which serIous ques- tions of validity had been raised, yet they were Included in the 1071/1972 AARP long after the discrepancies had been identified in the MOlt of 12-10-09 (40). In fact, one of these physicians, Dr. Sobotkn, had been `disqualified" by the Commissioner on 9-21-70! The Commissioner's letter to Ciba states: ". . In I.he absence of evidence validating Dr. Sobotka's work, his data, regardless of date, cannot lie considered reliable to support safety or efficacy - - The following studies from NDA ira-is were also included in the AARP despite the fact that the fourth MO to review this NDA had previously stated (23) that the studies were "inadeuuate individually and collectively to establish anorexi- genie efficacy."; #163 Gremmel; #165 EsposIto; #166 Gattereau; and #169 Noble. Of the 54 studies from NDA 16-880 which were included In the AARP, 10 studies had 5 or less patients completing the course of treatmeot and an additional 13 of the studies had only 6 to 9 patIents completing the course of treatment, i.e., in 23/54 of the studies less than 10 patIents completed the course of treatment. In NDA 1G-SSO the sponsor's summary states; "Any study in which 50% or less of the patients requested did not have ob- servations available for analysis of weight data was arbitrarily deleted from the weight analyses on the basis that the remaining data would not be a repre- sentative sample." (page 243, Vol. 1.1) Accordingly, the foliowinr studies were deleted from the sponsor's analysis: #148 Glenn; #162 Melvyn Wade; #164 Durk-in; #67 Slmkin; and #74 Grater. These five studies, were, nevertheless, included in the BuDrugs' AARP. 110w can the computerized statistical analysis provide a valid answer to the questloa of efficacy if invalid data are fed into the computer? OHSERYAflON5 ON LAB DATA sunM:rrED BY SPONSOR5 To,rnA When lab work is performed during a clinical investigation, it should he han- died as follows: 1. a well-trained technician should perform the work and know the "normal" values for any test he performs, If the values deviate from "normal" frequently or to an extreme degree he should check to see that his methodology was accurate, and preferably bring the matter to the attention of the clinical investigator. 2. the clinical investigator should review all lab data to detect any abnormal values in or,ler to protect the safety of the patient and to determine possible adverse reactions. (See CFR 130.3(a) (13), paragraph 4e; Form FD 1573). 3. "The sponsor monitors the progress of the investigations and currently evalu- ates the evidence relating to the safety and effectiveness of the drug as It is ob- tained from the investigators!' (CFR 130.3 (a) (5)), 4. the reviewing MO at the FDA should examine -the lab data to ascertain (a) whether there are abnormal values or trends which might have significance as to safety, and (-b) whether the values reported have characteristics ordinarily ex- PAGENO="0922" 15354 COMPETITIVE PROBLEMS IN `FilE DRUG INDUSTRY pected or have characteristics not ordinarily expected with respect to range, fre- quency distribution, etc. Sonic examples of invalid, spurious, or Inaccurate lab reports `o which the sponsor's summary failed to disclose adequately: 1. Dr. Melvyn Wade. NL)A 16-880, Vol. 1.49, 1967-68. Every one of the 44-pa- tients In this study had hematoecrits (Ret) below normal `1-the range was 31-36; I.e., every patient was anemic IL the licts listed are accurate. Most of the hemo- globins (Rb) listed for the same dates, however, were within normal" limits- the range was 1O.4-17.5. Jf we calculate the mean corpuscular hemoglobin concentration (MCHC) for the first three patients we get: Hb MCHC (percent) Patient No.: 17.5 52 1 2 3 46 32 15.3 15.3 42 48 Since the normal MCHC Is 34±2%, and cannot exceed this value by more than a very few percentage points in any known condition, It Is obvious that either the above Jibe or Hcts (or both) are spurious. The accuracy of the MCHC determlnation=±O.8%. In spite of the fact that the average hot in these 44 patients was almost 10 mm, or 25 percent, below normal, the sponsor's summary, Vol 1.1, p. 302, states that, except for a low WEC In patient 3, "no significant alterations were observed in any of the following parameters: CEO Judging from the diag- noses listed on the case report forms, it is unlikely that all of the patients were anemic. 2. Dr. Sobotka, NDA 16-880, Vol. 1.20, 1967. Analysis of the frequency distri- bution of Rb values reveals a rectangular pattern Inconsistent with normal biological variation. (41) Dr. Sobotka was "disqualified" Sept. 21, 1970 by the CommiSSioner. 3. Dr. Evangeista, NDA 16-880, Vol. 1.98, 1968 (Samber Research Co., Inc.). A. The cholesterol values fluctuated wildly without explanation, e.g.: Volume 1.98, page - Serum cholesterol,, repeated at 1-4 week intervals Number Number Number Number Patient No.: I 2 3 4 13 20 31 40 221 180 230 150 240 200 190 170 118 lOU 180 280 120 190 148 204 No comment or explanation concerning these values was made by either the investigator or sponsor, B. The pulse rates were recorded every 2 wks. br 26 wks.-about 300 pulse rates-and every one was listed as "80." Although Dr. Evangelista claimed in his letter of 5-5-69 that "80" was a method he used to designate a normal reading, it is noted that in another study u the actual pulse rates were listed, and that study was done about the same time as the above study. See also Samber Re- search Co. letter of 5-iD-CO. (42) 4. Dr. Diets, NDA 16-880, Vol. 1.79, 1967. The frequency distribution of flcts and Bbs and WBC are bizarre; there is an unbelievably narrow range of values for Sp. Gr. of urine, differential white blood counts, etc. 10 The fact that abnormal lab data could pass through the three levels of surveillanes listed above, before being submitted to the FDA. without eliciting any concern or comment raises sveral questions (a) Were the lab tests actually performed by a technician? (b) Did the investigator look at the lab data? Was the investigator aware of what the normal values were? (e) Did the sponsor fail to monitor the lab data received from the investigator? "Normals: Het=Male. 42-52; Female, 37-47. Hb=Male, 14-18; Female, 12-16. (win- trohe Mt Clinical Hematology, Cd 0, 1967, p. 86) n See NDA 16-421. I PAGENO="0923" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15355 In the first 20 patients: (1) out of 60 Sp. Grs. listed, 55 are "1.020"; the usual range if from 1.000 to 1.030. (2) the differential counts for neutropiñls are listed as ranging from 72 percent to 74 percent In two-thirds of all the determinations; the actual range for neutrophils is more likely to be 38 percent to 70 percent.u (95 percent confidence) (3) 92 percent of the WECs listed fall within the 5,000-7,000 range; a truer range Is 4,860-10,700 (95 percent confidence) `~ The accuracy of the WBC deter- minntion=425-600.1' The above matters were discussed with Ciba representatives on 2-9-71. Dr. Westlin stated that he had personally visited Dr. Diets' lab and could find nothing wrong and tbat Dr. Diets had told him he has turned over to his church the money he had been paid for the study-he added that they would never employ Dr. Diets again. (43) Although an Establishment Inspection was made of Dr. Diets's office on 1-13-70, no further action was taken in this case. 5. IND 466, Vol. 6, Supplement 23, TRE #130. Some examples of obviously spurious lab data found in the animal data. MCNC Net Nb (percent) I Dog No: 195 39 17.9 46 263 42 19.3 46 193 ?7 15.9 43 a Not provided by sponsor; calculated by Mo. See comments under paragraph 1 above. 6. Dr. Kahn, NDA 16-880, Vol. 1.60, 1967. Net Hb MCIIC (peicent) I Patient No.: 15 26 17.5 67 17 I? . 11.0 65 28 31 10.2 33 a Not provided by sponsor; calculated by MO. See comments under paragraph 1 above. 7. Dr. Sapienza, NDA 16-880, Vol. 1.45, 1968. No explanation Is offered for the fact that the males and females had almost the same average lily level: Average Hb Average from Number of for this literature I Sex patients study (grams) (gram) Male - IS 14.4 16±2 Female ~. 31 14.1 14±2 Wintrobe M: Clinical Hematology, edition 6, Lea & Febiger, 1967, p. 86. In additIon, 10 of the 31 females had the same Hb value, "14.2," a most im- probable occurrence. See MOlt 12-19-69. (40) 8. Dr. Maibach, NDA 16-002. A set of serum sodiums which were extremely low were passed on to the FDA without comment by either the Investigator or the sponsor. See attached MOE of 10-13-84, p.2. Since 1962, approximately 11,000 INDs and 2,000 NDAs have been submitted to the FDA. It is significant that certain clinical Investigators have been employed repeatedly by many different drug firms, e.g.: " wIntrob~, M. : Clinical Hematology, eel. 6, Lea & Febiger, 1967, p. 260. ~` Idein, p. 425. PAGENO="0924" 15356 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Number of INDs Number of tWA's for which studies for which studies Investigator were done were done Ayd I 20 20 Batternion 83 40 Berkowitz' 113 19 Carter2 52 31 Cohen,Burton' - 56 6 Collie 2 coirnore 237 58 Evangeiista 2 KIigman3 34 1 Lasagna I 20 2 sobetlia' g 2 Stough o Contributing author to Louis Lasagna's "Obesity: Causes, Consequences and Treatment," Medcorn Press, 1974. (For resume of this booli see vol. II, sec. if). gsisqualilsed by dommissioner. (See attached memo 08 Oct. 8, 1970). Included in the INDs and NDAs listed above, were many anorexiants. One of the principal means for acquiring evidence of irregularities has been scrutiny of the lab data, The fact that MOBs by a single FDA physician inciude analyses of studies by approximately % of the 16 Investigators who were disquail- fed by the Commissioner (largely on the basis of our analysis of their lab data) indicates that If more attention had been paid to the lab data In INDs and NDAs generally, throughout the BuDrugs, many more such instances might have been uncovered. A prime obstacle to detecting such data is the fact that It lies burled inside huge volumes of paperwork and thus there is a temptation to rely on the spon- sor's summary rather than to pore over the individual lab reports, scattered as they are through hvmdreds of separate volumes. (12) EXAMPES 01' INvALID SUMMARIES 1. IND 7342, Vol. Si, p. 2. Here is seen an example of an Invalid analysis of the adverse reactions results in a misleading conclusion. It is Improbable that such a glaring error Is due to lack of technical expertise-either medical or statistical. (See attachments dated 2-10-72, 2-14-72, and 3-3-72). 2. NDA 16-421. In Study No. 43 by Dr. Schmitz, the sponsor claims that the concomitant use of diuretics will not invalidate the results; whereas in Study No. 45, by Dr. Evangellsta, the sponsor makes no claims of safety or efficacy- purportedly because Dr. Evangelista added a diuretic to the regimen. (31) COMMENT: Dr. Schmitz found the drug to be effective, whereas Dr. Evangeista found the drug no better than placebo. (In addition, his study was embarrassing because all the pulse rates were recorded as `80."). (42) DEPARTMENT or HEALTH, EnUcATION, AND WELFARE, PUBLIc HEALTH SERVICE, FOOD AND DnUG ADMINISTRATION, Roe/ct 177, Md., March 13, 1975. ALEXANDER M. SCHMIDT, M.D., Commissioner, Food and Drug Administration, Roe/critic, Md. DEAlt Pg. SCHMIDT: On October 31, 1974 you requested copies of all documents identified in Dr. Robert Knox's chronology qf NDA 18-618 and Dr. John Gerda's letter of October 16, 1974. Enclosed are the documents related to NbA 113-618. The only Item we have been unable to fad is a written statement of reassignment on June 24, 1970 transferring the NDA from Dr. Moser to Dr. Dobbs. We do not know whether such a document exists. The documents described by Dr. Gerda appear to have been submitted to you previously by Dr. Margaret Clark. If any of them are niissing, I can provide duplicate copies, The documents related to fenfluramine are of some Interest In that they pro- vide two instances in which higher management reevaluated decisions favoring 2 PAGENO="0925" COZSflETITIVE PROBLEMS CT THE DBVG CTDUSTRY 15357 a drug anti reached negative conclusions. Thus, Dr. Hodges' June 7, 1968 memo Indicates that he and Dr. Ley reevaluated data in the NDA that had been considered adequate evidence of effectiveness by Dr. Zoppa and found the evidence unsatisfactory. Subsequently Dra. Knox (May 6, 1909) and Moser (October 23, 1969) revIewed data and found the N]JA not approvable. Dr. Moser eventually found the drug approvable (December 29, 1969). As noted by Dr. Knox the date of typing (February 6, 1970) is much later than the date on the review (December 29, 1969). It is possible, but undocumentable without the earlier version, if it exists, that the review was revised to describe the weight loss in pounds that would be considered evidence of effectiveness. Although omission of such data in the first place may raise issues regarding the quality of Dr. Moser's review, any subsequent change, while properly made as an amendment, does not seem to be an Indication of a devious Intent. In any case, the NDA was transferred to Dr. Dobbs after Dr. Moser recom- mended approval (March 30, 1970) Dr. Dobbs apparently asked Dr. Freemnn to review the data and another non-approval letter (September 11, 1970) re- sulted, reversing Dr. Moser's recommendation. Approval of the drug in 1973 followed an extremely complete reevaluation of the whole class of anorexogenic drugs. Sincerely yours, J. RICHARD Caour, M.D., Director, Bureau of Drugs. 0 PAGENO="0926"