PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~7O ~ HEARINGS BEFORE THF SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE NINETIETH CONGRESS-SECOND SESSION AND NINETY FIRST CONGRESS-FIRST SESSION ON PRESENT STATUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 10 DECEMBER 11 17 18 19 1968 AND JANUARY 23 1969 0 Printed for the use of the Select Committee on Small Business U S GOVERNMENT PRINTING OFFICE 81-280 WASHINGTON : 1969 OL/ ~7'~/ For sale by the Superintendent of Documents U;S Government Printing Office Washington D C 20402 Price $1 50 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS-i9OTH CONGRESS [Created pursuant to S. Res. 58, 81st Cong.] GEORGE A. SMATHERS, Florida, Chairman JOHN SPARKMAN, Alabama JACOB K. JAVITS, New York RUSSELL B. LONG, Louisiana HUGH SCOTT, Pennsylvania WAYNE MORSE, Oregon NORRIS COTTON, New Hampshire ALAN BIBLE, Nevada PETER H. DOMINICK, Colorado JENNINGS RANDOLPH, West Virginia HOWARD H. BAKER, JR., Tennessee B. L. BARTLETT, Alaska MARK 0. HATFIELD, Oregon HARRISON A. WILLIAMS, Ja., New Jersey GAYLORD NELSON, Wisconsin JOSEPH M. MONTOYA, New Mexico FRED R. HARRIS, Oklahoma WILLIAM T. MCINAItNAT, ~8taff Director and General Counsel MoNoPoLY SUBCOMMITTEE GAYLORD NELSON, Wisconsin, Chairman JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana WAYNE MORSE, Oregon GEORGE A. SMATHERS, Florida BENJAMIN GORDON, ~8taff Economist ELAINE C. Dva, Research As8lstant SELECT COMMITTEE ON SMALL BUSINESS-91ST CONGRESS (Created pursuant to 5, Res. 58, 81st Cong.] ALAN BIBLE, Nevada, Chairman JOHN SPARKMAN, Alabama JACOB K. JAVITS, New York RUSSELL B. LONG, Louisiana PETER H. DOMINICK, Colorado JENNINGS RANDOLPH, West Virginia HOWARD H. BAKER, Ja., Tennessee HARRISON A. WILLIAMS, Ja., New Jersey MARK 0. HATFIELD, Oregon GAYLORD NELSON, Wisconsin ROBERT DOLE, Kansas JOSEPH M. MONTOYA, New Mexico MARLOW W. COOK, Kentucky FRED R. HARRIS, Oklahoma THEODORE F. STEVENS, Alaska THOMAS J. McINTYRE, New Hampshire MIKE GRAVEL, Alaska Cnasrsa H. SMITE, Staff Director and General Counsel MoNoPoLY SUBCOMMITTEE *Ex officio member. GAYLORD NELSON, Wisconsin, Chairman MARK 0. HATFIELD, Oregon ROBERT DOLE, Kansas MARLOW W. COOK, Kentucky JACOB K. JAVITS,* New York BENJAMIN GoRDON, Staff Economl8t ELAINE C. Dvr, Clerical Assistant HUGFI SCOTT, Pennsylvania MARK P, HATFIELD, Oregon JACOB K. JAVITS, New York JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana THOMAS J. McINTYRE, New Hampshire ALAN BIBLE,* Nevada (II) PAGENO="0003" CONTENTS Statement of- Page Ayd, Dr. Frank J., Jr., FAPA, editor, International Drug Therapy Newsletter, 912 West Lake Avenue, Baltimore, Md 4144 Baehr, Dr. George, chairman, Public Health Council of the State of New York and distinguished service professor, Mount Sinai School of Medicine City University of New York, 625 Madison. Avenue, New York, ~ST.Y 4061 Bean, Dr. William B., professor of medicine, and head, Department of internal medicine, University of Iowa College of Medicine,. Iowa City, Iowa 3916 Faulkner, Dr. James M., chairman, committee on publications, Massachusetts Medical Society, 535 Boylston Street, Bostor~, Mass 4050 Ingelfinger Dr Franz J, editor, the New England Journal of Medi cine, 10 Shattuck Street, Boston, Mass 4017 Lowinger, Dr Paul, associate professor psychiatry Wayne State University School of Medicine and chief of the outpatient service of the Lafayette Clinic, 951 East Lafayette, Detroit, Mich - 3997 McGill, Dr. Clinton S., private physician, Suite 711-715 Medical- Dental Building, Portland, Oreg - 4084 Nichols, Dr. George, Jr., clinical professor of medicine, Harvard Medical School; consultant in medicine, Boston City Hospital; and senior associate in medicine, Peter Bent Brigham Hospital, Boston, Mass - 3977 SALIENT EXHIBITS Article, "Selling Drugs by `Educating' Physicians," by Dr. C. D. May, from the Journal of Medical Education, volume 36, No. 1, January 196L - - - - - - - - * 3938 Article, "The Medical Profession and the Drug Industiy `by Dr W B Bean, from Ethical Issues in Medicine, pp. 227-248 3957 Letter to Benjamin Gordon, staff economist, Select Committee on Small Business, U.S. Senate, from Dr. Lloyd C. Miller, director of revision, U.S. Pharmacopeia, dated December 10, 1968, re impressions of article "The Generic Inequivalence of Drugs" 3966 Letter to Senator Gaylord Nelson, chairman, Subcommittee on Monopoly, from Dr. Lloyd C. Miller, director of revision, U.S. Pharmacopeia, dated March 6, 1969 with accompanying letter to Dr Alan B Varley 3967 Richardson Merrell article and interdepartmental memorandums - 3970-73 I etter to Benjamin Gordon, staff economist, Select Committec on Small Business U S Senate, from J H Killian Legislative Attorney American Law Division, Library of Congress re responsibility of director to stockholders 3973 Letter to Dr Paul Lowinger department of psychiatry Wayne Statc University School of Medicine, from Dr. Herbert L. Ley, Jr~, Director, Bureau of Medicine, FDA, dated March 29, 1968, with accompanying chart 4008 Letter to Attorney General, Department of Justice, from William W. Goodrich, Assistant General Counsel, Food and Drug Division, dated June 5, 1961, re institution of criminal proceedings against Wallace & Tiernan, Inc - 4010 Letter to Attorney General, Department of Justice, from William W Goodrich, Assistant General Counsel, Food and Drug Division, dated April 20 1964 re institution of criminal proceedings against McNeil Laboratories, Inc.. 4012 (III) PAGENO="0004" Iv Letter to William W. Goodrich, Assistant General Counsel, Department Page of Health, Education, and Welfare, from Herbert J. Miller, Jr., Assistant Attorney General, Criminal Division, Department of Justice, dated September 28, 1964, re proposed prosecution against McNeil Labora- tories, Inc 4015 Letter to Senator Gaylord Nelson, chairman, Subcommittee on Monopoly, from Dr. Maurice R. Nance, medical director, research and development division Smith Kline & French Laboratories dated February 20 1969 re testimony of Dr. Lowinger 4016 Brief summary for Erythrocin Erythromycm 4042 Article Advertisements of Antibiotics by Dr Calvin M Kunin and Richard Hunter, University of Virginia School of Medicine, from the New England Journal of Medicine (correspondence), vol. 277, No. 20 - - - 4042 Article, "Advertisements of Antibiotics," by Joseph E. Grady, Ph. D. and Kurt F Stern, M 5, department of microbiology, Upjohn Co, from the New England Journal of Medicine (correspondence), vol. 278, No. 20 ~4043 New England Journal of Medicine rate schedules 4043-47 Article, "The Generic Inequivalence of Drugs," by Dr. Alan B. Varley, from the Journal of the American Medical Association, volume 206, No. 8, November 18, 1968 4071 Editorial, "Generic Drugs and Therapeutic Equivalence," by Dr. Dale G. Friend, from the Journal of the American Medical Association, volume 206, No. 8, November 18, 1968- 4077 Editorial, "Disease Drugs Cause," from the New England Journal of Medicine, volume 279, No 23 December 5, 1968_ - - -- 4078 Letter to Dr Philip R Lee, Assistant Secretary for Health and Scientific Affairs, Department of Health, Education, and Welfare, from Dr. George Baehr, chairman, Public Health Council of the State of New York, dated November 27, 1968, re cost of out-of-hospital prescription drugs as a medicare benefit 4079 Memorandum to Senator Gaylord Nelson, chairman, Subcommittee on Monopoly, from Benjamin Gordon, staff economist, Select Committee on Small Business, U.S. Senate, dated April 15, 1968, re testimony of Dr. McGill 4085 29 remedial letters (Dear Doctor) to all physicians from leading drug firms 4115-29 Drug efficacy study of the National Academy of Sciences*NatiOnal Re search Council, NDA 6655 (6D302) 4131 Statement, "A Practicing Physician Looks at the Nelson Hearings,' re marks by Dr Clinton S McGill Portland Oreg, before Pharmaceutical Manufacturers Association, New York Hilton Hotel, December 3, 1968 4138 Letter to Senator Gaylord Nelson, chairman, Subcommittee on Monopoly, from Dr. Clinton S. McGill, private physician, dated March 28, 1968, requesting to appear at subcommittee hearings 4141 Letter to Dr. Clinton S. McGill, private physician, from Senator Gaylord Nelson, chairman, Subcommittee on Monopoly, dated April 29, 1968, re reply to request 4141 Affidavit of Mrs Beulah L Jordan, employee, William S Merrell Co, Cincinnati Ohio dated March 13, 1962 - - - - 4142 Letter to Subcommittee on Monopoly, Select Committee on Small Busi ness, U.S. Senate, from Glenn Markus, Legislative Reference Service, Library of Congress, dated January 16, 1969, re origin of certain drugs used in the treatment of mental illness 4150 Letter to Benjamin Gordon, staff economist, Select Committee on Small Business, U.S. Senate, from Dr. Stanley F. Yolles, Director, Health Services and Mental Health Administration, Public Health Service, Department of Health, Education, and Welfare, dated January 22, 1969, re contributions by NIMH and VA to development of psychotropic and antidepressant drugs 4155 Chart, rise and fall of State and local government mental hospital popula- tion,1960-66 4172 Chart, inpatient population at Boston State Hospital, 1957-66 - - - 4172 Chart, Boston State Hospital prescriptions for outpatients, 1958-66 - - - 4173 Chart, Boston State Hospital psychopharmaceuticals, 1953-63 - - 4173 PAGENO="0005" V Memorandum to Senator Gaylord Nelson, chairman, Subcommittee on Page Monopoly, from Benjamin Gordon, staff economist, Select Committee on Small Business, U.S. Senate, dated April 15, 1969, re Dr. Frank Ayd's connectiOn with the pharmaceutical industry 4174 APPENDIXES I. Article, "Brief Recording-Acute Renal Failure After Drip-Infusion Pyelography," by L. A. Bergman, M.B., B. Sc., M.R.C.P., M. R. Ellison, M.D., and G. Dunea, M.B., M.R.C.P., from the New England Journal of Medicine, volume 279, No.23, December 5, 1968~... 4174B II. Article, "Chronic Nitrofurantoin Pulmonary Reaction-Report of Five Cases," by E. C. Rosenow III, M.D., R. A. DeRemee, M.D., and D. E. Dines, M.D., from the New England Journal of Medicine, volume 279, No. 23, December 5, 1968 4175 III. Article, "Renal Failure and Interstitial Nephritis Due to Penicillin and Methicillin," by D. S. Baldwin, M.D., B. B. Levine, M.D., R. T. McCluskey, M.D., and G. R. Gallo, M.D., from the New England Journal of Medicine, volume 279, No. 23, December 5, 1968_ 4183 IV. Statement of Dr. Donovan F. Ward, practicing physician, Dubuque, Iowa 4195 V. The MER-29 Case: Statement by T. M. Rice, Acting Chief Inspector, Buffalo District, Food and Drug Administration,. U.S. Department of Health, Education, and Welfare 4202 Statement by E. I. Goldenthal, Ph. D., Acting Deputy Director, Office of New Drugs, Bureau of Medicine, Food and Drug Administration, U.S. Department of Health, Education, and Welfare, with accompanying Curriculum Vitae 4204 Statement by R. C. Brandenburg, .Director, Office of Certifica- tion Services Office of Associate Commissioner for Compliance, Food and Drug Administration, U.S. Department of Health, Education, and Welfare 4210 Pharmacology review, dated August 19, 1959 4211 Incomplete letter to William S. Merrell Co., dated September 14, 1959 4211 Dr. Murray's letter to Dr. Epstein, dated September 24, 1959~ 4211 Memorandum of conference, dated October 6, 1959 4212 Dr. Murray's letter to Dr. Epstein, dated October 13, 1959 4212 Memorandum of conference, dated October 16, 1959 4213 FDA letter to William S. Merrell Co., dated November 6, 1959. 4214 Dr. Goldenthal's memorandum to Dr. Talbot, dated February 23, 1960 4214 Dr. Murray's letter to Dr. Goldenthal, dated February 29, 1960~ 4215 Incomplete letter to William S. Merrell Co., dated March 28, 1960 4216 Conditionally effective letter to William S. Merrell Co., dated April 19, 1960 4216 Effective letter to William S. Merrell Co., dated May 12, 1960 - 4217 Dr. Nestor's letter to William S. Merrell Co., dated October 23, 1961 4218 Dr. Goldenthal's memorandum to Dr. Nestor, dated November 7,1961 4218 Memorandum of conference, dated November 13, 1961 4219 Drug warning letter, dated November 27, 1961 4219 Report of the visit to the William S. Merrell Co., dated April 9, 1962 4220 Report of the visit to the William S. Merrell Co., dated April 10, 1962 4224 Dr. Goldenthal's memorandum to Division of Regulatory Man- agement, dated April 11, 1962 4226 Suspension order of NDA 12-066, dated May 22, 1962 4226 Drug warning letter, dated December 1, 1961 4227 PAGENO="0006" VI V. The MER-29 Case-Continued Memorandums to Bureau of Field Administration from Cm- Page cinnati District, dated: February 13, 1962 4228 February 27, 1962 4228 March 14, 1962 4229 April 12, 1962 4237 April 17, 1962 4238 April24, 1962 4239 May 4, 1962 4242 May 5, 1962 4245 May 30, 1962 4249 June 19, 1962 4251 June 20, 1962 4252 The United States of America v. The Wm. S. Merrell Co., Richardson-Merrell, Inc., H. W. Werner, E. F. Van Maanen, W. M. King, Criminal No. 1211-63 (Special Grand Jury sworn in on July 2, 1963) 4254 Richardson-Merrell interdepartment memoranda and corre- spondence 4264-96 HEARING DATES* December 11, 1968: Morning session 3911 December 17, 1968: Morning session 3975 December 18, 1968: Morning session 3997 December 19, 1968: Morning session 4049 January 23, 1969: Morning session 4081 Afternoon session 4144 The testimony for May iS, 16, 17, June 7 and 8, 1967, appears in pt. 1 of these hearings; the testimony for June 27 28 29 July 24 and Aug 8 10 1967 appears in pt 2 of these hearings the testimony for Sept 13, 14, 29, and Oct. 13, 1967, appears in pt. 3 of tbese hearings; the testimony for Oct. 31, Nov. 9, 15, 16, and 28 1967 appears in pt 4 of these hearings the testimony for Dec 14 19 1967 Jan 18 19 and 25 1968 appears in pt. 5 of these hearings; the testimony for Nov. 29, 1967, Feb. 6, 8, 27, 28, and 29, 1968, appears in pt. 6 of these hearings; the testimony for Apr. 23, 24, and May 1, 1968, appears in pt. 7 of these hearings; the testimony for May 2, 3, and Sept. 17, 1968, appears in pt. 8 of these hearings; the testimony for Sept. 18, 19, and 25, 1968, appears in pt. 9 of these hearings. PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WEDNESDAY, DECEMBER 11, 1968 US SENATE, MoNoPoLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D C The subcommittee met, pursuant to call, at 10 20 a m, in room `318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Elaine C. Dye, research assistant. Senator NELSON. The hearings of the Monopoly Subcommittee of the Senate Small Business Committee will come to order. After a brief statement by the chairman, we will hear from the dis- tinguished Dr. William B. Bean. There is growino concern, as reflected in medical literature as well as in testimony be~ore our subcommittee, that the medical profession has forfeited too much responsibility for the continuing education of physicians to the pharmaceutical industry and that the increasingly close financial relationship between the industry and the medical pro- fession may be contrary to the best interests of the profession and the public. The purpose of the series of hearings we are undertaking this week `md next is to explore further the questions raised in this regard, par ticularly as they involve the ethical implications, possible conflicts of interest, and professional responsibility, as, for example, in some of the following situations: When many physicians base their prescribing practices, to a large extent-I don't think anybody knows exactly to what extent-on information supplied them by industry salesmen-detail men-and other commercial sources. When many physicians prescribe dangerous drugs for nonindicated purposes. For example, during the past year a highly dangerous drug was prescribed by doctors-this was chlorampherncol-for 3.5 to 4 million people in the United States. Yet, testimony from eminent medical authorities who appeared before the subcommittee indicated that no more than 10 percent-at the most-should have received it. When many doctors prescribe drugs without adequate knowledge of the costs of these drugs relative to other drugs which have the same action. 3911 PAGENO="0008" 3912 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY When many medica' organizations and publications-national, local, and student-are substantially dependent on income derived from in dustry advertising When many doctors lend their names for articles and letters written by members of the pharmaceutical industry The implications for the medical profession and the public when the so called independent giveaway sheets and journals-which are easy to read and subsist entirely on drug advertismg-are becoming a factor of some importance in the physicians' education. When influential doctors or pharmacy educators, particularly in high academic positions, are stockholders and/or serve as policy- setting members of boards of drug corporations Since these men are in a position to mold the attitudes of other doctors and to make policy decisions in key medical and pharmaceutical organizations, might there not be a conthct of interest here ~ What are the ethical impli cations when doctors and pharmacy educators do not make known their industry affiliations ~ As long a~o as January of U~61, Dr Charles D May, of the Depart mont of Pediatrics of Columbia University, in an article in the Journal of Medical Education entitled "Selling Drugs by `Educating' Physi- cians," 1 asked Is the public hkeiy to benefit if practicing physicians and medical educators must perform their duties amidst the clamor and striving of merchants seeking to increase the sale of drugs by conscripting education in the service of promotion? Is it prudent for physicians to become greatly dependent upon pharmaceutical manufacturers for support of scientific journals and medical societies for enter tainment and now also for a large part of their education'? Do all concerned realize the hazard of arousing the wrath of the people by an unwholesome entanglement of doctors with the makers and sellers of drugs'? In an article in Ethical Issues in Medicine,2 Dr. William Bean, our witness today, of the University of Iowa Medical Center, stated that: The physician who is in the pay of pharmaceutical manufacturers is in no position to keep public confidence in his objectivity The editors and owners of medical journals which depend so heavily upon advertising are vulnerable and not only must be above taint but like Caesar s wife above suspicion n its efforts to study the far reaching implications of these and related problems, the Monopoly Subcommittee of the Senate Small Business Committee has invited several highly respected senior physi cians-whose integrity and courage to be forthright are well known to their peers-to present their views on these and other matters con- cerning these questions. We are pleased to welcome this morning Dr. William Bean, who is a widely known medical authority and is the former chairman of the section on Internal Medicine of the American Medical Association Doctor, do you have for the record a biographical sketch ~ Dr BEAN I didn't bring one with me I can get one for you and send it if you want Senator NELSON. If you would, please. We would simply like to have it in the record at the beginning of your testimony for the ref er- ence of those who read the record. - (A biographical sketch was subsequently received and follows:) 1 See article beginning at p. 3928, infra. 2 See article beginning at p. 3957, Infra. PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3913 BIoGRAPHIC DATA-WILLIAM BENNETT BEAN M D PERSONAL Professor of Medicine and Head of Department of Internal Medicine, University of Iowa, College of Medicine, Iowa City, Iowa, 1948- Residence: 723 Bayard Street, Iowa `City, Iowa. Date of Birth: 8 November 1909 at Manila, Ph~iiippi'ne Islands. Son of Robert Bennett Bean, M.D., and Adelaide L. Martin. (Biography of father was in Who's Who in America, American Men of Science, Who's Important in Medicine.) Married: Abigail Shepard, 17 June 1939. Children R Beiinett 25 March 1941 Margaret Harvey 9 July 1944 John Perrin 25 April 1946 DEGREES B A Univer~uty of Virginia 1932 M D University of Virginia 1935 Diplomate American Board of Internal Medicine 1947 Diplomate, American Board `of Nutrition, 1951. ACADEMIC AND HOSPITAL APPOINTMENTS Student Instructor in Anatomy, University of Virginia School of Medicine 1932-1933, 1933-4934, and 1934-1935. Intern, Medical Service, John's Hopkins Hospital, 1935-1936. Assistant Resident Physician Boston City Hospital 1936-1937 leaching Fellow Thorndike Memorial Laboratory Boston 1936-1937 Teaching Fellow in Medicine Harvard University 1936-1937 Senior Medical Resident Cincinnati General Hospital 1937-1938 Instructor in Medicine Cincinnati Medical College 1938-1940 Fellow in Nutrition Cincinnati Medical College 1938-1940 Assistant Professor of Medicine University of Cincinnati Medical Collegc 1940-1947 Medical Examiner for Draft Boards, 141-1942. Assistant Attending Physician, Cincinnati General Hospital, 1941-1946. Assistant Visiting Physician, Hillman Hospital, Birmingham, Alabama, 1940- 1942. Clinician Out patient Department Cincinnati General Hospital 1946-1948 Attending Physician Cincinnati General Hospital 1946-1948 Associate Professor of Medicine University of Cincinnati College of Medicine 1947-1948 Senior Medical Consultant Veterans Administration 1947- Physician in Chief University Hospitals Iowa City Iowa 1948- Special Consultant Iowa Selective Service 1949- Special Consultant Iowa Heart Disease Control Board 1949- HONORS John Horsley Memorial Prize University of Virginia 1944 Groedel Medal, American College `of `Cardiology, M'ay 1961. American Medical Writers Association Award for Distinguished Service in Medical Journalism as Editor in Chief of the Archives of Internal Medicine Octo ber 1962. Gold Headed Oane University of California June 1964 Citation Boston City Hospital Seventy Fifth Anniversary June 1964 University of Sydney Medal for Lambie Dew Oration March 1966 ITS ARMY Director, Hot Room Research, Armored Medical Research Laboratory, Fort Knox, Kentucky, 1942-1943. Director, Medical Research, Amored Medical Research Laboratory, 1943- 1945. Director, Nutrition Research Team, Pacific Theater, 1945. Commanding Officer, Armored Medical Research Laboratory, 1945-1946. Captain, MC AUS 8 August 1942; Major 30 March 1944; Lt Colonel 26 February 1946; discharged 28 May 1946. Commendation Ribbon 1946 PAGENO="0010" 3914 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Special Consultant to Surgeon General, US. Army, 1954-. Consultant to the Surgeon General, US Army, Advisory Committee to the Surgeon General of the Army on Nutrition, 1959. EDITORSHIPS Assistant Editor, Nutrition Reviews, 1945-1946. Editorial Board, Book Review Editor, Cincinnati Journal of Medicine, 1946- 1948. Associate Editor, Journal of Clinical Investigation, 1947-1952. Editorial Board, Journal of Laboratory and Clinical Medicine, 1948-1954. Associate Editor, Diseases of the Chest, 1951-1961. Editor-in-Chief, Monographs in Medicine, Williams & Wilkins Co., 1951-1952. Editorial Board, The Journal of Medical Education, 1953-1956. Editorial Board Archives of Internal Medicine 1953- Fditorial Board Medicine 1953- Advisory Board American Journal of Clinical Nutrition 1955-1959 Editorial Board, Pharos, 1955-1962. Advisory Board, Resident Physician, 1955-1962. Book Review Editor, AMA Archives of Internal Medicine, 1955-1962. Editorial Board, Perspectives in Biology and Medicine, 1957-. Contributing Editor Encyclopedia Britannica Medical Editor Stedman s Medical Dictionary 1958- Editorial Board American Journal of Clinical Nutrition 1960-1961 Editor in Chief Archives of Internal Medicine 1962-1967 Fditorial Consultant Modern Medicine 1964-1967 Editorial Board Familiar Medical Quotations Little Brown & Co 1964- Editorial Consultant Dictionary of American Portraits 1964 Consulting Editor Stedman s Medical Dictionary 20th Ed (1961) 21st Ed (1966) Williams & Wilkins Co Baltimore University of Iowa Editorial Board reappointed June 1906- Editor in Chief CMD (Current Medical Digest) 1967- Consulting Editor in Medicine for Medical Aspects of Human Sexuality 1967- COMMITTEES AND BOARDS Scientific Board of Directors The National Vitamin I oundation 1950-1953 Assocrite Member Commission on Liver Disease of the US Army Respiratory Disease Commission, 1949-1952. Executive Committee on Scientific Council American Heart Association Inc 1951-1954 Committee on Borden Award 1953-1955 Committee on Abraham Flexner Award 1958 Chairman 1959 Association of American Medical Colleges; Section of Olinical Cardiology, American Heart Association 1954-1958 Study Section, General Medicine, National Institutes of Health, 1957; Chair- man 1958-1961 National Advisory Committee, Grand Rounds Television Programs, 1957-1963. Board of Regents National Library of Medicine 1958-1961 Chairman 1960- 1961 re ippointed to the National Library of Medicine 1965- Iiiternational Committee on Clinical Cardiovascular Disease, American Col- lege of Chest Physicians, 1960-. Judging Committee Theobald Smith Award AAAS (Amer Assoc Advance ment of Science) 1960-1962 Inter-Study Section Committee on Influenza Research, National Institutes of Health, 1960-1961. Governor for the state of Iowa of the American College of Cardiology, 1962- 1968. Member, Pan American Medical Association Council on Cardiovascular Dis- eases, 1965-. Regional Representative, University of Virginia Alumni Fund, Inc., Oct. 1966. VISITING PROFESSORSHIPS Provide~ice Hospital Prrn idence RI 1955 Ohio State University School of Medicine Columbus Apr 1955 Georgetown University School of Medicine, Washington, DC, Nov 1955. PAGENO="0011" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3915 Mt. Sinai Hospital, Miami Beach, Fla, Sept 1956. Visiting Professor and Acting Chief of Department, Bowman Gray School of Medicine, Winston-Salem, NC, Apr 1958. Visiting Professor and Acting Head of Department of Medicine, University of Georgetown College of Medicine, Washington, DC, Apr 1958. Visiting Professor and Acting Head, Washington University School of Medi- cine, St. Louis, Mo, Nov 1958. Visiting Professor of Internal Medicine, Head of Department of Medicine pro tern, Washington Medical Center, Washington, DC, May 1959. Lackland Air Force Base Hospital, Department of Medicine, Texas, Apr 1959. University of Utah School of Medicine, Salt Lake City, Utah, Dec 1959. Baylor Medical School, Houston, Tex, Mar 1960. University of Mississippi School of Medicine, Jackson, Mar 1960. University of Oregon, Portland, Apr 1950. University of Oklahoma College of Medicine, Oklahoma City, Nov 1960. Johns Hopkins School of Medicine, Baltimore, Md, 1963. Sir Norman Paul Visiting Professor, University of Sydney Medical School and Sydney Hospital, Sydney, Australia, Mar 1966. Visiting Professor, Tampa General Hospital, Fla, Oct 1966. Second Master Teachers Course, San Diego, Calif, Feb 1967. Visiting Professor of History of Medicine and Internal Medicine University of Virginia, School of Medicine, Charlottesville (Grant from the Univ Va and Josiah Macy Foundation) Feb 1, 1968/July 31, 1968. Visiting Professor of Medicine, Medical College of Georgia, Augusta, May 22- 23, 1968. SOCIETIES Raven Society, University of Virginia, 1932; Alpha Omega Alpha, 1934; Central Society for Clinical Research, 1938, Council 1947-49, Vice President 1950, Presi- dent 1950-51; American Society of Tropical Medicine, 1938; Sigma Xi, 1939. American Heart Association, 1940; American Association for the Advancement of Science, 1940, Fellow 1952, Vice President and Chairman of Section N, 1957; American. Medical Association, Fellow 1941, Chairman, Section. of Internal Medi- cine, 1958-59; Ohio State Medical Society, 1941; American Society for Clinical Investigation, 1942, Council 1949-51; Association `of Military Surgeons, 1943; Charter Member Medical and Jockey Society of the Interior Valley of North America, 1946; Association of American Medical Colleges, 1948; American College of Physicians Fellow 1948 Ex Gov Iowa State Medical Society 1948 Chairman of Section of Internal `Medicine, 1958-59; Iowa Heart Association, 1948, President 1951; Tuberculosis and Health Association, 1948; Central Inter- urban Clinical Club, 1948, President 1958-59, Archaeology Institute of America, Iowa Chapter, 1948, President 1955-57; Iowa Clinical Medical Society, 1949; World Medical Association, 1949. Association of American Physicians, 1950; Society of Experimental Biology and Medicine, 1950; Research Club, University of Iowa, 1950; American Associa- tion for the Study of Liver Diseases, 1950 (Charter Member) ; American Clinical and Olimatological Association, 1951, Council 1956-59, Vice-President 1963, PresI- dent 1967 Council 1968-71 American Association of Medical History 1952 American College of Chest Physicians, Fellow 1954. Ex-Gov. Ta; The Horse Shoe Club, Regional President, 1954; Consultant in Internal Medicine to Surgeon General US Army 1954 American Medical Writers Association Fellow 1958 Dallas S'outhern Clinical Society, Honorary Member, 1954; Society of Medical Consultants to the Armed Forces, 1954; `American College of Sports Medicine, 1954, Charter Member; New York Academy of Sciences, Fellow 1956; American Academy of Political and Social Science, 1955; Royal Society of Medicine, Fellow, London, 1958; Consultant on Advisory Committee to the Surgeon General of the US Army on Nutrition, 1959; The Nockian Society, 1959. American Society for Clinical Nutrition, Council 1960, President 1962-63; Con- sultant in the Survey of Medical Research in VA Hospitals, `Division of Medical Sciences, National Academy of Sciences, 1960; History of Science Society, 1960; American Institute of Nutrition, 1960; The Honorable Order of Kentucky Colonels (rank of Colonel), 1963; Stuart and Tudor Club, Johns Hopkins Uni- versity, 1963; The John Fulton Society,' 1963; Hobart Hare Society, Jefferson Medical School, 1964; Board of Direct'ors, National ,Association for Standard' Medical Vocabulary, 1964; Sydney Hospitallers, 1966; American College Cardi- ology, Fellow 1967. Ex-Gov; Fellow, Council on Clinical Cardiology, American PAGENO="0012" 3916 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Heart Association, 1963; The Osler Club of London, 1967; Member, History of Medicine Section Richmond Academy of Medicine, Virginia, 19G8; Honorary member, Milton Anthony Medical Society, Univ Georgia Medical College, 1968. BOOKS Osler Aphorisms: Collected by Robert Bennett Bean, M.D. Edited by William Bennett Bean, M.D. Schuman, Inc, NYC, September 1951. Osler Aphorisms: Reprinted by Charles C. Thomas, Springfield, Ill., Septem- ber. 1961. Osler Aphorisms Third printing by Charles C Thomas Springfield Ill June 1968. Monographs in Medicine, Series I: Edited by William Bennett Bean, M.D., Williams & Wilkins Co Baltimore Md November 1952 Omphalosophy and Worse Verse: William B. Bean, M.D., privately printed, Iowa City, January 1955. Vascular Spiders and Related Lesions of the Skin: Edited by William Bennett Bean, M.D., Charles C. `Thomas, Springfield, Ill., December 1958. Aphorisms From Latham: Collected and edited by William B. Bean, M.D. The Prairie Press, Iowa City, October 162. Rare Diseases and Lesions-Their Contributions to Clinical Medicine William B. Bean, M.D. Charles `C. Thomas, Springfield, Ill., 1967. Senator NELSON Dr Bean, we are very pleased to have you appear here today. You are' free to present your testimony in any way you wish, and in any event, all of it will be printed in the record, and if you desire to elaborate or extemporize on anything that you have in your printed presentation, feel free to do so 1 I assume that as questions occur to the chairman you would have no objection to interruptions. Dr BEAN Very well Senator NELSON Thank you very much, Doctor STATEMENT OP D1~ WILLIAM B BEAN, PROFESSOR OP MEDICINE, AND HEAD, DEPARTMENT OP INTERNAL MEDICINE, UNIVERSITY OP IOWA COLLEGE OP MEDICINE Dr BEAN Senator Nelson, ladies, and gentlemen, I am here as an individual, and although I have many connections and affiliations, as a teacher, as a physician who is in a consulting practice, as a former editor of a number of journals, and as a member of the editorial board of four or five still today, and as someone who has done a certain amount of research and investigation, I have a broad background of interest in the problems presented As I commented' in my first paragraph, this sort of testifying I find extremely difficult and distasteful, simply because it puts one in the position of perhaps thinking he is a little better than others or being a critic of your family if you will Nonetheless, I think that someone must take responsibility in these matters, and I have done so in the past, and I suppose I `shall do so in the fu'ture, even though I find it difficult. . Some 18 years ago I was president of the Central Society for Clinical Research, and addressed myself to a number of prcthlems that I thought were important in American medicine. These had to `do with medical education, with licensing, with specialty boards 1 See prepared statement beginning at p 3927 infra PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3917 I included a paragraph on the moral responsibility to be intelligible, which I think is not always adhered to by people in various positions in the world `where they should be intelligible, and I `had the following `to say about the role which more or less willy-nilly detail men from drug firms had come to take in the postgraduate education of physi- cians in the country. I said as follows: What is the most effective general `teaching today at the postgraduate level? In sorrow we must admit that `the artistic and artful brochures of wealthy pharmaceutical houses, sped on by a crusading band of detail men, have effec- tively taken over graduate teaching. The blandishments of advertising, siren song of the purveyor of pills, now that there really is a multitude of specifics, puts professional judgment in a sorry place. Harnessed to' the lightning strokes of lay publicity, the demand for new miracle drugs often conies from radio or newspaper coaching, and `the practitioner, fearing `to "be not the first by whom the new drug is tried" because party to a conspiracy of ignorance, fraud, and twisted idealism which has run the gamut from vitamin craze to spurious cold cures and Hadacol. After all, we have some responsibility in this mess, and must provide leadership `to protect the public and embellish the name of medicine. Certainly many pharmaceutical houses are advancing the cause of medicine. More power to them. I do not grudge the honest dollar to the shareholders in drug enterprises, but when their advertising budgets exceed the total outlay for teaching and research provided by all our medical schools concern is justified, "for where your treasure is there will your heart be also." 1 Senator NELSON. May I interrupt just a moment, Doctor. Would this statement still stand today in your judgment? Dr. BEAN. I certainly think the problem exists, and I would imagine that the scope is pretty much the same. But real advances are being made in continuing education. For in- stance, the group interested in general practice, the American Academy of General Practice, has insisted that its members have a certain amount of formal postgraduate training every year. They are prob- ably going to have a specialty board in which a renewal of the see- cialty certificate will require a re-examination perhaps at 5-year in- tervals. This will require formal continuing education of the kind which has not been required by law, and is not in any sense uniformly fol- lowed by the individual drive incentive of the practicing physican. One of the great problems is time. Obviously if somebody is going to go back in school freshening up, he won't be treating the sick in his community, and this I think has been a real deterrent. So the problem is there. Certain formal and productive efforts are being made to up- grade the role of teaching at the postgraduate level in continuing education. This I think is a real advance. Many postgraduate courses of all sorts have existed for a very long time. These tend as a rule to be attended by those who are well abreast of what is going on anyhow. The people who should come do not, their function is very fine but it doesn't always reach the doctors who need it most. Senator NELSON. Thank you. Dr. BEAN. Ten years ago I addressed myself to the broad problem of the relationship of physicians to the pharmaceutical industry in an essay, entitled "Joint Responsibility," published in the ArchIves of Internal Medicine in May 1959. The main substance of my comments 1 J~ Lab. Clin. Med., 39: 7, January 1952. PAGENO="0014" 3918 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY was that a team of physicians and representatives of the pharma- ceutical industry should work out, voluntarily, means of evaluating claims for drugs, evaluating the therapeutic effect of drugs, and then seeing that advertising, sales, detailing, and retailing were managed according to regulations developed by joint action. Thus the manu- facturers of drugs and the physician prescribers might best serve their collaborative purpose in preventing, palliating, or curing disease This plea had very little effect. No formal study, joint effort, or confronta- tion of producer, distributor, dispenser, and user ever came about. Later the substance of my comments was recorded in presentations 10 years ago before the Kefauver committee, in this room Recently in an essay, entitled "The Medical Profession and the Drug Industry," published in Ethical Issues in Medicine, a book recently released by Little, Brown & Co. in Boston, I dealt with the present situation in regard to the ancient confrontation and sometimes an tagonism of apothecaries and physicians, and this as you know has a long and fascinating history. Among the comments made were the following At a time when scientific advance was slow and new drugs, such as they were, were likely to be found by painstaking evaluation of herbs and their essences, the introduction of new drugs was uncommon. Therapy, not very effec- tive, was about at a standstill. There was no incentive to go into the mass production of new compounds, for there simply were not enough new com- pounds. When advances began to develop explosively, the traditional function of ethical pharmaceutical houses was magnified and multiplied, and to some extent the directing forces were removed from individual or family enterprises into the large realm of big business. At the same time there was not at first a comparable awareness or alert ness to deal with the increasingly complex problem of drug testing In any society ~ hen problems which are new In kind as well as new in dimension arise its Institutions are tested Unfortunately it turns out often enough that the insti'tution~ and organizations, well geared for a slower pace and a simpler set of problems may prove not only insufficient but dangerous The evolution of medical practice and medical science as it relates to therapy and the employ- meat of powerful drugs Is moving fast but uncertainly. Institutions rarely have a built in autoanalyzer a central controlling monitor to examine and provide a dispassionate critique of purposes functions and the capacity to fulfill them This is why institutions change or fail and are replaced Human nature being what it is things may go along until some disaster appears Some threat becomes ominously evident Or a general quickening of the moral pulse of the community leads to an investigation or an intervention Often a crash program of poorly thought out schemes results ]fl passing laws to achieve ends which would be managed much better if collaborative `but voluntary arrangements and agreements could be worked out by those con- cerned. The two parties involved `here are pharmaceutical manufacturers on the one hand and the body of medical practitioners, teachers, and investigators, `those who must be responsible preservers and protectors of the public, on the other. ` The great majority of pharmaceutical manufacturers have a just concern for their good name and are wary lest this be sullied by entrepreneurs who have come into the field without the traditional background accumulated dur- ing the more leisurely days. `They have a steady sense of responsibility and wish it to permeate the drug industry. While many of the problems which are of concern to us now `have, more or less by default, gone into the hands of external agents or agencies it is still wise for physicians and those who pro duce pharmaceutical agents to review jointly their common material problems Senator NELSON May I interrupt for a moment, Doctor ~ Dr. BEAN. Yes, `sir. 3Pp. 231-232, 1968. PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3919 Senator NELSON. You referred to drug testing. As you know, when a company develops a new drug, the control of the testing is exclusively within the jurisdiction of the owner or the discoverer of the compound, and the testing is done at the direction of the company and the New Drug Application includes whatever testing is done, all of it under the control of the company. The question has heeii raised in the medical literature and testi- mony before this committee as to whether that is a satisfactory method 0± presenting the evidence for review; that is, should a person having a financial interest in marketing a drug also supply all the inforrnatioii about the drug. Do you have any observation abo~it this method of developing a New Drug Application? Dr. BEAN. Senator Nelson, I think everyone would agree that the better and certainly more nearly idea way to deal with this problem would be to have a neutral judging body professionally competent, and quite independent of any extraneous force of financial support or any hint of obligation or connection with the promulgators-the inven- tors-the promoters of the drug. I think anybody would realize it is human nature to react to in- formation one has in some relationship to those who will review it, those who support it., and the auspices under which studies are done. For example, somebody working for a very autocratic department head will fine that some of his own work, at least work that he thinks is his own, may be taken over in part by somebody whose name is on the paper, but who in fact had nothing more than a slight relationship, but was not in fact actually engaged in the work. Likewise, if a series of tests is supported, as it commonly is, though not invariably, by the people. who invent it and have the copyright or patent or control of a particular drug, and if this support comes to be important in the general academic progress perhaps of the person doing the studies, it is human nature for one to accentuate the posi- tive and to report things which a certain amount of human observer parallax, a little body english that creeps into interpretations. This is, I think, inevitable in the order of most of the relationships that people are in. It would be better if it were done in medical schools ~ nd in departments of clinical pharmacology. If a series of testing panels could be established, without any necessity for continuing sup- port from a particular group whose products are being tested, I think that the truth would have a. better chance of being reached than under the. Pre.Se1~ ~ system. I think it. is overidei.listic t.o sunpose that there will be a sudden, instant, radical change. I would hope that. in the. long run this is the direction in which we. aim-to have totally iudepenñent., and we hope unbiased obs~rvers-test.1ng under conditions in which they have no academic, scientific, financial, or personal equlty the various drugs that. come. along. The real difficulty is that this is a. very expensive, very time-con- sliming and very difficult thing t.o do. The actual testing of the effective- ness of a thug which would seem to be pretty cut and dried to the average laymen, is incteed a very complicated thing, ranging all the way from variation in. individual batches of a particula~ compound PAGENO="0016" 3920 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tO the enormous effect of the placebo. This is the effect that the mere giving of a drug, without regard to its pharmaceutical power at all, may have in influencing somebody who gets it, whether you test it out on medical students and tell them you are giving them a drug which will prevent nausea and vomiting when in fact it usually induces them You will find that some respond appropriately to the pharma ceutical power of the drug, some respond to the power of suggestion This is a complicated problem that I don't need to get into further. It is evident that if testing is done with financial support of those who obviously wouldn't be spending money if they didn't think they had a good and effective drug, and who want the test to come out favorably, a bias is introduced that it would be better to get rid of, if we could. Senator NELSON Is there any reason why you think it wouldn t be feasible to have a national or independent national institute of drug testing, which supervised testing with qualified people and delegated testing to, as you suggest, medical schools ~ Dr. BEAN. Some such central panel would be the kind of thing that I would certainly hope would come in and what its relationship should be to existing medical bodies, what its relationship to the Government I am not in any position to say. As you are aware, many years ago there was a seal of approval given by the American Medical Association to drugs that were tested under its auspices This was an independent panel They would not accept advertising from those drugs which did not pass this panel Its cost was said to have become far too extensive and expensive It was given up Whether that in fact was the reason I am in no position to say, but I do know that any testing of that kind does become tre mendously expensive in manpower, in dollars, and in actual clocktime Senator NELSON With respect to the question of expense, would you see any reason why the companies couldn't be charged by the inde- ~endent institute for the testing that was done, so long as the institute ~as totally responsible for how it was done ~ Dr BEAN This it seems to me is the proper direction As you may know, there are such things as the National Vitamin Foundation and the Nutrition Foundation, and life insurance companies all over the world have gotten together and supply money to do research which is quite independent of any particular company that supports this, and this is the sort of thing We have good precedent for it in the ones that I have mentioned. I should think that direction would be wise to go in. Senator NELSON. Thank you very much. Mr G0IWON May I ask a question at this point ~ Ooming back to your pievious statement about the tendency of someone who has a financial stake to try to accentuate the positive-a very good exam ple, incidentally, is a letter which is taken from our own record on indomethacin This is a letter from Dr Paul from the University of Iowa, in which he starts out To Merck Sharp & Dohme DEAR DR. OANTWELL I received your letter this morning and want to thank you for suggesting a grant for the Rheumatology Section at the University ~f Iowa PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3921 Then he talks about tests with indomethacin; This is a method we will follow for the time being, with our fingers crossed. Apparently he has a desire to show that it is a good drug. Now doesn't it seem reasonable that a person who is thanking a company for giving a grant to his department would be very reluctant to put in the next paragraph, "I am sorry your drug is a very poor one"? Dr. BEAN. I agree that you have stated it admirably. I think it would be asking too much of human nature to reckon that somebody could be absolutely fair under these circumstances, and though this comes from Iowa, I don't condone it and I don't think it is the way one should operate. Senator NELSON. Thank you, Doctor. Mr. GORDON. We have many letters like this, by the way.' Dr. BEAN. I am sorry to hear it. I hope no more from Iowa. Senator NELSON. Go ahead, Doctor. Dr. BEAN. The Medical Letter, which is a newcomer on the scene in the past dozen years or 10 years or so has provided a service which makes an effort to give an independent critique of both published work dealing with drugs, drug costs, drug efficacy, the relative merit of similiar drugs used for the same thing, and they have operated a clear- inghouse, collecting, reviewing, and evaluating, because they do not maintain any drug testing program of their own. There is a real effort to get authoritative information in a readily digestible, easily managed form as promptly as possible. To do this a certain amount of the material in Medical Letter is presented as preliminary appraisals. Naturally it is impossible for the accumulation of experience gathered from the periodical literature to be ready shortly after the introduc- tion of a new drug. Alternations in positions taken in Medical Letters, though uncommon, have occurred, which indicates that they have no claim to infallibility and are giving their considered and studied opinion, but it may be wrong.2 "Medical Letter helps the physician )udge the accuracy and signmfi cance of what may be reported as medical discoveries in the breathless tempo of newspaper and magazine. This may be very valuable in deal- ing with the insistent but perhaps confused patient who comes in with high expectations waving his clipping and calling for action. In this day of the mass media, we have not found a way to protect the average person, naive in his knowledge of science, biology, and medicine, from the booby traps of his own ignorance. "Cost and potency of comparable or identical compounds have been brought out from time to time. The lag in getting information about newly reported toxic reactions has been reduced. Recurring audits keep the physician up to date. An evaluation of over-the-counter drug products helps evaluate preparations widely advertised in extensive campaigns and provides a check on the hard face of reality. Thus sturdily realistic and impartial appraisals of drugs are available and can be referred to as a reasonable help in making decisions." ~ 1 See full text of this letter and other letters included in Competitive Problems in the Drug Industry;, Part 8, beginning at p. *34~2. 2 "The Medical Profession and the Drug Industry," Ethical Issues In Medicine. Little Brown & Co.. p. 236, 1968. "The Medical Profession and the Drug In.dhstry," Ethical Issues in Medicine, Little Brown & Co., p. 237, 1968. 81-280--GO-pt. 1O-2 PAGENO="0018" 3922 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. May I interrupt again a moment, Doctor? Dr. BEAN. Yes, sir. Senator NELSON. A number of witnesses before the committee, physicians and pharmacologists, as well as representatives of the drug industry, have expressed praise of the Medical Letter as being a very good source of information on drugs and other problems I `im glad to note that you concur. We also have had testimony on the question of the availability of an `idequate obiective source of information about all drugs Representa tives of the FDA as well as others have commented on this before the committee During the last session of the Congress I introduced a bill to create a national compendium of drugs The Food and Drug Admin istr'~tion has endorsed this bill, so has the President The HEW task force did a survey and announced some preliminary results-somethrng like 70 percent of their sampling indicated support for the idea. Have you given any thought to the idea of a national compendium which would list all drugs with indications for use, the precautions and so forth that would be available to all physicians? Dr. BEAN. As you know, there exist certain books brought out or brought up to date every year. There are two or three books on therapy which are private They are printed as private ventures by publishing houses quite independent of anything but the usual hope for sales that will take care of them, "Current Therapy" being just an example. It is a sort of a sampling of how several different physicians treat differ ent conditions I would agree that an annual that was fairly well up to date would he eminently desirable if this could be kept current in actual fact Inertia is built into any publishing and distributing venture, even something like the National Library of Medicine's current Index Medi cus, which m~y be anywhere from 3 to 10 months behind in actual appearing when you get it in terms of what is the most recent journal that you refer to If a forum or panel or group could do this across the board, so that all available drugs were cataloged in an up to date manner in the way you describe, it would be quite advantageous I have not thought under whose auspices this should be done or how it might be supported fi nancially, but again I think it might be supported like the Drug Index and the Desk References supported by the various manufacturers of drugs to identify their product, to tell the indications, the doses, the forms in which the medicine is available, the methods, whether it needs to be injected and if so how, or can be taken by mouth and so on. An annual or even more frequently updated document could be made `ivailable to all practicing physicians and could be used in teaching, could be used in residents in training, could be used particularly by the doctor in practice, who is writing most of the prescriptions today This would be much better than the way things are now. Senator NELSON. Some months ago we had testimony, I believe from Dr. Goddard and o:thers of the `FDA, on the question of a com- pendium. It was their testimony, if my memory is correct, that it would be important to send out inserts on a quarterly basis or at least several times a year in order that the compendium would be kept current. PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3923 Dr. BEAN. Some looseleaf format or something else would be de- sirable, I suppose or essential. Senator NELSON. Yes. Go ahead, Doctor. Dr. BEAN. "In a competitive, capitalistic society," and I am quoting again from the book on Medical Ethics, "those who gain the advantage by patenting discoveries have a clearly legitimate claim to profits. In the long run, however, when the pharmaceutical industry devotes so much of its talents to developing minor but patentable variations to deal with the competitive market rather than exploring unexplored territory, the major result is likely to be seen in conspicuous new allot- ments for advertising rather than a new boom for the sick man or the physician trying to take care of him. "A company with skill enough to make an original discovery in this field obviously should be rewarded for its effort. If the legal situation to insure this award were clearer, at least some of the troubles would disappear. Even the contemplated revision of the patent laws, however, gives no clear evidence that the ends desired would be achieved. As far as trade names are concerned, if the company making the original discovery were granted the patent, only a single trade name would be needed to be used by licensee as well as discoverer. If a sufficiently different new way were discovered for making the drug, the new dis- coverer would market it under the generic, or nonproprietary, name, thus at once easing the job of the patient, the pharmacist, and the physi- cian. By reducing the retailer's overhead of multiple duplicating stocks, the same drug with different names, the cost to the consumer would be reduced. The battle of generic names has gone on furiously and there seems to be very little hope that it will abate." 1 The concept of generic equivalence is not a cut and dried one as we may be led to think since what one really wishes to be able to iden tify is therapeutic equivalence rather than generic equivalence In the November 18, 1968, issue of the Journal of the American Medical As sociation, Dr Alan B Varley of the clinical pharmacology depart ment of Upjohn Co discussed "The Generic Inequivalence of Drugs," differentiating very sharply between chemical equivalence, `availability equivalence, that is to say, the amount actually taken into any pa- tient~s body which may vary absorption from the digestive tract as well as absorption from injections made under the skin. One would suppose that injections made into the bloodstream would insure any desiied level of effective drug This may not be true if the drug is sequestered in *some storage place where it is rendered inactive, is excreted, or changed to an inert form by the body's `own mechanisms. If a drug produces an easily measurable effect such as the lowering of blood sugar under the influence of the agent tolbutamide (Orinase), the availability of the drug to the patient m.ay not `be directly re- lated to the actual quantity taken if there is a `significant effect of the material in which the substance is packed or dispensed. It was Varley's contention that `the data in his study helped e'st'ab- lish the point that differences between generically equivalent drugs were not rare or unimportant. 1 "The Medical Profession and the Drug Industry," Ethical Issues In Medicine. Little Brown & Co., pp. 241-242, 1968. PAGENO="0020" 3924 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. Gom~oN. May I interrupt here, Doctor? When I read the article yesterday, I immediately got in touch with the USP and got a letter from Dr. Lloyd Miller,' its director. He says the following: The data Dr. Varley presents are not at all surprising or particularly new. For years the drug firms have been making and testing experimentally drug dosage forms that have been less than fully satisfactory in comparison with other very similar products. On'ly com~arativ'ely recently have good methods becom.e available to make such tests fruitful. There is very little evidence that such products get out on the market, but we can all agree that then even the risk of their doing so should be minimized. Let me ask this, Doctor. Is the data sufficient for an objective sci- entist to determine the validity of the results presented in `this article? Dr. BEAN. All the figures are not given, although many of them are. Much of the information is presented in line graphs and drawings which indicate the averages in a stated number of tests. This is a `field in which I `do not claim any special competence. It is not one in which I have done investigation or in which I have spent much time. I did not study the article the way an editor would read to see whether it was acceptable in terms of the security of the dat'i presented and the relationship of the conclusions as far `is they agreed is ith a presumably adequate base of the material presented I am not evading the issue, I simply am not qualified to make a statement in this particular circumstance It is something I should have gotten advice on before I came. Taking what he said as `he said it impressed me, `this again probably should be looked upon as testimony rather than evidence. Mr. GORDON. Dr. Bean, may I refer to your article, the "Medical Professional Drug Industry," in which you state The physician who is in the pay of pharmaceutical manufacturers' is in no position to keen public confidence in his objectivity Now, Dr Varley is in the employ of the Upjohn Co Do you think that if his results showed the opposite, this would have been pub fished? Dr. BEAN. Well, I think by the way that you frame the question you have given the answer. It seems to me that it would be not im- possible `but of the highest order of imprthability that such things would turn out against the product; or the man who did it would be turned out. So I think you have answered your own question.2 Senator NELSON. I note that the drug firms' through the Pharma- ceutical Manufacturers Association argue the issue, as they put it, of generic equivalence. I think what they are trying to say is that brand names are better than generic name drugs, although a good many of them, of course, buy generic drugs themselves from such distinguished manufacturers as Strong, Cobb & Amer and then put their own labels on them. It seems to me that that isn't really the issue at all. The industry testified before the subcommittee on several occasions. Not once did they present specific cases of instances where two drugs met USP standards or U.S. Formulary standards, and were not thera- peutically equivalent. The testimony of the U.S. Pharmacopeia and the National Formulary representatives is that there are, at most, half 1 See letter p. 3~66, infra. 2 Other correspondence related to this matter is on p. 3a67, infra. PAGENO="0021" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3925 a dozen instances where it has been proven two drugs meeting the USP standards, had a different therapeutic result. I think this kind of article by Dr. Varley, as well as continuous publicity by the industry, is an attempt to convince doctors that they should never use anything but brand names and to convince them that drugs that meet the TJSP standards do not necessarily have the same results. If the USP discovers that a brand name drug does not have the same result as a generic drug and that its standard is not adequate, then the standard is changed. I think the industry knows that pretty well, but I note this in all their advertising. In my judgment it is intended to confuse the medical profession and the pithlic, rather than to inform it. Mr. GORDON. Doctor, the USP does not have a dissolution rate. Apparently up until this time they have not had a satisfactory test for it. Now, if the Upjohn Co. has developed *a method for determin- ing the dissolution rate, isn't it a public and moral responsibility on its part to give it to the USP and the National Formulary ~ Dr. BEAN. The question you ask is a very logical and very difficult one to answer. The question in effect is at what stage altruism should take over and at what stage the capitalistic tendency of anybody with an equity in the discovery, the manufacture, the sale of drugs should have that be the determining factor. This is a little different from the drug industry coming up with a new invention or a patentable variation on a well-known or well- established molecular configuration which is therapeutically effective in one or another of the various circumstances. I don't know what the situation is from the legal point of view at all. I have no notion as to what legal requirement there might be. From the moral and ethical point of view, it would depend I should think on some judgment as to what was in the long run altruistic and thus better for the patient and to what degree making such a gesture would conflict by providing evidence for not only the Federal testing group but for competitors in this particular field. Do you know of any precedent in this situation where the problem has come to a solution One wayor the other? The point I suppose is that the majority of such circumstances would not be made known outside of a company which had the par- ticular skill involved, and at what stage they have an obligation to turn that over to the FDA or to those who do the work on the Na- tional Formulary. I know h~w I feel about it, hut I don't know that I know enough to tell you to what extent they ought to do this or should not do that. Mr. Go~noN. You have stated Varley's contention, and I assume it is Varley's contention, that "The data in his study helped establish the point that differences between generically equivalent drugs were not rare or unimportant." I don't see how you can come to that con- clusion. The only thing he shows is that it is possible for Upjohn Co., to manufacture a tablet which is not as good as another tablet they manufacture, of tolbutamide, which is highly insoluble. It is a com- pound, as I understand it, which is almost insoluble in water. Now how did he jump from that to his grand conclusion, when there is no such thing as a generic tolbutamide anyhow? PAGENO="0022" 3926 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BEAN. Well, I think you have said it. He jumped, whether he landed upright or not. Senator NELSON. Thank you, Doctor. Dr. BEAN. Well, the last two paragraphs in that particular quotation from his article you have dealt with in your question so I think we needn't go further with that. Then I say thus: "There seems to be no doubt that we need more, rather than less, and more careful, rather than less careful, testing of drugs. Limited facilities in medical school or hospital centers, an already overburdened staff in clinical pharma- cology might not shift satisfactorily into new lines of work. In medical education, in medical care, in medical ethics, in the extraordinarily complicated problems of precisely what and when death occurs, our institutions and our people seem overwhelmed by complexity. It be- hooves us then to see what can be done to correct the situation, repair the damage, and make all possible realistic efforts to plan more wisely for the future. It seems unlikely that anyone would condone doctors owning stock in drug companies whose products they are evaluating; special efforts to support special drugs for prescriptions; or doctors paid directly by a drug firm to evaluate its products rather than having it done by a testing panel or a team is certainly questionable. When influential physicians have important academic and administrative posts as drug promoters, the conflict of interest is automatic rather than merely possible. Retainer fees, control of publication, drug adver- tising, the teaching function of the detail man, each has the special problems of responsibility and honesty. "It is impossible even to touch many other vitally important aspects of the situation, for instance, the vast industry of quackery, fi and, nostrum, and poison which is so profitable and so hard to control. The use of psychedelic drugs, so widely used, so poorly understood, and so little tested, may have effects that could range all the way from those of an innocuous and banal holiday from reality to one in which psychosis, suicide, or genetic calamity are serious risks. The fact is that these things have simply not been studied. And I think it ulti- mately comes down to a paragraph in what I wrote back in 1959 about what is the professional responsibility of physicians, and particularly those who are teachers and those who are in the position of testing drugs, those who are doing research, be it basic or applied. "In `Ecelesiasticus,' a book which was relegated to the Apocrypha rather than put in the Bible as a result of a curious ecclesiastical popu- larity contest, we find these words, `For a man's soul is sometimes want to tell him more than the seven watchmen that sit above in a high tower.' Is our collective conscience too dependent on others at a time when the very word controversial has become anathema l Physicians and responsible members of the pharmaceutical industry have an obli- gation to examine controversial matters in order that, collaborating effectively, apothecaries and physicians chaiige their ancient traditions of antagonism. Only thus will the best interest of society be served." 1 That concludes my formal testimony. Senator NELSON. Thank you, Doctor. (The complete prepai ed statement of Di Bean follows ) 1 "Joint Responsibility," Arch. Intern. Med. 103: 685, May 1959. PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3927 STATEMENT OF DR. WILLIAM B. BEAN Assuming public responsibility in matters of drug use, advertising, testing, and control though critical to the proper function of medicine and the welfare of persons using drugs is inherently distasteful It is especially so to physicians No doubt this is why we neglect it. Seventeen years ago in an address before the Central Society for Clinical Research, entitled "A Testament of Duty: Some Strictures on Moral Responsibilities in Clinical Research," I bad this to say about postgraduate teaching. "What is the most effective general teaching today at the postgraduate level? In sorrow we must admit that the artistic and *artful brochures of wealthy pharmaceutical houses, sped on by a crusading band of detail men, have effectively taken over graduate teaching. The blandishments of advertising, siren song of the purveyor of pills, now that there really is a multitude of specifics, puts pro- fessional judgment in a sorry place. Harnessed to the lightning strokes of lay publicity, the demand for new miracle drugs often comes from radio or newspaper coaching, and the practitioner, fearing to `be not the first by whom the new is tried becomes party to a conspiracy of ignorance fraud and twisted idealism which has run the gamut from vitamin cral7e to spurious cold cures and Hadacol After all we have some responsibility in this mess and must provide leadership to protect the public and embellish the name of medicine. Certainly many pharma- ceutical houses are advancing the cause of medicine. More power to them. I do* not grudge the honest dollar to the shareholders in drug enterprises, but when their advertising budgets exceed the total outlay for teaching and research proVided by all our medical schools concern is justified, `for where your treasure is there will your heart be also'." (J. Lab. Olin Med., 39:7, Jan. 1952.) Ten years ago I addressed myself to the broad problem of the relationship of physicians to the pharmaceutical industry in an essay, entitled "Joint Respon- sibility," published, in the Archives of Internal Medicine in May, 1959. The main substance of my comments was that a team of physicians and representatives of the pharmaceutical industry should work out voluntarily means of evaluating claims for drugs, evaluating the therapeutic effect of drugs, and then seeing that advertising, sales, detailing, and retailing were managed according to regulations developed by joint action. Thus the manufacturers of drugs and the physician prescribers might best serve their collaborative purpose in preventing, palliating, or curing disease. This plea had very little effect. No formal study, joint effort, or confrontation of producer, distributor, dispenser, and user ever came about. Later the substance of my comments was recorded in presentations before the Kefauver Committee. Recently in an essay, entitled "The Medical Profession and the Drug Industry," published in EthicaZ Issues in Medicine, Little, Brown and Company, I dealt with the present `situation in regard to the ancient confrontation and sometimes antag- onism of apothecaries and physicians. Among the comments made were the following: "At a time when scientific advance was slow and new drugs, such as they were, were likely to be found by painstaking evaluation of herbs and their essences the introduction of new drugs was uncommon Therapy not very effective was about at a standstill. There was no incentive to go into the mass production of new compounds, for there simply were not enough new compounds. When ad- vances began to develop explosively, the traditional function of ethical pharma- ceutical houses was magnified and multiplied, and to some extent the directing forces were removed from individual or family enterprises into the large realm of big business. "At the same time, there was not at first a comparable awareness or alertness to deal with the increasingly complex problem of drug testing. In any society when problems which are new in kind, as well as new in dimension, arise, its in- stitutions are tested. Unfortunately it turns out often enough that the institutions and organizations, well geared for a slower pace and a simpler set of problems, may prove not only insufficient but dangerous. The evolution of medical practice and medical science as it relates to therapy and the employment of powerful drugs is moving fast but uncertainly. Institutions rarely have a built-in autoanalyzer, a central controlling monitor, to examine and provide a dispassionate critique of purposes, functions, and the capacity to fulfill them. This is why institutions change, or fail and are replaced. PAGENO="0024" 3928 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY "Human nature being what it is, things may go along until some disaster ap- pears. Some threat becomes ominously evident. Or a general quickening of the moral pulse of the community leads~ to an investigation or an intervention. Often `1 crash program of poorly thought out schemes results in passing la~ s to achieve ends which would be managed much better if collaborative but voluntary ar- rangements and agreements could be worked out by those concerned. The two parties involved here are pharmaceutical manufacturers on the one hand and the body of medical practitioners, teachers, and investigators, those who must be responsible preservers and protectors of the public, on the other. "The great majority of pharmaceutical manufacturers have a just concern for their good name and are wary lest this be sullied by entrepreneurs who have come into the field without the traditional background accumulated during the more leisurely days. They have a steady sense of responsibility and wish it to permeate the drug industry. While many of the problems which are of concern to us now have, more or less by default, gone into the hands of external agents or agencies it is still wise for physicians and those who produce pharmaceutical agents to review jointly their common material problems (pp 231-232) Medical Letter operates as a clearing house collecting reviewing and eval uating since it does not maintain its own drug testing program It has no eqrnty in a compound but in the truth There is a real effort made to get authoritative information in a readily digestible, easily managed form as promptly as possible. To do this, a certain amount of material in Medical Letter has to be presented in the form of preliminary appraisals Naturally it is impossible for the accumu lation of experience gathered in periodical literature to be ready shortly after the introduction of a new drug. AlteratiOns in positions taken in Medical Letter, though uncommon, have occurred. This indicates that they have no proprietary in;tere'st in pontification but try to let the facts speak for themselves." (p. 236) "Medical Letter helps the physician judge the accuracy and significance of what may be reported as medical discoveries in the breathless tempo of news paper and magazine. `This may be very valuable in dealing with the insistent but perhaps confused patient who comes in with high expectations waving his clipping and calling for action In this day of the mass media we have not found a way to protect the average person naive in his knowledge of science bology and medicine from the booby trips of his own ignorance Cost and potency of comparable or identical compounds hai e been brought out from time to time. The lag in getting information about newly reported toxic reactions has been reduced. Recurring audits keep the physician up to date. An evaluation of over-the-counter drug products helps evaluate prepara- tions widely advertised in extensive campaigns and provides a check on the hard face of reality. Th'us sturdily realistic and impartial `appraisals of drugs are available and can be refe'rred to as a reasonable help in making decisions." (p. 237) "In a competitive, capitalistic society, those who gain the advantage by patent- ing discoveries have a clearly legitimate claim to profits In the long run however when the pharmaceutical industry devotes so much of its talents to developing minor but patentable variations to deal with the competitive market rather than exploring unexplored territory the major result is likely to be seen in conspicuous new allotments for advertising rather than a new boon for the sick man or the physician trying to take care of him "A company with skill enough to make an original discovery in this field obviously should be rewarded for its effort. If the legal situation to ensure this award were clearer, at least some of the troubles would disappear. Even the contemplated revision of the patent laws, however, gives no clear evidence that the ends desired would be `achieved. As far as trade names are concerned, if the company making the original discovery were granted the patent, only a single trade name would be needed to be used by licensee as well as discoverer If a sufficiently different new way were discovered for making the drug, the new discoverer would market it under the generic, or nonproprietary name, thus at once easing the job of the patient the pharmacist and the physician By reducing the retailer's overhead of multiple duplicating stocks, the same `drug with different names, `the cost to the consumer would be reduced. The battle of generic names has gone on furiously and there seems to be very little hope that it will abate." ("The Medical Profession and the Drug Industry," Ethical Issues in Medicine. Little, Brown `and Company, pp. 241-242, 1968.) PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3929 The concept of generic equivalence is not a cut and dried one as we may be led to think since what one really wishes to be able to identify is therapeutic equivalence rather than generic equivalence. In the November 18, 1968 issue of the Journal of the American Medical Association, Dr. Alan B. Varley of the Clinical Pharmacology Department of Upjohn Company discussed "The Generic Inequivalence of Drugs," differentiating very sharply between chemiCa.l equiv- alence, availability equivalence, that is to say, the amount actually taken into any patient's body which may vary absorption from the digestive tract as well as absorption from injections made under the skin. One would suppose that in- jections made into the blood stream would insure any desired level of effective drug. This may not be true if the drug is sequestered in some storage place where it is rendered inactive, is excreted, or changed to an inert form by the body's own mechanisms. If a drug produces an easily measurable effect such as the lowering of blood sugar under the influence of the agent tolbutamide (Orinase), the availability of the drug to the patient may not be directly related to the actual quantity taken if there is a significant effect of the material in which the substance is packed or dispensed. It was Varley's contention that the data in his study helped establish the point that differences between generically equivalence drugs were not rare or unimportant. The evidence that he presented indicated that it was "possible to produce considerable differences in both availability of drug to human patient and in eventual therapeutic usefulness by making tiny changes in the formula- tion which are clearly within present DSP chemical equivalence standards. "It is not my contention that generic, therapeutically equivalent drugs cannot be formulated. Quite to the contrary. It is my contention that criteria for estab- lishment of equivalence cannot be made by chemical and physical standards as they are now established in the DSP, unless one is not interested in the patient's therapeutic response which concerns most physicians. "Without question, the ideal criterion for establishment of therapeutic equiv- alence is trial of comparative efficacy in appropriately disease-afflicted patients. While not within the scope of data presented in this communication, this is a concept probably not feasible in the context of today's clinical research meth- odology and standards of ethical medical research. Inasmuch as chemical or USP-type specifications are clearly not a satisfactory answer, the medical world is left with drug availability as the present most sensible and feasible way of establishing generic equivalence of drugs" (JAMA, 206 :1748, No. 1968). Thus there seems to be no doubt that we need more, rather than less, and more careful, rather than less careful, testing of drugs. Limited facilities in medical school or hospital centers, an already overburdened staff in Clinical Pharmacology might not shift satisfactorily into new lines of work. In medical education, in medical care, in medical ethics, in the extraordinarily complicated problems of precisely what and when death occurs, our institutions and our people seem overwhelmed by complexity. It behooves us then to see what can be done to correct the situation, repair the damage, and make all possible realistic efforts to plan more wisely for the future. It seems unlikely that anyone would condone doctors owning stock in drug companies whose products they are evaluating; special efforts to support special drugs for prescriptions; or doctors paid directly by a drug firm to evaluate its products rather than having it done by a testing panel or a team is certainly questionable. When influential physicans have im- portant academic and administrative posts as drug promoters, the conflict of interest is automatic rather than merely possible. Retainer fees, control of publi- cation, drug advertising, the teaching function of the detail man, each has the special problemsi of responsibility or honesty. It is impossible even to touch many other vitally important aspects of the situation; for instance, the vast industry of quackery, fraud, nostrum, and poison which is so profitable and so hard to control. The use of psychedelic drugs, so widely used, so fully understood, and so little tested, may have effects that could range all the way from those of an innocuous and banal holiday from reality to one in which psychosis, suicide, or genetic calamity are serious risks. The fact is that these things have simply not been studied. "In `Ecciesiasticus,' a book which was relegated to the Apocrypha rather than put in the Bible as a result of a curious ancient ecclesiastical popularity contest, we find these words, `For a man's soul is sometimes want to tell him more than the seven watchmen that sit above in a hightower.' Is our collective conscience too dependent on others at a time when the very word controversial has become PAGENO="0026" 3930 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY anathema? Physicians and responsible members of the pharmaceutical industry have an obligation to examine controversial matters in order that, collaborating effectively, apothecaries and physicians change their ancient traditions of an- tagonism. Only thus will the best Interest of society be served" ("Joint Respon- sibility," Arc/v Intern Mcd, 103: 685, May 195i~). Sen'vtor NET S~N You have touched upon the question of financial relationship between drug companies and physicians or institutions, medical schools, and so forth. Many doctors and others have commented on this kind of relation- ship. We intend to explore the matter in much greater depth than we have thus far But, for example, many medical journals, including the Journal of the American Medical Association, receive substantial sums of money for advertising from the drug companies. Does this raise, in your judgment, a serious question ~ Dr BEAN Well, it certainly raises a serious question The problem may be solved or may be left unsolved in a variety of ways. It depends, I think, to some extent as to who controls the editorial policy and who m'Ly veto or select or set the stand'irds for advertising This has varied with different circumstances. For instance, if a journal is the property of a medical society, the medical society assumes responsibility through an editorial board and an editor for not only the editorial content but all other features of the journal, including the advertising Having been an editor for a good many years of one of the journals published by the American Medical Association, the Archives of In- ternal Medicine, I was allowed to look ahead of time at all of the copy for advertising, and on only two occasions did I come upon things that I thought were either in such outrageously bad taste or were scientifically invalid that I requested, and this request was acceded to, that the material not be used, or it was changed in an appropriate way. I was in a position not of setting the policy, and my request of veto might itself have been vetoed in the circumstances of my arrangement with the American Medical Association, since the last say was in the hands of the chief editor of the Journal of the American Medical Association, and the 10 archives specialty journals. If a journal is owned by a publishing house, and if this is a commer- ci~l venture, then the responsibility of the publishing house or of the editor becomes the determining factor in what is accepted and what is not accepted, and as an example of in effect what amounts to an independent journal, the New England Medical Journal, which is one of the very fine ones, the determination and the acceptance of ad- vertising is in part determined in the first place by whether or not the American Medical Association has accepted it, and this, there- fore, becomes a kind of a model, not by rule but by custom They m `iy find other reasons for objecting or refusing advertising, which are determined by a fairly independent editor and the editorial board. This journal is the effective representative of all of the New England States, although their connection as medical societies with the journal is somewhat diffused, because it isn't one State-one journal, as it is with the majority of State journals. So there is no question but that there is a temptation, and this may operate at the conscious or the unconscious level, of a selection in which articles being unfavorable PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3931 to the use of drugs which had been heavily advertised in a journal might present qualms of consciousness, if they were not published freely, even though they might say things that weren't favorable to the promoter of a particular form of drug under those circumstances. I am not aware of any overt coercion in any of the reputable journals, but I can conceive that this might well happen, that there might be pressures to publish papers that were favorable to the use of a particular drug. I simply haven't run into that as a personal prob- lem. I was dealt with, I think, very liberally by those who were su- perior to me in the American Medical Association, and who might have objected to my request for deleting a particular thing. I didn't exert the option often. It was not a common problem. I don't know whether that answers your question or not, but I think the temptation and the risk is there, and it would depend on the scruples of the editor and the pressures which beset him, and what- ever adjustment or compromise he might make under those circum- stances. Senator NELSON. As I say, we have not gone into this in depth yet. It does seem to me, however, that if any journal receives a signifi- cant amount of its income from a certain advertising source, that the pressure is there, with nothing being said. The other question that would seem to me to cause some concern is the example we have had, with some extensive testimony befor~ this committee, on chioramphenicol. We had five or six very distinguished and nationally recognized authorities in various fields, including Dr. Darneshek from Mount Sinai, a recognized authority on hematology, who has written on chioramphenicol in the AMA Journal and other professional journals. Frankly, what concerned me is that chioramphenicol was widely advertised in the AMA Journal. I looked at the number of the ads. Now, as a person who is not a physician, I thought the ads were quite clever. However, I thought they were misleading, after care- fully reading the literature, as to the indications for use of the drug, and looking at the ads. Now, maybe it wouldn't be misleading at all to a qualified physician. But in testimony before the subcommittee-unrefuted by the com- pany itself-five or six witnesses stated that from 90 to 99 percent of the persons receiving chloramphenicol were receiving it for non- indicated cases. One of the doctors thought 10 percent was for indi- cated cases, and one of them thought less than 1 percent. As an example, `here we have a drug that is being widely advertised in medical journals, including the Journal of the American Medical Association; 3½ to 4 million people received the drug in 1967. Yet, Dr. Goddard, in testimony `before the committee, said that he was at his "wit's end" as to how to stop physicians from prescribing the drug for nonindicated cases. I raised the question that someone in the medical profession must he at fault. It shouldn't take a congres- sional committee to expose the fact. After wide publicity, as a result of our hearings, and after Dr. `Goddard's testimony, FDA sent a "Dear Doctor" letter to 200,000 physicians throughout the country defining and limiting the use of the drug. Following this, batch test- ing dropped from 23 million grams in the first 6 months of 1967 to PAGENO="0028" 3932 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4 million grams in the first 6 months of 1968, down to zero in terms of batch testing in June of 1968. This was a very dramatic drop as you can see I raised the question at the time that it seemed to me the medical profession was grossly in default of its responsibilities to allow this situation to go on for years, with distinguished people in the medical profession knowing it, the AMA. knowing it, and the journal accept- ing ads. I think it raises a serious ethical question and it raises a serious question in the mind of the public, valid or not, as to the Objectivity of the AMA. for not just screaming to the high heavens, to all the doctors in America, that the drug which is widely advertised and promoted is being vastly overprescribed, to the great detriment of many, many people. This is the kind of question it raises for me. Do you agree? Dr. BEAN. I think that is a very le~itimate question and I think your interpretation is right. The medical profession is sort of easy to name Then you begin to name and think of particular doctors Let me just give you my experience In our teaching program in the medical school at Iowa we have a very active hematology section and to the undergraduate and postgraduate courses and in the local State journal and in national journals, and especially in hematology journals, the position that you say has been supported by the.consultants who have discussed the matter with your subcommittee here has been sustained and maintained, and on the local scene for many, many years the drug was not used except for that five plus or minus percent of people for whom no other equally good drug was available and where the known risk which is numerically small but in terms of the severity of what happens is formidable, and so the people were taught and told about this. The AMA Journal and some of its subspeci'dty journals, the Archives of Surgery, the Archives of Internal Medicine, have had a number of articles dealing with the hematological bad effects of the drug. It is very evident from any rational or any ethical or, moral point of view, if you have a drug, excellent as it may be in the great majority of instances, that has a danger, serious danger, though not very often, you have to make a judgment about what level and what kind of disease you would require to occur before you used it, realizing that there is this risk, and that the problem is particularly serious in chil- dren. It has certain circumstances where it may be much worse to use it than in others. It is effectually a cure for typhoid fever and some of the other conditions which foitunately we don't have to use it for very often. So I would agree with you that this is a situation which the medical profession has dealt with on a more or less personal basis, with ex- perts in the field all agreeing, with many papers being available that show this, and it indicates perhaps two things. One is a breakdown in the lines of communication, where simply issuing information and printing it in a journal doesn't tell people, because they don't read it, and the other thing is that when .a circumstance of this kind exists, there has been no body in medicine which took responsibility auto matically, when such things come up. PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3933 Now there is afoot interest in forming what may become a National Academy of Medicine, with analogies or perhaps direct relationship either tandem or in parallel with the National Academy of Science. It might concern itself with many problems upon which the Govern- ment, the lay public, the pharmaceutical industry, and the medical pro- fessi on needs firm and authoritative counsel. It may be able to provide this and thus head off difficulties in the future which otherwise are not likely to be studied because nobody, or very few are willing to spend the time and effort and incur the unfavorable comments of people who think that they are appointing themselves the conscience of American medicine. This is simply human nature, which on the one handl, has a pro- found built-in inertia, and on the other hand is much more anxious to do something that brings praise or glory than brings blame, no matter how praiseworthy what they do may be in bringing blame or odium of some kind or other. I don't deny that `this is a deficiency. It is a glaring one. It is a `sad commentary on the present situation. I hope that we will be able to de- velop the corporate wisdom in medicine to correct such things as they may appear especially where one could not anticipate them ahead of time, as, for example, the thalidamide situation, unless the drug had been tested `in a great m'any pregnant women it wouldn't be known that it might cause a disaster under these circumstances although it could be taken with impunity otherwise. I would agree that this is a sore and serious point of neglect. We need to do `something about `it, `and I hope th'at `there will be developed along the lines I `have mentioned `a group which will automatically assume the monitoring watchdog function. This has not existed except within the individual conscience of individual physicians, and un- fortunately this `is not strong enough `to be an impelling force to make many people speak `out forthrightly on various controversial issues, `and very obvious `si'tu'a'tions. Senator NELSON. One of the experts who testified on this `subject stated that of `all the cases he had seen of aplastic `anemia caused by chloramphenicol, he had never in his career seen a single case in which the drug was administered for a properly indicated case. This gets back to the question of the advertisrng and promotion. All this advertising `and promotion `occurred in medical journals or through detail men or in the direct mailing of brochures `to the physi- cian. I am `sure there isn't a physician in the United States who, `if he really realized the consequences, would administer the drug, `as the testimony demonstrated, for cases `of `acne, sore throat, head'ache, in- fected teeth or infected hangnails. But it is pretty clear the advertising and promotion, especially the detail men, convinced the physician that this was a general use, broad spectrum antibiotic. I looked at the `ads myself some months back an'd can quote several `ads which `simply `said that "When it counts-Chloromycetin," n'ot a w'ord `about precautions, contra'indications, and side effects, but ju'st `a `continual pounding of very clever ads, "When it counts-Chloro- my'cetin." It was q~uite successful in promoting the drug. It seems `to me it raises a very `serious ethical question within the profession itself, when doctors responsible for the medical journals PAGENO="0030" 3934 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY know very well that it is being widely misused, and yet are accepting ads that successfully convince the doctor to prescribe it for nonindicated cases. In fact, the same journals carry articles by doctors such as Dr. Dameshek cautioning against this kind of use, while at the same time they carry the kind of clever ads that end up promoting this kind of use. Doesn't that seem to raise a serious ethical question? Dr. BEAN. It `absolutely does, and I think you have to take into effect human nature again. Man has been defined as the pill-eating animal or the medicine-taking animal, and there seems to be some instinct that exists that is satisfied by the ingestion of medicine which may symbolize the power of the physician or the power of medical knowledge. The change that has occurred is in part perhaps a reflection of I won't say the decay or decline of morale but a period of change in which responsibility is not perhaps so routinely or regularly assumed by those who should assume it, and there is no question but that under these circumstances in the nature of things, tragedies will occur, anct that I think `the blame can be laid nowhere but on the medical profes- sion. The best chance of some effectual monitoring will be a body of, we hope, wise physicians who will get together and, with their corporate power, be able to put things in their proper place, and be able to t'~ke the aggressive initiative in seeing that these things are done. It is when things go bad or when mistakes are made or when duty hasn't been done, it is fairly easy to identify what is wrong, it is not nearly so evident in the prOblem of how you treat a particular patient. It would be wonderful if all proper physicians included, had perhaps a sterner and more upright moral and ethical outlook It would be wonderful if this pervaded also those generally older, more con servative men who come to be effectual administrators within medical organizations, particularly the big ones, where the power structure accumulates in those who tend in their nature to be conservative, older, and so on. I think the best chance of coming to a solution is to have an inde- pendent medical body which will take upon itself responsibility in identifying problems and acting upon them and avoiding just such things-one could mention a great many, as Krebiozen, mineral oil being sold under high pressure to people who are in an agitated state because of tragic disease There is no evidence, only testimonial asser tions that it did anything. But even knowing this, the decisions about it have been determined before juries, a popularity contest rather than a scientific evaluation Senator NELSON. What scientific value is there in the kind of pro- motion of drugs we see? I think you comment that more money is spent on drug advertising than on all of medical education. Was that your comment or were you quoting from somebody else? Dr. BEAN. I made that comment. Senator NELSON. More than the whole cost of medical education? How necessary and valuable is it to have the kind of full-page ads we see in medical magazines and all the brochures? How useful is that to a physician ~ Or to put it another way, is it useful to him at all? Or is there another way that he could get the information that would be more reliable and that wouldn~t be misleading? PAGENO="0031" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 3935 Dr. BEAN. Well, it seems to me the very nature of the question sug- gests the operational answer, and that much of this is ineffectual in terms of an educational value which is objective. It does have a certain amount of information which gets to people that might not otherwise get there, and even allowing for the fact that it may, in terms of corn petition for the sale of drugs be soimewhat biased, it may still get* information to a physician who might not otherwise get it I don't think this happens in the majority of instances, and I don't think it should happen, and to some extent this is a reflection of two things, the enormous increase in the actual effectiveness of a multitude of powerful specific drugs to do a lot of things in medicine, and the inevitable parallel circumstance that undesirable effects are more or less in parallel with the desired effectiveness. For instance, if you have an anticancer drug, this is a drug that kills cells, and it is going to kill some cells that aren't cancer cells. You have to try `to devise such a drug with most of the effect that you do want and little of. the effect that you don't want. In the nature of the biological situation, we probably will never find a perfect drug Tinder these circumstances the problem of how one gets information to those who are perhaps in many ways reluctant to take it has been the brochure, the detail .man, `the sample, and the ad in the journals that the physician is supposed to look at. I think .that the answer to your question is almost automatically evi- de.nt in the fact that you ask it. A very considerable part `of advertising is not primarily education, and in many instances is not necessary at all.. Mr. GoiwoN. Doctor, I have here some documents which are part of the public record in a court case against the William S. Merrell Co. on MER-2'9; I don't believe these documents have been made public. How- ever, they are part of the case.'. Here is a document dated April 19, 1960,. an interdepartmental mem- orandum of the William S Merrell Co' It is from R H McMaster, medical doctor to Dr. R. L. Stormont. It is about Dr. Hyman Engel- berg and they say as follows: Although it begins to appear that any report from this study may be a negative one, we may .fln:d that we are money ahead to keep Dr. Engelberg busy at it for a while longer rather than to take a chance on his reporting negatively on so few patients. We are talking about MER-~9 now. And then in the next paragraph `they say: My personal recommendation is that the grant-in-aid he approved only to keep Dr. Engelberg occupied for a while longer. Another document dated August 19, 1959, to Dr. Van Maanen from the medical research department' says: I am strongly opposed to .the discussion of any finding from experimental ani- mals until we have agreed upon our Interpretation Further on they say: In this ease, I do agree that we can `show the pictures to our investigators in Syracuse, `but it is acknowledged that we are taking a calculated risk because 1 See p. 3970, infra. See also appendix V "The MER-29 Case," beginning at p. 4202, infra. PAGENO="0032" 3936 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of a great moral and ethical problem involved. Because of the careful selection of our investigator in Syracuse, I think that it is a reasonable risk for us to take. For example, in talking about a fee to Dr. Hollander, of Boston, Dr Hollander mentioned the matter of his consultation fee,' and then at the end they say My own feeling is that we can t afford to chance alienation of Hollander 3ust now. Perhaps I shouldn't regard this as blackmail. In another interoffice memorandum' a company officer says: The objective in contacting the Armed Forces was to lay the groundwork for the eventual sale of the product to the various hospitals serving each branch of the Armed Forces when the product is released. Now, note this: We are not thinking here so much of honest clinical work as we were of a pre marketing softening prior to the introduction of the product. What do you think of all this ~ Dr BEAN Well, it is unspeakable I don't think anybody anywhere would condone that I don't know why I should say selectively that I disapprove completely of everything that you reported there, but that is the fact Mr. GORDON. This was during the development of an investigational new drug, and this is what went on. In addition, the firm got a doctor to sign his name to a letter which was written by the company. The letter was then sent by the doctor to the Medical World News. It was then used as a testimonial to the Food and Drug Administration. The company also sent a copy of the letter to all its detail men, with the caption "Dr Lisan Speaks Up "1 So the detail men went to doctors saying: "Here is Dr. Lisan of Philadelphia, who says this," when it was actually the company who was saying it Also in another memorandum' we have the following quote: Dr Becker s paper prepared for the most part by (Richardson Merrell) was rejected by the American Journal of Cardiology and has now been accepted by the Journal of the Medical Society of New Jersey. We have received permission to purchase reprints. I ask Mr. Chairman, that these documents be put into the record at the appropriate place. Dr. Bean, in the chairman's opening statement, his last question is "When influential doctors or pharmacy educators, particularly in high academic positions, are large stockholders and/or serve as policy-set- ting members of boards or drug corporations, since these men are in a position to mold the attitudes of other doctors and to make policy decisions in key medical and pharmaceutical organizations might there not be a conflict of interest here?" Would you comment on that? Dr. BEAN. Well, let me put it in a personal frame of reference. I would find it impossible or perhaps intolerable if I were on a retainer fee from any concern, be it drug firm or book publisher or anything else to be put in a position where I had to offer independent informa 1 See pp. 5971-73. infra. PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3937 tion, advice, teaching, testimony, or whatever. I don't believe that it is possible, it wouldn't be possible for me to act in an unWased way under these circumstances. It seems to me this is quite different from acting under contract on a specific function someone might wish to have a certain subject re- viewed or `an opinion given to somebody who would then pay you as a consultant for this particular thing, but this is quite different from being in the pay, without any special requirement, but with the in- ference I think overwhelmingly evident, and with the legal require- ment also, I believe that one who is a member of a board of directors or who is in the employment of a different firm rather than, say, an educational, or a medical, or a hospital, or a practice arrangement, I think it is nearly impossible for people not to allow that to influence them. I don't say it is impossible. I guess it is possible, but it would be impossible for me not to be influenced under those circumstances. Therefore, since I don't keep secrets well, and since I `believe th'at what I know is freely available, and I like to let people share it if I think it is going `to help, I would find this personally an intolerable operating scheme for me, but I can reckon that there are people of such powerful goodness `and rectitude that they might be able to divorce themselves from this relationship in interpreting, teaching, or doing other things, but this must put them under a great deal of strain. Therefore it seems to me the part of w~sdom to avoid n'ot only the suspicion `of evil, but the temptation to evil, if you think these things are evil. Mr. GORDON. I would like to mention tO you `that an analysis of the responsibility of directors to the stockholders of a corporation is in- cluded in a memo from the Library of Congress.1 One of the sentences reads as follows: While directors are not strictly speaking trustees, they `do occupy fiduciary, or perhaps more accurately, a quasi-fiduciary relation to the corporation and its stockholders. Each director must exercise his unbiased judgment,' Influenced only by considerations of what is `best for the corporation. Many courts have spoken of the rule as being that a director owes a loyalty that is undivided and an allegiance that is influenced in action by no consideration other than the corporation's welfare. Now, what do you think of a director of a company, whO is also an academician, who writes articles and delivers speeches, and does not disclose his identity as director of the company? Dr. BEAN. Well, I don't think anybody could say anything good about that situation. It doesn't seem to me to be under any circum- stance, the law being what it is-which I was not aware of, although I am not surprised that is true-the difficulty of serving two masters is not a problem, if they are both aiming in the same direction and they have almost superimposable functions, But where they `are in conflict and you are aiming in two different directions, you have to mal~e a decision either to do nothing or to go in one direction or the other. Under these circumstances therefore it seems to me it is not only the part of rectitude bitt the part of wisdom to identify the hat that you may be wearing under the circumstances of a particular statement, or a particular article, or a particular speech, so that people will know where your bread is being buttered from and on which side. 1 See p. ~973, infra. 81-Z80-69-Pt. iO-3 PAGENO="0034" 388 CO~rPEtt'ITIvE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. I might bring up a specific case. Here I have a book entitled "The Medicated Society," There is an article in it, "The Coti- tributions of the Pharmaceutical Industry," by Chester S. Keefer, medical doctor, former dean of the Boston University Medical School, and who is also an adviser to government. This particular article is very laudatory of the industry. It was taken from a Lowell Institute lecture. Not once, in the lecture which I read, nor in the article which is in the book, does he mention the fact that he is a director of Merck & Co. Dr. BEAN. It seems to me to be, if an oversight, a flagrant one. If it is something else, I am greatly surprised that Dr. Keefer, who is a good friend of mine and an admirable man, has put himself into this awkward situation. I don't see how you can deny that it is awk~ ward. Senator NELSON. Doctor, I want to thank you very much for giving us so much of your time to come here and testify before the' committee. We' appreciate very much your contribution to these hearings. Thank you. Dr. BEAN. Thank you. (The supplemental information submitted by Mr. Gordon follows:) [From the Journal of ]kLedical Education, vol. 36, No. 1, January i9~6iJ SELLI1'IG DRUeS IIY "EDUCATING" PET5ICIANS* (By Charles P. May, M.D.t, Department of Pediatrics, College of J~hysicians and Surgeons, Columbia University, New York) The traditional independence of physicians and the welfare of the public are being thi~eatened by `the new vogue among drug manufacturers to promote their products by assuming `an aggressive role in the "education" of doctors. In the recent Congressional investigation of the cost of drugs it was repeatedly stated by executives of pharmaceutical concerns that a major expenditure in the promo- tion of drugs was the cost of "educating" physicians to use the products-and they mean doing what has always been expected of medical institutions. Is the public likely to benefit if practicing physicians and medical educators must per- form their dutie's amidst the clamor and striving of merchants seeking to increase the sales of drugs by conscripting "education" in the service of promotion? Is it prudent for physicians to become greatly dependent upon pharmaceutical man- ufacturers for support of scientific journal's and medical societies, for entertain- ment, and now also for a large pa'rt of `their edtieation? Do all concerned realize th'e haSard of arousing the wrath of the people `by an unwholesome entangle- ment of doctors with the makers and sellers of drugs? That these aie grave and pressing questions a~d not trivial fears should be- come `apparent in the ensuing presbntation of problems that surely deserve the serious attention of manufacturers, prescribers, and consumers of drugs. No one can be oblivious to the many fine contributions of both doctors and drug companies that certainly deserve the greatest admiration, but the dark side of things must be fully explored if the origins of the present problems are to be 4e1~ermined. The higher purpose of this analysis is to halt practices which are undermining sound medical care as well as degrading the reputation of the pharmaceutical industry and lowering the prestige of the medical profession- to a degree that has already aroused public concern and the probings of~ poli- ticians. *The author submitted this manuscript for critical revi'ew to the Physicians' Coun- cil-an independent group of eighteen eminent physicians who organized In 1O'5~ "to seek means for maintaining high standards for the material on health that is d~ssemi- nated through the media of mass communication." The Physicians' Council wishes It to be known that It endorses this essay as an aecurate, equitable, and constructive analysis of matters of major Importance in relations between the medical profession and the pharmaceutical Industry. Reprints will be available from the Physicians' Coun- cil, 2 East 63rd Street, New York 21, New York. tClInIcal Professor of Pediatrics. PAGENO="0035" COMPETITIVE P~OELEMS IN TIlE DRUG INDUSTRY 3939 After a general discussion of the deleterious practices, some specific proposals will be offered for preserving proper relations between physicians and manu- facturers of drugs ~nd thus spare them from unfortunate experiences in public investigations. PROMOTION AS "EDUCATION" Surely physicians realize that they cannot have faith in all drug promotion, but many assume that at least some reputable firms can be depended upon to consistently disseminate reliable information. The soundness of this assumption can be tested by a look at some current specimens of advertising. These items are from a considerable supply of the same kind, and regular scrutiny of the torrent reaching the physician will satisfy the curious that similar examples are easy to find. It will be seen that well known firms are guilty of sponsoring dubious "education" material on topics of vital importance, and so the physician is left without any assurance of authenticity e~cept from his own wits. Antibiotics.-Antibiotics are therapeutic agents which no one can deny should be used intelligently and with discrimination. Efforts to influence physicians tO prescribe these valuable remedies on an unsound basis would be particularly unfortunate; only clear and accurate information should reach the doctor. For the past 3 years major pharmaceutical companies have been engaged in a competitive struggle to increase the sales of their particular brands of anti- biotics by a confused and misleading barrage of promotion (Figs. 1-3). The ex- uberant campaign was based on meager and poorly controlled observations on the levels attained in the blood by various preparations of antibiotics; additions of certain agents (phosphate, critic acid, glucosamine) were claimed to enhance the absorption of antibiotics and enable higher levels to be reached in the blood more promptly. Soon after this hectic campaign was well under way, the premise was chal- lenged (9, 14) : actually, the action of these agents was to neutralize the unfor- tunate effects of `fillers used in the capsules of the antibiotics-these were calcium salts that combined with the antibiotics and hindered their absorption. When the various forms of antibiotics are administered to fasting persons without fillers, no advantage is observed from addition of phosphate, citric acid, or gluco- samine to the plain parent compounds (10). Furthermore, no sound evidence was ever brought forth that the levels and speed af absorption claimed for the widely heralded derivatives offered any practical clinical advantage or therapeutic superiority. Pointed criticism from competent authorities did not check the eagerness with which the promoters undertook to "educate" the physicians with inadequate and irrelevant data and misleading claims in material distributed for the drug companies. Note the triumphant tone in the examples of promotional material from this campaign-this is the sort of inconsequential contribution the industry sometimes refers to proudly as the result of great Investment in research in the companies' own laboratories. This achievement consisted of getting rid of the inhibiting effects of filler the manufacturer customarily used in the capsules of such products. The "educational" effect on doctors was to confuse them and lead them to believe wonderful new drugs were available and that minor differences in blood levels and the rate of absorption are significant therapeutic advantages. Similar tactics are now being applied to a derivative of penicilin (Fig. 4). The same substance is put forth under at least six brand names as if it were the discovery of each distributor. It is also slyly touted as synthetic penicilin while it is only a chemical modification of a fermentation product that is not isolated in pure form (15). The same chatter about higher levels being attained faster, without proof of clinical advantages, characterizes this latest "educa- tional" material reaching the doctor. Once again evidence `is lacking to prove the clinical superiority of the new derivative; the old penicilin V can be absorbed about as well if administered on an empty stomach (13). No amount of pleading (7) has discouraged the pharmaceutical industry from marketing and pushing products made up of mixtures of antibiotics. An example of low regard for the Intellect of the average doctor is the promotion of Panalba by Upjohn (Fig. 5), where one is asked to believe an in vitro sensitivity test is a demonstration of clinical "performance In pneumonia" (no references to clinical N0TE.-Numbered references at end of article. PAGENO="0036" 3940 COMPETITIvE PROBLEMS IN ~ PHE ~ ]~RUG INDUSThT ~ **~T* A s ~ ~ ~ ~ ~ ~ ~ I ~ flTP~c , ~,* , 1*11 .mprov~rzent I ~ ~ ~ ~nd ø~ u1tii~ de rept~iccrzc~? s~ ~ ` ~ for She older te1rac~!tne ~ ~ ~ ~ $~ ~ ~ ~ hyiroch~r*de 4~ ~1 ~ ~ S ~. ~ S ~ *~S *~ ** ** * . .5- .~ . ~ ,,~S$ ~ .; ~ ~%- ~e~/4*~# ~ ~ rn&r~~ h3t Ø~*S~ ~543' ~ ~,Lx~*o~ 555 ~ F~ ~I ~ht"~ ~~*`a~ - ~d ~ .~ 1u~x 1~14r~y~s~ &~I ~ Xy~ 1~ ~Iet re~~ ~ ~ ~gI~ O~fGIHAt UT*~&CYCt1W~ ~`4*~PW Y& COMPL~* ~ ~o ~ ~ ~ ~ t ~ I~t~5t~p t ~ CUr~*~Dlty ptov*x~- It irs P~1 4kt~rE~ ~ tb t hkn~~ ~ ,~S ~ ~ 4onntrz~rn;~ C >trt te ~ ~ ~4*t'~ tJ~ft `~flY r~. p~ ~ ~ 10 ~ th ~ wra~.~ di ~ J ~ w~ H hc~ ~ ~ p ~ ~.. ~fl~t.t s (I ~ v~ t ~ ~~n;e Ik'~ rn ~ ~tui~ pt t~ n~ dt,. ~ ~ ~ ~ t~:' ~e ~. ptibl o~ ~i ~ ~ ~ b~ n ~*Hy ~ ~ ~ ~. ~ ~ ~ ,~`- ~T~v1fl IH~ ~ ~ n~tt~c~ ~ p n~rt ~ ~ 03 ~ $ ~_ ~ `~ U ~ L~;~ rr ~$ ~th r ~ ~ * ~sT4~~tl~rC ~ 5)5 ~fl ~ ~ ~ w~ t (~tt~ 1 ~ f~c r ~ t tt r ~ ~ ~ ~ ~ ~ A~n~r~drLi~ ~ I ,` n~ ~ n ~ if ~d ~ ~ ~ ~ ~ t~. ~, ~. ~ ~ ~ rp~.~4 En fc L3d1 my Is ~, 4sç(~ r ~ rLs f ~ ~ ,~ ~ ~ `~ t~ 4 4~k F t ~i ~ t ~ tk ~ ~., q ~ ~ ~ dr4~'4k~f th~r-~ ~. ~ ~ :~ ~ ~ ~ f ~` ~ ~* )Ø(~ ~~5I k~14*(* S~4~*~ ~n~StOL LAUORATORIES ~NC s~~t*cu~e s~w ~øi~*( ~ ~.Dt~v :~P~'tA~ ~ ~-` ~ fr~s,ss~1 <~ 3 ~% ~ ~ ~ ~" `~~/ .~ K ~L ~*i M e ~ 3èPis~t 3 )~SS~'A~ ~ ~ 3% A $~`I *y II A. is ~ T sA~ *,~ a s~.a I 1 i~ ~Pa~ $.E~" * ~r.s~44 I ~ `15 * ~ (.~ 14 PI~ `15' .* 4~s' M * 3 `1) ~ At' ,tI1 Ps A' ~1&IHe~ ~ A~A* 4t,~s6 15's is,s% ~ 1% A! W AMf' ~ r45#: ~ ~ p ~s. ~ -S. 53% / t PAGENO="0037" COMP~3TITIVE PRODI~EM~ IN THE DRUG INDUSTRY ~394i tci I R0'sI YC1 N `I'et rar~ cli vie L~ uui%ersalls reeoi~riized ili.~' superLor arltLluUttc for the t~ontrol of a wi~ie range of ~u~ctptab1e org~iiii.~iii~. Constant re~arc)t ~ ~ h~ r.'tifted in an antiluotir ~ re~4v dr~i~ned to accentuate rapid. diffusion into btnlv ~ue~ and f1uid~, witiL minimal side t~ffect~. high and fast blood kvel~ are achk~ed for iiiort~ competent control of the di~ea.~e under treatment. for unexceiled an tib lot Ic action UOERLE LA8ORATORIES, A DIV1S~O~4 OF AUERtCA~4 CYA~AMi3 COMP~MY ?(ARt. RIVER, NEW YORK FIGURE 2 trials). The nature of this comhination is kept obscure by giving the company's brand names of the ingredients. What will this kind of "education" do to the physician after a few years of domination of his habits: and beliefs? How can one gain confidence in promoters as educators or believe in their sincerity in view of these typical disclosures? Thereis an astonishing disregard for expert opinion and the complaints of responsible physicians even in the present trend to repeat the tactics that characterized the promotion of "poten- tinted" tetracyclines in the current advertising of "synthetic" penicilin. The untrustworthiness of "educational" material employed to promote basic products is not peculiar to antibiotics. Similar disregard for the available evidence and for authoritative opinion can be seen frequently in the advertise- ments used by leading ethical pharmaceutical firms to instruct doctors. REVEALING ECONOMICS It has been estimated (1) that drug companies selling their products through doctors' prescriptions spent $750,00,000 in 1959 on promotional activities. How much of this sum was truly directed to "education" is a moot question. Advertising in medical journals and by direct mail to physicians amounted to $125,000,000. The expense of maintaining the army of 15,000 detail men busily engaged in spreading "education" must account for a huge portion. The remainder went for exhibits, films, trade publications, lectures, televised clinics, samples, etc. All this huge sum was in the last analysis devoted to One prime purpose-to get the physician to prescribe products of particular firms by brand names. ~`~-~: ~ PAGENO="0038" 8942 COMPETITIVE PROBLEMS IN THE DRUG INDUSTItY ~5 ~ `.~ E~ ` ~ ~` ~ an J~ ~ ~niii~iY ~ c:~/~ ~ concept ~ ~ ~. ~ 4 t 11~~~;4\i .~ In ~ !~1r~ broad-spectrum ~`1 therapy C~tM tt 0 1~> ~, h~ ~ t ~ ~ ~ L x * IE~ U ~ ø~ t ~. ~b ~ ~z u ~u o ~ I ~ ~ [Is *~ z ~t ~ ~ n P Is LI I I e fit ~s1 ~ ~sj*~ rui~ r I ~ ~ t~-I ~ r~< I. U)~ th~ ~ s ~ *$~~ ~., / i Irk n ecu.., It ~< I v~ s~ ~ 1*351 ttz u~ I s * 1'I~ r s( ( ~ ~ I ~ ~ ib t C ~ Ut~RcsL~~ (~11s(uls I ~ . t~ ~5t ~s.~t~tas~ ~ ~ ~ a~t I S S ~k ti ~L IC~ (I tt ~ ~d ~ >tt(5 ~j ~ 55 ~ t~tr-u I u ~ 4 ~s ~k ~s ~ I I ~1Is5j~tr f~s s ii~ ~ ts It I s I 2 \1s n. ( * X i~ 1 *j, ~t* * 3tf I I~, `st list ii. ~ 1 ~ n"t~*-fi ~ ~ Ikc* c `. ill s.ntiJJr~ i~' ~i*n ~t~fi~,er' r~ Ill `~ ~i~itt 4 cJ~l )tl~ `i ii ~ *t3 53 ~ ~ g,I~i ,, ~* *n s *fr }~ * i * * ~3~4 ItSi I .~ I ~& H St S1~ St i~ S S ~ 54 `ii 5% 1 *VIl~ ~ I t~ j~'~ ~ t 15 1, ~ 1* 5 5 5 `1 53 * ~ 5% .5 35 ~ 4 s I ~I I I I 5.5 3 t 5 1 5 `51 1 s( II ~ t (~`. .isP II L 1 S Ic 3*5 3115 t~ .*t 11 J~ D 5.5p#kI S *11*. MIis.'5i `III 35* 3. ~* *st s *tIdL*15* 43.1551.0 1..T~1I~4 1.11 Your patients will do better when you choose CCç~S antsbiotic~s Fzcui~E 3 Whether various aspects of this imm~nse promotional campaign are labeled as advertising or education, the medical profession and the public cannot safely ignore its effects on either the cost or the physician's use of drugs. The success of the promotional activities depends on gaining an influence over the habits and beliefs of the prescribing physician ("the funnel through which all ethical drug sales must pass"). Two-thirds of the spending for drugs and medications is attributed to items prescribed or recommended by a physician or a dentist, and these absorb 20 per cent of the funds spent by the public for personal health care. Between 1952-53 and 1957-58 the expenditures for drugs and medications in- creased 120 per cent (1.5-3.3 billion dollars), but the spending for physicians' services rose much less, or 42 per cent (3.8-5.4 billion dollars) (18). The item of interest here is in the share of the health dollar absorbed by expenditures for drugs (an increase from 15 to 20 per cent in 5 years) compared with the portion spent for physicians' services (a decrease from 37 to 34 per cent in 5 years). Another way of appreciating the factors involved is to note the changing picture revealed by estimates of the increase in the use of drugs (in contrast to merely a PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3943 r ~ ~`j~ 7 ~*7 ~ :` :~. .: pt~F~&,~ . . . . ."...,~ ~: ` : ~ ~ ` ~ :` : . ` dV~_et ~ `~ ~ This IS Panalba 4_, _\_~ ~ performance ,~<:et ~ 111 \ 1* ~ 4 ¼ C' 1!i `~¼4 b~'~ ~ ~ `~` r1 I th r~'- k I ¼ Pana1ba~' 2 1 / ~1j / z ~ .~ ~ jc~;~~c~t [~~~i~7} a 4 1 J FIGURE 4 FIGURE 5 PAGENO="0040" 3944 coMPi+IVE OBLEMS' T~ THE ~RUG DI~SThY ~ in the price of drugs). In the 5-year period bteween 1952-53 and 1957-5~ there was an increase of expenditures due to rising costs of drugs of only 9.5 per cent, but there was a 73.5 per cent increase in the use of drugs (18). Consider these figures in relation to the outlay for drug promotion in the same period: Between 1953 and 1958 expenditures just for advertising in medical journals and by direct mail to physicians increased by 219 per cent to reach the all-time high of $125,000,000 (1). By contrast, the total funds available to all medical schools in the United States for their educational programs in 1957 was only slightly greater, $200,000,000. THE QUESTION There is no way of ascertaining the extent to which improvement in the health of the population is due to a contribution of the medical profession, the achievements of drug manufacturers, public health measures, or socioeconomic conditions. It is evident to everyone that the pharmaceutical industry has made an important contribution to the public health and to the treatment that can be administered by physicians. The pharmaceutical industry and the medical profession have come to occupy prominent places in our society, and we must deal with them as permanent and useful enterprises. The principal subject under consideration here is the possible impact of promotion tactics aimed at "educating" the physician on the character of medical practice and on the extent and manner of use of drugs, and perhaps on an un- necessary high cost of pharmaceuticals. Of equally fundamental concern Is the need to examine the appropriate prerogative of each of the parties engaged in meeting the needs of the people for medical care. Only by a clear definition of their separate roles can the public be safeguarded from evil consequences of unsuitable entanglements between the manufacturers and prescribers of drugs. The essential purpose of this inquiry is. to search out the principles which will bring the trade and the profession into proper alignment in fulfilling their ob- ligations to the people. The objective should be to cultivate cooperation without drifting unconsciously into a collaboration that could undermine the inde- pendence of the physician, the free enterprise system of trade, and be dele- terious to the medical care of the public. There is sufflcient talent and idealism in industry and the profession to for- mulate a wholesome partnership, but unfortunately the best intentions of any group are liable to serious dislocation by the machinations of some eager spe- cialists In promotion who may be oblivious to anything but personal gain. Un- doubtedly some of the present problems stem from inadequacies in the profes- sion, and these must be dealt with forthrightly. TO EACH HIS OWN A wise division-The right to practice medicine granted to a physician by his license and the privilege given to others to manufacture and sell drugs are each derived through laws adopted by the people dependent upon their services. There is a vital division of responsibility and at the same time a joint obliga- tion inherent in those arrangements. This must always be clearly recognized by the parties to whom the people have assigned a share in the guardianship of their health. The working relations between the medical profession and the pharmaceuti- cal industry were not formed easily, as though it were a natural and inevit- able means of meeting the health needs of the people. There was a bitter struggle for several centuries between apothecaries and physicians for dominant control of both the privilege to manufacture and sell drugs and the right to prescribe treatment. The conflict was not resolved until late in the nineteeth century when the people, through the law of the land, segregated the right to prescribe from the privilege to trade in manufacture and sale of drugs. This safeguard was found necessary to protect the people from exploitation by any one group that might stand to profit by prescribing remedies of their own manufacture. Do not disturb-The people would not tolerate for long any tendency to bur- densome expenditures traceable to excessive influence of the manufacturer over selection of treatment or to uncritical use of costly drugs on the part of physi- ciana Life magazine (February 15, 1960) concluded a report of the recent Congressional investigations of ethical drug concerns by stating: ". . . in the long run it is up to better informed consumer~ to insist on being less captive and to pressure the doctors into using a finer discrimination." Neither the medi- PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3945 cal profession nor the pharmaceutical industry wishes to feel undue "pressure" from the public, and thus both have every reason to maintain wholesome work- ing relations and a sense of joint responsibility in strict compliance with the welfare and wishes of the people who granted them their privileges. The divi- sion of responsibility must be truly respected and not disregarded through any subtle entanglement that may arouse the indignation of the people. SOURCES OF CONFUSION AND CONFLICT Legal loopholes-A typical state law on medical licensure (New York) states that "a person practices medicine . . . who shall either offer or undertake by any means or method to diagnose, treat, operate or prescribe for any human disease . . ." Further, "No person shall practice medicine unless licensed . . ." The legal position of the physician is the basis `of operation of the Federal Food and Drug Administration a.s set forth in the Food, Drug and Cosmetics Act as amended in 1952 which states that a prescription is required for "any drug which because of its toxicity `or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary for its use, is not safe for use except under the supervision of a practitioner licensed by law to adminis- ter the drug." This places the practitioner squarely in the `path of the manufacturer and distributor of drugs which require a prescription; be must therefore he per- suaded to use the drug if it is to be commercially successful. The physician be- comes the prime target of promotional tactics and exposed to the craftiness of any unidealistic pursuers of prOfit. It is n'ot generally appreciated that the Food and Drug Administration is not empowered to control the claims made in the advertising of drugs regarding the usefulness of a product, but must restrict its concern to the safety and proper labeling of drugs distributed in interstate commerce. The Federal Trade Com- mission is assigned a responsibility in respect to false advertisements of phar- maceutical products distributed in interstate commerce, but somehow an interest- ing clause gained its way into the Act of 1914 outlining the powers of the FTC and has remained there to this day: "No advertisement of a drug shall be deemed to be false if it is disseminated only to members of the medical profession, con- tains no false representation of a material fact, and include's, or is accompanied in each instance by truthful disclosure of, the formula showing quantitatively each ingredient of such drug." Thus it is evident the promoter has a remarkably free hand in seeking to influence the physician. In essence the attitude behind th'ese Federal Acts is that the physician should be able to look out for himself in selecting drugs for treating patients and needs little protection from the law or regulatory agencies. This might be true if be did not have to con'tend with subtle overpowering promotion and the complexities of modern medicine, especially if he is to be "educated" by the very purveyorS of products which require his prescriptionis. Semantic smog.-Tbe compai~ies sgilin~ drugs through doctors' ~reseriptions have enjoyed the distinction of being referred tO as in the "ethical" drug trade in contrast to the proprietary firms engaged in sale of drugs direct to' the public ("over-the-counter"). Ethical as here used refers only to the channel of distribution `and not `to the manner and morals of promotion. The distinction be- comes even less `meaningful when companies deal in both routes of sale'; many large "ethical" companies sell products in both categories or have subsidiaries in the proprietary field, and some proprietary firms have acquired cohtrol of ethical companies (6). A recent trend h'as been to exp'and `the market for so- called "over-the-counter ethicals," i.e., products sold directly to the public but not generally advertised as yet in lay media. The Food and Drug Administra- tion permits a product to be sold wit'hout a doctor's prescription when it i's deemed safe to do so, and no objection comes frouf the profession after custom- ary n~tification in the Federal Register. An increasing number of products are making this transition from the ethical to `the proprietary realm each year (2). This should be of greater concern to the physician who may become by-passed ex- cessively and the people urged to drug themselves directly by the manufacturer. The movement in this direction may be a considerable factor in the greatly in- creased use of drugs in the past 5 years, already mentioned. It is easy to see that the retail druggist can also be drawn into the struggle to influence the phys'iciacn and the public to use particular brands of drugs. PAGENO="0042" C~MP~TI~IVE PROBLEMS~ IN THE DEtJG iNDU~RY D~UGS FOR ?~tERGIIA±ThISE OR FOR HEALING? Temptations of bigness.-The di~c~jti~es in ~i~int~tthing p~op~ ~uç1~pcPde1~é of phy's1~ians f~ota tb~ oellei~s of drugs haive been aggravated by th~ growth Of the pharin'ac~utical industry to a "big business"-4rug sales elii~bed to `about 3.3 billion dollars ~n.i958. It has been pr~dicted that this volume will triple within the coming 15 years (16). It is Inevitable that such a promising market, unless carefully watched, will be the prey of fierce competition and the hard-hitting promotional tactics of the commodities market. This may be within the legitimate functioning of our free enterprise `system of economy, but there are special con- uiderations callin.g for restraint in seizing upon the public health as a commercial plum. Certainly the medical profession wnuld be well advised to take care that the public doe's not `come to believe doctors are too entangled with the hustling in the market place. Manufactured complecvity.-One result of the eagerness to share in the profit- able busines's of making and `selling drugs is an energetic effort to launch new products. At present about 400 new prodnets are introduced by pharmaceutical companies each year (4). Actually, not more than forty `of these are new chemical entities, most being slight modifications or different preparation's and mixtures of established agents put forth with claim's of `advantages such `as flavor or absorb- ability, etc. As a matter of fact, the really new drugs of material assistance in treatment, and requiring advancement in the knowledge of the `physician for their use, probably amount to less than six compounds a ye'ar. Thus the task of keeping :abrea!st of significant new therapeutic agents i's complicated for the physician by the difficulty of identifying these among the avalanche of minor va~i'a'tions, often heralded In the promotional material as striking achievements. The physician might not need so much "education" If there was not so much d~pli- catinn In brand's produced for profit rather than t'o meet real needs `of patients. It is commonly believed that catchy brand name's `are better chosen for ea'sy remembrance than proper or generic names for drugs, but see if the following list is familiar or informative. UNREVEALING BRAND NAMES Madribon Medr'ol M&radon Mars'alid Mephyton Mode'ril Maredox Meprolone Mo'noçlral Mebaral Methium M'uividren Med'omin Midicel Mysoline Any potential advantage `of a catchy name i's lost when one is faced with new trade nanies for 400 products a year for perhaps a tenth this number ~f different specific agen'ts. One wonders whether the few generte names that actually should be learned could not be even better mastered than the numerous variants In brand na~nes far a `single drug, if comparable promotion ("education") were devoted to implanting the fewer generic uames in the mind of the physician, for example: SINGLE GENERIC NAMES FOR DRUGS WITH MULTIPLICITY OF BRAND NAMES DEXAMETHASONE PEEDNISONE TETRACYCLINE Deoadron Deltra Aehromycin Deronil Deltasone Panm'ycin Gammacorten Meticorten Polycycline Tetracyn PIIENETHICILLIN ("SYNTHETIC" PENICILLIN) Alpen Darcil Syncillin `Maxipen Chemipen The arguthent that `a brand name affords assurance of quality and purity be- cause of `a responsibility imposed on the company having e~clusive rights to its use is unimpressive. This responsibility should be fully assumed by the Food PAGENO="0043" COMPETITIVE :;PROBLEMS IN THE DRUG INDUSTRY P3947 and Thu~g Adminiatratiion; which has the power of inspection and shouhi linve mOre meaps to exercis~ it. We do `not: need a complicated system of private:owner- ship of names of drugs to p'r&tect~ the public As a matter of fact, drugs presently distrihuted by generic names have not often been found inferior in the limited inspections the FDA ha's been able to make. It is evident that a vicious circle is created by a mad scramble for a share of the~ market: the doctor is made to feel he needs more "education" because of the prolific outpouring of strange brands but not really new drugs, produced for profit rather than to fill an essential purpose; and then the promoter offers to rescue him from confusion by a corresponding brand of "education." TIlE STYLE or PROMOTION S~mart and sly.-The goal of promotion, even when traveling a circuitous path under the guise of "education," is to achieve uncritical acceptance of a precon- ceived message-to captivate the mind; stimulation of skeptical thinking could block the purpose. This is in sharp contrast to the objective of true education, which seeks to cultivate the use of the mind for independent judgments. The success of promotion does not depend on the authenticity of the message but on the skill in manipulation of belief. The psychology of persuasion has been studied more assidously and is better mastered by promoters than by professors. Not only are the rewards and competition in commerce stimulating, but the best techniques of promotion can be ascertained ~y the concrete measure of sales figures. The educator is hampered in evaluation of his methods because the results are deep in the mind and cannot be given specific price tags. Preparation of promotional material is generally farmed out to specialized advertising agencies, and these have not always shown a notable sense of respon- sibility in their use of the mass media in matters of health. It is to be expected that an advertising agency would be more concerned abou4 the success of a pro- motional campaign than its impact on medical practice. Whereas medical men of integrity may be consulted in the preparation of promotional material, it seems that they may be overruled by executives occupied with maintaining sales and profits. Payola ?-In conjunction with the actual advertising material, the pharma- ceutical companies go to great extremes to sell an appealing "House Image" to the physician to soften his resistance. Lowest on the scale are overt gestures like ordinary entertainment and personal favors. One "ethical" drug company (Eli Lilly) gives medical students new diagnostic instruments each school year to foster "the close association of our two professions," with the proud boast of having enlisted "the co-operation of the dean of your college !" A particularly regrettable maneuver is the erploitation of the natural sympathy between doctors and students by hiring the needy and unsuspecting student as a detail man (Pfizer, Schering). More subtle wooing takes the form of conspicously sponsored conferences and television clinics and give-away lavish medical magazines and newspapers some- times made more fetching with pseudo-culture and racy human interest. Grants are made in partial support of independent research, but these usually cover only part of the cost and tend to favor utilitarian studies; and the investigator may unwittingly find his results subject to exploitation (11). Medical organizations are given monies to support a large part of their activi- ties, and then are in a poor position to criticize practices that infringe on the pre- rogatives of the medical educator and imperil the knowledge of the physician. The question might well be raised: How does all this courting differ from payola? Promotion is to commerce what propaganda is to politics. The physician, like the citizen, had better have a clear notion of its trustworthiness. I~ the applica- tion of information to the care of the ill, it is not enough for most of what is offered to be accurate; the difficulty of avoiding error is compounded when clever means of misleading the unwary are common practice. And remember, the physi- cian is left by the present laws to look out for himself in matters of promotion to a considerable extent. New proposals are under consideration to remedy this situation. Tricks of the trade-Innumerable ingeniOus devices have been contrived to give promotional material an air of authenticity. Some of these can be mentioned to warn pl~ysicians to watch for them in "educational" material prepared by pharma- ceutical concerns. PAGENO="0044" 3948 COMPETITIVE PROBLEMS IN THE DRUG. INDUSTRY Reference is often made to unpublished data from "personal communications," "ease reports in the company's flies" which are collected at random, and even individual testimonials. None of these can be readily evaluated in an acceptable fashion. Quotations lifted out of context are a favorite means of misusing sound sources, and inferior articles in the medical literwture may be selected to $upport the claims even when superior work is available to refute them. Only one or two of an impressive list of references may have any pertinence to the claims being propounded. Certainly the copy writers cannot be counted on to. evaluate the evidence critically; There are a few privately owned magazines published in the format of medical journals that are favorite repositories for superficial studies and common sources for references in promotional material. One of these was edited a~id published by a drug company that then used the teferénce~ in its advertisements, thus having a handy closed system of quotation. Implied endorsement by vague allusions to use of the product by "many" phy- sicians or hospitals is expected to be conviii~c'lng, as are the results of inadequate surveys showing "9 øut of 10" answering a mail questionnaire favored the product although it is not mentioned that only a small percentage of those questioned bothered to answer. The appeal to the eye is seldom neglected, but the mind may not be taxed at all with useful information as to contraindications, side effects, toxicity, etc. Least of all can one hope to find any discouraging, data on actual or comparative cost of "new" preparations versus established forms of a drug. THE PHYSICIAN'S PuEDICAMENT Learning made difficuU.-The body of knowledge which should be assimilated by the physician is burdensome enough without complicating his access to it. The legitimate medical journals have multiplied like insects; one must now seek his Information from 5,000 journals (over 600 in the United States alone) con- taining about 100,000 articles a year. These publications are almost all edited and written by amateurs in the skills of communication. The usual medical journal is more a repository of data than an organ designed tO interest and enlighten the reader. There are plenty of sound articles if one can find time to locate them and dig out the information. Even the review articles tend to be pedantic. The biblio- graphic aids such as mnde~-v Medicus list all articles regardless of merit and are of no help In checking on curreat promotion because they are months behind the journal, which in turn are months behind the clsttas in advertisements ba~ed on "personal communications," "exhibits," and "eases ta the con~ipany's flies." Editors and publishers may seem to pursue their lonely ways without regard to duplication of effort or real concern fOr the practicing physician, but this is partly due to inadequate staff. Usually the editor snatches time fronl some pri- mary task to turn out a journal as best he cali withoct specially trained assist- ants. Quite limited resources are available to the editor fot making the journal more attractive with art work and colored ihlustratioits or taOte interesting through enlisting the aid of skilled writers. Because of lavish expenditures for drug promotion, the income ftoin advertise- ments `is eno'ugth to make the owners of medical journals ~cwetou5 `of the profits. Two official journals of national societies can `be cited as bracketing the field: One general journal publishes 6,000 pages of advertising a `~ear, at $1,100 a page, or an annual income of $6~600,000; another speCialty journal recelve~ $260,000 a year from 1,300 pages at $200 a page. All the costs of producing these journals probably do not come to. more than ~0 per cent of the income from ads plus sub- scriptions, thus leaving 40 per cent for the owners. It ~Oirld' be hard to `beat this as a profitable business, since the raw materials-the talentS of the contributors- come free! Most lamentable is the lack of concern for the authenticity of material In the advertising pages in medical journals, which almost outweigh the editorial text in bulk and influence. Few journals show signs of a determined effort to reject misleading advertisements, and in none are the standards oct acceptance high enough. In this respect the owners of the journals exert a strong influence over editors, some of whom surely resent the encapsulation of the editorial text by objectionable material. Advertisements in otherwise reputable journals are not depOndable sources of education. Conflict between promotional "education" and scientifiC information in PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3949 the editorial text appearing in the same professional periodical is dramatically illustrated by an article and an advertisement in the same issue of the Journal of the American Medical Association (March 5, 1960). Wilkins (19) reviewed the experience with occurrence of female pseudohermaph- roditism in 3G infants born of mothers who during pregnancy bad been given nore- thindrone (marketed as Norlutin by Parke, Davis & Company), a synthetic pro- gesteroid compound, as treatment for habitual or threatened abortion. The natural hormone, progesterone, does not cause fetal masculinization. Norlutin and similar synthetic compounds have androgenic as well as progestational effects. The masculinizing effects of synthetic progesteroids can lead to the genitalia of female infants being mistaken for male, with dire consequences if they are reared as males and then subsequently feminize and menstruate at puberty; they may also be mistakenly assumed in the neonatal period to have congenital virilizing adrenal hyperplasia. The same advertisement for Norlutin (Fig. 6) has continued to appear regularly in the J.A.M.A. for the ensuing 3 months since the article by Wilkins appeared in that journal; in spite of his warning: "During the past year or two, Norlutin has caused fetal masculinization with sufficient frequency to preclude its use or adver- tisement as a safe hormone to be taken during pregnancy." The advertisement contains no clue to this complication and no information that is "educational" or enlightening. The startled expression of the woman in this advertisement may have more significance than the artist intended! The financial subsidy gained through advertisements is a doubtful blessing. The journals come to be regarded as profitable property and as vehicles for advertising rather than scientific periodicals. A journal with an eye toward the glitter of gold may become diverted from its proper function as an outlet of free and pointed criticism. This lush support inflates the number of publications beyond the natural needs, and the plethora of pages encourages acceptance of inferior articles-and so the bulk with which the reader must grapple is bloated as a consequence of the very promotional material he ought `to check against a discriminating literature. Little wonder that few physicians have the stamina to struggle with the over- whelming task of keeping abreast of new developments through their own medical literature. Medical educators must be especially cbargrinned to have succeeded no better in cultivating sound reading habits in students that should last through the lifetime of a busy doctor, and to have done so little to keep the medical literature serviceable and free from external influence. Believing made e~isy.-Tbe deficiencies in the medical literature and short- comings in the education of physicians have provided the golden opportunity for the promoter. The intense discomfort the doctor feels from the frustrations of using his own literature makes him quick to turn to the appealing "educational" material of the pharmaceutical concerns. The sellers of drugs have launched an impressive array of publications (the paramedical literature) and other devices to gain an influence over the habits and beliefs of doctors. Enviable skill and ingenuity have been devoted to production of attractive and well composed material. It cannot be denied that much of this is dignified and more useful than the journals and postgraduate programs sponsored from within the profession. The temptation to the busy physician, driven by desperation to seek short-cuts through the forbidding jungle of academic crea- tions, is so great that in all probability the readenship of the trade publications far outstrips that commanded by professional sources. Less harm would be done if the "educational" material furnished in behalf of promotion was free of bias. It is risky to depend on materials beyond the scrutiny of independent editorial staffs and of necessity dedicated to vested interests. Tardy and tacving aids.-Valuable reports on the nature and use of drugs by au- thoritative bodies are regularly published, e.g., the Councils of the American Medi- cal Association and the National Research Council. One might suppose the physican would use these to judge the accuracy of material reaching him through the channels of promotion. Reports such as these are widely scattered in medical journals or `apipear as separate documents `not generally received by many practitioners. It would be a tremendous task for an individual to keep track of ~dl tbese reports. Compilation of critical ev4luations by committees takes time, and ~ublication of their reports lags too far behind the current promotional campaigns to apply the findings when `they are most urgently needed. Even if such reports could be more timely', a `busy physician does not have time or energy to check the claims in promotional material by searching out PAGENO="0046" 3950' COMPETITIVE PROBLEMS IN ~HE IDRUG7 INDUSTRY oral!; ;fr~;!lvo proycs(-~?la;zal lb r\FL ~ flS)fl [1 T1~?9flJ]3 F I thi ~ssiS~i Li ud'J ~ tat 4,~PkD3n) in conditions involving deficiency of prays sic: one pnnrtn and scon'an aflKIlOflt) I Ifluistril d tnq~,uht t~ finK tion-d U1ttIII~ I>kttlit g (IIdOL!IIIL i oruon thrcarnd ;l,ni ton PACk'AOSNC: ~-t% s.&t tub! a.ta u ~oC 30 r, DAViS & COMPANY * 0(71*1 FIGURE 6 corresponding statements from comprehensive authentic reports. It is absurd to expect the truth to prevail when It is given relatively slight circulation In a single publication or is repeated af rare intervals,' while promoters `have dis- covered `that their message can be hammered home against grékt odds by `massive relentiss repetition. Another limitation of most scholarly reports is the polite reluctance to' single out specific products deserving criticism, as could be done `bF naming brands PAGENO="0047" COMPETITIVE PROBLEMS IN T~IE DRUG INDVSTRY 1~ or identifying fallacious presentation's in promo~ional material by direct re- production and quotation. A notable effort is being made to overcome these inadequacies by nn independ- ent group of competent physicians who are circulating a Medical Letter' con- taining pointed comment on the newest products while they are still `being inten- sively promoted. Unfair competition.-Advertlsing experts maintain that their methods would not be `so su'ccessLful if medical educators and editors `did their jobs better and physicians were so well informed that `they could not be influenced `by unauthentic promotional material. There is enough truth in this `to make sincere professors and editors wince, but the sides in the battle to dominate the habits and beliefs of the physician are not fairly matched. As things operate in our society, far larger resources can drift into the hands of pharmaceutical enterprises than can be raised by medical schools and pro- fessional organizations. While spending about $125,000,000 in 1959 on journal and direct-mail advertising alone, the "ethical" drug industry placated the deans and professors with donation of an unrestricted `sum o'f approximately $243,000 as their mite to the National Fund for Medical Education (3), or about 0.12 per cent of `the `total budget of $200,000,000 for medical school's for that year. To a large extent the paramedical publicatIons thrive as `parasites on the basic contributions of the profession. They `may `select what `they wish and remold it to their purpose without the tedious `task of doing the `original work. The drab and prosaic legitimate journals must limp along on* relatively meager resources openly raised through pai'd subscriptions or stoop to sharing the pro- m'oter's `bounty by carrying `his `advertisements, which enshroud and often com' filet with the editorial text. The beautiful and exciting magazines and news- papers from industry ean be given away, u~hatever `the cost, because the ex- pense is conveniently included iii the price of products the physician is led to prescribe. Alarming trends.-Only a lapse of~judgment can account for the willingness of prominent medical authorities to contribute their talents to further embellish- ment of the contents of the paramedical literature and other promotional schemes, as is increasingly the custom. A moment's reflection should make them realize that dominance of physicians' "education" can easily pass into the hands of those who are capturing doctors' attention with their aid and for the client's purposes. As an example, one handy little parasitic commercial magazine offers pithy extracts from the legitimate literature sandwiched between fulsome, adver- tisements, and frequently manages to draft an illustrious panel of professors who seem content to sell rehashes of their original works to dress up the collec- tion of abstracts gleaned from proper journals-presumably to the owner's great profit. Prominent men seem ready to lend their names as sponsors and thus add an air of authenticity, not only to paramedical magazines, but also to subtle schemes for closed-circuit television performances and for piping information and promo- tion into the offices of doctors via radio and phonograph and telephone; all these devices are subject to the influence of the advertising agencies and drug com- panies which support them.2 These entanglements can become confusing and unwholesome; cooperation can unconsciously come perilously close to collaboration. The net result is to under- `Published by Drug `and Therapeutic Informa'tion, Inc., 130 East 57th Street. New York 22, N.Y. 2 Examples are: The Advisory Committee for Grand Round's (television), niad,e up of distinguished names, with headquarters at `the same address as the largest medical advertising agency (William Douglas McAdams), and a lay employee of that company is the Executive Director for the Committee. Voice of Medicine, a phonograph record service, teams up Excerpta Med,lca Founda- tion with Recordo-Med, Inc. Medical Radio System is~ a service of RCA-NBC for special FM radio broadcasting of medical news and promotion. Medtpbone (developed by Johnson and Lanman ad agency) will arrange for free telephone calls between physicians seeking infermatlon on any topic and drug com- panies which will seek the chance to provide It. The fate of Dr. Henry Welch, who was obliged to resign as chief of the Division of Antibiotics of the Feed Administration, should be a warning to others drawn Into promotional enterprises. His involvement In the schemes and dealings of two profitable trad'e magazine (distributed, free to doctors) was brought to light `In a Congressional Hearing (17). PAGENO="0048" 395~ COMP1~tT~PIVE P1~tOBLEMS IN THI~ DRUG INDUSTRY mine the audience for the journals and postgraduate programs which were once the prerogative of the profession. Furthermore, a mass medium is established beyond the influence of the pro- fession which can be used to comment freely upon the affairs of doctors, while their own private and official medical publications must hesitate to examine the doings of the industry upon which they have come to depend for subsidy. When the medical audience has been more completely won over by the promotional "educational" activities, and if the pinch of a less flourishing economy should be felt, what is to prevent the subsidy to medical journals and societies from being decreased? Would enough loyalty of doctors to their own professional journals remain to make it risky for industry to force these journals to rely on their own resources? THE POwER OF PROMOTION At times the effectiveness of promotion may be exaggerated by the promoters. They `are not so powerful `as to excite fear and worship, but it would be foolish to discount the impact of their efforts. Keen businessmen do not continue to lay out huge sums without results. The aim of the promotional campaign is to sell a particular brand of a product. Listen to the terms mentioned in discussions of treatment by students in the classroom by residents in staff conferences ~r whenever doctors meet, and you will note h'ow successfully trade names have been implanted-even though the brand name may not be simpler than the generic term and it may not give any `clue as to the chemical nature of the product. Also notice how quickly' a new product gains favor in the best of medical circles, whether proved superior to `an old product or not, If your own observations are unconvincing, look ~t the following sales figures of a few "ethical" products and i~sk yourself if disc$minating ~utbo'rities could l~e recommending such profligate usage ot residents and practicing physicians. Estimated total eth'ical drug sales at manufacturers level (19~7) (8), Antibiotics $400, 000, 000 Vitamins and hemantinics 230, 000,000 Adrenal hormones 88, 000,000 Other hormone preparations 50, 000, 000 Sulfonamides 42, 000, 000 Biologicals 150, 000, 000 Tranquilizers 195,000, 000 Promotion has the power to lift a product to prominence regardless of its usefulness, and though this may be a fleeting accomplishment, the "education" of physicians will be distorted and the resources available for health care will be dissipated `by the `hectic campaign to influence the doctor's prescription. Your attention is not being directed to a harmless "tempest in a teapot" but to a force that can twist the profession from a true course. THE POWER OF CRITICISM There is a remarkable dichotomy in the prevalent attitude in the medical profession toward criticism. Forthright public comment is expected from col- leagues who review `scientific books an'd articles for medical journals and during scientific meetings, but any tendency to comparably open criticism aimed at par- ticular brands and specific abuses in promotion is frowned upon as "negative" and unsuitable for dissemination in the medical literature. Thus, a valuable exercise in the evaluation of evidence is eliminated from the continuing educa- tion of physicians from within their own rank's. Other fields have not hesitated to employ higher criticism to foster good taste and excellence. Dramatists, authors, and artists are continuously exposed to unfettered critics who pass judgment on their creations without sparing mention of individuals and specific works. Indeed, the full `benefit of higher criticism cannot be gained by vague generalizations alo'ne. That this procedure is equally constructive when applied to promotional material was demonstrated to the profession by the effect of a series of pointed criticisms published in a lay magazine in the past year. The ~aturd,cty Review (January 3, September 5, 1~59) `permitted their science editor to point out a few abuses in promotional material of a major ethical drug firm. Reproductions of actual advertisements for specific brands were used to illustrate the reasons for PAGENO="0049" COMPETITIVE PROBLEMS I~ THE DRUG INDUSTRY 3953 concern. The effect was salutory. These articles were so disturbing to the profes- sion as well as the public (and the company u~ider fire could not deny their validity) that the Federal Trade Commission was stimulated to issue two injunctions calling for explanations from the offender. Such action had not been taken previously by the FTC in connection with the promotion of ethical drug firms, presumably because it was deemed sufficient to let the doctor look out for himself as was stipulated in the Act of 1914 (quoted in a preceding section of this essay). Far from being "negative," this was a positive service to the public and the profession. It does not seem sensible for the profession to relegate the function of higher criticism in medical affairs to even enlightened laymen, particularly in public media. The results may not always be so fortunate for doctors, and the public may view a reluctance on the part of the profession to assume responsibility for independent criticism of any agencies affecting the public health as a form of negligence (12)-in which case the privilege may be assigned to a governmental bureau. This turn of events would seem more likely to lead directly to excessive regulation of industry and the profession than the superficial notions of "censor- ship" set forth by promoters to hold potential critics at bay. Criticism from individuals submitted privately to drug houses is easily dis- sipated by polite evasion, but public comment cannot be dealt with so con- veniently. The profession needs to bring its collective weight to bear on abuses and poor taste through pointed criticism in official journals of medical societies or by some form of ptiblic expression of pointed opinion from independent groups of physicians. BtGABOO5 Certsorship,-Whenever the suggestion is made that the consumer deserves more protection from unrestrained promotion, cries of "censorship" are heard from the captains of industry and the masters `of the moss media. This word "censorship" is made more repulsive by opposing it to "freedom" gnd the sanctity of "self-regulation." The hackneyed trick violates sound concepts. To censor is to suppress expression of fact or opinion-and this is evil. To oppose abuses in the use of the mass media for promotion by pointed public criticism is not censorship but legitimate restraint-in the best tradition of freedom. Censorship is abhorrent to all who aspire to freedom, but articulate criticism in the higher sense cannot be construed as unwarranted restraint or an in- fringement of rights. Freedom can be maintained only by providing for con- tinuous, unhampered expression of opinion from all parties through equal access to the media of mass communication. There must be comparably effective presentations to the identical audience at nearly the same time; an open clash of opinion between fairly matched adversaries will finally disclose the closest approximation to the truth. This process is stifled when industry can afford to make blatant use of the mass media, while the profession remains con- tent to express its opinion softly through outlets partially stilled by a feeling of dependency on subsidy from advertisers. Self-regulation is a myth not likely to be realized outside Utopia. Neither citizens nor nations, professions nor trades have evolved to this day that deserve such trust, least of all when profit is at stake. It is actually pre- sumptuous to seek exemption from that degree of regulation which safeguards the welfare of all members of society. Socialism-Whenever the pharmaceutical industry feels the sting of political probing, as was so apparent in the recent Congressional investigations, the most promising means of eliciting sympathy from the profession is to play on the fear `of socialized medicine (5). It is argued that if private industry is sub- jected to further government control, medicine will soon he the next target. It cannot be denied that should the profession become too closely entangled with the drug industry, they are liable to rise and fall together in the estima- tion of politicians and the people. Physicians will have to recognize the purpose of these bugaboos or they may unconsciously accept a flimsy pretext for unbridled use of the mass media and adopt an unreasonable attitude toward social advances. THE ENTICING WEB A look at the entire net cast out by the promoter to catch the; physician's favor Will reveal how easily the unwary could become entangled. The suave and mischievous methods used to entice doctors into this web a~e deplorable: 81-280-69-pt. 10-4 PAGENO="0050" 3954 COMPETITIVE ~OWJE~M~ IN ~L I~DUSTRY the whole is camouflaged as a noble plan to promote the public health and made tempting to the unsuspecting victims by the bait of "education." The grand scheme appears to be to confuse and then capture the prey. The capacity for entangling doctors built into the ~twork of promotion and `education" spread out by the ethical pharmaceutical industry can be readily estimated by simply listing some familiar elements in the design. 1. Entertainment and gifts (wining, dining, and ~floor shows, free supplies and equipment to individuals and institutions) that soften resistance to overt promotion. 2. Subsidies of medical journals through advertisements `and of medical so- cieties through direct support of activities and indirectly `by commercial exhibits at meetings-that interfere with their function as outlets for objective criticism. 3. Grants for applied research and testing of products-with the risk of ensuing exploitation of favorable results. 4. Sponsorship of conferences-thus made vulnerable to infiltration by trades- men and biased presentations. 5. Free distribution of lavish and beguiling paramedical publications, radio and television programs (exempt from independent review)-that draw the attention away from legitimate medical outlets and transfer dominance of the mass media to the promoter. 6. Attractive invitations to talented physicians to contribute to paramedical publications-that divert their talent from publications of the profession and add a veneer of authenticity to the promotional "educational" materiali 7. Manufacture of a plethora of brands and preparations-that complicates the burden of keeping doctors informed without corresponding enrichment of the therapy at his disposal. 8. Clamorous competitive c1aims-~-that permeate the practice of medicine with the confusion of huckstering in the market place. 9. Loose allusions to censorship and socialism_that startle conservative free- dom-loving physicians. 10. Modest unrestricted contributions to the' profession's own educational enter- prisés (like the National `Fund for' Medical Educa'tloli)-that may exonerate the abundant expenditures for industry-dominated "educational" programs. The individual physician is left to escape this enticing web with too little help from his un-united, cautious, subsidized organizations, while the ethicnl drug companies have combined "their resources in a Pharmaceutical Manufacturers Association that can effectively pursue a coherent plan and ample use of public relations to guard their interests~ THE' MENACE OF ENTA~tGLEMENT The prospect for free pursuit of a chosen trade or profession affecting the public health is most promising when the welfare of the people governs all actions. This means no selfish effort should be made to intrude upon the pre- rogattives of others or to exert undue influence through entanglement, confusion, or eQilaboration among the parties to whom the people have `assigned separate responsibilities. The invasion into the province of `the medical educator by the drug companies must be eliminated; conscription of "education" in the service of prom'otion must cease. Sooner or later what may now seem like benign and noble overtures will be recognized as ominous intrusion that threaten the hard-won and reasonable boundary between the sellers and prescribers of drugs. Neither `the drug industry nor the profession would profit by mortal combat, and `the public would be the victims of unseemly collusion. There is only one way to better health care for the people-cultivation of cooperation and avoidance of entanglements. If the public is the first to sense the danger, matters will pass into their hands and governmental regulation will be m'ade the order of the day. PROPOSALS TO LOOSEN THE PROMOTER'S SNARE To physieians.-It would not be surprising to find th'at some physicians re- act with anger at any criticism of ethical drug companies, for surely all the boun- tiful gestures from industry mus't have forged some warm friendships. Let t'hem hold their fire and consider! There are ample grounds for kindly feelings between doctors `anc~ `those who furnish them with invaluable remedies without the ardent wooing of promo- PAGENO="0051" COMPETITIVE PROBLEMS IN TI~E DRUG INDUSTRY 3955 tion. However, as long as the prescription remains the means to a sale, short- sighted promoters will consider it "good business" to make prescribers feel some- thing close `to kinship with the purveyors of drugs. This is a shaky foundation for true and lasting friendship. A little reflection should lead physicians to beware the eroding effects on their traditional independence and on the trust they have received from the people. Doctors must adopt universal skepticism toward "educational" material ema- nating from sources outside their own publications and institutions, and even these will be suspect so long as there is any reluctance to apply critical stand- ards in acceptance of advertisements, or to sneak out freely on other abuses, for fear of losing the subsidy of promoters. The legitimate medical literature needs overhauling, as to both source of support and techniques of communication. In addition tQ looking out for himself the physician must be willing to pay his own way. He would bridle at the prospect of being considered a "sucker," or a puppet of any vested interest-a possibility be faces when be becomes beholden for entertainment or deeply entangled in the web of promotion. Never forget that the patient pays the bill. Physicians should not discount their latent power nor hesitate to assume their full stature and call a halt to invasion of their province. Prestige is a fragile flower that demands conscientious cultivation to save it from pests and weeds blown in by the winds of promotion. In the light of reason the bugaboos of censorship and socialism will be dispelled, and the indispensabiity of higher criticism for maintenance of excellence and gool taste will be acknowledged. Watchfulness will be required to check the increasing transfer of products from "ethical" channels Into the category of "Qver-the-counter ethicals," a source open to patients without recourse to a doctors prescription. Casual tolerance of this trend is a form of professional suicide, which might be a boon to promoters, but not to the people, who appear only too anxious to drug themselves at the beckoning of unscrupluOus bucksters~ In essence, physicians should hold themselves aloof in unhampered devotion to their calling, while exchanging a wbplesome respect with others contributing to the public health but never beiiig guilty of prescribing drugs under un- conscious influence of personal favors or subtle entanglement with the affairs of drug manufacturers; nor can the profession ever shirk the task of setting its own housç~ in order, particularly with regard to the unkempt medical literature, to inadequacies in the techniques of medical training, to easy-going wayS of financing activities of medical societies, and to indulgence of wayward physicians who may be unwittingly aiding and abetting the schemes of promoters. None of these proposals should be allowed to provoke conflict between the groups making equally vital contributions to the public health; the best interests of all parties can be fostered only by suitable cooperation, which is distinct from collaboration. Conferences between responsible representatives of medical edu- cators and the pharmaceutical industry would be desirable, e.g., the Association of American Medical Colleges and the Pharmaceutical Manufacturers Associa- tion. To the ethical drug firms-The position of managers of drug companies dependent on doctors' good will to sell their products Is not altogether enviable. It takes a reasonable profit to make the stockholders happy, and this must be gained in a fiercely competitive market. The manufacture of drugs is an exacting business, not only because of legal standards but because imperfections in the product can be disastrous and no excuses will satisfy the pu,blic. There are enough internal problems in such an industry, but a final obstacle must be overcome before the volume of sales will permit a profit-ithe man who writes ttbe prescription must be won over to favor the product. The great body of pre- occupied, conservative, and proud physicians is no slight obstruction to place in the path of any enterprise; lthtie wonder a great blast of promotion was found necessary to move them,. Even allowing for all these difficulties, the ethical drug firms may have over- shot their mark. Physicians and the public are beginning to feel they are pushed around too much. Unless the medical educator is completely overpowered, sooner or later there will be a wholesale opposition to pharmaceutical invasion of the field of medical education. To be sure, doctors and their organizations are no- torious for accepting almost any offer of s~bsidy or entertainment, but their feeling of gratitude will not be strong enough to check their ire when they PAGENO="0052" * 3956 COMPETITIVE PROBLEMS IN THE IThUG INDUSTRY realize their prerogative to exercise dominant influence over the habits and beliefs of physicians has been bought. Ethical drug firms should reconsider the appropriateness of attempting to in- fluence physicians by subtle infiltration into the educational process and through a vast meddlesome subsidization that is hard to distinguish from payola. If the pharmaceutical industry can afford to subsidize medical affairs, they should do so through larger unrestricted contributions to organizations devoted to the interests of the profession, such as the National Fund for Medical Education, rather than allowing their resources to be used as a means of undermining the control of physicians over their own a1~fairs or as a nefarious scheme of public relations. Matters would improve if the ethical drug industry shook of1~ the exuberant promoters who have drawn them into the use of techniques customary in the sale of ordinary commodities but highly questionable for application to promotion of medical remedies. This industry had better take another look at that word "ethical" and make certain its meaning is applied to the manner of doing busi- ness and not just the channel of distribution of their products. No doubt it would be impossible to curtail the plethora of brands and prepa- rations of products in a laissez-faire market. This is one of the chief causes of promotional puffery and an aggravating contribution to the confusion of the doctor that makes him feel he needs more "education." The Pharmaceutical Manufacturers Association might well consider whether its members would in the long run be better off with lower sales volume and less bigness and less aggressive competition-the alternative appears t~ be an ever-increasing tempo of promotion until the whole business is discountei b3r the profession and the public. The promotional campajgns which are tecilifred to compete in a market depending on sales direct to the public are esI~ecially costl~V; the last barrier to this drain will be gone if the physiciah is removed from. th~ path of drug promo- tion by loss of stature or further tendency `of ethical firms to get around `the doctor via the "over-the-counter ethical" ljne of remedies. Acquisition of propri- etary subsidiaries by ethical firms and vice versa must complicate matters. Cooperative projects.-A good step in the right direction has been the adoption of a Statement of Principles of Ethical Drug Promotion by the members of `the Pharmaceutical Manufacturers Association. The next step is to abide by it faith- fully. Even better would be a really comprehensive statement of principles prepared and adopted jointly by representatives `of industry and the profession to define and govern their proper relations and separate prerogatives. This could be coupled with the establishment of a Board or Overseers made up of representa- tives of the public, ln~ustry, and the profession. This Board would not function as a government regulatory agency but as a private group that would be em- powered to call to account either party for any infringement of the stated principles, resorting when necessary to public comment in the mass media. The freed'om of each group to pursue its endeaver could be guarahteed by `this con- tinuous and equal opportunity for confrontation of opinion and exercise of in- fluence. The people could be reassured by periodic reports from this Board of Overseers. Here again the Association of American Medical Colleges and the Pharmaceutical Manufacturers Association could cooperate in developing such a plan. To the people-In the final analysis, the people of a democratic society have the power to take things into `their own hands. If any enterprise threatens the welfare of the public, especially in matters of health, a brisk reaction can be expected. No good will come from encouraging eager politicians to seize upon health enterprises as a ladder to power. The people should not lean too heavily on bureaucratic governmental regulation, for there is no substitute for high ideals in the development `of sound practices in a free society. Should it appear that unduly large renources have drifted into the possession of industry for the purposes of promotion, the structure of taxation may well be critically examined. It is not inconceivable th'at a plan could he devised that would limit the sums which can be charged to promotion in the cost of marketing drug products, thereby shrinking the size of the web the promoter could fabricate for his clients and freeing the professipn from the threat of entanglement or undue influence from pbarm,aceutical "education." The people do need some assurance of responsible behavior from those to whom they have assigned the rights and privileges of serving their health needs. This can only be obtained by insisting upon some arrangement for PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3957 continuous public accountability from the profession ~nd the drug industry, such `as `the Board of Overseers suggested in the preceding section of these proposals. PRESERVATION OF FREEDOM FOR ALL Censorship is justiftably condemned in a free society, and the mass media should be open to free and equal use `by all responsible persons. Restraint through higher criticism is not to be confused with censorship-on the contrary, it should be liberally applied in every field of endeavor to encourage excellence and good taste. The mood of the times must be changed from a squeamish feeling that open criticism is "negative" to a more wholesome regard for pointed public comment and public accountability. There is no more effective way to discourage artful attempts to enlist physicians in the sale of drugs by disguising promotion as "education" and to prevent misuse `of `the mass media by selfish interests rather than for the welfare of everyone. REFERENCES 1. Advertising Age, February 1, 1960. 2. Drug Trade News, December 16, 1957. 3. , May 5, 1958. 4. ~, February 9, 1959. 5. - , April 18, 1960. 6. , February 22, March 21, 1960; and Advertising Age, March 24, 195& 7. Editorial, New England J. Med., 262: 255, 1960. 8. Facts about Pharmacy and Pharmaceuticals, p. 54. Health News Institut~ New York, 1958. 9. FINLAND, M. Editorial. New England J. Med., 258: 87, 1958. 10. , Editorial, Ibid., 261: 827, 1959. 11. GARB, S. Letter to the Editor. J. M. Educ., 34: 942, 1959. 12. LEAR, J. Public Health at 71/2%. Saturday Review, May 28, 1960. 13. MCCARTHY, C. G., and FINLAND, M. Absorption and Excretion of Four Penicillins. New England J. Med., 263: 315, 1960. 14. MAY, C. D. Gilded Antibiotics and Therapeutics, 22: 415, 1958. 15. Medical Letter on Drugs and Therapeutics, 2: 73, 1960. 16. New York Times, Financial Section, February 15, 1959. 17. , May 19, 1960. 18. Our Increased Spending for Health. Progress in Health Services, 9: Febru- ary, 1960, New York: Health Information Foundation. 19. WILKINS, L. Masculinization of Female Fetus Due to Use of Orally Given Progestins, J.A.M.A., 118: 1028,1960. [From Ethical Issues in MedicIne, pp. 227-~248]~ THE MEDICAI~ PROFESSION AND THE DRUG INDUSTI~Y (By William B. Bean, M.D.) Dr. Bean received his BA. and M.D. degrees from the University of Virginia. Further training in intermal medicine and nutrition was received at Johns Hopkins, Harvard, and at the UniversitV of Cin- cinnati. He is a Diplomate of the American Boards of Internal Medicine and Nutrition. Since 1948 he has been Professor of Medi- cine and Head of the Department of Internal Medicine at the Uni- versity of Iowa College of Medicine and Physician-in-Chief of Uni- versity Hospitals. lie is the former Chairman, Section of Internal Medicine, American Medical Association, and is a member of the Board of Regents, National Library of Medicihe. For the past five years he has been Editor-in-Chief of the Arellive's of Internal iliedi- cine and is presently Editor-in-Chief of Current Medical Digest~ A prolific writer, Dr. Bean has made almost 400 contributions, includ- ing five books, to the niedical literature on internal medicine, nutri- tion, medical philosophy, and history. His most recent book is Rare Diseases and Lesions. He appeared twice before th~ Kefauver Com- mittee investigating the pharmaceutical industry. PAGENO="0054" 3~'8 cOMPE~rfrIvi~ ?~O~3tAEMS IN' T~fl~ D~U~ IN~STR~ E~c~l1ent herbs had our fathers of old- Excellent herbs to ease their pain- Alexanders and Marigold, Eyebright, Orris and Elecampane. Basil, Rocket, Valerian, Rue, (Almost singing themselves they run) Vervain, t~ittany, call-me-to-you- Cowslip, inelilot, I~ose of the Sun. Anything green that grew out of the mould. Wa~ an excellent herb to our fathers of old. -RucI yard Kipling. t'hysicians and apothecaries have had a long and turbulent history In which one sees examples of effective and friendly collaboration as well as explosively violent antagonisms with long and bitter feuds. While the problems of pharmacy and the diminishing function of the pharmacist make the skillful compounder of remedies and potions almost a thing of the past, that Is another problem. Its story needs to be told elsewhere. To some extent, the doctor-drug polarizations have shifted. We see on the one hand the academic physician trained in clinical Investigation and on the other, leaders of the pharmaceutical Industry who have been brought up in the free- wheeling competition of the marketplace, where policies and practices are always influenced and sometimes actually determined by the financial goals. There may be enormous profits from' a new drug. Such bu~1ne~, furthermore, has sharp time limitations upon it since competing drugs may soon rec~ch the market and greatly reduce the yiØd the price comes down. It was, I thjnk, largely the failure of responsible physicians and members of the pharmaceutical industry to recognize these conflicts that led to the hearings on the manufacture and marketing of drugs before the Senate Subcommittee on Antitrust and Monopoly (the Kefauver Com- mittee). Certainly these, hearings were useful for catharsis and an excellent ventilation of some of the problems but cUd not settle or solve them all. That would be expecting too much. The points still at issue in, the controversy are vital and range over the whole spectrum of contemporary life, varying from the free enterprise system on the one hand to the frustration of a family with a c~esperately sick member, unable to buy necessary drugs. While to some extent the coming Qf Medicare has al- leviated an element of the difficulty, there is still plenty of r~oui for wisdom apd statesmanlike consideration of how a cost accountant figures out the profit' a company can make on a newdrug, a sophisticated study of laboratory and animal reactions, the performance of a company's stock on the stock exchange, and the relationship of statistics on mortality to the wider use of certain drugs, emotional- ly defended by partisans on either side. RECENT ADFANCES AND NEED FOR CHANGE It seems evident now in the day of molecular therapeutics that we will have more `tailor-made drugs, more compounds designed on the basis of expectations of performance from a sound knowledge of biophysics and biomedical reactions, and fewer compounds derived from `plants. Ttauwolfia was `the last important new eiltity to come'in this way. Once steroid hormones became available, newer ones and those' with sometimes greatly different function,. though very slightly different structure, introduced new problems. The mass production of penicillin and other antibiotic's has been a marvel `of industrial skill. Mass production of such things as live virus vaccines is beginning to make inroads on the bio- medical equilibrium of human ecology, with all manner of implications for the future. The application `of such advances to an understanding `of human physiological functions and applications of newly won knowledge to the `treatment~ of sick people have not been a smooth and steady progression forward. In fact, I am not aware that any one has made a careful study of the very large number of therapeutic dropouts, I.e., compounds introduced with a loud noise in all the media and ballyhoo from brochure and detail man, only to vanish within a period of months or years when their lack of new virtue or better efficacy became apparent. At the very best' this represents a wasteful system; at the worst it smacks of sk~ld~ggery and cant. PAGENO="0055" COMPETITIVE : PROBLEMS IN T1~ DRUG INDUSTRY 3959 Conflicting interests may simply generate slightly uneasy pressure or they may result in al~itost exp1osi~re c~onfrctitatiOns. In periods when the tempo of change is extremely rapid and when the stakes are high, whether it be in terms of the financial reward fér an entrepreneur or the health and well-being of man and man's society, a genuine cOncern bOcomes the awesome and Increasing responsibility of thoughtful Inenibers of the society because of the enormity of the stakes. At a time when scientific advance was slow and new drugs, such as they were, were likely to be found by painstaking evaluation of herbs and their essences. the introduction of new drugs was uncommon. Therapy, not very effective, was about at a standstill. There was no incentive to go into the mass production of new compounds, for there simply were not enough new compounds. When advances began to develop explosively, the traditional function of ethical pharmaceutical houses was magnified and multiplied, and to some extent the directing forces were removed from individual or family enterprises into the large realm of big business. At the same time, there was not at first a comparable awareness or alertness to deal with the increasingly complex problem of drug testing. In any society when problems which are new in kind, as well as new in dimension, arise its institutions are tested. Unfortunately it turns out often enough that the insti- tutions and organizations, well geared for a slower pace and a simpler set of problems, may prove not only insufficient but dangerous. The evolution of medical practice and medical science as it relates to therapy and the employ- ment of powerful drugs is moving fast but uncertainly~ Institutions rarely have a built-in autoanalyzer, a central controlling monitor, to examine and provide a dispassionate critique of purposes, functions, and the capacity to fulfill them. This is why institutions change, or fail and are replaced. Human nature being what it is, things may go along until some disaster appears. Some threat becomes ominously evident. Or a general quickening of the moral pulse of the community leads to an investigation or an intervention. Often a crash program of poorly thought out schemes results in passing laws to achieve ends which would be managed much better if collaborative but voluntary arrangements and agreements could be worked out by those concerned. The two parties involved here are pharmaceutical manufacturers on the one hand and the body of medical practitioners, teachers, and investigators, those who must be responsible preservers and protectors of the public, on the other. The great majority of pharmaceutical manufacturers have a just concern for their good name and are wary lest this be sullied by entrepreneurs who have come into the field without the traditional background accumulated during the more leisurely days. They have a steady sense of responsibility and wish it to permeate the drug Industry. While many of the problems which are of concern to us now have, more or less by default, gone into the hands of external agents or agencies, it Is still wise for physcians and those who produce pharmaceutical agents to review jointly their common material problems. I have commented upOn the method by which the man In the street or, more generally, society protedts Itself In a democratiC state. Such an organism has its being through dependence upon a capitalistic system In which ultimately the good of the people depends upon the knowledge, foresight, wisdom, and an effectual sense of responsibility. Of course, it is no discovery that these very virtues should be diffused widely throughout the whole of society to create and maintain stability in the various guiding forces which govern people in all walks of life. In the past, the function of the physician, various as it has been, was to a large degree to provide support and hope, to restore confidence, and to bring comfort where disease was progressing to its fatal termination. Any spectacular interference from drugs or therapeutic programs was the ex- ception, not the commonplace. In fact, if the physician was under the governance of an erroneous set of motions, he did more harm than good; and the heroic therapy of our pioneer forefathers with their masses of calomel and huge doses of quinine, with their calamitously enervating purges and their exsanguinating program of bleeding, in many melancholy Instances, were the embodiment of disaster. The few specifics were used well enough although often in heroic proportions. In this country, pharmacy in the modern sense arose with the mass produc- tion of medicines and drugs in the Union during the Civil War. Here, for the first PAGENO="0056" 3960 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY time, the notion of quality control, the pharmacological necessity for pure and dependable compounds, and the slow introduction of new specifics all began. Thus out of the ancient brews of alchemy and witchcraft, the chemical and pharmaceutical Industry arose, supported in part by their own research, in part by. work done in university science laboratories, and in part by the increasing sophistication of clinical pbarmacolo~y and applied therapeutics. PURITY sTANDARDS, EFEICACY, AND SAFgeUARPING. THE USER One hardly needs to emphasize that before a drug Is released for use through the orthodox distribution In sales channels, it mtist ~atisfy stringent require- ments for purity. It must not exceed certain tolerable lithits of acuth toxicity afld of chrOnic toxicity. Regulations governing the purporthd efficacy of drugs have always been less than satisfactory, no doubt because getting convincing evidence rather than effusive testimony has always bCen so difficult. Efforts to safeguard the user against the ill effects of accumulation of drugs in the body, intolerance to prolonged as compared to brief therapy for acute disorders, the risks of sensi- tivity reactions, and the danger of particular kinds of cell damage, particu- larly that of the hematopoletic system, have been much more difficult. RESEARCTI Very conspicuous research contributions have been made in the privately owned laboratories of individual pharmaceutical concerns as well as their support of research in hospitals and medical schools. Their grants-in-aid for research may vary from completely free basic research to the applied pharma- cology of specific drug testing. Within the pharmaceutical industry the freedom of the individual scientist in a laboratory varies considerably. Surely it is unrealistic to suppose that there is not some pressure to work on problems of urgent or potential interest to the parent company in the production of new or improved drugs. Investigators relieved of the responsibilities of teaching and practice may enjoy work in industry. Often financial arrangements are very attractive indeed, but just as in government laboratories, so in industry, the movements of investigators are such that they are one-way streets. They do not reproduce their own technical staff and they provide no general return to the academic arena. A burden assumed by universities and medical schools has been not just that of replacing their own corps of teachers and investigators but to supply government agencies as well as industry. This has not been a matter of much concern since we have become accustomed to it and do not worry, particularly, about those matters which have small emotional charge. NEWS LETTER-THE INDEPENDENT CRITIC AND CRITIQUE A very critical need of the medical profession was met rather unexpectedly, nearly ten years ago, when, in the middle of the winter ~f 1958-1959, the Medical Lctt~~r on drugs and therapeutics appeared. The first issue was dated 23 January 1959, and the long unfilled purposes of the Letter weve evident at once. Its value has been demonstrated by its increasingly importapt fi~nction i~ graduate med- ical education and in the practice of medicine. It stands as a beacon in the sometimes bewildering crosscurrents and shoals of the conflicting and at times far from clear testimonial support particularly of new &id heavily advertised drugs. Looked at in the light of history, the Medical Letter assumes the function of protecting the people. The function has not always been uppermost in the minds of various organizations related to and in medicine which may speak for different fragments of medicine but have not always had equal concern for the well-being of the patient and of society. ,s a journal produced by a totally independent, nonprofit group, the publication is in a good position to try to provide unbiased critical evaluation of drugs. Na~uraily the special emphasis has been on drugs recently introduced or new variations. It has no advertising and this leaves it clear of any charges of multiple loyalties. T1~e efforts of this journal and a few others have been conspicuous almost from the start. We have a place to which we can repair for information. Those receiving graduate training under our supervision can find new authoritative information. Fortunately, it has become increasingly important to the conscientious busy doctor. It can serve PAGENO="0057" ~bMP13iTITIVE PROBLEMS IN T~IE DRUG LNDTJSTRY 3961 as a court of appeal when be is bewildered, by lack of information or conflicting claims. It is not surprising that the advertising' supporting some ethical drugs sm- phasizes what is desirable in the Way of therapeutic effect and underemphasizes the side effects which may be undesirable. No one physician, in fact, no single department or laboratory, can make a satisfactory check of the accuracy of claims for all neW drugs or even a few. The sad experience of the recent past and indeed medical history generally records that many more drugs are introduced than fulfill earlier expectations. In fact an enterprising and forward-looking pha nan ceutical manufacturer might benefit from a comprehensive study of the discon- tinued drugs, the ones that never made the grade. Obviously it is greatly to every- one's a'dvantage not to introduce drugs which do not fulfill apparent early promise or live up to expectations because of either inactivity or unwanted effects. Medical Letter operates as a clearing house, collecting, reviewing, and evaluat- ing, since it does not maintain its own drug-testing program. It has no equity in a compound, but in the truth. There is a real effort made to get authoritative information in a readily digestible, easily managed form as promptly as possible. To do this, a certain amount of material in Medical Letter has to be presented in the form of preliminary appraisals. Naturally it is impossible for the accumu- lation of experience gathered in periodical literature to be ready shortly af'ter the introduction of a new drug. Alterations in positions taken in Medical Letter, though uncommon, have occurred. This indicates that they have no proprietary interest in pontification but try to let the facts speak for themselves. As a teaching device for undergraduate medical student, house officer, and practicing physician. Medical Letter has been invaluable. Modern drug therapy with its array of powerful, helpful, and dangerous drugs is dependent upon a vigilant alerting system which will give accurate data on side effects and dangers as well as precise information on therapeutic properties. Sound practice must be based on a knowledge of the natural history of a disease, the effect of a placebo tablet or a placebo personality, the exact pharmacological effects, and the risks of minor or serious reactions. What might be well worthwhile in treating a neoplasm might be ridiculous in treating constipation or the common cold. Thus risks of serious unwanted effects may be taken in treating grave diseases but would not be permissible in minor and self-limited disorders. A drug might be used for a short period which would be unsafe for long-term use. Medical Letter helps the physician judge the accuracy and significance of what may be reported as medical discoveries in the breathless tempo of newspaper and magazine. This may be very valuable in dealing with the insistent but perhaps confused patient who comes in with high expectations waving his clipping and calling for action. In this day of the mass media, we have not found a way to protect the average person, naive in his knowledge of science, biology, and medi- cine, from the booby traps of his own ignorance. Cost and potency of comparable or identical compounds have been brought out from time to time. The lag in getting information about newly reported toxic reactions has been reduced. Recurring audits keep the physician up to date. An evaluation of over-the-counter drug products helps evaluate preparations widely advertised in extensive campaigns and provides a check on the hard face of reality. Thus sturdily realistic and impartial appraisals of drugs are available and can be referred to as a reasonable help in making decisions. The fact that the statements in Medical Letter are not signed has been distress- ing to some, but the nature of the publication and the fact that the statements do genuinely represent a consensus rather than an individual opinion seem to justify this. I do not believe it is because the persons concerned would be reluc- tant to have their names attached. As might be expected, the pharmaceutical industry at times has been less than cordial in its reception of the Medical Letter. There have been a few frays here and there. But the continuing and growing demand and the immediately evident importance of the publication have justified its growing success. Its vital importance on the medical scene increases. A few efforts to tar with the brush of guilt by association or look for the devil in Sunday clothes have proved com- pletely ineffectual. The wisest and best of the producers of therapeutic compounds recognize it as a friend which may at times act with parental sterness or even as a Dutch uncle. But every, pharmaceutical manufacturer recognize~ that' he cannot `thrive unless be knows and remembers that what is good for the patient is good for him, not the other way around. PAGENO="0058" 3982 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY OF DOLLARS, DEALERS, AND DEANS No one has to be a biblical scholar to realize that it is Impossible to serve two masters If their objectives are radically different and especially if their pur- poses are so different as to be inconsistent one with another. Other things being stable, or, as they say, equal, any doctor who happened to own ~t drugstore would direct his patients there to fill prescriptions rather than to a competitor. Like- wise, if a physician owned stock in any pharmaceutical enterprise which was in competition with another similar organization, it would ~o against nature fo~ him to promote his competitor's wares selectively against his own or evei~ to be neutral. Thus whenever the doctor is also the apothecary, when a physician pre- scribes, manufactures, and sells glasses, or when we learn that an important member of a medical school's administration is promoting business for a pharma- ceutical firm in which he is involved financially, we know that the profit motive will not be subservient to a calm and scholarly consideration of the scientific evaluation of drugs. When such a person actively campaigns in the promotion of certain material and exhorts his colleagues who are shareholders to try to bring in a little extra business, the public is appalled at the crass cupidity and stupidity. In no place is a conflict of interest more flagrant and more sinister in its im- plications. This picture of physicians revealed to the lay public, however minuscule a fraction of all practitioners it may represent, is necessarily a shoddy and shabby one. While this might be condoned as a maneuver to promote business, those engaged in the treatment of the sick and those directing teaching In a medical school have responsibilities which outweigh their far from picayune financial interests. Theirs still is the responsibility of protecting the consumer, in this case, the patient. ADVERTISING One could write tomes on the bad taste as well as the extraordinary ends to which pharmaceutical concerns have gone to attract and support sales. A sad spectacle at a contemporary medical convention is the doctors' wives and friends, eyes alert with the trained skilled of the "hawk of the supermarket," making off with bundles of samples and miscellaneous gimmicks. The promotion of sales of drugs is aided and abetted by the detail man, many of whom are con- scientious and reasonable. Few are steeped in the critique of scientific training. It is deplorable to have so large a proportion of physicians depend upon these men, competing as secondhand teachers, echoing the carefully prepared produc- tions of Madison Avenue but not always separating testimony from evidence, false from true. The burden of mail that accumulates in a physician's office, including the ~lrug samples which occasionally are tested by enterprising children, are a nuisance and may be a danger. The advertising In medical and controlled circulation journals varies from what is sensible and helpful to what is appall- ing and sometimes dangerous nonsense. No one of these methods is necessarily bad in and of itself. They do lend themselves readily to abuses whenever there is no internal check or external monitor to control them. Among the unprecedented developments of modern medicine, the valuable life-sustaining and sometimes life-saving drugs made available by the pharma- ceutical industry should be praised in lavish terms. This does not give a carte blanche for wasteful advertising, for foolish competition, or for license which permits the distribution of `unsafe or useless compounds. The ease with which gullible man is gulled is incentive enough for imposition, imposture, or downright fraud. Although patent medicine quackery is not a thing of the past, much larger fortunes are now being made from the legitimate sale of ethical drugs. DRUG TESTING In testing a new drug, there are many tasks. The investigator has to obtain true and relevant data, expunge error, correct earlier mistakes, and see that the Information is widely disseminated and acted upon. Some of the rare frauds of clinical testing as well as many of the dubious tests quoted In support of the value of this or that drug do little to win confidence. The physician who is in the pay of pharmaceutical manfuacturers is in no position to keep public confidence in his objectivity. The editors and owners of medical journals which depend so heavily upon advertising are vulnerable and not only must be above taint but, like Caesar's wife, above suspicion. PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3963 THE BUSINESS ARENA Those who have been experienced in the field of medicine for 25 years or more can remember the dreary scene where therapy was so largely expectant, so much that of providing support, reassurance, and perl~aps the display of character. One is noW amazed at the multiplication of specifics and the increasing power of drugs and chemicals. The industrial production of chemicals properly safeguarded so as to prevent contamination of the atmosphere, earth, air, and water, stand over against the vast and general contamination. In the manufacture of powerful pharmaceutical compounds, industrial wastes are those tiiat result from the frenzied market competition where slight modifications in manufacture or in molecular structure may give a great though temporary advantage. We have now an array of powerful medicines; for example, a burgeoning tribe of antibiotics, the large family of descendants of the original sulfonamide clone, scores of adrenal steroids and the related sex hormones which go to make up "the pill," as well as tranquilizers, barbiturates, and antihistamines. Each new one joins in an array which produces confusion from two sides. On the one hand, the minor molecular modifications do not often produce significant therapeutic advantages. On the other, the multiplicity of trade names for identical compounds multiplies the confusion. Metabolic antagonists, a variety of drugs used to assault the effects as well as the processes of neoplasms and the maze of psychedelic drugs, perhaps more symptomatic than causative of many of today's confusions, preseut us with a whole new order of problems. Of their nature, they are controversial. Perhaps, of their nature, they are insoluble just as many problems confronting us today are insoluble but more urgent problems squeeze them off to the side. In a competitive, capitalistic society, those who gain the advantage by patenting discoveries have a clearly legitimate claim to profits. In the long run, however, when the pharmaceutical industry devotes so much of its talents to developing minor but patentable variations to deal with the competitive market rather than exploring unexplored territory, the major result is likely to be seenin conspicuous new allotments for advertising rather than a new boon for the sick maii or the physician trying to take care of him. A company with skill enough to make an original discovery in this field obviously should be rewarded for its effort. If the legal situation to ensure this award were clearer, itt least some of the troubles would disappear. Even the contemplated revision of the patent laws, however, gives no clear evidence that the ends desired would be achieved. As far as trade names are concerned, If the company making the original discovery were granted the patent, only a single trade name would be needed to be used by licensee as well as discoverer. If a sufficiently different new way were discovered for making the drug, the new discoverer would market it under the generic, or nonproprietary, name, thus at once easing the job of the patient, the pharmacist, and the physician. By reducing the retailer's overhead of multiple dufilicating Stocks, the same drug with different names, the cost to the consumer would be reduced. The battle of generic names has gone On furiously and there seems to be very little hope that it will abate. THE GOVERNMENT AND THE PHARMACEUTICAL INDUSTRY At times the complexity of the problems vexes the ordinary citizen as well as the physician in trying to determine what should be the proper relationship between pharmaceutical manufacturer and the legal agents of the government which test the drug. There is the feeling of "a plague on both your houses." History gives us little cause to be encouraged that such conflicts in society can be eliminated. Social science has not yet provided any vital clues for resolving the difficulties. Thus it remains the responsibility of the physician and the scientists to study the conduct of the opposing forces and try to adjust them if society is to be healthy. Look at it. the other way around. Is it humanly possible that drug safety can be legislated any more than morality could be legislated as we found out very expensively with the Prohibition experiment? An approach to the problem within channels already operating under present laws might be achieved if the Food and Drug Administration could become an organization with a large and wise staff of well-trained men whose professional PAGENO="0060" 3~4 COMPETITIVE ~O~LEMS IN THE PRUG INDUST1~Y ability was simply paid for and whose prestige could be brought to the level of those who work in the National Institutes of Health. This idea may be Utopian but if the vast volume of tests and the Increasingly cumbersome paraphernalia of approval could be speedod up without the loss of accuracy, we would all be much better off. Consider a list of facts dealing with drug testing: 1. More new drug applications are filed with the FDA each year than it can properly classify. 2. Eighty to ninety percent of all prescriptions written today in this country are for drugs not known or not available two decades ago. ~. Phe impetus for manufacture of new drugs comes as much or more from industrial exploration as from professional requests. 4. In testing drugs for human use, there has to be a first person and a first group if they are ever to be introduced. 5. The odds of launching a truly satisfactory drug, one with some new efficacy and minor toxic or undesired side effects, is not better than one in many, many thousands. The cost of developing new drugs with the necessarily large proportion of failures is very high. 6. Animal screening is not sufficient as a safeguard. 7. Such standards as we have, for the most part, have been established by leading, reputable pharmaceutical concerns. There is a great need for a con- frontation with a meeting of minds between physicians and members of the pharmaceutical industry to settle on programs and details for clinical testing in the light of the multitude of new complexities introduced by the explosive proliferation of new, powerful, and dangerous drugs. On the average, great therapeutic power tends to be associated with more risk of undesired compli- cations, toxicities, or idiosyncrasies. It is impossible to examine all aspects of the question of how fair is the price of brand-named pharmaceuticals and what should be the regulation about the employment of generic names. Solution of the generic versus proprietary name is but one of a host of unsolved problems. In a recent issue of Medical World News [11, the president of a large corpora- tion, which we shall call "X," was confronted by a member of the Monopoly Sub- committee on the Senate Select Committee on Small Business. Arguments were presented in equal' space. On the side of the drug industry, these points were made, each' explaining expenses of production. 1. A constant search for new and better compounds is necessary and most are failures. 2. Each investigation is expensive. 3. Multiple dose forms increase the cost. 4. A new drug may require new manufacturing processes of varying complexity. 5. Pilot runs to supply adequate drugs for testing are costly. 6. Mass production introduces new problems after pilot studies. 7. The Investigations must be supervised and monitored critically. 8. The design and supervision of quality control are expensive. 9. Marketing to ensure rapid distribution Is expensive. 10. Clinical and scientific documentation of all aspects of a new drug must be established by the manufacturer. 11. Release must be cleared by the Food and Drug Administration. 12, A staff of detail men constitutes a large and an expensive element of the marketing organization. 13. Advertising by direct mail, journals, brochures, and exhibits is expensive. The senator's rebuttal was as follows: Many other pharmaceutical llrms which sell manufacturer "A's" products under license have comparable research going on. They license their own products to company "A." Much of the initial rsearcb, for instance, on steroid hormonOs had been done in independent clinic, hospital, and university laboratories a~ well as in the National Institutes of Health. The quality control of licensed competing companies making and selling the drug under a generic name is as good as parent company "A's." In some instances, costs to pharmacists are so nearly identical, $17.88 per one hundred 5-mg. tablets from company "B" compared with $17.90 from company "A," as to imply price fixing. Company "A's" President was unable to give a breakdown of costs of research on the one hand and promotion and sales on the other. If typical of the industry as a whole, costs of promotion and advertising are 4 to 10 times the cost of research and development. NoTz.-Numbered references at end of article. PAGENO="0061" COMPETITIVE PROBLEMS IN TH~ JM~UG IIThUSTRY 3965 But the real flaw in the pharmaceutical company's argument about prices is the fact that they vary all over the map, depending upon the purchaser and the country where the drug is marketed. The compound under consideration might cost the pharmacist roughly 18 cents a tablet in the United States, around 8 cents in Australia, and a little less than 5 cents in Switzerland. The disparity between bids for the huge quantities involved in government purchases and the cost to the retail pharmacist is in the order of more than 2,000 percent. To quote the article, "One Is left with the inescapable conclusion, which [Company A.] has done little to dispel, that the price . . . is determined primarily by nothing more than a business judgment of what the traffic can bear." *The arguments solidly favored the part of the senator. The fact was obvious that the patient and the scarcely patient taxpayer foot the bill. But it is not really so simple. FOOD AND DRIJO ADMINISTRATION Despite what at times seems to be an effort to perform the labors of Hercules, there is a creeping suspicion that the Food and Drug Administration is an anachronism, an institution which has not been able to get or keep itself prepared to deal with its responsibilities in the age of superscience and powerful drugs. One does not find on its staff, with rare exceptions, outstanding or distinguished scientists, competent to make judgment on today's drugs. They are in the leading research laboratories of medical schools and the pharmaceutical industry. The competent people attracted to FDA rarely stay, for neither salary nor j~restige has kept up the incentive. Its responsibilities have long outdistanced its capacities. Whnt should be the relationship between government agencies which function as protectors of the people and the pharmaceutical industry? The doctor and patient seem to occupy a sometimes uneasy middle ground. The fact is that such organization and governmental institutions have not been studied scientifically. Movements to protect the consumer now have broad government support. Experience has accumulated under the aegis of the National Academy of Sciences-National Research Council and their panels which review efficacy of drugs approved before the passage of the Kefauver-Harris Act of 19432. Dr. James L. Goddard-who, to say the least, has stirred up the animals-will serve at least one more year. The depth of the increased government interest is evident. It goes beyond the ordinary governmental and Department of Health, Education, and Welfare hierarchies, for the Congress and the President have introduced Medicare and Medicaid. This requires Health, Education, and Welfare to take a vital interest in the rulings and decisions of the Food and t~rug Administration. Not only does government support under Medicare and Medicaid increase the respon- sibilities of Health, Education, and Welfare, but its support of medical research through the National Institutes of Health implies an interest i~ the develop- ment of new methods, drugs, devices, and regimens in therapy. Basically the question comes down to what good may be achieved for the consuming public, The individual patient must be the standard agginst which not only the orga- nization and the staff but the practices of the Food and Drug Administration are judged. An effort to measure the effect on public health is probably beyond the pro- gramming of any modern computer but it certainly should be thought about. We have made assumptions that a more rigid review of drug advertising, with emphasis on toxic and side effects, as well as therapeutic virtue, will be of benefit to the patient. What is the evidence that this is true? Do we know, indeed, that improving the Food and Drug Administration's staff would improve the lot of the consumer, i.e., the patient? Would the actual application of medi- cine to the patient, that is, the prescription practice, change substantially or be improved by requiring uniform display of generic names on all drugs? We need serious study to get valid answers to these difficult questions. As an example of the multitudinous difficulties that the Food and Drug Admin- istration illustrates or perhaps generates we may take Dr. Walter Modell's charges of Food and Drug Administration censorship. These arose from a statement by Mr. William Goodrich, counsel to the Food and Drug Administra- tion, that "publishers, authors, and editors who have written, approved, and published drug dosages which deviate from those recommended by the FDA are liable for damages to the patient and to the pharmaceutical manufacturer as well" [2]. Modell's pressing of the charges hinged around the threat that PAGENO="0062" 39~6 COMPETITIVE PRQBI~EMS IN TW~ DRU~ INDUST~Y Goodrich's statement posed to medical authors, editors, and educators. He supported this by the fact that Saunders pub1i~hing company had thought it wiSe to remove the unbound sheets of Beeson and ~EcDermott's revision of Cecil and Loeb's Te~otbook of Medicine to print a disclaimer. B~t j~erhap~ the main focus of the charge was the FDA's allege~ dereliction of duty when, in a particular case, it made an arbitrary decision to lower a dose 1~or the pur- pose of reducting toxicity without any regard to the efilcacy of the lower dose. One's conclusion is inescapable that the Food and Drug Administration Is overworked and understaffed; that It may have totally unrealistic demands put upon it. It is necessary for physicians, investigators, and teachers, as well as the drug producers, to attack the questions in scientifically evaluated study in order to find what is the best method of achieving reasonable legal control of drug manufacture and use, one which would protect the public and at the same time not stifle the ethical pharmaceutical industry which depends, for survival, upon a reasonable profit. In the long run, in this continuing debate, the sub- stance of the argument on all sides hinges upon a definition of what is reason- able and then being reasonable. REFERENCES 1. Medical World Nev,s 8 (Sept. 1, 1967), 56-61. 2. Modell, W. FDA Censorship. Clin. Pharm. Tlverap. 8: 359, 1967. THE UNITED STATES PHABMACOPETA, Bet hesda, Md., December 10, 1968. Mr. BEN~rAMIN GORDON, Stafj' Economist, Select Committee on Small Business, Old Senate Office Building, Washington, D.C. DEAn MR. GORDON: In response to your call, I am sending my impressions of the article entitled "The Generic Inequivalence of Dru~gs" by Alan B. Varley, 1\f.D. that appears in the December 2, 1968 issue of the Journal of the American Medical Association. I have noted the frequent and i~ather derogatory references to the United States Pharmacopela in the text, which in departing from the usual 3rd-person style, regrettably becomes almost a personal attack on the U.S.?. We can agree at once with Dr. Varley that the concept of "generic equivalence" Is muddled, semantically and otherw1~e. The three proposed terms, which I believe are used in the H.E.W. Task Force Second Interim Report, should help clarify future discussion. The data Dr. Varley presents are not at all surprising or particularly new. For years, drug firms have been making and testing experimentally drug dosage forms that have been less than fully satisfactory in* comparison with other very similar products. Only comparatively recently have good methods become avail- able that make such tests fruitful. There Is very little evidence that such products get out on the market, but we can all agree that then even the risk of their doing so should be minimized. We must take Dr. Varley at his word that both of his products A and B tact the present U.S.?. specifications; certainly the 7.6 minutes disintegration time be reports for Product B is well within the 30-minute limit specified in U.S.P. XVII. It may be useful to point out, however, that the U.S.P. test was capable of discriminating between Products A and B. The one difference that was picked up in the laboratory, i.e., in dissolution time, is quite significant. The test method used is not cited, but we would assume that it cannot differ greatly frota that which is being studied currently with a VieW to lct~ inclusion in the U.S.P revision now in preparation for release within a year. I would enpect that a dissolution time as long as 103 minutes would certa1nl~V disqualify Product B under any standard approved for U.S.P. XVIII. We are preparin4~ a ~ommtinicatiofl to the Editor of JA.M.A. and will send a cOpy to you If you wish to have it. Sincerely yours, LLOYD C. MILLER, Ph. P.. Director of Revision. PAGENO="0063" COMPETITIVE PROBLEMS IN TI~E DRUG INDUSTRY 3967 IThe following additional material from Dr. Lloyd ~. Miller, Director, U.S.P., was received by the Subcommittee Chairman before this vqlurne went to press.] Tun UNITED Sv~TEs P~IARMACOPEIA, Bethesda, Md., March 6, 1969. Senator GAYLORD NELSON, U.~S. $enate, Old S~enatc Office Building, Washington, D.C. DEAR SENATOR NELSON: Enclosed is a letter to Dr. Alan B. Varley, of the medical staff of the Upjohn Company, which takes him to task for the tone of an `article that appeared prominently in the November 18, 1968, issue of the Journal of the American Medical Association. Mr. Gordon and I have discussed the article and I promised to make a copy for you of any comments we might have on it. This article reports nothing more than the successful execution of a pharma- ceutical trick. For medical newsworthiness, it doesn't begin to compare with some of Houdini's exploits. Thus it seems to me that the Editor of J.A.M.A. is due criticism for assigning the lead-article position to this report and for making the very exceptional grant of 2-color treatment to the two charts. You may note the mention made of the fact that Mr. Graham of the Upjohn staff Is one of the 60 members of our current Revision Committee. Mr. Graham was not aware that the article was in preparation and has been unable to obtain for our testing any of the two lots of Tolbutamide Tablets that Dr. Varley studied. In short, through accident or deliberate company policy, this attack on U.S.P. standards was planned to exploit the differences observed and to avoid making use of the most effective means of correcting them. We have seen discussion of your bill on a federal compendium on prescription drugs S. 950. May we ask for 2 copies of it `and of that portion of the Congres- sional Record in which your remarks concerning it appear? While we understand that the terms o~ S. 9~0 are much the same as a similar bill introduced last year, we wish to study It further. Our renewed study will be made from the standpoint of the plan now in motion for the U.S.P. to provide information of the sort that the compendium might contain. We would like to have an opportunity to discuss this plan with you at some mutually convenient date in the near future. We would hope to have present also the chairman of our U.S.P. Board of Trustees, Paul L. McLain, M.D., who can arrange to come in from Pittsburgh if given sufficient notice to allow him to arrange for meeting any scheduled lecture commitment at the Medical School that might conflict. I will be in touch with your office by telephone shortly in respect to the appointment. Sincerely yours, LLOYD 0. MILLER, Ph. D., Director of Revision. Enclosure. U.S. PHARMACOPEIA, March 4, 1969. ALAN B. VARLEY, M.D., Kalamazoo, Mich. DEAR Dn. VARLEY: Perhaps the long delay in its arrival will be the only cause for surprise in our offering comment on your article, "The Generic Inequivalence of Drugs," J. Am. Med. Assoc. 206:1745 (Nov. 18) 1968 which o'bvious'ly has the object of downgrading the U.S.P. Actually, we are not sure we would be writing had you not repeatedly include~l the name of the Pharmacopeia in your blanket condemnation of physical-chemical specifications of drugs and drug products. However, we do see other grounds for criticism also. Clarification of the semantically muddled concepts of "equivalence" is a laudable objective; however, we wonder if at this stage the muddling is not far beyond the corrective efforts of any single individual. The Academy of ~harma- ceutical Sciences has recently issued a draft of a statement and, in our view, that distinguished body has failed utterly to improve matters. Your former colleague, Dr. John Wagner, has perhaps kept you advised on that score. On the constructive `side, we believe that it would help greatly to reserve the word "drug" for the active agent only, and to use the term "drug products" for PAGENO="0064" 3~8 COM?ETITIVfi PROBLEMS IN TKE DRuG' INDUSTRY the drug combined with other ingredients in the form by ~hieh `the drug reaches the physicians, pharma~i5t, nurse, and ultimately, the patieut~ :Tl2e~e two terms seem to be on their way to acceptance through rather consistent use by the Pharmaceutical Manufacturers Association, the American Society of Hospital Pharmacists' computer file of drugs, by FDA staff in recent talks, and in much of the recent, pharmacy-oriented literature. I am sure tlntt, on re-reading your article, you would find it clearer if this distinction bad been made, and we will use the terms, drug and drug product, in that context in the following comments enumerated below. 1. A general condemnation of "chemical" specifications (your last sentence) for drug products is not justified, we believe- (a) Pharmaceutical manufacturers generally have had excellent results in controlling batch-to-batch consistency of most of their drug products with physical and chemical tests alone: (5) Such tests are usually far more sensitive in establishing differences among drug products than clinical studies of therapeutic efficacy can pos- sibly be. For example, with physical-chemical tests we can reasonably require that Aspirin U.S.P. be 99.5% pure acetylsalicylic acid and be sure that water accounts for almost all of the remaining 0.5%; with these same tests, we might require that Aspirin Tablets U.~.P. contain 99.5 to 100.5% of the labeled amount of pure acetylsalicylic acid-but this would scarcely be reasonable, since there are more variables in the manufacture of the drug product than in making the drug, Therefore, the U.S.P. standard for Aspirin Tablets, a chemical equivalen~ce speci/lcatiea, sets 95% and 105% of the labeled amount as the limits on the content of pure acetylsali- cylic acid. This is a reasonable production standard even though it repre- sents a degree of precision quite beyond that attainable by measurement of therapeutic response. On the basis Qf some pers~n'al experience with tests of analgesics and other drugs, I suggest' that your "ideal criterion for establishment of therapeutic equivalence-trial ef cornTarative ethea~ In appropriately disease~afflicted pa'tien1~s" is wholly U~re'allstlc for distin- guishing among Aspirin Tablets or for, that matter, diflerebt formulations of most other drug products. In sbo~t, at b~t, pl~ysician~ can seldom detect drug product differences o~ the sort generally picked up readily by properly chosen and applied chemical and physical tests. 2. Your general condemn'atiQn of "U.S.P.-type" specificaiions f~r drug products is not justified, in our view- (a) Equating "chemical" and "U.S.P.-type", as you have, betrays a glaring unfamiliarity with U. S.P. specifications, For i~e'asons set forth above, the U.S.P. Revision Committee prefers `the precision of physical-chemical tests whenever they are appropriate. However, numerous U.S.P. drug and drug product specifications are biological in nature, e.g. insulin, digitalis, tubo curarine, etc. Prior to the development of p'hysicaPc'beinical metheds for * quantifying cya'nocobalamin, your "ideal criterion" was the best we could muster in standardizing Liver Extract, Liver Injection, and Crude Liver Injection on a batch~by-hatch `basis for nearly 15 years. The U.S.P. has a colid history of using the types of tests consistent with the expertise and scientific knowledge of the `times `which are best suited to the needs of the particular drug product. (5) We heartily agree with the substance of your comment that "The fact remains that it is (italics yours) clearly possible to produce considerable differences in both availability of drug to the human patient and In eventual therapeutic usefulness by niaking tiny changes in the formulation which are clearly within present U.S.P. chemical equivalence standards." In short, the ingenuity `of our very talented pharmaceutical chemIsts can be put either to good or bad use. In the light of this, what sets U.S.P. policy in this area? Briefly st'a'ted, the pharmaceutical scientists' of the ~ try to `set standards `that will give the physicians reproducible ~esul'ts both between lots of a given brand and between brands of the same generic drug product. All too often, physicians are of no help whatever in th'is regard. For example, there `has never been an assay for Coal Tar because no o~~ie seems to know what it contains that accounts for its usefulness to dermatOlogists. Thus, in effect, neither the active, ingredient nor its vehicle are standardized, As another example, the physicians on the TJ.S.'P. Revision Committee `have agreed that 1.1% PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY 3969 of hydrocortisone acetate is a desirable amount of drug to have in an ointment but decree that the choice of base should be left to the individual prescriber for the particular condition be is treating and the area of the body being treated. We might elaborate at length on the differences, but the fact is that they are numerous and substantial. We have exchanged considerable correspond- ence with experts in your company of this very point. There are TJ.S.P. scientists and practitioners who believe that every U.S.P. drug product should have a specified formula. The very thought of such a requirement would raise hackles of foot high all through the drug industry! 3. It should be recognized that tightening of standards is rarely due to physi- cians' requests as a result of therapeutic failure~ but nearly always to efforts of pharmaceutical scientists aimed at improving the product. A case in point is the dissolution testing which you report using with Tolbutamide Tablets. Studies of dissolution rates came about as a result of attempts to improve on the disintegration properties of tablets and to correlate those properties with absorption of the drug from the drug product into the blood. I do not wish to imply that physicians are not interested in drug standards, least of all the physicians of the 1J.S.P. Committee of Revision. I am merely saying that the physical-chemical methods of the pharmaceutical scientist generally lead to more sensitive and precise standards for drug products than do any measurement of therapeutic response by a physician. The foregoing applies to "availability equivalence." The pharmaceutical scientist can set dissolution rates which help to assure batch-to-batch uniformity of the drug product. Your article reported this as the distinguishing measurable difference between the two Tolbutamide Tablets discussed. Yet absorption does not vary consistently with differences in dissolution rates. When does a dissolu- tion rate profile, obtained with a spGcific instrument and procedure, reflect real differences in availability equivalence? If we can establish that for a U.S.P. drug product, it will promptly become a part of the standard even if availability equivalence is not an indication of detectable therapeutic differences! This position evolves from the conclusion that a dissolution rate test is a reasonable addition to the physical-chemical testing armamentarium, and that some day the art of therapy using that drug product may advance to a point of greater sensitivity in detecting therapeutic differences. Conversely, if availabil- ity equivalence can indicate therapeutic differences but no dissoibtion rate test can be devised which consistently reflects availability from different formulations of a particular drug product, the absorption test itself can become a part of the U.S.P. standard. Theii the U.S.P. Revision Committee will have to decide how the standard shall be applied; i.e., whether all formulations of that drug product should meet a specific availability standard, or whether to allow varia- tions in the rate of availability provided the label declares the rate for each. specific formulation. 4. As a physician, you individually have a responsibility for U.S.P~ standards. (a) In almost all other countries, an agency of the governnlent sets the stand- ards of quality for drugs and drug products. In America the professions do it (except for antibiotics and biologicals where, for one reason or another, a gov- ernment agency has been given specific authority by the Congress). The Unitc~t States Pharmacopelal Convention antedates both the American Medical Associ- ation and the American Pharmaceutical Association, not to mention federal food and drug legislation. The lISP. Convention is the only organization in this coun- try based equally on institutions and organizations representing the scientists- educators and practitioners of medicine and pharmacy and supplemented by organizations of scientists of related skills. The members of the tJ.S.P. Commit- tee of Revision, 20 physicians and 40 pharmaceutical scientists, are elected by the delegates from these organizations. Many of those elected are associated with pharmaceutical manufacturers, either at the time of their election or subsequently during their term of service. As a physician and as a researcher employed by a pharmaceutical manufacturer, you should have a special interest in ensuring that this professionally-responsible organization establishes the best standards for drug products of your manufacture. lISP. standards are not set by the U.SP. staff; they are worked out through the concensus of the experts on each drug and drug product, whoever and wherever they may be. (b) At present, your company is the only American manufacturer of Tolbuta- mide lISP. and Tolbutamide Tablets, IJ.SP. Therefore, our tSP. standards largely reflect the experience and needs of ,your company. If there is any defi- 81-280-69-pt. 10-5 PAGENO="0066" 3970 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ciency in `these stamlards, we would expect your firm to be `the first to call them to our attention. As a matter of fact, the late Dr. Glenn Bond and Mr. C. Leroy Graham of your firm were elected to the U.S.P. Committee of Revision in 1960. In rendering service on the U.S.P. Committee, both distinguished themselves as first-rank statesmen. Mr. Graham also serves on the National Formulary Board and, furthermore, is a member of the U.S.P./N.F. Joint Panel on Physiological Availability, a panel which has been working diligently on the very object of your complaint. The Panel was recently advised the U.S.P. and the N.F. to standardize on two dissolution test procedures from among the many which have been proposed. To build up experience and data, we welcome the receipt of samples of two formu- lations of any chemically equivalent drug product which have been found `to pro- vide consistent and significantly different blood levels. Sincerely yours, LLOYD C. MInLER, Ph. P., Director of Revision. THE WM. S. MERRELL COMPANY, AprU 19, 1960. INTERDEPARTMENT MEMORANDUM To: Dr. R. L. Stormont From: R. H. McMaster, M.D. Subject: Hyman Engelberg, M.D., Cedars of Lebanon Hospital, Los Angeles, Cali- fornia in the amount of $500. Dr. Engelberg has made a verbal request for $500 to support his continued study of the effects of MER/29 on the lipoprotein fractions as assayed by the Codman technique using the ultracentrifuge. The results with the first two or three patients in whom this technique has been tried have been rather equivocal if not completely negative. Dr. Engelberg, however, is of the opinion that before any conclusions can be drawn, the experiment should be extended to Include a larger group. He does not wish to subject these private patients to the expense of having these rather elaborate laboratory studies down and feels that The Wm. S. Merrell Company should foot at least a part of the bill. He believes that $500 will cover the costs of cholesterol determinations and the separations of the high and low density lipoprotein fractions by ultracentrifuge in another ten to twelve patients. Although It begins to appear that any report from this study may be a negative one, we may find that we are money ahead to keep Dr. Engelberg busy at it for a while longer rather than to take a chance on his reporting negatively on so few patients. As you are aware, the Codman technique is in some disfavor and certainly has never been generally accepted as providing for a true "atherogenic index" as claimed. My personal recommendation is that the grant-in-aid be approved only to keep Dr. Engelberg occupied for a while longer. THE WM. S. MERRELL COMPANY, August 19, 1969. INTERDEPARTMENTAL MEMORANDUM To: B. F. Van Maanen From: Medical Research Department Subject: M.F.R.-29-Effects on Monkey Ovaries (your memorandum of August 14 to Doctor Scanlan). DEAR FL0R: Many thanks for the tactful way in which you defined the condi- tions under which the monkey ovary pictures can be used clinically. I am strongly opposed to the discussion of any finding from experimental animals until we have agreed upon our interpretation. Some potential investigators were frightened abput M.E.R.-29 a year ago because of a very similar problem. In this case, I do agree that we can show the pictures to our Investigators in Syracuse, but it is acknowledged that we are taking a calculated risk because of a great moral and ethical problem Involved. Because of the careful selection of our investigator in Syracuse. I think that It is a reasonable risk for us to take. R. C. P000E, M.D. PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3971 THE WM. S. MERRELL COMPANY, July 5, 1961. INTERDEPARTMENT MEMORANDUM To: Dr. H. W. Weriier From: R. H. McMaster Subject: William Hollander, Boston, consultation fee Holl!ander mentioned the matter of his consultation fee. You will recall that we have had him on a personal retainer amounting to $2,400 per year payable in 2 semi-annual installments. If we wish to maintain this relationship (which is apart from Wilkins' grant), a payment of $1,200 is now due. My own feeling is that we can't afford to chance alienation of Hollander just now (perhaps I shouldn't regard this as blackmail). Certainly we need his help and counsel. THE WM. S. MERRELL COMPANY, May 20, 1959. INTERDEPARTMENT MEMORANDUM To: Mr. F. H. Gelman. From: Robert H. Woodward. Subject: MER-29 Clinical Status and Plans. Your comments on May 11 concerning this subject were certainly appropriate and helped to focus our attention further on the job to be done. As a matter of further information, it is our intention to closely follow the cross reference of the investigators and the problems which each investigator is assigned. It was not thought desirable to do this, however, until the investi- gators which we have selected have been approached and have been assigned these subjects which are best fitted into their own research knowledge and facilities. When this has been done, we certainly will then cross check the needs and determine if each has been adequately met. The comments which you made at the end of your memo regarding the NIH and their interest in MER-29 confirm the emphasis which was placed upon this source of clinical knowledge during our planning of the entire program. In Dr. Pogge's memo to Dr. McMaster of May 15, I notice where he mentions a prelini- mary contact which was made by himself while in Washington on May 6. He men- tions or rather suggests that no grants be made, and I think, In view of our present policy, that we should make this an emphatic point rather than a sugges- tion. By means of a copy of this memo I am also asking Dr. Pogge to make each of those individuals in the Medical group who may be following up this subject in Washington completely familiar with the preliminary work which he has undertaken. In fact, it appears to me that this is a special project worthy of the best effort by Dr. McMaster as a follow-up to whatever was done by Dr. Pogge. I am sure that we can get action in this area and that it will provide a case of clinical evidence which can be most useful. The objective in contacting the armed forces was to lay the groundwork for the eventual sale of the product to the various hospitals serving each branch of the armed forces when the product is released. We were not thinking here so much of honest clinical work as we were of a pro-marketing softening prior to the introduction of the product. [From William S. Merrill Co. Sales Talk-News, Tips, Ideas-An Answer to Medical World News, July 26, 1960] DR. LI5AN SPEAKS U~ The following letter, written to the editor of Medical World New8, was pub- lished in the July 15 issue of that magazine: "IIYPEROHOLESTEROLRMIA "As one of the participants in the Symposium on Hypercholesterolemic Drugs at the AMA meeting, Miami, I was quite surprised and concerned about your article `Breakthrough on Cholesterol' (MWN, June 17) . PAGENO="0068" 3972 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "In our experience with more than 100 carefully studied patients given MER/ 29 (Merrell) for periods up to two years, there has been no evidence of hepatic disease or dysfunction. Clinical side effects (nausea and skin reaction) have been almost negligible and certainly not serious. "Dr. William Hollander, of Massachusetts Memorial Hospitals, reported at the American Therapeutic Society, June 10, that he and his associates have fol- lowed their many long-term patients with serial liver function tests. In several patients liver biopsies were obtained, and in none of these was there evidence that MER/2~ altered bepatic morphology. "The relative safety of MER/29 has been reported by others. Dr. J. Earle Estes (Mayo Clinic) has administered MER/29 in doses as high as 3 grams daily for months at a time without side or tone effects. These studies, in addition to our studies on the safety of MER/29, were published in the May issue of Progress in Cardiovascular Disease. "Your writer failed to stress that Dr. Corday's study indicated that T4F (Lilly) is not effective in eutbyroid patients for lowering cholesterol. Most pat- ients with coronary artery disease and bypercholesterolemia are euthyroid, therefore, T4F is not the `potent answer' for cholesterol-lowering. On the other hand, MER/29 significantly lowered cholesterol in 85 percent of the patients, all of whom were euthyroid. "PuILIP LISAN, M.D. "Hahnemann Hospital, Philadelphia, Pa." Tnz WM. S. MmumI~L Co., June 21, 1961. INTERDEPARTMENT MEMORANDUM To:Dr.Bunde (3). From: R. H. McMaster. Subject: Trip Report, New York City, American College of Cardiology, May 16-19, 1961. Dr. Michael Winzenried, Hamburg, Germany, JlCevadon Upset because of failure of Chemie Grttnenthal to provide subsistence funds. Put him in contact with Dr. Jones. LouisE. $chaefe'r, M.D., Now Yorh, N.Y., MER/29 Has followed some 25 patients very carefully. Believes that triglyceride re- sponse is favorable in ITypercllolesterolemic patients whose triglycerides are initially high but that a similar triglyceride response is not evident In hyper- cholcoterolemics with initially low triglycerides. This is not substantiated by reports we have bad from other sources. It is expected that Dr. Schaefer ~i1l report his findings in the very near future. I expect to contact him on my next visit to New York City to see if be has made definite plans toward this end. Robert A Bo~g~r, M.D, and Norman Orentreich, M.D., N.Y., MER/29 and Kevadon These dermatologists are probably doing more research on the human hair than any other group in the nation. In addition to excellent private facilities, they are on the dermatology staff at New York University, Bellevue Medical Center and have access to patients here and from certain others of the city's chronic disease facilities. They are greatly interested in the hair effects of MER/29 and are willing to study these effects, with the hope of determining causes. Will require some financial support and have agreed to submit a protocol. Since this has not yet arrived, I shall contact them on my next visit to New York. Dr. Orentreich has also been working with Kevadon, which be presumably obtained from sources other than Merrell. He reports that some 10 of approxi- mately 30 cases have developed dermatologic reactions. He considers the incidence much higher than reported in the literature. Dr. Jones is now in touch with Dr. Orentreich. Marvin C. Becker, M.D., Newark, New Jersey, MER/29 Dr. Becker's paper (prepared for the most part by us) was rejected by the American Journal of Cardiology and has now been accepted by the Journal of the Medical Society of New Jersey. We have received permission to purchase reprints. Continues to obtain favorable results with MER/29 and may make a follow-up report for publication later if results warrant. PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3973 Arthur DeGraff , M.D., New York, N.Y., MBR/29 Dr. DeGraff remains convinced that MER/29 was the responsible agent in causing the hepatomegaly and fatty metamorphosis in the patient of Dr. Mario V. Bisorcli, Mount Vernon, New York. However, be was very gracious and permitted me to present our accumulation of data which certainly do not support his contention. No mention was made of an impending publication concerning this case. I was unable to contact Dr. Bisordi, who bad previously promised to send us the pathologic sections and medical and pathologic report about this patient. I expect to contact him during the meeting of the A.M.A. THE LIBRARY or CONGRESS, LEGISLATIVE REFERENCE SERvIcE, Washington, D.C., December 6, 1968. To: Senate Small Business Committee (attention Mr. Gordon). From: American Law Division. Subject: Responsibility of director to stockholders. This is in response to your query for a brief statement of the measure of re- sponsibility which a corporate director owes to the corporation's stockholders. The courts have developed standards for deciding issues relating to the per- formance of a director's duty to the corporation and its stockholders and these are generally applicable in state and federal courts. The basis of the duty may be expressed in Justice Cardozo's phrase, a "duty of constant and unqualified fidelity." Globe Woolen Co. v. Utica Gas Co., 224 N.Y. 483, 489, 121 N.E. 378, 379 (1918). While directors are not strictly speaking trustees, they do occupy a fiduci- ary, or perhaps more accurately, a quasi-fiduciary, relation to the corporation and its stockholders. McCandless v. Eurlaud, 296 U.S. 140, 156-57 (1935); Ander- son v. Bean, 272 Mass. 432, 172 N.E. 647 (1930) ; Markovitz v. Markovitz, 836 Pa. 145, 8 A. 2d 36 (1939). Each director must exercise his unbiased judgment, in- fluenced only considerations of what is best for the corporation. Lattin on Cor- porations, 241, 242 (1959). Many courts have spoken of the rule as being that a director owes a loyalty that is undivided and an allegiance that is influenced in action by no consideration other than the corporation's welfare. Hazard v. Wright, 201 N.Y. 399, 94 N.E. 855 (1911). However, to note one element in the problem, courts have not prohibited a di- rector of a. corporation from entering into and engaging in a business enterprise independent from but similar to the business carried out by the corporation. Grange, Schwartz, Gray, & Woodbury, Manual for Corporation Officers, 756 (1967). But his participation in the other business must not injure the corpora- tion and it appears to be the general rule that if a director's private venture comes into direct competition with the corporation be must give up one or the other. Guth v. Loft, Inc., 25 Del. Oh. 255, 5 A. 2d 503 (1939); Lincoln ~Stores v. Grant, 309 Mass. 417, 34 N.E. 2d 704 (1941) ; Ralnes V. Toney, 228 Ark. 1170, 313 SW. 2d 802 (1958). Generally, state statutes in this area do not attempt to explicate the duty of a director but maintain the common law developed by the courts by simply re- quiring that directors "shall discharge the duties of their respective positions in good faith. . ." N.Y. Bus. Corp. Law. 717. See, Kavanaugh v. Commonwealth Trust Co., 223 N.Y. 103, 119 N.E. 237 (1918). JOHNNY II. KILLIAN, Legislative Attorney, American Law Division. (Whereupon at 1~ noon the subcommittee recessed to reconvene at 10 a,m., Tuesday, December 17, 1968.) PAGENO="0070" PAGENO="0071" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TUESDAY, DECE1VLBER 17, 1968 13.5. SENATE, MONOPOLY SUBCOMMITrEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to call, at 10:10 a.m., in room 318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee), presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Elaine C. Dye, research assistant. Senator NELSON. The Monopoly Subcommittee will open its hear- ings at this time. Tomorrow, December 18, we will be hearing from Dr. Franz In- gelfinger, editor of the New England Journal of Medicine; Dr. Paul Lowinger, associate professor of psychiatry, School of Medicine, Wayne State University. On Thursday, December 19, we will be hearing from Dr. James Faulkner, chairman, Committee on Publications of the Massachusetts Medical Society, and Dr. George Baehr, chairman, Public Health Council of the State of New York, and a professor at Mount Sinai School of Medicine, City University of New York. Today our witness is Dr. George Nichols, Jr., clinical professor of medicine at the Harvard Medical School. This week, the Monopoly Subcommittee of the Senate Small Busi- ness Committee continues its study into the relationships of the medi- cal profession and the drug industry, particularly in regard to pos- sible conflicts of interest, professional responsibility, and ethical implications. Last Wednesday, the subcommittee heard from Dr. William Bean of the University of Iowa Medical Center-a widely known medical authority and former chairman of the section on internal medicine of the American Medical Association. Dr. Bean asked, as far back as 19~2: What is the most effective general teaching today at the postgraduate level? In sorrow we must admit that the artistic and artful brochures of wealthy pharmaceutical houses, sped on by a crusading band of detail men, have effec~ tively taken over graduate teaching. Dr. Bean ~rent on to say: * * * when advertising budgets exceed the total outlay for teaching and research provided by all our medical schools, concern is justified, "for where your treas- ure is, there will your heart be also." 3975 PAGENO="0072" 3976 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY When Dr. Bean was asked how necessary and valuable it is to have the kind of full page ads that we see in medical journals and all bro- chures-how useful these were to the physician, he said: "I think * * * that probably a very considerable part of advertising is not primarily educational, and in many instances is not necessary at all." Dr. Bean noted that as long ago as 1950 and again in 1959 `he had called attention to the fact that "physicians and representatives of the pharmaceutical industry -should work out voluntarily means of evaluating claims for drugs, evaluating therapeutic effect of drugs, and then seeing that adv~rtising, sales, detailing, and retailing were managed according to regulations developed by joint action * * No formal study, joint effort, ~r confrontation of producer, distribu- tor, dispenser, and. user ever came about." And so it seems that 10, even 20, years ago we were well aware of the problems involved in the relationship between the drug industry and the medical profession. Tn my judgment, this is a sad com- mentary upon the leadership of the medical profession, the pharma- ceutical industry, and the Federal Government as well. Had they jointly or even severally begun to resolve these p.rdblems, it would not have taken the action of this subcommittee to `bring these issues into focus. It is my hèpe that these hearings will act asa forum for the clari- fication and future solution of the problems involved in the relation- ship between the drug industry and the medical profession. We &re, in these hearings, reviewing the relationship between the pharmaceutical industry and the medical professiOn, and the medical institutions such as schools, medical societies, their publications, and so forth. The tie~in is obviously quite close. Is this good or had for the indus- try, the profession, and the public? As I noted, our first witness is the distinguished Dr. George Nichols, clinical professor of medicine at the Harvard Medical School, also consultant in medicine, the Boston City Hospital, and senior asso- ciate in medicine, Peter Bent Brigham, Boston, Mass. Doctor, the committee is very pleased to have you appear today to participate in a discussion of this very important issue, and we under- stand what an imposition it is in terms of taking time off from your busy schedule, but we, the committee, appreciate it, and your state- ment will be a valuable contribution to this whole record in which we are attempting to explore objectively and in depth the relation- ship between the medical profession and the pharmaceutical industry. Your statement will be printed in full in the record. You may present it in any way you desire. If you find it most useful to just proceed to read it, that is fine. Should you wish to depart and extempo- rize, at any time, please feel free to do so. I take it you will have no c~bjection if we ask questions during the course of your presentation-which I think is probably the most fruit- ful way to proceed. Dr. NICHOLS. That is fine. Senator NELSON. Thank you very much, Doctor. PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3977 STATEMENT OP DR. GEORGE NICHOLS, JR., CLINICAL PROPESSOR OP MEDICINE, HARVARD MEDICAL SCHOOL; CONSULTANT IN MEDICINE, BOSTON CITY HOSPITAL; AND' SENIOR ASSOCIATE IN MEDICINE, PETER BENT BRIGHAM HOSPITAL, BOSTON, MASS. Dr. NIcHoLs. Senator Nelson, ladies, and gentlemen, I feel deeply honored to have been invited here to place before you my views about some of the problems which face medicine today, and I might interject that I changed the last two pages of my original statement slightly. I had to be out of town and my secretary and I didn't see quite alike on how the things should be said and she left out the piece. I must confess that when the chairman first asked me to appear, I hesitated, for the issues at stake in these hearings involve the ethics of the profession and we all know that ethics are affairs of the heart which are far easier to feel than to put into words. However, as I considered the matter further, I realized that what was being offered was not just an opportunity to decry undesirable practices or become incensed over specific instances of malfeasance. You have already read and heard plenty about both from far greater authorities than I. In- stead, it seemed to me that what was offered was an unusual oppor- tunity to restate for the public record the principles of conduct which every medical teacher tries to inculcate into each of his students and which serve as guides for the majority of the profession in their lifework. I would like to recall, therefore, the rights and privileges which the public affords the physician and the responsibilities which he assumes in return through his symbolic affirmation of the Hippocratic oath. It is my belief that it is only through returning to these first principles that one can look clearly at the whole matter of potential conflict of interest between the physician, the patient, and the pharmaceutical manufacturer on the one hand and examine calmly and constructively on the other the ways in which the Federal Government, through its granting and regulatory agencies, can help protect all three from unwarranted attack and exploitation by the unscrupulous. The M.D. degree, unlike any other, gives its recipient the right to pry deeply into the most intimate, personal affairs of his fellow citizen and to make life and death decisions in his behalf. Clearly such a license can only be given to those of the highest moral character who can be trusted to carry out the solemn undertakings symbolized in the Hippocratic oath. These include four basic provisions: (1) to learn the "art" by which we mean medicine, and to teach it; (2) to place the interest of the patient first with the additional stricture, to restrain from consciously doing anything which might be deleteri- ous to him; (3) to leave the execution of special procedures to those with special skills; and (4) to maintain inviolate any private secrets of the patient which are learned in the course of helping him to solve his problems. These are solemn undertakings indeed which are unfortunately sometimes thought more appropriate to the hot idealism of the years of professional education than they are to the hard, cold, disillusioning PAGENO="0074" 3978 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY facts encountered often in professional practice. It is hard for the physician under any circumstances to live up to these high ideals; it requires constant work, constant relearning, constant sacrifice, not only of his own comfort and time, but that of his wife and family as well. In recent years, his problems have been enormously intensified by two factors: Fii~st, the geometric expansion of knowledge applicable to medicine and the huge increase in the number of new therapeutic agents of great power and specificity which has resulted from it have required that the physician virtually totally reeducate himself at shorter and shorter intervals. By this I mean that he must really com- pletely revise his concepts of the causes of certain diseases and of the ways in which they can be handled. Second, the public ~attitude toward medical care and medicine is rapidly changing. Good medicine is no longer considered a privilege but rather a basic human right-an attitude which has been greatly encouraged (and rightly so, I believe) by the Congress of the United States, through enactment of the medicare and medicaid provisions of the social security law. Both these factors are clearly socially desirable and should be en- couraged. Indeed, all would be well were it not for the fact that there are nowhere near enough physicians to meet the enormously increasing demand for medical care which the public is now making. It is small wonder, therefore, that the practicing physician, already unable to find time in the day to meet the demands of his patients, turns to the eye- catching advertising pages of his professional journals rather than to the much longer, far more complicated, even though objective, scientific articles for information about new therapeutic agents with which to minister to his patient's needs, especially if he is unaware of the existence of any simple and unbiased source of reliable informa- tion such as the Medical Letter, which has been mentioned in these hearings in the past. In view of the pressures placed upon him, it is equally understandable why the physician, in his earnest effort to help his patients, has turned so often to the ubiquitous lay drug sales- man for guidance and information and to inevitably biased commercial institutions for financial support of his public meetings and so forth, moves which, on more mature and calmer reflection, he would not consider in keeping with the high principles of his calling for one instant. These pressures do not bear on the practicing physician alone, but have extended beyond him to the very school from which he originates. Medical educators, like practicing physicians, have a strong sense of responsibility toward the care of the public, which they discharge in two ways: through research and the development of new understand- ing of disease and therapeutic agents, and through the selection and instruction of new recruits to join the ranks of the profession. Medical education is enormously expensive and these days rapid technological development requires constant change of curriculum content and con- stant retooling with extremely expensive equipment. Tuition charges could not begin to provide the necessary funds even if they could be paid in full by every candidate. Medical schools are being forced, there- fore, to seek money they desperately need elsewhere. In the absence of adequate public support for teaching, it is small wonder that dona- PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3979 tions, often generous, which may have carried with them subtle pres- sures have had to be accepted gratefully from groups which might at some later time even insist in return that their special interests be placed ahead of those of the general public. It is against this background of high professional principle, in- tense pressure from insatiable public demand, and the blandishments of seemingly easy guidance and support that the issue of conflict of interest between the physician and the pharmaceutical manufacturer must be viewed. Clearly certain practices are undesirable and should be stopped under any circumstance. For example, it is obviously not in the public's interest that the task of keeping the practicing physician abreast of new developments should fall to the necessarily biased drug salesman. Senator N1~LSON. May I interrupt? Does the detail salesman have a function to play? Dr. NICHOLS. I don't think his function should be to educate the doctor, Senator, although unfortunately it ends up all too often being his function. Senator NELSON. You referred above to the reliance upon advertis- ing. Supposing you didn't permit the kind of advertising that is now in the medical journals. For example, the kind that does not give information such as on chloramphenicol, the reminder ads state: "When it counts-Chloromycetin," and that is all, a full page. Do you see any value to the profession and the practicing physician in this kind of an ad? Dr. NICHOLS. I don't; no. The problem, as I see it, is that the physi- cian once he leaves medical school and gets off into practive becomes aware of new therapeutic developments more often through the detail men who call on him two or three times a week than he does from reading medical journals. This is a sad fact but it nevertheless is true, and some of the reasons for it are the pressures under which he is placed by the demands of his patients. So that the drug salesmen who are very carefully schooled by their companies, I am told, in what should be said, and how the mode of action and usefulness of one of their new drugs should be touted, end up by really educating those physicians who don't read too well or too often. Their education is thereby inevitably biased because one can hardly expect a drug sales- man to present totally unbiased views since his job depends on his selling drugs. Senator NELSON. What about a case of this kind? I don't know whether it is true in all hospitals, but we have found in some that there are detail men who are assigned to the hospital. It is their main function to contact the personnel in the hospital who are responsible for the purchasing of drugs. These salesmen are there daily. Assuming that those responsible for purchasing drugs in a hospital are informed, of what value are these salesmen? What is the detail man's function in this circumstance? Dr. NICHOLS. In a good many hospitals, sir, the detail men are specifically excluded if they can be identified. This leads in some instances to a remarkable cat and mouse game. The reason that the detail men have an effect, and I am sure that the reason they are assigned very often in many hospitals, is that the hospital is a con- PAGENO="0076" 3980 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY venient place to find the doctor and that he can exclude detail men from his office by telling his secretary not to let him in but it is much more difficult to avoid him in a hospital corridor. But perhaps most effective, the most effective place that the detail men work is with the younger men who are in training, the interns and residents, since they are ultimately the ones who actually write in the order book such and such a drug shall be given to so and so at such a time and in such an amount. If the detail man is successful in persuading one of those young men to try a different drug or one that he is particularly interested in selling, then, in effect, he has made a sale. It is not a direct one but, in effect, he has still made a sale, and I am sure that this is the reason that so many of them do appear in the hospital corridors and in such large numbers, and you are quite correct, hospitals that I have worked in have had individuals assigned to them. Senator NELSON. Even then, I suppose that if they simply persuade whoever is doing the prescribing to change from one brand of the same compound, that also is a sale. Dr. Nicuoi~s. It is a sale, sure, and for that particular salesman. In point of fact I doubt that-well, I don't really know how often that would happen in a practical sense. Mr. GORDON. We have had some testim~ny to the effect that in addition to getting the residents and iu1~erns to prescribe certain drugs, the companies also give gifts-through the detail men-to resi- dents and interns. Is that your experience? Dr. NICHOLS. You know, Mr. Gordon, if you are responsible for a service you see some things and other things are kept carefully hidden from your view even though everybody else knows all about it. My experience as a house officer was some while ago, but I can quote from that directly. At that time detail men did appear in the hospital, and we were occasionally given gifts of drugs for tria]. This still occurs. One was occasionally offered a book, and as a matter of fact, this still goes on in medical schools where drug companies frequently make availa~ble to medical students, sometimes through the dean's office, literature, some of which is worth while and some of which is clearly trash. I have not personally had the experience of being offered anything by a drug company salesman that I can think of beyond samples of wares. On the other hand, it wouldn't surprise me unduly if such blandishments as dinners and so forth were offered on occasion. Senator NEr~soN. In a paragraph on page 4 you refer to absence of adequate public support for teaching, and suggest it is small wonder that donations, often generous, which may carry with them subtle pressures, have had to be accepted gratefully from groups which might at some later time insist, in return, that their special interests be placed a~head of those of the general public. I want to refer to a paragraph in a book by Morton Mintz entitled "By Prescription Only," and on page 69 he states: Most immune from criticism, for reasons that by now should be apparent, are the drug companies. In an interview in 1962 published by the Center for the Study of Democratic Institutions at Santa Enrbara, Calif., Dr. Herbert Ratner of the Stritch School of Medicine of Loyola University, told what happened in the 1940s: PAGENO="0077" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3981 I showed a former dean of our medical school a talk I had prepared for a religious emphasis week at the State medical school. When he came to the lines, "Modern man ends up a vitamin-taking, antacid-consuming, barbiturate-sedated, aspirin-alleviated, benzidrene-stimulated, psychosomatically diseased, surgically despoiled animal; nature's highest product turns out to be a fatigued, peptic- ulcerated, tense, headachy, over-stimulated, neurotic, tonsilless creature," the dean said: "Gee, Herb, I wish you had not used that line. It will antagonize the drug houses, and we are trying to build up research funds." You are aware, of course, that funds are given for research, test- ing, scholarships, student loans, to medical schools, and to schools of pharmacy. Would you think that this kind of a reaction by this dean would be a common one Dr. NIchoLs. Senator, I can't tell you how common and I don't know exactly the date of the conversation. Senator NELSON. This was in the 1940's. Dr. NIchoLs. It is, however, true, that in the 1940's, `and particularly in the early part of the 1940's, as you know, the only funds that were available for research in any real amount were from private foundations, and through the drug houses, which were at that point beginning to really put a great deal of money into the development of new products. So I suspect that it was probably more common in those days than it is now, but I can envision such a comment being made today, too. Senator NELSON. You referred in your paragraph from which I quoted, to the fact that these funds are accepted `and might `have an influence. We have had examples of it. It may very well be, as you suggest, that it is subtle and unrecognized more often than not. Dr. NICHOLS. Well, this was in my mind, and I think `when I wrote that line, those lines, I had in min'd rather particularly the notion that this was potentially possible, and to the extent that it was poten- tially possible it might cast doubt upon the validity of teaching or it might raise questions of conflict of interest which iii their turn might cast doubt on the validity of the instruction that was being `offemd or the lack of bias of the information that was being used. For example, it is obviously not in the public's interest that the task of keeping the practicing physician abreast of new de~veiopm~nts should fall to the necessarily bi'a'sed drug salesman. Similarly, a physi- cian should never lend his name as author of any professional article of whose factual content and conceptual bias he is ignorant. By the same token, the teacher has a direct responsibility to his `students and the patients whom they may treat in the future to make sure that his instruction is based on the best information available and that he does not appear by any `word or `act to favor any one mode of treatment over another simply because the proponents of that system or the manufacturer of that medicament `has provided him with professional renown or financial support. Other situations are more difficult to judge. Yet, if the solemn respon- sibilities which the profession has assumed in return for its rights and privileges are borne in mind, these questions are relatively easy to answer. Thus, while it is theoretically possible that a man might pro- vide an objective judgment regarding the efficacy, safety, or power of a drug from whose manufacturer he was receiving ongoing financial support, it might be difficult for the public in these days of doubt and PAGENO="0078" 3982 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY disillusionment to believe in his objectivity with regard to that particu- lar drug, a doubt which could not help but expand to include his pro- fessional judgment in other areas. Thus, the physician, like Caesar's wife, must be beyond suspicion if he is to hold the confidence of his patients and to whatever degree this confidence may be shaken or even potentially shaken through his association with a pharmaceutical manufacture-such association must be eschewed. This brings us to the final and interesting question: What if any- thing can the Federal Government do to prevent some of the undesir- able practices which have developed and which have led in `turn to sus- picions of conflict of interest between the physician's responsibilities to his patients and his debts to the pharmaceutical industry? In this regard, I think it is important to remember `that ethical behavior has never been enforced successfully by legislation. The 18th amendment did not abolish alcoholism, the narcotics laws have not stopped our youth from smoking marihuana and the laws against prostitution and adultery, both public and religious, have certainly not put an end to extramarital sex. On the other hand, certain changes in the powers and responsibilities of some of our Federal regulatory and. supportive agencies would go far toward relieving the pressure on bo'th the phar- maceutical industry and the physician thereby, I believe, improving the situation considerably. For example, medical research in this coun- try has become probably the finest in the world, `thanks to the vision of the Congress which created the National Institutes of Health and the National Science Foundation to provide the financial support which it required. This must be continued, if the impetus already gained is to carry us forward to new and better ways of understanding and treating disease. Similar support has been proposed for medical education, but has been much slower in coming, even though the need for educated men `to carry on the research has been as pressing as the need for the research itself. Unable to obtain support for educational programs di- rectly from Federal sources, medical schools-especially private ones- all too often. have had to accept funds from private enterprise such as `the pharmaceutical industry for the support of critically needed programs. Many, I am sure, have been aware of the potential conflict of interest which might be considered to exist in so doing, yet have re- gretfully felt that the need for educational support, whether paid di- rectly `to their students or faculty, or used to provide badly needed teaching equipment outweighed such considerations. Thus, I believe that a program which provided adequate Federal support for both education and research in medical schools would go far to relieve the pressures which have led to undesirable situations. Another area where a revision of Federal programs might well assist is in the matter of drug evaluation. The newly created Consumer Con- trol Division under the Department of Health, Education, and Wel- fare-if I have the name correctly-may be a greater step in improving the system for drug evaluation that I know. Certainly the old Food and Drug Administration was often in an impossible position, lacking as it did the manpower needed to police manufacturing and packag- ing of drugs in truly adequate fashion. As a result, it perforce had to fall back on hopelessly complicated regulations which in more than occasional instances, I am sure, unnecessarily delayed the availability PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3983 of potent and highly useful agents. Just as, of cou~se, they also pro- tected the consumer on many occasions from highly undesirable agents. Senator NELSON. What kind of instances do you refer to here-un- necessarily delayed availability of potent- Dr. NICHOLS. Well, I have had some personal experience in that par- ticular respect, Senator. There is a drug which I happen to use in the kinds of patients I see quite often who have bone disease which is sodium fluoride. This is a common chemical which one can buy in a laboratory supply house, but it is unpleasant to take and so it is pack- aged in a capsule. The way the present regulations are written, the development of a package of a sufficient size for convenience of the patient which can be markete.d requires months and months and months of delay and long involved applications to the FDA in order to get clearance. The regulations are understandable, and they can be met, but in the meanwhile I have to supply my patients directly through my author- ization to use an experimental drug. Yet the drug is available in other packaged forms which don't happen to be the right size. Senator NELSON. This is not a drug that is on the market in this package form, it is being used experimentally? Dr. NICHOLS. It is on the market and being used experimentally in the packaged forms which I dispense but there are other forms which are available on prescription, nonexperimental, and yet it is the same drug. The way the regulations are written the two forms have to be separately cleared is the problem. Senator NELSON. Is that an ongoing problem or does it occur just once in a while? Dr. NICHOLS. No; it apparently occurs more-according to my friends, more-frequently than I had realized. I thought this was just an odd instance `but apparently this does occur not too infrequently. Senator NELsoN. You are, then, referring to a dosage of a particular drug? Dr. NICHoLs. Yes, correct. Senator NELSON. And for the purpose for which you use it they require a certain specific dosage form? Dr. NICHOLS. Well, very specifically the package size that I dispense is 50 milligrams of sodium fluoride in a capsule. The commonly avail- able kind that is marketed by one of the well-known drug companies, I am sorry I can't remember which, contains some other stuff plus about 2 milligrams of sodium fluoride. If I am going to give my patient 50 milligrams of sodium fluoride at a dose I have got to give that poor lady 25 pills and she doesn't like that, not unexpectedly, so that what I end up doing is persuading a drug house to package an experimental form. Senator NELSON. Is this a case where the drug has not been ap- proved? Dr. NICHOLS. That is right. Senator NELSON. Is there a New Drug Application pending? Dr. NICHOLS. Yes, this is a question of having approval, final ap- proval, for packaging this form which is larger obviously by 25 than the one which has already been approved. In the past it was thought the dose level we were currently using was perhaps going to be ex- PAGENO="0080" 3984 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cessive or at least unnecessary. Our present opinion is that this prob- ably is the dose level we should be using. Senator NELSON. Isn't that a kind of an unavoidable problem? In other words, isn't the FDA in a position where they are waiting for adequate demonstrated proof from clinical use by people like you and by the experiments done by the company as proof that it is a safe dosage form? Dr. NIcHoLs. Yes; I think that is quite correct, and the question really comes up how long that waiting period should be and were the arrangements such that all our experience, those who use this drug in this particular dosage form, were pooled in a convenient way and in a convenient place and made readily available to all workers then perhaps the whole time interval required to process this final approval would be considerably shorter. Senator NELSON. Is your use of the drug also for the purpose of developing a history of experience that will be furnished to the FDA so that they- Dr. NICHOLS. Yes; my experience will be, and is being, through the manufacturer who has the license to package it on an experimental basis, or for experimental use, I guess, is the proper term. Others are also, I am sure, trying it through him. Senator NELSON. I am trying to clarify-what size dose is this? Dr. NICHOLS. These are 50 milligram capsules. Senator NELSON. The mechanics of the company putting together 50 milligram dosage in a capsule form they have solved that-that is no problem, is it? Dr. NICHOLS. No; no problem at all. Senator NELSON. What is the problem? When you wish to use it on each occasion you have to get approval of the FDA ~ Dr. NICHOLS. No; I have to be approved as an investigator who will, who has the necessary background and experience to administer this drug and to give it clinical trial, so I signed a form which says, which testifies to the fact that, I have the following experiences in dealing with bone diseases of this type and have had some experience using the drug with someone else, and then submit this to the company and this permits me then to write a prescription for that particular experi- mental drug in the State of Massachusetts. Senator NELSON. Once you have done that, where is the delay in getting the dosage? Dr. NICHOLS. I don't have any delay in getting the drug but if any patient who doesn't happen to live in Boston but lives across the State line, say, in O~nnecticut, gets a prescription for it from me, she can't fill it at home. She has to get the drug from me in Boston or at least buy it in Massachusetts from a pharmacy there which has the permission to carry it, which means my hospital pharmacy is what it really boils down to. Senator NELSON. So in developing experience with this drug you have been authorized as a physician to use it? Dr. NICHOLS. That is right. Senator NELSON. Then it can only be dispensed from just one place in the State of Massachusetts? PAGENO="0081" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3985 Dr. NICHoLS. It can't be dispensed for interstate sale, I believe, is the proper term. So that my patient in Connecticut must find a friend in Massachusetts to buy it for her and take it to her, or she has to call me up and my secretary buys it for her and puts it in a parcel and mails it off. This is the only way in which she can get it and this is cumber- some, and- Senator NELSON. In doing scientific experiments of this kind prior to approval of the drug, what would you suggest could be done to im- prove the situation? That is the problem is it not? Dr. NICHOLS. Yes; this is indeed the problem, and my feeling is that what is happening now is that the regulations which are compli- cated, and necessarily so in order to protect us, physicians and the public both, I believe that these could be m.ade simpler if we had a more centralized system which was much less likely to be biased and in which information from many sources could be pooled conveniently. I believe, therefore, that careful consideration should be given to overhauling the whole method for Federal control of drug manufactur- ing and evaluation. Perhaps a central agency for drug testing could he set up, jointly financed by the pharmaceutical industry and the Federal Government. If such an agency could be established and positions within it made sufficiently attractive to entice able scientists to join its staff, I believe the whole matter of evaluation of a new product could be speeded up immeasurably and many of the questionable prac- tices revolving around payment to investigators for clinical trials could be eliminated to the ultimate advantage of the patient, the doctor and manufacturer alike. Senator NELSON. If I may interrupt you, this suggestion, or some- thing similar to it, has been discussed before the committee on other occasions, and the witnesses have commented on it and raised the same issue you have, that is, the company that, in fact, has a financial interest in putting its compound on the market is the same one that, under the present practice, is solely responsible for developing the evidence for the NDA. In other words, the same company which must prove to the FDA that the drug is safe and effective therapeutically to put on the market. What you are suggesting is to remove the responsibility from the applicant who has an interest in the drug, as well as those who might experiment with it who are paid by the company for the experiment, and put this responsibility into a central place, where the evaluating group would have no financial interest at all in whether or not the drug got into the market, is that what you are saying? Dr. NIcHoLS. Yes; that is correct, Senator. I must confess that when this notion was first suggested to me as a possible solution to some of the problems that we are discussing here, I felt as many of my colleagues, I am sure have, that this kind of an idea wasn't going to work and it wasn't going to work because the test- ing of drugs is not very exciting work, and the problem of developing such an agency, making sure that it was free of bias, making sure that the men and women who worked in it were highly skilled-because after all there is a lot at stake here-were going to be problems which were going to be much larger than the ones engendered by the present system. 81-280-69-pt. 10-6 PAGENO="0082" 3986 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Yet the more I thought about it the more it seemed to me that this was really the only solution that I could see at the moment to remove what clearly couldn't help but be an arrangement subject to bias. Whether it is biased in a given instance or not one cannot predict. But we might say parenthetically that one of the reasons that the drug companies, I believe, end up paying clinical investigators to test their products is that the job is a dull one; it requires a lot of paper- work, and beyond a certain level of experience it is more drudgery than anything else. I think this is the reason that a good many people do end up giving or accepting financial awards for doing the work. Senator NELSON. On the question of `bias we do have some examples of cases where the company changed the investigator's results or the investigator was not allowed to express his own results. MER-29 is one of them. In a big lawsuit in Europe over Thalidomide, the charge was made that even though two witnesses had supplied information raising serious d'oubts about the use of this drug, their evidence was simply `ignored. Now, I would assume even if you had an independent agency of some kind who w'as responsible for evaluation you would still contract with medical schools and physicians who have expertise in the problem that is involved, since you would never have all those people on `the staff, and you have to test drugs not only on animals but also on patients in a clinical situation. Is there any problem that couldn't be solved `as well by contracting with an independent agency rather than by a pharmaceutical house itself? Dr. NicHoLs. Your point is well taken. I have to think about it for a second. Senator NELSON. In other words, what I am saying is if a drug com- pany can seek out the expertise of well-known blood dyscrasia experts, well-known doctors treating certain types of `diseases in `big clinics, or hospitals or medical schools, teaching hospitals-if they can find people who have the' ezpertise, is `there any reason that an independent agency couldn't do the `same and thus remove any possibility of inten- tional `bias creeping in because the company is involved? And on those rare ocea~ions ~wh'ere an individual might unconsciously or consciously be biased because he is working for a company, might not that `aspect be' eliminated,, also? Dr. NICHOLS. I think that it would be possible for such an `agency to `find these people without any question `at all. In fact, I believe through medical schools and medical educators it would be quite pos- sible to find suitable testers outside of Government itself. The thing that was running through my mind when you asked the question was how one might protect the public from the drug com- panies discovering that so and so had actually got the contract to test their new contract from the central agency, and so that this potentially might be another place where infiltration with conflicts of interest might occur. But I think having the intervention of a formal central agency between the two would go far to relieve the pressures that are placed upon physicians at the moment. Senator NELSON. Thank you. Please proceed. PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3987 Dr. NICHOLS. One further and final suggestion I would like to make relates to the controversy over the use of generic versus brand names of drugs in prescription writing-a topic in which my colleague, Dr. Richard Burack, has been deeply immersed and to which I `have con- tributed in a minor way. At issue is the right of the manufacturer to give his product any name which he wishes versus the ability of the physician to prescribe a specific chemical agent of known purity re- gardless of the identity of the manufacturer. Obviously, the right of the pharmaceutical manufacturer to reap the commercial benefits from his new development is a deeply rooted principle in our society. Al- though I might personaily question whether it is truly desirable for products of such enormous importance to the public health as anti- biotics, synthetic hormones, and other such potent therapeutic agents to be patented for private gain, I would be willing to accept the pres- ent system as a necessary evil, if its abolishment would truly threaten the benefits which our pharmaceutical industry brings to us all. I be- lieve, however, that many of its detrimental aspects `could be overcome by the simple expedient of requiring that any manufacturer who patents a new tiheropeutic agent market it under its generic name. In order to protect his interest he might even be allowed to add his firm's name to the generic one in advertising material. Such an arrangement would allow him to collect the profits of his discovery but would at the same time allow the physician to know precisely what he is pre- scribing and would ultimately establish the generic name as the ac- cepted common name of the drug in question rather than the particular brand name of the company which produced it. Senator NELSON. So long as you maintain the pa~tent system, which I suspect we will for a long time to come, there isn't any danger in the manufacturer not reaping the benefits `of his research and enterprise, is there? Dr. NICHOLS. No; I wouldn't think so. Senator NELsoN. In other words, he has got a patent. But you are requiring that he market it from the day he goes into the marketplace and for the next 17 years under the generic name, and he is the only one who can market it for 17 years under the generic name? The pur- pose of the patent is performed. He makes his profit because he has no competition. He may charge what he wishes. At the end of 17 years anybody who is qualified can manufacture and market the drug. Then, as you suggest the doctor would be free to prescribe by the generic name. But if tl~ie doctor, for any reason, decided the drug ought to be a particular company's product-say, Merck, Pfizer, Lilly, or any other-he would write the name of the company after the generic name. I think that is a very good suggestion. The problem we get to now is brand names. A good example of the reason the drug companies would oppose your suggestion is illustrated in the case of prednisone. I do not single out a particular company, here, because it applies to all companies. However, prednisone was marketed for many years under the trade name of Meticorten, and it still is. At least up until the time of our hearings, Meticorten domi- nated the marketplace at a price of $17.90 per 100 when it was `avail- able at $1.50 per 100 and even 59 cemts per 100 elsewhere. But the PAGENO="0084" 3988 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY dominance of that name for so long a time preserved its place in the retail marketplace; however, not in the wholesale, not in the com- petitive marketplace where you have knowledgeable buyers like gov- ernment and big hospitals. I think it is a very effective way to extend the patent monopoly. A very fine doctor told me, after I had explained to him that the Medical Letter's evaluation of 22 drugs showed that they were all equal but that they varied in price from $17.90 for 100-wholesale- to as low as 59 cents-upon hearing this, the doctor concluded "that may be all true but I have been used to prescribing Meticorten for many, many years and I suppose I will do it for the rest of my life." That is the reason for brand name identification, and the reason we have had objection to it. But you do believe that in terms of medical practice to use the generic name in prescribing would be valuable? Dr. NIcHoLs. I do; yes. There is no question at all about it, Senator, and the problem, as you know very well, and I am sure it has been said in this room many times before by others, is that really drugs have three names now, they have a generic name which is assigned to a great extent by the drug manufacturers. Then it has a brand name which is the way it appears over the counter for 17 years if it is pat- entable, and then it also has a chemical name. Well, its chemical name nobody expects anybody to remember because it is based on its struc- ture, and it is impossibly complicated. The generic name is a shorter formulation, some of which are quite complex, but the brand name is usually a catchy title sort of affair, apt to be rather brief. Meticorten is actually a very nice example because it is a `derivative of cortisone and it was named in that catchy form, I am sure, realizing that people would recognize it for being a minor chemical variation with certain specific benefits. It would have been much better if the name MTeticor- ten had been its generic name from the start; everybody would have recognized it for what it is and prescribed it that way. What we end up with, as you point out, is in effect a long extension of a patent which may cause the doctor often, I think completely unconsciously, to really make his patient pay a great deal more for his treatment than he needs to, and I think that is bad, `bad-undesirable. Senator NELsoN. We `h'ad testimony `here on thalidomide. Dr. Taus- sig~, whom I am sure you know, testified `she had been instrumental in informing the FDA of what was happening in Germany, as I recall it. She made a point-I don't have her testimony `before me-but she made a point that quite some time after it was known all over the world in the medical professi'on that thalidomide `had disastrous side effects on pregnant women, it `was `still being marketed under `a num- ber of different names and being used in other countries. Spain, I believe she mentioned, and South America, Brazil, it was being mar- keted there under brand names w'hich the physician did not recognize as thalidomide. She testified, Mr. Gordon says, that it was being marketed under some 50 names. In any event, she made the point t'hat she felt it would be valuable if on the prescription, itself, which the patient got, both the `generic and the brand name appear-unless, of course, there was a particular reason for the doctor not wanting the patient to know what drug he was getting. It was `her opinion th'at this would not only result in better prescribing, but in greater safety. PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3989 She mentioned that in the case of a person allergic to a particular drug, he would not be able to identify the drug withoi~t the generic name on the label-4his could have dire consequences. Is there, in your judgment, any value to requiring that a label that the patient gets contain the generic name, as well as the brand name? Dr. NICHOLS. I think I would rather endorse such a view. As you spoke, I thought of one of my friends who recently was prescribed a drug by a physician. She accepted the prescription, looked at the name which was a brand name, didn't know much about it, filled it, took the drug `and promptly developed a rash, she being allergic, as it turned out, to `one of the several ingredient's which was contained in this particular proprietary mixture. Had she known what was in it she would not have taken it because she is well aware of her allergy, having had trouble before. So I believe that, yes, that it probably would `be an excellent proviso th'at the names of `drugs, and incidentally, as you well know, I think it should he reiterated most or many of the patented new medicaments are actually mixtures of well-known agents but they happen to be combined in `a somewhat different w'ay than some others, and so forth. So that many drugs that we buy under a brand name are not just one drug `but four perhaps combined in `a single capsule or pill. I think all the names ought to be included `and I `believe that it probably would protect the patient. I happen to believe, too, that patients are kept in the dark too much by many physicians about what they `are getting in terms of treat- ment `and what their problems are. I think that, as I wrote in the foreword to Dr. Burack's `book, the days w'hen `a certain amount of mumbo-jumbo was needed in order to encourage the patient and pro- tect `both him and the physician from the unvarnished truth probably are gone now. I don't think that we need to protect ourselves in that way and I doubt that our patients are really very pleased to be kept in the dark about what their problems are really all about. Senator NELSON. You raised a question that hadn't occurred to me before, and that is a combination drug in which you might have one, two, three, or four active ingredients. What kind of time problem does that impose upon the physician if he is going to have to identify on the label everything that is in the drug. Or might that requirement be imposed upon the pharmacist when he labels it? Dr. NICHOLS. I think it could be done through the pharmacist, my- self. The physician, however, should know, I believe, what is in the combinations. Most of the- Senator NELSON. I was thinking of the mechanics of actually having to write out four compounds for one combination drug. Dr. NICHoLS. I am sure that my colleagues would hate me for the rest of theirs and my lives if I imposed upon them more writing than they already have to do. So I think that in a mechanical sense it could he done by the pharmacist and, as a matter of fact, it could even eon- sist of the pharmacist being provided by the manufacturer with stock labels with the information printed on them which he can `simply glue on his dispensing vials. Senator NELSON. Please go ahead. PAGENO="0086" 3990 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. NICHOLS. In closing, I would like to reiterate one thing. The practice of medicine is rooted in the solemn acceptance of high prin- ciples and heavy responsibilities by the physician. The essence of these is that he should place the interest of his patient ahead of his own and I believe that the remarkably high level of medical care which it is possible to obtain in this country provides ample evidence of the de- gree to which the rank and file of the profession adhere to the best of their ability to these principles. Despite this,' the levels of health in this country are not as high as they should be and the physician is constantly being subjected to a barrage of new and often irrelevant information and increasing demands for care without having any time to digest the former or any way of meeting the latter save by taking shortcuts whose long-term implications he may have neither the leisure nor the vision to appreciate. If conflict of interest arises under these circumstances, and many specific instances of it can be oited, it is understandable, even if it should be stopped.' But the method of putting an end to these situa- tions is not ~fl: specific legislation, I believe, which' makes each of them a crime, but rather in findings ways to relieve some~ of the pres- sures which create them.' Ultimately, cures for most of the ills we have been talking about including the argument about generic versus brand names lies with the individual physician who has been properly provided with un- biased up-to-date information. Only he can know specifically what he has done and for what motive. Only he can know whether his acts have been consonant with, or have violated the principles which he has espoused and only he, thinking of these things in the privacy of his inner mind, can create the control for himself which will eliminate them. However, his job would be made easier and his ability to give high quality medical care immeasurably increased if (1) new drugs had only one instead of three (brand, generic, and chemical) names; (2) a simpler, quicker centralized system of new drug evaluation were devised which would provide unbiased information about new drugs; and (3) adequate support of medical education, as well as research, were provided so that schools could spend more of their time on the content of their curriculums, including the teaching of clinical pharma- cology, and less at chasing the money to pay for it. Senator NELSON. We have had testimony before the committee con- cerning a proposal for a compendium of drugs, a complete compendium of drugs. The FDA testified in favor of it, and the proposal was intro- duced in the Congress, and the President recommended it. The proposal contemplates that all drugs would be listed in this independently published compendium with a description, of course, of their indi- cations for use and precautions and side effects. Do you believe a compendium would be valuable to the profession? Dr. NICHOLS. I think basically; yes. I think there are some problems with the compendium, however. One of them is the large number of drugs that everybody has to learn about. I have no idea how many different preparations of digitalis there are, for example, but there must be dozens, and ultimately each physician ends up learning about one particular type thoroughly if he is wise, and uses the others only when his particular favorite happens to be for one reason or another contraindicated. PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 3991 Senator NELSON. They would, of course, list all drugs by their generic names. Dr. NICHOLS. Oh, sure, yes; I understand that. No; I think that the problem, Senator, is that there might be, well, to use prednisone, for example, prednisone is an excellent drug with certain very specific effects but there might be a dozen, say, of other drugs and they would all be listed as having similar kinds of effects as far as one could tell, but their relative usefulness might or might not be clear to the man who had no experience, and he might have difficulty picking out which one would really probably be the best. Senator NELSON. How does he do it now? Dr. NICHOLS. Well, right at the moment, he usually ends up learning about one which he uses and uses frequently. The compendium would certainly be convenient. It wauld certainly be a basic reference. I can conceive of it being an expensive proposition to prepare. But ulti. mately, if it was readily available to all physicians, I am sure that it would be a big step in the right direction. As you also know, the only thing that approaches such a compendium really at the moment is an interesting volume called the Physician's Desk Reference which is in actual fact, nothing but a reprinting of a large list of individual drug manufacturers' broadsides about their particular drugs. The mforma- tion is there but the bias in the information is there, too. Senator NELSON. The witnesses for FDA stated that a compendium should have inserts and that probably the new drug information, as it was developed, should be sent out on either a quarterly or a 6-month basis so that the physician could keep his compendium current. Dr. NICHOLS. I just think this is one way of solving that problem. This obviously is another one of the problems that goes with such a volume. Senator NELSON. I wish to call attention to an article by Dr. Charles May in the January 1961 issue of the Journal of Medical Education 1 in which he referred to subsidies of medical journals through advertise- inents and of medical societies through support of activities and in~ directly by commercial exhibits at meetings that interfere with their functions as outlets for objective criticism. We have not had the representatives of the medical journals, AMA or others, here to testify exactly as to what share of their publication, their income, and so forth, comes from pharmaceutical company ad- vertising. We have noted comments by others that it was in the nature of 50 percent in some journals. Do you see any problems, possible conflicts of interest, when medi- cal societies and their publications rely heavily upon pharmaceutical manufacturers' ads-and promotion? Dr. NICHOLS. These are hard questions because obviously, sure, there could easily be conceived of a conflict of interest arising in such situations. I think the problem that we have to face, and I don't really know how to face it, is sort of a quantitative one. Would the journals that are supported cease to exist were the advertising entirely withdrawn? And if they should cease to exist, would that be a bad thing or a good thing? The general impression is that it would be a bad thing because ~ See article beginning at p. 39~38, supra. PAGENO="0088" 3992 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY scientific material of worth would no longer have a place to be published. I suspect that probably a good many of the journals would get pub- lished anyway. Many of the ones in which I have published, even with what advertising they do carry end up having to charge the author page costs particularly in certain- Senator NEI~soN. Charge what? Dr. NIcHoLs. Page costs for publication. In other words, if I write a scientific article and it exceeds a~ pages, say five, some journals will charge me a cost per additional printed page for production of that article. Now these journals are not the kind that we probably really have reference to here, being more purely scientific but they do contain advertising and I think in thinking about it one should include not just the drug manufacturers and their advertising, but the hardware manufacturers, if one can use a sort of generality, who also have large ads now in the medical journals; people who make various kinds of equipment for monitoring heart action, respiratory action, and so forth in hospitals, and these-this kind of equipment is very expen- sive, and is widely advertised, and I am sure contributes consider- ably to the journal income. Senator NELSON. Do you think that raises the same kind of question, however? Dr. NIcHoLs. So far I don't think `that they have contributed in quite the same way as the pharmaceutical industry, and also the equip- ment which they sell is more directly a matter between the doctor and the manufacturer than it is between the doctor, the patient, and the manufacturer, because the patient doesn't buy that kind of equipment directly so that the conflict, the potential conflict, of interest is differ- en't, and less in risk, I believe. But they are there, and they are ad- vertisers and I think they need `to be thought about in the whole picture. Senator NELSON. I don't know whether it would be possible to evaluate what happened with regard to chioramphenicol, but `the testi- mony the committee heard, from Dr. Dameshek of Mount Sinai as well as other witnesses, was that from 90 percent to over 99 percent of `the cases in which chloramphenicol was prescribed, it was prescribed for nonindicated cases. Further this testimony was unrefuted by the company-or anyone else. One doctor testified that he had never once in his prac'tice to date seen a case of aplastic anemia caused by chloram- phenicol for which the drug was administered for an indicated case. Now I realize `that these things are rather complicated. Bu't the fact is that Chloromycetin was widely advertised in medical journals all over this country. There were people in `the AMA, for example, who were aware of the vast overprescribing and misuse of this drug. Yet, the ads in JAMA continued. As a result of our hearings, `the FDA sen't a "Dear Doctor" letter to every doctor in the country and to all medical journals, explaining the dangers of chloramphenicol and spelling ou't the extremely limited conditions for which it might be indicated. The use of the drug dropped dramatically. In the batch testing by FDA, it dropped from 23 mil- lion grams the first 6 months of 196T to 4 million grams for the first 6 months of 1968, and in June of [968 zero amount was batch tested. PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3993 In other words, following the subcommittee's hearings and the action of FDA, a very, very dramatic drop occurred. Whatever the reason for this wide misuse, I think it is pretty clear that the advertising had a lot to do with it. The company was the one that promoted it through the journals, detail men, and direct advertis- in~. And it seems to me it just indicates that there were some dramatic failures of responsibility on the part of the medical profession. The medical profession was well aware of the dangers associated with the use of chloramphenicol-and of the vast amount of overprescribing and misuse of the drug. Yet there were no blaring headlines, no emergency conferences, no attempt `to alert the general public. That responsibil- ity fell to a congressional committee, that has no expertise at all, to expose what was going on. I don't know what influence the advertis- ing may have had, but it raises the question that here were journals accepting ads for 15 years or more while at the same time carrying articles regarding the misuse and overuse of the drug. The ads were part of the method of misleading the physician. Doesn't that raise a serious question? Dr. NIcHoLs. With all due respect to you and your committee, I agree with you I think it was most inappropriate to happen to fall to your lot to call public attention to; the attention of the medical public to, misuse of this drug by its members. It seems reasonably clear that a lot of people have been prescribing chloramphenicol with little or any reason. The use of the drug outside of certain very specific infections is probably not needed, and in view of the risks involved, not justified. On the other hand, there are individuals, and it is quite easy, actually quite simple to identify them by testing, who need that particular drug if their particular infection is going to be brought under control, and in these instances the drug should be used obviously because the risks of infection may be greater than the risks of the anemia. But I think really what you are saying is something which I don't know quite how to handle at this point. It is the whole problem of the dissemination of information within the profession in a form and in a way which can be rapidly assimilated. At the moment what we are saying in effect is that much of this is being done by the detail man who goes from door to door. He is biased; he has to be, and he shouldn't be doing this. Some other mechanism needs to be found. Whether the elimination of advertising or perhaps better policing of advertising within a journal is going to really solve the basic problem I rather doubt, and I think that you share my view on that. Senator NELSON. I doubt whether any single thing would solve the problem. Dr. NICHOLS. Yes, I doubt that any single thing would. I think a compendium would be helpful, perhaps, in this respect. I think that more availability of, well unbiased material such as is published in the Medical Letter to more people would be valuable. One of the prob- lems with the Medical Letter is that I know a lot of physicians don't know about it. Maybe something like the Medical Letter ought to be circulated to all physicians perhaps by some central agency. Maybe this is one of the functions that a central drug testing service should perform. PAGENO="0090" 3994 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I think that the removal of the barrage of bad information is going to help but I think we have got to put in its place a barrage of good information if we are going to be really effective in terms of putting right these obviously undesirable situations. Senator NELSON. On the advertising aspect-I don't mean to leave the impression that 1 think the advertising in journals was solely re- sponsible for what happened, I am certain that it was not, but if there were better control over the advertising it would seem to me that at least, in a drug which does have dramatic side effects and very, very limited indications for use, that at the minimum, a responsible journal ought to require that every time an ad is printed, it disclose the fully approved FDA indications for use and precautions and side effects so that we don't end up with an ad that is nothing more than promotion of a name. Here was a case where something like an estimated 31/2 to 4 million people were using it and doctors testified that they didn't think more than a few thousand indicated cases occurred in the country per year. Dr. Dameshek, I believe, said that 10 percent of the cases at the most would be indicated. In that case it certainly is a serious question whether the company was justified in advertising the drug in this fashion because there isn't that much use for the drug. In other words, the only justification was to get a vast use of the drug for nonindicated cases, otherwise you couldn't justify the advertising. So there is some breakdown someplace. I don't know what the answer is but it raises a serious question. I don't know whether it is true of other drugs or not. We just happened upon this one, because some knowledgeable physicians told us-we wouldn't have known it otherwise. Dr. NICHoLs. Well, I think that happens to be a good example be- cause it has been so widely used. It is in most people so relatively be- nign, and yet it carries with it this sort of sword of Damocles which may destroy the patient once and for all quite unexpectedly. That is the risk, and it certainly is one that shouldn't be taken unless it is abso- lu;tely necessary. It is a small risk but it is there, it is real. I suspect that there are other drugs that have been abused, and I find it difficult to believe that many of the drugs that I see pe2ple taking are that necessary. Mr. GoRDoN. You mentioned the possibility that if you eliminated advertising some of the good journals might go out of existence. Now, what would be wrong with having the doctors pay for their own journals; that is, raise the subscription rates to the point where they cover the costs of the journal. As I understand it, the medical profession is the highest paid profes- sion in the United States. I would think they would be able to afford $15, $20, or $25 a year for a fine medical journal. What do you think about that~ . Dr. Nicnor~s. I would-I don't have any objections at all to raising the subscription rates to the cost of publication. But I suspect that some of my colleagues might he less likely to read them because they thought the price was high. Of course, a lot of the journals come to us sort of pan passu through membership in the medical societies, and the New England PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3995 Journal of Medicine, as you know~ is a good journal and is published by the Massachusetts Medical Society and I guess tomorrow you will hear from its editor. I think most medical journals are, subscriptionwise are, really quite modestly priced at the moment, even though the price does look sort of high because their circulation is relatively small. The New England Journal happens to be a rather inexpensive one and a rather good one. The mass of advertising material in those journals, frankly I don't think adds to them at all. In fact it is rather a detriment. It mal~es a bulky journal and it makes it more difficult to find what you are looking for. Many, as you know, confine their adver- tising to the beginning and end very specifically but the advertising frequently slips in betwixt and between stuff like the index and the stuff that you don't want to read. Senator NELSON. Do you believe that many physicians would drop their subscription? Dr. NICHOLS. I don't know. I think it is very hard to tell. I have no idea what the statistics are of physician journal buying on a national basis now, that is, journal buying outside of those that they get auto- matically through society membership. I think it would be an interest- ing number to know, because my suspicion is that it is not very large. I suspect it is quite small. Mr. GORDON. Dr. Charles May stated in the article that the chair- man previously referred to, and I quote: The invasion into the province of the medical educator by the drug companies must be eliminated; conscription of "education," in the service of promotion must cease. Sooner or later what may now seem like benign and noble overtures will be recognized as ominous intrusion that threaten the hard-won and reason- able boundary between the sellers and prescribers of drugs. Is it your opinion that good medical practice requires a wall of sepa- ration between the profession and the industry? Would you comment on this subject, please? Dr. NICHOLS. Well, Mr. Gordon, I read Dr. May's article, and re- viewed it not too long ago. I suspect that there should be some kind of separation and certainly the ethics of most societies of medicine more or less stipulate that a physician, for instance, won't own a drugstore which he sends his patients to to have their prescriptions filled. The problem with medical education being supported or education coming through the drug salesman I have already commented on; I think this is an undesirable situation because of the bias that is automatically written into it. I don't know exactly how one can erect a wall between the prescriber and the dispenser of the prescription in a legislative sense. I think that this is one of the things that the profession has to monitor for itself and keep its own skirts clean. Mr. GonDoN. Has the profession been monitoring it ~ Dr. NICHOLS. I suspect it has, yes, in many instances and if there are obviously some who don't-in every profession there are individ- uals who will do almost anything for gain, but I think that where, in general where, this separation has been transgressed is probably more from a matter of ignorance or a matter of just not thinking of where the information that they are using is coming from, that physicians get involved in this clearly undesirable situation. PAGENO="0092" 3996 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Y~u know men get used to seeing the same detail man, for instance, many of whom are very friendly people and fine human beings, and after a while one of them gives you a drug and you try it out in one of your patients, and the patient is pleased, then you are likely to use that drug again, and you may even use that man's offering in another line or prefer it over the offering of another man who isn't as friendly or isn't as available, and so forth. So these things build up in a subtle fashion without people being really aware of what they are doing. Yet if they stopped to think about it, they wouldn't. do it that way, and this is the problem, and that is why fri my statement I tried to emphasize that the pressures under which a physician finds himself in practice are really very e~treme now, and it is very difficult for a man really to meet the kind of demands for personal care from his patients that he must if he is going to live with his own conscience and still keep up with some reading and occasionally see the kids, this sort of thing. Mr. GORDON. Take a professor who teaches pharmacology and tries to teach his students how to prescribe rationally. Is there a potential conflict of interest when he receives grants from drti~flrms? Dr. NICHoLs. Well, potentially yes, obviously. Whether this actu~ ally creates an undesirable situation in most instances I rather doubt, because I think most of the people that I know who teach, basically are honest men who are often aware of these pressures and do try to avoid them. Really, however, they'could be accused of or suspected of a conflict of interest. Mr. GORDON. Do the departments of anatomy or preventive medicine generally get funded by firms? Dr. NICHOLS. That is a good question, Mr. Gordon. I don't know the answer to it. I aii~i not in a department of anatomy, or in one of preventive medicine. I suspect that preventive medicine may get such grants occasionally. I doubt anatomists do. Mr. GORDON. But pharmacology does to a great extent? Dr. NIcHoLS. Pharmacology has been the place that is most obvious for the drug companies to be interested in promoting. Senator NELSON. Doctor, I want to thank you very much for your very fruitful contribution to these hearings. Again we appreciate your coming. We will adjourn until tomorrow morning at 10 o'clock. (Whereupon, at 11 :45 a.m., the hearing was recessed, to reconvene, Wednesday, December 18, 1968, at 10 a.m.) PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WEDNESDAY, DECEMBER 18, 1968 U.S. SENATE, MONOPOLY SUBCOMMITTEE OP THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 10:10 a.m., in room 318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Elaine C. Dye, research assistant. Senator NELSON. Our first witness this morning is Dr. Patil Lowinger, associate professor of psychiatry, Wayne State University School of Medicine, and the chief of the outpatient service of the Lafayette Clinic in Detroit. Dr. Lowinger, we appreciate very much your taking the time to come here to these hearings this morning. You may present your statement however you wish. If you wish to read it, you may proceed, and if you wish to depart from it, to elaborate in any way, feel free to do so. I assume if we have any ques- tions as you go along you don't object to interruption. STATEMENT OF DR. PAUL LOWINGER, ASSOCIATE PROFESSOR, PSYCBIATRY, WAYNE STATE uNIvLTts:ETY SCHOOL OF MEDI- CINE, AND CHIEF OP THE OUTPATIENT SERVICE OP THE LAFAYETTE CLINIC, DETROIT, MICH. Dr. LOWINGER. Thank you very much, Senator. It is a pleasure to be here, and I will read my statement and make some explanatory statements as I go along and welcome any questions or interruptions. I have been in clinical pharmacology as part of my duties in psy- chiatry as a teacher and a researcher over a 15-year period. I am now at Wayne State University, department of psychiatry. Before that, I was in the Public Health Service at the Marine Hospital, New Orleans, where I began my work in clinical pharmacology. At that time, I was on the faculty of the school of medicine at Tulane University. I have been concerned throughout this time with the development and the evaluation of new drugs in an effort to increase the effective- ness of the treatment of mental and emotional disturbances. This has been a particularly exciting 15 years because the psychopharmacologic 3997 PAGENO="0094" 3998 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY revolution in psychiatry has reduced the number of people in mental hospitals and made the treatment of mental illness much more effective. However, I have been concerned throughout this time about the protection of people receiving these drugs, both during and after the research projects. I have always been told and believed that the re- suits of my studies as they concern safety were reported to the Food and Drug Administration by the pharmaceutical companies. This belief is based on the new drug section of the pure food and drug law of 1938 which required a manufacturer to test each drug for safety and submit the data to the Government, as well as the 1962 Kefauver- Harris amendments. With the exception of one study which we did for the Food and Drug Administration itself, the 28 studies in which I participated were all initiated by well-known, ethical pharmaceutical compames. The scientists and doctors representing these manufacturers had ex- cellent reputations and each assured me that their research was con- ducted in a responsible and lawful manner. The seeds of dou'bt began in 1965 when I learned that our findings on the safety of Dornwal studied in 1961 for Wallace & Tiernan had not been reported to the Food and Drug Administration. As a result of the suppression of information about Dornwal, which is a tran- quilizer, a Federal district court imposed a maximum $40,000 fine on the company and placed its medical director on probation for 1 year. The reason for the Government prosecution of Wallace & Tiernan was that toxic effects of Dornwal on the blood had not been reported to the FDA. This experience led me to publish a letter in "Science" on July 8, 1966, asking how often pharmaceutical houses conducting new drug investigations failed to report the results of their studies to the Food and Drug Administration. I received no answer to this letter from my colleagues in medical science, the pharmaceutical in- dustry, or the Government so I decided to conduct my own investi- gation. The reports of 27 new drug studies made between 1954 and 1966 were reviewed and the FDA was asked in April 1966, if these reports about the safety of these drugs had ever been received from the phar- maceutical companies. Oommissioner Goddard said promptly that the FDA would cooperate in this study. I sent a copy of this rather voluminous file of my correspondence with each of these companies to the FDA and 2 years later I received a report from the Food and Drug Administration, on March 29, 1968.1 In 1967, the FDA refused to release this information `because they felt, quoting from the letter which I received from Dr. Herbert Ley: "it would be inappropriate to divulge the names of firms who have failed to submit certain clinical data." But this was overcome when I appealed to two Senators. My full report' shows that the data on only nine of the 27 drug studies had been submitted to the FDA. Despite this problem of reporting on drug safety, Dr. Ley commented in his March 1968 re- port to me that the manufacturers were in compliance. Senator NELSoN. May I interrupt? Dr. LownmEn. Yes. 1 See pp. 4008-09, infra. PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3999 Senator NELSON. You state that the data on only nine of the 27 drug studies were sent to FDA. All 27 were studies you had worked on, is that correct? Dr. LOWINGER. Yes. I had either been the principal investigator or a coinvestigator. The work had all `been done in institutions such as the Lafayette Clinic in Detroit, the Marine Hospital in New Or- leans, and the Pontiac State Hospital in Michigan, where I `was either full time or affiliated. Senator NELSON. Did the other 18 studies have information in them indicating toxicity? Dr. L0wINGER. Yes, all the studies indicated toxicity. Senator NELSON. Including the nine? Dr. LOWINGER. Yes. Senator NELSON. So these were 27 studies, on how many different drugs? Dr. LOWINGEIi. There were 27 drugs studied. Senator NELSON. Twenty-seven different compounds? Dr. L0wINGER. Yes. Senator NELSON. And nine `of these studies on nine different drugs were submitted to the FDA? Dr. LOWINGER. Yes; according to the report from the FDA they had in their files copies of information which I had given the plìar- maceutical companies. Senator NELSON. Did the nine studies that were submitted, indicate toxicity in each of those nine drugs? Dr. LOWINGER. Yes, just like the ones that had n'ot been submitted. I was able to find out from my own files what I had said years earlier. Senator NELSON. Were there indications of toxicity on the other 19 that were not filed with the FDA? Dr. LOWINGER. Yes; there were. Sen'ator NELSON. Was there any difference in the gradation or qual- ity or seriousness `of the toxicity between the nine that were filed and the 19 that were n'ot? Dr. L0WINGER. No; there was no essential difference in the serious- ness. I was very fortunate in not finding serious toxicity in any of my studies although I studied such drugs in the course of my work as thalidomide. Senator NELSON. Were these all different companies or were some of the 27 duplicates? Dr. LOWINGER. The 27 drugs were sent to us by 19 companies of whom 12 did not report to the FDA while five did submit reports to the FDA. Two companies si~thmitted a report with one drug te'sted but did not with `another drug. So there were a total of 19 companies in- volved `and 27 drugs. Senator NELSON. I see. Please go ahead. Dr. LOWINGER. Drug safety problems of some of the drugs which were unreported included the following: Dizziness, drowsiness, mood depression, anxiety, insomnia, `blurred vision, loss of anal sphincter control, ringing in the ears, headaches, itching, dermatitis, weakness, fatigue, nausea, diarrhea, abdominal distress, constipation, and a pos- sible case of hepatitis. The 27 drugs were sent to us for research by 19 companies of whom 12 did not report to the FDA while five did submit reports to the FDA. PAGENO="0096" 4000 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY There were two companies which submitted a report with one drug tested but did not with another drug. We made 23 reports to com- panies before the Kefauver-Harris amendments in 1962. Sixteen of these were not submitted by the manufacturer to the FDA, while seven were, in fact, sent. During and after 1962, we made four studies, two of which were not submitted to the FDA, and two of which were sent to the FDA. Senator NELSON. Were any of these studies being made on drugs that were already in the marketplace? Dr. LOWINGER. The drugs we tested included drugs that were al- ready on the market. Also included were drugs that were not on the market and drugs that were in the process of being prepared for marketing. In some cases the company that asked us to test the drug was not the company that was later to put the drug on the market. Senator NELSON. You mean it was a company that was contracting with the manufacturer to get testing done for them? Dr. LOWINGER. My record shows, Senator, that the situation you just mentioned was true in some cases. In other cases there were com- panies that gave up a drug to another company although they were not originally a contracting agent. The presence of violations of law in these situations is a matter for Government lawyers to determine. My concern is with the ques- tions of organization, ethics and secrecy in scientific work which affects the safety of the population at large. It is quite .apparent that the coordination of clinical drug evaluation is beyond the capacity of the individual investigator, the university, the Government, and the pharmaceutical industry. Avoidance of the problem, lack of de- termination, secrecy, and limited perspective by these institutions calls for a new public approach with enforcement provisions. The goal to be achieved is to raise the standards of clinical pharma- cology by using the most responsible investigators. These investiga- tors require well equipped and staffed programs. They also need the right of full access to the scientific information about the products under study. Senator NELSON. May I interrupt here? Dr. LOWINGER. Yes; you may. Senator NELSON. What exactly do you mean by that? Do you mean that when investigators are asked to do some testing of a drug that the companies do not furnish them all of the scientific information avail- able about this compound? Dr. LOWINGER. My primary concern, Senator, is the fact that often- times there are a number of people studying the effects of a new drug on human beings in clinical settings and they do not know who the other investigators are and, as a result of this, minor and seem- ingly irrelevant effects according to one investigator or perhaps an isolated serious effect are unknown to the other investigators. If the investigators knew each other's names and could communicate that way they would be more effective and more prompt in assessing serious toxicity. In other words, if I am investigating a new drug, it is only by a chance meeting over a cocktail at a scientific meeting that I discover another doctor in Chicago or Seattle is doing the same thing and we compare notes. PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4001. It has been characteristic that I have not been given the names of other investigators, and that is true of my colleagues who have been in clinical drug investigations. That is the kind of trade secrecy which I think is unnecessary and undesirable. Senator NELSON. Well, if it would benefit the quality of the investi- gations being conducted by several investigators, why isn't it simply automatic that the company would furnish the information they accumulate, and the names of the other investigators? Why wouldn't that just automatically be done if it is of scientific value? Dr. LowINoErt. I think it should automatically be done. I can't say what the motivation is. I can only speculate about that, Senator. But I think it very desirable that this be part of our pattern of future drug investigations. Senator NELSON. You don't see any disadvantage to it? In other words, if a contracting company has a number of medical schools and individual investigators investigating a drug, there is no disadvantage to the scientific value of the proceedings if all of them know what the others have found out? Dr. LowINorn. No; I can see no disadvantage to investigators being identified as doing new drug studies if they are in fact so doing. This is characteristic of the National Institutes of Health which publishes lists each year of everyone doing all kinds of studies, and everyone knows what everyone else is doing and can communicate informally, outside official Government and public channels. I think that is very desirable. I can see no disadvantage to it. Senator NELSON. Thank you. Please go ahead. Dr. LOWINGER. There is a need for a federally sponsored institute which will fund and supervise drug research and psychopharmacology with a special emphasis on new drug clinical investigation. Such an institution while federally controlled and funded should rely heavily on the use of outstanding scientific civilian consultants much in the fashion of the National Institutes of Health committee system. The work they approve should be conducted by universities and institutes, which conform to the highest standards of science in personnel, equip- ment and research design. The pharmaceutical industry would not be relieved of its obliga- tion to demonstrate the efficacy and safety of its products but there would be a Federal capability which would set standards and en- force them. The primary involvement of the FDA with food, cosmetics, and manufacturing indicates that this new research program should be conducted separately. Senator NELSON. May I interrupt again? You say the pharmaceutical industry would not be relieved of its obligation to demonstrate the efficacy and safety of the products. Are you suggesting that the company which is having its drug tested and which will be making a New Drug Application follow the same proceedings it does now in developing its ND.A but in addition to that there be an independent experiment, investigation, conducted by anothersource? Dr. LOWINGER. Yes; I am suggesting that. Senator NELSON. So would you have the independent agency, what- ever it may be, conduct a comprehensive investigation of the drug that 81-280-69-pt. 1O-7 PAGENO="0098" 4002 COMPETITIVE PROBLEMS IN THE DRLrG INDUSTRY would stand on its own without any proof of efficacy and safety by the companies themselves? Dr LOWINGER Well, 1 can see such an agency making any one of several decisions. I can see them conducting their own survey, funded, perhaps, by the pharmaceutical industry. I can see them supervising and approving research protocols for investigations by the pharma- ceutical company, or some combination of these patterns. But the important thing, I think, is to have `a Federal scientific capability in new drug evaluations which we simply don't have now, and in this way we can either fund these investigations out of Federal or industry funds, we can supervise them or we can conduct them as a Federal agency. Senator NELSON. So, as I understand it, :the company that desires to market the new drug will conduct its own proceedings as it does now, its own investigations, contracting with individuals and research groups and prove its own case just as it now does for NDA, and then additionally, there would be an independent agency that may set some standards or supervise whatever the private company does and which may also conduct investigations of its own. Who makes the final decision on the NDA? Dr. LOWINGER. Well, that decision is now made by the Food and Drug Administration, is my understanding. Senator NELSON. Yes, it is. Would you leave it there ~ They would then evaluate the NDA by the company as well as the independent investigation done by this other agency and, using both of them, approve or disapprove the NDA, is that what you are suggesting? Di LOWINGER I am suggesting that the ~pproval of new drugs be taken out of the FDA and be placed with this new institute of `pha~- macology leaving the FDA to its many present functions, supervising manufacturing and setting other kinds of standards. Senator NELSON. And you are talking only about new drugs now? Dr. LOWINGER. Yes. My own experience has been in the clinical human trial on sick or ill individuals of new drugs. I have had no direct personal experience with the many other problems; the FDA supervises, food, cosmetics, manufacturing, and so on I am com menting about clinical pharmacology which is only a part of pharma- cology, not basic pharmacology, which is the animal work It is of importance that each investigator be required by law to send a copy of each of his reports to the `~ppropriate Fedei al agency, which at the present time is the Food `and Drug Administration. Senator NELSON. You think the investigator should send a copy of his report directly to `the appropriate Federal agency? Dr. L0wINGER. Yes; I do, Senator. Senator NELSON. The present practice is that that report, the in- vestigational information, goes to the company? Dr. LOWINGER. Yes; that is the present practice. Senator NELSON. And it is `their responsibility to furnish the FDA with it. Dr. LOWINGER. Yes. Senator NELSON. Whu~h they sometimes in the past have not done. Dr. LOWINGER. Yes. Such `a law will close the loopholes about re- porting new `drug findings on safety and efficacy to the Federal PAGENO="0099" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 4003 Government. This will do away with any po~sibility of misunder- standing, delay, and omission. The Government office which receives this data needs a staff to evaluate and communicate about these reports. Senator NELSON. If I may interrupt again- Dr. L0wINGER. Yes. Senator NELSON. An investigator, I assume, may develop some~ rather elaborate detailed reports on an investigation which extend over a period of time, what about the simple mechanics of producing an extra copy? Dr. LOWINGER. Actually that is not a serious problem. I was sug- gesting that the investigator be obliged to send perhaps a report once a year, and his final report to the appropriate Government agency, and this is, this would be a relatively small volume of informatiom but a very important type of data. In other words, I am not suggest- ing the investigator be obliged to send his research design or all the paperwork he generates about the subjects in his study, but rather to report once a year and his final report, which is, generally speaking in my case, two or three typed pages. Senator NELSON. In which you draw conclusions, from what you have found as to the effects, and side effects, is that what you are saying? Dr. LOWINGER. Yes; that is correct. Senator NELSON. So if there were questions of efficacy or safety which the investigator had found, that would be in the report that would goto the FDA? Dr. LOWINGER. Yes. This would be in each of these reports since nearly all these studies are concerned with both efficacy and safety. Finally, the veil of secrecy around new drug development needs rad- ical reappraisal in the interests of public safety. New drug investigators need to be informed about the products that are under investigation. In this way if two scientists are work- ing on a new drug in di iferent parts of the country, they will know about the full effects of the studies each is conducting. The minor and seemingly irrelevant drug effects noted may be better understood by the doctors studying the same product. It has been characteristic in the past that each investigator studying a new drug did not know the others who were conducting similar investigations in other parts' of the country. This led to a delay and sometimes, a loss of valuable scientific information. A drug surveillance study by Borda in the August 26, 1968, Journal of the American Medical Association shows that 35 percent of hos- pital patients on a medical service have adverse drug reactions. The frequent use of potent drugs to treat disease demands better methods and more safeguards. The prevention of dangerous drug reactions begins with the evaluation of the drug. The improvement of the eval- uation of the new drugs requires direct reporting by investigators to the Government, the free exchange of information among scien- tists and a National Institute of Pharmacology. Senator NELSON. The National Institute of Pharmacology-is this the independent agency to which you were referring earlier in your remarks? PAGENO="0100" 4004 COMPETITIVE PROBLEMS I~ THE DRUG INDUSTRY Dr. LOWINGER. Yes; I have simply given it this name for dramatic emphasis. Senator NELSON. Under the present system of drug evaluation- did you conduct your investigations as part of a proceeding of the medical school itself? Dr. LOWINGER. Yes; that is correct. Senator NELSON. What was the arrangement? Was the arrange- ment to conduct the investigation between you and the company or between you and the medical school or how was that handled ~ Dr. LOWINGER. Usually the initial contact was made by the com- pany to myself or to another member of the f'Lculty If it was another member of the faculty or another scientist in another laboratory, the matter was referred to me, and ordinarily the arrangements were made between the institution with which I was associated and the company. I simply. represented my institution in making the arrange- ments. Senator NELSON. Was some kind of a contractual arrangement. made? Dr LOWINGER Ordinarily the kind of contract that exists in these matters is an exchange of letters in which I am asked to do some thing in writing and I reply that I will do so, and we set forth our agreement in that form. On occasion I was asked to fill out a Federal Government form which was also sent to the company duplicating or amplifying some of the information in the letter between myself and the company. Senator NELSON. Is this a personal, private contract or agreement between you and the company or is it an agreement between the school, the dean of the medical school or somebody else, the institution itself and the company? Dr. LOWINGER. It is an agreement between the Lafayette Clinic which is the department of psychiatry of Wayne State University, and the pharmaceutical company in which I act as the representative of the Lafayette Clinic. But you are quite right, it is between the medical school department in question and the company. Senator NELSON. Are you paid a fee for your investigational work? Dr. LOwINGER. No; I am not. The company pays for expenses over and above the ordinary cost of salaries and laboratory procedures. So they pay expenses to the department of psychiatry in the Lafayette Clinic for the work that is being done. Senator NELSON. But you are not paid anything in addition to your salary with the clinic, is that right? Dr. LOWINGER. No; I am not. I would regard that as an undesirable state of `affairs. Senator NELSON. In making the arrangement with the school or the clinic, do they pay the school, then, for the time that you use in doing their investigation on their product? In other words, if you spend half the time on it, that is half your salary, do they pay that or don't they? Dr. L0wINGER. No; they don't, Senator, and I think that is one of the problems in clinical pharmacology. The things they pay are considerably below the real cost, and I think the reason is the prob lem you identified. In other words, they pay for laboratory work, PAGENO="0101" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4005 for secretarial time and for some time by resident physicians, but they do not pay for any proportion of my salary or for the other kinds of institutional upkeep that go into running a research pro-. gram. I would hope that with the development of the new Gov- ernment institute that clinical pharmacology would become be.tter supported. Senator NELSON. Let me see, is your university publicly supported? Dr. LOWINGER. Yes.; Wayne State University is a State university under a board of governors and money for salaries of faculty comes from the State legislature. Senator NELSON. It comes under the university board of regents, doe's it? Dr. LOWINGER. Yes, that is correct, Senator. And in order to clarify this, I am at Lafayette Clinic which is the department of psychiatry at Wayne State University, but is `an institution of the State depart- ment of mental health which is likewise supported by tax money but is not directly under the board of regents of the university. Senator NELSON. What do the firms pay for then? What are they paying for when they contract `wi'th your department? Dr. LOWINGER. They are paying for the cost o'f laboratory tests. Senator NELSON. What do you mean by laboratory tests-the mate- rials and equipment? Dr. L0wINGER. They are paying a proportion .~f the technician's time In other words, the head of the l'tboratories does not have a pro portion of his salary paid. They are paying for technicians' time to complete extra work in the laboratory. The workweek can be extended by the use of this extra tecimicians' salary money. Senator NELSON. Who are the technicians? Are they students? Dr. LowING1~iii. N'o. The technicians are full-time employees. Senator NELSON. Do they pay only for the overtime put in by the technician or do they- Dr. LOWINGER. It is assumed that the technicians in the research and clinical laboratory of a department have a full or even a'bove a full workload to do. If we ask the director of our laboratory to under- take a certain number of blood `and urine t.ests in connection with a new drug investigation, he quite correctly po'ints out to me that this is going to interfere or hold up some of the work that his laboratory is doing. So we add a proportion of money to his budget, which he may use `by extending the work hours of his technicians, using over- time to complete the workload that wouldn't ordinarily get d'one be- cause of this new work which has come into the schedule. Senator NELSON. So then the objective `here is simply to pay the salary cost or time cost that the technician puts in for research on the contract, is that correct? Dr. LOWINGER. That is correct. Of course, work in a laboratory like the one I am describing goes in cycles and it may `be that he. doesn~t need that extra time until `a little later, so he has that money avail- able to `him. Senator NELSON. That is one item of cost. Materials or whatever is another `item. What other items are there? Is there an overhead cost for the use of the lab-general overhead? Dr LOWINGER We h'we ne ~er had that in the budgets that I ha~ e PAGENO="0102" 4006 COMPETITIVE PROBLEMS IN THE ~ DRUG INDUSTRY prepared or been familiar w ith I think that should be in these budgcts but we have~ never put that in The other items include secretarial costs, and the costs of time fot work on the project by resident physicians Senator NELSON What do you mean by time of resident physicians Dr. LOWINGER. We assume that the time spent by doctors in the training program who fill out forms and carry out more extensive studies of pati~nts than they would ordinarily do is a legitimate budg- etary charge So that comes into making up the total costs, `md also we have additional secretai ial `~ ork so we introduce a secretarial charge, whatever the hour1~ rate is in our institution at tlic time the study is being done. Sen'ttor NIIL50N Why do they pay some amount for the residents' time and none for yours, as the primary researcher, the one in charge of the project2 Di L0WINGER I have no good answer for that question, Senator It simply has been the custom This has contributed to part of the problem, which is a kind of financial anemia of this kind of research program which is inadequately funded as compared to the adequately funded research of the National Institutes of Health. They do pay full institutional costs, including the senior investigators and an over head to the institution. I think we have fallen `into the habit of using these small stipends rather than a re'iiistic `ippraisal of the full costs At least I have been guilty of this practice over the years Senator NELSON Well, as I have examined some of the agreements that `ire made between NIH and the University of Wisconsin on any Federal contracting, of which there is a great deal, they always pay the full salaries of everyone involved. They pay it and they compute an overhead cost of the physical facilities. If 10 people use a facility and you add two from outside, then one-twelfth of the overhead costs, in- sofar as personnel are concerned, ought to be assigned to each of the additional people and paid for outside. Furthermore, many times they have a certain amount in addition to cover un'tnticipated costs If this is the general practice, it r'us s `~n interesting question Why should any publicly supported institution in this country-~ hy should the taxpayers in any Stite be paying the cost of investig'ttions which `ire being done in beh'il F of `i profit oriented corporation2 Why shouldn't the corporation pa~ `ill of it ~ I know this isn't nen I h'td `L comment from: Morton Mintz' book yesterday, I don't believe I read it into the record, in which a study was made of the fact that the com- panies end up using institutions, public and private, to get what amounts to subsidiied research They then turn around and put the product on the market, at a profit, `md I might s my, at `m h'mndsome profit, in many of the cases we looked into I `mm curious to know why public institutions tolerate it I don't know why the heads of the med ical schools and presidents of the universities don't say to the drug com pany, "You will pay on a basis that covers the total cost `md there has to be some benefit to the university or why should we let you use the f'mcilities 2" If this practice is acceptable, I don't know why General Motors shouldn't get subsidized research at our universities, or for that matter, anybody else It is rather a puzzle I realize that is not a determination of yours This is a practice which has been going on for many, many PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4007 years, but it is one that interests me and I think our committee ought to pursue it further. I don't know why the pharmaceutical industry should be paying on a less equitable basis th'in the Federal Government, which has lots of research done by the great private and public institu- tions of America. I have had to listen to quite a bit from the drug companies about the high cost of research. I just wish I could get research done for myself on that basis if I were in private enterprise some place. Mr. Gordon, did you have something? Mr. GouroN. Yes. Mr. Chairman, in the early part of Dr. Lowinger's statement he refers to Dornwal, a product of Wallace & Tiernan, and the subcommit- tee has documents on this particular subject in its files, including a letter to the Attorney General from the Food and Drug Administra- tion,1 in which the FDA asks the Justice Department to prosecute this company. Let me read a couple of paragraphs: The indictment charges violation of 18 USC 1000 based upon the acts of de fendants in knowingly `and willfully concealing material information and sub- mitting and causing submission of false and fictitious statements, in writing and orally as to material facts, to the Department of Health, Education, and Welfare, Food and Drug Administration in a matter within the jurisdiction of the Food and Drug Administration. Between January 27, and October 11, 1961, 28 such contacts were made by the defendants in which they knowingly and wilfully concealed material facts from Food and Drug Administration, to wit, medical evidence that Dornwal was the causative agent of a severe and often fatal blood dyscrasia in man. Furthermore, subsequent to the submission of the New Drug Application for the drug Dornwal, the defendants made 10 mail submissions to the Food and Drug Administration concerning the New Drug Application In which false and fictitious statements and representations were made concerning the safety and lack of serious side effects in the use of Dornwai. Apparently some people also died as a result of taking the drug, and I ask that the relevant material in the committee files be put into the hearing record. Senator NELSON. That will be put in the record. I think that is one of a number of cases that does support the concept that you talked about, Dr. Lowinger, of having some independent evaluation, so that the public would be protected against cases like this which may occur from time to time. Mr. GORDON. Mr. Chairman, there is another case which, I don't think, Dr. Lowinger referred to. Here is another letter on the drug called Flexin, which was manufactured by McNeil Laboratories, a sub- sidiary of Johnson & Johnson, in which the FDA asked the Attorney General to institute criminal proceedings.' Senator NELSON. For the same reason? Mr. GoRDoN. For the same reason. The offenses complained of were committed in 1959 and 1961, the knowing and willful concealing of material information and the submission of false and fictitious state- ments in writing to the Department of Health, Education, and Welfare. Apparently some people died of hepatitis which they contracted as a result of taking this drug I ask that the relevant material of this case also be put in the record. 1 See pp. 4010-16, Infra. PAGENO="0104" 4008 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. This will be done. Thank you very much, Doctor. We appreciate your very fine contribution to the hearings. (The supplemental information submitted by Dr. Lowinger follows:) Date of report Company Drug to company FDA record of report Armour Pharmaceutical Co Lustica Nov. 30, 1962..... Yes. Ayerst Laboratorie& Suvren July 16, 1957 Yes. Aug. 6, 1957 Ciba Pharmaceutical Products Serpasil Dec. 9, 1954 No. Dec. 9, 1955 Geigy Pharmaceuticals Tofranil Feb. 24, 1960 Yes. May 27, 1960 Nov. 7, 1960 Feb. 13, 1963 Mar.4, 1965 January 1966 Eli Lilly & Co. ..~ Compound F (or) Compound 18132 (or) Jan. 10, 1957 No. Ultran. Lloyd, Dabney & Westerfield Benactzine July 25, 1956 Yes. National Drug Co Contergan (or) Covatin (or) Thalidomide.. Mar. 111960 Yes. Methylnonyl dioxolane Jan. 6, 1958 No. Parke.Davis & Co C1393 Aug. 26, 1960 No. Pfizer Laboratories Niamid February 1960.... Yes. May 27, 1960 Nov. 7 1960 Feb. 1~, 1963 Mar. 4, 1965 January 1966 A H Robbins Co Mephenoxalone (or) AHR233 (or) Trepi Apr 20 1959 Part;al done. Mar. 11, 1960 Roche Laboratories Marplan Feb. 19, 1960 Yes. May 27, 1960 Nov. 7, 1960 Feb. 13, 1963 Mar. 4, 1965 January 1966 Librium July 22 1964 No Nov.7 1960 Feb. 1~, 1963 Riker Laboratories Riker 548 (or) Trimeglamide Nov. 17, 1958 No. Deaner Jan. 6, 1958 No. Rauwiloid Dec. 9, 1954 No. Mar. 21, 1955 Dec. 9 1955 Sandoz Pharmaceuticals LSD25 June ~ 1964 No. Smith, Kline & French SKF 7003 (or) Proformiphen Feb. 1~ 1959 No. SKF 385 (or) Parnate Apr. 8, 1959 Yes. Stelazine Nov. 7, 1960 No. Feb. 13, 1963 July 24, 1964 Squibb Institute for Medical Research... Raudixin Mar. 21, 1955 Dec. 9, 1955 Upjohn Co U-12480E December 1962__ No. Wallace & Tiernan.. Dornwal 1961 No. Wyeth Laboratories WY 2149 Apr. 30, 1959 No. Equanil Nov. 7, 1960 No. Oct. 8, 1962..___ Feb. 13, 1963 July 24, 1964 Sparine October 1956 No. Winthrop Laboratories Win 12,267 Apr. 1, 1960 No. DEPARTMENT OF HEALTH, EDUCATION, AND WiimFAixE, Washington, D.C., March 29, 1968. PAUL LOWINGER, M.D., Department of Psychiatry, Wayne state University, EJchooZ of Medicine Detroit, Mich. DEAR DR. LowINoElt: This acknowledges your letter of February 5, 1968. We appreciate your kind indulgence throughout the lengthy investigation under- taken to determine whether reports you submitted to various pharmaceutical manufacturers where in turn submitted to the Food and Drug Administration in `accordance with `the existing legal requirements. Our investigation has revealed close compliance with requirethents in effect at the time your studies were conducted `and reported to the manufacturers. The at- tached summary will carry a notation "Not Required" in such instances. As we PAGENO="0105" Product Comments Firm Armour Pharmaceutical Co__ Listica Dr. Lowinger's report of Nov. 30, 1962, was included in the firm's submission. Ayerst Laboratories Suvren On Sept 23, 1957, firm submitted 2 letters and a report en- titled "Final Clinical Report on Suvren." Firm also sub- mitted the report "Outpatient Drug Therapy Evaluation Project;" also a reportentitled "Explanation and Data on M Y-2241." Ciba Pharmaceutical Corp~._ Serpasil Dr. Lowinger's reports of Dec. 9, 1954, and Dec. 9, 1955, were not submitted. Not required. Geigy Pharmaceuticals Tofranil Dr. Lowinger's reports were included in the NDA submission. Eli Lilly & Co Ultran Dr. Lowinger's report of Jan. 10, 1957, was not submitted. Not required. Lloyd Dabney & Westerfiel& - Benactyzine A letter and 3 page report date July 26, 1956, were sub- mitted. National Drug Co Contergan The Mar. 11, 1960, report entitled "Interim Results in a Comparative Modified Double Blind Study of Tranquilizars in Psychiatric Outpatients" was submitted. Do Methylnonyl Dioxolane No IND or NDA filed therefore no submission by firm of Dr. Lowinger's report of Jan. 6, 1968. Not required. A. H. Robins Co Mephenoxalone Report of Apr. 20, 1959, was included in NDA for Lederle, Trepidone-Letter of June 10, 1960, authorized Robinson to Lederle's NDA for its Mephenoxalone sub. Parke, Davis & Co C-1393 No IND or NDA filed-Dr. Lowinger's report was submitted. Not required. Chas. Pfizer & Co Niamid Reports were submitted by firm. Roche Labs Marplan May 27, 1960, and Mar. 4, 1965, reports were submitted. Do Librium No reference to either the capsules or reports tablets. Riker Labs Trimeglamide Studies were discontinued on June 10, 1963. Dr. Lowinger's report of Nov. 17, 1958, was not submitted. Do Deaner Submitted as part of annual report of Aug. 6, 1964, was bibliography section which included 3 references Dr. Lowinger. No other repnrts were located. Do Rauwiloid No reference to Dr. Lowinger's reports of Mar. 21, 1955, or Dec. 9, 1955, were located. Not required. Sandoz Pharmaceuticals_ -- -- LSD IND 306 listed Dr. Lowinger as an investigator. IND 302 con- tained references to Dr. Lowinger as follows: (a) a letter dated Apr. 20, 1966, to Mr. Craig D. Burrell of Sandoz; (b) 2 letters dated Apr. 11, 1966, and May 18, 1966, to Dr. Lowinger from the firm; (c) a statement listing the amounts of LSD-25 Psilocybin given to Dr. Lowinger. No clinical reports submitted by Dr. Lowinger located. Smith, Kline & French Proformiphen No IND or NDA filed-no reference to Dr. Lowinger reports of Feb. 19 or Feb. 23, 1959, was located. Not required. Do Parnate Report of Apr. 8, 1959, was submitted. Do Stelazine Report of July 24, 1964, was submitted. Squibb Raudixin Reports of Mar. 21 and Dec. 9, 1955, were not located. Not required. iJpjohn Co U-12480 E Studies were discontinued on Mar. 1, 1963. Report of Decem- ber 1962 orJanuary 1963 were not submitted. Not required. Wallace & Tiernan Dornwal The 1961 report was not located. Not required. Wyeth Labs Equanil Report of July 24, 1964, was submitted. Other report (Nov. 7, 1960, Oct. 8, 1962, and Feb. 13, 1963) were not 10. cated. Not required. Do Sparine The October 1956 report was not located in the NDA files. Winthrop Labs Win 12-267 No IND or NDA filed. No reference to Apr. 1, 1960, located. Not required. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4009 stated in our letter of December 28, 1967 there was no requirement prior to passage of the Kefauver-Harris Drug Amendments of 1962 that FDA be advised of all in- vestigators and investigations conducted. However, products marketed under the new `drug provisions of the Act prior to 1962 are currently being evaluated by the National Academy of Sciences of the National Research Council. Additionally, the manufacturers of prescription drugs are required to provide the medical profession with full information necessary for the safe and effective administration of the drug for the condition for which it Is recommended In the labeling. Such required information includes side effects, precautions to be ob- served and contraindications. Such labeling information is periodically reviewed to insure compliance with the requirements of the Act. Regulation 130.13 `of the New Drug Regulations currently makes it mandatory for a firm to advise FDA `of all investigators and investigations conducte& A copy of this section of the regulations is attached for your information. We have terminated our investigation with the feeling that requirements in existence at the time were met. We believe this has been a valuable study and we wish to express our appreciation of your interest and cooperation in this matter. Sincerely yours, HERBIORT L. LaIr, Jr., M.D., Director, Bureau of Meiic4~e. PAGENO="0106" 4010 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (The supplemental information submitted by Mr. Gordon follows:) DEPARTMENT OF HEALTH, EDUCATION AND WELFARE, Washington, D.C., June 5, 1961. The HONORABLE ATTORNEY GENERAL, Department of Justice, Washington, D.C. DEAR Mn. ATTORNEY GENERAL: We request the institution of criminal proceed- ings under Title 18, United States Code, Section 1001, against Wallace & Tiernan, Inc., 25 Main Street, Belleville, New Jersey (a Delaware Corporation) and the following individuals, all employees of Wallace & Tiernan, Inc. at the time of the alleged offense: Charles B. Hough, M.D., Medical Director, Maltbie Laboratories Division, Wallace & Tiernan, Inc. Robert T. Conner, Ph. D., Successively Director of Research and Develop- ment for Maitbie Laboratories Division and Strasenburgh Laboratories Division, Wallace & Tiernan, Inc. John F. Reinhard, Ph. D., Successively Director of Pharmacology Labora- tories for Maltbie Laboratories Division and Strasenburgh Laboratories Division, Wallace & Tiernan, Inc. Harold 0. Thomas, Sales Manager, Maltbie Laboratories Division, Wallace & Tiernan, Inc., Now with Strasenburgh Laboratories Division in a sales capacity. Henry C. Marks, Staff Director of Research, Wallace & Tiernan, Inc. Harold W. Crogan, Vice President, Wallace & Tiernan, Inc., Manager of Maltbie Laboratories Division. Robert T. Browning, Executive Vice President, Wallace & Tiernan, Inc. (now President). Robert J. Strasenburgh II, President, Strasenburgh Laboratories Division, Wallace & Tiernan, Inc., Vice President, Wallace & Tiernan, Inc. The offense complained of was committed *between January 27, 1961, and October 18, 1961, and it involves the knowing and willful causing of material facts to be concealed and false and fictitious statements and representations to be made in a matter within the jurisdiction of the Food and Drug Adminis- tration. NATURE OF VIOLATION ALLEGED The indictment charges violation of 18 U.S.C. 1001 based upon the acts of the defendants in knowingly and willfully concealing material information, and submitting and causing the submission of false and fictitious statements In writ ing and orally as to material facts, to the Department of Health, Education and Welfare Food and Drug Administration in a matter ~sithin the juiisdiction of the Food and Drug Administration. On May 13, 1959, Wallace & Tiernan, Inc. submitted to the Food and Drug Administration, pursuant to section 505 of the Federal Food, Drug and Cosmetic Act [21 U.S.C. 3551, a New Drug Applica- tion for a drug known as "Dornwal". This application was made conditionally effective on April 16, 1959. In the letter to Wallace & Tiernon, Inc. which made the application conditionally effective, the firm was notified that a label state- ment limiting the duration of treatment by this drug to three months would have to be maintained until the safety for prolonged use had been established. In the same letter the firm was notified that if further experience with the drug showed it to be unsafe for use, the effectiveness of the New Drug Application No. 11-973 could be suspended. Subsequently, the ñrin made mail, telephone and personal contact with the Food and Drug Administration concerning the New Drug Application for "Dornwal". Between January 27, 1961 and October 11, 1961, 28 such contacts were made by the defendants in which they knowingly and willfully concealed material facts from the Food and Drug Administration, to wit, medical evidence that "Dornwal" was the causative agent of a severe and often fatal blood dyscrasia (disorder) in man. Furthermore, subsequent to the submission of the New Drug Application for the drug "Dornwal", the defendants made 10 mail submissions to the Food and Drug Administration concerning the New Drug Application in which false and fictitious statements and representations were made concerning the safety and lack of serious* side effects in the use of "Dornwai". A discussion of the count and the evidence already acquired in regard to the count is contained in the two loose-leaf notebooks transmitted with this letter. Further material has been collected and we will gladly furnish it if you so desire. PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4011 BACKGROUND The defendant corporation has for several years been a manufacturer of phar maceuticals The acts alleged took place shortly after acquisition of another corporation Maltbie Laboratories The acquired corporation had developed a New Drug subsequently referred to as Dornwal Dr Crane was the mechca]. director for Wallace & Tiernan, Inc. during the period of final development of the drug. He felt the drug was therapeutically ineffective and this resulted in dis~ agreements with the management which led to his severance from the firm. Dr. John Vincent Scudi, under whose direction research and development of "Dorn- wal" was carried out, stated that he warned the management, and many of the individual defendants, that "Dornwal" was a compound which could cause agranulocytosis, a form of blood dyscrasia. After laboratory and clinical trials, a New Drug Application No. 11-973 was submitted and made conditionally effective. The firm then marketed the product throughout the country The Dornwal labeling approved by the Food and Drug Administration limited the use of the product to 3 months. In order to remove this sales inhibiting restriction, the company proceeded to supply the Food and Drug Administration with further clinical, pharmacological, and toxicological evidence of safety. The firm submitted supplements to the New Drug Application between October, 1959 and October, 1960. In a transmittal for one such supplement dated. October 31, 1960, the firm reported that a patient to whom "Dornwal" bad been administered had developed a blood dyscrasia. However, the company noted that the patient had been taking many other drugs and that it was highly unlikely that "Dornwal" had been the cause of the blood dyscrasia. In a reply letter dated December 29, 1960,. the Food and Drug Administration notified the firm that the Supplemental Application of October 31 1961 would be considered incomplete until all available details of this case of blood dyscrasia were obtained and pre sented to the Food and Drug Administrition In a communication of late January of 1961 to the Ii ood and Drug Administration concerning the case great em phasis was placed by the defendants upon the use of other drugs in order to con- vince the Food.and Drug Administration that "DornwaI" could not have been the causative agent. However, prior to this January, 1961 letter the firm had been notified of an additional case of blood dyscrasia in which "Dornwal" was strongly implicated as the causative agent. It will be clearly demonstrated that Dr. Hough and the other individual de- fendants had full knowledge of this later case when providing evidence to con- ince the Food and Drug Adimnisti ation that the previous case of blood dyscrasia was not caused by "DornwaL" In the process of concealing and making false state- ments and representations, the defendants concealed from the Fo'od and Drug Administration and from the medical profession sigmficant information which created a threat to the public health Before this concealment was finally discov ered by the Food and Drug Administration, 11 cases of blood dyscrasia attribut- able to Doinwal had occurred When it became clear that ome of the physi cians whose patients had developed blood dyscra~iia upon the use of Dornwal were planning to publish the reports of their adverse experience Dr Hough rec ommended that the Food and Drug Administration he notified at once. However, even then the Food and Drug Administration was not so notified. In October of 1961, while attending a medical conference, Dr. Frances 0. Kelsey, then a medical `officer of the Food and Drug Administration, came across information of a case of blood dyscrasia causied by the use of Dornwal When cont~tcted in regard to this case, the defendants admitted they knew of five other `such cases. Subsequently, the defendants were requested to submit full information `on all cases of blood dyscr'xsia of which they had knowledge A total of e1e~en cases were reported to the Aidministration The New Drug Application for Dornwal was suspended on January 19 1962 by order of Commissioner Larrick of the Food and Drug Adminp4r'ttion VENUE In view of the proi r~ions of 21 U S C 355 for the filing of New Drug Applica tions with the `Secretary of Health, Education, and Welfare, in the District of Columbia, the venue in regard to a violation of 18 U.S.C. 1001, in the case of a New Drug Application, the concealment Øf material facts and causing false and fictitious statements t'o be made in a report to an agency of the United States Government, must be placed. in ;the District of Columbia,:the District in which the office of the ISecretary is located. .. . . PAGENO="0108" 4012 COMPETITIVE' PROBLEMS IN THE DRUG INDUSTRY WITNESSES The principal witnesses will be former employees of the ~lefendant corporation who ~viIl testify to the knowledge of the corporation and the individual defendants of the danger involved in the drug Dornwal md of the adver~e reactions It may also be desirable on trial to have the te,timony of some of the physicians- who submitted reports of ad verse sidm. effects to the defendants There will also be consideiable documentary evidence in the form of letters memoranda data sheets and monthly reports which will show the fact that all the individual defendants had knowledge of the ~idverise reaction produced by Dornwal at the times that they communic~tted with the Food and Drug Admini tratioii and concealed `this knowledge from the Food and Drug Administration and made false and fictitious statements to the Food and Drug Administration as to the safety and absence of adverse side effects in the drug Dornwal R~SPOi\ SIBILITY OF `1 HE DETENDAN I 5 The defendant company and individual defendants willfully concealed ma- terial facts and made false and fictitious statements and representations to the Food and Drug Administration. The defendants knew of cases of blood dys- crania resulting from the use of "Do'rnwall". They concealed reports of cases of blood dyscrasia with knowledge of the importance of this information and the fact that the Food and Drug Administration should be informed of it. In the many communications with the Food and Drug Administration, for which the indi- vidual defendants and the corporation are responsible, there were false and fictitious statements as to the safety of "Dornwal" an'd the complete absence of serious side effects. The individuals,' as the responsible officers of the corpora- tion, are responsible for the occurrence of the acts'. It is requested that if the Indictment is changed, the United States Attorney furnish us with a copy thereof. Also, `that we be kept informed of the progress' of the case and other cases that may arise from. it, and their dispositions. Upon re- quest, we shall be glad to furnish any such further `assistance as. may be pos- sible. The services of those who have conducted the investigation and counsel who assisted are available at your reqttest. Sincerely yours, WILLIAM W. GOODRIOH, Assistant General Counsel, Food and Drug Division. By direction enclosures [omitted]. DFPARTMENT OF HEALTH FDUCATTON AND WFLrARF Washington, D.C., April 20, 1964. The Honorab~e ATTORNEY GENERAL, Depa~ tment of Justwe Washington D C DEAR MR ATTORNEY GENERAL We request the institution of criminal pro ceedings under litle 18 United States Code ~echon 1001 against the Mc~ei1 Laboratories Inc Fort Washington Pennsylvania and the following individ ual.s, employees of the McNeil Laboratories at the time of the alleged offenses: Robert L. McNeil, Jr., Chairman of the Board, McNeil Laboratories, Inc. James Shaffer M D Director Division of Clinical Investigation Mc Neil Laboratories Inc and any others who may have shared responsibility for the alleged offenses The offenses complained of were committcd beta een 1959 and 1961 and mu oh e the knowing and willful concealing of material information, and the submission, and causing of the submission of false and fictitious statements in writing to the Department of Health, Education, and Welfare, Food and Drug Administration in a matter within the jurisdiction of the Food and Drug Administration. `There is transmitted herewith a suggested `form of criminal indictment enclosed in two looseleaf notebooks which also contain a selection from the evidence de- veloped by the AdministraUon. NATURE OF VIOLATION ALLEGED The indictment consists of 8 counts. Four ~f the counts charge violation of 18 U.S.C. 1001 involving the drug Flexin. These are based upon the acts of defendants PAGENO="0109" COMPETITIVE PROBLEMS IN * THE DRUG INDUSTRY 4013 in knowingly and willfully causing the submission of : a supplemental New Drug Application on September 28 1959 [Oount I] a New Drug Application on January 6, 1960 [Count Ifl ; a document in connection with a New Drug Ap- plication on March 21 1960 [Count III] , and a letter in connection with a New Drug Application on April 17 1061 [Count IVI which submissions con tamed statements and representations which were false fictitious and fraudu lent or which concealed material facts concerning the safety and lack of side effects of the drug, Flexin, when used by man. Counts .1 and IV are concerned with the drug marketed under the name Flexin and Counts II and III Involve Tablets Triurate a drug consisting primanly of Flexin Counts V through VIII also charge violations of 18 U S C 1001 and involve the drug Parafiex [Count VI] and `two parafiex-containing products: Parafon [Counts VII and VIII] and Pai~afon with Codeine [Count VI. The company is charged with knowingly and willfully causing the submission of: A New Drug Ap- plication for Parafon with Codeine on May 18, 1959 [Count VI; a Supple- mental New Drug Application for Paraflex on June 10, 1960 [Count VII; a Supplemental New Drug Application for Parafon on June 10, 1960 [Count VIII;; and an additional Supplement9i New Drug Application for P'irafon on Feb ruary 8 1961 [Count VIII] Each of the submissions contained false and fraudulent statements as to the lack of side effects in man associated with use of the drug involved. BACKGROUND The defendant McNeil Laboratories Inc for a number of years has engaged in the research, development, manufacture, and distribution of drugs in this coun- try. It is a `Pennsylvania corporation. On January 1, 1957, the company became a wholly owned subsidiary of Johnson and Johnson, Inc., but has retained its sepa- rate identity. Some of the drugs are New Drugs [drugs defined under the Federal Food, Drug, and Cosmetic Act as not generally recognized `by experts to be safe and effective for use under the conditions recommended in the `labeling. At the time of these alleged violations, effectiveness was not `a part of the definition]. A New Drug may not be legally marketed in this country without a New Drug Application having been approved by the Food and Drug Admrnistiation Any ap phcation or supplemental New Drug Application [proposed changes by the holder of an effective New Drug Application] must include among other things full reports of investigations which have been made to show whether or not such drug is safe for its intended use Pursuant to these requirements McNeil Laboratories Inc on November 14 1955 submitted to the Food and Drug Administration a New Drug Application for Flexin. Data in the application included clinical and pharmacological studies. The application was made conditionally effective on January 13, 1956. On Decem- ber 2, 1955, however, a physician had notified the firm that one of his test patients using Flexin had developed hepatitis and died On January 5 1956 a pathologist who reviewed sections of the liver from the deceased patient had informed the company that death of the patient may have been due to the drug therapy. The J~ ood and Drug Administration was not informed Petween April 1956 and July 1956 the company received reports of ~ additional cases of Flexin telated hepa titis and in four of these cases the reporting physician ascribed the damage di reetly to the drug During this period and until August 1956 the bi ochure in use br Flexin bore the following statements Flexin has produced no irreversible toxic reactions when administered to patients daily for periods of 6 months and that "Anemia, leukopenia, agranulocytosis, jaundice or kidney damage has not been reported in any patient receiving Flexin." In August, the phrase "jaundice or kidney damage" was removed from the labeling. There was no other change. Between August 1956 and October 13, 1958, McNeil Laboratories, Inc., received reports of 26 cases of liver damage in Flexin patients, including 7 deaths. During this time, McNeil Laboratories made several submissions of information relating to the New Drug Application for Flexin. No reports of liver damage were made to the Administration The company took very little action to investigate the liver damage cases reported to it. Count I is concerned with the submission by the company of a supplemental New Drug Application filed pursuant to the provisions' of 21 U.S.C. 355 on September 29, 1959 False stitement~ contained in that submission are set out in detail in the looseleaf notebooks accompanying this letter. Among other false statements' are statements that a lower number of Flexin associated hepatitis cases had been re ported to the firm than was actually the case, false statements concerning a lack of causal relationship between the drug and hepatitis, and exaggerated reports of PAGENO="0110" 4014 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the extent of the investigation made by the company into the hepatitis cases reported to it. In addition, no report was made concerning the deaths of patients. On January 6 1960 the company filed a New Drug Application for the New Drug known as Tablets Triurate One of the major components of that drug is Flexin The false and fraudulent statements and representations as well as con cealed material facts concerning the safety and lack of serious side effects in volved in the use of Flexrn form the basis of Count II These statements involve the liver damage associated with use of Flexin The company on March 21 1960 as a part of the New Drug Application origi nally filed on January 6 submitted samples of proposed labeling In a paragraph entitled Side Effects the only reference to hepatitis and its connection with the administration of the drug Flexin is a statement that in isolated instances hyper sensitivity reactions thought to be due to Flexin have been reported such as transient reversible renal irritation or hepatitis The firm had been informed of 50 cases of Flexin related liver damage including 11 deaths This is the basis for Count III On April 17 1961 the firm submitted a request for a change in the N ew Drug Application relating to the packaging of Flexin No reference was made to the association between the use of Flexin and liver damage By this time the company had learned of at least 57 cases of Flexin related hepatitis including 15 deaths. This is Count IV. On July 13 1961 officials of the company contacted the Food `md Drug Admin istration and related that the firm had receii ed a considerable number of reports of Flexm related hepatitis and they believed that the labeling should carry a ~tionger warning about these possible reactions After an exchange of corre ~spondence between the Food and Drug Administration and McNeil Laboratories during which the firm sought to de\ ise some way to label the drug to keep it on the market, the Food and Drug Administration determined that the risks involved in the use of Flexin outweighed any therapeutic value contributed by its use. Therefore, on October 13, 1961 the New Drug Application for Flexin, and all amendments and supplements were formally suspended by order of the Com missioner of Food and Diugs P'mraflex a chemical analogue with similar properties to Flexin was developed `mbout the same time as Flexin A New Drug Application uas filed on November 1 1957 for this product and two New Drug Applications for drugs containing Para flex were filed on May 23 1958 One application concerned Parafon a mixture of Parafiex and `lylenol and the other concerned a product called Tablets Paraflex Tylenol Prednisolone which contained the drugs as named All were made effec tive Between June 28 1958 and July 15 1959 McNeil Laboratories had been in formed of three cases of hepatitis which occurred during Parafiex therapy Count V is concerned with the submission by McNeil Laboratoiies of a New Drug Application for Parafon with Codeine on May 18, 1959. An accoi~anying draft of the physicians index card for the product stated "Parafiex . . . has not caused serious toxic reactions or undesirable effects on liver Two eases of Parafiex-associated hepatitis had by this time been reported to the firm. On June 10, 1960, the company submitted a Supplemental New Drug Application concerning the basic product Parafiex An accompanying proposed brochure stated Parafiex has produced no serious toxic reactions Daily administra tion for as long as one year had produced no evidence of damage to the liver . . .". This is Count VI Count VII involves the submission of a Supplemental New Drug Application for Parafon on June 10 1960 which contained wording in its brochure identical to the above. Count VIII is involved with similar false statements made in a subsequent New Drug Application for Parafon submitted on February 8, 1961. In addition, the false statements made in each of Counts VI through VIII, were repeated by the company in forwarded specimens of final printed labeling submitted to the Food and Drug Administration at a later time. In response to a letter mailed to McNeil Laboratories by the Administration on August 23 1961 which had requested reports of hepatitis associated with 1~ lexin or of any chemically and pharmacologically related chlorzoxazone, the company admitted that they had received 3 reports of Parafiex-related hepatitis. RESPONSIBILITY OF THE DEFENDANT5 The defendant company and individuals not only furnished false information in their submis~'mons but also concealed information directly rel'iting to the safety ~of Flexmn and Parafiex when used by man Safety of course is the prime con PAGENO="0111" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY .4015 sideration in evaluating New Drug Applications. Each of the submissions by the company to the Food and Drug Administration involved in Counts I through VIII were signed by Robert L. McNeil, Jr., Chairman of the Board of McNeil Labora- tories. All of the reports concerning liver damage which were received by the company from the various doctors' were routed directly to Dr. James Shaffer ai~d Dr. Shaffer signed all correspondence emanating from the firm to the doctors con- cerning these complaints. The falsification of the documents~ was so wide spread that one can only conclude that `there was a deliberate attempt on the part of the company and the individual defendants to deceive the Food and Drug Adminis- tration as to the safety of Flexin and Parafiex. VENUE In view of the provisions of 21 U S C 355 for the filing of New Drug Applica tions with the Secretary of Health, Education, and Welfare in the District of Columbia, the venue in regard to a violation of 18 U.S.C. 1001 must be placed in the District of Columbia. WITNE55ES The principal witnesses in the case will be officials from the New Drug Division of the Food and Drug Administration who received and reviewed the New Drug Application and Supplements in regard to the drugs and who, upon request, were sent copies of the letters written to the company from physicians reporting liver damage and replies sent to those physicians by the firm. Evidence will also be obtained by means of subpoenas duces tecum to be issued to McNeil Laboratories and its parent company, Johnson and Johnson, Inc. A suggested form for such a subpoena is included in the looseleaf notebooks enclosed with this letter STATUS OF THE DRUGS INVOLVED Flexin was removed from the market on October 13, 1961. This was accom- plished by a suspension order signed by the Commissioner of Food and Drugs. No New Drug Application is currently pending for Flexin or Flexion-containing products. Parafiex is still subject to an approved New Drug Application, but the company is required to include in the labeling the number of cases in which these drugs were suspected as being the cause of liver damage. It is requested that if the Indictment is changed, the United States Attorney furnish us a copy thereof Also that we be kept informed of the progress of the case and any other cases that may arise from it and their dispositions. Upon re- quest, we shall be glad to furnish any such further assistance as may be possible. The services of those who have conducted the investigation and of counsel who assisted is available at your request if you feel it may be of any possible assist- ance to you. Very truly yours, WILLIAM W. GooDRICH, Assistant General Counsel, Food and Drug Division. Enclosures [omitted]. U.S. DEPARTMENT OF JUSTICE, Washington, D.C., September 28, 1964. Re Proposed prosecution against McNeil Laboratories, Inc., et al., under Title 18 U.S.C. 1001 Mr. WILLIAM W. GOODRICH, Assistant General Counsel, Department of Health, Education, and Welfare, Washington, D.C. DEAR MR. GOODRICH: This is in reply to your letter of April 20, 1964, to the Attorney General, concerning the possible violation of Title 18, United States Code, Section 1001, by McNeil Laboratories, Inc., Robert L. McNeil, Jr., and James Shaffer, M.D., in connection with the submission of New Drug Applications for compounds containing the drugs known as ~Flexin and Parafiex. As you are no doubt aware, any criminal action which may have arisen by virtue of falsehoods or omissions in the New Drug Application submitted prior to April 20, 1959 were already barred by the statute of limitations at the time of your referral After a careful review of all the evidentiary material petaining to PAGENO="0112" 4016 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY this matter we have concluded, that criminal proceedings are not justified as to later submissions. One of the principal factors in our determination is the fact that from time to time the Supplemental Application with reference to Flexin and Flexin containing compounds contained language which progressively gave greater recognition to the possibility that Flexin might cause jaundice. This rec- ognition was highlighted In the September 29, 1959 Application which revealed that in 82 instances Flexin patients had suffered hepatitis. The literature reported disclosed that on some occasions the disease had been fatal. Since the Applications, do therefore, disclose on their face the possibility that Flexin might cause jaundice, we are of the view that criminal action is not war- ranted, especially since the Food and Drug Administration medical officers ap- proved the Applications, including that of September 29, 159 without further inquiry concerning the `hepatitis cases. Prosecution Is therefore declined. Sincerely, HERBERT J. MILLER, Jr., Assistant Attorney General, Criminal Division. By HAROLD P. SHAPIRO, Chief, Administrative Regulations ~8ection. RESEARCH AND DEVELOPMENT Divisxou, SMITH KLINE & FRENCH LABORATORIES~ Philadelphia, Pa., February 20, 1969. Hon. GAYLORD A. NELSON, Ohavirman, senate ~8ubcommittee on Monopoly, select Committee on ~$mall Busi- ness, Washington, D.C. DEAR SENATOR NELSON: A misleading and possibly injurious reference to Smith Kline & French Laboratories appears in the testimony presented to your Monopoly Subcommittee on December 18, 1968, by Dr. Paul Lowinger, Associate Professor of Psychiatry, School of Medicine, Wayne State University. Dr. Lowinger testified that, for the eriod 1954 through 1966, some 19 drug com- panies, including Smith Kline & French, had passed along to the Food and Drug Administration reports on only 9 of the 27 "new drug studies" he transmitted to them. Whether intended or not, the implication in Dr. Low'inger's testimony is that the alleged failure of the drug house's to turn his reports over to the Food and Drug Administration was violative of the federal drug law and contrary to the best interests of `the American public. This implication is regrettable. Our handling at Smith Kline & French of the five reports relating to three different drugs received from Dr. Lowinger for the period in question complied in every detail with applicable federal drug regula- tions. Moreover, our conduct in these matters conformed to the highest ethical and scientific standards and we acted in a fully responsible fashion. Let me place the matter of Dr. Lowinger's reports to Smith Kline & French and all relevant facts in proper perspective for the benefit of your Monopoly Subcom- mittee and those who are following i'ts drug hearings: 1. Dr. Lowinger advised the Monopoly Subcommittee of `a report on SK&F 7003 (proformiphen) which he said was sent to our company on February 19, 1959, but was not then passed on to the Food and Drug Administration. In this report, Dr. Lo'winger described the result of a clinical investigation with this compound in out-patients with symptoms of depression and anxiety. Among the ten patients described in the report, three reported side effects of `tinnitus, feeling of unreality, dizziness, and rash. Prior to the Drug Amendments of 1962, there was no requirement to submit information on investigational drugs to the FDA outside of the NDA procedure. The information on this compound was not submitted to the FDA because in March 1959 Smith Kline & French management decided to discontinue `the clinical investigation `of SK&F 7003 and no NDA was ever filed. 2. Dr. Lowinger also told the Subcommittee of three r'eports he sent us regarding a "double blind study" he made of a number of tranquilizers, including our Stelazine Other drugs in Dr Lowrnger s study were Librium Equanil Marplan Tofranil, Niamid, and a placebo. Interim progress reports on the double blind study were sent to Smith Kline & French by Dr. Lowinger on November 7, 19430, and again on February 13, 1963. PAGENO="0113" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 4017 These reports did not contain any information on new or serious side effects and, thus, were not sent on to the FDA. Such routine reports were not required for `Stel:azine' until October 29, 1963, when the FDA approved a supplement to the new drug application for `Stelazine'. On July 24, 164, Dr. Lowinger sent Smith Kline & French a final report on his "double blind study" and, again, there was no reference to any new or serious side effects. Our records show that this final report was included in our annual report for `Stelazine' submitted to the FDA on September 24, 1964. 3. Dr. Lowinger's final mention of Smith Kline & French was in connection with his report on `Parnate', dated April 8, 1959, a report which he noted was sent on to the FDA by our company and this is correct. This Lowinger report was submitted to the FDA as a component of our com- pany's new drug application for `Parnate', dated March 2, 1960. Receipt of the `Parnate' including the Lowinger report, was promptly acknowledged by the FDA. I respectfully request that this letter be made a part of the public record on your Subcommittee's hearing held December 18, 1968. Sincerely yours, MAURICE: R. NANCE, M.D., Medical Director. Senator NEr4soN. Our next witness is Dr. Franz J. Ingelfinger, editor of The New England Journal of Medicine; also clinical professor of medicine at Boston University School of Medicine. The committee appreciates your taking time to come here today. Everyone in the medical profession has a high regard for the very famous magazine of which you are the editor. I find it approvingly re- ferred to by physicians from all over the United States who have testi- fied from time to time before this committee. Doctor, your full statement, including your biographical summary, will be printed in the record.' You may proceed however you desire. If you want to depart from the text, to elaborate on any particular aspect, feel free to do so. I realize that to reduce everything to writing takes a great deal of time. You may want to comment somewhat more broadly on some as- pects of your written testimony. I assume you have no objection if we interrupt with a question from time to time ~ STATEMENT OF DR FRANZ J INGELPINGER, EDITOR, THE NEW ENGLAND JOURNAL OP MEDICINE, BOSTON, MASS. Dr. INGELFINGER. Thank you very much, Senator Nelson, for asking me to come here, and I hope we proceed as you proceeded with Dr. Low- niger, and I will be perfectly ready to answer questions if I can. Possibly I should amplify a few things. My main reason for being here, the reason you invited me, I presume, is because I am the editor of The New England Journal of Medicine. This journal, of which I have the latest copy with me, fortunately is respected not only by the medical profession, but also by the lay press. The lay press-I hope this continues-practically never mentions it without the adjective "pres- tigious," and this is not due to me, because the credit belong to my predecessor, Dr. Joseph Garland. I have been editor of the journal for a year and a half. He had previously been editor for 20 years. The journal, I think, is a good example of some of the problems that one faces with respect to news about drugs and drug advertising. 1 See p. 4037,, infra. 81-28O-69-pt. 10~-8 PAGENO="0114" 4018 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY It is highly respected. It also has, I believe, the second largest cir- culation of the regular, not the controlled circulation journals, but the regular subscription medical journals in the world, the Journal of the American Medical Association being No.1. Senator NELSON. What is the circulation of the New England Journal? Dr. INGELFINGER. It is currently 110,000. Senator NELSON. And how much of that is domestic circulation with- in the continental United States? Dr. INGELFINGER. Practically 90 percent of it. Senator NELSON. Ninety. Dr. INGELFINGER. Close to 100,000, somewhat short of 100,000. Senator NELSON. Out of the total of- Dr. INGELFINGER. Out of 110,000, approximately 90 percent is do- mestic. One other `thing of, I think, importance, at least to us, is `that we have a very high subscription list among medical students and interns and residents, that is house officers, people who might be lumped together as `trainees in medicine. About 35,000 of our subscribers are in this category, roughly a third. We are, we believe, the largest-have the largest circulation in terms of voluntary subscriptions. The New England Journal of Medicine is owned by the Massachu- setts Medical Society, so the only captive audience we have, so `to speak, are the members of the Massachusetts Medical Society, some 8,000 in number. - So our voluntary subscription of about 100,000, I think, is about the highest there is of that type. Well, I am saying this not `to boost the Journal so much as to indi- cate that even a journal with such favorable and fortunate position has problems that I will discuss later. Second, as I have indicated in my statement, previous to becoming edi'tor of this journal, my work was chiefly in academic medicine, in the subspecial'ty of gas'troenterology, diseases of the intestines, esoph- agus, liver, pancreas, and gall bladder. I have had extensive experience in this, and have conducted a long- lerm research and training program. As part of this, and also this may come up later when we discuss some other problems related to NIH-like institutions-I have served for more than 12 years on various NIH advisory bodies, including 4 years on the Advisory Council of the National Institute of Arthritis and Metabolic Diseases. Earlier in my career, when I was doing less administrative and edit- ing work, I carried out drug studies, support for which came from drug companies, which you may want to question me about more later. Now, I have tried to answer chiefly two of the questions or two majOr questions in the letter that you sent, Senator, relating to some of the problems of drugs, of pharmaceutical firms, and `the influence they have on the education of physicians and on physicians' use of drugs in treating patients. One of the questions deals with `the payment by firms to investigators to evaluate drugs, and also payment to academic institutions for gen- eral support. PAGENO="0115" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4019 The other deals with the problems of the Journal. Would you prefer I start with the Journal, because that may be slightly different from Dr. Lowinger's testimony, or should I go right ahead? Senator NELSON. Any way you desire. It is all right to follow just the way you have it here. Dr. INGELFINGER. All right. Well, the first item relates to the acceptance by physicians of funds paid by drug companies for the evaluation of their products or for other purposes, such as fellowships, salaries, general research support. It is my impression that `the objectivity of such studies and the free- dom from undue influence related to the source of support depends a great deal on the circumstances under which this testing is carried out. Currently, at least, the `testing is often carried out, not invariably, often carried out, (a) in a medical school setting, and `this means that administrative officials ra'ther than the investigator will handle the fi- nancial arrangements; `that is, with no direct payment to the investiga- tor, and (b) which, I think is also important, others besides a solitary investigator, `that is, technicians, referred to by Dr. Lowinger, graduate students, other physicians, house officers, will participate in the test procedures. These young people are some of the most severe critics in the world, and their involvement in this type of work makes in very difficult, I think, to fudge the results. So I think the study of this type is safe- guarded, in that there is participation by a number of people who have no financial interest in the nature of the results. Senator NELSON. Let me ask this: I do not know what percentage of investigatory drug testing is done under `this precise circumstance; that is, where it is in a medical school setting, and so forth. We have not had any testimony from the companies on that. However, it does appear that some percentage of `the testing is done by contracts with individual physicians who may or may not be involved in a teaching hospital and who are paid a fee for the testing they do. As I say, we have not taken testimony to find out just how wide- spread this practice is. We do have, however, specific examples of drug testing and there have been questions as to the validity of the results obtained. What is your view of that kind of an investigation, an individual contract for a fee, not under the supervision of an institution of any kind? Dr. INGELFINGER. I come `to that on the next page, Senator. May I continue because it gives sort of a little more background? Senator NELSON. Yes, of course. Dr. INGELFINGER. Another reason why testing, particularly in aca- demic settings and under certain conditions, is not too much of a con- cern to me is that the testing is carried out during the preliminary stages of the development of a drug. For example, my laboratory used to screen agents for their ability to affect gastric acid secretion or to decrease the motor function, the contractions of the gut. On other times we were asked to determine whether or not certain drugs were well absorbed if injected into the upper part of the intestine, into the stomach or lower down, in an PAGENO="0116" 4020 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY effort to determine where the absorptive functions might be most effec- tive and applicable. Now, testing of this type means that measurements are taken with various types of equipment. We can record contractions, we can meas- ure chemical levels in the blood and, therefore, again this type of testing, I think, is more difficult to distort by bias unless one is pur- posely unscrupulous. The objective data so obtained cannot easily be distorted, as I say, by personal bias. Furthermore, this is `an important point and possibly I am prej- udiced, but under such circumstances an investigator who misleads a financial sponsor is not doing that sponsor any favor. Drug com- panies, I have found, are not anxious to spend money on developing an inferior product, and for their own protection tend to seek a valid appraisal. For example, if I were testing a drug on its intestinal contraction- inhibiting effect, and it turned out to be no more effective or even less effective in our screening type of tests than atropine, a standard well- established drug known for many, many years, then I felt that the manufacturer or the man developing this drug would benefit by my telling him so, so I was under no pressure to tell him good news. I thought I was doing him a favor by telling him bad news. So far I have been talking about measurements and of specific bi- ological activities, that is contractions, chemical measurements, things that you can record on a device, done in a university setting. Clinical testing of a product, the type of testing that Dr. Lowinger carried out, that is, where you give a drug to a patient and determine whether or not it is helping him or harming him or doing nothing, I think, is ex- ~remely difficult under any conditions; and my belief is it is the most difficult type of investigation that can be done. The criteria available for measuring a drug effect are often extremely vague and highly subjective. There is no yardstick, for example, wheth- er an abdominal pain is better or worse. The desires of both patient and investigator may color the interpretation. Hence, studies of this type must be carried out under optimum conditions-and here I am coming to answer your question, Senator-optimum conditions mean investigators who are equipped by training and facilities to carry out such testing, and who use a protocol incorporating procedures that characterize a well-controlled study. If these conditions are observed, I doubt that the results are likely to be influenced in any way by subtle economic pressures. However, if a study is carried out by an individual without such facilities, without a protocol which is generally accepted as being satis- factory, and under direct payment of that individual evaluating that study, possibly in a solo private office setting where the facilities are not available, I would disapprove of such studies. Senator, may I ask you a question-a question for my information as to how to proceed. I do not want `to repeat what you have been told many times at `these hearings, but have you been told about some of the difficulties clinical testing, what a terribly tough job it is? Senator NELSON. We have heard such testimony. However, we would be pleased to have for the record anything you wish to present on this subject. PAGENO="0117" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4021 Dr. INGELFINGER. Let us assume that we are studying whether a certain agent, let us say X, helps a certain condition-and once in a while there is a dramatic new agent, such aspenicillin or oral diabetic agents where the results are obviously clearly beneficial. But in the case of the vast majority of agents, the difference between drug A, B, C, and X may be not great, it may be an improvement in one fashion or another. The first condition that has to be set up is a controlled situation. The investigator has to choose `two groups of pa- tients or subjects. Group A gets `the drug and group B does not. Under the usually practiced procedure it is a double blind study in the sense that nei'ther the investigator nor the patient knows whether he is receiving a `tablet with the active agent or with a so-called placebo, that is, just a dummy tablet that looks identical. This is a standard type controlled condition. It is not easy to achieve without an adequate study population, sev- eral groups of large enough size. You cannot do this with three or four people. You need enough `to make the observations statistically valid, unless `the drug happens to be a most unusually effective one. Then `the investigator runs into the problem of ethics, medical ethics, quite apart from drug advertising. He may be challenged for (a) giving a new agent to the study group or (b) he may be criticized, as some have been, in the past when this sort of study was carried out with penicillin early in the study of `that agent-he may be criticized for not giving the active agen't to the control group who, in retro- spect, should have had it. Do you understand what I mean Senator NELSON. Yes. Dr. INGELFINGER. Then the investigator has to establish yardsticks of improvement and, finally, he has to show that improvement is greater with drug X than the control, and sometimes the control is not a dummy placebo but may be a competitive agent or one that has already been used for the same purpose. So the differences between the substances tested may be even closer, and the investigator has to show that the side effects are the same or less than with the competitive agent or with the dummy. I would not have talked about this until I heard Dr. Lowinger men- tion, among the side effects he described, headache, lassitude, and con- stipation. I wish I could remember the exact figures-I cannot-but the New England Journal of Medicine recently published an account of a study in which the investigators merely went around and inquired as to the appearance of such common complaints in normal subjects who had not taken any drugs within 3 days. Well, in about 20 percent of the people, as I recall the figure, maybe a little bit more, those symptoms will start spontaneously for no ap- parent reason.1 Therefore, to prove that a drug is causing side effects of this gen- eral type, you have to have higher frequency of such side effects in the drug group than you do in the control group. Conversely, placebos often are credited, that is a dummy preparation, with making about a third of the people feel better or think they feel better. 1 Dr. Ingelfinger subsequently submitted th.e following: "The exaet figure is 81 percent (New Eng. J. Med., vol. 279, p. 678, 1968,)" PAGENO="0118" 4022 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY So I thought it is important to point out-and I did not want to belabor the question if you had heard it many times-that you are deal ing, Senator, with clinical investigations which are extremely tough It is much easier to study a bunch of mice and give them a drug and then measure whether their blood ievel, hemoglobin, the redness of their blood, is more or less. I could do this tomorrow with no trouble at all. I would shy away from a big clinical study because it is so difficult. Mr. GORDON. Dr. Ingelfinger, you referred to studies that you have conducted in which you have tested one drug against another drug, a competitive product. Did you find in your experience that pharmaceutical houses would finance the type of study in which their product would be tested against another product? Dr. INGELFINGER. Oh, yes. Mr. GORDON. Do you have any specific examples? Dr. INOELFINGER. Well, many times we studied so-called antispas- modics, drugs which inhibit the contractions of the intestines. It is. a field I got into fairly early. We inserted balloons at the end of long tubes in people's intestines and measured the squeeze on the balloons on a recording drum. That equipment which we used early in the 1940's gradually became more sophisticated, but that is more or less the @ssence of it, and we almost invariably compared the agent under study to atropine, which I mentioned a while ago. It did not seem worthwhile for any company to develop an agent which was not at least as effective as atropine. Now, if a drug company could make an agent as effective as atropine, but has less side effects, relative to the specific beneficial effect desired, then, of course, they would be justified in developing it. Mr. GORDON. Do you know if comparative studies, such as we are talking about, are carried out in antibiotics as well as in other cate- gories of drugs? Dr. INGELFINGER. Again it is somewhat harder to measure. One can measure certain blood levels with antibiotics, and certainly compare that, and I believe that has been done. The comparative clinical efficacy of giving somebody with active pneumonia one agent versus another in a controlled study is very difficult. On the other hand, one may compare a study done in New York with agent A with a study done subsequently with agent B, but there the problem. is that the patient and the locale are not the same, although they both got the same ingredients. Mr. GORDON. Do you have any knowledge as to the amount of testing done in medical schools under situations such as you `have described as compared with testing done by individuals who get direct `pay- ments? I looked through the New Drug Application for indomethacin at the Food `and Drug Administration, and most of this testing seemed to have been done by individual physicians. Dr. INGELFINGER. I do not know the answer to that. I have no idea. It would be nice to know, but possibly one suggestion that I should like to make is that this be an avenue of exploration in terms of trying to obtain more valid judgments. I am not trying to say that all universi- ties are honest or that they are so much better than an individu'tl PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 4023 I am just saying that safeguards are provided when a group of people with less personal involvement than that of a solitary inves- tigator are at work, and the general attitude of clinical investigation which obtains in these institutions, is much more likely to yield a valid evaluation It is not going to be perfect Mr. GORDON. What do you think of testing done by private firms for the drug industry? I have in mind, for example, the Cass Associates in Massachusetts. Dr. INGELFINGER. Well, you are picking on one in which I think, that there is some specific evidence that their reports were not reliable. On the whole, I would not recommend this type of testing but again I would have to be a little bit informed as to the nature of the firm and who was running it and what their qualifications were. I do not think I can make a categorical statement. Senator NELSON. We will take a 5-minute recess to let the reporter rest his fingers. (Short recess.) Senator NELSON. You may proceed, Doctor. I do not know exactly where we left off. Dr. INGELFINGER. On page-I interpolated quite a bit of extraneous discussion on clinical testing, but I am going back to page 3, the next to the last paragraph. Senator NELSON. Right. Mr. GORtON. There is just one more question I want to ask you. As I told you before, I have looked through the New Drug Application for indomethacin which numbers, I think, well over 65 volumes, and I noticed that most of the reports were from individual investigators. Many of them merely have cards on which the investiga~tor checks off certain things. Would you comment on that type of clinical investigation? Dr. INGELFINGER. I have seen the same in the past, not recently because I have not been `doing that type of work, but certainly previously. I do not think this is appropriate. It is too hard for the individual to make these judgments. The reason I talked so much about the dif- ficulty that clinical investigation encounters, was to indicate that un- der even optimum conditions, with some of the best facilities avail- able it is difficult. How much more difficult it would be if I-and I am not trying to attack the competence of the individual physician, I am just talking in terms of his general medical ability. I am saying if I, as gastroenter- ologist, tried to evaluate a certain antacid, along with a busy practice taking care of my patients, I do not see how I could get a meaningful result. Senator NELSON. As I understand it from what you said, I believe on the first page, the ideal circumstance for testing is in the institu- tional, the medical school or teaching hospital. Is that what you are saying? Dr. INGELFINGER. Yes. I mean where there exist facilities in terms of training, that is, intellectual facilities, and educational of the in- vestigators, as well as whatever equipment is needed. Most of these drugs we are talking about, most of the drugs reported in the task force report are drugs given for chronic conditions that PAGENO="0120" 4024 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY fluctuate; spontaneous changes in the illness make it very hard to know whether one's treatment has really helped or not, and this is why these carefully controlled studies are so necessary. Senator NELSON Please go ahead, Doctor. Dr. INGELFINGER. One suggestion that has been. made to prevent undue influence of sponsor on investigator is the establishment of a central independent agency that would act as a clearinghouse in ar- ranging for the testing of drugs. Under such an arrangement, drug testing for its clinical efficacy would be, in a sense, triple blind in that the investigator and the agent's maker would also be unaware of each other's identity. Such a central agency might be established under the jurisdiction of a committee in which pharmaceutical firms, Government and the American Medical Association would have adequate and satisfactory representation. I am here talking about sort of a variant of what Dr. Lowinger discussed, I believe it should be sort of a tn or multi partisan type of structure rather than something analogous to one of our National In- stitirtes of Health studying categorical types of illnesss. And the reason I do this is because I believe findings have to be ac- cepted, and they have to be accepted by the medical profession. The medical profession and the Government have their problems of un- derstanding each other, and it seems to me the way `one can' overcome some of this unfortunate distrust is to have-if there is to be such an agency that will supervise drug testing-all the people concerned rep- resented, including the pharmaceutical manufacturers because, after all, they are making the drugs. It `is an industry which, in our free enterprise system, we depend on. if we had such an agency or institute however, the increased ob- jectivity and the trustworthiness of drug testing procedures so at- tained, would have to be balanced against the added expense and delays entailed if such a scheme were implemented. Furthemore, I am not sure that total blindness could be achieved. Why not ~ Well, the investigator certainly is going to know something, he is going to know what conditions he is going to use his drug on. He is going to be given the chemical formula, he is going to be given background information on animal studies. If Dr Lowinger's proposal is implemented, and I certainly agree that exchange of information with other investigators be required, it seems to me the man who is experienc~d in a given field is pretty well alert as to who is making certain kinds of agents, and he knows what drug companies have reported preliminary studies in various pharma- cological journals. Hence, I am not sure .that a completely blind ap- proach would be easily achieved in the sense that the investigator and drug firm's would be completely unaware as to who is testing what. Senator NELSON. But it would be true, would it not, that if the group to which the investigator were responsible was an independent group and not a company that had a financial interest, the possibility of bias or of being unintentionally influenced is rem' oved? Is it not ~ Dr. INGELFINGER. Well, it could be partly removed, but possibly I am a little more cynical about it. Suppose that company cam.e up to my professor, dean, or chief of medicine and said, "Would you PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4025 like another fellow in that department? We will be glad to contribute $10,000 a year for its support." In other words, there are other ways of getting around if you are determined to get around it. Senator N~soN. But all I am getting at is that it reduces it. Dr. INGELFINGER. It reduces it, yes. Senator NEI450N. As to the delay factor, why is there necessarily any delay if you followed something like the procedures suggested by Dr. Lowinger in which the company proceeded with its own method of producing its new drug application, but you also had a group, such as you suggest, that was independent of it that contracted arrangements with medical schools for some independent testing along with it. Why would they necessarily take any longer that way than they do the present way? Dr. INGELFINGER. I am not sure that it would necessarily, but I sus- pect it might in terms of the arrangements that are necessary. If it is a plum, so to speak, if the study is of a financial magnitude and particularly also of intellectual content so that a number of in- vestigators were interested, then somebody has to make a decision. A. study section might consider contract applications and award prior- ities as at the National Institutes of Health. Conversely, if it is a rather dull study, why then you have to go out and scout around to find someone, and in this connection again, I think it is very difficult to get good people to do this: kind of study. I have already indicated how difficult, how hard clinical drug studies are to do mechanically. But beyond that is the motivation, and again, I would much rather carry on an investigation designed to find out what causes a peptic ulcer than testing some new antacid which is ter- ribly dull intellectually. It is not stimulating, it is not motivating. Occasionally a drug may produce an unusually dramatic effect, and the investigator, can feel that he has achieved some status by studyin this drug. But most drug studies are pretty humdrum affairs, and do not think it would be easy to get many people for this. Therefore, it seems to me it would be more direct if drug firms tried to make their own arrangements with universities, to have drugs studied rather than having an intermediate agency, which in its arrangements with investigators would unavoidably introduce delays. I also mention at the end of the next paragraph perhaps some honor system, such as the NIH has established with various medical schools, could be initiated, with the individual universities assuming respon- sibility for the trustworthiness of drug studies carried out by their staffs. This is an amplification of what I mentioned before. The question of fellowships, salaries, and general research support may be similarly answered. If funds made available by the pharmaceutical industry for such purposes are paid to educational or other nonprofit institutions, a hos- pital, say, through regular administrative channels, there is little chance that the donation will distort the scientific efforts of any laboratory or individual. Even if a dean received a huge sum of money from a certain drug firm to build a new building, for example, he would not be well advised to tell one of his professors that he must find in favor of that firm's products. PAGENO="0122" 4026 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY On. the other hand, and this goes back just to complete the same statement I made before extemporaneously, I would tend to disapprove of direct payment to individual physicians who might be tempted to evaluate a drug in spite of the limited investigational facilities that usually characterize the sole and private practice I have a paragraph here on retainer or consultation fees paid to professors by the drug industry. . . . . This, 1 am sure, is a difficult question because in this situation cer- tainly it would be a private transaction with payment to the consultant. I try to point out, however, that the problem is the same one faced by NIH in choosing its advisory boards. Although an expert might himself be a grantee of the Institutes, h.e must also at times be an adviser to the same Institutes, unless these Institutes would deprive themselves of his exceptional and, perhaps, unique knowle.dge.. Similarly, in matters pertaining to t.he pharmaceutical industry, I do not see how this industry can be prevented from seeking the best advice it can obtain. The same men will be sought by the Govern- ment as advisers, and it is likely they will occupy major academic positions, and the only safeguard I can propose is that all consultants and advisers who are paid for their services by drug firms on any sort of basis be publicly identified as employees of such firms. This more or less completes what I have to say about drug testing, Senator, unless you wish to ask me some questions about it. The next section deals with the journal. Senator NELSON. Please go ahead. Dr. INGELFINGER. And is related to the dependence of medical pub- lications on the income derived from drug advertising. Now, a year's subscription to this journal, the New England Journal of Medicine, costs $10. For students, interns, or residents, a third of our subscribers, the price is only $5. Now, the actual cost of publishing and mailing a year's subscription, including advertising, is close to $30. What makes up the difference so that we can survive economically? Advertising, and three-fourths of this is pharmaceutical advertising. On the way down I counted the pages of advertising in this recent issue, that of December 12. We have 52 pages of advertising, and it just turned out that 13½ were nonpharmaceutical, so three-quarters of the advertising in this issue was pharmaceutical. Mr. GoimoN. How many pages of text do you have? Dr. INGELFINGER. Usually we run about 60. Mr. GORDON. And you .say 53- Dr. INGELFINGER. I have not counted this particular one, but it will be pretty close. Mr. GORDON. Sixty text, and how many of advertising? Dr. INGELFINGER. This particular one is 52. Mr. GORDON. Fifty-two pages of advertising? Dr. INGELFINGER. Dr. Garland and I, too, although I have had less of a probelrn this way because we are not besieged by advertisers the way we used to be, `had `the policy that during a year `he would never publish more advertising pages than text pages. So the average ratio per year would never be more than 50-50. It might be per issue, you understand, but another issue would balance it. PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4027 Currently our average is running about 60 text versus 50 pages `idvertising Sometimes the advertising has been as low as in the thirties, occasionally up in the seventies, but our average is 50 Mr GORDON Why do you have a 50-SO sort of understanding ~ Dr. INGELFINGER. I suppose a line has to he drawn somewhere. This was a decision Dr. Garland made that he did not want his journal, when you pick it up, to be a great big fat thing, in which one has to search in the middle for a few pages of text, and I think he decided this might be an appropriate balance, and as one that we have kept up, although there really has been no problem about it recently. Senator NELSON. What does a page of `advertising cost in the journal? Dr INGELrINGER I cannot tell you that, I am sorry I can provide you with that information It depends a great deal on how often it is- whether it is' run 52 times a year or just a one-shot affair. Senator NELSON. If you could provide us with that we would wel- come it. Dr. INGELPINGER. I can give you that, and I can tell you also what our total advertising revenue for the year is, but I will have `to send you a schedule' Senator NrLsoN Thank you Dr INGELFINGER One other thing we maintain that some other journals do too, and some do not, namely, we still keep advertising and text pages quite separate You will not find an advertising page in the text as you go through it. Others, of course, have them inter- digitated. Advertisers would like it, but Dr. Garland kept the text separate and I have not made a change. Again you may ask why? I suppose it is a feeling of trying to keep some sort of balance. Senator NELSON. Yes. Dr INGELrINcIFR Because so much of our economic support depends on advertising, the potential exists that (1) in our efforts to please `a big advertiser we will accept and print advertising that contains mis leading information `tnd, (2) allow our editorial judgment to be warped when we evaluate acceptability of a manuscript for publication. A number of safeguards against such threats can be erected by the respectable medical journal. It can and does create its own advertising committee or some comparable group to evaluate both the pro'duct and the copy, that is, what the advertisement claims for the agent. Such a committee, however, functions better in theory than in prac- tice. Most journals cannot command the expertise necessary to co~rer the `broad range of pharmacology. As a result, a committee tends to operate unevenly with harshness tow'ird some and leniency toward other products, harshness being evident in the field of the committee members' competence, and leni- ency in the areas about which they know little. The advertising committee of the New England Journal of Medi- cine, for example, has benefited `from having experts in infectious disease among its members for a number of yearsi. For this reason, antibiotic advertisements have, by and large, been very carefully scrutinized. 1 Dr. Ingelfinger subsequently submitted the following: "Total advertising revenue for 1967-$2,109,684.25; 1966-$2,055,673.74." See also schedule beginning at p. 4043, infra. PAGENO="0124" 4028 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY On one occasion indeed, the sharp-eyed committee found that an FDA approved package insert quoted in an advertisement was not up to date in that it identified lymphogranuloma and trachoma as virus diseases; I have submitted this in appendix 1.1 Toward gastro- intestinal advertising, on the other hand, the committee has been rather permissive. But even if there were no variable of competence, evaluation `of the propriety of an advertisement i's like trying to draw a `fine line in loose and dry sand, and I am going into this whole problem of committee evaluation of advertising because it is such an important thing. If we could really have a very effective, dependable censorship, and never have a questionable advertisement and never a misleading one, never one of questionable taste, then I think some of the questions you and others have about advertising in journals would not be so serious. But I am trying to indicate why efforts in this direction are difficult in spite of conscientious efforts. Even if there were no variable of competence, evaluation is difficult. As examples, and I want to show you some of the fine borderline cases that have been faced by the committee, and I am dealing with anti- biotics because in this area the committee has been particularly tough. A copy of an ad claimed that a penicillin-type agent had "unsurpassed bactericid'al activity." The committee objected because they knew that it was just like many other penicillins. But literally, even if the agent was no better than 20 other penicillins, the advertisement was correct. I mean it could not be challenged for falsehood as long as it was equal, even if it was equal to many others. Another `ad for a penicillin derivative occasioned unfavorable com- ment by the committee because of the claim "no risk of tooth staining." Now, the committee pointed out that this statement, though true, was superfluous and misleading, for penicillin-like agents as a class do not stain teeth. This was a penicillin agent, so this statement they said was superfluous. It was put in, I suppose, because other types of antibiotics may stain teeth, but the committee objected because this agent was obviously penicillin. So the statement in itself is perfectly valid bu't was thought to be misleading in its implications. Sometimes the advertising committee objects to advertisements on other grounds, and recently a submitted copy contained the following lines, and this is similar to ones Mr. Gordon has shown me-nothing really wrong in terms of the scientific claim, but a questionable type of wording: When bacteria proved wilder than children and cause a complicated upper respiratory infection, you can choose no better antibiotic than X. Wild children are healthy children-and antibiotic X helps brings about cures that are prompt and uneventful. We felt this copy was undignified and meaningless and, hence, un- suitable for the journal. In another instance, and this is possibly one of the most extreme cases of how one can get tangled up, a firm appropriately advertised an agent `as a prophylactic for a common illness, that is, to be used to prevent the illness. This ad was eventually accepted, but acceptance was delayed for some time because the advertising committee feared 1 See pp. 4042-43, Infra. PAGENO="0125" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4029 that physicians, in spite of the legitimate claim of the advertisement, would use the agent not only to prevent the illness* but also to treat it once it had started, which would be a definite misuse. In spite of the efforts, ability, and high standards of our advertising committee the New England Journal publishes material which phar- maceutical houses subsequently under FDA pressure have to with- draw. I have indicated how carefully they go over some ads to pick on wording which may be questionable, and yet we have published ads which contained false information, particularly as seen in retrospect. A number of years ago, I am sorry to say, we accepted and published advertising material extolling the now notorious agent MER-29 I can only conclude that advertising committees are unevenly effective, but the reasons are operational, not moral. What actually happens in the journal as a result of some of these advertising committee activities, and what are our policies? Because of the recommendations made by the advertising committee and, at times for other reasons, the journal rejected 14 new product advertise- ments during the 2 years 1967-68. During the same time we accepted 54 advertisements for new products. During one volume of the journal, that is during the first 6 months of 1968, we published 26 text items, and by that I mean articles, letters, editorials, dealing specifically with drug actions favorable and unfav- orable. Six of these were major articles dealing with the untoward effect of drugs. If someone sends us a letter that is critical of a drug or a drug ad- vertisement, we do not hesitate to publish this provided its point ap- pears valid and informative. Appendix II presents such a letter. It happens to question an advertisement which appeared 22 times in the journal, in other words, a fairly big advertisement. This same adver- tisement was featured in other medical publications. We have not hesitated to publish letters from such critics of medicine as Mr. Morton Mintz. On the other hand, this is not a one-way street. The journal believes that all sides should be heard. Hence, we also published a reply from the drug manufacturer to the letter which criticized the advertisement. This reply is shown in appendix III. In a forthcoming issue of the journal there is another letter from another firm objecting to a statement made in one of our regular articles. However, and I want to emphasize this as much as I can, neither during my relatively brief tenure as editor or during the 20 years' tenure of my distinguished predecessor, Dr. Joseph Garland has, to the best of my knowledge, any material either been suppressed or printed in an effort to please the advertiser. I cannot speak with firsthand knowledge concerning other medical publications, but I believe that other respectable and standard medical journals observe the same policy. In essence, what it comes down to, we have published ads, and we are still publishing them, that can be criticized. Some possibly contain or probably contain misleading information, but our errors, our diffi- culties, are that we have not got the expertise and screening procedures to detect this. We do not know, for example, in the case of MER-29 when this was accepted, which was before my time, but I doubt if there was any PAGENO="0126" 4030. COMPETITiVE PROBLEMS IN THE DRUG INDUSTRY discussion about it. The toxic effects of the drug were not known to the committee, and they were misled as much as anybody else Now, it has been suggested that the journal accept no drug adver- tising whatsoever. This suggestion is based on the assumption that our readers are indifferent to pharmaceutical advertising-dan unwar- ranted assumption in my opinion. This is a very difficult question, Senator. But I ask myself: suppose our advertisements were impeccable, that they promoted a drug with the claims were circumspect, and they could not be criticized for bad taste or for false indications, would we thereby provide our reader with valuable information as to what is available ~ In the absence of a drug compendium that is all-inclusive and all-informative, I feel that some of our readers look at our advertisements for information to see what is on the market and where they can get it But I am really not sure how much they really depend on it, and `if we stopped all advertising, I am not sure bow many of our readers would complain I would suspect some, but I have no idea of the percentage I believe the students, the house officers, would not object, for they use agents that the hospital has available But I would guess that some 20,000 or 30,000 of our subscribers look at the ads for informa tional purposes Furthermore, if pharamceutical advertising were omitted our sub scription price would be raised to at least $25 Why not, it may be asked, shouldn't this be done, since physicians are well-to-do, and even residents these days make a living wage? Bargains, however, are also sought by the well to do Hence, I suspect that an increase in our subscription price to $25 would reduce the number of our subscribers in a rathei drastic way Since our principal reason for existence is education, we would, indeed, have created a paradox-this is the important point, I think-if in a backward lean ing effort to avoid misleading advertising we decreased the number exposed to whatever information and education we may bring them We are currently planning to provide our readers with an abstract sei vice, at the beginning of each of our articles ~ e have a short sum mary These now appear in the regular soft pages of our journal, but we hope to print them in addition on little perforated cards, on card `stock with little perforations, so the reader can tear out abstracts and file them. We estimate. from preliminary surveys that `some 30,000 of our read- ers we have heard would make use of this particular device Senator NELSON What kind of information will be on that ~ Dr INGELFINGER A summary of the article Each `uticle is pre ceded by what we call an abstract, a summary, stating in as concise way as possible what it is about and what was found. Many students and doctors like to keep such abstracts as a quick reference. They can file it under index terms which the National Li- brary of Medicine provides. So it is a nice ,retrieval `system for an individual, and it a1so helps quickly to decide whethei you want to go back and read this article in more detail. It is a retrieval system. To publish and mail such abstracts would `cost us $100,000. The only ~ ay we can do it is if some firm is willing to put some ad on the front and the back of a booklet containing these abstracts which we are thinking of mailing out once every month. PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4031 You see, here is the dilemma. Should we J?rovide this service and, at the same time, send out advertising which might be criticized ~ Or should we not do it at all? Do we give up educational efforts to avail whatever stigma drug advertising produces? These considerations lead me to the following conclusions: (1) Economic pressures dictate that we continue to carry adver- tisements, including advertisements of drugs. (2) An individual journal cannot adequately evaluate the pro- priety and accuracy of such advertising. Through ignorance and error, but not because of venality, misleading advertisements will at times be included; and at other times, basically proper advertisements will be excluded. (3) It is not realistic to expect business enterprises that are actively competing in a capitalistic society to impose upon themselves the tra- dition and ethics of a profession. (4) Legislative control of improper information or advertising is extremely difficult, particularly when fine semantic problems or questionable implications are at issue. I have tried to give some ex- amples of those. (5) The proper use of drugs in the final analysis rests with the physician, and it is the physician who must be amply provided with broad and inclusive information, with all sides represented, so that he may have the opportunity of making a sound judgment. He must be even more aware than he is that drug advertisements, or the state- ments of detail men, like many other advocating the virtues of a prod- uct in the best terms possible. Rather than attempting to restrain this publicity of the advertiser, a more persuasive case can be made, I believe, for increasing publicity to the consumer. The danger of smoking has been emphasized for some time, but it is only recently, with increasing publicity-not increasing knowledge but with increas- ing publicity-that the number of new smokers seems to he increasing less rapidly than previously. Through proper publicity, with cons as well as pros emphasized, the physician will be in a better position to decide whether or not a drug is worthy of being advertised. How can this be done? Basically, I would favor a compendium listing, describing and evaluating all drugs that a patient may pur- chase. Eventually, this might be a two volume affair devoted to pre- scription and nonprescription drugs respectively It is most important, however, that such a compendium be issued under the auspices of a united, multipartisan authority that is satisfactory to the major parties concerned. Perhaps the new AMA publication will satisfy the need; I do not know enough about it to discuss it. If it does not satisfy the need, I believe a compendium should be issued under the joint sponsorship of the AMA, the Pharmaceutical Manufacturers Association, the FDA, and the American Pharmaceutical Associa- tion, possibly represented in a ratio of 2:1 :1 :1, that is, with the AMA with major representation. Such a joint sponsorship is essential if the compendium is to be an acceptable, and I emphasize acceptability, authority to all users. Other devices also deserve consideration. Medical journals that ac- cept drug advertising such as ours might index the agents advocated with a bibliography of appropriate references to the established and recognized medical literature. If no such references, that is acceptable PAGENO="0128" 4032 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY references, could be provided because of limited or questionable docu- mentation, the absence of a citation should alert the physician that the agent in question is of uncertain effectiveness or safety. Mr. GORDON. These devices that you are mentioning actually are designed to try to counter or undo any possible damage from adver- tising; isn't that correct? Dr. INGELFINGER. This is to give both sides. Perhaps an arrange- ment could be made with the Medical Letter to reprint evaluations that appear in its publication. A number of such schemes could be tried with a two-fold objective:' on one hand, they would not infringe on the right of a company to advertise and praise its products, but on the other, they would present the physician with all available in- formation and opinions so that he could be misled only if his reading of a given journal were decidely one-sided. After all, this is what we do in the journal anyhow. Somebody publishes an article which says this disease is caused by such and such an agent. Well, pretty soon somebody publishes an article which says, no, it does not, he is wrong. Then a discussion develops. I do not see why a journal could not also attempt to present all sides with respect to drug use, but it would have to make a conscious, not only con- scientious but conscious, effort to increase the evaluation of drugs that are mentioned, whether in advertising or in regular text. The crucial question, of course, is whether an individual practicing physician has the time and the ability to `make the necessary judg- ments, especially since I have indicated that journals cannot screen advertising properly, even with committees. I believe the answer is "yes", because an individual physician presumably uses only a limited number of drugs to which he adds, once in a while, a new product. Before he does so, it should be his responsibility to check on all the information he can, that provided in a compendium, that to be found in the pages of his medical journals, and that provided by any consultant whose advice he seeks. The American Medical Association, I hope, would be willing to emphasize this responsibility of the physician and, indeed, has done so at times. If the physician's management of patients is to be relatively free- this is what he wants, to be relatively free-from outside interference- and I believe it should be relatively free-this freedom can only be sustained by the physician's determination to keep himself well informed. Actually, I wrote this before I read the task force report, and I was interested to find the task force report also ends up with the point that the person who is really responsible, one who has to make the ultimate decision, is the physician, and that it is his continuing education which will support his judgment as to whether or not to use a given drug. The task force may be a little more pessimistic than I am that this education can be achieved, but to me it is the main area deserving of emphasis in trying to encourage a proper use of drugs. This, I believe, is more practical and ultimately more effective than imposing restric- tive legislation on advertising or exactly on what the doctor can or cannot do. This more or less concludes, sir, my rather long discourse on drug advertising in medical journals. The rest is just rather brief statements PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4033 dealing with other questions which are of relatively minor importance in terms of the discussion. Senator NELSON. The committee has been interested in the question of the promotional practices involved in advertising in medical jour- n'ils, ~ hich is the only place that they advertise, that is, medical publi cations of some kind, and direct mailing and the promotion of drugs through detail men. Part of this still puzzles me. You state, as you go along here, that there should be competing sources o-f information to the physician and that perhaps the drug companies should be permitted to advertise as they see fit so long as it meets some kind of a standard. In the fac~ of `dl this, neverineless, there is the lack of response on the part of the medical profession. Look at the situation of chloram- phenicol The point is that some $700 million a year is spent in adver tising and promotion by the industry. As in the case of chlorampheni- col, it obviously is very effective. Here is a specific case of a drug widely promoted in medical journals and by direct advertising, too, the consequence of which was that the medical profession in this country was prescribing the drug for non- indicated cases on a massive basis. In fact, here is a case where it was perfectly clear to the medical profession, including the AMA which understood the drug, that indications for the use of the drug were very, ~ erv limited In fact, the six witnesses who testified before this com mittee, I think it was six, including Dr Dameshek of Mount Sinai, and a number of others-these eminent medical authorities all testified that in their judgment 90 to 99 percent of the people who were admin istered this drug were receiving it for nonindicated cases One of the witnesses testified that he had never yet, in his practice, seen a patient suffering from aplastic anemia who had received the drug chloramphenicol for an indicated case. It was being prescribed for sore throats, acne, tooth infections, head colds, and the like. The most conservative estimate was, I think Dr. Dameshek's, who stated that, in his judgment, only 10 percent of the patients who received this drug received it for indicated cases. One of the witnesses thought there could not be more than 10,000 c tses a yar for which the drug would be indicated in this countiy Dr. Goddard felt the same. But 31/2 to 4 million people a year were receiving the drug. The drug Was widely advertised in medical journals. I did not look at any- Dr. INGELFINGER. I am sure we had it. Senator NELSON. I looked at a number in the Journal of the AMA, very clever promotional ads, "When it counts use Ohloromycetin." A full page, that many words or about that many. The consequence was that one way or another the medical profession ~ `is convinced th'tt they should use the drug for nomndicated cases Our files are full of letters, tragic letters, from parents whose children received it, who h'id sore throats As Dr Dameshek said, most of these patients, the patients who received it for nonindicated cases, would have gotten well if they had taken nothing at all. This went on a long, long time The medical profession did nothing about it. At the same time many of these journals were carrying the ads on chloramphenicol, they printed articles warning of the danger 8i-280--69----pt. iO-9 PAGENO="0130" 4034 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of the drug and its extremely limited indications. One article by Dr. Dameshek-was it the New England Journal which carried that? Dr. INGELFINGER. It was the New England Journal. Senator NELSON. Yet, at the same time, the ads continued to be carried. We conducted hearings, and Dr. Goddard said, "I am at my wit's end as to how to stop the medical profession from misprescribing this drug." I would have thought the medical profession somewhere, some place would have felt a sense of responsibility. They might have called a national conference of leaders, headlined stories in all medical journals, told the doctors they were killing people by improperly, using this drug. * But it did riot happen. So it came to the committee's attention-a committee of Congress with no expertise in this field at all-and we conducted hearings. As a result of our hearings, Dr. Goddard's testi- mony, and the FDA's "Dear Doctor" letter sent to all 200,000 doctors and to all medical journals, front page stories appeared acr9ss the country, solely as a consequence of these hearings, the certification of the drug dropped froni 23 million grams in the first 6 months of 1967, to 4 million grams in 1~68, and down to zero in June of 1~68. Now, here is an example, it seems to me, where the argument about balance in informing doctors just collapses. Here is a case where a company successfully and widely promoted a drug. Where ads were ac- cepted by medical journals even though every consultant they had who knew anything about the use of chloramphenicol would have told them it is a strange thing that a company should be spending lots of money to advertise a drug which has such extremely limited use and further that if the drug were used only for the purposes for which it was indi- cated, it would not come anywhere near repaying the cost of the ads. So in my judgment it raises very serious ethical questions as to the whole business of advertising, promotion, and acceptance of ads. The ads are still running and~ in fact, one of the officers of the company stated-I do not have his exact quote-that once all the fuss and feathers were over-those are not his words-he assumed the use of the drug would rise again. Well now, I think it is a sad commentary on the medical profession as a whole, with everyone having some responsibility for what hap- pened, but it seems to me, if a company came with a chloramphenicoi ad, it ought to be told "You run the whole package insert in your ad or we won't take it because the history is that you have misled the profession." What is your comment on that whole picture? Dr. INGELFINGER. Well, Senator, I cannot defend the whole story that developed on chloramphemcol, and I am sure most physicians and all of those responsible, editors and people connected with journals and the like, feel very badly about the fact that on occasions the agent was so indiscriminately overused. But is not the problem now-you and your group having demon- strated this-what can be done to prevent it in the future, and this is really what I have been trying to come to grips with a little bit I do not think, just to take the easiest thing first, that merely for the New England Journal of Medicine to stop taking advertising would do anything since there are thousands of others- PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4035 Senator NELSON. I have not suggested that. Dr. INGELFINGER. No, I mean it has been suggested-I know you did not, but I mean that for one, two, or five journals not to accept pharmaceutical advertising would accomplish nothing. In fact, you would lose something, thereby. Second, I doubt that overuse of a drug is entirely attributable to ad- vertising. People who have testified here before your committee prob- ably have indicated that other agents have also been overused. I am sure penicillins have been greatly overused-many articles in medical journals have said so. But, fortunately, except for patients who have been sensitive to the agent, serious side effects have been few. I am not sure it is all due to the advertising, for when physicians are called to see an acutely ill patient, their tendency is to use something that is fairly powerful. If they fail to treat a patient with an antibiotic sensitive infection, they are severely criticized. Even, the patient is often inter- ested in getting that powerful new drug he has been reading about in his papers and magazines. I am sure patients have demanded penicillin on many an occasion. So here is this physician-he is under pressure to use a new agent and an effective agent. He has not had the time possibly, or the facilities to determine why the patient is having a fever. He is not sure of the indi- cation. This is continuing dilemma for the physician, and when faced with the alternative of over- or under-treating, he will usually avoid undertreatrnent. Third, I do not know enough about `business or law to indicate what the Government can do to keep `people from advertising, but I do not see how the Government can tell an industry, "You cannot advertise." You can apply certain rules to advertising, but I am not sure, Senator, that insistence on including in the advertisement the pack- age insert, or a long list of counterindications is worthwhile. Indeed, I think it is self-defeating. Few read this. One of the main things we are taught as editors is `the importance of `brevity and succinctness. Here we have in this advertisement in our December 12, 1968, issue, four pages about an antibiotic. The first three pages present dramatic pictures, and here on the fourth page, complying with the rules, is the package insert. Who is going to read all of this? One out of 100 at the most. I think it is useless. This is why I think it is a mistake for the Government to say that in advertising you have to list all the toxic effects, or, for that matter, to make many detailed rules. More practical ways have to be found. Now, I agree that medical journals, including the New England Journal of Medicine, and all medical educators were delinquent in not emphasizing more the dangers of chloramphenicol. T'he fact that it caused aplastic anemia was recognized early when the drug was tried, there was no question about it, and in medical school these dangers were taught. However, apparently it was not emphasized enough in general, and this is why I am making the :suggestion that besides any rules that are made, beside any compendium which necessarily would have to be printed in small print, journals have to accept the responsibility or possibly be forced to accept the responsibility, of publicizing `the dangers as well as the advantages of certain drugs not emphasizing the PAGENO="0132" 4036 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY dangers out-of-proportion, but giving a fair evaluation of the pros and the cons. Suppose the New England Journal or the Annals of Internal Medi- cine had come out early during this story of chioramphenicol that you have recited and had kept emphasizing its dangers and its re- stricted indications, I am not sure whether it would have prevented anything or not, but at least these journals would have discharged their responsibility My guess is if there was enough publicity which had been given to some of these dangers, along with indicating conditions in which the drug was valuable, then possibly so many people would not have suffered from the untoward consequences. So I am really agreeing with you, Senator Nelson. If we medical journals instituted a procedure whereby any actively advertised agent that we carry would be accompanied by evaluations other than those provided by the drug companies-evaluations from the Medical Let- ter or from other objective reports, for example-then I think the doc- tor would be exposed to the whole picture. And this is what counts, for he is the one who prescribes the drug. Is not this a possible approach? Senator NELSON I do not know what the answer is I would wonder whether any method would be successful against $710 million worth of advertising and promotion. The ads are clever, they are eye-catching, as I suggested earlier. The fact is, at least so far as chioramphenicol is concerned, the whole coun- try would be better off if they had never run a single ad. If the only thing told about chloramphenicol was in medical publications stating that in certain extremely limited conditions-rickettsial diseases, and SO forth, where the patient was seriously ill and no other antibiotic was effective, this would be the only type case in which the drug is indicated. After all, if there are only 10,000,20,000 people a year for whom it is indicated, we probably would have been a whole lot better off if there had never been an ad on it in this country. It raises the whole question of what is the effect, purpose, and value of advertising. In fact2 I notice you mentioned this earlier yourself. Dr. Frederick Wolff, director of research, Washington Hospital Cen- ter and professor of medicine at George Washington University School of Medicine, stated before our subcommittee that the advei tising promotion of drugs has had a great impact on prescribmg habits of doctors, no less than advertising has had on the buying habits of the average American housewife Dr Wolff also estimated that out of every $10 spent on drugs about $6 are spent unnecessarily, and that advertising and promotion of drugs are to a great extent responsible for the situation Dr INQELFINOER Senator, that is it I am not an economist nor am I an expert in what is possible by legal means, but also it is not eco nomicafly and legislatively possible and justified to just prohibit ad- vertising by pharmaceutical firms which it seems to me is rather incôn-* ceivable in view of all the advertising that goes on about all sorts of things The only answer to prevent what you have just said, meaning what you have just recounted about chloramphenicol, is counter publicity and if the medical profession is SO unresponsive that they will no~ PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG. INDUSTRY 4037 listen to it, then I think it is a terrible indictment of the medical profession. I hope the profession is better than that, and I think it is better than that. Senator NELSON. I do not know what the answer is either. Dr. INGELPINGER. Well, I am sure our common aim is to prevent misuse of drugs? . Senator NELSON. Yes; just as I said, it raises a question of whether there is, in fact, any way that counterinformation, so to speak, can successfully compete- Dr. INGELFINGER. May I say one more thing? Senator NELSON. Yes, sir. Dr. INGELFINGER. You have achieved much through the medium of counterinformation. Senator NELSON. Yes. This happened to be a very dramatic case. We got involved in it accidentally. It would not have occurred at this time if it had not been for this congressional committee. But it has been going on since 1953. In other words, the problem has existed for many, many years with everybody wringing his hands but no one con- cerned enough to do' something about it. When it came to the commit- tee's attention and we decided to look into it, the consequences were quite dramatic But I do not think you can `count on that kind of a circumstance to be a balance wheel to the improper promotion of drugs. That is what bothers me Dr INGELFINGER Yes, I think this is more potent publicity than one can develop in the pages `of a medical journal. Senator NELSON. Well, that is `the question we are exploring. I do not have the answers to it Perhaps we will find some It seems to me it will not be resolved until the medical profession itself becomes involved it. And that is as itshouid be. lonly regret the profession did not see fit `to take the initiative in the beginning Had it done so, this subcommittee would not be holding these heaiings today We appreciate your coming here today and we thank you for your very thoughtful contribution to our hearings We want to thank both of you tor contributing so much of your time to these hearings Dr INGELFINGER fhank you for letting us speak Senator NELSON. Thank you. We will adjourn until tomorrow at 10 o'clock (The complete prepared statement and supplemental information submitted by Dr Ingelfinger follows ) STATEMENT OF Da FEAN~ J INGELrINGEE EDITOR Tur NEW ENGLAND JOURNAL 01 MEDIcINE My name is Franz T Ingelfinger and I am Editor of The New Fngland Journal of Medicine, a position 1 have held for one and a half years. I ani also Clinical Professor of Medicine at Boston University School of Medicine. Prior to July 1, 1967 I was Professor of Medicine at that institution for a period of ten years. My sub-specialty interest is gastroenterology, a field in which I have taken care of patients, taught, edited, carried out clinical research, and conducted a produc- tive post graduate training program I am also a past president of the Amex ican (rastroenterological Association In the 27 years during which I was engaged in gastroenterological investigation, I carried out numerous drug studies for at least one half dozen pharmaceutical firms, the funds received for such studies being used to support the unit of which I was in chdrge O1~ the various aieas ot possible confli t of interest cited in Senator Nelson s letter of November 22, 1968, may I su'bmit cOmments on the following: PAGENO="0134" 4038 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1. Acceptance by ph~/sicians of funds paid by drug companies for the evaluation of their products, or for other purpo$es such as fellowships, $alaries, or general research support Physicians niay test drugs with support from pharmaceutical firms under various circumstances, and the nature of these circumstances will to a large ex- tent determine the objectivity and the integrity of the work. Under many cir- cumstances, the likelihood that the source of the support will influence the result is negligible for the following reasons: A. The testing is often carried out in a medical school setting. This means (a) that administrative officials, rather than the investigator, will handle the financial arrangements (i.e., there is no "direct" payment to the investigator) ; and (b) that others besides a solitary investigator (i.e. post-graduate students, other physicians, laboratory workers ) will participate in the test procedures. Thus the study is safeguarded in that there is participation by a number of people who have no financial interest in the nature of the results. B. The testing is often carried out during the preliminary `stages of the de- velopment of a drug. For example, my laboratory used to screen agents fo.r their ability to affect gastric acid secretion or to decrease intestinal contractions. On other occasions, we measured the absorption of certain drug formulations in different parts of the intact human intestine. In all these instances, effects could be measured by means of mechanical recording devices or by chemical deterini- nations. The objective data so obtained cannot be easily distorted `by personal bias. Furthermore, under such circumstances, the investigator who' misleads a fln'sn'cial sponsor is not doing that sponsor `any favor. Drug companies are not anxious to spend money on developing an inferior product, and for `their own protection tend to seek a valid appraisal. Clinical testing of a product ready for marketing or already marketed is, however, extremely difficult under `any conditions. The criteria available for measuring a drug effect are often extremely vague and highly subjective. There is no precise yardstick, for example, to determine whether or not pain is worse. Furthermore, the `desires of both patient and investigator may color the inter- pretation. Hence studies of this `type must be carried out under optimum condi- tions by investigators who are equipped by training and facilities to carry out such testing, and who use a protocol incorporating procedures that characterize a well-controlled study. -If these condition's are observed, I. doubt that the results are likely to be influenced many way. by subtle' ec:onomic pressures. One suggestion that has been' made to prevent undue influence, of sponsor on investigator is the establi'~hment of a central independent agency that would act as a clearing-house in arranging for the testing of drugs. Under such an arrange- ment drug testing for i'ts clinical efficacy would be, in `a sense, "triple `blind" in that `the investigator and the agent's maker would be unaware of each other's identity. Such a central agency might be established under the jurisdiction of a corn mittee in which pharmaceutical firms government and the AMA would have adequate and satisfactory representation However the increased objectivity and trustworthiness of drug testing procedures so attained would have to' be balanced against the added expense and delays entailed if such a scheme were implemented. Furthermore, I am. not sure that total "blindness" could be achieved. Although. this `is a- pure "armchair" opinion, I doubt that such a clearing-house is worth the effort provided that the conditions under which clinical tests are carried out are reasonably well standardized along, the lines indicated in t'he proceeding paragraphs. In this connection I sould like to recommend that any specifications that the government establishes for the control of clinical testing be not too detailed and rigorous Observation of certain broad principles should be required but If the regulations are too elaborate and rigid, the very investigators whom one would like to `see at work at the task would shy away. Perhaps some honor system such as the NIH has established with various medi-dal school could be initiated, with the individual universities assumin.g responsibility for the trust- worthiness of the drug studies carried out by their staffs. The questio'n of fellowships, salaries, and general research support ~nay be similarly answered. If funds made -available by the pharmaceutical industry for such purposes are paid to educational or other non-profit institutions through regular administrative channels, there is little chance that the donation will distort the scientific efforts of any laboratory of indiviual Even if a dean receives a huge sum of money from a certain drug firm he would not be well advised to tell any of -its professors that they must find in favor of that firm's PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4039 products. On the other hand, I would tend to disapprove of direct payment to individual physicians who might. be `tempted to evaluate a drug in spite of the limited investigational facilities that usually characterize the solo private practice. 2. Retainer or consultation fees paid to professors by the drug industry In this case, direct payments to individuals by drug firms does constitute a theoretical conflict of interest. The problem, however, is' the same one faced by the NIh in choosing its advisory bodies. Although an expert might himself be a grantee of the Institutes, he must also' at times `be an advisor to the same Insti- tutes, unless they would deprive themselves of his exceptional and perhaps unique knowledge. Similarly, in matters pertaining to `the pharmaceutical in- dustry, I don't. see how this industry can be prevented from seeking the best advice it can obtain. These same men will be sought by government as advisors and it is likely that they will also occupy major academic positions. The only safeguard I can propose is that all consultants and advisors who are paid for their services to drug firms be publicly Identified as employees of such firms. 3. Dependence of medical publications on income derived from drug advertising A ye'ar's subscription to New Englasui Journai of Medicine now costs $10.00. For students, interns, or residents-I.e., a medical trainee-the price Is only $5.00. The actual cost of publishing and mailing a year's subscription Is close to $30.00. What makes up the difference so that we can survive economically? Advertising, and three-fourths of this Is pharmaceutidal advertising. The poten- tial therefore exists that in our efforts to please a big advertiser we will (1) accept and print advertisements: that contain misleading information and (2) allow our editorial judgment to be warped, when we evaluate the acceptability of `a manuscript for publication. A number of safeguards against such threats can be erected by the respectable medical journal. It can and does create its own advertising committee to evalu~ate both the product and the "copy"-i.e., what the advertisement claims for the agent. Such a committee, however, functions better in theory than in prac- tice, Most journals cannot command the expertise necessary to cover the broad range of pharmacology, As a result, a committee tends to operate unevenly, with harshness toward some and leniency toward other products, harshness being evident in the field of' the committee:' member's competence, and leniency* in the areas about which: they:know' little. The advertising~: committee of:' The New England Jo~urnai of Medicine for examp'e has benefitteci from having experts in Infectious disease among its members For this reason antIbiotics have been most carefully scrutinized. On one occasion, Indeed, the sharp-eyed com- mittee found that an FDA approved package Insert, quoted In an advertisement, was not u.p~to-date In tha:t It Identified lymphogx~anuloma venereum and trachoma as virus disease (see appendix I), Toward gastrointestinal drugs, on the other hand, the committee has been rather permissive. Even if there were no variable of competence, evaluation of the propriety of an advertisement is like trying to draw a fine line In loose and dry `sand, Re- cently, for example, our committee rejected an advertisement because the copy claimed that the penicillin-type agent had "unsurpassed bactericidal activ- ity". The committee objected because they said, "the agent is like other peni- cillins". Literally then there is nothing wrong with the word "unsurpassed", pro- vided that the agent is as good as other penicillins, even if there are dozens of others. Another advertisement for a penicillin derivative occasioned unfavorable comment by the committee because of the claim "no risk of tooth staining". The committee pointed out that this statement, though true, was superfluous and mis- leading, for penicillin-like agents as a class do not stain teeth. Again the state- ment in itself is perfectly valid, but its implication is mlsleadng? Sometimes the advertising committee objects to' advertisements on other grounds. Recently a submitted copy contained the following lines: "When bacteria proved wilder than children and cause a complicated upper respiratory infection, you can choose no better antibiotic than X." "Wild children are healthy children-and antibiotic X helps bring about cures that are prompt and uneventful." This copy was regarded as both undignified and meaningless~and hence unsuit- able for the Journal. In another instance, a firm appropriately advertised an agent as a prophylactic for a common illness'. Eventually we accepted this advertisement, but acceptance was delayed for some time because the adver- tising committee feared that physicians, in spite of the legimate claim in the PAGENO="0136" 4040 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY advertisement, would use the agent not only to preven~t the illness but also to treat ~t once it had started In spite ocf the efforts ability and high standards of our advertising corn mittee, the New Ertgland Jo*urna~l publishes material which pharmaceutical houses subsequently, under FDA pressure, have to withdraw. A number of years ago, I am sorry to say, we acce~ted and published advertising material ex- tolling the now notorious agent MER 2. I can only conclude that advertising committees are unevenly effective, but the reasons are operational, not moral. Because of the recommendations, made by the advertising committee, and at times for oth:er reasons, the Jowrnal rej~ected 14 new product drug advertisements during the 2 years 1967-1O~8. During the same time 54 advertisements of this type were accepted. During one volume of the Journal, that is., during the first six months of 1968, the Journal published 26 text items dealing specifically with drug actions, favorable and unfavorable. Six of these were major articles dealing with the untoward effect of drugs. If someone sends us a letter that is critical of a drug, or a drug advertisement, we do not hesitate to publish this provided its point appears valid and informative Appendix II presents such a letter It happens to question an advertisement which appeared 22 times in the Journal it also was featured in other medical publications. We have not hesitated to publish letters from snch critics of medicine as Mr. Morton Mintz. On the other band, ~ this is not a one-way street. The Journal believes that all sides should be heard. Hence we also published a reply from the drug manufac- turer to the letter which criticized the advertisement (appendix III). Iii a ~orthcoming issue of the Journal we are printing a lett.er from another firm objecting to a statement made: in one of our regular articles. Neither during my ~`elative brief tenure as editor, nor during the twenty years' tenure of my distinguished predecessor, Dr. Joseph Garland, has, to the best of my knowledge, any material either been suppressed or printed in an: effort to please the advertiser. I cannot speak with firsthand knowledge concerning other medical publications:, but I believe that o:ther respectable and standard medical journals observe the same policy. . It has been suggested that the Journal accept no drug advertising whatsoever. This suggestion is based on the assumptiOn that our readers are indifferent to pharmaceutical advertising, an unwarranted assumption in my opinion. In addition, if pharmaceutical advertising were'. omitted, our subscription price would be raised to at least $2500 Why not it may be asked since physicians are well-to~do', and even residents thes:e days' make living wages. These considerations lead me . to. th.e'...fOilowing conclusions: (1) Economic pressures dictate. that `~ve continue to carry advertisements, including adve'rtis'enients.o'f drugs.~ . .;. . .., . (2) An individual journal cannot adequately~ evaluate the propriety and accuracy of such advertising. Through ignorance and errOr, but not because of venality, misleading advertisements will `at time's be~ included; and at other times, basically proper' advertisements will be excluded. (3) It is not realistic to expect business enterprises.tbat are actively competing in a ëapitalistic society to impose upon themselves, the tradition and ethics of. a profession. . : . .` . (4) Legislative control of improper information or' advertising is extremely difficult, particularly when fine semantic problems or questionable implications are at issue. . (5) The proper use of drugs in the final analysis rests with th.e physician, and it is the physician who must be amply provided with broad and inclusive information, with all sides represented, so that he may have the opportunity of making a sound judgment. He must be' even more aware than he j5: that drug advertisements:, or the statements: of detail men, like any other advertisement~ represent the prejudiced statements of an interested party advocating the virtues of a product in the best terms possible. Rather than attemptin.g to restrain this publicity of the advertiser, a more persuasive case can be made, I believe', for incr~asing he publicity of the consumer. The danger of smoking has been em- phasized for some time, but it is only recently, with increasing publicity, not increasing knowledge, that the number of new smokers: seems to be increasmg less rapidly than previously. Through proper publicity, with coas as well as pros emphasized, the physician will be in a better position to decide whether or not a drug is honestly advertised. How can this be done:? Basically, I would favor a compendium listing, describ- ing and evaluating all drugs that a patient may purchase. Eventually, this might be a two volume affair devoted to prescription ad non prescription drug'~ PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4041 respectively. It is most important, however, that such a compendium be issued under the auspices of a united, multi-partisan authority that is satisfactory to the major parties concerned. Perhaps the new AMA. publication will satisfy the need ; ~ do not know enough about it to discuss it. If it does not satisfy the need, I believe a compendium! should be issued under the joint sponsorship of the AMA, the Pharmaceutical Manufacturers' Association, the FDA, and the Amen- can Phanmaceutical Association, possibly represented in a ratio of 2 :1 :1 :1. Such a joint sponsorship is essential if the compendium is to be an acceptable authority for all users. Other devices also deserve consideration. Perhaps medical journals that accept drug advertising should index the agents advocated with a bibliography of ap- propriate references to the established and recognized medical literature. If no such references could be provided because of limited or questionable documen- tation, the absence of a citation should alert the physician that the agent in question is of uncertain effectiveness or safety. Perhaps arrangements could be made with Medical Letter to reprint the evaluations that appear in this publica- tion A nunTher of such schemes could be tried with a two fold objective one one hand they would not infringe on the right of a company to advertise and praise its products but on the other they would present the physician with all available information and opinions; so that he could be "misled" only if his reading of a given journal were decidedly one-sided. [`he crucial question of course is whether an individual practicing physician has the time and the ability to make the necessary judgments especially since I have indicated that journals cannot screen advertising properly, even with committees. I believe the answer is "yes," because an individual physician presumably uses only a limited, number of drugs to which. he adds, once in a while, a new product. Before he does so, it should be his responsibility to check on all the information he can, that provided in a compendium, that to be found in the pages of his medical journals, and that provided by any consultant whose advice he seeks.. The American Medical Association, I hope, would be willing to emphasize this responsibility of the physician If his management of patients is to be relatively free from outside interference-and I believe it should be relatively free-this' freedom can only be sustained by the physician s determi nation to keep himself well informed May I submit briet comments concerning some of the other questions put by Sen'itor ~ el~on 4. If doctors lend their names for articles and letters written by members of the pharmaceutical industry, and these letthrs represent the opinions and state- ments of such members and not of the doctors, I would term the practice fraudulent. 5. Except if large holdings are involved, presumably an infrequent situation, I doubt that ownership of stock in a drug company will influence either the man carrying out an evaluation of a drug or the man prescribing it for patients. If physicians hold stock in chemical or pharmaceutical firms, they often have multi- ple holdings. Furthermore, a vast proportion of physicians probably have invested in mutual funds. 6. Physicians obviously should not prescribe merely on the say-so of a detail man. As I have suggested above, the pressures. by a detail man can be better i esisted if measures are taken to provide physicians with better information and if their responsibility in choosing drugs is vigorously publicized 7. The problem of "so-called independent giveaway sheets" would be taken care of if all medical publications were required to provide full information- for example, compendium, Medical Letter, or other evaluations as well as advertisements. May I conclude with a philosophic comment. Critics as well as admirers of medicine have recognized that doctors are placed in a position that reciuires unique trustworthiness. The relation of physician and . patient is such that an unscrupulous doctor can exploit a patient's illness unmercifully; the same un- scrupulous physician will exploit other opportunities such as drug testing To re strain such practices by legal means is extremely difficult Fortunately the overwhelming majority of physicians are not unscruplous. They do not order unnecessary treatments or report dishonesty on the action of drugs merely for economic gain. Some may sneer at the physician's claims of adherence to ethical standards. but the care of the patient by the physician, as we know it now, could not survive without a large measure of `trustworthiness. If I am correct in this assessment, and I believe most of our population would subscribe to it to a greater or lesser degree, then the more effective approach to a PAGENO="0138" 4042 COMPETITIVE PEOBLEMS IN THE DRIJG INDUSTRY correct use of drugs by physicians i.s through education rather than through leg- islation. The average physician is not out to do the patient in, and if he has an unconscious basis this is best controlled by providing him with the information that he needs to make the best choice of which he is capable. His patients will not benefit from a series of hard and fast rules, a set of do's and don'ts with respect to a multitude of drugs. They will benefit if he is provided with the necessary information, and, even more important, with the motivation to keep his education up to date. APPENDIX I BRIEF SUMMARY FOR ERYTHROCIN, ERYTHROMYCIN, ABBOTT INDICATIONS For all infections susceptible to erythromycin; primarily, gram-positive cocci- staphylococci (most strains), pneumococci and streptococci (including enter- ococci). Also active against other pathogens, such as Corynebacterium, Hemophi- lus, (Ylostridium, Nesseria, Treponema pa~flidum, the agents causing trachoma and lymphogranuloma, venereum and Mycoplasma pneumonia,e (Eaton agent). When practical the susceptibility of the pathogenic organism should be established. Therapeutic levels should be maintained for 10 days in the treatment of strepto- coccal infections to prevent rheumatic fever and glomerulonephritis. In localized infections, antibiotic therapy does not obviate the need for local measures or surgery whenever these are indicated. CONTRAINDICATION Known hypersensitivity to erythromycin. PRECAUTIONS, SIDE EFFECTS Side effects are infrequent. Occasionally mild abdominal discomfort, nausea or vomiting may occur; generally controlled by reduction of dosage. Mild allergic reactions (such as uticaria and other skin rashes) may occur. Serious allergic reactions have been extremely infrequent; if encountered, appropriate counter- measures (e.g. epinphrine, steroids, etc.) should be administered and the drug withdrawn. Overgrowth of nonsusceptible organisms is rare. If this should occur, withdraw drug and institute appropriate treatment. APPENDIX II [From the New England Journal of Medicine, vol. 277, No. 20, p. 10991 (Correspondence) ADVERTISEMENTS OF ANTIBIOTICS To the Editor: In a recent series of full page color adveitisements carried in many journals sections of fre~h tissue obtained from animals gii en large intramuscular injec tions of lincomycin are shown as producing a small, but clear, zone of inhibition on plates seeded with various bacteria. The statement "for antibiotic tissue pene- tration" is juxtaposed. These advertisements stimulated us to conduct a simple, short-term experiment that can be performed by medical students interested in antimicrobial chemotherapy. We wondered whether other antibiotics might also be shown to "penetrate tissues" by this method and whether it would he important to consider variables such as dose, time of sacrifice, species, test organism and route of administration. We wish to report the first experiment. A series of mice were given 1 mg of penicilin G, tetracycline, erythomycin or hncomycin intraperitoneally and sacrificed at intervals The organs were rinsed of blood, sliced and applied to a plate seeded with a staphylococcus sensitive to all these drugs. The plates were examined after twenty-four hours' incubation at 37° C for zones of inhibition about the pieces of skin, muscle, liver, heart and bone. Large zones were noted with all the drugs except lincomycin, which, as in the advertisements, showed only a small, clear area about the tissue. Thus, we have preliminary evidence that other antibiotics do "penetrate tissue" under the condi- tions of this experiment. The student who conducted this study is now a somewhat more sophisticated PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4043 reader of advertisements. He cannot be satisfied with his own experiment, be- cause many more questions can be raised. He will have to consider whether the drugs penetrate into areas of abscess formation and, of course, examine some of the variables noted above~. In addition, the significance of zones about tissues will have to be critically compared with ability of the drugs to cure experiment- ally infected animals and eventually man. We hope that others may benefit from the message of this simple exercise. CALVIN M. KUNIN, M.D., RIcHARD HUNTER, University of Virginia $choot of Medicine. CHARLOTTESVILLE, VIRGINIA. APPENDIX III [From the New England Journal of Medicine, vol. 278, No. 20, p. 1125] (Correspondence) ADVERTISEMENTS or ANTIBIOTICS To the Editor: Recently in this journal (New England Jo'urnal of Medicine 277:1099, 1967), Kunin and Hunter commented on "Advertisements of Antibiotics." Lincomycin was the subject of the particular advertisement that was discussed, and the pres- entation involved "sections of fresh tissues obtained from animals given large intramuscular injections of lincomycin * * **" The statement "for antibiotic tissue penetration" was juxtaposed. The fact of lincomycin tissue penetration was demonstrated by the inhibition of microbial growth in the vicinity of the tissue sections. Only the fact of penetra- tion was shown-without attempt to quantitate the amount of the antibiotic in the tissue section or to make comparison with the tissue penetrating qualities of other antibiotics. We have made such quantitative comparisons, however, of the bone-penetrating characteristics of erythromycin, tetracyline and lincomycin (Antirnicrobia~t Agents and Chemotherapy-1965, pp. 201-205), and as Kunin and hunter suggest, these antibiotics and lincomycin do penetrate this tissue to the extents reported. The fact of erythromycin and tetra:cyelin~ penetration of tissue is demonstrated well in the long record of clinical effectiveness of these anti- biotics. Lacking such a long clinical experience, a graphic representation of linco- mycin's tissue penetration has been made in the cited advertisement. Even only moderately sophisticated readers of antibiotic inhibition data and photographs of zones of inhibition of microbial growth will recognize that the area of inhibition is dependent on diffusion characteristics of the antibiotic mole- cule, agar concentration of the medium, temperature of Incubation, sensitivity of test organisms and so forth. If more experiments are to be done as Kunin and Hunter indicate and quantita- tion Is desired, these important variables are also recommended for consideration: route of administration (intraperitoneal, as in Kunin and Hunter, or intra- muscular, as in the subject advertisement); and dose (approximately 50 mg per kilogram as in Kunin and Hunter or 25 mg per kilogram as in the subject advertisement) JOSEPH E. Gn~n~, Ph. D., KURT F. STERN, M.S. Department of Microbiology, Upjohn Company. KALAMAZOO, MICH. EFFECTIVE JANUARY 1 1969 NEW ENGLAND JOURNAL OP MEDICINE BOSTON. MASS. 02115 THREE COLUMN PAGE RATES I Time 13 Times 26 Times 52 Times PER INCH $40.00 $38.00 $36.00 $34.00 CLASSIFiED ADVERTISEMENTS PAYABLE IN ADVANCE $5.00 per line 6 words per line MINIMUM -3 lines CONFIDENTIAL REPLY BOX NUMBERS -$1.00 per week DEADLINE - Three weeks prior td publication dote. We mointoin a 16.day notice to cancel. PAGENO="0140" 4044 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Pige One AIJGUST 1968 F.aster,e Weatern NEW ENGLAND JOURNAL OF MEDICINE itepresentative: Representative: Publisher: THE NEW ENGLAND JOURNAL OF MEDSCINE A. DOUGLASS BREWER JOHN H. HAULING 10 Shattuck St 1160 Third Ave. 104.S. Michigan AGe. Boston, Mass. 02115 .Nese York Cit~' Suite 314 . Tel. 6177349800 Tel. 212-249.9330 Chicago, Illinois 606113 GENERAL INFORMATION 1. ISSUANCE: a. Fs'eqssesicy.' Weekly b. issue dale,' Thursday c. Zvlaelisag daie, mail class, mailing cover.' Mondsy, second class mailing, wrapper 2. ESTABLISHED: January, 1812 3. ORGANIZATION AFFILIATION: Massachuselis Medical Society 4. SUBSCRIPTION DATA: a. Subscription Rates,' $10.00 per year, postage 1,aid, for the Un:ted Stales (residenti, interns and medical studenls, $5.00 per year). Long-teem rates: 2 years $18.01), 3.yenrs $25.00. All foreign eates, United Slates funds: Canada, $11.00 per year; other foresgn, $12.50 per year. Long-term rates: Canada, 2 years 320.00, 3 years $28.00; other foreign, 2 years $23.00, 3 years $32.50. I,, Assne:al Percentage of Subscription Resteuc'als.' 80% c. Nuntber of lsseaes Sent after Ssabscuiption Expiration: 4-6 S SPECIAL ISSUES No 6 EDITORIAL Edt 1C I tOg I pt bt I bSp lEdt lEt C R d fM h tlsG IN ptlkm Md 131h1 11-I ptl B I Phy Igyt Phy 7 RFQUIREMENTS FOR ACCEPTANCE OF NEW PROFESSIONAL PRODUCTS FOR ADVERTISING 8.~ REQUIREMENTS FOR AD CLEARANCE: Copy for advertisements is accepted by the Advertising Committee of the 1 th b of the app t q I ty d ef 1 ss of th p d ct d the m f t p t t P op names of pharmaceutical producis must be accompanied by the chemical, or generic or offidiol names, and tlae quantity of all I b I c t d the m ded d se sh Id b stated Copy ho Id be f ct I c I e d good taste. Documentation for new products should be sent to tlte Ads'erti.sing Manager. Allow two weeks for clearance. 9 ADVERTISING ACCEPTANCE OF NONPROFESSIONAL PRODUCTS OR SERVICES Copy ho id be bm tEed t Ad Is gM g 10 POLICY ON PLACEMENT OF ADVERTISING F 11 p g o l)e f o t f m whe ye hI f 11 d f t I p g rear form. . . S 11 ADVERTISER S INDEX If p p m 12 EDITORIAL ADVERTISING RATIO (1 t t ma th a e age) 20 / Ad t s ng 50 / Ed t I 13. SERVICE TO ADVERTISERS: a. Availability of Mailing List: Information on request. b A I b 1 ly of Edt I R p t Ad 1 s m t get th p m I bI she p 8 rs to ply p to Ad t M g sholdb c tcted gardagrepr Is q ttyof rep nb Imted 14. STAFF: Ed I D F J I g 111 g 10 Sh It k St Bo t M 02115 734 9800 A Cod 617 Advertioaasg Manager: Mslton C. Paige, Jr., 10 Shattuck SI,, Boston, Mass, 02115, 734-9800, Area Code 1317 PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4045 CIRCULATION 15. CIRCULATION Jan-June 1967 Jan-June 1968 Paid 99,596 Paid 107,912 Comp. 370 Camp. 320 16. G0ARAN'rEED CIRCULATION: 100,000 17. CIRCULATION VERIFICATION: Post Office Receipts 18. RATES PER THOUSAND (Based on latest six-month average circulation): a. Full page, black-and-white, one-time: $8.33 h. Full page, black-and-white, based on number of issues per year: $6.94 19. COVERAGE AND MARKET: a. Coverage. Journal circulates nationally and internationally. b. Market Served: Physicians in all specialties and general practice subscribe to the Journal independently in addition to the 8,300 members of the Massachusetts Medical Society. Also subscribing are approximately 13,000 medical students who receive the Journal at the special rate of $5.00. The Journal is in its onrhundred and fifty-seventh year of publi- cation, and is the oldest medical journal in the world today. c. Breakdown of Circulation by Classz,lcaoiost of Reader: See "Classification Chart." 20. TERRITORIAL DISTRIBUTION: June 27, 1968 New England States East North Central States West South Central States Connrcnicuc 2,053 Illinois 4,537 Arkansas 386 Maine 403 Indiana 1,121 Loassiana 861 Massachusetts 10,809 Michigan 3,321 Oklahoma 652 Ne-u HanTlpshire 446 Ohio 3,950 Texas 3,368 Rhode Island 493 Wisconsin 1,544 Vermont 400 5,267 -~ 14,473 14,604 Mountain States Arizona 520 Colorado 1,075 Idaho 146 Montana 166 Middle Atlantic States East South Central Stales Nevada 105 New Jersey 2,947 Alabama 767 New Mexico 382 New York 13,181 Kentucky 937 Utah 373 Pennsylvania 5,738 Mississippi 372 Wyoming 64 Tennessee 1,248 - 21,866 2,831 3,324 Pacific States California 9,794 Oregon 931. South Atlantic States Washington 1,355 Delaware 159 Alaska 91 Piorida 2,138 West North Central States Hawaii 253 Georgia 1,386 Iowa 680 Maryland 3,389' Kansas 729 12,424 North Carolina 1,636 Minnesota 1,777 u.s. Territorien 2,057 Virginia 2,083 Nebraska 546 p - 8348 Washington, D.C. 1,220 North Dakota 151 g West Virginia 525 South Dakota, 1-43, 16,129- 13,031 -6,203 Grand Total 1JO,152 PAGENO="0142" 4046 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY RATES 21. ISSUANCE: a. Frequency: Weekly b. Issue date: Thursday Mailing date, mail clacs, mailing cover: Monday, second class mailing, wrapper 22. CLOSING DATE FOR SPACE: ~ RCea:e7l~zl:Onns~s: 17 days prior dale of issue; copy and set-up, 23 days prior. 23. AGENCY COMMISSION: 15% 24. CASH DISCOUNT: 2% fifteen days 25. RATES: Effective Jan. 1, 1966 1 6 53 26 52 78 104 . 130 156 One page (pee insertion) $900 $860 $825 $790 $730 $725 $701 $688 $666 Half page (per insertion) 475 460 440 420 400 Quarter page (per insertion) 250 240 230 220 210 Eighth page (pee insertion) 150 141 133, 126 118 26 EARNED RATES: Rates are based on total amount of space used within a 12-month period. Minimum rate on unit size will apply when several sizes are used. 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DISPOSITION OF PLATES: Plates not called for within one year will be destroyed without notification. 42. ADDRESSES: ~: ~ ~~orders and other instructions, publication set copy.' 10 Shattuck St., Boston, Mass. 02115 c. For complete plates and patch electros: NEW ENGLAND JOURNAL OF MEDICINE, c/n POOLE PRINTING CO., 85 W. Harrison St., Chicago, Ill. 60605: d. Fos inserts:~ NEW ENGLAND JOURNAL OF MEDICINE, c/o POOLE PRINTING CO., 1909 N. Magnolia, Chicago, Ill. 60614. Propared i,i accarda,zce ,shsh ,~eco~~is~ e:sdatioo of the Media Co,s,,,,s/ee, The Pharnsaceosicat Adrertisi,:,ç' Club, isis. (Whereupon, at 12:40 p.m., the committee adjourned to reconvene tomorrow, Thursday, December 1~, 1968, at 10 a.m.) PAGENO="0144" PAGENO="0145" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, DECEMBER 19, 1968 U.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 10:10 a.m., in room 318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; and Elaine C. Dye, research assistant. Senator NELSON. The hearings of the Monopoly Subcommittee will open. We have two very distinguished physicians here this morning, Dr. George Baehr and Dr. James Faulkner. Before we commence, I would like to say that we know that we have, in addition to these two distinguished physicians, a distinguished visi- tor in the audience today, Dr. Frances Kelsey of the Food and Drug Administration. The American public will be forever grateful to her for her untiring efforts and devotion to duty which prevented a thalid- omide disaster from occurring in this country. Dr. Kelsey, despite great pressure from the drug firm, Richardson- Merrell, refused to approve the drug because she was not satisfied with the research work submitted in the New Drug Application. It is heart- ening to know we have such public servants like Dr. Kelsey, who are dedicated to protecting the public. We are pleased to have you here as.a visitor this morning, Dr. Kelsey. Our first witness is Dr. Faulkner, of Boston. Dr. Faulkner has a long and distinguished record as a practicing physician and as a professor. Doctor, your full statement, including youi biographical summary, will be printed in the record. You may proceed however you desire. If you think it is more economical to read your prepared text, you may proceed that way, and if at any time you viish to elaborate on anything that you have reduced to writing, please feel free to do so. I trust that if some questions occur to us, you won't mind being interrupted. The committee is very appreciative of your appearing today to make your contribution to these rather extensive hearings which we have been conducting for nearly 2 years now We have had the privilege of having ~ number of distinguished members of the medical profession testify before the committee, and we certainly welcome your testimony this morning. Go ahead, Doctor. 4049 81-280-69-pt. 10-i0 PAGENO="0146" 4050 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT OP DR. JAMES M. FAULKNER, CHAIRMAN, c!OMMITTEE ON PUBLICATIONS, MASSACHUSETTS MEDICAL SOCIETY, BOSTON, MASS. Dr. FAULKNER. Thank you, Senator Nelson. With your permission, I will read my biography and then proceed with my statement. Senator NELSON. Fine. Dr. FAULKNER. I want to make it clear that I am speaking here completely as an individual, not representing any particular institu- tion or organization. Mr. Chairman, my name is James Faulkner, from Boston I am a retired physician and medical educator. I graduated from ~iarvard Medical School in 1924, was intern in medicine at the Massachusetts General Hospital and assistant resident in medicine at the Rockefeller Institute and the Johns Hopkins Hospital. Up to World War II I was in private practice in internal medicine and cardiology, and did part-time clinical research and teaching for Harvard. I served in the Medical Corps of the USNR for 4 years and was discharged as a captain. After the war I went to Tufts Medical School as professor and chairman of the department of medicine. From 194~7 to 1955 I was dean of Boston University School of Medicine. From 1955 to 1960 I was medical director of Massachusetts Institute of Technology. I was a member of the Council on Medical Education of the AMA from 1949 to 1960, of the National Board of Medical Examiners from 1956 to 1968, of the National Fund for Medical Education since 1959 and president from 1964 to 1966. I was a member of the board of overseers of Harvard College from 1958 to 1964. I have contributed about 80 ar- ticles to the medical literature. Since 1960 I have been chairman of the committee on publications of the Massachusetts Medical Society which is responsible for the publication of the New England Journal of Medicine. In November, Dr. Philip R. Lee, Assistant Secretary for Health and Scientific Affairs of the Department of Health, Education, and Wel- fare sent a letter to physicians throughout the country calling their at- tention to the Second Interim Report of the Secretary's Task Force on Prescription Drugs and inviting their comments on it. In his letter, Dr. Lee called particular attention to certain recommendations of the task force, namely: that Federal support be given to improving the teaching of clinical pharmacology or drug therapy at both `the under- graduate and postgraduate level; that a journal of prescribing com- pletely independent of the drug industry for support be established to provide practicing physicians with "objective evaluations of new drugs and reevaluation of old ones;" and, finally, that the Depart- ment of HEW be authorized to distribute to all physicians without charge a regularly updated compendium of all prescription drugs in- cluding an indication of relative costs. With these recommendations I heartily agree. Senator NELsoN. May I interrupt a moment, Doctor? Dr. FAULKNER. Yes, sir. Senator NELSON. Dr. Lee recommended Federal support for the teach- ing of clinical pharmacology-is this because it is necessary if the PAGENO="0147" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4051 subject matter is to be adequately taught in the medical schools? I don't know the present status of the teaching of pharmacology in the medical schools and whether or not it is sufficiently emphasized. I know that you and/or Dr. Baehr- Dr. FAULKNER. I am going to develop that a little further on. Clini- cal pharmacology, or therapeutics, as a discipline used to be taught in the medical schools, usually by part-time practitioners of medicine. Of course most of the faculty were part time 20 years ago2 but there were members of the faculty who took a special interest in medical therapeutics as opposed to basic pharmacology, physiological action of drugs. As the full-time system took over, more and more of the positions in the medical school, the basic pharmacologists more or less pre- empted the field, and the part-time teachers of clinical medicine be- came fewer and fewer. So that the emphasis became much more on physiological aspects of pharmacology, basic pharmacology, and less emphasis on bedside therapy, ambulatory therapy, as well and the actual practical application of the use of drugs. This, I think, has become somewhat neglected in recent years. Senator NELSON. Isn't that because those who decide policy for medi- cal education in the school haven't considered it of preeminent im- portance? Or is it because they don't have sufficient money? What would Federal aid accomplish? If they don't teach it now as one of the fundamental subjects, what would cause them to teach it if there were some Federal assistance to do so? Dr. FAULKNER. In recent years Federal aid has been very largely for research and not for instruction, and this has increased the inter- est in basic aspects of pharmacology and research in that field, with- out concomitant improvement in the actual practical application of the use of drugs. The physician who is going to follow me, Dr. Baehr, is a magnifi- cent example of the physician in practice who has been particularly interested in the actual application of the use of drugs, but he is be- coming a very rare type on the faculties of our medical schools. Senator NELSON. Is it becoming generaly recognized in the medical profession that the teaching of clinical pharmacology has been neglected? ~Dr. FAULKNER. I can't say that it is recognized very generally as yet. The medical schools are in the midst of tremendous changes in curriculum now, and what will issue from it within the next few years is very difficult to say, but I don't think this has been recognized generally. Senator NELSON. I believe that it was the Task Force's position that it hadn't been given adequate emphasis. That is why Dr. Lee and the Task Force recommended it, and I assume why you endorsed the recom- mendation. Is it your feeling that if there were some Federal assistance for the teaching aspects, as contrasted with research, that in fact the medical schools would more quickly, more rapidly begin to teach clinical pharmacology? Dr. FAULKNER. I would hope that would be the case. I wouldn't be able to say. Senator NELSON. Is it that the profession, or those who manage the curricula, just don't think it is that important? Is that the problem? PAGENO="0148" 4052 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. FAULKNER. .1 think it could be much more effectively done if the teaching were concentrated at the postgraduate level I here, I think, is no question but what it would be accepted, and you would find graduate physicians who would be impressed with the actual problems that they were up against in practice, and it would he much easier to develop this kind of teaching which must be constantly changing with new discoveries so that in every year there would be fresh subjects to teach, it would be more effectively taught at that level than at the under- graduate level. Senator NELSON. When you say postgraduate, are you referring to the practicing physician or to the intern? Dr. FAULKNER. I am-well, both, but particularly the practicing physician. It must be taught athoth levels. Senator NELSON. And you would expect that if such a course were available that practicing physicians would or could take the time to take courses in clinical pharmacology? Dr. FAULKNER. Yes, I think they could be made attractive enough so that they would be interested. I think practicing physicians, when they are given the opportunity of choosing whast they want to hear at county medical society meetings and that sort of thing are very apt to choose what is the latest treatment for this or that and are par- ticularly interested in therapy. Senator NELSON. But if you were talking about the suggestion of Dr. Lee that support be given to improving the teaching of cliiflcal pharmacology, that would mean more than occasional lectures, would it not? Are you talking about a course at a teaching hospital or medical school? Dr. FAULKNER. Yes. I would strengthen the teaching of clinical pharmacology, not necessarily by formal courses, as encouraging people skilled in clinical pharmacology to participate in the clinical teaching in the hospital, in the ward rounds and in the seminars that are constantly going on, in the teaching hospitals. Senator NELSON. Then you endorse the recommendation of the Task Force that a journal of prescribing, completely independent of *the drug industry for support, be established to provide practicing physicians with objective evaluations of new drugs and reevaluations of old ones? I assume you are referring to what might be called a compendium of all the drugs, Is that what you are referring to? Dr. FAULKNER. Well, I think the compendium would be something different. It might be something that is issued annually to bring it up to date. But the journal would contain articles of current interest of new drugs recently that have become available to keep the practicing physicians abreast of the times without depending entirely on the detail man and `the throwaway journals. Senator NELSON I see So you are `thinking of a periodical Dr. FAULKNER. Yes. Senator NELSON. Didn't the American Medical Association once have a periodical on new drugs? Dr. FAULKNER. Yes, they did, and it was useful. Senator NELSON. Have they started another? Dr. FAULKNER. I believe they are starting one now. I haven't seen it. But I believe they are starting one. PAGENO="0149" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4053 Senator NELSON. So what you are recommending is a `journal which would he available to all physicians and which would devote itself exclusively to drugs and their use. Dr. FAULKNER. Yes. sir. Senator NELSON. What part of that function does the Medical Letter now perform? Dr. FAULKNER. The Medical Letter I don't think has a wide enough circulation, for one thing. Senator NELSON. That is the issue `that has been raised a number of times, something like 15,000 circulation. Dr. FAULKNER. Yes. Senator NELSON. Then are you referring to a journal that would go free to all physicians? This one, the Medical Letter, is subscribed to and widely praised by the medical profession, `at least in the testimony before this committee over the past years. Two questions occur to me. Is there any reason to believe that a journal such as you refer to would be `more widely subscribed to and, two, does the Medical Letter seek to accomplish the same purpose that you recommend a journal for? Dr. FAULKNER. I think t'he Medical Letter substantially seeks the same purpose, but perhaps a journal designed to go to the practitioners of medicine across the country could be livened up and made more appealing to the perhaps casual reader. I think it would have to be subsidized in large part. It probably would be better to charge some- thing for it, hut I doubt if it could be, it would be, popular enough to be subscribed to by the majority of physicians. The problem is that it is the ones who need it most who would not subscribe to it. Maybe it would be worthwhile to subsidize it corn- :P~t~y, just as the so-called giveaway journals are subsidized by the pharmaceutical industry. Senator' NELSON. Do I understand that the reason for' the recom- mendation by the Task Force, and' your endorsement of it, is the belief on your part that the objective information, available to physicians on the use of drugs tothy, is inadequ~te ~ Dr. FAULKNER. Yes, it is not readily enough available to them. If it came on their desks periodically, I' think it would be availed of mu,ch more than it is now. " ` Senator NELSON. And then in the last sentence of the recommenda- tion of the Task' Force, with which you agree, was the regularly up- dated compendium on all prescription drugs. Could you suggest to the committee w'hat that compendium should' i'nclude, how it might be designed? ` ` ` The Food and Drug Administration appeared before the committee recommending a compendium that would include all drugs. Some people have raised the question, as `a matter of fact the Pharmaceutical Manufacturers Association, I believe, that that would be an unwieldy, mas~ive document. The FDA doesn't think it would. What would you recommend about a compendium? Dr. FAULKNER. I am not familiar `enough with the field to answerS that question, Senator. I don"t know how large such a compendium might be. It might have to be cut down to reasonable size to make it acceptable. Senator NELSON. You may proceed, Doctor. PAGENO="0150" 4054 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. FAULKNER. With these recommendations I heartily agree. It is my opinion that medical education has failed to grasp the significance of the vast proliferation of new drugs which has taken place over the lust couple of decades. When the number of effective drugs on the market was small, it was possible for a physician with a good grounding in basic pharmacology to make a reasonably intelli- gent choice from the drugs available in writing a prescription. Now the practicing physician finds himself obliged to choose between a bewildering array of drugs for which competing claims are made and more often than not he finds himself not only ill prepared to make correct judgments but at a loss to know where to turn for unbiased information. A factor which has to be taken into account in any discussion of the teaching of medical therapeutics in recent years is the increased ratio of full-time teachers in the faculties of the medical `schools. Relatively few are engaged in private practice except as consultants. Their skill with drug therapy is apt to be highly specialized. Perhaps the time has come to revive comprehensive medical therapeutics as a respectable part of the clinical curriculum. At the undergraduate level this might be more effectively taught by a physician whose practice was not limited `to a narrow specialty. Another factor which has entered the picture is the hi'gh cost of some of the new drug preparations. Themedical student and the practitioner shoul'd have readily available to them an `authoritative reference book describing `all the prescription drugs and their relative costs. The compendium recommended by the task force would fill this important unmet need. It is indeed deplorable that so much of what the medical student and the practitioner learn about drug therapy come's to them from pharma- ceutical firms who are actively promoting their own produ'cts. The hlam,e for this situation, it seems to me, must rest in large part on the failure of medical educators to int~re'st `themselves in therapeutics as such. Certainly the average medical graduate finds himself ill equipped to make informed judgments regarding the relative merits of the countless prepara'tions available to him. Mr. GORDON. Dr. Faulkner, may I interrupt at `this point? As it: is now, "very few' studies are made of the relative merits of drugs. Very few drug manufacturers, as 1 understand it, are willing to `sponsor such studies. The FDA requires a showing only of efficacy and safety, not of relative efficacy and relative safety. How do you propose we finance such studies? Dr. FAULKNER. I would think this is a field for research that may be financed by any funds available for valid clinical research, com- paring one drug with another, and this might `be financed by foun- dations, `by NIH, or by any other neutral source of funds. It is quite understandable that under `the circumstances .the drug houses would rush to fill the void in medical education by bombard- ing ~`the physician with direct mail advertising, throw-away maga- zines, samples and detail men, not to mention supporting most of the professional medical journals. If the drug houses have more or less preempted the area of medical education dealing with drug therapy, the appropriate approach to PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4055 the problem is for the medical educators to meet them on their own ground. If physicians have been unduly influenced by the claims of the drug houses it is not because they are particularly gullible. Physi- cians are trained to be critical of evidence and if they are given all of the evidence can be expected to make reasonably sound judgments. They are getting one side of the case superbly presented by the drug houses now. Thanks to the Food and Drug Administration the claims of the drug companies can now be accepted as true. However, it is not the whole truth and the practitioner must be given reliable infor- mation which will allow him to make comparative judgments of potency and price of the drugs available to him. This is a matter of continuing education for every physician in the country-a job which will require the resources of the Federal Government and the dis- interestedness of the Department of Health, Education, and Welfare. Senator NELSON. May I interrupt, sir. You say: "thanks to the Food and Drug Administration the claims of the drug companies can now be accepted as true," but not the whole truth. I assume one of the things you are getting at is that there are in the marketplace a large number of compounds all of which have about the same effect, and are used for the same purpose. The Food and Drug Administra- tion has the authority, and attempts conscientiously to exercise it, to prohibit the specific misrepresentation of the use of the drug. So whereas a company may state truthfully what a drug does, at the same time there is no presentation to the physician that there may be a half dozen other drugs produced by a half dozen other companies that have the same effect, some of which have not only the same quality but same effect, and some of which may be much cheaper; is that what you are talking about? Dr. FAULKNER. Yes, exactly. Mr. Chairman, in your letter inviting me to appear before your committee you listed a number of specific ethical questions which the Monopoly Subcommittee would like to explore. With your per- mission, I shall present these questions and my own individual re- action to them, particularly as they involve ethical implications, possible conflicts of interest and professional responsibility in the following situations: 1. When doctors lend their names for articles and letters written by members of the pharmaceutical industry. I regard it as dishonest for anyone to lend his name as an author to an article or letter not written by himself. 2. When dOctors own stock in drug companies whose products they are evaluating. A doctor who evaluates the drug of a company in which he owns stock cannot avoid the suspicion of bias even if the financial relation- ship is made known. If he does not reveal his stock ownership he is not being honest. 3. Whether ownership of stock in a drug company can influence a decision to prescribe in the first place, and what to prescribe in the second place. I think it would almost never influence a decision to prescribe but might influence the choice of a drug and, therefore, I regard it as an undesirable practice. PAGENO="0152" 4056 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4. When doctors are paid directly by a drug firm to evaluate its products. I think my good friend, Dr. William Bean, puts it too strongly when he writes, "The physician who is in the pay of pharmaceutical manufacturers is in no position to keep public confidence in his objec- tivity." A physician's reputation with his peers is based on the quality and integrity `of his work rather than on the source of his income. Much sound clinical research has been done by physicians in the pay of pharmaceutical houses. However, when such work is published it is desirable to include a footnote to the effect that the work has been supported in whole or in part by a drug firm. This is an honest disclosure which can alert the reader to any possible bias. I thmk I can add here that this is perhaps not as simple as it sounds. So many articles have multiple authors, sometimes four or five; each of whom have a different source of support, and this becomes a little complex. 5. When influential doctors or pharmacy educators, particularly in high academic positions, are large stockholders and serve as policy- setting members of boards of `drug corporations. Since these men are in the position `to mold the attitudes of other doctors and to make policy decisions in key medical and pharmaceu- tical organization's, might there not be a conflict of interest here? What are the implications when `doctors and pharmacy educators do not make known their industry affiliations? I can speak here only from the point of view of a medical educator to whom the principles of medical ethics apply. I cannot speak for the pharmacy educators. I share the view of many but not `all members of the medical profession in feeling that it `is unethical for a physi- cian to take out a patent on a new drug for his own benefit. A logical extension of this principle makes it unethical for a physician who is prescribing drugs to profit from the sale of drugs patented by others. It is, therefore, in my view particularly undesirable for a medical educator who should exemplify the highest standards of medical ethics to be getting a significant portion of his income from the profits of drug companies It is positively reprehensible if such a financial dependency on the drug industry is not made known. 6. When promi'nent professors receive regular retain'er fees from the drug industry for consultation while simultaneously advising Gov- ernment or private agencies `on matters of policy which c'an severely affect drug firms' products. I believe that collaboration `between drug houses and medical pro- fessors has not infrequently resulted in important `advances in medi- cine. I would not condemn, `out of hand, the practice `of drug houses paying retainer fees to medical professors if the relationship is made public including the nature and `amount of services rendered. A medical professor is on safer ethical gi ound if his financial reli tion ship to the `drug house is in the form of recompense for specific services rendered `in the form of consultation or research. 7 When medical organizitions and pubhcations-nationil, local, and student-are largely dependent on income from industry advertising. . No organization which purports to represent the medical profession should allow itself to get into the position o'f being largely dependent PAGENO="0153" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4057 on income from drug advertising. It is difficult for an organization in this position not to allow its policy to be influenced by considerations which may not be in the long-term interest of the pulblic and the medi- cal profession. The medical publications of this country show a complete spectrum of dependency on drug advertising, ranging all the way from the throwaway journals some of which include well-edited text of high quality, to strictly scientific journals containing no advertising whatsoever. There has also been `a wi'de discrepancy in the quality of the advertis- ing in the different journals. The best journals screened their advertis- ing for accuracy long before the Food and Drug Administration began to enforce their stand'ards !on all, and one could make a judg- ment as to the quality of `a journal by the reliability of its advertising claims. Now, the better journals `which do accept advertising tend to limit it in amount, to restrict it to the front and back sections, never interleaving it with the body of the text and to adhere to certain standards of good taste. It is undoubtedly true that just as there is `a complete spectrum of dependency on drug advertising among the medical journals, there is also a spectrum of reliability on their textu'tl matter There is a gen eral cQrrelation between. the two, but not an exact one. Senator NELSON. May I ask a question here? On page 6, at the beginning of your statement on advertising, you state that no organization which purports to represent the medical profession should allow itself to get into a position of `being largely dependent on income from drug advertising. I don't have the figures but I believe that some years back it was disclosed that the Journal of the American Medical Association received some 50 percent of its income from advertising Do you include them-is your statement heie critical' of that amount? Would you term that `being largely dependent on the income from drug advertising? Dr. FAULKNER. Your statement is that t'he American Medical Asso- ciation itself got 50 percent of its income? Senator NELSON. I believe the JAMA. Mr. Gordon says that it is the American Medical Association which derives about 50 percent `of its income from drug advertising. Dr. FAULKNER. This gives me great ,concern. Senator NELSON Mr Gm don thinks it is about 50 percent, in any event We will want to recheck to be positive about it and correct the record if that is not correct, but he states that that is his information, that it is about 50 percent of the support of the whole AMA itself, not just the pithlication of the JAMA. Dr. FAULKNER. In my opinion, this is a highly undesirable situation. Senator NELSON. What about the journals which are sometimes called throwaways, those which `are totally dependent upon advertising-in other words, there is no subscription price paid. `They go to all mem- bers of the profession. T'hey depend solely upon advertising. I believe it w'is Dr O'Brien, who said in evaluating this situation, that the entire contents of the throwaways ought to be consi'dered advertising. The significance of that, of course, is that if it is considered advertising it would be subject to the control of the FDA. PAGENO="0154" 4058 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Do you have any opinion about those which are totally dependent upon advertising? Dr. FAULKNER. I would agree that the entire content of such jour- nals should be subject to the same regulations that apply to the overt advertising matter in these journals. Senator NELSON. In other words, all the written material, whether it is in the nature of an ad or an article, should `be considered advertis- ing, is that what you are saying? Dr. FAULKNER. From the point of view of making claims for drugs, yes. Senator NELSON. Go ahead, Doctor. Dr. FAULKNER. Rather than to attempt to impose restrictions on the amount of advertising, I would favor taking positive steps to provide the practitioner with up-to-date information about drugs which would act as a counterpoise to the limited and strongly biased literature put out by the `drug companies. I believe the doctor should be given the opportunity to form his own judgments about drugs on the basis of all the evidence. On the other hand, I don't think advertising should be permitted to hide behind a cloak of pretended objective presentation. A most nefarious practice utilized `by some of the purely advertising journals is to plant articles `whjch purport to be scientific evaluations of new drugs and which `are, in fact, promotion. `Claims made in such articles are not subject to the control which the Food and Drug Ad- ministration has over straightforward `advertising matter. I hope action can be taken to bring such surreptitious advertising under control. 8. The implications for the medical profession `and the public when the so-called independent giveaway sheets and journals, which are e'tsy to read and subsist entirely on drug advertising, are becoming a factor of some importance in the physicians' education. I reg'ird it `ts deplorable that practitioners of nieithcine receive~ so much of their information regarding' new drugs' from the giveaway journals. The drug companies have simply moved into a vacuum here and the busy doctor seldom has available an alternate source of infor- mation. Every effort must be made to get good reliable up-to-date information on all new drugs to the doctors in their offices. it may not be~ as eye appealing as some of the drug handouts, but I think it will be well received. 9. When many physicians accept fellowships, salaries, and research support directly from the drug industry I do not see anything inherently `improper in such arrangements as long as they are carried out openly. A good deal of excellent research h'~s been carried out in medical schools with drug industry support Ideally, research supported entirely or in part `by `drug company funds should have an `acknowledgment to that effect attached to the published articles resulting from the research. 10. When many physicians base their prescribing practices, to a large extent, on information supplied them by industry salesmen, detail mcii and other commercial sources. Senator NELSON. Doctor, may I interrupt for a moment? From 1941 to 1955, from your biographical sketch, you were `dean of the Boston University School of' Medicine and from 1955 to 1960 medical director of the Massachusetts Institute of Technology, then PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4059 one of the directors of the National Fund for Medical Education since 1959. We had testimony yesterday from Dr. Lowinger of Wayne State University Medical School in which he discussed the same subject matter and responded to the same question. We raised the issue of what cost, what percentage of the cost of research did the pharmaceutical companies pay in the research that he did, and he responded that they did not pay the cost of his salary, did not pay the so-called overhead cost -for use of the facility. They did pay some other costs, includm the technicians, and so forth. I am contrasting this with the researc costs assumed by NIH for research done for them in graduate schools, or the National Science Foundation for research done by them for the military, in which they cover costs of the time invested by the re- searcher, overhead cost of the facility, and so forth. In .any event, the situation that Dr. Lowinger presented is one in which it appeared that the school itself was, in fact, not receiving full cost of the research they did, which ended up in a situation in which the university was in fact subsidizing the cost of the research. The company was getting the research without paying the full cost. It that a typical circumstance? Do I state the question clearly enough? Dr. FAULKNER. Yes. I haven't had enough recent experience in this problem as it affects a medical school. My previous experience has been a good deal the same as the doctor from Wayne State. The support has been partial. It was paying a salary for a technician and not often in the form of comprehensive grants that covered all ~xnenses. However, often it was work that would have needed to be done. It wasn't particularly-it might have interested the pharmaceutical com- pany but was not initiated by them. In general, I have not::been impressedwith the largesse of the phar- maceutical companies in supporting research in the medical schools. Senator NELSON. From observations I made at our university when I was Governor, it seems that all the larger universities were very pleased to have the opportunity of a research contract with NIH or the National Science Foundation or HEW. One, of course, because they would be interested in the subject matter and it would help induce scholarships at the universitie~, and, two, because the total cost was paid by the contracting agency, including the overhead costs of the institution. - What is the explanation, in your judgment, of this relationship that Dr. Lowinger referred to from his relatively recent experience, I think through 1966, or thereabouts, and your own. What is the explanation of this relationship, how did it develop this way instead of the way the National Science Foundation, NIH, and so forth, may deal with the universities? Dr. .FA~KNER: Well, my impression is that the drug companies have been interested in really supporting studies which had a practical bearing on their own problems, and were less interested in giving broad support to basic research, although I think there is a great deal of van ation. I know of one drug company which supported the complete salary of a man who was in a local hospital in Boston, attached to one of the medical schools over quite a period of years, absolutely no restrictions whatsoever on what he did. PAGENO="0156" 4060 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Just any kind of research he desired in the phar- maceutical or drug field? Dr. FAULKNER. Yes. He was a biochemist. Senator NELSON. Did he have any relationship in reporting results directly to the company? Dr. FAULKNER. He sent copies of his reprints to the company. Senator NELSON. His research was public information? Dr. FAULKNER. Yes. Senator NELSON. Go ahead, Doctor. Dr. FAULKNER. The problem posed by the growing dependence of the medical practitioner on the itinerant drug salesman for inform't tion on the new drugs is to offer more complete and more reliable in- formation to all practicing physicians. This could be accomplished by distribution of a Journal of Prescribing and the periodic issuance of a compendium of drugs as recommended by the task force. 11. When many physicians prescribe dangerous drugs for nonindi- cated purposes. For example, during the past year a highly dangerous drug was prescribed by doctors for 3.5 to 4 million people. Yet, testimony from eminent medical authorities who appeared before the subcommittee indicated that no more than 10,000 people in the United States should have received it. What explanation can be found for this? It is a sad. reflection on the medical profession that this drug, pre- sumably chloramphenicol, continues to be prescribed for a wide variety of minor infections in spite of the widely advertised risk of serious blood dyscrasias resulting from its administration It apparently achieved great popularity before its dangers were appreciated a.nd practitioners who have not had direct experience with its toxic effects have not been sufficiently impressed by the statistics, which. came out later, certainly there `has been no dearth of literature on the subject. Perhaps the time has come for hospital staffs to put this drug on a restricted list to be prescribed oniy after consultation with an intern ist and a justification for its use written into the hospital records 12 When doctors, actijig as purchasing agents for the consumer, prescribe drugs without adequate knowledge of the cost of these drugs relative to other drugs which have the same action I am afraid that medical educators have generally ignored this sub ject as too mundane for their consideration. Certainly medical students should be made aware that there are discrepancies in prices that need to be taken into account and it would be highly desirable for every physician to have: at his elbow, a compendium of all available drugs with their prices Mr Chairman, your committee has accumulated plenty of evidence that the present. system of evaluating the effectiveness of new drugs is unsatisfactory Claims are made based on subjective evidence, on un controlled experiments, and often by biased investigators. The Food and Drug Administration with its limited staff has difficulty in mak ing prompt judgments in some instances where there may be a wealth of published material but a dearth of well controlled data. Perhaps confusion could be avoided if the `clinical testing of all new drugs were made the responsibility of a top level group of experts representing both the Government and the pharmaceutical industry. The group PAGENO="0157" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4061 would establish procedure for testing, select panels of qualified indi- viduals to evaluate new drugs on a completely objective basis and make appropriate recommendatioIis. The operation would be funded by the pharmaceutical industry on a cost basis. Such an arrangement would go far toward insuring an accurate appraisal of new drugs in the beginning and make unnecessary much of the reappraisal of drugs which has proved both costly and con- fusing. Senator NELsoN. Thank you very much, Dr. Faulkner for your most thoughtful statement. I wonder if Dr. Baehr would like to come to the witness table at this time. Dr. Faulkner, if you would not mind staying where you are, perhaps you both may wish to comment on some of the questions that are raised. Dr. Baehr? STATEMENT O~ DR. GEORGE BA~KR, ~HAiRMAN, PUBLIC HEALTH COUNCIL OP THE STATE OF NEW YORK, AND DISTINGUISHED SERVICE PROFESSOR, MOUNT SINAI SCHOOL OP MEDICINE, CITY UNIVERSITY OP NEW YORK Dr BAEHR Senator, I shall skip the biographical data with which you are fam~liar,~ because it is included in the~ statement that I sub- mitted.' Senator NELSON. Doctor, I think we will just take a 3- or 4-minute break to allow the reporter a little time, if you don't mind (Brief recess) Senator NELSON Our next witness is Dr George Baehr, chairman of the Public Health Council of the State of New York, a member of the Board of Hospitals of the City of New York, and distinguished service professor at the Mount Sinai School of Medicine of the City University of New York. Dr. Baehr, the committee appreciates very much your taking the time to come here today. Your statement as well as the biographical sketch will be printed in toto in the record, and you may proceed to present your statement as you desire. If you wish to extemporize from it, elaborate on it at any stage, feel free to do so. Dr BAEHR I should like to read the statement and then from time to time with your permission introduce some exhibits to support some of the statements that I may make Senator NELSON. Fine. Dr. BAEHR. I shall begin by saying that during many years of prac- tice, I have served as consultant to many local physicians and have been bewildered by the enormous number and variety of brand-named drugs which they prescribe It is what has been derisively called poly pharmacy and today this practice has become almost the rule For example, a few days ago I was consulted by a patient who took out of her bag eight different medicines that she was taking, not one of which was indicated 1 See statement beginning at p. 4070, infra. PAGENO="0158" 4062 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Not one of which was indicated? Dr. BAEHR. Yes. She had had the Hong Kong flu, mild type, and her doctor had started to treast each symptom with a different medicine, including a drug which is totally ineffective in controlling a viral infection; namely, tetracycline, an antibiotic which has no effect upon virus infections. The result was that the disease from which she ~ as suffering at the time she consulted me was caused by the medication she had been tak- ing. She had what is called aphthous stomatitis, ulcerative lesion in the mouth, and lesions in the colon giving her distressing bowel dis- turbances. It may take months before she recovers from the effects of the drug which'wasn't indicated. Senator NELSON. Is this, in your experience, a common occurrence? Dr. BABUR. Exceedingly common. Senator NELSON. Exceedingly common? Dr. BAEHR. Exceedingly common. The prescribing of expensive brand-named drugs to the exclusion of their generic equivalents has been fostered by the pharmaceutical industry through its 15,000 or more detail men who visit physicians' offices and also by retail pharmacists themselves. Both have been spread- ing the false gospel that generic preparations are universally unreli- able and that brand names are a guarantee of reliability. There are retail druggists in New York City who do not stock any generic drugs on the excuse that they are generally unreliable. A New York State law, quite properly, forbids a druggist to dispense a generic equivalent when the physician specifies a brand-named pre- paration. Paradoxically, however, the State law permits a druggist to substitute a brand-named drug when a generic drug is specifically prescribed by the physician-although it may mean 10 times the retail price and 10 times the markup profit tO the druggist. When the physician specifies a generic drug, neither he nor his patient is protected from substitution. The consultant experts of the Medical Letter have made a compara- tive study of some of the most frequently used drugs purchased by them in the marketplace under their brand names and, also, under their generic equivalents. They found that the brand name is not a guar- antee that the preparation meets required U.S. Pharmacopeia standards. Senator NELSON. Doctor, I notice that you were formerly director of medicine and clinical research at the Mount Sinai Hospital in New York and clinical professor of medicine at the College of Physicians and Surgeons, Columbia University. In Mount Sinai Hospital, were generic drugs used? Dr. BAEHR. They have been for some years. A formulary containing a list of generic drugs and brand-name drugs that are considered re- liable from the evidence within the hospital and from evidence of other reputable institutions are listed in the hospital's drug formulary, and corrected, kept up to date, from month to month. The medical staff of the hospital has agreed that if they can only remember a brand name but have no objection to the dispensing of a generic equivalent, the hospital's pharmacist has the right to dispense the latter. If they want a brand-name drug for some special purpose they can have it. PAGENO="0159" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 4063 They are not denied the use of it, but unless they specify that they want it, a generic equivalent is dispensed. This is the practice in many good teaching hospitals. I think New York Hospital in our city was the. first to adopt a hospital formulary. Hospitals have saved at least 50 percent of the cost of drugs used in the hospital and in their outpatient services. The hospital staffs have been encouraged to distinguish between effective generic preparations which are purchasable at lower cost, and those brand-name, drugs which must be used. They also learn to appreciate that the brand name alone is not a guarantee of reliability, but is a guarantee of much higher cost. Senator NELSON. Do you have any knowledge of what percentage of the drugs dispensed at Mount Sinai, while you were there, were generic drugs? Dr. BAEHR. I cannot answer your question. In my early days, the profits of the pharmaceutical industry were made largely through the over-the-counter sale of patent medicines, but in recent years the major share of the profits of the pharmaceutical industry is derived from indoctrination of the medical profession in regard to the prescrib- ing of brand-named preparations. Most teaching hospitals have a drug formulary of their own, and compare it with the formularies of other hospitals. They usually have a committee on pharmacy and therapeutics which determines the drugs included in the formulary. This assures the medical staff that the quality of a generic drug included in the hospital's forrntiiary has been passed upon by the committee on pharmacy and therapeutics of, the hospital. Senator NELSON. `Does Mount Sinai purchase its own drugs direct or does lit have another purchaser who purchases for it? Dr. BAEIIR. Some are purchased directly from the manufacturers and some through an intermediary distributor. I think that is the case in most hospitals. Senator NELSON. How does the pharmacy and the formulary com- mittee assure itself that the drugs `being dispensed meet USP standards and N.F. standards, do they assay these drugs to see from time to time that they do meet the standards? Dr. BAEHR. In part they depend upoil an assurance from the distribu- tor or from the drug firm that they meet IJSP standards. But they also rely upon a constant survey of the literature by the hospital's committee on drugs, upon the Food and Drug Administration, and upon the Medical Letter. The Medical Letter has played a very important role in guiding institutions and individual physicians in the use of drugs that are dependable and, if possible, of low cost. Senator NELSON. I take it then that the experience of a hospital `and the physicians in the hospital have been as satisfactory with generic drugs as with brand-name drugs? Dr. BAEHR. I can reply affirmatively with a few reservations. There are some generic preparations that are not purchased because they may not be packaged in a form regarded by the committee as reliable as the brand-named equivalent The staff experience with `all drugs is watched by the committee. Any untoward effects must, by rules of the medical board of the hospital, be reported promptly to the commititee for investigation. PAGENO="0160" 4064 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY From month to month drugs in the formulary may be eliminated and new ones added as they prove to be reliable in the experience of the institution. The chairman of any departmental specialty may also request the inclusion of a new drug for temporary trial by the staff of his clinical department. Senator NELSON Did I understand you to say that by the use of generics the hospital has been able to reduce its drug costs by about 50 percent? Dr. BAEHR. Yes; I think that is true of most hospitals that have adopted a drug formulary. Senator NELSON. Thank you. Dr BAEHR May I say that the Medical Letter has proved to be exceedingly valuable in the education of physicians who have used it. When its publication was started without subsidy by the pharma- ceutical houses or advertising, I considered it to be so important that I subscribed through my organization-Health Insurance Plan-to a thousand subscriptions The Medical Letter has been distributed since that time to a thousand physicians who provide medical serv ices to 780,000 New Yorkers enrolled in the Health Insurance Plan of Greater New York. Now subscriptions to the Medical Letter have risen to about 20,000, but it still does not reach the vast majority of the medical profession who could profit by it. Incidentally, I would like to call your `ittention to the fact that it has been reprinted in several foreign countries, such as England and Holland, where it has been distributd free by the government. Senator NELSON. Some time earlier when Dr. Faulkner was testi- fying, I said the circulation was about 15,000 Counsel corrects me and says that the circulation of the Medical Letter, as he understands it, is now about 35,000 to 40,000. Dr. BAEHR. The unnecessary prescribing of brand name drugs is fostered by the distribution to physicians of free samples and persua- sive literature through thousands of detail men and by hundreds of free magazines published by pharmaceutical firms to encourage the use of their innumerable products Their use is also encouraged by voluminous advertising in virtually all reputable medical journals A recent issue of the weekly Journal of the American Medical As sociation devotes 85 pages to text and 186 pages to such advertisements I would like at this point to introduce an exhibit, the Journal of the American Medical Association, November 18, 1968 The lead article, the most conspicuous place in the journal, is given to a paper entitled "The Generic Inequivalence of Drugs." 1 The drug tolbutamide, which is used in the treatment of diabetes and is sold under the name of Orinase by the Upjohn Co, w'ts tested by an employee of the company In this article the results of a test on 20 prisoners is reported, which revealed that tolbutamide in the way it is ordin'irily sold by the Upjohn Co, is compounded with a gum like substance, so that it holds its form, but also acts as a dispersing agent, so after it reaches the upper gastrointestinal tract it is liberated `ind can be promptly absorbed 1 See article beginning at p 4071 infra PAGENO="0161" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 4065. When they reduced the gumlike ~ubstance, which is inert, to half that amount, the tolbutamide was not dispersed as promptly, and its. effect upon the blood sugar of normal prisoners was not as good as with the cQmmercial preparation. The article is given conspicuous place as the lead article, although it concluded with the statement: The ideal criterion for establishment of therapeutic equivalence is trial of comparative efficacy in appropriately disease-afflicted patients. Yet they did not try it in a dis'ease~afIlicted patient, but only on 10 normal prisoners. They then admit: This is a concept probably not feasible in the context of today's clinical research methodology and standards of ethical medical research. The medical world is left with drug availability as the present most sensible and feasible way of establishing generic equivalence of drugs. This article is obviously designed to foster in physician's minds the belief that they cannot depend on generic drugs. In the same issue of the Journal of the American Medical Association there follows an editorial comment on the article by the Upjohn Co., entitled "Generic Drugs and Therapeutic Equivalence." 1 In other words, from this one instance of pseudo scientific research on normal persons, the editorial takes the liberty to generalize about generic drugs and their thera- peutic equivalence, and says, "factors which may influence the thera- peutic usefulness of a drug even though the preparation contained the stated amount of the active ingredient. "Unless a preparation has been proven to be as effective as the standardized preparation"-~by "standard" they are implying, I be- lieve, a brand-name drug, although it is not so stated. By the use of this form of obscurantism, the idea is being fixed in the practitioner's mind that he better not prescribe generic drugs because they may be unreliable. The Medical Letter has demonstrated that both kinds of drugs, the brand named and the generic may at times be unreliable due to' the method of compounding. It is up to some official agency to determine that all drugs, whether brand name or generic, meet standards of re- liability and therapeutic efficiency. Senator NELSON. ii read that article, and I thought it was a most unscientific procedure to write an editorial based on one article. There are of cour~e, several thousand drugs in the marketplace, and as one doctor commented after reading the article-it was mighty strange that in order to find a case `of therapeutic inequivalence, gen- eric inequivalence, they had to manufacture it. Tolbutamide is in the marketplace under only one name, Orinase. There is no generic, there is no other brand name in the marketplace. So instead of finding one of the thousands of drugs in the marketplace where they could show a drug meeting USP standards that was not equivalent, they had to' manufacture an example. The testimony before this committee by USP and the National Formulary and others is that there are-at the outside-only a half dozen or so proven cases of generic inequivalence when the two drugs compared both met USP standards or National Formulary standards. Dr. BAEUR. What I also object to is that the employees of Upjohn must have known in advance what they were going to find. The reason `See editorial beginning at p. 4077, infra. 81-280-69--pt. 10-11 PAGENO="0162" 4066 COMPETITIVE PROBLEMS IN THE DRUG INDUSTItY that this inert gum was used in the first place was to get dispersal and prompt release into the gastrointestinal tract and prompt effect on the blood sugar. They must have known in advance what the effect of eliminating the gum substance would be. An editorial to emphasize the general unreliability of generic drugs based on such unscientific research is to be condemned. Senator NELSoN The article and the editorial will be printed at the appropriate place in the record. Mr. GORDON. Dr. `Baehr, may I interrupt here? Isn't this really an illustration of what Dr. Faulkner said before about the danger, pos- sible danger, of relying so heavily on financing by the drug industry? Do you think that this kind of article, this kind of an editorial, would have been written if the American Medical Association had not been so heavily dependent on the drug industry? Dr. BAEIIR. You are right. To be charitable, the least I could say about it, is that it may have been influenced by subconscious bias. Senator NELsoN. Thank you. Dr. BAEHR. Could I introduce another exhibit at this moment? This is an editorial in the New England Journal `of Medicine,1 which I and many others in our profession regard as one of the most reliable journals published in this country. It states that: About 5 percent of all inpatients suffer adverse drug reactions severe enough to cause marked morbidity, prolonged hospitalization, result in permanent sequelae or contribute to a fatal outcome. The risks for outpatients are also con- siderable, and three to four percent of all admissions to medical service are for pathologic states resulting from drug therapy. All of us have seen much too serious illness from drugs for which the patient had no real need. Senator NELSON. Pardon, I did not hear the last sentence. Dr. BAEHR (reading): All of us have seen too much serious illness from drugs for which the patient had no real need. This form of polypharmaceutical prescribing is fostered by adver- tising through throwaway journals, through articles in these com- mercial journals, and through wholesale and retail distributors to the medical profession. Senator NELSON. Yes, sir. Dr. Frederick Wolff, who is director of research, Washington Hos- pital Center, and professor of medicine, George Washington Univer- sity School of Medicin&-in his testimony before us, estimated that out of every $10 spent on drugs, in his judgment, $6 was unnecessarily spent. What, in your experience, would your judgment be as to this state- ment of Dr. Wolff's or what is your own guess? Dr. BAEHR. From my own experience with doctors generally, I would say that that is a conservative statement. In the treatment of ambulatory patients outside of a hospital by physicians, the cost of unnecessarily prescribed drugs is probably more than 60 percent. Senator NELSON. Thank you, Doctor. Dr. BAEHR. May I continue? Senator NELSON. Yes, sir. 1 See editorial beginning at p. 4078, infra. PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4067 Dr. I3AEHR. It would be of interest to you to know that some years ago I was approached by the head of a pharmaceutical drug-testing institute with an offer of an appointment as editor in chief of a new ~journal designed to enable physicians testing new drugs to secure prompt publication of reports of their therapeutic experiences. I was to receive 15 percent of the profit for the use of my name and two as- sociate editors were each to receive 10 percent in return for doing all the editorial work. The new journal, I was told, would take no ad- vertising and would not receive any subsidy from the pharmaceutical industry. I was assured that the venture would nevertheless be ex- tremely profitable and I could expect a substantial income. Upon inquiring about the mysterious source of such income, I was informed it would come from the purchase of reprints by firms whose drugs were favorably mentioned in the published articles. There was much money to be made from the sale of reprints by the hundreds of thousands for mailing by the drug manufacturers to physicians throughout the country. I rejected the humiliating proposal and the new journal never saw the light of day. The New England Journal of Medicine, and some of the house journals published by good teaching hospitals, will not sell more than a limited number of reprints for distribution by the authors to sci- entists and physicians who ask for them. They reject orders from pharmaceutical firms for tens or hundreds of thousands of reprints because it is obvious that this is intended to promote the commercial sale of the product. Mr. GORDON. Dr. Baehr, may I ask one question here? I noticed that several of the throwaways have names of well-known physicians on the masthead "as members of their advisory boards." I put this in quotation marks. Is it your impression that these names are used for purposes of im- pressing the readers or do these people on the advisory board perform a real service? Dr. BAEHR. To some extent. I think most members of the editorial board wish to keep the text educationally useful. They have as little to do with the advertising material in such throwaways as with the advertisements accepted by the reputable scientific journals. They scrutinize the text in their various special fields of expertise so as to make it as far as possible a valuable educational publication. I would like to introduce at this point a letter which I addressed to Dr. Philip R. Lee on November 27, 1968, in response to his inquiry, which was also commented upon by Dr. Faulkner. The letter may be of interest to the Senate Coramittee. Senator NELSON. That letter will be printed in full in the record.1 Dr. BAEHR. In that letter I point out the experience of the Health Insurance Plan of Greater New York, which is one of the questions that you wished me to comment upon. Could I read that part of the letter? Senator NELSON. Yes, sir. Dr. BAEHR (reading): The Health Insurance Plan of Greater New York has included prescription drugs as a benefit since January 1, 194f~T, in the form of a rider to its basic con- 1 See letter beginning at p. 4O74~, intra. PAGENO="0164" 4068 COMPETITIVE PROBLEMS IN THE DETJG INDUSTRY tract. Approximately 120,000 persons out of our total enroilmexit of 780,000 are presently covere~l by the drug rider. Covered enrollees may have Uieir prescrip- tions filled in any licensed community pharmacy, in which case they are subject to a $25 annual deductible and 20 percent coinsurance, or they may have their prescriptions filled by mail through a nonprofit HIP-operated pharmacy, in which case there is no charge whatever. The drugs dispensed by the central pharmacy are purchased either directly from manufacturers or through intermediary distributors and their efficacy and reliability are passed upon by a committee of experts in pharmacology and therapeutics. About one-third of the subscribers have thus far used the mail-order route. The monthly premium for the drug rider is $0.98 for a single person, $1.96 for a couple, and $2.94 for a family of three or more persons. The premium would be much less If all prescriptions were dispensed by our own local outlets. This cannot be done without the cooperation of local pharmacists. and they will not cooperate in this manner. A prepaid drug benefit is especially important for the medicare- population. As your Department has observed, annual expenditures per person for pre- scribed drugs for persons 65 and over, amount to over $40, compared to about $15 per persons of all ages. (U.S. Department of Health, Education, and Welfare, National Center for Health Statistics, series 10, No. 39.) Because drug costs for the elderly are so high, it is imperative to take full advantage of all possible means to keep costs to a minimum while maintaining control over quality. Based on our experience, which admittedly is as yet rela- tively limited, the following suggestions are offered for your consideration- Do you wish me to read this or should we leave it for the record? Senator NELSON. Whichever you desire. It will be printed in the record in full. If there is something you wish to emphasize in it you may proceed to do so. Dr. BAEHR. The only thing that I would like to emphasize is cvhat has already been stated by Dr. Faulkner. As in many hospitals, the use of a formulary which emphasizes the prescribing of generic drugs is, of course, the major means of reducing costs. Also central pharmacies ca~i assure the physician of quality controls of generic as well as brand-name products. For the mail-order delivery, special prescription blanks may be sup- plied on which the doctor may indicate by a checkmark or initial that the dispensing of a reliable generic equivalent is permissible. This has been done through mail order by the Association of Retired Persons in Washington, D.C., for quite a long time. They have been filling pre- scriptions for years for retired persons living all over the United States, and the distribution would, under different circumstances with local distributors, be feasible for all medicare and medicaid beneficiar- ies if regional facilities were used. This suggestion is offered for reducing the cost and maintaining standards of quality under the medicare and medicaid programs. A statewide association of retail pharmacists in New York endeav- ored to interfere with the HIP drug program described in the letter to Dr. Lee by having a bill introduced in the 1968 session of the New York State Legislature which would amend article TX-C of the State insurance law governing the operation of nonprofit health insurance plans. The amendment would remove a provision of the law which had, for more than 20 years, authorized a nonprofit, comprehensive pre- payment plan to include drugs as a benefit in its comprehensive health insurance coverage. In spite of the efforts of a powerful lobby of the PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4069 retail pharmacists, the bill failed to pass. The pharmacists then sought an injunction which. was denied by the courts. Efforts to eliminate HIP's endeavors to control the quality and the cost of prescription drugs required by its beneficiaries will probably be renewed when the State legislature reconvenes next month. Senator NELSON. Thank you, Doctor. I neglected a few moments back, when you were commenting on the use of generic drugs in the hospital formulary, to ask Dr. Faulkner to comment on that. Dr. Faulkner, you were dean at Boston University-with what hos- pital is Boston University associated? Dr. FAULKNER. It is now called the TJniversity Hospital. We have our own formulary there with a pharmacy committee very much like the setup, which Dr. Baehr described. Senator NELSON. Historically, when did hospitals in this country begin establishing formulary committees which initiated this practice of using both brand- and generic-name drugs? How recent is that? Dr. BAEIIR. I should say it is about 8 or 10 years. I think as far as I recall perhaps the first one:.was the New York Hospital at Cornell Uni- versity, and then other hospitals followed along, good teaching hos- pitals-and controls over quality and great savings in cost. Senator NELSON. What is your experience in the hospitals you have been in On this issue, Dr. Faulkner? Dr. FATJIJKNER. Well, I think the Massachusetts General Hospital, where I had my internship, already had a formulary there. But, as Dr. Baehr pointed out, in those days there were not very many brand name drugs. It was mostly digitalis, and we generally, naturally, used generic drugs and very seldom prescribed a brand name. Senator NELSON. What has been your experience in recent years with the use of generic drugs in the hospital formularies in the hospitals with which you have been associated? Dr. FAULKNER. Well, actually I have not been closely associated with the clinical aspects of hospitals enough to really be able to answer that question. Mr. GORDON. I would like to ask you about throwaways once again. Do you consider that these throwaways we were discussing constitute a threat to the circulation of distinguished educational journals such as the New England Journal of Medicine? Dr. FAULKNER. I do not think so; no. Mr. GORDON. Do you think that these throwaways are really impor- tant in influencing the average practicing physician? Dr. FAUi*NER. Yes, I think they do. I think it partly is because there is not any counterpoise of factual information about new drugs to balance out the information they get through the throwaway journals. Senator NELSON. I want to' thank you, Dr. Baehr, and you, Dr. Faulkner, for yOur~ very thoughtful and useful contribution to these hearings. The committecappreciates your taking the time to come here very much. We will adjourn until ~ometime in January. (The complete prepared statement and supplemental information submitted by Dr. Baehr follows:) PAGENO="0166" 4070 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT OF DL GEOROE B~zim I am Dr. George Baehr of New York, a physician engaged in the practice of medicine and medical education~ I am Chairman of the Public Health Council of the State of New York, a member of the Board of Hospitals of the City of New York, and hold the rank of Distinguished Service Professor at the Mount Sinai School of Medicine of the City University of New York. I have formerly been President of the New York Academy of Medicine, Vice President of the American Public Health Association, Director of Medicine and of Clinical Research at the Mount Sinai Hospital, New York, and Olinical Professor of Medicine at the College of Physicians and Surgeons of Columbia University. I was at onq time President and Medical Director of the Health Insurance Plan of Greater New York, now providing more than 780,000 persons in the New York area with prepaid comprehensive medical care. I should like to emphasize that I am testifying as an individual and not as a representative of any of the organizations or agencies with, which I am or have been associated. During many years of practice, I have' served as consultant to many local physicians and `hare been bewildered by the enormous number and variety of brand-named drugs which they prescribe. What has been derisively called poly- pharmacy is almost the rule. The prescribing of expensive brand-named drugs to the exclusion of, their generic equivalents has been fostered by the pharmaceutical Industry through its 15,000 or more detail men who visit physi~ians' offices and by retail pharmacists. Both have been spreading the false gospel that generic preparations are unreliable and that brand names are a guarantee of reiiability. There are retail druggists in New York who do not stock any generic drugs on the ex±use that they are unreliable. A New York State law, quite properly, forbids a druggist to dispense a generic equivalent when the physician specifies a brand- named preparation. Paradoxically, however, the State law permits a druggist to substitute a brand-named drug when a generic drug is specifically prescribed by the physician-although it may mean ten times the retail price and ten times the mark-up profit to the druggist. When the physician specifies a generic drug, neither he nor his patient is protected from substitution. Actually, the consultant experts of The Medical Letter have made a compara- tive study of some of the most frequently used drugs purchgsed under their brand names and under their generic equivalents. They found that the brand name Is not a guarantee that the preparation meets required U.S. Pharmacopeial standards. The unnecessary prescribing of brand-named drugs is fostered by the distribu- tion to physicians of free samples and persuasive literature through thousands of detail men and by hundreds of free magazines published by pharmaceutical firms to encourage the use of their innumerable products., Their use is also encouraged by voluminous advertising in virtually all reputable medical journals. A recent `issue of the weekly Jonrnal of the American Medical A&sociation devotes 85 pages to text and 186 pages `to such advertisements. Some years ago, I was approached by the head of a pharmaceutical drug-testing institute with an offer of the editor-in-chief of a new journal designed to enable physicians testing new drugs to secure prompt publication of reports of their therapeutic experiences. I was to receive 15 per cent of the profit for the use of my name and two associate editors were each to receive 10 per cent in return `for doing all the editorial work. The new journal would take no advertising and would not receive any subsidy from the pharmaceutical industry. I was assured that the venture would nevertheless be extremely profitable and I could expect a substan- tial income. Upon inquiring about the mysterious source of such income, I was informed it would come from the purchase of reprints by firms whose drugs were favorably mentioned in the published articles. There was much money to be made from the sale of reprints by the hundreds of thousands for mailing by drug manufacturers to physicians throughout the country. I rejected the humiliating proposal and the new journal never saw the light of day. Herewith is a letter which I addressed to Dr. Philip H. Lee on November 27, 1968, in response `to his query. It may be of interest to the Senate Committee. A State-wide association of retail pharmacists endeavored to Interfere with the HIP drug program described in the letter to Dr. Lee by having a bill intro- duced in the 1968 session of the New York State Legislature which would amend PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4071 Article IX-C of the State Insurance Law governing the operation of nonprofit health insurance plans. The amendment would remove a provision of the law which had, for more than 20 years, authorized a nonprofit, comprehensit~e pre- payment plan to include drugs as a benefit in its comprehensive health insurance coverage. In spite of the efforts of a powerful lobby of the retail pharmacists, the bill failed to pass. The pharmacists then sought an injunction which was denied by the courts. The threat to HIP endeavor's to control the quality and the cost of prescription drugs required by its beneficiaries will probably be renewed when the State Legislature reconvenes next month. As members of the Senate Committee are aware, most good hospitals have adopted a hospital drug formulary and have entered into an agreement with their medical staff to prescribe under the generic terminology as far as reason- ably possible. The agreement permits the hospital pharmacy to dispense equiva~ lent generic preparations if a physician can only remember a brand name, provided the generic equivalent meets the required standards of the U.S. Pharmacopela and of the hospital's own committee on drugs. If a staff physician actually wishes the brand-named preparation to be dispensed, it is provide~l without question. In this manner, hospitals have reduced their annual drug bills ~0 per cent and have exercised control over quality standards. ~From the Journal of the American Medical 4ssocIat1on~ vol. 206, No. 8, Nov. 18, 1968] Tun GENERIc INEQUIvALENCE or DrtnYos (By Alan B. Varley, M.D.*) Generic equivalence of drugs is a semantically muddled concept. To be meaningful, the criteria for equivalence must be stated. In this simple study, two different formulations of tolbutamide, both generally equivalent in terms of chemical content and specifications of the Uiaited States Pharamacopeia, were found to be clearly not equivalent as meas- ured by availability of drug to the patient (serum drug levels or thera- peutic efficacy (hypoglycemic response. Clarity in pronouncements on this subject should be established so that confusion in terminology and meaning does not lead to "generic inequlvalence" of therapeutic response. In the past several years, much has been written both in the lay anc~ the technical press regarding the concept of generic equivalence of drugs. Phe purpose of reporting this simple but tightly controlled clinical study is to ~llus- trate the belief that just as some drug formulations are generically "equivalent," some are also generically "inequivalent" and, thus, the term "generic equiva- lence" badly needs better definition or abandOnment. The physician's researchers, or lawmaker's usual reference to generically equivalent drugs is in terms of expected pharmacologic or therapeutic effect in the human patient. The usual criterion for establishing this equivalence, how- ever, is the amount of bulk chemical in the commercial drug or the specificittions of the United States Phctran,acopeia (tTSP) for the chemical and physical charac- teristics of the formulation or both. It is the purpose of this study to demonstrate that this simplistic notion Is not satisfactory for establishing criteria for generically equivalent drugs if equfralent therapeutic results are intended and expected. For the purposes of this communication, three different types of genric equivalence are discussed: 1. Chemical Equivalence.-Drugs considered chemically equivalent h~ave the prescribed amount of drug chemical in a prescribed stable condition ai~d meet IJSP specifications for chemical and physical characteristics. 2. Availability Equivalence-In addition to being chemically or USP-equiva- lent, the formulation must also insure that equivalent amounts of the d~,ugs are delivered to the patient, as measured most frequently by serum druk levels. Availability equivalence presumes that equal amounts of drug absorbed from the site of administration to the circulating blood (as demonstrated l~y serum levels) will indeed have similar or identical therapeutic effects. 3; Therapeutic Equivalence.-Crlteria for this level of equivalence require that therapeutic or clinical effects of the drug, as seen and measured in tl~e human *From the Department of Clinical Pharmacology, the Upjohn Co., Kalama/zoo, Mich. Reprint requests to 7171 Portage Rd., Kalamazoo, MICh. 49O~1 (Dr. Varley). PAGENO="0168" 4072 COMPETITIVE PROBLEMS IN THE DRTJG I~DtSTE~ patient, are also equivalent. Tids is obviously the acid test of drug equivalence and one which, though ideal, is not generally easy to quickly establish, consid- ering our ptesnt clinical tools for measuremnt of therapeutic effectiveness and the ethical constraints in establishing such proof in sick human patients. It is the ~ontention of this communication that chemically equivalent drugs are not necessarily equally available to the patient or therapeutically equivalent in the patient. MATERIALS AND MISTIIODS Inasmuch as therapeutic effectiveness is' the most difficult aspect to simply and accurately monitor, it was decided to test this hypothesis with use of an orally administered hypoglycemic agent as the test drug variable and to accept labora- tory demonstration of chemical hypoglycemia as evidence of clinical "thera- peutic" efficacy. It is our belief that hypoglycemia is generally accepted by physi- cians as evidence of therapeutic effect. Inasmuch as' a dependable and accurate assay method Is available for measurement of tolbutamide serum levels (drug availability) and a historical experience in pharmacy technique has been devel- oped with. this agent, tolbutamide (Orinase) was selected as the particular test drug. In this study, we have considered only this question: Does "generic" chemical equivalence guarantee simultaneous avallebility and therapeutic equivalence? Our pharmacy department was asked to prepare two lots of tolbutamide tab- lets, both' `containing 0.5 gm of the chemical and both meeting USP specifications but which, based upon past pharmacy formulation experience, might be expected to behave very differently in the human patient. Two formulations were deliv- ered: one taken from a' commercial production lot (Orinase) and the other identical in all composition and manufacturing respects except for a halving of the amount of the disintegrant (Vee Gum). This single and seemingly minor pharmacy change did effet~t an increase in both the disintegration time (commer- cial, two minutes; experimental 7.6 minutes) and dissolution rate (commercial, 3.8 minutes; experimental, 103 minutes) of the tablets, although blood formula- tions meet completely the tolbutamide specifications of the TJSP and, therefore, meet our criteria for cheniioaZ equivalence. A double-blind, cros'sov~er clinical study was arranged in which ten healthy, nondil'abetie, volt~nteer subjects at the Southern 1~ichigan~ State Prison at Jackson received both formulations of drug. The group of ten was randomly assigned into two groups of five subjects each. After prestutly physical examine- t~on and laboratory work-up demonstrated absence of disease and suitability for study, a zero-hour `blood `sample was drawn and each subject in each group re- ceived 1 gin (two 0.5-gm tablets) of one of the two test medications. Blood samples for glucose and drug .assay were drawn at 1%, 3, 5, and 8 hours after drug ad- ministration. All subjects remained, fasting from midnight preceding drug in- gestion until the eollectio~ of the last eight-hour blood sample. The study was repeated one week later under identical conditions with the test medication crossed over and assigned to the opposite group. All subjects, therefore, received both test medications in `a blind, randomly assigned, crossover fashion over the eight-day study period. A 15-cc sample of blood was drawn at the indicated times after drug admini- stration. The `specimen was promptly centrifuged, and the serum separated into two aliquots and frozen immediately. One `aliquot was sent to our Olinical Re- search Laboratory in Kalamazoo, Mieb., for determination of blood glucose values by the Somogyf-Nelson method.1 The second frozen aliquot was sent to the Huffman Laboratories, Inc., in Wheatridge, Cob., for determination of serum tolbutatfilde levels by the Tooian~Wagner method.1 Results were submitted to me under `code label, and the data were analyzed before the formulation identification' was decoded. RESULTS The study was completed a~ described. The serum glucose and drug levels' after medication are presented in Tables 1 and 2 and summarized graphically in Figs. 1 and 2. 1 Hoffman, W. 8: Rapid Photoelectric ]SIethod for Dete~nnhuition of Glucose iii Blood and Urine, J. Biot. Cheni. 120 :51-55 (Ang.) 1937. 2 Toolari, T. J., and Wagner, H. L., Jr.: The Physical Properties of Clilorpropamide and Its Determination in Human Serum, Ann. N.Y. Aced. Sci. 74 :449-458 (March 30) 1959. PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4073 PAGENO="0170" ~~W4 COMPETITIVE P~EOBLEMS iN~ ~TI~ DRUG `INDUS~R~ PAGENO="0171" CD C,, C) 00 00000000 C) C) C)~~OQC)C)C) C) -4 00 C/, C, C) 0 Cl) C,, P C) 0 t~~J C (/2 t12 C;' -- 00C)~4~4C// 0000000000 U~ C)0000~ (/, C) C) C) C) 000000 0C)C)C)C)~C)C)C) 00 PAGENO="0172" 4076 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY obtained in hyperglycemic patients, though, as can be seen, it is a valuable method in distinguishing the hypoglycemia-inducing potency of two or more drugs.) Serum Tolbutamide Levels.-Every subject, at each sampling time, bad a higher serum drug level after receiving the commercial lot of tolbutamide than after receiving the experimentally coutrived, but USP-equivalen't, formulation. At each sampling time, the group difference between average serum tolbuta- mide levels was highly significant (P <0.001, based upon analysis of variance for crossover design). The area under the average serum drug curves over the eight-hour period was 3.~S7 times greater with commercial tolbutamide than with the experimental formulation, as follows: 47.1 13.2 Serum Glucose Levels.-The average zero-hour blood glucose levels after fasting for the two groups were 78.7 and 79.1 mg per 100 ml. These averages do not differ statistically (P> 0.25). The differences between the average serum glucose levels at the five-hour (74.8 and 74.7 mg per 100 ml) and the eight-hour (78.5 and 77.9 mg per 100 ml) sampling times also are not different statistically (P> 0.25). However, at the 11/2~ and 3-hour sampling intervals, the difference between average serum glucose levels with the two formulations differed markedly. At 11/2 hours (65.1 and 75.6 mg per 100 ml) and at 3 hours (70.2 and 76.1 mg per 100 ml) differences between average serum glucose levels of commercial tolbutamide and the experimental formulation were highly significant (P <0.001, based upon analysis of variance for crossover design). The area under the curve for the average serum glucose level over the eight- hour period was 2.09 times higher (less glucose) for commercial tolbutamide than for the experimental formulation, as follows: -909 21.5 - COM1~4ENT Statements such as the following have been made with some regularity of late: "There have been probably fewer than five well-conducted, clinically ac- ceptable studies which have demonstrated significant difference between two or more products clinically where they have met all the chemical and physical standards as provided by the official compendia." It is believed that the presented data will help establish the error in the im- plication that clinical differences between generically equivalent drugs are, there- fore, rare and not important. Oriticisms of this study can be raised insisting that the experimental formulation was not a "product," that clinical differences can- not be established in nondliseased patients, that the study was not large or small enough, or is not in one way or another completely acceptable to the objector. The fact remaIns that it is clearly possible to produce considerable differences in both availability of drug to the human patient and in eventual therapeutic useful- ness by making tiny changes in the formulation which are clearly within present USP chemical equivalence standards. It is not my contention that generic, therapeutically equivalent drugs cannot be formulated. Quite to the contrary. It is my contention that criteria for estab- lishment ~f equivalence cannot be made by chemical and physical standards as they are now established in the USP, unless one is not interested in the patient's therapeutic response which concerns moSt physicians. Without question, the ideal criterion for establiShment of therapeutic equiva- lence is trial of comparative efficacy in appropriatel~' disease-afflicted patients. While not within the scope of data presented in `this communication, this is a concept probably not feasible in the context of today's clinical* research meth- odology and standards of ethical medical research. Inasmuch as chemical or USP- type specification's are clearly not a satisfactory answer, the medical world is left with drug availability a~ the present most sensible and feasible way of establishing generic equivalence of drugs. PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4077 GENERIC AND TRADE NAMES OF DRUG Polbutamide-Orinase. [From the Journal of the American Medical Association, vol. 206, No. 8, Nov. 18, 19681 (Editorial) GENERIC DRUGS AND THERAPEUTIC EQUIVALENCE In recent years, there has developed the belief that nonproprietary or generic drugs are much cheaper than, and as effective as, trade-named items. Thi" b~- lief has led to a widespread detsand that prescribing and use of generic drugs be encouraged. Studies conducted by impartial groups such as the Medical Let- ter on Drugs and Therapeutics have applied United States Pharmacopeial metlt~ ods to assay certain drugs prepared by many different maiitifacturers.1~ rflIese analyses have shown that, generally, these preparations are chemically equiva- lent in that they contain the amount of drug claimed. These findings have led many to the conclusion that drugs prepared by various manufacturers should be equally effective in therapy. While this seems to be true in many instances, there are situations where this is not so. For some time, workers in the pharmaceutical field have been compiling a list of factors which may influence the therapeutic usefulness of a drug even though the preparation contained the stated amount of the active ingredient. The list in- cludes appearance, taste, availability for absorption, solubility of the dosage form, effect of other ingredients, binders, p1-I, particle glze, stability, age of the prepa- ration, compression of the tablet, and thickness and type of enteric coating. All these factors have been shown to influence the therapeutic efficacy of drugs. Recently interest has focused on the purity of drugs. For example, even a "pure" commercially available preparation of penicillin G was found to harbor impurities capable of causing allergic reactions. When the preparation was fur- tlier purified it could be given to some individuals who were previously allergic to it.4 Apparently, the allergen caine from the fermentation process, and minute traces remained with the penicillin. This information raises questions about the present method of handling penicillin. For example, the United States Pharma- copeia requires penicillin G preparations to contain at least 85% of penicillin G. Commercially available penicillin G from reputable manufacturers contain 98% or more of penicillin G. It is reasonable to suspect that the less-pure preparation may contain more of these sensitizing allergens and that some reactions thought to be caused by the penicillin molecule may actually be caused by contanilnat- ing allergens. Thus a cheaper, less-pure penicillin may not be cheaper as far `as the patient is concerned, should he manifest a serious reaction to the con- taminant. How extensive this problem may be remains to be seen. Certainly, it points out the desirability of etting as pure a preparation of penicillin as possible. A communication by Varley (p 1745) stresses the importance of the slightest alteration in ingredients in affecting the therapeutic efficacy of the drug. The halving of an inert binding ginn in tolbutamide tablets, prepared to contain the same amount of tolbutamide as the commercially available tablet, resulted in a serious lowering in the level of the drug absorbed and in a consequent reduced ability to lower blood glucose. This points out the necessity by making sure by measuring patients' blood levels or by adequate therapeutic testing that a drug preparation varying in any way from one performing satisfactorily is also capable of doing what is claimed for it. It is important that we demand the highest purity for our drugs. Unless a preparation has been proven to be as effective as the standardized preparation, it should be considered as a possible source of therapeutic nonequivalence. Where a drug may be critical to the proper treatment of a disease, physicians should make certain that it has not only chemical equivalence hut also therapeutic or at least blood-level equivalence. DALE G. FRIEND, M.D., Boston. 1 Tests of Dlethylstllbestrol Tablets, Med Lett Drugs Ther 4 :15-16 (Feb 16) 1962. 2 Chlorphenlramine Maleate Tablets, Med Lett Drugs Timer 7 :18-19 (Feb 26) 1965W Tests of Pred~n1sone Tablets, Meet Lett Drugs Timer 9 :41-43 (June 2) 1967. Stewart, 0. T.: Allergenic Residues in Penicillin, Lancet 1 :1177-1183 (June 3) 1967, PAGENO="0174" 4078 COM~IVE I~ "TH~ iYRtG~ ~III~DUSThY [From the New England. Journal of Medicine,. vol.' 279, No. 23, Dec. 5, 1968] (Editorial) DISEASE t~RUGS CAUSE Three articles in this issue of the Journal* describing noxious efrects of thera- peutic or diagnostic chemicals once again point up this vexing problem. Although most of the sick benefit from their contact with the treasure chest of modern pharmacotherapy, the experience is unhappy for too many. Several recent studies have quantitated drug-related morbidity, sequelae and mortality in hos- pitialized patients.1~ About 5 percent of all inpatients suffer adverse drug reac~ tions severe enough to cause marked morbidity, prolong hospitalization, result in permanent sequelae or contribute to a fatal outcome. The risks for outpatients are also considerable, and 3 to 4 percent of all admissions to a medical service are for pathologic states resulting from drug therapy. No matter how skillfully used, a drug that helps anyone will occasionally harm someone. Some adverse reactions to drugs are the price of progress in effective drug therapy. Regrettably, however, today's sinn total of drug-induced disease greatly exceeds the irreducible minimum. Many untoward consequences of drug therapy could easily be avoided, and others would become evitable if carefully studied and reported. The challenge to the medical profession is pressing. Ad- verse drug reactions can and must be minimized through improved recognition, investigation and awareness of these events. It is not easy to recognize a previously unsuspected causal relation between a drug and an untoward change in a patient's course. The difficulty i~ compounded when the drug rarely causes the adverse reaction and when the reaction is a common clinical event usually occurring from nondrug causes. The adverse re- actions related to pharmacologic actions of drugs can generally be predicted from animal testing, but such testing is unrevealing about the most important reactions that have immunologic or idiosyncratic mechanisms specific to man. Much of the adverse potential of a drug in man can be defined during its' early clinical testing, but the number of subjects exposed is small and only a happy accident would lead to the discovery of a rare reaction. The same problem is encountered by studies prospectively surveying limited populations for adverse reactions to widely used drugs. Only the population at risk during general clinical use is large enough for uncommon drug4nduced diseases to display themselves. Thus, the practicing physician becomes a key figure.4 Knowledge of new drug-induced diseases has always come primarily from practitioners who observed their patients with a discerning and open mind and who were willing to report their observations. Unfortunately, some suppress their suspicions by asking an Inapt question ("Has this drug caused such trouble before?") instead of relying on their clinical judgment and realizing that some report must always be the first. Others fear that a patient's drug-induced disease reflects unfavorably on his physician-an unreasonable concern if the drug was prescribed appropriately. Most initial *reports of a suspicious association between drug and disease cannot prove a causal relation. Repeated reports are required to harden the suspicion. Suspected new adverse reactions of clinical importance should be de- scribed promptly in the medical literature to alert other physicians and to induce them to report their observations. Other reports can be directed to hospital drug committees, medical associations, drug manufacturers or the Food and Drug Administration. Systematic nationwide and international colla- tion of such communications is essential to `translate them quickly into effective warnings and is now being attempted. Such programs must not be clogged by myriad meaningless reports of well known, minor, accepted side effects of drug therapy.5 *Articles appear as appendixes I, II, and III, pp. 4174B-94, infra. 1MacDonald, M. G., and MacKay, R. R. Adverse drug reactions: experience of Mary Fletcher Hospital during 1962. J.A.M.A. 190:1071-1074. 1964. 2 Seldl, L. 0., Thornton, 0. F., Smith, J. W., and Cluff, L. E. Studies on epidemiology of adverse drug reactions. III. Reactions in patients on general medical service. Bull. Johns Hopkins Hosp. 119 :299-315, 1966. 3Ogilvie, R. I., and Ruedy, J. Adverse drug reactions during h~spital1zat1on. Casued. M.A.J. 97 :1450-1457~ 1967. 4Koch-Weser, J., Sidel, V. W., Sweet, R., Kanarek, P., and Eaton, A. Faëtors determining physician reporting of adverse reactiofis. New Bag. J. Med. (in press). Koch-Weier, J. Definition and classification of adverse drug reactions. Drug Informa- tion Bull. 2 :72-78, 1968. PAGENO="0175" COMPETITIVE PROBLEMS IN TUE DRUG I~MJ~S~I~Y 4O~9 Qualitative and quantitative investigation of drug-induced disease is also urgei~tly needed. Since experimental reprpductior~ of serious, drug, r~actions 1S rarely feasible, each sñch event deserves careful study with ~jl appropriate technies to el~icidate it~ mechaiaism'~nd all ç~ontributing fac~tor~. Much remainS to be learned about the prevalence ofadversé reactions to individual drugs. Such quantitative knowledge of speci6c risks is one prereq~isite of proficient pharmacotherapy. Risk figures should tà1~e into aceQunt such factors as age, sex, genetic characteristics, pathologic states and coucomftant therapy with other drugs. All this requires carefully planUed studies relating d~~ug reactions to drug usage and characterizing the population.sstudled. Most importantly we should be more constantly aware of the noxious potential of drugs. I)rug usage and adverse reactions would surely decrease if every drug not clearly indicated were to be considered contraindicated. Before prescribing any drug, we should weigh the need for pharmacotberapy and consider the benefit-risk ratio of the drug in question and of therapeutically equivalent agents. All of us have seen too much serious illness fi~om drugs for which the patient had no real need. Another urgent task is the creation of a foolproof system warning physicians of serious drug reactions suffered by their patients in the past. Finally, medical-school and postgraduate education in clinical pharmacology must be expanded. Much disease caused by drugs could be pre- vented if all physicians were conversant with factors influencing the metabolic disposition of drugs, with modification of drug action by disease and with dangerous interactions between drugs. Greater familiarity with all features of drug-induced syndromes would make for more timely diagnosis. Nobody can remember all important information about all of today's drugs, but each of us should know every drug be prescribes. NOVEMBER 27, 19(38. Dr. PHILIP R. LEE, Assistant Elecretary for Health a'iicl Scientific Affairs, Department of Health, Edacation, and Welfare, Washington, D.C. DEAR DR. LEE: This is in respect to your letter of November 7, 1968 referrIng to the Task Force established in May, 19~7 to examine the possibility of including the cost of out-of-hospital prescription drugs as a Medicare benefit. The Health Insurance Plan of Greater New York has included prescription drugs as a benefit since January 1, 1967 in the form of a rider to its basic contract. Approximately 120,000 persons out of our total enrollment of 780,000 are pres- ently covered by the drug rider. Covered enrollees may have their prescriptions filled in any licensed community pharmacy, in which case they are subject to a $25.00 annual deductible and 20% co-insurance, or they may have their pre- scriptions filled by mail through an HIP operated pharmacy, in which case there is no charge. About one-third have thus far used the mail order route. The monthly premium for the drug rider is $.98 for a single person, $1.96 for a couple and $2.94 for a family of three or more persons. The premium would be much less if all prescriptions were dispensed by our own local outlets. A prepaid drug benefit is important for the Medicare population. As your Department has observed, annual expenditures per person for prescribed drugs for persons 65 and over, amount to over $40.00, compared to about $15.00 for persons of all ages. (U.S. Department of Health, Education, and Welfare, Na- tional Center for Health Statistics, Series 10, Number 39.) Because drug costs for the elderly are so high, it Is imperative to take full advantage of all possible means to keep costs to a minimum while maintaining control over quality. Based on our experience, which admittedly Is as yet rela- tively limited, the following suggestions are offered for your consideration: 1. In addition to community pharmacies, use regional mail order facilities as a yardstick with which to control costs and quality. As you doubtless know, the Association for Retired Persons in Washington, D. C. has' been filling pre- scriptions for years for retired persons living all over the United States. This method of distribution would be feasible for all Medicare and Medicaid bene~ ficiaries if regional facilities were used. As you are well aware, a regional mail order facility offers substantial economies because it permits mass pur- chasing and quality standards. 2. A substantial proportion of the prescription drugs required by persons over 65 are maintenance drugs which lend themselves very well to a mall order PAGENO="0176" 4080 COMPETITIVE PROBLEMS IN TBE DRUG INDUSTRY operation. Regional mail order facilities should take care of a much larger share of prescription drugs required by Medicare recipients than by HIP's overall New York City experience with a population of all ages. 3. Some restrictions should be placed upon the quantities of drugs dispensed at one filling. In our experience, doctors tend to write for larger quantities when there is no cost to the patients. This seems to be particularly true when pre- scriptions are to be filled by mail. For this reason, Medicare prescriptions should not be honored for more than a 30-day supply, whether filled in a community pharmacy or through a mail order facility, with a few specified exceptions. 4. As I~ many hospitals, the use of a formulary which emphasizes the pre- scribing of generic drugs is, of course, ~ major means of reducing costs. Also, use of central pharmacies can assure the physicians of quality controls of generic as well as of brand-named products. 5. For mail order delivery, special prescription blanks may be supplied on which the doctor may indicate, by a check mark or initial, that the dispensing of a reliable generic equivalent is permissible. Sincerely, GEORGE BAEHR, KD. (Whereupon at 11:45 a.m., the committee adjourned, subject to the call of the Chair.) PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, JANUARY 28, 1969 U. S. SENATE, MoNoPoLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Was hiugton, D.C. The subcommittee met, pursuant to notice, at 10 a,m., in the caucus room, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson and Hatfield. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; and Elaine C. Dye, research assistant. Senator NELSON. We will resume the hearings of the Monopoly Sub- committee. Our two distinguished witnesses this morning are Dr. Frank J. Ayd, Jr., psychiatrist in private practice in Baltimore, Md., and Dr. Clinton S. McGill, internist in private practice in Portland, Oreg. There is on the floor of the Senate an agreed time limitation forde- bate on the appointment of the Secretary of the Interior which starts at 11 o'clock. At some stage thereafter I may have to recess to go to the floor to make some remarks. I would hope that we would be able to finish with our two witnesses before then. The two witnesses this morning are physicians in private practice, both of whom have requested the opportunity to come before the sub- committee. Repeatedly these hearings have been attacked by the Phar- maceutical Manufacturers Association, and by others, on the grounds that they are not balanced hearings. I would like to state the policy that we have pursued from the begin- ning. Since there are a1mos~ unlimited numbers of witnesses who would like to be heard and since it is not possible to hear all the witnesses at once, we have attempted to establish a policy, which I think is fair. First, it is the policy of the committee to hear every viewpoint on any of the matters that are raised before this committee. it is the policy of the hearings to give the first opportunity to the drug industry itself, since it is the industry whose business is being discussed here. We have stated publicly on numerous occasions that our first priority is to the industry. I do not know of anybody who would think that that is unfair, unless some of the critics of the indus- try might consider it unfair. We have invited all the major drug com- panies to appear before the committee. Secondly, whenever any drug company is criticized before this com- mittee, we forthwith give them the opportunity to respond, with pri- ority over anyone else. We have always done that. 4081 81-280-69-pt. 10-12 PAGENO="0178" 4082 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We have already heard from the Pharmaceutical Manufacturers Association on three occasions and have offered to have them back. In listening to the speeches of Mr. Stetler-which I suppose many doctors around the country have done-one would get quite a different impression. We have made it a~, policy to' give the representatives of the major medical .organizatioiis an opportunity to appear: Incidentally, we have been trying to get the AMA for the past year without success. And we invited them again in the latter part of last year. We then have heard from Government witnesses-the Federal Trade Commission, Bureau of Labor Statistics, FDA, and so forth. After that in priority-last and properly so-would be individual witnesses representing solely themselves, although we have had such individuals, already. I asked the staff to go through the hearings so that we could just summarize what the breakdown has been. The largest single group of witnesses represented before this committee `has been the members of the pharmaceutical industry and people representing the industry. There would have been more if all of them had accepted my invitation to appear. Only a half dozen companies have volunteered, perhaps fewer than that. There have been a total of 114 witnesses before the committee. Some of them appeared more than once, particularly Government witnesses. The largest single group represented in testimony before the subcom- mittee constitutes members of the pharmaceutical industry and people representing the industry. There have been 44 witnesses from the drug industry, far and away the largest single group. We have had 27 emi- nent medical authorities from the academic field, men who are na- tionally and internationally known; 27 from the Federal Government; five or more physicians devoted exclusively to private practice; and the `breakdown continues, to include a couple from State and local government, four from consumer groups, and two from the area of re- search, and the representatives of the highly regarded National For- mulary and the U.S. Pharmacopeia. Thus, considering that we have not begun to `hear from all the people who will be heard, I think the balance, despite Mr. Stetler's criticism, has been strongly biased in favor of the industry. Our first witness this morning is Dr. Clinton McGill. Doctor, you have submitted a biographical sketch which will be printed in the record. (The biographical sketch of Dr. McGill follows:) BIoGn~rHIoAL DATA-CLINTON S. MoGiLt, M.D. Born in Long Beach, California, June 27, 1921. Moved to Portland, Oregon in early childhood. Father-Clinton S. McGill, Sr., electrical engineer, mother- Ada McGill, one brother-Robert, three years older.. Attended public schools in Portland, graduated from Grant High School. Earned letters in three sports-football, soccer, and track (shot and discus). High school activities included student government, debate, drama, creative writing and scholastic honor society. Attended University of Oregon, majored In Psychology. Joined Phi Gamma Delta, social fraternity. Elected to Skull and Dagger, sophomore honor club. PAGENO="0179" COMPETITIVE' PROBLEMS IN ~TI~ DIlU~" INDUSTR1 4083 Junior year elected to Askiepiads, pre-medical li~aor'~~y.S~ior yea~' elected to Phi. Beta Kappa~ national `scholastic jionora.ry. aclua'tcd with Honors (BA.). Other college activities included athletics-earned letters in foQt~ball and swim- ming, student government. Editorial staff, Qregana ( college annual), three years. Attended University of Oregon 1\iedical School~ ~l1ult1lled academic require- ments for Master's degree in Physiology. Junior year elected 1~ Alpha Omego Alpha (national scholastic honorary). Graduated with Honors-thesis in pul- monary physiology. Academic rank-second in a class of seventy two. Social fraternity-Nu Sigma Nu. Internship and Residency in Internal Medicine at Henry Ford Hospital, De- troit, Michigan. Served in the Army Medical Corps. Stationed at Bruns General Hospital, Santa Fe, New Mexico; Brooke Army Medical Center, San Antonio, Texas; Beau- mont General Hospital, El Paso, Texas; and Madigan General Hospital, Tacoma, Washington. Discharged with rank of Captain. Entered private practice in Portland, Oregon, in association with Dr. Leon A. Goldsmith, Internist and Cardiologist. Appointed Instructor in Physiology at Oregon Medical School (part time). Taught Physiology one year at Portland State College. 1950 (following death of Dr. Goldsmith) appointed Medical Director of the State Public Welfare Commission (part time). Served in that position ten years, at which time a full-time Director was appointed. During this period co-authored the nation's first Permanent and Total Disability program and served as a consultant for the Federal APTD program. Also served as con- sultant for the Social Security Department in the development of the disability benefit program. Appointed Attending Physician, Good Samaritan Hospital. Served on various committees including Chairman of the Internship and Residency program (five years) and Executive Committee (three years). Married, wife-Trudie, four children (ages 15 through 24). Hobbies include- hunting, fishing, skiing, swimming, gardening. Civic Activities: Medical Director, Oregon School Activities Association (10 years). Portland Boxing Commission (10 years-Ohrm. 2 years). Eoard of Directors, Community Child Guidance Clinic (3 years). Board of Directors, Oregon Cancer Society (3 years). Board of Directors, Oregon Heart Association (3 years). Junior Chamber of Ctommerce (Legislative Committee and Health Affairs Comm.). Senior Chamber of Commerce (Legislative Committee.) Board of Directors, Consumer Credit Counseling Service (at present). Lecturer, Division of Continuing Education, Oregon State Board of Higher Education (at present). Lecturer, Portland State College (at present). Lecturer, Portland School District No. 1 (at present). Multnomah County Medical Society: Immediate Past-President (present position). President (one term). Vice President (one term). Board of Trustees (two terms). Delegate to House of Delegates (16 years). Chrm. Puilic Relations and Public Policy. Various Committees. Speakers Bureau. Oregon Medical Association: Speaker of the House of Delegates (3 years). Board of Trustees (6 years). Executive Committee (3 years). Public Policy Committee (Legislative Comm.)-(10 years; ~Jhrm. 5 years). Charitable Medical Care (5 years; Ohrm. 2 years). Ethics Committee (Chrm. 3 years). "Operation Hometown"-Co-chairman (Medicare campaign). Committee on Title XIX Legislation. Committee on Public Law 89-749. Various other committees. Speakers Btireau. PAGENO="0180" 4084 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY American Medical Association: Delegate, Western Conference of National Commission on Community Health Services. Delegate, AMA Kerr-Mills Conference. Delegate, AMA National Conference on Ethics. Delegate, AMA National Conference on Socio-1~comomies. Member of Speakers Buream Delegate, House of Delegates. AMPAC-OMPAO Activities: Board of Directors (4 years). Steering Oommittee (3 years). Ohrm. Oregon Conference on Good Government (Co-author, handbook on State Government). Delegate, National AMPAC Workohop, Washington, D.C. (4 years). American Society of Internal Medicine: Charter.Meniber, Oregon Chapter. Board of Trustees (2 years). Senator NELSON. The committee certainly appreciates your taking time to come here. I defer to my distinguished colleague, Senator Hat- field from Oregon, who will introduce the witness. Senator HATFIELD. Mr. Chairman, I am proud to present to the committee this morning Dr. Clinton McGill, who is a product of the Oregon schools, the University of Oregon Medical School, with intern- ship and residency in internal medicine at Henry Ford Hospital in Detroit, Mich. He has been a teacher. He has been a practitioner. He has been a public servant working in the State public welfare com- mission as the medical director. He has been very active in his profes- sional life, in the activities of the Multnomah County Medical Society, American Medical Association. I would not attempt to list all of the honors and all of the distinc- tions that have been bestowed upon him for his professional and civic activity, but I think they speak for themselves and I think you will find him to be a very direct, frank witness and able to take care of himself. Senator NELSON. Thank you, Senator Hatfield, Doctor, you may proceed to present your testimony in any manner that you wish. You may read it directly, and.if you wish `to depart from your prepared testimony and discourse~ at greater length on points you have raised, the committee certainly will be pleased to have you do so. I trust you have no objection to questions as you proceed. Dr. MCGILL. None whatever, Senator. Senator NELSON. Thank you, Doctor. Go ahead. STATEMENT OP DR. CLINTON S. McGILL, PRIVATE PHYSICIAN, PORTLAND, OREG. Dr. MCGILL. Senator, if I may just start by pointing out something which has come up since I submitted my testimony, and I point to the article in U.S. Medicine, the copy of Janu~ry 1, 1969, that was an interview with your counsel, Mr. Gordon, seated on your right, in which he chose the opportunity to make a personal attack on me. I resent this attack and I would like to set the record' straight right now about the facts in this case, if you will allow me. Senator NELsoN. Yes. I was not familiar with the article. PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4085 Dr. MCGILL. In this article, and I shall quote only a few lines from it, Mr. Gordon made the comment charging the drug trade associa- tion with promoting a physician for these hearings. The disparaging comment that individual witnesses are a dime a dozen, which I resent, that I have had communication with the PMA regarding the testi- mony that I would give before the subcommittee. He said the sub- committee knows of several instances in which the PMA has promoted individuai witnesses and in some instances PMA will even write their statements. Now, I would like to make this perfectly clear. The statement I submitted today is my own and has not-was never seen by the PMA until after it was submitted to this committee. I wrote every line of it and the views are my own. And the comment, Mr. Gordon, that what happens in these hearings is completely irrelevant to us I think is a little unfair. The hearings are relevant to us. We are the ones that practice medicine in this coun- try. What possible purpose would be served by having my statement copied and sent to other physicians? That would serve no one's purpose.1 But I would like to set the record straight right now. I have never been employed by the pharmaceutical industry. I do not own stock in any drug company nor have I ever. I have iiever received an hono- rarium, stipend, gift, or fee of any kind from the pharmaceutical industry and I would like the record to show that. With that point clear, I will proceed. The first paragraph of my testimony included some of the biograph- ical data that Senator Hatfield has already covered. I would like to point out that from 1940 to 1959, a period of 10 years, I did serve as the part-time medical director of Oregon State Public Welfare Commission. During that period I was called as a consultant for the Federal Government in the development of the permanent and total disability program under the Department of Public Assistance. On another occasion I was called as a consultant to the Federal Govern- ment when the disability amendments were added to the Social Security Act. I have included this information to establish my famil- iarity with the problems involved in purchasing necessary medications for low-income families and welfare recipients. I have followed with great interest the hearings of this committee for the past ~0 months. I felt a growing concern that no one from the private sector of medicine had been .heard. 1 (Subsequent in~ormatio'n follows:) MEMORANDUM April 15, 106~ TO: Senator Gaylord Nelson chairman, Monopoly Subcommittee FROM: Benjairdn Gordon, S'ta~ Economist RE: DR. McGILL'S TESTIMONY During the course of Dr. McGill's testimony before our Monopoly Subcommittee, the witness stated: "And the commenl, Mr. Gordon, that what happens In these hearings is completely irrelevant to us I think is a little unfair. The hearings are relevant to us. we are the ones that practice mediqine in this country. what possible purpose would be served by having my statement copied and sent to other physicians? That would serve no one's purpose.~' In the February `10 Issue of the AMA News, which goes to every physician In the country whether he is ~ member of the AMA or not, two-thirds of the editorial page is devoted to excerpts of Dr. Mccill's prepared statement which be submitted to the Committee. Not a single word is mentioned about the proceedings In the hearing room. PAGENO="0182" 4O8~ COMPETITIVE PEOB&I~MS I~ TI~E DRT.~G' ~N~JS~RY Senator NELSON. May I interrupt just a moment? Dr. MCGILL. Surely. Senator NELSON. Have you read the testimony of the hearings? Dr. MCGILL. I have read a great deal of the testimony, Senator Nelson. Senator NELSON. Yesterday I glanced through the record after reading your statement and I notice that there have been several from private practice who have appeared before the subcommittee. The record shows that Dr. Albe Watkins appeared, Dr. Franklin Far- man, Dr. Richard Burack, Congressman Durward Hall- Dr. MCGILL. Dr. Hall and Dr. Burack, neither one represents pri- vate practitioners. Understand, I know Dr. Hall, Durward Hall, and have great respect for him but he is a U.S. Congressman. Dr. Burack is a professor of pharmacology at Harvard. Senator NELSON. He is in private practice. Dr. MCGILL. There is a difference between the academically oriented practitioner of pharmacology and the private practitioner. Senator NELSON. He is from private practice but' in any event your statement is that none have appeared, and the record shows otherwise. Dr. MCGILL. All right. Senator NELSON. Incidentally, Dr. Hall practiced in Missouri for 25 years. I suppose he did not lose `his experience as a private prac- -titioner when he became a Congressman. He was appearing against the hearings. He has your viewpoint. Dr. MCGILL. I have seen his testimony. Senator NELSON. Dr. James Faulkner, now retired, was in private practice of internal medicine and Dr. George Baehr of New York is in private practice. I just wanted to point out that there have been at least five witnesses who have had an extensive private practice. There may `be 500 more private practitioners who want to appear. We have had to establish a policy, as I stated earlier, of hearing from the drug companies and organizations and others before we get to the private practitioner. We have not even had the Academy of General Practice before us yet, and I would think you might agree that the spokesman for the Academy of `General Practice would have some priority gen- erally, over individual practitioners, hut we will get to the practi- tioners and that is what we' are doing this morning. Dr. MCGILL. I would certainly agree and I am also aware of the fact that the American Academy of General Practice has made the request many months ago to be heard `before this committee. Senator NELSON. Yes. As I told Mr. Stetler when he was-here, if we followed his theory we would have to hold the hearings all at once in the stadium and everybody testify at the same time. We have to have some order in which to present witnesses. Dr. MCGILL. I realize that. Senator NELSON. The Academy of General Practice has been in- vited. The AMA was invited a year ago, and again last December. It seems to me that, a large' share of the information concerning witnesses who have been invited to appear. before the sub~dmmittee has come from the PMA rather than the subcommittee. We would be glad to let you have this information, and we invite you to examine our' files so that you might hav~ firsthand .~nowJedg~ of the persons we have in- PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTEtY 4087' vited, those who have declined, those who have not given any indica- tions as to their intentions and, of course, those who have accepted our invitation. Dr. MCGILL. The only reason I even raise the point is the fact that many of the witnesses that this committee has already heard have made some very serious charges which I think we should be allowed the privilege of answering, not many months later but as soon as the charge is made. This is my concern, that somebody be `able to answer the charges that have been made I think I will answer them in my testimony. Senator NELsoN. Please go ahead. Dr. MCGILL. As I mentioned, on March 28 of last year I wrote to Senator Nelson and Senator Hatfield volunteering my services, hop- ing my testimony might add a useful dimension to these hearings. In the final analysis we are the ones who prescribe the medicines and must evaluatetheir worth on a day-by-day basis. We are also `the ones toward whom the pressures and promotions of the drug companies are directed. I should add that we carry the moral, medical, and legal responsibility for the effects of those drugs on our patients. I am grateful to the committee for inviting me to testify. From the outset I would like to make my position clear as I have tried to do. I am here today representing no vested interest except the health of the American public. My interest in your proceedings stems solely from my concern for the welfare of my patients and for our health care system. The views that I am expressing today are strictly my own. A number of very strong opinions have been voiced before this com- mittee. Although I agree with some, I take strong exception to others. These committee hearings, I think, have the potential for aecomplish~ ing `much that is good and I sincerely hope this will be the case. But, I would submit that this committee also has the potential for creating a great deal of mischief, and this is my greatest concern. Senator NELSON. Did you document the mischief? Dr. MCGILL. Yes. I think it will be pointed out, `Senator. I would like to direct my attention `to several areas that I think need to be clarified from the point of view of a practicing physician. First, I would like to briefly point to the great strides that have been made in medicine during the 20 years of my private practice. In this period we have been given more effective therapeutic agents than were produced in the entire history of medicine before that time. In these few years, the progress of our science has achieved a "health ~ beyond the `wildest expectations of the last generation in medicine. There can he little doubt that a great share of the credit is due the pharmaceutical industry. I find it a curious paradox that the drug industry is suffering its severest criticism at the very time it has pro- duced its greatest progress. The therapeutic agents I have available to me today have made it possible for me and others like me to be far better doctors than we ever dreamed we could be. I am grateful for the~e new products and my patients are grateful. Senator NELSON. May I interrupt a moment? So is the committee. I would not want your statement to leave the impression that the committee and all of its members do not recognize many fine contri- butions pharmaceutical manufacturers have made. From what Mr. Stetler and some of the other critics `of our hearings have said, you PAGENO="0184" 4088 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY would think that we did not. We have repeatedly expressed our respect for the drug industry. These hearings are not aimed at taking credit from the industry for their many accomplishments. These hearings are aimed at evaluating some problems within the drug industry which are of public concern-congressional concern. If there were no such prob- lems, we would not be conducting hearings at all. Certainly, no one- not eyen the industry itself-denies that there are problems, and I might add serious problems, within the industry today. Please go ahead. Dr. MCGILL. Ours has truly become the "Golden Age" of medi- cine * * * as opposed to the "Golden Age" of surgery, which occupied the first 50 years of this century. It should not be surprising then, that those of us who are fortu- nate enough to practice medicine `during this rather exciting period will view with increasing alarm any influence which we feel threatens our system. I cannot believe it is the intent of this committee to cripple the `drug industry or hamper our continued progress in medicine., But, Iwo'uld caution the committee that.these hearings may produce exactly that result. It deeply concerns me `that many of our excellent drug products are becoming better known to the public,, for their occasional harmful effects, than for the en~rmous good they accomplish. .The publicity given these hearings, with the emphasis that has `been placed on a small number of `serious side effects, has the effect of undermining the public's confidence in our pharmaceutical industry. More than. that, many patients become sufficiently alarmed' that they stop taking medi- cines they badly need, and we have had th'is experience. Senator NELSON. Would you give the committee some specific ex- amples of the publicity given to drugs emphasizing their serious side effects? Dr. MCGILL. Well, `by far the best example `of it is t'he terrible wring- ing out Chioromycetin got `before this committee. The birth control pill, `another product that has extreme value in private practice of medicine. Senator NELSON. Let us talk about Chioromycetin for a moment. Do you use it in your private practice? Dr. MCGIlL. I certainly do. Senator NEL5ON~ What are the indicated uses of Chloroniycetin? Dr. MoGUL. The indications of Chioromycetin are very well known and should `be known to all practitioners who use the drug. This is the only effective drug for typh'oid fever, the most effective drug in any of the salmonella infections, resistant staph infections. Most of the gram negative and gram positive respiratory infections will respond, although I will agree other antibiotics can do the trick here, too. Senator NELSON. For what indication is it the drug of choice? Dr. MCGILL. It is the drug of choice in any bacterial infections that are resistant to other drugs and sensitive to ~hloromycetin. Now, that can be demonstrated in the laboratory. It is the drug of choice in typhoid, the d'rug of choice in ricketsial fever, it is the drug of choice in hemophylis meningitis, staph pneumonia. Shall I go on? Senator NELSON. Certainly. Dr. MCGILL. This is a valuable antibiotic. This is a lifesaving drug. PAGENO="0185" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4089 I am well familiar with the blood dyscrasia. I have seen one, not in my own practice but in one of my near associates. Chioromycetin also saved my own son's life and that has a lot of meaning to me. Senator NELSON. I ath just trying to get at the publicity as to the serious side effects of chloramphenicol that seems to concern you. What concerns you about that publicity? Dr. MCGILL. The side effects? There has been- Senator NELSON. No; I mean the publicity of the side effects. Dr. MCGILL. The publicity of the side effects often carries over to the use of other effective antibiotics. Individuals in the public often are not able to differentiate between one drug and another. While tak- ing one of these powerful antibiotics, they will say, Doctor, do you really think I should do this, because after all I read in the paper about all these harmful effects- Senator NELSON. Are you aware of how widely chloramphenicol was misprescribed in this country? Dr. MCGILL. I am aware of the testimony that has been heard by this committee. In fact, that is this whole copy. And I have read it from cover to cover. And I challenge much of the testimony that has been given because a great deal of this is after the fact testimony. Senator, this is Monday morning quarterbacking. That is not quite fair. Senator NELSON. You are welcome to peruse the committee's files on chioramphenicol, if you wish. But let me ask you a few questions. Would you prescribe it for acne? - Dr. MCGILL. This is a good question about acne. I have never pre- scribed it for acne but I know dermatologists that do. Let me put a hypothetical case. Senator NELSON. To our knowledge, every single expert in the United States agrees that it is nonindicated for acne. There are doc- tors throughout the country with judgments against them, and more developing all the time because the doctors prescribed chloramphen~i- col for nonindicated cases-and acne is one. Dr. MCGILL. Part of which has been the product of these hearings and that is the point I am getting at. Senator NELSON. That is the good part of the hearing. Dr. MCGILL. I disagree. Senator NELSON. Would you prescribe it for a hangnail? Dr. MCGILL. Certainly not. Now, understand, Senator Nelson, I am not recOmmending the misuse of any drug and I will not deny the fact that these drugs are being misused. But may 1 point out it is very well for Dr. Dameshek to sit up here and say, well, all the cases we have investigated in the past have not been proper indica- tions for thei drug. I have the world's, greatest respect for Dr. Dame- shek. I know him and respect him as a great hematologist. However, every one of these judgments is made after the fact. He did not have the decision to make at the time in a patient with a serious illness. That is an entirely different story. Now, let us take the case of acne which they say is `nonindicated and I would like `to put that as a hypothetical question. Acne can be a serious disfiguring psychologically imparing problem to young peo- ple, particularly young women. PAGENO="0186" 4090 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY Now, let us take a hypothetical case. Supposing we had such a young lady with a pustular acne, that it was seriously affecting her emo- tional, and believe me this happens, her whole emotional development. We have cultured the bacteria and find it to be a staph infection which is Chloromycetin `sensitive and not sensitive to any of the other staph preparations, and this is entirely conceivable. Now, the clinician has this choice, do I put this patient on a drug that perhaps one in 40,000 times produces a blood dyscrasia but perhaps can help her, not only her `skin but her whole emotional complex, or do I deny her the ad- vantage of a drug that I know will help her? Senator, that is not an easy decision to make and I challenge whether this may not be a very logical decision. Senator N1~soN. You have, of course, cited a hypothetical case with special circumstance. That is not the issue here at all. Are you aware that the testimony presented to our subcommittee is that nearly 4 million people a year have had chloramphenicol prescribed-and our witnesses all agreed that at the very maximum only 10 percent of those people should have had it. Ninety precent or more Were getting it for nonindicated cases. Dr. MCGILL. That is a spurious figure.. Again, thi~ is Monday morning quarterbacking. This is by hematologists that make some sort of a wild guess without any figures to guess from at all. I have read the testimony, Senator. Senator NELsON. Are you aware, for example, that Dr. Weston, a State medical examiner, said that in all the cases of death from aplas- tic anemia, from the use of Chloromycetin,, he had yet to find one that was prescribed for an indicated case? Dr. MCGILL. Yes. And I find that very regrettable but it also points out how relatively rare aplastic anemia is. Senator NELSON. We do not have any statistics on that, you see, because- Dr. MCGILL. They are hard statistics to get, I know that. Senator NELSON (continuing). The case ends up with a specialist at some stage who finds out the drug has been prescribed for a nonindi- cated case. It does not become a part of any record any place. So, the only statistics we have are from California. Those are gross statistics of cases which are provable. Obviously the number-the percentage is much higher-but no one knows how much higher. Dr. MCGILL. Let me put it this way, Senator. Let us take the kind of a decision I have to make as a physician. I have a patient in the hos- pital with a serious salmonella infection, let us say. Now, there are other drugs, Ampicillin; for example, which will work, not as well but it will work in `a serious salmonella infection, but I have a critically ill patient tonight. Do I prescribe a drug I am almost certain will work, which is an excellent drug, or do I prescribe a drug I think will work as well and not have as much liability, still bearing in mind the one in 40,000 possibility of apalastic anemia? If the patient is sick enough we will `chose the drug we are certain will work. Now, Dr. Dameshek at a later date will say, Dr. McGill, you could have used another product, therefore, it was not indicated. I do not agree. The decision was the physician's at that time and that was a proper indication. PAGENO="0187" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4091 Senator NELsoN. That is not at all the kind of case these doctors are talking about. For example, the kind of case they are talking about- Dr. MCGIlL. Colds, things like that, I agree. Senator NELSON. When Dr. Dameshek was here, he used as an illus- tration, I believe, a case involving a lady who ended up in his care because her doctor gave her chioramphenicol for headaches. The doctor told her to take it any time she had a headache. She kept it in her medicine cabinet and that is exactly what she did. And she died. The kind of cases we are talking about is the child who has an infected hangnail. There has been no lab testing. Or an infected tooth- or any number of such miscellaneous cases. This, doctor, is the point we are talking about. The physicians who testified before us-the tremendous number of letters we have re- ceived-none of them are talking about the kind of case where a patient `was critically ill and a decision had to be made forthwith. So that we understand each c~ther, the issue here is the overwhelming misprescribing of this drug all over the country for the nonindicated cases. Dr. MCGILL. I understand that, but my cases, the case 1 described to you with the salmonella infection, will never come to Dr. Dameshek's attention because the patient got well and- Senator NELSON. The kind of case that comes to his attention is the gross misuse. Dr. `MCGILL.' I do not disagree the drug ~s overprescribed and mis- used and I will not defend that. We have all variations of abilities as physicians just as we do in lawyers and engineers and every other pro- fession, but my point is chioramphenicol is a very worthwhile, hf e- saving drug and it has become too well known for its side effects and not well enough known for its good effects. I think you will find that this point of view is generally shared by the medica~lcommunity. Do you wish meto go on? Senator NELSON. Anyone, of course, is entitled to disagree with the doctors whose testimony we have heard to date on this matter. But all of them agree with Dr. Paul Hoeprich of the University of California Medical School when he said "I think something should be done, the prescribing of the drug certainly far exceeds the indications of its use." Dr. MCGILL. Every single one of those individuals-I have read this testimony. None of them suggest that it really be restricted and even Dr. Goddard before this committee said he would not suggest seriously restricting its use because it is too valuable a drug. Senator NELSON. What do you mean by restricting its use? Dr. MCGILL. The suggestion has been made it be restricted only to hospital use; for example, and I think in a moment you yourself said perhaps it should be taken off the market because it has done more harm than good. That is not so. Senator NELSON. I never said that, sorry. Dr. MCGILL. I think perhaps this may have been in a heated moment and I understand these things. But your testimony yourself: "We would be better off actually in view of what has happened if we never gave the drug at all." Now, that is not true at all. PAGENO="0188" ~4O92 COMPETITIVE PROB~LEMS IN THE DRUG' INDI1~TRY Senator NJ~LSON. However, that is read out of context. The patients involved had been given it for nonindicated cases and if the testimony we have heard to date is correct, 10 percent or less of the people receiv- ing chioramphenicol last year should have had it. In fact, Dr. Weston thought that less than 1 percent of those getting it should have it. Dr. MCGILL. I challenge Dr. Weston's figures and I do not think he is-I recognize Dr. Weston as an authority in his area but I do not feel he has correct figures. Senator NELSON. Do you know what happened to the use of the drug after the publicity? Dr. McGrE~L. It probably accelerated. Senator NELSON. No. In the first 6 months of 1968, versus the first 6 months `of 1967, it dropped from about 20 million grams of use for- Dr. MCGILL. Now, when the first reports of aplastic anemia and blood dyscrasias came out and were reported in 1951 to the medical profession the use of Chloromycetin dropped almost to zero. It dropped very sharply because of this potential danger, once the facts were known. My point is this information is not wasted. This does reach the m~dical profession and `any doctor `that has practiced in the last 1~5 years and does not know that ~hloromycetin can produce serious blood dyscracias must be blind,' dumb, and deaf because there h~we been all kinds of warnings. Senator Nzi~so~-. That iS exactly what the experts' testimony has been-that many doctors have'been blind, dumb, and deaf. `It has been a hOrrible tragedy in this country `and it is an indictment of the medical profession. If you wish to go through our files you will find letters from parents whose children died as a result of the drug being admin- istered for such nonindicated cases as hangnails, acne, sore throat, and the like. It is incredibl&-simply incredible-and it is an indictment of the medical profession. Dr. MCGILL. Senator, I do not disagree but you are talking today to a physician whose son's life was saved by the ~hloromycetin. Senator NELSON. In your son's case perhaps it was given for au in- dicated condition. No one would criticize that. Certainly none of the doctors from whom we have heard. These doctors said it is an excellent drug but that because of the serious risks involved in its use, it must be restricted to the extremely limited conditions for which it is indicated. Dr. MCGILL. But you will notice the statement is made all through the testimony that were' it not for the blood dyscracies, this would doubtless `be the best antibiotic ever made. That is in the record. Senator NELSON. No one disputes that. ` Dr. `McGu~. Well, my point is, I think something should be said about this valuable drug which has an unfortunate hut rare compliea~ tion. The fact that it is being overprescribed or prescribed for indi- cations that are not correct, 1 will not defend. Not at all. And I think we within the fraternity try to do' our best on this score. Senator N~LSON. Of course, that has been the testimony. All the ex- perts say it is an excellent drug.'A i~ery valuable drug, but it should be used only in indicated cases. The testimony is that they think' that in 90 percent or more of the cases, it has been used for nonindicated cases. That is the real issue here. Now-- PAGENO="0189" COMPETITIVE PROBLEMS IN TII~ DIWG INDUSTRY 4O93~ Dr. MCGILL. And all I would like to add, I do ~ot think their figures are correct. Mr. GORDON. Dr. McGill, May I interrupt? You said that chloram- phenicol is the drug of choice for hemophilus- Dr. MCGILL. Infiuenzal meningitis. Mr. GORDON. Here is a recent study 1 the National Research Coun- cil of the National Academy of Sciences. It says that: It is likely that this claim (drug of choice in hemophili influenzae meningitis) is no longer Justified. In meningitis of the newborn, Kanamycin is preferred as the drug of choice for empiric treatment. Dr. MCGILL. There is no question Kanamycin has come along but for many years Chloromycetin was the drug of choice, and inciden- tally, Kanamycin is not without its side effects. Mr. GORDON. I might mention that the recent study by the National Academy of Sciences limits even further the uses of Cliloromycetin. Dr. MCGILL. Yes; but that limitation was not based on the tailure of Chioromycetin. It was based on the fact that there are newer prod- ucts on the market. Mr. GORDON. That is right. Dr. MCGILL. That is fine but this is not an indictment of Chloro- mycetin and that is the way it has been made to sound. Now, we will get better drugs than these, I am sure, I sincerely hope we do, but these things all have to be interpreted in terms of the time of reference they were made. For a long time Chloromycetin was the only drug effective in this area. Mr. GORDON. But not now, is that correct? Dr. MCGILL. Not now, although Kanamycin has its problems. I have used it. Mr. GORDON. Incidentally, it goes into many other uses for which you said it was the drug of choice and for which it no longer is the drug of choice. Dr. MCGILL. Well, what I say at one particular moment and what may be true tomorrow may be two different things. As I mentioned, the drug industry does make progress. They put out new products and I am sure we will see the day when Chloromycetin is an obsolete drug, but for a long time it was the drug of choice of many, many physicians. Senator NELSON. You may proceed, Doctor. Dr. MCGILL. To make matters worse, this committee has givn a public forum to certain arrogant professors of pharmacology who have openly discredited the drug-prescribing abilities of the American physician. I deeply resent this insult to our clinical integrity. The end result of this unfortunate publicity is unnecessary suffering by many individuals who are fearful of using drugs of any kind-and this is tragic. Senator, I have had this ex~perience. Now, a large part of the practice of internal medicine is the treat- ment of cardiovascular disease. I would like briefly to point to some of the improvements that have taken place during recent years:. The anticoagulants have cut the death rate in half during the critical first month following a heart attack. Incidentally, those anticoagulant de- 1See information beginning at p. 4131, infra. PAGENO="0190" 4094 COMPETITIV]~ PR0BL~MS~IN TH~3 DRUG INDUSTRY rivatives were developed in the University of Wisconsin; a great contribution to us. In arterial occlusive disease they have allowed us to add many years of life to the individual. Thanks to our antihypertensive drugs we have managed to cut the death rate from hypertensive heart disease to about half of what it was 15 years ago. Another great breakthrough was the development of the effective oral diuretics. They not only pro- long life but they have added immeasurably to the comfort of people suffering chronic cardiovascular disease. Yet, in spite of all these ad- vances, cardiovascular disease still kills more Americans than all other causes combined. There is much more that can be done in this field and the need is urgent. This committee would be well advised to think in terms of providing greater incentives to accomplish this task rather than discrediting the system. Senator NELSON. In what way have we been trying to discredit the system? I am curious about that. Dr. MCGILL. We certainly have seen many areas of the drug industry criticized for their practices, and there may be some validity. I am not an expert in the drug industry and do not pretend to be~, but I find it difficult to reconcile the criticism of the drug industry in these hearings with the accomplishments they have actually produced. Senator, as a practicing physician I am concerned about new prod- ucts. I want things I can treat my patients with. This is my point of view. This is my concern. Senator NELsoN. I am concerned about that, too, and your general, casual statement regarding the committee's discrediting the system. Is it your opinion that any great industry-such as the drug in- dustry, the automobile industry, the chemical industry-that these industries are sacrosanct? That problems which arise within an in- dustry, whether it is price fixing, price setting, misrepresentation in advertising-and so forth-is it your view that because these com- panies do good things---and no one denies that they do-that `as a mat- ter of public policy we should avoid exposure of their bad practices? Dr. MCGILL. Certainly not. Senator NELSON. Well then, the purpose of the hearings has been to examine some of their bad practices. I don't understand the point you are trying to make when you talk about "discrediting the system." Dr. MCGILL. There may be a difference of opinion, Senator, on what are bad practices and I will get to a couple of those later in the testimony. I think you may want to question-P' `Senator NELSON. Of course there always are differences of opinion. That is' why we permit the industry to come in and answer whenever a point is raised regarding a particular industry. In that way we have both sides in the record. But I do not understand what you mean by our "discrediting the system." You must have something in mind. Specifically, in what way do you feel we have been discrediting the system? Dr. MCGILL. The criticism of the detailing, for example, and that is covered later in my testimony. A couple of areas that I think perhaps will come out as we go along, and I will be glad to enlarge on them if you would like. PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4095 Of the various issues heard by this committee, and here is one right here, none has created greater controversy than the question of generic prescribing or generic equivalency. In my view, most of the testimony has completely missed the point. It seems evident that there are both good and bad brand-nam.e products on the market and there are both good and bad generic~~name products on the market. The impor- tant point is that the product be indentified. If I prescribe a specific brand of drug products, I do so for very good reasons. And, under no circumstances do I want a pharmacist substituting an equivalent product. Any more in this direction will meet with very serious ob- jections from the medical community. Senator NELSON I am sure it would. You are not saying that I have suggested this? Dr. MCGILL. No, sir. But it has been suggested before this committee. Senator NELSON. Oh, yes. It has been suggested, and it has been opposed before the committee. Dr. MCGILL. Do I understand your point, then? You have no ob- jection to product identification as a matter of committee policy. Senator NELSON. We have heard testimony, which has impressed me, to the effect that every doctor ought to be required to put the ge- neric name on the prescription and that he may, if he wishes, designate any brand name he desires. Is that objectionable? Dr. MCGILL. No. That is fine. That is the point we are after. Senator NELSON. After listening to the experts, I believe that to be the correct position. But you see there is a problem. I do not want to be unfair to you, but I would like to ask you a question. There is no reason you should know the answer-but do you know what Thalinette is? Dr. MCGILL. I am sorry. Senator NELSON. Do you know what Thalinette is-or Profamil-dr Valgis? There is no reason why you should know but I ask you- Dr. MCGILL. I am not familiar with the products you are talking about. Senator NELSON. Do you know what thalidomide is? Dr. MCGUL. Certainly. Senator. NELSON. The three brand names I read are all thalidomide. There are 84 listed here in an article by Dr. Taussig who appeared before the committee some months ago. One* of the reasons she gave (and almost everyone supports it) for putting the generic name on the label was that after thalidomide was on the market, it was being sold throughout the world under 34 different brand names. In many coun- tries it was repeatedly prescribed by physicians simply because they did not recognize it by the name under which it was being sold. Dr. MCGILL. Senator, I do not think any doctor would have the slightest objection to this. The generic name of the drug on the prescription is something I always do myself. Now, I have read Dr. Taussig's testimony. I know her and have enormous respect for her. iler point was so that the drug could be identified by someone else, unless there is some specific reason why the doctor does not want to list it, and this could happen, but most of the time no objection. I think this would be a fine thing. Senator NELSON. Fine. PAGENO="0192" 4096 COMPETITIVE PROBLEMS IN TBE ~RUG INDUSTRY Mr. GoRDoN. Dr. McGill, this is exactly what, the piiaamacoiogists advocated, putting the official or generic name on the prescription and the nume of the manufacturer. 1 do not think we had a single pharmacologist who testified otherwise. Dr. MCGILL. This is correct, and as far as generic vcrsus brand name is concerned, I am sure this committee is aware that at least three-fourths of the drugs that we are using do not have generic equivalents. Theref ore, you are talking about an academic point. Many times the reason we favor brand names is that they are simpler names to use. Generic names are often very complex and sometimes very hard to remember. All of us, I am sure, know the generic name when we first start using a drug but then the drug company will provide us with an easier name to use, a more popular name; so we use it and it might require a great deal of going back and restructuring our thinking to get into the generic thinking. I am sure it could be clone if it needed to be, but I do not think it serves a useful purpose, as long as it is identified and I think the name should be on the label. I would have not the slightest objection to that. Shalllgoon? Senator NELSON. Please. Dr. MCGILL, As I mentioned, regulations that interfere with the decision, and you clarified that for me, Senator, would not be in the patient's interest and would be met withopposition. It has been argued before this committee that some sort of a national formulary~ should be developed. I would like to point out an example on this business of switching products by generic names, an example in my own household. I have a diabetic son, that is the same one I refer to, saved by Chiorornycetin, who takes insulin every day. Over a period of years he has always taken insulin manufactured by the Lilly Corp. On one occasion a brand of insulin made bya competitor was substituted. This was precisely the same generic type of insulin he was taking, except it was manufactured by a different company. He promptly had a rather violent allergic reaction to the new product. That is a local reaction in the skin; a large wheal. Obviously, there is something in the competing product that is not present in the Lilly product. That does not mean the competing product is not a perfectly good one for someone else. It ma;y be; but for this particular individual it is not the drug of choice. I would lilce to point out this is the type of information no pharmacist could knew. Only the physician has this information available to him. Mr. GORDON. Are you aware that insulin was not developed by the drug industry? Dr. MCGILL. You~~ are talking about the development of Banting & Best insulin; yes. In fact, I also know Dr. Best and I see him every time I visit there. But the development of a product in a laboratory is nothing more than a clinical curiosity until one of the drug companies is able to make it available through production. Mr. GORDON. We know it is their business to produce it. Dr. MCGILL. I am not criticizing this. My only point is by substatut- ing the same generic insulin, it produced a reaction and I would never give him that brand of insulin again. Again, I am not being critical of the product. I am only pointing out this is the kind of information that PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 4097 only a doctor has, you see. Another point in this area. One of the oldest drugs in common usage today is digitalis. There are many brands of digitalis on the market, all of which must meet lISP standards. Yet, in my clinical practice I prescribe just one brand because I am thoroughly familiar with its effects. Among my colleagues I find this to be standard practice. In fact, we teach our students this. Mr. GORDON. Which do you prescribe? Dr. MCGILL. Upjohn's digitora 1.28 grains, in my own practice. Mr. GORDON. When you write the prescription do you write "digitora," or "digitalis"? Dr. MCGILL. I usually write "digitora" because it is easier. I would write "Upjohn" and "digitalis" but it is a little longer and more complicated. Certainly there is variation between products bearing the same ge- neric label. In most instances, no harm results from tius variation as long as the prescribing physician is thoroughly familiar with the prod- uct he is using. The substitution of another product can easily harm the patient. This is why product identification is important. This com- mittee would be well advised to insist on product identification. Then any kind of an abnormal reaction, any question of therapeutic value, any problem involving the quality of the product could be traced right back to the source. Certainly this would be in the public's interest. In my view, the choice of a given drug for a given problem in a given patient is a decision that only the attending physician can make. Senator NELSON. So far as I am aware, we have no1~ had any testi- mony which would argue with that. Dr. MCGILL. Fine. I am very glad we agree on that point. Senator NELSON. Certainly the witnesses we have had agree on that point. The problem is the propaganda which has been circulated and which is responsible for the misunderstanding. Dr. MCGILL. I am not worried about the propaganda so much as I am sure if we agree on this point, I will feel much comforted. Mr. GORDON. Dr. McGill, just one more point. Digitalis, was also not discovered or developed by the drug industry. Dr. MCGILL. No. It was discovered and developed about 400 years ago, as a matter of fact, by Dr. Withering who wrote an astonishing treatise on it. We have not had-we have not added much to his de- scription, in 400 years. The basic issue in generic prescribing revolves around the problem of drug costs. It has been argued before this committee that some sort of a national formulary should be developed and used where Federal funds are involved. The contention is that generic prescribing would result in a considerable saving of funds. I seriously question this con- tention and I have some firsthand knowledge in this area. I referred earlier to my experience as the medical director of the Oregon State Public Welfare Commission. During the e~irly 1950's, the rapidly rising drug costs became a major problem. In an attempt to solve this problem I developed, with the consultation of others, a formulary for the use of welfare recipients. To my knowledge this was the first such formularly of this type that was ever introduced in a welfare program. Frankly, I consider the development of this formu- lary to be the single biggest blunder that I committed as medical di- 81-280-69-Pt. 10-13 PAGENO="0194" ~tO98 co'M?E~rITIvE PROBLEMS IN THE DRUG INDUSTRY rector. First of all, it Was almost imposible to keep it current with the rapidly developing drug products. It also produced a universal storm of protest on the part of my colleagues. We, of course, made allowances for exceptional conditions, or where life-threatening situations were involved. We soon learned that the administrative costs and the al- ienation of the medical community far outweighed any savings we might have realized by use of the formulary. I would caution the com- mittee to carefully weigh any such decision. The effects are indeed far reaching. Senator NELSON. What about hospital formularies? Dr. MCGILL. Hospital formularies are quite different, Senator Nel- son. They usually represent the agreement of committees on what are the most appropriate drugs being used today and they do not restrict the physician. The reason most hospital formularies are put together is so they can buy by large quantity and therefore get certain savings which would be appropriate to quantitypurchase. Now, in my particular hospital, Good Samaritan Hospital in Port- land, we have a recomrnex~ded formulary but it in no way restricts the physician to the choice of those drugs. If he wishes a specific drug, he may have it. What we a~re talking about is the most likely drugs to be used so they can take advantage of quantity buying. That is quite different from restricting a doctor's choice to the drugs the program can pro- vide. This is the problem of a closed-end budget, you see. Senator NELSON. What do you do about a situation where the public money is being spent-this is the kind of problem that I think Con- gress and the taxpayer, and I would presume the doctors are concerned about. You are, of course, familiar with the Medical Letter. In June of 1967 they published their evaluation of prednisone. This is just one of any number of examples we could use. Now, the price of Schering's Meticorten, which was far and away the predominant brand in the market, was $17.90 for 100 tablets, and Parke, Davis' Paracort was $17.88 a hundred on down the line to $10, $8, Merck's at $2 and finally down to 59 cents a hundred. There was a price gradation from 59 cents a hundred to $17.90 a hundred to the pharmacist. So the markup for Meticorten `and Paracort is somewhere in the twenties or thirties. As a result of the chemical tests and the advice of their clinicians, the Medical Letter said that in their judgment they are all equivalent. And they so advised the physicians. Dr. MCGILL. The price differential on prednisone is really well known in the medical fraternity and I myself don't know wh7 they don't use-have greater use of the less expensive products. On the other hand, I would not prescribe it generically without specifying the brand because where we may haVe five or 10 or 15 on the market today which meet certain equivalent performance, we may have 200 tomor- row, and this is why I would identify the product. Senator NELSON. But the fact is the Meticorten at $17.90 dominated the marketplace and it was- Dr. MCGU4L. It is a good product. Senator NELSON. Yes, but it is no better than Merck's according to the Medical Letter. PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4099 Dr. MCGILL. I will agree, and I think that you have picked an extreme example but I don't disagree with you. I think this does not make sense and the less expensive Merck product should be used which I wotild use myself. Senator NELSON. This isn't an exceptional example. Dr. MCGILL. That is an extreme example of price gradation. Senator NELSON. I can give you any number of other examples right now. Dr. MCGILL. I am aware that there are price variations but I think probably the Meticorten story which has been told many times is an extreme. Senator NELSON. The reason I used Meticorten is that otherwise the witnesses might argue that the other brands aren't as good. None of the experts before the committee felt that they would quarrel with the judgment of the Medical Letter on this. I will give you another example. Chlorpromazme was developed by Rhone-Poulenc in France. They licensed its use to a single manufac- turer in the United States and a single manufacturer in Canada. There was no research money involved on the part of either company. They were just licensed to sell it exclusively as a monopoly. In the United States, the Defense Supply Agency paid $32.62 a thousand. I suppose this was the lowest price anyone could get in this country, since of course they purchase in large quantity. But-in Canada the Department of Veterans Affairs paid $2.60 per thousand. The same drug. Dr. MCGILL, Senator, there are several points with which I would take issue. First of all, Parke, Davis Co. has a great deal of research money in Chioromycetin. Senator Nri~soN. I said chlorpromazine. Dr. MCGILL. I am sorry. Well, also there are several hundred manu- facturers of these drugs in Europe and other countries where there is a very definite competition between product manufacturers. Chlor- promazine is licensed by one company and that, incidentally, will no longer be true next year, I understand, and I have no doubt the price will come down. Senator NELSON. All I am saying is that there are vast price differ- ences. Here we had the same drug licensed to one company in this country and one in Canada-selling at $32 a thousand in this country and around $2 a thousand in Canada. I just don't want you to think these are extreme examples, as you stated-we can give you dozens of examples. My point, however, is what does the taxpayer say, and properly so, when all welfare patients in one particular community are getting prednisone at $17.90 plus the markup, and then 10 miles away in another community the doctors are prescribing Merck's at $2. Dr. MCGILL. I don't disagree. We are in agreement on that point. Senator NELSON. Well, if you don't establish some kind of a formu- lary situation, how do you decide the issue? Dr. MCGILL. By price information, and I think that is where price information needs to be distributed more generally and it is being dis- tributed more generally. This has become almost a standard procedure with detail men, to give price information right along with product information, and this may be one of the effects this committee has had. PAGENO="0196" 4100 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY One such effect is to encourage the growth of the small parasitic drug companies who cash in on the research and development of the major pharmaceutical houses. Most of these small companies make no contri- bution whatever to the health of the public or the growth of our science. It's only natural then, that we will favor the product of the company that developed it. The parent organization has vastly more experience in the production and quality control of the product; therefore, it is reasonable to assume greater reliability. This is what concerns us. Senator NELSON. I don't quite follow that. Let me ask you a question. Every other company in America is in the same situation. If you discover a new drug, you patent it for 17 years and charge anything you please. At the end of the patent period anybody is free to manu- facture it. That is true whether it is automobiles or anything else. Dr. MCGILL. Fine. Senator NELSON. Why shouldn't that apply here? Dr. MCGILL. It does. Senator NELSON. What, then, is the criticism? Dr. MCGILL. This refers back to the formulary. A formulary requir- ing for public money the use of generic equivalents would have the effect of favoring the small company at the sacrifice of the big company who produced all the research and development. That is my concern. Senator NELSON. That is the point I am getting at. Why does it favor the-~as you say-the parasitic company. Do you call Strong, Cobb & Amer a parasite, one of the biggest generic manufacturers in America who sells to all the major companies? Dr. MCGILL. I call any company a parasite, a parasitic company, that does not do research and development of their own. This is our concern. Senator NELSON. All right. You say that a formulary based on price would favor generic pro- ducing companies. I don't quite follow that. The company that dis- covers the product has 17 years in which to make whatever profit it sees fit. Their product is without any competition whatsoever in the marketplace-a total monopoly for 17 years. Then the patent runs out. is there any reason in the world why the patent should be extended- giving them further preference, s~ to speak? Dr. MCGILL. No. I am not suggesting that. Senator NELSON. What preferential treatment is there if, on the basis of price, you purchase from a generic company? Dr. MCGILL. No, but if they were required to choose, in other words, if you put a price-oriented national formulary that we must use in public welfare or any kind of public money program, that has the effect of favoring the generic prescriber. Senator NELSON. Why is that? Dr. MCGILL. On a price, competition only, basis. Senator NELSON. Why does that favor the generic prescriber? Dr. MCGILL. Well, the assumption is that the generic prescribers, having no research and development program; can put their product mit cheaper, plus they can also use the research information and patei~t information of the other company. Again I don't know all the eco- nomics of the drug industry. My concern is that if we-what we are going to end up doing is to eliminate two classes of drugs and end PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4101 up with drugs in the middle. The generic houses will come up to line and the few instances of very high-priced trade names will probably come down. That might be a good thing, but what I am concerned about is if we cripple research and development, we won't get the tools we need. This is my concern as a physician. Senator NELSON. That is why I am pursuing this. I don't under- stand how you cripple research and development. You have a 17-year patent. They can charge 100 or 1,000 times the production cost. In fact, it is pretty clear that in Meticorten at $17.90 a hundred v~rsus ~59 cents a hundred that they are doing this. Here is a cornpa~iy that can manufacture at 59 cents a hundred and make a profit, You give them the 17 years. The patent runs out. They have made all their profit. Then I think Government, the physicians, anyone-ought to buy the cheapest equivalent drug in the marketplace. 1 emphasize equivalent. Dr. MCGILL. Well, this is, of course, a different issue, whether it is equivalent or not. Senator NELSON. There is no argument that I know of about the prednisones listed here. That is why I stressed equivalent. What hap- pened with Meticorten? In the retail marketplace they charged $17.90. After these hearings, they reduced their price from $17.90 to $10.50 a hundred. Another company reduced from $17.88 to $3.45 a hundred. Dr. MCGILL. Incidentally, may I say this is one of the good effects this committee has had. Everybody has gone back and taken a close scrutiny of their price structures. Senator NELSON. Yes, but the issue here is that these companies- in this case it was Schering-was selling to the pharmacies at $17.90 a hundred while to New York City Schering was bidding and offering to sell at $1.20 a hundred. Why? Because they were taking bids in competition with these other companies. That is why they were willing to sell at $1.20 a hundred. I don't quite understand your position with regard to a formulary. The patent runs out. You choose the lowest price equivalent drug that is reliable. Why, then, is that a disadvantage to the company which has already recovered all their research moneys and made their profit-- and is now competing, like everyone else, in the free competitive economy? Dr. MCGILL. Which they have to do right now as far as that is concerned. But my concern, and I can't help but be a little critical of the small company who does not make any contribution to me or my clients, but simply wishes to cash in on somebody else's product. Now, call that prejudice if you like but I don't favor such a com- pany. I also think it is up to them to establish, I repeat, it is up to them to establish, whether or not their product is equivalent. I don't mean USP. I mean therapeutically equivalent, and I will not use their product until that is established. Senator NELSON. Well, I guess- Dr. MCGILL. As a matter of fact, I think this is the area that your committee would be well advised to view, what the practices are among the small companies who do no research and development. The extent PAGENO="0198" 4102 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of their research and development is the Patent Office, whose drug expires next. What contribution do they make except a pricewise contribution? They make nothing to the `science. The price is im- portant. I don't mean to be discrediting that, and I will have some- thing to say about that a little bit later, but our concern is growth and development `and we will naturally favor the' ones who help us on this score. Senator NELSON. What I am getting at is what more should you do for a company aside from giving them, a 17-year monopoly? I think all of us would be very happy if, for example, in the automobile industry some one who had never designed or done anything' at all would take all the patents on automobiles and come up with a car that w~s one-third the price of those in the marketplace and ]ust as good. Would you atta'ck them as a parasitic competitor? That is what a free oompetitive economy is all about. Otherwise you would have a monopoly forever. Dr. MCGILL. I am glad you brought that up because I think the point should be made that the patent, the 17-year patent right is not unique to the drug industry. This is unique to the patent system of this country. Senator NELSON. That is correct, but in every other industry, when the patent runs out, everyone is free to produce the product. Whether it be the private citizen, businessmen, or Government, everyone is going to take the best product they can get at the lowest price. They aren't going to sit back and say "I am going to pay twice as much out of gratitude to General Motors because they invented this de- vice." Why shouldn't we do this with drugs? Dr. MCGIlL. None at all, and I think perhaps I may have over- emphasized the loyalty type of argument, not that I don't think loyalty is important. I do. Yet up to a point. The drug products made up by other manufacturers that I know and where I know the reliability of their organization, if produced at a much lower price, we certainly will use the one at the lower price. Our loyalty will only go so far for a product, I don't think it serves any purpose to get into the equiv- alency argument in front of this committee, again, it has been heard so many times. I think that the small companies should be required to prove their product is equivalent and then I would use them if they have a better price. No objection to that at all. Until that time we may very likely favor the original manufacturer because we have great faith in him and feel he has the experience he needs to produce the product, and there are examples of this, Senator. Senator NELSON. Please proceed. Dr~ MCGILL. Well, I wish to go on. In my view, if this committee wishes to critically examine any seg- ment of the pharmaceutical industry, it should direct its attention to these noninnovators whose sole purpose in the drug field is to profit on the products other companies have developed. Senator NELSON. I think Senator Hatfield had a question. Dr. MCGILL. Yes, surely. Senator HATFIELD. Dr. McGill, on this point of having no alternative but to reduce their research and deVelopment programs, don't you PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4103 think they might also have the opportunity if they are in this kind of a situation that you describe to reduce their advertising budget? As you might know- Dr. McGiii.. I have no idea, Senator Hatfield. I don't know that much about drug economic&. Senator HATFIELD. I think there are about $400 to $600 million spent by the industry each year. Dr. MCGILL. The figure $600 million has been used quite often. Senator HATFIELD. It seems to me there might be another alternative than to cut into their research and development programs. Dr. MCGILL. In fairness, as it has been described to me, that. $600 million does include their total marketing costs and not just advertising. Senator HATFIELD. Excuse me. Dr. MCGILL. As far as marketing is concerned, I am sure it would be obvious to the committee that when we hear about a new product and read about it in our journals, it is little more than a curiosity until it is on the market where I can use it. Well, in the advertising and promotional practices of the pharma- ceutical houses, I have found it difficult to reconcile the testimony heard by this committee with the procedures actually followed in the field. I have found the drug advertising in our professional journals to be very useful. It has also been my experience that the ethical drug houses are very careful to accurately describe their products and include all the possible side effects. We are all aware that the FDA has regulatory authority over drug advertising. I would also like to point out that journal advertising is not the only source of information on new products. And, in fact, is probably not the most important source. In any major breakthrough of a new drug product a number of articles will have appeared in our pro- fessional journals. In all probability, it will be described in the JAMA section on new drugs. We may likely hear of it when reported in a scientific paper in one of our many professional meetings. The point is, there are many sources of information on new drug products and they are all useful to us. I think a word should be said here `about the detail men. It is my practice to see one detail man every day. In fact, the detail man is the first appointment I have every morning. In my office we keep a file of our detail men so we can contact them if we have questions about their products. The vast majority of detail men are trained pro- fessionals `and they provide us with valuable information. We learn from them such important details as package size, how a given drag is supplied, whether it's liquid, tablet, injectable, suppository; whether it is in general distribution. The detail m'an also supplies me with price information right along with product information. This is becoming more general `all the time. Contrary to what has been said in this committee, most doctors are price conscious. If they are not, they soon hear about it from their patients. To be perfectly objective, I must admit to an unhappy experience or two with detail men, but such an individual doesn't get another appointment to see me. As a rule, he's not long on the job. Such in- PAGENO="0200" 4104 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY staiices are rare. I have many times called upon detail men to contact their parent organization for special information. I've always found them very willing to. do so. Not long ago, I ran into an unusual side effect with a drug that was not described in the package literature. The detail man called hi~ parent company-i: might point out I called him at home at 5 ~ in the evening. I received a return call at 8 o'clock that same evening, which was 11 o'clock t1~at night by thelr time, but ~ithin a ni~tter' of hours I reeeived a call from one of the research scientists~ of that organization. He gave me the information I was looking for and was mast helpful in all respects. I would like to cite one further example of the services provided by detail men. I am c*rentl~ treating a i~ather rare eye condition in a patient in consultation with one of our professors of ophthalmology at the medical school. It was his recommendation that laro~e doses of an adrenal steroid be used in a near-heroic attempt to save~her. vision. These are very e~pensive producth and we both were hesitant to subject the patient to this financi~J burden. I cintacted the detail than of one of the large drug houses ~nd presented my problem, hopitig he Could provide us with enough' samples for at least a tri~1. More than that, he contacted l~tis parent organi~ation who willingly provided all the steroid the caSe will require. I am happy tQ add that our treatment appears to be successful. Granted, these are but small examples of special service in one doctor's practice, but they are by no means unique. Multiply these exf~eriences by the more than 200,000 practicing physicians of this country and I think a mOre realistic concept of the value of the detail man emerges. I would like to point out that these are services that could not be obtah~ed through any published jour~aJ of drug informa- tion or through the AMA's Council on Drugs. Such services, can only be provided by person-to-person contact. It has been suggested to this committee that a federally sponsored journal of drug information should be published for the use of the medical profession. A national compendium of drugs has also been recommended. These proposals have merit and deserve further study. However, if any proposal of this committee is to serve a useful purpose, it must have the confidence of the medical profession. It is imperative, then, that this committee establish and maintain its credibility with the scientific community. Anything ]ess will not only lead to certain failure, it will provoke outright a rid vigorous opposition. Senator NELSON. I~et me say, Doctor', that is also my position. It has been the position of all the witnesses who have testified in favor of a formulary, from Dr. Goddard on. Everyone agreed that the formulary has to be one in which the physician has confidence. It would have to be one that- Dr. MCGILL. Or it would not be useful. Senator NELSON. Certainly the medical profession as well as the Government would have to be represented. You could not have a successful compendium, or anything like it, without the acceptance and broad participation of the medical profession. `Dr. `MCGInL. I ~im happy to hear that. You are awaFe,' of course, of the compendium being drawn up by the AMA's Council on Drugs. Senator NELSON. Yes. PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4105 Dr. MCGILL. At our own expense we are doing this, and I wonder if it serves any additional purpose, but perhaps I am not the one to judge that. Senator NELSON. We haven't adequately explored this question. I introduced legislation to create a compendium for the purpose of having extensive hearings on that specific proposal so that we could get the viewpoint of everybody who might in any way be involved and see whether or not a consensus could be reached. If, in the mean- time, however, a compendium were developed that was adequate to serve this purpose-I don't know that I would see any point in involv- ing the Government. I have an o~h mind in this regard. Dr. MCGILL. Fine. I would like to make just this final statement. As doctors, our primary consideration must always be the welfare of our patients. We have many medical problems yet to solve, most of which will depend on the discovery of new chemical agents. We are very concerned that nothing interfere with the research and devek opment of these new agents. We are acutely aware of what delay means in terms of human suffering. These are values which cannot be measured by cost-benefit ratios. Any fair appraisal of our pharmaceutical industry would have to credit it with a remarkable record of achievement. Our system of providing medicines may not be perfect but it has achieved excellence. The industry has earned our respect where it counts the most-at the patient's bedside. I am certain the doctors of this country will continue to place quality and reliability ahead of price in their choice of therapeutic agents, not that cost can be ignored, but it should never, be the primary factor. For the instrument of government to recom- mend we do otherwise is unthinkable. Senator NELSON. Thank you, Doctor. Senator Hatfield, I have to leave in a few minutes because I am directly involved in a matter pend- ing on the floor. But I would like to make an inquiry or two before I leave. In a widely circulated, widely publicized speech1 which you gave on December 3, 1968, at the Pharmaceutical Manufacturers Associa- tion conference in the New York Hilton you stated in part-I would like to quote from the copy I have here: For the past 18 months I have watched with increasing alarm the proceedings of `Senator Nelson's `subcommittee. It was evident from the very beginning that the hearings were slanted and the facts were being distorted. We have been exposed to a `steady stream of handpicked witnesses whose testimony became as predictable as the rising sun. Over and over again we heard the same tired charges of excess profits, price gouging, unreasonable patent protection, and the like, without even the pretense of fairness Or objectivity. Not that I was surprised by the tenor of the hearings. I am aware that Senator Nelson is not one of our admirers. Then, too, none of us in the health industry has (been treated gently in the Halls of Congress these past several years, but I kept expecting to hear testimony from the other side. I though surely they would call witnesses from the various specialty groups, the Academy of General Practice, the AMA, the individual practitioner like myself, but when none was forthcoming, 1 decided to have a try at It. As it happens, one member of the Subcommittee is Senator Mark Hatfield from my own State. Last spring I had occasion to visit the Senator in Washington 1 See information beginning at p. 4138, infra. PAGENO="0202" 4106 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and we discussed the Nelson hearings at some length. He was sympathetic to my point of view that the hearings were being used to malign the drug industry and the medical profession for political purposes. He agreed to help me get called as a witness, Since that time I have had a `series of pOlite but noncommittal letters from Senator Nelson. I discussed this situation again with Senator Hatfield just 10 days ago and he expressed his frustration in the selection of witnesses before the Committee. It seems very dear that Senator Nelson does not want anyone to tell the story from the private praedtior~er's point of view or even to allow us to defefld our- ~elves against the ecürrllous attacks that are now a part of the public recOrd~ Elortuna,teiy Joe Stetler learned of my dilemma and invited me here today to express my views. I am Indebted to Joe for finally giving me a platform. I think It is about time that somebody speaks out against this travesty of justice, against the misuse of congressional authority. Of course, I don't have the lofty forum that Senator Nelson enjoys nor do I have his troops. First, I am curious about your statement saying "sth~e that time I ha~ve had a serres of polite but noncommittal letters from Senator ~el~Oh "We searôh~d our files, Doctor, and all ~we can find is otie letter from you dated March 28, 1968,1 which I *ill read from and then put in the record. Dear Senator Nelson: I have followed with great Interest the hearings of the Monopoly Subcommittee. The testimony of Dr. James Goddard `has' been very impres5i~~e. Through your efforts, the public has gained a great deal of information about drugs and `drug manufacturers. I am in total. agreement that such facts should be made known, both to the medical profession `and the public at large. I feel certain that much more could l~e revealed. I also feel that the testimony of the private practicing physician, like myself, would add a useful dimension to your hearings. I would like to ~olunteer lily services for that purpose. and so forth. Tha't is the pertinent part of the letter. In our files we have a copy of one letter which I wrote in response to your letter. It is dated April 29, 1968.1 So 1 month after I heard from you I wrote: DEAR Dn. McGiu~. I `appreciate your letter expressing an interest in testifying at our hearings on the prescription drug industry. Senator Hatfield has also contacted me in thte regard. As you know, the Committee Is covering a number of facets of the competitive problems in the prescription drug industry. I would appreciate learning from you which phase you are Interested In discussing. Because of the number of witnesses who have been scheduled tO appear, we have not been~b1e to'set a time inthe near future for additional witnesses. How- ever, If you Will send me a copy of your statemOnt, we will include it in the Committee re~ords~ Then, if a time can be worked out for your personal appear- ance, the Committee will be happy to contact ~ou again, hopefully in not too long a period of time. Isn't thait the oniy letter you ever. received from me? Dr. MCGILL. I have received several letters from your ëomm~ttee, but some of them pertinent to this hearing today. Senator NELSON. No, I mean, isii't that the only letter you had from mo prior to .ydur PMA speech in which you thadC reference to "a series of polite but noncommittal letters" you had received from me? Dr. McGILL. Well, there were two letters sent to me about today's appearance. I See pp. 4141-42, infra. PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4107 Senator NELSON. Of course, I sent you a letter inviting you to appear today, confirming time and place and so on. But we are talking about the reference you made to a series of "polite but noncommittal letters" you said you had received from me during the course of the past year. Dr. MCGILL. But I have also corresponded with Senator Hatfield in this area as well, and I know Senator Hatfield perhaps felt that we are still talking to the same members of the committee. What is the point that you wish to make? Senator NELSON. In your speech, you said that following your letter to me of March 28, 19687 in which you requested to appear, and I quote-"I have had a series of polite but noncommittal letters fr~m Senator Nelson." Now, I can find only one and it wasn't noncommittal. I asked for yQur statement. I said it would be put into the record and I offered to set up a time for you to appear, hopefully in the not too distant future. You never answered that letter. So I am wondering how you could give a public speech saying you bad received a~ series of polite but noncommittal letters from Senator Nelson. Dr. MCGILL. Well, Senator Nelson's committee-as a matter of fact, I did write back and wrote to Senator Hatfield that I thought the type of testimony I had would be more valuable in open hearing than it would be in a written statement. Senator NELsoN. That isn't the point I am raising. I am sure you talked to Senator Hatfield. I am referring precisely to your speech say- ing that, "I have had a series of polite but noncommittal letters from Senator Nelson." I thought my letter of April 29 was quite committal. I said, "How- ever, if you will send me a copy of your statement, we will include it in the committee record. Then if the time can be worked out for your personal appearance, the committee would be happy to have you." How did you come to the conclusion that that is a series of non- committal letters? Dr. MCGILL. Well, this is a general statement in the fact that I have known of others that have made requests to this committee who have not been heard, and hopefully some of us would be heard. The differ- ence between Senator Nelson and Senator Nelson's committee may be an error on my side, from my point. Senator NELSON. That isn't the way I read it. It says, "I have had a series of polite but noncommittal letters from Senator Nelson." Dr. MCGILL. Perhaps that should have been stated as Senator Nel- son's committee. Seiiator NELSON. Have you written a series of letters to the commit- tee asking to appear? Dr. MCGiu~. If I count the letters of yours and also to Senator Hat- field I think it makes a series. Senator NELSON. I would like to point out that we have searched the committee files and we find no letters from you whatsoever. Of course the committee files and my personal office files would not include any correspondence you may have had with Senator Hatfield and his office. If, however, you have any additional letters from me or the committee prior to the date of your speech, I would certainly appre- ciate your sending them 1~o us. I want to make sure that our files are in order. PAGENO="0204" 4108 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. MCGILL. I will be glad to. Senator NELSON. I will put the full text of your speech to the Phar- maceutical Manufacturers Association convention into the record- as well as my letter to you. If you have copies of any other letters from me or the committee prior to the time of your speech, we will put that in the record also so that the record will be clear. I want to be fair with you. If you bave some other such letter or letters it will be in- cluded in the record. If you don't, ~ think your letter to me of March 28 and my response to you of April 29 speak quite well forthemselves and your speech before the manufacturers association is rather loose with the facts. Just one more comment and again, I quote from your speech: We have been exposed to a steady stream of handpicked witnesses who~e testi- mony became as predictable as the rising sun. I want to emphasize again that the industry itself that you are here defending, the industry itself has an open standing invitation to every single drug manufacturer in America to come before this committee any time it wishes, and any time it is criticized by any witness, to come back and reply. That firm will have precedence over anybody else because it is my feeling that if somebody in industry is criticized, he ought to have a ch~ince to answer. The industry has had 44 witnesses, which is more than anybody else. I think that probably the fact is that many of those letters that I received from doctors or statements made by them are based upon information the Pharmaceutical Manu- facturers Associatipn has given them. It seems that doctors have been misled about what i~ going on at these hearings. Dr. MCGILL. W~il, I think the thing we have resented the most is some of the comments that have been made before this committee de- scribing practitioners as stethoscope carrying ignoramuses and simple boobs and other language which I resent, and I think we should have a chance to answer, and I am grateful that you have given me the chance. Senator NELSON. OK. Thank you very much, Doctor. I apologize for having to leave but I don't have control over the proceedings in the Senate. Dr. MCGILL. I know you don't. Senator NELSON. And I do not like `to leave while a witness is still here bu't I must. Senator Hatfield, my very able colleague, has agreed to complete the hearings. I am going up and take care of one of his party members. [Laughter.] Senator HATFIELD (presiding). Doctor, at the bottom of page 4 of your testimony you were talking about the materials and the sources of information that doctors receive as to a new drug or drug product, and you state that they are all valuable. We have had a number of witnesses before this committee who have testified to the effect that they received voluminous amounts of materials and many of them are duplications, repeats, and that in many instances it becomes so much an inundation of material `that they don't find it as valuable. Dr. MCGILL. I agree. Senator HATFIELD. So my question is, do you feel tha't all the mate- rials which you receive from the drug manufacturers really are of value to you as a practicing physician? Dr. MCGILL. No. PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4109 Senator HATFIELD. Would you like to comment on this matter? Dr. MCGILL. I think there is reduplication. I think many of them, in fact, put out products and information and material that is almost totally ineffective. However, this will always be a problem when a company is trying to find a specific way by saturation or special in- formation or `that will work the best. After all, they do have a product to sell. We are aware of the fact and much of it never reaches me. It ends up in the wastepaper basket by the girls in front. Journal advertising, I think, does draw attention more because it specifically is of more help. Senator HATFIELD. Well, in line with that, just above you mentioned, "It has also been my experience that the ethical drug houses are very careful to accurately describe their product and include all the pos- sible side effects." Just to make the record clear, it seems to me on page 5, second para- graph, there may be some slight contradiction. Dr. MCGILL. Where is that, sir? Senator HATFIELD. There is a contradiction to that statement be- cause in the middle of the second paragraph it says, "Not long ago I ran into an unusual side effect with a drug that was not described in the package literature." Would you like to clarify that? Dr. MCGILL. I would be very happy to. As a matter of fact, this was only recently recognized by the company. Now, the product that was being used was one of our more common analgesics that people take for pain, modern amounts of pain. This young man had a serious back problem, should have been operated on and was trying to get by until next year when he could do it, and had taken an overdose. I called the company and the company pointed out they had had several suicide attempts that had been recently reported. On suicide attempts there is no telling what drugs people will use or what devices. In taking an excess dose, it produced a convulsion much the same as an epileptic convulsion and in the particular copy of PDR which has the package literature, it was not listed. He called the company and they mentioned they had just recently recognized this complication because of the suicide attempts, and it would be in the product literature. By `the way, it is there now. They did it as they said `they would. They didn't know this reaction either until they had a chance to see the toxic doses of the drugs used. This will sooner or later happen with any drug. You can't very well do that on an experimental basis. Senator HATFIELD. So there is no contradiction in this statement of yours. Dr. MCGILL. Not really. Senator HATFIELD. Because there has been exceptions to the fact that most generally the side effects are listed, but in this instance was there an exception? Dr. MCGILL. Right, and many side effects are late occurring and sometimes they are hard to identify. The example of the aplastic anemia with Chloromycetin is a good one here. This was hard to identify. There are many other drugs that can produce it. Sometimes it is without apparent cause. However, once it was well recognized, the company certainly did point it out. PAGENO="0206" 4110 COMPETITIVE PROBLEMS IN THE DREG INDUSTRY Senator HATFIELD. Going back to another part of your testimony relating to the larger drug operations with their research and develop- ment divisions as contrasted to the generic or the parasitic industries, as you call them. You mentioned that as to the therapeutic equivalency, the burden of proof should be on the small firms. Would you like to elaborate a little bit on that point for us? Dr. MCGILL. Yes, and I am sure this is the value that generally will be held by the medical community. When any company brings its product on the market, I don't care whether it is a new product or whether it is a remake of an old product or whether it is somebody else's product that is now off patent, we feel the burden of proof is on them to establish the fact that it is just as good a product, and I mean therapeutically-I think this has been well heard in this com- mittee-before they will have won our confidence to use the product on a price basis. Their only competitive point is price. If they can establish to me that they have gone through satisfactory studies to establish their therapeutic equivalency, I will use their product. Now, there is an element- Senator HATFIELD. Is that not required at the present time? Dr. MoGn4i4. No. That is not required at the present time. They meet USP standards which are chemical standards. There is nothing wrong with those standards and we have great confidence in TJSP but it doesn't go far enough to establish therapeutic equivalency and most of the drugs are becoming very sophisticated, very complex products to put out. We have learned in antibiotics that we have to have batch-by-batch certification. Senator HATFIELD. Should the FDA perform this or some other agency and how? Dr. MCGILL. I think the individual companies should produce their own clinical material stating "we have done a comparison study and find this product manufactured under our process is equivalent thera- peutically." Then we would have no objection. Senator HATFIELD. Would it have to be authenticated or Verified by any outside agency? Dr. MCGILL. Well, that would always be nicer if it was, but I have confidence that the companies will do this, plus there is spot checking and inspections of factories. There probably should be more of this, to be sure they are doing what they say they are doing. Senator HATFIELD. I appreciate your approach to the committee this morning in terms of the thrust of your testimony as being positive in listing and identifying the contributions, the valuable contributions of the drug industry. Now, as a practicing physician I am sure that you have found areas where the drug industry might improve as any industry or any or- ganization has always something to improve them. Dr. MCGILL. Surely. Senator HATFIELD. Now, the committee here, even though the pub- licity may have been on the negative side as you point out, and I think we have had some sensational testimony that has received a great d~ad of headlines and the indictment always gets more play than the answer. Dr. MCGILL. Always. PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4111 Senator HATFIELD. Surely there must be areas in which you could indicate to us where you think improvement could be made without detracting from the valuable contributions the drug industry has already made. Dr. MCGILL. Well, possibly. You have already pointed to one, of them. I think some advertising processes or procedures are excessive and anything that would encourage their research and development programs, of course, would very much have our support, although tIi~y have quite a remarkable record in this. Most of the practices that have been described in front of this committee, and this may be one of the very good effects this committee's hearings have had, have been stopped. I think more price information could be distributed. I think this would be good. And if a compendium or formulary, like the ones you have suggested in the bill you have entered, that is essentially educational and has the information for the use of the physician and is not restricted to his choice, I think that would be valuable. We need more sources of education. One area that the drug com- panies are just getting into is to help sponsor postgraduate education in the use of drugs. I think this is fine that they are doing it, I think they will enlarge it at this point. Whether or not a drug journal would be valuable I am not sure. I would have to see the format, the nature of it and who put it out, but that is a possibility. Senator HATFIELD. Do you have any comments in the area of quality control or any of that type of manufacturing? Dr. MCGILL. Well, quality control is terribly important to us. Senator HATFIELD. Do you feel that you are satisfied with the re- sults of the present system used? Dr. McGiri4. I am satisfied with the results of the present system in certain organizations. I think you will find most of us feel that no product is any better than the established reputation of the company that made it. Now, we may be doing an injustice to a new company starting on the market, just starting to manufacture drugs. I realize that. Yet I think this way. We are not about to buy a new kind of an automobile when you know the one that you have been driving is a reliable prod- uct until the new product has established its identity and its quality. Then we will use it. Senator HATFIELD. One of the things that has bothered me a great deal in the testimony we have heard before this committee, relating to the medical practice, has been witness after witness indicating that because of the large numbers of new drugs coming into the market each year out of the research laboratories of our pharmaceutical houses and other sources, that the average practicing physician is not in a position to actually keep abreast with all of these new drugs.. Jt is difficult to maintain his schedule of appointments with his patients and keep abreast of the new publications or the listing of the drugs in various journals, plus the fact related to that has been the indica- tion that in the average medical school today there is not sufficient time given in the curriculum for pharmacology and the basic better understanding of the whole use of drugs and their applications. This really starts in with the educational program of the physician and moves right on into his practice and demands upon his time. This has been stated by professors of medicine. PAGENO="0208" 4112 COMPEITITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. MCGILL. Professors of pharmacology primarily. Senator HATFIELD. It has been made by people who are practicing physicians in hospitals and by others as well. So what I am asking is basically your view on this point. Dr. MCGILL. Well, first of all let me say keeping up with drug information and the rapidly developing advances is not easy. It is vpry difficult, and it is a strain on all of us to try to do this. My point is the information is available to us if an individual makes any effort at all to get it. Now, one of the things that I have resented about the pharmacol- ogists that have come before this committee is, well, the doctor's drug therapy or his knowledge of drugs ended at the end of the sophomore course in pharmacology. This just isn't so. I am an internist. I don't know what happens in other fields but I know what happens in my field. A very, very large part of our field deals with drug training- drugs are the tools we use, just as a surgeon uses instruments, and this occupies a large part of our time and effort. We have many profes- sional meetings. We have, for example, staff meetings at the hospital. Questions have come up in these hearings, that if we had better reports aboñt Chloromycetin, we would not be using Chioromycetin. I doubt it. However, in my own hospital, and this is true in every accredited hospital in the United States, we have a death and complications conference once a month. Every death in our department-~I am in the department of medicine-every death or complications is listed and is discussed and we must attend 80 percent of those meetings or lose our hospital privileges, so we have pretty effective discipline, plus the pressure of the individual's own consciende. We would like to have our people get the best possible treatment they can. We do have sources. I am not saying, perhaps, Senator, we should not have more. We can always use more. Senator HATFIELD. Do you have a way to divide in your own practice the dependency that you have upon one source as, say, con- trasted to another source for information of new drugs including the so-called detail men and their visits and their promotional activi- ties and materials as contrasted, say, to a journal, as contrasted to your fellow physicians and other sources that you may have? Dr. MCGILL. I would say if we track the new drug all the way through, perhaps this can illustrate the point. The last important new drug that I think has come on the scene is Vibrarnycin by Pfizer Co. which is a very promising antibiotic because it is a long acting product. It has long-term effects and therefore has certain uses that are important to us. This was reported in the New England Journal of Medicine, I recall-I may be wrong on this because I am recalling from memory- at least a year, probably 2 years before it was introduced to the mar- ket. First it was under its generic name, doxycycline. Then the Ameri- can Journal of Medicine I believe had an article on it. We heard about it in other journals and then it shows up in the JAMA section on new drugs. This is sort of the process that goes on. Now, we have a new antibiotic coming that looks very promising. PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4113 We still haven't gotten it and it is still on'y a curiosity until finally that detail man shows up in my office and says, Doctor, I am from the Pfizer Oo. We are now producing Vibramycin. It is in your local pharmacy and you can start using it.' In the meantime some of our hospital people have had it, as many do, for clinical trial and we will have heard about it in medical meetings. Then, as we start using the drugs, I can't emphasize enough the informal consultation that takes place between doctors. We will discuss among ourselves whether the current hot throats are respond- ing to this new antibiotic or should it be used. This is informal infor- mation we trade around. We learn from each other, of course, pooling our information. It has been said sometimes we pool our ignorance. That is possible, too, but this is the way we become familiar with a new product. If late complications develop, and I am sure this will be the case in the future, it is the detail man who points it ~ut very quickly because they do not wish their product to develop a reputation for bad effects. Senator HATFIELD. Knowing you to be an exceptional man as well as an exceptional physician, are you describing to us an exceptional situation or is this an ordinary common practice that physicians engage in? Dr. MCGILL. This always comes up. What does the average physi- cian do? Senator Hatfield, I don't know an average physician. I hope I don't know an average lawyer either. I know that they are a dedicated, hard-working group of men. I have heard them described in here as the guy that sees 75 patients a day and hasn't read a medical journal in a year as if this is typical, and I object to this. I do not believe it is typical. It is not typical of doctors I know. Senator HATFIELD. Another matter that has bothered me a great deal from the testimony here and in my visit to one of the major pharmaceutical houses is the lack of the knowledge today of what long- term use of certain drugs might create in a person. Dr. MCGILL. It is always a possible hazard. Senator HATFIELD. Now, how are we going to solve that, with greater use of primate centers or other experiments with animals, or how are we going to accomplish this? Is it the responsibility of the pharmaceutical house? Is it the responsibility of the FDA? Where does this responsibility lie? Dr. M0GIEL. Well, let me start by saying I certainly think the pharmaceutical industry shares this responsibility. They certainly are responsible for the effects of their product and if they discover by their own sources that certain long-term effects are occurring, it is their responsibility to inform us and it has been my experience that they do. FDA-and there is a good working relationship between the FDA and the pharmaceutical manufacturers-perhaps might think more in terms of long-term testing or long-term recordkeeping on possible late complications. All of us are aware of this. Very late complica- tions may occur many, many months, even years later. There is no way to avoid this by trying to wait that many years for 1 TestImony on vibr&mycin will be found in Competitive Problems in the Drug Industry, Part 9, Pp. 3537-8568. 81-280-69-Pt. 10-14 PAGENO="0210" 4114 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY clinical trial which would mean keeping a very useful drug off the market. We can't justify that either. I think we will always have to remember that when we say, well, you are getting some late oomph- cations, therefore, withdraw that drug, you may have hurt a lot of people who needed the drug. Senator HA'rFIEi~n. But aren't there ways that they could accelerate the information-gathering activity through the generations that they could experiment with? Dr. MCGILL.. Yes. Senator HATFIELD. Could this be done with the primate as compared to waiting for the human being to exist that long through many generations of use? Dr. MCGILL. We can get some information on this and as you know, a good bit of this is going on in our own primate center in Portland. It does, of course, not necessarily mean they are comparable but it does give us leads that we should be watching in certain areas, and ~~am hoping there will be more of this. Senator HATFIELD. We were talking to Dr. Montagna about this whole matter and the. thing that disturbs me is that we have now 12 such primate centers I believe in the United States and if they are typical of ours, they are underutilized and at least this could be utilized to a greater extent. Further, it seems to me that the pharma- ceutical industry has a greater responsibility than they are thus far performing in utilizing such sources and centers to do a little bit more on contractual relationship work. Dr. MCGILL. I think that is a very worthwhile suggestion. Inci- dentally, Dr. Montagna has just this fall visited our medical society and described the activities of what is going on in ~iie primate center. Mr. GoiwoN. On page 5 o~ your, statement you talk `about unhappy experiences you~ have had with a couple of detail men. Could you give us n little more information about that, including the ~lrug involved? Dr. MCGILL. No. I don't have any specifics. I was thinking more in terms of the manner of the jndividual who attempts the hard sell type. He won't get very far with me. In fact, be won't get past the front desk the next time around. This occasionally. happens but it is rare. Most of these men are professionals and they do a good job. Mr. GORDON. On page 4 you say it has also been your experience that~"the ethical drug houses are vei~y careful to accurately d~soribe their products and include all the~ possible side-effects." I was just wondering if you were aware of the 29 "Dear Doctor" letters that went out in the last 18 montlis-~-~they were sent out by the leading drug firms, at the insistence of the FDA, to correct false and misleading statements in their advertising claims? Dr. MCGILL. Most of which was nitpicking in our opinion. Mr. GORDON. You don't think it was really worthwhile? Dr. MCGILL. Usually most of us already knew this. This doesn't mean it doesn't have a certain purpose and I am not against any source of information. As I mentioned, w~ need all the information we can get. We are glad to have it. And 1 don't believe any major drug company deliberately obscures complications of a drug because that would only serve to hnrt them. " (The letters follow:) PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4115 Regnlatory actions, remedial letters (Dear Doctor) 1. Ortho-Novum-SQ, Ortho Pharmaceutical Corp 2. Llbrium, Hoffman-LaRoche Laboratories - 3. Deprol and Miltown, Wallace Pharmaceuticals 4. Enduron and Enduronyl, Abbott Laboratories 5. Renese, Renese-R, and Rondomycin, Pfizer Laboratories 6. Hygroton and Regroton, Geigy Pharmaceuticals 7. Oracon and Questran, Mead Johnson Laboratories___- 8. Choloxin, Flint Laboratories 9. Diutensin-R, Neisler Laboratories 10. Citanest, Astra Pharmaceutical Products 11. Mysteclin-F, Squibb & Sons 12. Cortroph'in Gel, Cortrophin Zinc, Hexadrol Phosphate Inj., and Hexadrol Tablets and Elixir, Organon, Inc__ 13. Predsem, Salcort, and Salcort-Delta, The S. E. Massen- gill Co 14. Norpramin, Lakeside Laboratories, Inc 15. Medrol, The Upjohn Co 16. H. P. Acthar Gel, Armour Pharmaceutical Co 17. "PDR Products," Medical Economics 18. Ponstel, Parke, Davis & Co 19. Norquen and Norinyl-1, S~yntex Laboratories 20. Ovulen-21, G. D. Searle & Co 21. Persantine, Geigy Pharmaceutical 22. Erytbrocin, Abbott Pharmaceuticals - 23. Dynapen, Bristol Laboratories 24. Atromid-S, Ayerst Laboratories 25. Nebair, Warner-Cldlcott 26. T A 0, Roerig 27. Enzopride, Shick Safety Razor Co 28. Symmetrel, E. I. duPont deNemours & Co 29. Ismelin, Ciba February 1, 1967. March 10, 1967. March 30, 1967. April 13, 1967. May 22, 1967. June 2, 1967. June 30, 1967. July 20, 1967. August 11, 1967. August 23, 1967. October 2, 1967. October 27, 1967. November 1, 1967. November 1967. November 15, 1967. November 16, 1967. November 27, 1967. January 15, 1968. January 22, 1968. January 26, 1968. February 15, 1968. June 3, 1968. June 8, 1968. June 12, 1968. June 27, 1968. September 3, 1968. September 30,1968. October 14, 1968. January 20, 1969. ORTHo PHARMACEUTICAL CORP., Raritan, N.J., February 1, 1967. DEAR DoCTOR: The Food and Drug Administration has asked us to call your attention to the fact that a claim in our recent advertising of ORTIlO-NOVUM i~Q" may be misleading. In our introduction of this product to the medical profession we featured the theme, "The Most Effective Sequential," based on a comparison of pregnancy rates published in manufacturers' package inserts. The Food and Drug Administration has pointed out that such a comparison is invalid because there has been neither a direct comparative study of the efficacy of the three sequential oral contra- ceptives in the same population nor individual studies of the three products in population groups shown to be comparable. We are therefore discontinuing the promotional theme in question. ORTHO PITARMACEUTICAL CoRP. RoCHE LABORATORIES, DIvIsIoN or HOFFMANN-LAROCHR, INC., Nutley, N.J., March 10, 1967. DEAR DOCTOR: At the request of the Food and Drug Ajdmiitistration, we are extending the "brief summary" of prescribing information for Librium® (cblor- diazepoxide HC1) which appears in medical journal advertisements by adding several phrases and items from the unchanged official package circular. The revised "brief summary" for medical journals is attached, indicating by capitalization the requested added material. Prescribing infotmation in all Librium (chlordiazepoxide HC1) package circulars, direct mail information and brochures is complete and requires no change. The safety and effectiveness of the product are not is question. *Trademark PAGENO="0212" 4116 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In addition, in future medical journal advertisenients for Librium (chlor- diazepoxide HC1) In geriatric patients, we are amplifying statements which have appeared concerning possible slide effects and initial dosage: The statement that "Side effects in most instances are mild in degree and readily reversible with reduction of dosage," will be extended by the observations made in our package circular which point out that drowsiness, ataxia and con- fusion have been reported in some patients, particularly the elderly and debili- tated, occasionally at lower dosage ranges, and that in a few instances syncope has been reported. Whereas in geriatrics, the usual daily dosage is 5 mg, two to four times daily, the initial dosage in elderly an:d debilitated patients should be limited to 10 mg or less per day, adjusting as needed and tolerated. We hope the additional detail in medical journal advertising clarifies the use of the product in accordance with the enclosed package circular. Sincerely, ROBERT B. DIXON, M.D., Dfrector, Professional Services. Enclosure [omitted]. WALLACE PHA1n~sACRUTICALS, DIVISION OF CARTER-WALLACE, INC., Urcsnbury, N.J., March 30, 1967. DEAR Docron: At the request of the Food and Drug Administration, we are calling your attention to one of our recent advertisements captioned, "Ti? e published ilinical studies indicate: 3 of 4 non-psychotic depressions respond to `lieprol'." The FDA considers that this advertising may have been misleading. In the advertisement, we listed 21 studies comprising the total published "Deprol" literature containing data on non-psychotic depressions. While the ad does not reflect the fact, data from these studies were ecvcluded~ in whole or in part if (a) the diagnosis was not entirely clear; (b) the recommended maximum dose of 6 "Deprol" tablets per day was exceeded; (c) other psychotropic drugs or electroshock were part of therapy. Moderate, marked, excellent, and complete responses were counted as favor- able, while mild, fair, slight, and no responses were counted as unfavorable. Using the above criteria, the final number of patients included was 323 se- lected from ten of the 21 listed studies. Nine of the ten studies were, uncon- trolled, and most patients in the ten studies concomitantly received informal or structured psychotherapy. The reported therapeutic results (ranging from 0% in a study with two non-psychotic depressed patients, through 64% in a study with 53 such patients, to 90% in two studies with 38 and 41 such pa- tients respective'y) also include, to an undetermined degree, placebo responses and spontaneous remissions known to occur in the therapy of neurotic depression. The factors noted above represent problems that exist in working with any literature and are present in some "Miltown" advertisements carrying the theme "one of a series". In order to avoid any misunderstanding, we have discontinued the use of these "Miltown" advertisements as well as the de- scribed "Deprol" advertisement. Sincerely, WALLACE PIIARMACETJTICALS. ABBOTT LABORATORIES, North Chicago, Ill., April 13, 1967. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to a recent advertisement on Enduron® (rnethyclothiazide) and Enduronyl® (methylclothiazide and deserpidine). The advertisement, headlined "Thiazide-potassium problems, doctor?" is regarded by the FDA as misleading. The ad states that the advertised drugs provide "excellent sodium output with less potassium loss than either ehiorotbiazide or hydrochlorothiazid~." The consensus of expert medical opinion is that there is no significant difference PAGENO="0213" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 4117 in the amount of potassium loss caused by thiazide agents, including methyclo- thiazide (Enduron). The ad suggests that any physician taking a patient off a thiazide-potassium combination may wish to consider Enduron as alternative therapy. It states that the product will "do an outstanding job for you, without routine potas- sium supplementation," and that it has "potassium-sparing characteristics." The FDA believes that these claims could lead to the erroneous conclusion that hypokalemia is less likely to occur, and consequently, that potassium sup- plementation is less often necessary with Encluron than with other thiazides. In point of fact, the need to consider proper potassium supplementation, dietary or otherwise, is no less with Enduron or Enduronyl than with any other thiazide drug. Because the ad's "brief summary" of warning information was considered in- adequate, a new one Is enclosed. The information capitalized in the attached revised "brief summary" is not present in current ads, but will be incorporated into future ads for these products. ABBOTT LAnm~ATonIns. Enclosure [omitted]. PFIzER L&B0RAT0RIE5, New York, N.Y., May 22,1967. DEAR DOCTOR: The Food and Drug Administration has requested that we call your attention to recent promotional messages for our products (Rondomy- cm, Renese, and Renese-R) which the FDA regards as potentially misleading. Renese and Renese-R The monograph in the 1967 Physicians' Desk Reference for Renese and Renese-R is considered inadequate in presenting information necessary for their safe and effective use. To provide you with the necessary additional information, we are enclosing a revised monograph for insertion into your PDR. The changes include additional warnings and precautions concerned with electrolyte im- balance, hepatic coma, maintenance dosage, and, in the case of Renese-R, the possibility of Parkinsonism and confusion. Rondomycin The FDA has also asked us to call to your attention certain features of our current advertising for the broad spectrum antibiotic, Rondomycin. The ad does not disclose that it is a member of the bacteriostatic tetracycline family and that administration for ten days is especially important in the treatment of Beta-hemolytic streptococcal infections. In referring to the "Protective dose (PD50) tests," the ad did not specify that they were performed in mice utilizing laboratory strains of organisms injected Intraperitoneally. While demonstrating the activity of Ronclomycin against these test strains, the PD50 tests cannot be extrapolated directly to the clinical situation, in which sensitivity testing is recognized to be important for selection of the most appropriate antibiotic for a specific patient's infection. In addition, the "Brief Summary" of wa~,ning information In the above ad, and also in the current journal ad for Renese-R, is considered inadequate. We are modifying the advertisements in question and future advertising will include the requested additional warning information. Sincerely yours, ~1oHNL. WATTERS, M.D., Medical Director. Enclosures [omitted]. GEIGY PHARMACEUtICALS, Ards~ey, N.Y., June 2, 1967. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to recent journal advertisements for our products (Hygroton® and Re- groton®) which the FDA considers to be misleading. Hy~'roton Advertisement This ad is headlined, "Do your patients shell out too much for a diuretic?". It states that a published report on a new short-acting diuretic supports the claim that "If one considers maximum recommended doses for each product, PAGENO="0214" 4118 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tablet for tablet Hygroton was clearly superior. Two tablets of Ilygroton were found to produce almost 40% more natruresis and 20% more weight loss than five tablets of the other diuretic." The FDA points out that the studies were based on staalI numbers `of patients (6 to 13), that the actual differences reported were' clinically insignificant, and that the ad's claim for. superiority was not supported by the' data Or by the authors' conclusions. Further, the report was not a direct comparative study of the two drugs, but rather a comparison of data obtained on the new diuretic with data obtained on HygrotOn in a previous study. In additiOn, the tablet-for-tablet. comparison in the ad is not regarded as sound because single tablets ~f Hygroton and the other diuretic do not contain comparable `threapeutic dosages. Regroton Advertisement This ad displays a single Regroton tablet in relation `to two sets Of `five tablets representing drug regiments for treating hypertension. The ad states that "in moderate hypertension" Regroton was "better than reserpine + hydralazine + hydrocblorothiazide in 41 of 43 patients and better than reserpitie + methyl- dopa + hydrochlorothiazide in 34 of 37 patients". These numbers, taken from a paper referenced in the ad, refer specifically to a comparison of average mean blood pressures after two years on Regroton with responses to prior therapy utilinthg the other drug combinati'Ons~ The FDA pOints out that the differences observed `in the blood pressure response to the various treatments were neither statistically nor clinically significant. Further, the study was n'ot done on patients diagnosed as "moderate hyperten- sion", and the authors did not state that the effect of Regroton on the patients' blood pressure was "better". The FDA also considers the summary øf presCribing information in each ad to be thadeqnate~ Each enclosed "Brief Summary" . contains information in capital letters that was nut Included in our current ads. We are discontlnuhlg the ads in question and future advertising will incorporate the revised "Brief Summary". The safety and effectiveness of the products are not in question when used in accordance with the official package 1n~erts. GEIGY PHARMACEUTICALS. Enclosures [omittedi. MEAn-JoHNSON LABORATORIES, Evansville, md., June 30, 1967. DEAR Docuon: The Food and Drug ~dministrat1on has requested that we call your attention to current medical journal advertisements for Oracon and Ques- tran which the FDA regards as misleading. Oracon® The ad claims that the drug provides ". . . oral contraception with effects which closely parallel those of the natural hormonal cycle" and also contains a related slogan implying such effect's are "So Olose to ~ature." The FDA points out that not neary all effects of oral contraceptives parallel those of the natural hormonal cycle and that some of the effects of these drugs are of, profound or undetermined nature. The ad emphasizes the low incidence of certain less serious side effects such a's amenorrhea, breakthreugh bleeding, weight gain, etc. However, it fails to give adequate emphasis to more serious kno'wn side effects-~or adequate emphasis to `the possible occurrence o'f thromhophlebiti'c, pulmonary embolism o'r cerebral vascular accident. The FDA points out that the pregnancy `rates claimed in the ad were incor- rectly based on 1065' women instead of only 880, and `that the ad improperly features a pregnancy rate of 0.2 per 100 wouian-years. While available data do not provide a reliable scientific basis for a statement of true pregnancy rates, experience reported to us shows that the unadjusted rate for all women who were given Oracon was 2.0 per 100 woman-years. The rate of 0.2 used in the `ad included only those patients who insisted that tbey.'had adhered to the `regimen. Questran® The FDA considers the summary of warning Information in the journal ad- vertisement for Questran to `be inadequate in that It did not contain `any infor- PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4119 mation on precautions and warnings. We have attached a revised "Brief Sum- mary," which contains the omitted precautions and warning information in capital letters. We are discontinuing the ads in question, and tuture advertising will in- corporate the' above corrections: The safety and effe~tivenes's of Orecon and Questran are not in question when the drugs are used in accordance with the official package inserts, Sincerely, P. A: WALTER, M.D., Director, Medical Researclv Department. Attachment. [omthted]. FLINT L4BonAToRrEs, DIVISION OF, TRAVENOL LABORATORIES, INC., Morton Grove, Ill., July 20, 1967. DEAR DocToR: The Food and Drug Administration has asked us to call your attention to the initial advertisements for `Choloxin® (sodium dextrothyroxine), currently appearing in several journals, which are regarded by the FDA as misleading. The headline, "A significant new advance in the management of hypercholes- terolemia", does not include the qualification that Oboloxin is indicated for the treatment of `hypereholesterolemia in selected patients, i.e., euthyroid .patients with no known evidence of organic heart disease. Also, the ads fail to stress that Choloxin is not intended to replace or to lessen the desirability of con- sidering dietary regulation ii~ the management of hypercholesterolemia. The FDA points out that, while the ads emphasize that Choloxin effectively lowers blood cholesterol levels, they fail to emphasize that this effect has not been proven to alter the morbidity and mortality of atherosclerotic disease. The claim in the ads that Oheloxin (sodium dextrothyroxine) Is "significant in its accepted physiologic mode of action" is considered to oversimplify the extent of knowledge of its mode of action. Further, the reference to "over 6,000 patients treated in clinical studies" overstates pertinent clinical experience, since only 2,967 patients were in the diagnostic categories for which the drug is currently indicated. The FDA also considers the summary of warning information in the ads to be Incomplete. The enclosed "Brief Summary" contains information in capital letters that was not present in the current ads, but will be incorporated into future ads for Ohoiox~in. We are discontinuing the ads in question. The safety and efficacy of Choloxin are, not in question when used In accordance with the official package circular, which remains unchanged. Sincerely, THOMAS A. GARRETT, Vice President, Medical Affairs. Enclosure [omitted]. NEISLIrR LABORATORIES, INC., SUBSIDIARY OF UNION CAREmE CORP., New York, N.Y., Aig,iust 11, 1967. DEAR Docuon: The Food and Drug Administration has asked us to call your attention to a' recent advertisement for Diutensen-R which th' FDA regards as misleading.' The Food and Drug Administration regards the warning information in the ad to be so substantially deficient that the ad represents a potential dang~r to health. Therefore, we have rewritten our "Brief Summary", and the nature and extent of the changes are shown in capital letters in the attached revision. We have discontinued the ad in question and all future ads will carry the new "Brief Summary". The safety and efficacy of Diutensen-R are not in question w'hen used in accord- ance with the prescribing information in the official package insert. Sincerely, NEISLER LABORATORIES. Enclosure [omitted]. PAGENO="0216" 4120 COMPETITIVE PROBLEMS IN THE I~RUG INIYL7STRY A5TRA PHARMACEUTICAL PRODUCTS, INC., Worcester, Mass., August 23, 1967. DEAR DOCTOR: The Food and Drug Administration has asked us to call to your attention two of our recent mailing pieces for Oltanest® which th~ FDA regards as so substantially misleading and lacking in adequate professional use information that in its view they represent potential hazards to health. These mailing pieces, identified as 118-67 and 119-67, should be discarded if still in your possession. 1. Intraveaol4s Rcj$onaJ Anesthesia.-Malling piece 118-67 recommended the use of Citanest in intravenous regional a~esthesia. The FDA regards use of this drug by that technique as experimental. The package insefl f~t' Oltatiest contains no information for its use in intravenotts regional anesthesia and the drug has not been approved for use in that procedure. 2. Ma~vinsun1~ Single Dosa~/e~-~Mailing pieces 118:-67 and 119-67 contained state- ments which implied that dosages of Citánest iii ~excess of the maximum single dose (600 mg.) could be employed in clinical use. No such implication was in- tended by Astra, and Astra reaffirms that on more than 600 mg. of the drug should be used during any two'hour period. 3. Professional Use Information.-Both booklets omitted hssential and re- quired professionals use information. The attached page contains the warning, precautionary, and adverse reaction information which was omitted from the "full disclosure" sections of the booklets. The safety and effectiveness of Citanest (prilocaitie), when used In accordance with the conditions specified in thb enclosed package insert, are not in question. Sincerely yours, ASTEA PHARMActiUTICAL PRODUCTS, INC. Enclosure [omitted]. SQUIBB, October 24, 1967. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to certain advertisements for Mysteclin®-F products which the FDA regards as misleading. The main theme of the advertising, which we have stopped, suggests that "almost every candidate for broad-spectrum antibiotic therapy, is a candidate for Mysteclin-F." We wish to emphasize that those patients selected for tetrac~'cllne therapy who are known to be particularly susceptible to candidal superinfection are the potential candidates for Mysteclin-F therapy. The FDA points out that recent journal advertisemetits for these prodhcts suggested that candidal superinfection is a serious problem ~`itb the use of ampicillin. This was not supported by the reference used in the ads. Although the reference cited included the statement that candidal overgrowth may follow ampicillin therapy, the~ FDA has asked that we point out that the significance of this overgrowth has not been established. Further, the same ads omitted important warning information relating to precautions and side effects. The nature and extent of the omission are capitalized in the enclosed "Brief Summary". Sincerely, SQUIBB. Enclosure [omitted]. ORGANON, INC., West Orange, N.J., October 27, 1967. DEAR DOCTOR : The Food and Drug Administration has requested that we call your attention to the monographs for Oottrothin® Gel, Cortrophin® Zinc, Hexadrol® Phosphate Injection and Hexadrol® Tableta and J~ilixir in the current Physicians' Desk Reference. The FDA considers these monographs to be incomplete in presenting necessary information for the safe and effective use of these drugs, and, therefore, potentially misleading. To provide you with the necessary information, we enclose revised monographs for insertion in your PDR. The nature and extent of the additions and other revisions in the enclosed monographs are emphasized by use of italics. Sincerely yours, JOSEEII D~ Cuo~o, M~D., Director, Professionai Services. Enclosure [omitted]. PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4121 THE S. E. MA55ENGILL Co., Bristol, Tenu., November 1, 1967. DEAR DOCTOR: The Food and Drug Administration has requested that we call your attention to the monographs for our products, Predsem, Salcort and Salcort-Delta, in the current (1967) Physicians' Desk Reference. The FDA con- siders these monographs to be Incomplete in presenting the necessary informa- tion for the safe and effective use of these drugs and therefore potentially mis- leading. To provide you with the necessary information, we enclose revised monographs for insertion at page 812 of your current (1967) VDR. The nature and extent of the additions and other revisions in the enclosed ~nonograpbs a~e emphasized by use of Italics. Sincerely, ROBERT P. EWING, Vice President, Marketing. E~iclosure [ouiitted]. LAKRSIDE LABORATORIES, DivisioN OF COLGATE-PALMOLIVE Co., Milwaukee, Wis., November 1967. DEAR DOCTOR: The Food and Drug Administration have requested that we call your attention to the monograph for Norpramin (desipramifle hydrochlo- ride) in the 1967 PDR: page 687, white section. The FDA consider this mono- graph incomplete (in relation to, the oMcial labeling, the package insert), and therefore potentially misleading as prescribing information to allow safe and effective use of the drug. T~ provide you with the necessary adequate reference, we enclose a revised monQgraph for 1967 Physicians' Desk Reference in which the changes have been emphasized by italics. Please insert this revision opposite page 687. Sincerely yours, WILLIAM C. JANSSEN, M.D. Enclosure [omitted]. _______ TuE UP~rOHN Co., Kalamazoo, Miclv., November 15, 1967. DEAR. Docron: The Food and Drug Administration has asked us to call your attention to certain promotional messages for Mecirol Tablets which the FDA regards as misleading. Some journal advertisements have recommended use of Medrol 16 mg Tablets by an alternate day dose regimen. Although reports of this usage have appeared in the literature, the FDA points out that information currently available and submitted by us to them is not adequate to justify this regimen as advertised. Consequently, we are ceasing all reference to alternate day therapy in our promotion of the product. The monograph for Medrol Tablets in the 1967 Ph~ysicians' Desk Reference is considered by the FDA to be inadequate in presenti1~g information for the safe and effective use of the product. To provide you with the necessary information, we enclose a revised monograph for insertion at page 1143 of your current (1967) PDR. The nature and extent of revisions in the enclosed monograph are empha- sized by printing in bold type. Sincerely yours, FENIMORE T. J0HN50IS, MD. Enclosure [omitted]. ARMOUR PHARMACEUTICAL Co., Chicago, Ill., Nov ember 16, 1967. DEAR DOCTOR: The Food and Drug Administration has requested that we call your attention to the monograph for H.P.* ACTHAR ® GEL in the current (1967) Physicians' Desk Reference. The FDA considers this monograph to be incomplete in presenting necessary information for the safe and effective use of this drug and, therefore, potentially misleading. *Hlghly purified. PAGENO="0218" 4122 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To provide you with the necessary information, we enclose a revised mono- graph for insertion at page 527 in your 1967 PDI?. The nature and extent of the additions of previously omitted information are indicated by the use of italics. Sincerely yours, J. A. HTJ~ATA, M.D., MedieoZ Director. Enclosure [omitted]. PuYsIcL~Ns' DESx REFERENCE, Oro)defl, N.~i., Noii~3~tber ~7, 19ii7~ DEAR Sin: The Food a~d Th~ii~ Admth~Atrat~Qn ~ias i~eci~iest~d that, w& dali ~your attention to the n~onográp~s for the f ~w1izT~ produot~ Tn the current'(1967) Physicians' Desk Reference: Page HP Aethar Gel 527 Cortrophin Gel .898 Cortrophin-Zinc 898 Hexadrol -- 899 Hexadrol Phosphate Injection 899 Norprainin 687 Predsem 812 Salcort 812 Saloort-Del'ta ~ - 812 The FDA consIders these nxonographs to be incomplete in presenting the neces- sary information for th~ safe and eff~ctlve use of these drugs and therefore poten tially misleading. To provide you with the necessary Information, we enclose revised monographs for insertion in your 1967 PDR at the pages IndIcated at the top Of each sheet. The nature and extent of the addition's and other revlalonis In the enclosed monographs are emphasized by the use of italics, Sincerely, ALBERT B. MILLER, GeneraZ Manager. Enclosures [omitted]. PARKE, DAVIS & Co., Detroit, Mich., Jan14 ary 15, 1968. DEAR DOCTOR: The Food and,, Drug Administration has asked us to call your attention to our recent Ponstel~ (mefenamic acid) journal advertisement and certain promotional mailing and detailing pieces which the Food and Drug Ad- ministration regards as misleading. The introductory campaign featured results from mon-~bllud ciinic~l trials using only .a single 500 mg. dose for several types of pain. The Food and Drug Administration points out that P'onstel has also been studied in several double- blind clinical trials in which the drug was compared to aspirin and other non- narcotic analgesicis. These trials demonstrated that Ponstel was essentially equal to the comparison drug and better than plae~ho. liowever, In certain Individual trials aspirin was found better than Ponstel a1~d the latter could not be dis- tinguislied from placebo; in some `trial's pain relief `with placebo was obtained in as high as 40% of the patients. In `other trials the rcou!Its with Ponstel were better than those with aspirin or placebo. ` ` ` ` The Food and Drug Administration considers th;at the i1it~oductory campaign failed to give adequate prominence to the fact that Ponstel is indicated for short- term administration not exceeding one week of therapy. Also, in a promotional brochure~ results were reported from a double-blind effectiveness comparison with codeine and placebo, which represented that Ponstel was equal in effective- ness to 25 mg. of codeine. However, the dosage of Ponstel employed In this study was at a level which is still In the investigational phase. We are discontinuing the advertising campaign in question. Sincerely, J, 1~i. GAJEWSKI, M.D. SVNTEX LABORATORIES, INC., Palo Alto, Calif., January 22, 1968. DEAR DOCTOR: The Food and Drug administration has asked us to call ivour attention to the fact that certain statements in recent advertising for our oral contraceptives, NORQTJEN® and NORINYL~-1, may be misleading. PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4123 In the NORQT3EN advertisement, the paragraph headed "Low incidence of side effects" emphasizes the low incidence of certain less serious side effects such as spotting, break-through bleeding, nausea, vomiting and other gastrointestinal disturbances, but fails to give adequate emphasis to the more serious known side effects such as choiestatic jaundice, rise in blood pressure in susceptible mdi- viduals, and mental depression which also occur In low incidence. Further, al- though `a cause and effect relationship has neither been established nor disproved, the advertisement does not give adequate emphasis to the possible occurrence of thrombopblebitis, pulmonary embolism, and neuro-ocular lesions which have been observed in users of oral contraceptives. The advertisements for both NORQUEN and NORINYL-1 state that "careful observation and caution are required for patients with symptoms or history of... cerebrovascular accident, psychic depression. . . ." The ads should have been morO specific it~ stating: Oral contraceptives should be used with caution in patients with a history of cerebrovascular accident and should be discontinued if there is a sudden partial or coniplete loss of vision, or if there is a sudden onset of proptosis, diplopia, or migraine, or if examination reveals papilledema or retinal vascular lesions, since these may be symptoms of cerebrov'ascular accident. The advertisements disclose that careful observation and caution are required for patients with symptoms or history of psychic depression but do not specifically state that oral contraceptives should be discontinued if psychic depression recurS to a serious degree. Also, the ads fail to disclose that a decrease In glucose tol- erance has been observed In a small percentage of patients on oral contraceptives. We are modifying all future advertising to reflect these changes. Sincerely, BEN Z. TABER, M.D., Medical Director. G. D. SEARLE & Co., Clvieago, Ill., Jannary 26,1968. DEAR DOCTOR: In June 1967, the Food and Drug Administration and all manu- facturers of oral contraceptives agreed on certain changes in the uniform por- tions of the labeling for all oral contraceptive products. These changes were to be included In all advertisements after October 1, 1917. The FDA has asked us to call your attention to recent journal advertisements for Ovulen®-21, which departed from the new uniform labeling in several respects. The original uniform labeling stated: The following occurrences have been observed in users of oral contra- ceptives A cause and effect relationship has not been established: Thrombophiebitis Pulmonary embolism Neuro-ocular lesions. Because that labeling did not accurately represent the present status of opinion concerning the possible danger of side effects, the warning statement was changed to read: "A cause and effect relationship has been neith~er establish/ed nor proDed:" (emphasis added). The FDA. regards the advertisements a~ potentially misleading because they omitted this important change which emphasizes the possibility of these serious hazards. Further, the advertisements failed to include the following side effects which, although causation has not been established, have been reported In users of oral contraceptives: anovulation post treatment, premenstrual-like syndrome, changes in libido, changes in appetite, cystitis-like syndrome, backache, nervousness, dizzi- ness, fatigue, headache, hirsuitism. We have modified our current advertising to reflect these changes. Sincerely, HERBERT HELLING, Food and Drug Adm4nSatration Affa4rs, 0. D. $earle ~ Co. GEIGY PHARMACEUTICALS, DIvIsIoN OF GEIGY CHEMICAL Coal?., Ardsley, N.Y., February 15, 1968. DEAR DOCTOR: In our promotion of PersantIne~ (brand of dipyridamole) for long-term therapy in anginal patients, we sent a letter to physicians stating that "Several studies document the effectiveness of Persantine in extending walking PAGENO="0220" 4124 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY distance and generally increasing exercise tolerance." Enclosed with~ the letter was a reprint of a study in the Journal of Chronic Diseases of March 1967 to support the claims for effectiveness. The Food and Drug Administration has asked us to inform you that the claims for effectiveness of Persantine, and many other drugs marked prior to 1962w have been neither approved nor disapproved hy the Agency. The FDA is proceeding on the basis that the Drug Amendments of 1962 require the Agency to evaluate the effectiveness of ~uch drugs, and this is currently being done with the assist- ance of. the drug efficacy panels of the National Academy of Sciences/National Research Council. The FDA regards the promotional letter as petentially misleading because it presented only favorable information regarding the drug's effectiveness when there is a substantial body of opinion that does not support the claimed, effec- tiveness of the product. For example, the AMA Council on Drugs (in New Drugs 1967) has stated that double~blind studies comparing clipyridamole with a placebo have shown equivocal results and that the drug has not been convincingly shown to be effective in the long-term treatment of angina pectoris, `Recently, in `the J~&MA issue of Septemher. 11, 1967, a paper by Sbar and Schiant disclosed results of a six-month double~blind study. The authors con- cluded that "The study failed to detect a statistically significant difference between the improvement in patients receiving dip~ridamole and the improvement In patients receiving a placebo." Our future promotion will express the range Of expert medical opiniQn on the effectiveness of Persantine when any segment of that opinion is referenced. GEIGY PHARMACEUTICALS. ABBOTT LABORATORIES, North Chicago, Ill., June 3, 1968. DEAR DOCTOR: The Food and Drug Administration has requested that we call your attention to a promotional letter on Erythrocin® (erythromycin) directed to you in February of this year. This letter, discussing the mode of action and the in vitro spectrum of erythromycin, is regarded as potentially misleading. The letter included bactericidal values for Mycoplasma pneurnoniae, H. infiuenzae, pneumococci, Group A streptococci, and several other organisms. The FDA points out that the values cited from the' referenced articles represent a limited number of strains, and that other investigators, using other strains and methods have reported that higher concentrations of drug are needed for bactericidal effect. The letter also stated that: "In addition to cidal action, Erythrocin provides the wider in vitro and in ovo spectrum associated with the bacteriostatic `mycins, including- Gram positive cocci and bacilli Large viruses Gram negative cocci Mycoplasmas Many Gram negative bacilli Rickettsias (except the Enterobacteriaceae) Protozoa Spirochetes Atypical Myco bacteria" The FDA notes that this section can `be interpreted to mean that erythromycin is bactericidal against all organisms in the listed caegories. In point of fact, the statement refers to the results of in, vitro testing designed only to demonstrate inhibition of organisms by the drug; distinctions between bacteriostatic and bactericidal effects were rarely made. The letter failed to make clear that erythromycin is active against only certain organisms within these broad cate- gories. Also, clinical experience with erythromycln in certain of these categories, particularly Rickettsias and Atypical Mycobacteria, is limited and does not presently warrant the use of erythromycin. They particularly note that the term "Enterobacteriaceae" inadequately identified the fact that it includes such important pathogens as Salmonella, Shigella, Proteus, Pseudomonas, Escherichia, Aerobacter, and Klebsiell'a, against which erythromycin is not generally active. In reference to the letter as a whole, we wish to emphasize that bactericidal activity is an in vitro effect, subject to variation accoding to the organism and strains involved, and the conditions of the study. Further, in viro activity does not necessarily imply clinical effectiveness, and direct extrapolation to the clinical situation,, therefore, is not justifiable. In clincal use, as opposed to laboratory tests, no methodology exists, which can accurately determine whether a drug's action is bactericidal or bacteriostatic in the patient. So'~e authorities, however, PAGENO="0221" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4125 have expressed the opinion that erythromycin is primarily bacteriostatic under some clinical conditions. The promotional letter did not mention the advisability of choosing or continu- ing Erythrocin therapy on the basis of approprate sensitivity tests. Furthermore, while the letter did state tha Eryhroein has ". . . no known toxic effects on body organs or systems," it did not point out that serious allergic reactions, through extremely infrequent, do occur. We sincerely regret that the construction of the letter may have allowed interpretations extending beyond the limits of the approved package labeling and the full content of the cited references. We are discontinuing the current adver- -tising campaign in question. Future advertising will be appropriately modified. ABBOTT LABORATORIES. BRISTOL LABORATORIES, DIVISION OF BRISTOL-MYERS Co., Syracuse, N.Y., June 8, 1968. DEAR DOCTOR: The Food and Drug Administration has asked that we call your attention to our letter of May 17, 1968 which announced the coming availability of Dynapen (sodium dicloxacillin monohydrate). The Food and Drug Adniirtis- tration has expressed concern that our discussion of this drug in terms of treating skin and soft tissue infections created misleading impressions concerning the proper use of Dynapen in its limited appropriate indications. Therefore, we wish to specify the indications and limitations for use of this drug in detail as follows: 1. The principal indication for Dynapen is in the treatment of infections known to be dhe to penicillinase-producing staphylococci which have been shown to be sensitive to it. 2. If antibotlc therapy is considered necessary in potentially serious infections while awaiting reports of cultures and sensitivity studies, Dyna~en may be used to initiate therapy in such patients in whom a penicillinase- producing staphylococcus is suspected. (See Important Note below.) Important Note Bacteriologic studies to determine the causative organisms and their sensitivity to dicloxacillin should be performed. When it is judged important that treatment be initiated before definitive culture and sensitivity results are known, the choice of Dynapen should take into consideration the knowledge that it has also been shown to be effective only in the treatment of infections caused by pneumococci, Group A beta-hemolytic streptococci and penicillin G-sensitive staphylococci. In serious, life threatening infections oral preparations of the penic'illinase-resistant penicillins should not be relied on for initial therapy. Methicillin, a compound working through a similar mechanism against peni- cillin G-resistant staphylococci, has been available for nine years. It is a fact that strains of staphylococci resistant to methicillin have existed in nature and it is known that the number of these strains reported has been increasing. It has been demonstrated that such strains are almost always resistant to other penicillinase- resistant penicillins, such as the isoxazole group of which Dynapen is a member. When such a strain is isolated, use of routine antibotic discs cannot be relied on to differentiate relative sensitivity. Such strains of staphylococci have been capable of producing serious disease, in some instances resulting in fatality. Because of this, the Food and Drug Administration is concerned the widespread use of the penicillinase-resistant penicillins in infections other than those due to penicillin G-resistant staphylococci may result in the appearance of an increasing number of staphylococcal strains which are resistant to these penicillins. Therefore, if the bacteriology report indicates the infection is not due to a penicillin G-resistant staphylococcus, the physician Is advised to continue therapy with a drug other than Dynapen nor any other penicililnase-resistant semi- synthetic penicillin Indicated surgical procedures should be performed. Contraindications A history of allergic reactions to penicillin should be considered a contra- indication. Information in our announcement letter, or that you may have received from one of our sales representatives, should be carefully considered in light of the preceding clarification. PAGENO="0222" 4126 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We have discontinued the advertising in question. Future advertising will be appropriately modified. The drug is not available for prescription at this time. We will notify you when it becomes available. Sincerely, H. C. PELTIER, M.D., Vice President, .Zlledical Director. AYERST LABORATORiES, DIvIsIoN OF AMERICAN HOME PRODUCTS CORP., New York, N.Y., June 1~, 1968. DEAR DOCTOR: A recent advertisement for ATROMID_S® (clofibrate), "Answers to some questions physicians are asking about ATROMID-S," is regarded by the Food and Drug Administration as misleading. Accerdingly, we have been asked to clarify certain points in the ad relating to effectiveness and safety of this drug. Among other things, the ad contains statements which imply there is an association between the lipid-lowering effect of ATROMID-S and a beneficial effect on atherosclerosis or atherosclerotic heart disease. We emphasize that the drug is indicated solely for the reduction of serum lipids. In the absence of st~bstantial evidence that reduced serum lipids results in amerlioration of the atherosclerotic process, no claim may be made for ATROMID-S in this regard. Further, we wish to state that any implication iij the ad that ATROMID-S reduces the risk of recurrence of heart `attacks Is not a valid one. Any relation- ship between the lowering of serum lipids by drug therapy and a reduction in initial or recurrent coronary thrombosi~ will not be known until pre'sent long term clinical studies have been completed. The FDA also pointed out that the ad failed to stress the important role of diet in the management of elevated serum lipids. Because of the possibility of long term `administration of clofibrate, adequately repeated baseline studies should be performed to determine that the patient has significantly elevated `serum lipid levels. If so, attempts should be made to control serum lipids with appropriate dietary regimens before considering the addition of therapy with clofibrate. En addition, while the ad copy did emphasize some side effects of more frequent occurrence but mild severity, it did not likewise call attention to a number of the more serious side effects which have been reported to occur (e.g., weakness, urticaria, stomatitis, and polyphagia; as well as leukopenia and alopecia although relationship to clofibrate administration has not been established). We have discontinued the advertisement in question. Future advertising will be appropriately modified. Sincerely yours, JOHN B. JEWELL, M.D. WARNER-CIIILCOTT LABORATORIEs, DIvIsIoN OF WARNER-LAMBERT PHARMACEUTICAL Co., Morris Ploins, N.J., June 27, 1968. DEAR DocToR: We have been asked by the Food and Drug Administration to call to your attention recent advertisements for Nobair, an inhalation aerosol con- taining isoproterenol and thonzonium bromide. It regards these. ads as potentially misleading because the insufficient distinction between severe bronchospasm and severe bronchospastic disease can be constructed to extend recommendations for use of Nebair beyond approved indications. In addition, FDA maintains that these ads fail to balance important warning ideas in the same section of the ads containing claims of safety, and cite some abstracts of research reports in such a fashion as to exaggerate the performance and efficacy of Nebair. Recent advertising reads "For the patient with severe bronchospasin it [Nebairl may be more effective than isoproterenol alone." This sta;tenieiit does not `sufficiently reflect the fact `that Nebair is not indicated for all forms of "bronchospasm," but Is indicated for patients with moderately and markedly severe ~hronlc obstructive pulmonary disease with reversible bronchospasm. Specifically, Nebair Is indicated for the relief of acute bronchospasm only in those patients with the following disease states: PAGENO="0223" COMPETITIV1~I PROBLEMS IN THE DIIUG ~NDUSTRY 4127 1. Moderately and markedly severe bronchial asthma. 2. Moderately and markedly severe chronic brotichitis with reversible bronehospastic components, and 3. Emphysema. It is only in the above mentioned subgroup of patients that there is some evi- dence to indicate Nebair may be more effective than isoproterenol alone. The FDA has expressed concern that the ads did not list those side effects which may occur in association with any isoproterenol aerosol therapy. These side effects include: vomiting, headaches, flushing of skin, tremor, weakness, sweating, and anginal type pain. In addition, it feels adequate prominence was not given to the fact that frequent or continuous use of Nebair on a long-term basis is not recommended, and that use in children under twelve years of age is not indicated. The `above mentioned advertisements have been discontinued. All future promo- tion, including advertising, will b~ appropriately modified. Very truly yours, WARNER-CHILCOTT LABoRAToRIEs. J. B. R0ERIG & Co., DIvIsIoN, CHA5. PFIZER & Co., INC., New York, N.Y., ~Septernber 3, 1968. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to our advertising and promotion of TAO~ (~riacety1o1eandomycin) which the FDA regards as misleading. At our display booth at the recent American Medical, Association Convention in San Francisco, two TAO promotional pieces were distributed to physicians, One of `these, a folder titled, "Travel on Us," emphasized that TAO does not cause tooth staining (a side effect of tetracyclines). The FDA regards this as an implied comparison suggesting that triacetyloleandomycin and tetracycline have a similar antibacterial spectrum of effectiveness, and that triacetylo- leandomycin has less toxic potential. Any such implication is not intended and of course would be invalid. The other promotional piece-a booklet-emphasized that TAO is indicated "for the frequently seen respiratory infection in the office or the problem pathogen . . ." (the latter identified as staphylococcus aureFs). In the opin- ion of FDA, the booklet suggested that the antibiotic is useful in the treatment of diseases caused by microorganisms including viruses beyond the spectrum of its effectiveness, and did not provide adequate prominence to the fact that it should be used only as a possible alternative to other less toxic agents. We emphasize that: (1) Triacetyloleandomycin is recommended only for acute, severe `bac- terial infections where adequate sensitivity testing has demonstrated susceptibility to this antibiotic and resistance to other less toxic agents. (2) In view of the possible, but reversible, jaundice and hepatotoxicity of this drug, other less toxic agents should be used unless the organism is resistant to those agents, or in those cases where hypersensitivity precludes their use. (3) TAO (triacetyloleandomycin) is contraindicated in pre-existing liver disease or dysfunction, and In individuals who have shown hypersensi- tivity to the drug. We are discontinuing the promotional pieces in question and correcting the journal advertisements in which the same themes were featured. Sincerely yours, J. RALPH FowLxa, M.D., Medioal Director. SCHICK SAF~ETY RAZOR Co., DIvIsIoN OF EVERSHARP, INC., Culver City, Cali~f., ~Jeptember 30, 1968. DEAR DocToR: Recently you received a booklet entitled "Alcohol-Who is Allergic?" In it reference was made to a drug product, Enzopride®, [DPN (Diphosphopyridine Nucleotide) 3, whIch is currently being tested by our `sub- sidiary, Enzomedic Laboratories, Inc. PAGENO="0224" 4128 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY The Food and Drug Administration has asked us to inform you, in relation to statements made in the booklet, that Euzopride® is still in the investi- gational phase and that available data are inadequate to siibstan'tiate its safety or efficacy in the treatment of chronic alcoholism. In addition, the theory that alcohol may produce a condition leading to chronic alcoholism as a result of an enzymatic deficiency is not proven. Sincerely, P. J. FRAWLEY, Jr., Chairman of the Board. E. I. DTJ PONT DR NuMorn~s & Co., INC., Wilmington, Del., October 14, 1968. DEAR DOCTOR: This letter is sent to you at the request of the Food and Drug Administration to correct implications about "Symmetrel" (amantacjine hydro- chloride) in our recent statement to the medical press. It implied there may be outbreaks of influenza this winter due to the recently identified new strain of A2/Elong Kong/68, as reported by the National Communicable Disease Center (NCDC) in Atlanta. According to our press release, laboratory tests suggested that "Symmetrel" can be used for the prevention of illness from this new strain of influenza virus, and such a suggestion is regarded by the FDA as misleading. We are writing to inform you that there have been no clinical tests in man with respect to infections due to the new A2/HOng Kong/68 variant. We are at- tempting to arrange fOr á~propriate controlled clinical tests of this new A2 strain under conditions of natural exposure. `I~l~we~rer, it will be many months before definitive results can be obtained. Until stich tithe as these tests are completed, We are not in a position to claim that "Symmetrel" is efficacious in man for the prevention of~influenza due to A2/Ilong Kong/68 strain. The FDA has asked us to point Out that the NODO, in á'recent release, has stated that "amantaditie'hydrochloride is not presently' recOmmended asa public health measure for commtinity contrOl of infli~enza nor as ~ `substitute for in- fluenza vaccine immunoproph~4axis." Furthermore, according to FDA, "cur- rent information from the NCDC suggests that influenza due to the Hong Kong variant may be mild, of short dhration (one to three days), and generally without serious sequelae. Even so, the sequelae may be significant, especially in the known high-influenza risk patient groups, smch as those of all ages who suffer from chronic debilitating diseases and persons in older age groups." However, our press release did not point to the faet that it Is in these special groups where precautionary considerations in the use of "Symmetrel" are' most important. For example, when "S~mmetreP' Is administered to patients with central nervous system disease, particularly geriatric patients `with cerebral arteriosclerosis and patients with a history of epilepsy or other "seizures", possible untoward central nervous system effects may* occur. Very truly yours, ROBERT E. ROWAND, M.D., Medical Manager. CIBA PIIARMACETJTICAL Co., ~ummit~ N.J., January 20, 1969. DEAR DOCTOR: At the request of the Food and Drug Administration, we are calling your attention to a recent adveFtisement for our antihypertensive drug, Ismelin® (guanethidine sulfate), which the FDA regards~as misleading. This advertisement suggested that Ismelin will prevent stroke if the drug is added ". . . before organ damage complicates hypertension." The FDA believes that in the absence of substantial and convincing clinical evidence, we are not in a position to validate any claim that Ismelin has such prophylactic benefit. In addition, the FDA regards the "Brief Summary" section of the advertise- ment as misleading because it failed to provide all of the necessary side effect and warning information. For example, the ad failed to appropriately emphasize that exertional hypotension is a potential hazard in the use of guanethidine, that patients should be cautioned to avoid exercise ~hile taking the drug, and that guanethidine causes blockade of the sympathetic nervous system. Also, PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4129 the advertisement omitted listing side effects such as bradycardia and angina, and omitted warnings that guanethidine may cause congestive heart failure, weight gain or edema, and may cause excessive postural hypotension, excessive bradycardia and depression when used concurrently with rauwolfia derivatives. We are discontinuing the Ismelin advertisement in question and other pro- motional material of a similar nature. Sincerely ~~ours, CIBA PHARMAcEUTICAL Co. Mr. GorwoN. Well, suppose that I read to you part of an affidavit, where a particular drug company, Richardson-Merrell, asked its em- ployees to fake data. Let me read it to you. Dr. MCGILL. Well, you are submitting in evidence a study that I have never had any opportunity to see and I am quite sure where this sort of thing might have happened, disciplinary devices would be used very quickly. Mr. GorwoN. Yes. As a matter of fact, they were convicted in a criminal case, but here is an affidavit1 signed by Beulah Jordan, an employee of Richardson-Merrell. She swore that the officials in the company, doctors, by the way, asked her to substitute data to the Food and Drug Administration. I just want to point out that this sort of activity goes on. Dr. MCGILL. Mr. Gordon, I am not denying that such things can happen and where they happen, they should be disciplined just as they have there. Certainly FDA has this authority- Mr. GORDON. Yes. Dr. MCGILL (continuing). And should have it. I dOn't think even the pharmaceutical industry disagrees with this. I might point out the AMA, my own organization, was one of the instrumental groups to get the FDA originally formed and has sup- ported it. No argument there. Mr. GORDON. Just one more question regarding the parasitic com- panies you referred to. Now, I think that you defined a parasitic company as one that didn't do research. Dr. MCGILL. No research and development. Mr. GORDON. No research at all or no research on a particular item? Let me give you an illustration. Carter Products did the research and has a patent on meprobamate. Carter Products licensed American Home Products and American Home Products exclusively. The latter company did not do the research on it. That wouldn't make American Home Products Co. necessarily a parasitic company, would it? Dr. MCGILL. Does the American Home Products have a research and development laboratory where they are searching for new drugs? Mr. GORDON. I presume they do. Dr. MCGILL. If they do, then they are not a parasite. This is my definition. I am thinking about getting more products, new tools we can use. Mr. GORDON. How about the new process, a new process producing maybe the same drug more efficiently at a lower cost? Dr. MCGILL. That is research. 1 Information begins at p. 4~I42, Infra. See also app. v, "The MER-29 Case," be~inni~g at p. 4202, infra. 81-280--69-pt. 10-15 PAGENO="0226" 4130 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY Mr. GORDON. Isn't that a type of research? Dr. MoGuL. It certainly is. Mr. GORDON. Many of these small companies do research in that line. They try to produce drugs at a lower price. Dr. MoGuL. If you want me to give you a good example of that, the original adrenal steroids, since they were taken from the adrenal glands of cattle, they would always be limited. We would never have a supply that was adequate. It wasn't until our research scientists synthesized it and made it that they became useful tools. Certainly I don't object to that and I don't object to price competition. I think I have made that point clear, as long as reliability goes with it. Mr. GORDON. So you would include new processes or better methods of production as a type of research, is that right? Dr. MOGuL. Well, again we get into semantics here and I will de- fine my terms if you wish to define yours. Developing a new product, process, that makes it a more effective agent, that makes it do what it is supposed to do better or to bring it within the reach of the patients where it has been expensive, yes, I would consider that within research and development. Not quite in the same sense of developing new products but that is still worthwhile. Mr. GolmoN. What about a company not necessarily a drug company but any company, that can bring to the consumer a product at a much lower price, whether he eliminates certain things or adds certain things? Would you call that company an innovative company? Dr. MCGILL. No, not really. Mr. GORDON. Not according to your definition. Dr. MoGuL. Not by my definition. Mr. GORDON. I have nothing further. Senator HATFIELD. Dr. McGill, once again we express our apprecia- tion. I have heard many witnesses `and I must say that I think you have been one of the most articulate. You have handled the dialog and the questions in a most admirable fashion. You make us `all very proud of the medical profession and of the kind and quality of people who make up their vast numbers. I wish to express, and I am sure I speak on behalf of my colleague, Senator Nelson as well, our appreciation, our deepest appreciation for your presence here today. Dr. MoGuL. `Could I just finish by adding one personal observa- tion? I think the mere fact that a practicing physician like myself from nearly 3,000 miles away who happens to have strong feelings on a given subject, `as you know I do in this area, the fact that I can get before a U.S~ Senate subcommittee and be heard I think in itself is a remarkable thing. And I think this is the third time I have testified before Congress and I always go away feeling better about my Govern- ment. However `ponderous and distant it might seem to the individual citizen, the system works and I am delighted. Thank you for inviting me. Senator HATFIELD. Thank you very much. The committee will recess until 1:30 and Dr. Ayd will be given his opportunity to testify. (The information previously referred to follows:) PAGENO="0227" COMPETITIVE PROBLEMS IN THE bRTJG IND'tISTRY 4131 NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIl. Division of Medical Sciences DRUG EFFICACY STUDY Form A (To be submitted in duplicate by applicant) NDA 6655 1. NSA Nnmbar_____17.fl3fl2_..________- 3. DotS Oniginnily APP,O,.d_ ~eO~mh~I 8, 1950 3, e~ ~ OTC ~i 4. Stand Nano~ Chloromycetin, 50 nig. & ~ S Applicant's Namn~ , Davis & Company and 6. Ouantitative Formula Ostabltstead tbnn-Pnnp.Iataryt Noon of Actina tegr.d)snt. tin nnd.n shoon on lobcll Amount )p.r tablat, par ml., of,.) 1. Chioromycetin, 50 mg. Cap~~ Chloramphenicol 50 isg./capsule 2. Chioromycet in~ 100 mg. Capsule Chloramphenicol 100 mg./capsule 3. Chlorontycetin, 250 mg. Kapseal Chloramphenicol 250 mg./kapseal 7. Dosage Form (tobtate, at,.) 5. Rout. at Adm. (One), etc. Where 0 ron drug cpp(iucticv canons difarent routes of adminictrution, separate forms should be used.) oral 9. Ttterapaotic Claims-Attach tO )obs)s and TO pockone ircaSe (if csnd) to ermine) Form A )btua) end 1 copy to duplicate Fenm A Inhito). 10. 1.1sf at t(tarctura entar.necs most past)n.nt to an aoeluatlcn of the aftestinenaseat the dmg for the purpaf.e for whtct, It Is eftsrod Ic the )ab.t0 the peekoca Insert, or bruchere. Apprecinrotely S to tO bay tolerances era requestad, it aneilob(e. (Attach to copies to origins) Porn A (blue) and cupy to duptinofa Form A )nh)fe) .1 11. Tho Opp)iconl is incited, it ha so desires, to submit any unpublished roland that is pertinent to the eoek,ctinn at the drug by the Academy.- Research Council. This supplementary material shniild be pccbcged mith Form A )vhtte), A single copy at this matorlo) Is raqeested. 12. I, this spoee, please list and descnlbe bniafy thu supplementary motoriot hot Is submitrod nith Form A labile). Ohioramphenicol 50 MG, 100 MG capsules, 250 MG kapseals, NDA 6655, LOG PANEL ON ~&NTI-INFECTIVE DRUGS (III) INDICATIONS I. Staphylococcal infections, by implication of the discussion on the first page of the insert, may be an Indication: "in a survey of experimental and clinical experiences of susceptibility of staphylococci to chloramphenicol, it was found that the incidence of chioramphenicol-resist~nt staphylococci appears unrelated to frequency or to intensity of use of this antibiotic. Development of resistance to chloramphenlcol can be regarded as minimal for staphylococci and many other species of bacteria." Eva~Zuation Possibly effective. PAGENO="0228" 4132 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Comments Although chioramphenicol was useful for the treatment of some staphylococcal diseases during the anid-1950's, it now seeems to be rarely indicated. Its major trial was in the staphytocoecal pneumonias accompanying the iniiuenza epidemic of 1957. Its effectiveness was somewhat less than expected, even for sensitive strains. The statement concerning resistance is not true in the opinion of the Panel (see below). In the description of in vitro work just before the sentence plotted above, there Is no reference to the transfer of episomal particles carrying chloraanphenicol resistance. The advent of better agents for staphylococcal disease relegates this drug to `a very rareiy needed alternate choice. Documenation 1. Bloomer, W. E., S. Giammona, G. B. Lindskog, and R. B. Cooke. Staphylococ- cal pneumonia and empyema in infancy. J. Thorac. Surg. 30:265-274, 1955. 2. Carmichael, D. B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 3. Hausrnann, W., and A. J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 4. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and einpyema. Pediatrics 11 :385~-392, 158. 5. Lepper, M. H., P. Tillman, and R. Devetsky. Patterns of transmission of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965. 6. Martin, C. M., C. M. Kunin, L. S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:582-542, 1959. 7. Wallman, I. S., H. 0. Godfrey, and J. R. H. Watson. Staphylococcal pneu- monia in infancy. Brit. Med. J. 2:1423-1427,1955. II. Rickettsial diseases: epidemic and murine typhus, Brill's disease, scrub- typhus, Rock3~ Mountain spotted fever, and rickettsial pox. Evaluation Effective, but * * * Comments That chloramphenieol is effective in the diseases listed is well established, except in rickettsial pox, a conditon so infrequently seen that few data are available. However, if the warning is to be taken seriously-"cblOramPheflicol should not be used when other less potentially dangerous agents will be effec- tive"-the tetracyclines, which have been shown to `be as effective as chioram- phenicol, should be considered the choice and chlorampbenicol used only if tQxicity to these or failure to respond has occurred. The duration of therapy recommended appears adequate. Docuiinentation 1. Knight, V. W., McDermott, and F. Ruiz-Sanchez. Aureomycin and chioram- phenicol: use in typhus, typhoid and brucellosis. J. Olin. Invest. 28:1052- 1053, 1949. (abstr.) 2. Knight, V., F. Ruiz-Sanchez, ~nd W. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer. J. Med. Sci. 219:627-638,1950. 3. Ley, H. L., Jr., T. B. Woodward, and J. B. Smaclel. Chloraiflpheni'cOl (chioro- mycetin) in the treatment of murine typhus. J.A.M.A. 143:217-219, 1950. 4. Murray, B. S., G. Baehr, G. Schwa,rtzman, T. A. Manderbaum, N. Rosenthal, J. 0. Doane, L. B. Weiss, S. Cohen, and J. 0. Snyder. Brill's Disease; clinical and laboratory diagnosis. J.A.M.A. 142 :1059-10~36, 1950. 5. Pincoffs, M. C., B. G. Guy, L. M. Lister, T. B. Woodwarci, and J. B. Smadel. The treatment of ~ocky Mountain spotted fever with chrioromycetin. Ann. Intern. Med. 2~ :656-663,1948. 6. Smadel, J. B., !I~. ~. Woodward, ii. L. LeV, Jr., and H. Leuthwaita Chloranl- pbesiical (chloronl~cetifl) In the treatmei~t of tsrutsugamushl disease (scrub typhus). J. Olin. Invest. 28 :1196-1~15,1949. ii~T. Typhoid fever. Evualation Effective, but * * * PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4133 Comment$ Ohioramphenicol has oftea been listed as the drug of choice in typhoid fever. It is not clear that ainpilicfflin has changed this claim, but if they were of equal activity, the claim of "drug of choice" would have to be revised because of the toxicity warning. There is no mention of the carrier problem and relapses of positive stool cnlture~. Documentation 1, Knight, V., W. McDermott, and F. R~iz..Sanchez. Aureomycin and chioram- phenicol: use in typhus, typhoid and brilcellosis. J. Olin. Invest. 28 :1O52~- 1053,1949. (abstr.) 2. Smadel, J. E., H. L. Ley, Jr., and F. H. Diercks. Treatment of typhoid fever. I. Combined therapy with cortisone and chioramphenicoL Am. Intern. Med. 34:1-9, j951. IV. Other salmoneiloses. Evaluation Possibly effective. Comments Because of variability of clinical course with each species and the large variety of species, there is litle reason to presume that a generalization is possible. In a condition of short symptomatic duration like gastroenteritis, the use of the drug is most difficult to evaluate. The variable courses of the systemic forms do not allow the assurance of effectiveness that has been derived for typhoid fever, which is more uniform. These differences between typhoid and the other salmonelloses illustrate the difficulty or generalization from one species to the next. It is likely that localized salmonella infections, stitch as osteomylitis, empyema or other dis- eases should have a therapeutic trial with chloramphenicol. The treatment of carriers with positive stool cultures should not be recommended and the insert should so state. Although the stools may be negative while the drug is con- tinued, there is no evidence that the carrier state is terminated more frequently than would occur otherwise with a similar passage of t1me~ Obviously, the in- ability to define drug effectiveness in salmonelloses also applied to other drugs, such as ampicillin; hence a reliable comparison between drugs is not possible. Documentation 1. Woodward, T. E., and C. L. Wisseman, Jr. Ohloromycetin, pp. 56-58. Anti- biotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. V. Urinary tvact infections. Evaluation Effective, but * * * Comments As specified in the insert, outcome of treatment of urinary tract infections is influenced by anatomic factors, but these have little importance in the choice of drug except that, in situations in which cure is unlikely, the use of toxic agents is probably not justified. The susceptibilities of the organisms involved are of prime importance (cbloramphenicol does not work any better against chloram- phenicol-susceptible organisms than other agents work against organisms sus- ceptible to them.) Hence, when organisms are susceptible to less toxic agents, chloramphenicol should not be used even if It is effective in vitro unless the others have failed. It is unusual for chloramphenicol to succeed when other agents with satisfactory in vitro activity have failed. Of the three species singled out, Es- cherichia coli is often treatable with other chemotherapy, but chloramphenicol may be a secondary choice. $treptococcus fecalis infections are probably better treated with other agents, such as penicillin and streptomycin or erythroanycin. Various Proteus species are different in their susceptibility to different drugs; hence, the generalization "Proteus species" should be avoided. Proteus morgani, vulgaris, and rettgeri are often susceptible only to chloramphenicoh Documentation 1. Woodward, T. E., and C. L. Wisseman, Jr. Chloromycetln, pp. 105-108. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc. 1958. VI. Surgical infections: postoperative wound Infections. PAGENO="0230" 4134 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY Evaluation Possibly effective. Cornment8 Pqstoperative woum3, lnf~ctlons have a variety of etlologic agents, but eta- phylococcus aureus Is the single most common. Chioramphenicol Is effective against many of these agents, but is not the most effective against the Sta- phylococcus. For this reason, plus the toxicity warning, it is not the first choice in most infections unless an organism is isolated against which chloramphenicol is most active in vitro, or other preferred drugs cannot be given or have been ineffective. Documentation Most i~avorable report Is reference 1 (Altemeler). 1. Altemeir, W. A., and W. R. Culbertson, Chioramphehicol (chloromycetin) and auremycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W. E., S. Giammona, G. E. Lindskog, and R. E. Cooke. Staph- ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 80: 265- 274, 1955. 3. Carmichael, C. B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A. J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 4. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphyloceal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, M. H., P. Tillman, and H. Devetsky. Patterns of transmission of staphylococci. Ann ~.Y. Acad. Sd. 128:404-427, 1965. 7. MartIn C~ M., C. M. Kunin, L. S. Gottlieb, and M. Finland, Asian influenza A in Boston, 1957~-58. IL Severe~ staphylococeal pteumonia complicating influenza. A.M.A. Arch. Intern. Med. 103 :532~-542, 1959. 8. Wailman, I. S., R. 0 Godfrey, and J. H. H. Watson, Staphylococcal pneu- monia In infaney~ Brit Med. J. 2:1428-1427, 1955. VII. Surgical infectIons: cellulitis. Evaluation Possibly effective. Comments Cellulitis (other than postoperative) is. most often caused by streptococci or staphylococci for which chloramphenicol is not the, most effective drug. For this reason, plus the toxicity warning, it Is not the ftr~t chE~1ce unless an organ- ism against which chloramphenicol is the most active has been isolated, or the preferred drug cannot be given or has failed. Documentation Same as for Indication VL VIII. Surgical infections; infected sinus tract. Evaluation Possibly effective. Comments Ohloraanphecnicol may be useful in some instances in which the organisms have been shown to be sensitive only to it. Many sinus tract infections are caused by tuberculosis and aeti~om.ycosis, Chloramphenicol is not indicated in tuberculosis, and other agents are preferred in actinomycosis. Some sinus tracts associated with fistulas from viscera, including intestines, may be predominantly infected with fecal flora. In these, chloramphetnicol may be the single most effective agent. When other agents appear equally effective in laboratory testing, they should be tried first. There is rarely. great urgency in treating sinus tract infections with antibiotics. The specific organisms for which chloramphenicol has been proved effective therapy (in this condition) should be listed. Documentation, 1. Altemeier, W. A., and W. H. Culbertson. Chloramphenicol (chloromycetin) and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. PAGENO="0231" COMPBTIPIVE PROBLEMS IN THE DRUG INDUSTRY 4135 2. Bloomer, W. E., S. Giammona, G. E. Lindskog, and R. Fl. Cooke. Staph- yloccal pneumonia and empyenia in infancy. J. Thorac. Surg. 30: 265- 274, 1955. 3. Carmichael, D. B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A. J. Karlish. Staphyloccal pneumonia In adults. Brit. Med. J. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I Mauss. Staphylocoecal pneumonia and empymea. Pediatrics 11:385-392, 1953. 6. Lepper, M. H. P. Tiliman, and R. Devetsky. Patterns of tranSmission of staphylococci. Ann. N.Y. Acad. Sd. 128 :404~-427, 1965. 7. Martin, C. M., C. M. Kunin, L. S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch Intern. Med. 103:532:542, 1959. 8. Wallman, I. S., R. C. Godfrey, and J. R. H. Watson. Staphylococcal pneu~ monia in infancy. Brit. Med. J. 2:1423-1427, 1955. 9. Woodward, P. Fl., and C. L. Wisseman, Jr. Chloromycetln, pp. 122-124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. IX. Surgical infections: peritonitis or intra-abdotainal abscesses from ruptured inteStines, diverticula, or appendix. Evaluation Possibly effective. Comments These infections are often caused by mixed flora from the intestinal content. In the acute stage of peritonitis, a drug often must be selected empirically for surgical preparation or immediately postoperatively. Tudged by statistical prob- ability chloramphenicol is a good choice in such a situation, It should be given parenterally, however, because oral therapy in these Infections is probably in- appropriate. In other less acute complications listed in the insert, chioramphenicol should be shown to be the most effective agent against the organisms isolated before it is used, or other less toxic agents should have failed or be contra- indicated. The specific causative organisms for which chloramphenicol has been proved effective therapy (in these conditions) should be listed. Documentation Same as for indication VIII. X. Respiratory tract infections. Evaluation Possibly effective. Comments This heading Is ambiguous. The package insert should list specific organisms (and the site of respiratory Infection) for which chlorampheiticol has been proved effective therapy. In general, the etiology of these conditions is varied and chioramphenicol is the best agent for only a few. In streptococcal, pneumococcal, and staphylococcal diseases of the respiratory tract, other drugs are preferable. Obloramphenicol should be used only in Klebslella infections and perhaps other necrotizing pneu- monias caused by E. coti or related organisms when they are shown in vitro to be resistant to ampicillin, cephalothin, and kanamycin. Hemophilus influenzae infections of the respiratory tract respond well to ampicillin; hence chloram- phenicol is best used only when ampicillin is not tolerated or fails. Documentation 1. Woodward, T. E., and C. L. Wisseman, Jr. Chloromyeetin, pp. 63-72. Anti- biotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. XI. Meningeal infections. Evaluation Probably effective. PAGENO="0232" 4136 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY ciom'menta The three most common causes of meningitis are the meningococci, pneumo- cocci, and Hemophil'uu influenzae. All are susceptible to chlora~pbenicol, as are many staphylococci and the gram-negative aerobic rods that often infect new- borns. Moreover, it is true that the drug does get Into the spinal fluid well. ~s a drug of choice for empiric use, however, It is probably not first, because it is likely to be less effective In pneumococc'al disease than is penicillin. Al- though many believe it Is first choice in Hemophilus infections, tetracycline is probably a~ good and `ainpicillin Is, too. It Is likely that this claim (drug of choice in H. influenzae meningitis) is no longer justified. In meaiigitis of the newborn kanamy~in Is preferred as the drug of choice for empiric treatment. In older patients, when a diagnosis has been made and the organisms shown to be more `snsceptible to chlorampbenicol than to other agents, it may be the drug of' choice. As indicated, in the insert, initial treatment should be parenterally administered. The package insert should list the specific organisms for which ehioramphenicol has been proved effective therapy in meningitis. Doewmentation 1. Parker R. T., M. J. Snyder, It. S. J. Liu, J. W. Looper, Jr. and P. E Wood- ward. Therapeutic range of chioramphenicol `in purulent meningitis. Antibiot. Med. Clin. Thor. 1 :192-200, 1955. XII. Brucellosis. Evaluation Effective, but * * Comments ~hlorampbenicol, like other drugs, is capable of controlling symptoms of acute brucellosis, `hut the relapse rate is high. It does not appear to be superior to the less' to~ic tetracyclines. Dooumn eat ation 1. Knight, V., F. Ruizz-Sancliez, and W. McDermott. Ohloraniphenicol in the treatment of the acute manifestations of brucellosis. Amer. J. Med. Sd. 219 :627-638, 1950. 2. Spink, W. W. The Nature of Brucellosis. ~inneapolis: The Tjnive'rsity of Minnesota Press, 1956.464 pp. 3. Woodward, P. E., J. E. Smadel, W. A. Holbrook, and W. T. Raby. The bene- ficial effect of chioromycetin in brucelloats. J. Olin, Invest. 28 :96&-976, 1949. XIII. Bartonellosis. Evalnation Probably effective. Comnmaeats O~ora'mphenicol is reported to be au effective antibiotic in these infections. Of the references suggested by the manufacturer (see Documentation below): two are reports of studios involving a tQtal `of 25 patients whose bartonellosis was treated with chloramphenicol with good success, `and two are textbook dis- cussionis of b'~rtoueil'o'sl~ and its treatment. Of the latter discussions, one feels that the effectiveness of chl'oramphenicol is best documented, the other feels that other agents are probably as go'o'd. Documentation 1. Eartonéllosis, pp. 603-606. In G.W. Hunter, III, W. W. Frye, and J. 0. S'wartzwel'der, Eds. A Manual of Tropical Medicine. (3rd ed.) Philadel- phia: W. B. Saunders Co., 1960. 2. Payne, E. H., and 0. Urteaga. Oarrion's disease treated with chloromycetin. Antiohiot. & Chemother. 1:92-99, 1951. Pinkerton, H. Bartonollosis (Car- rion's disease, Oroya fever, Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott, Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia: W. B. Saunders Oo., 1063. 3. Urteaga, B. 0., and E. H. Payne. Treatment of the acute febrile phase of Oarrion's disease with chl'oramphenicol. Amer. J. Trop. Med. 4 :507-~511, 1955. XIV. Relapsing fever. PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4137 Evaluation Possibly effective. Comments Treponema (Borrella) rectirrentis infections in experimental animals are susceptible to chioramphenleol. On a weight basis, however, penicillin G is morn active. In human infections, no direct comparison has been made, and, although chioramphenicol has been used successfully, penicillin should be tried first if it is tolerated. Docwmentation 1. Hirschboeck, M. M. Use of chioramphenicol in relapsing fever. Amer. J. Prop. Med. 3 :7'12-713, 1954. XV. Granuloma inguinale. Evaluation Effective, but * * Comments It has been reported that chlorantphenicol caused the disappearance of Dona- van bodies more rapidly than either tetracycline or streptomycin. Relapses after chioramphenicol have seemed to be less than 10%. Although chloramphenicol may be slightly better than tetrocycline, the latter may be preferred for to~dco- logic reasons. Documentation: 1. Greenblatt, R. B., W. E. Barfield, R. B. Dienst, R. M. West, and M. Zieses. Five-year study of antibiotics in treatment of granuloma Inguinale. Amer. J. Syph. 36:186-191, 1952. 2. Robinson, R. 0. V., and T. L. Wells. Intramuscular chioramphenicol in the treatment of gonorrhea and granuloma inginale. Amer. J. Syph. 36:264- 268, 19~2. XVI. Plague. Evaluation Effective, but * * Comments All forms of plague have been shown to respond to chloramphenicoi when it is given in large doses early in the disease. There is no clear evidence that it is superior to tetracycline or streptomycin. Documentation 1. MeOrumb, F, It., Jr., S. Mercier, J. Robic, M. Bouillat, J. E. Smadel, T. E. Woodward, and K. Goodner. Ohloramphenicol and terramycin in the treatment of pneumonic plague. Amer~ J. Med. 14:284-293, 1953. XVII. Ornithosis, Evaluation Possibly effective. Comments In embryonated eggs and experimental animal infections, chloraniphenicol is less effective than the tetracyclines. Results of therapy of human infections have been variable and relapses have been frequent. The role of the drug in this disease is not well established. Documentation 1. Woodward, T. E., and 0. L. Wisseinan, Jr. Chloromyeetin, pp. 70-71. AntI- biotics Monographs No. 8. New 3~ork: Medical Encyclopedia, Inc., 1958. General comments The "Warning" section appears justified in view of the seriousness of aplastic anemia. Absorption after oral administration is good, in that 70-90% of a dose can be accounted for by metabolic products found in the urine. Tissue distribution appears to be favorable. The distribution into the cerebrospinal fluid is good, as pointed out in the insert, and is reasonably good into brain tissue, which is PAGENO="0234" 4138 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY important when cerebritis accompanies meningitis. The distribution into bile is not `as high as that of the tetracycline and some of the penicillins. The very small amount in the feces is of interest as is the fact that the fecal content is' higher when the palmitate has been given. The penetration into the eye is a plus factor for this drug. Transpiacental transfer was shown by chemical methods which may not measure the active drug. 1~niphasis should be put on the recommended dose, because a smaller dose is often given, particularly postoperatively. The fate of the drug when `the metabolic mechanisms are disturbed should remain as `stated. As to blood dyscrasias, it sho'tdd `be mentioned that frequent bl'o'od counts do not necessarily assure that aplastic anemia can `be prevented. In fact, it may occur after the `drug has been stopped. The roles of organisms other than canida and staphylococci in resistance and superinfection have been demonstrated, particularly Pse'udomonas and some other gram-negative aerobic rods that are resistant. This should be pointed out in the section discussing resistance. Intravenous `administration of chlo'ramphenicol produces a rapid peak in blood levels and is preferred over oral or intramuscular administration in critically ill `patients. However, because the oral form is so highly absorbed, as soon as the patient can take it, there is little reason to continue the I.V. use. This package insert is identical in every way with that for Ciilo'r'omyce'tin Pal- mitate Oral Suspension, Log 2263. This preparation is `the straight drug without p'almitate. The dose `recommendation's are accurate. Approved `by: WM. KInBY, Chairman. `The Drug Efficacy Study of the National Academy of `Sciences-National Research Council has requested that the following qualifying addendum be con- veyed with their reports to the ultimate recipients of these reports: "Drugs of identical chemical composition (so-called generic drugs) formu- lated and marketed by numerous individual firms under generic or trade- marked names have been evaluated for efficacy as a group without considera- tion Qf `therapeutic equivalence.' In the event that no evidence for pharma- cological availability or therapeutic efficacy in man can 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 modified if regu- lations of the Food and Drug Administration require such proof." A PRACTICING PHYSICIAN LOOKS AT THE NELsoN HRARINGS (Remarks by Clinton S. McGill, M.D., Portland, Oreg., before Pharmaceutical Manufacturers Association, New York Hilton, Dec. 3, 1968) Mr. Chairman, ladies and gentiemen, I consider it a privilege to be here today and to address your mid-year meeting. For the record, let me make my position clear. I'm here today representing no vested interest except the health of the American Public. I earn my living in the full-time practice of internal medicine in Portland, Oreg. I have never been employed by a drug firm nor have I ever owned stock in any pharmaceutical house. My interest In your present dilemma stems solely from my concern for the welfare of my own patients and for our health care system. For the past 18 months I have watched with increasing alarm the preceedings of Senator Gaylord Nelson's subcommittee. It was evident from the very beginning that the hearings here slanted and the facts were being distorted. We have been exposed to a steady stream of hand-picked witnesses whose testimony became as predictable as the rising sun. Over and over again' we heard the same tired charges of excess profits, price gouging, unreasonable patent protection, and the like . . . without even the pretense of fairness or objectivity. Not that I was surprised by the tenor of the hearings. . . . I'm aware that Senator Nelson is not one of our admirers. Then too, none of us in the health industry has been treated gently in the halls of Congress these past several years. PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4139 But, I kept expecting to hear testimony from the "other side." X thought surely they would call witnesses from the various specialty groups, the Academy of Gen~ eral Practice, the AMA, and individual practitioners like myself. When none was forthcoming, I decided to have a try at it. As is happens, one member of the subcommittee is Senator Mark Hatfield from my own State. Last spring I had occasion to visit the Senator in Washington and we discussed the Nelson bearings at some length. He was sympathetic to my point of view that the hearings were being used to malign the drug industry and the medical profession for political purposes. He agreed to help me get called as a witness. Since that time I have had a series of polite but non-committal letters from Senator Nelson. I discussed the situation again with Senator Hatfield just ten days ago and he also expressed his frustrgtlon in the selection of witnesses before the committee. It seems very clear that Senator Nelson does not want anyone to tell the story from the private practitioner's point of view * * * or even to allow us to defend ourselves against the scurrilous attacks that ~re now a part of the public record. Fortunately, Joe Stetler learned of my dilemma and Invited me here today to express my views. I'm indebted to Joe for finally giving me a platform. I think It's about time somebody speaks out against this travesty of justice * * * against the misuse of congressional authority. Of course, I don't have the lofty forum that Senator Nelson enjoys, nor do I have his "troops". But, I think I do have one thing going for me * * * and that is the truth * * * and perhaps * * * just perhaps * * * I can stir the members of the press to take a second look at what's really going on in the Nelson bearings. From the start, the fundamental theme has been that all of you drug manu- facturers are liars and thieves * * * gouging excess profits out of the sick and the poor. And, we doctors are simple boobs, so snowed under by drug advertising that we can't select the right therapeutic agents for our patients. Well * * * I deeply resent this slur on the clinical Integrity of the American physician and I equally resent the slashing attack on our great pharmaceutical industry. But let me be more specific. I'd like to submit to you the views of one practicing physician on some of the charges made by the Nelson subcommittee. First, the nonsense of "Therapeutic Equivalency". This morning we have heard convincing evidence to the contrary by Dr. Cavallito and I don't think it would serve any purpose for me to belabor the point. Yet Senator Nelson has allowed such unfounded statements to become part of the public record. We've heard high-placed government officials, such as Wilbur Cohen, Dr. James Goddard, Dr. Milton Silverman and Dr. Philip Lee, state that therapeutic equivalency ecrists * * * on mere assumption * * * without a shred of scientific evidence to back it up! I'd like to make just one point on the issue of "therapeutic equivalency" and that is how it can effect me in my everyday practice. I'd like to choose Chloro- niycetin as an example. Probably no drug in history has received as much adverse publicity as this drug has because of the very occasional blood dyscrasia it pro- duces. The uses and abuses of Chioromycetin became a personal vendetta between Dr. James Goddard and the Parke-Davis Company * * * and all the while Dr. Goddard was indicting the medical profession for using it. Why is it that so little was ever said about the thousands of lives that were saved by this marvelous antibiotic? The truth is-Chioromycetin is a life-saving drug. It's use involves a small but significant rtsk of serious abreactions. But, calculated risks are nothing new in medicine. There are many such small but significant risks * * * every anes- thetic, every surgical operation, in fact, almost all medical procedures contain them. This does not mean that such risks are taken lightly * * * they are not, and every effort is made to eliminate them. But it is my contention that risk must be weighed against the value of a given drug or a given procedure and the decision made accordingly. Making this type of decision is a part of our everyday experience. However, this is only part of the story. The patent rights ran out on Ohioro- mycetin and last year competitive brands of chloramyphenlcol appeared on the market. Bear in mind, if you will, that we were being told, over and over again, that we doctors should be prescribing by generic name only, since after all the products were therapeutically equivalent. Well * * * such was not the case. The competing brands of chioramphenicol were not equally effective and the FDA, PAGENO="0236" 4140 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY somewhat reluctaniy, o~,dered them withdrawn from the market * * * and I should add, on evidence developed by Parke-Davis instead of their own laboratory. This isolated incident may seem like an academic exercise In pharmacology * * * but I would submit that to a practicing physician it is mu~h ~tore than that. There is just one way we would have learned about tb~ ineffectiveness of those products * * * when the patient died I I refuse to subject my patients to such a risk. I will continue to insist on product `indentification. I wonder how may peo- ple died. as a direct result of the bureaucratic jungle? I dare say more than ever died from sensitivity to Chloromycetin. It seems to me that if the Nelson subcommittee were seriously considering the best interests of the public they would be the first to demand product identifica- tio~. Then, * * * any kind of an abnormal reaction, any question of therapeutic value, any problem involving the quality of the product * * * could be traced right back to the source. Why then, this bull-headed insistence on generic prescribing, regardless of the source of the product? You know the answer and so do I. For the Nelson com- mittee to do otherwise would be an admission that there is a difference between products bearing the same generic lable that there is such a thing as quality control * * * and that the well-earned reputation of the ethical drug companies is something of value! I commented earlier on the false impression Senator Nelson* * * and others * * * have tried to create on the competence of the average physician in his drug prescribing habits. I have here in my hand a letter dated November 7, 1968, from Dr. Philip Lee, Assistant Secretary for Health and Scientific Affairs of HEW. I would like to read just one paragraph from that letter, which was sent to all doctors in this country "As you know, most of the drug information used by physicians comes from the advertising and promotional activities of drug manufacturers. The task force has seriously questioned whether these sources provide or should be ex- pected to provide the objective and comparative Information needed by pre- scribers. We believe that an Independent grOup of well qualified clinicians and pharmacologists could provide objective evaluations of new drugs and reassess- ments of older ones through a regularly published journal of prescribing. The task force has recommended that such a publication be made available on a regular basis to all physicians, and it has recommended Federal support for this activity." I find it incredible that Dr. Lee would write such a letter. If he did, in fact, write the letter, It tells me that Philip Lee has forgotten he's a doctor and iS now thinking like a bureaucrat. Anyone with even a casual acquaintance with medical literature knows that long before an important new product is ever marketed there will `be a number of articles on it in our professional journals. Next, it will be described in some detail in the JAMA section on new drugs. We may likely hear of It when reported In a scientific paper in one of our many pro- fessional meetings. In all probability we will read about it, or have it pointed out to us In the Ladies' Home Journal, Reader's Digest, or the Sunday supple. mont !--all of this, mind you, before the product is distributed, I can see little value In his recommendation that a federally supported drug journal be published. Dr. Lee conveniently ignores the Important work being done by the AMA's Clouneil on Pharmacy and Drugs. The obvious bias of HEW would discredit the journal before It was ever published. I am sure the physicians of this country have a great deal more confidence in our own council on drugs than we would ever have In a publication of the De- partment of HEW at least, as long as the present atmosphere exists. I do not mean to down-grade the Importance o~f information provided us through journal advertising. It's been my experience that the reputable drug companies are very careful to correctly describe their new products, and take great pains to point out the possible side effects and contraindications. And, right here, I'd like to say a few words in defense of the "detail man." I'm sick of hearing him described as a fast-talking con-artist, something akin to the snake oil peddler of the nineteenth century. The vast majority of detail men are trained professionals who provide us with valuable information. We learn from them such important details as package size, how a given drug is supplied-liquid, tablet, Injectable, suppository, and price information. They pro- vide many services for us, and we are grateful. Can anyone really believe' that PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4141 a fast-talking hard-sell type would ever get past the front desk let alone take up the doctor's time? It's a curious paradox that our system of medical care is being subjected to its severest criticism at a time when that very system is producing its greatest progress. We have managed to create a "health miracle" that is beyond the wildest dreams of the last generation. There can be little doubt that a great share of the credit is due the pharmaceutical industry. I consider myself fortunate to have been born at a time when I could share ~m this exciting process. In my twenty years of practicing medicine I have seen the development of more important therapeutic agents than were produced in the entire history of medicine. You have made it possible for me i~nd others like me to be better doctors than we ever dreamed we would be. I'm very grateful for the wonderful products you have given me. I can't help but feel alarmed when I see the drug industry under attack. Some very unfair charges have been made by Senator Nelson and others about excessive profits and unreasonable patent protection. I'd like to give you my point of view on this Issue. I sincerely hope you continue to make a profit-a very good profit. I hope you can afford to hire the very best research talent you can find so that you can continue to provide us with the great new products that you have in the past, and in this effort, I wish you God's speed! CLINTON S. MCGILL, M.D., Portland, Oreg., March 28, 1968. SENATOR GAYLORD D. Nnnsox, 1]. ~. senate, D.C. Dear Senator Nelson: I have followed with great interest the hearings of the Monopoly Subcommittee. The testimony of Dr. James Goddard has been very impressive. Through your efforts, the public has gained a great deal of informa- tion about drugs and drug manufacturers. I'm in total agreement that such facts should be made known, both to the medical profession and the public at large. I feel certain that much more can be revealed. 1 also feel that the testimony of a private practicing physician, like myself, would add a useful dimension to your hearinga I would like to volunteer my services for that purpose. After all, we are the ones involved in direct patient care and `the cost of that care. We are the ones who prescribe the drugs and must evaluate their worth on a day-by-day basis. We are also the ones towards whom the pressures and promotions of the drug companies are directed. I feel I have certain qualifications that may be of interest to your committee. I am a specialist in Internal Medicine and have been in private practice for the past twenty years. Earlier in my career I taught in the Physiology and Pharma- cology departments of the University of Oregon Medical School where I partici- pated in drug research. Perhaps of greater interest to your committee is the fact that I served ten years as the Medical Director of the Oregon State Public Welfare Commission, part of that time under Governor Mark Hatfield. It was during this period (1949- 1959) that the great boom in drug usage first began. The cost of drug therapy increased so rapidly that we could not realistically budget It. My chief problem was to relate the cost of a given drug product to its therapeutic efficiency. In an attempt to control these costs, I compiled and published a Drug Pormulary for Welfare recipients, which I believe was the first of its kind. I have first hand knowledge of the pressure and the problems encountered In this kind of under- taking. I would be happy to make this information available to your committee. If in your judgment you feel `that the information I have would serve a useful purpose to your committee, I will be happy to make myself available at your convenience. Sincerely `CtINTON S. MCGILL, M.D. cc: Senator Mark 0. Hatfield. U.S. Sx?tATR, Washington, D.C., April 29, 1968. CLINTON MCGILL, M.D. Portland, Oreg. D&&n DR. MCGILL: I appreciate your letter expressing an interest in testifying at our hearings on the prescription drug industry. Senator Hatfield has also con- tacted me in this regard. PAGENO="0238" 4142 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY As you know, the committee is covering a number of facets of the competitive problems in the prescription drug Industry. I would appredate learning from you which phase you are interest in discussing. Because of the number of witnesses who have been scheduled to appear, we have not been able to set a time in the near future for additional witnesses. However, if you will send me a copy of your statement, we will include it in the committee records. Then, if a time can be worked out for your personal api~ear- auce, the committee will be happy to contact you again-hopefully in not too long a period of time, Sincerely yours, GAYLORD NELSON, U.S. Senator~ cc: Senator Mark Hatfield, Senate Monop9ly Subcommittee. AFFIDAVIT STATE OF OHIO, County of Hamilton: Before me, Thomas M. Rice, an employee of the Department of Health, Educa- tion, and Welfare, Food and Drug Administration, designated by the Secretary, under authority of the Act of January 31, 1925, 43 Statutes at Large 803 (5 U.S.C. 521); Reorganization Plan No. IV, Sees. 12-15, effective June 30, 1940; and Reorganization Plan No. 1 of 1953; Sees. 1-9, effective April 11, 1953, to administer or take oaths affirmations, and affidavits, personally appeared Mrs. Beulah I. Jordan in the county and State aforesaid, who, being first duly sworn, deposes nd says: My name is Mrs. Beulah L. Jordan. I reside at 3825 Trebor Drive, Cincinnati 36, Ohio. I worked as a technician in the Toxicological Laboratory of the William S. Merrell Co., Cincinnati, Ohio, for approximately 23's years from the fall of 1956 to the early summer of 1950. During this time I assisted in a toxicological study on Mer 29 using monkeys. This experiment ran approximately 16-18 months. It involved 6 to 8 monkeys of which 3 or 4 were in a control group, and 3 or 4 were in the drug group. Three control and three drug monkeys were carried through the entire experiment, while one of each group was autopsied after approximately 6 or 7 months. My duties included bleeding the monkeys, runing blood counts, assisting with the autopsies making up capsules of Mer 29 and placebos for the drug groups and control groups, assisting with dosing both control groups and drug groups by pushing the respective capsules down the throats of the monkeys, make notes about the food the monkeys ate or refused to eat, weighing the monkeys weekly, checking the monkeys reactions, preparing weight graphs each week and after autopsy, and weighing each organ at autopsy. Notes of observations made were recorded in ink in a loose leaf 3 ring black note book, together with the recordings of the drug and placebo dosages and weights of the monkeys. This note book was always retained in the laboratory, and was never turned in to the firm's record office. The estimates of food eaten by the monkeys and the observations of eating habits were entered on a separate sheet and maintained in a separate loose leaf note book which was also retained in the laboratory. During the first part of the experiment, I was under the direction of Mr. James Knox Smith, but toward the close of the experiment he was replaced by Dr. William King. Toward the end of the experiment one. male drug monkey was sick and doing very poorly, and weighed approximately 8 or 9 pounds. He had lost approximately 5 pounds or more during the course of the experiment. This sick male drug monkey had become somewhat mean and acted angry. He had been a healthy, active monkey at the ~bart of the experiment. After being on the drug he first became aaore active than usual, but later became very inactive and lay on the bottom of the cage. The expression in his eyes and his disposition indicated he was very ill. He could not jump into the box from his cage for weighing, and back into his cage as the other monkeys could. During the first part of the experiment, this monkey could also do this very easily. Later on o'~e Qeca~sion when be tried to do this he missed the box. PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4143 At the close of the experiment I worked up the weight graphs, and showed them to Dr. King. He in turn discussed them with his superior, Dr. B. F. Van Maanen. Dr. Van Maanen, with the concurrance of Dr. King, decided to throw out the sick male drug monkey mentioned above, and substitute another control monkey in his place which had never been on Mer 29. The male monkey substituted weighed about 18 or 20 pounds, or about 10 pounds more than the sick monkey for which he was substituted. Dr. Van Maanen then called me into his office and instructed me to make this substitution in working up the weight chart. Be- cause of this decision, I had to make up the charts 3 times. The sick male monkey was never autopsied in my presence, but the substitute control monkey was autopsied in his place. The weight charts would have been very much different, had the data from the sick male drug monkey been retained in the final reports because of his loss of weight from approximately 13 pounds at the start of the experiment to approximately 8 pounds at the close of the experiment. Dr. King ordered me to never mention the substitution. I was told this was the way the company wanted it and to forget it. I was told that the order had come from higher up. Also during this experiment, I know that on a number of occasions the cap- sules of Mer 29 were not given to the monkeys as they should have been. This would happen over a weekend, when people in other groups would work relief shifts in the place of regular employees of our group. I knew this because I was the one who weighed up the capsules for each individual drug monkey for a week at a time, and prepared just enough to last 1 week until the monkeys were weighed again and the calculations were made in terms of the monkey's new weight. My routine was to have 1 capsule left for Monday morning, but sometimes there would be 2 or 3 capsules remaining. During the experiment the monkeys on the drug became difficult to catch for doseing, which would explain why the weekend relief employees may not have always dosed the monkeys. The charts however, were always marked as if the capsules were given. I also participated in similar studies on dogs and white rats involving Mer 29. I had similar duties in respect to these studies. I noticed nothing unusual about the conduct of these dog and rat studies. I participated in the autopsies of the dogs and rats on these studies, and also worked up the weight charts at the close of these experiments. In the case of the rat studies, duplicate records were kept by means of record- ing the data into a bound book with carbon paper, but this was not the case with the monkey studies, and dog studies. Other employees who helped with the monkey studies were: Bruce Umberger. He was still with the firm a few months after I left, but is no longer with the firm. He now lives in Columbus, Ohio. His duties included conditioning and handling the monkeys prior to the start of the experiment. He helped autopsy the monkeys at the close of the experiment. During the studies he helped weigh, dose, observe, and care for the monkeys. He helped catch, weigh, and dose monkeys. He had nothing to do with working up the final data at the close of the ex- periment on the monkeys. He also did similar work with respect to the studies on dogs and white rats. Dorthy Miner. This individual also no longer associated with this firm, and left 1 to 11/2 months after I did. She is presently in Florida, but I do not know her exact address. She was employed during the Mer 29 studies on monkeys. Her job was primarily the preparation and staining slides. These were simply from the organs supplied her. Mary Ann ~8tephens. This individual is now married and her present name and address is not known. Her duties primarily involved making blood counts on rats. She did not work directly with the monkeys. She has also left the firm. Mike. I do not know this individual's last name. He worked for the firm during the last part of the Mer 29 studies on monkeys. He assisted Bruce Umberger, and his primary duties were to take care of the monkeys. He also helped weigh the rats on Mer 29 studies. I resigned my position with the firm at the conclusion of the Mer 29 studies on the monkeys, because of my dissatisfaction with the way the work was being run by Dr. King. BEULAII L. JORDAN. PAGENO="0240" 4144 COMPETITIVE PROJ3LEMS IN TI~E DRtTG INDUSTRY Subscribed and sworn to before me at Cincinnati, Ohio, this 13th day of March 1962. THOMAS M. Rion, Employee of the Department of Health, Education, and Weif are designated under Act of January 31, 1925, ReorganS~ation Plan IV effective June 30, 1940; an,Z Reorganization J'lan No. 1 of 1953, effectiDe April 11, 1953. (Whereupon, the subcommittee recessed at 12 o'clock to reconvene at 1:30 p.m., the same day.) AFTERNOON SESSION Senator NELSON. Doctor, I apologize for holding you up this way. Dr. AYD. No apologies necessary. Senator NELSON. Thank you, Doctor. The committee appreciates your taking the time to come here today to testify. You may proceed to present your testimony in any way you see fit. STATEMENT OP DR. PRANK J~. AYD, SR., PAPA, EDITOR, INTERNA- TIONAL DRUG THERAPY NEWSLETTER, BALTflVIORE, MD. Dr. Arr. With your permission, Senator, I will dispense with my qualifications since they are on the last page of my prepared statement.' I appreciate the opportunity to be here today to outline some of the advances made in the last 15 years in the care and treatment of the psychiatrically ill. I requested this opportunity to testify because', in my opinion, too much of the testimony presented to the committee to date has been critical of the medical practitioner and the phar- maceutical industry. In my opinion, the outstanding accomplishments of both should be acknowledged and spelled out in detail in the interest of a more balanced record. Senator NELSON. May I say at this stage, Doctor, that the state- ments are always made in the interest of a balanced record. I just want to emphasize that we have heard more testimony from the drug industry than from any other source. We have given them an open invitation to come in at any time they feel the record needs further balance. They have had the greatest chance of anybody to offset any criticism that is made here. We have had only a half dozen general prac- titioners, although we have had a number of distinguished doctors who practice in the finest hospitals in America who are recognized by their colleagues throughout the profession as distinguished physicians, and they are not just theoreticians. They ~re practicing in the major teaching hospitals and general hospitals. So, I just keep emphasizing, I think the record is being kept in balance. Furthermore, I just want to make clear to you that I recognize that the industry has made great contributions. You know, it is somewhat like when I introduced the tire safety legislation and the auto safety legislation, I was attacked all across the country as being anti-auto industry and I was told how many good things the auto industry does. Of course, they do a lot of good things, but the fact is they have some classical weaknesses and one is the neglect of safety. So, we took this up as a matter of public interest. 1 See p. 4d71, Infra. PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4145 So, I personally object to continuous argument of Mr. Stetler, the president of the PMA, and others, about the balanced record. We are keeping it as balanced as we can. They are free to come back at any time. Certainly, they have a thousand times more resources than I have. I have myself, Mr. Gordon, and his research assistant, Mrs. Dye. The industry is not put upon. They have at their disposal, many tech- nicians, scientists, and doctors and they are always welcome here. If they cannot balance the record, it will be because the merits are not on their side. Dr. AYD. Senator, I would like to retort in this respect. No. 1. I am not here as a representative of the pharmaceutical industry. No. 2. What I have to say represents exclusively my own personal opinion, the opinion of no one else. It has not been influenced by anyone else. No. 3. I am acquainted, because of professional activities, with many of the witnesses who have appeared before your committee. I do not question their sincerity, their integrity, their professional standing. However, I must say that in a large number of instances these are academic individuals who are not involved in the everyday practice of medicine and who, therefore, are not in full appreciation of the complexities of the everyday practice of medicine, or I might point out since I am here not only as a private practitioner, but as an individual who has devoted the greater portion of my professional career to the clinical evaluation of drugs, many of these individuals have not been in this area and, therefore, although they are competent to speak in one direction, they are not as qualified to speak in another area. And I think that I am correct in saying that if we are going to have a balanced record, then testimony from individuals who have taken upon themselves the grave responsibility, and it is a grave responsibil- ity, to clinically evaluate drugs in a patient and who have also, in addition, taken upon themselves the grave responsibility in day-to-day practice of medicine treating patients with drugs, and I would insist that the record clearly show that what I have to say represents not the opinion of Mr. Stetler or the PMA or the pharmaceutical industry, but the opinion of Dr. Ayd and no one else. Senator NELSON. I did not suggest that but it coincides with Mr. Stetler's in many respects. I did not say your statement was written by them or that you were here in behalf of them. Mr. Stetler travels throughout the country saying, "We have got to have a balanced record. Senator Nelson is not producing a balanced record." Then I get letters from doctors who believe what Mr. Stetier says and they say I have not produced a balanced record. I ask them if they have read the record, and in the vast majority of cases they have not. They tell me they simply read or heard somewhere that the record of these hearings is not balanced. All I am pointing out is I do not know how you can get a better balance. If you have hearings extending over a long period of time-almost 2 years now-and they will go on for another 2 or 3 years, then, of course, you are going to have 2, 3, or 400 witnesses. I suppose the one who is called last can always say, "Well, your record is not balanced." 81-280-69-pt. 10-16 PAGENO="0242" 4146 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY He can say that to the day he is called. There is no way to avoid that. But, you see, if you are undertaking to conduct hearings to evaluate the problems as we see them, it does not make much sense to call in a general practitioner or an internist and say, now, there has been no criticism of the way medicine is practiced in this country but will you give us your answer to the criticisms that you anticipate we might get here. That is rather ridiculous. Mr. Stetler wanted to testify before we had any witnesses that were critical of the industry. In fact, he gave a speech 2 months before our first hearing indicting the hearings as unfair, and that they were going to be unfair and dishonest. We are scheduling witnesses as fast as we can. I do not see how you can ask people to testify until they have something to respond to. We are glad to have the profession come in and tell us how good they are. I come from a medical background. My father is a doctor, my wife a nurse, my uncle a male nurse. I have lived with doctors. I am not antidoctor. But if you are going to examine a given situation you have to have the opinions of people who are critical of it, you must know why they are critical and then you must give the parties of whom they are critical a chance to respond. And that is just what we have been trying to do. Dr. AYD. I appreciate that. Well, to proceed, Senator, in commenting on the health of the Na- tion, former President John F. Kennedy in a talk said: * * * Mental illness and mental retardation are among our most critical health problems. They occur more frequently, affect more people, require more pro- longed treatment, cause more suffering by the families of the afflicted, waste more of our human resources, and constitute more financial drain upon both the public treasury and the personal finances of the individual families than any other Single condition. The history of 20th century psychiatry is an exciting narrative of the evolution of psychodynamic and physical methods of treat- ment, of therapeutic nihilism yielding to the spirit of expectant op- timism, of a struggle against prejudice, inertia, and indifference, of the blossoming of multidisciplinary scientific interest in mental ill- ness, of an unprecedented availability of money and manpower for psychiatric research, and of remarkable strides forward in the conquest of diseases of the mind. These accomplishments constitute a tribute to the genius and the boldness of dedicated men and women who persisted in the pursuit of their goal despite many obstacles. They made slow but steady progress until the early 1950's. Then came the chemical revolution in psychiatry. This began when the pharmaceutical industry made available chlorpromazine and resperine, the first of the major tran- quilizer~ for the treatment of emotional and mental aberrations. Senator NELSON. Who produced chlorpromazine? Dr. kim. Chlorpromazine was synthesized in France by the Rhone- Poulenc Laboratories. If you want, sir, I am thoroughly familiar with the history of chlorpromazine. Senator NELSON. I got the information from the Library of Con- gress. I just raise the point because there is a tendency, I might say, on the part of the industry itself, to claim credit for everything that happens. They do not think that NIH does very much nor do they think anyone else does. PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4147 The Library of Congress research indicates that most of the drugs you are talking about, major ones, were discovered elsewhere-not by the industry. I think that is an important point to make. Dr. AYD. Well, sir, here I would like to state very categorically since I was one of the first in the United States to administer chlor- promazine to a human being, that although it was synthesized by the Rhone-Poulenc Laboratories, its efforts were to find a substance which would be a potentiator of other pharmaceuticals. And in the course of evaluating or looking at in the animal a variety of derivatives, chlorpromazine was discovered. This was early 1952 and 1953 when this initial work was done. It was then used-historically these are the correct facts-initially not in psychiatry but to test it as a potentiator of anesthetic agents. In the course of this work, two observations of clinical significance were made. First, that in addition to potentiating anesthetic agents this particular compound possessed the property known as an anti- emetic property in that it reduced the tendency to cause emesis or vomiting. An observation was also made that it produced not only potentiation of anesthetic agents and antiemetic effects but that it had sedative properties as well. It was this third observation that led to the possibility of its use in the management of certain psychiatric conditions. Now, by this time we are talking of late 1953, at which time Smith, Kline & French in this country also were looking at chlorprom- azine as a potentiator of anesthetic agents, as an antiemetic, and almost simultaneously as a possible tranquilizing agent. Now, I know this because in February of 1954 I received my first ~upphes of chlorpromazine to administer. to patients for psychiatric evaluation, and if you look- Senator NELsON. When was that ~ Dr. Ai~n. February 1954. Senator NELSON. The Library of Congress does mention Smith, Kline & French finding it highly effective in the prevention of vomiting. This factor was to be the major sales promotion idea. However, Leh- man and Hanrahan had begun in the Protestant Hospital in Montreal to report the successful use of chiorpromazine in the treatment of psychotic cases. Apparently, they think they were first to use the drug in this way. Dr. Ayo. Well, to be absolutely correct it is true that the first publication on the use of chlorpromazine was by my good friends Heinz Lehman and Hanrahan and this was published in September of 1954. I would point out to you that just a few weeks after that, I reported on the use of chlorpromazine in the treatment of psychiatric patients at the Southern Medical Association meeting in the United States and even preceding that, Dr. John Kinross Wright of Texas now-he was not in Texas at that time-gave a paper in May of 1954 at the American Psychiatric Association's meeting in St. Louis and `also Dr. Nathan Winkleman from Philadelphia had published a report in the Journal of the American Medical Association on the use of chlorpromazine in the treatment of psychiatric patients. Now, if you go through the bibliography, of chlorpromazine in psychiatry, you will find, sir, that the bulk of the work that was done PAGENO="0244" 4148 COMPETITIVE PROBLEMS IN TITE DRUG INDUSTRY demonstrating its efficacy in this area was done principally by psy- chiatrists in the United States. Now, I am not saying that others did not do work. It is certainly true that my friends Delay and Deniker in Paris did work in this area and friends that I have since made in England also did work. But I must say to you in all honesty since I have lived with chlor- promazine from its birth in psychiatry that the chemical revolu- tion not only began with the introduction of this drug and reserpine but as I say in my statement, psychiatrists, primarily in the United States, quickly demonstrated that these drugs were invaluable agents which radically altered the treatment, the course, and the prognosis of various psychiatric ailments. Senator NELSON. I just want to make the point that this was origi~. nated by Rhone and Poulenc in France. Dr. Am. Rhone and Poulenc synthesized the drug. They were not the first to demonstrate its efficacy as a neuroleptic. Senator NELSON. Who was the first to do that? What year? Dr. AYD. The first real definitive demonstrations on a large scale in a short period of time of the neuroleptic efficacy of chiorpromazine was done in the United States by American psychiatrists who were sup- plied this drug in 1954. Beginning-actually some got it in late 1953. As I say, I got it in February of 1954. This was way before the drug ever became commercially available. And we did the work and I think if you speak to the French or to the Briti~h or anyone else who is familiar with the history of chlorprom- azine in psychiatry they would say that the lion's share of credit for demonstrating the value of this drug in psychiatry goes to the Ameri- can psychiatrist. Senator NELSON. The Library of Congress has a date 2 years in ad- vance of your date, 1954. It says the first use of chiorpromazine alone in the treatment of mental illness was undertaken by Delay and his associate in 1952. That was in France. The only point I am making is that the thrust of your argument is to say the pharmaceutical industry has done great things, which I concede. I just want to point out that it appears from the Library of Congress research, which may not be exhaustive but consists of several pages, that a large proportion of the drugs used in your specialty originated in foreign countries, and I just want the record to show that. Dr. Am. Well, that record is incorrect. Senator NELSON. Since it does not support any particular argument about the pharmaceutical industry as to this particular field? Dr. Am. No, no. I agree. But I think the record should show that although it is true that the initial psychiatric evaluation of ohlor- promazine was done by Delay and Deniker and that this work was initiated in late 1952-there is no question about this-~this was a very small study involving a very small number of patients. It would hardly be accepted by scientists as demonstrative of the neuroleptic efficacy of this drug. What I am saying is this, that it is oue thing to say that the French did the first study but it is another thing to say who did the important studies, who demonstrated whether or not this particular drug is not only a neuroleptie but an effective neuroleptic and in what kind of conditions, PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4149 If you compare the fact that just in the American literature alone, before the drug came on the market, thousands of patients had been treated with this drug, compared to a few hundred patients, say, in France, with this drug. One reason for that was they did not have the facilities that wo had to do clinical evaluations, and I think that the record should show justifiable pride in the fact that there is no doubt that if it had not been for the aggressive pursuit of clinical leads by American psychiatrists, that the neuroleptic efficacy of chlor- promazine might not have been demonstrated at all or at least not for many years. In fact, I feel a personal pride in the role that I played in demon- strating this at a very early stage. As I say, I started working with this drug in February 1954. The only information available to me at that time was a very brief report on the results obtained by Delay and Deniker, and a very brief report on the results obtained by Heinz Lehman which was not even published yet. This information was supplied by Smith, Kline & French to me. If you look in the medical literature, my article, which was one of the first published in an American journal where you have to give a bibliography referring to what previous work had been done, cites only one publication and that is Lehman's publication because that was the only one in the English language prior to the publication of mine. Senator NELSON. Doctor, I would not- Dr. Am. I am sorry. I beg your pardon. And Winkleman's. Senator NELSON. All right. I defer to your superior knowledge about the quality and importance of the work done by American psychia- trists including yourself. But the thrust of your statement has to do with expounding how much the pharmaceutical industry in this coun- try has done, and no one denies that they have done a good deal. The report from the Library of Congress indicates that a substantial or major porportion of the drugs being used in the area of mental ill- ness were developed or originated elsewhere. I want the record to show that. You know, the fellow who invents the wheel is the fellow I have the highes;t regard for-not the fellow who makes the most rounds with it-although, of course, both functions are important. I just think the invention is the major step. Since you were making comparisons, I just thought- Dr. Am. I am afraid, Senator, in due respect, that it is not yet clear that this vital distinction must be made between synthesizing chlor- promazine, recognizing that it possesses certain pharmacological problems, and then demonstrating it has a certain clinical efficacy. This is a different situation. What I am trying to say is the clinical efficacy of chlorpromazine as a neuroleptic was demonstrated by American psychiatrists who were supplied this compound by Smith, Kline & French. The Americans were the first to demonstrate also not only its efficacy, I must say, but also some of its complications. I have the dubious dis- tinction of being the first one to have had a patient develop jaundice on chiorpromazine in the world. At least that is my understanding be- cause when it occurred, since this was so new, Smith, Kline & French PAGENO="0246" 4150 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY had not had it reported to them nor had Rhone-Poulenc who had been contacted immediately. So we did the real pioneer work in demonstrat- ing its application in the field of psychiatry. Now, what we did with it as a potentiator, as an antiemetic, that I am not familiar with, but .1 am familiar with ch1o~proinazine frankly, from the day of its clinical birth. Senator NELSON. As I understand it, Smith, Kline & French was licensed by Rhone-Poulenc and that is why they got the compound. They get credit for experimenting with it but without the compound they could not have done the job. Dr. A~rn. Being licensed to have a compound is one thing, but hav- ing the ingenuity to exploit and find out what this compound is really good for, that is another kettle of fish. I agree with you, it is perfectly true, no one can deny that the original synthesis of this compound was done by Rhone-Poulenc, nor can anyone dispute the historical fact that it was licensed to Smith, Kline & French. What I am trying to stress, so that this was what I mean by a balanced record, is the fact that demonstrating the efficacy of this compound as a neuroleptic agent and, therefore, really contributing to the revolution that took place in psychiatry, the credit for this `must go to the American psychiatrists, the clinical investigators, who did this initial work with the supplies made available to them by Smith, Kline & French, and the financial support to do the necessary work. Senator NELSON. I do not quarrel with that. This is what I mean by a balanced record, too. Your statement gives no credit to the develop- ment of the compound by Delay, so I thought I had better put- Dr. AYD. I acknowledged in the beginning, Senator, that it was synthesized by Rhone-Poulenc. But I am sure that if you really investigate the facts as demonstrated in the medical literature or, for example, the American College of Neuropsychopharmacology last year had a 10th anniversary type thing in which we reviewed the history of the psychopharmaceuticals. There was no question in any- one attending this particular conference, which is a conference of the best men in the field today, that chlorpromazine's efficacy as a neuro- leptic was primarily, not totally, but primarily, demonstrated by American psychiatrists beginning in late 1953 and early 1954. Senator NELSON. I have no reason to doubt that at all. I am sure you have-I just wanted the record balanced to show where it came from. (The material follows:) THE LIBRARY OF CONGRESS, LEGIsLATIvE REFERENCE SERVICE, Washington, D.C., January 16, 1969. To: Senate Committee on Small Business, Subcommittee on Monopoly From: Education and Public Welfare Division Subject: Origins of certain drugs used in the treatment of mental illness This is in reply to a request from the Chairman of the Subcommittee for a brief review of the origins of certain drugs used in the treatment of mental illness. Because of the deadline attached to the request, we have had to rely upon published references to the origins of `these drugs and have included relevant quotations in each ease from a number of sources. In the event you require a more complete review of the development of these drugs, please let us know. There is a wide-range of pharmaceutical agents now used in the treatment and management of mental diseases. Each of these agents is usually classified PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4151 according to the anticipated changes in behavior likely to result from using each drug. Among these classifications are the major tranquilizers, the minor tran- quilizers, certain narcotics, the antidepressants, psychomotor stimulants, and the psychotomimetics.' In connection with this request, we have limited the discussion of origins to the major and minor tranquilizers. In the case of the major tranquilizers, the references are to the phenothiazines and also to the rauwolfia alkaloids, the latter being included because of the role they have played in the development of psychopharmaeology. As far as the minor tran- quilizers. the drugs for which references are provided are meprobamate and the benzodiazepine derivatives. Among the drugs included in the phenothiazine category are chiorpromazine hydrochloride (Thorazine, Largactil, Megaphen), promazine hydrochloride (Sparine), trifulpromazine hydrochloride (Vesprin), fiuphenazine hydrochlo- ride (Permitil, Prolixin), perphenazine (Trilafon), prochiorperazine maleate (Comparine), trifiurperazine hydrochloride (Stelazine), and thioridazine hydro- chloride (Mellaril) *2 Among the rauwolfia alkaloids are rauwolfia serpentina (Raudixin, Rauserpa, Rauval), alseroxylon (Itauwiloid), reserpine (Serpasil, Serpate, Sandril, reser- poid, Rau-sed Serfin, Vio-Serpine), deserpidine (Harmonyl), rescinnarnine (Moderil, and syrosingopine (Singoserp) .~ Among the minor tranquilizers, the references are to meprobamate (Miltown, Equanil) and to the benzodiazepines, such as chiordiazepoxide hydrochloride (Librium, Libritabs) and diazepam (Valium) .~ The Phenothio~vines.-According to the Pharmaco~ogica1 Basis of Therapeutics, phenothiazine itself was synthesized in 1883, but it was not until 1934 that it was first used as an anthelmintic, urinary antiseptic, and insecticide.5 In the late 1930's a derivative of phenothiazine, promethazine, was found to have anti- histamic properties, and like many antihistamines, a strong sedative effect. The French bad made some unsuccessful attempts at treating psychoses with anti- histamines in 1943, and others attempted to use promethazine in the treatment of agitation in mental disease in 1950.6 The developments leading to the findings associated with cblorpromazine are recounted as follows: Meanwhile, the ability of promethazine to cause a marked prolongation of barbiturate sleeping time in mice was discovered, and in 1950 the French surgeon Laborit introduced the drug into clinical anesthesia as a potentiating agent. This prompted a search for other phenothiazine derivatives with potentiating actions as well as greater central activities, and in the same year Charpentier synthesized drug number 4560 RP, or chiorpromazine. Two years later, Laborit and co-workers (1952) described the ability of this compound to potentiate anesthestics and produce "artificial hibernation." They noted that chlorpromazine by itself did not cause a loss of consciousness but produced only a tendency to sleep and a marked lack of interest in what was going on. In 1952, Courvoisier and her associates described an amazingly large number of actions manifested by chiorpromazine (hence largactil, the French trade name). These included gangliolytic, adrenolytic, antifibrillatory, ayitie- dema, antipyretic, antishock, anticonvulsant, and antiemetic properties. in addition, chiorpromazine was found to enhance the activity of a number of other analgesic and central depressant drugs. The first use of chiorpromazine alone in the treatment of mental illness was undertaken by Delay and his associates in 1952.8 Not until 1954 did there appear 1 See, for example, "A Rational Framework for the Development, Evaluation, and Use of Psychoactive Drugs," In Drug Therapy-~8upplement to the American Journal of Psy- chiatry; vol. 124, No. 8, February 1908. List Is not exhaustive. See the Pharmacological Basis of Therapeutics, the MacMillan Company, New York, or New Drugs, American Medical Association, Chicago. Words in upper-case designate trade-names of drugs within class. (See Appendix A.) ~ See Footnote No. 2 above. 4There are a large number of other agents used as anti-anxiety drugs, many of which resemble meprobamate in their actions. See Footnote No. 2. "The Phenothiazine Derivatives," The Pharmacological Basis of Therapeutics, The Mac- Millan Company, 1965; page 163. 6 "Essai de therapeutique abortive d'aecess maniacodepressifs par le 2339 RP (antergan) ." Annls me&~psyohol, 1943, 101, 432-435, Daumezon, G. and L. Cassan. "Traltement de 1 agitation motice par um stntlhlstamlnique (3277 RP on phenergan) ," XLVIII Congres des Al. et Neurol; Paris 1950, Gulraud, P., and C. David. "See Footnote No. 5. 8 See footnote No. ~5. PAGENO="0248" 4152 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a report in the Western Hemisphere (Lehmann and Hanrahan) of the use of chiorpromazine in the treatment of psychomotor excitement and manic states.9 The Pharmacological Basis of Therapeutics notes: Subsequently, the drug was released for marketing in the United States. It was first employed as an antiemetic, but it was also noted that it produced sedation, relaxation, and hypothermia In the mid-1950's, many psychiatrists expressed skepticism that chlor- promazine was any more effective than a placebo and felt that it would noj~ long endure in the treatment of mental disease With the rapid success of this drug, it was natural that congeners should soon be introduced. Variations of the phenathiazine molecule have resulted in compounds that differ in potency and toxicity from chlorpromazine, but the relative therapeutic superiority of one over the other has yet to be demon- onstrated clearly. The 1968 Merck Indeco attributes chlorpromazine to Charpentier In 1952 with a U.S. patent, 2,645,640 in 1953 to Rbone~poulenc.U In the case of proniazine, the Merck-Incle~v lists "Charpentier U.S. pat. 2,519,886 in 1950 to Rhone-Poulenc." 12 The preparation of triftuprorriazine is attributed to Yale and others in 1957, with a British patent 813,861 in 1959 assigned to Smith, Kline, and French.13 In the ease of fiuphenazine, the preparation is attributed to Yale and Sowinski in 1960 with a British patent 829,246 in 1960 to Smith, Kline, and French and 833,473 in 1960 to Sherico Ltd.'4 In the case of perphenzzine, the preparation IS given to Cusic together with a patent in the United States 2,766,285 in 1956 and to Sherlock and Sperber under U.S. patent 2,860,138 in 1958 to the Schering Corporation.'5 Prochiorperazine is attributed to Ilorelois, British patent 780,193 in 1957 to Rhone-Poulenc, a French patent In 1958, 1,167,627, to Rhone-Poulenc, and U.S. patent 2,902,484 in 1959 to Rhone-Poulenc.'° In the case ot trifluoperazine, the In,dea.~ attribiites the preparation to Craig and others in 1957, with British patents 813,861 and 829,246 assigned to Smith, Kline, and French in 1959 and 1960 respectively.'7 In the case of thioridazine, the preparation is attributed to Borquin and others (Sandoz), and no patent indication is reported.'8 Most of the literature we have reviewed indicates that the phenothiazines produce Substantially the same effects, although each is purported to have differ- ing specific side-effects and intensity for use in different circumstances. Most of the literature which discusses the origins of the phenothiazines gives the credit to the French. For example, the British psychiatrist, Donald Blair, in Modera Drugs for the Treatment of Mental Illness observes :`° Chlorpromazine (Largactil) was the first of the ataractic phenothiazine drugs to be synthesized (in 1950). This synthesis was the outcome of the thorough systematic study of the many phenothiazine derivatives by the Rhone-Poulenc Specia Laboratories of France In an endeavor to discover a drug with a more pronounced and extensive central depressant action than Promethazine (Phenergan) In Price and Profits in the Pharmaceutical Industry, Michael H. Cooper corn- meats :~` * . . the start of psychotropical medicine only dates back to the invention, ironically enough by the French of chioropromazine in 1956. In 1961, the Canadian Director of Investigation and Research of the Department of Justice submitted a report to the Restrictive Trade Practices Commission in which the history of chlorpromazine was described: ° See footnote No. 5. 10 See footnote No. 5. 11 The Merck Index of Chemicals and Drugs, Merck and Co., Rahway, New Jersey, 1968; in the 1068 revision of the Inclece there is a reference tO Cailliot and Gaudechon, as well; page 250. 12 See footnote No. 11; page 860. `~ I 968 Merck Indea'; page 1074. 14 1968 Merck Indea' ; page 466. 15 1968 Merck Indes; page 800. 16 1968 Merck Indeco,; page 867. `~ 1968 Merck Indec; page 1073. `° ~?s8e a~~'ri~~ ti~i~iern Drugs for the Treatment of Mental Illness, Staples Press, London, 1963; by Donald Blair; page 37. 21 "Price, Patents, and the International Scene," Price and Profits in the Pharmaceutscal Industry, Pergamon Press, London 1966; by Michael H. Cooper; page 149. 22 "Development of New Drugs Within Recent Years," Report of the Restrsctsve Trade Practices Commission concerning the Manufacture, Distribution, and Sale of Drugs; Ottawa, Canada, 1063: See Appendiao Q-Material Collected. PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4153 Chiorpromazine was discovered by the Rhone-Poulenc company of France while searching (by synthesizing new compounds of basic antihistamine structures) for a compound that would potentiate the action of sedatives. In the course of use, the French psychiatrists noted that chlorpromazine seemed to cut through the psychotic state. This report was somewhat casually received by the American psychiatrists who at the time did not evidence too great an interest. Smith, Kline, and French had found that Thorazine (chlorpromazine) was highly effective in the prevention of vomiting. This factor was to be the major sales promotion Idea. However, Lehmann and Hanraban (Verdun Protestant Hospital, Montreal) reported the successful use of chiorpromazine in the treatment of psychotic patients. The Ra,uwolfla Alkaloids. The origins of the rauwolfia alkaloids can be found considerably far back in history. According to the Pharmacological Basis of Therapeutics, the use of the rauwolfia plant can be found among the writings of primitive Hindu medicine.~ The climbing shrub of the Apocynaceae family was named in 1703 by a French botanist named Plumier in honor of Dr. Leonard Rauwolf of Augsberg, a 16th Century botanist, who apparently never even knew of the plant's existence.24 The modern therapeutic uses of rauwolfia serpentina, according to the Pharma cological Basis of Therapeutics are as follows: Therapeutic applications of the whole root for the treatment of psychoses and hypertension were described in an Indian medical journal in 1931 by Sen and Bose. Little attention was paid to this finding until 1955 when Vakil wrote the first report in a Western medical journal of its antihyper- tensive effects. In the meantime, Schlittler and colleagues (1954) isolated a number of alkaloids, one of which was then named reserpine. In 1953. Wilkins was the first American investigator to report on the results of a trial of rauwolfia in the treatment of hypertension. About the same time, Bein (1953) found that remarkably low doses of the purified alkaloid, reserpine, were enough to keep rabbits quiet for several hours . . . In 1954, Kline reported that rauwolfia or reserpine was helpful in the treatment of psychotic patients, particularly those manifesting marked anxiety reactions, restlessness, and hypermotility According to the Pond Du Lao study, published in the Kefauver hearings, efforts to isolate the active ingredients in rauwolfia serpentina were undertaken by the Swiss firm of CIBA in 1947. 20 In 1952, the company isolated reserpine. In May 1953, CIBA marketed the powdered whole root under the name of Raudixin, while in November 1953, it placed on the market the isolated reserpine under the name of Serpasil. The products were originally marketed as new hypertensive agents, until, according to the Canadian report: 27 Nathan S. Kline, Rockland State Hospital, treated approximately 400 patients (mostly scbizopbrenlcs), some with reserpine, some with placebos. The results were astounding. Twenty-two percent of the patients (chronically psychotic females) who had not responded previously to other treatment were sufficiently improved so that they could be discharged. According to one source, Kline's attention to reserpine was drawn on the basis of a report by the American heart physician, Robert W. Wilkins: Reserpine was first administered in the United States to a group of heart patients whose physician, Dr. Robert W. Wilkins (now president of the American Heart Association), had read about its beneficial effects on high blood pressure In a British medical journal article by an Indian doctor. When Wilkins and his associates reported in 1952 on the drug's effectiveness in reducing hypertension, they observed also that patients using the drug seemed more relaxed, less anxious, happier. ~ See footnote No. 5. 24 See footnote No. 5. ~ See footnote No. 5. ThIs account of events appears to be Inconsistent in one respect. Other sources Indicate that Wilkins became interested In the drug after reading Vakil's report In a British medical journal. According to the account in the Pharmacological Basis of Therapeutics, Wilkins was already working with the drug (195~3) before Vakil's article appeared In a Western journal (1955). Editorial Research Reports Indicates that Vakil's article appeared In a British journal In 1949 whIch at least provides a logical sequence of events, We have not had the time to verify this sequence, but would be happy to do so. 20 "The Story of CIBA's Serpasil," Hearings before the ~5enate Subcommittee on Anti trust and Monopoly on 5. 1552 : part 2, page 744. 27 See Footnote No. 22; Appendix Q. 28 "Drugs and Mental Health", Editorial Research Reports, No. 20, 1957, page 868. PAGENO="0250" 4154 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Each of the other sources we have reviewed establishes a similar sequence of events for the origins of reserpine and other rauwolfia alkaloids. For example, in Medicine At Risk, the author observes: * . the root of the shrub Rauwolfia Serpentina (snake root) was taken up for investigation by CIBA after the war. It was found that out of 24 alkaloids present, only three had sedating and antihypertensive properties of the preparations from the whole root. Separation by chemical means proved virtually impossible so CIBA worked out the structures of the isolated alkaloids and devised synthetic methods for making them. The result was reserpine, CIBA's Serpasil. The Merck Indeao credits the isolation of reserpine from the root of rauwolfia serpentina to Dorfman and others with U.S. patent 2,833,771 awarded (Schwyzer, Mueller) to CIBA in 1958.~° The Merck Inde~r provides the following data for the alkaloids (other than reserpine) of rauwolfia serpentina: rescinnamine (MODERIL) attributed to Haack and others with the U.S. pat. 2,876,228 (Ordway, Guerico) in 1959 to Chas. Pfizer and Company and to Riker Laboratories (Klohs and others) in 1961 under U.S. pat. 2,974,144; 87 deserpidine (HARMONYL) isolated by `several researchers including Stoll, Hoffman, Schlittler, Klohs, and others `with British patents (in 1958) to Penick and Company, Inc. (791,241) and to CIBA (1959) under 809,912 and a Canadian pat. 678,216 to Roussel-UCLAF; 22 syrosingopine (SINGOSERP) attributed to H. A. Lucas and others with a U.S. pat. 2,813,871 in 1957 to CIBA; and alseroxylon (RAUWILOID) which the Indee simply notes is the generic name for fractionally purified extract of rauwolfia serpentina.~ Meprobamate. According to a number of sources, the origins of meprobamate can be traced to work with mephenesin. The Pharmacological Basis of Thera- peutics notes: Developed by Berger (1954) as a longer-acting successor to mephenesin, meprobamate was originally synthesized as a potential muscle relaxant (Ludwig and Piech, 1951). Mephenesin had been introduced in 1946 and tried in a vCriety of conditions involving not only muscle spasm but also different types of neuroses and psychoses. Its usefulness was felt to be seri- ously limited because of its short duration of action and unreliable absorp- tion following oral administration. Over 1,200 compounds were investigated before meprobamate was selected and its pharmacological properties wore described. The first papers reporting Its use in clinical psychiatry appeared in 1955 (Borrus, 19:55; Selling, 1955). The origins of the drug were discussed during the Kefauver hearings: 36 Early in the 1940's, Dr. Frank M. Berger as working on muscle relaxants for British Drug Houses in England and there discovered mephenesin. Be- cause of the statutory absence of patent protection on drug products in England at that time, he could not secure a product patent. In 1947 Dr. Berger emigrated to the United States; in 1949 he became director of re- search for Carter Products; and in the followIng year a patent applica- tion was filed on ineprobamate, assigned to Carter Producta. In 1953 an arrangement was made for Berger to receive a share in the profits derived from the sale of drugs developed by him. The patent was issued on Novem- ber 22,1955, and will run until 1972. The Canadian report notes ~ Meprobamate was developed as a result of initial work in synthesizing pre- servatives for use in penicillin preparations. Frank M. Berger had noticed that one of the compounds tested on mice had a muscular relaxant effect. In the search for a more efficient muscle relaxant, Berger and Bradley de- veloped mephenesin. Further work on mephenesin-llke compounds resulted in the synthesis of meprobamate. 29 See footnote No. 20; page 58. 3° 1968 Merck Indeco; page 912. ~` 1968 Merck Index; page 912. 32 1968 Merck Index; page 831. ~ 1968 Merck Index; page 1010. ~° 1968 Merck Index; page 41. 3° See footnote No. 5. 3° "A Study of Administered Prices in the Drug Industry," ,&enate Report No. 448; 87th Congress, 1st ~8ession; July 27, 1961 ; page 143. ~ See footnote No. 22; appendix Q. PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4155 The Merck Indeco attributes preparations to Ludwig, Piech and to, Berger, with U.S. patents 2,724,720 in 1955 to Carter Products/Inc.; for synthesis to Fries, Monkemeyer under a Swiss patent 373,026 i~i 1963 to Chemlsche Werkehtils~°° Chlordiazepocvide HydrochZoride, and Diazepam. The Pharmacological Basis of Therapeutics observes that two benzodlazeplne derivatives are presently available, chiordiazepoxide and diazepam. Both are used for the same purpose as meprobamate, mainly for the treatment of anxiety but also for skeletal muscle relaxation and combating alcoholism. According to this source :4° Compounds of this type were initially synthesized by Sternbacb in Poland in 1933, and congeneric substances were studied in the United States (see Sternbach and Reeder, 1961). Animal tests indicated that chlordiazepoxide had Interesting muscle relaxant, antistrychnine, and spinal reflex-blocking properties. Randall and coworkers (1960) reported that it produced "tam- ing" of a number of species of animals in doses much lower than those pro- ducing ataxia or measurable hypnosis. The difficult problem of defining "taming" in animals and of relating this effect to human therapeutic needs has been discussed by Cook and Kelleher (1963) ; but it was this "tani- ing" effect in monkeys' that led to the clinical trial of the drug in human subjects for the determination of antianxiety effects (Randall et al., 1961). Cooper comments: 4° In the 1960's the Swiss have added Librium and Valium to the field... Speaking of Roche, he observes: Their discovery, Valium, was actually being marketed in Italy by Ravizza under the name "Noan" one and a half years before Roche had even reg- istered the drug there. In fact clinical trials of the drug were still in prog- ress in the U.S.A. Librium, its slightly older discovery, is being sold by eighteen other companies under eighteen different brand names The reference in the Merck mdccv to chlordiazepoxide (LIBRIUM) shows the preparation to Strenbach under U.S. patent 2,893,992 in 1959 to Hoffmann-La- Roche: 42 the reference to diazepam (VALIUM) attributes the preparation to Sternbach and Reeder. U.S. patents 3,106,843 in 1963 to Hoffmann-LaROche and 3,136,815 In 1964 to Iloffmann-LaRoche.43 If additional information is needed in connection with any of the above, or a more detailed analysis is required, pleaselet us know. GLRNN MARKUS. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, HEALTH Sanvicus AND MENTAL HEALTH ADMINISTRATION, Chevy Chase, Md. Jannary 22,1969. Mr. BENJAMIN GoRDoN, Staff EconomIst, Senate Committee on Small Business, Room 424, Old Senate Of/ice Building, Washington, D.C. DEAR MR. GORDON: Although many of the psychotropic and antidepressant agents were synthesized or "discovered" by private pharmaceutical companies, there were some notable exceptions. Dr. H. Laborit, of the French Army, first noted the tranquilizing properties of chlorpromazine when he used this substance as an anesthetic. The first clinical trials of chiorpromazine with psychiatric patients were performed by Drs. Delay and Deniker of St. Anne's Hospital in Paris. These latter investigators have received some financial support from NIMH but I do not believe their early work with chlorpromazine was under NIMH support.. The pioneer work with demethylated analogs of imipramine, an antidepressant drug, were performed by Dr. B. B. Brodie of the National Heart Institute. Dr. Brodie synthesized desmethylimipramine which is reported to be a faster acting antidepressant than the parent compound, imipramine. Finally, the early work with lithium salts for the treatment of psychotic excite- ment was performed by an Australian, Dr. J. F. J. Cade. 3° 1968 Merck Indeco; page (187. 39 See footnote No. 5.. 4° See footnote No. 21; page 6. 41 See footnote No. 21 ; page 163. 4° 1968 Merck Indev; page 235. ~ 1968 Merck Indeco; page 341. PAGENO="0252" 4156 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY For many years, both the VA and NIMH have been supporting research on the clinical efficacy of the major tranquilizers and antidepressants. The first multi-hospital collaborative study of drug treatment with schizoplirenics was conducted by the VA in 1957. This study compared the clinical efficacy of corn- pazine, chiorpromazine and a placebo on 640 schizophrenic patients and defini- tively established the superiority of cblorpromaziiie over a placebo in the treat- ment of schizophrenia. Both the VA and NIMH have also conducted multi- hospital trials of drug efficacy in chronic schizophrenia and in Uep~ession. A recent report on the NIMH chronic schizophrenia study indicated that high doses of chlorpromazine were especially efficacious for younger patients, iq., those under 40, with at least five years of continuous hospitalization. These large col- laborative studies have been of particular value In delineating the subgroups of schizophrenic and depressed patients who are likely to be helped most by certain of the tranquilizers and antidepressants. For example, Dr. Colomon Goldberg of the Psychopharmacology Research Branch of NIMH has developed equations, based on pretreatment symptom profiles, that predict the response of schizo- phrenics to a variety of tranquilizers including chlorpromazine and thioridazine. Drs. Hollister and Overall of the VA have also reported that thioridazine, a tranquilizer, was particularly efficacious in a subgroup of anxious depressions whereas imipramine, an antidepressant, was especially efficacious for an addi- tional subgroup of withdrawn-retarded depressions. Similarly, a recent NIMH supported collaborative study of drug treatment in depression revealed that imi- pramine was efficacious for psychotic depressions, but of little value for neurotic depressions. The collaborative VA and NIMII studies have also made major contributions with regard to the methodology of evaluative drug trials. Symptom rating scales for evaluating patient change were developed which are now widely used and accepted by Investigators at individual hospitals. Statistical techniques for dis- cerning drug effects were also developed. The VA and NIMH have also been very active in establishing centers for early clinical trials with new agents for the treatment of mental disqrders. Dr. Hollister of the VA has established a drug screening center at the Palo Alto VA Hospital. The Psychopharmacology Research Branch has an Early Clinical Drug Evalua- tion Unit which includes investigators from appro~imately 15 psychiatric hos- pitals. Standard rating forms are used by these investigators to facilitate comparisons of drug effects across hospitals. Finally, as you know, the VA and NIMH have recently undertaken a joint effort to evaluate the effects of lithium carbonate in both manic and depressed patients. As you are also aware, Dr. Cole, who was formerly Chief of the Psychopharmacology Research Branch, was instrumental a number of years ago in making this compound available to investigators in this country for early clinical trials. If I can be of further assistance, please let me know. Sincerely yours, STANLEY F. YOLLES, M.D., Director. Senator NELSON. Please go ahead. Dr. AYD. All right. It came from France, but its value was demon~ strated in the United States. We both agree. All right, sir. Within 3 years after chlorpromazine and reserpine were made avail- able, American psychiatric hospitals were reporting a decrease in the use of physical restraints, seclusion rooms, hydrotherapy, shock ther- apies, and other somatic methods of treatment; a reduction in destruc- tiveness, combativeness, and assaultiveness; a greater number of ground privileges; and, above all, an increase in the discharge rate, especially of chronic patients who previously had been considered hopeless cases, and by some as "the living dead." Private practicing psychiatrists claimed that, properly used, these drugs increased the number of patients who could be treated in the office, facilitated psychotherapy, and made hospitalization unnecessary in many cases, thereby decreasing the number of admissions to overcrowded public mental hospitals and reducing the cost of psychiatric care. PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRIJG INDuSTRY 4157 IMPORTANT ADVANCE The therapeutic successes with chlorpromazine and reserpine stimu- lated an intensive search for additional psychopharmaceuticals. With- in 5 years pharmaceutical firms produced not only more major tran- quilizers, such as prochloperazine, perphenazine, and fiuphenazine, but minor tranquilizers, such as meprobamate and, equally important, for the millions who suffer from melancholia, antidepressants, such as imipramine and amitriptyline. And because medical progress will not be checked, additional tranquilizers and antidepressants have been and are being developed by the pharmaceutical industry. The tran- quilizers and antidepressants now available have made it possible for all American physicians-not just psychiatrists-to treat their emo- tionally and mentally disturbed patients-something previously not possible. Concurrent with these significant developments were other trends which augured well for the psychiatric patient. A steadily increasing number of general hospitals became general in fact as well as in name by admitting psychiatric patients who now could be treated with psychoactive drugs. Prior to this, despite the prevalence of psychiat- rically ill patients, more than half of the general hospitals in the United States would not admit a known psychiatric patient, one-third admitted such patients solely for diagnosis or emergency treatment, and only 1 percent had a psychiatric ward. Yet in the first 4 years after these drugs became available the National Association for Mental Health and the American Psychiatric Association reported that studies of psychiatric admissions in 1958 showed 257,300 patients in com- munity general hospitals as against 210,117 in the public mental hos- pitals. Furthermore, among community general hospitals, the num- ber of beds set aside for psychiatric patients increased in 1954-58 from 10,608 to 14,383. This trend has continued so that today most general hospitals admit and provide treatment (primarily with psy- choactive drugs) for more psychiatric patients than at any time in history. Simultaneously, there was a sharp increase in the number of outpatient clinics and aftercare progranis, and the opening of day and night hospitals. Within psychiatric hospitals an attitude of pessimism and despair toward mental illness was replaced by one of hopefulness and confi- dent optimism. Mental hospitals were transformed into active treat- ment centers and no longer were primarily places of detention. Many discarded the "lock and key" system of imprisoning patients in favor of an "open door" policy which provided liberties more consonant with the individual needs and the human rights of the psychiatric patient. It can be stated forthrightly that these significant changes were due largely to the advent of the tranquilizers and antidepressants. HOSPITAL PATIENTS DISCHARGED In 1955-I must point out to you this would be 1 year before the tranquilizers became commercially available in the United States- Dr. Francis J. Braceland, past president of the American Psychiatric Association, cognizant of the annual national increment to the mental hospital population, wrote: PAGENO="0254" 4158 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY However we try to minimize or rationalize the figures, the fact remains that if any other disease reached such stratospheric proportions, a national emer- gency would be declared. One year later, due to the advent of chemopsychiatry and the im- provement made in other forms of treatment, psychiatric hospitals became able to discharge patients at an unprecedented rate. In 1956, for the first time in 175 years, the number of patients in U.S. psy- chiatric hospitals began to decline. By 1963, a U.S. Senate committee noted "with pleasure" continued progress in the field of mental health. For the seventh straight calendar year the population of mental insti- tutions dropped, this time by the largest number in any year to date, leaving 516,000 patients in the institutions in December 1962. Senator NELSON. What is the best estimate of the total, the maxi- mum total number we ever reached and in what year, do you recall? Dr. Am. If I may, sir, I can show this with a chart. Senator NELSON. Fine. Dr. Am. This is getting a little ahead of schedule but to answer your question I will be glad to do that. As I mentioned, for 175 years the patient population had been going up. Now, this chart,1 sir, demonstrates the patients, number of patients in thousands, so that you can see in 1950 we had 511,000 patients confined. Senator NELSON. 511? Dr. Am. 511,000. Senator NELSON. Is that the top, the highest figure? Dr. Am. The top figure was 559,000 in 1955. You see, it was going up from 511,000 in 1950, 1951, 518,000; 1952, 530,000; 1953, 543,000; 1954,552,000; 1955,559,000 patients. Now, in 1955 the tranquilizers were first being used on a large scale in psychiatric hospitals in the United States, and immediately look what happened. In one year we dropped from 559,000 ~atients down to 551,000 patients, and as this chart shows, it has continued to decline right on down. I apologize for not having for you, because the figures are not yet released by the National Institute of Mental Health, the 1968 figures and unfortunately, I got the 1967 ones too late to put on this particular chart. But let me say that the 1967 figures show that the resident popula- tion had dropped again, this time by 26,000, to an all time low of 426,- 000 patients. Mr. GORDON. Doctor, may I ask a question? Dr. Am. Yes, sir. Mr. GORDON. Do the drugs relieve the symptoms or do they actually cure mental diseases? Dr. Am. I would have to say in all honesty that the drugs do for the psychiatric patient what practicaily speaking all therapies do for all other patients. They do not cure. They relieve Symptoms, minimize disability, they rehabilitate. We do not cure diabetes. We do not cure cancer at this moment. We do not cure tuberculosis, nephritis, and things of this sort. We do our best to rehabilitate. 1 See p. 4172, Infra. PAGENO="0255" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 4159 Now, whether the drug is curative or not at this particular moment is immaterial. The question is, does it sufficiently control the symptoms of the patient so that it is possible for him to return to the community and to live with his family, and I must point out to you, as I did, in- cidentally, when I first testified before Senator Lister Hill's commit- tee in 1955, I pointed out then that already we were showing that many patients who were a tax liability are now becoming an asset because they are earning money and paying taxes. Senator NELSON. How good are the statistics? That is, how ac- curate a survey are we able to make of the number of mental patients in hospitals? Dr. An. These particular figures, sir, are compiled by the U.S. Government, National Institute of Health. They are released annually by the National Institute of Mental Health and I assume because they are very able people working there that these are the most accurate figures one could possibly obtain. They are obtained because it is my understanding that in each State the hospitals report to the local State authorities, the local State au- thorities in turn send their figures into Washington, and then all the compilations are done. I believe this comes under the HEW. They do it in their statistical division. Now, I would point out, sir, that I was quoting from that 1963 Sen- ate committee report. We had gotten to the point of the reduction in the number of patients. "The reduction in the population of these institutions," this com- mittee reported, and I am quoting again, "over the last 7 years is estimated to have saved $700 million." I am still quoting and I would stress this. "This is more than the total accumulated appropriations of the National Institute of Mental Health since its founding in 1948. This $700 million is only part of the savings, however. Some 559,000 patients were overcrowded in hospitals in 1955. Replacement of obso- lete beds and addition of new ones would have required about 89,000 additional beds to maintain the 1955 level of hospital occupancy. The cost of adding each bed would be $15,000; thus, there has been an addi- tional saving in capital investment of $1,300 million by virtue of the de- clined in patient population, or a noteworthy total in patient main- tenance and construction of about $2 billion since 1956." (Senate Committee Report No. 383, Aug. 1, 1963, on DHEW appropriations for 1964.) At the end of 1965, 10 years after the psychoactive drugs appeared, the total reduction in patients in State and county public mental hos- pitals was roughly equivalent to the combined mental hospital popu- lations of 19 States: Alabama, Arizona, Arkansas, Colorado, Connecticut, Delaware, District of Columbia, Florida, Idaho, Kansas, Kentucky, Maine, Mississippi, Missouri, North and South Dakota, Minnesota, Vermont, and Washington. Statistics reported by the National Institute of Mental Health showed that the resident popu- lation in public mental institutions dropped from 475,202 in 1965 to 452,000 in 1966-~a decline of 4.8 percent and the largest annual reduction. There is a little discrepancy between the figures here and on that chart. These figures that I have on this chart came from preliminary PAGENO="0256" 4160 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY reports and then the final report I got later. But it does not change the basic downward trend. This NIMH report pointed out that although more money was being spent for each patient in 1966 than a decade earlier, overall hospital costs of mental illness had fallen because of the drop in the resident patient population. Patient care cost $1,301 million in 1966, the report said, whereas, if the hospital population had grown at the pre-1955 rate, some 720,000 patients would have cost State and local govern- ments $4,400 million. Commenting on these facts Dr. Stanley F. Yolles, Director of NIMH, stated that "the break in the upward trend occurred in 1955 because of a number of factors, the principal one, perhaps, the introduction of the trauquili~ing drugs." (Emphasis mine). In 1967 the resident population in State and county mental hospitals dropped again, this time by 26,000, to an all time low of 426,000 patients. This prompted Dr. Yolles to remark: "If the old pattern had continued uninterrupted, there would be over 717,000 pa- tients in our mental hospitals-291,000 more than is actually the case." In July 1965 the Psychopharmacology Service Center bulletin of the NIMH contained this significant report: When the first of the modern tranquilizing drugs was introduced in 1952, hope was expressed by a number of clinical investigators that these drugs would lead to a drastic reduction in the number of patients in our public mental hospitals. For a variety of reasons, including the effective use of drugs and other improve- ments in psychiatric treatment, the number of resident patients in our public mental hospitals has been declining at the rate of approximately 1 percent per year since 1955. However- And this is important, Senator- if one examines the population changes within the mental hospitals in a good deal more detail, it is apparent that a more substantial decrease in the number of resident schizophrenic patients between the ages of 25 and 44 is underway. The number of hospitalized patients in the 25- to 44-year-old age group carrying a diagnosis of schizophrenia has been decreasing at a rate of 3.3 per year. If the present rate of decrease continues, the number of resident schizophrenic patients in this age group by 1970 will be one-third fewer than the corresponding number resident in 1960. There is a concomitant decrease in the number of patients being admitted to public mental hospitals carrying either the diagnosis of manic depressive psychosis or involutional, melancholia. From this it can be seen that two major psychiatric conditions, severe depression and schizophrenia, insofar as they cause prolonged hospitalization of individuals in their adult years, are being relatively well controlled. Sir, if I may digress for a moment from my prepared statement, I had the good fortune of getting my psychiatric training in the Navy. In part of my duties I was ass%ned at the U.S. veterans' hospital at Perry Point. While at this hospital for 2 years I worked in what was called the continuous treatment service which was a euphemism, frankly, for the chronic patients. There were approximately 800 patients under the care of myself and my colleagues, who were few in number. Very few of these pa- tients were over 60 years of age and the majority of them had been in that hospital no less than 20 years. Some of them had been there 30 years. Most of them had only one hope, and this is in the predrug era, and that was that death would give them a merciful release from their schizophrenia. And yet since the advent of the drugs, we not only can PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4161 get schizophrenics better so that they do not have to stay in the hos- pital but we can do it in a very short period of time, and for these people and their families and for the American public, this is a phe- nomenal accomplishment. Now, if I may also have the next chart,' I would like to show you- this shows you what has happened on a national level. With the per- mission of my good friend Dr. Milton Greenblatt, who is the com- missioner of mental hygiene for the Commonwealth of Massachusetts, I would like to show what happened in the Boston State Hospital where he was superintendent prior to becoming commissioner of mental hygiene for the Commonwealth of Massachusetts, This just shows what happened, the same thing that has happened nationally, in a large State hospital each year, a continuous decline in the resident patient population of the hospital. This never happened in the history of Boston State Hospital as it never happened in the history of any psychiatric hospital in the `United States until we got the psychoactive drugs. Because of continued development of psychoactive drugs and their effective use, `there are good reasons to believe that the decline in men- tal hospital patient populations will persist. It is a worldwide phe- nomenon which deserves to be called one of the most dramatic events of this century in medicine. Ever since the famous French psychiatrist, Phillippe Pinel, in 1795 unshackled the institutionalized insane in Paris and promoted a humane regimen of treatment of the mentally ill, psychiatrists have yearned to care for most psychiatric patients in the community.. This dream is now becoming a reality. When it was realized what had been and could be accomplished by the judicious use of psychopharma- ceuticals, the late President Kennedy called for the Congress to pass legislation for the establishment and staffing of conununity mental health `centers. In 1966 Federal grants totaling $57 million were made for the construction `and/or staffing of 128 new community mental health centers in 42 States, Puerto Rico, and the District of Columbia to make mental health services available to some 22 million Ameri- cans in their home communities in a way not possible before. In 1967 President Johnson requested and Congress approved' `a 3-year, $238 million extension of the program of Federal aid for building and staffing community mental health centers. This is laudatory, indeed, but what must be stressed is the undeniable fact that without effective drugs to treat patients community mental health centers could not achieve their objective. If I ma.y have the next chart,' I would like to show you again ma- terial from Massachusetts which Dr. Greenblatt put together. This shows what happened. I have to give you a little bit of background, Senator. When the drugs first came out, we were not as expertise in their use as we are today and many people had the idea that when patients improved, they did not have to have the drugs any longer, and they could be discontinued. Patients left the hospitals, did not continue to take their medicine, they relapsed and they came back in. This led to what we psychiatrists 1 See pp. 4i72-73, infra. 81-280-69-pt. 10-17 PAGENO="0258" 4162 COMPETITIVE PROBLEMS IJ~ THE DRUG INDUSTRY call the revolving door syndrome where the patient came in, got bet- ter, went out, relapsed, and came back in. To stop this revolving door, State hospitals began to set up out- patient departments, making drugs available to patients after release from hospitals, to keep them out of hospitals and in some instances to keep them from ever coming in in the first place, thus avoiding the stigma of having been in a mental institution. Dr. Greenblatt compiled these figures showing the number of pre- scriptions written year by year as psychiatrists in the hospitals began. not only to discharge greater numbers of patients hut to recogmze the value of these drugs not only in controlling the symptoms so that mad. men were no longer acting like mad men but their value in keeping patients in a state of remission so that they could continue to reside in the community. Now, if I may have the next chart,1 there is just one other point I would like to make because in reading through the testimony which has been presented before this committee, reference from tin~e to time has been made to drug advertising and things of this sort. Now, I would like to stress for you that at least from the standpoint of psychiatrists, drug advertising is important in that it acquaints us with the existence of a compound and gives us some information about its indications, its contra-indications, dosa~e, et eetera. How- ever, it is not the most influential thing in deciding whether a par- ticular drug should `be used. What is important is the demonstrated effectiveness of the drug. Consequently, if you look at this chart, you will see that some drugs which were introduced early have been replaced by other drugs which have proven to be more effective, and some drugs which initially ~were widely used like chlorpromazine or thorazine which was the first one we had, as Other ones came along and their effectiveness for individual patients was demonstrated to be superior to that of thorazine, psy- chiatrists began to use those. What I am simply saying is that what dictates the, use of a drug is effectiveness and safety. Safety, of course, is relatIve and I will have a word to say about that later. But I must stress for you `that state- ments which have been made which would imply that physicians are very much influenced in their prescribing habits by `what the adver- tising and promotion says, by what the detail mn say, and so forth and so on, are not consonant with the facts. I know of some psychopharmaceuticals which have been very widely advertised and promoted~but they are not used very often at all. Why? Because they have been made obsolete by more effective drugs. The primary obligation of the prescribing physibI~an is tO choose for his individual patient that drug which offers the greatest hope of relief with the least risk and at the least expense. Now, I would like, because I have portrayed for you, sir, what hap- pened since the advent of the drugs, to tell you what it was like before we had the drugs because fortunately, or I should say unfortunately, I worked in psychiatry before we had the drugs. 1See p. 4173, Infra,. PAGENO="0259" COMP1~TITIVE PROBLEMS IN THE DRUG INDUSTRY 4163 HORRORS OP PREDRUG ERA So to return to the predru~ era in psychiatry, it would `be well to recall what conditions were like then. This makes it possible to ap- preciate what has been accomplished. Within the bare walls of isolated, prisonlike asylums were housed many screaming, combative individuals whose ammahstic behavior required restraint and `seclusion. Catatonic patients stood day after day, rigid as statues, their legs swollen and bursting with dependent edema. Their comrades idled week after week, lying on hard benches or the floor, deteriorating, aware only of `their delusions and halluci- nations. Others were incessantly restive, pacing back and forth like caged animals in a zoo. Periodically the air was pierced by the shouts of a raving patient. Suddenly, withou't notice like an erupting volcano, an anergic schizo- phrenic would burst into frenetic `behavior lashing out at others or striking himself with his fists, or running wildly and aimlessly about. Nurses and attendants, ever in danger, spent their time protecting patients from harming themselves or others. They watched men and women who either refused to eat or gorged themselves. They tube fed to sustain life. Trained to be therapists, they functioned as guards and custodians in a hellish environment where despair prevailed and surcease by death offered the only lasting respite for their suffer- ing charges. Compounding this ghastly situation was the restricted therapeutic armamentarium of the psychiatrists. I]Iow frustrated and impotent they felt and I know this because I felt this `way, as they watched the number of chronically ill swell the burgeoning population of long~~ term resident patients. They knew from bitter experience that psycho- therapy for psychotics was fruitless, that insulin-coma and electro- shock therapy offered little or no improvement to schizophrenics con- tinuously ill for more than 2 years, and that psychosurgery benefited oniy a very small percentage of the chronically ill, For lack of more ef- fective remedies, they secluded dangerously fretietic individuals be- hind thick doors in barred rooms stripped of all furniture and lacking toilet facilities. They restrained many others in cuffs and jackets or chained them to floors and walls. Daily they sent patients for hydro- therapy, where they were immersed for long hours in tubs, or packed in wet sheets until their disturbed behavior subsided. These measures, barbaric and inhumane as they appear in retrospect, euphemistically called therapy, at best offered protection to patient and personnel and a temporary respite from the most distressing symptoms of psychoses. This lack `of effective antipsychotic therapies accounted for the bleak outlook for the chronically ill. Unless they were released within 2 to 3 years of admission, they were destined to remain indefinitely, prisoners of psychoses-unresponsive to the existing therapies. Chlorpromazine and reserpine were the first therapies to change the dire prognosis for the chronic schizophrenic. Shortly after these became available psychiatrists realized that, unlike previous psycho- logical and physical methods of treatment-the effectiveness of which PAGENO="0260" 4164 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY `declined to near zero for patients ill for more than 2 years-these drugs benefited many chronically ill psychotics to a degree hereto- fore unattainable. Soon other psychotropic drugs were added to the list of effective antipsychotic agents. The result: unprecedented hope for chronic psychotics, an incredible change in mental hospitals, in the organization of mental health services, and the virtual abolition of involuntary admissions. The `transformation that has occurred in mental hospitals in the past two decades defies description. Visit one today. You will be im- pressed by the serenity you observe and feel. You will sense the attitude of realistic optimism which predominates. Flowers, curtains, paintings, music, fresh air, comfortable tidy lounges make a pleasant environment for clean, tranquil patients being `offered a myriad of therapies designed to make their hospitalization profitable and not a living hell. Some modern psychiatric hospitals have almost a country club atmosphere. All are becoming what we have always wanted- attractive, active centers of treatment, offering hope of rehabilitation and return to the community, to family and friends, after a relatively short period of effective treatment. This brief review of the current revolution in psychiatry is essen- tial, if we are to maintain a proper perspective. There are people who seem unaware of what has been accomplished and of what has made these salutary achievements possible. A lion's share `of the credit in justice goes to the major pharmaceutical companies. As a pioneer in the clinical evaluation of most of the available psychopharmaceuticals, I can testify that these firms-not university or Government research- developed the drugs which have transformed the care and treatment of the mentally ill. These drug `companies were responsible for the basic research-the biochemical, the pharmacologic, the toxocolo~ic evaluations of these invaluable medicines. These drug companies sought the services of able, highly competent physicians to clinically `test their psychoactive drugs and financed clinical trials which other- wise would not have been possible. In short, the innovative manufac- turers provided the medical profession, especially psychiatrists, with the essential tools-available from no other source-which have en- ábled us to do what has not been done before in the history of medicine. No psychiatrist, I assure you, absolutely no psychiatrist, would want to return to the ~redrug era. We are justifiably proud of what we have accomplished with the products developed by their manufacturers. We sincerely hope that what we have achieved with psychopharma- ceuticals and other therapies wifi cause mankind to finally realize that mental illness does not make its victims inferior members of society. We are painfully aware, Senator, of the 426,000 patients still in U.S. public mental hospitals and the large number of patients in the com- munity making only a marginal adjustment. These are "silent wit- nesses" who have not benefited optimally from the drugs we have, and it i's for these silent witnesses I am here today. They bear witness to the need for more psychopharmaceuticals. These we rightfully ex- pect will be developed by the unrelenting research of the creative scien- tists employed by the progressive drug firms, large and small. Other conditions for which present-day pharmacotherapy is not very effective are mental deficiency, criminal psychopathy, and drug addic- PAGENO="0261" COMPETTTIVE PROBLEMS IN THE DRUG INDUSTRY 4165 tion. Psychiatrists are concerned about the increasing admissions, com- pulsory detentions, and the trend toward longer stay in the hospital because of these disorders. The drugs required to help these unfor- tunate people we also expect will be developed by the research-oriented manufacturers. There are those who think there are too many psychoactive drugs and those who contend that the number of such drugs in a hospital for- mulary should be restricted. These individuals fail to recognize that none-and I stress this-none of the available compounds is univer- sally effective and safe. They overlook the indisputable fact that, despite all the psychoactive drugs on hand, there are in and outside of mental hospitals many thousands of patients either partially or totally refractory to these drugs or intolerant of them. For these unfortunate, suffering individuals there is an urgent need for more psychoactive drugs. Those who would limit the number of psychoactive drugs also ignore what every psychiatrist exp~rienced in testing and using these drugs knows; namely, that some patients benefit only from one com- pound and are unresponsive to, or are intolerant of, all other drugs. Thus, for those patients who respond to a particular tranquilizer or antidepressant-old or new-that one drug is invaluable; it means for them the difference between sickness and health even if, in comparison to all other drugs, it would seem to be the least effective. This is most important for these patients because humans and not a statistic suffer. Furthermore, physicians dedicated to easing emotional and psychic suffering, to eradicating or minimizing disability and to restoring mental health should be able to prescribe whatever drugs in his pro- fessional judgment offer the greatest prospect of benefiting his indi- vidual patient. Physicians cannot achieve their objectives and patients will suffer, if the physician's right to independent medical judgment is infringed by a hospital formulary which does not include all available psychoactive drugs or insists on the use of products other than those specifically prescribed. The challenge, Senator, to the medical profession comes not from the number of drugs available, but from the need to learn the art of using these drugs correctly. The simple clinical fact is that the more drugs we have at our disposal, the greater is the number of patients who will be helped. For 15 years it has been my privilege to evaluate clinically drugs for the mind. During this time I have never once been asked by the manufacturer of strictly "me too" products to test a compound for them. Nor, to the best of my knowledge, have any of the reputable and dedicated physicians who evaluate psychopharmaceuticals in the United States ever been requested to study a new compound developed by the research of such a manufacturer. I polled by mail 130 members, which is practically I must say the entire membership, of the American Colleg~e of Neuropsychopharmacology, which is composed of the most experienced and well-trained specialists in the testing and evaluating of tranciuilizers and antidepressants in the United State~s and Canada, asking if any producer of what are commonly called "generic drugs" ever requested them to test a new psychopharmaceutical or provided them with any financial support for any of their research in psychopharmacology. PAGENO="0262" 4166 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I received replies from 119 or 91.5 percent, which is a very good record, I am sure you will agree. Not one had been asked by such a manufacturer to test a new psychopharmaceutical or had received sup- port from such a manufacturer for their research in psychophar- macology. The reason for this is simply that these manufacturers have not developed any effective major or minor tranquilizers or antide- pressants. By contrast, every effective psychopharmaceutical which a physician can prescribed for our citizens has been developed and made available by the well known and research based drug houses. It is this truth which compels me to forthrightly acknowledge the debt of every American to these manufacturers for they are helping immeas- urably in the conquest of mental illness. This indisputable fact merits your recognition and serious consideration. Senator NELSON. I do not understand that last sentence. Dr. AYD. This indisputable fact? Senator NELSON. Yes. Dr. AYD. Well, the sentence makes sense, sir, if you read what pre- cedes it. What I am trying to say, in essence, is that the only drugs that we have ever had made available to us to treat the psychiatrically ill have come from the research oriented pharmaceutical firms, and no other source. They have not come from the Government, they have not come from the university centers, they have come only from the research oriented manufacturers. We have a debt to these people. They provided the psychiatrists with the tools, not only psychiatrists, every physician in America, with the tools to take care of the emotionally and mentally ill in a way heretofore impossible. They have done this. Nobody else. And I think this fact is not only indisputable but I think it merits recognition and consideration in evaluating their contribution. Senator NELSON. Well, I might say that no one on this committee, nor anyone who has testified, has been at all reluctant to pay appro- priate tribute to the drug industry for its contribution. I do not think we have had a sthgle witness who addressed himself to the question who was not prepared to pay the appropriate tribnte. The implication is that somehow or other we have not given recognition. It is not the purpose of these hearings to fill volumes with the lauda- tory things that the drug industry has done. The purpose is to explore some very serious problems which exist in the industry. And inciden- tally, many companies privately concede that problems do exist and some of them even acknowledge thispublicly. That is our purpose here. Any time they want to come in and tell us about the great things they have done, they may do so. If there were no problems in the industry, if it were a perfect industry, if it were making no mistakes and the public had no interest in evaulating some of the things the industry was doing, we would not be having any hearings. We are exploring the problems of the industry. We are glad to have you be laudatory of them. I am glad to be laudatory myselt. But at the same time, there are serious problems which have got to be called to the public's attention and we are doing that. The pharmaceuticalindus- try is doing things that it should not be doing and that is the purpose of the hearings. So, I just point that out to you. There is hardly any criticism of the industry in this country. Everybody thinks of miracle drugs, and so forth and so on. We are pointing out some of the problems in it. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4167 Dr. AYD. May I make two observations, Senator? Senator NELSON. Surely. Dr. AYD. One, I am well aware of the fact that you are not out, shall I say, to damn the pharmaceutical industry. I am appreciative of that fact. What I think, though, needs to be stressed is, No. 1, much of what your hearing has brought out is an indictment, not of the pharmaceu- lical industry, but of physicians. Senator NELSON. And some of it is very justifiable, I must say. Dr. Am. Yes. I have become known worldwide as an expert on the side effects of the psychopharmaceuticals. I write a great deal on this, lecture a good deal on this, and I am well known for repeatedly making the statement that frequently when I review the world's literature each year on the side effects and complications of the psychopharmaceu- ticals, I am compelled to draw the conclusion that it is not the drug that should be condemned but the prescribing physician who should be indicted. Senator NELSON. That has been suggested before the committee. Dr. Am. Yes. Now, that is point No.1. Point No. 2. It is all well and good, sir, for any of us, senatorial com- mittee, a `body of physicians, to get together and to recite the `litany of side effects that a compound can cause. But this can do a grave injus- tice, a grave injustice not only to the compound and to its manufac- turer, but it can do a grave injustice to patients because there is no doubt in my mind that concern `about side effects can be responsible, in fact, it has `been responsible for denial of treatment. I wrote an edi- torial on this last year. I think, for example, to say that a compound causes agranulocytosis is all well and good, but what needs to be said is how often it causes agranulocytosis. If it does it one in ~5 million cases, that is not a very grave risk as, say, one in `25 cases. The prescribing physician's moral c~bligation as well as his profes- sional duty is to always balance risk against benefit. To do this, he must know several things. He must first know the patient for whom he is prescribing, not just an illness but the patient with the illness. He must know the physical condition independent of the illness. He must `also know that we live and work today in an era of what I call poly.~ pharmacy. Patients are receiving multiple drugs for multiple condi~ tions. You keep people alive and they develop high blood pressure and they develop diabetes and this, that, and the other thing each of which requires treatment. S'o that many patients receive multiple drugs. The physician who does not take this into consideration can get into difficulties by producmg drug interactions. This is `a matter of medical information, how to evaluate a drug, when to prescribe a drug, under `what circumstances. But I must point out to you, sir, that there has been and there is a trend in the United States for individuals who would like to take over `the control of the prescribing of medicine.'I mean, I wrote an editorial~ also entitled "Drug Use by FDA Fiat," in which I take issue with the fact that a physician is supposedly limited by dosage recommendations `in the package insert. If the physician chooses to prescribe doses in excess o'f those in the~ package insert, `he `does so, to quote Dr. `Goddard whom I respect very' highly, "He does so at his own peril." PAGENO="0264" 4168 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY No. 2, I would point out to you that, for example, there are indica- tions for drugs which have been well validated in the scientific litera- ture worldwide which are not in the package insert, `however, and, therefore, the physician who would prescribe a drug for that par- ticular indication again "does so at his own peril." A physician's right `to independent medical judgment, to assume responsibility for the care and treatment of the patient, to decide what is the `best drug for this particular patient in what dosage, and so forth, is an obligation that he can never escape. He just cannot escape t'his obligation. And yet if we `have people who say that we have too many drugs already, we should not have any more, or that this drug is the least effective of the series, therefore, we will not have this drug avail- able, and so forth, he is by that statement infringing upon the right `of the physician to treat the patient. He is also denying the patient the right to treatment. And I would stress for you, sir, that much of the emphasis which the press has given to the complications of drugs which have been mentioned in these `hearings has increased concern about side effects `and this is one of the reasons why I wrote the editorial last year in Medical Science called "Concern about Side Effects and Denial of Treatment," because I see patients who have been denied effective treatment because of concern about side effects. Instead of their being not only ineffectively treated, the cost of their illness in dollars and cents w'as increased, but their personal human suffering was prolonged and magnified because an alarmist attitude has been created by side effects. This is what I mean by let us have a balance. If we are going to say such and such a drug is responsible for this, this and this, fine. Let us also say what the incidence of these ~omplications i's. Let us also say how can we find out w'ho `are the risk patients. Did the physician balance risk against benefit in this par-~ ticular case? Did `he take a legitimate risk? And should we not take legitimate risk? If we do not take legitimate risk there will be no tiiedical therapy at all. Senator NELsoN. We have not had anybody before the committee who suggested we should not take any form of risk. The most classic case is still chloramphenicol, which we will have further extensive hearings on. That is a dramatic case of a widely abused drug in which a number of people have died because of the carelessness of the doctor in not knowing what he was doing. I have now two friends, two acquaint- ances, who because of what they read in the paper, when their child just got chloramphenicol prescribed as a broad spectrum antibiotic for a not very sick child, t'hey refused to take it. The child got perfectly well. There was no clinical test given the child, no testing to find out what was causing the fever to find out if' it should be treated by chloramphenicol. If that child had gotten it and died, it would have been a catastrophy. This has happened hundreds o'f times in this country an'd the best exp'erts we have, and we are going to get more, say that this has been a widely abused drug. We have had nobody in here say to the contrary. Now, if the publicity of this committee has had the conse4uence of warning the doctors w'ho are abusing this drug, as the experts say, and I will be glad to have any doctor in the country come in and present the evidence that they are not, if that publicity has done that and he PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4169 had indicated the profession, all the time spent by this committee is well worthwhile. Now, I said several times the tragedy was that the American Medical Association did not throw up the alarms, call a special conference, warn the doctors, do everything it could. It took a congressional com- mittee with no expertise at all to bring it out and we cut the usage in one 6-month period from 20 million grams to four compared to the previous year. I have seen no one come in and say we quit using it for indicated cases. They quit using it for nonindicated cases. We have had testimony here-and we are going to get into this much more deeply later-from doctors who specialize in drugs and the use of drugs, saying that six to seven, perhaps $8 out of $10 spent on drugs are spent needlessly. I think this ought to be made a matter of public knowledge. I think the profession ought to discipline itself and in many ways they have not, and if these hearings contribute to that, which I think they are, they will be worthwhile. Now, when you get to the question of limiting a doctor's prescribing, referring to a formulary, I do not know of any better way to get the collective judgment of the best people in the profession and in a hos- pital formulary, as you are well aware, if the doctors on the staff are competent and if the formulary committee and the specialists there know what they are talking about, I would guess that the collective judgment of the internist and the surgeon, the pharmacologist, and the pharmacist and all the rest of the specialists sitting down and deciding on a formulary, that their collective judgment based on their special knowledge is better than a single judgment of any single doctor. I would guess that that is true in any operation and that is why formularies are used in hospitals. Now, if the formulary committee is so ignorant or careless that they will bar the use of a drug that will do a job that no other drug in the formulary will do, well, that is another indication to this com- mittee of the incompetence of the profession or at least of this f or- mulary committee. But to have doctors saying, as individual practi- tioners, without special expertise, just reading the literature, that they are better prepared to decide what drug ought to be given than a group of people who practice and have experience in it, I think is a lot of nonsense and so does every professional man I know of. Dr. Aim. Senator, there are several comments I would make. One, I did not have in mind chloramphenicol when I was talking about side effects. No. 2- Senator NELSON. I think that is the one that has gotten big publicity here. Dr. AYD. I agree with you wholeheartedly that there has been in- judicious prescribing of medications, not only in the United States but in every country in theworld. Now, this I must stress, is due in part to the fact that there are physicians who are casual individuals, just as there are lawyers who are casual individuals, or businessmen who are casual individuals, and so forth. Even in the 12 Apostles there was a Judas. We cannot hope to eliminate human frailty by legislation. PAGENO="0266" 4170 COi~tPETITIVE PROBLEMS IN THE DRUG INDUSTRY I applaud your committee for calling attention to some things. I sincerely believe that there are areas in which the practice of medicine can be improved upon. That, however, I say is `the responsibility of the medical profession, not the pharmaceutical industry. For example, I agree and `have written editorials urging doctors to label prescriptions so that when a patient walks into my office and puts down a brown paper bag full of bottles of medicine I can easily identify what they are. I think this should be done. I think it should not only have the name of the drug, it also should have the strength of the medication. Senator NELSON. I have introduced a bill to that effect. I hope you wIll come and testify for it. Dr. AYD. Well, I would be very happy to, sir, because I feel very strongly about this. Let me illustrate one of the reasons why. Today's drugs are very potent. They can smite and they can heal. Let us face that fact. We are dealing with potent remedies. Their judicious use is imperative. Now, if a doctor is unaware of what the patient is taking, he may add another drug `which can really be tragic for the patient~ T'his would lead me to point out something to you which I think this committee needs to seriously consider. If we are going to have an array of generic drugs when patents go off of a particular substance, this is fine. I have no objections to this at all. I have this one thing, though, that I consider imperative and this is based on actual every- day practice of medicine experience, that that generic drug be in some way identifiab~Ie. Now, let me illustrate. In the city of Baltimore where'I practice, if the patient gets a generic drug at a hospital pharmacy and I am called on a Saturday or a Sunday to see this patient because some complication has arisen, and you get this unidentifiable thing and the hospital pharmacy is closed, you cannot find out what the patient is taking. Now, at least we have this advantage today, I can recognize every commercially available brand name psycho-pharmaceutical. I cannot recognize the generic ones. If we are going `to have them when the patent comes off of a partic- ular one, fine. There is nothing wrong with that. But let us make sure not only that it is identifiable but I do think that in the interests of pro- tecting the health, not just the pocketbook, the health of the American public, that you should have some way of making sure through con- gressional action that these generic equivalent drugs are indeed not only labeled but that they have been tested and proven to be thera- peutically effective, `therapeutically equivalent. This is not always the case, as you know. If we have this, fine, I am for you 100 percent. I think `the last part of my statement does not need to be read ex- cept that I would stress that at the rate we are going, in 50 years we may not have mental hospitals as we know them today. We need more drugs, not less. That is why I said the task of the physician is not the number of drug's we have available but learning the art of how to use them judiciously. Now, in this area, I must say in defense of the pharmaceutical in- dustry, I think that they have made fantastic efforts to educate physi- cians. I know how difficult it is to educate doctors. I have been trying PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4171 to do this, teaching interns, teaching residents, lecturing at State medi- cal society meetings, and so forth and so on. It is tough, a very tough job. And I do not know if there is ever going to be a simple solution to the question of educating physicians. I must also point out something else, that we speak of having so many drugs in this country but we are in a small ball park when it comes to the number of drugs compared to the other Western nations. One thing is going to happen if we look into the future a little bit. Doctors are going to have less and less time to spend with j~atients. It is going to be a production line thing as it has become in E~ngland where the average general practitioner has 3 minutes to see a patient, write a precription and hand it to him. This may happen in this country. All the more reason why your committee and everybody else ought to be stressing for the profession how important it is for physicians to recognize that today's drugs are like the hand of God. They can heal and they can smite and from this standpoint I have no quarrel with you or your committee and I hope I did not give you the impression that I came here as an attacker. That was not my objective. My objective, sir, was to come and plead for those patients to whom I have dedicated my life, that we will not, in our desire to rectify some errors in any way infringe upon the continued development of the drugs that these people need if they are going to be restored to health, and for that reason I am here and I think you for the opportunity to be here. Senator NELsoN. We would not want to infringe in any way and the committee appreciates very much your testimony and your taking the time from your busy practice to come over here and testify before the committee. We appreciate it very much. It was very useful. Thank you. I am sorry again that I had to delay you. Dr. Aim. No apologies necessary. Thank you, sir. (The supplemental information submitted by Dr. Ayd follows:) BRIEF BIOGRAPHICAL SKETCH Frank J. Ayd, Jr. received his medical degree from the University of Maryland, School of Medicine, in 1945. The American Board of Psychiatry and Neurology, Inc. certified him as a Diplomate in Ps~rchiatry in 1951. Dr. Ayd is an inter- nationally known lecturer, writer, and psychiatrist. He has lectured in Europe, Asia, Africa, The Orient, Australia, New Zealand, and North America. He is a member of numerous national and international medical societies. He is a Fellow of the American Psychiatric Association, The American, Academy of Psychoso- matic Medicine, The American Geriatrics Society, a Fellow and a founder of the American College of Neuropsychopharmacology. In 1955, Dr. Ayd was the recipient of the Distinguished `Service Award and designated Most Outstanding Young Man of the Year by the United `States Junior Chamber of Commerce for Baltimore and the State of Maryland. In 1960, Ayd was the recipient of the Holy Name Society Award for outstanding service to `Church and Community. In 1962, Dr. Ayd began broadcasting over the Vatican Radio on a program called Religion and Science. In 1963, Dr. Ayd was honored by being the first American Layman to be appointed to the Faculty of the Pontifical Gregorian University in Rome. In 1964, Xavier University (Cincinnati, Ohio) conferred on Dr. Ayd an honorary Doctor of Laws degree. Also in 1964, Dr. Ayd was the recipient of the St. Vincent Pallotti Award for Oustanding Contributions to Religion and Psychiatry. In 1965, Dr. Ayd was the recipient of the Rev. Joseph M. Kelly, S.J. PAGENO="0268" 4172 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Medal awarded to an Outstanding Alumnus of Loyola High School. Dr. Ayd has pi~blisbed over two hundred scientific articles. He is a contributor to over thirty books. He is editor and publisher of The Medical~Moral Newsletter and the In- ternational Drug Therapy Newsletter. Dr. Ayd is Associate Editor of Medical Counterpoint and is on the editorial staff of several other medical journals. Dr. Ayd is listed in Leaders in American Science, American Men of Medicine, and the American Catholic Who's Who. He is a member of The National Association of Science Writers, Inc. Dr. Ayd is married and the father of twelve children. PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4173 EOITILJIAJL HOSPITAL tRJi$iiipIIi$i_f_c Lwt!~ti~ui tQQt PrqQgflQjjQa$ 1958_____- 658 t959~ ~- --"- z,iOO 1960- - 2,731 196*L ~-- 4,601 1962- - 8,506 1963 _-- _11,261 1984 - 16,702 1965 20,353 1966 over 24,000(esttrnOted) ~I$I~$JIMJJOSPI1AL psycuepHARMJ,..cFj1peA~s. - Year rolal a &Merie Mq~p It imduted P1$rP$&I9~S THORAZiNE ChkflrmmazTheHO S K F - 1954 455~413 $151 AZ1P4t Stllvniwcinr 14(1 $ K F r4C39 3 2 49/ MCIaMIL Nt rtkvne 14(1 Sandoz I9~9 -JO J3 Th1LAW1~: - - - Rate Sthérlng 1957 90~ 308 PROKBMNt MALEE~ ospltwctnMaieate WyOh 962 *2 770 ttr4A01*N cna-paithmn Pooie 1982 41 800 - *-. Frrchhrra4ne $KF.,. ass ~3, 983 FIuØ-ant neUCl *01 tt WI 17 ~88 AWN4 tIC Promc~inr 14(1 Wj~ h Ci53 10 9(6 nia Sflxhi'i %t4Q??/A U8RIUM 2htcrdiazeaozde 14(1 Ilothe. 1960 90 928 I/eixo~-omafe RI Wallow 19561 M r-~ E C.. 000o0CD..c,cD o cc o C,, H C,, o W ~ ddo' .sco.c~ -c-c*c -J CC~ C~JC~ 0~C\JW CO - _J CC!!! 00 00 ~C) (0 N.. ~ ..C.-CC~D..-~ C) w ~ ~ 0< ~ ~ $ 0.. H .HH LLC L~ ~ -0 v,~j~< o~u.. ~ _j~ o~La~ 0 E 0 PAGENO="0284" 4186 COMPE~FXTIVE PROBLEMS IN THE DRUG INDUSTRY The first three patients listed in Table 1 (S.F., L.C. and WK.) were receiving methicillin in doses of 6 to 24 gm per day; the fourth (A.J.) was given penicillin, 20,000,000 units per day, in addition to me'thicillin, 4 to 6 gm per day, and the last three (0.0., M.L. and F.H.) received penicillin 12,000,000 to 60,000,000 units per day. The underlying infection for which the antibiotic was being given was staphylococcal sepsis in two patients receiving inethicillin, and osteomyelitis in the third. A.J., who was given both penicillin and methicillin, was being treated for presumed bacterial endocarditis without the isolation of an organism. The three patients who received penicillin were being treated for bacterial etidocarditis, caused by Streptococcus viridan,s in 0.0. and F.H. and by neisseria in ML. In each patient the fever associated with the underlying infection had subsided within a few days of the start of treatment, only to recur after a variable period, which ranged from eight to 44 days. In four cases the fever was preceded or followed shortly by a morbilliform rash, and in all seven eosinophilia occurred being marked in six. Urinary abnormalities and azotemia appeared eight to 36 days after the institution of antibiotic therapy, following the recurrence of fever by a few days in six of the seven patients, and preceding the fever by almost three weeks in the seventh (S.F.). Hematuria occurred in all patients, minimal to moderate proteinuria in all, and pyuria in five of the seven, Blood urea nitrogen increased in all patients, the maximum level in individual patients ranging from 50 to 130 mg per 100 ml. The duration of urinary abnormalties was as short as four days and as long as 39 days, whereas the period of renal insufficiency was usually somewhat longer. Impairment of urinary concen- trating ability and metabolic acidosis occurred in six patients. In four patients, acidosis persisted beyond the time that `the blood urea nitrogen and urinary abnormalities had returned to normal. Recovery, as judged by clearing of urinary abnormalities and return of blood urea nitrogen to normal levels, ensued in six of the seven patients. The interval between the appearance of urinary abnormalities and the discontinuation of penicillin or methicillin varied between `three and 32 days, and recovery then followed within five weeks. However, in `S.F. (Fig. 1) the urinary abnormalities subsided while methicillin was still being given, although the blood urea nitro- gen did not return to normal until eight days after the drug was discontinued. In `the single patient who died (M.L.) fever developed on the twenty-first, eosinophilia on the twenty-third, and rash on the thirtieth day of penicillin therapy, followed by seizures, coma, urinary, abnormalities and progressive renal insufficiency, with death occurring on the forty-second day. Penicillin was continued throughout this period. Urinary output was less than 300 ml on the last three days of life; this was the only case in which significant oliguria was observed. Renal biopsies were obtained in S.F. and L.O., who manifested nephropathy to methicillin, and in 0.0., who received penicillin. In addition, post-mortem material was available for study in M.L., who had been given penicillin. The lesions were characterized by irregular interstitial accumulation of leukocytes and by tubular damage (Fig. 2 and 3). The infiltrate contained large numbers of mononuclear cells and eosinophils. Most of the mononuclear cells appeared to be large or small lymphocytes, al- though a few typical macrophages were present. In most areas mononuclear cells predominated, and in a few places eoslnophils were absent. `Few neutrophils were seen, and they were generally in direct association with necrotic tubules. No plasma cells were found. Tubular damage and intertitial edema were observed in association with the leukocyte accumulation; the damage was manifested by changes ranging from slight distortion of cells to destruction of a portion or the entire cross-section of the tubule. Many of the damaged tubules contained amorphous or fibrillar eosinophilic casts as well as desquamated epithelial cells and neutrophils. In most cases the affected segment of tubule could not be iden- tified, but all levels appeared to be involved. Necrosis was conspicuous in two of the four cases. Regenerating tubular epithelium was also found in areas. The lesions were irregularly distributed; in the case studied at autopsy, they were seen to be predominantly In the cortex, although a few were present in the medulla. Most of the glomeruli appeared normal, but In one patient (L.O.), a few showed equivocal increase In neutrophils. The blood vessels appeared normal. In M.L., who was studied at autopsy, arteritis was found in the kidneys or in other organs. PAGENO="0285" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4187 75 REP~AL BUN BIOPSY MG 50 ~\ j 0I ~ `° 0- URINARY ________ L_~c u FINDINGS ______ ____ 40* 30 EOSINOPHILIA 20 0/ 10 0~ METHICILLIN 20 GM. 10 _____________________________________________ 10 20 30 40 50 60 DAYS FIGURE 1. Clinical Course in S.F., a 47-Year-Old Man in Whom Nephropathy Followed Met hicillin Therapy for a Scrotal A t~scess and Staphylococcus aureus Septicemia. IMMUNOLOGIC OBSERVATIONS Immunologic studies were carried out in one patient (L.C.). His serum assays for benzylpenicilloyl-specific antibodies were done by passive hemagglutina- tion. (22, 23) Serums obtained seven and fourteen days after methicillin therapy was discontinued both showed a titer of 1 :1600. After treatment with mer- captoethanol the titers were 1:640, indicating the presence of both 1gM anti- bodies (mercaptoethanol sensitive) and IgG antibodies, mercaptoethanol resistant), (22, 23) Direct skin tests (21) for skin-sensitizing antibody with 10AM penicilloyl-polylysine were positive when tested 40 days after methicillin had been discontinued. Tests with dimethoxyphenyl-peniciloyl-polylysine (the methicillin homologue) were negative. Delayed skin tests (24) 14 days after methicillin was discontinued were positive with 0.1 M methicillin and negative with 0.1 M penicillin. IMMUNOFLUORESCENT OBSERVATIONS In the first experiments an attempt was made to determine whether dimethoxy- phenylpenicilloyl (DPO) haptenic groups, the major baptenie antigenic deter- minant of methicillin, were present in the kidney sections. It is known that methicillin can react with protein to yield hapten protein conjugates in which DPO is bound covalently to lysine epsilon amino residues. (25) Sections of kidney were treated with fluorescein-conjugated rabbit antl-DPO antiserum. Figure 4 shows that intense staining was seen in a well defined, continuous linear pattern outlining glomerular basement membranes and to a lesser extent tubular basement membranes, as well as in tubular epitbelium and the interstitium. That this staining was specific for the DPO hapten group was indicated by two kinds of controls; renal biopsies from patients with acute glomerulonepbrltis, PAGENO="0286" 4188 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Irregular interstitial leukocytic infiltration and edema are seen with necrosis of some of the tubules. The glomeruli appear normal. lipoid nephrosis, lupus nephritis and sections from normal kidneys obtained at autopsy did not stain with this serum; and addition of the univalent hapten, DPO-amylamine, at a final concentration of 1O~M to the fluorescein-conjugated auti-DPO antiserum completely inhibited the staining. Inhibition was specific sjnce the same concentration of DPO-amylamine did not inhibit fluorescent staining by the antiglobulin serum. The kidney section stained very faintly FIGURE 2. Section of Renal Cortical Tissue from ML. (Hematoxylin and Eosin Stain). PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4189~ Most of the leukocytes are mononuclear cells although numerous eosinaphils are also seen. The tubule shows various degenerative changes and several areas of' necrosis. with antibenzylpenicilloyl serum. Thus, the presence of DPO haptenic groups was demonstrated in the kidney. Whether the DPO groups were coupled directly to the kidney structural pro- tein or whether they were present as part of soiluble antigen-antibody complexes FIGURE 3. Interstitial Accumulation of Leukocytes in Biopsy of ML. PAGENO="0288" 4190 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Bright, smooth staining is seen outlining glomerular (on the right) and tubular basement membranes. deposited in the kidney was investigated in the next experiments. If the DPO hapten were part of deposited complexes, extensive washing of the sections with univalent penicilloyl hapten would be expected to dissolve these complexes, thus FIGURE 4. Frozen Section of Renal Biopsy of L.C. Stained with Fluorescein-Conjugated DPO Antiserum. PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4191 reducing or preventing subsequent staining of the sections with fluorescein- conjugated anti-DPO serum. Accordingly, the sections were washed six times with BPO-propylamine or with DPQ-amylamine 2X 102M, washed thoroughly with saline solution and then stained with the fluorescein-conjugated anti-DPO antiserum. No reduction in staining with the antl-DPO s~rum was seen. On the contrary, staining of glomerular and tubular basement membranes appeared to be enhanced. The staining in areas of tubular necrosis was markedly enhanced; in these areas, clusters of brightly stained droplets appeared that were not evi- dent in sections that were not first washed with hapten. These findings Indicate that the DPO hapten detected was bound to kidney structural proteins rather than being part of a deposited antigen-antibody complex. The enhancement of staining produced by washing with hapten may have been due to specific elution of antibody, which would make more DPO baptenic sites available to bind the fluorescein-conjugated anti-DPO antiserum. This enhancement did not appear to be due to binding of DPO-amylamine by the tissue, since treatment of sections from other kidney diseases in the same fashion did not cause staining with the anti-DPO serum. Sections were also stained for 1gM, IgG, IgA, fibrinogen and complement (beta1A-beta1C). IgO was seen in a patter~1 similar to that observed for DPO hapten, whereas no staining was seen for IgA, 1gM, complement or fibrinogen. Gamma-globulin staining appeared to be specific, since the antiserum did not stain normal kidney, and specific sl~aining was obliterated by absorption of the anti- serum with purified gamma globulin. Whether or not the gamma globulin was antipenicilloyl antibody could not be determined. DIscussIoN The sequence of events in the seven cases included in the present report leaves little doubt that in each the nephropathy could be attributed either to methi- cillin or to penicillin therapy. The clinical picture was remarkably similar in the seven patients, and in all, high doses of the drug were used for relatively long periods. The histologic findings were principally interstitial nepliritis and tubular damage. Arteritis or glomerular lesions were not seen by light microscopy. Simi- lar pathological findings have been described as manifestations of methicillin reactions in two reports (16, 17) and of a penicillin reaction in one patient who had also received, sulfonamide and died with sepsis. (2) In addition, several cases of interstitial nephritis due to drugs have been reported in association with phenindione (26, 27) and sulfonamide therapy. (28, 29) Although we and others have referred to the lesion as interstitial nephritis, tubular damage was present as well, and it is not clear whether the initial event occurs in the tubules, the tubular basement membrane or the renal interstitium. The pathogenesis of the nepbropathy that occurs with naethicillin or penicillin is unknown, but several considerations indicate that the lesions result from hypersensitivity. In the first place, in our patients a syndrome characterized by fever, rash and eosinophilia, which is generally accepted as evidence of an allergic reaction, developed. Secondly, only a small number of patients receiving methicillin or penicillin, even in very large amounts, have such a reaction, sug- gesting that it is not due to direct toxicity of the drug. Thirdly, DPO hapten (derived from metbicillin) and gamma globulin were found in the kidney of the one patient studied by immunofiuorescence (L.C.). Fourthly, the same patient, whose antibody response to penicillin was investigated, was found to have an unusually intense immune response, characterized by a high 1gM titer, the presence of IgG and skin-sensitizing antibodies against penicilloyl determinants, as well as by delayed hypersensitivity. This kind of immune response is rarely observed in patients treated with penicillin without an allergic reaction. (24, 30) The IgG, 1gM and skin-sensitizing antibody were shown to be specific for the benzylpenicilloyl group rather than the dimethoxyphenylpenicilloyl group. (31) The observation that serum antibodies specific for the benzylpenicilloyl group rather than for the dimethoxyphenylpenicilloyl group were stimulated by methicillin may be due to an anamnestic immune response, because he had been treated with benzylpenicillin three years previously. (31) The delayed hyper- sensitivity, however, appeared to be specific for methicillin rather than for penicillin, as indicated by the results of delayed skin tests to these drugs. De- layed hypersensitivity may thus represent a primary immune response. These considerations favor a hypersensitivity basis for the renal lesions. How- 81-280-69-pt. 10-19 PAGENO="0290" 4192 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ever, conclusive evidence is lacking, and probably could not be obtained without a suitable experimental model, which is not available at present. If one provisionally accepts the interpretation that the renal lesions result from hypersensitivity, it remains to be determined what the underlying patho- genic mechanisms are, and why this reaction occurs in only a small percentage of the many patients receiving these drugs. Two general possibilities can be con- sidered: in patients receiving large amounts of methicillin or penicillin, deriva- tives such as penicilloyl hapten may normally couple with structural renal pro- teins, and the damaging immune reaction may depend primarily upon an unusual immune response; or, alternatively, it may be considered that the patients in whom nephropathy develop's, in contrast to the vast majority of persons, are uniquely capable of forming these hapten-kidney conjugates from the penicillins. The first explanation seems more likely, since penicillins are known to be chem- ically reactive with a wide variety of proteins. However, the data do not permit a definite decision. We have no Immunofluorescent observations of renal tissue from patients given large amounts of methicillin or penicillin In whom inter- stitial nephritis has not developed. Such ~bservatlons would provide information concerning this problem. The question of the type of immunologic mechanism responsible for the damage remains. Despite the presence of gamma globulth (presumably specific antibody) and hapten in the lesions of the patient studied by i'mmunofluorescenee, several considerations indicate that the renal damage may not be initiated by antigen- antibody interaction. First of all, complement (beta1A-beta1C) was not detectable in association with the gamma globulin and hapten. Secondly, although gamma globulin and hapten were present in glomeruli, glomerular abnormalities were not apparent; since it is well established that glomerular damage is readily brought about by antigen~antibody complexes, (32) it seems likely that the type of complexes present in this patient were not tissue damaging (possibly because complement was not fixed). Finally, the histologic character of the lesion, with a predominantly mononuclear cell infiltrate, suggests the possibility that the damage was due to delayed hypersensitivlty.* This possibility is further supported by `the observation that the patient exhibited delayed sensitivity to methicillin. Dosage of drug appears to have a role in the nephropathic reaction since the patients receiving methicillin were given a maximum dosage of 20 to 24 gm per day except for one patient (A.J.), who received only 6 gm per day. However, this patient was also receiving penicillin in a `daily dosage of 20,000,000 units, and the other three in whom nephr'otoxicity developed during penicillin therapy were receiving up to 20,000,000, 30,000,000 and 60,000,000 units per day. Further- more, the shortest interval between `the initiation of therapy and the appearance of urinary abnormalities was eight days, with a range between 16 and 34 days in the other six patients. Thus, it appears that high doses of drug for prolonged periods are more likely to produce nephropathy. At lower dosages of penicillin or me'thicillin the extraction by the kidney is almost complete, leaving little or none of these materials in the peritubular capillaries or interstitial fluid beyond the proximal tubules. At higher blood concentrations, the rate of transport by the proximal tubules increases, but extraction is Incomplete, resulting in greater concentrations of drug in the blood leaving the proximal peritubular capillaries and in the interstitium. It sems likely that the increased rate of tubular transport and the increased concentrations of drug in peritubular capillaries and intersti- tial fluid that exist during administration of large doses have some effect on the occurrence of nephropathy. Since equivalent doses are frequently administered without any clinical evidence of renal damage, it is obvious that dosage is not the only factor responsible for nephropathy, and it is likely that the kind of immune response made to the drug is the critical feature. `The mechanism responsible for the marked azotemia that occurred in each of our patients is not clear. The absence of glomerular abnormalities and the con- sisten't finding of Interstitial inflammation and tubular damage might lead one to postulate that the reduction In glomerular filtration was due, at least in part, to increased interstitial pressure opposing filtration. Additional hemodynamic alterations other than those attributable to increased interstitial pressure, or perhaps tubular back diffusion, might also be Involved. The impairment of uri- nary concentrating ability and the presence of striking metabolic acidosis even *The question could be raised why a delayed sensitivity, reaction did not occur in the gloineruli. Although the reason is not known, it can be stated that there is no experimental evidence that it i~ possible to produce a delayed reaction in glomeruli. PAGENO="0291" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 4193 beyond the period of azotemia suggest the occurence of distal tubular dysfunction as well as glomerular insufficiency. Hematuria, which was gross in `four of the seven patients, pyuria and pro- teinuria occurred consistently. Although it is possible for these to be glomerular in origin without demonstrable structural glomerular abnormalities, it seems more likely that these urinary findings arose from damaged tubules. Thirteen other cases of nephropathy to methicillin have been reported in the literature. (11, 17) The clinical picture of fever, often with skin rash and eos'inophilia, as observed in the present series, was also typical of the previously reported cases. Hematuria was observed in all, and in nine of the 13 patients was gross. In six of the 10 cases in which such data are given there was an in- crease in blood urea nitrogen or serum creatinine. All patients appear to have recovered, although `in two serum creatinine was still elevated at the time of last observation. The pathological findings are described in two patients, both of whom showed interstitial nephritis without glomerular abnormalities. (16, 17). The clinical and pathological features of alleged nephropathy to penicillin as previously reported in the literature (1, 11) differ greatly from what has been reported to follow methicillin, and from what we have observed after either methicillin or penicillin. The dosage of penicillin has been relatively low, in no case more than 1,200,000 units per day, and the evidence of nephropathy has ap- peared promptly, usually on the second day and occasionally a few days later. Although skin rash is cited in most cases as evidence for a hypersensitivity reac- tion, eosinophilia and fever have been noted only rarely. The clinical and patho- logical features of the renal disease have varied widely among the 15 cases re- ported. Two groups seem to predominate. In one group of five patients the findings were characterized by periarteritis and glomerulonephritis, either diffuse or focal necrotizing in type. In another group of five patients acute renal failure and anuria developed in association with infection. All the five patients in this second group underwent diuresis and survived; no pathological data are available. Two other patients had antecedent renal disease, and two showed the clinical picture of Ilenoch-Schönlein's syndrome and have had persistent evidence of renal disease. `The evidence supporting a causal role of penicillin in these cases of nephropathy cited in the literature is not conclusive. The patients, mostly children, in whom acute renal insufficiency with oliguria followed a single injection of penicillin may have been suffering from renal failure due to circulatory failure and sepsis, or perhaps from acute diffuse glomerulonephritis. The pathological findings in the kidneys have not been reported in any of them. The patients with periarteritis and glomerulonephritis or with Henoch-SchSnlein's syndrome (presumably with a form of glomerulonephritis) who have received penicillin may be suffering from a reaction to the drug, but the apparent relation could be coincidental, since either of these conditions can occur in the absence of any penicillin administration. In fact, it seems likely that In some cases the clinical features for which penicillin was given were those of already existing periateritis or glomerulonephritis. In any event, if periarteritis or glomerulonephritis can, in fact, represent manifes- tations of hypersensitivity to penicillin, the mechanism appears to differ from that responsible for the occurrence of interstitial nephritis as reported here. It must be concluded that the lesions commonly accepted as evidence of a hyper- sensitivity reaction-that is, arteritis and glomerulitis-are much less firmly established than interstitial nephritis as manifestations of penicillin hypersensitivity. REFERENCES 1. Anderson, A. B. Anaphylactic purpura following intramuscular penicillin therapy. M. J. Australia 1: 305, 1947. 2. Barksdaie, E. E., Frost, D. M., and Nolan, J. J. Reactions from penicillin, with case report of one fatality. U.S. Navy M. Bull. 48: 883-886, 1948. 3. Langdon, E. Exfoliative dermatitis following administration of penicillin. U.S. Armed Forces M. J. 1: 210-213, 1950. 4. Spring, M. Purpura and nephritis after administration of procaine penicillin. J.A.M.A. 147: 1130-1141, 1951. 5. Swann, R. 0., and Merrill, J. P. Clinical course of acute renal failure. Medicine 32: 215-292, 1953. 6. Carré, I. J., and Squire, J. R. Anuria ascribed to acute tubular necrosis in infancy and early childhood. Arch. Dis. Childhood 31: 512-522, 1956. 7. Zilberg, 13. Anuria following penicillin administration. South African M. J. 32: 350-352, 1958. PAGENO="0292" 4194 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 8. Unger, H. M., and Nemuth, II. I. Penicillinase treatment of acute renal insufficiency due to penicillin hypersensitivity. J.A.M.4. 167: 1237-1239, 1958. 9. Rich, A. R. Tissue reactions produced by sensitivity to d~rugs. In Sensitivity Reactions to Drugs. Edited by M. L. Rosenbeim and IL. Moulton. Spring- field, Illinois: Thomas, 1958. Pp. 196-208. 10. Peters, G. A., Moskowitz, B. W., Prickman, L. E., and Carryer, B. M. Fatal necrotizing angiltis associated with hypersensitivity to penicillin 0 and iodides. J. Allergy 31: 455-467, 1960. 11. Schrier, B. W., Bulger, B. J., and VanArsdel, P. P., Jr. Nephropathy associated with `penicillin and homologues. Ann. mt. Med. 64: 116-127, 1966. 12. Hewitt, W. L., Finegold, S. M., and Monzon, 0. T. Untoward side effects `asso- ciated with metbicillin therapy. Antimicrobial Agents ~ Uhemothcrapy 1: 765-769, 1961. 13. Lamy, P., Anthoine, D., Rebeix, G., and Viniaker, P. Nephropathies par intolerance ~ la métbidilhine. 4nn. med. Nancy 2: 1489-1496, 1963. 14. Grattan, W. A. Hematuria and azotemia associated with administration of metbicillin. J. Pediat. 64: 285-287, 1964. 15. Feigin, B. D., and Fiascone, A. `Hematuria and proteinuria associated with methicillin administration. New Eng. J. Med. 272: 903, 1965. 16. Brauninger, G. E., `and Remington, J. S. Nephropathy associated with `methi- cillin therapy. J.A.M.A. 203: 103-105, 1968. 17. Simenhoff, M. L., Guild, W. R., and Dammin, G. J. Acute diffuse interstitial nephritis: review of literature and case report. Am. J. Med. 44: 618-625, 1968. 18. McCluskey, R. T., Vassalli, P., Gallo, G., and Baldwin, D. S. Immunofiuores'cent study of pathogenic mechanisms in glomerular diseases. New Eng. J. Med. 274: 695-701, 1966. 19. Levine, B. B. N(a-D-Penicilloyl) amines as univalent hapten inhibitors of antibody-dependent allergic reactions to penicillin. J. Med. ~ Pharmaceut. Chem. 5: 1025-1034, 1962. 20. Levine, B. B. Preparation of penidilloyl-polylysines, `skin test reagents for clinical evaluation of `penicillin hypersensitivity. J. Med. Uhem. 7: 675, 1964. 21. Levine, B. B., and Redmond, A. P. Nature of antigen-antibody complexes initiating specific w'hea1~and-fiare reaction in sensitized man. J. Olin. Inves- tigation 47: 556-567, 1968. 22. Levine, B. B., Fellner, M. J., and Levytska, V. Benzylpenicilloyl-specific serum antibodies to penicillin in man. I. Development of sensitive bemagglutina- tion assay `method and ha'ptenic specificities of antibodie~. J. Immunol. 96: 707-718, 1966. 23. Levine, B. B., Feilner, `M. J., Levytska, V., Franklin, B. 0., and Ali'sberg, N. Benzylpenicilloyl-specific serum antibodies to penicillin in man. II. Sensi- tivity of liemagglutin'ation assay method, molecular classes of antibodies detected, and antibody titers of randomly selected patients. J. Immunol. 96: 719-726, 1966. 24. Redmond, A. P., and Levine, B. B. Delayed skin reactions to benzylpenlcillin in man. Internat. Arch. Allergy 33: 13-206, 1968. 25. Batchelor, F. R., Dewdney, J. M., and Gazzard, D. Penicillin allergy: forma- tion of penicilloyl determinant. Nature (London) 206: 362-364, 1965. 26. Galea, B. G., Young, L. N., and Bell, J. R. Fatal nephropathy due to phen- indione sensitivity. Lancet 1: 920-922, 1963. 27. Baker, S. B., and Williams, B. T. Acute interstitial nephritis due to drug sensitvity. Brit. M. J. 1: 1655-1658, 1963. 28. More, R. H., MeMillan, G. C., and Duff, G. L. Pathology of sulfonamide allergy in man. Am. J. Path. 22: 703-735, 1946. 29 French, A. J. Hypersensitivity in pathogenesis of histopatbologic changes asso- ciated with sulfonamide chemotherapy. Am. J. Path. 22: 679-701, 1946. 30. Levine, B. B., Redmond, A. P., Feliner, M. J., Voss, II. EL, and Levytska, V. Penicillin allergy and heterogenous immune response of man to benzyl- penicillin. J. Olin. Investigation 45: 1895-1906, 1966. 31. Levine, B. B., Levytska, V., and Zolov, D. Penicillin hypersensitivity `and doc- trine of original antigenic sin. J. Olin. Investigation 47: 61a, 1968. S2. Unanue, B. B., and Dixon, F. J. Experimental glomerulonephritis: immunolo- gical events and pathogenetic mechanisms. In Advances in Immunology. Vol. 6. Edited `by F. J. Dixon and J. H. Humphrey. New York: Academic Press, 1907. Pp. 1-90. PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4195 APPENDIX IV STATEMENT OF DR. DONOVAN F. WARD, PRACTICING PHYSICIAN, DUBUQUE, IOWA Mr. Chairman, I am Donovan F. Ward, `a practicing physician, of Dubuque, Iowa, and I appreciate this opportunity to offer my Views on questions regarding the prescribing of drugs, which have been raised before your Committee since May 15, 1967. A considerable store of technical and scientific testimony has been adduced in the course of this inquiry. This is as it should be, of course. You must have scientific explanations for vastly complicated scientific questions if you are to begin to resolve differences in statements and claims which stud the record- not only of this hearing-but also that of the public controversy over drug prices and the relative efficacy of drug products. But there are other considerations, too, and that is why I asked for an oppor- tunity to testify. I would like to discuss for a few minutes the subject of drugs from the standpoint of the physician who prescribes them, and who, alone, is responsible to his patient for their effects. It is, after all, the delivery of the care most likely to meet a particular illness situation that is the urgent and immediate concern of the physician at his patient's bedside. At that moment-and I cannot overstate this point-the physician must know what he is prescribing, what it does and where it came from. He must have every freedom to `select those medicines which he knows are of the highest quality and which his experience tells him will produce the best results. Frankly, my apprehensions have been aroused by statements and proposals, which are becoming increasingly famiii'ar-~and a good many of which have been heard here-that seem to disc'ount `the importance of that freedom, or appear designed to take it away altogether. Let me, at this point, provide some brief `biographical information. I am a graduate `of the University of Iowa College of Medicine, Class of 1930. I have practiced medicine and surgery in Dubuque since 1931, interrupted only by years spent in additional `professional training `and war service, 1942-1946, in the U.S. Navy Medical Corps. In 1964 and 1965, I was president-elect and president `of the American Medical Association. Over the years, I have `also `served on a number of AMA councils and committees, including the Join't Council to I'mprove `Health Care of the Age'd, of which I was director from 1963 to 1965, the Committee on Medical Practices, the Committee on Medical Education a'nd Hospitals and the special AMA Advisory Committee to the Department of Health, Education and Welfare; at pres'ent, a member of `the AMA Council on Legislative Activities `and medical advisor on the Advisory Board to the Bureau of Veterinary Medicine u'nder the F.D.A. I am a Fellow of the American College of `Surgeon's `and `of the International College of `Surgeons and a past president of the Iowa Clinical Surgical Society. I am presently serving as `senior surgeon at The Finley a'n'd Mercy Hospitals in Dubuque and consulting surgeon at Xavier Hospital. Since 1956, I have been the U.S. Public Health Service Designated Physician in Dubuque and since 1962, the F.E.C.A. Designated Physician. From 1950 to 19~35, I was the Dubuque County Designated Health Officer. I am a member of the Iowa Division of the American Cancer Society, was co-editor of its early manuals, and have served on its Professional Education Committee since 1952. More than a dozen papers and articles, which I have written on medical and surgical problems, have been published in professional journals. As I have indicated, Mr. Chairman, I do not represent any organization or group. Rather, I am submitting this statement as an individual who has had the good fortune to participate in an era of unparalleled medical and `scientific advances and who sincerely believes that this progress may be retarded or halted by the emotionally-charged actions which are being urged. There is far more involved in your hearings than criticism of the drug industry's merchandising and pricing policies, although I will say that if the industry is made the victim of some kind of restrictive legislation, its ability to contribute to medical progress cannot fail to suffer-and the patient will be the ultimate loser. Also at stake here is the threat of scientific truths being submerged and lost in a raging national debate over socio-economic questions PAGENO="0294" 4196 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY with strong political overtones. In jeopardy, too, is the historic right of the physician to prescribe the precise treatment for his patient which he believes to be the most suitable in each instance, based on his professional knowledge. This is the point of deepest concern to me. Under the American system of medical care, the physician alone arrives at a diagnosis and he alone should decide what medicine is to be administered to his patient. This is a vital part of the physician's professional responsibility and it cannot be delegated without endangering the quality of the care each individual receives. Much has been said before this Subcommittee about the so-called "therapeutic equivalence" of drugs-regardless of who produces them-if they contain the same active ingredient and meet U.S.P. or N.F. standards. The argument is made that products sold under their generic names are generally cheaper than those bearing the brand name of a particular manufacturer; hence, patients would save money if their physicians would only prescribe by generic names. The popular appeal of this approach is undeniable. If a less expensive drug will accomplish as much, why pay for the higher-priced one? I would like to answer that by stating categorically, on the basis of some 36 years in the practice of medicine, that the argument is fallacious on its face. There are no such things as identical or equivalent drug products, which can be depended upon to have the same effects on all p~tients under all conditions-any more than there are identical or equivalent patients, who can be counted on to react the same to the same product under the particular condition of their illnesses. I am sure I do not have to take your time to discuss the many variables existing among drug products, from different manufacturers, even though they bear the same generic name. In previous testimony, you have heard of the differences in manufacturing processes. Yo~i are aware, from the hearing record, that substances such as binders, excipients or lubricants added to the active ingredient by one producer may be omitted or unlike those used by another pro- ducer. The active ingredient itself may vary in important respects-degree of fineness, crystalline state, etc., even assuming compliance with standards set forth in the specifications for the drug product in the official compendia. Each of these differences can have significant effects in the treatmcnt of ill- ness. As a physician, I know-I have learned-that individual patients react differently to same treatment. The physician's task is to find the most effective medicine to meet the situation with which he is confronted. And I believe it must be accepted that the judgment of the therapeutic results of a medicine can only be made by the physician in cooperation with his patient. Thus, it follows, the patient's interests will best be served under a system which continues to permit the physician to specify those pharmaceutical products which the physician knows are of the highest quality and which his experience tells him will most effectively meet the patient's individual needs. Most of us prescribe by specifying the brand name of the desired drug or by selecting the product of a particular manufacturer. From time immemorial, this has been our means for making sure our patients get their medicines from sources we can trust. Under legislation, which would require-by direct or indirect means-the pre- scribing of drugs by their generic names, the physician would lose the control over the medicines he designates for his patient, and the patient would lose this safeguard over the quality of medicines he receives. We know that substandard drugs are being marketed every day. These are often sold under their generic names. We cannot be certain who produced them or under what conditions. They may or may not give consistent therapeutic results. Yet, one of these questionable products, of indeterminate origin, could be used to fill a generic prescription. I cannot imagine a member of my pro- fession, who would willingly gamble with his patient's health in this fashion. I do not, for a moment, assert or imply that all generic-named products are inferior to brand-name products. To the contrary, there are excellent generic- named products on the market. Many quality drugs have no brand names. Many of these are produced and* sold under generic names by ethical drug houses that also manufacture brand-name drugs. The fact remains that unless the product (whether marketed under generic or brand name) is made by a reputable and qualified manufacturer, there is absolutely no way to tell which is good and which is poor before it is used, without access to analytical and biological laboratory facilities more elaborate than most physicians, pharmacists and hospitals are likely to possess. PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4197 There is another point I would make here. When the treatment is long-term, several refills of the same prescription probably will be required. Under a prescription, specifying the drug by name or by the name of its manufacturer, each new supply would have the same variables as the one before-coating, base, solubility, disintegration time, etc.-and could reasonably be expected to produce the same response from the patient. But, with a generic prescription, the refills could come from products of different manufacturers with different production methods and different quality standards, depending on whose products the pharmacist might have on hand when the refill was ordered. There could be, in this situation, changes in therapeutic response, which might mislead the physician in his diagnosis or alter the patient's progress. The effect simply would be to deprive the physician of a margin of control over this patient's treatment. It may be that in certain instances and with certain drugs, there is no signifi- cant therapeutic difference among competing products. Indeed, they may have all been checked and found reliable. Moreover, I am aware of no limitation existing at the present time which prevents a physician from prescribing gen- erically, if he so desires. I do myself, on occasion when I feel it is compatible with the best interests of my patient. But, if there is the slightest question in my mind, I prescribe only those pharmaceutical products with which I am familiar. If a pharmacist wishes to use another preparation, he would have to assure me that the product he was recommending measured up to very rigorous criteria. And, unless I had confidence in the pharmacist, and unless he in turn could assure me of his faith in the integrity of the manufacturer, I doubt that I'd permit my choice to be altered. Chances should not be taken with any drug; they absolutely cannot be taken in the area of critical drugs. When, for example, I prescribe digitalis or nitro- glycerin for my heart patients, I must know-beyond any doubt-the precise medicine that is being administered. Therefore, in every case, I will specify a product of demonstrated reliability, manufactured by a firm whose reputation I know and whose `products I trust. There can be no other way. The range between a therapeutic dose and a toxic dose is too narrow for me to be able to sleep nights if I thought my prescription were being filled from a bottle bearing simply the generic label of an unknown or unfamiliar manufacturer or repack- aging firm. I would have nothing on which to base an evaluation of the medicine; of the care with which the raw materials were selected; of the quality controls exercised during production; of bow products from the `same manufacturer have performed in the past under given conditions; of what the manufacturer's reputation is for marketing drugs of ,proven potency, purity and safety. Indeed, if the drug has passed through the hands of a repackager and jobber, I have no way of knowing who the manufacturer is, and neither does the pharmacist in this situation. `The dispenser is obliged to use reasonable care in selecting a drug and no one doubts that 999 out of 1,000 do. But, under the conditions' I have outlined, this is meaningless. An experienced salesman can separate quality from trash in such commodities as clothing on the basis of the feel of the material, the skill of the cutter, the fineness of the stitch. What can the pharmacist do? Look at the pills or capsules? There is hardly a clue here, since even the most vilely impure drug may look completely normal and pure. The pharmacist has neither the time nor the equipment to establish the potency and purity of me~1icine cloaked behind the anomymity of the generic name of its active ingredient. An altogether different situation exists when the medicine bears the trademark identification of a reliable manufacturer, or, if packaged under its generic name, is identified as the product of a reliable manufacturer. For all of us-the physi- cian, the pharmacist, the nurse-this has to be our most practical measure of trust. We know that the makers of quality drugs stake their reputations on, and are answerable for, the integrity of medicines carrying their names. For very simple and direct economic reasons they cannot afford to be linked with shoddy merchandise. They h'ave invested grea't amounts of effort and money in gaining their position in the drug field. With greater folly could there be than for them to risk it all through `the distribution of even one or two inferi'or prod- ucts? How long could they hope to remain pre-eminent in `the eyes of the medical profession? PAGENO="0296" 4198 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In our competitive system, this is `the patient's strongest safeguard, far more effective than any government policing efforts could provide for an industry as fragmented and scattered as is `the pharmaceutical industry. It is also my great- est assurance, as a physician, that my prescription is being filled with a medicine of high quality, which is exactly the same as a medicine I have used in the pas't under similar circumstances and found to be effective. As far as I am concerned, I will state quite catididl~ that when a manufacturer fails me the first `time-and I don't care how renown he may be-4t is the last time. The drug industry is fundamentally a supplier of a service to the medical profession. Such has been its historic and highly-useful role. I am as critically concerned with the merit of this supplier and the quality of his service as I am with the services of the nurses, the hospital technicians and other staff members, my medical assistant and all others associated with my efforts to serve my patients. In no case is second best good enough. The prescribing system `tha't places `a premium on product and manufacturer identification exerts a strong `and unrelenting pressure on the supplier to excel and thereby earn the specification of his products in the market place. It encour- ages him, not only `to adopt practices most likely to result in superior products, but also to' increase his commitment to research that may lead `to still newer and better products. Yes, `the phra'se "newer and better products" has real meaning for a physician of my generation. Perhaps that is why I feel so strongly on this subject. I remember a bustling and eager young doctor in Dubuque almost four decades ago, who came out of medical school with every confidence and faith that be would conquer the ills of mankind. Then when I think of how pitifully limited his resources were, I marvel at the boldness of youth. It is a wonderful attribute, no't always realistic. In those early years of my career-for I was that new doctor-I was destined to watch patients die by degrees from tuberculosis witbotit the means to do ar~y'tbing about it. I learned what it was to sit the night through at the beds'ides of typhoid fever victims and sufferers from pneumonia, doing what I could but watching them slip away because I could not stop the infection. Today it is all different. Drug development, medical progress-these are not abstr'act terms to me. S'ince I ~egan prac'ticing medicine, the world has seen the emergence of new drugs, new vaccines, nE~w therapies and new techniques at a pace remarkable beyond belief. Tremendous inroads have been made in our battle against in- fectious diseases. The fear of `contageous disease, which once swept entire com- munities, has become largely a thing of the past. Drugs have been develo'ped that are so extraordinary in their curative and preventative powers that the American people-not the physicians or the pharmac~utical industry-have named tbem~ "wonde'r drugs." With the advent of penicillin in the late 1940's, many bacterial infections were conquered for the first time. Then came the broad spectrum antibiotics, which worked against itifec'tion's penicillin couldn't reach. Tranquilizers, steroids, radioactive materials-the list is long-all have come into wide use In the past quarter of a century. An amazing 80% of the drugs commonly prescribed today were unknown just a decade ago. These valuable pharma~ceuticals didn't just pop out of the ether. They are the fruits of years of research by a comparative handful of drug manufacturers. We `know their efforts a're co'n'stant'ly frustrated by failure. But we are `also aware that they go on maintaining expensive facilities and highly s1~ecialized teams of scientists, whose sole mission is to attack and, as we have seen, to solve disease projlems. These firms are known to physicians as stout allies in a never-ending struggle against man's deadliest adversaries. We respect their intense rivalry as they strive to Outstrip their peers in the manufacture of the best products and the discovery of new ones. We trust their pro'ducts and we prescribe them. Now, it seems to me, a fundamental question which cries fot an unequivocal answer is being raised by this issue and by certain easy generalizations, which have been made regarding it. Do the American people want `the best medicines ~that science and the industry know bo'w to' make, or, will they settle for the lowest-priced generic drug? Will they support continued pharmaceutical re- search for new and more effective drugs, or, will they say, "Let the next gener- ation worry about its own disease problems and medicines to cure them?" PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4199 The peril in the debate now raging is that the generic case will be overstated in the consuming zeal of its advocates, and the public will be convinced that price is the primary consideration in the choice of drugs. This is wrong and it is dangero us! Quality must remain the paramount consideration if people are to continue to receive the maximum benefits from a system that produces the best, the safest and the most effective drugs in the world. And quality must continue to be recognized in the market place if the system is to remain strong and creative. If the aim is to grind all drug manufacturing firms down to the lowest common denominator, which I cannot believe, there will be no incentive to excel, no motivation (indeed, no resources) for discovery, and we will begin an un- precedented process of medical retrogression in this country. There can be no other result. On the question of the price of drugs, about which so much has been said in hearings, let me first point out that this is by far the smallest part of the cost of sickness. Moreover, I believe figures from government sources have been placed before you, showing that this is the one element of health care expenses which has declined in recent years-both as to the prices of drugs themselves and the proportion of the total bill for a sickness which they represent. It is a remarkable record in this inflationary period when the prices of virtually all other commodi- ties have been rising steadily. It should also be remembered that the efficacy of modern drugs has reduced the average length of stay in hospitals, as has been demonstrated in testimony before you, and thus has helped to reduce hospital costs to the patient. However, I do not want to be misunderstood on this point. Let me state cate- gorically, no physician should overlook the opportunity to prescribe a drug costing less if there is no risk to the patient's health or if it makes no difference in the therapy of the patient. The AMA, on at least three occasions including the period when I was president of the Association, adopted resolutions urging physicians to supplement their medical judgment with cost considerations when prescribing for their patients. I am heartily in accord with that position and, I might add, it is a rule of profes- sional conduct I have followed throughout my career. I am no stranger to practice among people of limited means. The memory of some of my earliest experiences as a doctor has been awakened by this controversy, involving, as it does, the attempt to institute government control over the prescribing of drugs for the elderly and financially unfortunate. I came out of medical school and completed my internship in the depths of the Depression. As a member of the Dubuque County Medical Society, I agreed to do my part in the community to help care for the needy. Accordingly, I received a list of the drugs that could be prescribed for the so-called county patients and for which the county would pay from its slender resources of the time. That was more than 30 years ago; yet the system was strangely similar to the legislation which was proposed last year on a national scale for millions of beaeficiaries of federally-financed health programs, proving. I suppose, that there is really nothing new under the sun! I had, as I have noted, just finished my internship and supposedly was in command of the pharmacology of the day. But, when I looked at the list of drugs for welfare patients, I found to my dismay that I was not familiar with half of them. My inquiries disclosed that many dated from before I bad started medical school and by then were largely obsolete. I was, I realized, unable to use the knowledge I had gained as .a medical student if I were to prescribe from this list which was the only way my welfare patients could have free drugs. There was no choice for me. I had to confide my dilemma to the patients and explain that I could not write a suitable prescription in a great number of cases. How well I remember their answer, which I heard-not once or twice, but time after time, "Okay, Doctor, give us the prescription which you think is the best and we will get the money to pay for it." The attitude of those people made a lasting impression on me. More than any other experience which I have had, it led to the formulation of beliefs which I hold very strongly to this day: No man in his illness and misfortune should be treated as seco~ri~d class. No one insulated in a government bureau from contact with human need and suffering should have the authority in this day and age to tell those who are devoting their lives to the treatment of disease what they can or cannot prescribe for any patient; particularly for the most pathetic group of patients PAGENO="0298" 4200 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of all-those whose lack of financial resources has deprived them of control over their own destinies and made them dependent on the government for care. They are the helpless ones and should be the subjects of our most com- passionate concern. Mr. Chairman, I abhor the thought of a national formulary for federal welfare patients, selected "by committee," listing the only drugs available at government expense to this group of Americans, and favoring generic termi- nology as an economy measure unrelated to medical considerations. Generic drugs will not assure quality, as I have tried to show; often they will not meet individual illness requirements. Thus, the proposed formulary would discriminate against the beneficiaries of government programs. The number and kinds of drugs which their physicians would be able to prescribe for them-for which they would be reimbursed-would be limited. Other more fortunate citizens would continue, as a matter of course, to enjoy the advan- tages of the full range of the nation's drug armamentarium. I foresee the time when, under this arrangement, countless physicians across the country would face the same Impossible quandry I faced years ago with the county welfare's list of acceptable drugs-whether to prescribe a drug from the formulary so the patient could be reimbursed, even though the drug might not be the most desirable under the circumstances, or whether to prescribe a drug not listed in the formulary, and thereby penalize the patient financially. There is. the further problem of combination products, those medicines con- taining two or more active ingredients. There are no generic names for these. Yet the supporters of the national Formulary proposal are placing all their emphasis on generic names for their listings. Would combinations be excluded? Certainly they would be disadvantaged in competition for a place on the list by limitations which have been placed on the acceptance of non-generic drugs by the Formulary Committee. There are many outstanding combinations. I have used them for years. About 100 medicines which would fall under this particular stricture were among the 200 most frequently prescribed by phy- sicians in 196(3. While the legislation to which I have referred is not before this Committee, I am sure it is in your minds. It is significant, for purposes of discussion, be- cause it illustrates so clearly the manner in which enforced generic prescrib- ing by any approach can interfere with sound medical practice; can dis- criminate against any segment of the population at which it is aimed, and can jeopardize the ability of top-quality pharmaceutical companies to perform effectively by sapping their resources and robbing them of the incentive to compete for recognition. Getting back to my original premise, when all the emotional polemics which have been evoked by this issue are stripped away one fundamental point remains: Some companies consistently make medicines of high quality and some do not. The names of the drugs, in themselves, really have very little to do with the problem except as they indicate the source. What is important to me as a physician is the demonstrated reliability of a product and my being able to act with confidence on the reputation and resources of a particular company. Even a new product with which I have no direct experi- ence carries a greater presumption of safety and effectiveness if the past per- formance of the manufacturer bespeaks excellence. It is not simply a commodity that the pharmaceutical manufacturers are deliv- ering; it is relief from aches and pains and conditions that bedevil people. Just as a man who goes to a hardware store to buy a brace and bit isn't only buying a brace and bit, he is buying holes; so drug firms are dejivering therapy which just happens to come in the form of pills, capsules, elixirs, etc. But it is that therapy that counts and there Is more to it than merely stirring together certain proportions of chemicals and other substances. Quality and performance must be built in and the hard fact is, as all physicians know, some manufacturers do not do this. My guide in selecting a medicine (whether by generic or brand name) which I am sure will provide the desired therapy, has to be the maker of whom I have some knowledge and in whom I have confidence. Before I conclude, I would like to take a moment more to refer to services to the medical profession which leading drug manufacturers perform and which PAGENO="0299" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 4201 also contribute to the best standards of medical care. To the extent that they impose an extra financial burden on the companies, they enter into questions regarding drug prices. Are these services helpful and worthwhile? Do they achieve results commensurate with their costs? I would certainly say a loud `Xes to both questions. The information which we are provided about new drugs--and the periodic updating of information about established products-is an invaluable aid to physicians. Without the journals, the mailings and the personal visits from manufacturers' representatives, I would be hard-pressed to keep abreast of today's rapid medical advances and still work 12 to 18 hours a day at my practice. Inven- tion of a drug is pointless if the medical profession doesn't have knowledge of it~ its indications, contraindications, dosage forms, etc. I have noted a tendency in some of the earlier te~timony to deride doctors because they deal with detailmen. I don't understand this. While I cannot speak for other physicians, I know for myself I have found detailmen helpful and in- formative. They bring me information on new developments. They can answer preliminary questions. They often serve for the exchange of information with other doctors. If I have a problem relating to one of their products, they can, and frequently do, contact their home offices to get me an answer. I realize they are trying to sell me. That's their job. I don't have to be sold if I don't want to be. My feeling about them is the same as about the products of their firms. I trust them on the basis of my past experience with them and my belief in their integrity. It is pure hogwash, of course, to suggest that any physician worthy of the name would depend on detailmen and advertising pages of professional journals for his continuing medical education. It is true the ads and the company repre- sentatives often provide the first information on a new product. If I am interested, I would turn to the package insert and the literature. Then I would check it out with my colleagues in my county and state societies and, perhaps, consult the hospital pharmacist. Finally, if the product seems to have possibilities for my practice and I am satisfied after these inquiries, I might give it a try under close observation. This is the point where the services of the reputable companies really shine. I know that whatever the dosage form in which I want to use the drug, the company will make it available in my community in its full line. I don't have to prescribe a tablet when I want to prescribe a tablet when I want to prescribe an injection because the manufacturer hasn't found it profitable to produce or widely distribute less popular forms. Further, if questions arise about the action of the drug, I can report promptly to the manufacturer because I know who the manufacturer is. If it is necessary, I know I will obtain the assistance of the company's medical staff in identifying and evaluating the problem, and applying the proper corrective measures. This is not only true for new drugs but holds equally well for older, established products. When I have identified the manufacturer in my prescription, I know precisely where to go If difficulty arises. This would not be true in cases of generic prescriptions filled by the pharmacist from whatever stocks he has on hand. He might or might not be able to determine where the medicine caine from. If he could identify the source, the company might or might not have a medical staff capable of advising me. If it were a -small company engaged in copying successful drugs, the chances are it would have a limited staff and would not be able to support the scientific personnel to provide service. Beyond this, it must be assumed that the originating company, whose labora- tories discovered the drug, is going to be far better acquainted with its good and bad points than the secondary manufacturer who produces the imitation after the originator has already demonstrated its worth -and successfully made the medical profession -aware of its existence. The manufacturer who has developed a drug must keep an accurate and up-to-date record of adverse reactions and other data pertaining to it-s effectiveness. I know I can get the swiftest and most accurate information from him about his pro-duct when I need it. This is not true of the imitator in many cases. Moreover, the originator has every incentive to make sure his product serves the public in the best possible way to preserve his reputation among physicians and pro-tect his name in the market place. In closing, I should like to point out that throughout my professional life I have been concerned with the economic factors affecting the quality of medic-al PAGENO="0300" 4202 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY care. I believe, and I have often stated, that he who controls the economics will control the quality of care. The quality of drugs is inescapably a vital part of the quality of care. Now, there is growing clamor to make the price of drugs the primary considera- tion in their selection to relegate quality to secondary consideration. Any such approach could not fail to adversely affect the quality of care. It would not, as I have tried to show, appreciably lower the nation's health care bill. It could do irreparable harm to the nation's health care system. I present this statement to you because I am anxious to do my small part in alerting you to this peril. Our present balanced and flexible health care `system is the wonder of the rest of the world. As you proceed with your inquiry, I sincerely hope you will conclude that it is in the best interests of all concerned to keep it that way, and that you will summarily reject demands for such chancy experiments as the imposi- tion of controls over the prescribing of drugs for economic, not health reasons. APPENDIX V THE MER-29 CASE STATEMENT BY THOMAS M. RICE, ACTING CHIEF INSPECTOR, BUFFALO DISTRICT, Foon AND Dnuo ADMINISTRATIOR, U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Mr. Chairman, it is a pleasure to appear before you today to discuss my part in the investigation of ME'R/29. During the time of the field investigation of ME'R/2P, from 14161 to 1963, I was employed as a Supervisory Inspector at FDA's Cincinnati District Office. I was the principle field investigator in the MER/29 case. In early 1962, there was considerable publicity In the Cincinnati area, as a result of `the drug warning letter mailed by the William S. Merrill Company to all physicians, the previous December. ThIs warning letter informed phy~icians of the incidence of cataracts, hair changes, ichthyosis, and other skin changes, de- pression of adrencortical function and other side effects assoCiated with MER/29 therapy. This publicity was the topic of a conversation in my Cincinnati car pool in February 1962. One of the car pool members, Mr. Carson Jordan, who knew that I was employed by the Food and Drug Administration said that his wife had been involved in animal studies on M'ER/29 during the time she worked at Merrell, when this drug was being developed. His wife, he said, suspected the records on the animal studies had been falsified to make the reports look good. He told me that Mrs. Jordan later resigned her job in the animal testing laboratory, where she was employed under the supervision of Dr. William M. King, because she was dissatisfied with the way Dr. King was directing the work. He said she felt very strongly that Dr. King would have no qualms about "doctoring" the results of the studies. Recognizing the Importance of what Mr. Jordan had said, if true, I reported this incident to our Bureau of Field Administration. At the request of our Bureau of Field Administration, I interviewed Mrs. Jordan on the evening of February 26, 1962. She told me that she had the responsibility of dosing and weighing both the test monkeys and the control monkeys during a toxicological study of MER/29. Mrs. Jordan said that at the end of the study, which took a number of weeks, she worked up cha rts depicting the observations and weights. Three or four monkeys were on MER/29 and a similar number were in the control group in the study, she said. Dr. King and his superior, Dr. Evert F. Van Maanen, were not satisfied with the charts, Mrs. Jordan said. She said one test monkey on the drug, MER/29, bad been sick and doing very poorly; its eyes "did not look right." This monkey subsequently was not autopsied with the rest. In addition, her superiors decided to substitute a control monkey in its place. Because of this decision, Mrs. Jordan said it was necessary for her to rework the charts three different times. She believed that the results on the charts would have been very unfavorable if the sick monkey had been left in the test group. She stated that she was told never to mention this substitution of data on the charts because this was the way the PAGENO="0301" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4203 company wanted it. She named other former Merrell employees who were familiar with this experiment, particularly Bruce I. Umberger. I interviewed Mr. Umberger that night of March 12-13, 1962. Since his recollec- tions substantiated Mrs. Jordan's to a considerable extent, they were prepared in affidavit form. I again interviewed Mrs. Jordan on March 13, and her recol- lections were also prepared in affidavit form. Following this, I attended a conference in Washington, D.C., to plan further investigation. It was decided to send a three~man inspection team, consisting of a medical officer, a pharmacologist, and me, to inspect the firm and review the raw data from the chronic studies on rats, dogs, and monkeys, and to get up-to- date information on adverse effects to humans. I made the inspection on April 9 and 10, 1962, with Dr. John 0. Nestor and Dr. Edwin I. Goldenthal, from FDA Headquarters. During this inspection, discrepancies were found between the raw data note- books and charts kept by the firm with respect to the monkey chronic oral toxicity studies and the data and charts on these studies which bad been sub- mitted to FDA by the firm in support of the MER/29 NDA. For example, as submitted in the NDA, monkey M51 was reported as having received 40 mg/kg body weight MER/29 for six months and 20 mg/kg for ten months. The NDA data showed no weight loss at the end of the experiment. The raw data showed that monkey M51 was started on MER/29 about half way through the experiment and was placed on 20 mg/kg body weight of MER/29 for only about eight months. There was a significant weight loss toward the end of the experiment. Monkey F49, according to the NDA submission, showed a wieght gain in the last month of the experiment, but the raw data showed a significant weight loss from 9.9 kg to 7.5 kg-a loss of 2.4 kg (5.3 lbs) in this last month. Furthermore, discrepancies were found between the NDA submission and raw data in the dates of autopsies of the monkeys. In particular, no record of any autopsy on drug monkey M34 was found in the raw data. The charts showing discrepancies with the NDA submission were copied, but the firm refused to permit us to take the raw data notebooks the evening of April 9, although promising to make copies of the pages we wanted. No one at the firm was able to explain the discrepancies noted. We returned to the firm on April 10, 1962, and still no one could explain the discrepanies. They did not have the copies of the pages of the raw data notebooks as promised. How- ever, they assured us that copies would be made available as soon as possible. On April 12, 1962, I called Mr. E. R. Beckwith. Executive Vice President of Merrell, because we still had not received the promised copies. He said they were trying to get a complete picture of the situation, but because of changes in personnel during the time the data was compiled, information was scattered. He told me it was taking time to get the pieces of information together. He again assured me he would get me the copies as soon as possible. On April 17, 1962, I paid another visit to the firm because we bad still not been supplied with the copies of the pages from the raw data notebooks. At the same time, we discussed the details and status of the firm's recall of MER/29, which was by then, underway. At this time, I was told by Mr. Fred Lamb, attorney for the firm, that he could not give me copies of the requested pages because the notebooks bad been sent to an attorney for the firm in New York City for examination. He said it was up to this attorney, dealing at the Wash- ington level, to decide whether the pages would be made available. I understand that copies of the requested pages were finally turned over to a Food and Drug Inspector in New York on April 19, 1962. On April 24, 1962, I interviewed Dr. King at his home, accompanied by Mr. T. C. Maraviglia, Director of FDA's Cincinnati District. At this time, Dr. King told us that a control monkey, M35, had actually been on an analogue of MER/29, known as compound 5066, for a time prior to being used as a control animal. He also stated that his findings from the autopsy of monkey F49, which had received MER/29, indicated morphological changes in the ovaries. He said that it was Dr. Van Mannen's decision to omit this in- formation from the second edition of the MER/29 brochure so that the inves- tigators supervising clinical studies on MER/29 wouldn't know about it. I again visited Mr. Umberger the night of May 3 and 4, 1962. He reviewed copies of pages from the bound raw data notebooks which had been supplied to me by this time. From these, he was able to recall that the sick test monkey was number M34. He recalled that at autopsy be was told that the monkey, PAGENO="0302" 4204 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY M34 had had a "reverse heart attack," when he asked why this sick monkey behaved abnormally-for example, missing a box it attempted to jump into after being weighed. ~1e could not explain why there were no autopsy results recorded in the raw data notebooks for M~4. The autopsy report submitted with the NDA on this monkey indicated nothing abnormal about the heart. After reviewing the raw data, Mr. Umberger signed another affidavit reaffirming the affidavit of March 13. On May 30, 1962, I interviewed Mrs. Jordan again. This time, she was shown copies of the pages from the raw data notebooks and charts which she had helped prepare, including Figure 7 submItted with the NDA. She now was able to recall that the sick monkey she referred to in her earlier affidavit was M34, which agreed with Mr. Umberger's recollection, and that this monkey did not lose a dramatic amount of weight, but did poorly. She confirmed the fact that M34 was the monkey that was mean, withdrawn, and couldn't see properly, missing the box when he tried to jump into it. She also recalled that monkey, M34 was not autopsied in her presence, which was the reason no record was in the raw data book. She advised us that Dr. Van Mannen was the one that told heir to falsify the chart (Fig. 7) turned In with the NDA. He supplied the weights to be used for the curve on monkey M34, which did not agree with those in the raw data notebooks, and insisted on the other changes which: (1) showed M51 as being on MER/29 during the entire experiment rather than the last eight months only; (2) showed monkey M35 as being a control monkey for the entire time, though she knew it was on 5066, another test drug, during the first part of the experiment; and (3) eliminated weight figures for the closing weeks of the study-figures which would have shown the dramatic weight loss of P49 and the weight loss of M51. She also knew there were some suspicious looking rats on MER/29 studies and that about `one-third of the MER/29 rats died. On June 19, 1962, I interviewed Dr. K. S. Grady. He had been a consultant veterinarian for Merrell since about June 1961. He said he had made specialized examinations on dogs' eyes once a week for three or four months for Merrell and noted abnormalities which developed slowly until some were diagnosed as cataracts. Some of the dogs' eyes showed fingernail-like opacities. He also noted dermatological problems in the dogs. These findings were reported to the firm, primarily to Dr. King. Dr. Grady later found that these dogs were being dosed with MER/29. On June 20, 1962, I interviewed Frank A. Nantz, M.D. He is an ophthalmol- ogist and bad done some examinations of dogs' eyes for Merrell on November 9, 1961. These dogs had developed cataracts while on a high-level MER/29 study. He later made about six trips to the firm over a four-month period to examine these dogs. In addition to cataracts, he noted that these dogs developed skin rashes. On June 22, 1962, I interviewed Dr. Irvine H. Page, M.D., Director of Re- search, Cleveland Clinic, at the request of our Bureau of Enforcement. A dog study on MER/29 which had been performed by his group and which had been completed about two years previously, bail shown results which were unfavor- able to Merrell. This was submitted for publication in the Archives of Pathology, but Dr. Page decided to withdraw publication after he had sent his manuscript to Merrell and they urged him to delay publication. I understand that the paper eventually was published in June 1962. This was the final field investigation I made of any significance in respect to this case. If you have any questions, I will try to answer them for you. STATEMENT BY EDWIN I. GOLDENTHAL, PH. D., ACTING DEPUTY DIRECTOR, OFFICE OF Nnw DRUGS, BUREAU OF MEDICINE, Foon AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Mr. Chairman, I appreciate the opportunity of appearing before you today to discuss my involvement with the drug triparanol, or MER/29, with regard to (1) the initial review of the pharmacological and tox4cologieal data submitted in support of safety of the drug, and (2) the investigation at the William S. Merrell Company and the subsequent review of some of the raw data upon which the reports submitted to FDA were based. MER/29 is a drug formerly marketed by the William S. Merrell Company `for lowering cholesterol levels. PAGENO="0303" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4205 With your permission, I will submit for the record `a statement of my educa- tional and professional background. At the time of the review of data submitted lfl support of MER/29, I was a pharmacologist in the Division of rharmacology. At that time, pharmacologists reviewing data on New Drug Applications (`NDAs) were located organiza- tionally in the Division of Pharmacology of the Bureau of Biological and Phy- sical Sciences, `and not part of the Bureau of Medicine. Comments or recommen- dations by the pharmacologists on N'DAs were of an advisory nature. In this same adviso'ry capacity, individual pharmaeologists frequently participated in meet- ings at the Bureau of Medicine with representatives of the pharmaceutical industry. The New Drug Application for MIDR/29 was submitted by the William S. Merrell Company on July 21, 1959. I did not make the initial review of the application but wa's involved, in a supervisory capacity, with pharmacological reviews of all New Drug Applications. Based on the pharmacology review of the application, FDA notified the drug's `sponsor, in `a letter dated September 14, 1959, that the application was incomplete because of a questionable margin of safety. We suggested a one-year oral study in rats `and a three-month oral study in dogs, with one dosage level in e'ach of these experiments selected with production of specific evidence of toxicity as a goal. Dr. F. Joseph Murray, Executive Assistant to the Director of Research of the William S. Merrell Company, by letter of September 24, 1959, to Dr. Jerome Epstein, the medical officer assigned this application, indicated his firm's disagreement with our conclusions. Dr. Murray maintained `that the su'bmitted `animal d'ata, partic- ularly the results of the monkey study, showed MER/29 to have an "excep- tionally good" margin of s'afety. On October 6, 1959, Dr. Murray and `another Merrell representative, Dr. Wil- ham King, met with several members of the Division of Pharmacology to discuss the New Drug Application. I `w'as present at that meeting. `They advised us that they bad some additional animal studies underway; specifically, a six- month dog study and a six-month rat study. They indic'ated that these tes'ts were not mentioned in the initial NDA submission because no results had been obtained. We recommended that they administer the drug to one group of dogs for a minimum of three months, at the highest dose the dogs could tolerate, in an attempt to produce some evidence of toxicity. We also recommended that they start an additional two groups of rats at dosage levels higher than those used in previous studies, and that treatment be continued for a perio'd of one year. In a letter to Dr. Epstein of October 13, 1959, Dr. Murray again asserted that the animal studies had demonstrated safety of MER/29, and stated: "We feel that the significance of the studies carried out in monkeys has been entirely overlooked." On October 16, 1959, representatives of the William S. Merrell Company met with members of the Administration to' discuss further the toxicological studies which we felt were necessary to support the safety of MER/29. They indicated they were planning to initiate a six-month dog study at dosage levels expecte'd to produce toxicity and a rat study of twelve months' duration. In a letter dated November 6, 1959, the Administration acknowledged the firm's correspondence of September 24 and October 13, and said the results of the additional toxicity studies agreed upon would be reviewed when submitted. On February 12, 1960, the firm submitted additional toxicity data on MER/29 consisting of results of three-month and nine-month s'tudies in rats and a `three- to six-month study in dogs. These data were reviewed in my memorandum, dated February 23, 1960, to Dr. Frank Talbot, the medical officer who was handling the MER/29 application at that `time. The conclusion was that, on the basis of the animal toxicity data, there was little margin of safety with the drug. I indicated my serious concern about the safety of the use of such a drug for reducing blood cholesterol. I was concerned about the inherent toxic potential of the drug and the possible long term effects of elevated blood desmosteroL MER/29 was believed to reduce cholesterol levels by blocking the metabolic conversion of desmosterol to cholesterol. My recommendation was tha't the application should not be approved in the absence of satisfactory results from extensive, well-controlled clinical studies in which individuals received the drug for a period of several years. This was based on the high potential toxicity of the drug shown in the animal studies. By letter of February 29, 1960, Dr. Murray referred me to our telephone conversation in which adverse effects of MER/29 on the eyes of rats were discussed. He alleged that "the corneal changes have now been found in the PAGENO="0304" 4206 CO1~flETITIvE PROBLEMS IN THE DRUG INDUSTRY control animals" and stated that the firm's consulting pathologist "feels that the changes are inflammatory," and not caused by the drug. By letter of March 28, 1960, FDA acknowledged six communications from the firm and commented that the application was incomplete in that it failed to report clinical studies in full detail. Our letter further stated: "As brought out in our meeting of March 7, 1060, with representatives of the William S. Merrell Company, we are ullable to resolve the a~paten't discrepancy in interpretation of the pharmacologic studies in cldgs between your pe~ople and ours. Becattse of this dispute, because of th~ potential ha~ards df liver toxicity with this dog, and further because of the highly theoretical value of taking such a drug as MER/29 (to our minds), we are making the application incomplete until longer term `clinical sttidies have been made utilizing periodic liver func- tion studies to show that this blocker of intermediate cholesterol `metabolism is not producing liver damage." On March 81, 1960, FDA i~eceive'd personally from Dr. Murray, a tabulation of liver function tests. The firm continued to emphasize that an earlier toxicity study in monkeys, had likewise shown a total absence of toxicity from MER/29, and that monkeys being primates, were phylogenetically closer to man than either rats or dogs. Thus, he argued, the drug was safe under the conditions of use set forth in the New Drug Application. On April 19, 19~0, ~DA notified the William S. Merrell Company `that the application was macic conditionally effective and that the action allowing the `application to become effective was based solely on the evidence of the safety of the drug. On May 12, 1960, FDA acknowledged re- ceipt of the final printed labels and labeling and made NDA 12-066 fully effective, subject only to the terms set forth in the FDA letter of April 19, 1960. My next involvement with this application was on November 7, 19~31. I sent a memorandum to Dr. John Nestor, the medical officer then handling the ap- plication, in which additional data were reviewed. In light of reports of adverse reactions in humans, particularly the eye changes, the question had been raised as to whether or not the application should be suspended. While I agreed that the application should be suspended, I was not convinced that the new data sub- mitted by the firm would be sufficient to support a revocation of the application. On November 13, 1961, various personnel within the Administration met to evalu- ate the situation and to decide on a course of action. The decision reached wes that the drug should be removed from the market and the application suspended. In the absence of new clinical evidence that the drug was unsafe, however, this could not be `done under the provisions of the Federal Food, Drug, and Cosmetic Act at that time. Th'is ~*u'estion was `reviewed with FDA scientists and the con- clusion was reached that the available evidence would not support suspension action. On November 27, 1961, a drug warning letter was agreed upon by the Wil- liam `S. Merrell Company and FDA. This letter informed physician's of the in- cidence of cataracts `and the necessity of early detection by slit lamp examina- tion. It also advised that they be on the look out for hair changes, ichthyosis and other skin changes, depression of a'drenocortical function, and other side effects associated with ME~R/29 therapy. In March 1962, FDA was informed by a former employee of the firm that sonic parts of the chronic monkey data `on M~lR/29 submitted t'o the Food and Drug Administration had been falsified. We were advised that one of the drug-treated monkeys had become ill and lost considerable weight during the latter part of the study :a~nd that a normal, untreated, healthy animal had been substituted. She `stated that `the report submitted to the FDA by the William S. Merrell Company, a's part `of `the N'ew Drug Application, had been modified to include data on this untreated monkey instead of the monkey receiving MER/29. There was also some question as to whether or not this sick monkey had been subject to autopsy. It was `decided that members of the Administration should visit the William S. Merrell Company to investigate this alleged falsification. On April 9, 1962, Dr. J'ohn N'estor `of the Bureau of Medicine, Supervisory Inspector Thomas M. Rice, and I visited the firm's Cincinnati facilities and met with representatives of the firm. During the morning, a discussion was held regarding clinical experience with MER/29, `particularly report's `of the `adverse effects. In the course of `our discussion, we asked to `see `the raw data from t'he monkey studies. Pertinent laboratory record's were made `available to us. Our `search f'or `specific data was difficult because of the confusing manner in which these `record's had been kept. Upon reviewing some of their laboratory notebooks and weight charts, however, it became evident that `the `d'a'ta w'ere `somewhat different from those submitted in the New Drug App1ic~k4on. PAGENO="0305" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4207 Discrepancies such `as the following were uncovered: Notebooks and weight charts indicated that a marked loss of weight occurred in one monkey during the last five weeks of the reported study; the data submitted in the New Drug Application indicated that there was a weight increase of this monkey during that period. We could not find the record of autopsy for another monkey in this study. According to the NDA, a third monkey bad received MER/29 for 16 months, whereas the firm's notebook and charts indicated that this monkey had received MER/29 for only 8 months. The laboratory records on three of the mon- keys showed three different dates for the `ant'opsy of these animals. Moreover, the autopsy dates given in the New Drug Application did not correspond to those found on the charts and `notebooks. Delving further into the records, I discovered reports on another monkey which bad `been treated with MER/29, apparently as part of a `second toxicity `study `in `this species. Only one monkey study had been mentioned in the New Drug Application. The officials of the firm responsible for these `studies were asked if they could explain the discrepancies. They bad no im- mediate explanation. Before leaving the firm `that day, we were a'sked if we were satisfied with the results of `our visit. We replied `that while we had received the utmost cooperation, we h'ad disc'ove'r~d `some discrepancies in the monkey studies which had not been explained to our satisfaction. The senior officials of `the firm indicated that they would discu's's our findings with `thei'r personnel in an attempt to clarify the matter. We indicated that we would return on the following day. On the morning of Ap'ril 10, 1962, we again visited the firm. A conference. was held with comp'any representatives. An `official told us that, although they bad worked late into the evening, they were still unable to find any explanation for the discrepancies which we had noticed on the previous day. We met further with the `officials `of the firm wh'o were directly involved with these studies and they, `too, indicated they hkd been unable to explain the discrepancies. On Api-il 11, 1962, a memorandum summarizing our findings was sent to our 1)ivision of Regulatory Management. I indicated that we had found certain discrepancies between the chronic monkey studies submitted in Merrell's New Drug Application and those found in their laboratory records. We felt that these discrepancies did not represent an oversight on the part of the William S. Merrell Company, but constituted evidence of the submission of fradulent and misleading data to the FDA. I indicated that the net effect of these misleading data was to make the drug a~pear less toxic to monkeys than was actually the case. These data were of particular significance at the time of our consideration of the NDA, when representatives of the William S. Merrell Company had vigorously maintained that evidence of safety obtained in these monkey studies outweighed any questionable findings in lower species, i.e., rats and dogs. It was apparent that the discrepancies uncovered in our visit supported the allega- tion by the former Merrell employee that fradulent monkey data bad been submitted to the Food and Drug Administration. On the basis of these findings, I recommended that the NDA be suspended. Moreover, I felt that sufficient evidence had been obtained to support prosecution of the William S. Merrell Company and the individuals involved and recom- mended such action. On April 12, 1962, representatives of the firm met with FDA and advised us that they were immediately withdrawn MER/29 from the market. They requested that we suspend the New Drug Application. On May 22, 1962, a formal order suspending the New Drug A~~plication for MER/29 was signed by the Commis- sioner of Food and Drugs. Subsequently, as our investigation continued, we found that two of the reports of rat toxicity studies submitted in the New Drug Application contained falsified data. Regarding a six-week, two-dosage level study, the William S. Merrell Company reported in the NDA that four of the eight females at the high dosage (75 mg/kg) had died during the course of the experiment. Exami- nation of Merrell's notebooks revealed that no females at that dosage level were alive at the end of six weeks. Seven of the female rats had died, and the eighth had been sacrificed. The firm's failure to report truthfully the results of this experiment resulted in further complications. Final organ weights and hematol- ogical values were reported in the NDA for these animals at the six-week period. In checking the firm's laboratory records, no organ weights or hematological values were found for these animals. This is not surprising sinCe the animals did not survive for these determinations. The values which were reported were 81-280-69-pt. 1O-20 PAGENO="0306" 4208 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY identical to those reported for rats in another study on MER/29-at a different dosage level and for a different duration. In a second rat study, according to the New Drug Application, 20 rats per dosage group received MER/29 for three months. The NDA states that "In the rats receiving 40/mg/kg/day of MER/29, 8 out of 20 had grossly visible opacity of the cornea . . . there was also an associated conjunctivitis." The firm held that this was not a drug Induced phenomenon since it was also observed in control rats. When we checked their laboratory records, however, we found that actually 60 rats per dosage level had been administered MER/29. At the time of our review of the New Drug Application, we had no knowledge of these further studies~ These additional data, which were withheld by the William S. Merrell Com- pany, established conclusively that MER/29 was capable of inducing cataract formation. After the three month sacrifice, there were approximately 40 rats per dosage level still receiving MER/29. On March 28, 1960, approximately four months after the start of the experiment, and before the New Drug Application was approved, the eyes of the remaining rats were examined. The firm's note- books state that the eyes of many of the rats receiving MER/29 "did not react to light or motion, therefore giving the appearance of being blind." At the highest dose level, 25 out of the 36 rats showed this blinding effect. Only 1 of the 38 control rats showed `this effect. None of this data was submitted for Inclusion in the New Drug Application. This omission Is extremely serious since knowledge that MER/29 was causing cataracts in rats certainly would have caused the FDA to delay, and probably to withhold, permission to market the drug. As it devel- oped, cataracts were one of the most disturbing features of toxicity which oc- curred in patients after the drug was released. As early as November 1960, the William S. Merrell Oompany had been notified by another pharmaceutical firm, Merck, Sharp and Dohme, that MER/29 had shown extremely serious adverse effects in their experiments with rats and dogs; the drug had produced cataracts and other eye changes. Moreover, Merrell repre- senta'tives had actually visited Merck, Sharp and Dohme during January 1961, to examine the affected animals. No mention of these findings to the Food and Drug Administration was made by the William S. Merrell Oompany until Janu- ary 2, 1962, when FDA and the William S. Merrell Company had received reports that this drug caused cataracts in human beings. The original brochure contained a caution that MER/29 should not be admin- istered during pregnancy. On September 23, 1960, approximately five months after the New Drug Application became effective. Dr. Talbot sent a letter to the William S. Merrell Company. In this letter, Dr. Talbot made mention of adverse effects of ME'R/29 in pregnant rats. He stated his concern over the admin- istration of MER/29 to premenopausal women who would know whether they were in the first trimester of a pregnancy. On October 23, 1961, Dr. NeStor re- quested the William S. Merrell Company to submit all data concerning adverse and toxic reactions resulting from MER/29 therapy in both animals and humans. On October 26, 1961, the William S. Merrell Company submitted results of fer- tility and sterility studies on MER/29 in rats to Dr. Nes'tor. Part of `this study was conducted by the William S. Merrell Company `and another part was con- ducted by Eindocrine Labs., Madison, Wisconsin. These studies' showed that at certain dosage levels MER/29 caused a marked reduction in the rate of concep- tion. In addition, the percentage of the litters Surviving was also affected. Those effects were observed when the female received MER/29 prior to and during cohabitation with male rats. These experiments were all completed in March of 1960 and a final report was prepared in October of 1960. However, these results were not submitted to FDA until one year later, and only at the urgent request of Dr. Nest'or. The William S. Merreil Company did not submit these data even though Dr. Talbot questioned them about this matter in his letter of September 23, 1960. These data should have been submitted much earlier. If we had had this information in the file, we would certainly have inserted at least a caution in the brochure against the use of MER/29 in women of childbearing age. Dr. Talbot was even considering this caution without having these adverse data at his disposal. In this statement I have described my part in the MER/29 investigation and outlined the major aspects of those investigations insofar `as my involvement was concerned. I feel `that it c'an be concluded, from the evidence available, that the William S. Merrell Company withheld some important information and mis- PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4209 represented ciber important information with the result that an unsafe drug was allowed to go on the market. Thank you for your attention. If you have any questions concerning MER/29, I will be happy to answer them for you. CURRICULUM VITAE Personal data: Name: Edwin I. Goidenthal. Place and Date of Birth: Plainfleld, New Jersey, February 2, 1930. Marital Status: Married in 1950; 3 children. Education: B.S., 1952-The George Washington University, Major: Chemistry. M.S., 1953-The George Washington University, Major: Biochemistry. Ph. D., 1956-The George Washington University, Major: Pharmacology. Present Position: Acting Deputy Director, Office of New Drugs, Bureau of Medicine, Food and Drug Administration, Department of Health, Education and Welfare (July 1966 to Present). Previous Positions: Chief, Drug Review Branch, Division of Toxicological Evaluation, Bureau of Science, Food and Drug Administration, Department of Health, Educa- tion and Welfare (May 1963 to July 1966). Research Pharmacologist, Division of Pharmacology, Bureau of Biological and Physical &iences, Food and Drug Administration, Department of Health, Education and Welfare (February 1962 to May 1963). Pharmacologist, Division of Pharmacology, Bureau of Biological and Physical Sciences, Food and Drug Administration, Department of Health, Education and Welfare (April 1956 to February 1962). Research Fellow, Pharmacology Department, The George Washington University Medical School (February 1952 to April 1956). Society Memberships: `Society of Sigma XI. Society for Experimental Biology and Medicine. European Society for the Study of Drug Toxicity. American Society for Pharmacology and Experimental Therapeutics. Publications: Lamar, J. K., Jackson, 0. E., and Goldenthal, E. I., Effects of Pen.iciliin-G on the Reproductive Processes in the Mouse, Rat, and Rabbit, Fed. Proc., 1968. Jackson, 0. K., Johnson, M. L., Lamar, J. K., and Goldenthal, K. I.; Effects `of Hyd'roxyurea ~n the Axial Skeleton of `the Rat, Fed. Proc., 1967. Golden'thal, E. I.: FDA Criteria for Evaluating Safety Data, Colloquium on Drug Regulation, Washington, D.C. 1967. Goldenthal, E. I., D'Aguanno, W. and Lynch, J. F.; Hormonal Modification of the Sex Difference Following Monocrotaline Administration, Toxical and Appl. Pharmacol., 1964. D'Aguanno, W. and Goldentbal, E. I.; Studies on the Toxicity of Monocrota- tine. Fed. Proc., 1962. Goldenthal, B. I.: Determination of Monocrotaline in Biological Material, The Pharmacologist, 1961. Goldenthal, E. I., Nadkarni, M. V. and Smith, P. K.; A Study of Compara- tive Protection Against Lethality of Triethylenemelamine, Nitrogen Mustard and X-Irradiation in Mice, Radiation Research, 1959. Young, R. S., Hurwitz, L. and Goldenthal, E. I.; The Effect of Chlorambucil (CB1348) on Growth and Metabolism, J. Cell, and Comp. Physiology, 1958. Goldenthal, K. I., Nadkarni, M. V., and Smith, P. K.; The Excretion of Radioactivity Following Administration of Tri-C14-Ethylenimino-S-Triazine in Normal Mice, J. Pharmacol. and Exptl. Therap., 1958. Nadkarni, M. V., Goldenthal, E. I. and Smith, P. K.; The Distribution of Radioactivity Following Administration of Triethylenephosphoramide-P~ in Tumor-Bearing and Control Mice, Cancer Research, 1957. Nadkarni, M. V., Goldenthal, E. I. and Smith, P. K.; The Distribution of Radioactivity Following Administration of Triethylenimino-s-Triazifle-C14 in Tumor Bearing and Control Mice, Cancer Research, 1954. PAGENO="0308" 4210 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT BY ROBERT C. BRANDENBURG, DIRECTOR, OFFICE OF CERTIFICATION SERVICES OFFICE OF AssoCIATE O0MMI55I0NER FOR COMPLIANCE, FOOD AND DRUG ADMINISTRATION, U.S. DEPARTMENT OP HEALTH, EDUCATION, AND WELFARE Mr. Chairman, it is a great privilege and pleasure to appear before this Sub- committee this morning to discuss my part in the investigation of MER/29. During 1962, my duties included the direction of investigations, the evaluation of their results, and the preparation of recommendations for legal actions ap- propriate to the offenses demonstrated, if any. During early May 1962, I was assigned the dire!tion of an investigation involving the new drug, MER/29 or triparinol. This investigation had already begun in April 1962, with the inspection of the drug firm, the Williams. Merrel Company, Cincinnati, Ohio, by Supervisory Inspector Thomas Rice, Dr. B. I. Goldenthal, and Dr. John 0. Ni~stor, of the Food and Drug Administration. During May and June 1962, I had the FDA inspection force visit all William S. Merrel employees ~who had participated in these studies, and a number of other individuals Who had been concerned with animal studies of the drug. As we compared the results of these investigations and the raw data on animal studies (which we obtained from the firm), with the data on these studies sub- mitted to FDA in the new drug application, it became obvious that the submis- sions to FDA had been changed to conceal or withhold adverse effects of the drug on the test anintals. Our investigation developed leads concerning animal studies performed by other firms and individuals on MER/29, of which the William S. Merrell Oompany was aware, and I had the FDA Inspectional force conduct the indicated visits. In addition to the significant descrepancies and withholdings in animal studies which Dr. Goldentahl and Mr. Rice has dicussed, our investigations disclosed that the firm was aware of additional animal studies on the drug which showed it to be extremely toxic, and not only failed to report the results of these studies to FDA, but had actively attempted to keep some of this information from both FDA and the medical community. In one instance, by letter dated November 3, 1961, Dr. Murray of William S. Merrell, sent FDA a manuscript entitled "Lethal Effect in Dogs of Prolonged Oral Administration of Triparinol" written by Doctors Scanu, Hawk, and Page of the Cleveland Clinic Foundation. Dr. Nestor of FDA, had heard of this paper and has requested the firm to submit it. This paper reported extremely toxic effects produced by the drug in the test animals. At my request, Mr. Rice visited the Cleveland Clinic and interviewed Dr. Page on June 26, 1962. He found that the William S. Merrell Company had been ap- prised of the results of the Cleveland Clinic study in January 1960, almost two years previously. Drs. Blobm and King of the William S. Merrell Company bad actually visited the clinic sometime in March 1960, to discuss the study with those who had performed it. This investigation revealed that the William S. Merrell Company had prevailed upon those who had prepared a paper concerning the results of this study to permit representatives of the firm to edit it, since they claimed that the adverse effects of the drug found by the researchers could possibly have been caused by some other factor. Dtte to this intervention, the paper was not published until June 1962. We also learned that although no brochures, proposed labeling, or other documents submitted to FDA had referred to any blood dyscrasias produced by MER/29 in rats, the firm had actually prepared a brochure, never submitted to FDA, which did refer to this condition. Our investigations revealed that a number of these so-called "preliminary" brochures had been distributed, including one to the American Medical Associa- tion. From this brochure and from information obtained during an interchange of correspondence with the firm, the American Medical Association prepared a pro- posed monograph on MER/29 which was to appear in the 1962 edition of the book "New and Non-Official Drugs," now known as "New Drugs," which the Association publishes yearly. The interchange of correspondence shows clearly that the firm made determined efforts to baTe any reference to a blood dyscrasia in rats asso- ciated with MER/29 deleted from this monograph. We also learhed that the Upjohn Company, like Merek, Sharpe & Dohme and the Cleveland Clinic group, had conducted a M~lR/29 dog toxicity study in March 1961, which ~horWed the drug to be quite tOxic ; had notified the William S. Merrell Company of this fact by July 14, 1961; and had shown their data on this study to Dr. King of the William S. Merrell Company on July 31, 1961. PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4211 No report of this study was ever submitted to FDA. by the William S. Merrell Company. The results of our investigations were subsequently submitted to a Federal Grand Jury, and a twelve count true bill was returned on December 20, 1903, against the William S. Merrell Company and three employees, Dr. Harold W. Werner, Dr. Evert F. Van Maanew, and Dr. William M. King. All the defendants entered pleas of nob contenclere 011 June 4, 1964. The firm was sentenced to pay a total fine of $80,000, and the individuals were each placed on probation for a period of six months. Thank you for the opportunity in allowing me to discuss my part in the MER/29 investigation. I will be glad to respond to any questions which the Committee may have. AUGUST 19, 1959. To: New Drug Branch. Attn: Dr. Epstein. From: Division of Pharmacology. Subject: NDA 12-066, M.E.R. 29, The Wm. S. Merrell Co. This application lacks information on the safety of the drug in animals with respect to the selection of: (1) animals in chronic toxicity studies and (2) doses. Since the drug may be used for long periods of time, one year oral studies in rats and three month studies in dogs would be desirable. In both groups a dose causing toxic effects should be included. The evidence presented in the NDA suggests that the margin of safety of the drug is low. The chronic toxicity study in monkeys included in the application is helpful but lacks (1) a "toxic dose" and (2) enough animals to be significant, particularly for long term studies. H. MEGIRIAN. U.S. DEPARTMENT OF HEALTH, EDUCATION, AN~ WELFARE, Washington, D.C., September 14, 1959. The WM. S. MERRELL Co., Locicland Station, Cincinnati, Ohio. (Attention of Dr. Joseph Murray.) GENTLEMEN: Reference is made to your new drug application dated July 31, 1959, submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act for the preparation M. E. R.-29 (Triparanol Capsules). This also acknowledges yQur letter of August 14, 1959. The application is incomplete under section 505(b) (1) of the Act as follows: The drug is by nature one which will receive chronic use. The data you have submitted suggests a low margin of safety. We feel that the following studies are in order to demonstrate safety. A one year oral study in rats and a three month oral study in dogs should be performed. In both animal groups one dosage level should be selected to produce toxicity. We shall reserve our comment on the labeling until the foregoing has been resolved. Since the application is incomplete under section 505(b) (1) of the Act, it may not be filed as an application provided for in section 505(b). Sincerely yours, JEROME H. EPSTEIN, M.D., Medical Officer, New Drug Branch, Bureau oj' Medicine. Tnn WM. S. MERRELL Co., SCIENTwIC DIVISION, Cincinnati, Ohio, September 24, 1959. JEROME H. EPSTEIN, M.D., New Drug Branch, Food and Drug Administration, Washington, D.C. DEAR DOCTOR EPSTEIN: I have your letter of September 14 advising us our New Drug Application for M. E. R.-29 (NDA 12-066) is incompiete. We are some- what surprised by the statement that our data "suggest a low margin of safety." PAGENO="0310" 4212 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We felt we had demonstrated a reasonably high margin of safety, and after careful reevaluation of the d~ata we still feel we have demonstrated a low level of toxicity with a wide margin of safety. The dosage we are recommending for M. E. R.-29 is 250 mg. once daily. On a weight basis, this would constitute a dose range of 3.6 to 4.16 mg/Kg. The acute toxicity studies we reported showed the LD50 dose to be 1600 mg/Kg. intraperitoneally and 2000 mg./Kg. orally. We consider this to be extremely low acute toxicity. Data submitted showed no untoward hematopoietic response at dose levels used in rats or monkeys. The dose range used in rats went as high as twenty times our proposed clinical dose, and monkey dosage was ten times the proposed clinical dose. Body weight gains were not affected in rats or monkeys at doses far in excess of the proposed clinical dosage. Relative organ weight changes in rats were due to total body weight changes, and in each case histopathologic examination failed to suggest other causes for such change. Three male and three female dogs with appropriate controls have been on M. E. R.-29 for better than 3 months at 25 mg./Kg. We have evaluated bema- topoietic response, body weight and food consumption, and liver studies (serum bilirubin, alkaline phosphatase, serum transaminase, and B SP retention deter- minations). At 3 months all were within normal limits. We plan to autopsy these ~animals after 6 months to complete our records. We are agreeable to making the autopsy data available to you at that time. However, we strongly feel that the 16-month study In monkeys has more than adequately demonstrated the safety of M. E. R.-29. We would, of course, be willing to withdraw the product from the market if real toxicity problems were uncovered in our autopsy work. As I indicated, we have very carefully and objectively re-evaluated our safety data and we feel that the margin of safety demonstrated is exceptionally good for a metabolic drug. I hope this will enable you to complete your consideration of our New Drug Application for M. B. R.-29. I should greatly appreciate a telephone call if there are any further problems needing discussion. Sincerely yours, F. Jos. MURRAY. OcTonira 6, 1959. MEMORANDUM OF INTERvIEw Present: Dr. Wm. King and Dr. F. Jos. Murray, The Wm. F. Merrell Company, Cincinnati, Ohio. Dr. Ill. L. Goldenthal, Dr. R. Megirian, and Dr. B. J. Vosi, Division of Pharmacology, Food and Drug Administratiop. The visitors called to discuss their NDA 12-066, M.E.R.-29, Triparanol cap- sules, intended for lowering blood cholesterol. They have a 6-month dog study which has been in progress 5 months at dose levels of 10 and 25 mg./kg. No adverse effects have been noted. A rat study at 3 and 10 mg. per kg. has also been completed in 5 months. These tests were not included in the original NDA because no results had been obtained. We said `tbe top dose in both the dog and the rat tests should be higher. We advised starting a minimum of one group of dogs for a minimum of three months at the highest dose they could tolerate in the hope of producing some evidence of toxicity. Also, we advised starting 3 additional dosage groups of rats as the dosage employed was far too low. The rat study will go for one year. We stated the earliest that we could pass on safety was after these rats had completed 6 months. B. J. Vos, M.D. THE WM. S. MERRELL Co., SCIENTIFIC DrvIsroN, Cincinnati, Ohio, October 13, 1959. Dr. JEROME H. EPSTEIN, New Drug Branch, Food and Drug Administration, Washington, D.C. DEAR DOCTOR EPSTEIN: This will confirm our plans for meeting in your office at 10:00 a.m. on Friday, October 16, to discuss our M. B. R.-29 New Drug Application. We have once again reviewed our animal studies in the light of your Pharma- cology Division's opinion that we have not satisfactorily demonstrated safety PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4213 of the product. We, of course, continue to have confidence in the safety of M. E. R.-29, as evidenced I~y our intention to market in Canada where we have an effective New Drug Submission. As you well realize, we can ill afford to be wrong in our judgment on the introduction of any new product, and we do not feel that M. E. R.-29 is going to spoil our record. We feel that the significance of the studies carried out in monkeys has been entirely overlooked. We submitted data on three monkeys dosed continuously for sixteen months. If a new drug fails to show untoward effects in three animals, such effects would probably show up only in unreasonably large groups of twenty-five or more. Such groups are impractical and not used generally. As discussed with representatives of your Pharmacology Division, we have drug diet experiments in progress in rats at 3 mg./Kg. and 10 mg./Kg. This was set up to be a lifetime study for our own information, and because of this objec- tive we used a dose which we were sure would not interfere with eating. A second rat experiment was carried out with oral tubing for six weeks at 75 mg./Kg. and 37.5 mg./Kg. Some adrenal and liver (fatty infiltration) changes were recorded at the higher dose. If we had continued at this dose, we assume this would have led to more serious damage. However, it is obvious that this damage could have been nutritional instead of drug-induced, since food consumption decreased. A third rat study was carried out with tubing for three months at 25 nig,/Kg. and 50 mg/Kg. At the higher dose level there was a 36 per cent reduction in body weight gain in males starting in six weeks~. Again, it is our feeling that when the animals stop eating and lose weight there is no point in going on with the experiment, since nutrition enters into the picture and findings on the tissues would be meaningless. Your Pharmacology Division has insisted that it is essential to show toxicity (even though we feel it is more important to show lack of toxicity at therapeutic dosage and at reasonable excesses of therapeutic dosage), and we would like to point out that lack of eating has been a consistent sign of toxicity in the rats. On this basis, one might assume that the first clinical evidence of toxicity would be loss of appetite. This is borne out by our clinical experience. You will note that the Hollander and Chobanian paper reports four cases of nausea, epigastric distress or heartburn on a daily dosage of 750 mg. The symptoms disappeared on a dosage of 250 mg. The paper by Oaks and Lisan reports 13 per cent (5) subjects with nausea and vomiting at 1000 mg. per day. It was not necessary to discontinue the drug In these patients. No side effects were encountered at 250 mg. We again stress that the decrease in food con~ttmption in animals on moderately high doses suggests we will not be able to obtain tissue damage in animals (other than fatty infiltration of the liver) without complicating tbe picture with inadequate nutrition. I appreciate your taking the time to meet with me, and I hope we may be able to reach some satisfactory solution on this problem. Sincerely yours, - F. Jos. MURRAY. MEMORANDUM OF A CONFERENCE OCTOBER 16, 1959. Present: Dr. F. Jos. Murray, Dr. R. McMaster, The Wm. S. Merrell Company, Cincinnati, Ohio; Dr. Robert Megirian, Dr. Edwin Goldenthal, Division of Pharmacology, Food and Drug Administration; and Dr. Irwin Siegel (part time), Dr. J. H. Epstein, New Drug Branch, Bureau of Medicine. Subject: Toxicity data for M.E.R.-29, FDA 12-066. The representatives of the Wm. S. Merrell Company came in to discuss the existing differences concerning the toxicity data submitted in support of their new drug application for "M.E.R.-29." Since there is a wide difference of opinion concerning what they feel is suf- ficient data and what we feel is sufficient, it was agreed that the company would submit additional animal work in support of their application. The following types of studies shall continue or be instituted: (1) Present animal work will be continued to completion. (2) A six-month study in dogs will be run at these level(s) calculated to produce toxicity. PAGENO="0312" 4214 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (3) Rats will be run for 12 months at several dose levels, one group being a pan-fed control group to determine the actual toxicity of the drug. Results of the above studies will either be submitted at the end of three or six months for our review. JEROME U. EPSTEIN, M.D. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Washington, D.C., November 6, 1959. THE WILLIAM S. MER5ELL Co., Lockland station, Cincinnati, Ohio. (Attention of Dr. F. Jos. Murray.) GENTLEMEN: Reference is made to your new drug application dated July 21, 1959, submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act for the preparation "M. E. R.-29." We also acknowledged receipt of your additional communications dated Sep- tember 24, 1959 and October 13, 1959. As agreed upon by you and your colleague, Dr. R. McMaster, you will perform additional toxicity studies to further demonstrate the safety of this drug in chronic administration. We shall be happy to review this data when you feel that the evidence in the animal work is conclusive. We shall withhold any comment on the revised labeling until the aforementioned toxicity studies are complete. The application remains incomplete as stated in our letter of September 14, 1959. Sincerely yours, JEROME H. EPSTEIN, M.D., Medical Oy~icer, New Drug Branch, Bureau of Meduici~ne. Office Memorandum, U.S. Government. FEBRUARY 23, 1960. To: New Drug Branch: Attn: Dr. Talbot. From: Division of Pharmacology. Subject: Triparanol Capsules, MER-29 (Wm. S. Merrell Co.) NDA 12-066. The additional toxicity data submitted by Merrell have been reviewed. The orig- inal toxicity data submitted for rats included a 3 week study at 40 mg/kg/day, a 3 month study at 25 and 50 mg/kg/day and a 6 week study at 75 mg/kg/day. The consistent finding in these studies was a marked decrease in weight gain. The new data include a 9 month study in rats administered 3 and 10 mg/kg/day in the diet. No significant effects attributable to drug administration were observed with respect to weight gain, food consumption, hematology and pathology. In addition, rats were administered 20 and 40 mg/kg in the diet for 3 months. Reductions in weight gain of 15-20% In the 20 mg/kg dosage group and 32-40% in the 40 mg/kg dosage group were observed. The food ~onsumption paralleled the body weight response (15% less at 20mg/kg and 36% less at 40 mg/kg). If the concentration of the drug in the diet was not increased to compensate for the reduced food intake, the actual dosage given to the animals would have been considerably less than stated. The relative weights of the liver, heart and adrenals were significantly increased over control values at both 20 and 40 mg/kg in both the male and female rats. In the rats receiving 40 mg/kg, 8 out of 20 anImals had grossly visible opacity of the cornea at the end of the 3 month study. There was also an associated conjunctivitis. Several drugs (e.g. more potent narcotics, certain insecticides) have caused this effect in either mice or rats acutely and has been reversible. However, we would consider this observation In a chronic study of a more serious nature and something to be concerned about. Histologic examination of the cornea revealed inflammatory changes. The company states that an evaluation of the dog studies is difficult because of concomitant, spontaneously occurring diseases in their dog colony with four cases of distemper being diagnosed. Whether the effects described below were due to poor animals, distemper or drug administration would be hard to evaluate. However it is our opinion that the drug is producing some of the observed effects. Three dogs were administered 10 mg/kg of MER-29 for 4 months. No effect on the peripheral blood counts were observed and in general the weights of the animals remained constant. However, both of the male dogs in the study showed some inhibition of spermatogenesis upon histological examination. PAGENO="0313" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4215 Six dogs were administered 25 mg/kg for 6 months. Three of the male dogs died early In the study. They indicated that one died of congestive heart failure secondary to heart worm infestation, and the cause of death of the other 2 was undetermined due to post mortem changes. Two of the three dogs surviving the study had distended gall bladders but the organs were normal upon histologic examination. In the one male dog surviving the study there was no indication of an effect on spermatogenesis. Five dogs were administered MER-29 for 3 months at a dosage of 40 mg/kg/day. Three of these animals died within 6 weeks after the start of the experiment. With respect to the cause of death, they indicated that in the first dog the changes in the liver and massive interstitial hemorrhage are changes consistent with canine viral hepatitis. They indicated that the cause of death of the second animal could have been due to either the bronchial pneumonia, the acute hemor- rhagic pneumonia, or bepatic failure secondary to the necrosis and inflammatory response of the liver. Gross examination of the third animal revealed the liver dark and mottled and the entire intestinal tract edematous and hemorrhagic. Histological examination of the liver showed a general ballooning of the parenchymal cells, some disruption of the hepatic cord, areas of coagulative ne- crosis, and extensive inflammatory response. They indicated that the most likely cause of death in this animal was hepatic failure secondary to chronic inflamma- tory response and cirrhotic changes in the liver. In the two dogs surviving the study, no effect was seen in the hematological studies. Gross examination revealed the gall bladders distended and in one of the animals the liver was mottled and there was extensive mesenteric lympha- denopatby. The urinary bladder was very thick and purulent material was present in the urethra. Histological examination revealed some changes in the liver and a reduction in the number of mature spermatocytes in the seminiferous tubules, and a paucity of spermatozoa in the vas. The lymph nodes showed simple hyperplasia. As you know the clinical dose of this drug is 250 mg daily or about 4-S mg/kg. We would conclude on the basis of the animal toxicity studies conducted that there is little margin for safety with this drug. Certain changes seen in these animals appear to be due directly to the toxic action of the compound. The inhibition of the spermatogenesis in the dog, the effect on the cornea in the rat, the marked reduction in weight gain in the rats at relatively low dosages, all the liver changes, and the deaths of the animals lead us to conclude that this compound is producing toxic effects in the animals at relatively low dosages. We are not convinced that the changes observed in the dogs were due to distemper or hepa- titis, particularly since the Inclusion bodies characteristic of these diseases, par- ticularly viral hepatitis, were not mentioned. We are seriously concerned about the safety of the use of such a drug for reducing blood cholesterol. In the first place, we don't know if a reduction in blood cholesterol really helps the patient. To use a compound that is poten- tially toxic to produce such an effect is highly questionable. Besides the specific toxic potential of the drug itself, we are worried about the effects of a build-up of desmosterol in the blood. What are the long term effects of this material in the blood stream? It is certainly an abnormal condition. We do not know that perhaps desmo~terol is itself atherogenic? On the basis of the results of the studies conducted so far, we cannot see the necessity for any further animal studies. On the basis of the studies seen so far we would he opposed to this type of compound being marketed for reduction of serum cholesterol. Of course, the final evaluation of safety must be in the clinical studies. Before we release this drug for general distribution, it is our view that the company should submit results of well controlled extensive clinical studies in which the individuals have received the drug for periods of several years. E. I. GOLDENTHAL. Thu W~d. S. MEEnELL Co., Cincinnati, Ohio, February 29, 1960. Dr. EDwIN GOLDENTHAL, New Drug Branch, Food and Drilg Adi~th'dstration, Washington, D.C. DEAR Docron GOLDENTHAL: This will confirm our recent telephone discussion on the corneal opacity reported in rats in our MER/20 NDA. As I indicated, these corneal changes have now been found in the control animals. PAGENO="0314" 4216 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY These findings have been discussed with our consultant, Dr. Joel 41 Brunson of the University of Mississippi Medical School, who advises that such corneal changes are common in the laboratory rat. Dr. Brunson has studied sections of the eyes of rats autopsied at Merrell and he feels that the changes are inflam- matory and he reports the presence of acute inflammatory cells in the sections. I regret that this information was not availahie to us at the time we submitted data on corneal changes. Sincerely yours, F. Jos. MURRAY. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Washington, D.C., March 28, 1960. The WM. S~ MERRELL Co., Lockland Station, Cinci~tnati, Ohio. (Attention of Dr. F. Joseph Murray). GENTLEMEN: Reference is made to your new drug application dated July 21, 1959, submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act for the preparation "M.E.R.-29 (Triparanol Capsules) ." We also acknowledge receipt of your additional communications dated Janu- ary 26, 1960, February 4, 12, 22, and 29, 1960, and March 7, 1960. We also acknowledge receipt of a communication dated February 5, 19~O, from Maumee Chemical Co., 2 Oak Street, Toledo 5, Ohio, outlining the methods, facilities, and controls they will employ in manufacturing the new drug substance, 1-p-(beta-diethyl (aminoethyl) phenyl-1-(p~tolyl) -2-(p-chloro- phenyl) ethanol, they will supply you. We have not received any statement from Strong-Cobb-Amer concerning their methods, facilities~ and controls they will employ in encapsulating the material for you. The supplemental application is incomplete under section 505(b) (1) of the Act as follows: It fails to report the clinical studies In full detail. The reports should include detailed information pertaining to each in- dividual treated, including age, sex, conditions treated, dosage, frequency of administration, duration of administration of the drug, results of clinical and laboratory examinations made, and a full statement of any adverse effects and therapeutic results observed. As brought out in our meeting of March 7, 1960 with representatives of the Wm. S. Merrell Co., we are unable to resolve the apparent discrepancy in interpretation of the pharmacologic studies in dogs between your people and ours. Because of this dispute, because of the potential hazard of liver toxicity with this drug, and further because of the highly theoretical value of taking such a drug as MER-29 (to our minds) we are making the application in- complete until longer term clinical studies have been made utilizing periodic liver function studies to show that this blocker of intermediate cholesterol metabolism is not producing liver damage. Since the application is incomplete under section 505(b) (1) of the Act, it may not be filed as an application provided for in section 505(b). Sincerely yours, FRANK J. TALEOT, M.D., Medical Officer, New Drug Branch, Bureau of Medicine. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARR, Washington, D.C., April19, 1960. The WM. S. MERRELL Co. Lockland Station, Cincinnati, Ohio. (Attention of Dr. F. Joseph Murray.) GENTLEMEN: Reference is made to your new drug application dated July 21, 1959, submitted pursuant to section 505(b) `of the Federal Food, Drug, and Cosmetic Act for the preparation "M.E.R.-29 (Triparanol)." We also acknowledge receipt of your additional communication dated March 31, 1960. Our action in allowing this application to become effective is based solely on the evidence of the safety of the drug. All claims are on your own responsibility. PAGENO="0315" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4217 It is our understanding that liver function studies will continue to be pe- riodically carried out in all of the patients who are on long term study with this drug as discussed with your representatives Dr. F. Joseph Murray and Dr. Mc- Master personally on March 31, 1960. It is also our understanding that imme- diate report will be made to the administration `of all abnormalities developing in liver function tests in patients on long term study as they relate to this drug. We further understand that precautionary remarks regarding the advisability of periodic liver function tests will be made in the proposed brochure. In accord with the provisions of section 130.10 of the regulations and with the under~tanding that all of the conditions agreed to and listed above will be met, the application is now conditionally effective. It will be effective when you submit specimens of final printed labeling, incorporating the changes agreed to above, and when all of the other agreed to conditions are fully met. If the new drug is marketed prior to the submission to the New Drug Branch of speci- mens of such labeling, or without meeting all of the above stated conditions, the application will be considered not effective. We recommend that you give consideration to the provisions of section 502(c) of the Act by designing the printed labeling to bear information required by the Act prominently and conspicuously as compared to other words, statements, designs, and devices; and to those of section 301(1) which prohibits the use in the labeling or in any advertising of any representation or suggestion that an application with respect to the drug is effective under section 505, or that the drug complies with the provisions of this section, Paragraph (9) of the new drug application form is regarded as a commitment on your part that all representations in this application regarding the compo- nents, composition, manufacturing methods, facilities, controls, and labeling ap- ply to the drug produced until an effective supplement provides for a change or the article is no longer a new drug. Section 505(e) of the Act provides for the suspension of the effectiveness of the application if further experience and tests with the article show it to be unsafe for use or if it is found that the application contains any untrue statement of a material fact. The application may contain an untrue statement of a material fact by reason of any labeling or advertising in which you prescribe, recommend or suggest conditions of use of the drug differing from the conditions of use provided for in the application (see regulation 130.30 and paragraphs (6) and (9) of the new drug application form). The effectiveness of this application does not extend to the drug labeled with another distributor's name, or repacked or relabeled by another person, unless covered by an effective original or supplemental application. The effectiveness of this application under section 505 in no way relieves you of the responsibility for complying with all other provisions of the Act. Please submit five copies of the final printed labels and other labeling and three finished market packages of the drug when available. Sincerely yours, FRANK J. TALBOT, M.D., Medical Officer, New Drug Branch, Bureau of Medicine. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Washington, D.C., May 12, 1960. The WM. S. MERRELL Co., Lockland Station, Cincinnati, Ohio. (Attention of Dr. F. Jos. Murray.) GENTLEMEN: We acknowledge the receipt on April 25, 1960, of your communica- tion dated April 22, 1960, enclosing printed labeling pursuant to your new drug application for "M.E.R.-29 (Triparanol Oapsules)" We have completed our study of this application which became conditionally effective on April 19, 1960, and in accord with the provisions of regulation 130.10 under the Federal Food, Drug, and Cosmetic Act it is effective. Our letter of April 19, 1960, detailed the conditions relating to the effectiveness of this applicstion. Sincerely yours, FRANK J. TALBOT, M.D., Medical Officer, New Drug Branch, Bureau of Medicine. PAGENO="0316" 4218 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY U.S. DEPARTME~P O5~ I~EALPH, EDucATIo]~l, ~rtD WELFARE, Washinyton, D.C., October 23, 1961. The WM. S. MEERELL Co. Division of Richardsosv-Merrefl Inc., Locklaiui $tation, Cincinnati, Ohio. (Attention of Dr. Robert McMaster.) DEAR DOCTOR MCMASTER: This is in reference to our forthcoming meeting at 10:00 AM. on Thursday October 26, 1961 to discuss the problem adverse reactions attendant on the use of MER/29. As discussed at our recent conversations while we were both attending the American Heart Association Annual Meeting, it is our considered opinion that the meeting on Thursday must include a detailed discussion of all that is known from both experimental and clinical studies concerning the toxicity of MER/29. Since your labeling and promotional literature has repeatedly stressed the freedom from major side-effects and lack of danger connected with the use of this drug, we feel it is now necessary for you to give us the complete background information to date. Of necessity, this would include all the information concerfiing eye changes in humans and animals with reference to both the corneal and lenticular (cataracts) changes. It would include information concerning the role of MER/29 in the inter- ference with steroid hormone metabOlism and endocrine balance with resulting effects on ovulation, potency, reproduction, and response to stress. Of particular importance would be information that this drug has been shown to produce a reticulocytosis in animals which implies that it produces a compensated hemolytic anemia. Of lesser importance, but still necessary, are the ~kin and hair changes (icthyosis, thinning, color changes, and baldness). We feel that It is particularly important that you correct the information previously provided concerning the degree of cholesterol lowering activity exerted by MI43R/29. Detailed analysis of your data Indicates: (1) that the degree of cholesterol lowering effect is markedly less than you have previously indicated, (2) that the distribution of cholesterol levels on patients with heart disease in the MER/29 studies is significantly higher than that expected in the typical coronary population. These factors are important since your data indicate to us that there exists a relationship between pre-treatment cholesterol levels and the cholesterol lowering effect of MER/29. The implications are that a significant proportion of patients with coronary artery disease do not experience the degree of hypocholesteremic effect stated. In conclusion we re-emphasize the point made in the phone conversation with Dr. F. Joseph Murray on October 19th to the effect that the William S. Merrell Co. must furnish us all data concerning adverse and toxic reactions resulting from MER/29 therapy in both animals and humans. Sincerely yours, Jonu 0. NESTOR, M.D., Medical Officer, Division of New Drugs, Bureau of Medicine. U.S. Government memorandum. NOVEMBER 7, 1901. To: Division of New Drugs; attention: Dr. Nestor. From: Division of Pharmacology. Subject: MER-29, TRIPARANOL; The Wm. S. Merrell Co., NDA 12-066 (At' 1-542). We have reviewed the new data submitted. We are In agreement that this application should be suspended, but are not sure of how much help we can be on the basis of this recently ~ttbPiitted data. We were of the opinion that this application should never have been made effective because we were not sure of its safety (See our original comments 2/23/430). On the contrary, the com- pound appeared to be unsafe on the basis of the chronic animal toxicity studies. However, the data submitted by the firm might not be sufficient to support a revocation of the application. We are particularly concerned with the ability of the adrenal of patients treated with the drug to respond to stress. In animals large doses of the drug PAGENO="0317" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4219 caused adrenal enlargement with depletion of the steroids in the zona fa:scicu- lata. A recent study (Hollozy and Ei~enstein, Proc. Soc. Exper. Biol. & Med. 107, 347, 1961) shows that triparanol feeding to rats results in a reduction in the amount of corticosterone (the main glucocorticoid produced by the rat) secreted by the rat adrenal in response to the stress of surgery and bleeding. The list of publications cited by the firm to show that a dose of 250 mg. per day has no effect on the adrenals of humans is not convincing. The paper by Melby, et al., New England J. of Med. ~64, 583 (1961) refers to this dose only in a footnote and submits no data although the paper does show that the adrenal function is severely impaired on 1000 mg. per day. The paper by Ford in Progr. Cardiov. Dis. 2, 548 (1960) shows a trend towards adrenal depression but the author says it is not significant. HQwever, the original data was not given for calculation of the significance. In the unpublished paper by Ford, data are presented, and although the author states that the response to ACTIi is not significantly changed due to the treatment with 250 mg. of triparanol daily, we have recalculated this data and find it is significant at the 5% level and approaches significance at the 1% level. The paper by Rollander, et al., J.A.M.A. 174, 5 (1960) states that following treatment of 13 patients with 250 mg. of triparanol daily, there was a non-significant tncrease in the 17-ketosteroid excretion and a significant decrease in the 17-bydroxycorticosteroid excretion. The patients were not challenged with AOPH or stress in this study. This raises the question as to whether or not the pattern of steroid production ~y the adrenal may not be altered under trip~ranol therapy, so that less glucocortic~ids are secreted by the adrenals or those that are secreted are less active. So far as we have been able to ascertain whether ~r not this question has not been studied. The paper by Goodman, Avigon and Wilson presented at the First International Congress of Pharmacology, Stocltholm, 1961, may have a bearing on it `but the details are lacking. In addition, this paper does not mention the dose of triparanol to the humans nor the period of treatment. If the NDA is not suspended, we strongly recommend that a caution on impair- ment of adrenal function be included in the brochure. E. I. GOLPENTEAL. ERNEST J. UMBREGER. MEMoRANDUM OF CONFERENCE WILLTAM S. MEERELL Oo., Cincinnati, Ohio, November 13, 1961. William M. Kessenicli, M.D. John. 0. Nestor, M.D. Memo of meeting. (1) Eyes.-Cataracts, Corneal `opacities. (2) Hair.-~Los's of hair, thinning and changes in color and texture. (3) ~kin.-4cthyosis, Urticaria, Drying, scaling, and Itching. (4) Reproduction.-Impotence, Loss of Libido, Reduced Spermatogenesis, Prevention of Ovulation and conception. Abnormal offspring. Vaginal smear al- terations, temporary menstrual bleeding. (5) 4drenals.-Reduced production of adrenocorticoids with associated diminished ability to respond to stress. (6) Blood.-Hemoly'tic Anemia. Leukopenia. (7) Liver.-Fatty Metamorphosis. Transient increase in BSP retention. (8) G. I.-Nausea and vomiting. JOHN 0. NESTOE, M. D. Dnuo WARNING-MER/29 (TEIPARANOL) DEAR DOCTOR: In cooperation with the United States Food and Drug Adminis- tration, we `are writing to Inform and caution you concerning adverse effects, including some unpublished reports, associated with the use of MER/29 (Tn- paranol). Although comparatively few serious clinical injuries have been reported to date, their possible significance l's emphasized by findings from animal studies. PAGENO="0318" 4220 CO~flETITIVE PROBLEMS IN THE DRUG INDUSTRY Cataracts.-Four case's of cataracts in human's are rep'oited in patient's who have `received MER/29. One o'f these cases occurred in a patient receiving the rec- `om'mende'd dosage of 250 mg. of MER/29 `daily. Cataracts and co'rne'al opacities have also ieen produced with M~R/29 in animals. Slit lamp examinations are necessary for early detection of developing ~at~racts. For this reason such cx- a~m'ination's are indicated prior to `and periodically during therapy. Before this problem came `to `our attention, approximately one thousand per'sons being treated with MER/29 were patients of ophthalmologists. Most of them have `h'ad careful eye examinations, including use `of the `slit `lamp, before and during drug therapy. Result's on these patients will be reported to you as soon a's they are available. Hair C1van~es.-Tbe~re have been many cases `of hair loss, either baldness or thinning of h'air, ~h'anges in hair color and texture, and loss of body hair. Such hair changes may be r~late'd to the skin change's discussed below as well as `to the ey'e ch'ange~s described above. It l's reco~nmended that MER/29 therapy be dis- continued promptly at the first evidence `of h'air or skin changes `to minimize progressive effects possibly including eye injury. fl~hthyosis and other skin changes.-There are reports of skin reactions ranging from dryness, itching, and scaling to severe exfoliation, and ichthyosis. Some of these changes were `also associated with hair loss *and cataracts. It is recom- mended that MER/29 therapy be stopped Immediately if such skin changes occur. Depression of Adrenocortioal Function.-Adrenoeortie'al function depression as shown by reduced output of adrenal steroids ha's been produced by MER/29 in animals, and in man at high dosage levels. This effect has not been ruled out in humans at recommended dosage levels. Appropriate precautions should be observed if MER/29 is employed in patients with suspected borderline adreno- cortical function or in patients wh'o are subjected to stress. Other Adverse Effects.-Other adverse clinical effects reported include 4 possible eases of leukopenia and scattered cases of abnormal liver function tests, impotence, diminished libido, vaginal smear alterations, nausea, vomiting and urine test changes simulating proteinurla. At a level of 25 mg/kg per day of MER/29 deaths have occurred in some dogs `within 35 days, with liver damage In some animals. It has caused abortion and prevented conception in rodents, diminished spermatogenesis in dogs, stopped egg laying in chickens, and was a'ssumed to cause `acute intravascular hemolytic episodes in some dogs in one study. The side effects of `all types reported to us to date total substantially less than one percent of the patients treated. This includes a number of patients who have been treated with MER/29 In clinical research studies for continuous periods of more than a year, including `a few in excess of three years. In view of all reports concerning adverse effects, it is recommended that MER/29 be used only in patients who can be maintained under very close super- vision and frequent observation. Dosage should never exceed 250 mg. per day. Further studies are under way to assess more fully the incidence and serious- ness of adverse effects, with a view to a re-evaluation of the conditions and indications for use of MER/29. We will appreciate any information you may contribute from your clinical experience with MER/29. Sincerely, CARL A. BUNDE, Ph. D., M.D. Director of Medical Research. U.S. Government Memorandum. WILLIAM S. MERRELL Co., Cincinnati, Ohio, April 9, 1962. To: Administration: Attention: D'ivision of Regulatory Management. From: Cincinnati District. Subject: MER 29 investigation. As arranged in the telephone conversation between Mr. Goldhammer and Mr. Maraviglia of 4/3/62, Dr. John 0. Nestor, Dr. Edwin Goldenthal, and Supervisory Inspector Thomas M. Rice proceeded to the referenced firm on April 9, 1962. Mr. Fred Lamb, Attorney for the firm was first interviewed and given the N'otice of Inspection, copy a'tt'ached. This notice was given at 10:55 A.M., and shortly thereafter, Mr. Lamb arranged for a conference with officials of the firm and `the callers. Those present during the morning are as follows: Fred Lamb; Dr. Geor'ge 0. Sharp; Dr. F. Joseph Murray; Dr. Harold W. Werner; Dr. Carl Bunde; Dr. PAGENO="0319" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4221 Robert H. McMaster; Frank Getman; E. R. Beckwith; and Dr. E. F. Vaa Maanen. During the morning, only three of the above individuals participated actively in the discussion and were present during the bulk of the morning visit. These were Dr. F. Joseph Murray, Dr. Robert H. McMaster and Dr. Carl Bunde. The morning discussion was spent primarily in discussing clinical problems relating to the worl~ on humans, primarily between Dr. Nestor and these three gentlemen. Dr. Nestor pointed out that he was primarily interested in getting details of reports concerning adverse effects of MER 29 since February 23, 19132. During this phsae of the investigation, it was agreed that the firm had already furnished a list up to March 9, but without individual case histories. The representatives of the firm assured Dr. Nestor that these case histories would be forwarded to him. During the morning, we had a general discussion concerning the incidence and prevalence of cataracts in both the general population and in people who are treated with MER 29. At this time, Dr. McMaster informed us of two additional cases of cataracts which bad been reported to the company since March 9th. One of these was a six year old boy at the Mayo Clinic. We agreed to meet with Dr. Van Maanen after lunch to discuss some animal toxicity studies on MER 29. After lunch, we met with Dr. Van Maanen, Dr. F. Joseph Murray and Dr. Wil- 11am King in Dr. King's office. Dr. King asked us what information we desired to see, and Dr. Goldenthal advised him that we desired to see some of the raw worksheet data on the chronic studies on rats, dogs and monkeys adminiStered MER 29. First, a general discussion was had in regard to the general occurrence of cataracts in these three species who had received MER 29 chronically. Dr. King stated that in their recent dog studies, all of the dogs receiving 40 milligrams per kilogramS body weight of MER 29 developed cataracts after six and a half months of treatment, They had conducted similar studies in dogs in which the dogs had received supplemental vitamin administration, and after approximately 7 months of MER 29 administration, the compound was stopped, and the animals were given 2 gm of cholesterol per animal daily. Two of the five dogs in the study died earlier in the study. They showed all the signs typical of adrenal insufficiency. The three surviving dogs were not sacrificed and were kept on a normal control diet plus cholesterol supplement. Dr. King reported that the cataracts in these dogs appeared to be regressing. At this point, Dr. King was asked if they saved all tissues and slides from the autopsies on all of the animals receiving MER 29. Dr. King replied in the affirmative. At this point, Dr Nestor asked if they had any way of detecting MER 2' in the tissues. Dr. Van Maanen replied that they had no method for detecting MER 29 in the tissues. Dr. Nestor then asked if the eyes of the monkeys had been examined, and if they had been preserved. Dr. King checked and then replied that the, eyes had not been studied and had not been preserved. As a result of this line of questioning, we then asked to see the raw data on the monkey studies. Dr. King then got a bound notebook and showed us a monkey study on MER 29. However, the notebook produced contained a monkey study which was not included in their New Drug Application. None of the monkey identification numbers matched the numbers in the New Drug Application. During this time, Dr. Murray had sent from his office a copy of their animal data on MER 29 which was part of the NDA. On the autopsy sheet of the monkeys in the New Drug Application, it was stated that the data on the monkeys was contained in Notebook 848 R. We then asked Dr. King if we could see this notebook. Dr. King ordered this notebook produced. A reference to these monkeys labeled M25, M34, and M51 were found on page 16 of this notebook. On this page, It was stated that the monkeys were started on the drug, MER 29 on 4/7/58 at a dose of 10 milligrams per kilo body weight twice a day. From the autopsy sheets in the NDA, these three animals were autopsied in February, 1959. Dr. King was asked how this represented sixteen months of administration as represented in the NDA. At first, he was unable to explain this and later Dr. Van Maanen stated that this was a second phase of this study and that the animals had received a higher dose of MER 29 for six months prior to this. PAGENO="0320" 4222 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY At this point, it should be noted that the raw data was not recorded on separate sheet in sequence, but was reported in four separate notebooks together with many other studies. These notebooks were labeled numbers 770 R, 799 R, 848 R, and 904 R. These were bound notebooks which contained carbon copies of the original data. These originals reportedly have been filed in the firm's library. Upon review of the raw data, it was observed that animal M51, a male monkey first appeared on 6/19/58. This animal was started on MER 29 on 6/23/58. On page 19 of Notebook 904 R, it was stated that this animal was autopsied on 3/4/59. As submitted in the NBA, this animal had received sixteen months of medication with MER 29. Dr. King was asked to explain this discrepancy of approximately 8 months. He had no immediate explanation, in fact he could not explain this discrepancy. He searched through the earlier part of this study and could find no mention of animal M51. At this point, be asked one of his assistants to obtain the, original weight charts on this study. Dr. King then presented a weight chart titled Fig. 8 on three monkeys receiving MER 29 and three control monkeys. A copy of this is attached. Dr. King looked over this weight chart, and admitted that monkey M51 bad not been started on MER 29 at the beginning of the experiment (9/9/57). At this point, Dr. Goldenthal pointed out that the weight charts submitted with the NBA indicated that this animal had received MER 29 for sixteen months. In fact, monthly weights were given for this animal from zero to seventeen months. Dr. King was asked to explain this discrepancy. Dr. King then asked his as- sistants to see if they could get more information on this point. During this time, Dr. Goldenthal pointed out that on this chart (Fig 8) that monkey #49 had a severe weight loss between 45 and 50 weeks of the experiment. At this point, Dr. King's assistant brought in four additional weight charts which were titled, "Monkeys Chronic Oral Toxicity WSM 5052 (MER 29) Body Weights". (Oopies attached). Dr. King studied these charts for several minutes and then said these were the original weight charts of this monkey study. This study covered from 0 to 352 days. rt is apparent that this is only tbe last year of the study rather than the full study. On the first sheet, it is indicated that monkey #51 was started on the drug (MER 29) on day 96. Dr. Goldenthal again asked Dr. King about the severe weight loss on monkey M49 on the last sheet of these charts between days 2/5/59 and 3/5/59. Dr. King could not explain this weight loss. Dr. King and Dr. Goldenthal then looked over the notebooks to find the source of these body weights. On page 100 of Notebook 848 R, the weights for monkey 49 on 2/5/59, 2/12/59 and 2/19/59 were given. On the continuation of this study on page 18 in Notebook 094 R, the weight of monkey 34 was given at 7.5 kilograms on the day of autopsy 3/5/59. These body weights in the notebook corresponded to the weights in the fourth page of the charts. Dr. Goldenthal asked Dr. King to explain the discrepancy between this data and the data re- ported in the NDA. In the NBA, animal 49 showed a weight gain in the last month of the study rather than a weight loss. Dr. King was unable to explain this discrepancy. It shotiid be noted that this weight loss was from 9.9 kilograms to 7.5 kilograms or a loss of 2.4 kilograms equivalent to 5.3 lbs. Dr. Goldenthal asked Dr. King who prepared the four weight charts. Dr. King was also asked if he prepared them personally. Dr. King replied that be d.id not prepare the cbarts personally, but that he assumed that they were prepared by the two em- ployees named Jo Jordan and B. Umberger whose names were signed at the bot- tom of the raw data sheets. Dr. Goldenthal pointed out to Dr. King that monkey # M25 from data in the NDA was autopsied on July, 1958, monkey # M34 was autopsied on 2/19/59, monkey # M51 on 2/19/59, and monkey F49 on 2/26/59. Dr. Goldenthal asked Dr. King the meaning of the autopsy numbers. Dr. King replied that the first number 59 indicated the year of autopsy, and the second number indicated the number of the animal autopsied that year. Dr. Goldenthal asked Dr. King if the autopsy numbers were assigned in sequence as the monkeys were autopsied. Dr. King replied in the affirmative. Dr. Goldenthal then asked Dr. King why monkey F49, which the NBA states was autopsied on 2/26/59, actually had an autopsy number of 59-101, while animals M34 and M51 which the NBA states were autopsied on 2/19/59 actually bad autopsy numbers of 59-102 and 59-103. Dr. King was unable to explain this break in normal sequence. Dr. King speculated that perhaps animal F49 had been planned to be autopsied earlier than animals M34 and M51. However, no satisfactory answer was given. PAGENO="0321" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4223 We then turned our attention to pages 18 and 19 of Notebook 904 It. On these pages, It was stated that monkeys number P49 and M51 were autopsied on 3/4 and 3/5/59. The NDA states these days as 2/26/59 and 2/19/59 respectWely. Dr. King was asked to explain these discrepancies between autopsy dates and those given in the NDA. Dr. King asked who Initiated the date in the NDA and soon saw that he had initialed it. He had no explanation for this discrepancy. Dr. King then asked his assistant to see if he could get some explanation for this from the Pathology laboratory. Dr. Goldenthal pointed out that weights for these animals were given through 3/5/59 on the company's own charts. (Oopies attached.) Dr. King's assistant returned and said that hematology studies were per- formed on monkey M49 on 3/3/59, so this animal had to be alive on this date. Dr. King then assured us that this animal was sacrificed on 3/5/59 as given in their worksheet (Bound notebook 904 It) rather than on 2/26/59 as reported in the NDA. Dr. Goldenthat asked Dr. King the location of the autopsy notes in their bound notebook on monkey M34. Dr. King was unable to answer or find this autopsy information in the hound notebooks. At this point, Dr. Van Maanen questioned Dr. King as to the location of this data and stated that thd~ data should be in the notebook. Dr. King assured Dr. Van Maanen that this data was ~som'ewhere hi the notebooks, and that he would search all of the notebooks and locate It. Dr. King's assistant then came In with some information from the firm's Pathology laboratory which gave new dates for autopsy of these animals. These were on S x 8 cards, and gave autopsy dates of other monkeys in addition to those monkeys receiving MER 29. Dr. King then expialned that the Pathology lab received the tissues on the same date that the autopsies were conducted. A third date for the autopsy for animal M34 was obtained from these 5 x 8 cards, ~namely 2/26/59. From these cards also was obtained an autopsy date of 2/19/59 for monkey M51. This date agreed with that given in the NDA for monkey M51, but differed from the date of autopsy found in the raw data notebook, which was 3/4/59. From these 5 x 8 cards, an autopsy date of 3/5/59 was given for monkey nurxther M49. This agreed with the data in the bound notebook, but dif- fered from that given in the NDA which was 2/26/59. Dr. Goldenthal pointed out that on their own weight charts (copies attached) weights were given for theseS monkeys through 3/5/59. Dr. Goldenthal asked Dr. King to explain these discrepancies. Dr. King had no explanation for these discrepancies in the autopsy 4ates. Dr. Goldenthal then asked Dr. King if the charts could be borrowed reproduc- .tlon purposes. Dr. King turned to Dr. Van M~anen and Dr. Murray and ob- tained their permission to lend us these charts. Dr. King was then asked for per- mission to borrow the raw data notebooks for purposes of reproducing the data sheets. Dr. King stated that he would have to have higher authority for this. Dr. Murray consulted with Mr. Lamb, the firm's attorney, and then reported that It was against company policy to permit removal of the notebooks from the premises, `but that the firm would duplicate any pages we desire. We mdi- fated we would like copies of the following pages: Notebook 770-~R--~page 40. Notebook 770-R-~page 78. Notthook 799-R-page 16. Notebook 799-fl-page 45. Notebook 799L~R~_page 59. Notebook 799-R---~page 75. Notebook 848-It-page 16. Notebook 848-fl--page 56. Notebook 848-fl-page 75. Notebook 848-fl-page 100. Notebook 904-fl--page 18. Notebook 904-fl-page 19. These pages were to be reproduced from the originals in the firm's library, and also the firm was going to attempt to copy the carbon copies in the bound notebooks. We then left Dr. King's office, and while proceeding from Dr. King's labora- tory to the firm's conference room in the Administration Building, Dr. Van Maanen stated that Dr. King had already called the firm's librarian to locate the desired pages and start the desired reproductions. 81-280-69--pt. iO-21 PAGENO="0322" 4224 COMPETITIVE PItOELEM'S IN THE `T~Ti~ T~1UST~Et~Y Before leaving the firm, Dr. Murray stated `that Dr. Wdrtier ~csanted. to confer with us. We then met in the conference room in the Administration Building and the following people were present during the final diseussion on April 9, .1962: Mr. B. R. Beckwitb; Mr. R. H. Woodward; Dr. H. W. Werner; Mr. Fred Lamb; and Dr. F. Joseph Murray. Dr. Van Ma'anen was excused at this time to return to work and to col- lect the data which we had requested. During this final conference, Mr. Beck- with asked if we were satisfied with the results of our visit and Dr. Nestor replied that we had received the utmost cooperation and that nothing was denied us except the bound notebooks which the firm agreed to duplicate for us. We stated that w'e had discovered some discrepancies in the monkey studies which had not been explained to our satisfaction. Mr. Beekwith thereupon stated he intended to discuss this matter with Dr. Icing and get some, explanations of his own. Dr. Murray asked If we would be returning to their firm on the following day. We replied that we would like to have some answers to the questions we bad raised and we would either phone or return the following day. Inspector Rice promised to return the borrowed weight charts as soon as copies had been made. We left the plant at approximately 5 :15 P.M. Dr. NE5T0IL Dr. GOLDaNTIJAL. THOMAS M. Rica, Inspector. Bncl'osures [omitted], U.S. Government Memorandum. WILLIAM S. Mannatt Co.,. Cincinnati, Ohio, April 10, 19,62. To: Administration; Attn: Division of Ttegulatory Management.' From: Cincinnati District. Subject: 1\4ER 29. Refer to our memorandum of April 9, 1962 concerning this investigation. This is a continuation of this same investigation. On the morning `of April 10, 1962, Dr. Nestor, Dr. Goldenthal, and Supervisory Inspector Rice returned to the firm. Mr. Fred Lamb was first interviewed and be was asked if be desired another Notice of Inspection. He replied that insofar as he was concerned, he would consider this a continuation `of the inspection of April 9, 1962. At this time, a conference was `held between the callers, Mr. Fred Tiarpb, Mr. B. R. Beckwith, Mr. R. H. Woociward, and Dr. F. ~ose~ph Murray, and the weight Charts we had borrowed to reproduce were returned `to Pr. ivt~rray. These gentlemen were first asked whether or not they had uncovered any explanations for the discrepancies in the monkeys receiving MER 29 which we noticed on April 9, 1962. Mr. Beckwith replied that although they had worked late the evening of April 9th, and the morning of April 10th prior to the time we had arrived, they had still not been able to find any explanation for the discrepancies we had noticed. Mr. Beekwith asked that we set forth in detail a summary of the discrepancies we had noticed. Dr. Nestor enumerated the following points: 1. Marked loss of weight in monkey P49 during the last five weeks of the study which was not reported in the NDA, but which was in the raw data in their notebooks, and on the charts. 2. No record of any autopsy was found on monkey #M84 in the raw data recorded in `the no'tebooks. 3. The conflict in dates of autopsy for monkeys #M34, M51, and 1~49. We had found there were up to three dates given for the autopsy of some of these animal's.. The dates for the autopsies in the NDA were at variance with `the dates found on the charts, the notebooks, and the 5 x S card's kept by the Pathology laboratory. 4. The fact that monkey #M51 according to `the NDA bad been on MER 29 for sixteen months, while in the notebooks and the charts supplied by the firm, this monkey was placed on MER 29 about the midpoint in the experiment and received MER 29 for only eight months. 5. A discrepancy was noticed in the autopsy number's as to proper sequence in respect to the date of the autopsy, especially with respect to monkey #F49. PAGENO="0323" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4225 Dr. Nestor brought out the fact again that there were no studies on the eyes of the monkeys on MER 29 and these tissues had not been examined nor had the eyes been preserved. In connection with this, Dr. Nestor pointed out the great significance we had attached to these monkey studies in connection with approving the NDA for MER 29. Dr. Nestor pointed out that our Division of Pharmacology had made an issue of the Pathology in rats and dogs, and the William ~. Merrell Co. representatives had countered by pointing out that monkeys were of a higher order and, therefore, closer to man, and that their monkey studies had not demonstrated any pathology and that this was, therefore, a very strong argument for making their NDA. effective. Dr. Nestor further pointed out that had the Food and Drug Administration known of these discrepancies in the monkey studies, it was conceivable that the NDA would never had been made effective. Dr. Nestor stated that we desired to make some further checks on raw data of the monkeys, and in particular we desired to review any data they had in regards to the feeding of the monkeys. Dr. Nestor stated that in particular, we were interested in any notes which could be located which wOuld bear upon any abnormalities observed in connection with monkey #F49 which had lost so much weight during the final month of the studies. Dr. Nestor stated that we were interested particularly in any notes regarding the monkeys appetite, activities, and any evidence of illness. At this point, Mr. Beckwith arranged for us to interview Dr. King again in his office, and asked that we return and see him prior to leaving the firm. We then proceeded to Dr. King's office with Dr. Murray, and Dr. Van Maanen. Dr. King was then interviewed and he was asked whether or not he had been able to account for the discrepancies which we had observed the previous day. Dr. King stated that up to this point, he has not been able to explain any of these discrepancies. At this point, we again checked the data on monkey #~49 to be sure that there was no misunderstanding on our part concerning the duration of the experiment, the weight 1o~s, and the dates. We found our previous understanding to be completely correct, and although Dr. King attempted to convince us that there had been an error on projecting the data onto the charts and that the loss of weight was small, he finally had to admit that our figures were correct, iii that monkey P49 had lost 2.4 kg. during the last 5 weeks of the study: Dr. King then recalled that monkey P49 had lost considerable weight toward the end of the experiment and that he would attempt to find some notes to explain what happened. Dr. King was asked for any records or notes he might have of observations concerning the feeding of the monkeys on this MER 29 experiment. Dr. King said that he could not recollect whether or not they had any such records, but he had a hazy memory that there was something. lie said that up to this point, he had not been able to locate any such records, but that he would continue searching for such. Dr. King said that it was very difficult to keep an actual record of food consumed beeau~e the monkey threw the food around a great deal, making c~ileu- lation of food consumed very difficult. Dr. Nestor asked Dr. King the name of the employee who had secured the charts for us yesterday. Dr. King said that this was one of his assistants and his name was Fred Hoithaus. Mr. Holithaus came in briefly during this interview. Mr. HoIthaus said that he had been employed by the firm during the time the MER 29 studies were being conducted, but be was in a different department, and knew nothing of the studies himself. He said he had been working with Dr. King since June of 1059. Dr. Nestor then asked Dr. King as to the whereabouts of Jo Jordan and B. Umberger whose names appeared at the bottom of the raw data charts in the bound notebooks. Dr. King said that he bad heard nothing from Jo Jordan for sometime and did not know her whereabouts, but B. Umberger had left the firm to attend Ohio State University at Columbus~ Ohio. He said neither of these employees were with the t~rm at this time. Also, we inquired as to Mr. J. K. Smith whose name appeared at the top of the raw data charts in the bound notebooks. Dr. King stated that Mr. Smith was his predecessor. He said that Mr. Smith left the firm In June, 1059. HG said Mr. Smith is now with Riker Laboratories In North Ridge, California. Dr. King stated that he joined the firm in September of 1958 and was definitely in charge of the MER 29 studies at the close of the experiment. He admitted that he personally had con- ducted all of the autopsies. PAGENO="0324" 422~ COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Pvior to leavingthe firm, we retutned to the conference room in the Administra- tion Building and conferred with Mr. B. R. Beckwith, Dr. Harold W. Werner, R. H. Woodward, Fred Lamb, and Dr. F. Joseph Murray. We told these gentlemen that we had not been able to find any notes regarding the food consumption and observations made on the monkeys, and that Dr. King still had not been able to offer any explanation for the discrepancies noted. Mr. Beckwith reconfirmed his earlier statements of their intention to explore this very thoroughly to try to find answers for their own satisfaction. Mr. Beck- with also stated that he would try to get all of the copies of the records we desired as soon as possible. Du. JOHN 0. NESTOB. Da. EDWIN GOLDENTHAL. THOMAS M. RICE, $upervisOr7/ Inspector. Enclosure (omitted]. U.S. Government Memorandum. WILLIAM S. MERRELL Co., Cincinnati, Ohio, Aprii 11, 1962. Division o~ Regulatory Management, Attu: Mr. Goldha;mmer. Division of Pharmacology. MER-29 Investigation (AF 1-942). Along with Dr. Nestor of Division of New Drugs and Thomas K Rice of the Oincinnati District, I visited the William S. Merrell Company in Cincinnati, Ohio on April 9 and 10 and copies of our memoranda of thes'e visits have been directed to you. As will be noted in these memoranda, certain discrepancies between the original chronic monkey studies submitted in their new drug application and those found in their data notebooks have been disclosed. These discrepancies are not mistakes on the part of the William S. Merrell Company, but represent the submission of fraudulent and misleading data to FDA. The net effect of this misleading data was to make the drug appear less toxic In monkeys than was actually the case. This is particularly significant since at the time of our con- sideration of the NDA, representatives of the William S. Merrell Company pre- sented strong arguments against the toxicity observed in rats and dogs in that a higher species, monkeys, which are closer to man than rats or dogs, showed no signs of toxicity upon chronic (16 months) administration of MER-29. These discrepancies uncovered in our recent visit support the affidavit of Mrs. Jo Jordan in that fraudulent data was submitted to FDA on the monkeys admin- istered MER-29 chronically. On the basis of the affidavits of Mrs. Jo Jordan and Mr. Bruce Umberger (former employees of the William S. Merrell Company) and of the numerous discrepancies disclosed in Merrell's monkey study on MER-29, we strongly recommend that NDA 12-066 be suspended. In addition, we feel that sufficient evi- dence has been obtained to support prosecution of the corporation and the individuals involved and would recommend such action. EDWIN I. GOLDENTHAL, Ph. P. United States of America Department of Health, Education, and Welfare FDC-D-71 In the Matter of MER/29 (triparanol) capsules. New Drug Application No. 12-066 WM. S. MEERELL COMPANY, CINCINNATI, Onio, APPLICANT SUSPENSION ORDER Wm. S. Merrell Company, Cincinnati, Ohio, the applicant for and the holder of effective New Drug Application No. 12-066 applying to MER/29 (triparanol) capsules, having requested the suspension of the effectiveness of said application, on the ground that clinical experience shows the drug is unsafe for use under the conditions of use upon the basis of which the application became effective and thereby having waived Notice of Hearing as provided by Section 505(e) of the Federal Food, Drug, and Cosmetic Act, prior to such suspension; PAGENO="0325" COM?ETIT~VE PROBLEMS IN THE DRUG INDUSTRY 4227 The Commissioner of Food and Drugs, by virtue of the authority vestea In the Secretary by the provisions of the Federal Food, Drug, and Cosmetic Act [Section 505(e); 52 Stat. 1052; 21 U.S.C. 355(e)] and delegated to `the Commis- sioner by the Secretary (20 FR 1990) finds that clinical experience shows that MER/29 (triparanol) capsules are unsafe for use under the conditions of use upon the basis of which the application became effective; Wherefore, on the foregoing finding of fact and the request of the applicant, the effectiveness of New Drug Application No. 12-066 applying to MER/29 (triparanol) capsules is suspended, effective May 22nd, 1962. Dated May 22, 1962, at Washington, D.C. G. P. LARRICK, Commissioner oj' Food and Drugs. THE WM. S. MERRELL Co., Cincinnati, Ohio, December 1, 1961. Dxuo WARNING-MER-29 (T1urABAN0L) DEAR Docron: In cooperation with the United States Food and Drug Admin- Istration, we are writing to inform and caution you concerning adverse effects, including some unpublished reports, associated with the use of MER/29 (tn- paranol). Although comparatively few serious olini0al `Injuries have been reported to date, their possible significance is emphasized by findings from animal studies. Uataracts.-Four cases of cataracts in humans are reported in patients who have received MER/29. One of these cases occurred in a patient receiving the recommended dosage of 250 mg. of MER/29 daily. Cataract and co'rneal opacities have also been produced with MER/29 In animals. Slit lamp examinations are necessary for early detection of developing cataracts. ror `this reason such exam- inations are indicated prior to and periodically `during therapy. Before this prob- lem came to our attention, `approximately one thousand persons being treated with MER/29 were patients `of ophthalmologists. Most of them have had careful eye examin'ations, including use of `the slit lamp, `before and during drug therapy. Results on these patients will be reported to you as soon as they are available Hair Changes.-There have been many cases of hair loss, either baldness or thinning of hair, changes in hair color and texture, and loss of `body hair. Such hair changes may be related to the skin changes discussed below as well as to the eye changes described above. It is recommended that MER/29 therapy be dis- continued promptly at the first evidence `of hair or skin changes `to minimize progressive effects possibly including eye injury. Iekthyosis and other skin changes.-There are reports of skin reaction ranging from dryness, itching, and scaling to severe exfoliation, and ichtbyosis. Some of these changes were also `associated with hair loss and cataracts. It is recom- mended that MER/29 therapy be stopped immediately if such skin changes occur. Depression of Adrenocortical Function.-Adrenocortical function depression as shown by reduced output of adrenal steroids has been produced by MER/29 In animals, and in man at high dosage levels. This effect has not been ruled out in humans a't re'commeiided dosage levels. Appropriate precautions should be ob- served if MER/29 is employed in patients with suspected borderline adrenocor- tical function `or in patien'ts who are subjected to stress. Other Adverse Effects.-Other adverse clinical effects reported Include 4 pos- sible cases of leukemia and scattered cases of abnormal liver function tests, im- potence, diminished libido, vaginal smear alterations, nausea, vomiting and urine test changes `simulating protoinuria. At a level of 25 mg/kg per d'ay `of MER/29 deaths have `occurred in some d'ogs within 35 days, with liver damage in some animals. It has caused abortion and prevented conception in rodents, diminished spermatogenesis in dogs, stopped egg laying in chickens, and was assumed to cause acute intravascular hemolytic episodes in some dogs in one study. The side effects of all types reported to us to date total substantially less than one percent of the pa'tients treated This includes a number of p'atients who have been treated with MER/29 in clinical research studies for continuous period's of more than `a year, includIng a few in exce's's ~f three ycars~ In view of all reports concerning adverse effects, It is recommended `that MER/ 29 be used early in patients who can be maintained under very close supervision and frequent observation. Dosage Should never exceed 250 mg. per day. PAGENO="0326" 4228 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I'urtiher studies are under way to assess more fully the incidence and serious- ness of adverse effects, with a view to a re-evaluation of the conditions and indi- cations for use of MER/29. We will appreciate any information you may con- tribute from your clinical experience with MER/29. Sincerely, CARL A. EUNDE, Ph. D., M.D., Director of Medical Research. U.S. Government Memorandum. WM. S. MERRELL Co., Cincinnati, Ohio, February 13,1962. To: Bureau of Field Administration. From: Cincinnati District. Subject: MER 29; NDA 12-066; NDA 13-320. For your information in connection with your consideration of the status of this new drug, the following interesting sidelight was recently encountered: Mrs. Jo Jordan, who is the wife of a member of the same car pool of Inspector Rice, formerly worked at the Wm S. iVierrell Company under Dr. King. She ~worked about two years ago during the time when the research was being done on the Mer 29. Mrs. Jordan suspected that Dr. King falsified the records on the animal studies concerning the Mer 29 to make the reports look good. After about one year working in the animal testing laboratories under Dr. King, Mrs. Jordan resigned her job `because of dissatisfaction with the way Dr. King was running the work She feels very strongly that Dr. King was dishonest In his dealings with her and had no qualms about doctoring up the results of `the studies. ThoMAs M. RICE, supervisory Inspector, Cincinnati District U.S. Government Memorandum. WILLIAM S. MnimuLL Oo., Cincinnati, Ohio, February 27, 1962. To: Bureau of Field Administration. From: Cincinnati District. Subject: Mer 29. In response to your memo of February 23~ 1962, Mrs. Jordan was interviewed the evening of February 26 and the following information was secured. Mrs. Jo Jordan presently resides at 3825 Trebor Dr., Cincinnati 36, Ohio. She was somewhat reluctant to discuss the events which occurred while she was working at this firm, but agreed to do so provided the information was kept strictly confidential. Mrs. Jordan is a graduate of Holmes High School in Covington, Kentucky. Following this, she worked one year in a hospital In the field of nursing, and worked with Dr. C. J. Hudson, who is an oral surgeon for six years. She worked as a technician at Wm. S. Merrell Co., of Cincinnati, Ohio for approximately 2 years during 1957 and 1958. She was under the direction of Dr. William J. King, during `the latter part of tltis period, and it was during this time that she was engaged in the study in toxicology on Mer 29 using monkeys. Mrs. Jordan's duties included bleeding the monkeys, running blood counts, assisting with autopsies, making up capsules of Mer 29 and placebos for the control groups, assisting with d~sing both control groups and drug groups by poking the respective capsules down the throats of the monkeys, weighing food the monkeys ate, weighing the monkeys periodically, checking the monkeys re- actions, preparing the graphs following autopsy, etc. She recalls that Mer 29 was used on this toxicological study for a number of weeks. There were three or four monkeys In the drug group and a similar number in a control group. Mrs. Jordan carefully weighed up the capsules containing the Mer 29 for the drug group, and prepared similar capsules containing sugar for the con- trol group. The capsules of sugar were poked down the throats of the con- PAGENO="0327" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4229 trol group in the same manner as the Mer 29 was poked down the throats of the drug group so that the same irritation would be present in both groups. At the close of the study, Mrs. Jordan had to work up graphs depicting the observations and took these to Dr. King. He asked which were the control monke~ys and which were the drug monkeys. Dr. King's superior, whose name was not specifically recalled at this time, but which starts Dr. Vaughn or Dr. Van, decided to throw out a drug monkey and replace it with another control monkey which was never on the drug prior to autopsy. Mrs. Jordan said the one monkey that was thrown out at the end of the experiment and was never autopsied was doing very poorly after being on the drug. She said you could tell by the expression of the monkey, his' actions, the expression in his eyes and his disposition. This monkey had become somewhat mean and acted angry. Mrs. Jordan believes that if this monkey had been left in, the results would have been very unfavorable. She said this monkey was definitely sick, that the eyes did not look right, and that the monkey laid on the bottom of the cage. She said because of the decision to take this monkey out of the drug group, that it was necessary for her to work up the charts three dif- ferent times. She said that Dr King went along with the decision of his superior 100% and ordered all of those who worked on the monkeys never to mention it. The workers were told that this was the way the company wanted it and just to forget it. Mrs. Jordan said that the following individuals were also in on this ex- periment, and all of these individuals are no longer employed at Merrells. 1. Dorthy Miner: This individual is now in Florida and her address is not known. Her job was primarily preparing and staining slides. 2. Mary Ann Stephens: She is now married and her married name is not known. Her duties involved drug work, but she did not work directly with the monkeys. 3. Mike: Mike?s last name is not known~ This individual quit and went hack to school. His primary duties were taking care of the monkeys. 4. Bruce Umberger: This individual is now living in Columbus, Ohio, but hi~ exact address is not known. This individual did the same work as Mrs. Jordan. One of his duties wa~ to weigh the monkeys that Mrs. Jordan was unable to catch. Mrs. Jordan also knows that on a number of occasions the capsules of Mer 29 were not actually given to the drug `monkeys because they became very leery and were difficult to catch and hard to force the capsules down their throats. She knows that the reports were simply marked to the effect that the drugs were given, but `since she is the individual who made' up the capsules for the experiment, she knows exactly how many she made and knew that all of them were not used which were supposed to have been used. Mrs. Jordan stated that Dr. King was an alcoholic and frequently was drinking on the job. Personally be owed money to Mrs. Jordan at the time she resigned her position becaCse be did not `repay her for supplies purchased for some of the experimental work. She resigned because she became "fed up" with the manner in which Dr. King was operating this research facility. ThoMAs M. Rica, Buperoisory Inspector. U.S. Government Memorandum. WILLIAM S. MEaRELL Co., Cincinnati, Ohio, March 14, 1962. To: Bureau of Field Administration; Attention: D. C. Hansen. From: Cincinnati District. Subject: Mer 29. In response to your memorandum of March T, 1962, we have, now interviewed Mr. Bruce I. Umberger, Columbus, Ohio, and have secured from him the enclosed signed affidavit. This three page affidavit was worked up the evening of March 12, 1962. Inspector Rice interviewed Mr. Uiniierger alone. The affidavit was finally completed, sworn to by Mr. TJmberger, and signed shortly after midnight so tile affidavit is dated March 13, 1962. Prior to signing the affidavit, M~. Umberger was formally sworn by bavi~g him hold up his rig~t hand and swearing that the affidavit he was about to sign wa'strue.. PAGENO="0328" 4230 COl~~ETITIVE PROBLEMS IN THE DRUG INDUSTRY Following Mr. Maraviglia's phone conversations with you on March 13, 1962~ Mrs. Beulah L. Jordan was again Interviewed the evening of March 13, 1962. Inspector Rice interviewed her in the presence of her husband, Mr. Carson F. Jordan. X$uring this interview a four page affidavit was drawn up, sworn to, and signed by Mrs. Jordan, and this is also enclosed. Prior to her signing this affidavit in the presence of her husband and Inspector Rice, she was sworn by having her raise her right hand and swearing that the affidavit she was about to sign was true. Mr. Tjmberger is presently the assistant manager of the Broad-Lincoln Hotel~ 631 East Broad Street, Columbus, Ohio. He also resides at this same address. He was employed at the Wm. S. Merrell Co., Cincinnati, Ohio, in the Toxicological Laboratory from September 1957 to September 20, 1959. Mr. Umberger is single,. and was in the Army for three years subsequent to his graduation from Annville High School, Annville, Pa., in 1954. Mr. Umberger left the Wm. S. Merrell Co. in order to register for college in the Ohio State University College of Veterinary Medicine. He recalls that he left the firm Friday, September 20, 1959, because he had to matriculate at Ohio State University on September 25, 1959. Mr. Umberger had planned to continue through schOol under the G.I. Bill, but because one of the checks was delayed he was forced to withdraw after two quarters because of financial problems~ Mr. Umberger was not dissatisfied with his job at the Win. S. Merrell Co. and would be interested in going back to work for them. He is not certain at this time whether or not he would be able to dO this since he left the firm at a rather inopportune time. It was learned in the subsequent interview with Mrs. Jordan that Mr. Umberger got along very well with Dr. William M. King. Incidentally, Dr. King's name was incorrectly reported as "Dr. William J. King" in our memorandum of February 27, 1962. With regard to the Mer 29 toxicity studies on monkeys, Mr. Umberger knows that the experiment ran approximately 18 months. He knows that it involved from ~ to 8 monkeys of which 3 wë~re in the "drug" group, and the remaining 3 or 4 were in the "control" group. He knows that S control monkeys and 3 drug monkeys were carried through the entire experiment, while one each of the control and drug monkeys were autO1~sled approximately 6 or 7 months after the start of the experiment. His duties included conditioning the n~onkeys for 6 weeks to 3 months before they were placed on the experiment. ~Fhis included assisting in treating the monkeys for dysentery if this was needed, and in holding the monkeys when they were `given penicillin shots and teSted for TB. He also, weighed, handled, and observed the monkeys during their period of acclimation to m'ake certain they were healthy `animals `and entirely suitable for the program. After the monkeys were `placed on test, he helped hold the monkeys when they were given the capsules so that the capsules could be pushed down their throats. In order to dose a monkey, it was sometimes necessary for Mr. Umberger to hold the monkey's hands behind the monkey's back with one band while limberger forced th~ monkey's cheeks' between the monkey's upper and lower jaw with bi~ other band. In this way the capsules could be placed in the back part of the monkey's mouth a~nd pushed down the monkey's throat so the capsules would have to be swallowed. The monkey's throat was then massaged to make sure the capsules actually were swallowed. During the course of this experiment on Mer 29 Mr. Umberger carefully observed the monkeys and helped in making notes and observations. Mr. Urn- berger recalled that these observations were recorded with a carbon copy in a book together with the recor~ings of the drug and placebo doseage's and the weights of the monkeys. In the subsequent interview with Mrs. Jordan, she revealed that this duplicate record in the hound book was ke'pt in this fashion for the rat studies on Mer 29, but that the re~ords for the monkey studies were recorded 1~ ink In a loose leaf 8.~ring slack notebook. Laboratory records were retained in the laboratory. The monkeys were kept track of `by having numbers tatooed on their' stomachs, and thus some of the control monkeys could be used lu later experiments. The laboratory records then would have a complete his~ory of every monkey and would have the history of previous or subsequent experiments. Mr. Umberger was very much interested in the, monkeys, and was skilled in earing for them and training them. During the course of the experiment he PAGENO="0329" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4231 trained the monkeys to jump from their cages into a box for weighing, and after being weighed to jump back into their cages. The monkeys were weighed weekly. Mr. Umberger noted that toward the end of the experiment one of the male drug monkeys developed an Inability to land in the box when he jumped from the cage as if he did not see properly or was sick. He also had to help this monkey back into his cage after weighing. In subsequent weighings Mr. Umberger had to help this monkey into the box and back into the cage. Mr. Umberger also noted that this monkey got to the point where he would not react normally when he put his hand on his head. Normally a well monkey would be very much aware of any `attempt to place a hand on his head and would have drawn `away, but this monkey got to the point where he would not do this. 1VTr. Umberger stated that this monkey was inltially a well and active m'onkey when placed on the Mer 29. After this the monkey first developed a higher degree of activity. This was eventually followed by `the monkey becoming very much less active than normal. Mr. tJniberger noticed thiS sub-activity l~rst started when the monkey began chewing on his i'nn~r cheek. Mr. Umberger does not recall speci. fically the weight of this monkey, but it was not a particularly large monkey. He estimated that this monkey weighed from 12 to 16 pounds. Mr. Umberger got to know the monkeys very well during this period the experiment was in progress because he took a particular interest in the work and was usually in the room with the monkeys by hi'tnself. A't the close of the experiment he assisted with `the autopsies of the monkeys. Be understood that this completed the study. He did not participate in working nip `the final data. He does not recall anything particularly unusual about the autopsy of the monkeys, but he does n'ot `recall specifically `that the sick monkey men- tioned earlier was autopsied. The remarks with respect to the actions of the sick monkey and the fact that he failed to land Iii the box when he jumped from the cage would have been recorded on the laboratory records, `according to Mr. tJmberger. During the first part of this experiment his supervisor was Mr. James Knox Smith, and he traiued Mr. Umberger In the care of the monkeys and insisted that any observations of this kind be properly recorded. Mr. Smith left the firm a few months prior to Mr. Umberger's leaving.. Mr. Umberger said that Mr. James Knox Smith left the firm because he was offered a chance to start up a new toxicity laboratory at the iiteichert Company In Los Angeles, Calif. He said this firm is a subsidiary of BexalL Mr. TJmberger said that Dr. William King replaced Mr. Smith. He said Dr. King ~tvas a pathologist that was just out of school. Mr. Umberger said he did not know for sure `that the sick monkey was included In the final data. Since he had not participated in working up the final da'ta submitted there would have been no reason for the firm to confide In Mr. Umberger that there had been a substitution. Mr. Umberger's observations about this sick, male, drug monkey were, made because of his general interest for the welfare of all the animals which were used In all studies. These observations did not appear to be particularly alarming to him from the standpoint of toxicity and he is quite certain that this monkey continued to be dosed until the termination of the experiment. Mr. Umberger also recalls that toxicological studies were made on dogs. He does not recall anything specific or unusual about these studies but believes there were at least two experiments on dogs, with Mer 29. HIs duties included condi- tioning the dogs prior to placing them on test, and weighing, feeding and generally caring for them. He knows that approximately 6 dogs were in a "drug" group an.1 approximately 4 dogs In a "~ontrol" group. He also aseisted In the autopsy of the dogs. He does not recall anything unusual about the autopsies of the dogs. Mr. tTmberger also participated in Mer 29 studies on white rats. These also were considered routine and he does not re~a1l anything unusual or specific about these studies. He had approximately the same duties with respect to the white rat studies `that he had with the dog and monkey studies. He does not recall the length of time the dog and white rat studies required. Mr. Umberger remembered that twowomen technicians helped with the experi- ment with monkeys on Mer 29. These were as follows: Mrs. Carol Root: Mrs. Root left the firm early in the experiment. There was some doubt in Mr. Umberger's mind as to whether or not Mrs. Root was actually present at the start of this experiment on monkeys. Mrs. Jo Jordan: Mr. Umberger said that `this woman's name was really Beulah, PAGENO="0330" 4232 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY but that everyone called her "Jo". He said that Mrs. Jordan also left the firm several months before he did. In the interview with Mrs. Jo Jordan, it was determined that her correct name Is Mrs. Beulah L. Jordan. Mrs. Jordan is the wife of Carson l~. Jordan, and they currently reside at 3825 Trebor Drive, Cincinnati 36, Ohio. Mr Iordan works in the engineering department of the Telephone Co. He is the one who rides in the same car pool with Inspector Rice. He was present at the time of all the interviews with Mrs. Jordan at the time of her being sworn, and signing the submitted affidavit. The Jordans have an unlisted phone number, and it is 891-6365. Mrs. Jordan was employed as a technican in the Toxicological Laboratory of the Wm. S. Merrell Co., Cincinnati, Ohio for approximately 2% years from the fall of 1956 to the early summer of 1959. During this time she assisted in the toxicological study on Mer 29 using monkeys. She now recalls that `this experi- ment ran approximately 16 to 18 months, and it involved 6 to 8 monkyes of which 3 or 4 were in a "control" group and 3 Or 4 were In a "drug" group. She now recalls that 8 "control" monkeys and 3 "drug" monkeys were carried through the entire experiment, while one of each group was autopsied after approximately 6 or 7 months. Her duties included bleeding the monkey's, running blood counts, assisting with the autopsies, making up capsules of Mer 2~ and placebo's for the respective drug and control groups, assisting with dosing both control groups and drug groups by pushing `the `respective capsules down the throats of the monkey's, making notes about the food `the monkeys either ate or refused t'o eat, weighing the monkeys weekly, checking `the monkey's' reactions, preparing weights graphs after each week and after autopsy, and weighing each organ at autopsy. During the course of experiment notes of observations m'ade were recorded in ink in a loose leaf 3-ring `black notebook, together with the `recordings of the drug and placebo d'os'eages and weights `of the monkeys. This o'oteb'ooit was always retained in the laboratory `and was never turned in to the firm's rOcord office. Phi's was a continuing record of `any animal's used, and since most of the control animal's would n'ot he `autopsied they may be used In later experiment's. ~Eacli of the monkeys was assigned a number `so that a complete history of each monkey would be in this laboratory notebook. In `the case `of the monkeys the food eaten wa's no't weighed because the eating habits o'f the monkeys were `s'uch that they would not necessarily eat any given weighed out `amount. ~lstimates `of the food eaten however were made, `and `any observation's `of `the eating habits were entered `on a separate sheet and maintained in a separate loose leaf notebook. This was also always retained in the labora- tory. t~uring the first part of the experiment on Mer 29 Mrs. Jordan was under the direction o Mr. James K'n~x `Smith, `bu't toward the end `of the experi.~en't he was replaced by Dr. William King. Mrs~ Jordan noted that toward the end of the experiment one male monkey was `sick `and wa's doing very poorly, and had, lost considerable weight. $he recalls that `at the end `of the experiment he probably weighed n~o more than 8 or 9 pound's., `and had lost . approximately 5 pounds or more during the course `of the experiment. Also this sick male monkey had become somewhat mean `and `acted angry during the experiment. Originally he `bad been a healthy a~tive monkey, After being put `on the drug he first became more active than usual, but as time wore on be became very in- active and lay on the bottom `of the c'age. She knew from the expression in hi's eyes `and hi's `disposition `tha't `he wa's very ill. She knew tha't he w'a~s the `o'nl~ mon- key that could not jump from hi's cage into the box for weighing `and `back into his cage after weighing. During the first part of the experiment this. monkey could also do this very easily. She knew that on one occasion this monkey tried to jump in the box `and ml'~~ed the box entirely. A't the close of the experiment it was `her duty to wark~ up `the weight graphs `and show them `t'o her superior, Dr. King. lie in turn discussed this with his superior, Dr. ~. ~. Van M'aanen. Dr. Van M.aanen, with the concurrence `of Dr. King, then decided to throw `out the `sick male drug monkey mentioned a'bov'e from the experiment and substitute another control monkey in his place which had ~never been on Mer 29. The male monkey substituted weighed about 18 or 20 pounds, Thi's would be `about 10 pounds more tha'n the sick monkey for which he was substituted. Apparently this monkey had originally been about the `same size as the sick monkey for which be was substituted, that is he originally was the same `size as the sick m'onkey originally was at the `start `of the experiment. After PAGENO="0331" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4233 this decision Dr. Van Mannen called Mrs. Jordan into his office and instructed her to make this substitution in working up the weight charts. Because `of this decision it was necessary for her to make up the charts three different `times. Al- though Mrs. Jordan was `present during the autopsy of `all of the monkey's and the substitute monkey used In her charts, the sick male drag monkey was never autopsied in her presence. She knows that the weight charts would have been very much different had data from the sick male monkey been retained In the final reports. She knows that this `sick monkey had a weight loss from a'pp'roxi- m'ately 13 pounds at the `start of the experiment to approximately 8 pound's at `the close `of the experiment. Mrs. Jordan resented being asked to make this substitution and render a false report, and refused to sign her charts. Dr. King ordered her to never mention the substitution. She was told that this was the way the Oompany wanted it and to forget it. She w'as told that this order had come from higher up and there was nothing she could do about It but obey the order and do as the "higher-ups" wanted. Mrs. Jordan also knows that during this experiment `the capsules of Mer 29 were not given to the drug monkeys as they should have been on a number of oc- casions. She has no record of how often this was, but knows this did happen sometimes over a weekend. This came `about ~ecause other people in other groups would be called In to `work relief shifts in place of the regular employees of her group on a weekend. She was the one who' weighed up the capsules and prepared them specially for each individual drug monkey. She prepared these Mer 29 capsules for a week `at `a time. She prepared just enough capsules to last one week until the monkeys were weighed again, after which it might be necessary to change the capsule to conform to the monkey's new weight in terms of milli- grams per kilo body weigh't. In her routine the monkeys would ordinarily b~ weighed on a Friday, but the new calculations would not be made until Monday. Thus `she made up the capsules on a Monday, and made enough so that there would be one capsule left to dose the following Monday morning until the new calculation's could be m'ade. She noticed that sometimes there would be ~ or ~ capsules remaining on Monday morning Indicating that the monkeys had not been d'osed on Saturday or Sunday as they should h'ave been. She knows that during the experiment the monkeys on the drug became difficult `to catch for dosing and became very "leery" of anyone who tried to catch them and dose them. She believes that this would explain why the weekend relief employees may not always have been able to catch and dose the monkeys. She knows tha't the charts were always marked as if the capsules were given however. Mrs. Jordan also participated in similar studies on dogs and white rats In- vo'lving Mer 29. She had similar duties in respect to these studies but she noticed nothing unusual about `the conduct of these dog and white rat studies. She also participated in the auto'psies of dogs and white rats, and worked up the ~*ei~ht charts at the close `of these experiments. She knows that in the case of the rat studies duplicate weight reco'rds were kept in the laboratory by means of record- ing the data in a bound book with a carbon paper between two' pages. Phi's w'as not the case, however, with the monkey and dog studies. She reported that other employees who helped wi'th the monkey studies were as follows: Bruce Umberger: This employee was still with the firm a few months after she left but is no longer with the firm now. She knows that he lives in Columbus, Ohio. She knows that hills `duties included conditioning and handling the monkeys prior to the `start `of the experiment. She knows that he helped autopsy the monkeys at the close `of the experiment, `and during the studies he helped weigh, dose, observe, and care for the monkeys. He was very much Interested In the monkeys and spent a great deal of time wi'th them, and he helped ~rntch the monkeys and was working with them all the time. She knows that he had nothing to do with working up the final data at the close of `the experiment on the monkeys, an'd thus s'he d'oes not jjelieve that he would~ have known of the `substitution of the control monkey for the sIck, male, drug monkey. She knows that Mr. Urn- berger also did similar work with respect to the studies on the dogs and the~ white rats. Dorothy Miner: This individual is also no longer associated with, the firm and Mrs. Jordan knows that she left the firm one month to a month and a half after she did. Dorothy Miner is presently in the State of Florida but Mrs. Jordan does no't know her exact address. She knows that she was employed during the Mèr PAGENO="0332" 4234 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 29 studies on monkeys. Her job was primarily the preparation and staining of slides. These were simply from the organs supplied to her at autopsy, and she would not necessarily know that a substitute monkey bad been supplied for the sick, male monkey. Mrs. Jordan hOwever did mention this at one time to Dorothy Miner, but she is not certain whether or not Dorothy Miner would have paid any attention to this sort of comment or remembered it as she was prone to drink heavily, frequently drank the test alcohol in the laboratory, etc. Mary Ann Stephens: This individual is now married and her present name~ and address are not know to Mrs. Jordan. Mrs. Jordan knows that her duties primarily involved making blood counts on rats, and she does not believe that she had very much to do with the monkey studies and doubts that she knew that there had been a substitution. She knows that this individual did not work directly with the monkeys, and that she has also left the firm. Mike: Mrs. Jordan does not know this individual's last name. She knows that he worked for the firm during the last part of the Mer 29 studies on the monkeys :and he assisted Bruce Umberger in caring for the monkeys, which was his pri- mary job. She knows that he also helped weigh the rats on the Mer 29 studies. She knows that Mike was very good with the monkeys and while he was present she was sure that the monkeys were properly dosed and cared for. She said that he liked a good time and would frequently come in late on a Mon- day morning after being out all weekend. She was sure that if Mike were one of the individuals on duty on a weekend that the monkeys would be properly dosed, but it was during the times when neither she nor Mike were on duty on a weekend that she noticed the discrepancies in the number of remaining Mer 29 capsules. Mrs. Jordan finally resigned her position with the firm at the conclusion of the Mer 29 studies on the monkeys because of her dissatisfaction with the way the work was being run by Dr. King. She refused to sign her final work charts which she had to work up at the insistanee of Dr. Kipg using the substitute monkey. Although Dr. King had ordered her not to tell about this substitution, she was not sworn not to tell. Mrs. Jordan and her husband are high class public spirited people. Mrs. Jordan is understandably very much distressed about this whole affair and was initially reluctant to sign the enclosed affidavit. She finally did willingly swear to and sign the affidavit, however, because of her realization of her duty as a public minded citizen to the general public. Mrs. Jordan was told that I personally did not know what the final outcome of this investigation would be, but I assured her that it was of vital importance, and that the matter was being given very careful top level consideration. THOMAS M. RICE, Supervisory Inspector. Thielosures: 4-pg. affi. of Beulah L. Jordan. 3-pg. affi. of Bruce I. Umberger. AFFIDAVIT STATE OF OHIo, County of Hamilton: Before me, Thomas M. Rice, an employee of the Dep'artment of Health, Educa- tion, and Welfare, Food and Drug Administration, designated by the Secretary, under authority of the Act of January 31, 1925, 43 Statutes at Large 803 (5 U.S.C. 521) Reorganization Plan No. IV, Sees. 12-15, effective June 30, 1940; and Re- organization Plan No. 1 of 1953, Sees. 1-9, effective April 11, 1953, to administer or take oaths, affirmations, and affidavits, personally appeared Mrs. Beulah L. Jordan In the county and State aforesaid, who, being first duly sworn, deposes and says:' My name is Mrs. Beulah L. Jordan. I reside at 3825 Trebor Drive, Cincinnati 86, Ohio. I worked as a technician in the Toxicological Laboratory of the William S. Merrell Co., Cincinnati, Ohio, for approximately 2% years `from' the fall of 1956 to the early summer of 1959. During this time I assisted in a toxicological study on. Mer 29 usIng mon~mys. This experiment ran approximately 16-18 months.. It involved 6 `to 8 monkeys PAGENO="0333" COMPETITIVE PROBLEMS IN THE ])RUG INDUSTRY 4235 of which 3 or 4 were in a control group, and 3 or 4 were In the drug group. Three control and three drug monkeys were carried through the entire experiment, while one of each group was autopsied after approximately 6 or 7 months. My duties included bleeding the monkeys, running blood counts, assisting with the autopsies, making up capsules of Mer 29 and placebos for the drug groups and control groups, assisting with dosing both control groups and drug groups by pushing the respective capsules down the throats of the monkeys, take notes about the food the monkeys ate or refused to eat, weighing the monkeys weekly, checking the monkys reactions, preparing weight graphs each week and after autopsy, and weighing each organ at autopsy. Notes of observations made were recorded in in,k In a loose leaf 3 ring black note book, together with the recordings of the drug and placebo dosages and weights of the monkeys. This note book was always retained in the laboratory, and was never turned in to the firm's record office. The estimate of food eaten by the monkeys and the observations of eating habits were entered on a separate sheet and maintained in a separate looseleaf note book which was also always retained in the laboratory. During the first part of the experiment, I was under the direction of Mr. James Knox Smith, but toward the close of the experiment he was replaced by Dr. William King. Toward the end of the experiment one male drug monkey was sick and doing very poorly, and weighed approximately 8 or 9 pounds. He had lost approxi- mately 5 pounds or more during the course of the experiment. This sick male drug monkey bad become somewhat mean and acted angry. He had been a healthy, active monkey at the start of the experiment. After being on the drug he first became more active than usual, but later because very in- active and lay on the bottom of the cage. The expression in his eyes and his disposition Indicated he was very ill. He could not jump into the box from his cage for weighing, and back into his cage as the other monkeys could. During the first part of the experiment, this monkey could also do this very easily. Later on one occasion when he tried to do this he missed the box. At the close of the experiment I worked up the weight graphs, and showed them to Dr. King. He in turn discussed them with his superior, Dr. ~. P. Van Maanen. Dr. Van Maanen, with the concurrance of Dr. King, decided to throw out the sick male drug monkey mentioned above, and substitute another control monkey in his place which had never been on Mer 29. The male monkey substituted weighed about 18 or 20 pounds, or about 10 pounds more than the sick monkey for which he was substituted. Dr. Van Maanen then called me into his office and Instructed me to make this substitution in working up the weight chart. Because of this decision, I had to make up the charts 3 times. The sick male monkey was never autopsied in my presence, but the substitute control monkey was autopsied in his place. The weight charts would have been very much different, had the data from the sick male drug monkey been retained in the final reports because of his loss of weight from approximately 13 pounds at the start of the experi- ment to approximately 8 pounds at the close of the experiment. Dr. King ordered me to never mention the substitution. I was told this was the way the company wanted it and to forget it. I was told that the order had come from higher up. Also during this experiment, I know that on a number of occassions the capsules of Mer 29 were not given to the monkeys as they should have been, This would happen over a week end, when people in other groups would work relief shifts in the place of regular employees of our group. I knew this because I was the one who weighed up the capsules for each individual drug monkey for a week at a time, and prepared just enough to last 1 week until the monkeys were weighed again and the calculations were made in terms of the monkey's new weight. My routine was to have 1 capsule left for Monday morning, but some- times there would be 2 or 3 capsules remaining. During the experiment the monkeys on the drug became difficult to catch for doseing, which would explain why the week end relief employed may not have always dosed the monkeys. The charts, however, were always marked as If the capsules were given. I also participated in similar studies on dogs and white rats invovling Mer 29. I had similar duties in respect to these studies. I noticed nothing unusual about the conduct of these dog and rat studies. I participated in the autopsies of the PAGENO="0334" 4236 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY dogs ajid rats on these studies, and also worked up the weight charts at the close of these experiments. In the case of the rat studies, duplicate records were kept by means of record- ing the data into a bound book with carbon paper, but this was not the case with the monkey studies, and dog studies. Other employees who helped with the monkey studies were: Bruce Umberger: He was still with the firm a few months after I left, but is no longer with the firm. He now lives in Columbus, Ohio Ills duties included conditioning and handling the monkeys prior to the start of the experiment. He helped autopsy the monkeys at the close of the experiment. During the studies he helped weigh, dose, observe, and care for the monkeys. He helped catch, weigh, and dose monkeys. H~ had nothing to do with working up the final data at the close of the experiment on the monkeys. He also did similar work with respect to the studies on dogs and white rats. Dorothy Miner: This individual is also no longer associated with this firm, and left 1 to 1½ months after I did. She is presently in Florida, but I do not know her exact address. She was employed during the Mer 29 studies on mon- keys. Her job was primarily the preparation and staining slides. These were simply from the organs supplied her. Mary Ann Stephens: This individual is now married and her present name and address is not known. Her duties primarily involved making blood counts on rats. She did not work directly with the monkeys. She has also left the firm. Mike: I do not know this individuals last name. He worked for the firm during the last part of the Mer 29 studies on monkeys. He assisted Bruce Umberger, and his primary duties were to take care of the monkeys. He also helped weigh the rats on Mer 29 studies. I resigned my position with the firm at the conclusion of the Mer 29 studies on the monkeys, because of my dissatisfaction with the way the work was being run by Dr. King. BEiXLAH L. JOEDAN. * Subscribed and sworn to before me at Cincinnati, Ohio, this 13th day of March 1962. THOMAS M. RICE. AFFIDAVIT STATE OF OHIO, County of 1~'rankZin: Before me, Thomas M. Rice, an employee of the Department of Health, Ed- ucation, and Welfare, Food and Drug Administration, designated by the Secre- tary, under authority of the Act of January 31, 1925, 48 Statutes at Large 803 (5 U.S.C. 521) ; ReorganiEation Plan No. IV, Sees. 12~-15, effective June 30, 1940; and Reorganiration Plan No. 1 of 1953, Sees. 1-9, eff~etive April 11, 1958, to ad~. minister or take oaths, affirmations, and affidavits, personally appeared Bruce I. Utuberger in the county and State aforesaid, who, being first duly sworn, de- poses and says: I am Bruce I. Umberger, 681 E. Broad St., Columbus, Ohio. I am Assistant Manager of the Broad-Lincoln Hotel, 631 B. Broad St., Columbus, Ohio. From Sept., 1057 to Sept. 20, 1959 I was employed at William S. Merrell Co., Cincinnati, Ohio, in the Toxicology Laboratory. During this time, I assisted with a number of experiments. One of these was designed to study the toxicologi- cal effects of Mer 29. This experiment ran approximately 18 months. It Involved from 6 to 8 mon- keys of which 3 or 4 were in the "drug" group, and the remaining three or 4 were in the "control" group. Three control and 3 drug monkeys were carried through the entire experiment, while one of each were antopsied approximately 6 or 7 months after the start of the experiment. My duties included conditioning the monkeys for 6 weeks to 3 months before they were placed on the experiment. This included assisting in treating the monkeys for dysentry if needed, and holding the monkeys when they were given penicillin shots and tested for TB. I also weighed, bandied, and observed the monkeys during their period of acclimation to make certain they were well and suitable test animals. After the monkeys were placed on test, I helped hold the monkeys when they were dosed so the capsules could be pushed down their throats. PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4237 During the course of this experiment, I carefully observed the monkeys and made notes and observations. These observations were recorded (with carbon copy), in a book together with like recordings of the drug and placebo dosages and weights of the monkeys. The monkeys were weighed weekly. The original pages from the book were taken out and sent to the firm's record office. The carbon copies of the pages were retained bound in the book in the laboratory. During the weighing, I trained the monkeys to jump from the cage into a box, and after weighing, to jump back into the cage. Toward the end of the experi- ment I noticed one of the male drug monkeys developed an inability to land in the box when he jumped from the cage as if he didn't see properly or was sick. I also had to help hith back into his cage after weighing. Also he did not react normally when I put my hand on his head, as he normally would have drawn away. `This initially active monkey, when placed in Mer 29 had at first developed a hyper-activity. This was followed by a sub-activity. I noticed this sub-activity first started by his chewing on his `inner cheek. Ths monkey weighed 12-16 pounds. I got to know the moneys well during this period, because I took particular interest in this work, and I was usually in .the room by myself with them. I assisted with the autopsies of the monkeys at the eloise of the experiment, and it was my understanding that this completed this study. I did not participate in working up the final data. I do not recall anything particularly unusual about the auto'psy of the monkeys autopsied, but I do not recall specifically the autopsy of the sick monkey mentioned earlier. It was normal procedure for me to set up the autopsy table. During the first part of the experiment, my supervisor was Mr. James Knox Smith, but he left the firm a few months prior to my leaving, and he was replaced by Dr. William King. I was assisted during `the latter part of the experiment by Mike Piel who helped `me dose, weigh and care for the monkeys. Two women technicians who helped with the experiment were Mr's. Carol Root and Mrs. Jo Jordon. Mrs. Root however~ left the firm early in the experi- men't. Mrs. Jordon also left the firm several months before I did. These observations made by me on this sick male monkey were made because `of my general interest `for the welfare `of aU the animals which we're used on all studies. At `the time `of their occurrence these obs'er~ations did not appear to be particularly alarming to me `from the standpoint of toxicity and I think the drfig was continued until the termination date of the experiment. I also recall that toxocological studies were made on dogs with Mer 29. I do not recall anything speeific or unusual about these studies, but I believe there were at least two experiments on dogs. My `duties included conditioning the dogs prior to placing them on test, and weighing, `feeding and generally caring for them. Approximately 6 dogs were in a drug and approximately 4 dogs in a control group. I also assisted in autopsies of the dogs. I do not recall anything unusual with the autopsies of the dogs. I also participated in the Mer 29 studies on white rats. Nothing unusual is recalled about the white rat studies~ I `do no't recall the length of time the dog & white rat studies required. Bnucn I. UMEERGER. Subscribed and sworn to before me at Columbus, Ohio, this 13th day of March 1962. THOMAS M. RICE. U.S. Government Memorandum. To: Administration. From: Cincinnati District. Subject: Memorandum of telephone conversation, April 12, 1962, between Mr. E. R. Beckwith, llxecutive Vice President, William S. Merrell Co., at Cincinnati, Ohio and Thomas M. Rice, Supervisory Inspector, Cincinnati i)istrict. I called Mr. Beckwith today for the purpose of inquiring as to the raw data charts the `firm was duplicating for us in line with our visits to the firm on April 9 and 10 in connection with the MER `29 Investigation. PAGENO="0336" 4238 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I reminded Mr. Beckwith that they had promised to secure copies of these charts for us as soon as possible, and I again emphasized that we were anxious to get these copies as they were needed in the evaluation. Mr. Beckwith stated that they were trying to get a complete picture of the whole situation, and that they would collect and duplicate the charts as soon as possible. He said because of the change in personnel about the time these charts were prepared, the data was scattered, and it was taking some time to get all of the pieces of Information together. I suggested that If the firm was unable to get the originals of the pages we wanted, that we would be happy to attempt to photograph the carbon coplea in the `bound notebook. Mr. Beckwith assured me that they would make every effort to get the material together as soon as possible and would notify .me when it was ready. During the conversation, it was also verified that the information they were getting for Dr. Nestor relative to the clinical .stu'die~ would be sent directly to him In Washington. THOMAS M. Ricn U.S. Government Memorandum. WILLIAM S. MEERELL Co., Cincinnati, Ohio, AprIl 17, lJiiC2. To: Administration. From: Olncinnati District. Subject: Mer 29 investigation, and recall; refusal to supply data. During a visit to the firm today by Supervisory Inspector Thomas M. Rice and Inspector Charles W. Gressle, inquiry was made as to the copies of the raw data bound notebooks and copies of the original pages from these notebooks sent to the library, which had been promised to us at the time of our visits to the firm on April 9th and 10th. This was `~rst discussed in the presence of Dr. George 0. Sharp, Mr. Fred Lamb, and Mr. Ed R. Beckwlth, Executive Vice-President. The point was not resolved ~t the time of the discussion with these three gentlemen, but the point was again raised with Mr. Lamb and Mr. `Sharp later on during the same visit. Mr. Lamb was advised that our record showed that we had made this request in detail at the time of our visit of April 9th and 10th and that both numbers and page numbers were set forth in detail. Mr. Lamb claimed, that he did not recollect that the pages were written `down in detail, and he produced a confidential memorandum of the visits which did not show that the pages were given. I pointed out that this was at variance with my recollection, and pointed out that Mr. Lamb personally was in the group of individuals during the final~ conferences when these pages were enumerated specifically. I also pointed out that at the time we were in Dr. King's office, Mr. Lamb had been called by Mr. Murray to seek permission at our request when we had requested that the notebooks be loaned to us so that we could make copies of the pages ourselves. I pointed out that at this time Mr. Lamb refused to deliver the books to us on the grounds that it was against company policy, but that he promised to `have the pages we desired duplicated for us. Mr. Lamb made a point that this request was not made in writing, and that he did not consider it was a p~roni1se, but rather that he had said he would try to get `them for us. I pointed out that we had given a Notice of Inspection at the time of our visit on April 9th, and, that we had given another Notice of Inspection at the time of our visit today. Mr. Lamb made a point of the fact that the notices we had given related to Section 704 of the Act, and no where in this section dId it state that It was mandatory that records of this type be given d'uring an inspection I pointed out that I considered such records an Integral part of an inspection of a new drug product. I also pointed out that Mr. Beckwith, had been called again about April 12th to ask why the copies had not been supplied us. Mr. Lamb made a point of stating that he was' not refusing to provtde this' Information as an individual, but he did not "run the company". He said that' he did not want the record to show that he or the firm were refusing our request, but that inasmuch as' discussions were being held at the Washington level in regard to the whole matter, and the fact `that the firm had already Instituted a recall, he did not see why it was necessary to produce these records for us. He said he felt It was a decision that he personally could not make, and it would be up to the attorneys at the Washington level to make this decision. PAGENO="0337" COMPETITIVE PR6BLEMS IN THE DRUG INDTJSTRY 4239 It ultimately developed that Mr. Lamb called some undisclosed individual believed to be an attorney presently conferring with our people in Washington. As a result of this call be reported that he would be unable to give me copies of the notebooks because he did not have them, and they were not on the premises. at this time. He said he was embarrassed to have to report this, but he did not know that they had been sent to an attorney in New York City. He identified this attorney as Mr. Andrew Graham. At this point Mr. Lamb said that he would. give us the copies if he had them and they were under his jurisdiction as an individual. He then said he would make every effort to get the desired copies for us and that I should call him again Thursday, April 19, 1962. I told Mr. Lamb that it was my position that as of now I had been refused by the company because they had promised to produce these charts at the time of our visit of April 9th and 10th and now a week later I still had not been provided the charts. At this time I again gave Mr. Lamb the numbers of the notebooks and pages,. copies of which we required. These were as follows: Notebook 770 Pages 40 and 78. Notebook 799'R Pages 16,45, 59 and 75. Notebook 848R Pages 16, 56, 75 and 100. Notebook 904R Pages 18 and 19. Again I emphasized that we desired copies both of the originals which had been removed from the notebooks and found in the library, and copies of the carbon copies remaining in the bound notebooks. Mr. Lamb tried to make a point that this was now the first time that he was receiving this specific request. See also another memorandum under today's date captioned "Mer 29 Recall" in which the details, present status, and enclosures concerning the recall are dis~ cussed In detail. THOMAS M. Rion, Supervisory Inspector. U.S. Government Memorandum. WILLIAM S. MERRELL Co., Cincinnati, Ohio, April 24, 1962. To: Administration; Attn: Division of Regulatory Management From: Cincinnati District. Subject: Mer 29. In response to the phone conversations between Mr. Maraviglia and Mr. Gold- hammer of April 18 and 19, 1962, William M. King was finally interviewed by Mr. Maraviglia and Mr. Rice at his residence, 481 Deanview Drive, Cincinnati, Ohio, the evening of April 24, 1962. Dr. King's phone number is VA-1-6435. We bad been attempting to locate and interview Dr. King since Thursday,. April 19, 1962. It was determined that Dr. King bad been visiting his father and family in Johnson City, Tennessee over the Easter holidays. King has six children, and he had returned to Cincinnati so that his children might enter school again on April 25th. King has been on "involuntary" vaca:tion since Monday April 16th. He was told by Mr. Beckwith that he needed a vacation, and that he should not come back to work until be was called. At the present writing, King does not know his status with the firm. He plans to phone the firm on April 25th to find out what his status is. King talked fairly freely with us, and although we doubt if he gave us all of the facts, the following information was supplied which ties in genetally with information from other sources, and sheds some light on heretofore un~ known facts. He admitted that his Ph. D. degree has not been completed at this time. He said that the granting of his degree was awaiting rewriting of his thesis. His graduate work was being carried on at the University of Minnesota where he was teaching pathology. Prior to his work at the University of Minnesota, he graduated from St. Thomas College, St. Paul, Minnesota. He had transferred to Thomas from St. Louis University. He said that his adviser at the University of Minnesota bad certified that all of his work was completed on his Ph. D. degree, and that it would be granted in absentia when his thesis was finally accepted. 81-280-69-pt. 10-22 PAGENO="0338" 4240 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY King emphasized throughout the interview that Dr. Van Maanen was respon- sible for all data `in the final form which was `submitted. to the Food and Drug Administration. He said that Dr. Van Maanen was the only man who could have ordered the addition of Monkey 51 in the middle of the study. King was of the in~pression that this was the only ~e~joijs mistake in the studies. King stated that Dr. Van Maanen is not a citizen of the United States. He said that he had a Ph. D. degree from the university of UtreciLt in Holland, in organic chemistry, and also had a Ph. D. degree from Harvard University in pharmacology. He said that Dr. Van Maanen had been with `the firm since 1954 or 1955. Dr. Van Maanen is Director of Biological Sciences. Tie in turn is the subordinate of Dr. Werner, who is a vice president of the firm and Director of Research. King said that Dr. Werner was about ready to retire and did not know what was going on and relied entirely on Van Maanen for anything of this nature. King said `that he joined the firm in September, 1958 and took over where Mr. Smith left off in April, 1959. Thus, there was an overlapping during the time when both King and Mr. Smith were present in the firm, and both were present at the time of the termination of the monkey studies. King played down his knowledge of the raw data and said that he knew nothing about the discrepancies until the visit of Dr. Nester, Dr. Goldenthal, and Supervisory Inspector Rice. He pointed out that Monkey M51 was added to the studies on June 23, 1958 several months prior to the time when he came with. the firm. He said this order could have been given by only one person, and that would have been Dr. Van Maanen. He said that he had done a great deal of "digging" to try to find out what bad happened and be was under the impression that the weigh'ts of monkey M51 had been taken from `the weight records prior to June 23, 1958 when the monkey had not been on iVEer 20, and that these weights bad been used on the charts submitted with the NDA. He said that after the tenth month of the experiment, the weights of Monkey M51 were correct on the charts' submitted and that dosing had been performed as indicated after that time. King feels that Mer 29 is a safe drug if used properly, but blamed the doctors for not dosing properly. King had a number of records he had taken from the firm. He said that he had been requested to prepare a summary for the firm's attorneys to explain all of the discrepancies. He was not willing to let us have copies at this time, but said that h'e knew most all of this by memory. We asked if he would be willing to sign a staitement for us and he indicated that while be would not sign such a state- ment at the time of this interview, he would probably be willing to do so after he had resolved his status with the firm. He gave us to understand that be was dealing 100% above board with us and giving us the true facts as be knew them. In respect to the female Monkey P49, King said that the records showed that this monkey had been taken off the drug on March 14, 1958 for some reason and restarted on the drug again on April 7, 1958. Except for this period, this monkey was on the drug continuously from 9/9/57 until February 19, 1959. On February 19, 1959, the drug was withdrawn again. It was after that time that the greatest weight loss developed. He said in trying to figure out what `was wrong with the monkey, he believed that the monkey had ga~tro enteritis. He said that the monkey was not autopsied until March 5, 1959. He said that the responsibility for taking this monkey on and off the drug would fall directly on Dr. Van Maanen. He also said that the decision to wait for autopsy until March 5, 1959 on this monkey would also have been Dr. Van Maanen's responsibility. King showed us a yellow sheet of paper which he said proved the dates of autopsy on the various monkeys because he had the weights of the organs recorded there. He also said that the actual dates could be checked because the dates were fixed on the slide's, and were also fixed on the tissue in the paraffin blocks which were taken at the time of autopsy. King furnished us from his report he bad written for the attorneys the following actual dates of autQpSy. Monkey Number Sex Autopsy date Control monkey Drug monkey - Do Control monkey Do Drug monkey Do Control monkey 39 Female Mar. 5, 1959 49 do Do. 34 Male Feb. 26, 1959 35 do Do. 33 do Feb. 19, 1959 51 do Do. 25 do Mar. 14,1958 48 do Do. PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4241 King also spoke of another monkey which he gave as number 35 which had been on compound 5066 which be said was an analogue of Mer 29. He was under the impression that Control Monkey 35 Male had actually been on this drug prior to being used as a control animal. In explaining why all autopsies were not made the same day, King said that this was becapse they were freezing tissue at the same time, and it would thus be impossible to prepare and freeze the tissue for all of the monkeys on any one day. He mentioned that it was obvious the firm was looking for a scapegoat. He said that he couldn't care less, because he could always get a job. One interesting sidelight was that he told us he had copies of all the pages of the notebooks for us the afternoon that Dr. Nestor, Dr. Golcienthal and Inspector Rice were at the firm (April 9), but he was told not to turn them over to us. King admitted that he personally prepared all the microscopic sections of the tissues and examined them himself at the end of the study, and he personally had autopsied the drug `monkeys 49, 34, and 51. He could not explain why there was no raw data on the autopsy of monkey 34 in the notebooks, but felt that the records he had of the weights, the fact that they actually had the tissues in paraffin blocks, etc. proved that the money was in fact autopsied on 2/26/59. King stated that' the second edition of the brochure sent out with Mer 29 made no mention of his findings on female monkey 49 which he had reported. He said `that he had observed morphological changes `in the ovaries and had so reported these on his autopsy reports. He said that it was Dr. Van Maanen's decision to leave out this in'formation so that investigators supervising clinical studies on Mer 29 wouldn't know `about it. King mentioned that Mr. Hoithaus, w'ho he has as his assistant, was not in this department `at the time these Mer 29 studies submitted with the NDA were going on. He said that he was, however, in the endocrinology department and had transferred to his department later. He identified him as the individual he asked to get the raw data when it was asked for at the time of our visits ,on April 9 and 10. King stated that he had searched for the original records of weights and observations made out by the technicians. He admitted that these were kept in loose-leaf fashion on a clip board and these were the original sheets on which the weights were recorded. He said that these weights would have been tran- scribed into the bound notebooks by the technicians. He identified these tech- nicians as Umberger and Jordan. It appears significant `tha't this corroborates Mrs. Jordan's statement that the original observations and weight's were recorded on a loose-leaf type sheet on clip boards. It would appear that any information regarding illnesses observed, any substitutions, etc. would have been on these original `sheets which according to King cannot now be located. Incidentally, King admitted to us that he had been severely reprimanded by Mr. Beckwlth and Mr. Lamb for turning over the weight charts to us at the time of our visit on April 9th, and also for letting us examine `the bound notebooks. One `other point In respect to Monkey P49, according to King was that there w'as a weight loss of 1.1 kilograms on this monkey while it was on the drug. He said this weight loss was shown on the chart submitted with the NDA to Food and Drug Administr'atoi'n, but the serious loss of weight after the drug was with- drawn was not shown. He tried to play down the significance of the weight loss by telling us that it was common for monkeys to lose a great amount of weight just `as children `do when they become dehydrated. King refused to have us look at or copy any records in his possession at this time. He said the company would have a "fit" if `they knew he had them. He said be had to remain "loyal" to the firm within the bounds of "intellectual honesty", and until he knew definitely wh'at his status was with the company, he would not sign anything or allow us to make copies of anything in his possession. At the termination of the interview, he said he was getting in touch with the firm tomorrow to find out where he stood. We `told him we were giving him an opportunity to cooperate fully with the government to supply us with the real facts as he knows them. We told him that we would be getting in touch w'ith him again in the next day or two'. He professed that he wanted to cooperate, but wants to know his true status with the company first. We then left his residence. On April 25, 19132, while Mr. Rice was at Merrell on an assignment concerning Kevadon, Mr. Lamb made `a remark indicating that he knew' `about our visit to PAGENO="0340" 4242 CO~TITIvE PROBLE1~tS T~ THE ~Rt~ThTD~1STRY King the night before. He told Rice, "I hear you were out working late last~ night with Mr. Maraviglia", or words to that effect. He did not say how he~ knew about this, but obviously King must have told him. We intend to see King again soon. THOMAS ~f. Rica, &~pervisory Inepector. T. C. MARAvIGLIA, Director. U.S. Government Memorandum. WILLIAM S. Mmrau~ Co., Cincinnati, Ohio~ May 4,. 1962. To: Administration; Attn: Division of Regulatory Management. From: Cincinnati District. Subject: Mer 29. In response to Mr. Goidhammer's phone conversation of 4/18/62 with Mr. Maraviglia, we were requested to develop every possible source of information in connection with the Mer 29 investigation. To this end, Inspectors Brods'ky and Rice interviewed Bruee Umberger at Columbus, Ohio the night of May 3 and 4, 1962. This Interview was~ conducted at the Broad Lincoln Hotel, Columbus, Ohio where Umberger is currently employed' as the assistant manager. The following information was developed. Mr. Umberger has not been contacted by Merreil since Inspector Rice's Inter. view with him on March 12th and 13th, 1962. Umberger did not contact anyone from Merreji in connection with Mer 29 or this Investigation. Umberger did take a trip to Cincinnati a few weeks ago subsequent to the interview of March 12th and 13th to visit relatives. During that visit, by chance he met Mr. Herb O'Bannion (correct spelling not known). Mr. O'Bannion performed janitorial services at Merrell's and his duties included cleaning the monkey cages, waxing' the floors etc. Mr. O'Bannion was encountered In Mt. Healthy, and no mention was made of Mer 29. Tip until our interview with Mr. Umberger, he was not aware that `the recall had been instituted. He had heard from his brother that there was something reported about Mer 29 in the paper, but he did not seem to know exactly what the trouble was. Mr. Uxnbe.rger said the recall information was not published in the Columbus papers in so far as he knew. Umberger was appraised of the present recall and the seriousness of the problem, the fact that the adversary actions had developed Including cataracts,. etc. He was told that this visit was being conducted for the purpose of deter- mining complete facts surrounding the investigation of Mer 29 by the company. We told him that the reason for our visit with him at this time was to secure factual Information which he had part in obtaining in connection with these studies. We showed Umberger photo copies of the several pages of the bound raw data notebooks. We also showed him copies of the four~page charts and Fig. 8 composite graphs. Umberger recognized these as data drawn up from Information compiled by Jo Jordan, Carob Root and himself. We made' a special point in being very cartful not to show Mr. Umberger any data or Information which appeared in the NDA. We had him review these data carefully in order to clarify and refresh his memory regarding certain Information contained therein, so that he might explain the significance of these entries. We asked him about the signatures at the bottom of the pages, the unsigned pages, and the dates and weights recorded on the charts and graphs. He ex- plained the following: 1. MissIng signatures at the bottom of the pages may have been an oversight on the technician's part. He said that whoever made entries on the pages signed the pages. If more than one technician made entries on anyone page, both tech- nicians signed the page. If only one individual made entries on a page, then that individual signed the bottom of the page. Uinberger stated that the monkey weights and dosages were originally recorded at the time of weighing and dosing on laboratory worksheets which were kept in loose leaf fashion in a three ring black notebook in the laboratory. These data were later transcribed In duplicate Into the bound raw data notebooks. The original pages from the bound note- books, would then be torn out and sent to the firm's records library, while the PAGENO="0341" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4243 ~carbon copies remained In the bound books. From these data, he would pre~ pare a rough graph showing weight Information over the period of time the experiment was conducted. From this rough graph, a neater and more accurate graph would be prepared. Umberger carefully scrutinized the individual graphs and charts and affirmed that these had been prepared from the raw data re corded on the pages of the bound notebooks. He stated that these graphs were the types of data he helped compile. He said that the printing and dates, and some headings on these graphs were not done by him, but that these were in part his. He explained that sometimes Jo Jordon or Carole Root would prepare the ilnal graphs arid charts from his rough charts because they could do a neater job. He indicated however that the information contained therein appears to be information actually compiled by Jo Jordan, Carole Root and himself. 2. From the graphs and raw data, Umberger was able to deduce that the sick monkey reported in previous memorandums was number M34. There had been some speculation that the sick monkey might be female monkey M49. Umberger was very positive that this female #49 was not the sick monkey he had been referring to because this particular female monkey was a pet of his, and he bad his picture taken with this monkey and was very familiar with It. `He also recalled that female 49 had bitten the end of a finger off the small sick male monkey. This was referred to by him in his affidavit of 4/13/62 as the "sick male monkey". 3. Umberger was able to identify the "sick" monkey as male #34 for the following reasons': (a) He was sure the sick monkey wa~ a drug monkey and was a small male animal. (b) He was sure it was not a control monkey. (c) He was sure it was not a female. monkey. (d) He was sure this animal had been used in the entire study, i.e. was not started late in the study, was not sacrificed prior to the completion of the entire experiment, and was used as a `drug monkey to the end of the entire study. These facts, tlmberger stated. ruled out all of the monkeys except male 34 because there `were only ten monkeys on the study and from the data the status .of each of the ten monkeys is as follows: No. 39 was a female control monkey. No. 4fi was a female and he remembers this well because it was his pet, he bad his picture taken with it, etc. No. 40 is a female and was not present at the termination of the study. 1'his animal had not been on drug 5066 and there are no further entries on this monkey `after 3/13/58. No. 25 was sacrificed before `the completion of `the study. It was a male ~animal on 5052 or Mer 29 for only the first approximate six months. No. 48 was a male control animal sacrificed early in the study. No. 51 was a male animal on 5052, but this animal did not start the study. it was inserted on 6/12/58 and was somewhat larger than monkey 34 during the closing months of the experiment. No. 35 was a male monkey that was on 5066 at the start of the study, but later this monkey appeared as a control monkey. No. 36 was a male monkey was on 5066 and this monkey was sacrificed before `the completion of the experiment. No.33 was a male control monkey. No. 34. This is the only animal which could have been the sick monkey, because it was a male monkey on the drug from the start of the finish of the entire experiment. It had about the same weight remembered by Umberger to be that of the "sick monkey". 4. Umberger noted discrepancies on autopsy dates for monkeys #33 and 51 in the notebook data. These discrepancies showed 2/19/59 and 3/4/59 as autopsy dates for these monkeys. Since the weight graphs and charts show weights for these monkeys subsequent to 2/19/59 and 3/4/59 as autopsy dates for these monkeys. Since the weight graphs and charts show weights for these monkeys subsequent to 2/19/59, Umberger believes that `the 2/19/59 date is not the correct date of autopsy. He said that weights would not be taken after autopsy and recorded. Umberger stated that blood samples are taken before autopsy by Mary Ann &evens. If there was a crowded autopsy schedule, the blood might, be taken a PAGENO="0342" 4244 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY day or two before the autopsy. This could establish which is the correct date of autopsy because samples of blood are not taken after autopsy. He explained that Mary Ann Stevens learned under Mr. Knox Smith and that she was the type of employee that would not make any false entries as to dates that was taken from animals on any data she helped to prepare. Umberger stated that Mr. Smith had told all technicians that if they were always truthful in their entries, they had nothing to worry about when they signed their names to a report. Knox Smith bad always emphasized that only the truth should be recorded. 15. Umberger said that monkey # 35 was used as a drug monkey on 5066 according to the notebook `data at the `beginning of the study. He said this animal could have been used as `a cOntrol for the 5052 study ]ater in the study as it appears on the graphs and charts. He said that since it is recorded on the charts, It must have `been used starting 6/12/58 as a control. Umberger further stated that thIs information should have been shown in the raw data notebook as a control, but that whoever made the entry for # 51 as a test animal on 5052 must have simply overlooked entering monkey 35 in the book as a control. 6. Umberger was unable to explain why no autopsy information was recorded for `monkey 34 and monkey 35 in the raw data notebook. He believes the only explanation is that Dr. King may have bad the `data. lie noted that in the raw data notebook for monkeys number 51 and 53 such an entry was made that Dr. King had the data. Later on entered in the notebook for animals 51 and 33. Urn- berger felt that in the case of monkeys 84 and 35 for some reason their entry into the raw data notebooks had been `overlooked. Followin'g our interview with Um;berger, a three page affidavit was prepared attesting to the above information. This was signed by Umberger after he swore with his right hand raised that the Information contained In the affidavit is "the truth, the whole truth, nothing but the truth, so help Inc God." The oath was administered by Inspector Rice and wltne'sses'd by Inspector Brodsky. tTmberger wa's asked if he would be willing to testify to the above statements if the need should ever arise. He stated that he would be willing to testify to anything he had signed his name to, but only to the true facts He then asked us what he should do If he were contacted and questioned by representatives of Merrell. We told him that while it would be up to him to uto his own judgment, we strongly suggested that be holds completely to the truth. We indicated that if be were contacted by any representative of Merreil, we would appreciate his contacting us. He indicated that he would do this One final interesting point `should be reported in connection with monkey 34 as follows. Mr. TJmberger told us that monkey #34 for which no autopsy result appears in the raw data notebook was in fact autopaled. He remembers this because he asked at the autopsy why the monkey behaved abnormally; i.e. why did It miss the `b'ox at the time It attempted to jump when being weighed. Umberger told us that he was advisOd that the monkey bad a `~reverse heart at- tack." Umberger could not further explain or elaborate on what this meant. This may be significant since clinical studies In the NDA mention that' in several instances, patients died, but this was attributed to the type of patients being given the drugs. These were explained away because they felt the patients such as had heart conditions would have died any way. Note that the autopsy report on monkey 34 submitted with the NDA indi- cated nothing abnormal about the heart whatsoever. Pinup ER0O5KY, THOMAS M. Ricz, Iaspectors. Enclosure-Affidavit. STAT OF Onro, County of Fra~ekHn: Before me, Thomas M. Rice. an employee of the Department of Health, Educa- tion, and Welfare, Food and Drug Administration, designated by the Secretary, under authority of the Act of ~tanuary 31, 1~25, 43 Statutes at Large 803 (5 IJ.S.O. 521); Reorganization Plan No. IV, Sees. 12-15, effectIve tune 30, 1940; and Reorganization Plan No. 1 of 1953, Sees. 1-9, effective April 11, 1953, to ad- minister or take o'aths, affirmations, and affidavits, personally appeared Bruce I. Umberger in the county and State aforesaid, who, being first duly sworn, de- poses and says: PAGENO="0343" COMPETITIVE PROBLEMS IN THE DRIJO INDUSTRY 4245 I am Bruce I. Umberger, 61 E. Broad St., Columbus, Ohio. I am assistant manager of the Broad-Lincoln Hotel, 631 E. Broad St., Columbus, Ohio. This reaffirms my affidavit which I gave to Inspector Rice on March 13, 1962. After reviewing copies of pages from the bound raw data note books Num- bers 770R, pages 40, 78; 779R, pages 16, 45, 59 & 75; 848R, pages 16, 56, 75 & 100; and 904R, pages 18 & 19; the 4 page chart titled "Monkeys Chronic Oral Toxicity Mer 29 Body Weights"; and Fig 8, shown to me by Inspectors Rice and Brodsky today, the following is recalled by me as factual to the best of my knowledge and belief. 1. The monkey referred tO In my affidavit of March 13, :W62 as the "Sick Male Drug Monkey" was monkey #34. I recall this for the following reasons: (a) I clearly recall the "sick" monkey to be a male drug monkey. (5) I clearly recall the "sick" monkey was a monkey that both started and finished the studies. (c) There were only ten monkeys in the studies; namely. 3 female and 7 male as follows: F39'-control F40-~on 5066 P49-on 5052 (Mer 29) M25-on 5052 (didn't finish study) M48-~control (didn't finish study) M51-~-on 5052 (didn't start study) M35-on 5066 at start-4ater a control monkey M36-on 5066 (didn't finish study) M33-control M34-5052 (Mer 29) All of the above, except M34 are ruled out because they are either female, control monkeys, didn't start studies or didn't finish the studies because they were sacrificed prior to the termination of the studies. (a) I clearly recall the "sick" monkey was one of the smallest mOnkeys on Mer 29 and my estimate of the weight of this monkey agrees with the weights from all of the data reviewed, which was supplied by Inspectors Rice and Brodsky. 2. The information sho'wn on the copies of the pages from the bound raw data note books mentioned above, reDresents data supplied jointly by Carole Root, Jo Jordon and myself. This material was transcribed from data obtained by us in the laboratory and originally written on loose-leaf data sheets at the time the data, such as weights were obtained. These data are correctly shown, in substance, in the copies of the bound raw data note books, the 4 page chart, and Fig. 8, mentioned above except for the following: (a) No weight and dosage entries were made between 3/13/58 and 4/3/58 in the raw data books, but were entered on the charts. (b) Weights for all monkeys completing the Mer 29 study are shown on the charts through 3/5/59, but the bound raw data notebooks show M51 and M33 autopsied on 2/19/59. 3. Any data projected showing additions or deletions from those recorded in the aforementioned bound raw data books, the 4 page graph, and Fig. 8 are not true representations of the data submitted in which I participated~ ~WtTOI~ I. UManacan. Subscribed and sworn to before me at Columbus, Ohio, this 4th day of May 19~i2. Witnessed by Philip Brodsky. TIIOMAS M. Rica. U.S. Government Memorandum. WILLIAM S. MEfliIELL Co., Cincinnati, Ohio, May 5, 19d2. To: Administration; Attn: Division of Regulatory Management. From: Cincinnati District. Subject: Mer 29. This is a continuation of the Mer 29 investigation. Please refer to the Con- fidential Administrative memo of 5/4/62 by Inspector Rice and Brodsky. After returning to Cincinnati the evening 5/4/62 after concluding our interview with Bruce Umberger in Columbus, Ohio, Inspector Rice phoned Mrs. J0 Jordan PAGENO="0344" 4246 COMPETITIVE PROBLEMS IN THE DRUO INDUSTRY to arrange for an appointment in order to try to obtain certain additional in. formation and explanation with the help of the raw data book pages and charts. At this time, Mrs. Jordan agreed to the appointment, and an appointment was se up for 1:00 PM Saturday May 5, 1962. During the the conversation, she men- tioned at the time she was working for Merrell she had been required to sign a statement that she would never reveal any information which came to her atten- tion while In the employment of MerreiL She was fearful that if she spoke further with us that she might open herself to suit by Merrell for revealing Information. At any rate, she did not appear to be to alarmed and agreed to the appointment. The morning of May 5, 1962 at about 10:30 AM, Mrs. Jordan's husband, Carson Jordon phoned Inspector.Riee sit his residence. He first said they would be busy the afternoon of the appointment, He then went on to say they would be busy all day, that they would be busy from now on, and he then ordered me never to call his phone number again, or to come out to see him at his house. He said that the reason for this was that it upset his wife too much, and he was very fearful of the consequences to her. He said I could call him at his office, hut never to call her again. The afternoon of May 5, 1962 Inspector Brodsky and I then proceeded to the residence of Mrs. Gladis Gebert, 401 131. Vine St., Reading, Ohio. After introducing ourselves and presenting Mrs. Gebert our credentials, we explained we wished to talk to her in connection with an investigation we were conducting of the William S. Merrell Co. Mrs. Gebert said this sounded interest- ing and that she would be glad to speak with us about it. We asked her about the circumstances involved in her leaving the firm and when and why she had left. Mrs. Gebert said she worked at the firm from 1953 through the summer of 1956. She knew she had left the firm sometime after July 4, 1956, but before the fall of 1956. She said she left because she "couldn't stand to work down there any more". She said she worked as a technician under Knox Smith. She took care of :animals Including monkeys. She dosed, weighed, made observations in connection with animal studies. Mrs. Gebert said that Mr. Charles Thompson was in charge of the department. Under him were two sections in this* research unit. Knox Smith was in the rear of this unit, and under him were the following technicians in addition to Mrs~ Gebert. (1) Ann Estep. This is Ann Estep Dover now residing at 314 Cleveland, St. Bernard, Ohio. Her phone is PL 1-8183. According to Mrs. Gebert, this woman drew the blood and did the blood studies on virtually all of the ex- perimental work in this laboratory. (2) A woman by the name of Pat. This Pat married Fritz Hoithaus who is presently working with Dr. King at Merrell. At this time, Holthaus was not in this department. (3) Dorthy Meyer. This woman took care of the tissues. She later was dis- charged sometime after Mrs. Gebert left the firm. Dorthy Meyer is now in Florida. (4) Tom Beaver. This individual was quiet, calm, honest, "kept his mouth shut", made up formulae, and may still be with the firm. At least Mrs. Gebert said he was still there two years ago. She said Beaver is honest and would give truthful information. (5) Tom Cashman. This individual according to Mrs. Gebert, was brought in to take her place. He came in shortly before she left. She knew nothing about this individual. Also under Mr. Thompson was a second branch headed by a Dr. Brown. This is a woman whose first name was not recalled. This Individual is no longer with the firm, and was either discharged or left the firm prior to the time of Mrs. Ge- `bert's termination of employment. It is apparent that Mrs. Gebert left the employ of the firm prior to the Mer 29 Oral Toxicity studies on the monkeys. Mrs. Gebert, however, did have some very definite impressions about the man- ner in which business was being conducted at this firm, and felt compelled to tell us all about this "intrigue" which she was withholding within and had been wanting to tell someone for a long time. Mrs. Gebert emphasized that these things could not be proved, but they are true, and felt that the "whole place needed an ~expose". She said that Dr. Brown and Mr. Thompson were having a "war'. Em- pioyees in the middle were forced to take sides. Dr. Browzi was busy setting pee- PAGENO="0345" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4247 pie against each other. She said people in authority were mixing up data in data books. She said "You couldn't be honest and work there". At this point, Mrs. Gebert mentioned that Ann Estep was a "crooked, foul mouthed person in cahoots with the crowd". `She told us that she lives in St. Bernard and did the dirty work for Knox Smith. She said her brother-inlaw runs a bar in St. Bernard. That Es- tep's brother-in-law ran a bar in St. Bernard was later confirmed during our Inter- view with Ann Estep Dover. Mrs. Gebert said that she was attempting to stay out of the controversy, but later she was drawn into it and was fired. Prior to her being discharged, she actively took sides and tried to call to the attention of Mr. Thompson what was going on. She said Smith and Brown were working together against Thompson. She said they bad no principles, and they tried 1x~ influence Dr. Werner who was above all of these individuals against Mr. Thomp- son by spreading rumors regarding illicit sexual activities between Thompson and the female employees. Mrs. Gebert did not think there was anything to this,. but rather Thompson was a fatherly type individual who treated the employees or thought of his employees as his children. Later, there were rumors of familiari- ties between Dr. Werner and Dr. Brown (female). Eventually, Brown was re- leased. She said that both sides In this feuding attempted to accuse opponents on the opposite side of illicit sex relations with employees. She again emphasized that Ann Estep "messed up" studies for Knox Smith. She said as a result of this jealously, intrigue, lack of principle, and down right Interference with experiments that she would suspect anything put out by this firm. During her conversation, she said that several high principled individuals left the firm because of the atmosphere and the way things were bing run. One was Dr. Jake Stuke. She said that he was an endocrinologist, and finally left the company to take a job with another firm in Kalamazoo. She was certain the firm Dr. Stuke joined after leaving Merrell was Up John. Another high principled Individual was Dr. Leonard Lerner. She said he left to go with another drug firm In New Jersey. She said this was the "worst dog eat dog, cut throat, cheating, lying place she ever worked at". She said she was "a wreck from this confusion and went to two psychiatrists". Her impression was that the people she was working with were capable of fixing tests to improve their own status and making money. She believes that Knox Smith with the help of Estep, would have data fixed In the record books. It should be noted that Mrs. Gebert's employment with the firm was terminated because she was "fired". This came about or at least came to a head because a vicious monkey had been turned loose in a room with her. This monkey was known as No. 13 and she believed Knox `Smith deliberately turned the monkeY loose in this room, This monkey had bitten the animal room attendants. Knox Smith said that he had been turned loose accidentally, however, she accused Smith of doing it purposely. Again it should be emphasized that all of the above is information Mrs. Gebert cannot prove, `but because she felt so strongly about it, and wanted it off her mind she felt compelled to tell us. We next interviewed Mrs. Ann Estep Dover, 314 Cleveland Ave., St. Bernard, Ohio. Mrs. Dover worked with Merrell from June, 1944 through May, 1958. From 1944 through 1950' her duties were in the factory in the packaging department, etc. From 1950 through May, 1958, she worked in the department of Pharmacology. Her duties involved working with the animals and included feeding, weighing, closing, and especially doing blood work in connection with the animals, par- ticularly monkeys. The blood work on the monkeys consisted of examining the blood for red blood count, white blood count, hemoglobin, hematocrite and dif- ferential counts. She actually withdrew the blood from the monkeys herself. This information was recorded directly onto 8" x 5" cards in the laboratory. Following this, she transcribed them into bound notebooks. While this mainly was done fairly soon after the studies, it might have been as much a~ one ~r two weeks before the transcriptions were made into the bound notebooks. The note- books were kept in the laboratory. The entries were made in duplicate and the original copy was torn out of the book and sent to the firm's records library. The carbon copy of the reports remained in the bound notebooks. All entries were signed by the technician doing the work. Mr. J. Knox Smith was her immediate supervisor. Mr. Charles R. Thompson PAGENO="0346" 4'248 COM1~fl'Wt PROBLEMS IN ~THE DRUG* IND~t~SPE~ was the supervisor of Knox Smith. Thompson left before Mrs. Dover left the firm. Mrs. Dover left the firm because of pregnancy. It was revealed that Mrs. Dover received a long dl~t~noe telephone call from Knox Smith in Los Angeles on April 27, l9~2. Mr. Snilth had told her that `she might have visitors. Mr. Smith was checking on names of former em~ioyees under him when he worked at Merrell's. Mrs. Dover stated that during anti subsequent to her employment with Merrell, she had been very friendly with Mr. and Mrs. Knox Smith, and as a matter of fact, they correspond frequently. Mrs. Dover stated that she was aware of the fact that she had worked on Mer 29 when she was with the firm. She said that she made graphs, and had access to data bound in the notebooks and the rough graphs, and her duties in- volved entering data into bound notebooks and making rough graphs in con- nection with her work. We showed her some of the raw data which she would have had access to at the time she worked at the firm. She said that she took blood and made studies on the blood on both control animals and drug animals on the experiments. These studies included animals on 506G as well as on 5052 and the control animals. She said that any animals on these studies would be in the raw data books, and that the entries would have been made In her own handwriting, she would have signed the pages, and if confronted with this raw data, she would be able to swear that this data was in fact the true facts rep- resenting her original work. She confirmed that if she were confronted with data which were different from the data recorded In the raw data notebooks in her own handwriting and signed by her that she would emphatically say that the other data was false and her data was true. Mrs. Dover said that also working in this department at the time she was there was Dorothy Meyer whose last name now is Sekins. Mrs. Sekins has left the firm and is now living in Florida. Mrs. Sekins was still empio~7ed by the firm after Mrs. Dover left the firm. Mrs. Sekins did the tissue work primarily. Another employee in the department while Mrs. Dover was workIng there was Mrs. Carole Root. She was the wife of a Merrell employee in the sales department whose name was Charles A. Root, III. The Root's are presently living on Carolina Ave. In Kin'gsport, Tennessee. As far as Mm. Dover knows, be is still with Mer- rell's. Mrs. Dover saw the Root's last July while on vacation in the Smokies. C'arole Root had the job of dosing, feeding, and weighing monkeys. Note that Carole Root's name appears on many of the pages in the first part of the monkey studies in the raw date notebooks. Another employe in the department during the time Mrs. Dover was with the firm was Bruce Umberge'r. He left the firm to go to Ohio State University. He has been in touch with Mrs. Dover whenever he comes to Cincinnati, and called her about a year ago. Other memos contain full information on this individual. Another employee in the department was Mary Ann Stevens. This is Mrs. Wil- 11am Stevens who lives in Mt. Healthy, Ohio. Her husband is dead, sand as far as Mrs. Dover knows, she m'ay still be working with the firm. Another individual working in the department was a female technician whose first name is Jo. She does not know her last name, but her husband's first name is Carson. This is, of course, Mrs. Jo Jordan; whom we have previously interviewed. Phi's individual w'as employed at Merrell at the `same time that Mrs. Dover wa's employed there. Mrs. Dover in response to a question `stated that she recalled nothing out `of the ordinary in connection with `these monkey studies. It might be interesting to note that Mrs. Dover stated that `the firm has not been in touch with her concerning this matter, except for the phone call from Mrs. Smith. There was one interesting observation which Mrs. Dover made without our mentioning it which ties in with information secured from Mr. tT'mberger. This was that she recalled that one of the monkeys bit a finger off a second monkey. She did not `seem to knOw whether or not the whole finger had been bitten `off, but at least she knew `one of the monkeys bad hit `the finger of another. This would tend `to confirm the fact that this incident occurred `sometime while the monkeys were on tests, and it would of necessity have had to occur between September, 1957 and May, 1958 in order to have both Umberger `and Dover observe this inci- dent, `since Umberger did not join the firm `until September, 1957, and Dover left the firm in May, 1958. TI1oi~us M. RICE, PHILIP BRODSICY, Inspectors. PAGENO="0347" COt~E~fI~r1~VE 1'BOBLEMS IN T~EIE X~$RUG INDUSTRY 4249 U.S. Government Memorandum. WILLIAM S. MEIIRELL CO., Cincinnati, Ohio, May 30, 196~. To: Administration; Attn: Division of Regulatory Management. From: Cincinnati District. Subject: Mer 29. On the evening of 5/28/62, Supervisory Inspector Rice again interviewed Mrs. Jo Jordan in the presence of her husband Carson Jordan as planned, and reported in our memo of May 26~ 1962~ A photocopy of Mrs. Jordan's affidavit of 3/13/62 was given to her at this time as a result of her request. Mrs. Jordan had agreed to allow only 30 minutes for this interview, but be- cause she became more cooperative, the interview continued for nearly two hours. While Mrs. Jordan would not permit our copying or borrowing Dr. Bunde's letter and no further affidavits were taken, the following points were developed during this interview. 1. Mrs. Jordan is still undecided as to whether or not she will ~ee any repre- sentative of Merrell. She has been very much irritated by their use of private detectives, fake credit bureau calls, and inquiries from the neighbors, and contacts with her and her husband's employers. She is still extremely upset, nervous and on occasion nearly hysterical as a result of the entire matter. It is something she has been unable to cope with and she fears she may lose her present position aaa result of this. 2. Mrs. Jordan has decided she will tell the truth it she does talk to the Merrell representatives. 3. Mrs. Jordan `will cooperate with FDA and give tvutbful answers in the event she is called as a witness. At one time when she was so extremely upset about the whole matter, she had wanted to have nothing further to `do with it. 4. Mrs. Jordan was shown the copies of (1) the pages from the monkey raw d'ata books (located April 9, 1962), (2) the 4 p. chart "Monkeys Chronic Oral Toxicity Mer 29 Body Weights," (3) the chart "Figure 8, and (4) the chart "Figure 7" supplied us with the NDA, since she had access to all this material and bad helped prepare it. She was able to clear up some of our questions as follows: (a) the copies of the pages we have from the monkey raw data books are correct and have not been altered as far as she can tell. She recognized her writing and signatures. She now believes she took these books into the monkey room and made direct entries. (b) the `sick male drug monkey she referred to in her affidavit of 3/13/62 was M 34. (Note this agrees with Bruce Umberger's recollection). She know it was a small male drug monkey on 5052 (Mer 2i~). It could not be 49 since it was female, and it could not `be male 51 because it was added in the middle of the experiment and was a large monkey. M 25 could not be the one `as he had been sacrificed early. M 34 Is thus the only possible monkey it could be. (c) she now believes she was mistaken as to the amount of weight loss of M 34, but now recalls `that he was sick and did poorly and failed to gain normal'y over the experiment as the other monkeys in the same weight bracket did. This monkey did lose weight from 8.5 Kg on 12/18/58 to 8.1 Kg on 2/19/59, the last entry. (d) She confirmed that M 34 was the one that couldn't see properly and was mean. He became withdrawn and just sat In the corner of the cage. He couldn't jump in and out of the box when being weighed and was the one that missed the box when he tried to jump into it. (c) She recalled F 49 was Umberger's pet and was called "Forty-niner." She now recalled this female drug monkey was sick toward the last and lost a dramatic amount of weight. (f) She recalled male drug monkey M 51 also lost weight toward the end and was somewhat sick. (g) She further confirmed that M 34 was not autopsied in her presence. This is the reason no record of this was found in the raw `data book. She could not explain what happened to this monkey after 2/1~/G~. (h) She confirmed that the 4 p. chart "Monkeys Chronic Oral Toxicity Mer 29 Body Weights", and Figure 8 were correct graphs based on the actual weights PAGENO="0348" 4250 COMP~TIT1~ ~PROBt~El~fS IN TH~ ~DR~T~STRY as recorded in the raw data books, except for the discrepancies in the autopsy dates and possibly some graph entries toward the end. She was inclined to think that the weights at autopsy were used in the last week or two for some of the animals autopsied prior to 5/5/50 to carry the chart. out to 3/5/59 for all animals. (1) She said Dr. Van Maanen was the one that told her to falsify the chart (fig. 7.) turned in with the NDA. He had her cut off the final several weeks shown on Figure 8 which showed the dramatic loss of weight of F 49. She bad to make this chart over 3 times. He was the one who supplied the weights to be used for M 34 in the final charts. Note that the curve for M 34 on Fig. 7 does not agree with Fig. 8 or the raw data books, or the 4 page chart although the weights are In the same general range. Dr. King went along with these falsifications 100%.. (j) Mrs. Jordan noticed that there was no reference anywhere of monkey M 52. She was under the impression that this monkey had some connection with this experiment, but could not recall exactly. It is possible that the weights of this monkey were the ones supplied her by Dr. Van Maanen to be included in Fig. 7 supplied with the NDA, and perhaps this Is the monkey whose autopsy resultn were used in place of M 34. (k) Mrs. Jordan said that Dr. Van Maanen had insisted on her showing M 51 on Figure 8 as having been on Mer 29 for the entire experiment rather than for only the last 8 months. Also he insisted on her showing M 35 as a control monkey for the experiment for the entire time. She knew that this monkey had been on 5066 during the first part of the experiment. Note the weight for this monkey goes up rapidly on the charts, after the raw data books have no further record of the 5066 dosing on 3/13/58. There are no records of weights of this animal as a control and no records of any kind In the raw data books after 3/13/58 for this animal, (~) Mrs. Jordan said that because of the cost it was common practice for this firm to use monkeys for a number of experiments: Thus, monkey.s previously used as drug monkeys might wind up as controls in a later experiment. Normally all drug monkeys had been used as controls in previous experiments. 51, 49, 34 and 33 were fairly old monkeys while 35 was fairly young. She did not recall the ages of the others. (m) Mrs. Jordan stated that she had written on a form at the time of her resignation her reasons for resigning as not wanting to be a party to falsifying records as she was required to do by Dr. King. The firm now claims this form of hers Is missing, and she suspects Dr. King took it. She does not recall in how much detail she spelled out the falsifications on this form. (n) Mrs. Jordan recalled there were some very suspicious looking rats on the Mer 29 studies, but she knows of no record falsification. She did recall that about 1/3 of the Mer 29 rats died. We do not have our copy of the NDA here to check this point as we have sent it to you, but It is our recollection that deaths of rats of this order were not reported. This point should be checked out. (o) Mrs. Johnson did not recall that any of the dogs on Mer 29 died while she was there, and knew of no falsifications in the record. (p) The firm has now asked Mrs. Johnson about other irregularities concern- ing Dr. King. She has been given to understand he has been fired because of improper relations with the female employees, and for dishonest fiscal prac- tices and that Dr. Van Maanen is on extended leave. Mrs. Johnson said on one occasion, Dr. King had her pick up supplies in her personal car. After somO delay, Dr. King paid her by personal check at the rate of 4~ a mile for this company business. She later found out that Dr. King bad collected 7~ per mile from the firm for this. The firm has now asked Mrs. Jordan to put in her claim to the company for this difference which she is entitled to. (q) Mrs. Jord5n reaffirmed that Dr. King had sent a number of slides to the University of Mississippi for reading, confirmation, or interpretation. (r) Mrs. Jordan is now convinced that the falsification of records not not known by the officers of the firm above Dr. Van Maanen, and that the entire falsification picture was their joint responsibility. (s) Mrs. Jordan does not know the whereabouts of Dorothy Miner except that she believes she is running a motel and restaurant in Florida. She seemed certain that it was not Coral Gables. She believed she may now be married to a man whose first name Is Frank, who she was living with. (His last name was not known, but this is apparently Frank Sekins) Her only clue was that PAGENO="0349" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4251 ~ie was an officer in the VFW, when It was located on Ridge Ave. In Cincinnati, `Ohio. We will attempt to locate Dorothy Miner Sekins address from the VFW. We ~a1so will contact Dr. Van Maanen as soon as we are able. THOMAS M. RICE, supervisory Inspector. U.S. Government Memorandum. WILLIAM S. MEREILL Co., Cincinnati, OMo, June 19, 1962. ~To: Division of Regulatory Management. From: Cincinnati District. ~Subject: Mer 29. In response to Mr. Robert C. Branderburg's phoned request of 6/14/62, Super- visory Inspector Rice and Inspector Brodsky interviewed "Dr. Grady" who was named as "our consultant veterinarian" by Merrill. This individual was found to be Dr. K S. Grady, operator of Northern Hills Animal Clinic, 9211 Winton, Cincinnati, Ohio, and he was interviewed at his *office on 6/18/62. He indicated he was expecting us to call. Dr. Grady advised that he is a consultant for the firm, and has been under contract with the firm for about one year. He is paid a yearly stipend plus per diem when calls are made. Prior to this time he was called only as needed on a few occasions. He emphasized that he had nothing to do with dosing or running tests, and ~didn't necessarily know which animals he was examining or which experiment they were on. He was primarily consulted in connection with the health of the * animals, and except for a few instances, his work was confined to dogs. In response to a question, he said he might have on occasion been asked an opinion as to how to treat a sick monkey or two. Dr. Grady said he bad maintained no records of the examinations he had made of these animals for Merrell, and had no record of when these examinations had been made. He explained that he usually went to Merrell once a week at his convenience which was usually Tuesday, Wednesday, or Thursday. During these visits, he spent approximately 3 to 4 hours and examined the animals (primarily ~dogs) as requested on an individual basis and dictated his findings to a Merrell secretary. These animal summaries he explained, consisted of one or two page reports with 3 or 4 sentences on each animal. These reports were never signed by' Dr. Grady. He hay have seen some of them after typing on subsequent ~Isits. He probably could recognize these reports, but could not vouch for their accuracy at this time since he had not normally signed them or retained copies. He said most ~of the reports were taken by Dr. King's secretary whose name was "Bonnie". He believes she is still with the firm. All of his work was done during the time Dr. King was present. He had never worked with Knox Smith, but bad met him. He did have a few contacts with Dr. Van Maanen, but most of his contacts were with Dr. King. He said that Fritz Holthause was Dr. King's assistant, and he should have knowledge of any of his dictated reports. He stressed the point that when the firm received shipments of monkeys, and beagles, he picked them up and examined them at his clinic merely from a health standpoint. The examination of the monkeys was a chest X-ray only. He did no routine examinations on the monkeys and he did not receive or examine rats. Dogs other "than the beagles were not examined. Sometime prior to June 1961, before Dr. Grady's first contract with the firm, Dr. Grady was called in because the firm had on hand a number of sick dogs. His examination revealed hepatitis. The dogs were treated with hepatitis and distemper shots and were given antibiotics, fluids, and supportive B complex therapy. He was unable to recall the date, but he remembers he didn't have enough serum on hand to treat this large number of animals, so it was necessary ~to secure the serum from the American Cyanamide Warehouse. He recalls this was on a Friday, and it should be possible to determine this date from the warehouse If needed. Dr. Grady stated that subsequent to his contract (June 1961) he made specialized examinations primarily on dogs eyes, once a week for a period of 3 to 4 months. He noted abnormalities in several of the dog's eyes, and he observed #hat these abnormalities developed slowly through various stages or progressions PAGENO="0350" 4252 COMPET~VE PROBLEMS IN THE DRUG INDUSTRY until some of them were diagnosed as cataracts. The firm made photographs of some of these eyes, and he worked at these but was not asked to study them. Some of the dog's eyes showed fingernail like opacities. Some of these same dogs also had severe dermatitis problems. He pointed out these findings to responsible individuals of the firm through his reports, and discussions primarily with Dr. King. Although he did not know at the time he noted these abnormalities, he later found out that the dogs under study were being dosed with Mer 29. He did not know if any of these dogs died. He recalled dog identification numbers of dogs he examined In the 140-150 series. Some may have been as high as 165. He does not know but what some of these dogs were on Kevadon and there could have been several Mer 29 experiments for all he knew. He did recall that he heard some of the dosages were 10 mg/kg., 20 mg/kg., and 40 mg/kg body weight. He also was requested to look at a few rats that had dye opacities, but he does not know what studies these rats were on. He recalls that at least one Mer. 29 dog bad one eye removed, and he had been consulted as to which eye to remove. He assumed slides bad been prepared from this eye. Dr. Grady said he has not been consulted since the suspension of Dr. Van Maanen and Dr. King. Dr. Grady said he had gone to Merrell, but on finding that Dr. King and Dr. Van Maanen were not there, he called Dr. Warner who advised that they had been suspended. In speaking with Merrell personnel, Dr. Grady was not given any instructions as to what to say if contacted by Food and Drug. Prior to leaving, Dr. Grady assured us that he wanted to cooperate with us completely and that if he recalled anything of significance, he would get in touch with us. THOMAS M. Ricn. PHILIP BR0D5KY. U.S. government Memorandum. WILLIAM S. MEBRELL Co., Cincin~nati, Ohio, June 20, 1962. To: Administration: Attn: Division of Regulatory Management. From: Cincinnati District. Subject: Mer 29. In response to Mr. Robert C. Brandenburg's phone conversation with Super- visory Inspector Rice of 6/19/62. Inspector Meyring and Supervisory Inspector Rice interviewed Dr. Frank A. Nantz, M.D. 240 Doctor's Building, Cincinnati, Ohio, on 6/20/62. Dr. Nantz advised us that his first contact with the firm developed because of his friendship with Dr. Isaac Ruchman who was employed in the depart- ment of virology at the firm. 1-le has been a friend* of Dr. Ruehman for 10 to 15 years. During this period, he has visited with Dr. Ruehman and other members of the staff at the firm, and has been called out to the firm for several occasions for purposes other than those connected with Mer 29. He h~s never had any formalized relationship with the firm, and has never had any compensation for his contacts including those contacts which resulted as a result of work on Mer 29. Dr. Nantz is an M.D. and an Ophthalmologist, and in his regular practice he has been interested in research connected with the lowering of ehole~terol. As a matter of fact, Dr. Nantz told us that he had been doing some research on sito- sterol for Lilly. After Mer 29 became available, Dr. Nantz was naturally very much interested in this new drug and as other doctors, he began prescribing it. In November, 1961, as a result of his previous relationships with the firm, Dr. Van Maanan called him and asked him to come out and take a look at some dogs who were on a high level Mer 29 study. He apparently went out to the firmi and examined these dogs eyes on Thurs- day, November 9, 1961. While he was out at the firm, he was also asked to review a clinical description of four patients who had been on Mer 29. Re did not see these patients, but the firm wanted to know whether or not there was a relationship between the cataracts in the dogs eyes and the cataracts in the patients eyes. PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG. INDUSTRY 4253 Because the firm wanted an immediate opinion, Dr. Nantz wrote a letter to the firm explaining his off hand opinion, and this is apparently his letter of November 10, 1961, addressed to Dr. Van Maanen. Dr. Nantz could not remember the exact date of his visit or the letter, but knew that it was in November or December. The dates supplied here were the dates provided from Mr. Branden- burg in his phone conversation with Supervisory Inspector Rice of 6/19/62. Dr. Nantz verbally told the firm apparently Dr. Van Maanen, that he did not believe there was any relationship between the cataracts in the dogs and the patients because of the very high levels of Mer 29 in the dog study opposed to the lower levels being taken by the human patients. In his letter, he recalls that he did `believe the cataracts were the result of `the Mer 29 because of the high levels in dogs, but he believes that he finally mentioned in this letter tha't be could not say whether or not there was any relationship between the cataracts in the patients and those found in the dogs. Subsequent to his first trip and letter, Dr. Nantz made additional trips to the firm to examine the dogs' eyes. He does not recall exactly how many trip's were made or when they were made, but he did make in the neighborhood of six trips extending over a four month period. The last time Dr. Nantz has been out to the firm looking at the dogs" eyes wgs approximately one month ago. As far as Dr. Nantz knows, these dogs have not been sacrificed as yet, because the firm promised to call him when the dogs were sacrificed so that he could observe histological technics and examine sections of the lenses. When Dr. Nantz was out at the firm, he was shown slides' o'f eye tissue sections of dogs which were fed Mer 29 and sacrificed prior to his vi~it. Dr. Nantz had never examined the eyes of these dogs while the dogs were alive from which the section's were taken. Dr. Nantz knew that the dogs he had examined and who were apparently still alive now had been on a large dose of Mer 29 for approximately six months. He said that these dogs apparently developed `the cataracts rather rapidly after the six months' period, and that the formation of the cataracts was quite variable from dog to' clog. He said that in some eases, the abnormalities of the lenses tended to rec'ede even while the dog was on the drug, and then after being retained on the drug, the opacity would continue to progress and develop. Dr. Nantz also stated that there were skin disorders or rasibes which developed on the dogs who developed cataracts'. He stated that the rash developed prior to the cataracts as far as he could recall. Dr. Nantz recalled that there were other dogs on another drug which may have been related to Mer 29. He did not know how many months the dogs were on the other drug, and at this time he is not certain as to whether cataracts were observed in these dogs on this other drug. Dr. Nantz recall's that a second letter was written to' the firm about February 20, 1962. The reason for this letter was `that he had been asked by Dr. Bandie to come out to the firm to meet a well-known opthomolo'gist from Des Moines, Iowa, who had made a special trip to Merrell to examine the eyes o'f the dogs on Mer 29. Dr. Nantz was about ready to depart for a professional meeting and vacation in New Orleans, and since this request came the day before be was to leave~ be was unable to go out to the firm and meet this' do'ctor, but he did write an informal letter to Dr. Bundie explaining what he had already seen, and this letter enumerated specific points he had observed in technical terms for the use o'f this doctor. This letter was much more detailed than the letter be had written in November to the firm. Dr. Nantz and his secretary searched his files to see if they could find copies of these letters or any o'the'r correspondence, but they were unsuccessful. Dr. Nantz promised to continue to search for any correspondence and to look at home, and if he wasi able to locate any correspondence with the firm in this connection, he would advise us, so that we could secure such correspondence. At this time, Dr. Nantz recalled that he wrote only the two letters to the firm. Although Dr. Nants has not seen any cataracts in his own practice on Mer 29 patients, he inferred he changed his mind since his original letter, or original opinion `that there was no connection between Mer 29 and cataracts in humans. ThoMas M. Ricr~ JAMSS A. MEYnING. PAGENO="0352" 4254 COMPETITIVE PROELEMS IN THE DRUG INDUSTRY United States District Court for the District of Columbia Holding a criminal term SpecIal July 1963 Grand Jury sworn in on July 2, 1963 TRE UNITEn STATES OF AMERICA V. THE WM. S. MERRELL COMPANY, RICHARDSON-MEIIRELL, INC., HAROLD W. WERNER, EVERT F. VAN MAANEN, WILLIAM M. KING Criminal No. 1211-63; Grand Jury No. Original; VIolation: 18 U.S.C. 1001 The Grand Jury charges: On or about July 24, 1959, within the District of Columbia, the defendants, The Wm. S. Merreil Company, a body corporate, Ervert F. Van Maanen and William M. King, wilfully and knowingly made and `used, and caused to be made and used, In a matter within the jurisdiction of the Food and Drug Administration of the Department of Health, Education and Welfare, an agency and Department of the United States, a false writing and document knowing the same to contain fa]se, fictitious and fraudulent material statements and entries, In that the defendants knowingly and wilfully filed and caused to be filed, on or about July 24, 1959, with the said Food and Drug Administration, in Washington, D.C., a new drug application, designated as NDA 12-066, for MBR/29 (Triparanol), a new drug then `subject to' the provisions of section 505 of the Federal Food, Drug, and Cos- metic Act (21 U.S.C. 355) and which was then a matter within the jurisdiction of the said Food and Drug Administration, containing certain reports of in- ¶estigations made to show whether or not the said MER/29 (Triparanol) was safe for use, that Is, the results of toxicity studies in animals, in which the de- fendants knowingly made and caused to `be made false, fictitious and fraudulent material statements and entries, to wit: 1. The report of the six-week subacute toxicity study in rats on 37.5 and 75 mg/kg per day regimen of MER/29 contained statements and entries that four cut of eight female rats on a daily regimen of 75 mg of MER/29 per kilogram of body weight had survived six weeks of experimentation and study, and it act forth figures and amounts showing the body weights and organ weights of said four surviving rats, their food consumption during the six-week study period and statements and entries showing that the hematologic values of rats administered MER/29 during the six-week study period were within normal limits and similar to the h'em'atologic values of the control rats (i.e., rats which were .a part of the study but not administered any of the drug MER/29), all of which statements and entries the defendants knew to be false, fictitious and fraudulent in that all of the female rats on the 75 mg/kg per day regimen of MER/29 had died before the completion of the six-week study and no final organ weights, body weights or blood values were obtained covering the entire six-week period, and that in certain of the remaining rats adverse blood effects consisting of changes In leukocytes, granulocytes and lymphocytes had been observed but were not reported. 2. The report of the twelve-week chronic toxicity study In rats on 25 and 50 mg/kg per day regimen of MER/29 contained statements and entries showing that hematologic and blood determinations were within normal limits, said state- ments and entries beln.g `false, fictitious and fraudulent In that, as the defend- ants well know `but did not report, a marked increase in lenkocytes and reticulo- cytes and a number of vacn'olated and binucleated forms of lymphocytes had been observed in rats to which MER/29 had been administered. 3. The report of the chronic study in monkeys covering the period from on or about September 9, 1957 to on or about March 15, 1959 contained statements and entries that (a) rhesus monkey designated `as No. 51 in `the study had been adminis- tered MER/29 at a dosage of 40 mg/kg per day for a period of six months and thereafter at a dosage level of 20 mg/kg per day for an additional ten months, which was false, fictitious and fraudulent, as the defendants well knew, in that rhesus monkey No. 51 had not been administered a dose of 40 PAGENO="0353" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4255 mg/kg per day at any time during the course of said study, and had not been administered the dose of 20 mg/kg per day for the time specified but for a less time, to wit, approximately seven months and 26 days; (b) monkey designated as No. 35 had been a control monkey for the entire period of the study and had been administered placebos for the entire 10 months, which was false, fictitious and fraudulent, as the defendants well knew, in that said monkey No. 35 had been administered another drug which was an analogue of MER/29 for the first six months of the study and had not been used as a control monkey during that period; (c) the oral administration of MER/29 to test monkeys had caused no significant effect on the body weights of the monkeys receiving MER/29, which was, as the defendants well knew, false, fictitious and fraudulent, in that test monkeys Nos. 49 and 51 had each suffered significant loss of weight during the latter part of said study; (d) microscopic examination upon autopsy showed the liver and gall bladder organs of female monkey No. 49 to be normal, which was false, fic- titious and fraudulent, as defendants well knew, in that such examination disclosed that monkey No. 49 had an enlarged gall bladder, s~verai small necrotic areas in the liver and many adhesions between the lung and chest cavity; (e) microscopic examination upon autopsy of monkey No. 51 showed a normal heart organ, which was false, fictitious and fraudulent, as the cle- fendants well knew, in that the said examination of the heart of monkey No. 51 revealed a condition described as possible left ventricular hyper- trophy, and (f) during the aforesaid chronic study, the MER/29-treated monkeys and the control monkeys showed similar hematologic Values, and the mor- phology of the peripheral blood was similar in both the MER/29.treated monkeys and the control monkeys, which were false, fictitious and fraudu- lent, as the defendants well knew, in that various blood dy~cr~sias such as vacuolated and binucleated lympl~oc~rtes, and lymphocytes with irregularly- shaped nuclei had been observed in the blood smears taken from monkeys receiving MER/29 but not in those taken from the control monkeys. $econd Count 1. At the times mentioned herein, The Wm. S. Merrell Company hfid submitted to the Food and Drug Administration a New Drug Application, and amendments thereto, for a new drug known as M'ER/29 (Triparanol), said application stating and representing that attached thereto were full reports of all investigations that had been made to show whether or not the drug was safe for use. 2. During the period from on or about February 17, 1900 to March 31, 1900, within the District of Cqlumbia, the defendants, The Wm. S. Merreli Company, a body corpo~rate, Harold W. Werner, Evert F. Van 1\?Eaanen and William M. King, knowingly and wilfully concealed and covered up, and caused to be concealed and covered up, by trick and scheme, material facts in a matter within the jurisdiction of a Department and agency of the United States, in that during the period above-mentioned and at the place aforesaid, the defendants caused to be submitted to the Food and Drug Administration of the Department of Health, Education and Welware, as an amendment to the New Drug Application of The Wm. S. Merrell Company for MEI~/29 (Priparanol), a new drug then subject to the provisions of section 505 of the Federal Food, Drug and Cosmetic Act (21 U.S.C. 355) and which was then a matter within the jurisdiction of the Food and Drug Administration of the Department of Health, Education and Welfare, certain reports purporting to be full reports of the results of all investigations which were made by The Wm. S. Merrell Company to show whether or not said drug `was safe for use, said defendants knowingly and wilfully withholding, and omitting to include therewith, reports of the results of certain Investigations, and data and information obtained therefrom, which had l~een made to show whether or not the drug was safe for use, and failing to disclose the fact that certain investigations had been made, and that adverse and toxic effects had been observed in animals to which the drug had `been administered, said investigation's being more particularly described as follows: A. An investigation made by The Wm. S. Merrell Company, begun on or about June 23, 1959 with three female monkeys, to study the effect of dosages of 10 81-280-69-pt. 1O-23 PAGENO="0354" 4256 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mg/kg per day of MER/29 upon the ovaries of such animals, in which it was ob- served (a) that one monkey bad ovarian changes in the form of an increase in the number of ovarian folliéles which did not appear to have matured to a state of ovulation, (b) that one monkey had developed severe leukopenia and agranulocy- tosis, and (C) that two monkeys had a depressed granulocyte count, *atypical lymphocytes and high leukocyte counts. B. An investigation made by The Wm. S. Merrell Company in which four female monkeys were started on a toxicity study on or about September 15, 1959 for the purpose of determining the eftect of an administration of 5 mg/kg per day of MER/29 on ovarian morphology, at the end of which investigation no evidence of recent ov~liation was found. C. A. recovery toxicity investigation made by The Wm. S. Merrell Company with femalo rats, started on or about January 10, 1058 to determine the etiology of abnormal bloOd changes, in which it was observed that eight out of ten rats being administered a dosage of 50 mg/kg per day of MEtR/2~ had died as of Jan- uary 27, 158, and the surviving two rats whose dosage as of that date was re- duced to 25 mg/kg per day of M~R/29 had'died as of February 3, 1958. D. A recovery toxicity Investigation made by The Wm. S. Merrell Company with female' rats started on or about January 30, 1958 to determine the etiology of abnormal blood changes whIch had been observed in previous toxicity studies, the results of which showed that rats being administered MER/29 developed abnormal blood changes in the form of bini.~cleated lymphocytes, blood dyscrasias and an incre~tse in reticulocytes. E. A toxicity investigation in male apd female rats which was conducted during the period between July 1959 through October 1959 by The Wm. S. Mer- rell Company to determine the effect of MER/29 on fertility and gestation, such rats having been administered 5 mg and 15 mg/kg per day of MER/29, in which it was observed that doses of 15 mg/kg per day reduced the conception rate when given prior to and during cohabitation, and F. A toxicity investigation in malé~ and female rats at dosages of 10 and 25 mg/kg per day `o~ M~E1~/29 which was conducted between on `or about July 7, 1959 and October t959 by The Endocrine Laboratories of Madison, Inc., Madison, Wisconsin, pursuant to a contract with The Wm. S. Merrell Company to deter- mine the effect of MEEj29 on fertility and gestation, in which it was observed that there was a reduced conception rate among rats receiving doses of 25 mg/ kg per day of MER/29 during pregnancy, the size of the litter was reduced and there was an increase in rate of. the deaths of the young during the 24-hour period after delivery. Third Co~t 1. The Grand Jury realleges all ~f the allegations of the first paragraph of the Second Count of this Indictment, 2. On, Or about February 17, 1960, within .the District of Columbia, the de- fendants, The Wm. ~. Merrell Company, ~ body corporate, Evert F. Van Maanen and William M. King, in a matter within the jurisdiction of the Food and Drug Administration of' the Department of Bealth, Education and Welfare, an agency and Department of the United states,. knowingly and w~lful1y made and used, and caused to be made and used, a false writing and document knowing the same to contain false, fiètltious and fraudulent statements and entries, in that on Febru- ary 17, 1960, the defendants caused to be submitted to said Food and Drug Admin- istration, at Washington, D.C., on behalf of said The Wm. S. Merrell Company, as an amendment to its New Drug Application for MER/29 (Triparanol), a new drug then subject to the provisions of section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 855) and which was then a matter within the jurisdiction of the Food and Drug Administration, a writing containing reports of investiga- tions that had been made to show whether or not the drug was safe for use, such writing containing the following false, fictitious and fraudulent statements and entries, to wit: (a) The report of a six-thonth study in mongrel dogs receiving a dosage of 25 mg/kg per day of MER/29, which contained false and fraudulent state- ments and entries that three of the dogs had died early in the experiment and that two of the remaining dogs had maintained their body weight dur- ing the course of the study, when in truth and in, fact, as the defendants well knew, the dead dogs had been replaced by three additional dogs and all of the dogs in the study had lost body weight. PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4257 (b) The report of a three-month study with five beagle dogs receiving a dose of 40 mg/kg per day of MER/29, which contained false and fraudulent statements and entries, as follows; (1) that microscopic examination of dog No. 69 had disclosed a reduction of the number of mature spermatocytes in the seminiferous tubules and a paucity of spermatozoa in the vas, when in truth and in fact, as the defendants well knew, no spermatocytes were so found and vitally important portions of the gonads had undergone marked tubular and interstitial atrophy; (2) that between the sixth week of the study and its conclusion dog No. 69 had gained weight when in truth and in fact, as the defend- ants well knew, it bad lost weight; (3) that the evaluation of the dog study was difficult because of the existence of concomitant diseases in The Wm. S. Merrell Company's dog colony and particularly the outbreak of distemper in October 1959, when in truth and in fact, as the defendants well knew, the original study which started on October 21, 1959, had been discontinued on October 30, 1959, and a new study begun on November 3, 1959, with different dogs, which had not contacted distemper during the aforesaid outbreak. (c) The report of a four-month study in three adult mongrel dogs re- ceiving a dose of 10 mg/kg per day of MER/29, which contained false, fictitious and fraudulent statements and entries, as follows; (1) that the administration of MER/29 at a dosage of 10 mg/kg of MER/29 did not affect the peripheral blood values of these dogs and that the hematologic values for dog No. 57 during the study showed the initial and final hemoglobin in grams per 100 cc as 11.8 and 14.2 respectively, and the initial and final bematocrit percentum packed cells as 34 and 40 respectively, when in truth and in fact, ~ts the de- fendants well knew, the initial and final hemoglobin values for dog No. 57 remained at 9.0 grams, and the initial and final hematocrit values for dog No. 57 were 27 and 32 percentum respectively; (2) that although dog No. 58 showed an intial weight loss when the drug administration was started, it showed a gain for the remainder of the study so that the loss amounted to approximately one kilogram (2.2 lbs.), when in truth and in fact, as the defendants well knew, dog No. 58 had lost 3.7 pounds during the last week of the study. Fourth Count On or about February 8, 1960, within the District of Columbia, the defendants, The Wm. S. Merrell Company, a body corporate, Harold W. Werner and Evert F. Van Maanen knowingly a~d willfully made, and caused to be made, false, fictitious and fradulent statements and representations of material facts in a matter within the jurisdiction of a Department and agency of the United States, in that on said date The Wm. S. Merrell Company submitted to the Food and Drug Administration of the Department of Health, Education and Welfare, at Washington, D.C., a letter dated February 4, 1960 enclosing a revised brochure for MER/29 (Triparanol), a new drug then subject to the provisions of section 505 of the Federal Food, Drug, and Comestic Act (21 U.S.C. 355) and which was then a matter within the jurisdiction of the Food and Drug Administration, in which letter was falsely and fraudulently stated and represented that a caution statement reading, "Since cholesterol plays an important role in the development of the fetus, the drug should not be administered during pregnancy" had been inserted in the brochure "purely on theoretical grounds", when in truth and in fact, as the said defendant well knew, investigations and experi- ments had been conducted by said The Wm. S. 1VEerrell Company, `and by an independent laboratory pursuant to its request, the results of which disclosed that the administration of the drug to animals had resulted in adverse and deleterious effects upon the ovarian cycle, the rate of conception, the size of litters and the ability of the offspring to survive. Fifth Count 1. At the times mentioned herein, the William S. Merrill Company had sub- mitted to the Food and Drug Administration of the Department of Health, Education and Welfare, a New Drug Application, and amendment thereto, for ME'R/29 (Triparanol), a new drug then subject to the provisions of section 505 PAGENO="0356" 4258 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of the Federal Food, Drug & Comestic Act (21 U.S.C. 355), and had submitted as a part thereof, reports of investigations that had been made to shoW whether or not the drug was safe for use, said reports being submitted in an effect to persuade the Food and Drug Administration to permit said New Drug Applica- tion to become effective. 2. Among such reports was one reporting the results of a three-month toxicity study in rats being administered doses of MER/29 at the rate of 20 mg/kg per day and 40 mg/kg per day, in which it was reported that corneal opacities had been observed in the eyes of eight out of twenty rats which had been administered 40 mg/kg per day in the course of the investigation, such rats having been autop- sled at the time of the report. 3. Said three-month toxicity study of the effect of the administration of MER) 29 to rats at dosage levels of 20 mg/kg and 40 mg/kg per day was only one part of a continuing investigation which had been set up to continue for a period of one year; as of February 24, 1960, following the submission of the report per- taining to the three-month investigation, corneal opacities had been observed in the eyes of live rats being subjected to such continued investigation, corneal opacities being observed in 2 out of 38 rats used as controls, and in the eyes of one out of 35 rats being administered MER/29 in doses of 20 mg/kg per day, and in the eyes of 22 out of 36 rats being administered MER/29 in doses of 40 mg/kg per day. 4. On or about March 2, 1960, at Washington, D.C., the defendant, The William S. Merrell Company, a body corporate, knowingly and wilfully concealed and covered up, and caused to be concealed and `covered up, by trick and scheme, a material fact in a matter within the jurisdiction of a department and agency of the United States, in that it knowingly and wilfully concealed `and covered up and caused to be concealed and covered up in a matter within the jurisdic- tion of the Food and Drug Administration of the Department of Health, Edu- cation, and Welfare, to wit, the New Drug Application by The William S. Merrell Company for ME~R/29 (Triparanol) a tme~v drug then subject to the pro- visions of section 505 of the Food, Drug and Cosmetic Act (21 U.S.C. 355) the fact that corneal opacities had been observed in the eyes of rats to which MER/29 was being administered at doses of 20 mg/kg per day and 40 mug/kg per day, by the trick and scheme of submitting to the Food and Drug Adminis- tration a letter dated February 29, 1960, from The William S. Merrell Company pertaining to said drug in which it was stated, with respect to corneal opacities in rats which bad previously been reported in the amended New Drug Appli- cation for drug MBR/29, that "Corneal changes have now been found in the control animals." but which omitted any statement that additional corneal opacities had been observed in the eyes of live rats to which ME~R/20 was being administered for experimental purposes during the month of February 1060, as alleged in paragraph three of this count, and that the control animals were different from those which bad been used in its previously reported three-month study. Violation of 18 U.S.C. 1001. Skoth Count On or about March 7, 1960, within the District of Columbia, the defendants, The Wm. S. Merrell Company, a body corporate, Evert F. Van Maanen and William M. King, in a matter within the jurisdiction of a Department and agency of the United States, knowingly and wilfully concealed and covered up, and caused to be concealed and covered up, by trick and scheme, material facts, in that at the aforesaid time and place during a meeting with representatives of the Food and Drug Administration of the Department of Health, Education, and Welfare to discuss the toxicity of MER/29 (Triparanol), a new drug then sub- ject to the provisions of section 505 of the Federal' Food, Drug, and Cosmetic Act (21 U.S.C. 355), for which a New Drug Application had been filed with said Food and Drug Administration, and which was then a matter within the juris- diction of the FoGd and Drug Administration, the defendants did submit to said Food and Drug Administration a document and writing entitled "Summary of Toxicity Studies" and did discuss the results of animal and clinical investiga- tions of MER/29 which The Wm. S. iVEerrell Company had made to show whether or not the drug was safe for use, but the defendants wilfully and knowingly failed and omitted to make known, either in said summary or in their oral con- versations, the fact that The Wm. S. Merrell Company was then conducting a chronic toxicity study in rats in which during the month of February 1960 PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4259 corneal opacities had been observed in rats receiving dosages of 40 mg/kg per day and 20 mg/kg per day of MER/29, and that in two dogs which had received 40 mg/kg per day of MER/29 for three months, observations had. been made that one dog appeared to be blind and an opthalmoscopic examination revealed an opacity of the crystalline lens and that the retina was not visible, and that the other dog appeared to have an eye infection and an ophtlzalmoseopic examination revealed a slight opacity of the crystalline lens and that the retina was not clearly visible. Violation of 18 U.S.C. 1001. seventh Count 1. On or about June 29, 1960, Dr. Frank J. Talbot, Medical Officer of the Food and Drug Administration of the Department of Health, Education and Welfare, wrote to The Wm. S. Merrell Company advising that Lauretta E. Fox had re- jorted that certain test rats which had been administered MER/29, a new drug then subject to the provisions of section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), had developed an opaque cornea and lens in the eyes during an experiment and requested that The Wm. S. Merrell Company comment upon such study. 2. On or about July 25, 1960, within the District of Columbia, the defendants, The Wm. S. Merrell Company, a body corporate, and William M. King, in a matter within the jurisdiction of a Department and agency of the United States, knowingly and wilfully made and used and caused to be made and used a false writing and document knowing the same to contain false, lictitious and fradulent material statements and entries and knowingly r~nd, willfully concealed and covered up, and caused to be concealed and covered up, by trick and scheme, material facts in that they caused. to be submitted to the Food and Drug Ad- ministration of the Department of Health, Education and Welfare, at Wash- ington, D.C,, on or about July 25, 1960, in response to the reequest mentioned in paragraph 1 above, a memoradum, dated July 22, 1960 prepared by the de- fendant William M. King, concerning the Lauretta Fox study in which it was falsely and fraudulently stated that "thousands of rats have been involved in many different experiments with MER/29 here in our laboratories,": that "in only one group of animals in one experiment and at only one time did we observe eye changes," and that "We have no evidence from our experience or from the literature that MER/29 would in itself, produce such changes", said defendants then and there well knowing that in addition to the eight corneal opacities, pre- viously reported to the Food and Drug Administration in February 1960, at least three out of 35 rate being administered MER/29 since that date at a daily dosage of 20 mg per kg of body weight, and at least 25 out of 29 rats being ad- ministered MER/29 since that date at a daily dosage of 40 mg per kg of body weight, had developed corneal opacities, and that in a dog study completed in February 1900 opacities of the crystalline lens had been observed in two dogs which had received 40 mg/kg per day dosage of MER/29 for a period of three months, which facts were not disclosed in said memorandum but were know- ingly and wilfully omitted therefrom and concealed from said Food and Drug Administration. Eighth Count 1. On or about October 6, 1960, Dr. Frank J. Talbot, Medical Officer of the Food and Drug Administration of the Department of Health, Education and Welfare, inquired of The Wm. S. Merrell Company concerning the effect of MER/29, a new drug then subject to the provisions of section 505 of the Fed- eral Food, Drug, and Cosmetic Act (18 U.S.C. 355), upon the eyes of rats and concerning the rat studies of Lauretta Fox. 2. On or about October 12, 1960, within the District of Columbia, the defendant, The Wm. S. Merrell Company, a body corporate, in a matter within the juris- diction of the Food and Drug Administration of the Department of Health, Education and Welfare, an agency and Department of the United States, know- ingly and wilfully concealed and covered up and caused to be concealed and cov- ered up by trick and scheme a material fact, in that at the aforesaid time and place the defendant did conceal and cover up .and cause to be concealed and covered up in a matter within the jurisdiction of the Food and Drug Admin- istration, the fact that in October 1959, The Wm. S. Merrell Company h,ad initi- ated a toxicity study concerning the effect of MER/29 on rats which study was to be divided into three parts, one of three months', one of six months' and one PAGENO="0358" 4260 COMPETITIVE PROBLEMS IN TIlE DRTJG INDUSTRY of twelve months' duration, and that. during the period between February and on or about October 10, 1960, examinations had been made of the rats' eyes which disclosed that the number of corn~a1 opacities was increasing in rats receiving a daily dose of 20 mg/kg and 40 mg/kg of MER/29 and that by Sep- tember 1960 nearly all of the rats remaining on the study of the 40 mg/kg per day dosage had developed some degree of blindness; said material facts being con- cealed and covered up by the trick and scheme of submitting by letter to the Food and Drug Administration at Washington, D.C., dated October 10, 1960, in response to its inquiry as set forth in paragraph 1, a carbon copy of a letter to Lauretta Ii Fox dated September 29, 1960, in which it was falsely stated `and represented that the results of Lauretta Fox' study, indicating involvement of the cornea and lens of the rats' eyes, "are most surprising to us," and that "Our path- ologist states that he has never seen such involvement of the lens", The Wm. S. Merrell Company wilfully and intentionally omitting, In its letter to the Food and Drug Administration and in the carbon copy of the letter to Lauretta Fox enclosed therein, to disclose the true facts which it well knew, as set out above, concerning the existence of Its continuing toxicity study in rats and the observa- tioi~ of corneal opacities in the eyes of rats during the period from February to October 1960. Ninth Count 1. On or abotit September 23, 1960, Dr. Frank J. Talbot, Medical Officer of the Food and Drug Administration of the Department of Health, Education and Welfare, requested The Wm. S. Merrell Company to incorporate in its labeling a discussion of the effect on pregnant rats of large doses of MEEj29, a new drug then subject to the provisions of section 505 of the Food, Drug, and CoSmetic Act (21 U.S.C. 355), and stating `that the labeling for MER/29 should include a con- traindication of the drug In women of the childbearing age, and ál~o that, if the drug were prescribed for such women, a pregnancy test should be made every three months. 2. On'or about October 10, 1960, within the District of Columbia, the defend- ants, The Wm. S. Merrell Company, a body corporate, Harold W. Werner and Es~ert F. Van Maanen, knowingly and wilfully concealed and covered up, and caused to be concealed and covered up, by trick and scheme, material facts in a matter within the jurisdiction of the Food and Drug Administration of the De- partment of Health, Education and Welfare, in that at the time and place afore- said the defendants concealed and covered up, and caused to be concealed and coverd up, the fact that The Wm. S. Merrell Company had conducted various investigations In animals to ascertain the effect of the administration of MER/29 upon the ovaries of female monkeys and upon the fertility and gestation of fe- male rats and the effect of said drug upon the offspring of female rats to which it had been administered, said investigations being more particularly described as follows: (a) An investigation made by The Wm. S. Merrell Company; begun on or about June 23, 1959 with three female monkeys, to study the effect of dosages of 10 mg/kg per day of MER/29 upon the ovaries of such animals, in which it was observed that one monkey bad ovarian changes similar to the changes observed in the ovaries of a monky on a previous MER/29 toxi- city study. (b) An investigation made by The Wm. S. Merrell Company in which four female monkeys were `started on a toxicity study on or about September 15, 1959 for the purpose of determining the effect of an administration of 5 mg/kg per day of MER/29 on ovarian morphology, at the end of which in- vestigation no evidence of recent ovulation was found. (c) A toxicity investigation in male and female rats which was conducted during the period between July 1959 through October 1959 by The Wm. S. Merrell Company, to determine the effect of MER/29 on fertility and gesta- tion, such rats having been administered 5 mg/kg and 15 mg/kg per day of MER/29, in which It was observed that doses of 15 mg/kg per day reduced the conception rate when given prior to and during cohabitation. (d) A toxicity investigation in male and female rats at dosages of 10 and 25 mg/kg per day of MER/29 which was conducted between on or about July 7, 1059 and October 1959 by The Endocrine Laboratories of Madison, Inc., Madison, Wisconsin, pursuant to a contract with The Win. S. Merrell Company to determine the effect of MER/29 on fertility and gestation, in PAGENO="0359" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4261 which it was observed that there was a reduced conception rate among rats receiving doses of 25 mg/kg per day of MER/29 during pregnancy, the size of the litter was reduced and there was an increase in rate of the deaths of the young during the 24-hour period after delivery. Said concealment end covering up being effected by the trick and scheme of submitting to Dr. Frank J. Palbot, Medical Officer of the Food and Drug Admin- istration, a letter dated October 7, 1960, from The Wm. S. Merrell Company in response to his request set out in paragraph 1, in which letter lit was stated that "while high doses of MER/29 interfere with conception in rats there is no evidence that this is a clinical problem," and by substantiating this statement with memo- randa and references to studies and medical literature which showed that other well known and widely used drugs had similar effects upon rats, but wilfully omitting and failing to disclose and make known the existence of the aforesaid MER/29 animal studies and the results thereof. Tenth Count From on or about October26, 1961 to ou or about December 1, 1961. withIn the District of Colunibia, the defendants, Richardson-Merrell, Inc., a body corporate, Harold W. Werner, Evert F. Van Maanen and William M. King, for the purpose of and with the intent to influence the Food and Drug Administration of the De- partment of Health, Education, and Welfare, an agency and Department of the United States, in the exercise of its function of passing upon and approving the issuance of a warning letter by said Richardson-Merrell, Inc., to the medical pro- fession concerning MER/29 (Triparanol), a new drug subject to the provisions of section 505 of the Food, Drug, and Cosmetic Act (21 U.S.C. 355), and its function of determining whether administrative action calling for the suspension of the effeetivenes oct the New Drug Application for MEIt/29 sl~ou1d be instituted, know- ingly and wilfully concealed and covered up, and caused to be concealed and covered up, by trick and scheme, material facts in a matter within the jurisdic- tion of said Food and Drug Administration, in that, following the receipt, on or about October 18, 1961, from said Rlchardson-Merrell, Inc., of a report that MER/29 had caused eye injuries to humans, the Food and Drug Administration requested said Richardson-Merrell, Inc., to furnish complete data in its possession concerning adverseand toxic reactions resulting from MER/29 therapy in humans and animals, including all information concerning eye changes in humans and animals with reference to both corneal and lenticular changes; that thereafter between on or about October 26, 1961 and on or about December 1, 1961, certain officers and employees of said Richardson-Merrell, Inc., met from time to time with representatives of the Food and Drug Administration at Washington, D.C., to discuss the safety of MER/29, the preparation of `the warning letter and the question of whether the drug should. be withdrawn from public use; that during the course of the aforesaid discussions and by means of letters addressed to said Food and Drug Administration at Washington, D.C., said defendants did present and submit, and cause to be presented an submitted in purported compliance with the aforesaid request, certain data, reports of investigations and other. informa- tion pertaining to adverse and toxic reactions of the said drug in animals and humans, including information concerning eye changes in animals and in humans, which said defendants falsely and fraudulently led the Food and Drug Adminis- tration to believe constituted all of the aforesaid reports of investigations, date and information pertaining to eye changes in humans and animals possessed by defendent Richardson-Merrell, Inc., said defendants well knowing that they had failed and omitted to report and make known the following material facts, to wit: 1. That said defendant Richardson-Merrefl, Inc., bad in its possession data and information obtained by its former subsidiary~ The Wm. S. Merrell Com- pany, from an investigation which that company had conducted as to the safety of the drug between on or about October 26, 1959 and on or about November 1, 1960, during which period said drug was administered to rats at 20 mg/kg and 40 mg/kg per day and which rats developed eye opacities in a quantity and degree greater than those reported to the Food and Drug Administration on February 17, 1960; 2. That said defendant Richardson-Merrell, Inc., was then conducting an investigation, which began on or abokt April 19, 1061, to determine the effect of MER/29 upon the eyes of rats, during the course of which 1V[ER/20 and MER/29 plus Vitamins and Cholesterol was being administered to rats at a dosage of 40 mg/kg per day and in which eye opacities were observed first to PAGENO="0360" 4262 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY have developed in June, 1961, and to have continued to increase in number and develop in degree to the point that on or about November 15, 1961 eye opacities had developed in all female rats being administered MER/29 and MER/29 plus Vitamins and Cholesterol at a dosage of. 40 mg/kg per day, and opacities had developed in the eyes of 20 out of 24 male rats being administered MER/29 and MER/29 plus Vitamins and Cholesterol: at `a daily dosage of 40 mg/kg while none of the control rats had developed any eye changes in the aforesaid study. Eleventh Count On or about October 26, 1961, within the District of Columbia the defendants, Richards'on-Merrell, Inc., a body corporate; and Evert F. Van Maanen, in a matter within the jurisdiction of a Depattmetit and agency of the United States, kno~vingl~ and wilfnlly made arid used; and caused to be made and used, a false ~.vriting and document knowing the' sam~ to eontah~ false, fictitious and frau~u- lent statements and entries, in that at the time and place afor~aid, the defendant Riehardson-Merrejl, Inc., for the purpose and with the intent of influencing the Food arid Drug Administration of the Department of Health, Education and Welfare in the exercise of its function of passing upon and approving the issuance of a `warning letter by said Richarcl~sñ-Merrell, Inc., to the medical profession concerning MUR/29, a new drug subject to the provisions `of section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), siibmitted to the Food and Drug Administration of the Departrnept of Health, ~duca'tion and Welfare a report from E. F. Van Maanen to Dr. ~Vernei~, dated Qctober 24, 19~1, entitled "Chronic Study with MER/29 Tn Dogs I~rçgress, fleport," said progress report containing the following ~tatements and ~ptries whidh the 4efendants knew to be false, fictitious and frandulent, to wit: 1. A rtatethent that on or about `October 18, 19~i, the fundi `of the eyes of dogs Nos. i5S, 166 and `171 appeare~ normal, when in' truth and in fact, as the defendants well knew, there ~as',an inability to' visu,al'i~e the fundus of the left eye and difficulty i~i visuaTi~ii~g the fundus' of the right eye of dog No. 158, in dog No. 166 spoke-like striations persisted bilaterally, and in dog No. 171 striations were seen at the innercanthus aspect of both eyes. 2. A statement that on or about October 18, 1961, the eyes of the sur- viving dogs Nos. 148, 149 and 169 which were being administered MER/29 plus Vitamins and Cholesterol were all normal, when in truth and in fact, as the defendants well knew,, on or about October 18, 1961, these dogs had developed the following eye changes: (a) Dog No. 14&-,8trlations had been observed at the inner-canthus aspect of both eyes deep `to the cornea. (b) Dog No. 149.-Left eye showed slight fluorescent reflections at 9 o'clock. (c) Dog No. 16~.-Striations had' been seen in the left eye extending inward 1/2 mm. at 9 o'clock and In the right eye at 8 o'clock. Twelft~i Count 1. Eetween December 22, 1961 and December 29, `1961, The Wm. S. Merrell Company, Division of Richardson-Merrell, Inc., bad `pending `before the Food and Drug Administration of the Department of Health; EduCation, and Welfare a supplementhi New Drug Ap~lication for MER/29, a new drug then subject to the provisions of section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. $55), which proposed changes in statements in the brochure of said drug pertaining to the safety `Of the drug' and possible adverse and toxic effects arising from Its use. During~the aforesaid period there were' submitted to the Food and Drug Administration at Washington, D.C.; as a part of said Applica- tion, reports" of investigations made to show the safety of MER/29, and data and information pertaining to the possible adverse and toxic reactions of the drug, said Richardson-Merrell, Inc., representing that said reports of investi- gations, data and information were full and complete and constituted all of the data and information in its possession relating to the safety of the afore- said drug and possible adverse and toxic reactions due to the drug in both animals and humans which it had observed or was reported to it. 2. On or about December 29, 1961, within the District of Columbia, the de- fendants, Richardson-Merrell, Inc., a body corporate, Harold W. Werner, Evert F. Van Maanen and William M. King, for the purpose and with the intent of Influencing the Food and Drug Administration in the exercise of its function PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4263 of determining whether to permit the aforesaid supplemental New Drug Appli- cation for drug MER/29 to become effective, knowingly and wilfully concealed mad covered up and caused to be concealed and covered up by trick and scheme material facts in a matter within the jurisdiction of the Food and Drug Ad- ministration of the Department of Health, Education, and Welfare, an agency and Department of the United States, in that by a letter dated December 28, 1961, said Riehardson-Merrell, Inc., made a submission to the Food and Drug Administration of results of investigations, made to show whether or not the drug was safe for use and pertaining to the changes in the aforesaid brochure and representing thereby that it had submitted full reports of all such investi- gations as of that date, said defendants well knowing that as of December 28, 1961, there were certain reports of Investigations, conducted by itself and by its former subsidiary The Wm. S. Merrell Company and data and information concerning the adverse and toxic reactions of MER/29 therapy in animals ifl the possession of Richardson-Merrell, Inc., which had not been submitted and the existence of which was concealed from said Food and Drug Administration, to wit: (a) An investigation made by The Wm. S. Merrell Company, begun on or about June 23, 1959 with threefemale monkeys, to study the effect of dosages of 10 mg/kg per day of MER/29 upon the ovaries of such animals, in which it was observed (a) that one monkey had ovarian changes in the form of an increase in the number of ovarian follicles which did not appear to have matured to a state of ovulation, (b) that one monkey had developed severe leukopenia and agranulocytosis, and (c) that two monkeys bad a depressed granulocyte count, atyptical lymphocytes and high leukocyte counts. (b) An investigation made by The Wm. S. Merrell Company in which four female monkeys were started on a toxicity study on or about September 15, 1959 for the purpose of determinIng the effect of an administration of 5 mg/kg per day of MER/20 on ovarian morphology, at the end of which In- vestigation no evidence of recent ovulation was fotind. (c) A recovery toxicity investigation made by The Wm. S. Merrell Com- pany with female rats, started on or about January 10, 1958 to determine the etiology of abnormal blood changes, in which it was observed that eight out of the ten rats being administered a dosage of 50 mg/kg per day of MER/29 had died as of January 27, 1958. and the surviving two rats whose dosage as of that date was reduced to 25 mg/kg per day of MER/29 bad died as of February 3, 1958. (d) A recovery toxicity investigation made by The Wm. S, i\'lerrell Com- pany with female rats, started on or about February 30, 1958 to determine the etiology of abnormal blood changes which had been observed in previous toxicity studies, the results of which shewed that rats being administered MER/29 had developed abnormal blood changes in the form of binucleated lymphocytes, blood dyscrasias and an increase in raticulocytes. (e) A toxicity investigation conducted by The Wm. S. Merrell Company between on or about October 26, 1959 and oh or about November 1, 1960, during which period said drug was administered to rats at 20 mg/kg and 40 mg/kg per day and which rats developed eye opacities in a quantity and de- gree greater than those reported to the Food and Drug Administration on February 17, 1960. (f) A toxicity investigation in rates conducted by Richardson-Merrell, Inc., which began on or about April 19, 1961, to determine the effect of MER/29 ~pon the eyes of rats during the course of which MER/29 and MER/29 plus Vitamins and Cholesterol was being administered to rats at a dosage of 40 mg/kg per day in which it was observed that on or about November 15, 1961 eye opacities had developed in all female rats being administered MER/29 and MER/29 plus Vitamins and Cholesterol at a dosage of 40 mg/kg per day, and opacities bad developed in the eyes of 20 out of 24 male rats being administered MER/29 and MER/29 plus Vitamins and Cholesterol at a daily dosage of 40 mg/kg while none of the control rats had developed any eye changes in the aforesaid study. A True Bill: Attorney of the United ~States in and for the District of Columbia. Foreman. PAGENO="0362" 4264 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY RICHARDSON-MERRELL INTER-DEPARTMENT MEMORANDt)MS AND CORRESPONDENCE [Inter-Derartrnent Memo, Oct. 7, 1058) To: Dr. H. W. Werner (3). From: Medj~»=a1 Research Department. Subject: ME~-29-IIEMATOLOGY (Dr. Van Maanen's memorandum of 10/6/58 to Dr. McMaster). The decision not to release blood smears from our toxicological studies to our hematological consultant, Dr. Jane Deaforges, represents a serious handicap in the MER-29 studies. As you know, Dr. MeMaster and I have a moral and medical obligation to use MER-29 snfely. Accordingly, we are both anxious to find out more about the blood changes which have been reported in experimental animals, The secon4 point is that if the changes, in question are ~f no importance, it might be that we would have been justified in not describing them in the brochure. This I would question but now, that. they have been described in the brochure, .theyare known to all of our potential investigators. We have routinely eor~ie up against unwillingness to administer MER-29 to human beings because the significance of those findings is not well understood. To some extent we have overcome this resistance, and actually we have succeeded in giving MER-29 to some human beings. Despite this we are encountering continued resistance to studies on MER~-29 because of the blood smears. It is comforting to know that, during the brief period of time that relatively large doses of MER-29 . have been given to a patient in. Rochester, Minnesota, the characteristic, changes have not appeared. If they do appear, I will direct your attention to the last paragraph in Dr. Van Maanen's memorandum and sug- gest that we will probably not obtain the smears for study in our Biological Research Department, on the.. grounds that the animal hamatologists are not sufilciently versed in clinical. hematology to interpret the human smears properly. R. C. P000E, M.D. [Inter-Department Memo, May 5, 1~59J To: Drs. Blohm, Holtkamp, King, Ktihn, and Ruchman. From: E. F. Van Maanen. Subject ~., MEI~-29 $rochure., )~esterday, it was rudely brought to my attention that the Medical Research Department~ is not too happy about certal~ items in our MER-29 brochure, Fur- thermore, the Medical Research .Dep~rtmeut complained that the latest Informa- tion on MER-.-29 obtained in our laboratories was not included in thern brochure. I have to admit that they are right on both accounts and :1 would like to remedy this situation as soon as possible. I would like to request the respective Department Heads to go over their secti~ns 1~ `the MER-29 brochure and to weed out extraneous material, such as windy descriptions of methods and results which were negative and are not contributing anything to clinical investigators. At the same time, add new mate- rial, particularly those experiments which indicate the safety of the compound as well as itsmechanism of action. In the toxicity section, I wOuld like to request Dr. King to delete all material on the funn~v lymphocytes. I wonder also whether the roticulocyte change in the rate experiment needs the emphasis it has. Naturally, we should include our new chronic toxicity studies in monkeys. , To my knowledge, neither the Pharmacology Department nor the Microbiology Department has anything new to add to the data. I would appreciate it, however, if both Department Heads would go over their sections and suggest construc- tive changes. 1)r. Carkhuff has found recently that MER-29-citrate solution (as well as the strong hydrochloric acid solution of the bnse) changes rapidly upOn standing. PAGENO="0363" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4265 The infrared spectrum indicates that MER-29 dehydrates to the ethylene (WSM- 45~4). This compound was tested by Dr. Blohm and, surprisingly, has no cholo- starol-lowering effects. I do not think that this finding alters all our biological observations, since most of our results were obtained with the base. However, our cardiovascular results were obtained solely with the citrate salt. I would appreciate, therefore definitive information whether the hypotensive effects relate to the ethylene or ethanol. Even though I know that you are all very busy. I would like to suggest that revisions of your sections be in my office by May 15. [inter-Department Memo, May 6, 1P59] To: Dr. K. D. Carkhuff From: Medical Research Deparment Subject: Intravenous MER-29 1 mg./cc. Many thanks for outlining the reasons for the difficulty, if not impossibility, in preparing an intravenous form of MER-29.' You will recall that during our conversation concerning this subject, it was decided that we should, as least temporarily refrain from telling Dr. Hollander or any other person outside the Merrell organization that MER-29 undergoes rather rapid acid hydrolysis. As soon as the patent situation concerning the ethylene derivative has been clarified, we shall decide what further steps to take with regard to the possibility of using an extemporaneous sort of intravenous preparation. R. H. McMA5TER,' M.D~ [Inter-Department Memo, May 20, l9~9~ To: Mr. F. N. Getman. From: Robert H. Woodward. Subject: MER-29 Clinical Status and Plans. Your comments on May 11 concerning this subject were certainly appropriate and helped to focus our attention further on the job to be done. A~ a `matter of further information, it is our intention to closely follow the cross reference of the investigators and the problems which each investigator is assigned. It was not thought desirable to do this, however, until the investiga- tors which we have selected have been approached and have been assigned these subjects which are best fitted into their own research knowledge and facilities. When this has been done,' we certainly will then cross check the needs and determine if each has been adequately met. The comments which you made at the end of your memo regarding the NIH and their interest in MER-29 confirm the emphasis which was placed' ~upon this sources of clinical knowledge during our planning of the entire program. In Dr. Pogge's memo' to Dr. McMaster of May 15, I notice where he mentions a prelimi- nary contact which was made by himself while in Washington on May 6. He men- tions or rather suggests that no grants be made, and' I think, in view of our present policy, that we should make `this~an emphatic point rather than a sug- gestion. By means of a copy of this memo I am also asking Dr. Pogge to make each of those individuals in the Medical group who may be following up this subject in Washington completely familiar with the preliminary' work which he has under- taken. In fact, it appears to me that this is a special project worthy' `of the best effort by Dr. McMaster as a follow-up to whatever was done by Dr. Pogge. I am sure that we can get action in this area and that it will provide a case of clinical evidence which can be most useful. The objective in contacting the armed forces was to lay the ground-work for the eventual sale of the product to the various hospitals serving each branch of the armed forces when the product is released. We were not thinking here so much of honest clinical work as we were of a pre-marketing softening prior to the introduction of the product. R. H. W. PAGENO="0364" 4266 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY [Inter-Department Memo, July 17; 19~9} To: Mr. E. P. Anderson. From: Frank N. Getman. Subject: MER-29. PERSONAL & CONFIDENTIAL DEAR ED: Following up our conversation this week, Woodward and Werner are proceeding with plans to be sure our clinical work gets well wrapped up during the current calendar year. I told you how we had unsuccessfully tried to get Oarlossi, Sterment and Holland. We now have under consideration two retired clinical research men from ethical companies-if they are able, and if their companies will permit it under their pension plan, our problem will be solved; otherwise, we will be in touch with you to see if we can borrow John Scanlan on a part-time basis. Woodward and Werner have been advised of his workload but also of your willingness to have him help us if we can confine the area to the cost. Of course the big end of this job is getting positive proof of how well the product works and how. In addition, we want to be in a position to follow through with personal contact and on all adverse reports to get the facts. For example, we have had reports from two clinicians that of the first two patients they placed on MER-29 one died at the end of a week from a coronary. This is not written to alarm anyone as we are confident it was independent of the drug and if these patients might `hate been cured. However, on the surface of the record, you can see how bad tbis~looks, and we need detailed case histories. There are also some toxicity questions found in laboratory animals which need to be carefully resolved. Summing up briefly, we app~ociate your offer of help but will not impose upon you unless we feel it is very important for the benefit of the Enterprise. [Iuter-Department Memo, July 27, 19591 To: Mr. Philip Hitter, III. From: Frank N. Getman. Si~bject: Let's Start Selling. Jumping to any conclusion on the basis of only a few days' sales* would be completely erroneous-and particularly when it is in the middi~ of a vacation period. However, this is the year when we have' every' reason to b4lieve Merrell should break into the truly "big time." We will do it only if we get off to a fast start and continue building throughout the year. On this basis~ I have been somewhat disappointed over July results since, with the month nearly over, we have an Increase of less than 8% against `a budgeted increase of 24% and MFiR/2D is running less than % our budgeted figure. `Since I will not be here next week when you return from vacation, I took the liberty of having a sh'ort meeting with those of your sales executives who were in the city on Tuesday, the 2Gtb, trying to get their opinion on why sales of our over~all line are lagging as well as MER/29. My only purpose was to start them thinking in order that they would be in a better position to give you recom- mendations when you return. Let's take a close, critical look at the way we are stimulating the field force on MER/29. Very frankly, I have seen almost nothing going out of here in the way of good sales promotion ideas. The last revision of the detail was not very out- standing in my regard. It still seems pretty complicated for the GP, with a lot of long terms where shorter words would work. This is one that we discussed, and I find that no change was made in the closing Which asked to put 10 patients on it. Why 10? To me it makes sense to ask a doctor to try a drug on two, three, or `possibly five patients, but if we're going above that, why not ask for all of them? What do you think of a closing th'at says in effect, "I am sure that you will want to place all of your post-coronary and coronary prone patients on MER/29." Admittedly, the above is only one single, short suggestion, but I think we ought to take a fresh look at our whole campaign on MEH/29 with the idea of retain- ing the essential flavor of the introduction, but getting much more positive in order `to motivate doctors to write scripts. PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4267 llnter-Department Memo, Aug. 14, 1959 To: Dr. J. S. Scanlan-Vick. New York. From: E. F. Van Maanen. Subject: MER-29-Effects on Monkey Ovaries. DEAR JOHN: Dr. King informs me that you have two prints, of sections from monkey ovaries. One represents a control monkey, the other, a monkey treated for 16 months with MER-29. As you know, we are in the middle of identifying these changes. At the moment, we are not certain whether these are produced by MER-29 or whether they repre- sent an idiosyncrasy of a monkey. Because we are not sure yet what these changes mean, we would appreciate it if these pictures would have a very restricted dis- tribution. It may be very harmful, for instance, when clinicians start interpreting our results and later we would find that these changes were an anomaly, On the other hand, we feel obliged to inform you as well as our Medical Research Depart- ment about these findings but do not think that these should have wide outside distribution until we have identiñed.the problem. At the same time, we are very much interested to know whether females during the reproductive period do ovulate in the presence of MER-29. [Inter-Department Memo, Aug. 19, 19591 To: E. F. Van 1\?Laanen. From: Medical Research Department. Subject: M.E.R.-29-Effects on Monkey Ovaries. (Your memorandum o~ August 14 to Dr. Scanlan). Dmu~ FLOE: Many thanks for the tactful way in which you detined the condi- tions under which the monkey ovary pictures can be used clinically. I am strongly opposed, to the discussion of any finding from experimental animals until we have agreed upon our interpretations. Some potential investigators were frightened about M.E.R.-29 a year ago because of a very similar problem.. In this case, I do agree that we can show the pictures to our investigators in Syracuse, but it is acknowledged that we are taking a calculated risk because of a great moral and ethical problem involved. Because of the careful selection of our investigator in Syracuse, I think that it is a reasonable risk for us to take. H. 0. P000E, M.D. [Inter-Department Memo Aug. 20, 1950] From: John S. Scanlan. To: Dr. E. F. Van M'aanen. Subject: M1~1R-29.~Effects on Monkey Ovaries. You may rest assured that the pictures of the monkey ovaries which I received from Dr. King have received indeed a restricted distribution. Whilst in my possession they were shown only to Dr. Lloyd in Syracuse. However, I did dis- cuss the matter with Gerry Mersen, although even he did not see the photographs. Phi~ may well be a question of making a mountain out of a mole hill, however, we should not leave any stone unturned. How is that for a mixed metaphor? No doubt Dorsey has informed you of the results of our discussions with Dr. Lloyd. Kind personal regards, JOHN S. SCANLAN, M.D. [Inter-Department Memo, Feb. 16, 1960] To: Dr. E. F. Van Maanen. From: W. H. King. Subject: MER-29 Monkey Ovarian Studies. Four adult cynamologue female monkeys were given MER-29 in a dose of 5 mg/kg/day. Two additional monkeys that were sacrificed in the course of bi- lateral nephrectomies for the department of Microbiology furnished control ovary sections. Monkeys No. 80 and 87 were continued on the drug for six weeks, at which time they were autopsied. Monkeys No. 88 and 89 were given MER-29 for PAGENO="0366" 4268 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the same six-week period, but were held without additional drug therapy for an additional six weeks and then sacrificed. The following summarizes the results of the study: Of particular interest in this study is the fact that MER-29 given in dose of 5 mg/kg/day for six weeks did not produce the characteristic adrenal changes ob- served in the monkeys that had received MER-29 at a dose of 20 mg/kg for 16 months. In a dose of 5 mg/kg/day for six weeks, MER-29 does not significantly affect the number of primary follicles, maturing follicles or matured follicles in the ovary of the monkey. However, in studying serial sections from both ovaries of the four monkeys so treated, no evidence was found of recent ovulation. By this, we mean that there were no corpora hemorrhagica observed, nor were there any evidence of recent corpus lateum formation. Although we cannot be sure that ovu- lation did not occur, there was no morphologic evidence to show that ovulation did occur in either of these monkeys. There was no quantitable changes observed between the two groups of mon- keys. Those ovaries examined at the end of six weeks of administration were very aimilar morphologically to those ovaries that had been off the drug for six weeks before the ovaries were examined. Conclusions: 1) MER-29, at a dose of 5 mg/kg in the monkey, does not affect maturation of the primate ovary. 2) There is negative evidence to suggest that MER-29 administration of this dose prevents ovulation. MARcH 26, 1960. ~Jonr~ G. FREEMAN, M.D., Nebraska Psychiatric Institute, ~Onzaha, Nebr. DEAR Dn. FREEMAN: I hope eventually to be able to get caught up on my ac- cumulated correspondence which has resulted from chronic' absence from the office. I hope you will excuse the delay in acknowledgement of your kind letter of March 11 and the accompanying data she~ts on the patients to whom you and ,you~ associates are administering MER/29. The nicely detailed information you have given us will be of considerable value in our. compilation of the assay of cholesterol response `and side effects to be expected from MER/29 administration. I might add that most of the side effects you have reported have been unusual ones in that they have not been reported by ~other investigators. I refer specifically to patient V. H. who apparently developed .a leukopenia while taking MER/29 and to patient M. H. who complained of blurred vision and headache after eight to ten weeks of therapy. I shall naturally ~be intei~ested in any follow up information you may acquire in these instances. Pa- tient I. W., who complained of edema and eye-watering during, his first course of MER/29, will also be of interest, especially since he has been restarteU on the medication. In reading down through the list, I r~otice, also that patient R. S. had a leukopenia during two periods of administration of MER/29 and ~that patient I. W. was again forced to discontinue the drug because of watery eyes and edema. Is it possible that the side effects such as those noted above could have been coincidental with the administration of drugs other than MIMt/29 concurrently? I would most certainly not ask such a question as this had there been similar reports from elsewhere. On the other hand, if these are indeed potential side effects of M]3~R/29, I think we need to be completely aware of them and to assess them as carefully as possible. I shall look forward to your further reports when you feel them to be justified. Sincerely yours, R. H. MCMASTER, M.D. NEBRASKA PsYcHIAmIc INSTITUTE, THE UNIVERSITY OF NEBRASKA COLLEGE OF MEDICINE, Omaha, Nebr., April 7, 1960. Re: MER-29 R. II. MOMASTER, M.D., Department of Medical Research, The Wm. ~. Merrell Co., Cincinnati, Ohio DEAR Da. MCMASTEII: Following is a more complete description of the side effects noted in three patients, about which I have written you earlier: PAGENO="0367" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4269 I. W.-(Rclema) 9-7-59 Medication started. 11-17-59 Eyes started to discharge and were swollen shut. 11-18-59 Medication discontinued. 12-24-59 Medication restarted. 1-4-60 Eyes red and discharging again. This continued in some degree until his death. A.C.-(Heart trouble) 5-25-59 Eyes red and watery until end of study. 6-3-~9 Study ended. 9-7-59 Started on medication again. 9-15-59 Eyes were discharging along with other complications and medica- tion was discontinued. 12-16-59 Re-started on Mer~29. 1-21-60 Eyes discharging. 2-1-60 Eyes were discharging more along with other complications, and medication was discontinued for last time. A.W. 4-20-59 Started on medication. 6-1-59 Eyes were a little red and discharging on last week of 6 weeks study. Sincerely yours, JOHN G. FREEMAN, M.D., Research Psychiatrist. (Inter-Department Memo, Apr. 19, ieooj To: Dr. R. L. Stromont From: R. H. McMaster, M.D. Subject: flyman Engelberg, M.D. (Cedars of Lebanon Hospital, Los Angeles, Oalifornia in the amount of $500.00) Dr. Engelberg has made a verbal request for $500.00 to support his continued study of the effects of MER/29 on the lipoprotein fractions as assayed by .the Codman technique using the ultracentrifuge. The restilts with the first two or three patients in whom this technique has been tried have been rather equivocal if not completely negative. Dr. Engelberg, however, is of the opinion that before any conclusions can be drawn, the experiment should be extended to Include a larger group. He does not wish to subject these private patleilts to the expense of having these rather elaborate laboratory studies down and feels that The Wm. S. Merrell Company should foot at least a part of the bill. He believes that $500.00 will cover the costs for cholesterol determinations and the separation of the high and low density lipoprotein fractions by ultracentrifuge in another ten to twelve patients. Although it begins to appear that any report from this study may be a nega- tive one, we may find that we are money ahead to keep Dr. Engetherg busy at it for a while longer rather than to take a chance on his reporting negatively on so few patients. As you are awtire, the Codman technique is in some disfavor and certainly has never been generally accepted as providing for a true "athero- genie index" as claimed. My personal recommendation is that the grant-in-aid be approved only to keep 1)r. Engelberg occupied for a while longer. A~nn~ 29, 1960. JOHN G. FREEMAN, M.D., Nebraska Psychiatric Institute, Omaha, Nebr. DEAR Dn. FREEMAN: As you will note, my ability to correspond adequately -~s still suffering considerably from chronic absence from the ofilce in connection ~rith the MER/29 development program. Accordingly, I again apologize for the delay in acknowledging receipt of your report of April 7 on patients 1W., AC., and A.W. I must confess that I am still at a loss to account properly for the apparent high incidence of conjunctivitis in patients in your series who are on MER/29 PAGENO="0368" 4270 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY therapy. At last count, there were well over two thousand patients under clinical study with MER/29; and to the best of my present knowledge, and certainly in terms of reports we have received, yours are the only patients who have offered this complaint. This certainly is not to say that the complaint must necessarily be unrelated to MER/29 therapy. In fact, patients 1W. and AC. suggest a very definite relationship in that discontinuation and restarting of the drug resulted, first, in clearing of the conjunctivitis and then in its reappearance. It is true that we have had reports, amounting to perhaps 2% of all patients, suggesting that MER/29 is capable of producing an allergic type dermatitis. This has been variously reported as simple pruritus to actual urticaria or dryness or scaliness of the skin. It is not inconceivable, therefore, that the conjuctive could become a shock tissue. I shall look forward to hearing from you again from time to time and will keep you posted as new developments Occur which' may be of interest to you also. Sincerely yours, R. H. MCMASTER, M.D. SAN DIEGO,' `CALIF., May 15, 1960. The WM. S. MERRELL Co., Cincinnati, Ohio DEAR Da. McM,AsTE1~: I have just receiyed very good news. My cholesterol c'ount just taken is 200 Mg.%. That is excellent! My count was 220 to 325 Mg.% and never under 220 before I ~tarte4~on Mer 29. I haveba~I some reports back from the different people in 50's age bracket, who are taking 1-250 mg. Mer 29 per day and after 2 to 3 months they have had itching eyelids, little (crusts) in inner corner of eyes. Also one had a 20- vision and says that he is getting a slightly blurred vision which clears up and then re-establishes itself when `the drug is discontinued and then resumed. I have a lady acquaintance who took it for 5 months and who bad always had a good firm head of hair. However it began to fall out qui'te heavily and upon dis- continuance Of MER 29 it became firmly embedded `and healthy. In your research, have you had `any experiences like these? I have % of a bottle of MER 29 left. If you would kindly send us enough for balance of year would greatly appreciate it. I was one a day plus a few extras each month in case I was invited out to dinn~r orc~1nbs where I cannotcontrol my diet. I trust your family is well `and enjoying life. I shall be wri'tipg up to Butte, Montana for some more Tamales shortly. If you enjoyed these I will send you some more `or'if you can think of anything else I should enjoy sending it. Respectfully yours, Dr. R. J. MCNAUL. [Inter-Department Memo, May 17, 1960] From: Marion W. Smith. To: Dr. R. T. Stormont. Subject Policy Re Licensing MER-29 Analog, and Analogs Generally. I talked to Frank Getrpan this morning and we agreed as to `the policy and procedure we should follow in connection with `the question of licensing our MER-29 analog. The facts seem `to be `that the animal work performed to date indicates some question's as to the toxicity of the analog In the lower animals (just as MER-29 itself does), but `the work with monkeys indicates it may even be better than MER-29. Although a lot more animal work would have `to be done to tie down better the question of toxicity, action of the product, etc., before marketing it, this could be done simultaneously wi'th the clinical work. In view of the tre- mendous importance of MER-29 and `this analog, it probably will be decided that Merrell should follow through with the additional animal work and the clinical work on this analog in order to prove out its relative inferiority or superiority and thus have it available as a substitute in the event MER-29 gets into trouble, or perhaps introduced later as an improved product. In the past, our policy with respect to the licensing of the analog of a successful PAGENO="0369" COMPETITIVE PROBLEMS IN THE DRTJG INDTJSTRY 4271 product has been that, when we do not feel justified in doing the extensive animal and clinical work needed to prove out its value and when we could use the analog advantageously for trading purposes with a pharmaceutical house who does ex- cellent screening work of this kind, we would be willing to give such a pharma- ceutical house an exclusive (except as to us) license on the analog for a re'asonable royalty in the licensee's home country, provided the complete pharmacological and clinical data is made available to us. If our hunch is that the analog probably isn"t much good, we might be willing to give such a license merely on the basis of hoping to improve our relationship with the licensee sufficiently `to be given an opportunity of licensing some future products that might develop. On the other hand, if our hunch is that the analog might be pretty good (but still not good enough to justify doing the work ourselves) we would, of course, insist on getting something more specific in return. The reasoning behind this policy is that since we do not feel justified in doing the necessary pharmacological and clinical work ourselves, we really might be getting something for nothing except the possibility of having one competitor in the country involved in the event the analog proved to be equal or superior to the original product. This established policy does not quite fit the present situation, since we probably will consider this analog sufficiently important to do the additional work to prove it out in any event. However, if we could get sometbin~ sufficiently worthwhile for it from an outstinding foreign concern . . . such as an exclusive license in the U.S. to a product which looks extremely good, or a firm contract to have first refusal over a period of years to, all their future new products, or on future new products in `an important field in which they are working . . . then we might be willing to give them such a license. This, of course, is a matter of bargaining and judgment in the light of the specific situation involved. So you see, Bob, we really should not give a clear answer at this time to the question whether we would be willing to give such a license to Rhone-Poulene. As we agreed before you left, I suggest that you go ahead and see Mr. Monnet in June as you have planned, double check as well as you can the quality of their pharmacological and clinical work which as you know has not been up to the quality one would expect from a concern of their size and standing, and feel out Mr. Monnet as to what he would be willing to give us in return for such a license. Than we can decide what to do in the light of such facts as you can develop. Fain going to give George Garlach a copy of this statement of policy in order that he may try out the. same type of trading with some of his outstanding Ger- man contacts on his next trip. Incidentially, I am having the visa situation checked in France. I understand we already have a French visa on Mer-29, but I don't know how much data will be needed to obtain a visa on the analog. Until we get this, we must be very sure not to disclose to anyone the structure of the analog. Hope your trip is progressing successfully and pleasantly. Best regards, MARIoN W. SMITII. [Inter-Department Memo, July 22, 1960] To: Mr. G. G. Totten. From: R. H. Woodward. Subject: Mer/29 Safety, I am attaching our recent mailing over Dr. McMaster's' signature in which I have circled certain words which, it seems to me, "gild the lily" to a great ex- tent. I honestly do not believe they add to the sales impact of the * * * or of the thought, but I do think they are likely to irritate people who feel that a drug of the potential possessed by MER/29 and a drug which has not yet been used long in a commercial sense may have certain toxic effects and when we claim that it is free from such effects, I believe we are asking for criticism. It seems to me that copywise, you can be just as strong without throwing in the adjectives that become obnoxious to some people. This is all meant as constructive suggestions for your consideration, Gil, as I know that writing copy is a job which everyone feels be is an expert and can do better than the guys who have the responsibility. 81-280-69-pt. 10-24 PAGENO="0370" 4272 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [Inter-Department Memo, Aug. 3, 1t~6O} To: H. W. Werner. From: F. J. Murray. Subject: Mer-29. I called Frank Talbot at the FDA to discuss the status of our liver function follow-up studies on MER-29. Talbot did not seem particularly worried about the liver problem and while data should be made available to him as quickly as possible, there is no emergency situation. Dr. Talbot expressed concern at our promotional literature and indicated claims appear to be getting excessive. He strongly suggests that we avoid stressing potential uses and stick to approved claims. Talbot asked whether we have any more information on the spermatogenic offset of MER-29. He pointed out that there was an Indication in our animal data that this might be a problem and he would like to know the effects of MER-29 on sperm count of young men taking the drug for extended periods. Dr. Talbot stated that he has been annoyed by letters and personal visits by physicians complaining about MER-29. In each case the complaint has been based on reports of hepatitis with the original information coming from Dr. Corday. Dr. Pollock was one of the visitors. Talbot wrote Corday some time ago making complete details and has received no reply (we likewise have been unable to get details from Oorday. Talbot plans to write him again and we state that since Corclay has been unwilling to document his claims, Titlbcst must assume the reports of Hepatitis are just rumors. [Inter-Department Memo, Sept. 20, 1960] To: Medical Department. From: Frank Belkflap 13850. Subject: MER-29 Alopecia. During a recent discussion of MER-29 with Fred S. Badman M.D., 274~ N. 2nd St., Harrisburg, Penna., the doctor mentioned that he Is and has been very inter- ested in the product but in discussing the drug with some of his medical friends in the western part of our state, one a dermatologist mentioned that a side effect that some of his patients might experience complete alopecia even pubic hair. The doctor asked if I would check to see if such was the case or whether it may be strictly a rumor. FRANK BELKNAP, [Inter-Department Memo, Oct. 5, 19t60] To: Drs., E. F. Van Maanen, H. W. Werner. From: T. R. Blohm/mc. Subject: Publication of Toxicology Studies on MER/29 There seems to be a general acceptance of the idea that MER/29 is reaching a sales volume which is worth protecting. According to Pall the information we can get, MER/29 will soon be challenged by one or more thyroid products. Our strategy in combatting this competition will be based on the danger associated with thy- roid medication in cardiac patients. In order to be effective, we must be able to point to a clean bill of health on the same score. For this reason, I believe it Is more important than ever that our safety data on MER/29 got in print. Of course, pub- lication of this information will also spike the 4'liver toxicity" rumors which con- tinue to circulate, and will render less effective certa!n private communications from bureaucrats to the effect that MER/29 "must be toxic." We also have data showing that desmosterol cannot be excessively atherogenic, since no arterial lesions were found in any of our chronic animals. I realize that Dr. King is pushed to the wall with studies on potential new products, but I believe this is of sufficient importance to receive a high priority. Dr. King concurs with me on this. PAGENO="0371" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4273 [Inter-Department Memo, Oct. 5, 1960] To: Dr. R. H. McMaster. From: R. H. Woodward. Subject: Irving S. Wright, M.D. In your trip report for September 15-16, it is surprising to note that Dr. Wright is unwilling at this time to provide us with a copy of the manuscript which he has already submitted to CIRCULATION. I realize that this circumstance is un- avoidable at times but in view of our relationship with Dr. Wright, the monies which we have expended to support the man and his work, and the importance of our knowing in advance what such a man will say; all indicate that we should still make some effort to get hold of this manuscript. This points up the need, it seems to me, in any of our clinical research projects, and particularly where a grant is involved, to reach an agreement in advance on the availability of data and manuscripts prior to publication. I am sure that we will never get top investigators to agree to publish or not to publish results based upon Merrell wishes, but I do think we should strive for agreement on the basic principle that at least we have an opportunity to review and offer constructive criticism of papers prior to submission. I realize we are dealing with one of the outstanding men in cardiology in the case of Dr. Wright and perhaps all of this is totally beyond our control. Depend- ent, however, upon how firm he was in refusing you, I wonder if we might still go back and ask for a copy of the manuscript. OCTOBER 12, 1960. FRED S. BADMAN, M.D., Harrisburg, Pa. DEAR DR. BADMAN: Our representative, Mr~ Frank Belknap, has informed us that you wish to know if MER/29 causes alopecia totalis. It is true that we have received reports (now totaling 8 cases from different geographic sources) of thinning of the scalp hair, but not total alopecia. In two other instances hair grew on previously bald heads in postmenopausal females. We are not sure what these results mean but the investigators reporting the cases have chosen to regard them as specific drug idiosyncrasies occurring in an insignificant incidence. Thank you for yotir interest in MER/29. Sincerely yours, ROBERT H. MCMA5PRR, M.D., Associate Director of Clinical Research. OCTOBER 25, 1960. Mrs. EVA E. LOUGHRAN, Pontiac, Miclv. DEAR MRS. LOUGHRAN: We appreciate your letter of October 22, in which you report that you have had excellent results in reducing your cholesterol level with MER/29. We also noted with interest your report that during the past few weeks you have experienced loss of hair, and your doctor requested that you discontinue use of MER/29. You ask for advice on this matter. Unfortunately, we are unable to answer your letter directly, since the etiology of falling hair can be quite difficult to determine. Therefore, I would suggest that you discuss the matter with your doctor and have him correspond directly with me, giving me facts about your case history and concurrent medication. Through him we shall be happy to discuss this matter. I am sure that you can appreciate our inability to answer your request, since the doctor-patient relationship is mandatory in any discussion of this type. Sincerely, R. H. MCMASTER, M.D. FEBRUARY 9, 1961. JAMOOL S. KUBARAK, M.D., Tomah, Wis. DEAR DR. KUBABAK: Mr. Stan Jangek passed along to us an unusual Observa- tion, reportedly a result of MER/29 therapy. You told him about one of your patients who noted a "film" which tended to effect vision. Because of the unusual PAGENO="0372" 4274 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY nature of this report and since it has not come to my attention before, I am writing to you for additional information. Actually, we would expect just the opposite to occur. We know of a paper soon to be published showing some improvement in vision in patients with diabetes and bypercholesterolomia. Although these reports are preliminary they are most interesting and will be followed. Thank you for bringing this to the attention of Mr. Junck.. We would appre- ciate hearing from you if you have more information. Cordially, JOHN B. CIIEWNING, MD. [Inter-Department Memo, Feb. 13, 1964) To: Department of Medical Research. From: Wm. J. Phelan, #48727, Houston, Texas. Subject: MER/29. Please find attached a brief case report on each of three patients referred to Herman J. Schultz, M.D., Dermatologist, by their internists when dermatitis developed while on MER/29 therapy. To conserve time and space on the individual reports I hereby list the doctors involved and their addresses Herman Glantzberg, M.D., Internist 703 Hermann Prof. Bldg., Ja 3-5129 Patient: 40 years, male, Prof., Univ. of Houston Harry Leland Kaplan, M.D., Internist 6448 Fannin Street, Ja 6-2051 Patient: 69 years, male, retired Alfons Salinger, M.D., Internist 2212 Calumet Street, Ja 3-4643 Patient: 50 years, male, dentist Herman J. Schultz, M.D., Dermatologist 800 Hermann Prof. Bldg., Ja 8-1521 Patients: Three list all above. All but Dr. Salinger practice practice in my territory. Dr. Kaplan and Dr. Glantzberg have had their office staffs telephone all large drug stores during the past three days the message: "Do not refill or fill any of their MER/29 prescrip- tions until further notice." Today I visited the offices and talked to Dr. Schultz, Dr. Kaplan and Dr. Glantzberg. Each of these men are quiet, stable doctors who assured me that they are in:terested only in more information on the possible MER/29 side effects of dermatitis, falling hair, color change of hair and loss of libido, and not in scare talk of the product. During my talk with each man I reviewed, as on all details, the detail card and promotional literature listing of side effects (nausea, headache, dermatitis) which are rare and have usually been associated with higher dosages than those recommended. It is my understanding that Mr. McMaster talked with Dr. Glantzberg and Dr. Salinger today and may visit Houston next week on this and other matters. Mr. Bristol has requested that I forward the attached Information, and while keeping the Houston Group informed, to restate that our detailing instructions are exactly as they have been since the release of the product, with no more or no less emphasis on side effects. Best regards, BILL PHELAN. [Inter-Department Menao, Feb. 13, 19i61) To: Department of Medical Research. From: Wm. J. Phelan, #48727, Houston, Texas. Subject: MER/29 Patient Report of Dr. Glantzberg. 1. Age-40, Sex-M, Prof. Univ of Houston 2. Diag. Prim: Familial hypercholesterolemia, hyperlipemia Xanthoma plaques One coronary occlusion 7 years ago PAGENO="0373" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4275 3. Patient responded to MER/29 therapy. Reduced from 600 mg/% to less than 400 mg/%. Plaques were reduced. Before adjusting diet, etc. as high as 1,400 mg. 4. MER/29 dosage range: June & July 1960-1 cap daily Aug 1960-2 caps daily Sept. Oct. Nov-i cap daily Dec taken off MER/29 when severe dermatitis and hair change occurred 5. Symptoms since December, 1960: 1. Dry, flaky alligator type skin ichthyosis type with secondary infec- tion, then yeast, mold, monilial type in crotch and inner thighs (be- fore antibiotic 2. Loss of scalp hair 3. Hair color change from dark brown to light blond, also eyebrows, etc. 4. LosS of libido 5. Skin condition such that patient finds it almost impossible to move to move around and carry out usual work, etc. 6. Patient referred to Dr. Herman Schultz who happened to have two more patients whose dermatitis may have been touched off by MER/29. These two patients are profiled on attached forms. 7. Dr. 0. had office call all important drug stores to not to fill or refill his MER/29 Rx until further notice. On Tuesday, February 7, 1961, I suggested to Dr. 0. that he call Dr. McMaster or other doctors at Merrell to report this seemingly severe dermatitis and hair problem that may or may not have been caused by MER/29. [Inter-Department Memo, Feb. 13, 1961] To: Department of Medical Research. From: Wm. J. Phelan, #48727, Houston, Texas. Silibject: MER/29 Patient Report of Dr. Kaplan. 1. Age-09, Sex-~M, retired 2. Diag. Prim: Chronic coronary insufficiency, rare anginal pain Elevated cholesterol One myocardial Infarction seven years ago 3. MER/2D dosage: 1 cap daily for only three weeks 4. Concurrent medication: Peritrate and nitroglycerin 5. Reason took off M~R/20: 1. Swelling in several places in skin of furunele (boil) type 2. Severe monilial mold type dermatitis in crotch and folds of arms and legs. Dr. K. reported that this patient had never bad skin trouble before. 6. Patient was referred to Dr. Herman Schultz (Derm.) who told Dr. K. that he (Schultz) was presently treating two more patients whose severe der- matitis may have been caused by MF~R/29. 7. Dr. Schultz presented to Dr. K. an opinion that the sharp drop of chol. brought about by MER/29 may disrupt the fatty protective film of normal skin and leave the skin susceptible to many infections. This opinion was disputed by Dr. Glantzberg. Dr. G.'s patient was in somewhat the same difficulty and still had around 400 mg/% and had been on MER/29 for some six months. 8. At this point Dr. Kaplan also learned of the dentist being treated by Dr. Schultz (referred to him by Dr. Salinger) as "being close to death" in a hospital and bad his office telephone all important drug stores to stop filling and refilling his M1~]R/29 Rx until further notice. 9. Having spotted this note from Dr. K. in two different drug stores on Friday I called for and got an appointment to see him today and promised him that I would (or Cincinnati would) keep him informed of any similar severe der- matitis possibly caused by MER/29. Dr. K. told me that Dr. Julian Fractman (one of my pre-marketing men) was also concerned of this. PAGENO="0374" 4276 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [Inter~Deipartment Memo, Feb. 13, 1961] To: Department of Medical Research. From: Wm. J. Phelan, #48727, Houston, Texas. Subject: MEiR/29 of Dr. Salinger. 1. Age-~50, Sex-M, dentist 2. Diag. Prim: Coronary heart attack Elevated cholesterol 3. MER/29 dosage range Can be obtained from Harry Davis, #48767, who calls on Dr. Salinger. 4. Reason patient taken off MER/29: i: Severe generalized iehthyosls 2. Loss of scalp hair 3. Definite lightening of color of hair, eyebrows, etc. 4. Virtual lack of beard now~ needs to shave but once a week 5. "Zero" libido 6. Severe and extremely painful monilial mold type dermatitis in groin, armpits and folds of arms. 5. I found the above information from Dr. Herman Schultz, 806 Ilermann Prof Bldg, while talking to him in his office today. This patient was referred to him by Dr. Alfons Salinger, 2212 Caluniet. Since Harry Davis calls on Dr. Salinger ro~tine1y Harry had received a carbon copy of a letter written by Dr. Salinger to Merrell in Cincinnati dated January 30, 1961, eO~eerning this patient. It is my understanding that Dr. MeMaster talked to Dr. Salinger today by phone and alsohas the note Dr. Salinger wrote in January. 6. Dr. Sehpltz reported that the patient was "just not doing well at all" in the hospital. The patient did not seen~i to respond to usual procedures and medi- cations for the dermatitis he has developed. HOUSTON, Tux., Feb. 16, 1961. WILLIAM S. MERRELL Co. Cincinnati, Ohio GENTLEMEN: It has come to my attention that several cases of severe alopecia have occurred in this area from the use of MER-29. Today, one of my colleagues showed me a case in which there was extensive alopecia, change in the color of the hair, severe skin reaction with secondary monilia infection. Do you have any additional: information regarding these skin reactions? If you do, please advise me as soon as possible, as 1 have a number of patients taking this preparation. Thank you for your courtesy. Yours truly, H. JULIAN FRACHTMAN, M.D. [Inter-Department Memo, Feb. 17, 19161] To: Dr. Robert S. Shelton. From: Frank N, Getman. DEAR Bon : I certainly did appreciate your kind letter on my recent promotion- and also greatly appreciate the advice and suggestions you have recently been giving Harold Werner on some of our more troublesome research projects. By staying with them, we are bound to come up with the answer. The excerpt you sent me from the February 11 issue of ~Phe Medical Tribune made interesting reading as I hadn't yet bad an opportunity to see that issue. As you are probably aware, that panel of experts is "anti" everything unless they have the idea for initiating the project. Their remarks are just about what you would expect. From the comments of several of our people, however, I understand that you distributed this excerpt rather widely. We want all of our people to be informed and kept up to date, but in a field as controversial as atherosclerosis and the lowering of cholesterol, we try to pass on the information with a positive, objec- tive appraisal from management. Accordingly, I would appreciate your going PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4277 hack to the suggested distribution list described in my memo of December 29, 1958 so that the added distribution can be made with appropriate interpretation. Mentioning the above reminds me that we haven't kept this list up to date although you may have been able to guess the proper substitutions. Carl Bunde should, of course, be slubstituted for Ray Pogge, and Jacobs should be deleted. Any ideas and evaluations for the acquisition of domestic products should go to Joe Murray with copy to Bob Woodward, and any ideas for acquisition of companies should go to Bob Woodward. The balance of the list remains as it was at that time. F. G. P. S.-As a conversation piece, desmosterol is giving us questions and creates an unwarranted, troublesome problem. Certainly, all the evidence definitely in- dicates it isn't harmful and, in fact, we theorize that it may be beneficial-I have found in talking individually to any of the ones who raise this question that he readily admits it is as likely desanosterol is beneficial as harmful. We are, how- ever, not ignoring the question and active research continues. Any suggestions you have on how we could augment or speed up our program on getting added proof to show that desmosterol is not harmful would be appreciated. We remain as convinced as ever that the only intelligent way to tackle the problem of lower- ing cholesterol is by interrupting its biosynthesis as MER-~29 does. MAYO CLINIC, ROCIIE5TEIR, 1VtINN., February 25, 1961. ROBERT H. MCMASIER, M.D. Associate J~irector, The Wm. S. Merrefl Company, Division of Richardson-Merre~ Inc~, Cincinnati, Ohio DEAR DR. MOMASTER: In reply to your letter of February 20, I can only say that you have underestimated us. You sent us two case report forms and we will need three more for we now have five cases with some effects on hair. I shall fill out the forms and send them on to you with the data such as is available at this time. You will probably want subsequent reports on some of these. Again our best regards to you and your staff. Yours truly, R. W. P. Acrion, M.D. [Inter-Department Memo, Mar. 18, ii~E~1J To: Professional Service Department. From: M. Tenenbaum No. 10251. Subject: MER/29. A pharmacist in my territory ~tated that when taking MER/29 for about a week or more his eyes started to tear atid burn slightly. When therapy was dis- conthiued these symptoms disappeared, but upon resuming MER/29 therapy he complained of the same problem. Do you have any information as to why he might be getting this reaction if it is possibly from M~R/29? Thank you for your consideration. Best regards, MARy. [Imter-Department Memo, Mar. 23, 1O~1J To: H. W. Werner, Ph. D. From: R. H. McMaster, M.D. Subject: MER/29-Complaints of hair changes. CONFIDENTIAL Attached is a tabulation of complaints received to date of changes in the scalp hair associated with MER/29 therapy. PAGENO="0376" 4278 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Fifty-one patients who have experienced hair loss have been reported by 31 physicians. Of these, 4 are males, 42 are females, and in 5 cases the sex is unre- ported. It will also be noted that regrowth has occurred in 10 patients, 9 female and 1 male, beginning as early as 10 days after discontinuation of therapy. In 2 additional female patients, regrowth occurred despite continued therapy. Color changes have been reported in 3 males and 2 females of the group, and change in texture (usually dryness and brittleness) has been reported in 5 females and 1 male. No consistency in relationship with other medications can be defined from this tabulation. Dose relationships, where reported, are also of no particular help. As addendum to this tabulation, the following paragraph from a letter of March 16 from Gordon Meflardy, M.D., Is of interest: "Since your recent request in regard to hair thinning, I have gone over 200 of our cases who have been on MER/29 eontthuottsi~ o~er a 1~tlod itt excess of 12 months. In this series there was included the one patient of hair thinning on whom I reported to you and on whom we discontinued MER/29. Additionally, there were 6 patients in the group who reported a definite increase in hair growth. These, however, were all males. The increase in hair growth is obvious in 1 par- ticularly obese individual who has grown a nice foreward flock of wavy black hair. We have encountered a second patient who has hair thinning, a female, age 52, who was on MER/29~, 250 mg daily fora period of only 42 days. During the same period, this patient had received intra-articular and oral corticosteroids. On noticing her hair loss, this patient 22 days ago discontinued MER/29 and has had a definite regrowth of new hair." The 2 patients reported here by M~Hardy who have exhibited hair loss are in- eluded in the tabulation. However, the tabulation does not include the 6 males who grew hair in alopecic areas. In view of Dr. McHardy's report, and the original reports of growth of hair in 2 elderly alopecic women by Kountz and Toro, we must also conclude that there are better classed as hair changes rather than simply as hair loss. It is, therefore, recommended that the words "changes in color, texture, or amount" be substituted for "loss" In the new brochure side effect statement. It is the feel- ing of the Department of Medical Research that there can be no doubt of the as- sociation of MER/29 thei~apy with these changes. Enclosure [omittedi. [Inter-Department Memo, Mar. 24, 1964] To: Mr. H. Smith Richardson, Jr. From : R. H. Woodward. Subject: MER/29-Complaints of Flair Changes. CONFIDENTIAL Before Frank left for vacation, we had initiated a review of reported thinning of the hair of people taking MER/29. It is our feeling that we are morally and legally bound to include our findings in the side effects statement in the FDA ap- proved brochure-even though the reported incidence is only 51 cases of roughly 300,000 treated. Attached for your review is a memo from Dr. MeMaster setting forth the facts as we have them, together with a copy of a proposed letter to FDA by Joe Murray which has not yet been sent. The reason for bringing this to your attention, Smith, is that we have made no changes to this point in any of our MER/29 literature, basically because we were afraid to "stir the pot" in Washington. We have heard from several sources that FDA at times has considered reopening our NDA file but, frankly, we do not know whether this is true. The risk we run in admitting this additional side effect must be realized, however, and weighed against our moral and legal obligations referred to earlier. Frank and I both feel that the approach should be made. Further, we feel that to protect ourselves against possible damage suits, we should make the approach promptly. I though it well to inform you, however, so that you may express your own opinion since, after all, the future of MER/29 is of interest to you and to others in the Enterprise as well as to Merrell. PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4279 [Draft of Proposed Letterl MARCH 24, 1961. Dr. FRANK J. TALBOT, Food and Drug Administration, New Drug Branch, Bureau of Medicine, Temporary Building "S" Washington, D.C. DEAR DR. TAusoT: Reference is made to our New Drug Application, 12-066, for MER/29 (triparanol). Our attention has been called to several reports con- cerning thinning or texture change of hair, and while it is difficult to access the importance of these reports (particularly since there have also been reports of increased hair growth), we feel some mention should be made in our literature. Accordingly, we propose to modify the last sentence under "side effects" in our existing brochure. This sentence now reads: "Isolated reports have been received of nausea, vomiting, temporary vaginal bleeding, and dermatitis." We would like to change this to: ". . . . temporary vaginal bleeding, dermatitis, and thinning of the hair." If you have no objection to the prOposed change, we shall plan to make it at the time of our next printing. Sincerely yours, F. Jos. MURRAY. [Inter-Department Memo, Mar. 28, 1961,]~ From: Robert T. Stormont. To: Mr. Smith Richardson, Jr. Subject: MER-29---Complaints of Hair Changes. According to Woodward's memo, the reported incidence of hair thinning in only 54 cases out of a total of approximately 300,000 cases who have received MER-29. This would mean that less than two people out of every 10,000 receiving MER-29 report some loss of hair. I wouldn't be at all surprised if two or more adult people out of 10,000 not receiving any MER-29 at all reported some definite hair loss during a few months period of observation. Furthermore, I wonder if there are any data on the incidence of hair-thinning associated with nicotinic acid therapy. Of course, it is quite probable that there are unreported cases of hair- thinning associated with MER-29 therapy, but I find it rather difficult to be con- vinced, on the basis of these data alone, that MER-29 is definitely responsible. The observations of Dr. McHardy are also somewhat puzzling. In addition to two cases of hair-thinning he reports six cases of definite hair growth. Ap- parently, there have also been at least two other cases of hair growth associated with MER-29 therapy. I don't know what this means, but `I find it difficult to be- lieve that MER-29 is perhaps the long awaited curE~ for baldness. We know that people observed spontaneous thinning of the hair or changes in its color or texture long before MER-29 was avaIlable. Furthermore, we know that a smaller percentage of people have experienced a spontaneous regrowth of hair. I don't wish to imply that there is no expectation for such phenomena. Systonic diseases accompanied by fever, thyroid therapy and certain hormonal imbalance states, undoubtedly, can result In alopecia or hair-thinning. Have all such known causative factors been ruled out in the MER-29 cases? I presume that they have in view of McMasters statement "that there can be no doubt of the association of MER-29 therapy with these changes." I will now put on my other hat and argue on the other side. Hair loss doesn't occur spontaneously without any cause whatsoever. If we rule out known prob- able causes and are left just with MER-29, is there any other reason to believe that MER-29 could be responsible. The answer is probably affirmative in that MER-29 probably does have some endocrine effect. This is inferred from Its chemical structure and the reports of vaginal bleeding associated with its use. Therefore, it is both possible and likely that those scattered reports of hair changes could be attributable to MER-29. In summary, I would say that the weight of the evidence seems to indicate that MER-29 may produce some hair changes in a very small proportion of cases. How- ever, I do not believe it is fair to say that this is proven beyond any doubt. Never- theless, I am inclined to go along with the recommendations of the Merrell group as I am sure that at least one or more of the physicians who have observed this effect on the hair of several of their patients during MER-29 `therapy will publish their findings in the near future. I don't particularly like McMasters sug- PAGENO="0378" 4280 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY gested phrase "changes in color, texture and amount," as this sounds rather frightening. After all, none of those cases developed green, pink or lavender hair, I hope. Therefore, I'm inclined to believe that Murray's simple phrase "thinning of the hair" should probably be sufficient, I believe it would be well also to stress the extremely low reported incidence of these hair changes. ROBERT T. STORMONT. [Inter-Department Memo, Apr. 7, 1961] To: Dr. C. A. Bunde. From: Harold W. Werner. Subject: MER/29-Complaint of Liver Damage, Class I. No. 70 (Memo McMaster to "Too Many People" 4/4/61). This memo should not have gone t~ Mr. Long and Mr. Ritter. In addition to reporting on what was learned, the memo needed to contain a final section describing what we did and, if there was any ctuestion to what we should do, making recommendations and carrying through to obtain needed action. We do need to arrive at a point where positive action of the proper type is taken quickly and effectively. P.S-In a casual conversation with Mr. Long and Mr. Ritter please explain to them what is wrong with DeGraff's thinking and conclusions. H.W. Tirz WM. S. MEERELL Co., Cincinnati, Ohio, June 28, 19~1. JAMES C. MELBY,M.D., Department of Medicine, University of Arkansas Medical Center, Little Rock, Ark.: Jim, I am sorry I could not see you again after our brief discussion following presentation of your paper. Dorsey Holtkamp told me that the many rumors and comments flying around frightened you and you had decided to discontinue your large-dose experiments temporarily. I want to comment on this, and I hope you will accept this as an opinion based on having available many more data than any one or dozen investigators could have, and also, in part, from experience in tracking down some Of these rumors, such as the one Seltzer was spreading. I also hope you can interpret this as being restrained to the extent of most of all wanting to protect our investigators from getting into any trouble, using MER/29 or aimy, of our drugs experimentally. I find in most cases that I am more conservative, and more cautious than' our investigators. Up to the present, we have had no evidence which could reasonably associate MER/29 therapy with hepatic toxicity, and this includes au cases treatedby the large `doses, such as you have used. I feel certain that if such toxicity were inherent in the drug, it would be obviously manifested by now and would occur with a very high incidence in tl~e 2,000 mg/day patients, if it occurred at all in the 250 mg/day patients. A~ I told you early in your studies, caution and close observation is necessary, because our experience in the large doses at that time was very limited. Most of the clinical data on the larger doses did not exceed 500 or 750 mg/day, with the exception of some work done at the Mayo Clinic. Now, however, since your report last December, we have had many Individuals asking for drug to use specifically for adrenal suppression in doses of 2,000 mg/day, and larger. Therefore, at present, I cannot tell you the number having received such a large dose, but it must be many times the cases you have studied. We still have no evidence associating hepatic toxicity with MERJ29. After MER/29 had been on the market for some six months' or more, we began receiving reports of hair loss. These were Isolated and mixed with reports of hair growth and color changes, so that it was difficult at first to decern a pattern or determine If the condition were truly drug-related. We immediately started a more intensive investigation of all complaints, using a definite form for obtaining uniform data, and soon concluded that, at least in some of the cases, the hair loss was related to M~R/29 therapy. The higher incidence found by the Mayo Clinic group using larger doses confirmed this. However, their data were not made available to us until March 20 of this year. We immediately changed our literature to include this under side effects. PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4281 Before the drug was put on the market, dryness, or scaliness, or a rash-like condition had been reported in a certain number of patients. This was listed under the term dermatitis as a side effect in the original literature. We have heard of a few cases since, most of them recently, where this dermatitis has been of a very severe nature and In some instances referred to as ichtbyosis. In the few which we were able to track down through the maze of rumors and have examined by dermatologists the term ichthyosis was found to be incorrect. Also it became apparent that some of these were not related to drug. At any rate, we are recognizing that if mild cases of dermatitis can occur, an occasional rare case will be severe. The two most severe cases which we have tracked down are the least likely to be drug-related. One was the case reported by Corday and which be has been ballyhooing around the country as If it bad been an epidime. This patient was on a least three other drugs known to produce allergic cutaneous reactions and had a previous histery of peuro- dermatitis. The other one also had a history of neurodermatitis, and there is some question whether the dermatitis developing under MER/29 started before that therapy began. We had further reports that MER/29 affected coagulation time of blood; some reports had an Increasing coagulation time, some a decreasing coagula- tion time, and in some the comments were referred to prothombin time. Studies had been initiated In this direction before the drug reached the market and another was set up when the first reports came in. The data from these studies definitely show that MER/29 has no effect on any of the known factors related to the clotting of blood. There Is a suggestion that It may actually de- crease platelet stickiness, and this we are investigating further. The only other complaint that we have received in more than six instances, which we use as our arbitrary number for being watchful, is the loss of libido. I defy anyone to make any sensible pattern out of these complaints. Almost 100 per cent of the complaints come from men, whereas about 80 per cent of the com- plaints on hair loss come from women. Some clinicians with more than 100 men on MER/29 have no complaints of loss of libido, whereas someone with 15 or 20 cases will report 2 or 3. One must always keep in mind that the majority of cases treated with this drug are middle-aged or beyond. Many have had recent infarcts and have fear of sexual activity as well as other activities, such as roller-skating or whatever you wish to choose. Again, we are not finding this complaint in those patients receiving the larger doses of drug, and if it occurs at all at the 250 mg dose level, it ought to be much more frequent at the higher doses, if it is a truth. I have a strong enough background in pharmacology to be suspicious of any drug action that deviates from some semblance of a dose-response curve. The above is as accurate a summary and interpretation of our total experi- ence with MER/29 toxicity as I can give you at this time. I will say that if you use the large doses you should exert extra precautions, especially in looking for the earliest manifestation of those side effects that now appear to *be drug- related. Most specifically these are: a type of dermatitis, loss of hair, and change in hair color. You are free to use this letter as you see fit, as it is only what I would com- ment to anyone asking me about the subject. We have somewhere around 3,000 case reports of unpublished data in our files and some 3,000 or more represented by published reports. In addition, Dr. McMaster and I have had personal inter- views or frequent correspondence with at least 300 reliable investigators work- ing with MER/29. CARL A. BuNDE, Ph. P., M.D., Director of Medical Research. [Inter~Department Memo, Iuly 5, 1961] To: Dr. H. W. Werner, F~rom: R. H. McMaster, Subject: William Hollander, Boston, Consultation Fee. Hollander mentioned the matter of his consultation fee. You will recall that we have had him on a personal retainer amounting to $2,400 per year payable in 2 semi-annual installments. If we wish to maintain this relationship (which is apart from Wilkins' grant), a payment of $1,200 is now due. My own feelings is that we can't afford to chance alienation of Hollander just now (perhaps T shouldn't regard this as blackmail). Certainly we need his help and counsel. PAGENO="0380" 4282 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JuLY 7, 1961. WILLIAM H0LLANDER, M.D., ~udbury, Mass. DEAE BILL: It is my pleasure to enclose our check in the amount of $1,200. This represents our consultation fee for the six-month period beginning July 1 and ending December 31, 1961. You will hear from me separately concerning the expenses you have inctirred during your recent speaking engagenients. With best personal regards, ROBERT II. MOMASTER, M.D., Associate Director of Clinical Research. JULY 5, 1961 $1,200.00 WILLIAM HOLLANnER, M.D. Massachusetts Memorial Hospital 750 Harrison A~venue Boston 18, Massachusetts Consultation fee for advice and counsel on MER/29 research for the 6-month period, June 1 thru December 31, 1961. R. H. McMaster 4407 02 1,200.00 AUGUST 4, 1981. W. D. FJIINBERG, M.D. Building 14, suite D, Medical Center, El Paso, Tea,. Diiu~ DR. FEcINBERG: Your Merrell representative, Mr. Theodore Rallis, has told us of the observations you have made in the cas'e of one of your patients who is taking MER/29. I understand that concurrent with drug administration this patient complained of double vision and a peculiar loss of taste. This oc- cured after six weeks of treatment, and complaints ceased upon discontinuation of therapy only to return three weeks late.r when therapy was resumed. We are completely unable to provide you with information from other sources which might help you to explain these observations. This is the first instance of this sort about which we have heard. Also, nothing in the animal studies pro- vides data which might shed some light on it. There is certainly a possibility that this patient is exhibiting an unusual sort of sensitivity to the drug and, in view of the experience, it would seem advisable that he should not use MER/29. Mr. Rallis enclosed your prescription blank listing these observations. I note that you have mentioned the patient had a Bell's palsy on the left side and am won- dering if this, too, was related in time with the occurrence of the other symp- toms. Any additional information you may care to provide would be most welcome. We thank you for letting us know of this experience through Mr. Rallis. Sincerely yours, ROBERT H. MOMASTER, `M.D., Associate Director of Clinical Research. [Inter-Department Memo, October 1961] To: Dr. H. W. Werner. From: T. R. Blohm/mc. Subject: Request for Radioactive MER/29 for Topical Use in Animal Eyes: Dr. R. M. Burnside. Some months ago, Dr. R. M. Burnside, of the Dallas Medical and Surgical Clinic, Dallas, Texas, wrote to Dr. Bunde requesting some radioactive MER/29, to be used in determining whether or not triparanol penetrates into the eye struc- tures of animals, when applied topically to the cornea. The request was turned over to me, and eventually bogged down in correspondence over the details of radioactive procedures. Now Dr. Burnside has renewed his request for this mate- rial, and we must decide whether or not to supply it to him. As I understand it, if Dr. Burnside were successful in demonstrating penetra- tion of triparanol into the internal structures of the eye, he would then proceed with a longer term study utilizing this mode of administration as an experi- PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4283 mental approach to the treatment of retinal arteriosclerosis. I think such a study at this particular time could be extremely dangerous to us. On the other hand, I don't see that we could prevent him from using unlabeled material if he were determined. I don't know how important this man's cooperation is to Medical Re- search's program, but I would certainly recommend doing everything reasonable to discourage him from carrying out this study. Since I must proceed one way or the other on the radioactive material, would you please let me have a decision on this? [Inter-Department Memo, Oct. 5, 1~61] P0: Dr. Werner (+2). From: E. F. Van Maanen/shh Subject: Fundus Camera for Eye Examinations. Earlier this year we were confronted with a study using MER/29 in dogs in which the experimenters observed certain changes in the dog eye. We were invited to examine the dogs and they also showed us a sequence of color pictures showing the progression of the lesions which they had observed. No matter what could be said about the temporal condition of the eyes, the progression shown by the photographs was far more conclusive and indicative. The person responsible for this study considers himself an export in canine ophthalmology. Considering the lack of competition, this is probably true. At the same time, this person was previously employed in the Toxicology Department of the Food and Drug Administration. His relationship with this branch of the government is still excellent. In order to substantiate his exclusive position, he is planning to write a monograph on the virtues of canine ophthalmology in drug evaluation. In view of the recent attitudes of the FDA, one can anticipate, there- fore, that the FDA might require in the future ophthalmological reports from dog and monkey studies, particularly when it concerns revolutionary new drugs. In view of the observations reported above, we started an extensive study in dogs and rats with MER/29 in which particular attention was given. to ocular side effects. Except for slight keratinic changes in some rats, no major changes were observed until two weeks ago. At that time we invited the canine ophthal- mological expert to examine our dogs. In most cases he gave them a clean bill of health. However, with two dogs he noticed some changes, but was not sure whether these were recent and whether they were drug-induced. Last week during the weekly routine dog examination, Drs. King and Grady wore worried about ocular changes having occurred in one other dog since the previous examination. Drs. King and Grady keep very careful records of their ophthalmological exami- nations. If no changes had occurred, this would probably be sufficient for our rec- ords. On the other hand, when changes do occur, the written protocol will not be sufficient for general judgment and for estimation of the progress of the lesion. Since much is at stake in this study and since tremendous efforts have been put into this study, I recommend that under these conditions we purchase a camera which can take colored pictures of the inside of the dog's eye. This will be im- portant also for the development of other new cholesterol synthesis inhibitors. [Inter-Department Memo, Oct. 17, i~aij To: Dr. Fl. F. Van Maanen (+2). From: W. M. King. Subject: ME~R-29--Eye Changes. Dog #173, a 8.5 kg male beagle was started on MER-29 on March 29, 1961. (40 mg/kg/day) On September 7, 1961, after twenty-two weeks of drug therapy, this animal developed a dermatitis, with a marked and progressive hair loss. These skin changes were particular noticeable on the ears. The skin on the ear showed a non-confluent macular rash, which the dog scratched. A skin scraping for mange mites on `September 7, 1961, was negative. The ears were treated with Neomycin/Hydrocortisone ointment with poor results. The eyes `were examined on September 7 and September 14 by King and Grady; on September 20, 1961 by King and Wazeter (Merck, Sharpe and Dohme) and again on September 21, 1961 by King and Grady. Up to and Including the ocular examination on September 21, 1961, no eye changes were observed. PAGENO="0382" 4284 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY On September 28, 19431, exactly six months after the onset of drug therapy, the following eye changes were noted: There was bilateral bazyness deep to the cornea which made visualization of the fundus very difficult. Although not able to definitely localize this lesion it was the impression of the examiners that this change was in the anterior lenticular capsule. At the examination on October 5, 1961, the dermatitis was severe and the ani- mal completely blind. The eyes were similar bilaterally and the impression of the examiners was anterior lens cataractoid changes. At the examination of October 12, 1961, no additional eye changes were noted, but the dermatitis continued to be widespread and severe. In the rat study, at 40 mg/kg/day, twelve out of twelve males and six out of seven females have opacity in one or both eyes. In a similar group where vitamins and cholesterol are added to the drug diet, there are nine out of twelve males and eight out of twelve females with eye opacities. In each case, the eye changes in the rats were preceded by hair loss and severe changes in the skin. W.M.K. [Inter-Department Memo, Oct. 19, 19611 To: Mr. F. N. Getman. From: F. Jos. Murray. Subject t ME1R/29. John Nestor of the FDA called at S :40 am. today to advise they had given consideration to the letter we proposed to send to physicians on MER/29 side effects. Nestor raised the following points: 1) The FDA does not have sufficient pertinent facts to enable them to make a decision on the letter. It is their fear that side effects may be more extensive and more severe than stated in the letter, and it might, therefore, be misleading and lead the physician to a false sense of security. 2) The FDA wants all facts available to us on the cases of eye changes, includ- ing the actual case records. They also request a written copy of the letter we propose to send. 3) The FDA wants a statement from us to the effect that we have supplied all toxicity data in animals and man, including that available to us from outside sources. (The implications here are obvious and on pressing Nester he offered as an example a comment that a Dr. Wong of Howard University visited us in April to describe results in chickens indicating interference with ovulation. Dr. Wong states. we ignored the results, and Nester declared this could be grounds for suspension of the NDA.) 4) Nester stated he had discussed MER/29 with several experts and there is concern that there are numerous other serious side effects involved. These in- clude: baldness, lenthyosis, impotence, interference with ovulation, induction of abortion, interference with adrenal function, and reticulocytosis together with hepolytic anemia as found by Page. Dr. Nestor stated he had discussed the problem last night with Dr. Siegel and it is their feeling they have enough evidence to suspend the NDA. He also stated that their statistician has advised them that our claims for significant lowering of cholesterol levels are not true. I told Nestor we would want to see him as quickly a's possible but that we would 1~ave difficulty pulling together material to answer all these charges before next week. He agreed and indicated he would make himself available any day of the week. We are aiming at a conference on Thursday, October 26. [Inter-Department Memo, Oct. 24, 1951] To: Mr. W. I~. Marschalk. From: Frank N. Getman. Subject: FDA a~tion on MER/29. Sherry Silliman and Fred Lamb have both advised me that a New Drug Appli- cation may not be suspended or revoked without a bearing-~s:ucb hearings are not public. Apparently, however, the fact that a bearing is being called does become publicized. PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4285 Bengert is away for several weeks, but Silliman, of Norwich, said that the notice of hearing came after failure to reach agreement following a number of discussions with the FDA. According to him, news of the hearing was first pub- lished in Werbie's "Pink Sheet," and he says Werbie appears to have a good "pipeline" into the FDA. He added that the FDA does publish notices of bearings to be held. (I am asking the Legal Department to run this letter down.) Going on with the Norwich case, the hearing technically is still in progress. All testimony on both sides was completed before the Examiner months ago. Briefs were filed in April, with no decision yet. Anticipating an adverse decision, Norwich plans an appeal to the courts. The product is still on the market and available to the physician. It has not been promoted in any way since the notice of hearing, and this was an agreement which Norwich made with the FDA. Naturally, sales have dropped drastically, but the product is still being prescribed by these physicians who have found it a very valuable drug. Norwich made its own publicity release to the public and to the stockholders after the notice of hearing had been received. In the McNeil case, I know nothing more than what I have read in the "Pink' Sheet," which stated McNeil sent out letters to MD's and drug whole- salers, setting in motion a "voluntary" recall program because of jaundice, hepa- titis and liver damage reports. As far as we can tell, McNeil, after conferences with Food and Drug in which `a hearing was probably threatened, took this action rather than go through a hearing. In the White Laboratories' Entecqual case, the Government seized the drug on the basis that representations in promotional material for MD's differed mate- rially from the labeling claims permitted by the effective New Drug Application- in other words, false and misleading labeling. Apparently this followed a failure to agree with the FDA on appropriate disclosure of side effects and also an appropriate dosage exclusion limitation for children-these negotiations going on while the NDA was in effect. Other actions such as multiple seizures or a suspension of the NDA were being considered by the FDA before White with- drew the drug from the market. This background is furnished in view of the request that I provide, in advance, a company statement in the event of government action. I told Art Bosehen `this morning that in view of our lawyers' advise on advance release didn't seem necessary, but after tying the above factors together I am making the following suggestions: In the event of rumor that the FDA is about to suspend the NDA "We have not received notice of any such hearing, as provided in the law. We are not in a positiOn to comment until we do-if we do." In the event of receipt of notice of hearing "The Wm. S. Merrell Company, Division of Richardson-Merrell Inc., has today received a notice of a hearing from the Federal Food and Drug Admin- istration to determine whether its effective New Drug Application on MER/29 should be suspended. In our opinion such suspension would be unwarranted and unnecessary, and we believe that evidence presented at the hearing will sustain this position," stated H. R. Marschalk, president of Richardson-Merrell (or Frank Getman, president of The Wm. S. Merrell Company Division). Let me know your final preference on who makes the announcement. Admittedly, the letter announcement is extremely brief, but I am proposing it in this form for two reason-~the first is that the less said, the better, as long as it `adequately covers our position-and secondly, it is hard to give added reasons until we get the notice of hearing, which is similar to a complaint and outlines the reasons why the NDA should be suspended. If it should be a claim we withheld evidence, that would call for one type of statement, whereas if it were based on certain kinds of toxicity, it would call for another. It seems to me this is as far as we can and should go at the present time, hut I will welcome any comments or suggestions. P.S-Needless to say, our preparation for the Thursday meeting is going on at full speed. OCTOBER 26, 1961. DEAR DOCTOR: The purpose of this letter is to advise you of those cases where MER/29 therapy should be discontinued. The types of cases where the drug is to be withdrawn more not apparent from the several thousand clinical cases studied during the two-year period prior to PAGENO="0384" 4286 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY marketing of MER/29. These cases have recently been observed following the widespread use of MER/29. There have been a number of reports of hair loss, changes in color and texture of hair, and dermatitis. More recently, less opacities have been observed in four patients following severe dermatitis. MER/29 should be immediately withdrawn if changes in hair or skin occur. Your patient should be informed to watch for hair or skin changes and directed to stop therapy and report to you if they should occur. For your information, the dermatitic usually is a dry, scaly type which may be associated with mild itching. It regresses following discontinuation of the drug. In a few patients, this mild dermatitic has progressed into a more severe ichtyoid type which is the type in which the four cases of loniticular changes have been reported. This has only occurred When drug therapy has been con- tinued for a period after the dermatitics appeared. The hair loss consists of a dift~use thinning unlike aleposia oreata or totalio. In some cases, hair loss has become catonoivo; and in a few of these, the thinning has involved body regions other than the scalp. Regrowth of hair occurs after varying periods of time following discontinuance of therapy. This letter is sent as part of our continuing policy of fully informing the medical proct~ess1on about MER/29. Your adherence to the cautions presented here will permit you to use MER/29 effectively in your practice. Sincerely, CARL A. BUNDE, PH. D., M.D., Director of Medical Research. OCTOBER 31, 1961. W. FREUD, M.D. S~kokie, Ill. DEAR Dn. FREUD: I have heard recently from your Merrell representative, Mr. Steven Andre, who reports that two of your patients who are on MER/29 therapy have complained of "black spots before their eyes." This is so unusual a report that I would like to ask you to provide us with additional details about these patients. In fact, we have never before heard of anything remotely resembling this. It would be important, for example, to know whether ophthalmologic examination has revealed anything of interest which may help to explain this phenomenon. It would also be important to learn whether these "black spots" are fixed or floating and whether the patients have experienced anything of this sort previous to MER/29 therapy. Also, have either or both of them had other possible side reactions-for example, dermatologic involvement? This would be important inasmuch as the eye and skin are both of ectodermal origin. Any information you might be able to provide would be very much appreciated. Sincerely yours, Ronnnr H. MCMASTER, M.D., Associate Director of Clinical Research. WHITE PLAINS, N.Y., July 8, 1964. BENJAMIN HEESH, Esq., Peekskill, N.Y. DEAR Mn. HERSE: At the request of Mrs. Elizabeth Ostopowitz I wish to ~nd you the following report: She was first seen In this office in September, 1963, complaining of difficulty in reading a newspaper in the three months prior. She stated that she took the drug known as MER 29 for seven or eight months following which there was loss of hair which has gradually returned. Examination showed her vision limited to the counting of fingers in each eye because of cataracts. The lenses were diffusely involved with degenerative cortical changes including clefts and scattered opacities. There was no view of the fundus of either eye but light projection was accurate. The diagnosis of bilateral cataracts was made and considering the patient's age and the history it was felt that these cataracts were very likely related to drug ingestion. PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4287 On October 29, 1963 the cataract was removed from the righteye and on April 19, 194~4 the cataract was removed from the left eye. In each instance the post- operative vision has been 20/20 and the patient is now wearing glasses which give her this vision. A fee for these services is enclosed. tours very truly, ARNOLD W. FORREST, M.D. DECEMBER 28, 1959. Dr. R. H. MCMASTER, The Wm. S. Merrefl Co., Uincinnati, Ohio. DEAR Dn. MCMA&riDR: I meant to catch you during the conference ta tell you that I had decided it would not be advisable for me to accept your generous offer an honorarium for my contribution to the MER/29 conference. Because of my Government affiliation and also because I am currently a member of the Metabolism Study Section which may have to pass on grant applications in connection with projects `involving your company, acceptance of an honorarium might be misunderstood by some. Therefore, I am returning your check with thanks. My expenses to this meeting were paid by the National Heart Institute. I enjoyed participating `in the conference and I believe it served a very use- ful purpose in bringing together people studying MER/29. The new information that we presented `at the meeting represented primarily the work of the few weeks preceding the conference and so I had not had time to communicate, with you about it before. There are several serious questions raised by these findings. First, we do not know yet whether 24-dehydrocholesterol is or is not athero- genic to the same extent or to a greater extent than Is cholesterol. Second, we do not know yet whether 24-dehydrocholesterol has other biochemical effects that make it unsafe to treat with MER/29. I know that you are~ of course, anxious to `Obtain FDA approval to market the drug but I do not feel that this would be wise In view of `the new data. What are your own thoughts on this matter? Have you any suggestions as to the kinds of Information that should be sought in order to clarify the status of the drug? Again, many thanks for your hospitality and for arranging a valuable con- ference. Sincerely yours; DANIEL STEINBERG, M.D., Nation,ai Heart In,stitute. [Inter-Department Memo, Feb. 18, 195O}~ To: Those concerned. From: Frank N. Getman. Subject: Minutes of MER/29 meeting, February 17, 1960. The following notes represent the pertinent questions raised and constructive suggestions made during yesterday's meeting on MER,/29. I. Cui~ic~ BACRGROUND Morson requested breakdown on patients with pre-treatment cholesterol blood levels of over 250 mg. Richardson, Jr.-wbat will be the doctor's reaction to Princeton Symposium? We feel that it will be the most terrific selling tool that Merrell has ever had, since it is a frank discussion of the product-we are telling both the good with the bad. (Getman.) Morson pointed out that Hollander used the dosage of 750 mg. per day to reduce the tissue level of cholesterol and has wondered whether 250 mg. per day would do this. Blohm answered that he believed it would, since higher dosage does not increase reduction of blood cholesterol levels. While we cannot prove beyond doubt that we reduce tissue levels at 250 mg. it has been universajly accepted by our clinicians that tissue level reduction does occur at this dosage. &1-2~0~-~9-pt. 10-25 PAGENO="0386" 4288 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dunning asked how long it would take to have established claims on periph- eral vascular disease. It is possible that we will have this data in ~ months but we have problems in getting reliable objective methods and It could take years. Morson asked whether we could get autopsies on patients who die while on MER/29 therapy. It was reported that all clinicians had been asked to do this. Following a lengthy discussion on the clinical support on anginal pain, Getman pointed out that we will have a statistical breakdown on the response of~anglnal patients to MER/29. However, we do not planto pt~sh angina initially. We have an important but complex story to tell on introductipn and by early fall, If clinical work remains favorable, we wjll really push the use of MER/29 In angina. Richardson, Jr. pointed out that it appeared to him that our claims on reduction of cholesterol were well supported whereas the other patient benefits were more nebulous. They might or might not occur with most patients. He wondered whether we should not establish it first and not make too strong a promise on the other patient benefits in order not to get doctors and patients disappointed. General agreement was expressed with this concept. However, we do not want to forget the promise of possible other patient benefits since our evidence to date certainly indicates *that we are well justified in promising these possibilities. In response to a question by Dunning on long term therapy, it was pointed out that approximately 500 patients have been on MER/29 for at least 9 months and about 150 for over 2 years. Many patients were on very high dosage (one on 3 grams a day for 14 moi~tbs). In answer to Mr. Richardson's request for more information on Desmosterol, the following was reported: Two chemical papers have been published on it-it had not been considered important until the Princeton Symposium. The question that must now be answered is whether it is atherogenic and if so is it more atherogenle than cholesterol? Studies are going to be, real tough since Desmosterol is not available. However, we are extracting it from MERY29 treated rats. We can be sure that it Is not toxic in the human and if its atberogenicity were as bad as cholesterol, we would not be getting the patient benefits that we have experi- enced. with MER/29. Getman requested a report from Morson on MNOL's clinical experience with MER/29. Morson reported that their work was very preliminary and that the only thing they had studied thus far was reduction in cholesterol. He stated they were following the same clinical protocol used in the U.S. Getman pointed out that our fee&back from MNOL is too casual and asked that the methods be buttoned-up so that we can be assured of getting reports of MNOL clinical findings on MER/29 as well as other drugs clinically evaluated abroad. Dunning stiggested that a quarterly report would be of value in New York and a copy of which could be sent to Merrell. Morson will follow up on this and see that it is done. II. MARKETING 1. COPY PLATFORM Richardson, Jr. pointed out that one of our stated objectives was to understate rather than overstate our claims on MER/29. He questioned whether our copy platform adhered to this objective. It was pointed out that we will, at times, make what appears to be strong claims but only when we can support these claims with published clinical data. Dunning suggested that safety appeared to be an important selling point for MER/29 and should be given more prominence in our copy platform. This was agreed to and will be done. Richardson, Jr. pointed out that iii our copy platforta we state that a large number of patients with angina would benefit from MER/29. He quOstioneçl whether this was an over-statement. This will be changed to read-"substantial nuntber"-or the equivalent "some patients". PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4289 2. THE INTRODUCTORY AD The 7-page introductory ad was thoroughly analyzed both as to copy content and layout. The following specific suggestions were made: Dunning suggested that lack of toxicity be covered in the letter from Dr. McMaster. Richardson, Jr. suggested that point #3 in the letter should be point #2. Anderson suggested that we insert "excess" in front of "production" in 2nd sentence of letter. Dr. Stormont questioned whether we could say-treatment of coronary artery disease as we do in the 1st sentence of the letter. He wondered if it might be confused as sole therapy-this will be checked out. Dunning pointed out that we should always say inhibits "ea~cess production of cholesterol"-this will be done. Von Rosenstiel-p. 3 par. 2-why not paraphrase to get a stronger statement. This is a good point and we will rewrite it. Ohewning-shouldn't we also quote other authorities in addition to National Heart Institute? This will `be checked out to see if `we have other suitable author- ities to quote. Jacobs pointed out that p. 3 par. 5 does not give the dosage level used. This will be rechecked with the clinical paper. Dunning wondered whether we couldn't use total numbers of patients and prepare our own charts. It was pointed out that we could not do this since we could not reference the data. Von Rosenstiel wondered whether on p. 3 par. 4-the doctor will understand "conversion of acetate". This was a good point and the ad will be changed to read "decreases production of cholesterol in the `body". Anderson wondered if on p. 3 par. 4 we were making our statement strong enough. It was agreed that we probably were not and the sentence will be c'hanged to read "acts by inhibiting * * *" Richardson, Jr. pointed out that our ad shows reduction in conversion of acetate and he thought that we should also have one that shows reduction in cholesterol blood levels. This was agreed to and we can prepare one from p. 3 par. 5. Von Rosenstiel pointed out that the fact that MER/29 does not reduce brain cholesterol is extremely important and should get greater emphasis. Richardson, Jr. again raised the question that he was concerned that we might be over-claiming on patient benefit. He pointed out that our major proof was for cholesterol reduction and that safety was an important feature. How- ever, our ad is devoted 50-50 to cholesterol reduction and other patient benefits with very little attention to safety. He said that our headlines concerning other benefits particularly bothered him. It was pointed out that we would give more prominence to safety although we didn't want to overdo It and that we would rework our headlines. However, we do not want to minimize the promise that MER/29 may, in some patients, in addition to reducing blood cholesterol, also result in beneficial effects on angina symptoms. Specific sug- gestions for doing this were made as follows: Von Rosenstiel-pick headlines out of Hollander paper-the quote may go further than you want to but you can modify in body copy. Getman pointed out that we were skeptical of riding one man's findings as headlines but we will recheck this possibility. Stormont suggested that we modify our headlines on anginal patients by in- serting "preliminary findings". The layout of the ad was discussed and since we no longer plan to use the calligraphic man, we have quite a bit of free space on the border of our ad which could now be utilized for additional clinical quotes. Dunning pointed out that in the summary section of the ad we might be in danger when we mention reduction of cholesterol in one week. This was agreed to and it will be changed to 2 to 3 weeks since there is no sense in running a risk when we don't have to. Dunning also pointed out that on p. 7, item 2 thru 4 may not show up in 5 weeks-this will be changed. The following additional general comments were made: As an over-riding principle in our copy we should keep it as simple as possible since we don't know the extent of the average physician's understanding of PAGENO="0388" 4290 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY technical terms in this field. A section should be at the end of the ad covering availability and contra-indication such as "not to be used during pregnancy". This would also be a good section to include the things that MER/29 does not do. For example, it does not reduce brain cholesteroL The indications section of the ad should be reworked to correspond to the brochure which includes the most recent FDA changes in our basic brochure. 3. DIRECT MAIL Anderson pointed out that the Princeton Symposium and the Western Union mailing were very unusual and he wondered whether we could capitalize on that with the rest of our mail. He was pointing to a desire for continuity in our over-all MER/29 image. It was pointed out that we were doing this with our gray and red color scheme and, of course, the calligraphic man would have appeared on all of our printed material and we are now looking for a sub- stitute for the calligraphic man. Von Rosenstiel suggested that all our mailings be designed to fit In the basic book on M1~R/29 which was delivered by Western Union. This may turn out to be an excellent suggestion and will be further evaluated. 4. SALES PROMOTION (a) The detail story Getman suggested that Dr. Wright's work on anti-coagulants be included in the safety section of our detail. Richardson, Jr. suggested that we rewrite the section covering "speculation" since reduction in tissue levels is a fact rather than a speculation. (b) Supportive materials Richardson, Jr. suggested that a piece of literature for the doctor to give to the patient concerning MER/29 might be helpful in keeping the patient happy while waiting for results. Chewning stated that we would like to get an article published in a magazine such as Today's Health and then make reprints available for patient distribu. tion. The idea of a-patient booket-is worth further investigation. Richardson, Jr. pointed out that since the majority of doctors feel that cholesterol is related to cardiovascular disease, it probably isn't necessary to go at great lengths during our detail to establish this importance. This impor- tant question will be re-appraised. _______ [Inter-Department Memo, Aug. 1, l~i6O] To: R. H. Woociward (and others) From: Frank N. Getman Attached is the August Issue of Family Circle containing an article on "Now- many strokes can be prevented." To me this is written in very simple, easily understood language on one form of cardiovascular disease. It seems to me that it may be of assistance in helping us along with lay articles to be written on MER/29. lit might also help in advertising and promotion, as I don't believe the average Co. yet understands our ME'R/29 story. Simplification should help. Enclosure [omitted.] TIMETABLE OF MEII/29 PR PROGRAM February.-Assist Marketing with submission of advertising copy for approval by the J.A.M.A. Advertising Committee, Dr. John Baum, chairman. March.-Effectlve NDA-begin 1) press contacts (see priority list attached) and 2) clinical speakers service (see plan attached). March 1-4.-Chicago Medical Society, Lisan ecohibit. Press release Only. March 18-25.-Ameriean Academy of General Practice, Philadelphia. Lisan (Hahnemann) ecohibit should be brought to attention of press. It Is proposed that this be done by Hahnemann PR director, Cy Lieberman. No major effort PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4291 will be exerted since the exhibit was reported at the Dallas A.M.A. meeting in 1959. April 4-9.---American College of Physicians, San Francisco. Ralph V. Ford (Baylor) paper on MER/29. Alert ACP press staff; San Francisco and Houston papers; national news magazines, Drug Trade News and American Dr~iggist; service medical editors. Report from San Francisco could be mailed to intern- ists to reinforce the press story. April-June.-Drug trade publications services with new product information and photo-features. April 11-15.-Federation meeting, Chicago. National press conference will be held to take advantage of the coverage given this meeting by the best of the scientific press. Merrell papers by MacKenzie, King and Kariya will be presented. A clinical consultant will be invited to the press conference to give clinical interpretation of the scientific papers. Complete background release will be made, with timetable of future events to guide the press. April 12.-American Chemical Society, Cleveland. Palopoll paper news release to press. April 28.-New York press conference, to announce publk~atlon of the Prince- ton Conference. Participants: Drs. Wright, Page, Wilkins, Blohm. Conference will be held at Cornell University Medical College (alternate, New York Academy of Sciences). The New York press corps would be invited to hear a report to the nation on heart disease and MER/29. A.M.A. and American Heart Association would be invited to send public information representatives. Special mailing of the Conference publication will be sent to Medical School libraries. May 2-4.-Louisiana State Medical Society, Baton Rouge. John T. Leckert (LSU) paper, Alert Baton Rouge and New Orleans papers; wire service medical editors. May or later-New England Journal of Medicine. Mellander paper to be pub- lished May or thereafter. Release from Merrell to all wire services, metropolitan newspapers, selected magazines and science writers. June 13-17.-American Medical Association, Miami. Kountz (Washington Uni- versity) and Lisan (Hahnemann) ecohibits tentatively scheduled. Notify A.M.A. press staff for daily bulletin coverage; handout for press room. Ruskin (Texas) has applied for a place on the program. CHECK Lisr or PR CONTACTS ON MEIt/29 When NDA is effective, contacts will be made with editors, publishers and public information people to establish rapport and develop specific ideas for PR support for MER/29. Each contact represents a point of departure for a special working relationship and the PR "product" which will result. 1. Priority contacts to be made by Mantell and/or Ohewning. Modern Medicine: Interview Insert, "Exclusive" interview with Princeton Con- ference participants. Geriatrics: Editorial Comment. J.A.M.A.: Special clinical communication. U.S. News & World Report: Interview. Time: Conference with medical editors. Life: Conference with medical editors. News Week: Conference with medical editors. RN: Staff story on cholesterol. American Druggist: Develop series of photo and news releases. Drug Topics: Develop series of photo and news releases. Drug Trade News: Feature stories and health column comment. Saturday Evening Post: Feature stories and health column comment. Look: Feature stories and health column comment. Reader's Digest: Feature stories and health column comment. Cosmopolitan: Feature stories and health column comment. Ladies Home Journal: Feature stories and health column comment. Red Book: Feature stories and health column comment. Metropolitan newspapers: Selection guided by Princeton Conference partici- pants list. PAGENO="0390" 4292 COMPETITIVE PROBtEMS IN THE DRUG INDUSTRY Also considered a priority job is the briefing of public inforni~tion jiersonnel at: American Heart Association. American Osteopathic Association American Medical Association National Institutes of Health American College of Physicians Federated Societies American Chemical Society 2. Important outlets for MER/29 news are the following groups or publications. These contacts will be developed as the plan unfolds or after the priority contacts are completed. Scope Today's Health Medical News. Argosy, Saga, etc. MD News Magazine Medical journals-Angiology Medical World New York Times (Sunday column) A.M.A. News Family Circle Drug and pharmacy Publications (including Medical News Letter): Business Week Wall Street Journal Fortune McCall's Chemical Week . Good Housekeeping Chemical and Engineering News Co~ronet American Weekly, Parade and other syndicated features FDC' Reports Syndicated health columns: Alvarez Dean Berton Herschensohn Bauer Hyman Brady Osborne Bundesen . Steincrohn Crane Van Dellen Science news editors (IJPI, AP, NIOA) National Association of `Science Writers 3. Special projects will be initiated at what seems to be the appropriate time Examples: Visits or communications with "sensitive areas" in the government. Development of radio-TV coverage of the Princeton Conference press release of the monograph. Coordinated PP program with the publisher of the Princeton Conference monograph. Development of international medical meeting feedback for U.S. news release. Special program (perhaps a small clinical conference) if indicated for Canada. Insurance and industrial physician awareness of MER/29. Presentation of awards or other evidence of recognition to Merrell scien- tists who developed MER/29. Public education materials for MD to give to patient (perhaps a reprint from Today's Health, MD News Magazine, or a "reliable" national `magazine). PR MAILiNG Lisr FOR MBR/29 National Association of Science Writer~;~. 190 Medical journals: National - 125 Local (county and State) 212 Hospital journals - 15 Nursing journals 10 Drug trade and pharmacy 75 Newspapers 250 Canadian publications 42 Total 919 PAGENO="0391" COMPETITIVE PROBLEMS I~ THE DRUG INDUSTRY 4293 (From Sales Talk-News, Tips, Ideas, June 2, 1960] ]~XTRA-MER/29 MAKES PIMt TIME MAGAZINE REPORTS ON MER-29 Time waits for no one-MEIt/29 is no exception. The "Medicine" section of the latest issue praises MER/29 in an article. "Cutting the Cholesterol." This issue will be in the hands of over 3 million persons. Publicity of this kind will send thousands of patients to their doctors asking about MER/29. Make sure they walk out of the offices with prescriptions. [From Campaign Strategy-The Wm. S. Merrell Co-Jan. 9 to Feb. 17, 19611 USE MER/29 CLINICAL TRIALS TO PU5H "WAIT AND SEE" G. P.'5 Youn ASSIGNMENTS Tills CAMPAIGN, JANUARY 9-FEBRUARY 17 In. the doctor's office: MI~R/29. In the hospital: MER/29 C~pacol Lozenges (military). In the drug store: Cepacol lozenge/troche deals. Also in the doctor's office: Idea sell, Tenuate Dospan, Simron. Profitunities: OB products, TACE, Alertonic. IN TIlE DOCTOR's OFFICE MER/2 9-MAJOR SELL Objective: To persuade "wait and see" G.P.'s and internists to prescribe MER/ 29 now for at least three patients. Materials: MER/29 patient trial kit (10 per man) ; new case history brochure (150 per man) ; supplementary materials: archives of internal Medicine Journal (Ruskin paper) ; direct mail and journal ad tear sheets. It is no longer possible for you to "wait out" undecided doctors. The time for very definite forceful action is now. Such action is far and away your major responsibility this campaign. "SICK PATIENTS FEEL BETTER" IS KEY TO CREATING DESIRE TO PRESCRIBE By now you can identify the doctors not using MER/29. Yet, you know they should be. Very often, you know most of their reasons for not using it.. . choles- terol may not be atherogenic, desmosterol is a question mark, possible liver toxicity, doesn't work, doesn't do anything fast enough, costs too much. Doctor "X" hasn't started using it yet, Are any of these legitimate? No! From our view- point: we know they aren't true, we know what MER/29 can do for a person who needs it, and we know they have not stopped top MER/29 salesmen. There is. no point in trying to overcome each of these objections. That's the long way around. The quick way to get the non-prescriber using MER/29 is to use every resource you have at your command to show him that he will be benefiting himself and his sick patients in a giant way just as soon as he uses MER/29. That's any doctor's hot button.. . and you must come down on it harder than ever before. Yes, MER/29 works by lowering cholesterol. .. doctors know this. Now, show them what they don't understand well enough yet.. . just how much MER/29 can benefit their patients! And, you can show any given doctor five benefits of MER/29 therapy In 5 minutes. Here are two powerful tools placed at your disposal for this important job: 1. A field tested structured presentation (with new selling aid). 2. The MER/29 patient trial program. MER/29 STRUCTURED DETAIL Doctor, when you are considering a course of therapy for a patient you must have good reasons for your selection. This is true in the case of ME:R/29. KnowS ing this and guessing that you have yet to decide in favor of MER/29, I would PAGENO="0392" 4294 COMPETITIVE PROBLEMS IN TH~ DRUG INDUSTRY like to summarize today, the important reasons why MER/29 should be a routine part of your treatment for patients with any manifestation of hypercholesterO- lemia. First, MER/29 is a proven drug. It has been administered under controlled conditions to more than 2000 patients for periods up to three years. There is no longer any valid question as to its safety or lack of significant side effects. There is no longer any doubt about its ability to lower significantly the total sterol content of the human body. But, here is what is most important. Here is the fact that recommends MER/29 for your routine use. You want to help sick people feel better while they are getting better. . . that is what is Important to you. Mounting evidence makes it increasingly clear that MER/29, in some but certainly not all cases, affects for the better such manifestations of hypercholesterolemia as intermittent claudi- cation angina pectoris myocardial infarction or ischemlc BOG patterns As evidence of concurrent benefits obtained by lowering cholesterol in some patients, let me illustrate what I mean with some case histories which might parallel cases you see in your practice . (Insert at least two case histories . . . local if you can and as many as you can . . . until he gets restless in his chair! !!) These results are occurring not because of some temporary change, but as the Wilkins' group at Massachusetts Memorial Hospitals afid others have pointed out, because MER/29 by lowering cholesterol may actually improve the adequacy of circulation. Reports from all over the United States, to our Medical Research Depart- ment, underline that this must be the change that is occurring. We have had verified reports of improvement in anginal pain, less need for nitrates, greater tolerance to exercise, reversal of BOG patterns of a type that has never occurred before. In peripheral vascular cases, there are verified reports of lessened leg pain and ability to walk greater distances. I don't mean to Infer that all. . . or even a majority of patients on MER/29 will get such results, but if you select patients whose history of hypercholesterolemla is relatively recent, there may be chances of such improvements occurring. It will take time because the action of MER/29 is too basic to work super- ficially . . . but a number of these patients will volunteer, after a month or two, that the little gray capsule, taken once daily, is helping them and they're glad to be taking it. Doctor, with such encouraging results a part of the background of MER/29, we feel it warrants personal evaluation by every physician who sees such patients. Using MBR/29 need not mean doing extensive determinations when there are such direct benefits to be looked for. Because of this, I would like to recommend a~ course~ofaetlok to you: Select five patients from your practice with a recent history of some manl~esta- tion of atherosc1erosis~ As pai~t of the therapy for these patients, initiate MER/29 one capsule daily for a minimum of two to three months. Be patient and have confidence in MER/29, and suggest to the patient that he cannot expect imme- diate improvement. Then, after three months, judge MBR/29 on the basis of the improvement your patients report to you. If you will do that, I'm confident you'll become one of the biggest users of MER/29 in this area-to the benefit of yourself and your patients. _______ FROM THE DEsK or PHILIP RITTER III The above detail Is as carefully worded, as carefully structured, as our original detail was. Again,as I did at French Lick, I ask you to follow this presentation word for word. Itrepresents the present ultimate in positive presentation of our basic MER-29 claims. Please practice it until it becomes a part of your selling personality. PHILIP RITTER III. Nzw MER/29 HOSPITAL EXHIBIT UNIT The highly successful "Announcing MER/29" hospital exhibit unit has served its purpose and now goes into honorable retirement. PAGENO="0393" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4295 The new unit, which utilizes the pernianent light, box sent you `with the old unit, will support your hospital~ exhibit detailing for the next 6-9 months. The theme on the center panel, How MER/29 Differs from Other Oholestero'l Low~ring Agents, was selected because of the real need to stress the fundamental ~,P~i~on why MER/29 is superior. Of the products now on the market, only -.--~ MER/29 has been clinically proved to lower the all-important tissue cholesterol. The quotation on the right wing panel hits the "I'm not sure cholesterol is atherogenic" doctor right between the eyes. "There is no question that coronary disease is more prevalent in individuals with an elevated serum cholesterol . . . A serum cholesterol below 180 mg percent can be regarded as `nonatherogenic,' a level above 250 mg. percent as constituting high risk." Silber, E.; Pick, R. and Katz, L. N., Eds.: CIrculation 21: 1193 (June) 1960. This strong statement, published in a highly respected journal and written by well-known cardiologists, should go a long way toward convincing the "fenc& sitters." We expect to ship these units early in January. The light box provided with the original unit is to be used with this one too. Continue holding MER/29 hospital exhibits as often as possible. Report after report proves they create MER/29 prescriptions in hospitals and drug stores. [From Sales Talk-News, Tips, Ideas-Mar. 21, 1961] SIMPLE QUESTION COUNTERS 90 PERCENT OF SIDE EFFECT QUESTIONS We heard eight words the other day that neatly handle one of your biggest problems. When a doctor says your drug causes a side effect, the immediate reply is: "Doctor, what other drug is the patient taking?" E~ven if you know your drug can cause the side effect mentioned, chances are equally good the same effect is being caused by a second drug! You let your drug take the blame when you counter with a defensive answer. Know how to answer side effects honestly, yes, but get the fcwts first: Doctor, what other drugs is the patient takin.g? Been doing it for years? Why didn't you tell us then? BOWEN QUOTES ALEXANDER POPE TO CLOSE MER/29 DOUBTERS Here's `one that seems like a red hot idea for MER/29 . . . if it's your style. It's from Tim Bowen, Charlotte, N.C. Aimed particularly at the "wait and see" physician, Tim's close goes something like this (we got it third hand): "Doctor, I can appreciate and admire your caution about any new drug, but MER/29 has been on the market almost a year now and was studied in thousands of patients for years before that. Its rate of use indicates that acceptance Is broadening rapidly. Perhaps these words of Alexander Pope have some bearing to your consideration of MER/29: `Be not the first by whom the new are tried, nor yet the last to lay the old aside'." Lots of power there . . . can your style be bent just a bit to fit? MER/29 PATIENT BOOKLET COMING . . . URGES PATIENTS TO STAY WITH rr! "Patients won't continue on therapy" and "It costs too much" are really the same objection aren't they? To help doctors overcome these objections, you will soon have quantities of a booklet designed to accompany the first Rx and explain the rationale of MER/29. You will receive this valuable `aid In April. NEW LOOK FOR MER/29 STOCK PACKAGES No doubt you've seen the new blue carton for MER/29 In many of your phar- macies. Soon all gray stock cartons will be replaced by "Merrell blue." The color coordinated Merrell "look" will lend prestige to the entire line of Merrell special- ties on the pharmacist's shelf. PAGENO="0394" 4296 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Note: MER/29 Complimentary Stock Packages will remain In gray cartons to carry out the color theme which pervades all MER/29 advertising and promotion. MER/29 PATIENT TRIAL STUDY PAYING OFF ALREADY We just had to buy a new file for the Orange Patient Trial cards-your re~ sponse has been terrific. Here's a typical example of how the Study is helping get new prescribers. Chuck de Garmo, Los Angeles~ writes that one of his "partici- pants" is so enthusiastic about the program, he is going to increase it to about 25 patients. At the conclusion he plans to write a paper for publication. All but 3 of the patients will be paying for their MER/29. How many of your "on the fenee" doctors are participating? 0