PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~7O(,~Z5$1 ii HEARINGS BEFORE THE SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE NINETIETH CONGRESS SECOND SESSION ON PRESENT STATUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 8 MAY 2, 3, AND SEPP1~MBER 17, 1968 SECOND OF TWO VOLUMES ON INDOMETHACIN- TRADE NAME: INDOCIN 0 Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 81-280 0 WASHINGTON: 1968 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 - Price $1.75 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS [Created pursuant to S. Res. 58, 81st Cong.J GEORGE A. SMATHERS, Florida, Charirman JOHN SPARKMAN, Alabama JACOB K. JAVITS, New York RU'S;S~lLL 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, Ja., Tennessee B. L. BARTLETT, Alaska MARK 0. HATFIELD, Oregon HARRISON A. WILLIAMS, JR., New Jersey GAYLORD NELSON, Wisconsin JOSEPH M. MONTOYA, New Mexico FRED R. HARRIS, Oklahoma WILLIAM T. MCINARNAY, staff Director and General Coun8el JAMES H. GROSSMAN, Minority Counsel MONOPOLY STJBCOMMITPEE GAYLORD NELSON, Wisconsin, Chairman JOHIi SPARKMAN, Alabama HUGH SCOTT, Pennsylvania RUSSELL B. LONG, Louisiana MARK 0. HATFIELD, Oregon WAYNE MORSE, Oregon. JACOB K. JAVITS,5 New York GEORGE A. SMATHERS,5 Florida BENFAMIN GORDON, Staff Economist SUSAN H. HEWMAN, Research ~tssistant ELAINE C. Drs, Research Assistant. 5Ex officio member. II PAGENO="0003" CONTENTS Statement of- Beyer, Karl H., Jr., M.D., Ph. D., senior vice president for research, Merck Sharp & Dohme Research Laboratories, Division of Merck Page & Co., Inc., Rahway, N.J 3311 Calabro, John J., M.D., associate professoi of medicine, Department of Medicine, UCLA School of Medicine, Center for the Health Sciences; and chief, Rheumatology Section, Wadsworth Hospital, Veterans' Administration Center, Wilshire and Sawtelle Boulevards, Los Angeles, Calif 3399 Case, Hon. Clifford P., U.S. Senator, State of New Jersey 3295 Chadduck, Harry, Deputy Director, Division of Medical Advertising, Bureau of 1VI edicine, Food and Drug Administration; accompanied Dr. Robert S. McCleery, Acting Deputy Director, Bureau of Medi- cine, FDA 3484 Cutler, Lloyd N., special counsel, Washington, D.C.; accompanied Henry W. Gadsden, president, Merck & Co., Inc., Rahway, N.J.. - 3296, 3429 Gadsden, Henry W., president, Merck & Co., Inc., Rahway, N.J.; accompanied by Lloyd N. Cutler, special counsel, Washington, D.C 3296, 3429 Goodrich, William W., General Counsel, Food and Drug Adminis- tration; accompanied Dr. Robert S. McCleery, Acting Director, Division of Medical Advertising, Bureau of Medicine, FDA - 3105, 3484 Lawrason, F. Douglas, M.D., vice president for medical affairs, Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., Rahway, N.J 3315 Ley, Dr. Herbert L., Director, Bureau of Medicine, Food and Drug Administration accompanied Dr Robert S McCleery, Acting Di rector, Division of Medical Advertising, Bureau of Medicine, FDA. 3105 McCleery, Dr. Robert S., Acting Director, Division of Medical Ad- vertising, Bureau of Medicine, Food and Drug Administration; accompanied by Dr. Herbert L. Ley, Director, Bureau of Medicine, FDA; and William W. Goodrich, General Counsel, FDA 3105 McCleery, Dr. Robert S., Acting Deputy Director, Bureau of Medi- cine, Food and Drug Administration (second appearance); accom- panied by Dr. B. Harvey Minchew, Acting Director, Bureau of Medicine, FDA; Harry Chadduck, Deputy Director, Division of Medical Advertising, Bureau of Medicine, FDA,; William W. Good- rich, General Counsel, FDA; and Morton M. Schneider, Assistant Director, Office of Legislative and Governmental Services, FDA - 3484 Minchew, Dr. B. Harvey, Acting Director, Bureau of Medicine, Food and Drug Administration; accompanied Dr. Robert S. McCleery, Acting Deputy Director, Bureau of Medicine, FDA 3484 Rothermich, Dr. Norman 0., clinical professor of medicine, Ohio State University; senioi~ physician, Columbus Medical Center; medical director, Columbus Medical Center Research Foundation, 1211 Dublin Road, Columbus, Ohio 3262 Schneider, Morton M., Assistant Director, Office of Legislative and Governmental Services, Food and Drug Administration; accom- panied Dr. Robert S. McCleery, Acting Deputy Director,~ Bureau of Medicine, FDA 3484 Scott, Hon. Hugh, U.S. Senator, State of Pennsylvania (written statement) 3451 Smyth, Dr. Charley J., professor of medicine; and director, Division of Rheumatic Disease, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Cob 3425 Tishler, Max, Ph. D., president, Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., Rahway, N.J 3303 (III) PAGENO="0004" IV CONTENTS SALIENT EXHIBITS Address, "The State of the Law and Compliance," by W. W. Goodrich, General Counsel, Department of Health, Education, and Welfare, presented at Pharmaceutical Advertising Club meeting, October 20, Page 1966 3105 Article, "Indocin," by Phyllis and Robert P. Goldman, from Pageant magazine, July 1966 3177 Article, "Indomethacin: A New Non-Steroid Anti-Inflammatory Agent," by Drs. F. D. Hart and P. L. Boardman, from Brit~ish Medical Journal, October 19, 1963 3227 Article, "Indomethacin and Phenylbutazone: A Comparison," by Drs. F. D. Hart and P. L. Boardman, from British Medical Journal, November 27, 1965 3236 Article, "A Clinical Trial of Indomethacin in Rheumatoid Arthritis," by Drs. A. M. Katz, C. M. Pearson, and J. M. Kennedy, from Clinical Pharmacology and Therapeutics, vol. 6, No. 1, June 5, 1964 3277 Article, "An Extended Study of Indomethacin," by Dr. N. 0. Rothermich, from Journal of the American Medical Association, vol. 195, No. 13, March 28, 1966 3286 Article, "Lind's Treatise on Scurvy," edited by C. P. Stewart and D. Guthrie, University of Edinburgh Press 3320 Article, "Poll on Medical Practice," a special preprint from Modern Medicine, August 1, 1966 3328 Article, "HydroxychIoroquine Sulfate in Rheumatoid Arthritis, A Six- Month, Double-Blind Trial," by Dr. D. Mainland and M. I. Sutcliffe, from Bulletin on Rheumatic Diseases, vol. 13, No. 2, October 1962. - - - 3349 Article, "Aspirin in Rheumatoid Arthritis, a Seven-Day, Double-Blind Trial-Preliminary Report," by Dr. D. Mainland and M. I. Sutcliffe, from Bulletin on Rheumatic Diseases, vol. 16, No. 3, November 1965~ 3354 Document, "Legislative History of the Drug Amendments of 1962" 3363 Article, "Evaluation of Indomethacin by a Controlled, Cross-over Tech- nique in 30 Patients With Ankylosing Spondylitis," by Drs. T. D. Kin- sella, K. R. Mackenzie, L. G. Johnson, and 5. 0. Kim, from Canadian Medical Association Journal, vol. 6, June 3, 1967 3405 Article, "Indomethacin in Ankylosing Spondylitis," by Drs. J. J. Calabro and C. M. Amante, from Arthritis and Rheumatism, vol. 11, No. 1, February 1968 3417 Indocin (indomethacin) instructional bulletins from H. Glassner to All Associate Western Districts: Bulletin No. 83, July 12, 1965 3491 Bulletin No. 84, July 14, 1965 3492 Bulletin No. 87, July 20, 1965 3493 Bulletin No. 88, July 21, 1965 3494 Bulletin No. 93, July 28, 1965 3495 Bulletin No. 95, August 4, 1965 3497 Bulletin No. 23, April 5, 1967 3498 Bulletin No. 66, July 17, 1967 3500 Bulletin No. 74, September 5, 1967 3503 Bulletin No. 77, September 11, 1967 - - 3503 Bulletin No. 80, September 13, 1967 3504 Bulletin No. 85, September 27, 1967 3505 Bulletin unnumbered, undated 3514 Bulletin unnumbered, undated 3516 APPENDIXES I. Article, "Indomethacin in In-Patient Treatment of Rheumatoid Arthritis," by D. A. Pitkeathly, N. R. Banerjee, R. harris, and J. Sharp, from Annals of the Rheumatic Diseases, vol. 25, 1966 - - - 3519 II. Article, "Rheumatoid Spondylitis: Manifestations and Management," by Drs. A. M. Lefkovits and J. R. Thomas, from Annals of Internal Medicine, vol. 49, No. 1, July 1958 3524 III. Letter dated November 3, 1967, from Irving H. Jurow, vice president and general counsel, Schering Corp., to Senator Nelson, with ac- cOmpanying materiaL 3533 PAGENO="0005" CONTENTS V HEARING DATES* May 2, 1968: Page Morning session 3101 Afternoon session 3262 May 3, 1968: Morning session - 3295 September 17, 1968: Morning session 3481 *The testimony for May 15, 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 these 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, ap- pears 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 April 23, 24, and May 1, 1968, appears in pt. 7 of these hearings. PAGENO="0006" PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, MAY 2, 1968 U. S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 10 a.m., in room 318, Old Senate Office Building, Senator Gaylord P. Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; Elaine C. Dye, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. We will open our hearings. Our witness this morning is Dr. Robert S. McCleery, Acting Three- tor of the Division of Medical Advertising of the Bureau of Medicine of the Food and Drug Administration, and Dr. Herbert Ley. Doctors, we appreciate your coming over here today. Dr. McCleery, you may present your testimony as you see fit. I see you have ap- pended biographical material of your distinguished background. That will be printed in full in the record at the beginning of your statement. (The biographical material follows:) BIOGRAPHICAL DATA OF ROBERT S. MCCLEERY, M.D. 1934: A.B. (Sürnma cum Laude)-Ohio State University. 1934: MA. (with Highest Distinction)-Ohio State University. 1938: M.D. (with Honors)-Ohio State University. 1938-40: Interne and Assistant Resident-Jackson Memorial Hospital. 1940-42: Assist. Resident in Surgery-Univ. of Minnesota Hospital. 1942-45: U.S. Army Medical Corps. 1945-46: Resident in Surgery-University of Minnesota Hospital. 1946-48: Assistant Professor of Surgery-Ohio State University. 1948-52: Associate Professor of Surgery-Vanderbilt University, and Chief of Surgery, Thayer V.A. Hospital, Nashville, Tenn. 1952-56: Private Practice of Surgery-Great Falls, Montana. 1956-57: Carnegie Fellow, Institute for Advanced Study and Princeton Theologi- cal Seminary. 1957-60: Vice President and Medical Director-Burdick & Becker, Inc. (Medi- cal Advertising), New York City. 1960-61: Associate Medical Director-Bristol Laboratories, New York City. 1961-62 :Vice President and Medical Director-R. A. Becker, Inc. (Medical Adver- tising), New York City. 1962-63: Vice President and Medical Director-Sudler & Hennessey, Inc. (Med- ical Advertising), New York City. 1963- : Bureau of Medicine, Food and Drug Administration. 3101 PAGENO="0008" 3102 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMBERSHIPS 1. Phi Beta Kappa. 2. Alpha Omega Alpha. 3. Sigma Xi. 4. Fellow, American College of Surgeons. 5. Diplomate, American Board of Surgery. 6. Society of University Surgeons. 7 Society for Vascular Surgery 8. Association of Medical Directors. 9. American Medical Writers Association. PUBLICATIONS Research papers in the medical literature-22. NOMINATION FOR DISTINGUISHED SERVICE AwARI Name of Nominee Robert S MeCleery M D Title of Present Position Acting Director Division of Medical Advertising Of lice of Medical Support Organization and Its Location Bureau of Medicine Food and Drug Administra tion Arlington Virginia Number of Years of Government Service 12 years Num'ber of Years of Service in DHEW/FDA: 5 years. Previous Grade and Years in that Grade: GS-45 for 2 years. Previous Grade and Years Held: GS-14 for 3 years. Other Honors Received: Phi Beta Kappa. Alpha Omega Alpha. Diplomate, American Board of Surgery. Carnegie Fellow Institute for Advanced Study and Princeton Theological Seminary FDA Award of Merit Citation Dr Robert S MeCleery is hereby awarded this Certificate for Distin guished Service Dr McCleery is the individual within the FDA most responsi ble for implementing the regulations insuring against faulty prescription drug advertising in the United States. NARRATIVE STATEMENT Education: Ohio State University: 1930-34, A.B. (summa cum laude), Chemistry & Biology. 1934-34 M A (with highest distinction) Chemistry 1934-38, M.D. (with honors). Princeton 1956-57 Carnegie Fellow Institute for Advanced Study and Princeton Theological Seminary Honors Received Phi Beta Kappa 19~34 Alpha Omega Alpha 1938 Diplomate American Board of Surgery 1947 FDA Award of Merit: 1967. Work Experience: Jackson Memorial Hospital 1938-40, Miami, Florida-Intern and Assistant Resident in Surgery. University of Minnesota Hospital 1940-42 Minneapolis Minnesota-Assist ant Resident in Surgery U S A MO 1942-45--Medical Officer University of Minnesota Hospital 1945-46 Minneapolis Minnesota-Resident in Surgery Ohio State University 1946-48 Columbus Ohio-Assistant Professor of $urgery Vanderbilt University 1948-52 Nashville Tennessee-Assistant Professor of Surgery Thayer VA Hospital 1948-52 Nashville Tennessee-Chief of Surgery Private practice of surgery, 1952-56, Great Falls, Montana. PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3103 Carnegie Fellow Institute for Advanced Study and Princeton Theological Seminary 1956-57 Princeton Burdick & Becker, Inc., 1957-GO--Vice President and Medical Director of Medical Advertising Firm. Bristol Laboratories, l~6O-6l-Associate Medical Director. R. A. Becker, Inc., 1961-62------Vice President and Medical Director of Medical Advertising Firm. Sudler & Hennessey, Inc.,, 1962-63--Vice President and Medical Director of Medical Advertising Firm. Food and Drug Administration Bureau of Medicine 1963 to present Wash ington D C and Arlington Va -Medical Officer and Acting Director Division of Medical Advertising. Present Position Administers and directs the activities of the Division of Medi cal Advertising Office of Medical Support Bureau of Medicine Prepares 01 manages the preparation of advertising critiques involving complex medical features. Analyzes medical advertising and promotional labeling and makes final judgment from the Division's standpoint on the merit of cases to be for- warded for regulatory consideration. Verifies and independently searches the medical literature in relation to advertising and promotional labeling which are based on literature references Evaluates the merit of cases in the regulatory stage and prepares comments for the assistance of General Counsel and other elements of the government as the cases proceed to completion Develops policy and programs relating to the functions of the Division Acts as the Agency 5 representative in seminars etc in presenting the knowledge of the Agency S responsibilities and functions for the education of the regulated industry Service or Achievement Which Merits Special Honor Dr McCleery has not only competently performed all aspects of the duties required for the administration and direction of the Division of Medical Advertising, but through his most exceptional ability in dealing with com- plex medical issues in relation to advertising and his keen analytical abil- ity, has contributed largely to the development of basic Agency principles on which advertising may be evaluated within the scope of the law and the regulations. Dr. McCleery pioneered in bringing the first case under the advertising provisions of the Federal Food, Drug and Cosmetic Act to successful con- elusion In the Pree MT case against Wallace Laboratories which was in itiated through critiques of journal advertising prepared by Dr. McCleery, the firm pleaded nob contendere and was fined $1000 on each of two counts in a criminal information. In the Peritrate-SA. case, which was initiated by Dr. McCleery, and which involved a most exacting analysis of complex advertising copy, a shipment of the drug based on misbranding through advertising was seized in 1966. Also, in 1966, the case against Serax was terminated through seizure of a shipment allegedly misbranded by advertising of the drug. Dr. McCleery's efforts in preparing the basis for seizure contributed largely in the suc- cessful completion of the case. Dr. McCleery presented two other critiques in 1966 that resulted in seizures involving Lincoln and Lasix. Further, he sponsored action leading to the `correction of many monographs in the Physicians' Desk Reference, the most important single' reference book for physicians. Dr McCleery concen ed a unique remedy for dealing with misbranding sltua tions involving advertising or promotional labeling in the form of a "reme- dial letter Early in 1967 Dr McCleery s concept was reduced to practice Sponsoring rapid action, Dr. McCleery presented a critique on initial ad vertisement for Ortho-Novum-SQ, the first advertisement for the product published after the drug was approved for marketing. Dr. McCleery's crit- ique, charging that the ad failed to include a true statement of effective- ness of the product, resulted finally and rapidly in issuance of a "Dear Doctor" letter by the firm to' other 200,000 practicing physicians in the United States. Dr. McCleery had provided detailed guidance and counsel to the members of his staff in achie~ ing greater ffe tn ene~s of the group in their devel opment of critiques earching the literature analysis of advertising copy etc He has consulted in relationship to the e~ aluation of references which entailed personal and independent study in many instances. For many months Dr. 1~icC1eery was the only medical officer exercising the duties of his unit. He has devoted many hours of overtime daily in keeping cur- PAGENO="0010" 3104 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY rent with the work of his Division. As a result of his personnel untiring efforts, the Division has not been in a backlog position on referred assign- ments. The above summary of Dr. MeCleery's accomplishments through 1966 was largely instrumental in his being granted the FDA Award of Merit in 1967. Beginning early in 1967, his personal participation and direction of the Division of Medical Advertising led to even greater demonstration of his effectiveness in bringing advertis'ing and promotions of prescription drugs into compliance with the requirements of the Act. 1~vidence of his success in accomplishing the mission of his Division is rep- resented specifically in the following examples. Following the introduction of the "remedial letter" concept which corrects faulty advertising of pre- .scription drugs, the efforts of Dr. McCleery in the areas of preparation of critiques, in participating in meetings held between the Commissioner, FDA officials and representatives of drug firms and in the development of detailed drafts of "Dear Doctor" letters, have resulted in the issuance of 20 such letters by manufacturers to all practicing physicians in the United States. Conservatively, a total of over 4 million remedial letters have been mailed to physicians as a result of action initiated by Dr. McCleery. Copies of the 20 letters are attached to show the nature and extent of the corrections involved. While some of the "remedial letters" involve corrections of monographs in the Physicians' Desk Refcrence (a comprehensive reference book used by physi- cians), Dr. McCleery directed the activities of his group in analyzing mono- graphs in the book and initiating various other actions leading to correction such as issuing letter and telephone calls to firms requesting correction, participating in conferences with firms on specific problems, etc. During the period January 1, 19437 to date over 150 corrective actions have been initiated by Dr. MeCleery. In addition to "Dear Doctor" remedial let- ters, there have been about 93 meetings with industry representatives, 35 requests made to firms for corrective actions, one seizure (Indoklon), four prosecutions, and support given in 33 cases. Approximately 245 monographs in the Physicians' Desk Reference, and 138 prescription drug advertise- ments were reviewed and assessed as forerunners to remedial consid- eration. In the support of cases forwarded for prosecution consideration, Dr. McCleery personally participated in citation hearings as well as in one judicial pro- ceeding. In the latter, Dr. McCleery's testimony was considered to be' largely Instrumental in `the success of the Government in obtaining a nob con- tendere plea from the defendant and a resultant `fine. In addition to matters involving regulatory attention, Dr. McOleery provided written advice in voluntarily submitted promotional materials or other in- quiries in over 80 instances. On May 23, 1967, proposed revisions in the advertising regulations were pub- liahed in the Federal Register. Dr. McCleery's participation in providing `the basis for policy and language of those proposed regulations was a contribution of paramount importance. Dr. McCleery's contributions to the mission of the Agency and the Depart- ment have been broadly recognized in the public press. A selection of copies of accounts in the press are attached to show the public impact of the efforts of Dr. McCleery. The Food and Drug Administration's responsibility in the area of prescrip- tion drug advertising is a recent one. Since the passage of these regulations in 1962, Dr. McOleery has been the individual most responsible for stimu- lating the efforts of the Bureau of Medicine in the implementation of these regulations. Senator NELSON. I assume you `have no objection to being inter- rupted by questions from time to time ~ Dr. MCCLEERY. No, sir. Senator NELSON. Please, go ahead, Doctor. PAGENO="0011" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3105 STATEMENT OP DiR. ROBERT S. McCLEERY, ACTING DIREcTOR, DIVI- SIGN OF MEDICAL ADVERTISING, BUREAU OF MEDICINE, FOOD AND DRUG ADMINISTRATION; ACCOMPANIED' BY DR. HERBERT L. LEY, DIRECTOR, BUREAU OF MEDICINE, FDA; AND WILLIAM W. GOODRICH, GENERAL COUNSEL, FDA Dr. MCCLEERY. Mr. Chairman, I appreciate this opportunity of appearing before you this morning to discuss our experience with the advertising of Indocin. Shortly after Dr. Goddard became Commissioner of Food %and Drugs, in early 1966, the agency's interests in prescription drug ad- vertising were sharply accentuated. It was felt that manufacturers had had time enough to adjust to new requirements concerning ad- vertising. Dr. Goddard spoke to the presidents of pharmaceutica] firms, to their medical directors and to their advertising agencies to note what we regarded as a continuation of advertising abuses that had been so largely responsible for the en'ictment in 1962 of the Kefauver-Harris drug amendments and the promulgation in 1964 of the first advertising regulations. Senator NELSON. Doctor, do you have any examples that you would like to give us of what you consider to be advertisin.g abuses, in addi- tion to those you have already mentioned? Dr. MC'CLEERY. The case we are describing today is in our view a case typical of some of the major abuses. We could submit for the record the act.ions we have taken against drugs in the past in terms of the use of the sanctions for criminal prosecutions-the use of seizure of products for bad advertising and for a large number of "Dear Doctor" remedial letters which have been sent, roughly 20 in number Senator NELSON I would like to have the examples you referred to Do I understand you to say that the case you are talking about to day is quite typical of other instances that you have of the same kind of advertising abuses ~ Dr. MCCLEERY. Well, in some sense, yes, in that it contains a number of faults which are common to many other ads against which we have acted, and these were present during the introduction and the subse- quent advertising of the drug under your interest here today. Senator NELSON The point I am interested in having clear for the record is whether or not this is an isolated case, or whether it is a gen- eral problem that you have to deal with. Dr. LEY. Senator Nelson, may I suggest that we submit for the record the examples of what the FDA. considered misleading advertising which were presented in October of 1966 by Mr. Goodrich, and sec- ondly, a file of "Dear Doctor" letters stimulated by the FDA over the past year. I believe this will set the picture in proper perspective. Senator NELSON. All right. If you would submit that for the record. (The material to be furnished for inclusion in the record follows:) * THE STATE OF TEE LAW AND COMPLIANCE* (Address of William W. Goodrich, Assistant General Counsel, Department of Health, Education, and Welfare, Washington, D.C.) Three years have passed since FDA first entered the world of prescription drug advertising. We are more intrigued with what we see today, than we were by our first viewing. To borrow a quote: "We are reading more flow and enjoying it less." *presented at "A Morning With FDA," Pharmaceutical Advertising Club, Roosevelt Hotel, New York City, Oct. 20, 1966. PAGENO="0012" 3106 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY And we are more convinced than ever that there is much room for needel improvement. Getting ~to know you is a refreshing experience. It has been said of you that you have a unique ability to make a virtue out of a serious side effect. The Kefauver investigations highlighted many excesses in drug promotion. But they suggested 110 remedies. The Executive Branch's first reaction was to strengthen the Federal Trade (1ommissioii Act. But the Congressional response was to require stronger control under the Federal Food, Drug, and Cosmetic Act. Instead of orders to cease and desist, new sanctions of seizure, injuiiction and criminal penalties were provided to do this job. While the legislative developments were fast moving-and the legislative history is relatively thin-the message was loud aiid clear that there had to be some basic changes in this phase of drug promotion. President Kennedy recornmended-~and the Congress enacted-~provisions intended to "help assure the American people . . . that the proniotioiial material [for Rx drugs] tells the full story . . . [the] possible bad effects as well as the good-and the whole truth about therapeutic usefulness." This is the guideline that coiitrols our operations. The only concession made for the special needs of advertising was that the essential information might be presented "in brief suimnary". This requires the presentation of information in your ads which will fairly show the effectiveness of any drug, along with any side-effects, contraindications, precautions and warnings, in a form t.hat is brief but neither false nor misleading. The central idea is to be sure that the message that conies through to the profession strikes a proper balance in telling what the drug ~S for, what the limitations are upon its usefulness, and what hazards may attend it.s use. Lest there be any ques!tioii as to pi'eci*sely what is required-the law provides that every prescription drug advertisement and any other descriptive matter issued to promote sales shall contain a true statement of- The formula; The established name of the drug along with the trade name: And "such other information in brief summary relatiiig to side effects, coii- trainchications and effectiveness as shall be required in regulations" issued by the Secretary. Prec'learance *of ads is not required except in extraoriliiiary circumstances. The I )epartrnent was authorized to specify which promotional material is labeling (requiring full disclosure) and which is advertising (requiring the brief summary). The regulations applicable to ad content were promptly issued--but only after a confrontation with 1)0th the pharmaceutical industry and the ine~lica1 plo- fession. Both professed to believe that advertising was not educational-that it served only a reminder role-and played no part in the physician's choice of drugs when be began to write on his prescription form. We took the more realistic view that if advertising does not sell drugs it will not continue to run. Therefore, the major issue requiring resolution was whether the regulatory controls would extend to the entire ad-or just to the little part that the ad- vertiser might designate as the "brief summary." Resolution of that issue was accomplished by final regulations, supplemented by a memorandum of understanding about their intent. The w-hole ad was controlled. The regulations themselves are simple indeed. They were offered as the first step in public supervision of this very vital means of communication between the drug producer and the medical professiomi. The controls were not set in con- crete: they can and will be improved as the need appears. To that end, we are announcing new proposals that would require that all new promotions-both advertising an~1 labeling-to be submitted as soon as they are developed for use. In essence, our current regulations require-insofar as the selling part of the ad iS cOildei'fledl-four tliiiigs A fair summary of the effectiveness ol' the ding in th( coll(litions for which it is offered, along with all of the ~ide effect~, contraiimdieations, pre- cautions, an(l w-arnings applicable both to the conditions for which the drug is ath-ertised and for which it i~ commonly prescribed A faii' balance in presenting the information on effectiveness md the re- lated information on side effects, etc. A reasonably close associatiomi of the thformnatioii on effectiveness and the information on side-effects, contraindicatiomis. etc., together with a discus. sion of the adverse data in the sanie degree of prominence that is achieved for the claims of effectivemiess: PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3107 And the use of oniy those promotional claims which have been approved in advance upon the clearance of the drñg for the market as a "new drug" or as a certified antibiotic or for drugs that required no preclearance claims of effectiveness that are generally recognized as true or which are supported by substantial evidence consisting of adequate and well controlled investiga tions or adequate clinical experience on the basis of which it can fairly and responsibly be concluded that the drug will ha~ e the effectiveness claimed This is not `i very big order Simply stated, drugs may be promoted only on the basis of proven effectiveness. The total advertising message must be fair and frank in discussing both the usefulness and the hazards that may attend the administration of the drug. And the layout of the ad must deal fairly with the scientific data that underlies the message. As Dr. Goddard said in his Chicago speech to the Midwest PA Club, we have difficulty in understanding how a group of creative people with the talents you so regularly display should have any difficulty at all in understanding the ad vertising restrictions of our regulations. Fair balance reasonably close association and the same relative degree of prominence are words of ordinary English `\o more inflexible words were used because the Agency wanted to move with the drug industry and the creatn e people in correcting what was an indefen'~ible state of drug promotion If these concepts in the present regulations seem perplexing-we offer the memoranda of understanding which passed between us and the industry back in October, 1963. And we offer also a statement we made public in 1964 calling at~ tention to the most common failings in drug promotion. More recently, at the medical section meeting of the Pharmaceutical Manufacturers Association on March 30, 1936, we described in great detail the basic premises underlying our evaluation of advertising and promotional labeling. Bearing in mind Ben Franklin s comment that Laws too gentle are seldom obeyed too severe seldom executed we are preparing to move the informal comments in the memo of understanding and in the policy announcement into the positive provisions of regulations ~nd we will continue to examine the perform ance of all advertisers under our rules so that misunderstanding and non compliance can be promptly corrected With this background as to the state of the law let s turn to the state of corn pliance by examining a few cases of actual performance. Remembering that "all things that hurt, instruct", I apologize in advance for any injured feelings that may flow from a critical examination of some examples of your most recent work. We would like to view with you the ads for the big eight -all of the eight new 1965 model drugs that entered the list of(the 200 most prescribed during tbø first years of their introduction They are Aventyl-Eh Lilly C Quens-Eli Lilly Indocin-Merek Sharpe Dohme Lincoein-IJpjohn Oracon-Mead Johnson Pediamycin-Ross Pre Sate-Warner Chilcott Tegopen-~Bristol Laboratories Without implying that there has been a complete medical work up as to the validity of all of the advertised claims for these drugs I can say that I asked our medical staff-including some of the physicians who were primarily respon sible for the clearance of the drugs for market-to comment on some current ads for these important new offerings of the pharmaceutical industry Here are the results ~No doubt this ad will sell huge amounts of Aventyl It is pretty impressive and seems to pack quite an emotional wallop However the term behavioral drift doesn t appear to be more than a Madison Avenue description It certainly is not a bona fide psychiatric diagnosis It is from the ad difficult to tell in the first 4 pages whether Aventyl is primarily an anti-depressant, primarily a tranquilizer or what. * * * * * * "The first sentence under side effects in both the ad and the package insert states that No single side effect can be considered as occurring frequently * * * PAGENO="0014" 3108 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY This could lure the unsuspecting physician into not looking much further. While the incidence is mentioned later of the common side effects, it's a bit too late. * * * * * * * "All in all, the sins in this ad are those both of omission and commission. They include poor arithmetic, poor terminology, invention of psychiatric terms, and an overwhelming intent to `snow' the practicing physician." As the medical officer's comment shows, we share the responsibility for some of the defects in this ad, because we approved the package insert. That does not make the ad any hetter. Aventyl was offered for a new psychiatric disorder, discovered right here on Madison Avenue. While this makes excellent ad copy, it does not promote the drug for the conditions for which it has been approved. Instead~, it uses a new catch phrase to cover a host of "target" symptoms, so that the drug is in- dicated and prescribed for the ordinary frustrations of daily living to reach a much larger patient population than the scientific data will support. 0-Quens and Oracon were approved as new sequential oral contraceptives. The central theme of the ad for Oracon is that is is safer than and superior to other oral contraceptives because it is so close to nature-that it is physio- logical, nautral, and normal. These claims are unsupported by scientific facts. Thus far, there is no sub- stantial evidence that any oral contraceptive is either more effective or safer than any other that has been approved for the market. This ad also make a point that Oracon was the first sequential oral contra ceptive It fails to inform the physician that it was approved only 13 days before C-Quens The apparent purpose of the claim is to bolster the asserted but un supported, superiority. The theme of the ad for C-Quens is directed to a single side effect of the oral contraceptives-weight gain. The claim that women using sequential oral contraceptives experience less significant weight gain is ungrounded in scientific fact, and the ad is thus misleading in its major implication. Yet, it may serve its purpose of influencing the physician to shift a patient to this product on the basis of this illusory promise. This ad, like the one for Oracon, claims "other advantages of therapy"-pre- sumably less side effects and this is bolstered by a claim that it contains the smallest amount of hormone substance The latter claim is literally false and the claim of lower incidence of side effects has no scientific support. The truth about the oral contraceptives is reported in an FDA publication, available from the Government Printing Office. It is that there is no adequate scientific data, at this time, proving these compounds unsafe for human use. There are nonetheless some very infrequent but serious side effects and some possible theoretic risks suggested by the experimental data. The physician must decide for his patient whether to accept the risk-small though it may be. And the Committee which advised us said: The physician "can do this wisely only when there is presented to him dispassionate scientific knowledge of the avail- able data." We leave with you the question whether these two ads present the physician with "dispassionate scientific knowledge". Indocin has been marketed for slightly more than one year Like most new drugs offered to replace established products this one was offered as safer and more effective. As new experience with the drug has been gained, more side- effects have been noted and more warning information has been required Only a few days ago the sponsor mailed a new revised brochure to the profession with new cautionary information In heavy print. Yet the current ad continues the headline "extends the margin of safety in long term management of arthritic disorders". There is not yet enough experience to support the claim for greater long-term safety. To the contrary, the longer the drug is used the more side-effect informa- tion appears. This ad quotes authoritative sources, without the full impact of the actual articles. And it uses one reference which is from a 2-inch abstract, apparently of a 1964 speech. This latter reference is used to support a claim for "ankylosing spondylitis but the ad does not inform the reader that this same abstract also states "Excellent results have also been obtained in some cases of rheumatoid arthritis . . . there have been striking failures as well." The claim for gout is not supported by the package insert or by the scientific data. And, finally, the "Brief Summary" omits some very important warning informa- tion that is required in the package insert-and thus in the ad. PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3109 As a side-light on this drug, it was featured in the July issue of "Pageant" magazine for "bursitis", "trick knee", "tennis elbow" and "a host of other less common disorders characterized by pain and swelling in and around the joints". The only support for these claims was user testimonials which, according to the article, were made available to the writers by the sponsor of the drug. Lincocin is a new antibiotic entry among the 1965 models. The ad to promote the drug is highly competitive in comparing the ease of use and the absence of some side effects expected from the established anti- biotics. It is "practically painless on injection", unlike older intramuscular tetracyclines; it "does not share antigenicity with penicillin"; it has "no serious renal or neurologic abnormalities" and "no oto'toxicity", unlike streptomycin or kanamycin. Yet after such elaboration on what side effects the drug does not have, the ad obscures the most important information that the physician needs in using this drug-that hem'atologic toxicity can occur, and that `the frequency of severe diarrhea is a unique feature of Lincocin therapy. Pediamycin was another 1965 model antibiotic. It `was featured as being especi- ally safe for infants but no substantial evidence existed to support the Ualm And the range of its usefulness was exaggerated Tegopen was the final entry on the 1965 list of antibiotic drugs. The headline was "This is a new every-day penicillin for common `bacterial respiratory infections". Plainly this was to encourage indiscriminate and routine use of a drug that was approved for use primarily against penicillin resistant staph infections. The brief summary failed to communicate the real mess'age that it is im- portant to identify the infectious organism and to shift to regular penicillin when the organism is later found to be senistive to penicillin G or V The artwork layout and design of the ad was to impress `the reader with the frequency with which Tegopen can be used and not to carry the real message which the approval of the drug intended. Pre-Sate is a new drug fo'r the `treatment of an impossible condition to treat-overeating and overweight. It is, we believe, the consensus of medical opinion that there are no true anorexiants, and that dieting is the only answer to obesity. This attractive ad is an admirable ef1~ort to crack this attractive market. While page 6 emphasizes the essential need for concurrent diet control, the total mes- sage is that Pre-Sate is a drug of superior efficacy in reducing body weight. Statistical data is offered to prove the superiority of this drug over its estab- lished competitors. Animal data are used to support the claim that the mech- anism of its action has been established. But the claims of superiority and that it acts on the human satiety center of the hypothalmus are not scientifically established It is generally assumed that the 1962 &mendment did not control relative efficacy but ads which make claims of that kind are subject to critical review and proof that the Company s claims of superior effectiveness are well founded This ad appeared about the time of the Peritrate seizure. We are pleased to note improvements in later presentations. Advertising prescription drugs should be a very special operation-wholly unlike advertising the 1967 model automobiles or `the tars and nicotine of ciga- rettes. It should be based on the scientific data that allowed the drug to enter the market-you need look and can look no further than the official brochure for the allowable claims and the required warnings. As tempted as you may be by a new piece of investigative work that may be whispered to you to mount a new campaign to capture an entire market, you must remember that the approved claims are the limits beyond which promotion cannot go. And in promoting newly developed and approved drugs, claims of greater safety and comparatively greater effectiveness can be made only on proven data-and then only with complete awareness that the limited experience with the drug accumulated during its investigational clinical practice; that clinical experience must be followed very closely and that ad campaigns will have to change as rapidly as clinical experience may require. Please remember the thoughts that prescription drug advertising can go no further than the scientific support which sustains its approval for marketing; that you have an obligation in developing ad copy to tell the whole truth-good and bad; and that the entire advertising message must be designed around these basic ideas. If the advertising copy for the "big eight" is typical of what is going on, Madi- son Avenue's new disease of "Behavioral Drift" is out of hand. Perhaps it can be cured by the placebo of talk, but m'ore likely some stronger medicine will be necessary. PAGENO="0016" 3110 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY /~ n~# [From Journal of American Medical Association, Sept. 19, 1966, pp. 52-56] PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3111 81-280 0 - 68 - pt, 8 - 2 PAGENO="0018" 3112 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3113 PAGENO="0020" PAGENO="0021" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3115 PAGENO="0022" 3116 COMPETITIVE PROBLEMS IN TIlE DRIJG INDUSTRY [From Medical Economics,, Sept. 19, 1966, pp. 34-36] J PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3117 PAGENO="0024" 3118 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0025" I COMPETITIVE PROBLEMS IN THE DRUG INDTJSIRY 3119 [From Journal of American Medical Association, Sept. 5, 1966, pp. 60-6 1] PAGENO="0026" 3120 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY in lower respiratory infections1~7 including pneumonia, bronchitis, and complications of influenza or common.c~Id caused by Staph-i Strep- and Pneu mococci practically painless on injection -therapy may be References; initiated parenterally and then followed through orally 1 Ho)) w y W J a d Sc tt E G Am J M Sc 249 691 (June) 1965 without Switching antibiotic 2 Dunca i B R a d J n B C n d M A J 93 685 (Sept 25) 1965. reactions rare even for patients sensetive to 3 K pi K Chew W H d W n t L Am J M Sc 250 137 penicillin -does not share antigenicity with the (A g) 1965 penicillin group of compounds. 4. Nunnery, A. W., and Riley, H. D.: Antimicrobial Agents and Chemotherapy.1964, Ann Arbor, Michigan, Am. Soc. Microbioi., no reports of serious renal or neurologic 5 Holloway W J K bib gh R A d Scott E G A timicrob ai abnormalities; no ototoxicity. Agents and Chemotherapy.1963, Ann Arbor, Michigan, Am. Soc. Microbiot., p. 200.- no tooth discoloration to date: tests ~` 6. Walters, LW.; Romansky, M. J., and Johnson, A. C,: Ibid., p. 210, 40 investigators involving 2,500 patients show 7. Harnecker, J.; Contreras, J.; Gilabert, B., and Ubilia, v. Ibid., no tooth discoloration with Lincocin. p. 204. II Lincocin (lincomycin hydrochloride monohydrate) Contraindications: Patients previously found hypersensitive to drug; atients with known preexisting moniliai infections; and, until further cllnlcat t dy m 4 th wb P ii U f tib ti i lip se g wth f so pt bi g I m If p I f tl f k appropriate measures. An occaslonai patient has developed jaundice while receiving iincomycin, although thin has not been definitely shown to be drug.relafed. Patients receiving treatment for lunger than one or two weeks should have liver function tests. One case of Irreversible toxicity to the hematopstetic system and only a few cams of neutropenla and/or leukopenia have been reported; however, it is recommended that blood counts be obtained early in course of therapy. Safety fur use in pregnancy not yet established. Limited experience with 345 women receiving the drug during various stages of pregnanc revealed no ill effects on mother or fetus. Due to lack of adequate clinical dala use in patients with pre.eaisting kidney liver endocrine or metabolic diseases nat recommended unless special clinical circumstances so indicate. Elf icacy in rheumatic fever not established. Side Effects: Most frequent-loose stools or diarrhea. Cases of severe diarrhea causing drug discantinuance have been reported. Side effects of small proportion; vaunea, vomitIng, abdominal cramps or pain, skin rash rectal Irritation, vaginitis, urticaria and itching. A few cams of hypersensitivity reactions reported. If an allergic reaction occurs, discontinue drug. l'he usual agents for emergency treatment should be available. Sup tied: 500 mg. capsules and pediatric capsuies 250 mg, In botties of 24 and 100; 2cc. disposable syrInges; 2cc. and 10cc. vials-each cc. of sterile solution contains lincomycin hydrochloride monollydrate eqaiv. to lincomycin bane, 300 mg.; aim 9 m . benzyl alcohol and water for injection q.s.' Lincocin syrup equlv. to 250 mg. per 5cc. iincomycin base In 60cc. and pint bottiesilncocin pediatric drops equiv. to 210 mg. per 5cc. lincomycin base ix 30cc. bottles with dropper. For more detailed prescribing infarmatton on this product, tee the package _____________ circular or consult your Upjohn repreuentatine. Class bvTh: Oplxhv Conpnvy The Upjohn Company, Kaiamazoo, Michigan PAGENO="0027" 3122 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ...physiologically ORACON® is so close to nature* simulates a natural menstrual pattern - produces a physiologically acceptable cycle - simulates a normal endometrial response - induces regular and predictable withdrawal bleeding PAGENO="0028" 3121 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Journal of American Medical Association, Sept. 5, 1966, pp. 205- 228] Certainly all oral contraceptives are highly effective and well tolerated ...yet is unsurpassed... 16 White-Ethinyl Estradiol, 0.1 mg. Tablets; 5 Pink-Dimethi- sterone, 25 mg., and Ethinyl Estradiol., 0.1 mg. Tablets. PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3123 ...in patient benefits ORACON~ affords few. side effects* month after month, women usually experience few side, effects - virtually eliminates amenorrhea - dramatically low early-cycle breakthrough bleeding low incidence of weight gain - significantly low incidence of monilial vaginitis *For full documentation, please write to The Medical Department Mead Johnson Laboratories, Evansville, Indiana 47721, for the Physician's Brochure. PAGENO="0030" - ci) ~ ~N~) ~W ~ ~rn~ - = - -` -1 c~) o ~ ~001 ~ r) 2, -. 0 0 02 0 CI) . . . 0 o~ PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3125~ [From Medical World News, Feb. 12, 1965, pp. 42-43] PAGENO="0032" 3126 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3127 [From Journal of American Medical Association, Sept. 5, 1966] 81-280 0 - 68 - pt. 8 - 3 PAGENO="0034" 3128 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY SPECIAL COMMUNICATION Life or Death-Whose Decision? W. P. Williamson, MD, Kansas CIty, Ken The Neurologist Reviews Pheochromocytoma J. E. Thomas, MD, E. D. Rooke, MD, and W. F. (vale, MD, Rochester, Minn Radiotherapy for Metastatic Testicular Tumors Norman Simon, MD, Fred Winsberg, MD, Marvin Rotman, MD, and S. M. Silverstone, MD, New York Drug-Resistant Ventricular Tachycardia 1. R. Kilpatrick, MD, and C. B. Moore, MD, New Orleans, and Efrain Maza S., MD, San Salvador, El Salvador Hepatotoxicity of Thioridazine Hydrochloride? M. J. Reinhurt, MD, R. M. Benscn, MD, S. K. Kwass, MD, and W. F. Storey, MD, CM, Ann Arbor, Mich EDITORIALS Diagnostic Procedures 810 Distortion of Clinical Recommendations 810 Anesthesia Problem of the Month 811 National Halothane Study 811 Drugs, Electroshock, and Ventricular Tachycardia 812 John Freke (1688-1756) 812 CLINICAL NOTES Sporotrichosis in Western Pennsylvania 81~ JBH h MD dEREik MD Ptt b gh Hemolytic Reaction Due to Anti.Jkb 81( E. S. Kurtides, MD, M. S. SalkIn, MD, end A. L Widen, MD, Evanston, Ill Sulfonamide Reactions in SLE 81~ Phin Cohen, MD, end F. H. Gardner, MD, Boston Poisoning by a Malathion-Xylene Mixture 81 Simon Gitelson, MD, Leonie Aladjemoff, MD, Solomon Ben.Hador, MD, and Ruth Katznelson, MD, Jerusalem, Israel AMAgrams 9 - . JAMA 75 Years Ago 21 - - - Washington News 27 . , . Medical News 35 Reference DirectorIes 53. . . Magazine-TV Report 83 ORIGINAL CONTRIBUTIONS Early Perforation in Appendicitis After Age 60 A. G. Coran, MD, and H. B. Wheeler, MD, West Roxbury, Mass Reversible Failure in Chronic Renal Disease G. L Ackerman, MD, and W. J. Flanigan, ~dD, Little Rock, Ark 793 PASSANO AWARD ADDRESS Dr John T. Edsall's Contribution to Science 796 J. L Oncley, ScD, PhD, Ann Arbor, Mich Forty Years Among the Proteins 799 J. T. Edsall, MD, CambrIdge, Mass DIAGNOSTIC PROCEDURES Cerebral Angiography 803' Oscar Sugar, MD, PhD, Chicago NEGATIVE RESULTS Failure of Corticosteroid to Potentiate Sympathomimetic Pressor Response During Shock 808 Herbert Shubin, MD, and M. H. Well, MD, PhD, Los Angeles 745. 749 754 759 762 767 770 CLINICAL SCIENCE Halothanè and Neuromuscular Transmission A. J. Gissen, MD, J. H. Karis, MD, and W. L. Nastuk, PhD, New York COOPERATIVE STUDY Summary of the National Halothane Study 775 ANESTHESIA PROBLEM OF THE MONTH-NO 1 Choice of Anesthetic Technique in Patients With Acute Pulmonary Disease 789 W. K. Hamilton, MD, and M. D. Sokoll, MD, Iowa City BOARD OF TRUSTEES ACTION Letter From the Chairman of the Board to Members of the House of Delegates 791 W. W. Hall, MD, Reno, Nev CONTENTS CONTINUED Adv Page PAGENO="0035" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3129 This is a new, everyday penicillin for common bacterial respiratory infections with extra therapeutic coverage at no extra cost: Clinical success. Tegopen (sodium cloxacillin monohydrate) assures you a high degree of clinical success against respiratory infections. A recent comprehensive analysis of office patients administered the drug proves the point: 96Y~ of 259 bacterial respiratory infections treated were cured or improved.' PKills common res1)iratory Cram-positive cocci. In contrast to the penicillinase-limited Gram-positive spectrum of penicillins G and V, Tegopen (sodium cloxacillin monohydrate) destroys strep, pneumo and virtually all staphylococci. Bactericidal in action. Tegopen (sodium cloxacillin monohydrate) is bactericidal, killing the offending organism. In contrast, erythromycin2 and triacetyloleandomycin:l are essentially bacteriostatic agents. Minimal side effects. There is little likelihood of (lose-related toxicity with Tegopen (sodium cloxacillin monohydrate). Low in cost. Even with all of its extra advantages, Tegopen (sodium cloxacillin monohydrate) is priced comparably to penicillins G and V, and 33% less than either erythromycin or triacetyloleandomycin. nutsToL TltcttAt'EtJTtC StIMM say: For contplete information, consttit Official Package Circular. Indications: Infections due to streptococci pnewtiococci and staphylococci, particttiarly penicillin Cre~ista,tt strains of tile latter. (ootraindications: A history of severe allergic reactions to penicillino. Precautiotts: Typical peiticillin-allergic reactions may occttr, t)artiCLllarlY in hy~tersenvitive Itersons. Mycotic or bacterial infections may occur. Safety for use in pregnancy is not estalslislted. Assess rettai, ltentatopoietic and Itepatic function periodically eluring iong.terot titerapy. Adverse Reactions: Nausea, epigastric discontfort, flattilenee, diarrltea, essinopltilia, and allergic titanifestations. Moderate SCOT elevations have been noted. Usual Dosage: Adt,lts: 250 mg. q. 6/t. Children: 50mg/Kg/day. Children weighing more than 20 Kg. shottld be given the adult dose. Treat heta-hemoiytic streptococcal infections for at least 10 days. Administer ito 2 hottrs lsefore meals. References: 1. Data on file at Bristol Lnboratorieo. 2. Geraci, J.E. (Panel Discussion, M. Finland, Moderator): Antibiot. Ann. 1958-59: BRISTOL LABORATORIES 1051, 1959.3. Thompson, WT., Jr.: Sotith. M. J. BRISTOL Division of Bristol.Myers Co. 56:844 (Attg.) 1963. Syracttse, New York IN TONSILLITIS * PHARYNGITIS * OTITIS MEDIA * SINUSITIS BRONCHITIS * PNEUMONITIS new1j~4o1%ji SODIUM CLOXACILLIN MONOHYDRATE PAGENO="0036" 3130 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3131 10:38 AM. 10:42 AM. 1100AM here is a new, everyday penicillin for common bacterial 1120AM respiratory infections. An improvement over penicillin G and V, and the medium- 1147AM spectrum anti iotics. Just lift the page at the left and read why. 12:01 P.M. 115PM PAGENO="0038" PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3133 [From Journal of American Medical Association, Oct. 18, 1965, pp. 11-16] PAGENO="0040" 3134 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3135 PAGENO="0042" 3136 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ ~i ~ ~ ~i :~i~ i:, dy we gh loss, ~ ~ ~ ~ iignihc~i~tfy fewer Ct4S side eHe$~ ~ pati ntadrapout~I tkdn~ ~Mh ~ ~ than with ci ampbetamins'~ me ~ne ~ 4~ ~ ~ ~rnd phenmetr~zin&~ _; ~ ~ r~s the~w~d i~cb~d~p~ ~IfL ~ ~ 4~th~ S~~hd:phte~1t~ ~ ~Q*~ ~ cai~numb~r~f Q4~ ~td~eff*d~ PreSate~h~pbe~er ~ ~ I ~ ~ s~~nce~ t~ ~ov~e ~ ~ ~4 $~I ldiiiP $~)d ~t~tca~ ~ f~!~:~:~1r? ~ ~ ~ ~I!I!mI~s~ ~*ie H~ I I Yb ~v~en~ed~ u~t~w~d ~1~IP!I~ ~ ` ~ ~w~n~or~ed ~ t ~ ~ ~ ~ W*ev~den~eofd*~frd~ ~ system ~m~oi~d~ ~ ~ IP~'~~N ~ ~ ~ ~ !~Ur week ~ `~L ~ ~ ~ ~ pe~d ohio~pheMermMetP~e~$ate~ ~ ~o~w~aw~h*e ~ ~ ~ ~ %~ ~ ~ ~ ~ ~ ~ Aa~~N~q~ ~ ~ ~ ~ai~W &~ .*rr ~ ~**ade~oneated~1e~t ~ *eS~ ~ ~ ~ ~ i~t~t~ pr~esse~ dr~r*~e~e~ ~g~Ot~Ø~ o~ ~ ~iw*~W ~ ~ ~ ~ ~ ~ ~c~~)w ~ ~rme~usiot~Thte~d ibs~ ~*e~fti~n~ iv#~W3~~~ ~wc i~ehöb~e ~ ~ ~~:::~~t 4~ ~ ~ ~ ~ ~ ~" ~ ~ ~ ~ ~ ~ ~ ~ 4 ~ ~ ~ ~i ~ 2 ~ ~ ~ ~ %~W ~, \% ~ ~e ~ ~ ~ ~ ~44 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~M~'1 `;~i~~ ~ ~ ~ "~ ~ ~ ~ ~ ~ ~; ~/ ~ ~, ~ ;$~~I'~ ~: L~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ :~ ~ `~ ~ ~ : ~ ~ c~ ~ ~ ~ ~ ~ ~ 4~ ~ ~ ~ ~ : ~ ~ ~ ~ ~ ~: : ~ ~ ~ ~N ~ ~ ~ ~ A ~ Th1Lte~w~hMIY ~n ~ ~ .~ V ~ ~ b~M~fd~bt~n$'O ~ ~ ~ ~A7 ~ 1*~~ ~ ~ ~ ~ 81yM~gbe~moN~ght ~ k W W ~ * ~ ~ ~ ~ ~ Y ~ ~ ~ML ~t ~ ~ ~ ~ Ip~ ~_~vrj~ ~ t~ ~ ~ ~ 4j~~*~ ~ ~ ~ ~ ~ `~ ~ ~ ~ ~1 ~\ ~ ~ ~ ~ WM~e~k~ ~ ~ ~ ~ ~ ~ ~ ~ ~i; $2~ ~ $ ~ ~ L~ ~ ~ ~ ~ ~ ,1~ ~ ~ ~ ~E; ~ ~ ~ ~ 4~4~! I~~wc!1~1 ~ r t~~p%~;~:; ~ S 5 ~ ~JP~J~mL ~ ~. S ~ :~ ~ ~ ~ ih~~:~ 4r;~1~ ~ ~ ~ ~ ~ ~ & T~t :~ ~ ~ ~ PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3137 L ~ C f 4 S I o øèt ma effec an the ~ 4 thom proiongcd cntrex;a F tck*vascu c puromSte s" ~ k I Thah with phentermine, I. 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M1wmSs&*F**$Masa4ca ~MSflMtte~h1arphefltSt1ae44tOflnMe ~ ~ tônflcttsgMa$e4* ~p$ttre~tppSSt*aissh~v4~ ~ wIthsanvørnns~peçSpdós~ge1 NeSad4~c~ ~ I 4~°n aarhbbftuattti $O&*tcUftS With PV*tt5 ~ w~at*mtrnSh4ws~hknwst~uØ4~fl21IV ` ~ ~ ~ ~ w&~I(patsPr4.~ .&~jrqfl*4~~W~t ~ ½ ~ Iv `~ k ~ ~ ~ ~ ~ ~ ~ ~ ( 4~i ~ ~ ~ ~½~e½~ S j~ IS ~ &tst~siiI ~ / /~ f~~gga~ 1~ 4 / tMe$54*om1*SMA Am h1145 ½ /// ~ ~ xft &øu.st~~in ~ 4 I' : ~ ~ /st4'Ø~I/Wfl PAGENO="0044" 3138 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY T1 ~ ~ ~ ~ fu~ I ~ $fl re L P R ~ : SME ~ ~v ~ chIornkf~ 1~ ~ ~ ~ ~ ~ ~ ` ~JI!1I~p~ hCI ~m:a: ~ \ ~` ~ ~; ~ ~ p~bI~m O*se~ ~ ~ 2~; 4~ ~ ~ 2L:~ 3~ ~ ~ ~° b~ fg~~ ~ ~ ~ ~ ~ ) ~ Y /? ~4 ~ ~rj~c~;m~1v t~A ~ ~ ~ ~ & ~ ~ ~ ~ `V ~ ~ ~ *~v~: ~ ~ ~* ~ ~ ~ L~V~ ~ i~ ~ ~ ~ I an~~~Th ~ ~ ~ ~ .~ ~ p ~ ~d) ~ ~rô ~( ~ 1W~ ~ _ ~ (t~ ~ ~ ~ ~ FQ~a ~ ~ ~ ~iM~ ~ ~ b~~W ~ ~ ~ ~ j~MJeh~ ~M ~ ~ ~ ~ ~ ~ I ~ ~g ~r~t ~m ~ ~ ~ ~ ~ Je ~ ~ ~i ~ Mt~L~d~ ~ ~ 4 $ I PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3139 21 REMEDIAL ADVERTISING LETTERS ISSUED BETWEEN JANUARY 1967 AND APRIL 1968 Firm Drug(s) Date of letter Ortho Ortho-Novum Feb. 1, 1967. Wallace Deprol and Miltown , March 1967. Roche Librium ~ Do. Abbott Enduron and Enduronyl Apr. 13, 1967. Pfizer Renese, Renese-R, Rondomycin May 22, 1967. Geigy Hygroton and Regroton June 1967. Mead Johnson Oracon and Questran June 30, 1967. Flint Choloxin July 20, 1967. Neisler Diutensen R Aug 11 1967 Astra Cintanest Aug 23 1967 Squibb Mysteclin F October 1967 Organon Cortropin Gel Cortropin Zinc Hexadrol Hexadrol Phosphate Oct 27 1967 Lakeside Norpramin November 1967 S E Massengill Predsem Salcort Salcort Delta Nov 1 1967 Upjohn Medrol Nov. 15, 1967. Armour H. P. Acthar Gel Nov. 16, 1967. PDR H. P. Acthar Gel, Cortropin Gel, Cortropin-Zinc, Hexadrol, Hexadrol Nov. 22, 1967. Phosphat7, Norpramin, Predsem, Salcort, Salcort-Delta. Parke-Davis Pontsel Jan. 5, 1968. Syntex Norguen and Norinyl Jan. 22, 1968. G. D. Searle Ovulen-21 Jan. 26, 1968. Geigy Persantine Feb. 15, 1968. 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 Ortho Novum SQ* 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 Admin- istration 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 contraceptives in the same population nor individual studies of the three products in population groups shown to be comparable We are therefore dis continuing the promotional theme in question ORTH0 PHARMACEUTIOAL Coin' CRANBtTRY N J DEAR DocToR At the request of the Food and Drug Administration we are calling your attention to one of our recent advertisements captioned The pub lished clinical studies indicate: 3 of 4 non-psychotic depressions respond to `Deprol'." 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 ecocluded 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 favorable while mild fair slight and no responses were counted as unfavorable Using the above criteria the final number of patients included was 323 selected from ten of the 21 listed studies. Nine of the ten studies were uncontrolled, 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 patients, to 90% in two studies with 38 and 41 such patients respectively) also include to an undetermined degree placebo responses and spontaneous remis sions 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 *Trademark PAGENO="0046" 3139a COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "one of a series". In order to avoid any misunderstanding, we have discontinued the use of these "Miltown" advertisements as well as the described "Deprol" advertisement. Sincerely, WALLACE PHARMACEUTECALS. Rocnz LABORATORIES, Nutley, N.J., DEAR Doepon: At the request of the Food and Drug Administration, we are extending the "brief summary" of prescribing information for Librium® (Chior- 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 information in all Lib rium (chlordiazepoxide HOl) package circulars, direct mail information and brochures is complete and requires no change. The safety and effectiveness of the product ar¬ in question. In addition, in future medical journal advertisements for Libruim (chlor- diazepoxide HC1) in geriatric patients, we are amplifying statements which have appeared concerning possible side 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 ob- servations made in our package circular which point out that drowsiness, ataxia and confusion have been reported in some patients, particularly the elderly and debilitated, 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 and debilitated patients should be limited to 10mg 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 E. DIxon, M.D. Director, Professional services. (NOTE.-Phls revised "brief summary" for use in future medical journal ad- vertising contains additional phrases and items (printed in capital letters) from the official package circular which remains unchanged.) BRIEF SUMMARY OF PRESOBIBING INFORMATION FOR LIBRrcrM® (CHLORDIAZEPOXIDE HC1) Before prescribing please consult complete product information a summary of which follows: Contraindications: Patients with known hypersensitivity to the drug. Warnings: Caution patients about possible combined effects with alcohol and other CNS depressants. AS WITH ALL CNS-ACTING DRUGS, CAUTION PA- TIENTS against hazardous occupations requiring complete mental alertness (Ed., OPERATING MACHINERY,, DRIVING). THOUGH PHYSICAL AND PSYCHOLOGICAL DEPENDENCE HAVE RARELY BEEN REPORTED ON RECOMMEND'EtD DOSEIS, use caution in administering to addiction-prone indi- viduals or those who might increase dosage; withdrawal symptoms (including convulsions), following discontinuation of the drug and similar to those seen with barbiturates have been reported Use of any drug in pregnancy lactation or in women of childbearing age requires that its potential benefis be weighed against its possible hazards. Precautions In the elderly and debilitated and in children over SIX limit to smallest effective dosage (INITIALLY 10 MG OR LESS PER DAY) TO PRE- CLUDE ATAXIA OR OVERSEDATION, Increasing gradually as needed and tolerated. NOT RECOMMENDED IN CHILDREN UNDER SIX. THOUGH GENERALLY NOT RECOMMENDED, IF COMBINATION THERAPY WITH OTHER PSYCHOTROPIC5 SEEMS INDICATED, CAREFULLY CONSIDER * INDIVIDUAL PHARMACOLOGIC EFFECTS, PARTICULARLY IN USE OF POTENTIATING DRUGS SUCH AS MAO INHIBITORS AND PHENOTHIA- ZINES. Observe usual precautions in presence of impaired renal or hepatic func- * tion. Paradoxical reactions, E.G., EXCITEMENT STIMULATION AND ACUTE RAGE) have been reported in psychiatric patients and hyperative aggressive PAGENO="0047" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3139b children. Employ usual precautions in treatment of anxiety states with evidence ot impeding depression suicidal tendencies MAY BE PRESENT AND PRO TECTIVE MEASURES NECESSARY. Variable effects on blood coagulations have been reported very rarely in patients receiving the drug and oral anti- coagulants; causal relationship has not been established clinically. Adverse Recwtioiis: Drowsiness, ataxia and confusion may occur, especially in the elderly and debilitated. These are reversible in most instances by proper dosage adjustment, but are also occasionally observed at the lower dosage ranges. IN A FEW INSTANCES syncope HAS BEEN R1~PORTED. Also en- countered are isolated instances of skin eruptions, edema, minor menstrual ir- regularities, nauseau and constipation, extra-pyramidal symptoms, increased and decreased libido-all infrequent and generally controlled with dosage reductions; changes in EEG patterns (low-voltage fast activity) may appear during and after treatment; blood dysrasias (including agranulocytosis), jaundice and hep- atic dysfunction HAVE BEEN REPORTED occasionally, making periodic blood counts and liver function tests advisable during protracted therapy Usual Daily Dosage Individualize for maximum beneficial effects Oral- Adults Mild and moderate anxiety and tension 5 or 10 mg t i d or q i d severe states, 20 or 25 mg t.i.d. or q.i.d. Geriatric patients: 5 mg b.i.d. to q.i.d. (See Pre- cautions.) Supplied: Capsules, 5mg, 10 mg and 25mg-bottles of 50. NORTH CHIcAGO, ILL., April13, 1967. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to a recent advertisement on Enduron® (methyclothiazide) and En- duronyl® (methyclothiazide and deserpidine). The advertisement, headlined Thiazide potassimum 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 chlorothiazide or hydrochlorothiazide." The consensus of expert medical opinion is that there is no significant difference in the amount of potassium loss caused by thiazide agents, including methyclo- thiazide (Enduron). This 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 potassium supple- mentation," and that it has "potassium-sparing characteristics." The FDA be- lieves that these claims could lead to the erroneous conclusion that hypokalemia is less likely to occur, and consequently, that potassium supplementation is less often necessary with Enduron than with other thiazides. In point of fact, the need to consider proper potassium supplementation, dietary or otherwise, is no less with Enduron or E~iduronyl 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 LABORATORIES. FLINT LABORATORIES, Morto'a 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 mis- leading. The headline, "A significant new advance in the management of hypercholes- terolemia does not include the qualification that Choloxin is indicated for the treatment of hypercholesterolemia in selected patients i e euthyroid patients ~ ith no known evidence of organic heart disease Also the ad fails to stress that Choloxin is not intended to replace or to lessen the desirability of considering dietary regulation in 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 1 Retained in committee files. PAGENO="0048" 3140 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY proven to alter the morbidity and mortality of atherosclerotic disease. The claim in the ads that Choloxin (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 oniy 2 967 patienits 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 let ters that was not present in the current ads but will be incorporated into future ads for Choloxin We are discontinuing the ads in question The safety and effi cacy 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. (NoTE -This revised Brief Summary for use in future medical journal ad vertising contains additional phrases and items (printed in capital letters) from the official package insert which remains unchanged) SUMMARY THE USE OF CHOLOXIN® (SODIUM DEXTROTHYROXINE) DOES NOT REPLACE OR DIMINISH THE DESIRABIT ITY OF DIETARY MANAGE MENT OF HYPEROHOLESTEROLEMIA THE INFLUFNCE OF LOWERED SERUM CHOLESTEROL ON MORBIDITY AND MORTALITY OF ATHERO- SCLEROTIC DISEASE CANNOT BE ASSESSED UNTIL LONG-TERM CLINI- CAL TRIALS HAVE BEEN COMPLETED INDICATION~S~: THIS IS NOT AN INNOCUOUS DRUG. Strict Attention should be paid to the indications and contraindications Indicated for treatment of hypercholesterolemia in euthyroid patients with no known evidence of or ganic heart disease Also indicated for treatment of hypothyroidism in patients with cardiac disease who cannot tolerate other types of thyroid medication UONTRAINDIUATION~ (1) Known organic heart disease INCLUDING ANGINA PECTORIS HISTORY OF MYOCARDIAL INFARCTION CAR DIAC ARRHYTHMIA OR TACHYCARDIA EITHER ACTIVE OR IN PA TIENTS WITH DEMONSTRATED PROPENSITY FOR ARRHYTTLMIAS rheumatic heart disease HISTORY OF OONGESTIVE HEART FAILURE AND DECOMPEN5ATED OR BORDERLINE COMPFNSATED CARDIAC STATUS. (2) Hypertensive states (OTHER THAN MILD, LABILE SYSTOLIC HYPERTENSION). (3) Advanced liver or kidney disease. (4) Pregnancy. (5) Nursing mothers. (6) History of iodism. A relative contraindication is impaired lii ei or kidney function WH} `~ EITHER OR BOTH ARE PRESENT, THE ADVANTAGES OF SODIUM DEX- TROTHYROXINE THERAPY MUST BE WEIGHED AGAINST THE POSSI- BILITY OF DELETERIOUS RESULTS. WARNINGS Because the effects of anticoagulants may be potentiated RE DUCE DOSAGE OF ANTICOAGULANTS BY ONE THIRD ON INITIATION OF THERAPY and readjust as necessary ON THE BASIS OF WEEKLY TESTS OF PROTHROMBIN TIME Concentration of Factors VII VIII I~ and platelet activity SHOULD ALSO BE MONITORED, since these factors may be de- creased CONSIDER WITHDRAWAL OF CHOLOXIN (SODIUM DEXTRO THYROXINE) 2 WEEKS BEFORE SURGERY IF USE OF ANTICOAGU- LANTS IS CONTEMPLATED. Careful consideration of dosage schedule in hypothyroid patients WITH CAR- DIAC DISEASE is required, and the drug should be withdrawn or dosage re- duced if `AGGRAVATION OF ANGINA, INCREASED MYOCARDIAL ISCHE- MIA, CARDIAC FAILURE,' OR CLINICALLY SIGNIFICANT ARRHYTHMIA develops HYPOTHYROID PATIENTS ARE MORE SENSITIVE THAN EUTHYROID PATIENTS ESPFCIALLY IF TREATED CONCOMITANTLX WITH OTHER THYROID PREPARATIONS SPECIAL CONSIDERATION TO THE DOSAGE OF THE LATTER MUST BE GIVEN Thyroid preparations may enhance the effects of epinephrine injections pre disposing to arrhythmias OR CORONARY INSUFFICIENCY DRUG WITH DRAWAL OR CAREFUL OBSERVATION OF PATIENT'S RECEIVING SUCH INJECTIONS IS REOOMMENDED, ESPECIALLY BEFORE ELECTIVE SURGERY. PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3141 In diabetic patients, increased blood sugar levels may be observed, requiring upward adjustment of antidiabetic drug dosage, and SUBSEQUENT READ- JUSTMENT IF DEXTROTHYROXINE IS LATER WITHDRAWN. USE IN WOMEN 01? CHILDBEARING AGE: In women exercising birth con- trol procedures, the drug should only be administered AFTER WEIGHING POS- SIBLE RISK TO THE FETUS AGAINST POSSIBLE BENEFITS TO THE MOTHER, TERATOGENIC STUDIES IN TWO ANIMAL SPECIES HAVE BEEN NEGATIVE. PRECAUTIONS: UNUSUALLY HIGH PBI VALUES ARE C'OMMON IN TREATED PATIENT'S AND ARE NOT EVIDENCE OF HYPERMETABO- LISM. IN CHILDREN, USE ONLY WHEN A SIGNIFICANT CHOLESTEROL LOWERING EFFECT IS OBSERVED. Withdrawal is indicated if iodism or new cardiac signs or symptoms develop. ADVERSE REACTIONS: For the most part due to increased metabolism, AND `THUS MORE COMMON IN THE HYPOTHYROID PATIENT, ESPE- CIALLY THE HYPOTHYROID CARDIAC. Cardiac changes have rarely been precipitated in non-cardiac patients. Angina pectoris (0.2% incidence), arrhy- thmia (0.5%), MYOCARDIAL ISCHEMIA (<0.1%), CARDIOMEGALY (<0.1%), FATAL AND NON-FATAL myocardial infarctions (<0.2%). Insom~ nia, nervousness, palpitations, tremors, WEIGHT LOSS, LID LAG, SWEAT- ING, FLUSHING, HYPERTHERMIA, HAIR LOSS, CHANGES IN BOWEL HABIT'S, DIURESIS, AND MENSTRUAL IRREGULARITIES MAY ALSO BE RELATED TO THE MILD METABOLIC ACTION, A FEW PATIENT'S DE- VELOPED ITCHING AND SKIN RASHES, APPARENTLY FROM IODISM. DYSPEPSIA, NAUSEA AND VOMITING, AND CHANGES IN APPETITE OCCURRED IN LESS THAN 1%. HEADACHE, CHANGES IN LIBIDO, HOARSENESS, TINNIT'US, DIZZINESS, PERIPHERAL EDEMA, MALAISE, TIREDNESS, VISUAL DISTURBANCES, PSYCHIC CHANGES, PARES- THESIA, MUCLE PAIN, AND BIZARRE COMPLAINT'S WERE REPORTED IN LESS THAN 1% OF TREATED PATIENTS. GALLSTONES WERE NEWLY DISCOVERED IN 13 PATIENTS, AND CHOLESTATIC JAUNDICE IN ONE, ALTHOUGH RELATIONSHIP TO DRUG THERAPY WAS NOT ESTAB- LISHED. IN A TOTAL OF 19 PATIENTS, PRE-EXISTING PERIPHERAL VASCULAR DISEASE, EXOPHTHALMOS, RETINOPATHY, AND DIS- TURBED SENSORIUM CONTINUED TO WORSEN. CEREBROVASCULAR ACCIDENTS, THROMBOPHLEBITIS, AND G.I. HEMORRHAGES EACH OC- CURRED IN LESS THAN 1% OF PATIENTS, BUT THERE APPEARS TO BE NO RELATIONSHIP TO DEXTROTHYROXINE THERAPY. In the nearly 3,000 patients studied, the withdrawal rate was less than 3%. PHARMACOLOGY: MOST EVIDENCE INDICATES THE MECHANISM OF ACTION IS TO STIMULATE THE LIVER TO INCREASE CATABOLISM OF CHOLESTPIROL; SYNTHESIS OF CHOLESTEROL IS NOT INHIBITED, AND ABNORMAL METABOLIC END PRODUCTS DO NOT ACCUMULATE IN THE BLOOD. DOSAGE RECOMMENDATIONS: Dosage should start at 1.0 or 2.0 mg daily to be increased monthly in 1.0 or 2.0 mg increments to a maximum of 6.0 to 8.0 ing daily if necessary for control of serum cholesterol in the adult. In hypothyroid patients, the more conservative dosage schedule s'hould be observed. Pediatric dosage is 0.05 tug/kg daily, increased monthly in 0.05 mg/kg increments; to 0.1 mg/kg or 4.0mg daily if necessary for control. SUPPLIED: 2.0 mg and 4.0 mg scored tablets in prescription bottles of 30. MEAD JoHNsoN LABORATORIES, Evansville, Ind., Juae 30, 1967. DEAR DOCTOR: The Food and Drug Administration 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 effects are "So Closo to Nature." The FDA points out that not nearly 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. 81-280 0-68--pt. 8-4 PAGENO="0050" 3142 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The ad emphasizes the low incidence of certain less serious side effects such as amenorrhea breakthrough bleeding weight gain etc However it fails to give adequate emphasis to more serious known side effects-or advquate emphasis to the possible occurrence of thronibophiebitis, pulmonary embolism or cerebral vas- cular 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 fea- tures a pregnancy rates of 0.2 per 100 women-years. While available data do not provide a reliable scientific ba is for a statement of true pregnancy rates exper ience reported to us shows that the unadjusted rate for all women who were given Oracon was 20 per 100 women years The rate of 02 used in the ad included only those patients who insisted that they had adhered to the regimen Questran® The FDA considers the summary of ss arning information in the journal adver tisement for Questran to be inadequate in that it did not contain any information on precautions and ss arnings We has e attached a revised Brief Summary which contains the omitted precautions and warning information in capital letters. We are discontinuing the ads in question, and future advertising will incorpo- rate the above corrections. The safety and effectiveness of Oracon and Questran are not in question when the drugs are used in accordance with the official pack- age inserts. Sincerely, P. A. WALTER, M.D., Director, Medical Research Department. (Noi~s -This revised Brief Summary for use in medical journal advertising contains additional information in capital letters taken from the official package insert.) BRIEF SUMMARY OF WARNING INFORMATION FOR QUE5TRAN® (CHOLE5TYRAMINE) Indication-Questran relieves pruritus associated with partial biliary obstruc- tion. Contraindication-Patients svith complete biliary obstruction Warning-ALWAYS ADMIX QUESTRAN WITH WATER OR OTHER FLUIDS BEFORE INGESTING TO PREVENT DEFICIFNCIES OF VITA MINS A D AND K SUPPLEMENT THE DIET AND SEE PREC ~UPIONS BELOW Usage in Pregnaiicy-THE SAFE USE OF QUESTRAN BY PREGNANT AND LACTATING WOMEN HAS NOT BEEN ESTABLISHED. Precautions-WITH PROLONGED QUESTR ~\ ADMINISTRATION GIVE VITAMINS A AND D DAILY. INCREASED BLEEDING TENDENCIES MAY DEVELOP. PROMPT RESPONSE TO PARENTERAL VITAMIN J(~ MAY BE ANTICIPATED. ADMINISTER CHLOROTHIAZIDE, PHENYLBUTAZONE OR WARFARIN ONE HOUR BEFORE QUESTRAN. AS A PRECAUTIONARY MEASURE, ADMINISTER ALL OTHER DRUGS 30 MINUTES TO 1 HOUR BEFORE QUESTRN. A THEORETICAL POSSIBILITY EXISTS THAT PRO- LONGED USE MAY LEAD TO DEVELOPMENT OF HYPER~HOLOREMIC ACIDOSIS. HERE IS NO ESTABLISHED RATIONALE FOR USE OF QUES- PRAN IN THE RELIEF OF PRURITUS ASSOCIATED WITH OTHER DIS- EASE PROCESSES. Adverse req~oti,ons Gastrointestinal and Dermatological-Constipation, diarrhea, nausea, gastroin- testinal distress, and vomiting have been reported by about 20% of patients using cholestrymine. Reported less frequently were ABDOMINAL PAIN AND DISTEN- TION, rash, irritation of the skin, tongue and perianal area. Bleeding-In 1% of patients, increased bleeding tendencies occurred due to hypoprothrombinemia. Steatorrhea-Steatorrhea occurred but rarely, and then on doses in excess of 24 grains per day. Cholesterol-In patients with pruritus associated with partial biliary obstruc- tion serum cholesterol levels usually decreases during Questra therapy (Clinical experience has not establi~thed the therapeutic use of Questran to reduce serum chlosterol.) Biliary Calciflcatioiv-Two possible instances have ~been dbserved, but a casual relationship has not been established PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3143 ARDSLEY, N.Y. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to recent journal advertisements for our products (Hygroton® and Regroton®) which the FDA considers to be misleading Hygroton 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, tablet for tablet Hygroton was clearly superior. Two tablets of Hygroton 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 small 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 au thors' 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 of Hygroton and the other diuretic do not contain coin- Darable theraDeutic dosages. Regroton Advertisement This ad displays a single Regroton tablet in relation to two sets~ of five tablets representing drug regimens for treating hypertension. The ad states that "in moderate hypertension" Regroton was "better than reserpine + hydralazine + hydrocholorothiazide in 41 of 43 patients and better than reserpine + 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 utilizing the other drug combinations. 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 not 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 of prescribing information in each ad to be inadequate. Each enclosed "Brief Summary" contains information in capital letters that was not included in our current ads. We are discontinuing 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 inserts. GEIGY PHARMACEUTICALS. (NOTE -This revised Brief Summary for use in future medical journal ad vertising contains additional words and phrases (printed in capital letters) taken from the official package insert) BRIEF SUMMARY OF HYGROTON®-BRAND OF CHLORTHALIDONE Indications: Hypertension and many types of edema involving retention of salt and water. Contra,Indicati~ons Hypersensitivity and most cases of severe renal of hepatic disease. Warning With the administration of enteric coated potassium supplements WHIOH SHOULD BE USED ONLY WHEN ADEQUATE DIETARY SUPPLE MENTATION IS NOT PR&CTICAL the possibility of small bowel lesions (OB STRUCTION HEMORRHAGE AND PERFORATION) should be kept in mind SURGERY FOR THESE LESIONS HAS FREQUENTLY BE~EN REQUIRED AND DEATHS HAVE OCCURRED DISCONTINUE ENPE'RIO COATED POTASSIUM SUPPLEMENTS IMMEDIATELY IF OBDOMINAL PAIN DIS TENTION, NAUSEA, VOMITING, OR GASTROINTESTINAL BLEEDING OCIOUR. Use with caution in pregnant patients, since the drug may cross the placental barrier and adverse reactions which may occur in the adult (thrombocytopenia, hyperbilirubinemia altered carbohydrate metabolism ete) are potential prob lems in the newborn. PAGENO="0052" 3144 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Preea'utions: ANTIHYPERTENSIVE THERAPY WITH HYGROTON SHOULD ALWAYS BE INITIATED CAUTIOUSLY in postsympathectomy patients and IN PATIENTS RECEIVING GANGLIONIC BLOCKING AGENTS OR OTHER POTEiNT ANTIHYPERTEINSIVE DRUGS, or curare. Reduce dos- age of concomitant antihypertensive agents by at least one-half. Barbiturates, narcotics or alcohol may potentiate hypotension. BECAUSE OF THE POS- SIBILITY OF PROGRESSION OF RENAL, DAMAGE, PERIODIC DETER- MINATION OF THE BUN IS INDICATED. Discontinue if the BUN rises or liver dysfunction is aggravated. HEPATIC COMA MAY PRECIPITATED. Electrolyte imbalance, SODIUM AND/OR potassium depletion may occur. IF POTASSIUM DEPLETION SHOULD OCCUR DURING THERAPY, HY- GROTON SHOULD BE DISOONTINUED AND POTASSIUM SUPPLEMENTS GIVEN, PROVIDED THE PATIENT DOES NOT HAVE MARKED OLIGURIA. Take special care in cirrhosis or severe ischemic heart disease and in patients receiving corticosteroids, AOTH, or digitalis. Salt restriction is not recommended. Adverse Reactions: Nausea, gastric irritation, vomiting, anorexia, constipa- tion and cramping, dizziness, weakness, restlessness, hyperglycemia, hyperuri- cemia, headache, muscle cramps, orthostatic hypotension, aplastic anemia, leu- kopenia, thromboeytopenia, agranulocytosis, impotence, dysuria, transient myopia, skin rashes, urticaria, purpura, necrotizing angiitis, ACUTE' GOUT, AND PANOREATITIS WHEN epigastric pain or UNEXPLAINED 0.1. symptoms DEVELOP after prolonged `administration. Other reactions reported with this class of compounds include: jaundice, xanthopsia, paresthesia, and photo- sensitization. Average Dosage: One tablet (100 mg.) with `breakfast daily or every other day. Ava4labittty: White, single-scored tablets of 100 mg. in bottles of 100 and 1000. (NOTE-ThIS revised "Brief Summary", for use in future medical journal ad- vertising, contains additional words and phrases (printed in capital letters) taken from the official package insert.) BRIEF SUMMARY OF REGROTON®-CHLORTHALIDONE, 50 MG., RESERPINE U.S.P., 0.25 MG. Indications: Hypertension. Contraindications: History of mental depression, hypersensitivity, and most cases of severe renal or hepatic diseases. Warning: With the administration of enteric-coated potassium supplements, WHICH SHOULD BE USED ONLY WHEN ADEQUATE DIETARY SUPPLE- MENTATION IS NOT PRACTICAL, the possibility of small bowel lesions (OBSTRUCTION, HEMORRHAGE, AND PERFORATION) should be kept in mind. SURGERY, FOR THESE LESIONS HAS FREQUENTLY BEEN RE- QUIRED AND DEATHS HAVE OCCURRED. DISCONTINUE COATED POTASSIUM-CONTAINING FORMULATIONS IMMEDIATELY IF ABDOMINAL PAIN, DISTENTION, NAUSEA, VOMIT- ING, OR GASTROINTESTINAL BLEEDING OCCUR. Use cautiously during pregnancy since adverse reactions (thrombocytopenia, hyperbilirubinemia, altered carbohydrate metabolism, etc.) are potential prob- lems in the newborn. Discontinue 2 weeks before general anesthesia, 1 week before electroshock therapy, and if depression or peptic ulcer occurs. Precautions: ANTIHYPERTENSIVE THERAPY WITH REGROTON SHOULD ALWAYS BE; INITIATED CAUTIOUSLY in postsympathectomy patients and IN PATIENTS RECEIVING GANGLIONIC BLOCKING AGENT'S, OTHER POTENT ANTIHYPERTENSIVE DRUGS, or curare. Reduce dosage of concomitant antihypertensive agents by at least one-half. BECAUSE OF THE POSSIBILITY OF PROGRESSION OF RENAL DAM- AGE, PERIODIC KIDNEY FUNCTION TESTS ARE INDIOATED. Discon- tinue if the BUN rises or liver dysfunction is aggravated, HEPATIC OOMA MAY BE PRECIPITATED. Electrolyte imbalance, SODIUM AND/OR potassium depletion may occur. IF POTASSIUM DEPLETION SHOULD OCCUR DURING THERAPY, REGRO- TON SHOULD BE DISCONTINUED AND POTASSIUM SUPPLEMENTS GIVEN, PROVIDED THE PATIENT DOES NOT HAVE MARKED OLIGURIA. Take particular care in cirrhosis or severe ischemic heart disease and in patients receiving corticosteroids, ACTH, or digitalis. Salt restriction is not recommended. BILIARY COLIC MAY BE PRECIPITATED (IN PATIENTS PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3145 WITH GALLSTONES) AND BRONCHIAL ASTHMA MAY 000UR IN SUS- CEPTIBLE PATIENTS. Adverse Reactions: The drug is generally well tolerated. The most frequent side effects are nausea, gastrict irritation, vomiting, diarrhea, constipation, muscle cramps, headache, dizziness and ACUTE GOUT. Other potential side effects include angina pectoris, anxiety, depression, bradycardia and ectopic cardiac rhythms (especially when used with digitalis), drowsiness, dull sen- soriam, hyperglycemia, hyperuricemia, lassitude, restlessness, transient myiopia, impotence or dysuria, orthostatic hypotension which may be potentiated when chiorthalidomie is combined with alcohol, barbiturates or narcotics, leukopenia, aplastic anemia, skin rashes, THROMBOCYTOPENIA, AGRANULOCYTOSIS, nasal stuffiness, increased gastric secretions, nightmare, purpura, urticaria, ecchy- mosis, weakness, uveitis, optic atrophy and glaucoma, and PRURITUS, ERUP- TIONS AND/OR FLUSHING OF THE SKIN, A REVERSIBLE PARALYSIS AGITANS-LIKE SYNDROME. INOREASED SUSCEPTIBILITY TO COLDS, DYSPNEA, weight gain, decreased libido, DRYNESS OF THE MOUTH, deaf- ness, ANOREXIA, AND PANCREATITIS WHEN EPIGASTRIC PAIN OR UNEXPLAINED CI. SYMPTOMS DEVELOP AFTER PROLONGED ADMIN- ISTRATION. Jaundice, xanthopsia, PARESTHESIA, PHOTOSENSITIZATION and necrotizing angiitis ARE POSSIBLE. Average Dosis: One tablet daily with breakfast. Availability: Pink, single-scored tablets in bottles of 100 and 1000. PFIZER LAB0IiAT0RIES, 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 (Rondomycin, 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 Re- nese-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 imbal- ance, hepatic coma, maintenance dosage, and, in the case of Renese-R, the pos- sibility of Parkinsonism and confusion. Rosidomycin The FDA has also asked us to call to your attention certain features of our cur- rent advertising for the broad spectrum antibiotic, Rondomycin. The ad does not disclose that it is a member of the bacteriostatic tetracycline family and that ad- ministration for ten days is especially important in the treatment of Beta-hemo- lytic 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 ac- tivity of Rondomycin against these test strains, the PD50 tests cannot be extrap- olated 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 warning 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, JOHN L. WATTEBS, M.D., Medical Director. NEW YORK, N.Y., August 11, 1967. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to a recent advertisement for Diutensen-R which the 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 danger 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 PAGENO="0054" 3146 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 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 when used in accordance with the prescribing information in the official package insert. Sincerely, NEISLER LABORATORIES. (Norn This revised Brief Summary for use in future methcal journal ad vertising contains additional words and phrases (printed in capital letters) taken from the official package insert) BRIEF SUMMARY or WARNING INFORMATION FOE DIUTENSEN R (For prescribing information consult official package insert) Indications Hypertension Contrain,du,c&tions SEVERE DEPRESSION and KNOWN HYPERTEN SITIVITY TO reserpine, VERATRUM VIRIDE OR THIAZIDE COMPOUNDS. WARNING: WITH THE ADMINISTRATION OF ENPERIC-COATED P0- TASSIUM SUPPLEMENTS, WHICH SHOULD BE USED ONLY WHEN ADE- QNATE DIETARY SUPPLEMENTATION IS NOT PRACTICAL, THE POS- SIBILITY OF SMALL BOWEL LESIONS CONSISTING OR STENOSIS WITH OR WITHOUT ULCERATION, AND CAUSING OBSTRUCTION, HEMMOR- RHAGE, AND PERFORATION, SHOULD BE KEPT IN MIND. SURGERY FOR THESE LESIONS HAS FREQUENTLY BEEN REQUIRED AND DEATHS HAVE OCCURRED. DISCONTINUE COATED POTASSIUM-CONTAINING FORMULATIONS IMMDIATELY IF ABDOMINAL PAIN, DISTENTION, NAUSEA VOMITING OR GASTROINTESTINAL BLEEDING OCCUR DISCONTINUE 2 WEEKS BEFORE GENERAL ANESTHESIA OR ELEC TROSHOOK THERAPY AND IF DEPRESSION OR PEPTIC ULCER OCCURS Precautions ELECTROLYTE IMBALANCE HYPOCHLOREMIC ALKA LOSIS SODIUM AND/OR POTASSIUM DEPLETION MAY OCCUR. IF P0-' TASSIUM DEPLETION SHOULD OCCUR DURING THERAPY, DIUTEN- SEN-R SHOULD BE DISCONTINUED AND POTASSIUM SUPPLEMENTS GIVEN, PROVIDED THE PATIENT DOES NOT HAVE MARKED OLI- GURIA. HYPOCHLOREMIC ALKALOSIS MAY BE TREATED WITH AM- MONIUM CHLORIDE IF NO LIVER DISEASE IS PRESENT PARTICULAR OBSERVANCE OF THE SERUM ELECTROLYTE BAL ANCE AND/OR POTASSIUM SUPPLEMENTATION IS NECESSARY IN PATIENTS RECEIVING HIGHER DOSAGE LEVELS DIGrITALIS POTAS SlUM DEPLETING CORTICOSTEROIDS AND IN CIRRHOSIS ESPECIALLY WHEN THERE IS IMPENDING HEPATIC COMA IF PROGRESSIVE INCREASE IN SERUM NITROGEN (BUN NPN OR CREATININE) OCCURS THERAPY SHOULD BS DISCONTINUED USE WITH CAUTION IN PATIENTS WITH A HISTORY OF PEPTIC ULCER, ULCERATIVE COLITIS, OR DEPRESSION. DIUTENSEN-R MAY INCREASE THE POSSIBILITY OF DIGITALS IN- TOXICATION. Reduce dose or discontinue if myocardial irritability occurs (extrasystoles bigeminy or AV block) Adverse Reactions Occasional urinary frequency nocturia nasal congestion DRYNESS OF THE MOUTH muscle cramps skin rash joint pains due to gout nausea VOMITING and dizziness POTENTIAL SIDE EFFECTS INCLUDE HYPERGLYCEMIA RISE IN SERUM URIC ACID, PURPURA, THROMBOCYTOPENIA, LEUKOPENIA, PARKINSONISM BRADCARDIA AND EXCESSIVE HYPOTENSION WITH PROSTRATION. (TREAT BRADYCARDIA WITH ATROPINE AND HYPO- TENSION WITH VASOPRESSORS.) DRUG SHOULD BE DISCONTINUED IF SUFFICIENT HYPERGLYCEMIA IS OBSERVED OR IF PURPURA THROMBOCYTOPENIA, OR LEUKOPENIA OCCUR. Usual Dosage: One `tablet twice daily at morning and evening meals. Daily dosage should not exceed 4 tablets 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 Citanest® which the FDA regards as so substantially misleading and lacking in adequate professional use information that in its view they represent potential hazards to health PAGENO="0055" COMPETITIVE PROBLEMS IN THE DRUG INDUSPRY 3147 These mailing pieces, identified as 118-67 and 119-67, should be discarded if still in your possession. 1. Intravenous regional anesthesia Mailing piece 118-67 recommended the use of Citanest in intravenous regional anesthesia The FDA regards use of this drug by that technique as experi mental. The package insert for Citanest contains no information for its use in intravenous regional anesthesia and the drug has not been approved for use in that procedure. 2. Maximum single dosage Mailing pieces 118-67 and 119-67 contained statements which implied that dosages of Citanest in excess of the maximum single dose (600 mg.) could be employed in clinical use. No such implication was intended by Astra, and Astra reaffirms that no more than 600 mg. of the drug should be used during any two- hour period. Professional use information Both booklets omitted essential and required professional 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 (prilocaine) when used in accord ance with the conditions specified in the enclosed package insert are not in question. Sincerely yours, ASTRA PHARMACEUTICAL PRODUCTS, Ivc~ ASTRA® The following warning, precautionary, and adverse reaction information con- tained in the approved (November 18, 1965) Citanest labeling (identified "120" and "Issued October, 1965") is omitted from the product information text of Citanest® mailing pieces 118-67 and 119-67: Warning It should be remembered that all local anesthetics are p z~tentially toxic drugs. Therefore, the minimum amount of local anesthetic agent necessary to produce adequate anesthesia and avoid toxic reactions should be used at all times. Moreover, as with other types of drugs, the use of local anesthetics such as Citanest (prilocaine) should be minimal during pregnancy. This, of course, does not exclude the use of local anesthetics at term for obstetrical analgesia. Citanest (prilocaine) has been used effectively for obstetrical analgesia with no adverse effects noted on the fetus, course of labor, or delivery. Precautions: The peridural space can be approached from the thoracic, lumbar and sacral (caudal) regions. It must be kept in mind that these areas contain venous and arterial plexuses and lymph vessels. Further, the close proximity of these regions to the subarachnoid space constitutes an additiOnal hazard of which the anesthesiologist must be constantly aware. Consequently, the tech- nique of peridural anesthesia should be~ attempted only by skilled individuals. Close familiarity with, and readiness to make use of every known precautionary measure are mandatory Further in addition to the accepted procedure for lo eating the peridural space, a test dose of 5 cc should be administered at least 5 minutes prior to injecting the total required volume. While desirable in most instances, the application of the test dose cannot be regarded as a completely effective safety measure. The judicious selection of needles of the proper length and bevel is also important; e.g., in the case of the sacral (caudal) approach, it is necessary that the sacral canal be penetrated for a distance of only 1~/2 to 2 inches. Since it is possible to puncture the dura by this approach, the use of excessively long needles is definitely precluded. Local anesthetics react with certain metals and cause the release of their re spective ions which if injected may cause severe local irritation Adequate pre caution should be taken to avoid this type of interaction Treatment 1. In adverent subarachnoid injection: a) Resusciate with oxygen and control blood pressure with vasopressor agents. b) Aspirate spinal fluid until 50 cc is removed. PAGENO="0056" 3148 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2. Barbiturates may be used prophylactically but offer only a small degree of protection against a lethal dose. Side effects and their treatment: 1. Syncope-Stop injection, recumbent position with legs raised, oxygen, aro- matic spirits of ammonia, cold compresses. 2. Hypotension-Stop injection, recumbent position with legs raised, assure adequate ventilation with oxygen. Support circulation with vasopressor if neces- sary. 3. Apnea-Stop injection, recumbent position, maintain patent airway, ar- tificial respiration with oxygen. 4. Headache and/or backache-Bed rest, analgesic agents as needed. It should be remembered that these side effects most often accompany spinal anesthesia and Citanest (prilocaine) is not recommended for spinal use at this time. 5. Nausea and vomiting-Stop injection, maintain patent airway, prevent aspiration, anti-emetics as needed. Methemoglobinemia: At a dose of 600 mg of Citanest (prilocaine), which is the maximum recommended dose for any anesthetic procedure, methemoglobin formation did occur but was less than 15% of total hemoglobin in all patients studied. With respect to the clinical symptoms associated with methemoglobinemia, the following statement has been made in textbooks: In general, levels of less than 20 per cent methemoglobin are usually not associated with symptoms. At levels of 20 to 50 per cent fatigue, weakness, dyspnea, tachycardla, headaches, and dizziness may occur. In studies conducted to date no patient in whom the maximum recommended dose of 600 mg of Citanest (prilocaine) was used de- monstrated a methemoglobin value in excess of 15% and no clinical symptoms have been observed. Moreover, in clinical studies involving approximately 9000 cases in which Oitanest (prilocaine) has been used, only one patient who received a single injection of 900 mg has been reported to have exhibited clinical symptoms of lightheadedness and dizziness may have been related to methemo- globin value in excess of 20%. Ad~ninistration and Dosage: With the exception of therapeutic nerve blocks, 20-30 ml of Citanest (prilocaine) hydrochloride 1% or 2% and 15-20 ml of Citanest (prilocaine) hydrochloride 3% will usually produce adequate opera- tive anesthesia. The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration of local anesthetic used. Thus, an increase in volume and concentration of Citanest (prilocaine) will decrease the onset of anesthesia, prolong the duration of anesthesia, proS vide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. It should be remembered, however, that increasing the volume and concentration of Citanest (prilocaine) may result in a more profound fall in blood pressure when used in peridural anesthesia. Although the incidence of side effects in clinical trials was quite low, caution should be exercised partic- ularly when employing large volumes and concentrations of Citanest (prilo- caine) since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected. Ma~vimum recommended dosage: Normal Healthy Adults: No more than 600 mg of Citanest (prilocaine) hydrochloride should ever be administerd as a sin- gle injection, i.e., no more than 8 mg/kg or 4 mg/lb should be given as a single injection. The maximum total dose which may be administered over a period of several hours (e.g., for continuous peridural anesthesia) without side effects is not known as yet. Doses in excess of 2000 mg have been administered over a five-hour period with no toxic symptoms. However, until further data. is avail- able we would recommend that doses in excess of 600 mg not be administered at intervals of less than two hours so that one should not exceed a total dose of 1200mg in a four-hour period. Children: Experience in children under the age of ten (10) is limited. It is extremely difficult to recommend a maximum dose of any drug for children since this varies as a function of age and weight. With respect to Citanest (prilo- caine) hydrochloride, 400 mg have been used without toxic effects in children of 10-15 years. However, for children of less `than 10 years who have a normal lean body mass and normal body development, we recommend the use of one of the standard pediatric drug formulas (e.g., Clark's rule or Young's rule) to deter- mine the maximum dose. For example, in a child of five years weighing 50 lbs., the dose of Citanest (prilocaine) hydrochloride should not exceed 150-200 mg PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3149 when calculated according to Clark s rule or Young s rule In order to minimize the possibility of toxic reactions in children use of the 1% concentratIon of Citanest (prilocaine) hydrochloride is recommended Patients with Liver Disease and Debilitated Patients The use of any general or local anesthetic agent is undesirable in patients with liver disease or severely debilitated patients However for emergency or definitive surgical procedures where a local anesthetic is required, care should be taken to use the lowest dose and concentration of Citanest (prilocaine) hydrochloride necessary to provide adequate anesthesia. It is extremely difficult to recommend a maximum safe dose of any drug for such patients, since this will depend on the degree of liver damage and degree of debilitation For most anesthetic procedures it is advis able to use the 1% concentration of Citanest (prilocaine) hydrochloride in order to obtain the minimum dose that will provide adequate anesthesia and thereby avoid possible toxic reactions in patients with liver disease or debilitated pa tients In ~,uch patients it is probably not advisable to exceed a maximum dose of 400mg _____ DEAR DOCTOR The Food and Drug Administration has asked us to call your attention to certain advertisements for Mystechn-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 tetracycline 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 advertisements for these products suggested that candidal superinfection is a serious problem with 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 pre cautions and side effects. The nature and extent of the omission are capitalized in the enclosed "Brief Summary". Sincerely, SQUiBB. (Norii -This revised `Brief Summary for use in future medical journal adver tising contains additional phrases and items (printed in capital letters) from the official package insert) Oontramdications History of hypersensitivity to either component Warmsig If renal impairment exists lower than usual doses are indicated to avoid `systemic accumulation and possible liver toxicity on prolonged use tetracycline serum level determinations may be advisable. Photodynamic reac- tions, although rare with teracycline, may occur; if they occur, discontinue drug. Advise photosensitive patients to avoid direct sunlight. Preoautions: Watch for signs of secondary infection due to nonsusceptible organisms; discontinue drug and/or institute appropriate therapy i,f this, occurs. SUPERINFEOTION OF THE BOWEL BY STAPHYLOCOCCI MAY BE LIFE- THREATENING Use of tetracycline particularly long term use BUT ALSO IN USUAL SHORT TREATMENT COURSES during the LATTER HALF OF GESTATION NEONATAL PERIOD AND EARLY CHILDHOOD tooth devel opment may cause discoloration of teeth TETRACYCLINE MAY FORM A STABLE CALCIUM COMPLEX IN BONE FORMING TISSUE WITHOUT HARMFUL EFFECTS REPORTED THUS FAR During long term therapy, perform periodic renal hepatic and hematopoietic function studies Increased intracranial pressure with bulging fontanels has been observed rarely in infants taking therapeutic doses of tetracycline USE WITH CAUTION IN PERSONS WITH A HISTORY OF ALLERGY, ASTHMA, HAY FEVER, OR URTIOARIA DUE TO GREATER POSSIBILITY OF SENSITIVITY REACTIONS. CROSS- SENSITIZATION WITH OTHER TETRACYCLINES IS COMMON. IN THE TREATMENT OF GONORRHEA, PATIENTS WITH A SUSPECTED LESION OF SYPHILIS SHOULD HAVE DARK FIELD EXAMINATIONS BEFORE RECEIVING TETRACYCLINE AND MONTHLY SEROLOGIC TESTS FOR A MINIMUM OF THREE MONTHS PAGENO="0058" 3150 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Note: SOME SPRAINS OF STAPHYLOCOCCI, STREPTOCOCCI, PNEUMO- COCCI, E. COLI, AND SHIGELLAE HAVE SHOWN RESISTANCE TO TETR~CYCLINE5. MICROORGANISMS THAT HAVE BECOME INSENSI- TIVE TO ONE TETRACYCLINE INVARIABLY EXHIBIT CROSS-RESIST- ANOE TO OTHER TETRACYOLINES AND TETRACYCLINE RESISTANT GRAM NEGATIVE BACILLI MAY SHOW OROS'S RESISTANCE TO CIHLOR- AMPHENICOL. THEREFORE, INDICATED LABORATORY STUDIES, IN- OLUDING SENSITIVITY PESTS, SHOULD BE PERFORMED. side Effects: ANOREXIA, EPIGASTRIC DISTRESS, NAUSEA, VOMIT- ING, BULKY LOOSE STOOLS, DIARRHEA, STOMATITIS, GLOSSITIS, ENTER000LITIS, PROOTIPIS, PRUITUS ANT, BLACK HAIRY TONGUE, SORE THROAT, DYSPHAG-IA, HOARSENESS, MAOULOPAPULAR AND ERYTHEMATOUS RASHES, A RARE CASE OF EXFOLIATIVE DERMA- TITIS, rarely PHOTOSENSITIVITY, rarely ONYCHOLYSIS AND NAIL DIS- COLORATION, DOSE-RELATED BUN RISE, URTICARIA, SERUM SICK- NESS LIKE REACTIONS ANGIONEUROTIC EDEMA ANAPHYLAXIS BULGING FONTANELS IN INFANTS, DENTAL STAINING (see Precau- tions), TOOTH-ENAMEL HYPOPLASIA IN CHILDREN, ANEMIA, THROM- BOCYTOPENIC PURPURA, NEUTROPEIA, EOSINOPHILIA, AND RARELY CHOLESTASIS ASSOCIATED WITH HIGH DOSAGE, URNARY NITROGEN LOSS WHICH MAY RESULT IN NEGATIVE NITROGEN BALANCE AND IN- CREASED SODIUM EXCRETION, DELAYED BLOOD COAGULATION, AND DEVELOPMENT OF PEPTIC ULCERS AND BLEEDING IN IJREMIO PA- TIENTS. IF ALLERGIC' REACTIONS OCCUR, OR IF AN INDIVIDUAL IDIOSYNCRASY APPEARS, TETRACYCLINE THERAPY SHOULD BE DISCONTINUED. ORGANÔN, INC., West Orange NJ October27 1967 DEAR DOCTOR The Food and Drug Administration has requested that we call your attention to the monographs for Cortophin® Gel, Cortrophin® Zinc, Hexadrol® Phosphat Injection and Hexadrol® Tablets and Elixir in the cur- rent 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 mono- graphs for insertion in your PDR. The nature and extent of the additions and other revisions in the enclosed monographs are emphasized by the use of italics. Sincerely yours, JOSEPH D. CUONO, M.D., Director, Prof essional services. (N0TE.-Prescriblng information for Cortrophi~® Gel, Cortrophin® Zinc, Hex- adrol® and Hexadrol® Phosphate Injection, which appears on pages 898-899 of your 1967 PDR, has been revised and is completely replaced by the following. The nature and extent of the additions and other revisions in the monographs are emphasized by use of italics.) ORGANON, INC., WEST ORANGE, N.J. PURIFIED CORTROPHIN® GEL Repository Corticotropin Injection TJ.S.P. Purified Cortrophin Gel is purified corticotropin (ACTH) in a sterile solution of gelatin for prolonged activity. It is supplied in two strengths: 40 U.S.P. Units and 80 U.S.P. Units per cc. Each cc. of each strength also contains 0.5% phenol (preservative), 15.0% gelatin, pll adjusted with 1101. This product requires fewer injections ncr dax than aqueous corticotropin preparations to maintain adreno- corticotropic activity It is solid at or below room temperature before use the gel should be liquefied by holding the vial under warm tap water. It should be in- jected subcutaneously or intramuscularly, never intravenously; a 20 or 21-gauge needle should be used. Injection sites should be alternated, and brief, firm pres- sure should be applied on the siteafter each injection. Properities-This product offers prolonged ACTH activity. It stimulates the adrenals to an increased production of all the adrenocortical hormones. Three types of adrenal hormones are produced in this way: compound F-like hormones PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3151 (cortisone-like) , which are the most abundant ; desoxycorticosterone-like hor- homes ; and the adrenal androgens. The production of compound F-like hormones is clinically the most significant, for these particular steroids are the ones that produce striking clinical response in so many diseases, and which enable the tis- sues and the body as a whole to meet serious stress. Adequate therapy usually produces the following desirable general changes: Temperature, if elevated, usually returns to normal within 6 to 18 hours. Pain is abolished within a short time and becomes an index of the reversibility of the disease under treatment. Pa- tients develop a sense of well-being and of mental activity bordering on euphoria. Fibroblastic proliferation and inflammatory processes are blocked. SPECIAL PRECAUTIONS WITH ADRENOCOIiTICOTROPIC THERAPY This product functions by stimulating the production of steroid hormones by the adrenal cortices, and in this manner influences protein and carbohydrate me- tabolism, alters the metabolism of electrolytes with retention of sodium and ecu- cretion of potassium. In this same manner the steroid hormones of the adrenal cortices induce atrophy of the thymus a~nd produce an increase in antihyaluroni- dase activity. Prolonged or excessive stimulation of the adrenals may produce undesirable effects, and for this reason each patient should be carefully observed to determine his response. 1. Edema-With large doses or during prolonged use, sodium retention with intake, giving a diuretic, or by temporarily discontinuing therapy until diuresis results. If potassium deficiency with muscular weakness or edema occurs, supplemental potassium should be given: 1 Gm potassium citrate or chloride given orally three times a day. 2. Temperature and Infection-This product may mask signs of concomit- ant serious infections and therapy should be discontinued temporarily in order to permit diagnosis of the infection. Therapy may be resumed if war- ranted after specific therapy for the infection has been given. 3. Disturbed Psyche-If psychotic changes appear, these isolated cases should be treated by reducing or discontinuing dosage of corticotropin and the use of sedatives should begin 4 Hyperglycemia and Glycosuria-Ecucessive dosage may increase the blood sugar and glycosuria may occur this can be ehminated by reduction of dosage or cessation of therapy (see contraindications for diabetes below). 5. Hypertension-In certain individuals a marked increase in blood pres- sure may occur, and in these instances the dose should be reduced or elim- inated. 6. Acne and Hirsutism-Prolonger therapy may cause overstimulation of androgenic hormone secretion which may induce these symptoms in some women; and these conditions may be controlled by suitable reduction in dos- age. In severe cases, therapy may have to be discontinued. 7. Hypersensitivity-Busceptible individuals may become sensitized to traces of protein that accompany corticotropin so that subsequent infections given after intervals of several days may give rise to hypersensitivity phe nomena Therefore patients who have previously been treated with cortico tropin should be tested for sensitivity and sensitive individuals should be desensitized before treatment is begun. Test of Acirenocortical Activity-One of the requisites to successful cortico- tropin therapy is a functioning adrenal cortex. The functional capacity of the adrenal conditions clinical response. A reduction in the number of circulating cosinophils is considered to reflect increased secretion of adrenal steroids and indi~ates a positive response to corticotropin. Normal subjects respond to the injection of adequate doses of ACPH with at least a 50 per cent fall in circulating cosinophils. The test (known as the Thorn test) is applied in the diagnosis of Addison's disease, as a test of adrenal reserve pre- and post-operatively, to deter- mine the patient's ability to react to stress, and to differentiate between panhypo- pituitarism, functional hypopituitarism and Addison's disease. In hypopituitarism, where hypofunction lies in the hypophysis reaction to the test is positive In Addi son's disease, where the deficiency resides in the adrenals, the response is negative. Dosage Considerations-Because functional capacity of the adrenal varies with the patient, the dose must be individualized, the aim being to obtain a thera- peutic effect with minimal dosage and minimal metabolic changes. In severe cases, it may be advisable to initiate treatment with aqueous corticotropin (not PAGENO="0060" 3152 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the geZ form) by the intravenou$ route, ohangiQig to thi$ product for ma~tntenance therapy. Although the dosage mU$t be individuaZized to the patient anã the disturbance being treated, the initial dose requirements will probably be in the vicinity of 40 to 60 units of cortwotropin per day Ordinarily where the preparation is to be used continuously or for prolonged periods, the daily dose should not be over 20 units and usuaUy less It is preferable to maintain the dosage of AUTH at a leveZ that will atvo~d ii~ndemrable side effects even though this dosage be insuffi cent to prodt~ce complete relief of the climcal disorder under treatment M~n~mum dosage levels should be used in afl cases of pro'onged therapy The amount re qusred per day governs the frequency of ~n2ectwns for example if 60 units are required, the amount is given as two equally divided doses, if less than 40 units is required the dose is administered as a single daily injection It is best to decrease the dosage as quickly as possible after the desired response is obtained. First, the dose is reduced to about three-fourths that needed initially; this is continued for about a week to determine its adequacy. The dose is again reduced step-wise by one-fourth every 5 to 7 days until the lowest maintenance dose is established. After about a week, this dose is administered every other day. If improvement is maintained then the interval is lengthened to every three days The general principle is to give the smallest dose in the longest interval If the dose needed for full relief produces significant side effects it should be reduced and the physician shonld content himself with less than full suppression of the disease being treated CONTRAINDICATIONS 1. Tuberculosis-Active or latent tuberculosis is a definite contraindication for prolonged therapy. 2. Congestive Heart Failure and Hypertensio~n-Corticotropin therapy, through its tendency to induce electrolyte and fluid ~etention, is undesirable for these conditions. 3 Psychotic and Psychopathic Personalities-Corticotropin therapy may pre cipitate undesired incidents and hence persons with psychopathic personalities should usually not receive the drug until further studies have been made 4 Diabetes Mellitus-Corticotropin therapy may increase the blood sugar levels especially of controlled diabetics or latent diabetics so that glycosuria may result This may be controlled by increasing the insulin do$age and adjust ment of diet and in most cases discontiivuance of the corticotropvn brings blood sugar levels and insulin requirements back to pretreatment values 5 Chronic Nephritis-It is essential that the patient be able to eliminate excess water which tends to be retained on corticotropin therapy due to sodium re tention. The inability of the nephrotic to eliminate excess fluid requires caution. 6. Cushing's syndrome-This disease is due to ea~cessive function of the adrenal cortea' or to tumors, and corticotropin therapy is contraindicated. 7. Addison's Disease-Corticotropin therapy is ineffective in the absence of adrenal tissue. 8 Thrombophlebitis-Since ACTH therapy tends to increase the thrombo philic tendency patients particularly those confined to bed or chair should be watched for signs of phlebothrombosis which should be treated with anticoagulant therapy before and during the ACPH therapy INDICATIONS The following dosage recommendations for this product to be administered subcutaneously or intramuscularly are intended as suggestions for initial therapy and thereafter the dosage must be adjusted. to the individual needs of the patient. Rheumatoid Arthritis-The initial dose is 60 units once a day; for severe cases, 30 to 40 units every 12 hours. If clinical response is not obtained after several days, increase dose to 80 uniUs every 24 hours. After remission occurs, gradually reduce dose as described under Dosage Considerations Acute Rheumatic Fever-In young children 40 units per day as one injection if acutely ill 30 units every 12 hours For older children 60 units once a day Full treatment for 4 days then gradual tapering off and treatment discontinued Acute Lupus Erythematosus-The initial dose is 60 units every 24 hours The patient should be maintained on the effective dose for 2 to 3 weeks at which time the dose should be reduced to the minimum maintenance level These patients must be carefully observed for edema with cardiac and nephritic involvement Low sodium diet and increased potassium intake is advisable. * PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3153 Severe Hay Fever-40 to 60 units once a day. Treatment period averages 3 to 5 days with a gradual tapering off afterward. Drug Sensitivities a'nd Contact Derm~atitis-A dosage of 80 units once a day for 2 days will usually control symptoms; dosage reduced gradually and then dis- continued. Urticaria-A dosage of 80 units once a day for 1 to 3 days, with gradual taper- ing off. Some cases may require maintenance of 10 to 40 units every 1 to 3 days. Acute Inflammatory Diseases of the Eye-In ivitis, keralitis, uveitis, choroiditis, optic neuritis, sympathetic ophtkalmia, acute secondary glaucoma, and conjunc- tivitis, 40 to 60 units are needed once a day until the eye lesion has fully healed. After gradual tapering off of dosage, treatment can be discontinued for most patients; in some who have had the disease for an ertended period, maintenance therapy of 10 to 40 units once a day or every 2 to 3 days may be required. Attempts should be made periodically to discontinue treatment. Acute Inflammatory Diseases of the Skin-In acute psoriasis, e~rfoliative der- matitis and severe pemphigus, from 40 to 60 units a day for a short period, with gradual tapering off. Most patients will require maintenance therapy of from 10 to 40 units once daily or every 2 to 3 days, unless the cause is known and elimi- nated. Ulcerative Colitis-For less severe cases, 40 units once daily; for severe cases, 60 to 80 units daily until mucosa appears relatively normal. Maintenance dose of 10 to 40 units every 1 to 3 days may be required in chronic cases. Acute Gouty Arthritis-Emergency treatment of 80 units per day. Less ill pa- tients should receive 40 to 60 units once daily. Treatment is repeated until symp- toms subside-usually after 1 to 3 injections. Other therapy for gout should be concurrently administered. ACT H therapy is usually not required Congenjital Idiopathic Hypoglycem'ia-20 to 40 units once a day for small chil- dren. Full treatment entends to at least 10 days after adequate control. Mainte- nance dose of 10 to 20 units every 1 to 3 days after patient is well under control~ Alcoholism (acute delirium tremens)-40 units twice a day until symptoms have disappeared (usually within 24-36 hours.) When symptoms are controlled, reduce dosage to 20 units twice a day for 2 to 3 days, then 20 units per day for 2 to 3 days; finally 20 units three times a week for 2 to 4 weeks. ACT H therapy is not recommended for Korsakoff's psychosis. Packages-This product retains potency for at least three years. It should be kept in a refrigerator. Available in 5-ce vials, in two strengths: 40 U.S.P units and 80 U.S.P. units of purified corticotropin (ACTH) per cc. and in 1-cc ampuls containing 40 U.S.P. units. CAUTION: Federal law prohibits dispensing without prescription. CORTROPHIN"-ZINC" &erile Corticotropin Zinc Hydroxide Suspension U.S.P. Oomp'osition-An aqueoits suspension of purified corticotropin (AOTH) with alpha zinc hydroxide for repository action. It is available as 40 U.S.P. units of corticotropin 1<1 (1,0 mg. of zinc content per cc), which provides therapeutic A0!TH activity for a period of from one to three days, depending upon individual patient requirements. Each cc also contains: 1A~% benzyl alcohol (preservative) and made isotonic with NaCl, pH adjusted with 1101 and NaOH. This is a fine aqueoua suspension which flows readily through a 24-26 hypodermic needle. It should be given intramuscularly to avoid any possible local reaction. Properties-This product supplies pituitary corticotropin in a form which pro- vides sustained action of the hormone, causing the adrenal cortex to release its essential steroids in physiological proportions over a longer period of time than would be the case with corticotropin in equal amounts in other forms This period of activity ranges from 1 to 3 days depending upon the patient's requirements and upon the strength administered. The response is conditioned by the functional capacity of the adrenal cortex; a highly active gland would respond dramatically, while an inactive adrenal cortex would respond less, particularly at first. This response takes the form of an outpouring of three types of adrenal hormones: compound-F-like hormones which are the most abundant; desoxycorticosterone- like hormones; and the adrenal androgens. The production of compound-F-like hormones is clinically the most significant, for it is this aspect of therapy that promotes striking clinical response in so many diseases, and which enables the tissues and the body as a whole to meet serious stress. PAGENO="0062" 3154 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Adequate therapy usually produces the following desirable general changes: Temperature, if elevated, usually returns to normal within ~l to 18 hours. Pain is abolished within a short time and becomes an index of the reversibility of the disease under treatment. Patients develop a sense of well-being and of mental activity bordering on euphoria. Fibroblastic proliferation and inflammatory proc- essas are blocked. Test of Adrenocortical Activity-One of the requisites to successful corticotro- pin therapy is a functioning adrenal cortex. The functional capacity of the ad- renal conditions clinical response. A reduction in the number of circulating cosino- phils is considered to reflect increased secretion of adrenal steriods and indicates a positive response to corticotropin. Normal subjects respond to an adequate dose with at least a 50 per cent fall in circulating cosinophils. This test (known as the Thorn test) is applied in the diagnosis of Addison s disease as a test of adrenal reserve pre- and post-operatively, to determine the patient's ability to react to stress, a~d to differentiate betwe~en panhypopituitarism, functional hypopitui- tarism and Addison's disease, in hypopituitarism, whore hypofunction lies in the hypophysis, reaction to the test is positive. In Addison's disease, where the defi- ciency resides in the adrenals, the response is negative. Dosage Considerations-As with corticotropin in gelatin and aqueous corti- cotropin the dosage must be individualized to the requirements of the particular patient and the disturbance being treated. Because of the enhanced and prolonged activity, fewer injections are required. In general, it seems practical to gain initial control of symptoms with an in- jection of 40 U.AS~.P. units, (in more severe cases, 60 units) daily. Once symptoms have been controlled, the interval between injections should be increased to 48 hours and then to 72 hours. Thereafter, if symptoms are still controlled, the dose per injection should then be reduced. For maintenance therapy, 20 U.S.P. units (or even less) daily to twice weekly may suffice The general principle is to give the smallest dose in the longest interval If the dose needed for full relief pro duces significant side effects it should be reduced and the physician should con tent himself with less than full suppression of the disease being treated In the treatment of acute diseases physicians who have had ecoperience with cortwotropin~-in gelatin preparations should consider the following dosage sug gestions. In view of the fact that this product has an action which is prolonged for at least 24 hours and in most cases for a longer period and its activity is at least as great as that of the gel preparations, the initial dose should be the same as that employed per single dose of the gelatin preparation; however, this dose should be given only once in the 24-hour period, and seldom in more than 60 units. The interval between in)ections should be ecotended to 48 hours and to 72 hours as soon as ecepedient and the dose per injection should then be reduei d as described in the foregoing paragraph When immediate therapeutic results are mandatory as in acute status asth mat'icus it `may be desirable for the physician to administer aqueous corticotroptn initially by the intravenous route and at the same time to give the first dose of this product intramuscularly into the deltoid muscle (This product must not be given intravenously) Once the initial control of the disease have been effected the patient may be satisfactorily maintained intramuscularly. Withdrawal of therapy results temporarily in relative adrenocortical deficiency because the patient's own production of AUTH has been suppressed. Withdrawal should be gradual to prevent a rebound reaction of relative deficiency. It is note- worthy, however, that this period of inactivity is usually shorter than that follow- ing cortisone therapy TNDIOATTONS The indications for this product are the same as those for other corticotropin preparations. In general the following dosage schedules have been employed successfully: In derinotologic disorders (atopic dermatitis schorrheic psoriasis pemphigus vulgaris), dosage has been 40 units every two to four days. Maintenance treat- ment ha's in some cases been achieved with 40 units once a week. In rheumatoid arthritis, dosage in, general has been 40 to 60 units per dajj until control is achieved, then reduced to 20 to 40 units every other day for mainte- nance. It has `been possible in some cases to reduce the dosage even further. In drug sensitivities, dosage has been 20 to 40 units per day until symptoms are controlled. This dosage has also been employed in the treatment of poison ivy. In acute lupus crytivematosus, dosage has averaged 40 to 60 units or more per PAGENO="0063" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3155 daV to ga/in control of the symptoms with ina4ntena~nce treaknent po8sible in 801fl ccises with 20 i~nits every other day. However, mGniy of these pa4ients ha~ve reks~- tiveZy high tiosage requirement$ even durnvg ma~ntenanoe trea~tment anZ ~n these cases the siistained action seems to be partie'ularly benefloia~I to satisfaetory con- troZ of the disease. In bronchio~Z asthma~, inc'uding sta~tus ~sthma~ticus, 60 ~n~its o~ day were reqwt red for controZ and 40 units twwe a week has in some instances provuled sucoessfuT maintenance. In polyarteritis and periarteritis nodosa the ~mtia1 dosage suggested is 40 un~ts per day, maintenance may be achieved with 40 units twice a week. In pulmonary emphysema, initial dosage has been 60 uniits per day, reduced to 20 units per day or every other day for maintenance. These dosages are, of course, only gauges for the physician to follow. As with other corticotropin preparations, either the gel-form or aqueous, the dosage must be adjusted to the needs of the particular patient being treated. Contraindications-The use of corticotropin is contraindicated in Addison's disease. Tuberculosis, active, latent or questionably healed, herpes simplex of the eye and acute psychoses are usually absolute contraindications Peptic ulcei psychotic tendencies diverticulitis fresh intestinal anastomoses thromboembolic tendencies local or systemic infections including fungal and exanthematous diseases osteoporposis renal insufficiency congestive heart failure and pregnancy (except in severe disease) are relative contrainthcations This product shotild not be used in patients with a history of previous reac- tions to any form of corticotropin or who are known to be allergic to products of porcine origin. Precautions and Side Effects-This product functions by stimulating the pro- duction of steroid hormones by the adrenal cortices, and in this manner in- fluences protein and carbohydrate metabolism. It also alters the metabolism of electrolytes with retention of sodium and excretion of potassium should sodwni retention and edema occur this may be controlled by restricting sodium intake, giving a diuretic or by temporarily discontiuing therapy until diuresis occurs If potassium deficiency with muscular weakness occurs supplemental potassium should be given 1 Gm potassium citrate or chloride orally three times a day Periodic determinations of serum potassium during prolonged therapjj is advised. In this same manner the steroid hormones of the adrenal cortices induce atrophy of the thymus and produce an increase in antihyalu.ronidase activity. Because the action of this product is enhanced and prolonged as compared with other corti- cotropin preparations, the possibility of overdosage symptoms must be borne in mind. Oorticotropin will produce the same type of side effects as corticosteroids and these include: Ol4shing-like syndrome, purpura or petechiae, electrolyte mi- balance insomnia osteoporosis spontaneous fractures peptic ulcer euphoria psychic disturbances menstrual irregularities weight changes hyperglycemia hypertension edema bloating or gastric distress aseptic necrosis of the hip protein depletion pancreatitis increased intracranial pressure convulsions and hirsutism Vascular changes such as polyarteritis nodosa or an increased tendency for thrombophlebitis have been reported The incidence type and severity of un toward reactions is usually related to `the size of the dose and duration of therapy. For example prolonged use of corticotropin may also cause growth suppression (reversible on withdrawal) in children, delayed wound healing, or posterior subcapsular cataracts in adults. Susceptible individuals may become sensitived to traces of protein that ac- company corticotropin so that subsequent injections given after intervals of several days may give rise to hypersensitivity pheno~nena ranging from mi~ld urticaria to anaphylactic shock. The first sign of developing hypersensitivity may be localized itching or wheal formation at the injection site This product should not be used in patients with a history of previous reactions to any form of corticotropin or who are known to be allergic to products of porcine origin. It may be used as adjuvant therapy in certain infectious diseases providing such infections are adequately controlled by appropriate antibiotics or chemo- therapeutic agents. It must be remembered that the anti-inflammatory effects 0) corticotropin may mask signs of infection and such patients should be care- fully observed. While average doses will usually not increase insulin require- ments in controlled diabetics, when the drug is used in such patients, they should be observed closely for evidences of increased hyperglycemia or glycosuria. Pe- riodic determinations of blood sugar during prolonged therapy is advised. PAGENO="0064" 3156 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Packages-This product should be refrigerated. Available in 5-cc vials con- taming 40 U S P units of corticotropin (ACTII) per cc Caution Federal law prohibits dispensing without prescription IIEXADROL Decoa~methasone Organon Description and Action-Hexadrol (dexamethasone Organon') is an analogue of prediusolone Its spectrum of anti inflammatory activity is similar to other corticosteroids but it is clinically effective in much lower doses Chemically it is 9 alpha fluoro 16 alpha methyl prednisolone Indications-It may be used singly or as ad)uvant therapy in a wide variety of clinical states known to be responsive to steroid therapy Such conditions include rheumatic and other collagen diseases hypersensitivity sthtes certain inflammatory eye diseases, blood dyscrasias, certain neoplastic diseases, and other miscellaneous disorders. Contraindications-Tubercuiesis, active, 1atei~t o~r questionably `healed, herpes simplex of the eye and acute psychosis are usually absolute contraindications. Peptic ulcer psychotic tendencies diverticulitis fresh intestinal anastomoses thromboembolic tendencies local or systemic Infections including fungal and exanthematous diseases osteoporosis renal insufficiency are relative contraiuth cations Corticosteroids have produced teratogenic effects in animal fetuses and for this reason dexainethasone should not be used in pregnant women except in severe disease In the event that corticosteroids must be used in pregnant women newborn infants should be carefully observed for possible postnatal hype adrenalism Precautions and Side Effects-All corticosteroids, including clexamethasone, produce the same type of side effects and these include: Cu~hing-iike syndrome, purpura or petechiae, electrolyte imbalance, Insomnia, osteoporosis, spontaneous fractures negative nitrogen balance peptic ulcer euphoria psychic disturbances menstrual irregularities weight changes hyperglycemia hypertension edema bloating or gastric distress, aseptic necrosis of the hip or humerus and mr sutism Vascular changes such as polyarteritis nodosa or an increased tendency for thrombophlebitis have been reported Ulcerative esophagitis and acute pan creatitis have occurred during and may be related to corticosteroid therapy Some conticosteroids such as the fluoro analogues of prednisolone appear to exert a relatively greater muscle wasting effect The incidence type and severity of untoward reactions is usually related to the size of the dose and duration of therapy For example prolonged use of corticosteroids may also cause growt1~ suppression (reversible on withdrawal) in children, delayed wound healing, or posterior subcapsular cataracts in adults Because of the greatly enhanced anti inflammatory activity of clexamethasone lower doses can be used thus preventing or mimnuzing abnormal salt and water retention or potassium loss Periodic serum potassium determ~inations are advised during prolonged therapy It may be used as adjuvant therapy in cectain infectious diseases providing such infections are adequately controlled by appropriate antibiotics or chemo therapeutic agents It must be remembered that the anti inflammatory effects of corticosteroids may mask signs of infection and such patients should be carefully observed While average doses will usually not increase insulin requirements in controlled diabetics when the drug is used in such patients they should be ob served closely for evidences of increased hyperglycemia or glycosuria Pen odrn determinations of blood sugar during prolonged therapy are advised It is safest to assume that prolonged therapy will result in depression of adrenocortical function For this reason the drug should be withdrawn gradually when treatment is to be discontinued. It may be advisable to administer ACT II during this period to hasten the return of normal function should the patient be subjected to surgery severe trauma or shock within one year following with drawal it may be advisable to give a temporary course of corticosteroid therapy Deccamethasone is not the drug of choice in adrenal insufficiency Dosage-Rheumatoid Arthi itis It will effectively suppress the inflammatory reaction seen in rheumatic disorders generally within 24-~8 hours Improvement is characterized by relief of pain decrease in redness pain swelling stiffness and a sense of well being S'o predictable is the response of this disorder to steroid theraphy assuming adequate dosage that if no response is noted within seven days the diagnosis should be questioned In general an initial daily dose of 1.5 to 3.0 mg. will produce a good clinical response although a few patients may require more. The effective minimal main- PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRTJG INDUS~1tY 3157 tenance dose should then be determ%ned /or each patient and this will usitctlly range between O?/~ and 14 my, per day. Dosage titrati'on is ea.~ily accomplished by decreasing the datty dose by 0.~5 my. or ().3'Y5 mg'. every three dtiy~ or ~o. ~the use of a single dall~j dose may prove effective ~n certain pdtients and may be worthy of triat initially. however, if the response is not satisfactory the daily drug requiremont should then be given in divided dosqs. Because of the spontaneous rem4isions seen in this disease it may be advisable from ti'me to time to discontinue thertipy to evaluate this point, particularly in patients whose daity drug requirements a?e low. It should be emphastzed that this agent is most effectiv~e when used in conjunction with other standard meas- ures such as rest, physiotherapy, orthopedic ~orreotions, etc. Acute 1i~heumatic Fever-It can be ecopected to ecoert t4e same type and 4~gree of beneficial effects ij,oted wit/v other coi~tioostqroids in the treatnient Qf this disease. TJsvl4ke ea~i~ier ccirticosteroidus, it has the added advantage tMt salt and water retention are rarely observed, at least at the tower dosage levels. The true rote of these agents in preventing ~alvular damage has yet to be determined. High doses are usuatly required to bring this disease under control and initially these may range from ~/4 to 10 my. da~ty. As symptoms improves dosage should be decreased gradually until a satisfactory maintenance level is r~qched. Jlyperivnsitiivity ~tates-Alteryic diseases such as bronchial asthma, angion~ enrotic edema, allergic dermaloses, allergic purpara, certain drug reactions, transfusion reactions,. etc. constitute another group of .~hsorders responsive to corticosteroid theretvpy. In general a single daily dose will usually provide ade- quate symptOmatic control. Sufficiently high doses should be given~ initially to provide relief and these may rctnge from 3~0 to 13.0mg. per day. When long-term therapy is required, the effective minimal dose should be determined for each potient by gradually reducing dosage by 01f?~5 my, to 047$ my. every second or third day. For relatively minor conditions such as intractable hay fever or allergic rhinitis, the use of this agent may usually be discontinued after 10 to 14 days. Standard antialleryic therapy should be tried initially with oortieosteroid supple- nientation only if required. Inflammatory Eye Diseases-Ocular diseases which are known to respond to such therapy include: iritis, iridocyclitis, ureilis, choroiditis and choriorclinitis. In iritis or iridocyclitis topical treatment should be tried before restoring to systemic use. The drug is contraindicated in herpes simptew and herpes keralitis. Beginning doses range from 3.0 to 6.0 my. per day. When symptoms are satis- factorilty controlled, dosage should be decreased by 0.50 to Q.75 my. daily until a satisfactory maintenance dose is acivieved. In acute or setr-limited conditions. corticosteroids should be discontinued at the earliest possible moment. Skin Disorders-Dermatitis of the atopic, contact, ecofoliative, or drug reaction types respond rapidly and favorably, a single daity dose usually providing symptomatic relief. Skin diseases of a more serious impact such as pemphigus vulgairis and mycosis fungoides may also resØond to corticosteroid therapy. The skin lesions associated with collaren diseases such as lupus entimatosus, sclero- derma, and clermatomysitis do not require treatment but may respond favorably to courses of corticosteroid therapy b'eing given for the underlying disease. Dosage requirements for these various skin disorders should be based on the degree of involvement and severity of the underlying disease. Minor afilictions require therapy for a fen) days or `u~eeks at most while the more serious ones may drunand continuous treatment. In general mit/hal doses ran~7e from ~.0 to 6.0 my. per day with gradual reductions down tO a satisf actor/I maintenance level. Higher daily drug requirements should be given in divided doses. Dosage recommendations for the treatment of pemphiyus, scieroderma, and mycosis fungoides vary considerably and the interested phjjsician is advised to consult the latest literature for suggested therapeutic regimens. Adrenogenital Syndrome-It will effectively suppress adrenocortical hyper- secretion with. prompt decreases in urinary 17-ketosteroid levels. Optimal main- tenance doses must be determined for each individual as reflected by continua- tion of normal urinary 17-ketosteroid levels. A dose of 0.75 to 1.5 my. daily will usually provide the desired effect. Bursitis-Soft tissue inflammations such as bursitis, synovitis, and len- osynovitis will respond favorably to corticosteroids. Initial daily doses of 1.5 to 3.0 my. will provide a rather prompt and satisfactory result and short courses of therapy usually suffice. The majority of patients will respond satisfactorily to a single daily dose. 81-280-68-pt. 8-5 PAGENO="0066" 3158 COMPETITIVE PROBLEMS IN T~ffE DRUG INDUSTRT Miscellaneous Diseases-The anti-infiç~mmatory corticosteroids may provide a medsure of relief in, certain other dis&&ses such as: pulmonary fibrosis, pul- monary emphysema, lupus c thematb~ius, nephrosis, ulcerative colitis, idiopathic thromboO~jtope~ic purpura, and may provide a temjibrary palliative effect in lymphatic leukentla and lljmphofnas. It is co~iraindicated in metastatie car- cino~na. Dosage requirements for th~ above indications thust be individualized since most of these diseases have a serious, if not greater prognosis, and vigorous therepy may be justified. The use of high ~1~ose~ will increase the inoidehee of undesirable side effects. If the risk is accepted, the patient must be carefully o~erved for their Occurre~c~and trea~ted'accot'dingiy., As with all potent' drng~ the dosa~ of 4~OrticosterQ1dssholild be Individualized. The' best dose is the s~naflcst dose 4~hioh `wijl p~'o~tuce adequate but not neces- sarily eomp~ete relief Of s~ympto~,ns, H~kjher do~es or protonged periods of thcr~apy lend to produce/an' increased ~icidenoe of side effects and this risk must be balanCed against antiCipated benefits in every' instances. Where large doses are required the patient should be `carefully ieat&iCd for the appearance of the classical signs of overdOsage when it n~ay' b'Scosie necessary to decrease the dose or stop therapy. Corticostcroids are usually given in divided doses. Clinical studies, however, have convincingly denionstrated that a singte daily dose is effective for the majorit~j of `patients suffering from hypersensitivity states, demratoses, barsitis or other mild connective tissue diseases, etc. While the response has been tess striking in rheumatod arthritis the inoidence of effective control is sufficiently hit/h to make `this regitnen worthy of trial. E~1ingle doses are best gi'ven in the morning unle,~s clinical reasons dictate an evening dose. It is advisable, `when discontinuing cortioosteroid therapy, to reduce dosage gradually and not abruptly. The administration of ACT II during the With- drawal period may help, to accelerate the return of normal adrcnocortical function. Patients currently being treated wIth other corticosteriods may be transferred conveniently to this `ägént using the following dosage ecpiivalents: 0.75 dexamethasone equivalent to: 25 mg. cortisone. 20 mg. hycirocortisone 5 rag. prednisorie or prednisolone. * 4 rag. methyl~rednisolone 4 mg. trianicinOlone. Caution: Federal law prohibits dispe~ising without)~rescription. Supplied: 0.50 mg. tablets (yellow, scored), bottles of ~0 and 500. 0.75 mg. tablets (white, scored), bottles of 100 and 500. 1.5 rag, tablets (peach, scored), bottles of'50. 0.50 mg./5 ml. elixir (alcohol 5%), bottles of 120 ml. H~XADR'OL® P1IOS1~EATE INJECTION (Dexamethasone Sodium Phosphate, N.F.) Description-Hexadrol phosphate injection (dexamethasone sodium phosphate N.F.) is a water-soluble inorganic ester of dexamethasone which produces a rapid reeponse even when injected intramuscularly. Chemically it is 9-alpha-fluoro, 1l- alpha-methyl prednisolone 21-phosphate. Each cubic centimeter contains: Dexamethasone sodium phosphate, N.F. , 4.0mg. Sodium Bisuiphite U.S.P. 8.5 mg. Sodium Citrate U.S.P. - 10.0 mg. Sodium Chloride U.S.P. 3.2 mg. Disodium ethylene diamine tetra-acetate 0.1 mg. Methylparaben tJ.S.P. 0.85 mg. Propylparaben U.S.P. . 0.15 rag. Sodium hydroxide U.S.P. q.s. to pH 7.7. Water for Injection U.S.P. q.s. 1.0 cc. Action and Uses-Dexamethasone sodium phosphate N.F. exhibits the intrinsic properties and hormonal effects of the parent substance and other corticosteroicis. When administered intravenously, intramuscularly, intrasynovially or locally it PAGENO="0067" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 3159 is an effective anti-inflammatory and anti-allergic agent. Because it is highly solu- ble, speed of absorption following intramuscular injection is almost as rapid as that following intravenous injection. Since this pro~uet is intended for emergency, abort-term or local therapy the pronounced hormon~il. effects associated with long-term therapy usually will not be seen. It is. important, however, to watch ~for any untoward effect when ad- ministering ~ potent. agent such as this. Local injections of therapeutic doses into joints or soft tissues ire usually well-tolerated and significant systemic hormonal effects are unlikely if injections are few in number or are given at in- frequent intervals, When this, product is given intravenously or intramuscularly it is useful in the following conditions: 1. Hypersensitivity reactions such as: (a) Anaphylactic reactions (b).Drug reactions (e) Status asthmaticus (d) Transfusiqu reactions (c) Severe urticaria (f) Laryngeal edema (g) Acute derinatosea (b) Severe reaction to insect `bites 2. Acute or relative adrenal insufficiency: (a) Medical (b) Surgical (c) Jatrogenic 3. Shock not responding to conventional therapy. 4. Overwhelming infactions with severe toxicity. 5. To initiate therapy in: (a) Acute rheumatic fever (b) Acute dissem~nated lupus erythematosus. (c) Acute gout In treating anapbylactic shock or other severe allergic reactions nonepinephrine or epinephrine should be used initial~y together with other accepted procedures; This may be followed by the parenteral administration of this corticoid to provide' a more prolonged effect. Patients who have received prolonged corticoid therapy may develop a state of relative adrenal insufficiency which may persist for a year or more following cessation of therapy. If such patients suffer sudden stress such as trauma, shock, surgery, overwhelming sepsis etc., reinstitution of corticoid therapy during this period may be indicated. This product may be employed for emergency use in these patients. However, because dexametbasone sodium phosphate N.F. lacks significant mineralocorticoid activity supplemental therapy with salt and a salt- retaining steroid such as desoxycorticosterone is required when it is used for the treatment of adrenal insufficiency. Because of the supplemental therapy required, dexaznethasone is not the drug of choice in the treatment of adrenal insufficiency. It may prove lifesaving in critically ill patients suffering from severe over- whelming infections for which specific antibiotic therapy is available. It may permit survival until the anti'biotic has had time to take effect. Since corticoids mask the classical signs of infection `their use in such cases must be undertaken with the greatest caution. Bacteriological studies and adequate antibiotic therapy must be started before the first dose of this corticoid and its use should be dis- continued as soon as possible and at least 3 days before antibiotic therapy is stopped. Surgical infections requiring corrective surgery should be performed as soon as possible. Olinical improvement following steroid therapy is not an indication to postpone surgery. Increased doses of antibiotic may be indicated while the steroid is being given. When given intrasynovially or locally Into soft tissue sites this product may provide relief of symptoms in: (a) Rheumatoid arthritis. (b) Acute gouty arthritis. (c) Traumatic arthritis. (d) Osteoarthritis. (c) Bursitis. (f) Fibrositis. (g) Strains and sprains. (h) Ganglia. PAGENO="0068" 3160 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (1) Tendinitis. (j) Localized myositis (k) ileloma. Contraindieations-T'uberculosis, active, latent or questionably healed, herpes simDlex of the eye and acute psychosis are usually absolute ecuitraindleations. Infectious arthritis is also an absolute con~ra1nd1catien to hitra-articalar Injec- tion. Peptic ulcer, *psç~cliotic tendOncies, divertieulitis~ fresh Intestinal anas- tomoses, thromboembolie tendeneies~ local or syntemic InfecHorls Including fungal and exanthematous diseases, osteoporosis, renal insilffieiency are reIatFt~e ton- traindications. Corticosteroids have produced teratogenic effects in an1~ial fetuses and for this reason .dexaniethasone sholild not be used in pregnant ~othen ex- cept in severe disease. In the event that corticosteroids must be used hi pr'~gflant women newborn infants should be carefully observed for possible postnatai bypo- adrenalism. Precautions and Side Effeets-Hexadrol phosphate injection (deuamethasone sodium phosphate N.F.) is usually given for short periods of time and the known signs of corticoid overdosage are rarely seen. The appearance and nature of un- toward effects depends largely on dosage, duration of treatment, and route of administration. Faintness, weakness, nausea, dyspnea, weight gain, increased ap- petite and mental stimulation have been reported as immediate or short-term side effects following its parenteral use. Untoward systemic hormonal effects from the intrasynovial or soft tissue injection of this agent are not ahticlpated when In- jections are few in number or are given at infrequent intervals~ All corticosteroids, including dexamethasone, produce the same type of side effects and these include: Cushing-like syndrome, purpura or petecblae, electro- lyte imbalance, insomnia, osteoporosis, spontaneous fractures, negative nitrogen balance, peptic ulcer, euphoria, psychic disturbances, menstrual Irregularities, weight changes, hyperglycemia, hypertension, edema, bloating or gastric distress, aseptic necrosis of the hip, and hirsutism. Vascular changes such as polyarteritis nodosa or an increased tendency for thrombophiebitis have been reported. Ul- cerative esophagitis and acute pancreatitis have occurred during, and may be related to, corticosteroid therapy. $o~ine corticosteroicis swch as thc~ fluoro ana- logues of prednislone appear to ewert a reiativelp greater muscle wasting effect. The incidence, t~pe and severity of untoward reactions is usually related to the size of the dose and duration of therapy. For example, prolonged use of corticost- eroids may also cause growth suppression (reve'rsible on withdrawal) in child~cen, delayed wound healing, or posterior subcapsular cataracts hi adults. Because of the greatly enhanced anti-inflammatory activity of dexamethasone, lower doses can be used thus preventing or minimizing abnormal salt and water retention or potassium loss, Periodic serum potassium determinations are advised during pro- longed therapy It may be used as adjuivant therapy in certain, infectious diseases providing such infections are adequately controlled by appropriate antibiotics or chemo- therapeutic agents. It must be remembered that the anti-inflammatory effects of corticosteroids may maSk signs of infection and such patients should be carefully observed. While average doses will usually not increase insulin requirements in controlled diabetics, when the drug is used in such patients, they should be ob- served closely for evide4nces of increased hyperglycemia or glycosuria. Periodic dctermincntioas of blood sugar during prolonged therapy are advised. Post-injection flare-up of foint pain may sometimes be seen following intra- articular injection. Instability of a joint followiag repeated intra-articular in- jeetions is a rare occurrence. It is safest to assume that prolonged therapy will result in depression of adren- oeortica~l function. For this reason the drug should be with drawn gradually when treatment is to be discontinued. It may be advisable to administer AUTH during this period to hasten the return of normal function. should the patient be sub- jected to surgery, severe trauma, or shock within one year following withdrawal it may be advisable to give a temporary course of corticosteroid therapy. If this product is employed, supplementary salt and/or desoxycorticosterone should be used. Because of supplemental therapy requireçt~ dewamethasone is not the drug of choice in adrenal insufficiency. Dosage-The dose for intramuscular or intra\rënous administration varies from 4 to 20 mg, depending on the nature and severity of the disease being treated. Intravenous doses exceeding 8 mg. (2cc) should be given slowly over a period of one minute. The initial dose may be repeated as necessary until the desired re- sponse is noted but the daily dose, with few exceptions, need not exceed 80 my. PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3161 Maintenance doses average 2 to 4 mg. daily. Alter achieving satisfactory control the patient should be switched to oral therapy as soon as feasible. The dose for intrasynovial administration is usually 4 mg. for large joints and 0.8 to I mg. for small joints. For soft tissue and bursal injections a dose of 2 to 4 my, is recommended. Ganglia require a dose of 1 to 2 my. A dose of 0.4 to 1 my is used for injection into tendon sheaths and helomata. Injections into inter-verte- bral joints should not be attempted at any time and hip joint injection cannot be recommended as an office procedure. Intrasynovial and soft tissue injections should be employed only when affected areas are limited to 1 or 2 sit ç~s. It should be remembered that corticoids provide palliation only and that other conventional or curative methods of therapy should be employed when indicated. $upplied-5-co (4 mg/cc) multiple dose vial; 1-cc (4 mg/cc) vial, boa~ of 25. LAKESJDE L~noR~ToaIEs, Milwaukee, Wis., November 1967. DuAR Dooxon: The Food and Drug Administration have requested that we call your attention to the monograph for Norpramin (desipramine hydrochloride) in the 1967 P1111: page 687, white section, The FDA consider this monograph in- complete (in relation to the official labeling, the package insert), and therefore potentially misleading as prescribing ipiormation to allow safe and effective use of the drug. To provide you with the necessary adequate reference, we enclose a revised monograph for 1967 Pbysi~ians' Desk Reference in which the changes have been emphasized by italics. Please insert this revision opposite page 687. Sincerely yours, WILLIAM 0. JANSSEN, M.D. (Insert opposite p. 687-PDR, 1967 edition) (NoTE-Prescribing information for Norpramin which appears in the 1967 edition of PDR has been revised. The following is the new monograph and com- pletely replaces the old one. Changes are emphasized by means of italics.) NORPEAMIN (Desipratnine hydrochloride) Composition: Norpramin (desipramine hydrochloride) (10, 11-dihydro-5-(3'. methylamlnopropyl)-SH-dibenz [b, fj azepine hydrochloride), available in twa dosage sizes: 25 mg. tablet, round, sugar coated, yellow; 50 mg. tablet, round, sugar coated, light grOen. Action and Indications: Norpramin (desipramlne hydrochloride) is a primary active metabolite of imipramine. It differs from earlier antidepressants in its rapid onset of action. Approximately 60 to 70% of patients with neurotic or psychotic depressions will respond satisfactorily. More than half will begin to improve In 2-S days, others within a wek. Usually, patients not responding within one week are less likely to improve. Narpramin is useful in the treatment of neurotic and psychotic depressive reactions, and in manic depressive or in- volutional psychotic reactions. It may be used as co-therapy with tranquilizers in the treatment of markedly agitated forms of repressions. Oontraindications: (1) Norpramin should not be given in conjunction with or within two weeks of treatment with a monoamine oxidase inhibitor. (2) Be- cause of its physiologic effects (both anticholinergic and eplnephrine potentiat- ing), it is contraindicated in patients with glaucoma, urethral or ureteral spasm and recent myocardial infarction. (3) The presence of severe coronary heart disease with EKG abnormalities indicating a progressive disahiliity and symptoms of heart fa'ilu're due to this disability is likewise a contraindication. (4) Active epilepsy as it lowei~s the threshold for epileptiform seizures. Warnings (Relative c'ontraindioatlons) : Pa7pit at ions, due to taehyeardia, have been observed with desipramine hydrochloride therapy. Desipramine hydro- chloride should be given therefore to patients with a history of parenysma.l tachy- eardia only with awareness that palpitations may be induced. In some such pa- tients, the myocardison may not be in condition to tolerate well the increased work and decreased perfusion incident to such parowysms. PAGENO="0070" 3162 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY In two instances transient jaundice, probably analogou,~i to that ,s~een previously with ehlorproma~ine and (infrequently) with lmipranlinc, has been noted; liver function studies in suspect cases, prior to and during prolonged desipramine hydrochloride therapy are thus advised. In patients suspected of having glaucoma or urinary or gastric retention, the antiehoiinergic nature of the drug may be deleterious. Patients receiving thyroid hormone, or sympathornirnetic drugs may ecvperience potentiation of the effects of these drugs, resulting i'i'i, behavioral and/or eardio~ vascular toa,icity. Patients receiving dcsipramn'ine h~jdrochloride and anticholiner- gic drugs simultaneously are known to ewperience enhanced atropine-like side effects. Animal teratology studies have proved negative. However, the drug is new and there is little clinical informatiofl about its use during preçjnaney. Uonsidercttion of the possible risks relative to benefits should guide the decision to use Norpramin (desipramine hydrochloride) in women i&ho are pregnant or who may be an- ticipated to become. so. Precautions: (1) Norpramin treatment should not be substituted for hospi- talization or restraint if the risk of homicide or suici~e is considered grave. (2) In patients with manic depreSsive illness, Norpratnin may induce a hypo- manic state after the depressive phase terlnLnates. (3) As with any drug, death may ensue from the suicidal ingestio~i of large dosei of t~Zesipra~m4ne hydro- chloride. (4) Discontinue therapy prior to elective surgery. (5) Use with caution in patients receiving sympathomimetic thugs or thyroid hormone as potentiation of the action of these drugs may occur. (6) Reduce dosage, or alter treatment, if serious adverse elf cuts occur. Adverse Effects: Undesired side effects in the desipramine hydrochlOride treated patients were usually well tolerated; o*ly oecasionall~j did therapy have to be discontinued because of them. The side effects of desipramine hydroOhioride were considered to be ~~imi2ar to those of imipramine; in general, these can be expected in about one of four patients. The following side effects have been encountered: dry mouth, constipation, dizziness, palpitation, delayed urination, agitation and stinpilation ("jumpiness", "nervousness", "ancsiety", "insomnia"), `bad taste, sensory illusiop, tinnitus, sweating, drowsiness, headache, hypotension (ôrthostatic), flushing, nausea, cramps, weakness, blurred vision anlt myiriasis, rash, tremor, allergy (general), altered liver function, ataxia and extrapyramidal signs, agrariulocytosis. Additional side effects more recentty reported include: seizures, eosinophilia, confusional states with hallucinations, purpura, phQtQsensitivity, galaetorrhea, gynecom astia, and impotence. side effects which could occur (analogy to related drugs) include weight pain, hearburn, anore~.ia, and hand and arm parasthe~ias. Dosage and Administration: Qptin~a1 results are obtained at about 150 mg./day. Dosage over 200-225 mg./day in~~eases incidence of :side effects~ Norpramin may be administered as follows: two tablets (50 ing.) t.i.d. (150xng./day). Partial response may be expected within 2-5 days; optimal response within 2-3 weeks. After optimal results are achieved a maintenance dose . . . 50-100 mg./day - should be sought. An alternate method of giving Norpramin (desipramine hydrochloride) which may, however, delay the rapid onset of therapeutic respones is: One tablet (25 mg.) three or four times a day= 75 or 100 mg. with a 25 mg. increment every few days, if needed, to a macoimum dose of 200 mg. per day. Overdosage: (1) Prevention: Keep out of reach of children. (2) Treatment: Gastric lavage, catharsis. For coma and circulatory collapse: adequate fluids, oxygen, assisted respiration, assisted cardiac impulse. Do not hesitate to digi- talize. Use sympathomimetic dru s with caution. For seizures: parenteral bar- biturates or diphenylhydantoin (note: diphenylhydantoin, though having an antiarrhythmic effect, has not be n fully defined in respect of its effect on the heart or its rhythm.) Blood dialysis is of little avail; continuous gastric lavage has been advocated on the basis of desipramine resecre ion in gastric juice. Supplied: Norpramin (desipra inc hydrochloride) tablets of 25 mg., in bottles of 50, 500, and 1000; and tablets f 50 mg., in bottles of 30, 250, and 1000. PAGENO="0071" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3163 THE S. E. 1V.LASSENGILL Co., Bristei, Teltn., November 1, 1967. DEAR Docron: 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 Itef ereiace. 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 misleading. To provide you with the necessary information, we enclose revised monographs for insertion at page 812 of your current (1~67) PDR. The nature and extent of the additions and other revisions in the enclosed monographs are emphasized by use of italics. Sincerely, ROBERt P. Ewixo, Vice President, Marketing. PROFESSIONAL PRODUCTS INFORMATION (P. 812) PREDSEM Composition: Each multiple-compressed white tablet contains: Prednisone 50 mg. Calcium pantothenate 10 mg. Aluminum hydroxide gel, dried 0.2 Gm. Magnesium trisincate 0.1 Gm. Prescribing information for Predsem which appears on page 812 of the 1967 PHySICIAN'y DE$K REPERENUE has been revised and is completely replaced by the following. The nature and e~stent of. the additions and other revisions in the monograph are emphasized by use of italics. Action and uses: For the treatment of the acute phase of rheumatoid ~rtbriti$ and related diesases. Also of value in other conditions in Wh~c1L corticosteroid theraphy is indicated. Antacids are incorporated to reduce ga~tric distress caused by hyperacidity in relation to steroid therapy. Contraindications: Tuberculosis (active or latent), chronic nephritis, acute psy- chosis, Cushing's syndrome, peptic ulcer and in patients prone to thrombophle- bitis. Herpes simpler' of the eye is usually an absolute contraindication. The ap- pearance of ocular herpes simplca in patients receiving adrenocortical~ steroids systernica fly, or locally in the eye for other conditions, has been reported. If this occurs, Predsem Tablet should be discontinued unless the need for them is greater than the risk to the function of the eye. Relative Contraindications: As in the case of other powerful therapeutic agents, the physician must weigh the advantages of treatment with prednisone against the possible harmful effects. In cosgestive heart failure, hypertension, diabetes, frank osteoporosis associated with senility or with rheumatoid arthritis, renal insufficiency, history of peptic ulcer and mental diesase. Predsem must be administered with caution. In patients with diabetes millitus being treated for a concurrent disease amen- able to therapy with Predsem Tablets, the hyperglycemia may be aggravated; therefore, the diabetic status must be followed and regulated with great care. Usually it is possible to control the diabetes by increaSing the insulin dosage. While euphoria is the usual psychic reaction to large doses of prednisone, occassionally pronounced psychic derangements may appear. Early symptoms in- clude insomnia, swings in mood and increased psychomotor activity. Precautions: Corticosteroids should be used with caution in congestive heart failure, diabetes, renal insufficiency, history of peptic ulcer and mental disease. Predsem can mask infections by interfering with elevation of temperature, etc. If there is any question, drug should be temporarily discontinued until accurate diagnosis is made. May be reinstituted as soon as adequate measures have been taken to treat the infection. special Precautions: Furthermore, because edema and weight gain from pred- nisone are extremely infrequent, the physician must be especially on h is guard to ~7etcct less conspicuous si~'c effects. PAGENO="0072" 3164 COMPETITIVE P~O~3LEMS IN THE DRUG INDUSTJ~Y Management of Patient Dur~g $tress: Prednisone in large doses may produce adrenal atrQphy. The physician should assume the continued therapy with pred- nisone, similar to theraphy with cortisone and hydrocortisones, will result in some depression of adrenocortical function. It may be advisable to institute rest periods and to stimulate adrenocortiea,l function by the use of AUTH. If, after long-term therapy, the drug is to be stopped, it is recommended that it be with- drawn gradually rather than abruptly. However, a potentially critical degree of adrenal insu,fftcieneiy may still persist, and for at least .si~v nwnths hydrocortisone in increased dosage proportionately much larger than the previously used predni- sone should be ad'rnlnistered If the patient Is subjected to shock or significant stress such as surgery or trauma. Also, if a patient is subject to unusual stress, during predn'isone therapy it should be continued usually in markedly inoreased dosage at least for the duration of the stress and immediately following it. S1uperv'isiorn of Patient Following Prednisone Therapy: Continued supervision of the pa*ien~t after discontinuation, of prednisone is essential because there may be a. reappearance of severe manifestations of the disease for which the patient was treated. Clinical Effects: In rheumatoid arthritis initial benefit from prednisone has usually been seen in a day or two, diminution in subjective distress occurring promptly. The appetite improves rapidly, energy reappears, and a feeling of well- being develops. Objective conditiens, such as joint Involvements and pain on motion, recede gradually. The eo,tent of return to normal is limited by the degree of irreversible pathological change~ prese~it. Elevated sedimentation rates are decreased usually with q drop to or near nor- mal. Low hematocrit and hemoglobin values tend to increase when prednisone is administered. Discontinuance of therapy usually results in a return of symptoms in a few days. Dosage and Administration: The suggested suppressive dosage for severe rheu- matoid arthritis is 30 my. (sIrS my. tyblets) per day. In less nevere cases? 20 my. (four 5 my. tablets) per day `will generally suffice. The suppressive dosage .shoyld be continued untIl a gQod response is noted. This will usually be three or four days, but this dosage may, if necessary, be continued for a~ long as seven days. If no response is noted within seven days, consideration should be given to the question of whether or not the disease under treatment is true rheumatoid arthritIs. Maintenan,ce: Gradual retluction in dosaye every 5 to 6 days by steps of 5 my. (5 to 20 my. daily provides adeçiuate maintenance therapy for many patients). flow Supplied: In bottles of 30, 100 and 1,000 multiple-compressed mono- grammed white tablets. SALOORT Composition: Each pink tablet contains: Cortisone acetate. 2.5 mg. Sodium salicylate O~3 Gin. Aluminum hydroxide gel, dried 0.12 Gm. Calcium ascorbate 60 mg. (equivalent to 50 mg. ascorbic acid) Calcium carbonate 60 mg. Prescribing information for Salcort which appears on page 812 of the 1967 PHY- ASICIANS' DE$K REFERENCE has been revised and is completely replaced by the following. The nature and ectent of the additions and other revisions in the monograph are emphasized by use of italics. Action and Uses: Salcort is indicated in common rhetumatic disorders and as a means of adjusting corticosteroid dosages In treating chronic cases of rbeu- fatic disease. The complementary corticosteroid-salicylate supplemented with vitamin C) provides effective cortioosteroid therapy for a wid range of common rheumatic disorders with minimum risk of undesirable side effects. Salcort is of particular value for patients not responding to salicylates alone and with those in whom a larger does of corticosteroid is neither necessary nor advisable. Administration and Dosage: Maintenance dosage may require from 6 to 8 tablets to a's little as 3 or 4 tablets daily, depending on severity of symptoms. Acute stages may require a high dosage of 4 tablets four times daily for two or three days, or until the acute episode subsides. PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3165 Contraindications: Tuberculosis (active or latent), chronic nephritis, acute psychosis, Oushing's syndrome, peptic ulcer and in patients prone to throm- bophk~bitis. Relative Contraindications: In oongestivC heart failure, hypertension, diabetes, frank, osteoporosis associated with senility or with rheumatoid arthritis, and mental disease other than acute psychosis, Salvort must be administered with caution. Precautions: Coreticosteroids should be used with caution in congestive heart failure, diabetes, renal insufficiency, history of peptic ulcer and mental disease. Saicort will mask infections by interfering with elevation of temperature, etc. If there is any question, drug should be temporarily discontinued until accurate diagnosis is made. May be reinstituted as soou as adequate measures have been taken to treat the infection. Cortisone is a potent hormonal substance. Alt hough the greater anti-rheumatic action of cortisone is not accompanied by an increased tendency to produce unde- sired hormonal effects, patients receiving it should be observed for the possible development of any signs of such eacessive hormonal manifestation, Daily weighing of the patient and, as indicated, measurement of fluid intake and output should be alone to detect early evidence of fluid retention. Restriction of the daily sodium intake to 2 Gm. or less may prevent or correct fluid retention, If salt and water retention occur, sodium intake shouid be further restricted and the dosage of cortisone redu~ccd or discontinued. In the presence of hypopotassemia, as detected by blood potassium determina- tions, characteristic changes in the electrocardiogram, aind muscu~ar weakness, the dietary potassium intake should be supplemented with 2 to 4 Gm. of potassium chloride daily and the dosage of cortisone reduced or discontinued. Hyperglycemia and glycosuria `may occur in nondiabetic individuals receiving cortisone. In patients with diabetes mellitus, the insulin requirements are increased. While euphoria is the usual psychic reaction to cortisone, occasionally pro- nounced psychic derangements may appear. Early symptoms include marked in- somnia, swings in mood and increased psychomotor activity. $ince the use of cortisone tends to depress the normal pituitary-adrenocortical mechanism, the patient should be carefully supervised not only during but fob towing therapy, and treatment should be discontinued gradually. The occyrrence of any unea~pected stress, such as surgery, severe infections, or accidental trauma, during or for at least a year following treatment, is an indication for vigorous adrenocortical supportive therapy with cortisone acetate, or whole adrenocortical ewtracts. Dosage and duration of such therapy is governed by the severity of th~ stress and the patient's clinical status. How Supplied: In bottles of 100 pink monogrammed tablets. Literature Available: On request. SACORT-DEITA Composition: Each multiple-compressed yellow tablet contains: Prednisone 1.0 mg. Potassium salicylate 0.3 Gm. Calcium pantothenate 5.0 lug. Calcium ascorbate 30 mg. (equivalent to 25 ing. abeorbic acid) Aluminum hydroxide gel, dried 0.12 Gm. Calcium carbonate ~O mg. Prescribing information for Salcort-Delta which appears on page 812 of the 1967 PHYyIUIAN,s' DESK REFERENCE has been revised and Is completely replaced by tflc following. The nature and eatent of the additions and other re- visions in the monograph are emphasized by use of italics. Action and Uses: For the treatment of the subacute, severe phase of rheuma- toid arthritis and related disease. Saicort-Deita, provides a prednisone dosage which is relatively high but may be adjusted to "long-term" therapy. In the sub- acute phase, the prednisone-salicylate combination is more effecth~~ than either agent when used alone. Saicort-Delta includes antacids to guard against gastric distress related to corticosteroid therap~~. Contraindications: l3ecause of their prednisone content, Tdb~ets ElalcOrt-Delta are contraindicated in tuberculosis (active or tatent), chronic nephritis, acute psychosis, Cushing's syndrome, active peptic ulcer, and in patients prone to thrornbophiebit'is. Elalcort-Delta will mask infections by interfering with the PAGENO="0074" 3166 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY elevation of temperature, etc. If there is any question, the drug should be tem- porarily discontinued until an accurate diagnosis is made. It may be reinstated as soon as adequate measures ha've been taken to treat the infection. Herpes simplea, of the eye is usually an absolute contraindication. The appear- ance of ocular herpes siinplea~ in patients receiving adrenocortical steroids syste- mically, or locally in the eye for other conditions, has been reported. If this occurs, &i~lcort-Deita TaMlets should be discontinued unless the need for them is greater than the risk to the function of the eye. Relative Contraindications: As in the ease of other powerful therapeutic agents, the physician must weigh the advantages of treatment with prednisone against the possible harmful effects. In congestive heart failure, hypertension, diabetes, frank osteoporosis associated with senility or with rheumatoid arthritis, renal insufficiency, history of peptic ulcer and mental disease, Salcort-Delta must be administered with caution. In a patient with diabetes mellitus being treated for a concurrent disease amen- able to therapy with Balcort-Delta Tablets, the hyperglycemia may be aggra- vated; therefore, the diabetic status must be followed and regulated with great care. Usually it is possible to control the diabetes by increasing the insulin dosage. While euphoria is the usual psychic reaction to large doses of prednisone, occasionally pronounced psychic derangements may appear. Early symptoms include insomnia, swings in mood and increased psychomotor activity. Precautions: since edema and weight gain due to prednisone are infrequent, the physician must be eapecially watchful for the development of less conspicuous side effects. The use of preduisotve tends to depress the normal pituitary-adre- nocortica~l mechanism and the patient should be carefully supervised, not only during, but following therapy. The dosage should be reduced very gradually, but even then a potentially critical degree of adrenocortieal insufficiency may persist asymptomatically for some time. Therefore, if the patient is subjected to stress, such as surgery or trauma within at least sia niontli s after therapy has been terminated, steroid therapy should be reinstituted. Furthermore, if a patient is subjected to unusual stress while receiving Salcort-Delta Tablets, steroid therapy should be continued for the duration of the stress and immediately following it. in both instances, proportionately much larger dosages of prednisone, cortisone, or hydrocortisone than that of the previously used ~alcort-Deita should be used during the stress. As the prednisone, cortisone, or hydrocortisone is being discontinued, Salcort-Deita may be resumed in the former dosage. After discontinuation of ~1alcort-Delta Tablets, continued supervision of the patient is essential, because there may be sudden reappearance of the disease for which the patient was treated. In administering Salcort-Delta Tablets the possibility of the occurrence of the side effects of salicylates should be borne in mind. Any form of salicylates should be administered with caution to patients with hypop'rothrombinemia and bleeding or with asthma and other allergic conditions. Administration and Dosage: Can be started at 12 tablets daily in divided doses and dose diminished as symptoms subside. How Supplied: In bottles of 100 multiple compressed, monogrammed yellow tablets. THE UPJOHN Co., Kalamazoo. Mich., November 15, 1967. DEAR Doo~'on: The Food and Drug Administration has asked us to call your attention to certain promotional messages for Medrol 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 Physicians' Desk Reference is considered by the FDA to be inadequate in presenting information for the safe and effective use of the product. To provide you with the necessary informa- tion, we enclose a revised monograph for insertion at page 1143 of your current (1967) PDR. Sincerely yours, FENIMORE P. JOHNSON, MD. PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3167 (NoTu.-Prescribing information for Medrol (methyiprednisolone) Tablets which appears on pages 1143-4144 of your 1967 PDR has been revised and is completely replaced by the following.) MEDROL TABLETS (Methyiprednisolone) Composition: Each tablet contains metbyiprednisolone 16 mg., 4 mg or 2 mg. Action and Uses: Medrol is indicated in conditions known to be responsive to corticoid therapy, including: (1) collagen diseases, (2) allergic diseases, (3.) certain dermatological conditions, (4) acute ocular inflammatory disease, (5) certain leukemias and lymphatic neoplastic diseases, (6) ulcerative colitis, nephrosis and as adjunctive therapy in pulmonary and meningeal tuberculosis. Administration and Do~age: The average total daily doses recommended should be given in four equally divided dosages and should be individualized according to the severity, duration and patient's response. The average daily dosage of Medrol is approximately two-thirds (0.7) the required daily dosage of pre- dnisolone. Initial suppressive dosages should be continued for 3 to 7 days during which time satisfactory clinical response is usually obtained. Should there be no satisfactory response within 7 days, re-evaluation of the case to confirm the original diagnosis is indicated. Reduction of dosage to maintenance levels should be accomplished slowly in decrements of not more than 2 mg. at intervals of 7 days when the initial daily dosage isiS mg. or more. (see table below) Adjustment of the dose level is indicated from time to time in concert with fluctuations in the disease activity and patient response. Experience has indi- cated that long-term benefits are greater when steroid maintenance is accom- plished at the lowest possible dose level. Dose levels for protracted use of methyl- prednisolone should be in the range of 1.5 to 20 mg. daily for children and adolescents, 4 to 5 mg. daily for young women, 3 to 4 mg. daily for postmenopausal women, and 5 to 7 mg. daily for men. IMPORTANT-In the management of patients with chronic disease such as rheumatoid arthritis, methylprednisolone should be regarded as a valuable adjunct to be used in conjunction with but not as replacement for standard therapeutic measures. Diuresis and increased excretion of sodium have occurred following admin- istration of Medrol to adrenalectomized animals, normal human subjects and patients with cardiac edema or cirrhosis of the liver with ascites. These findings have suggested the value of this agent as adjunct to therapy of these and other forms of edema. Medrol has been reported to potentiate the actions of mercurial and carbonic anhydrase inhibiting diuretic agents and the restore response to diuretics in patients with resistant cardiac edema. The use of corticoids in tuberculosis, while usually contraindicated, may be life saving when given with adequate and effective dosage of antituberculosis agents to patients with fulminating pulmonary tuberculosis or meningeal tuberculosis. Rapid improvement with defervescence, weight gain and clearing of pulmonary lesions have been reported. A dverse 1?eoctions: Adverse reactions associated with use of corticosteroids, including Medrol (methyiprednisolone), include electrolyte imbalance, osteopor- sis which is reversible only with difficulty, spontaneous fractures, aseptic necro- sis of the hip, activation and complication of peptic ulcer including perforation and hemorrhage, hyperglycemia, glycosuria, hypertension, neverousness, acne, hirsutism, rounded fades, cutaneous striac, amenorrhea, cervicothoracic hump, acute pancreatitis, necrotizing angiitis, thinning of scalp hair, petechiae and purpura, posterior subcapsular cataracts occasionally requiring extraction, my- opathy, growth retadiation in children, relative adrenocortical insufficiency (par- ticularly in times of stress due to trauma, surgery or severe illness), protein ca- tabolism with negative nitrogen balance, weakness, aggravation or masking of infection, increased intracranial or intraocular pressure., thromboembolism ulcerative esophagitis, psychic disturbances, abnormal euphoria, insomnia, head- ache, vertigo, facial flushing, sweating, and abnormal fat deposits. When adverse reactions occur, they are usually reversible and disappear when the hormone is discontinued. Precautions: Medrol (methyiprednisolone) should be given only with full knowledge of the characteristic activity of, and the varied responses to, adreno- cortial hormones. PAGENO="0076" 3168 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Diabetes mellitus, hypertension and congestive heart failure may be ag- gravated by the administration of corticoids. However, concomitant adminis- tration of Medrol with diuretics may be beneficial in patients with cardiac edema. Negative nitrogen balance may occur with protracted maintenance therapy. Measures to counteract persistent nitrogen loss include a high protein intake and the administration, when indicated, of a suitable anaholic agent. Likewise, ecehymotic manifestations have occasionally been reported. If such reactions are serious or distressing to the patient, reduction in dosage or dis- continuance of methyiprednisolone tberap3~ may be indicated. While current investigations indicate that muscle weakness in patients re- ceiving cortic~ids may occur in the presence of normal or low potassium levels and may be due to a disturbance in muscle metabolism, data indicate that the incidence of this complication is low with MedroL This effect should be kept in mind and periodic serum potassium determinations perfottaded in patients on prolonged therapy. In some instances, steroid-induced myopttthy has actually improved when patients have been transferred to a predoisteroid such as Medro] from fiourinated steroids containing the 9-aipha-fiuioro configu]~ation. Because Medrol manifests little sodium retaining activity, the usual sign of cortosone or hydrocortisone overdosage (Le., increase in body weight due to fluid retention) is not a reliable index of overdosage. Hence, recommended dose levels should not be exceeded, and all patients should be under close medical super- vision. All precautions pertinent to the use of prednisolone apply. While corticoids may be considered as effective therapy in polyarteritis nodosa, current data indicates that such therapy may have an undesirable effect and may cause lesions characteristic of the disease. Likewise, data indicates that the use of corticoids may in some instances induce acute pancreatitis. Thedevelop- ment of posterior subcapsular cataracts has been associated with prolonged, high dosage corticoid therapy. To minimize this effect, doses should be kept `as low as possible when adminiStered for prolonged periods. Retardation of linear growth has ,jeen noted in children receiving corticoids for 6 months or longer. Wtth methylprednisolone this has been noted with doses of 5 mg. per square meter of body surface per day or greater, Retardation is usually proportional to dose and following cessation of therapy, the growth rate may be accelerated. The growth of children receiving prolonged therapy should be observed carefully. If growth has been retarded, the dose should be reduced sufficiently to permit recovery before epiphyseal closure. Continued supervision of the patient after cessation of Medrol (methylpredni- solone) therapy is essential, sincethere may be a sudden reappearance of severe manifestations of the disease for which the patient was treated. Warning: Because of its inhibitory effect on fibroplasia, inethyiprednisolone may mask the signs of infection and enhance dissemination of the infecting or- ganism. Hence, all patients receiving methylpeednisolone should be watched for evidence of intercurrent infection. Should infection occur, it must be brought under control by use of appropriate antibacterial measures, or administration of methyiprednisolone should be discontinued. Since methyiprednisolone suppresses endogenous adrenocortical activity, it is highly important that the patient receivii~g methlyprednisolone be under careful observation not only during the course of treatment but for some time after treatment is terminated. Adequate adrenocortical supportive therapy with cortisone or hydrocortisone, and including ACTH, must be employed promptly if the patient is subjected to any unusual stress such as surgery, trauma, or severe infection. To berculosis: Use of corticoid therapy as an adjunct in pulmonary or meningeal tuberculosis must be based on careful assessment of all factors. Such therapy should not be instituted unless the tubercle bacilli are shown to be Sensitive to the antituberculosis agent. Use of `adequate and effective antituberculosis therapy currently with corticoid therapy is mandatory, When the tuberculous condition is complicated by fungal infections, corticoid therapy in eonstiaindi- cated. "Rebound" fever, joint pains and temporary deterioration of pulmonary lesions `as indicated by x-ray may follow certicoid withdrawal. Hypersensitivity to the antituberculosis agent may be unmasked by withdrawal of corticoid, Hematological Disorders: Therapy with methylprednisolone has been effective in producing remissions with certain types of leukemia, in producing sympto- malic improvement of patients with other lymphornatous diseases and in throm- bocytopenia and hemolvtict anemia. As a general rule, the therapy with cor- ticosteroids produces remissions more frequently in acute lymphatic leukemia PAGENO="0077" COMPETITIVE PROBLEMS IN THE IiRUG IN1~USTRY 3169 than in other types of leukemia and remission occurs more frequently in children than in adults. The sodium retaining properties of cortisone and hydrocortisofle prevented the use of these agents in large doses. However, since Mdtol (methylprednisolone) demonstrates a 1e~ser propensity for salt retention, the administration of mas- sive doses of this compound may be less likely to be associated with troublesome fluid retention. It has been found that large doses of corticoids may be effective In producing remissions itt some patients with acute granulocytic, acttte monocytic, and chronic lymphocytic leukemia. Such therapy has been par- ticularly helpful in controlling thrombocytopenia and bemolytic anemia asso~ ciated with chronic lymphatic leukemia and ether chronic lymphomas~ Dosage-Dosage varies with the individual patient and the condition being treated and ranges from 1 to 2 tablets (16 mg. size) Ito 3 times daily. In some cases, doses of the order of 300 mg. daily have been employed. Following symp- tomatic control of production of a' remission, the daily dose should be reduced by decrement to maintenance level or discontinuation. LUPUO~ ERYTHEMAT0$UI~ Large doses of cortocoids may be necessary to control the manifestations of acute systemic lupus erythematosus. When a rapid onset of action is desired, Solu-Medrol (nlethylprednisolone sodium succinate) may be injected intravenously for the first two or three doses. When therapy is initiated orally, daily doses as high as 32 to 96 mg. (two 16 mg tablets 1 to 3 times daily) may be necessary to control symptoms. After symptoms have been controlled, the daily dose should be reduced by decerments to a maintenance dose of 8 to 20 mg. daily. coNTRAINDwAq'I0N~1: Medrol, like other corticoids, is usually cuntraindi- cated in patients with latent, questionably healed or active tuberculosis. How- ever, Medrol administered with antituberculosis agents may be life saving in certain cases. Absolute contraindications to corticoid therapy include herpes siinplen keratitis and acute psychoses. Relative contraindications include: peptic ulcer: 110W $UPPLIFJD: White, scored 16 mg. tablets In bottles of .50. White, scored 4 mg. tablets in bottles Of 30, 100 and 500. Pink cross-scored `2 mg. tablets `in bottles of 30 and 100. Medrol Dosepak-21 four tug. tablets with patient instrtic- tions for 0 days of countdown therapy. (Shown in Product Identification Section.) MEDROL® (METRYLPRED.NISOLONE): ADMINISTRATION AND DOSAGE TABLE Disease Initial daily dose Daily maintenance dose Rheumatoid arthritis: Severe 12 to 16 mg 6 to 12 mg. Moderate 6 to 8 mg 2 to 6 mg. Children 6 to 10 mg 2 to 8 mg. Lupus erythematosus ~0 to 96 mg 8 to 20 mg. Allergicdiseases l2to4Omg 4tol6mg. Ocular inflammatory diseases 12 to 40 mg 2 to 12 mg. Adreno8enital syndrome 4 to 12 mg. Ulcerative colitis 16'to 60 mg Nephrosis 20 to 60 mg. (for 10 to 14 days until 12 to 40 mg (3 consecutive days of each diuresis occurs), week tor 6 to 12 months). Refractory congestive heart failure 16 to 24 mg. (concurrently with other 4 to 12 mg. accepted therapy). Tuberculosis: Pulmonary and meningeal 16 mg. for 10 to 12 weeks Reduce by decrements in a period of (concurrently with antituberculous 2 to 7 weeks. agents). or 48 mg. for 14 days . Reduce by decrements over 2-week period.. ARMOUR PHARMACEUTICAL Co., Chica~jo, Iii., November 16, 1967. DEAR DOCTOR: The Food and Di~ug Administration has requested that we call your attention to the monograph for H.P.*ACTHAR® GEL in the current (1967) Physician's 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. PAGENO="0078" 3170 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To provide you witl~ the necessary information, we enclose a revised monograph for insertion at page 527 in your 1967 PDR. The nature and extent of the add!- tions of previously omitted information are indicated by the use of italics. Sincerely yours, J.. A. HUBATA, ~LD., Medloa~ Director. (NoTE-Prescribing information for Jj~~* AOTIIAR® ~4EL w~iich appears on Pages 527 and 528 of the 1967 PDR has been revised and is ~Qmpletely replaced by the following. The nature and extent of the additions of previo~isjy omitted information are indicated by the use of italics.) ARMOUR PHARMACRUTICAL COMPANY CHICAGo, ILL. H. P.~ ACTHAR® GEL (Repository Corticotropin injection) Highly Purified AND ACTHAR® (Corticotropin injection) Description: IHL,P.* MJTHAR GEL (Repository Corticotropin Injection) is a Highly Purified preparation of CORPIOOTROPIN in gelatin which has both rapid onset and prolonged action. One injection may have 24- to 72-hour effective- ness. The high degree of purity also allows its administration by intravenous infusion. Each milliliter contains the labeled activity of Oorticotropin U.S.P., 16% Gelatin, 0.5% Phenol, not more than 0.1% Cisteine (added) and Water for Injection, q.s. ACTHAR (Corticotripin Injection) is sterile powered lyophi- lized ACTH which in the dry form is stable at room temperature. Each vial con- tains the labeled activity of Corticotropin U.S.P. and approximately 9 milligrams of hydrolyzed Gelatin. Actions: ACTHAR (Corticotropin Injection) is the Armour Pharmaceutical Company brand of ACTH (Oorticotropin). ACTH is the anterior pituitary hor- mone which stimulates the functioning adrenal cortex to produce and secrete all of its steroids, which number over 30. In contrast, corticosteroids may de- press adrenal cortical function and produce adrenal atrophy. The fact that AUTH acts directly on the adrenal cortex provides a rationale for use of ACTH in treatment of the adrenal insufficiency produced by cortisone, hydrocortisone, prednisone and prednisolone. Indications: Allergic Diseases-Angioneurotic Edema, Asthma, Drug Reac- tions, Hay Fever. Serum Sickness. Note: Epinephrine is the drug of choice for acute allergic reactions, corticotropin or steroid therapy being adjunctive. Col- lagen Diseases-Acute Rheumatic Fever; Arthritis, Rheumatoid; Bursitis; Lupus Erythematosus; Periarteritis Nodosa; Psoriatic Arthritis; Scieroclerma; Spondylitis, Rheumatoid; Still's Disease; Tenosynovitis. lJermatologio Dis- eases-Anogenital Pruritus, Atopic Dermatitis, Dermatitis Venenata, Dermatitis Medicamentosa, Exfoliative Dermatitis, Dermatomyositis, Pemphigus, Psoriasis, Urticaria. Endocrine Diseases-Panhypopituitarism. Eye Diseases-Choroiditis; Conjunctivitis; Glaucoma, Acute Secondary; Iritis; Keratitis; Optic Neuritis; Sympathethic Ophthalmia; Uveitis. Hernolytic Diseases-Acquired Hemolytic Jaundice. Other Uses-ACTHAR (Corticotropin) preparations have also been used in numerous other disease states such as: Agranulocytosis; Aplastic Anemia; Bell's Palsy; Beryllium Poisoning; Burns; Erythema Nodosum; Erythroblastosis Fetalis; Fibrositis; Gout; Guillain-Barre Syndrome; Heat Sickness; Hepatic Coma; Hodgkin's Disease; Hypoglycemia, Idiopyathic; Infections, Acute Over- whelming (e.g., Peritonitis, Meningitis); Insect Bites; Leukemias, Acute and Chronic Lymphatic; Loeffler's Syndrome; Myositis; Nepbrotic Syndrome; Neuritis; Orchitis; Rhinitis ; Sarcoidosis; Shoulder-Hand Syndrome; Snake l3ite; Sprue Syndrome; Stevens-Johnson Syndrome; Thyroiditis; Ulcerative Colitis. PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3171 Contraindications: "Absolute Contra'indications": Tuberculosis (active, healed or questionably healed), ocular herpes simplex, and acute psychosis are usually absolute contraindicatlons to corticotropin therapy. Corticotropin is of no value in patients with Addison's Disease or after adrenalectomy since its action de- pends on the integrity of the adrenal cortex. `Relative Contraindications". (1) Relative contraindicatiOns are Cushing's Disease, congestive heart failure, diverticulitis, fresh. intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, throm.boembolic tendencies, osteoporosis, diabetes mellitus, psychotic tendencies and acute or ehronic infections (especially varicella or vaccinia) as well as other exanthema- tons and fungal diseases. (2) Pregnancy is a relative contraindication to corti- cotropin therapy, particularly during the first trimester, because fetal abnor- malities have been observed in experimental animals. (3.) If corticotropin is used in the above conditions, the risks should be weighed against the possible benefits. Warning: Skin testing should be considered prior to treatment of patients with known or suspected sensitivities to corticotropin (which Is a polypeptide) or porcine proteins. It is recommended that all patients be observed for a period of at least 15 minutes following administration of corticotropin. Epinephrine 1: 1000 for emergency treatment should be available. Precautions: (1) Corticotropin should be given only with full knowledge of the characteristic activity of, and the varied responses to, this preparation. (2) Average and large doses of corticotropin can cause elevation of blood pressure, salt and water retention, and increased potassium and calcium excretion. The hypertension may be transitory during a period of electrolyte and water reten- tion. Observe blood pressure responses until the maintenance dose is established. Dietary salt restriction and potassium supplementation may be necessary. If this does not control fluid retention, decrease the dose, omit a few injections until diuresis occurs, administer a diuretic, or consider discon~tinuatiOn of therapy. Daily weights should be charted as a guide to abnormal weight gains. Muscle weakness, fatigue or paresthesias may be a reflection of potassium deficiency, but are seldom observed if a potassium supplement is added to the diet. EKG's or serum potassium levels are recommended guides if AUTH or corticoids are ad- ministered at high dosage levels for prolonged periods. If necessary, decrease the dosage or temporarily interrupt treatment and resume at a later date on a high potassium regimen. (3) Corticotropin may mask the signs of infection and enhance dissemination of the infecting organism. Hence all patients receiv- ing corticotropin should be watched for evidence of intercurrent infection. Chest x-rays should be done at regular intervals during prolonged therapy. should in- fection occur, initiate vigorous, appropriate anti-infective therapy. Abrupt cessa- tion of corticotropin should be avoided if possible because of the danger of super- imposing adrenocorticctl insufficiency on the infectious process. (4) Since spontaneous remission of some diseases, such as rheumatoid arthritis, may occur during pregnancy, every effort should be made to avoid hormone treatment in pregnancy. (5) To avoid relative pituitary hypofunction, corticotropin therapy should be terminated gradually, particularly when patients are receiving large doses or have undergone prolonged treatment. Furthermore, if such patients are subjected to undue stress, such as surgery or trauma, while being treated or within one year after treatment has been terminated, hormone therapy should be augmented or reinstated and continued for the duration of the stress period and immediately following it. It is preferable to use corticotropin and/or cortisone or hycirocortisone in the Immediate preoperative and postoperative periods. (6) Continued supervision of the patient after cessation of corticotropin is essential, since there may be a sudden reappearance of severe manifestations of the disease for which the patient was treated. (7) Long-term corticotropin therapy may be accompanied by gastric hyperacidity and/or peptic ulcer. It is recommended, therefore, that patients with a hlstory of peptic ulcer be placed on an ulcer regimen (including administration of an antacid) as a prophylactic measure. Peptic ulcer patients complaining of gastric distress should be the subjects of ap- propriate x-ray examinations of the gastrointestinal tract. (8) Corticotropin may aggravate diabetes mellitus so that higher insulin dosage may become necessary or manifestations of latent diabetes mellitus may be precipitated. Frequent urine sugar determinations and two hour postprandial blood sugar determinations are recommended during the period of dosage adjustment. (9) Phychotic changes may be observed. If enaggerated euphoria, nervousness, pronounced insomnia or depression occur, reduce or discontinue therapy and administer sedatives as indicated. PAGENO="0080" 3172 COMPETITIVE . PROBLEMS IN THE DRUG INDUSTRY Adver.se Rea~ction$: Adverse reacUons, whei~ they occur, are u~ua1ly reversible and disappear when cortico~tropin is discontinueci. Abscess, ~teri1e. ~4ctivation and comphca~tian of peptic niQer (including perforq~tion and hcmorr1~age). Aggra- vation or masking of infection. AlteratjQn of Glucose Metabolism, with aggrava- tion of diabetes mellitus, including hyp~erglyc~mia and glyco~i~ria. Aseptic Necro- sis of Hip and Humerus. Convulsions. Cushing's Syndrorne (including moon facies, supraclavicular fat pads, hirsutism, striae, nud acne). Electrolyte iinbal- ance. Facial Erythema. Headache~ Increased Blood Pressure. Increaseti Intra- cranial Pressure with Papilledema (pseudo-tumor cerebri) Increased Intraocular Tension. Insomnia. Menstrual Irregularitje~. Myopatby. Necrotizing Anglitis. Osteoporosis (reversible only with diMeulty). Pancreatitis. Peteehiae and Purpm-a. Posterior Subeapsular Cataracts (o~casiona1ly requiring extraction). Postinjectjon Flare. Protein Catabolism (wftb negative nitrogen balance). Psy- chic Disturbanc~s (especiafly abnormal euphoria). Spontaneq~s Fractures. Sup- pression of Growth in Children. Sweating. TbroraJ~ioembolism. Uicez~a~ive Esoph- agitis. Vertigo. Weakness. Dosage and Adm,in4stration: Directions for Use of AUT2EIAR (Uortiootropin) Preparations-_Olinieal response is the criterion of adequate dosage. Unusual laboratory studies are not necessary. Because the adrenala vary in their sensi- tivity to stimulation by ACTH there can be no specific~ uniform dose effective for all individuals. The aim is to obtain a therapeutic effect with minimal dosage and with miiiimal or no metabolic alterations. A clinical response is secured within 2 weeks in the majority of conditions. Once the disease is under control, decrease the total daily dose as rapidly as possible consistent wit/s maintaining a remis- sion-thus try to reduce the total dose to about 75% of that needed initially. If adequate, tisis dosage is continued for 3-7 day~ before making a further similar reduction. When thalowest daily maintenance dose is thus established, attempts sho'~ad be made at lengthening the interval between doses. If 8ymptoms are not suppressed after dosage reduction, return to the previous effective schedule. If the nature of the disease requires maintenance therapy, aiim to employ the smallest effective dose with the longest possible interval between injections. If the doses needed for full relief produce significant "side effects", reduce the dose and be satisfied with less than full suppression of disease under management. Administration and Dosages of H.P. ACTIiAR GEL (Repository Corticotropin Injection) and A1JTHAJ~ (Corticotropin Injection): Either H.P. AOTHAR GEL (Repository Corticotropin Injection) or ACTHAR (Corticotropin Injection) may be given subcutaneously, intramuscularly, or as an intravenous infusion. Since ACTHAR (Corticotropin Injection) is a lyophilized preparation, it must be reconstituted before administration by dissolving in a convenient amount of Water for Injecton or Sodium Chloride Injection in such a manner that an indi- vidual dose will be contained in 1-2 cc. of solution. Like all aqueous solutions of ACTU, ACTHAR (Corticotropin Injection) is usually given every 8-12 hours. When reconstituted, the solution should be refrigerated. SUBCUTANEO US OR INTRAMUSCULAR TREATMENT OF SPECIFIC DISEASES-Note: The dosages expressed are for H.P. ACTHAR GEL (Repository Corticotropin Injec- tion) only. For AOTHAR (Corticotroplu Injection) give the same total daily dose stated for H.P. ACTHAR GEL (Depository Corticotropin Injection) but give this in 3 divided doses every 8 hours initially. Tapering and maintenance regimens should be carefully observed. For children under 40 lbs. in weight, reduce by one-third the dose recommended below. The dosages stated below for specific diseases are suggestive only and not absolute. ADRENAL INSUFFICIENCY-secondary to pituitary deficiency or to corticoid-induoed adrenal atrophy. As a rule, 100 Units daily for 3 days will reactivate the corticoid-suppresed adrenal and 40 Units twice a week or 100 Units weekly will prevent adrenal atrophy induced by the administration of corti- cost eroids. ALCOHOLISM and D.T.'S-40-60 Units once daily; recovery usually within 36 hours. Injections may be oontinued 3 times a week for several weeks. ANGIONEUROTI(J EDEMA-60-80 Units once daily or 40-50 Uniits bid, if severe; maintenance treatment not required if cause removed. ANOGENITAL PRURITIS-60-80 Units once daily or 40-50 Units b.i.d. if severe. ARTHRITIS, RHEUMATOID including SPONDYLITIS, STILL'S DISEASE and PSORI- ATIC-60-80 Units once daily; 40-50 Units b.i.d. for severe cases. Maintenance therapy usualhj required. ASTHMA-60-80 Units daily or 40-50 Units b.i.d.; maintenance treatment may be necessary. BURNS-60-80 Units daily or 40-50 Units b.i.d. if severe; give for 5-10 days reducing dosage as patient's Condition improves. BURSITIS...60_8O Units daily; results in hours especially in acute iases. COLITIS. Ulcerative-60-80 Units daily or 40-50 Units b.i.d. for severe PAGENO="0081" C~1VIPETITIVE PROBLEMS IN THE DRUG INi~USTRY 3173 ca8es; con~is~ue untli mucos~ appears re~tively * normal. The most dramcttio re~t$ (WC 8~1~ ~fl th~e cu~u,t~ cases., JJ~J$M4TI~1:Jtg, . ~1ONTAUT, DRUG, ETC.- 60-80 U~'øt& ~Za'~y or 40-50 ~ ~ it ~et~re; n~ai~ten~nee tre~ti~nt not required if c~u~e remoí&'ed. ~ `Units . 4a~y; 4O-~5O Units ?i.Ld. if severe; n ntenunee tr~n~ent .usssully required. L~J~1~ThIi~TIVE DERMA- TJTI$-4Q-~80 U~jtit& daiIy~ or 4Q-4Q rjuit& b.i.~. if severe; continue far ~ weeks after skin is essentially normal; ~ usually u~t required if cause deter- mined. EYE DI~E42E2.~ c5OkOJJ&lTi$.~ CON~UNCTIV1TI~; ACUTE EEC- ONDARY GLAUCOJtIA, IRITIS, KER4TITLS~, $YMPATIIETW OPTIIALMIA, OPTIC NEURI~IS-0Q-80 Units once thsiiy~or 40-50 Units b.i4. for severe cases; continue treatment until lesion healed. aOUT-60-~8O Units oswa daily or 40-50 Units b.i.d. if severe; result usually in 1-~3 injections. Concurrent colehicine therapy advised. GUILLAIN-$ARRE kSYN1J~ROME-60-80 Units daily or 40-40 Units b.i.d. if severe. H4Y EEVER-60-80 Unite once daily or 40-40 Units b.i.d. if severe; perindic ~njectlons advisable during pollen season. HYPOGLYCEMIA, CongenIal Idio~athic~40-60 !Jnits daily; small amount~ nusy be reqwtred to maintain conirol,JAUNDIIJE, Hemol$ic Aequired-46~-60 Units daily until blood piq~yre nor al;maintena'nce treatment nnless causq removed. LUPUAS~ ERYTHE- MAT QBUS-40--80 Units b.&d. and cOntinue for several weeks after adequate remission; maintenance treatment usually required~ NEPHROTIO SYNDROME- l~'or patients weighing 50100 lbs., 60 Units tmeedaikj; M~0 lbs. or over, SQ Units daily. Initial dose is continued 10-12 days and It/ten abruptly sI7op~ped to allow for spontaneoub d~iurusis; 4iut~esis may occur before 1~ days. If edema disturbing, stop treatment diuresis may occur. If diuresis inadequate, repeat after 5 days. Patients are kept on usual nepbrotic regimens during therapy. PANHYPOPI- TUITARISM-20-40 Units daily; maintenance therapy indicated with smaller doses and lengthened intervals between doses. PEMPHIGUS-60-80 Units daily or 40-60 Unite b.i.d. if necessary. Continue treatment for 10-14 days after old lesions heal and new lesions cease to appear. Most eases require maintenance therapy. PENICILLIN i~EACTIONS-~S'e~ Dermatitis (Contact and Drug). PERIARTERITIS NODOSA-60-80 Units daily or 40-40 Units b.i.d. if nec~s- sary; maintenance treatment usually necessary. POISON IVY-See Dermatitis (Contact and Drug). P$ORJASIS-60-80 Units daily or 40-40 Units bid. until skin lesions essentially gone; maintenance therapy generally required. RADIA- TION SICKNESS-20-60 Units daily; symptoms usually controlled within few days. RHEUMATIC PEVER-G0-80 Units daily or 40-SO Units b.i.d. if acutely ill. Continue for 2-3 weeks before tapering dose. Do not discontinue until clinical and laboratory signs of. disease disappear, usually a total period of 6-8 weeks. Cardiac decompensation is not a contraindicatio!n~-~diuretics may be used. SARCOIDOSIS-40-80 Units daily; improvement usually within 5-7 days; main- tenance therapy may be necessary. SERUM SICKNESS-40-80 Un'its once daily; if severe, 40-50 Units b.i.d. TRJNOSYNOVITIS-40-80 Units daily or 40-50 Units b.i.d. if severe; resulls usually within 24-36 hours. TJIYROIDITIS-80 Units daily for 3 days followed by 60 Units fOr 2 days, 40 Units for 2 days, 20 Units for 2 days, and 10 Units for 3 days. URTICARIA-60-80 Units daily or 40-50 Units b.i.d. if severe; maintenance therapy not required in cases with known etiology. ACTHAR (Corticotropin) preparations have also been used in a number of other diseases; Agranulocytosis (especially drug-induced), Aplastic Anemia, Bell's Palsy, Beryllium Poisoning, Erythema Nodosum, Erthroblastosis Petalis, Fibro- sitis, Heputic Coma, Heat Sickness, Hodgkin's Disease, Infections (acute over- whelming as Peritonitis, Meningitis, etc.), Insect Bites, Leukemia (acute and chronic lymphatic), Loeffier's Syndrome, Myositis, Neuritis, Orchitis, Rhinitis, Scleroderma, Shoulder-Hand Syndrome, Snake Bite, Sprue Syndrome, Stevens- ,Iohnson Syndrome. INTRAVENOUS USE: This method of administration may be used where a rapid response Is desired, ~ patients refactory to intramuscular ACTH, for reactivation of adrenals suppressed by cortisone, hydrocortisone, prednisone, prednisolone, etc., and for diagnosis. The recommended dose is 10-25 Units of AC- THAR (Corticotropin Injection) or 40 to 80 Units of TIP. ACTHAR GEL (Re- pository Corticotropin Injection) in 500 cc. of 5% glucose in water given as a con- tinuous intravenous infusion over an eight hour period, once daily. For children under 6 years, reduce the dosage to 50% of the adult dose recommended for the ACTHAII (Corticotropin Injection) preparation being used. There is no long- acting effect when H.P. ACTHAR GEL (Repository Corticotropin Injection) is used intravenously. Patients known to be highly sensitive to proteins should be carefully evaluated even though the slowness of infusion and the normal blocking effect of AUTH in hypersensitivities would appear to offset reactions. Patients 81-280-68-pt. 8-6 PAGENO="0082" 3174 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY should be watched closely for the first 30 minutes; epinephrine should be avail- able. Tapering can be started much sooner than when AOTH is given intramus- cular or subcutaneously because with continuous Intravenous Infusion, ~linIeal results are obtained mere rapidly. After obtaining a remis~ion by the Intravenous route, further therapy, if necessary, is usually given subcutaneously or intra- muscularly In the form `of H.P. ACTHAR GEL (Repository Corticotropin In- jection) which beehuse of its repository properties fewer Injections are required. LABORATORY TESTS OF ADRENAL CORTICAL FUNCTION: (1) The Four Hour or Thorn Test-An eosinophil count is made in' the fasting state and im- mediately thereafter 25 Units of AUTHAR (Corticotropin Injection) are in- jected intramuscularly. Another eosinophil count is made 4 hours later. Break-' fast may be given following the first eosinophil count bat lunch should be with- held until after the second. A fall in eosinophits of 50% or more below the pre- injection level indicates a satisfactory adrenal cortical response. (2) The 8 Hour I.V. Test-25 Units of AUTHAR (Corticotropin Injection) in 500 cc. of 5% dertrose are infused over an 8 hour perIod. EosinopMls aire counted at 0 and 8 hours; a fail of 50% or more is indicative of a responsive adrenal. PACKAGE FORMS: H.P. ACTHAR GEL (Repository Corticotropin Injection) is supplied in 5 milliliter multiple-dose vials in strengths of 40 and 80 U.S.P. Units (I.U) per milliliter; 1 milliliter vials containing 40 and 80 TJ.S.P. Units (I.U.) per milliliter; and 1 millIliter B-D disposable syringes contaIning 40 U.S.P. Units (I.U.) per milliliter. ACTHAR (Corticetropin `Injection) is supplied as a lyophilized powder in vials containing 25 and 40 U.S.P. Units (I.U.) per vial. PHYSICIANS' DEsK REFERENCE, Oradell, ~ST.J. DEAR Sin: The Food and Drug Administration has requested that we call your attention to the monographs for the following products in the current (1967) PhysicIans' Desk Reference: P~sge HP Acthar Gel 527 Cortrophin Gel 898 Cortrophin-Zthc 898 Hexadrol 899 Hexadrol Phosphate Injection 890 Norpramin 087 Predsem 812 Sialcort 812 Salcort-Delta 812 The FDA considers these monographs to be incomplete in presenting the 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 1967 PDR at the pages indicated at the top of each sheet.1 The nature and extent of the additions and other revisions in the enclosed monographs are emphasized by the use of italics. Sincerely, ALBERT B. MILLER, General Manager. PARKE, DAvIs & Co., Detroit, Mich., January 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 Administration regards as misleading. The introductory campaign featured results from non-blind clinical trials us- ing only a single 500 mg. dose for several types of pain. The Food and Drug Administration points out that Pon~tel has also been studied in several double- blind clinical trials in which the drug was compared to aspirin and other non- narcotic analgesics. These trials demonstrated that Ponstel was essentially equal 1 Retclned in committee files. PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3175 to the comparison drug and better than placebo. However, in certain individual trials aspirin was found better than Ponstel and the latter could not be distin- guished from placebo; in some trials pain relief with placebo was obtained in as high as 40% of the patients. In other trials the results with Ponstel were better than those with aspirin or ~1acebo. The Food and Drug Administration considers that the Introductory campaign failed to give adequate prominence to the f~ct 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 Ponatel employed in this study was at a level which is still in the investigational phase. We are discontinuing the advertising campaign in question. Sincer~ly, J. E. GAJEWSKI, M.D. SYNTEX, January 22, 1968. DEAR DOCTOR: The Food and Drug Administration has asked us to call your attention to the fact that certain statements in recent advertising for our oral contraceptives, Norquen® and Norinyl®-1, may be misleading. In the Norquen 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 cholestatic jaundice, rise in blood pressure in susceptible indi- viduals, and mental depres~don 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 ob- servation and caution are required for patients with symptoms or history of - . - cerebrsvasculstr accident, psychic depression. . . ." The ads should have been more specific in stating: "Oral contraceptives should be used with caution in patients with a his- tory of cerebrovascular accident and should be discontinued If there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia, o~ migraine, or if examination reveals papilledema or retinal vascular lesions, since these may be symptoms of cerebrovascUlar 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 tolerance has been observed in a small percentage of patients on oral contracep- tives. We are modifying all future advertising to reflect these changes. Sincerely, BEN Z. TABER, M.D., Medical Director. G. D. SEARLE & Co., Chicago, Ill., January 26, 1968. I)EAB DOCTOR: In June 1967, the Food and Drug Administration and all manu- facturers of oral contraceptives agreed on certain changes in the uniform portions of the labeling for all oral contraceptive products. These `changes were to be included in all advertisements after October 1, 1967. 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 contraceP- tives. A cause and effect relationship has not been established: "Thrombopbletbltis Pulmonary embolism Neuro-ocular lesions." PAGENO="0084" 3176 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Because that labeling did not accurately represent the present status of opinion concerning the ~ossible danger of side effects, the warning statement was changed to read: "4 cause and effect relationship has been ~ieither established nor dis- proved:" [Italic snpplied~J ~he FflA regards the advertisements as potenti- ally misleading because they omitted this important change which emphasizes the pos~ibiUty of these serioi~s hazards. Further, the advOrtisemehts failed to include the following side effects which, although causation has not been established, have been reported in users of oral: contraceptives: an ovulation post treatment, pretaenstrual-like syndrome, changes in libido, cha~nges in appetite, cystitis-like syndrome1 backache, nervousness, dizziness, fatigue, headache, hirsutism. We have modified our current advertising to reflect these changes. Sincerely, HERBERT HELLxxa, Food and Drug Administration Affairs. AjusLnv, N.Y.,. February 15, 1968. DEAR DocTog: In our promotion of. Persantine® (brand of dipyridamole) for long-term therapy in anginal. patient~ we sent a letter to physicians stating tha~ "Several studies document the ej'fectlveness of Persantine in extending walking distance and general increasing exercise tolerance." Enclosed with the letter was a reprint of a study in the JQ.u~flai of Qhronic Diseases of Mgrch 1967 to support the claims for effectiveness~ The Foo4 and ilvug Administration has asked us to inform you that the claims for effectiveness of Persantine, and many otber drugs m&rketecj prior, to 1962, have been neither `a~pro~ved nor disappr~vecl by t~e.Ageu~y~ The FD4 is proceed- ing on the basisythat the Drug Amendments of 196.2 requjre the Agency toevaluate thA effectiveness &f such drugs,, and this is currently being done with the assist- ance of the drug efficacy panels of the National Academy of Sciemce~/NationaI Research Ooundll. . The FDA regards the promotional letter as potentially misleading because it presented only favorable information regarding the drug's effectiveness when there is a substantial body of opinion that does not suport the claimed effective- ness of the product. For example, the AMA Council on Drugs (in New Drugs 1967) has stated that double-blind studies comparing dipyridamole with a placebo have shown equivocal results and that the drug has not been convincingly shown to be effective in the long-term treatment e~angina pectoris. Recently~ in the JAJJf A issue of September 11, 1967, a paper by Sbar and Sch- lant disclosed results of a six-month double-blind study. The authors concluded that "The study failed to detect a statistically significant difference between the improvement in patients receiving dipyridamole and the Lmprovement in patients receiving a placebo." Our future promotion will express the range of expert medical opinion on the effectiveness of Persantine when any segment of that opinion is referenced. GEIGY PHARMACEUTICALS. Dr. MOCLEERY. Also along the way of developing public awareness of the type of expectations which the FDA considered the law to re- quire, the Commissioner of Food and Drugs had appeared before the Fountain Subcommittee of the House Committee on Government op- erations, and had reviewed for them our programs in this important area of our public responsibilities. In short, and in many ways, we felt that the industry's attention had been brought emphatically to promotion excesses in specific and in many ways. As far as our experience with the problem represented by the drug under discussion today is concerned, we felt that there were three approaches to the promotion of this new product by Merck & Co., all of which had elements with which we disagreed-one of which was mentioned yesterday by Dr. Jennings, in his testimony, in the use of a "Dear Doctor" letter sent by the company, accompanying with it the PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3177 revision of the package insert, which was the occasion for the letter. We took exception to the promotional style of that letter, and that represented one episode in the history of this drug. There was a second episode which I would like to speak about next, which was in regard to an article in the Pageant magazine-and a third, which I want to cover last, the advertising campaign used by Merck & Co. in reference to the subject drug for the medical profes- sion in journals that go only to doctors. Now, in June 1966, the director of public relations for Merck & Co., Mr. John Fletcher, wrote to Theodore 0. Cron, our Assistant Com- missioner for Education, enclosing a print of an article that was about to appear in the July 1966 issue of Pageant magazine. Senator NELSON. Do you have a copy of that Pageant magazine article? Dr. MOCLEERY. Yes, sir, we will submit one for the record. Senator NELSON. Would you submit that for the record? Dr. McCnmRr. Yes, sir. (The article referred to, for inclusion in the record, follows:) [From Pageant Magazine, July 1966] Ixnocix A special report on a remarkable new drug that relieves the pain of arthritis, bursitis, gout, trick knee, tennis elbow, and sprains (By Phyllis and Robert P. Goldman) Two months ago a Miami housewife, aged 29, hobbled off the tennis court with a sharp, knife-like pain in her knee. `She went home and lay down. But within five hours the knee was tender, inflamed, and stiff. The housewife, Mrs. R. L., called her doctor, who, after examining the knee, declared, "Let's try something new, something that many of my patients are beginning to call a miracle drug." Mrs. R. L. took the drug, and the most incredible thing happened. Within 36 hours she was no longer limping in pain. The knee swelling and stiffness began to subside. She found that she could walk almost normally. In a week the pain and inflammation had become simply a memory. A Cleveland grandmother, Mrs. C. M., suffered for ten years from excruciating arthritis of the hip. Almost every available drug was tried, but not one provided sustained relief. She felt she would be cOndemned to a life of semi-invalidism. Four months ago her doctor decided to try a "new drug that Is producing dramatic results" in a number of joint pain and inflammatory conditions. Mrs. 0. M. took the drug, and within two weeks she was up and around- walking pretty much as though she had never suffered from arthritis of the hip. She's bccia comfortable and active ever since. "I can't believe it," she declares. "This medicine is marvelous. I would call it a miracle." Miracle or not, tens of thousands of patients throughout the United States and Europe, with a broad variety of physical ailments, are beginning to swear by the drug that is proving to have remarkable effects-in some cases within 36 to 72 hours. The drug, largely unheralded and unpublicized until now, is called Indocin (indometbacin Is its chemical name). Perhaps its most extraordinary quality is that it can relieve pain and inflammation caused by rheumatoid arthritis, gout, bursitis, arthritis of the hip, trick knee (usually the result of injured tendons and cartilage), "tennis elbow," and a host of other less common disorders char- acterized by pain and swelling in and around the joints. Indocif~ is encouraging news if only because a estimated 12 million Americans suffer from arthritis and related joint disorders, and a good many of them- perhaps twc~nillion-cannot tolerate previously developed drugs, or such drugs have had little if any beneficial effect. PAGENO="0086" 3178 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Actually, it is among many of these patients that Indocin is beginning to score its most impressive victories. These are individuals who have been "put on" almost every available drug-without lasting benefit. Indocin, however, provides such dramatic relief for some of these patients- and so quickly-that many of them are moved to sit down and write about their experiences with the drug to its producer, Merck Sharp & Dohme of West Point, Pennsylvania. The following are some samples of these letters to the pharmaceutical firm: From Kansas City, Missouri: "I have had rheumatoid arthritis for 12 years. And I have taken many different medications. But for the first time-with In- doctn-I'm free of pain. I'm no longer ornery. My wife says she's glad to have the old me back again. . . ." From Minneapolis: "Because of bursitis I bad to give up golf two years ago. But with your wonderful medicine I'm in good enough shape now to play golf once again. . . From Detroit: "For five years the pain of my arthritis of the hip was un- bearable. Now, with this drug of yours, I feel like a new person. Your Indocin is the best present anyone could have given me And from San Diego: "This is the first `love letter' that I have ever written to a corporation. . . . After a very short period of taking Indocin. I can walk again without a cane. . . . I pray that you will realize fully the rewards that your splendid discovery so richly merits. . . ." The "splendid discovery" actually took place several years ago at Merck Sharp & Dohme. Research workers there came upon a synthetic compound that had some surprising effects in animals. Not only could it reduce pain and in- flammation but, given together with older pain killers, liadocin was found to reduce the need for these latter drugs. This particular capability of Indocin is especially important. For in study after study, it has been found that if Indocin is given along with the corti- costeroids (a commonly used "family" of anti-inflammation drugs), the need for these steroids gradually diminishes. This, in turn, can be invaiuable, because very often when steroids are given for prolonged periods the side effects are worse than the disease itself. Steroids are known to produce changes In body fluid balance and can cause weight gain, stomach upset, changes in contour of the face, and they are suspected of having adverse effects on vision. The "steroid reduction" value of Indocin h&~ been commented upon in scientific papers by a number of medical researchers. But one group from the University of Buffalo School of Medicine summed up the entire subject after studying more than 200 patients who were taking Indocin. The Buffalo group declared: "At present 65.7 per cent of the patients have been improved for periods of six to 14 months. There has been a gradual decrease in the inflammatory indict±s, improvement in joint mobility and function. One of the most interesting facets of indomethacin administration has been the ability to gradually reduce the amount of steroid therapy in patients who had been using these hormones for periods of three to eight years. "This effect is very gradual and sometimes difficult to ascertain but does occur in the majority of patients under prior steroid therapy. . . ." The same effect has been noted-along with Indocin's other values-at other leading medical centers located at the University of Colorado, the University of Southern California, the University of Washington, and elsewhere throughout the nation. Despite Indocin's dramatic effects in some cases arid its increasing acceptance by even some of the most skeptical medical practitioners, a few facts should be borne in mind-facts that are indispensible to understanding the role of any drug-new or old. All prescription drugs, Indocin included, have side effects-that is, they pro- duce negative reactions, reactions that make the patient either mildly annoyed and anxious or profoundly distressed physically or mentally. All prescription drugs, Indocin included, work for some patients and not for others. No drug is a universal cure-all. In arthritis and related joint diseases, the actual causes are not known-and therefore there are at present no available drug "cures." At best, the drug provides relief from the symptoms. However, Indocin is a "new" drug-that is, it was approved for prescription use in igos. Therefore, it has been subjected to extremely rigorous tests-tests that were not required of certain of the older anti-inflammatory drugs. PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3179 Within the past four years the Federal Food and Drug Administration, which is charged with approving-or disapproving-new prescription drug applications, has tightened the requirements leading to a new prescription drug being permitted on the market.. Indocin has passed these new, much tougher standards. Despite this, Indocin does have side effects-itt least for some patients. And some patients get little if any therapeutic effect from the drug. Here, in brief, is a rundown on the "minus" side of the Indocin ledger Somewhere between ten and 25 per cent of the patients experience side effects, Some of these are mild, some are severe. Some patients experience headache nausea, dizziness, and a few have intestinal bleeding. However, it is estimated that these effects are mild much of the time. Only an estimated ten to 15 per cent of the patients must give up the drug because of negative effects. Says the Council on Drugs of the American Medical Association in a report not yet published: "With prolonged administration, ten per cent to 15 per cent of the patients who responded initially must stop taking indomethacin because of its untoward effects. . . ." However, also within the AMA report, the following appears: "Indoinethacin has been particularly useful in the treatment of . . . osteoarthritis of hip joint, a condition that is resistant to all other anti-inflammatory agents. "Indomethacin produces anti-inflammatory effects in patients with gout. It has produced relief in acute attacks within 48 hours. "Because it lacks the untoward effects of coichicine [another anti-gout drug], some clinicians consider it to be the drug of choice for these attacks One of the most striking talents of Indocin lies in its ability to go to work quickly on the painful joint. Animal and human tests have shown that once Indocin is given, it reaches peak levels in the blood in just 30 minutes to two hours. Thus, certain patients have begun to note relief from joint aches in two, three, six, or ten hours. One bursitis patient, for example, a 35-year-old executive from Hartsdale, New York, told his family doctor that once he took Indocin, "My shoulder began to feel better in just two or three hours. On just two Indocin capsules per day, I can feel pretty comfortable during an acute bursitis attack." A random sampling of a half-dozen doctors in various medical centers around the country produced the following assessments of Indociii: 1. When the drug works in a patient, the results are very dramatic. Relief conies quickly and may last for long periods. 2. In some patients, however, there are no beneficial effects at first. The drug must `be continued for some weeks `before it does any good at all. 3. Patients on Indocin should be watched very carefully for side effects. It has been reported that, following Indocin administration, some individuals have developed ulcers. However, it cannot be stated categorically that the drug had anything to do with the onset of this stomach ailment. 4. Somewhere around 75 to 80 per cent of all patients tolerate the drug well- and most of these patients experience real relief from symptoms. 5. Apparently, results are most remarkable among patients with arthritis of the hip, but many other patients with joint ailments do get dramatic relief in comparatively short periods. Actually, the first human trials with Indocin started in November 1961. Since that time, more than 5,000 patients have been involved in worldwide studies of Indocin. Prior to the "patient-testing stage" more than 100,000 animal experi- ments were conducted by Merck to establish that the drug was potent and had worthwhile effects. In those animal studies it was found that if researchers injected animals with a drug that itself could cause considerable infiarnation, Indocin could reverse the inflammatory effects. As is the case of so many other drugs, the exact mode of action of Indocin is not known. The same holds true for aspirin-the most widely used of all medications-and for penicillin-the miracle drug that has saved niore lives than perhaps any other drug in the history of man. Doctors know that aspirin and penicillin work `but are not exactly sure how they work. This is true, too, of Indocin. Once it was established that Indocin could reduce inflammation, further tests indicated that its site of action must be within the inflamed joint itself. In addi- tion, tests showed that its anti-pain capabilities at least equaled those of aspirin (which also is widely prescribed for arthritis) and in some instances exceeded the results aspirin could produce. PAGENO="0088" 3180 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Interestingly, Ind'ocin not only reaches peak levels in the blood quickly but it is eliminated from the body quickly, too. This is a distinct advantage, because pharmacologists (specialists interested in the chemistry of new drugs) are convinced that drugs that are quickly eliminated usually have a greater built-in safety factor. The feeling is that the quicker the drug gets in and then out of the body, the safer It is likely to be. Studies show that Indocin may be eliminated entirely within 48 hours, which, as prescription drugs go, is extremely quick. There are, for example, some drugs on the market that remain in the body for several days, or even weeks, after initial administration. During the clinical trials of Indocin the majority Of pfitients treated were suffering from chronic joint disorders and related rheumatic diseases that* had a "history" of at least five years' duration. Most of the patients selected for treatment had failed to get relief or had experienced serious side effects from other available drugs. Thus, from the outset, Indocin was designed as a sort of "trouble-shooter" drug that could help patients wh~ might not have gained beneficial effects from any other medication. There are, as a result, countless cases in the Merck files that show that Indocin works where no other drug has. Whenever a new drug is introduced, doctors wonder whether It will have major effects on the body's vital systems. Indoeln'~ record in this regard is good. Studies show that It has no significant effect on weight, pt1~se rate, Or blood pressure. Nor does it upset the body's glandular system or its blood-clotting mechanisms. Indocin's history is a fascinating story in itself. Research at Merck into Indo- cm-type compounds started about a decade ago, . but Merck's Interest in the entire subject of pain and inflammation goes back at least 30 years. In 1933 Dr. R. B. Gruber, a Merck vice-president, agreed to a request made by the Johns Hopkins School of Medicine, Baltimore, to develop a process for pro- ducing adrenal cortex hormones for the relatively few sufferers of Addison's disease and other adrenal disorders. Merck did this, and the spark of interest was rekindled during World War It when the company was asked to help Dr. Edward C. Kendall in research on adrenal hormones. Merck was told that this research "woflld be In the national interest." It seems that during the war American intelligence had heard ruthors that Germany was buying adrenal gland extract from. Argentine slaughtOrhouses and giving it to Luftwaffe pilots in the hope that the extract would enable the `pilots to fly at altitudes Of 40,000 feet or more. Obviously, the United States military wanted to know if adrenal extract conferred any `such capability upon airmen. (It didn't.) Dr. `Kendall went to work with a young Merck chemist, Dr. Lewis H. Sarett, who, in 1944, just before turning 27, developed the first synthesis of compound B. This development, in turn, paved the way for the discovery that compound 11 had therapeutic effects. The compound then became knOwn as cortisone. After the war cortisone `and its later modifications came into wide use for arthritis and `other inflammatory ailments, but gradually it was discovered that cortisone produced a great many undesirable side effects. Thus, from the early 1950s until the present, researchers have beeii `hard at work trying to develop anti-Inflammation drugs that work but ~io not produce cortisone-like side effects. In 1953 a Merck research group, led by Dr. Sarett, began to Wonder if they could develop a drug that was nonhormonal in nature, and thus unlike cortisone, hut a drug that would provide the same benefits as cortisone. In their search they worked on compounds at first thought to be valuable against certain emotional disorders. But the compounds later proved to be of very limited value in mental disease. One of the compounds screened, however, did have some positive effects on inflammation, and this in turn led to the syn- thesis of still another chemical. In March 1964 this chemical, indomethacin, became, in the words of one well-known sclenti~t, "the most promising drug since cortisone." After considerable testing, the drug was approved for prescription use in June 1965. Merck has deliberately avoided publicity for the drug for several rea Sons. Since the FDA's new tough line on all new drugs, pharmaceutical companies are becoming reluctant to blow their horns about any new compound. And more PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRTJG INDTJSTRY 3181 important, Indocin is designed to relieve symptoms of chronic disorders-illnesses that come and go or come and stay for years on end. The company han been under standably reluctant to sound the trumpets about Indocin until it had at least a year's experience with the drug on the prescription market. Now, with patients receiving lasting benefit from Indocin, Merck feels it can begin to bring some aspects of the story of the drug to the public. The drug is proving itself to even the most conservative physicians and laboratory scientists, Of course, each day the line of grateful Indocin patients becomes longer and longer. The drug does not have to prove itself to these people. It already has been ~ "lifesaver" to thousands, There is, for example, the 62-year-old New York City carpenter who could not work for nine years. His hands were so crippled by arthritis that he could not hold his tools. After five weeks on Indocin his hands improved markedly. "I can hOld a hammer again, and what's more, I can drive a nail-pretty straight, too," he says. Within a few months this man expects to be back at work. Indocin will have returned him to a reasonable level o~ personal dignity-not to mention to a reasonable level of income. But perhaps the most extraordinary Indocin success story of all involves a 68-year-old Connecticut wornai~ who has been a virtual invalid for the past eight years. Her arthritis was so bad that years ago she gave up going to the corner grocer for the absolute kitchen necessities. "After I began to take Endocin," she relates, "I noticed that I felt better. It was only a couple of days ~r so that I'd been taking the drug, but I began to feel bettei~. After ~ few weeks I felt that I could aeti~ally- take a little walk-perhaps down to the front of the house and back." Last week she walked about 60 yards to the corner grocer. When she left, still somewhat unsure of herself, though not In great pain, she was sobbing just a little bit. But it was a joyous cry. Dr. MCCT~ERY. The story, written by two science writers, in the July issue featured Indocin by name in the title of the article, and said it was useful for "bursitis," "trick knee," "tennis elbow," and "a host of other less common disorders characterized by pain and swelling in and around the joints." The support for these claims was largely lay testimonials some of which, according to the article and the firm, were made available to the writers by the sponsor of the drug. Mr. Fletcher said that the firm was in no way responsibile for the article, that the authors had heard of stories about the drug from a variety of sources and wanted to do an article about it, and that the firm had simply responded to this inquiry from responsible science writers. Mr. Fletcher said the article was in no way promotional and wanted to so assure the agency. The drug, of course, had not been approved for use for the above- mentioned conditions for which it was claimed to be effective in the Pageant article. We knew also that a popu]ar article of this sort is apt to create a demand for the drug by the patients who read it. Senator NELSON. As I understand from your testimony at the top of page 2, this article for Pageant magazine was submitted to the FDA prior to publication? Dr. MCCLEERY. Yes, sir. Senator NELSON. So there wouldn't be any question about what was in the article, and FDA could, at least, express their disagreement with claims made for the drug to Pageant magazine if they desired. Dr. MOCLEERY. That is right. I believe that the time interval from the submission of the letter, which was to Mr. Cron-that at that time we would have to assume that the article was already in press, al- though not yet mailed in the July issue. And again, it was, without any question in our minds, an article actually written by the authors PAGENO="0090" 3182 COMPETITIVE PROBLEMS IN THE DRIJ~ INDUSTRY who were independent, I guess well known, ~cience writers in their field. So it was their article in substance, and not that of Merck & Co., so far as we know. Senator NELSON. But they had ad Vance copies of it. Dr. MOCLEERY. Yes. My office, the Division of Medical Advertising in the Bureau of Medicine, was asked to review the article for possible violation of the law, and to review also the advertising of this drug in medical journals to determine if the drug was being promoted to the medical profession on the basis of unapproved claims~? Our concern was that if the firm would make these data on unau- thorized uses available to a free-lanceS team of writers, it might not be scrupulous in its advertising to the medical p~rofession. I would like to leave this now and go to the performance of the company- Mr. GoI~DoN. What did your Division do about this artiele? Dr. MaCLEERY. We responded to the internal inquiry from the èffice of Mr. Cron and gave our view of what the article in fact was, and we wrote a report of the deficiencies. which we thought the Pageant article contained and ~crhat our opinion was of whether or not the law might be considered to ha~ve heeti Violated by Merck & Co. as a consequence of this article. . .. Mr. GORDON. And what was your opinion about that ?Did you think the law had been violated? Dr. MOCLEERY. Yes.. Our opinion in the Division of Medical Adver- tising-which I would like to ask Mr. Goodrich to follow up on-our opinion of whether the law in fact had been violated, I have some apology for. But we thought thatthe. law had been violated because the article, in the form it took, could be considered to have been caused to be issued by the companybecause of the turning over of documents to the writers which were built into the article and which would have come from no other source. And for. this reason, the promotion of unauthorized, unapproved uses, which could be a consequence of the article, we thought should be laid to the door of the company. Senator NELSON. Well, now, this article was published in th~ July 1966 issue of Pageant. Dr. MOCLEERY. Yes, sir. Senator NELSON. I notice that in a letter dated March 8 of this yehr, 1968, you concur in the recommendation for prosecution of the company. Dr. MCCLEERY. That is true. Senator NELSON. And that on March 11, 1968, Dr. Ley stated, "The Bureau of Medicine recommends that prosecution of the firm be insti- tuted subject to approval by the Attorney General." What is the status of that recommendation now? Dr. MOCLEERY. I think Mr. Goodrich can speak better to that. Mr. GooDnIcli. The case is in my office. Senator NELSON. But the recommendation has not left your office. Mr. GooDRICH. It has not. Senator NELSON. Is it correct that the prosecution involved not only ~lie Pageant article, but also some other advertising materials? Mr. GOODRICH. Yes, sir. PAGENO="0091" COMPETITIVE PROBLEMS IN THE DR~JG INDTJSTRY 31~3 Senator NELSON. There are several documents here as well as letters by Dr. Weinstein, Dr. Ley, Dr. McCleery, and others; and since they explain this situation in some detail, and specify the kinds of viola- tions that the FDA believes do occur, and give examples of them, I would ask that they be printed in the record at the appropriate place.1 Dr. MCCLEERY. I would like to turn now to the third element of the promotional campaign with which we had to deal, and that concerns the medical journal advertising to the medical profession by Merck Sharp & Dohme. We have already supplied for the record copies of two major kinds of ads 2 which have been used by the company, ~ne characterized by a submission which you have in your hands dated July 18, and which is identical in content to the issues of the same ad in July 4 and August 15, 1966, issues of the .Journal of the American Medical Associ- ation. There is a second ad, with some minor changes, which you also have a copy of, and bears a handwritten inscription called the "The" Ad, which was published in November 1966, and I want to make com- ments on both ads. Mr. GORDON. Which ones are these? Dr. MCCLEERY. The first ad, you have a copy of the JAMA dated July 18, 1966. We happened to act in our memos on an issue dated July 4. All of these ads are identical. They are just prints of the same ad in different issues. The `one you have at hand is marked with the hand inscription "A." The "A" ad i~ July 18, 1966. As I go along, we will deal with the features which' are common t~ the second ad, marked November 1966, in the American Journal of Medicine. Senator NELSON. Are you referring now'to the AMA Journal? Dr. MOCLEERY. Right. Senator NBLSON. In looking at the ad, it shows a radiograph of .a left foot and says, "Indomethacin' is a drug of choice in acute gout." Is that correct? Dr. MCCLEERY. Are you reading correctly? Senator NELSON. "Indocin is a drug of choice in acute gout." Dr. MOCLEERY. I just wonder what your question is. Senator NELSON. Is it a drug of choice, do you know? Dr. MaCLEERY. One of the reasons we have submitted both this ad and the ad of November is because the author said "the drug of choice." You will note in the JAMA ad there is a bracket around the "a" which the company at this time inserted in place of the author's own statement that it was the drug of choice. Senator NELSON. Who inserted the "a"? Dr. MaCLEERY. The company and its advertising agency. We have assumed this was in a mood of good instinct and caution that the com- pany changed the author's quote from the word "the" which is cor- rect, and which is in the view of many a far less defensible statement. concerning the value of the drug. The complexities of what the state- ment says with the word "a" in instead of "the" is the problem. In any event, in answer to your question, in my opinion, and in the opinion of many who are expert in this field which I am not, indomethacin is a good drug for the treatment of acute gout-it had not reached the level of "the drug of choice" for acute gout. 1 See documents and letters beginning at p. 3246, infra. 2 See supplemental information beginning at p. 3221, infra. PAGENO="0092" 3184 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. it had reached the level of the drug of choice? Dr. MGCLEERY. That it had reached the level of "the drug of choice" at that time I think hardly anyone would accept-perhaps the authors would, but most would not agree that even today it is the drug of choice. Senator NELSON. They would not agree today that it is the drug of choice. Dr. MCCLEERY. I believe not. That it is a good drug, yes. But there is no evidence that exists on any scientific basis of comparative studies with Indocin and other drugs used in the treatment of gout. The kinds of studies that would be required to make an acceptable statement that this is the drug of choice have not yet been done. Senator NELSON. The phrase "the drug of choice" are words of art, aren't they, in the medical profession? That is, they have a special meaning. `When you say "the drug of choice," those are words of art in medical language, are they not? Dr. MCCLEERY. I would be more inclined to say that the company's use of the word "a" puts it into more the realm of art and not of science. Senator NELSON. I was using a legal phrase. I meant to say the phrase has a special meaning to the medical profession if you say a drug is "the drug of choice," does it not? Dr. MCCLEERY. I would say that the phrase "the drug of choice" should be based on science, and not on art. Senator NELSON. I am confusing you. I am using a legal phrase, so we will just skip that. The phrase "the drug of choice" has a special meaning in medical language. Dr. MCCLEERY. Yes. Senator NELSON. That is what words of art mean in legal phrase- ology. And what is the meaning of that phrase "the drug of choice',' in medicine? Dr. MCCLEERY. If one takes at face value the claim, and believes that the person making such a statement is to be believed, it is the highest accolade that one can give a drug in competition with other drugs used for the same treatment-4hat is the best drug, and it is the drug that should be chosen for the treatment of most cases-should be tried first if one is choosing from a number of drugs. Senator NELSON. That is my point. If you say "the drug of choice" you mean that it is the first drug recommended to be tried2 based upon all the scientific evidence that is available as of that tinie; is that correct? Dr. MOCLEERY. Yes. Senator NELSON. I had to read it twice before I saw the "a" in pa- renthesis. If you glance at this as I do you see "indomethacin, drug of choice for acute gout." This is this kind of very clever advertising which, it seems to me, can be very misleading. Isn't it easy enough to read something like that ad and not notice the little "a" in paren- thesis. You simply see "drug of choice," and interpret it to mean automatically, as medical people would, that this must be the drug of choice? Dr. MOCLEERY. You put me in the difficult position of defending the company, Senator, and I do not welcome it. But I must say that in our discussions with the members of the firm, they affirmed, and I for one believe, that their reason for putting in the word "a" was PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3185 that they were queasy about claiming it was "the" drug of choice, and this, in their mind, was to weaken the impact of the claim, and I believe they were telling the truth. Senator NELSON. It is weaker' than "the drug of choice." But why use the phrase "drug of choice" which are words of art to the medical profession unless you are trying to give the impression to somebody who glances at it that it is the drug of choi~e? I read all kinds of these ads. If you sit and analyze them long ~nough, carefully enough, you can end up defending them. But that is not the way people read ads. Dr. MoCLE1a~r. No, sir; but I think there i~ more of inter~et on this point than we have gotten to; and I direct your attention to the use of "a" in two other places in the saute ad'. If you start on your left, I believe you will see another quotation from the paper by the same' authors in reference to rheumatoid arthritis. At that point you will see the use of the word "a" in brackets again inserted into the quote. The article actually said at that point this is "the first noucorticosteroid drug" to do what follows. And the company again removed the words `~the first" and inserted in caution and I woWd say giod instincts, regardless of other attributes of the ad, the word "a." You will find it again in the third panel, in a quote from, not a paper, but remarks at a symposium sponsored by Merck & Co., by a Dr. Englund of Phoenix, Ariz., where his quote is changed to include the word "a" in the body of it. Do you see that? Senator NELSON. I see it. And if I understand what drug of choice means, I am impressed by the fact that every time the company can use the phrase "drug of choice" it is there. Why don't they say a useful drug? What would FDA say if under the reproduction of this radiograph of the foot it said "inclomethacin is a", and then in capital letters "drug of choice," and then back to lower case, "in acute gout." Dr. MCCLEEEY. We would have said it is very' little worse than we thought it was in its present form. Senator NELSON. You would say it was very little what? Dr. McCLr~tar. Very little woi~se. I say it is bad the way it is. What you suggest would make it very little worse. It is bad enough. Senator NELSON. These are words of art in the medical profession, so every time the words can be fitted in, the phrase "drug of choice," whieh captures any medical person's eye, the phrase is used. Then to techni- cally clear themselves they add a little "a" with a bracket around it. Dr. MCCLEERY. Yes, sir. We felt it was wrong, and the use of the word "a" in the insertion did not relieve them of the fault. We charged the ad as misleading in its JAMA form. I would only like to point out to you that you also have an ad which we labeled the "The" ad, which is a November 1966 issue. There the ad that you see appears in all of its glory with the quotes intact, so that the word "the" is in all of the places where the word "a" is here. And these `are the two ads that I want to discuss in detail this morning. Senator NELSON. All right. Thank you. These ads will be put in the record in the `appropriate place. Are you going to get to the October 24 issue of Modern Medicine, which carried almost the same ad as the Journal of the American Medicai Association, again where they say it is the drug of choice? Dr. MCCLEERY. Yes, sir. The reason we submitted that little magazine, PAGENO="0094" 3156 COMPETW[VE PROBLEMS IN TILE DRUG INDUSTRY in its October issue is to show the breadth of the November 1966 cam- paign containing the word "the'? iii place of "a," and you have copies of the October 26, I believe, issues of ~fodern Medicine, you also have copies of the. November 1966 issues of the American Journal of Medicine, and Arthritis and Rheumatism magazine, all of which are the same. They are just prints of the same ad ~n different journals. Senator ~LSON., Did the pae)~age insert at any. time include the same phrasing, "the drug o~hoi&? Dr. MoCi4r~ii~. No, sir; it d~id~not Senator NELSON. And the EDA did approve the pa~kage insert? So at the same time that the package insert is making a lesser claim, u~mg different language, the eom~iany is running advertisements in the Journal of the American Medical Association and other medical maga- zines claiming that Indocin was the drug of choice in gout; is that correct? Dr. MoCI~r~Br. Correct. Senator NEI~SQN. So there wa~, no question that the company knew what the viewpoint of FDA was as to the requirements for the pack- age insert at the time they were running these ads in the medical jQurnals. Dr. MOCLEERY. I should say not. The so-called A ads that we have been discussing appears as ide~n~ tical advertisements in the Journal of the American Medical Associa- tion in many issues, but also in issues of July 4 and August 15. And these were found to be featuring under the major headline the theme that the drug "extends the margin of safety in the long-term management of arthritic disorders." At the same time- Senator NELsoN. Where are.you, Doctor? Dr. McCI~ERY. The middle of page 3. Senator NELSON. Please. proceed. Dr. MOCLEERY. At the same time, the Office of Marketed Drugs, under Dr. Jennings, who appeared y~sterday, was negotiating with Merck for changes in the package labeling to emphasize newly recog- nized hazards that had emerged during the first year of clinical experi- ence since original approval of the drug. The JAMA ads in July 4 and August 15, 1966, issues were analyzed and found to be defective, in our opinion, in several respects. I am going to mention only a few of them. I would not want you to believe we have exhausted our objections.by what I point out today. Senator NELsoN. This is now in what edition of JAMA? Dr. MOCLEERY. The July 18 issue that you have in front of you. Senator NELSON. That is the one you are going to discuss now? Dr. McCu~iiv. Yes, sir. I would like first to mention generally the major defects of the ad in our view, and then will be more specific re- garding the details of our objections to certain of the features of this and of a later ad which appeared among others in the November 1966 issue of the American Journal of Medicine. The basic theme of greater long-term safety in the ads was not sup- ported by the clinical experience. Mr. GORDON. You say "greater"? Dr. MOCLEERY. It is a kind of advertising technique which has a great deal of value because it says "greater" but does not specify greater than what, and goes in the advertising world under the delight- PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3187 ful phrase called a "dangling comparative." And this is represented well by this headline. Senator NELSON. You are referring, to the headline that reads "ex- tends the margin of safety in long-term management of arthritic disorders"? hr. MoOL1~Y. Yes.. This implies that the drug,, as a them~ of advei~tising, has gieater long-term safety than something, else, or in el~ect, in. our view, every- thing else. To the contrary, in our experience the longer the drug had been on the market, the more seriQus adverse, experience information had been reported to us. Now, the ad, as you have, seen, and talked about, used four blocks of depictions of X-rays that were accurate representations of the four indications for the drug. And they quoted underneath these depic- tions, and in support, presumably, if the ad were a good ad-in sup- port of the headline claim. And they quoted apparently authoritative sources, but without the full impact of the limited experience con- tained in the actual articles they were quoting. And the ad features, for example, one reference which on checking proved to be only a 2- or 3-inch abstract of a 1964 speech. That,js the one on the second block by Dr. Rothermich. The ad quoted the author's opinion that "results have been uniform- ly excellent or good." Dr. Rothermich's same abstract, although brief, also included his view that while "excellent results have also been obtained in some cases of rheumatoid arthritis, there have been strik- ing failures as well," So it is perhaps not surprising that while the advertising included this author's favorable remark regarding his experience with spondylitis, which they did, they then turned to another author, namely Hart and Boardman for a more favorable quote concerning the possible value of the drug on rheumatoid ar- thritis, and did not reflect Dr. Rothermich's view on rheumatoid ar- thritis in the ad. We consider this as not quite cricket, at least. It offered the drng for "arthritic disorders," rather then solely for the specific four conditions for which it has been approved. This is a small point, and one of the kind of things we have been accused of "nit-picking" `about. All we would have asked here was they merely put in the. word "certain," to show the reader when he was getting a quick view of what the drug was for, that this was not for all arthritic disorders, but at least only for certain of them. And then he would look more carefully as to what he expected the drug to be indicated for. Senator NELSON. Did the company object to the insertion of the word "certain"? Dr. MCCLEERY. Well, we met them somewhat later than this time. Whereas I am not sure whether they objected or not, there was a marked change in their advertising subsequent to our meeting, so that this became an issue of no importance, because all of these claims disappeared subsequently. The ad goes on in a major way to characterize the drug as non- steroid, which of course it is, but failed to disclose in this connection that whereas it was not a corticosteroid, which is a class of drugs also used for the treatment of these conditions, and for which there are major side-effect concerns already well established in the minds of PAGENO="0096" 3188 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the profession-so they failed to disclose in this connection that Indocin has some of the major side effects of these steroids themselves- for example, an ulcer-producing effect. The ad goes on to claim that the drug extended the margin of long- term safety without any evidence in our view to support the cl~hn, and it quoted from isolated pieces of 1itera~ure to support thls-~-~~ne an excerpt from a symposhmi sp~sor~ b~ the comp y--and to claim that the drug was "the dru~ ~f choice" in go~it and in osteo- arthritis of the hip, neither of which. claims had. been approved for inclusion in the package labeling of the drug. it also quoted from two leadir~g ~nglish ~nthoHties to the eff~ct that the drug was useful in most cases of rheumatoid arthritis When these authors had used the tablet and nOt the marketed capsule, and when their actual opinion, known to Mei~ck, was `that the drug was useful in only selected caSes of rheumatoid arthritis. It featured the claim of one of the participants in a Merc1~-sp~u- sored symposium This is attributed to !)r Englund-they featured a claim, quoting from him at this symposium, that he had had ~OO patients on the drug for ~ years, when Merck's own reeords would have told them this was not true. And finally, in the "brief summary" of information On side effects and contraindications, some of the major warning infoThiation was left out, such as the fact that indomethacin itself had caused ulcers. of the stomach and so on, and that the drug should not be adminis- tered to chilcfren. Now, how they did this is a very interesting `operation-- Senator NEr~soN. Which ads were they? In which ads were the two warnings left out? Dr. Mo1Di~u~kr. They were left out iii both of the ads. Most of, these features that I have been discussing are' common to the 3~uly ads and the NoVember ads, Senator. ~ou see at the bottom of the page of the ad that you have in front of you what we call "the brief summary," and it contains information from the package insert that summarizes the warning information On the product. We say that, iii practical fact, they had left out significant warnings which they are required to include in that brief summary of warning information. Because it ~S a ~rery subtle, but v5ry important, advertising kind of language-I would like to point out why We say this. Senator NELSON. You are saying that in no place in the fine print of this ad do they include the warnings that indomthacin may cause ulcers, and that the drug should not be administered to children. Dr. MOCLEERY. Yes, sir. Senator NnLSON. And that was well known at that time, was it not? Dr. MOCLEERY. Yes. But the issue is much more subtle, because there are references to both of these subjects in the ad which We have found fault with, and I would like, to stress thiS kind of advertising technique which appears to fulfill the requirements of law, but in our view does not, because it is a very common practice, one' which we are trying to fight. It is often called nit-picking by our opponents, as a way to denigrate the significance of changes in words, which we think is very important. Senator NELSON. I have not read all the fine print. Are you saying that in this JAMA ad of July 18, 1966, somewhere in the fine print, there is the warning that it should not be used for children? PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3189 Dr. MoCi~ay. I am saying that in our view it is not, although the subject is discussed. I would like, if I can go on just for a moment, to point your attention to the way that the ad differs from the package msert in these respects. We believe that these that follow exemplify what might be called the euphemistic style of revealing warning information. The ad's "brief summary" translated the package insert's warning "Indocin itself may cause peptic ulceration * * ~" into the area of causal doubt in this manner: "Ulceration of the stomach, duodenum, or small intestine have been reported. * * *~ Senator NELSON. I do not see that in the ad. Is that the July 18 ad? Dr. MoCrj~y, Yes, under the "Precautions." "Ulceration of the stomach, duodenum, or small intestine have been reported." Senator NELSON. Is this under the warning section in the package insert? Dr. McCu~y. It is under the contraindications section-but it is in the ad's precaution section. Under the contraindications section in the package insert is the statement that I read first, which is a plain statement which carries the idea that the company has agreed with the Bureau of Medicine to say "Indocin itself may cause peptic ulcera- tion." We are saying that in no way is that statement in the package insert properly reported to the physician in the ad by the statement "Ulceration has been reported." This is a style of statement about side effects that is traditional in ads over the years. It only means that man side effects are reported to be associated with the use of a drug, whic may be by chance, and to say merely that it has "been reported" in no way suggests that it is "caused by" the drug in question. On the other hand, the package insert is very clear. Senator NELSoN. Where does this precaution appear in the package insert? Dr. MoCi `in'-. Under the contraindications section. It is a piece of information under the contraindications section. Senator NELSON. It does not appear under the warning section? Dr. MoC~'in~. I cannot tell you whether it also appears in the warning section. But it does appear in the package insert in the con- traindications section. Senator NELSON. There is also a warning section in the package insert, isn't there? Dr. MoCi~riw. Yes. Senator NELSON. Those warnings do not appear in the warning sec- tion of the package insert? Dr. MOCLEERY. I frankly cannot tell you. I do not know that well enough by heart. Senator NELSON. I wish you to submit for the record the package insert that was being used by the company at that time. I would like to have that in the record at this stage of the testimony. (The information to be furnished for the record follows:) 81-280 0-68-pt. 8-7 PAGENO="0098" DIRECTiON CIRCULAR 0 ~ ~ r MERCK SHARP £ DOHM~ I D'vI on of M k £ Co i~ L \~ ~ ~ J U Wost Point. Ponnsylvsnla (1üMEHAC1~) AHFS Category 9200 MURCK SHARP £ DOHM~ Effective May 1965 PrInted In U.S A PAGENO="0099" INDOCIN* (indomethacin) is a new "ante rheumatic" drug that has anti-inflammatory, analgesic, and antipyretic activity. It has a unique chemical structure which differentiates it from the salicylates, corticosterolds, phenyI~ butazone-like compounds, and colchicine. Un- like corticosteroids, it has no effect on pituitary or adrenal function. INDOCIN is an effective anti-inflammatory agent that is suitable for long term as well as short term use in adult patients of all ages. It has been found effective to relieve pain; reduce fever, swelling, and tenderness; and increase mobility in patients with rheumatic disorders. INDICATIONS * INDOCIN has been found effective in the treatment of: Rheumatoid arthritis Rheumatoid (ankylosing) spondylitis Degenerative joint disease (osteoarthritis) of the hip Gout In these conditions INDOCIN may often re- place other commonly used agents such as corticosteroids, salicylates, phenylbutazone- like compounds, and coichicine. (NDOCIN~ (fndomethacin) Rheumatoid Arthritis In many patients with chronic rheumatoid arthritis INDOCIN produces a significant de- crease of pain and stiffness within 48 hours, while in other patients treatment must be con- tinued longer before significantsubjective relief or objective evidence of decreased joint swell- ing and tenderness occurs. Treatment v'ith INDOCIN should be continued for at least a month before concluding that it has not pro- duced significant benefit. When a response to INDOCIN has been obtained, the daily salicylate requirements can usually be reduced and often stopped. Also, if patients have been receiving corticosteroids, the steroid dosage often can be gradually re- duced by 25 to 50 per cent, and in some patients it can eventually be completely ais- continued. In such instances the steroid dos- age should be reduced slowly. In acute rheumatoid arthritis, or in acute flares of chronic rheumatoid arthritis, INDOCIN will usually produce prompt improvement with relief of pain, tenderness, swelling and stiffness. Rheumatoid (Ankylosrng) Spondyl it is INDOCEN frequently produces marked relief of pain and improved motion of the spine within 3to 10 days. NDOCIN~ (~ndornethacin) C) 0 H H 0 ci~ z H C) ci (12 H RoglMered trademark of Merck d. Co., tNC. / PAGENO="0100" NDOCIN~ (~ndornothacifl) Degenerative Joint Disease (Osteearthritis) of the Hip INDOCIN has provided relief of pain and increased range of motion in patients with degenerative joint disease of the hip. Gout In acute attacks of gout the response to INDOCIN is usually rapid and often dramatic. Marked reduction of pain may be obtained within 2 to 4 hours. Tenderness and heat sub- side within 24 to 36 hours, and swelling de- creases over a 3 to 5 day period. During the interval phase of gouty arthritis, indomethacin together with adequate doses of uricosuric agent may provide relief of pain and prevent the recurrence of acute attacks. CONTRAI NDICATIONS As with other anti-inflammatory agents, 1NDOCIN may mask the signs and symptoms of peptic ulcer. INDOCIN itself may cause peptic ulceration or irritation of the gastro- intestinal tract. For these reasons it should not be given to patients with active peptic ulcer, gastritis, or ulcerative colitis, and should be used with caution if there is a history of these disorders. in 4 patients with regional enteritis treated for up to one month, and one patient treated for 6 months, INDOCIN was well toler- ated. However, in view of the paucity of data, INDOCIN(~ (Indomethacin) this drug should not be given to patients with regional enteritis until additional evidence of gastrointestinal tolerance is available. Reproduction studies In mice, rats, and rab- bits showed no effect on fetal development or the reproductive cycle, although in rats there was some decrease in fetal viability. Studies in mice demonstrated that INDOCIN crosses the placental barrier. Since the effects of INDOCIN on the human fetus cannot be pre- dicted with certainty from animal studies, the safety for use in pregnant patients has not béenestablished. Since the experience with INDOCIN in chil- dren is limited, it is recommended that this drug should not be administered to pediatric age groups until the indications for use and dosage have been established. WARNING Patients who suffer from dizziness, light- headedness, or feelings of detachment on INDOCIN should be cautioned against oper- ating motor vehicles or other machinery, climb- ing ladders, etc., if these symptoms are present. INDOCIN should be used with caution in patients with psychiatric disturbances, epi- lepsy, or parkinsonism, since it may, in some instances, aggravate these conditions. C ~J) PAGENO="0101" INDOCiN~ (indomothaCin) PRECAUTIONS AND ADVERSE REACTIONS The most frequent adverse reactions asso.) dated with INDOCIN are headache, dizziness, lightheadedness and gastrointestinal disturb- ances such as nausea, anorexia, vomiting, epigastric distress abdominal pain or diarrhea The central nervous system effects are often transient and frequently disappear with con tinued treatment or with a reduction of dosage. The severity of these effects may on occasion require stopping therapy. The gastrointestinal effects may be minimized by giving the drug immediately after meals or with food Studies in normal subjects with radioactive chromate-tagged red blood cells indicate that large doses of indomethacin (50 mg. four times a day) produce less fecal blood loss than average doses of aspirin (600 mg four times a day) Notwithstanding INDOCIN may cause single or multiple ulceration of the stomach duodenum or small intestine There have been reports of severe bleeding and of perforation WILh afewfatalities Patients may also develop gastrointestinal bleeding with no obvious ulcer formation If gastrointestinal bleeding occurs INDOCIN should be discontinued. In many patients with peptic ulceration a history of a iNDOCIN~ (indomothacin) previous ulcer was present or they were on concomitant steroids, salicylates, or phenyl- butazone. The possible potentiation of the ulcerogenic effect of these drugs cannot be ruled out at present. In some patients there was no history of a previous ulcer and other drugs were not being given As a result of obvious or occult gastrointestinal bleeding some patients may manifest anemia For this reason periodic hemoglobin determinations are recommended Rare reports where it is not known whether the effects can be attributed to the drug include bleeding from the sigmoid colon either from a diverticulum or without a known previous pathologic condition and perforatioi of pre existing sig moid lesions (diverticulu m carci noma). in other rare cases a diagnosis of gastritis has been made while INDOCIN was being given One patient developed ulcerative colitis and another regional ileitis while receiv- ing INDOCIN When INDOCIN was given to patients `with pre-existing ulcerative colitis, there was an increase in abdominal pdin Other adverse effects that have been infre- quently reported include drowsiness tinnitus mental confusion depression and other psychic disturbances blurred vision, stoma - C~) t~i 0 z ni i. PAGENO="0102" INOOCIN® (indómethacln) titis pruritus urticaria angioneurotic edema, skin rashes, arid edema. Extensive laboratory examinations have been made during treatment with INDOCIN. A slight, usually transient, increase in BUN has been reported in some patients. Although two in~ vestigators have reported apparent changes in renal function, the reliability of the techniques used was uncertain. The preponderance of evidence indicates that INDOCIN does not have an adverse effect on renal function. Nevertheless, renal function should be checked periodically in patients on long term therapy. Patients with pre existing renal disease have received INDOCIN without difficulty. A few cases of leukopenia have been re- ported in patients with rheumatoid arthritis; leukopenia is not uncommon in this disease. Transient elevations in alkaline phosphatase, cephaiin.cholesterol flocculation, and thymol turbidity tests have been observed in some patients and, rarely, elevations of SGOT values. The relationship of these changes to the drug, if any, has not been established. Unlike steroids, INDOCIN has not been asso- àiated with an increased incidence of infections. As with any new drug, patients should be followed carefully to detect unusual manifesta- tions of drug sensitivity. INOOCIN® (Indomethacin) DOSAGE AND ADMiNISTRATION INDOCIN Is available as 25 mg. capsules for oral use. In chronic disorders treatment should be started with a dosage of 25 mg. two or three times a day. Starting therapy with low doses, with gradual increases when necessary, will produce maximum benefit and minimize ad- verse reactions. Always gIve INDOCIN with food or immediately after meals to reduce gastric irritation, Dosage Recommendations for 1. Rheumatoid arthritis and rheumatoid ~`an- kylosing) spondylitis Initial dosage 25 mg two or three times a day If the response is not adequate increase the daily dosage by 25 mg. at about wee/dy intervals until a satisfactory response is ob. tamed or a dosage of 150 to 200 mg. a day is reached. If a satisfactory response is not obtained with 200 mg. a day, larger doses probably will not be effective. If adverse reactions develop as the dosage is increased, decrease to a tolerated level and maintain at that dosage for 3 to 4 weeks. If an adequate response has nottheri been obtained, gradually increase the daily dosage by 25 mg. 0 tI) PAGENO="0103" INDOCIN® (indomethaCifl) at about weekly intervals to 150 to 200 mg. a day. For patients with acute rheumatoid arthritis or with acute flares of chronic rheumatoid arthritis, increase the dosage daily by 25 mg. until a satisfactory response is obtained or a tota& daily dosage of 150 to 200mg is reached If adverse effects develop as the dosage is increased, it should be reduced to a tolerated level for 2 or .3 days and then gradually in- creased by 25 rag, every few days as tolerated. After the acute phase is under control, it is often possible to reduce the daily dosage of INDOCIN gradually to 75 to 100 mg, Reduction of steroid dosage: Use of INDOCIN often will permit a gradual reduction of steroid dosage by 25 to 50 per cent. In some patients steroids can be slowly discontinued over a period of several weeks or months. The usual precautions should be observed in withdraw- ing steroids. 2. Degenerative Joint Disease (Osteoa.rthuitis) of the Hip Initial dosage: 25 mg. two or three times a day. If the response is not adequate, Increase the daily dosage by 25 mg. at about weekly intervals until a satisfactory response Is ob- tamed or a dosage of 150 to 200 mg. a day is reached. If a satisfactory response is not obtained with 200 mg a day, larger doses will probably not be effective. If adverse reactiOns develop as the dosage is increased, decrease to a tolerated level and maintain at that dosage for 3 to 4 weeks. If an adequate response has not then been obtained, gradually Increase the daily dosage by 25 mg. at about weekly intervals to 150 to 200 mg. a day. 3. Gout To control acute attacks: 50 mg. three times a day until all signs and symptoms subside * Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradu. ally disappears in 3 to 5 days. To prevent acute attacks: During the interval phase of gouty arthritis the dosage may be reduced to as lithe as 25 mg twice a day, given with an adequate dose of a uricosuric agent such as probenecid. CHEMiSTRY AND PHARMACOLOGY The chemical name for indomethacin is 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole- NDOC1N~ (indomethacin) I. PAGENO="0104" Anti-Inflammatory Action In laboratory animals, IN4DOCIN is a potent anti-inflammatory compound. Results of gran- ulorna inhibition tests in rats receiving the compound either orally or by local application indicated activity about 85 times that of phenyl- butazone. Given orally, the compound was about 4 times as active as hydrocortisone. When given in effective doses to intact rats, indon~ethacin, unlike anti-inflammatory ste- roids, did not affect the size of the adrenals or INDOCIN~ (Indomethadn) thymus, or retard gain in body weight. Its anti- inflammatory activity does not depend upon activation of the adrenols, since it was fully active in adrenalectomized rats. The anti-inflammatory activity of INDOCIN was also demonstrated by its ability to inhibit edema formation induced by subplantar injec- tion of carrageenin in rats. By this test, the relative potency of indomethacin was: 30 times aspirin, 20 times phenylbutazone, and 2 times hydrocortisone. INDOCIN does not possess antihistaminic or antiserotonin activity, since it did not affect edema induced by injection of egg white, serotonin, or yeast. Combinations of indomethacin and a steroid were more effective than comparable doses of either drug alone in inhibiting granuloma growth or edema formation. Antipyretic Activity INDOCIN is an antipyretic in laboratory- animals. In rabbits it was about 20 times as -potent as phenylbutazone and 10 times- as potent as aminopyrine. Its duration of action was much longer than that of aminopyrine and comparable to that of phenylbutazone. In rats indomethacin appeared to be about 10 times as potent as phenytbutazone. The antipyretic activity of INDOCIN hasbeen INDOCIN® (Indomethacin) 3-acetic acid. It has the following structural - formula: CH3O CH2COOH - CH3 I. 0 0 w LTj C!) `-3 z C!) `-3 PAGENO="0105" 0 H H C H ~J2 H INDOCIN® (Indomethacin) confirmed clinically by observations in patients with Hodgkin's disease, acute rheumatic fever, and a variety of other acute febrile conditions. Analgesic Activity Laboratory tests designed to detect mild analgesic activity indicate that indomethacin is more potent than aspirin or aminopyrine. Absorption and Excretion INDOCIN is well absorbed after oral admin- istration in all animals, including man. In dogs, monkeys rats, and man, peak plasma levels after an oral dose occur within 0.5 to 2 hours. The drug present.in the plasma of dog and man is virtually all unchanged indomethacin, but a metabolite (probably the glucuronide conjugate) may be present for the first half hour after intravenous injection in the guinea pig. The route of excretion is related to the species of animal and is independent of the route of auministration or size of dose. Nearly all the compound could be recovered in urine and feces. The rabbit eliminates indomethacin al- most entirely in the urine, while the dog excretes nearly all the compound in the feces. Therat, guinea pig, monkey, and man eliminate it by both routes. In man, about two-thirds of the drug is excreted in the urine. INDOCIN® (Indomethacin) In rabbits, rats, guinea pigs, and monkeys, some indomethacin is metabolized by deacyl- ation or demethylation and the metabolites are excreted in the urine as such or as the glucuronide conjugate. In man, however, no evidence of molecular breakdown has been observed and virtually all of the material ex creted in the urine is indomethacin glucuronide AVAILABILITY No. 3316-INDOCIN capsules, 25 mg. each, are opaque blue and white, imprinted with an MSD trademark and potency, and are sup- plied in bottles of 100. REFERENCES Biika P J Wol helm F and Williams R C Jr indo methacin: A New Antirheumatic Agent, Minnesota Med 47: 717, July 1964. Boiand E W Nonspecific Anti inflammatory Agents Some Notes on Their Practical Application, Especially in Rheu- matic Disorders, Caiifornia Med. 100: 145, March 1964. Catogoto P M at ai indomethacin in Rheumatoid Arthritis Properties Side Effects Arthritis d. Rheumatism 7 300 June 1964 (in Soc. Proc.). Clark G M indomethacin In Rheumatoid Arthritis Arthritis & Rheumatism 7: 300, June 1964 (in Soc Proc.). PAGENO="0106" Datey. K. K., and Pandya, V. N.: The Value of indomothacin in Rheumatoid Arthritis, J. Indian M. A. 42: 166, Feb. 16. 1964. Herman, R. E.. Meisinger, M. A. P., Davis, G. E., end Kuohi, F. A. * Jr.: The Metabolites of Indomothacin, a Now Anti' Infltimmatory Drug, J. Pharmacol. & Exper, Thorap. 143: 215, Feb. 1964. Hart, F. 0., and Boardman, P. L.: Indomethacin: A Now Non. Steroid Anti~lnflammatory Agent, Brit. M J. 2: 965, Oct. 19, 1963. Hart, F. D. * and Boardman. P. L.: Current Therapeutics: Indomothacin, Practitioner 192: 828, June 1964. Hucker. H. B. * Zacchoi, A. G., and Cox, S. V.: Studies on the Physiological Disposition of indomethacin, Fed. Proc. 22: 544, March-April 1963. Katz, A. M.. Pearson, C. M. and Kennedy, J. M.: The Anti' rheumatic Effects of lndomethacin In Rheumatoid Arth- ritis and Other Rheumatic Diseases, Arthritis & Rheumatism 6:281, June 1963 (in Soc. Proc.). Katz, A. M. * Pearson, C. M., and Kennedy, J. M.: A Clinical Trial of lndomethacln in Rheumatoid Arthritis, Clin. Pharmacol. & Therap. 6: 25, Jan-Feb. 1965. Kelly. M.: lndomethacin: An Antirheumatic Drug, Lancet 2: 474, Aug. 29, 1964 (in Letters to the Editor). Kelly, M.: lndomethacin, Remarkable Antirheumatic Drug, M. J. Australia 2: 541, Oct. 3, 1964. L~varen, 0.. and Allander, E.: Side-Effects of lndomethacin, Brit. M. J. 1:118, Jan. 11, 1964 (in Correspondence). Norcross, B. M.: Treatment of Connective Tissue Diseases with a New Non.Steroidal Compound (lndomethacin) Arthritis & Rheumatism 6: 290, June 1963 (in Soc. Proc.). Paul, W. D.: indomethacin: A New AntI-Inflammatory Agent, Arthritis & Rheumatism Foundation Mod, information Bull., Vol.4, March 1963. Percy, J. S., Stephenson, P., and Thompson, M.: indornethacin in the Treatment of Rheumatic Diecosos, Ann, Uhoumat. * DIe. 23: 220, May 1004. Rothormich, N. 0.: indornothacin: A New l'hnrmnr;rtouio Approach to the MnrrntJ'nmr~nt of Rheumatoid Di'tnn.mn, Arthritis & Rheumatism 6: 295, Juno 1003 (In Soc. Proc.). Rothormich, N. 0.: Clinical Experiences with lndomothacln in Rheumatic Diseases, Arthritis & Rheumatism 7: 340, June 1964 (in Soc. Proc.); Some Pharmacologic Effects of indomethacin, Ibid. Smyth, C. J,, Amoroso, C., and Velayos, E.: Objective Evalua- tion of lndomethecln in Rheumatoid Arthritis, Arthrltia d. Rheumatism 7: 345, June 1964 (in Soc. Proc.). Smyth, C. J.. and Godfrey, R.: The Treatment of Rheumatoid Spondylitis with lndomethacin, Arthritis & Rheumatism 7: 345, June 1964 (in Soc. Proc.). Smyth, C. J., Velayos, E. E., and Amoroso, C.: A Method for Measuring Swelling of Hands and Feet: Part II. Influence of New Anti-inflammatory Drug, indomethacin, in Acute Gout, Acta rheumat. scandinav. 9: 306, 1963. Smyth, C. J., Veiayos, E. E,, and Amoroso, C.: Indomethacin In Acute Gout Using a New Method of Evaluating Joint Inflammation, Arthritis & Rheumatism 6: 299, June 1963 (In Soc. Proc.). Sunshine, A., Laska, E., Meisner, M., and Morgan, S.: Anal. gesic Studies of Indomethacin as Analyzed by Computer Techniques, Clin. Pharmacol. & Therap. 5: 609, Nov.- Dec. 1964, Wanka, J., and Dixon, A. St. J.: Treatment of Osteo-Arthritls of the Hip with Indomethacin: A Controlled Clinical Trial, Ann. Rheumat. Dis. 23: 288, July 1964, Wanka, J,, Jones, 1. I., Wood, P. H. N., and Dixon. A. St, J.: Indomethacin in RheumatIc Diseases: A Controlled Clin- ical Trial, Ann. Rheumat. Dis. 23: 218, May 1964. C') 0 0 z CI) PAGENO="0107" Winter. C. A. * Risley, E. A. * and Nuss, G. W.: Anti.Inflam~ matory and Antipyretic Activities of Indomethacln, 1. (p.Chlorobenzoyl).5.MCthOxY.2.MethYllndOle.3'ACetlc Acid, Fed. Proc. 22: 543. March-April 1963; J. Pharmacol. f Exper. Therap. 141: 369, September 1963. European Rhoumat&opy. 1963: The Fifth European Congress on Rheumatic Diseases. Canad. J. A. J. 89: 181 Oct. 12, 1963. PAGENO="0108" 3200 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Now, is there any place in this ad where the warning or precautions is made that it is not to be used in the treatment of children? Dr. McCu~iir~y. Yes. Senator NELSON. Where is' that? Dr. McYOIAELnY. The statement in the package insert is the one that was under considerable discussion yesterday, `but includes among other verbiage the statement that the drug should not be administered to children. Those words are contained in the original package insert for the drug, un'der the contraindications section. Senator NELSON. Are those the exact words? What are the exact words in the package insert? Dr. McCr~eERr. That the drug shall not be administered `to children. That is in the contramdications section. Senator NELSON. And is some reference made `to that under contra- indications in this ad? Dr. MCCLEERY. Yes. In the ad it is transformed into another style of transmitting information, and in the ad you will find near the bottom of the contraindications section the statement "safety in preg- nancy and pediatric age groups has not been established." That is the only reference `to children in the ad. Senator NELSON. So instead of saying it should not be administered to `children, as it says in the package insert, as required by the FDA, in the ad it says "safety in pregnancy and in pediatric age groups has not `been estthlished." Dr. McCu~'ar~nr. That is right. Senator NELSON. You consider that to be a much weaker cautionary statement. Dr. MoCLi~iri~y. Yes, I do. I consider it is not the same information. Deficiencies in the `ads were publicly noted in a speech before the Pharmaceutical Advertismg Olub in New York, on October 20, 19(36, by our General Counsel, Mr. Goodrich. The firm quickly protested, and shortly thereafter on November 11, 1966, a sort of "Armistice Day," the firm's principal officers met with Dr. Goddard and his staff to go over the problem. The prciblem took into account all of the elements of the advertising that we have discussed. At that meeting, the firm reported that on hearing Mr. Goodrich's comments in New York concerning Indocin advertising, that it had immediately ordered that ad discontinued, and was taking a close look at `all of its promotional efforts. Later on, not too much later, its physician and counsel responsible in the area of advertising came down to go over some ads for other products, that Merck makes an'd advertises, wi'th us. And I must say in defense of the company that from that point in time on, `they have behaved in a very exemplary way. We have watched their advertising on Indocin carefully subsequent to this point. We have watched their advertising on a number of their products for tranquilizers and anti- depressants. We `have seen them introduce two major new products subsequent to the meeting in Dr. Goddard's office, and we could find no serious objection to those. And so I am glad to say this concerning the performance of Merck & Co. And I regret I cannot say it very broadly concerning a number of other companies with which we have dealt. PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3201 Senator NELSON. I am glad to hear that the Merck Co. is now co- operating in their advertising. But something puzzles me about it. This is from a letter of March 8, 1968, signed by you. Maybe you will want to look at it. But quoting from your letter, it says "Attitude of the firm. The poor attitude of Merck~ regarding the advertising regulations has persisted since their promulgation. This is clearly shown in the following pages from Attorney Colburn's letter." And then there are some quotes. Then you say, "In effect, Merck challenges all of the principles of fair balance provided in the existing regulations, an'd even challenges the Government's aifthority in respect to reqtur- ing ingredient information in advertisements except as specified m section 502(n) ," and so forth and so on. How does this letter `dated March 8 conform to your present state- ment that they are cooperating in every way? Dr. MOCLEERY. It does seem contra~dictory, doesn't it? Senator NELSON. A little bit. Dr. MaCLEERY. I hope that is not a letter, because I do not like to write h~tters. Senator NELSON. I will show it to you. Dr. MaCLEERY. I am well aware of it, Senator. It is an internal memo. Senator NELSON. Yes. Dr. McCLEERY. What I said before Senator NELSON. Is the attitude internally different from what it is externally? Dr. MOCLEERY. No. I `hope without looking at it I won't contradict whet I said in that memo at least. What I said was, Senator, what Merck has done in reference to conforming to the law and the regula- tions-you did not ask, and I did not feel it necessary to say, what I think they think, why they are doing it, or what they think of our view of the law on proper advertising. So there is no contradiction. Senator NELSON. I see. What you are saying is that they have made some changes in their advertising policy of which you approve, but they sharply contest FDA's position of authority to regulate and so forth. Dr. MCCLEERY. Right. I did not feel compelled, knowing that Merck would testify tomorrow, to say they disagreed, feeling they would probably get around to that themselves `tomorrow. Senator NELSON. All right. I think the two fit together. Dr. MCCLEERY. Thank you. Soon after this episode, Merck began to show significant improve- ments in its advertising practices for preiscri~tion drugs but not before it ran, I would say inadvertently, because it is hard `to stop a hard- running advertising campaign-in the November 1966 issue of the American Journal of Medicine, another ad which contained most of the faults of the original July ad, plus some additional new faults. I will expand on this. S It represents a very serious kind of advertising practice that I would like for you to understand, and `to he aware of what kin'd of bases we are criticizing aids on, for your own purposes. You have heard me refer to the articles used in the July JAMAS ad, by two Englishmen, Hart and Boardman in the 1963 issue of the British Medical Journal. While the authors had in fact published the PAGENO="0110" 3202 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY report quoted in the Merck ad, we felt that Merck had no rig~ht to adopt the quotation m their 1966 advertising The quotation from an article by Hart and Boardman in the BMJ, October 18, 1963, was used under the ad's caption "Rheumatoid Arthritis," and the ~uote that the company chose and chase to adopt as their own, was `The first noncorticosteroid agent which produced a. predictable and measurable reduction in joint swelling in most cases of active rheumatoid arthritis." Senator NELSON. That is a quote from the Br~tish Medical Journal from an article by Hart and Boardnian. Dr. MCCLEERY. Yes, sir. Our comments wi:th reference to this 1963 quotation are that, first, it does not represent a true statement of the effectiveness of the advertised product, Indocin. And in this regard, the company, we feel, is responsible for choosmg and usmg an au thor's view; that it becomes in this effect their own, that they are responsible. Senator NELSON.What you are saying is that they quoted Hart and Boardman accurately, but Hart and Boardman were incorrect? Dr. MCOLEERY. I do not think I will get around to my view on that if I can avoid it. I am saying that they quoted the article correctly. Whether it represented a correct view of the drug, other than in the mind of the authors, is a responsibility, I say, that the company has to assume-that when they choose a view expressed by an author in scientific literature, that they have to stand on whether or not that represents a general view that is accepted widely by the medical pro- fession at the time that they use it in an ad-that they muSt assume re~ponsibiiity for making that view their own view. Senator NELSON. All right. Dr. MCCLEERY. Now, the approved package insert for the product does not contain the promissory concept represented by "n~ost cases" or "predictable," which were the views of Hart and Boardman. Senator NELSON. Will you explain that. You are referring back to the quote from Hart and Boardman? Dr MCCLEERY Yes, sir, all of this will be in reference to that one quote-all that follows. Senator NELSON. And you are saying that- Dr. MCCLEERY. That the approved package insert reflecting the agreed-upon view of the drug between the Government and the com- pany does not contain the concepts of the features of the drug expressed by Hart and Boardrnan in their view-that the company thereby chose an opinion of someone else which was not, and has not, been approved for representing the drug in the package insert. Senator NELSON. Are you saying that if the company requested to use the words "most cases," and "predictable" in the package insert, you would not have approved that language in the product package insert as of that date? Dr. MCCLEERY. That is not my responsibility, nor do I have enough information to make that judgment I am saying that the package insert of record at the time the ad was printed did not contain these concepts, these promises. The companies are obligated in our view by the law, and the regulations written* on it, to describe a drug, their drug, not beyond the terms included and, approved in the official label- ing for the drug. This is a baseline for' the judgment of advertising, PAGENO="0111" OOMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3203 and it is a baseline we are trying to establish in the mind of the indus- try. it should be their benchmark in keeping their claims within the approved concepts concerning the nature and effectiveness of the drug. It is the official document, negotiated for all drugs of this type, the so-called package insert. Senator NELSON. Do I understand you correctly that they may use words in ads that are not in the package insert, but they may not make claims for the drug's performance that extend beyond the authorized claims that they are able to make in the package insert? Dr. MCCLEERY. Right; we are saying if this kind of information ap- pears in the scientific literature, or as a result of research, the company has a very good legal method to begin to use this in advertising. They should gather together this kind of information and submit it to the Food and Drug Administration as a supplement to their New Drug Application, have this evidence judged and agreed on between the manufacturer and the agency, and get it into the package insert, and then they may indeed use it in their advertising. But the way not to do it is through the route of advertising. Senator NELSON. If this is correct, what you are saying is that you have the legal authority to prohibit them from putting in an ad a claim for the drug that extends beyond the approved claims made for it in the package insert? Dr. MCCLEERY. Yes, sir. I believe that is true. Senator NELSON. I am not familiar with your authority on that. Is there any question about the law on that? Dr. MCCLEERY. May I ask you to ask Mr. Goodrich? Mr. GOODRICH. No, no question on that, Senator. Senator NELSON. What are the penalties for violation of the law on that point? Mr. GOoDRICH. The same penalties for shipping any other mis- branded drug, which is a maximum of a thousand dollars, and in the case of an individual up to a year in jail. But the regulations, the au- thority to specify what should be in the ad, is granted to us by the Kefauver-Harris amendments, and our regulations provide, acquiesced in by the industry, that in advertising drugs that had been cleared througI~tjie new drug procedures, the only permissible claims were thO~that had been approved. Here the point is that the claim that this product is effective in most cases and gives predictable results were not approved We went over yesterday, in connection with Dr Hodges' statement, the points made at the time of approval, in which the limits of the claims were spelled out. The record yesterday will show that the breadth of this claim was not permitted. Senator NELSON. Well, I would assume that anybody reading the package insert, and reading the ad could easily see that the ad is making a claim beyond what is authorized in the package insert. Mr GOODRICH We think so That is the simplicity of our regulatory scheme-to have the approved label as an identifiable, usable bench mark for all promotional efforts-advertising or direct mailing. Senator NELSON. Do you have the authority to require that an ad be submitted for approval in advance of publication? Mr. GooDRICH. In extraordinary circumstances, yes. Senator NELSON. What are those circumstances? PAGENO="0112" 3204 COMPETITIVE PROBLEMS IN THE DRUG INDUSTR~! Mr. GOoDRIcH. Where the product has a possibility of serious adverse effects or of causing fatalities. This was one of the issues that was in dispute when the Kefauver-Harris drug amendments were passed. There was a strong feeling on the part of the industry that we should not have routine preclearance. Of course we did not want that. But we said it would be necessary in some circumstances to have advance pre- clearance. As the regulations worked out, a provision was inserted to require preclearance when a newly discovered serious hazard or fatal- ity came about, and we have a mechanism through which the company itself, on being notified by us of this new hazard and requirement of preclearance, can submit a program for their advertising that will assure prompt transmission of this important information to the profession through the company's promotional efforts. Senator NELSON. You referred to a new drug? Mr. GOODRICH. Any prescription drug, Senator, whether it be a new drug, or certified antibiotic, or even a prescription drug that has been on the market for a long time, and is under the grandfather protection for effectiveness. If we should learn that even an old drug suddenly had been discovered as a causative factor in serious adverse experience or fatalities, we have the authority to require preclearance of ads and to make sure the profession is notified through all mechanismsof this new hazard. * Senator NELSON. Supposing it is a new or an old drug and it is on the market; it is a very toxic drug, has dramatic side effects, such as this one or chloramphenicol, or any one of many, many more, and the com- pany continues to put in its advertisements, such as this one, claims that extend beyond what is authorized in the package insert-do you have the authority, when that happens, to say, "From now on we will insist on preapproval of the ad"? Mr. GooDRICH. Yes. Senator NELSON. Have you ever exercised that authority? Mr. GooDRIcH. We have not. In this case, as Dr. McCleery's state- ment shows, we met with the firm on November 11, 1966, which was less than a month after we challenged this ad, this promotional prac- tice, publicly, and the firm immediately developed a program to change its advertising practice. It was not necessary for us to require a pre- clearance. We have the authority to do so. Senator NELSON. If I understand your `testimony arid other pre- vious testimony before the committee, there have been a number of cases where the advertising for a drug has made a claim beyond the claims approved for the package insert; is that correct? Mr. GOODRICH. Yes. And our reaction to those ads has been prompt and decisive in calling the company in, Dr. Goddard himself meeting with the companies to go over the defects, and to make sure that the company does and will immediately communicate with the profession to call attention to these defects. There have been, I believe, 21 or 22 letters in the last year and a half involving these advertising practices. We will put those into the record for you, so that you can see both the details of the advertising abuses that called for the letters, and the mechanisms that we used to require the companies to communicate this information to the profession. SENATOR NELSON. What puzzles me a little bit is that this has been the law since 1963, has it not? PAGENO="0113" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3205 Mr GOODRICH The law was passed in 1963 It required that before we could do anything on advertising, we had to promulgate the regu lations We set to work promptly at that We promulgated the regu lations effective in 1964-after confrontation with the industry The regulations became effective at that time The original enforcement actions were-some were taken, but it was not until Dr Goddard became Commissioner that this program was sharply stepped up, and I believe since certainly March of 1966-he came in February or March-I forget which-but soon after he came, it became one of his most-one of his highest priority programs. It has been a high-priority program since Senator NELSON So the regulations were promulgated about 4 years ago Mr GOODRICH Yes, sir As a matter of fact, we now have under consideration-we have had over about the past year-an improvement in those regulations in terms of making them much more specific This improvement will be carried out very shortly. But meanwhile, wethink the regulations are entirely adequate to deal with the major problems of advertising. We are revising them simply to be more specific and to avoid any contention on the part of the pharmaceutical industry that they did not understand what was required, or what our attitude towards specific kinds of advertising practices were Senator NELSON Have there been any cases where the penalties under the law were levied against any of the companies~ Mr GOODRICH Yes There has been one prosecution involving a product called Pree MT There have been a number of others under discussion back and forth with the Department of Justice~ Several of them are in controversy. Senator NELSON. Do I understand you to say the penalty is a thousands dollars? Mr GOODRICH Yes, sir-for each shipment of the drug So there is a possibility of a substantial penalty Senator NELSON We are talking about advertising in a journal now Mr GOODRICH Yes But the offense is in terms of an interstate ship ment of a supply of the drug Senator NELSON The liability under the law is what ~ Mr GOODRICH The introduction into interstate commerce of a mis branded drug, and the drug is misbranded because its advertising failed to comply with the regulations. Senator NELSON. And what is the effective date from which you start measuring the penalty-the date of the publication of the ad? Mr. GOODRICH. Yes-the ad must be related to a shipment made after the date the ad appeared Senator NELSON And then the penalty is based upon the number of shipments, not the quantity ~ Mr GOODRICH Yes, sir Senator NELSON So if an ad were run on April 1 that violated the regulation by making claims that were not approved in the package insert, and one shipment of drugs was made after that, the maximum penalty would be a thousand dollars, is that correct? Mr. GOODRICH. Yes, sir. Regardless of the size. Senator NELSON. Do I understand you to say that in the last year and a half there have been 22 "Dear Doctor" letters sent out? 81-280 O-68-pt 8-8 PAGENO="0114" 3206 COMPETITIVE PROBLEMS IN THE DRUG INDUSTR~ Mr. GoODRICH. I do not have the exact count. That is very close to it. We will supply the exact count Dr MCCLEERY There have been I think 21 in just a little over 12 months. *Mr. GOODRICH. Right. Senator NELSON. Were all these "Dear Doctor" letters based upon violations of what we are talking about here, a claim in an ad ~in excess of what was approved for the package insert? Mr. GooDRIcH. Not all of them. Most of them were, but there were a few instances in which the promotion in Physicians' Desk Reference was not up to date and current. I believe there were about four or five in that category. And the rest of them were concerned with journal advertising. Senator NELSON. It seems to me from the cases I have seen, like the one today-would appear fairly clear violations of that-they clearly made claims beyond what was authorized in the package insert. How do you expect them to really conform if you are not tough about it? Mr. GOODRICH. Well, I would rather-if you will permit me-not discuss the case that is going on. Senator NELSON. I do not refer to any particular case. Mr. GOODRICH. We feel we have been, and Dr. Goddard feels, I am sure, we have been quite strict with them in requiring the mailing out these "Dear Doctor" letters. Senator NELSON. That is after the fact. Mr. GOODRICH. And it is the only way that we can effectively cor- rect that false message. The ad, after the fact, requires a communica- tion to the profession, to make sure that it is understood that FDA iegards the ad as misleading, and has requested the company to com municate with the profession, to tell what is wrong with the ad. This has been the pattern of the "Dear Doctor" letters. We think as of now it has been an effective mechanism for communicating with the pro- fession about proper advertising, and we hope that it has brought about improvement, industry wide, in terms of the quality of the adver tising messages. Senator NEI4SON Well, as to the question of its effectiveness, you were here yesterday at the hearing when we discussed the "Dear Doc tor" letter that was sent out by Merck and which ended up being a promotional plug for the drug The FDA subsequently had to get them to send another "Dear Doctor" letter to supplement the first one. But, in the second one you did not require that they say this is being sent because the first one was misleading. Mr. GOODRICH. The first one was sent without our approval, and the second one did not refer to the fact that Food and Drug had required it. It was stated to you, and I can assure you it is true, that a great many "Dear Doctor" letters have been sent since that time, and they have uniformly referred to the fact that the Food and Drug Administration requested that they be mailed. Just the point you made yesterday-which we ourselves recognized early in this-the impor tance of including in the message the statement that this was an action precipitated by Food and Drug. There was of course much argument about that at all stages. But it has been a uniform requirement, I am sure, for a year now PAGENO="0115" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3207 Senator NELSON. But you would agree, would you not, that one of these long closely typed "Dear Doctor" letters coming to a busy doctor is a whOle lot less effective than a series of R*oentgrams demonstrating how effectively this drug cures the patient's problem? So you end up with an after-the-fact situation where the doctor has been misled by the ad, and then you require that a letter be sent afterward which probably is not going to be read. As a matter of fact, since I have been conducting these hearings, many doctors, and good ones, have told me that the first thing they do with any of this material is throw it in the waste basket-~they do not have time to `read it all. Mr. GOODRICH. We have, as you know, made sure these "Dear Doc- tor" letters are sent first-class mail, that they are sent in a distinctive type of envelope-the letters themselves, I am sure you will read them, are devised to put across the essence of the complaint about the adver- tising, and the details are put on the next page. We think those letters are effective as a means of communication. Senator NELSON. They are not effective with the doctors who tell me they do not read them, any `more than they are with the doctors who tell me they do not read the package insert. If you are really going to make this work, why don't you do a couple of more things. One of them is, when they violate our regulations in an ad-this is a nice, beautiful, big color ad that I have `here-why don't you just tell them you are going to send the "Dear Doctor" `letter, and you are going to enclose a copy of the ad, because this is the ad that has been impressing the doctors; and, in addition, you are going to have the firm say "We have been required to correct this ad. This ad is inaccurate, and here is why." No. 2-if you are really going to be effective, why don't you just tell the firm, "we are gç~ing to review for the next year all of your ads." I think they would shape up pretty fast. But if all you have is a little thousand dollars penalty here and there, and a little discussion here and there, you will have 22 "Dear Doctor" letters in the next 6 months, and have another 22 in the following 6 months. In the meantime doc- tors are being misled in a very important matter involving the health of their patients. And you have the power to do this. I do not know why you do not say, "You clearly violated advertising regulations, and for 1 year you must submit to us all ad copy in advance of pub- lication." I think you would find that you would not have to send many "Dear Doctor" letters after that. They would' take the package insert and use it as a basis for their ads. Mr GOODRICH I think it is equally effective for the Commissioner to have the president of the firm come in and go over the faults in the ads, what was wrong with them, and then to require the company to mail out a first-class mailing to every physician in the United States, telling what was wrong with the ad. Now, this is the mechanism that has been adopted. We think it is effective. We have seen in the case of Merck Sharp & Dobme, that after the meeting between the Commissioner and the president of that firm there was a significant improvement. We have seen this same pat- tern with most of the other companies that have been involved iii. "Dear Doctor" letters But there have been some that have had more than one "Dear Doctor" letter We are constantly working on this Dr McCleery has a relatively small staff. But I am sure Dr. Ley will agree this is a PAGENO="0116" 3208 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY top priority item in the Bureau of Medicine. We understand its im- portance in having drugs prescribed. As Dr. Jennings testified yes- terday, the promotion of this drug was in part responsible for its tremendous use. it was launched with a message with which we can- not agree. So we adopted in March or June of 1966, a program of monitoring the initial promotion for every new drug approved to make *sure the drug was launched on the right foot, and promoted to the profession for the conditions for which we had actually approved it. Senator NELSON. Are you saying that you preexamine the adver- tising for all new drugs? Mr. GOODRICH. We require them to submit, as soon as the first pro- motion is run-we do not require it to be submitted before it is run- submit that to us. Dr. McCleery's office processes that. If it is not in accordance with the conditions for which the drug has been approved, we then take action to be sure that it is. Now, trying to preclear the ads at what you call the viewing board stage-this is just not a practical thing that we have felt we could do so tar. We are calling for the ads to be submitted as soon as they are first placed. We are exercising care to make sure they are promptly reviewed. Senator NELSON. Well, I do not know what the problem would be in preclearing all ads. I assume it would be massive. I am not talking about that. An ordinary layman such as myself can look at the ad promoting Indocin for gout, and knowing what I `do about it, see the misleading point there, when they use the phrase "drug of choice." I know why they did it. I know why their highly paid advertising experts sat all day long figuring out the best phrase they could use to convince the doctors to prescribe their product. The company know.s that. So I do not know why you should not say to the company, "This is an overt, gross violation, and you know it, and you are the one company that is going to spend the next year submit- ting your ads for preclearance from us." I think if you did that once or twice, you would end up with very, very few ¶~`Dear Doctor" letters, and then you would not be permitting the misleading of the medical profession by ads such as this one. My question is, Why don't you really get tough with these firms? Mr. GOODRICH. I think we have been as tough as possible within the limits of our people. This is a good suggestion. But if spending time to preclear all the advertising- Senator NELSON. Just a minute. I have never said that. I have sug- gested that you notify the industry that in clear cases of ads where the claims for a drug go beyond the package insert, the FDA will preclear the ads of this particular firm for the next 6 months or the next year. Then you are not going to have very many violations to bother with; that is my point. And if you told them also that they are going to have to send the ad to all doctors and tell the medical profession in the "Dear Doctor" letter, "We misled you in that ad; we made claims not permitted in the package insert and the FDA has told us to send you this ad and correct the ad," in my judgment you would not have much problem with this any more. The medical profession would no longer be subjected to misleading ads of the sort that caused Dr. Goddard to say of chioramphenicol, "I am at my wits end as to how to effectively warn the profession." I know why. Because the industry PAGENO="0117" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3209 runs ads like this If I were a practitioner out in the country someplace, with a patient, and saw an ad like this showing feet and hips and hands, and stating that Indocin "extends the margin of safety," I would be impressed, too After all, this is the Journal of the AMA- I am shocked that they would even run it But here it is I am a doctor And I have high respect for the JAMA They would not permit cheat mg in their advertising-I know that And this distinguished com pany would not try to mislead me. So I prescribe it. And that is why the testimony was yesterda~ that this drug is being widely misused All I am saying is, for heaven's sakes why don't you do something instead of all this fluff-fluff we get all the time that goes on and on. It is a simple answer You have the authority Tell them to stop it "or we are going to review all your ads" And I predict you will be able to come back in 6 months and say "Senator, we have no trouble with advertising any more" Mr GoODRICH Our answer is on that that we did tell Merck Sharp & Dohme, quite bluntly and quite pointedly, that the ad was bad, they stopped running it within 2 weeks after we told them, they destroyed, according to their statement, $73,000 worth of comparable promotional material. They have been, according to the statement from Dr McCleery made here, better since that experience And he has in fact been over some ads with them to-brand new products, to show that we did get the messages across to this company We think we have gotten it across to others But your suggestion is a good suggestion, and ~ e will certainly consider it Senator NELSON Well, if I am around here for that long, the next time I find an ad that extends the claims beyond what is allowed in the package insert, I am going to invite you back, and we will talk about it again, and find out whether you are still satisfied with the methods you are using. I am not saying you have not improved them a lot. Mr. GOODRICH. And I am not saying that the present method, Sen- ator, is a hundred percent or the best one available. But it was one that was within our capability, it was one that has been carried out, I believe, with effectiveness Senator NELSON Well, as you say, I think Dr Goddard has done a magnificent job I just think it is nonsense to permit this to go on, and you have been pretty soft on the industry They know what they are doing. They are fooling the public-particularly the doctors. And it ought to stop. A great industry like this should not be overpromoting drugs for nonindicated cases. Itis as simple as all that. Now, as long as they can get by with it, and make money, I guess this is what happens I am not saying that it is a criminal offense. We had the same thing with the auto industry As long as they could give us cheap tires that ~ould not even hold the car, they did so But, then we passed a law tell ing them to stop it That does not mean the automobile industry is not a great industry-it is But putting on cheap tires saved them $400 or $500 million a year, so they did it And, it took Congress to do some thing about it And the industry, or if necessary, the Congress ought to do something about this, because it has gone too far Mr GOODRICH We think Congress did do something about it And in dealing with patients taking drugs, we expect a higher responsi- bility even than the automobile manufacturers PAGENO="0118" 3210 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Well, I think if you told those who drafted the Kefauver-Harris law, passed in 1963, that we would still hate this kind of advertising going on in 1968, they would tell you that the will of Congress has not quite been complied with. Correction of such ought to happen sooner than 5 or 6 years. Mr. GOODRICH. And I would agree with them. Senator NELSON. We will take a 5-rninttte recess at this time. (At this point in the hearing a short recess was taken.) Senator NELSON. Let us resume, gentlemen. Doctor, the minority counsel has a couple of questions. Mr GROSSMAN Mr Goodrich, I want to get a clear idea of this preclearance authority which you presently have-I think we just sort of skimmed over the fact that you do have some preclearance authority. Where and when does it apply, and when have you used it? Mr GOODRICH It applies in the language that Congress adopted- except in extraordinary circumstances there shall be no requirement of preclearance of ads-section 502(n), Federal Food, Drug, and Cosmetic Act The implementing regulations say that when the Department learns of a newly discovered serious hazard that has not been widely dis seminated, not widely known to the medical profession, it can require the preclearance of ads. It specifies there that upon being notified of the necessity for preclearance, the company can develop a plan, develop and present a plan to us which will assure that promptly their ads will cover this new hazard in which case preclearance would not be repnred `There have been no instances so far in which preclearance has been required. Mr. GROSSMAN. Required. `Mr. G0ODRIC~I. Under those regulations. Mr. GROSSMAN. That there have been no instances? `Mr. GOODRICH. Right. Mr. GROSSMAN. You `have never sought to implement this, because you never thought there was anything serious enough. Is that what we are to interpret? Mr GOODRICH Haven't thought there was anything in terms of fatalities or serious side effects that was not promptly reflected in the ads. Mr. GROSSMAN. Now- Mr. GOODRICH. We have not run on to such a case. Mr. GROSSMAN. How many deaths do you need before something becomes serious enough? What is your criterion here? I do not under- stand when you are going to use the preclearance authority. Mr. GOODRICH. We are going to use it `when a newly developed, newly discovered hazard is learned by us, and the company fails to immediately provide for including this information in its promotional program. Our experience has been that this newly discovered informa- tion is processed through our supplementary review, and is promptly put into the promotion. Mr. GROSSMAN. What I am trying to say is-you talked about react- ing to this, having meetings with companies about actions that they have taken, following up-everything is reacting or following up. I want to know, in other words, in what circumstances you feel you should act, and not react PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3211 Mr GooDRICH Well, I think we have been doing most of the acting to initiate these meetings I am sure we have Mr. GROSSMAN. I think that the companies have done some things that have forced you to react to them. What-I am trying to say-in other words, as far as we are concerned, this section 502(n) is really worthless-it has never been used, and you do not think there have ever `been indications that tho- Mr. GOODRICH. I do not think that is so `at all. This preclearance proviso in the section, which `Congress told us not to routinely pre- clear, ads-- Mr. `GROSSMAN. I did not say you ~hould routinely preclear. In other words, there is authority for you here to use preclearance, as I understand it, in hazardous situations. Now, I want to know what you consider hazardous. Obviously this was not a hazardous situa- tion. Chloramphenicol-has there been anything you can think of that might `be hazardous? In other words, how many deaths do you require? Mr. GOODRICH. This was a serious situation, and we did get the company in within 2 weeks after the ad, and required the "Dear Doc- tor" letter shortly thereafter. Mr GROSSMAN Do you require preclearance on all their advertising now? Mr GOODRICH No But they have been (wer-after we first had our discussion about this, their lawyer and their physician in this area came down to Washington, and went over a series of their ads with us, to make sure that they did fully understand what we intended, and their performance and'behavior since that time has `been improved. Mr. GROSSMAN. Dr. MoCleery, do you have anyone in your division who is assigned to decide when a drug is hazardous, and should be- come part of the section 502(n) proceedings? Dr. MOCLEERY. No, I have no one specifically assigned. The infor- mation of the kind that you are talking about would be developed principally in the area of the Office of Marketed Drugs If they, m their work in surveillance of the reports of new adverse reactions of drugs on the market, would find an instance of this kind that they felt was not generally known-that the profession had not, been prom- inently and `widely informed, then at that point we would be able to enter in and to act as agents of this particular requirement of the law. We would not develop the information. Mr. GROSSMAN. Is it fair to say that the committee could interpret that since 1964, since section 502(n) went into effect, there have been no cases of hazardous drugs which would qualify for preclearance ~ There have not been any? Dr MaCLEERY The paragraph in the regulations ~which give form to this section of the law that Mr. Goodrh~h talks about, is paragraph 1.105(j), and we have not `as an agency invoked the provisions of that paragraph `of the regulations. We have, on the other hand, precleared many ads. Mr. GROSSMAN. I am just thinking back to what Mr. Goodrich was discussing before-there are a lot of questions on which Congress has gone far enough. I just wonder whether 502(n) does not give us au- thority; and whether authority that you have could be used and has not been used. PAGENO="0120" 3212 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In other words, it is one thing to say that the Congress should leg- islate. But when it has legislated, and there is a broad discretion that has not been enforced, it is not our job. Dr. MOCLEERY. I do not think I could agree with you that it has not been enforced. Mr. GROSSMAN. Section 502(n). Dr. MoCu~rarr. 502(n) is the broad language, and includes as one of its parts the exclusion that except in extraordinary circumstances we should not require a company to preiclear its ads, as a part of that section of the Kefauver-Harris amendment. Mr. GROSSMAN. I will not pursue this. I wonder if you can answer as to when you think an extraordinary situation exists? Dr. MOULEERY. I believe that paragraph 1.105(j) is the paragraph of detail in the regulations which gives form to one view of "extra- ordinary circumstances." In the negotiations with the industry in 1963, at the time the regulations were being proposed to the industry, this was a prominent feature of difficulty in the industry's acceptance of the original regulations written on the basis of the amendment to the act. That the paragraph exists at all, I think, has had an effect which has been salutary in causing companies to be aware of the need to move more quickly, than they might otherwise, to get new warnings into advertising. Mr. GROSSMAN. I would question whether they would act because of their fear of your implementation of it. We have not seen very many examples of it. Senator NELSON. Mr. Goodrich, so that I have this clear in my own mind-we have referred several times to your authority to preclear ad copy and I think, in that context, you have always referred to new drugs. Mr. GOODRICH. If so, I misspoke myself. The advertising provisions apply to all prescriptions. Senator NELSON. That was my impression. So if a drug is on the market, no matter how long it has been there, and the company at some stage makes claims that extend beyond the authorized package insert claims, you do have authority in that case to preclear a future ad or ads. Mr. GOODRICH. Yes-and even with drugs on which we have no approved package insert-that is the drugs on the market since 1938, without new drug clearance. If there should be discovered some new hazard about such a drug, it would be possible to preclear, and to require preclearance of the ad. Only, I believe, 2 years ago we reclassi- fied a drug on the market in 1936 as a new drug, because of a newly discovered hazard in it, and did take regulatory action. It was not advertised broadly, so it was not necessary to preclear advertising. But we did require its reclearance through the new drug procedure. It was a product called Dipyrone, discovered to have some blood hazards. Senator NELSON. You referred to drugs marketed before 1938. Do you approve a package insert from them? Mr. GOODRICH. No; they are totally exempt from preclearance. They are required to have a package insert with full disclosure information in it. But we do no preclear it. PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3213 Senator NELSON. You do not preclear the package insert? Mr. GOODRICH. We do not. The law exempted-just drew a 1ine~- products on* the market June 1938 and before. So long as they have the same claim they are not subject to new drug preclearance Senator NELSON Have the same what ~ Mr GOODRICH Same claims in use as in 1938 Senator NELSON Supposing you found out that these claims were not justified Do you have any authority to require that changes be made~ Mr GOODRICH Yes We would have the authority to proceed through the courts to charge them to be-as being misbranded, and then for us to bear the burden of proving the claims false rather than the burden under the new drug provisions being on the company to prove the drug's effectiveness That is just a difference in the burden there :Senator NELSON. Do you know what percentage of the prescription drugs in the marketplace are exempt from your authority to regulate ~ Mr GOODRICH No, we do not have any reliable figures on that We are pretty sure that a great majority of the drugs now in use are drugs that have entered the market since the enactment of the new drug law in 1938 There would be a number of oldtimers, of course, that were on the market in 1938, that are still around-phenobarbitol, thyroid, a lot of others. But the great majority of drugs, I think I am correct in saying, now in use are drugs that have been developed between 1938 and the present time This is why we regard as quite important, our contract arrangement with the National Academy of Sciences, to review the claims of effectiveness for these drugs marketed between 1938 and 1962, enabling us to bring to bear the new require ments of effectiveness on those products Congress' solution to this in 1962, rather than exempting all those premarketed drugs completely, was to give us the right to, through administrative action-to go back and review the clauns, product by product, and to be sure that they were effective as claimed. Senator NELSON. That authority extends just on drugs marketed from 1938 to 1962? Mr. GOODRICH. Yes, sir. Senator NELSON And you are in the process of reviewing them now Mr GOODRICH Yes, sir The contract has been virtually completed, I think We are getting the reports now, and we have begun to imple ment the reports by requiring changes in the labeling and packaging Senator NELSON Once the review has been done, do you then, under the law, have the authority to control the package insert ~ `Mr. GOODRICH. Yes, sir. But we have a dispute with the drug indus- try about the extent of our authority. But we think we have enough authority to carry this forward. Senator NELSON. `Go ahead, Doctor. Where were you? Dr MCCLEERY I would like to pick up in the middle of page 8, paragraph c We believe that the quotation that we have been talking about misleads in that it is obsolete when used in the ad in 1966, in that it fails to take into account more recent, more scientific, but less salubrious opinions of the same authors available to the firm in medical literature published about a year prior to the ad. The company was aware of the more recent literature, `and the facts are th~tr-(1) in 1965 the PAGENO="0122" 3214 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY same authors published the results of a `much `better controlled' and double-blind study on a larger population than the 1963 paper-here 26 patients crossed over on both indomethacin, and the competitive product, phenylbutazone. (2) This was `a study of the response `to the marketed capsules within the limits of approved dosage, the authors ended the paper with a note of thanks to company personnel "for generous supplies of indometh acm," it was published in the same journal as the first article (British Medical Journal, 2 1281, Nov 27, 1965), and was available well before the ad was created and published. (3) The overall patient response greatly favored the competitive product to an extent that was statistically highly significant, for ex- ample, when the 2-month blind trial was over "~ * * 15 patients pre- ferred phenylbutazone, 10 found them to be equally effective, and one preferred indomethacin." (4) The authors' `conclusions re Indocin were strikingly different (the key words "predictable" and "in most cases" no longer were in- cluded) after this study, that is, `"~ * * the first nonsteroid to produce a measurable `reduction in joint size in selected cases of active rheumatoid arthritis." Now, the phrase "the first nonsteroid" is common to both articles It should be noted that the authors' retention and the company's use of the phrase "the first" is in my view highly questionable. Within the authors' own results in the 1965 article, they included the observation that reduction in joint size occurred not only in pa- tients ` on indomethacin, but also on phenylbutazone as well, and that taking into account both the number of patients improved, and the extent of reduction, differences between the two drugs were not statis tically significant And yet the authors were still using the phrase "the first nonsteroid," and so on. It is difficult for me to see any validity or significance to the claim "the first" especially when the authors failed to find such difference in the reduction that they did find-to find any statistically significant difference between the amount of reduction. Mr. Chairman, since your committee may wish to consider the Hart and Boardman papers in some detail, I have made copies of both papers available to you and for the record, and I have gone into some detail on this point, because it typifies several advertising practices which we regard as seriously misleading. Senator NELSON. We will print those in the record. If I understand you correctly, what you `have said is that the company quoted from an early study `by these two doctors. Dr. MCCLEERY. That study being of less quality than the later. Senator NELSON. And was the second study which modified the posi- tion taken in the first study published and available at the time they ran the questionable ad? Dr. MCCLEERY. Yes, and known to the company long before that, because they were in contact with the authors of the study and sup- plied the drug to the authors, so that they were well aware of the study going on. Senator NELSON. So here you say there is a clear-cut case where they knew a subsequent study modified the original one; yet, they continued to use in their advertising a quote from the original study PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3215 Dr. MCCLEERY. Right. And whigh quote was not the opinion of the author at the time that the ad was created ~ Senator NELSON. Yes. Dr. MOCLEERY. You might wonder, as we did, why the company might choose-if they chose, it may be a matter of inattention to the literature-but whether they chose to use the `63 paper and ignore the `65, I do not know. But I think I would like to offer you evidence from the second paper-just a few brief recountings of the results reported by the authors in the second paper which may suggest why the second paper was undesirable as a form ~of promotion. And I would like to read a few excerpts from the Hart and Boardman paper of 1965. Senator NELSON. You say the company was aware of the second paper? Dr. MCCLEERY. I cannot say that, I can only assume that if they were not, that it was a matter of inattention which I would not find excusable. Senator NELSON. Since it was a trial run on their own drug. Dr. MCCLEERY. And it was published in the same journal, and was in print available well before they created the ad, and since they were clearly aware of the research of Hart and Boardman, having been in contact with them from the days of the IND I would like to read some of the comparative results which this ad did not point to-which a doctor might see if he read the 1965 article The following from the article, not used by the company in its pro- motion, are some of the results found by the same authors. As far as subjective signs are concerned, when they asked the pa- tients at the end of the trial which one was found by the patients to be more satisfactory, "15 patients preferred phenylbutazone, 10 found them to be equally effective, and one preferred indomethacin. This dif- ference is statistically significant with a `p' value less than 0.001." They go on at much greater length and deal with the question of pain as recorded by them for each patient during the month on each drug. And they found that the "improvement in pain"-that five on phenylbutazone, but only two on indomethacin found their pain relief better, and that 19 found no difference As far as "joint stiffness" was concerned, assuming a 25-percent dif- ference to be significant, five were less stiff during phenylbutazone, and only one less stiff on indomethacin-20 patients found no detect- able difference. As far as the very commonly used parameter of judgment, "early morning stiffness," for drugs in this category, they found that in the first month on phenyl1butazone seven patients were improved, and on indomethacin only three improved In the second month, on indometh acm improvement occurred in three patients, and on phenylbutazone four improved. As far as "grip strength" ~ as concerned, I won't review the com ments in detail, but there was no real difference between the two drugs on that parameter. As far as the objective "change in joint size," which is a common feature of the 1966 ad, and is related to the authors' comment about the "first nonsteroid" to produce reduction in joint size, these are the actual figures given by the authors in their paper, which precede their con~lusions So they say-assuming a change of three ring sizes PAGENO="0124" 3216 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY in joint size to be significant, there was no difference in 17 patients five were better on rndomethacrn, but also four ~ere better on phenyl butazone And they go on to conclude that this difference between the drugs' effect is not statistic'tllv significant But it is significant that the number of patients showing reduction in their joint size was almost equal between the two drugs, and that there also was a positive effect for phenylbutazone noted in the same study that showed a posi tive effect on some cases with indomethacin. Senator NELSON. That is from the second study. Dr. MOOLEERY. Yes, sir. Whether these results have any connection with its lack of desirability, or are related to the company's decision not to use it as a source of reference, I do not know But those are the authors' conclusions in the second paper Now, there are several other claims made in the JAMA ad to which we objected in detail in our internal memos For example, one of the most serious of all was this matter of a drug of choice, to which I i eferred Whereas in the earlier ads the company did change these quotes to tone them down by inserting the bracketed letter "a,' the last ad in the series, later, in November, quoted it unadorned, un- changed, as "the drug of choice." I might say in passing also that the Hart and Boardman article used in regard to the treatment of gout, which is the most right block of the ad, was based entirely on the indomethacin formulation that was not marketed, the tablets. Furthermore, the dosages used by the `tuthors, which gave the results that led to "the drug of choice" opinion, were far in excess of the upper approved safe limit when the drug was marketed in this country in capsule form Outside of all these features I would have to agree that the use of the quote is proper. Now, Congress has already recognized that it is dangerous to pro- mote a new drug with inadequately based claims for greater safety and comparatively greater effectiveness than established competitive products. Safe promotion can be based only on adequate clinical data, and then only with a complete awareness that the limited experience with the new drug as it enters the market, accumulated during its in vestigational state, may change rapidly and significantly when the drug is released for general use by physicians at large Also experience will dictate changes from time to time as you have seen in the testi mony yesterday, and for as long as the drug is marketed, very possibly Indomethacin was recognized from the first as a drug with signifi- cant capacity for adverse effects. We believe its promotion over the first year of its approved marketing improperly presented the drug to the medical profession-both as to the range of its effectiveness and as to the margin of its safety Mr Chairman, this emphasizes, for us at least, the need for our con tinued special attention to the advertising of newly released drugs as they enter the marketplace, as well as that for older prescription drugs, to help provide assurance-and, I might add, I would like to insert the word "help" for the record here as a qualifier, which we so often insist that our opponents in advertising use-so with your per mission, and with some seriousness, may I request that you insert the word "help" after the word "to"-to help provide assurance that they are fairly presented to the medical profession under the approved con- ditions of marketing Further it demonstrates a need for constant sur PAGENO="0125" COMPETITIVE PROBLE1\~LS IN TIlE DRUG INDUSTRY 3217 veiliance, both by us and by the manufacturer, of clinical experience to keep advertising messages in step with the realities for safe and effective prescribing of new drugs as more experience is developed during their marketing history. Thank you I will be glad to answer any questions ( The complete prepared statement anct supplemental information submitted by Dr MeOleery follows ) STATEMENT OF DR ROBERT S McOLEi~iiY ACTING DIREcTOR DIvISION OF MEDI CAL ADVERTISING BUREAU OF MEDICINE FOOD AND DRUG ADMINISTRATION U S DEPARTMENT OF HEALTH EDUCATION AND WELFARE Mr Chairman I appreciate this opportunity of appearing before YOU this morn ing to discuss our experience with the advertising of Indocin. For the sake of brevity and with your permission I will submit for the record a statement of my educational and professional background Shortly after Dr Goddard became Commissioner of Food and Drugs in early 1966 the Agency s interests in prescription drug advertising were sharply accen tuated It was felt that manufacturers had had time enough to adjust to new requirements concernthg advertising Dr Goddard spoke to the presidents of pharmaceutical firms to their medical directors and to their advertising agencies to note what we regarded as a continuation of advertising abuses that had been so largely responsible for the enactment in 1962 of the Kefauver Harris Drug Amendments and the promulgation in 1964 of the first advertising regulations The Fountain Subcommittee House Committee on Government Operations had reviewed with the Commissioner our programs in this important area of our public responsibilities. In short, industry's attention was brought emphatically to promotion excesses in many ways In June 1966 the Director ot Public Relations for Merck & Co Mr John E Fletcher wrote to Theodore 0 Cron our Assistant Commissioner for Education enclosing a print of an article that was about to appear in the July 1966 issue of Pageant magazine The story featured Indocin as useful for bursitis trick knee tennis elbow and a host of other less common disorders characterized by pain and swelling in and around the joints The support for these claims was largely lay testimonials some of which according to the article and the firm were made available to the writers by the sponsor of the drug Mr Fletcher said that the firm was in no way responsible for the article that the authors had heard of stories about the drug from a variety of sources and wanted to do an article about it, and that the firm had simply responded to this inquiry from responsible science writers. Mr. Fletcher said the article was, in no way promotional and wanted to so assure the Agency. The drug, of course, had not been approved for use for the above-mentioned conditions for which it was claimed to be effective in the Pageant article. We knew also that a popular article of `this sort is apt to create a demand for the drug by the patients who read it My office the Division of Medical Advertising in the Bureau of Medicine was asked to review the article for possible violation of the law and to review also the advertising of this drug in medical journals to determine if the drug was being promoted to the medical profession on the basis of unapproved claims Our concern was that if the firm would make these data on unauthorized uses available to a free lance team of writers it might not be scrupulous in its advertising to the medical profession.~ Identical advertisements which appeared in the JournaZ of the American iledical Assocuition issues of July 4 1966 and August 15 1966 were found to be featuring the theme that the drug extends the maigin of safety in the long term management of arthritic disorders At the same time the Office of Marketed Drugs was negotiating with Merck for changes in the labeling to emphasize the newly recognized hazards that bad emerged during the first year of clinical experience since original approval of the drug The JAMA ads in July 4 and August 15 1966 issues were analyzed and found to be defective in our opinion in several respects I will first mention generally the major defects of this ad and then will be more specific regarding the details of our objections to certain of the features of this and of a later ad which appeared in November 1966 The basic theme of greater long term safety in the ads was not supported by the clinical experience. To the contrary, the longer PAGENO="0126" 3218 COMPETITIVE PROBLEMS IN THE DRTJO INDUSTRY the drug had been on the market, the more serious adverse experience inforina- tion was reported. The ad quoted apparently-authoritative sources without the full impact of the limited experience contained in the actual articles. And it featured, for example, one reference which on checking proved to be only a 2-inch abstract of a 1964 speech. The ad quoted the author's opinion that ". . . results have been uniformly excellent or good in ankylosing spondylitis." The same abstract also included the author's view that, while "Excellent results have also been obtained in some cases of rheumatoid arthritis . . . there have been striking failures as well It is perhaps not surprising that while the advertiser included this author s favorable remark regarding his experience with spondyhtis the ad turned to another author for a more favorable quote concerning the possible value of the drug on rheumatoid arthritis. It offered the drug for arthritis disorders rather than solely for the four conditions for which it had been approved It characterized the drug as non-steroid-which of course it is-but failed to disclose in this connection that it had some of the major side effects of the steroids, e.g., an ulcerogenic effect. It claimed that the drug extended the margin of long-term safety, without any evidence to support the claim-it quoted from Isolated pieces of literature- one an excerpt from a symposium sponsored by the company-to claim that the drug was the drug of choice in gout and osteoarthritis of the hip neither of which claims had been approved It quoted from two leading English authorities to the effect that the drug was useful in most cases of rheumatoid arthritis when these authors had used the tablet and not the marketed capsule and wh n their actual opinion known to Merck was that the drug was useful in only selected cases of rheumatoid arthritis It featured the claim of one of the participants in a Merck sponsored sym posium that he had had 500 patients on the drug for three years, when Merck's own records would have told them this was not true. And finally in the "Brief Summary" of information on side effects and con- traindications some of the major warning information was left out-such as the fact that indomethacin Itself had caused ulcers, and that the drug should not be administered to children. This exemplifies what may be called the euphemistic style of revealing warn ing information. The ad's "Brief Summary" translated the package insert's warning, "INDOCIN itself may cause peptic ulceration . . ." into the area of causal doubt in this manner Ulceration of the stomach duodenum or small intestine have been reported Further the package insert s directness re garding administration of the drug to children became the Brief Summary s statement that Safety in pregnancy and pediatric age groups has not been established." Deficiencies in the ad were publicly noted in a speech before the Pharmaceuti cal Advertising Club in New York on October 20, 1966, by our General Counsel, Mr. Goodrich. The firm protested and shortly thereafter, on November 11, 1966, a sort of armistice day, the firm's principal officers met with Dr. Goddard and his staff to go over the problem. The firm reported that it had immediately ordered the ad discontinued after the October~ meeting and was taking a close look at all of its promotional efforts Later its physician and counsel responsible in the area of advertising came down to go over some ads for other products with us. Soon after this episode, Merck began to show significant improvements in its advertising practices for prescription drugs but not before it ran, in the November 1966 issue of the American Journal of Medicine, another ad which contained most of the faults of tha original ad, plus some additional new faults. I will expand on this. While the authors, in 1963, had published the report quoted, we felt that Merck had no right to adopt the quotation in their 1966 advertising. The quotation from an article by Hart and Boardman (Hart, F.D. and Board- man, P.L.: British Medical Journal, 2:965, October 18. 1963) and used under the ad caption rheumatoid arthritis namely the first non corticosteroid agent which produced a predictable and measurable reduction in joint swelling in most cases of active rheumatoid arthritis Our comments in reference to the quotation are that it PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3219 a. Does not represent a true statement of effectiveness of the advertised product, "Indocin :" (1) The approved package insert for the product does not contain the promis sory concepts represented by most cases and predictable represented by the words the first That the firm had previous knowledge of (2) The approved package insert provides no basis for the comparative claim represented by the words the first That the firm had previous knowledeg of the impropriety of the claim is evidenced by that in an earlier, similarly- appearing, ad the company more cautiously excluded this phrase from the quoted clause and substituted "a" for "the first." b. Misleads by its use out of the article's context in such a way as to present an unfair and distorted view of the drug's identity, safety and effectiveness: (1) The authors had not used the marketed "Indocin" capsules, but instead employed an experimental tableted formulation. (2) The authors had only 15 pertinent patients from which the represented conclusion was drawn. The reader would have been forewarned, and not overly impressed, if he had known the generalization "in most cases" rested not on a large experience from which a generalization might not be misleading, but on only a favorable result in 8 out of 15 patients. (3) An unknown and unspecified proportion of the above results were ob- tained by dosages well over the 200 mg. upper limit of approved dosage, e.g., 300 mg. per day. The physician reader could not know from the ad that he could not necessarily expect similar results by employing dosages approved as safe in the drug's package insert. c. Misleads in that it is obsolete and fails to take into account more recent, more scientific, and less salubrious opinions of the same authors available to the firm in medical literature published about one year prior to the ad. The com- pany was aware of the more recent literature and the facts are that: (1) In 1965, the same authors published the results of a much better controlled and double-blind study on a larger population (26 patients crossed-over on :both indomethacin and the competitive product, phenylbutazone). (2) This was a study of the response to the marketed capsules within the limits of approved dosage the authors ended the paper with a note of thanks to company personnel "for generous supplies of indomethacin," it was published in the same journal as the first article (British Medical Journal, 2: 1281, Noveni- ber 27, 1965), and was available well before the ad was created and published. (3) The overall patient response greatly favored the competitive product to an extent that was statistically highly significant, e.g., when the two months blind trial was over ". . . 15 patients preferred phenylbutazone, 10 found them to be equally effective, and one preferred indomethacin." (4) The authors' conclusions re Indocin were strikingly different (the key words "predictable" and "in most cases" no longer were included) after this study, i.e., ". . . the first non-steroid to produce a measurable reduction in joint size in selected cases of active rheumatoid arthritis." (5) It should be noted that the authors' retention and the company's use of the phrase "the first" is highly questionable. (a) Within the authors' results in the later article they included the observa- tion that reduction in joint size occurred not only in patients on indomethacin, but on phenylbutazone as well, and that, taking into account both the number of patients improved and the measured extent of reduction, differences were not statistically significant. Mr. Chairman, since your Committee may wish to consider the Hart and Boardman papers in some detail, I would like to make copies of both papers available for the record. I have gone into some detail on this point because it typifies several advertising practices which we regard as seriously misleading Congress already has recognized that it is dangerous to promote a new drug with inadequately based claims for greater safety and comparatively greater effectiveness than ~stabhshed products Safe promotion can be based only on ade quate clinical data-and then only with a complete awareness that the limited experience with the new drug, accumulated during its investigational state, may change rapidly and, significantly when the drug is released for general use by physicians. Also, experiepce will dictate changes from time-to-time as long as the drug is marketed. Indomethacin was recognized from the first as a drug with a significant capacity for adverse effects. We believe its promotion over the first year of its approved marketing improperly presented the drug to the medical profession- both as to the range of its effectiveness and as to the margin of its safety. PAGENO="0128" 3220 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. Ohairman, this emphasizes the need for our continued special attention to the advertising of newly-released drugs, as well as older drugs, to provide assurance that they are fairly presented to the medical profession under the approved conditions of marketing Further it demonstrates a need for constant surveillance by both the manufacturer and the FDA of clinical experience to keep advertising messages in step with the realities for safe and effective prescribing of new drugs as more experience is developed during their marketing history Thank you for your attention I will gladly answer any questions you may have PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3221 [From the Journal of the American Association Vol 197 No 3 July 18 1966] 81-280 0 - 68 - pt. 8 - 9 PAGENO="0130" 3222 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3223 ©ff fihi~s iM~ot:t D~F~i1b~~ ~IUThtb12~S~flflt1SC ~1D1t fl1Sift )1~~ 1iS.~i* ~ i;a~ iaciCt9 u jiljjj( (Q~Q&i 1Qa~, @Ji' ~ by ~ *~ JDoSi~a PAGENO="0132" 3224 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From the American Journal of Medicine November 1966] PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3225 PAGENO="0134" 3226 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I `` i 1; "`~ INDOMETHACIN ~ a new, highly eflective nonsteroiel anli-inflainnaul ary agent a(H )tt)I1 ~I\tX 1~eI~!k'(!)tkt LI amx!xjI~i!k~i~th:) 1k1~ \ \ I "vt 1I(~ .j,)?~j: `u1tj~) p)'bflnt4fc `it' iiaQ~)n(~ts1k9~ ~ ) ~ ~ ac~ j.t~ f hi I c ~ t44~g.~~ ~citte ~ ;~ 1ii3af ~ ~ ~ i a.t ii cui .i.ba ~ jfl, iXcj If 4J1,) (pi~i ~t'I' *$i Iit~.j:.i ~ i' IP. "i'i 4 ~ kWtkttMljibtUiUWJo', !1Jv5t b, ~ii5~in,'53it, iDjfj;~fjj;i "ks'' tEc ~ `d;!thi *j `i' :i'civsrna), and hematoria. In other rare cases, a diagnosis ot in a tew patients. Transient elenat ions in atkaline phosphatase, `istritis has been made white the drug was being ginen. One cephatin-cholenterol ttoccalation, and thymol turbidity tests bane i :tivnt deneloped sicerative colitis, and another, regionat iteitis, been observed in sonic patients and, rarety, elevations ot SGOT nc receiving INOOCIN; when the drug was given ta patients values; the relationship ot these changes to the drag, if any, .4 p;vosisting ulcerative cvlitis, there was an increase in ab- has sot been established. As with any new drag, patients should :~iival pain. lsfrnqaevtly observed side effects may include be followed carefully to defect unusual manifestations of drag `uisvinosv, tianitas, menial confasioa, depression and other sensitivity. ichic disturbances blarred vision stomatitis prarif as edema Before prescribing or administnrin,g Lead product circular with ;d hypersensitivity reactions. Slight BUN elevation, usually ~p!~je or Ovailable on request. - r,ssiest, has been seen in some patients, alfhsagh the prepon- -- s;ancv of evidence indicates that INDOCIN does not adversely utect renal function, even in patients with preenisfing renal (s)MERCI( SHARP& DOHME1,,,....,nn,n&c.,,'-" ~ i ~svase. Nevertheless, renal function shauld be checked periodi- -----"-`- - ---`-- -- -..~-- ;illy is patients on long-term therapy. Leakopenia hai been seen where today a theory is tomorrow s therapy PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3227 [From British Medical Journal, Oct. 19, 1963, pp. 965-970] INDOMETHACIN A NEW NON STEROID ANTI INFLAMMATORY AGENT (By F. Dudley Hart, M.D., F.R.C.P., and P. L. Boardman, M.B., M.R.O.P.) The measurement of joint-swelling in the human subject is not easy, but in the assessment of drugs purporting to have an anti-inflam~inat'ory effect in condi- tions characterized by the presence of chronic inflammatory swelling, such as rheumatoid `arthritis, some clinical measure is essential. We `have found that the only practical and reliable measurement which can be done repeatedly and rea- sonably quickly in the wards is finger-swelling measured by jewellers' rings (Hart and Clark, 1951). All patients with active rheumatoid arthritis entering our wards have finger-swelling measured in this way twice weekly by the same * clinician at approximately the same time of day as a routine measure. Also, the patient's own assessment of pain, stiffness, the number of analgesic tablets taken daily, the time taken to limber-up in the morning, and the clinician's assessment of grip strength, joint tenderness, and `sedimentation rate are done routinely on all patients as measures of progress irrespective of the treatment given throughout their stay in hospital. Measurable reduction of joint-swelling occurs regularly and demonstrably with steroid therapy, but not with salicylates, phenacetin, paracetamol, or the pyrazoles (phenylbutazone or oxyphenbutazone) as measured by this method; and since the early use of the corticosteroids and corticotrophin no other thera- peutic substances of the many we have tried have produced a measurable reduc- tion in `swelling of the interphalangeal joints. It was therefore a pleasant sur- prise when we found that in indometbacin (MK 615) we had the first non-corticos- teroid agent which produced a predictable and measurable reduction in joint- swelling in most cases of at~tive rheumatoid `arthritis. CHEMISTRY Indomethacin is a non-steroid anti-inflammatory and antipyretic agent. Its activity does not depend upon pituitary-adrenal stimulation and it is fully active in adrena'lectomized animals. Chemically it is 1-(p-chlorobenzoyl)-5-met'hOx~-2- methylindol-3-acetic acid, having the empirical formula of C19H10N0401 and a molecular weight of 357.8. It is relatively insoluble in `water `but `soluble in the common organic solvents. It is rapidly cleared from the plasma, having a half- life of 0.3-4 `hours in various `species. From 46 to 63% of an intravenous dose of indomethacin-2-C'4 is rapidly exreted in bile of dogs, guinea-pigs, `and monkeys (Hucker, Zacchei, and Cox, 1963). Its anti-inflammatory activity can be demon- strated in rats by the cotton-pellet granuloma-inhibition test and by inhibiting oedema on subplantar injection of irritant agents. Granuloma inhi'bition can be observed by oral `administration or `by local application to the cotton pellet in the same animal. After oral administration to rats the drug appears to be well ab- sorbed and gives an estimated plasma half-life of about 21 hours; about 90% of the drug in plasma is bound to the non-diffusable constituents. Excretion in rats is largely through the kidney, little being found in the faeces. That rat and the dog apparently tolerate the drug less well than does man or monkey. Antipyretic activity has been demonstrated by inhibiting the fever produced by injection of EsokerieMa ooli endotoxin in both rats and rabbits. Analgesic effects could not be demonstrated in mouse or rat by current methods. Toxic effects in rat, dog, and monkey consist largely of gastrointestinal irritation, monkeys tolerating larger doses of the drug than rat or dog. Judged by `the work on animals, gastro-intestinal toxicity seemed to be the only effect likely to occur in man, but early clinical trials in the United States of America indicated that it was usually well tolerated by the human `digestive tract (H. Hodgkinson, per- sonal communication, 1963). MATERIAL AND METHOD Indomethacin has been used in the treatment of a group of patients in whom a clinical response might `be `anticipated from administration of a compound with anti-inflammatory, antipyretic, and possible analgesic properties (see `Table I). PAGENO="0136" 3228 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 1.-OVERALL CLINICAL RESPONSE IN 99 PATIENTS TREATED WITH INDOMETHACIN Disease Number of Clinical No clinical Inconclusive patients improvement improvement Gout 15 13 1 AnkyIosin~ spondylitis 14 11 0 3 Rheumatoid arthritis: Measurable soft-tissue swelling 15 8 3 4 No measurable soft tissue swelling 37 14 14 9 Osteoarthritis 7 6 1 0 Miscellaneous 11 6 5 0 Total 99 58 24 17 At the beginning of the trial patients were started blind on either the drug or placebo It was soon apparent that on the high initial dose of 300 mg daily by mouth patients developed marked symptomatic improvement or side-effects, and, with few exceptions, were able to differentiate the true tablet from placebo. It was felt that a comparison against placebo would therefore provide less informa hon than against other potentially anti inflammatory agents such as phenylbuta zone or the corticosterolds In the absence of side effects patients received a minimum of 14 days' therapy, and some have been on treatment for up to one year. Indomethacin was used for the treatment of acute gout, ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis. Gout Fifteen patients (14 male, 1 female) with gout received indomethacin for the `icute attack It was given orally in high initial dosage and gradually reduced as symptoms and signs improved. The first four subjects received indomethacin 400-500 mg in the first 24 hours dosage then being reduced by 100 mg every second day This dose was found to require modification because side effects occurred not infreqently and most acute attacks responded satisfactorily to a smaller amount of the drug. Subsequently 200-300 mg. was given in the first 24 hours in divided dosage and this was gradually reduced to 100-150 mg daily for five days or longer if symptoms persisted Patients were not given a maintenance dose between attacks. Plasma uric-acid estimations were performed during and after the acute attack, but these revealed no significant changes. Patients were asked to record their impression of the effect on the acute attack, the rate at which relief ensued, the extent of relief, the occurrence of side-effects, and the presence or absence of symptomatic rebound on cessation of therapy. An attempt was made to compare the response with that previously obtained from phenylbutazone oxy phenbutazone or colchlcine Ankylosing ~pondyktis Fourteen patients with ankylosing spondylitis were treated with indomethacin These patients had all suffered from the disease for at least two years and six had a history longer than 10 years All had characteristic a~ ray changes All experi enced considerable pain and had taken different analgesics for a long time Ten of these patients received indomethacin 300 mg daily in divided doses for 14 days and four received 200 mg. daily. When a steady baseline was obtained this was changed blind to placebo and rebound noted. Some patients received the placebo first They were asked to assess their symptoms during this time and to compare the relief obtained from indomethacin with that previously obtained from phenylbutazone. Osteoarthritis Seven patients with ociteoarthritis were treated with indomethacin three of them had involvement of the hips, one severe disease in the knees, and three involvement of the cervical spine They received indomethacin 150-300 mg daily in divided doses for 14 days They were asked to note any change in symptoms while on the drug and to compare this with the effect of phenylbutazone taken immediately before Withdrawal symptoms on cessation of therapy were also noted Rheumatoid Arthritis Patients with rheumatoid arthritis were treated with indomethacin and assessed not only on their symptomatic response but also by reduction of joint- PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3229 swelling This group of 52 patients was divided into those exhibiting measurable inflammatory features (15) and those with less active but painful disease (37). Initially 300 mg was given daily in divided dosage but subsequently 50-150 mg. daily was found to produce similar change with a lower incidence of &ide~ effects The patients with inflammatory features all suffered from elasnical rheumatoid arthritis 7 out of 11 having positive sheep cell agglutination titres ranging from 1 32 to 1 512 The method of assessment varied according to whether the patient was seen regularly as an out patient or was admitted to hospital In patients were assessed by their own daily record of pain stiffness and morning limbering up time Twice weekly the size of proximal interphalangeal joints was measured by standard jewellers rings by one observer at the same time of day Joint tenderness over proximal interphalangeal and metacarpophalangeal joints was recorded, as was the strength of grip, using a soft cuff inflated to a pressnre of 30 mm. of mercury. A Westergren erythrocyte sedimenation rate (E. S.R.) was estimated each week. In addlition, four in-patients with swollen knees were assessed by daily clinical examination Out patients were seen weekly and the severity of symptoms was recorded as was their range of activity Their disease was also assessed by joint sue tenderness and grip strength Anti inflammatory effect was assessed by weekly change in swelling of the proximal interphalangeal joints No change in the basic rest exercise therapy was made during the trial The patient was started on an identical placebo and observed until a steady baseline assessment was obtained the genuine tablet was then substituted and when the new baseline was established indomethacin was withdrawn and identical placebo restarted In assessment of the patient s condition not only an improvement on introduction of the drug was required but also deterioration when the drug was withdrawn before the clinical response was considered positive. In addition to patients with rheumatoid arthritis and inflammatory disease, 37 without measur- able soft-tissue swelling were treated with indomethacin and the same parameters assessed These patients had classical rheumatoid arthritis and the sheep-cell agglutination titre was positive (1 32 to 1 2 048) in 22 Eight were in patients and 29 out patients Misceflaneovs Eleven patients with miscellaneous disorders were treated with indomethacin to assess its influence on fever as in glandular fever and Reiter s disease and pain from noninflammatory lesions such as bony metastases RESULTS Gout Of 15 patents with gout, 11 noted a dramatic and rapid response with full symptomatic relief, two noted a moderate analgesic response without complete alteration of symptoms, one patient noted no effect, and one developed immediate side effects The following case histories demonstrate the rapid response that may occur Case 1 -A man aged 52 who was diagnosed as having gout in 1956 and had acute episodes several times each year developed an acute attack in May 1963 Indomethacin 100 mg t d s was started After 100 mg he noted a dramatic improvement and within 24 hours pain and inflammatory features had settled completely Colchicine had produced relief in previous attacks only after several days and diarrhea had always followed Phenylbutazone 500 mg in 24 hours had produced some improvement but with this drug full symptomatic control occurred only after `four days or more. The patient felt indornethacin was quicker and more effective. Not all patients noted such benefit (see Case 6). Case 2.-A man aged 62, who had suffered from gout since 1941, developed an acute attack involving the right carpus the right elbow and the left hand After indomethacin 100 mg he noted complete relief within four hours and was able to sleep the following night The attack had previously been treated for four days with colchicine and phenylbutazone with little effect and he had been kept awake at night by the pain Case 6-A man aged 64 developed acute gout Indomethacin 100 mg t d s resulted in mild symptomatic relief but the joint remained painful and inflamed and after 48 hours he developed acute gout in another joint There were no side effects This may represent a failure of response or it may that indometha cm absorption from the gastro-intestinal tract was impaired. Response in previous attacks to phenylbutazone had been entirely satisfactory. PAGENO="0138" 3230 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Case 8.-A man aged 34 was admitted for observation after a hand injury sustained in a road accident The next day he developed acute gout in the right ankle Colehicine 8 mg in divided dosage in 48 hours had no therapeutic effect and diarrhoea ensued. Indomethacin 100 mg. was given and definite relief was noted within an hour. After a further 100 mg. he was able to walk a few steps and the signs of acute inflammation were reduced. He was maintained on 300 mg. daily for five days, in which time the acute attack completely subsided. After 48 hours he developed a feeling of muzziness~ and headache, but this cleared on chlorpheniramine (".piriton") 4 mg. q.d.s. and on reduction of the dose to 200 mg. daily. Case 0-A man aged 50 in whom gout was diagnosed in 1956 noted no relief and no side effects on indomethacin 100 mg t d s but obtained relief within 24 hours form 4 mg of coichicine in divided dosage He was the only patient who obtained no relief whatsoever from rndomethacin There seemed some doubt on his history that he took sufficient dosage to obtain therapeutic effect for he was against taking any new drug when his old favourite colchicine was available In Table II a comparison is made between phenyibutazone and indomethacin in the seven patients who had received both drugs for the acute attack. It was suspected that Case 7 did not take the indomethacin. TABLE 11.-COMPARISON OF EFFECT OF INDOMETHACIN AND PHENYLBUTAZONE IN TREATMENT OF THE ACUTE ATTACK OF GOUT Case Indomethacin Phenylbutazone No. ------~ - -~--------- - Preference Speed of action Degree of relief Speed of action Degree of relief 1 24 hours Full 4 days Full - Indomethacin. 2 4 hours do Nil Do. 3 2 hours do do Do. 4 24 hours do 12 hottrs Full Phenylbutazone. 5 2 hours do 24 hours do Indomethacin. 6 24 hours Partial do do Phenylbutazone. 7 Nil do do Do. Note: The speed of action Is the time between the initial dose and the onset of symptomatic relief. The degree of relief was assessed when the maximal clinical improvement had occurred Pa ient 7is suspected of not taking indomethacin Ankylomng fSpondylitss Of the 14 patients with ankylosing spondylitis who were treated with indo methacin nine noted marked relief from pain and thought mdomethacin 100 mg was more effective than phenylbutazone 100 mg., one had moderate relief of symptoms and considered 100 mg of indomethacin equal in effect to 100 mg of phenylbutazone and one noted mild improvement less than that obtained from phenylbutazone. Except for three patients with early side-effects necessitating withdrawal of treatment, all noted deterioration on blind introduction of placebo. Three patients had side-effects which prevented assessment. The following are examples of case histories of patients who benefited from :indomethacin. A Scotsman aged 48 with ankylosing spondylitis since 1945 was experiencing severe pain in the lower back and between the shoulders Previous therapy included phenylbutazone 300 mg daily which resulted in mild symptomatic relief but was associated with the development of dyspepsia On his own initiative he started taking compound tablets of codeine in large quantities and although this was hard to assess he probably took 25 tablets daily After some weeks he was admitted as an emergency to hospital unrousable and cyanosed from excess medication He started on indomethacin 100 mg t d s and this was increased to 100 mg q d s This dose controlled his pain to an extent that enabled him to stop taking any other treaitment. On stopping indomethacin he deteriorated to his previous state. A man aged 38, who was diagnosed in 1952 as having ankylosing spondylitis had episodes of severe low-back pain lasting from 10 to 21 days, with full remission of symptoms between attacks. On starting phenyibutazone 100 mg. b.d. he had partial relief of symptoms after three days Any increase in ~dosage produced a rash Indomethacin 100 mg b d controlled symptoms completely within 48 hours A woman aged 27 with ankylosing spondylitis and peripheral joint involve ment was maintained on 12 units of corticotrophin daily Indomethacin 100 mg PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3231 t.d.s. produced a marked improvement in pain and corticotrophin was reduced by 5 units a day. Within two days she developed a severe headache; indomethacin was withdrawn and symptomatic deterioration ensued. Corticotrophin was in- creased to the original dose level and symptoms improved only slightly; a further temporary increase of 5 units a day was required before her clinical condition was adequately controlled. Subsequently she was found to have a good clinical response to indomethacin 50 mg once or twice a clay dizziness on 50 mg t d s and headache on 100 mg. t.d.s. Osteoccrthritis Six of seven patients with osteoarthritis noted symptomatic relief. Four out of five in whom a direct comparison was made preferred indomethacin to phenyl- butazone. One patient noted no change in symptoms. Rheumatoid Arthritis Eleven patients with rheumatoid arthritis with measurable inflammatory features were assessed. Eight were out-patients and three `were in-patients. In addition, four in-patients with swelling of the knees were included, making a total of 15 patients with aotive inflammatory disease (Pable III) Of these 15 patients, eight showed clinical improvement with reduction in joint-swelling and two were inconclusive in that no rebound occurred on cessation of therapy The following are examples of patients who improved clinically and noted reduction of joint-swelling. A woman aged' `58, with rheumatoid arthritis of `two years' duration , (Fig. 1), was severely incapacitated `by pain, and the knees in particular had deteriorated to such an exten't that she spent much time in `bed and did not go out of doors. She was maintained on prednisone 20 mg. a day and aspirin 60 gr. (4 g.) a day. Indonieth'acin 300 mg. a `day produced a marked clinical improvement and reduc- tion in ring size. When she was changed `blind to placebo she deteriorated to such an extent that the house~physician, who did not know of the alteration, ultimately used pethidine for analgesia On reintroduction of indomethacin she improved once more, and after five weeks was discharged greatly improved and able to `take short walks. She has been on indomethacin for a year with sustained' improvement and with no side-effects. She had previously had a partial gastrec- tomy for duodenial ulceration and was able to `tolerate indomethacin satis- factorily. Butazolidin had been ineffective in dosage of 300 mg. a day. A 38-year-old woman developed rheumatoid arthritis at the age of 36. Neither paracetamol nor aspirin produced significant symptomatic improvement. Indo- methacin 100 mg. b.d. gave her a feeling of drunkenness after 24 hours, but this disappeared on 50 mg. t.d.s. Placebo was introduced blind and assessment showed deteriora'tion; improvement occurred on reintroduction of indomethacin. TABLE Ill-EFFECT OF INDOMETHACIN COMPARED WITH THAT OF PHENYLBUTAZONE IN ANKYLOSING SPONDY- LITIS AND RHEUMATOID ARTHRITIS Number of Better than Equivalent Less effective Disease patients Phenyl- to Phenyl- than Phenyl- InconclusIve butazone butazone butazone Ankylosin8 spondylitis Rheumatoid arthritis: 14 9 1 1 3 With measurable soft-tissue swelling With no measurable soft-tissue 15 8 3 4 swelling 37 9 4 15 9 Five patients failed to show reduction in ring sizes on indomethacin. In two the explanation was probably that treatment was given for `too short a time to cause much change as it had to be stopped after a few days because of side- effects Two patients probably did not respond because there was inadequate initial acute oedema to show measurable change The fifth patient responded to corticosteroids but not to indomethacin. PAGENO="0140" 3232 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ ~ L-~ UIDOMETHAC1N 3;L~io:4~s,oe~ DAYS Fia I -Chart of woman a~ed 58 treatcd with indorncthactn for rheumatoid arthritis of two years' duration. A man aged 61 developed acute rheumatoid arthritis over a period of nine months and required admission to hospitaL As can be seen in Fig. 2, his condition was not improved by salicylates Indomethacin was introduced without any pro nounced effect and he was changed to corticotrophin Tins resulted in clinical improvement and marked loss of inflammatory swelling In this case the rheumatoid disease was very active and a dosage of 60 units of corticotrophin was required initially to control the conthition In five cases where both drugs were used corticotrophin proved a much more effective anti inflammatory agent than the new one Of 37 patients with rheumatoid arthritis without measurable inflammatory features 14 noted a beneficial effect 14 noted no effect and in 9 the result was inconclusive. Of the 14 patients who noted a good effect 9 preferred indomethacin (100 mg.) to phenylbutazone (100 mg.), four noted a moderate improvement, equivalent to that obtained from phenylbutazone and one noted mild symp tomatic relief only Of the 14 patients who noted no improvement on indometha cm six benefited from phenylbutazone while seven noted no effect one had not received phenylbutazone Indomethacin was inconclusive in a further nine pa tients eight of whom experienced side effects and one developed an influenza like illness and stopped taking the tablets Six of these patients found phenylbutazone to be of value two noted no effect and one had never taken phenylbutazone PAGENO="0141" COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY 3233 SIDE-EFFECTS Side effects were frequent with indomethacrn on a dosage of 300 mg daily occurring in 26 of 50 patients Reactions at this dose level usually accurred 48 to 96 hours after starting treatment Seven patients who experienced side effects on 200-300 mg a day were found to be symptom free on a smaller dose more gradually introduced tSR $6 GRIP 60178 85/80 160/leo JOiNT TtNDCRNESS ~ 5 0 0 IP4ETHACIN J CORTICOTROPHIN DAYS Ho 2 -Chart of man aged 61 treated with mdomcthacm for acute rhcurn~toid arthritis with little cftcct Go~tt Of 15 patients who received indomethacin for the acute attack of gout three experienced side-effects. One developed a headache after 48 hours on 300 mg. daily, which cleared on 200 mg. a day and was relieved by an antihistanilnic preparation Another patient noted mild headache and giddiness on 400 mg 40 $00 z 60 .4 ., 4~ 20~ 0 S'S. 0' S. 10 15 .1% " 20 25 30 - ~ ~-1~u-- PAGENO="0142" 3234 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY daily after 48 hours. Only one patient had a severe but `transient reaction. This woman, aged 23, had hyperuricaeinia, a family history of gout, and congenital hypoplastic kidneys, and was subject to acute gout. Her blood urea was 52 mg./100 ml. and uric acid 13.2 mg./100 ml. She took indomethacin 100 mg. for an acute `ittack of gout and within 10 minutes became drowsy was unable to focus on any object, and later developed a severe throbbing headache. Symptoms im- proved after four hours but `the headache remained for 24 hours Several cups of coffee reduced her drowsiness. The reaction was thought to be too rapid in onset to be accounted for by high blood levels `of indomethacin due to impaired renal function. This was an abnormal incident, no similar reaction being observed in any other patient. Rheumatoid Arthritis Of the 52 patients with rheumatoid arthritis who received indomethacin 31 noted side-effects. The `age of these patients varied from 20 to 56. Symptoms developed within two to three days in 16. They occurred within six hours of the first dose in 10, and in five reactions were delayed until after six days. Patients' usually experienced several side-effects at the same `time. Of 37 patients with relatively inactive rheumatoid arthritis, 28 experienced side-effects, while only 3 of the 15 patients with measurable inflammatory disease were affected. Headache occurred an 14 of 31 patients This was characteristically a general Ized throbbing in the head and ears one was severe eight were moderate and five mild. Giddiness was present 12 patients. This was a sensation of unsteadiness with- out vertigo. It interfered with gait and driving a car. Three were mild, eight moderate, and one was severe. Faintness, coupled with a sense of impending loss of consciousness, was experi- enced `by two patients. This symptom occurred on'ly when other side-effects' were pronounced. In no case, however, was there loss of consciousness. Muzziness and mental change: two patients noted muzziness with inability to concentrate or think out intellectual problems, two felt `emotionally detached, and four said they felt drunk. Nausea and vomitting: nine patients experienced anorexia and nausea, two of whom vomi'ted. Diarrhoea: four patients experienced diarrhoea. This was usually associated with nausea or vomiting. Dyspepsia: four patients experienced dyspepsia, which was severe and neces- sitated cessation of treatment: one had no previous .ga:stro-intestinal history, two were intolerant of phenyibuta'none, and one, who had both a hia:tus henna and gail-stones, developed dyspepsia with soluble aspirin, paraeetamol, and placebo tablets identical in appearance to inclomethacin. Two patients developed dyspepsia within two days of starting the `drug and the other two first noted symptoms after seven days' therapy. Drowsiness: two patients developed drowsiness within one hour of the first dose. If they sat down they fell asleep. This symptom occurred only after the more severe reactions and was improved by taking coffee. Blurred vision was noted by `these patients. Side-effects usually cleared within 24 hours of cessation of treatment, but occasionally lasted fo'r two to three days. Five patients were given anithi'stamines, chlorpheniramine 4 `nag. q.d.s., and four noted improvement in the headache but not in gastro-intestinal symptoms. `The effect of a lower dose on side-effects has been studied in seven patients intolerant of high dosage. Of three patients who experienced side-effects on 300 mg. a day, two were symptom-free on 200 mg. and one on 150 mg a day. Three patients with side-effects on 200 mg. daily were able to tolerate 150 mg. a day, and one of these who suffered side-effects on 100 mg. b.'d. was found to become symptom-free on 50 nag. q.'d.s. One patient, intolerant of 100 mg. a day, was main- tained satisfactorily on 50 mg. a day. Anklosing Spondylitis and Osteoarthritis Six of the fourteen patients with anklosing spondylitis developed side-effects four were taking 300 mg a day one of whom later had no symptoms on 200 mg a day; one was on 200 mg. a day; and one on 100 mg. a day, experienced a mild headache. Of seven osteoarthritic patients treated none noted side-effects. PAGENO="0143" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3235 PATTERNS OF SIDE-EFFECTS Of 88 patients with disorders of the locomotor system treated with indometh acm 40 (454%) suffered side-effects These effects were commoner in patients with rheumatoid arthritis (596%) than with gout (20%) Side effects included headache giddiness faintness muzzines~ mental change anorexia nausea and vomiting dyspepsia diarrhoea drowsiness and blurred vision More than one symptom occurred in all patients. Headache was improved by antihistamines, and drowsiness by coffee. Seven patients with rheumatoid arthritis and one with ankylosing spondylitis who had side-effects on relatively high initial dosage were found to be symptom-free on a lower dose more gradually introduced. It is probable, therefore, that with a starting dose of indomethacin 50 mg. daily and gradual increase by 50 mg. every third day to a maximum of 200 mg., the inci- dence of side-effects may be much lower than this figure. A dosage of 300-500 mg. daily may occasionally be used, but side-effects are likely to be frequent. There was no evidence of toxic effect on the blood, liver, or kidneys. Side-effects occurred in four patterns: (1) Within a few hours the patient experienced severe symptoms independent of the dose. (2) Side-effects developed most often between. 48 and 72 hours and were reduced by adjusting the dose. This appars to be a cumulative effect. (3) A small number of patients developed symptoms after seven days, as in two of the four cases of dyspepsia. (4) Some patients experienced muzzy feelings and mild headache about two hours after each dose, which wore off after an hour and did not progress. This occurred only with the 100-mg. tablet, never the 50 mg. DISCUSSION It is clear that in indomethacin we have an agent that will reduce swelling and also relieve pain As an anti inflammatory agent it is less effective than the corti costeroids and corticothrophin, but it is the only non-steroid agent we have used to date which has produced measurable reduction in finger-swelling in active rheumatoid arthritis. In this disorder those cases with measurable inflammatory swelling did appreciably better and had fewer side-effects than those with less inflammatory change. In two cases the dose of corticosteroids previously needed to control symptoms was gradually reduced under cover of the new drug, but in 12 others it proved ineffective. The response in acute gout is, in our opinion, better than with any other therapeutic agents at present available, for its action is more rapid than is that of phenylbutazone and the patient is less subject to rebound attacks than with corticotrophia. The definite relief of pain in the few cases of osteoarthritis assessed makes it seem likly that the drug ha's analgesic properties independent of its anti-inflammatory ones, and its use in a few febrile cases demonstrated that it is also an effective antipyretic: in one case of glandular fever treated with indomethacin there was rapid improvement in symptoms and signs, with relapse as soon as it was discontinued. As regards toxicity, it is clear that our initial dosage was too high and we now seldom use 100 mg tablets but favour 50 mg one to four times daily On this lower dosage side-effects are much less troublesome and the headache and muzziness which are the commonest complaints often pass off on continuation of low-dosage therapy. Many patients intolerant of other drugs because of gastro- intestinal side-effects are tolerant of indomethacin, which in our hands has proved relatively non-toxic in this respect to man, unlike the results in experi- mental animals. Time will show if there are any other side-effects, but at present no changes in blood counts or liver- or renal-function tests have been noted, nor were skin reactions seen. We have not used it in children or in pregnant women. On present evidence we consider that indomethacin, in spite of its tendency to cause headaches and dizzy feelings has a definite part to play in the treat ment of the chronic rheumatic disorders and we regard it as the drug of choice in acute gout In ankylosing spondylitis osteoarthritis and active rheumatoid arthritis it has also much to offer. SUMMARY AND CONCLUSIONS Indomethacin (1-p-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetic acid) has proved to have anti-inflammatory and pain-relieving effects in gout and rheuma- toid arthritis. It has also proved effective in the treatment of ankylosing spondy- litis and osteoarthritis. As a dosage about 200 mg. a day headaches and dizziness were frequent, occurring in over 50% of those treated. At a daily dosage of 50- 200 mg. side-effects occurred in 43%. PAGENO="0144" 3236 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dyspepsia has been rare-in 4 out of 99 patients. Also rare were faintness (2), drowsiness (2), and feelings of drunkenness (4). Intolerance or resistance to the drug has not been observed in up to one year of continuous treatment Inclomethacin is the drug of choice in acute gout where relief is obtained more rapidly than with phenylbutazone It is useful also in ankyloning spondylitis in osteoarthritis and in cases of rheumatoid arthritis with inflammatory features and swelling of joints Although more time is needed before the true incidence of toxic effects can be evaluated indomethacin appears to be a useful addition to the treatment of these rheumatic disorders. ADDENDUM We have now followed up 123 patients for periods of up to one year other workers have reported dyspepsia and occasional gastrointestinal haemorrhage as complications of indomethacin therapy In our experience to date only 4 out of 123 patients have experienced dyspepsia and none has had clinically detectable haemorrhage. Three of these four patients have suffered dyspepsia on phenylbu- tazone. One patient who noted an initial symptomatic improvement on indomethacili has found that the symptoms have gradually i~eturned in spite of continued treat ment This was thought to be due to the possible development of tolerance Three out of 123 patients developed skin lesions; one of these suffered from disseminated lupus erythematosus The rash was irritating and consisted of dis crete red macules and papules on the limbs. It disappeared completely within 48 hours of stopping the drug. In one patient a reçluction of the drug from 350 to 150 mg. a day resulted in the rash resolving. We wish to thank Dr. J. Merry and Dr. R. Hodgkinson, of Merck Sharp and Dohme, for their co-operation and for the provision of supplies of indomethacin also Dr D Taylor of St Stephen s Hospital Chelsea who was responsible for the clinical care of some of the patients References Hart F D and Clark C J M (1951) Lancet 1 775 Hucker H B Zacchei A (1 and Cox S V (1963) Fed Proc 22 544 [From British Medical Journal, Nov. 27, 1965, pp. 1281-12841 INDOMETHACIN AND PHE.NYLBUTAZONE: A COMPARISON (By F Dudley Hart * M D F R C P and P L Boardman * M R C P) Ear~1y papers on indomethacin reported promising iesults from its use as a non specific anti inflammatory agent in the treatment of the chronic rheumatic dis orders (Paul and Strottman 1963 Ballabio et ai 1963) with dramatic results in gout (Smyth et al 1963) A controlled clinical trial demonstrated siginficant preference for indomethacin against placebo in rheumatoid arthritis (Dixon ci al 1963) Measurable reduction of joint swelling as a result of treatment with indomethacin was reported in active rheumatoid arthristis (Hart and Boardman 1964). There was no significant difference between indomethacin and phenylbu- tazone (Percy et al 1963)-in this trial the treatment period on each drug was one week and the indomethacin used was in tablet form, which, for various rea- sons, has been replaced by a gelatin-coated capsule. This paper reports the results of a double blind trial in which the effect of phenylbu'tazone is compared with that of indoniethacin capsules each drug being given for one month to patients with active rheumatoid arthritis A brief account is also given of the results obtaind from the treatment of rheumatoid arthritis osteo arthritis, and ankylosing spondylitis with indomethacin during a period of two and a half years. I. DOUBLE-BLIND TRIAL All 26 patients who took part in the double blind trial of indomethacan and phenyJbutazone had c1assical rheumatoid arthritis or definite rheumatoid arthri tis as defined by a Committee of the American Rheumatism Association (1969). *Westminster Hospitai, London. PAGENO="0145" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3237 The diagnosis of the classical form of the disease is applied to those patients in whom 7 out of the 11 criteria listed by the A R A are present A diagnonis of definite requires the presence of five of the criteria Phenylbutazone 100 mg three times a day was given to 13 patients in the first months and indomethacin 25 mg three times a day to 13 therapy being changed to the other agent at the end of the month To provide double-blind conditions they received active indo- methacin and dummy phenylbutazone in one month and in the other active phenylbutazone and dummy indomethacin The group who started on indometha ciii had a mean age of 47.6 years; five were males and eight females. The mean duration of disease was 6.7 years. The patients who received j~henylbutazone in the first month had a mean age of 48.8 years, an average length of history of 62 years and there were four males and nine females There were six patients with classical and seven with definite rheumatoid arthritis in each group. These patients were assessed by their own daily record of pain, stiffness, and loosen- ing up time and the measurement of joint tenderness jwnt swelling and grip strength at each visit (Hart and Boardman 1963) All were attending the out patient clinic at monthly intervals They were assessed at the start of treatiiient and at the end of each trial period of 28 days Their personal opinion as to the more satisfactory treatment period was recorded at the end of the trial RESULTS When asked at the end of the trial, before the identification of the specific treatment periods, which month was the more satisfactory, 15 patients preferred phenylbutazone, 10 found them to be equally effective, and one preferred indo- methacin. This difference is statistically significant (P<0.001). A comparison of the pain record of each patient in the month on phenyibuta- zone with that of those on indomethacin revealed that this parameter improved selectively in five in phenylbutazone and in two on indomethacin, 19 finding no difference A clinically significant alteration of pain was taken to be 25% or more in the month Likewise assuming a 25% difference to be significant five were less stiff during phenylbutazone therapy and one on indomethacin 20 findrng no detectable difference. There is obviously no significant difference in these symp- toms between the two groups. An alteration in the duration of early-morning stiffness was assumed to be of clinical significance if it exceeded 30 minutes. In the first month, on phenylbu- tazone, there was improvement in the loosening-up time in seven patients and deterioration in one, five being unchanged. On indomethacin there was improve- ment in three, deterioration in four, and no change in six. These changes are not statistically significant (X2=1.4; n1 ; 0.3>P>0.2). In the second month, on judo- methactn improvement occurred in three patients and this parameter worsened in two eight exhibiting no change On phenylbutazone there was no change In six four improved, and three deteriorated. A difference in grip strength of 50 mm. of mercury was assumed to be clinically significant In the first month on phenylbutazone none improved five deteri orated and eight i emained unchanged On indomethacin three improved one deteriorated and there was no chance in nine There was no statistically sig nificant difference between the groups (2X=1.5; n=1; 0.3>P>0.2). In the sec- ond month, on indomethacin, 11 patients remained unchanged, one improving, and one deteriorating. In comparison, on phenylbutazone, there was no change in 10 patients, improvment occurring in three. There was obviously no signifi- cant difference. As 17 of the 26 patients had no tender joints at any time during the trial this was an unsatisfactory parameter. Assuming a change of three ring sizes in joint size to be significant, there was no difference in 17 patients, five were better on undomethacin, and four on phenylbutazone The improvement in joint size in the first month in the patients on phenylbutazone was by four rings On mdomethacin the improvement was by 35 rings This difference is not statistically sigmficant (t = 1 n = 24 0.2>P>0.1). In the `second month indomethacin was associated with an improve- ment of 21 ring sizes, compared with 17 on phenylbutazone. II. LONG-TERM STUDIES Ninety-seven out-patients and 21 in-patients with classical, or definite rheuma- toid arthritis, osteoarthritis, and ankylosiug s'pondylitis were treated with indo- methacun. In sOme cases it was possible to compare results with those previously obtained with pyrazole derivatives~. 81-2800---68-pt 8-10 PAGENO="0146" 3238 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Rheumatoid Arthritis Ninety-seven out-patients an 21 in-patients with classical to definite rheuma- toid arthritis (American Rheumatism Association Committee, 1959) were fol- lowed up for two and a haJf years. Ninety were females and 28 males. Their average age Was 53.3 years, and the mean duration of rheumatoid arthritis was 8.1 years. The sheep-cell-agglutination titre was positive in 85 patients. The in-patients were assessed by their own daily record of pain, stiffness, `and the duration of early-morning stiffness, together with~ twice-weekly estima- tions of grip strength joint tenderness and joint size (Hart and Boardman 1963). Identical placebo was administerd to conceal the exact time of the start and the withdrawal of indomethacin by blind substitution. The E.S.R. was measured weekly. Four grades of response were recognized in the out-patients with rheumatoid arthritis, according to the criteria of therapeutic response defined by the American Rheumatism Association Committee (Steinbrocker et aZ., 1949, recorded in this paper as good, fair, poor, or nil; the E.S.R. was excluded from This assessment. In all patients in whom treatment had included a pyrazole derivative indomethacin was compared with phenylbutazone or oxy- phenbutazone, their relative effectiveness being recorded at arbitrary mainte- nance dosage. This was 300 mg. daily for the pyrazoles, 200 mg. daily for indomethacin tablets, and 75 mg. daily for the capsule preparation. The prolonged effect of indomethacin was checked by the observation of rebound deterioration on withdrawal of the drug. Oat eoart hritis With one exception the 52 patients with osteoarthritis were treated in the out- patient clinic. They included 35 females and 17 males with an average age of 61.2 years and a mean `duration of symptoms of 4.5 years. A good response was one with 85% control of symptoms as assessed by the sufferer, the residual pain constituting minor discomfort only and not interfering with daily activity. A fair response was one in which there was therapeutically useful improvement but not to the extent of removing all serious discomfort. A poor response was one in which there was some slight symptomatic improvement, insufficient to be of therapeutic value. Ankylossn~g ~pondyht&s There were 26 males and six females in the group of 32 patients with ankylos- ing spondylitis, the average age being 37.6 years and the mean duration of disease 13.4 years. RESULTS Rheumatoid Art hritis In-patients Pain and stiffness were reduced in 15 of the 21 in-patients, there being no change in five and side-effects in one. Early-morning stiffness improved in eight, remained static in six, and was too short initially for assessment in Six; in one patient side-effects prevented assessment. Grip strength improved by more than 50 mm. of mercury in seven patients. It improved slightly in one patient, remained unchanged in six, and was an unsatis- factory parameter in seven-in five as a result of side-effects, and in two because of lack of involvement of the hands. Joint tenderness improved in five patients, was unchanged in two, and side-effects interfered in five; in nine there were no tender joints. Compared with the baseline, there was reduction of joint size on indomethacin of 79 ring sizes in seven patients, while three deteriorated by 11 ring sizes. There was no change in five. Assessment was unsatisfactory in six because of side- effects and lack of involvement of the hands. There was no significant change in the E.S.R. in response to the administration of indomethacin. Of the 21 in-patients 19 had previously received a pyrazole derivative. The preference was for indomethacin in six, and for phenylbutazone or oxyphen- butazone in four; nine patients were unable to detect significant difference. Rheumatoid Arthritis Out-patients In the 97 out-patients the response to indomethacin was good in 28, fair in 21, poor in 10, and nil in 38 patients. A comparison with a pyrazole derivative was possible in 80 patients. Indomethacin was preferred by 30, a pyrazole deriva- tive by 19, and they were found to be equally effective in 31 patients. PAGENO="0147" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3239 Ankylosing f~ponIyfltis The response to indomethacin in the 32 patients with ankylosing spondylitis was good in 16 fair in six poor ~n one and nil in nine In 19 patients the treat ment of choice was indomethacin and in nine it was phenylbutazone or oxyphen butazone four patients considered them to be of equal value Osteoarthritis The response to indomethacin in the 52 patients with osteoarthritis was good in 30, fair in four, poor in seven, and nil in 11. It was possible to compare indo- methacin with the pyrazoles in 39 patients. Indomethacin was the drug of choice in 15 and phenylbutazone or oxyphenbutazone in 13; 11 found them equally satisfactory. SIDE-EFFECTS Side effects occurred in 104 of the 202 patients treated with indomethacin (51.48%); this consisted of 67 out of 101 (66.3%) on indomethacin tablets, and 37 out of 101 on capsules (36.6%). The following complaints were noted the incidence being recorded in brackets headache (46) giddiness (25) dyspepsia (16) muzziness (16) nausea (12) vomiting (5) rash (4) diarrhea (4) felt odd (2) sleepy (2) heavy legs (2) drunk (1), faint (1), mouth ulceration (1), unpleasant taste (1), depression (1), lassitude and nightmares (1), swollen tongue (1), costive (1), and shaki- ness (1). In 88 patients side-effects occurred within seven days of starting indomethacin, in nine patients within seven to 14 days, and in two patients between 14 and 21 days. Side-effects occurred after three weeks in five patients only. Dyspepsia occurred in 16 of the 202 patients (7.92%). In contrast, of the 170 patients who received a pyrazole agent 40 had dyspepsia (23.5%). In no patient was there overt evidence of gastro-intestinal haemorrhage, and none developed perforation. One patient with rheumatoid arthritis and one with osteoarthritis of the hip bad slow gastro-intestinal blood loss, the administration of indometh- acm being associated with a fall in the haemoglobin by 20-40% within a month Barium studies were available for 16 patients all of whom had dyspepsia on phenylbutazone or oxyphenbutazone and eight on indometbac4n. A duodenal ulcer was detected in seven patients all intolerant of pyrazoles indomethacin was tolerated by four of these patients and caused dyspepsia in three; these seven have received 995 patient days of treatment with indomethacin to date. In five patients with demonstrable gastric ulcers-one with a hiatus hernia also-all intolerant of phenylbutazone, indomethacin was associated with dyspepSia in one being well tolerated in four patients this group has received 571 patient days of treatment to date without serious gastro intestinal complications In three patients no abnormality was detected on barium-meal examination. All three were intolerant of phenylbutazone indomethacin was associated with dyspepsia in two patients, and in one may have been the cause of anaemia by slow continu- ous blood loss One patient with both a hiatus hernia and gall stones suffered from dyspepsia on indomethacin phenylbutazone sahcylates and placebo DISCUSSION It is increasingly apparent that the therapeutic effect of indometbacin has many similarities to that of phenyibutazone, irrespective of the mode of action. Though painful symptoms are relieved by phenylbutazone, the action being re- markably even throughout the 24 hours, reduction of joint swelling occurs in only occasional cases of rheumatoid arthritis. The regular, predictable reduction of joint size with the corticosteroids, offset by the untoward affects of prolonged therapy suggested that the advent of a new non steroid preparation with this property would be a considerable advance Of the many preparations tried in the last 17 years at the Westminster Hospital (F P H) indometbacin has been the first non steroid drug to produce a measurable reduction ~n joint size in selected cases of active rheumatoid arthritis. The spectrum of side-effects on indomethacin overlaps phenyIbutazone slightly with respect to the gastro-intestinal tract but is otherwise quite different. It is possible that the response to indometbacin is not as consistent as that obtained from phenylbutazone over the 24 hours; in this series the overall response was slightly less than 60%. The double-blind trial confirmed that, under defined conditions, there was no significant difference between indomethacin 75 mg daily and phenylbutazone 300 mg. daily, in the relief of pain and stiffness in rheumatoid arthritis. Though the alteration of joint size on the two drugs was not statistically significant, the PAGENO="0148" 3240 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY trend in each group suggested that this parameter improved specifically on indomethacin. The magnitude of the response obtained depends not only on the anti inflammatory effect of the administered drug but also on the amount of soft tissue inflammatory swelling present that is potentially capable of exhibiting reduction of size It is unlikely that optimal conditions existed in these patients for reduction of joint size they were selected from the regular attenders at the out patient clinic and had disease of moderately long duration That indomethacin was associated with reduction of )cint size as compared with the baseline was demonstrated in the patients admitted to hospital. Indomethacin was initially available in the form of tablets These proved to be unsatisfactory and gelatin-coated capsules were substituted. The patients in the long-term studies received both preparations. These results are not given separately, except for side-effects, because the capsule is the only preparation available; a comparison of the two preparations revealed that the only difference of `statistical significance was the incidence of side-effects. The most consistently satisfactory results from indomethacin ~ ere obtained in patients suffering from ankylosing spondylitis (687%) and osteoarthrltis (653%) Results for gout are reported separately (Boardman and Hart 1965) Excellent results did occur in rheumatoid arthritis In particular in patients with active disease, but there were also some dramatic failures, and overall benefit was obtained in only 505% Side-effects were a more frequent cause of therapeutic failure than inadequate drug potency. The change from the tablet to the capsule preparation was asso- ciated with a reduction in frequency from 66.3% to 36.6%, together with a de- crease ~in the severity of untoward reactions. The most common pattern of side- effects consisted in headache, giddiness, muzziness, and nausea. These were transient, dependent on dosage, and occurred within `the first few days of starting treatment. Dyspepsia was relatively rare during indomethacin administration. Smyth et al. (1964), in a study of 03 patients with rheumatoid arthritis during an 18- month period found one who developed peptic ulceration on indomethacin and one on placebo Catoggio et a~i (1964) had two cases of duodenal ulceration in a group of 33 patients Clark (1964) in a study of 100 patients with rheumatoid arthritis encountered peptic ulceration in 10 nine of whom also received cor ticosteroids there were three instances of perforation and one of hemorrhage Bilka et al (1964) reported one patient out of a total of 61 who developed a small gastric ulcer after 12 weeks of indomethacni therapy Haemorrhage and perforation do not appear to be serious risks as judged on the figures of this series in contrast to the findings of Lovgren and Allander (1964) Unlike their six patients with a history of gastric or duodenal ulceration treated in hospital in our series four of seven patients with duodenal ulceration and four of five with gastric ulcers tolerated indomethacin well the total period of therapy being 1 566 days Nevertheless with certain exceptions dyspepsia occurring oii indo methacin was considered an absolute indication for cessation of therapy In our series antacids were not used for symptomatic control Lovgren and Allander (1964) treated their patients in hospital with anticholinergics and antacid agents it is possible that some of their problems arose as a result of the masking effect of these symptomatic remedies on what should be considered a warning symptom The dose probably suitable for most patients is 25 mg three times a day administered after food It is suggested that to overcome the frequent early side- effects the dose should be increased slowly during the first week from an initial 25 mg. daily. Dyspepsia due to indomethacin is an indication for the withdrawal of therapy. During the two and a half years that Indomethaciri has been available to us it is of relevance to note that only three patients with rheumatoid arthritis have been started on long term corticosteroid therapy or A C T H The fact that a non steroid anti inflammatory agent is now available may well make a profound difference to the present use of corticosteroids in this condition SUMMARY A double blind cross-over trial was carried out to compare indomethacin 75 mg daily with phenylbutazone 300 mg daily each being given for a period of 28 days ~o patients with active rheumatoid arthritis No significant differences were found between the two groups in the relief of symptoms but the results PAGENO="0149" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3241 obtained were indicative of greater reduction of early morning stiffness on phenylbutazone and of joint swelling on indometbacin. The personal preference, expressed at the end of the trial was in favour of phenylbutazOfle In a mixed group of patients treated over two and a half years indomethacin was effective in improving the symptoms of osteoarthritis (65.3%) and of ankylosing spondylitis (687%) In rheumatoid arthritis failures were more frequent, a satisfactory response being recorded in 50.5% of cases. Side-effects on indomethacin capsules at an average maintenance dose of 75 mg daily occurred in 366% of patients in the mixed group The common side effects were headache, giddiness muzziness, nausea and vomiting Dyspepsia was not a major problem occurring in 792% of patients it was only rarely dose dependent and occurred at any time during long term administration in contrast to the other side effects which were dependent on dose and developed almost always within the first 14 days of treatment ADDENDUM Since the completion of this study, one patient on indomethacln, 200 mg. daily, and prednisolone 8 mg daily with a history of duodenal ulceration present 20 years earlier developed dyspepsia after six months on indomethacin This was followed by a haematemesiS which required blood transfusion In many of the cases of haematemesls reported this combination of drugs was used We would like to thank Dr R Hodgkinson of Merck, Sharp and Dohme Ltd for generous supplies of indomethacin References American Rheumatism Association Committee (1959) Ann rheum Dss 18 49 Ballabio C B Cirla E Girardi G Caruso I and Colombia B (1963) Rheumatism'o, 15, 487. Bilka, P. J., Woliheim, F., and Williams, R. C., jun. (1964). Minn. Med., 47, 777. Boardman, P. L., and Hart, F. Dudley (1965). Practitioner, 194,560. Catogglo, P. M., Centurion, A., Alberti, H., Roldan, H., and Canepa, L., (1964). Art hr. and Rheum~., 7,300. Clark, 0. M. (1964), Thid., 7,300. Dixon, A. St. J., Jones, L., Wanka, J., and Wood, P. (1963). Abstracts of Corn- munwat urns Fifth European Congress on Rheumatic Diseases p 174 Hart, F Dudley and Boardman P L (1963) Brst med F 2 965 - (1964) Practstsotier 192 828 Lovgren 0 and Allander E (1964) Br~t med F 1 118 Paul W D and Strottman M P (1963) Arthritss and Rheumatssni Foundatson (Iowa) Medical Information Bulletin, 4 (3), 1. Percy, J., Stephenson, P., and Thompson, M. (1963). Abstracts of Conunun4ca- tions, Fifth European Congress on Rheumatic Diseases, p. 176. Smyth, C. J., Valayos, E. E., and Amoroso, C. (1963). Artk. and Rheum., 6, 299. Amoroso, C., and Valayos, E. (1964). Ibid., 7, 345. Steinbrocker 0 Traeger C H and Batterman R C (1949) F Amer med Ass 140 659 Senator NELSON This is probably a question for Mr Goodrich As you know, all of these drugs are handled and promoted by detail men What legal control, if any, do you have over the informa tion presented by detail men to the physician ~ Mr GooDRICH Basically our control would be over the detailing pieces-the written, printed and graphic materials that the company develops to be used as detailing pieces As we move into some of the drugs, particularly Vi'bramycin which is coming up later, a detailing piece is one of the major pieces there we will be going over with you. In addition to that2 the regulations require that all promotions, whether it be advertising, direct mailings, promotional material left by the detail man, must all conform to the approved labeling, and must all present the full disclosure of both the good and the bad about the drug PAGENO="0150" 3242 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Now, in terms of what the detail man says in the doctor's office, legally we could do something about that But as a practical matter, we have no means of regulating that unless the doctor who is detailed tells us what happened and is willing to be a witness You will remember that in the hearings on Chioromycetin before the Kefauver committee, there was one instance in which one of our own men, one of our own physicians who was in private practice, was detailed by the company for Chloromycetm, and we did communicate with the company immediately about that improper detailing, and they represented that they had corrected it But we have no program of monitoring what the detail men say Now, we do have physicians attending meetings, and observing exhibits around the meetings, who hear the detailing of a public nature. In those instances, any time an oral advertising claim is made which exceeds the permissible bounds of the approved labeling, this results in the product being misbranded for failure to bear adequate directions for use. Senator NELSON If my recollection is correct, those who have com mented on this question before the committee felt that the detail man is frequently quite effective in influencing physicians' prescribing habits I am wondering how you, the FDA, can control the advertising that goes to the doctor and be effective yourself if one large aspect of the promotion of the drug, that is, the detail man, is not effectively controlled? Mr. GOODRICH. This is certainly a problem, Senator. But if we can be successful, as we hope we are, moving in this direction, in provid ing assurance that publications such as Physicians' Desk Reference, which is on the doctor's desk, all the advertisements in the journals, the mailing pieces that ~o out, fairly comply with. the requirements of the law, either by providing full disclosure in case of mailing pieces and adequate brief summary in case of journal advertising, that the physician who is detailed certainly has a place to turn where he can be adequately and completely informed about the drug, to have a basis on which he can make a comparison with the detail man's claim Another point is that PDR is a limited volume, as we all know, and this is one of the reasons we are advocating the bill you yourself intro- duced, to have a reliable compendium which will provide every doctor's office on his desk complete, reliable, adequate information on drug prescribing. Senator NELSON Do you evaluate and pre evaluate the literature that the detail man is permitted to give to a doctor ~ Mr GOODRICH We do not We certainly have the right to, and do, look at a good deal of this, that is promotional material The companies are required to submit with their records and reports the promotional material that is being used-not every piece, because they are quite voluminous But any piece that-any promotional piece that is differ ent in any significant way from one that has already been submitted is required to be submitted. That does not mean that Dr Ley's group adequately reads all that material, because its volume, even in terms of not being complete- not being the complete outpouring of promotion-the volume that we receive, only part of the total, is still quite large, and more than we can handle with our present people PAGENO="0151" COMPETITIVE PROBL.E~LS IN THE DRUG INDUSTRY 3243 Senator NELsoN. Do they hand out this type of promotional piece and so forth, like the ~JAMA ads? Mr. GOODRICH. Sure. The same kind. You will see in the ads you have before you some of them run several pages-it is not unusual to see an elaborate ad running several pages, that is suitable for reprinting, either for direct distribution or handout by the detail man. The coni- panies also use attractive visual aid type of promotional material to make their deta~hng more effective And they use a great many other promotional techniques I am constantly amazed at the creativity of the people on Madison Avenue who think up these ideas. But they certainly have a lot of ways of getting the message across. It could not be better stated than you did, that the problem of competing with a message such as the `ad you have in front of you is a difficult problem. Senator NELsON. In the event that some promotional material being handed to the doctor by the detail man exceeds the claims in the pack- age insert, do you have the authority to make them correct it ~ Mr. GOODRICH. Yes, sir. Senator NELSON Do you ever do that ~ Mr. GOODRICH. Oh, yes. Senator NELSON You say the material is very massive You do not review it all-or do you? Mr. GOODRICH. We just physically cannot review it all. I would cer- tainly recommend a substantial increase in the amount of effort, we have on this. But Dr. Ley is the one who `has to put the medical resources into it, and I believe the judgment has been made by him and by Dr. Goddard that we are at the level of maximum now that we can put into it-although it could `stand some more help. Senator NELSON Do you require the detail man to submit any piece of literature, the contents of which you regulate, like the package insert, to the doctor on each occasion that he is detailing the drug ~ Mr GOODRICH Only in the sense that every piece of written material, written, printed, or graphic material that he leaves or shows to. the doctor in the course of his detail, is required to have a full disclosure of the effectiveness, side effects, contraindications, warnings, precautions, and so forth, applicable to insure safe, effective use `of the drug by that physician-every piece of it. Senator NELSON. That is the requirement as to advertising. Mr. GOODRICH. The advertisement requirements differ only in the sense that a brief summary of information related to side effects and contrarndicwtions is permitted in general advertising In direct mail ing pieces and other labeling material the discussion must be in greater depth and detail. Senator NELSON. Well, `is it in as much detail as the package insert? Mr. GOODRICH. Not completely, but it has to be substantially the same-not in the same words, not in the same unattractive form as that you see in the package insert. But the message has to be `substan- tially the same. That is, all of the side effect, precaution, warning, con- traindication ideas that are presented in the package insert, must be presented in the mailing piece. Senator NELSON And you do review that ~ Mr. GOODRICH. To the extent of the facilities available for sur- veillance, yes. Senator NELSON. Do you ever find any of this literature that does not comply with your requirements.? PAGENO="0152" 3244 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GooDRICH. Yes, we do. And we find that some of it does not comply for many different reasons. We have had instances in which the company claimed that a paragraph was left out inadvertently. It is entirely possible that might have been so. There have been other instances in which the writeup was shortened unduly. There have been instances such as with the Merck Sharp & Dohme here this morning, in which a message that we thought was quite clear, that the drug did cause ulcers, is translated into a lesser language that ulcers have occurred. We find all types of this. The surveillance over prescription drug promotion is a full-time job for an active person-for several active persons who have a great interest in this problem. Senator NELSON. Dr. Ley? Dr. LET. The material which will be presented in subsequent hear- ings will give the concrete example of a preclearance operation of a promotional ground for the detail man's use in the physician's office. I think this review will answer many of the questions that you are directing at us today as a concrete example. Senator NELSON. We will leave the rest of the questions on the detail men until subsequent hearings. Mr. GORDON. As I understand it, then, FDA really does not know what the detail man is saying about Indocin; am I correct? Senator NELSON. Or any other drug. Mr. GooniucH. We know what his company tells him to say. Now, we do not know what he says when he goes to Dr. X's private office and talks with him about the drug. The only way we could know about it is if the doctor tells us. This is a delicate part of surveillance in which we have no mechanism of carrying it forth, except as the doctors tell us. Mr. GORDoN. I believe we have had testimony in the past that the oral presentation is probably the most important presentation of all to the doctor; that the doctor very seldom, if ever, reads the pro- motional material, printed material, that is left with him; that he relies to a large extent or mostly on the oral presentation. Now, you will also recall that in the Love v. Wolf case, the court held that the activities of the detail men in the case of Chloromycetin washed out the warnings in the printed material. Do you recall that? Mr. GOODRICH. Yes. Mr. GORDON, Even if you had adequate staff, and you were to re- vise your regulations, would this be enough to protect the public? Mr. GOODRICH. Well, I know that certainly the drug companies feel that detailing is an effective means of promotion. But I could not ac- cept the idea that the tremendous amount of money and effort and the elaborate outlays of printed material have no impact on the prescriber. I think myself that an ad, such as the one you have before you, has a tremendous impact on the doctors prescribing. Mr. GORDON. I do not say it would not be helpful in protecting the public. But would other measures be necessary. Would this alone be enough? Mr. GOODRICH. I do not know what you are suggesting, Mr. Gordon. It certainly would be fine with us if doctors who considered the de- tailing they got was wrong would communicate with us, we would be much interested in that. We would be prepared to take action if we found violations. But that is the only mechanism we have for get- ting at that, beyond assuring everyone that all the printed material, PAGENO="0153" COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY 3245 all the graphic material, does make a full breast of the whole thing Mr GORDON But that is a big problem, isn't it ~ Mr GOODRICH It is one problem, of course Mr GROSSMAN Mr Goodrich, `on this same pomt, I assume, then, that you believe physicians read these drug ads in the professional journais I was just wondering-you said you assumed they had a major impa;~t on doctors. Do we have any evidence-have we had `any survey, anything that shows what doctors actually read in this area, and what the1y believ&-or how they are influenced? Mi~. GooDRICH. Dr. McCleery says he has a survey. I base my state- ment on a quotation from an advertising man himself who made it over in Baltimore at a meeting soon after the law was passed, that we could be sure that if advertisements do not sell drugs, they will not continue to run And fo'r that reason, I am convinced that they do play a major role Mr GROSSMAN Has there been any study or survey on this, Dr McCleery ? Dr. MCCLEERY. Yes, there have been several, and several published. I brought one along today in case we were asked. I think it will rein- force Mr. Goodrich's point concerning the isolated effect of journal advertising alone. By saying that, I would not like to imply that I do not feel there is a general agreement amongst all sides of our dis- pute, on industry's and Our side, that the activities of the detail men constitute the most effective element of all elements of promotion, and as such is a very great and, as Mr Goodrich says, an uncovered area of our responsibility. But in terms of the evidence that a printed ad is effective in leading to a change in prescribing habits, I will make available copies for the record-from our library. In 1966, we received one of these studies conducted under the sponsorship of Modern Medi- cine magazine, and conducted by an expert polling outfit, the Politz outfit. What they set ou't to do, using all of the skills of isolating an area so as to measure effect-and, without going into all the details as to why, it seems that they succeeded What they did was to take old drugs, eight old drugs-the name of this publication is "The Important Thousand"-done as a Modern Medicine Politz study on advertising effectiveness We will make copies of it available, but the conclusions are very revealing, I think The magazine was interested in determining, for understandable reasons, was what it would be possible to learn-about the effects of ads for some selected drugs, that were not `being actively detailed, and had not been for some time, and for which there were no mail campaigns go'ing on, and which had not been going on for some time. They set up a control study to determine the effect of eight ads for eight products, and that is what the basis of this study was Now, among the effects and the results they found was that the "belief in excellence" of a product was increased 18 percent by the very simple one or two page black and white or color ads used in this study, and that, as to that most important parameter of effectiveness, the increase in that "intent to prescribe" was of the order of 21 per cent. All this from a very small ad, for only six consecutive issues in the Modern Medicine magazine', and in no other journals. There are numbers of studies like this which show that even the effect of journal advertising alone is quite substantial in leading physicians to change their prescribing habits PAGENO="0154" 3246 COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY I might point out, in contrast to this very simple, limited adver- tising on one and two pages for old drugs, that the Merck introduc- tory ad for Indocin in the JAMA (of which you have a copy) in November 1965, was a 10 page, very impressive, four color ad It ran for 6 months, approximately The impact of this kind of ad, in this and many journals, I believe would be likely to be substantially greater than the 21 percent results from these rather limited ads. Senator NELsoN. What study was that? Dr. MaCLEERY. It was an Alfred Politz study for Modem Medi- cine magazine. Senator NELSON. Is additional discussion of that going to be presented? Dr. MaCLEERY. I intend, if you wish it, to give you a copy of the entire study. Senator NELSON. Yes. Do you intend to discuss it further at a future hearing? Dr LEY If the Senator wishes, we may Senator NELSON I would like to see a copy of it, and then appropriate parts of it might be printed in the record~ But we ought to have a chance, as Mr Goodrich says, to evaluate it I want to thank all three of you very much You have made a most valuable contribution to the hearings. We appreciate your taking the time to come here and present this testimony (The information submitted by Senator Nelson follows:) Mnncx SHARP & DOIIME, West Point, Peiussyh'anla, July 14, 1966. H. I. WEINSTEIN, M.D. Director, Division of Medical Review. ACTING CHIEF Medical Advertising Branch/DMR. Indocin (indomethacln)-Misbranding under 502(n). I. "Indocin" article in July 1966 Issue of Pageant magazine by Phyllis and Robert P. Goldman. II. 3-page ad in the July 4, 1066 Journal of tue American Medical Association. III. Recommendation. I. PAGEANT ARTICLE, TITLED "IND0CIN" A. The subject article has come to our attention most prominently in connec- tioji with information accompanying a letter of June 21, 1966 from Mr. John B. Fletcher (Merck) to Mr Oron This was called to oui~ attention by Mr Goodrich who also asked us to check Indocin s medical journal ads Mr Fletcher attached a copy of his note of June 17 1966 to members of the Merck management admit ting that the firm cooperated with the Goldmans in making information available for the article, but disclaiming any responsibility of Merck in the matter on the grounds that the ailticle was not "promoted" or "sponsored" by the firm. B. Thus, the question whether FDA has jurisdiction over the article must be settled before proceeding to deal with the question of whether its contents mis- brand the drug. Even taking Merck's admission and disclaimers into account, we believe that the Pageant article is subject to section 502(n) of the Act and that Merck is a responsible party for causing issuance of the article 1 While section 502(n) excludes labeling defined by regulation 1 10'S(l) it includes all advertisements asz4 other descriptive printed matter that is not determined to be labeling. We believe that the Pageant article should be regarded as "other descriptive printed matter" that is not labeling. 2. Sectiun 502(n) of the Act does not require material subject to the Act to be "promoted" or "sponsored" by a prescription drug manufacturer, packer or PAGENO="0155" COMPETITIvE PROBLEM~S IN THE DRUG INDUSTRY 3247 distributor. It requires only that such material be issued or ca~used to be issued by the manufacturer, etc. We think it is clear from the dictionary meanings of ` cause that Merck caused the Pageant article to be issued For example a pertinent meaning is that cause applies to any event circumstance or condition or any combinaation of these that brings about or helps brings about a result." There are several statements in the article that could not possibly have been made unless the information had been furnished by Merck, thus, it is apparent that the firm can be considered to have caused `the article to be issued. Additionally, the article itself contajns direct confirmation of Merck's partici- pation in causing the article to be issued. For example, on page 8, the authors state: ". . . many of them [patients] ,are moved to sit down and write about their experiences with the drug to its~producer, Merck, Sharp and Dohme of West Point, Pennsylvania." "The following are some samples of. these letters to the pharmaceutical firms: . . 0 In our opinion the Pageant article by Phyllis and Robert P Goldman mis brands Indocin, a prescription drug, under section 502 (n) of the Act Having caused the article to be issued Merck then bad the obligation to insist that it meet the requirements of section 502(n). Merck did not meet this obligation. For example, the article fails to contain a true statement of informa- tion in brief summary relating to side effects, contraindications and effectiveness as required by section 502(n) (3) and regulations 1.105(e) and 1.105(f) (1). We believe that a most serious aspect of this misbranding situation is the flagrant appearance of claims in the article that go far beyond the indications for use approved in the package insert. For example, use of Indocin for "bursitis," trick knee tennis elbow and a host of other less common disorders cliarac terized by pain and swelling in and around the joints' has not been approved in labeling for the drug To demonstrate Merck s direct responsibility in causing such ~napproved claims to be published in the offending article the following sampte of a letter furnished to the writers by Merck is quoted: From Minneapolis Because of bursitis I had to give up golf two years ago. But with your wonderful medicine I'm in good enough shape now tO play golf once again..." It THREE-PAGE AD IN THE JULY 4, 1966, JOURNAL OF THE AMERICAN MEDICAL AssociATIoN A. Promotionai Copy (re effectiveness) 1. The headline, "extends the margin of safety in long-term management of arthritic disorders is misleading since a It implies that sufficient experience has been obtained to establish Indocin s long term safety This is neither the case nor does the approved package insert (FPL) contain such an affirmation b It contains an implication that Indocin is safer than all other effective anti arthritic agents for long term therapy This is neither proved nor does the FPL contain such an affirmation. c. The claim, ". . . of arthritic disorders," is too broad. It extends the FPL indications by implication to other arthritic disorders which have not been approved for inclusion in the FPL. At least it should be modified by a word such as certain." 2. The use of the quote from the Hart and Boardman article (attachment #1), under the caption rheumatiod arthritics is misleading since a It is taken out of the context of the article which reveals that the very impressive phrase ` in most cases of active rheumatoid arthritis refers to the small number of 8 out of a total of 15 cases b It fails to reveal that dosages far In excess of those approved in the FPL were employed (see pages 966 and 968) at least in the early phases of therapy e g 200-300 mg/day versus the FPL s upper initiating limit of 75 mg/day c It fails to reveal for fair balance that approximately 60% of the patients with rheumatoid arthritis got side effects and that all of these got more than one side effect (pp. 969L_970). d. . The duration of therapy (p. 966) in these patients' was far too short to support the layout s implication that this paper supports the headline s claim of long-term safety. PAGENO="0156" 3248 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. The use of the quote from the Rothermich reference (attachment #2), under the caption "ankylosing spondylitis," is potentially misleading: a The quote seems to come from a scientific article This is not the case-it is from a 2 inch abstract apparently of a talk presented at the American Rheu matism Association meeting in 1964 b The quote is aeeurate but it is surprising that the company used this abstract as a reference when almost certainly the full details have been published as a regular article later in 1964 or early in 1965 (We have not yet located this article c The use of the abstract is also potentially misleading since long term results (re the headline's claim for safety) and dosages were not included. Therefore, dosages that produced these results may well have been in excess of FPL limits. d. For fair balance, against the quote of good results described in the Hart article above, the company could have included Rothermich's results in rheu- matoid arthritis. In this same abstract, he stated that although "Excellent results have also been obtained in some cases of rheumatoid arthritis. . . there have been striking failures as well 4 The use of the quote from Englund under the caption degenerative )oint disease (osteoarthritis) of the hip is at least potentially misleading a It gives the appearance of being from an article in a symposium book Such are not ~idely distributed nor easily available b It was not available in BuMed Library Dr Standard of DSB/DMR made a trip to the NIH Library, which had a copy. c. There was no reference to Dr. Englund's work on page 27, as cited. d. There was no reference to an article by him in the symposium, either in the index or table of contents. e. We did locate a physician by that name, in the AMA directory, practicing in Phoenix, Arizona. f; We will search further to try to find the quote. It could be seriously mis- leading if Dr Englund did not as seems likely have all 500 patients on indomethacin for a~boat three years" (italic added). 5 The use of the quote from the same Hart and Boardman article (attach ment #1) under the caption gout `is misleading and shows a serious lack of fair balance a. The quote from a seemingly authoritative source from a leading foreign medical journal implies that this opinion must have been based on a large experi- ence (unspecified in q~iote), and that it was consistent with the general experi- ence of experts using the drug according to the FPL. b. It was not: (1) The implied claim that indomethacin is the drug of choice in acute gout is not supported by the FPL. (2) A reasonable source of early consensus on a relatively new drug about which drug of choice claims are being made is the view of the AMA Council on Drugs Its view is expressed in New Drugs (1966)- Because it has produced relief in acute attacks within 48 hours and because it lacks the untoward effects of colchicine some clinicians consider it to be the drug of choice for these at tacks however controlled trials are needed to determine how its effectiveness compares with that of colclucme If the company wanted properly to use the authors opinion it should have included the dosage they used and the numiber treated. Even then, "fair balance" would still require inclusion of an authoritative opposite or consensus view if such existed. (3) The experience was not large-the authors report on a sttidy of only 15 cases treated for relatively short periods (see pages 966 and 967) (4) The good' results that led the authors to make the quoted statement were based on dosages far in excess of permitted (150 mg/day) upper FPL dosage limits-they administered 200-500 mg /day for several days (see pages 966 `md 967) (5) Their opinion was not based on a well controlled experience In only 7 patients were any direct comparisons made and that only to one drug phenyl butazone (see Table II page 967) Even heie 3 patients out ofT preferred phenyl butazone to Indocin c it is very misleading that the company should employ this quote to imply it represents an accepted view of Indocin's effectiveness compared to all other drugs, especially when they know it is based on a very limited (15 patients) and uncontrolled experience-and when the results achieved are based on dosages far PAGENO="0157" COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY 3249 in excess of approved dosages. Both of these important and material factors are concealed from the reader of the ad. B. Re: the "Brief AS~ummary" The following important warning ideas in the FPL are omitted from the ad's "brief summary": 1. "As with other anti-inflammatory agents, Indocin may mask the signs and symptoms of peptic ulcer." (see Oontraindications) 2. "Indocin itself may cause peptic ulceration . . ." (see Contraindications) 3. ". . . Indocin may cause [single or multiple] ulceration of the stomach, duodenum, or small intestine." (see Precautions and Adverse Reactions) 4. "The possible potentiation of the ulcerogenic effect of these drugs [steroids, salicylates or phenylbutazone] cannot be ruled out at present." (see Precautions and Adverse Reactions) 5. A summary of the following cautionary information (see Precautions and Adverse Reactions) "Rare reports where i:t is not known whether the effects can be attributed to the drug include bleeding from the sigmoid colon either from a diverticulum or without a known previous pathologic condition, and perforation of pre-existing sigmold lesions (diverticulum, carcinoma). In other rare cases a diagnosis of gastritis has been made while Indocin was being given. One patient developed ulcerative colitis and another regional ileitis while receiving Indocin." III. RECOMMENDATION Seizure, with or without such injunctive measures as may be feasible. When Mr. Goodrich called, he asked that we expedite our review of the ad and article while they are still current. He felt that the two items might be joined in one regulatory action. For this reason, they are both included in this one memo. R. S. MOCLEERY, M.D. MERCK SHARP & DOHME, West Point, Pa., September 22,1966. Hon. L. H. FOUNTAIN, Chairman, Intergovernmental Relations Subcommittee, Committee on Govern- ment Operations, House of Representatives, Washington, D.C. DEAR Mn. FOUNTAIN: This is in reply to your letter of September 7, 1966, enclosing an ad from the August 15, 1966, issue of the Journal of the American Medical Association for Indocin (indomethacin, Merck). This advertisement and the labeling of the drug have been undergoing review by this agency. In our opinion, the ad is inconsistent with the prescription drug advertising provisions of the law. Further, we regard the quotes from the medical literature used in this ad as not being in conformity with the guidelines described in my statement to your Subcommittee on May 25, 1966. We are proceeding to take corrective action in this matter. Sincerely yours, JAMES I~. GODDARD, M.D., Commissioner of Food and Drugs. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, October 31, 1966. FRED BARTENSTEIN, Jr., Administrative Vice President, Merck 4~ Co., Inc., Rahway, N.J. Dis~&n FEEl): This acknowledges your letter of October 26, 1966, about my speech at the PAO in New York Oity, October 20. My points were based on a medical evaluation of your Indocin ad. Our Phila- delphia District has been instructed to issue citation to your firm. This involves both the Pageant article and the ad. You will, of course, have the opportunity to make your points in response to the citation. We feel that the effectiveness of the drug and its safety in use have been misstated. The things I pointed out involved the approved brochure (before the recent revision) and the ad which is still running. We do not agree that the "profile" of "Indocin" remains the same today as it appeared when the new drug application was approved. PAGENO="0158" 3250 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The revised mailing piece is also under review It was not approved by us in the form in which it issued. Our impression is that it is more a promotional piece than a warning letter. As to the gout claims, our position is as stated in New Drugs (1966). As to the omitted warning information, please compare the approved brochure with the advertisement. Very truly yours, WILLIAM W. GOODRICH, Assistant General Counsel, Food and Drug Division. (U.S. Government Memorandum] NOVEMBER 2 1966 To Herbert L Ley Jr M D Director Bureau of Medicine Through H I Weinstein M D Acting Associate Director for Medical Review From Acting ~Director Division of Medical Advertising/OMR Subject: Misleading promotional labeling piece under guise of apparent "Dear Doctor" letter re Indocin. fly first class mail a letter (copy attached) was sent 10/4/66 by the firm in an envelope flagged for the physician's attention by a beguiling euphemism, "Safety," in very large red letters. It contained the attached new FPffJ submitted, under 130.9 (presumably "justified" because it only added warning ideas), by 9/2/66 Company letter to Dr. John Jennings. Whether this was a legitimate act is open to serious question since revision of the FPL was under serious dispute in several details at the last meeting of BuMed and Company personnel on 7/15/66 The 9/2/66 letter (copy attached) affirmed the intent to put the FPL into use 0/A October 31, ~t966, without awaiting approval as would be necessary if it were a suplemental NDA submitted under regulation i3O.4-~thi.s is spite of the fact the 9/2 letter was really a "negotiating" communication turning down a number of specific requests made at the same 7/15/66 meeting. The above must also be viewed from the perspective that the Company therein rather imperiously turned down at least two important requests for "warnings" by BuMed-see paragraphs "2)" and "3)" of the letter's page 2. Their unwilling- ness to state, "NOT FOR UI~E IN CHILDREN," appears irresponsible in the face of their knowledge of deaths in children-deaths not prevented by the old FPL language they even here aver to be adequate. Further, they jumped `the implied 10/31/66 "use" date by putting the FPL into use via the 10/4/66 letter to the medical profession Misleading features of subject `October 1966 letter 1 The first sentence sets the tone of the letter as blatantly promotional It is both out of place and a non sequitur since experience in 98 of the 99 countries is largly if not solely beside the point This is especialy improper because of the tie in to the second sentence's idea that presumably only this massive "global" experience with circa 150 million patient days therapy resulted in the few and new additional warning idea "reflected in the revisions ~,. ." in the included FPL. 2. The Company's decision to highlight "one change in particular," namely the "potential of masking . . . ," must be judged against the following: a. It represents a unilateral act of rejection of a BuMed proposal to warn of the "Possible activation of latent infection." (See 9/2/66 letter, page 3.) b. The above "change" constitutes a minimized alert to a standard idea, which while important has competed successfully in the Company s mind against the prominent inclusion of the following new FPL contramdications and side effect ideas: (1) Contraindicated in aspirin~sensitive asthmatics and during lactation. (2) Convulsion, depersonalization. (3) Jaundice, hepatitis. (4) Angii'tis, elevated blood pressure. (5) Acute respiratory distress. (6) Agranulocytosis. (7) Hyperglycemia. 3. It subtly promotes use of the drug more widely than the FPL permits: a. Re: end of `first sentence, ". . . in the treatment of arthritic dis- orders . . . ."-and the end of the last sentence, ". . . next to `aspirin, the most frequently prescribed antirheumatic drug . . . ." (underscoring added); PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3251 (1) Although the "descriptive" first paragraphs of the old and new FPL begin with the latter phrase (notably it Is in quotes, "antirheu- matic ) and end with rheumatic disorders' this information refers only to the `generic capacity of the drug and is clearly not an approved broad indication for such `generic' use of Indocin (2) The forced association In the physician's mind with aspirin and its use in rheumatic fever acute rheumatic arthritis and carditis etc Is at least potentially misleading. Recommen,d Prompt and vigorous regulatory action, with serious consideration being given to the advisability of a forced "remedial" letter designed to correct the above misconceptions. R. S. MoCLEnisY, M.D. [U.S. Government Memorandum] DEPARTMENT OF HEALTiI EDUCATION AND WELFARE Foon AND DRUG ADMINISTRATION, November 4, 1966. To Herbert L Ley, Jr M D Director, Bureau of Medicine Through John J Jennings M D Acting Associate Director/ODS From Marvin Seife, M P Acting Deputy Director/DSR Subject: Indocin (indocmethacin)-~NDA 16-059 A *revised indomethacin package . insert, #6176404, dated August, 1066, sub- mitted on September 2, 1966, contained most of the changes suggested by the Bureau of MedIcine at a meeting with M.S.D. on July 15, 1966. Nevertheless, aditional revision of the proposed insert is cotaldered mandatory. A. A drug warning statement must appear at the beginning of the insert as follows: - IMPORTANT WARNING Indocin brand of indomethacin cannot be considered a simple analgesic and should never be administered casually Each patient should be carefully evaluated before treatment is started and should remain constantly under the close supervision of the physician The drug should not be used in chil dren because safe conditions for use have not been established and severe reactions, including fatalities, have been reported." B. The following misleading words, phrases and unsupported material should be deleted from the package insert introductory section, (paragraphs One and two). 1. Paragraph one, sentence one-omit the word "antirheumatic". 2. Paragraph one, sentence three-eliminate the entire sentence- ("Unlike corticosteroids, it has no effect on pituitary or adrenal function.") 3. Paragraph two, sentence one-omit the phrase "of all ages". 4 Paragraph two sentence two-omit the phrase in patients with rheumatic disorders". 0. Indications: 1. The first sentence should be changed from "INDO'CIN (indomethacin) has been effective in the treatment of :" to "IND'OOI'N (indomethacin) has been found effective in the symptomatic treatment of". 2. ElimInate the sentence following the listing of the indications: ("In these conditions indomethacin may often replace other commonly used `agents such as corticosteroids, salicylates, phenylbutazone-like compounds, and colchicine.") 3. Rheumatoid Arthritis Section: Eliminate the last sentence of para- graph one-("Preatment should be continued for at least a month before concluding that it has not produced significant benefit )-unless M'S D can substantiate the recommendation contained therein D. Contraindications: 1. Eliminate sentences four and five from paragraph one. 2. The third sentence of paragraph one should be changed from "For these reasons it should not be given to patients with active peptic ulcer, gastritis, or ulcerative colitis, and should be used with caution if there is a history of these disorders." to "For these reasons it should not be given to patients with active peptic ulcer, gastritis, regional enteritis, or ulcerative colitis, `and should be used with caution if there is a history of these disorders." PAGENO="0160" 3252 COMPETITIVE PROBLEMS IN THE DRUG INflUSTRY `3. The last paragraph of this section must be eliminated in favor of a straightforward statement such as-"This drug should not be used in chil- dren because safe indications for use have not been established and severe reactions, including fatalities, `have been reported." E. Dosage and Administration: 1. Paragraph three of this section must be eliminated in favor of a straight- forward statement such as-"This drug should not be' used in children be- cause safe indications for use have not been established and severe reactions, including fatalities, have been reported." The issuance of an Indocin (indomethacin) DRUG WARNING letter to the medical profession is necessary in view of the aforementioned package insert additions and changes, the extensive use of this drug, and the possibility of severe and fatal reactions. [U.S. Government Memorandum] JUNE 16, 1967. To: R. S. MeOleery, M.D., Acting Director, Division of Medical Advertising/ OMR. From: D. C. Hurwitz, M.D., Office of Drug Surveillance. Subject: Survey of NDA Data by Dr. D. W. Englunci. I have reviewed the Indocin studies conducted by Dr. D. W. Englund contained in Volumes 4, 11, 53 and 76 of the Indocin file. The specific material reviewed consists of two copies of a speech presented before the Merck Research Institute at West Point, Pennsylvania on February 11, 1965, one letter to Merck Sharp and Dobme describing the results `of clinical studies, and clinical data on 172 patients. Dr. Englund `has apparently had extensive clinical experience with Inclocin, and he discussed in his speech at West Point his experiences with 550 patients using Indomethaci'n. At the time of this speech, Dr. Englund had `been studying Indocin for `two years and 50% of his total patient group h'a'd been taking the drug for eighteen `months or more. Diagnostic categories included rheumatoid arthritis, rheumatoid *spondylitis, psoriatic arthritis, gout, scieroderma, lupus, osteoarthritis and primary fibrositis. The author claimed good results in all groups. The largest single diagnostic ca'tegory was rheumatoid arthritis in which 426 patients were treated with the drug and 362 or 85% showed "definite benefit and clinical improvement." Of 32 patien'ts with rehumatoid spondylitis, 30 showed definite clinical improvement. The percentage improvement varies from group `to group but in general the majority of patients were significantly im- proved. The only data available to support Dr. Englund's contentions is contained in Volume 11 in which the raw data for 172 patients is assembled. There `seems to be a representative cross section of the diseases that lie has treated. The treatment period varied from one to "over forty-eight" weeks with the largest number of patients (70) having undergone treatment for 13-24 weeks. Only `22 patients re- ceived the drug for longer th'an 48 week's at `the time the data was compiled- March 13, 1964. Forty patients remained unreported because the investigator did not feel `that they had been on the medication for sufficient time to enable evaluation. A's with most of the other Indocin studies the data consists of a clinical evalu- ation sheet on which various parameters are observed and an overall response to Indocin therapy graded none, poor, fair, good or excellent. In common with the ether studies of this type carried out by the company, thi's clinical trial is completely uncontrolled and lacks `the usual `elements contained in a well-de- signed study: a placebo controlled group, random patient selection, regulation of dosage and `length of administration of drug, as well as adequate and carefully designed response criteria. The `study therefore has testimonial value only and in no way can be construed to show any objective evidence of effi'cacy of the drug in question. Unfortunately, the author's all-to-obvious `bias has undoubtedly played a large role in his evaluation of the efficacy of Indocin. In conclusion, then, one can regard this study as having only testimonial value in determining the efficacy of Indocin. W'hile `such a study has some value for preliminary use in determining whether it is worthwhile to further investigate a compound, it certainly has no definitive value in determining efficacy in this group of diseases since they do not lend themselves to easy clinical evaluation. I am able to find data for only 172 of Dr. Englund's 550 patients; it is impossible to `tell at this time whether the rest of the d'ata was `submitted in' another volume PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3253 and has been overlooked or whether it was never submitted to Merck Sharp and Dohme. JULY 19, 1967. HOWARD I. WEINSTEIN, M.D., Acting Associate Director for Medical Review, Med. IL S. MCCLEERY, M.D., Acting Director Division of Medical Advertising, OMR. 126-350 B-Indocln (indomethacin)- Alleged Misbranding through Advertising- S & R Philadelphia District, January 26, 1967 ~ and I-AR DOG to Med 2/1/67. SUMMARY STATEMENT We have reviewed Philadelphia District's S & R dated January 26, 1967 and its attachments, as well as the written response by Attorney Coburn, representing. Merck, to charges set forth in Notice of Hearing dated November 23, 1960. In summary, we do not believe that the firm has presented adequate defense in rela- tion to the charges. Taking into account the shipment date (11/7/66) of sample 126-350 B; the fact that the 9/26/66 JAMA ad contained changes in the "Brief Summary" that affect the 1.105 (f) (1) charges which stemmed from the July 4, 1966 JAMA ad (which was the initial basis for our critique of July 14, 1966); more recent information suggesting new or revised charges; etc., we have re- evaluated the situation and conclude that the case should proceed in relation to Indocin advertising. However, the situation now indicates that the FDA should consider dropping the basis for the Notice of Hearing of November 23, 1966, i.e., the Indocin ad in the JAMA issue of September 26, 1966, but retaining the sample (126-350 B) as a basis for certain charges in relation to a more suitable Indocin ad. RECOMMENDATIONS It is recommended that the case be redeveloped in three categories as dis- cussed below and that a new citation be instituted, because it will be noted that the advertisement under this proposal that caused the misbranding is not the same as the one on which the initial citation was based, because the more recent ad is more closely dated in reference to the collected sample, and because the charges 1~ave been considerably expanded primarily due to more extensive violative fea- tures. Specifically, we recommend that advertisement for Indocin in The Ameri- can Journal of Medicine-November, 1966 be alleged as misbranding the Novem- ber 7, 1966 shipment of Indocin represented by sample 126-350 B. The package insert accompanying this sample is "Effective: August 1966" and identified in Collection Report of November 18, 1966. JANUARY 26, 1967. SUMMARY AND RECOMMENDATION Sample number, 126-350 B; Product, Indocin Oapsules, 25 Mg.; Date shipped (on or about), 11-7-66; Oarrier, Parcel Post; Seizure, None. CITATION ISSUED TO Merck Sharp & Dobme, Division of Merck & Co., Inc., West Point, Pennsylvania 19486 LEGAL STATUS The firm, Merck Sharp & Dohme Division, is a wholly owned subsidiary of Merck & Co., Inc., a New Jersey corporation with principal place of business at Rahway~ New Jersey. The officers are as follows: Stuart T. Henshall, President; John J. Horan, Executive Vice President, Marketing; Frederick K. Heath, Vice President, Pro- fessional Communications; John L. Huck, Jr., Vice President, Market Planning; Eugene L. Kuryloski, Vice President, Sales. ALLEGED VIOLATIONS Misbranded by failure of medical journal advertisement sponsored by the manufacturer to fairly show the effectiveness of the drug in conditions for which it is recommended in the advertisement and failure to achieve fair balance in its presentation. 81-280-68-pt. 8-11 PAGENO="0162" 3254 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Misbranded by failure of medical journal advertisement sponsored by the man- ufacturer to contain a true statement in brief summary relating to side effects, contraindications and effectiveness. WITNESSES FOR INSFECTIONAL AND ANALYTICAL FINDINGS $ample Collection: Inspector William M. Troetel (P), 126-350 B, November 18, 1966, DOC. 126-351 B. October 28, 1966. Analytk'al: Analyst John L. Mietz (P), 126-350 B, DOC. 126-351 B November 23, 1966. RECOMMENDATION Prosecution of: Merck Sharp & Dohme, Division of Merck & Co., Inc. (126- 350 B) REASONS FOE RECOMMENDATIONS ~urnm,ary and Findings The product, Indocin (Indomethacin), is a newly developed nonsteroid drug which was first marketed following the approval of NDA June 10, 1965. The medical journal advertisement for the product appearing in the September 20, 1966 issue of the JAMA, is one of the earliest ads for the product. Sample 126- 350 B represents a shipment made on November 7, 1966, 11 days after the publi- cation date of the journal. The product was shipped from the firm's West Point, Pennsylvania warehouse to The Drug House, Inc., Trenton, New Jersey, for dis- tribution to retail pharmacists in central New Jersey. The advertisement was critically reviewed by several members of the Bureau of Medicine and citation issued to the firm for various types of shortcomings: (1) The copy for the ad, particularly the headlines employed, utilized broad and unwarranted statements such as "extends the margin of safety in long-term management of arthritic disorders." (2) Unwarranted and misleading representations concerning quotations from articles describing clinical studies and failure to quote the unpleasing data from the same articles. (3) Lack of fair balance in omitting pertinent information on contra- indications. The firm was cited to a hearing scheduled to be held at Philadelphia District on December 6, 1966. At the request of the respondent firm the hearing was resched- uled for December 14, 1966. History of Firm About 10 years ago, Merck & Co. acquired Sharp & Dohme and incorporated this drug manufacturing firm as a corporate division presently doing business as Merck Sharp & Dohme. Corporate offices are maintained in the manufacturing facility located at Sunneytown Pike, West Point, Pennsylvania. According to our most recent inspections, this firm manufacturers and markets an estimated $130 million annually in prescription drugs for human use. A review of available files shows no record of formal regulatory action instituted against the West Point firm. A check of New York District records may disclose regulatory actions in- volving the parent corporation, Merck & Co. Our records indicate the firm has been involved in the recalls enumerated below: (1) 10-5-64-Sulfasuxidine, 0.5 Gm.-Carton mixup. (2) 10-30-64--Cortone Acetate, 0.5%-Carton mixup. (3) 1-14-65--Alflorone Acetate, 0.1%-Below potency. (4) 2-9-65--Hydropres Tablets, 25 Mg.-Tablet mixup. (5) 4-15--65---Cortisone Acetate Ophthalmic, 2.5%-Carton mixup. (6) 5-20-65--Emulsion Mephyton, 10 Mg. and 50 Mg.-Emuision break- down. (7) 9-22-65-Cathomycin Capsules, 250 Mg-PenIcillin cross-conta:n~ ination. (8) 9-22-65--Cathomycin Lyovac, 500 Mg. Vials-Penicillin cross-contain- in~tlon. (9) 110-10-65-DMSO (in all combinations, concentrations, and package sizes)-All current IND's terminated. (10) 12-19-65-Decadron, 0.1% and Decadron-N-Lacks pharmaceutical elegance. (11) 2-14-66-MK-665-Firm's IND terminated. (12) 5-20-66-Cremomycin. 8 oz.-Lack of expiration date. (13) 7-18-66-Tyroderm, 0.5 Mg/gm-Declared potency. PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3255 (14) 11-3-66-Humorsol, 0.25% and 0.125%-Increased incidence of eye irritations. In addition to the above, the firm recalled eight drug products which had been distributed to outside clinical investigators whose eligibility to handle investigational drugs was termin(ated. Investigations are presently continuing on the firm's handling of DM50 and MK-665 with view to ascertaining whether or not there is adequate evidence to sustain criminal action concerning the firm's handling of these investigational drugs. With the exception of the Humor- sol recall, all of the recalls are considered "closed" from the standpoint of ade- quate accounting for the returned merchandise. RESPONSIBILITY FOR ALLEGED VIOLATIONS Our investigations of the promotional practices of the larger pharmaceutical firms indicate the planning, drafting and approval of medical journal advertising involve essentially an institutional decision on the part of the firm. In addition, outside advertising agencies are generally involved. In the instant case we do not believe we have evidence to fix any individutd responsibility fo'r the placing of this ad beyond the responsibility normally carried by corporate officers. For this reason, we have not recommended the naming of individual defendants. INTERSTATE RECORDS AND LABELING The records covering this shipment consist of invoice issued by Merck Sharp & Dolme and identified by both dealer's statement and affidavit of the consignee firm. In addition, we have established distribution of the medical journal and pre- scribing of the product through affidavit of Mischa F. Grossman, M.D., Cherry Hill Hospital, Cherry Hill, New Jersey, whose affidavit states that he has received the September 26, 1966 issue of JAMA which bears an advertisement for Indocin, and that in the regular course of his practice he has prescribed Indocin for some of his patients. RESPONDENTS' views PRESENTED AT HEARING At the hearing held on December 14, 1966, the firm Was represented by house counsel Robert L. Banse and retained counsel Hayward H. Coburn of Drinker Biddle & Heath, Philadelphia, Pennsylvania. At the hearing the firm indicated that it would challenge the validity of regulations, disagree with our conclusions and question the wisdom of recommending prosecution for this type of violation. The respondents stressed, however, that the firm's actual response would be in the form of a detailed written response and asked that our evaluation be based on the written record. They did submit a tabulation (Exhibit A) hut indicated this would be resulmitted with their written response. During the hearing X asked to be provided with a copy of Dr. England's article in the Flcoerpta Medico Foandation because our medical officers had been unable to locate this publication. They promised to furnish me a copy, but stressed again this would be done apart from their response in that our Charge Sheet had contained no allegations concerning this publication. At the insistence of the respondents for adequate time to prepare their response, they were granted until January 10, 1967 to present this material. The firm's response to the charges is set forth In considerable detail in Exhibit B and will not be repeated here because the response, itself, should be studied in view of this proposed action. Briefly, the firm challenges our legal position con- cerning our jurisdiction over false and misleading statements in the body of the advertisement. The firm disagrees with our conclusions concerning use of terms such as "extends the margin of safety in long-term management of arthritic disorders." The firm sets forth Its disagreement with each of the inter- pretations we have alleged in the Charge Sheet. The firm contends that the quotations from the articles cited below the illustrations in the advertisement fairly represent the views of the author. The firm takes issue with our views on listing of contraindications in the brief summary and claims its condensation is both fair and accurate. The firm's views are supported with a tabulation com- paring information alleged to be omitted with information actually presented in the advertisement. The firm also advances the view that even if it were in error the circumstances do not merit institution of criminal action. It recites the history of Its dealings with General Counsel William W. Goodrich, Commissioner James L. Goddard PAGENO="0164" 3256 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and representatives of the Bureau of Medicine. The firm takes the position that since it has made forthright correction of the alleged violations prosecution should not ensue. Attached to the firm's response is a copy of the advertisement for the November 14, 196l issue of JAMA `which it contends fully meets the requirements of Section 502 (n). DISTRICT'S CONCLUSIONS In reviewing the firm's position in response to the hç~aring we find we cannot agree with most of the firm's contentions. With rega~d to the jurisdictional question concerning false and misleading claims in the body of the advertisement, we ullderstand this was one of the issues presented by the industry during its initial request for a hearing on jhe proposed regulations. Thereafter, in the ensuing dialogue the industry withth1ew its objections in light of `the exchange of memoranda of understanding. Although we do not have a record of these events at the District, we understand that Merck Sharp & Dohme was a party to these proceedings and its attack upon the validity of the regulation is somewhat belated. We believe the misrepresentations concerning the cOmparative safety of Indo- ciii are serious in nature, particularly in light of the continued receipt of medical data indicating this product must be prescribed with caution, The m~anner in which the clinical studies were quoted is' also of serious consequence, particularly when viewed from the standpoint that few' physicians have available to' them the original articles to compare for a more complete evaluation of the product. In this connection, we wish to point out that one of the articles (the Bxcerpta MediOa Fo dation booklet) could not be located in our ratl~er extensive medical library. The firm's comment concerning references in the brief summary to ulceration of the stomach, duodenum, or small intestine, may have some merit. If this recom- mendation is approved, I believe it would be well to delete reference to them lest we become involved in unnecessarily complex setmantics in presentation of our case. Although the firm presents persuasive arguments for mitigating circumstance's tending to establish that need for prosecution no longer exists. we do not agree with the firm's position. As one of the leaders of the pharmaceutical industry, the firm had available to it the, best brains and talent in the medical advertising ~eld, yet it chose to utilize advertising tactics that should have been abandoned upon passage of the Kefauver-Ilarris Amendment of 1962. The contention that mitigating circumstances can exist appoars to be of little consequence when we consider there exists no adequate method to correct `the improper advertising once it has been printed and disseminiated to prescribing physicians. SPECIAL REVIEW REQUESTED In separate communication of January 10, 1967 (Exhibit 0), Mr. Ooburn trans- mitted a copy of the Eecerpta Med4ca Foundation publication entitled "NON- STEROIDAL ANTI-INFLAMMATORY DRUG THERAPY IN RHEUMATIC DISEASE" (Exhibit D). Attached with the Summary and Recommendation is the sin~le copy of this publication which the Bureau of Medicine requested for re- view. Upon review of this material they inay consider inclusion of additional charges. If they do, we recomniend. no' additional citation issue because the charges would be included within the general scope of the first portion of our Charge Sheet enclosed with the Notice of Hearing. IRWIN B. BERCII, Director, Philadelphia District. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Philadelphia Pa., January 3, 1968. `Mmiorc SHARP & DOHME, Division of Merck c~ Co., Inc., West Point,Fa: ` Investigation by this Administration `indicates your responsibility for violation of the Federal Food, Drug, and Cosmetic Act, as described in the nittachod Oharge Sheet, with respect to the following: Consignment of an article labeled in part: (btl) "100 ~ CAPSULES INDOOIN (INDOMETHACIN) *** 25 mg. Merck Sharp & Do'hni~ West Point, Pa. Division PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3257 of Merck & Co., Inc. OAUTION Federal law *** 113088" shipped by you on or about November 7, 1966 to The Drug House Inc., 1880 Princeton Avenue, Trepton, New lersey. An informal hearing will be held on Monday, ranuary 15, 1968 at 10:00 (lIST) in Room 1204 U.S. Customhouse, 2d and Ohestnut Streets, Philadelphia, Pennsylvania, to give you an opportunity to present your views in the matter. The enclosed INFORMATION SHEIIIT explains the purpose and nature of the hearing, and bow you may reply. If no response is received on or before the date set, our decision on whether to refer the matter to the Department of Justice for prosecution will be based on the evidence at hand. By direction of the Secretary of the Department of Health, Education, and Welfare. IRwIN B. BEnCH, Director, Philadelphia District. Pn0HIBITED ACT Section 301 (a) of the Federal Food, Drug, and Cosmetic Act. The introduction or delivery for introduction into interstate commerce of any food, drug, de!ice, or cosmetic that is adulterated or misbranded. CHARGES A. The journal advertisement for Indocin appearing in the November 1966 issue of the A'inertcan Journal of Medic~nc causes the drug to be misbranded under section 502(n) of the Act in that said ad does not fairly show the effective- ness of the drug in the conditions for which it is recommended in the advertise- ment and fails to achieve fair balance in its presentation as required by regulation 1.105(e) in that: 1. The headline "Extends the margin of safety in the long-term management of arthritic disorders" misleadingly implies that Indocin is safer than all other effective anti~arthritic agents for long-term therapy. Furthermore, the unqualified phrase "arthritic disorders" misleadingly extends by implication the indications for use in the labeling accepted as part of the new drug application. 2. The quotation ". . . the first non-corticosteroid agent which produced a predictable and measurable reduction in joint-swelling in most cases of active rheumatoid arthritis" from an article by Hart and Boardman (Hart, F. D. and Boardman, P. L.: British Medical Journal, 2:965, October 19, 1963) under the ad caption "rheumatoid arthritis" does not represent a true statement of effec- tiveness for Indocin and presents a distorted view of the drug's effectiveness. In addition, the use of this quotation, along with the reference to the October 19, 1903 article by Hart and Boardman is further misleading in that the quotation and reference is obsolete since it fails to take into account a more recent and more scientific article by the same authors. 3. The quotation "Indomethacin is the drug of choice in acute gout, . ." at- tributed to Hart and Boardman (Hart, F. D. and Boardman, P. L.: British Medical ,Journal, 2 :965, October 19, 1963) appearing under the caption "Gout" mis- leadingly implies that the author's opinion was based upon a large experience and that it was consistent with the general experience of experts using the drug according to the approved labeling. Furthermore, the claim "the drug of choice" for this new drug, is not supported by the NDA and is contrary to all expert opinion. 4. The quotation "I have bad some 500 patients on Indomethacin now for about 3 years. I find it an extremely helpful drug. I think there are certain areas where it will be without question the drug of choice. One of these is osteoarthritis of the hip" attributed to Englund (Englund, D. W. in Non-$teroidal Anti-Infiam- matory Drug Therapy in Rheumatic Disease, New York Excerpta Medica Foun- dation, 1965, page 27) appearing under the caption "degenerative joint disease (osteoarthritis) of the hip" is misleading in that the statement "I have bad some 500 patients on Indomethacin now for about 3 years . . ." when considered in relation to the headline claim, "extends the margin of safety in the long-term management of arthritic disorders" misleading gives the reader the impression of powerful support through massive research experience of 3-years-long admin- istration to 500 patients on a new drug, when in fact, the statement is an "off the cuff" remark at a symposium supported by a grant from Merck, Sharp & Dohme. PAGENO="0166" 3258 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In addition, the advertisement falls to achieve fair balance in that the adver- tiseinent failed to give the reader a more properly balanced view of this new drug by net including the summary view, expressed by the moderator at the end of the symposium, that Indocin's use ". . warrants a lot mere study and observation. Its long-term effect in rheumatoid arthritis is still unknown, - ." B. The article is misbranded within the meaning of 502(n) in that the journal advertising failed to present information concerning those side effects and contra- indications that are pertinent with respect to the uses recommended or suggested in the advertisement as required by regulation 1105(f) (1) in that the following important information has been omitted: 1. The warning that "as with other anti-inflammatory agents, Indocin may mask the signs and symptoms of peptic ulcer." 2. The warning that "indomethacin itself may cause peptic ulceration or irritation of the gastrointestinal tract." 3. The contraindication that "indomethacin is contraindicated in asprin- sensitive asthmatics." 4. The precaution that "indomethacin should be used with caution if there is a history of ulcer, gastritis, regional ileitis, or ulcerative colitis, because of its potential for causing gastrointestinal bleeding." 5. The precaution that "It [indomethacini may cause simple or multiple ulceration of the stomach, duodenum, or small intestine" 6. The precaution that "a possible potentiation of the uleerogenic effect of these drugs cannot be ruled out at present." 7. The side effect information concei,ning "ulceration of the esophagus, con- vulsions, nausea, anorexia, vomiting, epigastric distress, abdominal pain, diar- rhea, gastritis, jaundice, hepatitis, elevation of blood pressure, hematuria, angi- oneurotic edema, angiitis, rashes, loss of hair, acute respiratory distress including dyspnea and a sthma, purpura, thrombocytopenia, agranulocytosis hearing disturbances, orbital or pariorbital pain, vaginal bleeding, hyperglycemia, and glycesiiria." C. The article is misbranded within the meaning of 502(n) in that the journal advertisement does not prominently display the name of at least one specific dosage form and quantitative ingredient information in direct conjunction with such display as required by regulation 1.105(d) (2). FEBRUARY 14, 1968. Froni: 11110. To: R100-~Mr. Barnard. Subject: 126-350B Indocin-Merck Sharp & Dohme. SUMMARY Attached is Philadelphia District's S&R of 2-6-68, renewing their recom- mendation of prosecution in this advertising case. Merck's response to the Notice of Hearing is a written response by the Law firm of Drinker Biddle & Reath. The response presents legal, administrative and medical arguments against forwarding. This matter was the subject of a conference between BRO, Med & GO last October. (See Memo of Conf. 10-16-67, cy. attached.) Your guidance in this matter will be appreciated. Bureau of Medicine has not reviewed the Merck's response to this most recent citation. D. W. JOHNSON. PJIILADELPHrA DISTRICT, February 6, 1968. SUMMARY AND RECOMMENDATION SUPPLEMENTAL Sample number, 126-350 B; product, Indocin Capsules, 25 Mg.; Date shipped (On or about), 11-~7--G6; Carrier, Parcel Post; Seizure, None. (This hearing involved additional citation on the sample which was the sub- ject of Summary and Recommendation submitted on January 26, 1967.) PAGENO="0167" COMPETITIVE PROBLEMS iN THE DRuG INDIJSTRY 3259 This hearing was held to afford the respondent an opportunity to present his views on additional advertisement appearing in American Jonrnal of Medicine, November 1966. The position of the firm with respect to the charges remains essentially the same. Our review of the written summation does not change any of our views as set forth in the January 26, 1967 Summary and Recommendation. Accordingly, we renew our recommendation for prosecution of Merck Sharp and Dohme, Division of Merck & Co., Inc., on this number. JRWIN B. BEnCH, Director, philadelphia District. FOOD AND Dnuo ADMINISTRATION, Philadelphia District, Febrva'ry 6, 1968. RECORD OP HEARING Sample number and product: 126-350 B, Indocin Capsules, 25 Mg. Firm cited [additional citatiOni: Merck Sharp & Dohme, Division of Merck & Co., Inc., West Point, Pennsylvania 19486. Date of Hearing: February 6, 1968. Where Held: Philadelphia District-FDA. Present: Mr. Hayward H. Coburn, Attorney-at-Law, Drinker Biddle & Reath, Philadelphia, Pennsylvania 19107. Mr. Irwin B. Berch, Director, Philadelphia District. This hearing was originally scheduled for January 15, 1968 and was resched- uled at the request of the respondent. Mr. Coburn presented an up-to-date Legal Status Sheet and acknowledged that the shipment was made as alleged and that the advertisement in question did appear as set forth In the Charge Sheet. Mr. Coburn stated that the firm's response would be the written response presented to me at the hearingS This is an 18-page statement to which are attached Exhibits A-i, A-2, B, C, D, E, and F. I asked Mr. Ooburn whether or not the firm had made any changes in it~ promotional or advertising prac- tices since the receipt of the current citation. He stated the firm's revisions are reflected in the mailing to physicians (Exhibit E) and the revised ad- vertisement (Exhibit F) which appeared following the earlier citation. He added that, in common with other newly-introduced drugs, additional data accumulated from human experience serve to identify other possible human re- actions. He assured me these were being regularly incorporated in the revised labeling which the firm submits in accordance with the new drug regulations. The respondent did not remain for the dictation of this hearing record. IRwIN B. BERCII, Director, Philadelphia District. MlmcK SHARP & DOHME, West Point, Pa., March 8, 1968. DIRECTOR Bureau of Medicine ACTING DIREcToR Division of Medical Advertising/OATS We concur in the prosecution recommendation of Philadelphia District in its S & R dated February 6, 1968, and we recommend that the subject number not be placed in permanent abeyance unless such action is advocated in an opinion from General Counsel. We think that there is a valid basis for prosecution on the issues. Further, the attitude of the firm, as reflected in the letter response to the Notice of Hearing dated January 3, 1968, is poor to the extent of inviting prosecution notwithstanding its pro forma conclusion that prosecution should no follow. Our comments will be directed to the written response dated February 6, 1968 and prepared by H. H, Coburn, attorney for Merck on the staff of Drinker, Biddle and Reath. Our purpose will be to show: (a) the poor attitude of the firm, (b) the inadequacy of the response, and (c) to point up tryalble issues that we believe exist on the basis of the clear language `of the statute, and apart from the regula- tions. Our comments are not intended to be all-inclusive. PAGENO="0168" 3260 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A. ATTITUDE OF THE FIRM The poor attitude of Merck regarding the advertising regulations has persisted since their promulgation. This is clearly shown in the following passage from attorney Coburn's letter: "Regulations 1.105(a)-(e) to the extent they purport to regulate or specify the contents or form of an advertisement for a prescription drug in other respect [except as provided in 1~he statutory langugae of section 502(n)] are, we submit, unauthorized by law and dQ not constitute an independent basis for determination of whether or not a violation of Section 502(n) has occurred." In effect, Merck challenges all of the principles of fair balance provided in the existing regulations, and even challenges the Government's authority in respect to requiring ingredient information in advertisements except as specified in 502(n). We believe that Merck's challenges present a basis for trying the validity of the promulgated-regulations 1.105(a) through (e). Because revisions of the regulations are in process, however, the time may not be advantageous to the Government to proceed toward a Federal Court determination of the validity of the existing regulations, particularly 1.105(e). We are omitting, for the present, comments in rebuttal of Merck's position in respect to the charges on the promo- tional copy of the ad. We have to say, however, that the Merck position in re- spect to each of the charges against the promotional message is, in our view, extremely weak should such issues come to trial. We would anticipate reframing charges in relation to the promotional message within the statutory language. B. ExAMPLES OF ISSUES AVAILABLE UNDEB SEcTIoN 502(n) RELATING TO OMIssIoNS 1~. The statute provides that the advertisement alleged to misbrand the sample must include a true statement of infoi"jnation in brief summary relating to side effects and contraindications. (a) A charge was that the ad omitted the warning (side effect) information that "As with other anti-inflammatory agents, INDOCIN may mask the signs and symtoms of peptic ulcer." The respondent implies evasively and erroneously that the contraindication in the ad applying to "active peptic ulcer" satisfied the test of a true statement in relation to the quoted side effect. The issue is whether that side effect information is in brief summary or otherwise In the ad. We contend that it is not. (b) A charge was that the ad omitted the warning (side effect) information that "indomethacin itself may cause peptic ulceration or irritation of the gastro- intestinal tract." The respondent claims that the information "is clearly set forth in the adver- tisement." The claim is untrue. The issue is whether any information in the ad meets the tests of a true state- ment with respect to the quoted side effect. We contend that it does not. A charge was that the ad omitted the precaution (relative contraindication) that "a possible potentiation of the ulcerogenic effect of these drugs [steroids, salicylates, phenylbutazone] cannot be ruled out at present." The respondent does not deny the omission but uses somewhat unintelligible language to reconcile the omission by stating that the omission "strengthened the specific warning against any use of INDOCIN in the presence of the condi- tions stated, with or without other agents." The issue is whether the quoted precaution is omitted from the ad. We contend that it is. (d) A charge was that the ad omitted side effect information concerning a list of specific side effects which included, among others: (1) nausea, anorexia, vomiting, epigastrict distress, abdominal pain, diar- rhea, gastritis; and (2) angioneurotic edema, rashes, acute respiratory distress, purpura, thrombocytopenia. The respondent does not deny the specific omissions but attempts to reconcile the omissions by stating that the side effects (1) were included under the "general side effect of `G.I. disturbances'" and that the side effects (2) were included under the "general side effect of `hypersensitivity reactions.'" PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3261 The issue is whether the general headings used by the respondent represent a true statement of information regarding the specifically named side effects. We contend that the test of a true statement has not been met through use of general headings. 2. A charge was that the ad misbranded the sample under 502(n) because it did not prominently display the name of at least one specific dosage form and quantitative ingredient information in direct conjunction with such display as required by regulation 1.105(d) (2). The respondent attempts to defend the charge (1) by making a general denial of the validity of the regulation and (2) by implying irrationally that regula- tion 1.105(d) (2) is dependent on 1.105(d) (1). The fact is that 1.105(d) (2) is an independent regulation, as a careful reading will disclose. Consistent with not proceeding toward Federal Court determination of the validity of existing advertising regulations now under revision, we do not believe that regulation 1.105(d) (2) is needed as a basis for continuing the essential element of this charge. Section 502(n) (2) provides the basis for requiring "the formula showing quantitatively each ingredient of such drug to the extent required for labels under section 502(e)." Possibly due to ignorance, the respondent appears to take comfort in relying on section 502(n) (2) as a basis for omitting quantitative ingredient information from the ad. He even goes so far as to recite the language of 502(e) to require "the label to bear . . . in case it is fabricated from two or more ingredients, the name and quantity of each active ingredient." The fact is that Indocin Capsules, 25 mg., are fabricated from 2 or more ingredients; this means that the quantity of indomethacin (the active ingredi- ent) in the capsule must 1e declared on the label and in the advertisement. The issue here is so clear cut that it needs no further comment. C. COMMENTS ON CERTAIN FEATURES OF THE RESPONDENTS LETTER OF FEBRUARY 6, 1968 1. The respondent claims that the contraindication that "indomethacin is contraindicated in aspirin-sensitive asthmatics" was included in labeling for the first time in a package circular put into general use on October 31, 1966. It claims, therefore, that it was not possible to make the change in this advertise- ment on such short notice. In this connection, the respondent states in paragraph 7 on page 13 of its letter, in relation to a separate charge of omitting a large number of specific side effects from the ad, that such side effects were only in- cluded in the labeling at the same time as the foregoing contraindication. The respondent also claims that the period of 90 days (suggested as a guide by Dr. McCleery on January 23, 1968) for conforming promotional labeling and~ advertising to package labeling had not expired when the ad appeared. It can be shown that the respondent is in error in respect to the claims regard- ing the timing involved. 2. Section D of the respondent's letter deals primarily with matters such as meetings between the Agency and Merck management; current more careful handling of clearances within the firm; voluntary destruction of substantial quantities of promotional material, presumably also violative; a prior citation; the fact that a prosecution would be punitive [which is admitted], etc. We believe that such information as that presented by the respondent to show good behavior would be properly the subject of an inquiry from a probation officer. Such information is often useful in determining the amount of fine, etc. This was the case when Wallace Laboratories was prosecuted in re Pree-MT; in that case Wallace not only had undertaken massive corrective action but also took Pree-MT off the market. We believe that the prosecution action taken against Wallace should be taken into account in determining whether Merck should be prosecuted in relation to this sample. R. S. MCCLEERY, M.D. MARCH 11, 1968. DIRECTOR, BUREAU or REGULATORY COMPLIANCE. DIRECTOR, BUREAU OF MEDICINE. The Bureau of Medicine recommends that prosecution of the firm be instituted, subject to approval by General Counsel. As you may note from the attached memorandum of March 8, 1968, subject as above, from the Division of Medical PAGENO="0170" 3262 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Advertising to the Bureau Director, specific comments are provided in response to the communication from the firm on February 6, 19(38. We will be pleased to discuss the matter with you and the General Counsel at any time. HERBERT L. LEY, Jr., M.D. Senator NELSON. Dr. Norman Rothermich, who conducted a trial with Indocin, has just returned from Europe. He has requested the opportunity to present a statement to the committee. We will recess until 1 :30. (Whereupon, at 12:35 p.m., the subcommittee was recessed, to recon- vene at 1:30 p.m., on the same day.) AFTERNOON SESSION Senator NELSON. Dr. Rothermich, I apologize for being late, but I was tied up and, until this moment, I could not get here. T1~e committee is pleased to have you appear before us today. We are well aware of your distinguished professional credentials. Did you submit a biographical sketch with your statement? STATEME~NT OP DR. NORMAN 0. ROTHERMICH, CLINICAL PROFES- SOR OP MEDICINE, OHIO STATE UNIVERSITY; SENIOR PHYSICIAN, COLUMBUS MEDICAL CENTER; MEDIOAL DIRECTOR, COLUMBUS MEDICAL CENTER RESEARCH FOUNDATION, COLUMBUS, OHIO Dr. ROTHERMICH. No; I did not, Senator. Senator NELSON. Would you wish for the record to simply give your professional credentials and background? Dr. ROTHERMICH. Either that, or I can save time by sending you it in writing- Senator NELSON. If you would prefer to do that for purposes of accuracy, we would be glad to print prior to your statement your biographical and professional background. Dr. ROTHERMICH. I will send you a complete biography. Senator NELSON. Thank you, Doctor. (A subsequent biographical sketch was received and follows:) BIOGRAPHY OF NORMAN 0. ROTHERMICH, M.D. Born: October 9, 1912; St. Louis, Mo. St. Louis University: B.S. 1934: M.D. 1936 (also special postgraduate student in biochemistry under Dr. E. A. Doisy, 1933-36). 1936 to 1940: Internship at St. Louis City Hospital; residency at Robert Koch Hospital in St. Louis and at Ohio State University and Columbus State Hospital. 1941: Appointed Chief of Arthritis Clinic at Ohio State University Hospital. 1942 to 1946: Military service; Army Medical Corps, Southwest Pacific Theater (special certificate, Army School of Roentgenology). 1946: Certified, American Board of Internal Medicine. 1950: Fellow, American College of Physicians. 1947 to 1959: Founder and Director, Division of Rheumatic Diseases at Ohio State University Colloge of Medicine. 1947: Post graduate study in Rheumatology at The Mayo Clinic. 1948 to 1950: American College of Physicians postgraduate courses in Internal Medicine at the Universities of Michigan, Pennsylvania, Northwestern, Harvard and Duke University. 1941 to Present: Faculty, Ohio State University College of Medicine, Full Professor of Clinical Medicine 1960. 1957: President, Columbus Academy of Medicine. PAGENO="0171" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3263 1955: Founder and Director of The Columbus Medical Center Clinic and Research Foundation. 1952: Founder and Director of the Arthritis Foundation, Central Ohio Chapter. Author of more than forty publications in endocrinology and rheumatology, complete bibliography upon request. Member, American Rheumatism Association and six other national medical scientific organizations. Senator NELSON. If there is any part that you wish to extemporize on or summarize, you may do so. In any event, your full statement will be printed in the record. Dr. ROTHERMI0TI. Thank you. First, Senator Nelson, I would like to express my gratitude for your accommodating me. I know this is at some trouble. I am appreciative ofit. Senator NELSON. We are glad to do so. Dr. ROTIIERMICH. I did not have an opportunity to see the testimony of Dr. O'Brien and Dr. Mainland until, I think, Monday night. So this has been prepared since that time. I have reviewed it once and corrected it, but it is not as detailed as I would like it.to be. However, I am satisfied that it carries my position and I think it will help to clarify it and I would like to read it. Senator NELSON. Because you wrote it so hurriedly, if there is some- thing you recollect subsequently that you would like to add to your statement, send it to the committee and we will include it with your statement.' Dr. ROTHERMICH. Thank you, sir. I would like to say at the start that in requesting the privilege of making this statement for the hearing records, it is not my wish to subject you to a medical backyard brawl. 1 would like to make clear that I carry no ill will nor any personal animosity toward Dr. Main- land or Dr. O'Brien, who appeared before you last week. My work on indomethacin needs no defense or apology, and I assume that my reports in the medical literature are not on trial. I do believe that Dr. O'Brien made some unwarranted statements which, though assuredly unintentional, cast reflection on my professional integrity and con'i- petency. I should like to reply to those statements and perhaps offer additional comments which may help to clarify for you some points, both in my reports and elsewhere, which apparently have not been entirely understood. Without intending any impertinence, I feel compelled also to offer a mild demurrer that the committee did not find it appropriate or desirable to invite me to appear before it, despite the acknowledged major influence of my reports in the Journal of the American Medical Association. I am not a statistician and know little of the ways of such, hut, as I will try to illustrate later on, it would seem that, contrary to a rather generally held impression, statistics is not an exact science. Further- niore, I am not a laboratory or test tube doctor, although I have a de- gree of experience with laboratory and animal experimentation. I am generally regarded, and consider myself to be, a clinical rheumatol- ogist, engaged primarily in the medical examination and treatment of people. I am a full professor of clinical medicine at Ohio State 1 See supplemental statement beginning at p. 3276, infra. PAGENO="0172" 3264 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY University College of Medicine on a part-time basis, and for this I receive a small annual salary. The major part of my time is engaged in private medical practice in a group association with other internists. All income derived from the application of my medical knowledge is received by me as a percentage from my share of the partnership receipts. A large proportion of my private patients suffer from various rheu- matic diseases, and I am particularly interested in the problem of rheumatoid arthritis, which in my opinion is one of the most devastat- ing, persistent, and painful diseases which affect mankind. Rheuma- toid arthritis is a major producer of disability, striking characteristi- cally in the most productive years. The degree of this disability has not been entirely recognized by business and industry, for reasons not clear to me. Rheumatoid arthritis is not one of the so-called glamour diseases and has not received the attention it deserves from the public nor, I am afraid, from some segments of the medical profes- sion, and in certain aspects it might be said to have an "untouchable" status. Patients with rheumatoid arthritis seem to sense this general attitude and feel almost apologetic or embarrassed at having their d~sease. The disability aspect is all too apparent, and the patient makes every effort to adjust to and compensate for disability. How- ever, the constant and relentless nature of the pain and suffering are little appreciated and not well understood. Now, I would like the c~pportunity to reply to certain of Dr. O'Brien's statements which I thought were unwarranted. On page 4528, he refers to my publication in the Journal of the American Medi- cal Association, volume 195, page 1102, May 1966 (although he fails to refer to the equally important paper published 1 month prior in the Journal of the American Medical Association, February 14, 1966, page 531). He states that the study is highly biased, but I must insist it was done without bias and with complete objectivity. He makes objection to my statement "placebo was introduced whenever the pa- tient seemed `to be established and well controlled on indomethacin therapy." Mr. GORDON. Doctor, may I interrupt you for a moment ~ My feeling when I heard Dr. O'Brien testify was that when he used the word "bias," he used the word "bias" from a statistical point of view. I do not know, but it certainly did not seem to me that he used it in an ad hominem sense. Senator NELSON. I do believe that he did not intend to say that you, yourself, were biased. I think that is correct. Dr. ROTETERMICH. I think he should have made that clear in his state- ment. He should have said it was statistically biased, because he refers later to a statistical bias, so I assume this statement that "it was biased" meant that it was personally biased. Senator NEJ~SON. I do not have the understanding that he intended that, and I do not think he would intend to imply that you were per- sonally biased. I think he was talking about statistics and I think that you may have interpreted it in a way he did not intend. Dr. ROTHERMICEE. Basing this exception on the fact that the disease is "cyclical," he introduces a non sequitur in his reasoning when he states that "since the disease is cyclical, introducing a placebo when a patient was doing well would probably be followed by a relapse." PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3265 There is just no connection between those two phrases. If the dis- ease is cyclical, it would be difficult if not impossible to have a patient established and well controlled on indomethacin or any other therapy. On the contrary, if any disease is under good control by an effective therapy, the introduction of a placebo would probably result in a relapse. Parallel examples of this could be demonstrated by the intro- duction of placebo in patients with congestive heart failure who are well controlled on digitalis therapy, patients with diabetes who are well controlled on insulin therapy, ~nd patients with thyroid defi- ciency who are well controlled on thyroid therapy. `clinicians know that in such instances severe relapse would consistently follow each placebo trial. Applying the term "cyclical" to rheumatoid arthritis would suggest a lack of actual clinical experience with the disease. It is true that the disease is characterized in some degree by exacer- bations and remissions, but these are highly capricious, both in onset and duration, and do not have any rhythmic circular aspects as sug- gested by the word "cyclical." A patient with rheumatoid arthritis may have an exacerbation with continuing activity of the disease for a year or two or more, and then he may suddenly develop a remission, that is, disease inactivity, for a variable period lasting a month, sev- eral months, or in a rare case, permanently. Exacerbations are much more protracted and tenacious, and remissions are usually brief and seldom total. Furthermore, even if the disease were cyclical, the intro- duction of a placebo would certainly not "probably be followed by a relapse." The introduction of a placebo relapse when the disease was apparently well controlled by a certain drug is evidence itself that the drug was actually controlling the disease, and this is reinforced when relapse is precipitated on more than one occasion by the repeated introduction of placebo. Mr. GORDON. Doctor, I have here an article from clinical Phar- macology and Therapeutics, by Drs. Albert M. Katz, Carl M. Pearson, and Joseph N. Kennedy.' I should like to read something from it: All eight subjects who received the drug (with benefit) followed by placebo experienced severe exacerbations within 24 hours of the change. One patient had a severe exacerbation lasting four days, after be was symptomatically the same as when taking indometbacin. Once again, he was given the drug, but derived no further benefit. The experience in this case e~t some doubt upon the validity of accepting an exacerbation which occurs after a drug has been discontinued or replaced by a placebo as proof of the drug's efficacy. Would you comment on that? Dr. ROTHERMICH. I would agree that one case does not prove any- thing. Mr. GORDON. He talks about eight subjects. Dr. ROTHERMICH. He only mentions the one case, though, as an exception to that. Mr. GORDON. Yes, and his conc~lusion is that the experience in this case casts some doitht upon the validity of accepting an exacerbation which occurs after a drug has been discontinued or replaced by a placebo as proof of the drug's efficacy. Dr. ROTHERMICH. Do you not yourself think that one case out of eight is rather a weak statement? ~ See p. 3277, infra. PAGENO="0174" 3266 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. I am not a doctor. I am just giving YOU the conclusions reached by a than~ of doctors. Dr. ROTHERMICH. I am asking you as a layman, not a doctor. One case in eight. Do you think that proves anything at all, really? Mr. GORDON. You do not agree with these people? Dr. ROTHERMICH. I think it has no significance i~t all. Mr. GORDON. There is no significance? Dr. ROTHERMICH. One out of eight, no. On page 4528, Dr. O'Brien states that "a study of this type was designed in such a way that the bias is in favor of the drug." This is a highly arbitrary statement, but Dr. O'Brien proceeds to use this as a false premise for further condemning my report. As a matter of fact, the study was not designed in such a way that the bias was in favor of the drug, and I have done other studies in exactly the same manner before and since Indocin, and my conclusions were discourag- ing and unfavorable to the drug under study. Mr. GORDON. Have these been published? Dr. ROTHERMIOII. No, sir. Mr. GORDON. Have these been given to the FDA? Dr. ROTHERMICH. Yes, sir. Mr. GORDON. Yesterday? Dr. ROTIIERMICH. No, I said yes, sir. Mr. GORDON. Could you supply them to us for the record? Dr. ROTHERMICH. I think the FDA has all the material I have given them. Mr. GORDON. I have looked through the files and I have not seen the studies. Dr. ROTHERMICH. This is not related to Indocin. This is other drugs. Mr. `GORDON. Oh, you said before and since- Dr. ROTHERMICH. Yes, I have done this same kind of study on other drugs and they did not come out at all. Mr. GORDON. I see. Dr. ROTHERMICH. `On page 4529, Dr. O'Brien states that my study, as submitted to the FDA, differs drastically from the manuscript that was published in the Journal of the American Medical Association. This would imply that somethin~ about this condemns my report. I would like to say that much of this was due to the fact that the editor considered my manuscript entirely too long and felt that he could not devote that much space to it. We had considerable correspondence, be- tween the editor and myself, but I agreed only to delete the word "blind" because `of differences with the statistician-reviewer of the journal. It was the opinion of the latter that the `blind and double- blind trial could not be done with Indocin, only because of my thor- oughly honest statement that "occasionally patients would suspect the placebo substitution by a change in side effects ;" and, in reference to and in deference to the statistician-reviewer, I made the further state- ment in the journal that "for this reason, from the statistician's view- point, the placebo trials in this report (and probably in most clinical drug reports) cannot be considered as true `blind studies'." My article goes on further to elucidate this point, and I should like to quote the sentences which follow immediately after that: Usually there was enough delay in this awareness (of a change in side effects) to permit the therapeutic assessment. Furthermore, the appearances of side effects are often capricious and inconsistent, thus further limiting the patient's ability to detect placebo. PAGENO="0175" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3267 I went on to state: The placebo substitutions were made in 8t of the patients, and in 70 of these there was a decisive clinical relapse on placebo. This clinical relapse was vera- fled on repeated placebo trials in 55 patients. In my opinion, these are well controlled observations, despite the fact that some statisticians would deny the validity of "single-blind" trials. I believe it should be emphasized right at this point that, if the statistician reviewing my manuscript for the Journal of the American Medical Association was of the opinion that the appearance of side effects from indomethacin invalidated any single- or double-blind trials, logic and consistency would demand that he deny the Validity of the double-blind trials carried out by Dr. Mainland and his group, and other double-blind trials. Apparently, what is one statistician's meat is another statistician's poison. There is not consistency. When Dr. O'Brien implied that it was demeaning of me and my report that it was published in "modified form," he is not being en- tirely fair to this committee. The fact is that medical journal editors are generally assuming more and more of an authoritarian position and demanding modification of practically every article or report sub- mitted to them. These modifications are based on recommendations from editorial boards and reviewers who no doubt are themselves quite human and fallible. And I might add at this point that Dr. O'Brien admitted in his own testimony last week that the article he submitted to Clinical Pharmacology and Therapeutics, to Dr. Modell and three reviewers, was found to contain errors. It was sent back to him, and he had to revise and modify those, so his report was also published in a modified form. Because of the increasing influence of the statistician in medical reporting, the double-blind trial has been given a position of infal- libility which is not entirely justified. For example, does Dr. O'Brien realize that patients will sometimes break open a capsule and taste the drugs to see if there is a difference? If they are taking a capsule one week and getting another one next week and getting a different effect, they may break open the capsule to see if there is a difference. These are difficult things to control when you are dealing with human beings. When you are dealing with animals, it is different. Even though the capsules may look identical, does he realize that some patients will reduce the dose or discontinue the drug if it is giving adverse reactions, but without informing the investigator? I think this is true especially if the work is being done in a large impersonal institutional clinic rather than the atmosphere of close rapport of the personal patient- physician relationship. This frailty of the double-blind trial is further illustrated in the report of Dr. Mainland for the Cooperating Clinics Committee of the American Rheumatism Association. I should like to add here for the benefit of the committee that this impressive and high-sounding title gives this committee and its work an aura of authority and Olympian omniscience which its own members would be the first to deny cate- gorically and emphatically. In the first place, with reference to Dr. Mainland's work, it is an extremely attractive hypothesis that a lumping together of observa- tions by a number of different clinics would, because of increasing size PAGENO="0176" 3268 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of the sample, increase the statistical validity. The weakness of this is the known remarkable variation between one observer and another. We in our own group, and there are three of us engaged in rheuma- tology in our group-have tested this repeatedly; and although we have tried on many occasions to standardize our observations and have seen patients jointly and in conference, we still find a distressing degree of variation between the three of us who work so closely and harmoniously as a unit. To have 11 different observers from 11 widely scattered clinics making observations which are then stated to be of an identical character seems hazardous at least. There were a number of exclusions in the ARA-CCC study which would certainly weaken the trial's validity. For example, the patients were to be "out-patients or domiciliary hospital patients," but it does not say how much of each sample com- prised the total. Certainly a rheumatoid arthritic in a domiciliary hos- pital environment is much more likely to have a quiescent disease than one in an outpatient environment. The exclusion of all patients who have had antirheumatic therapy would effectively eliminate all cases of even moderate severity. So you would have to assume that most of the cases in that study were cases of mild degree. Senator NELSON. I have a question in reference to your sentence that a rheumatoid arthritic in a domiciliary hospital environment is much more likely to have a quiescent disease than one in an outpatient environment. In setting up a double-blind test, or any kind of study, if those making the study were comparing the person in a domiciliary facility versus one who is outside of it, it would be a fault in the study immediately, would it not? Dr. ROTHERMICH. Oh, yes. Senator NELSON. In other words, do you not, in setting up studies, compare age groups and try to ~et them as comparable as possible? Dr. ROTHERMICH. Yes, and this factor, Senator Nelson, of putting an arthritic at rest, not necessarily bed rest, but outside of an environ- ment that is distressing to him, putting him away in a domiciliary hos- pital environment, you see, is much more likely to allow his disease to become quiescent. So they should have said "we have x number of patients who are hospital domiciliary type and we have ~r number of patients who are outpatients," and given the result of those studies in the given categories. Senator NELSON. In other words, you would compare domiciliary patients versus other domiciliary patients and the outpatients versus other outpatients? Dr. ROTHERMICH. Yes. I would like to add the point, too, that this study was being done by 11 different centers, and they have, I think, 110 total patients. I think half or more of the centers had less than 10 patients in their study group, and some of them as few as four patients. Now, Dr. O'Brien made the statement before this committee at another point that some of the reports in the literature were only of 10 patients or so and any work on such a small number-I cannot think of his exact words, but the substance of it was that it was meaningless, or had no validity. Now, he was referring to other types of work. But I would point out to you, Senator Nelson, that the components of this combined study, you see, had less than 10 patients in many of their centers. PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3269 Now, I would like to emphasize that not only do they have less than 10 in many of these, but their duration of therapy was only for a few weeks-3 months, which in my opinion is much too short a time to evaluate any drug. This is what I will try to emphasize later on. They allowed an unlimited consumption of aspirin in both the placebo and the treated patient. So they have no idea of how many aspirin tablets were taken by either group. Now, it is entirely con- ceivable that a patient may have been on the active drug and taking two aspirin tablets a day, or four aspirin tablets a day, and when placed on placebo, because of an increase of symptoms, he may have increased his aspirin consumption to 12 or 16 a day, but they do not know this. Senator NELSON. There is no way to be sure about it, is what you are saying? Dr. BOTHERMICH. They kept no records of it. Senator NELSON. Oh, I see. Dr. ROTHERMICH. I would like to emphasize, too, Senator Nelson, that I am not saying that this is not a worthwhile trial. I do not mean that at all. I think this kind of trial should be done. But I think it is wrong to assume that this particular type of study is the only study that should be done, and I think it is wrong to assume `that this type of study has no flaws. It has many flaws, because we are dealing with human beings. When you can take mice and rats and put them in cages and keep them under fixed control, then you can have the ideal, well controlled study. But when you are dealing with human beings, this is something else again. Senator NELSON. This has always been my view. I have always said politics would be a wonderful thing if you did not have to deal with human beings. Dr. ROTHERMICH. Yes. I did think it was rather significant that Dr. Mainland himself testified that if he were treating rheumatoid arthritis-although he disclaimed that he was treating any patients-he would select in- domethacin for a cautious trial in those patients who have failed to respond to basic therapy, including salicylates, despite the fact that his report indicated negative results. In this context, for the information of this committee, I would like to quote from my article in the JAMA in the section under comments: However, it should not be inferred that indomethacin replaces or eliminates the need for a sound basic therapeutic program for the patient with rheuma- toid arthritis which should include increased rest, salicylates, physical ther- apy, and other adjunctive or supportive measures. The patient with rheuma- toid arthritis who is not responsive to the basic program of therapy may have this supplemented by the cautious prescribing of indometbacin beginning with a dose, et cetera, et cetera. It would seem that Dr. Mainland and I have identical views on the clinical usefuh~ess of indomethacin. In my early studies, I was repeatedly admonished by my preceptors that it was unhealthy for medicine generally and unwise for the in- vestigator to rush into publication with short-term observations. For this reason, I went to great pains to delay my report in the Journal of the American Medical Association until I had accumulated more than three and one-half years of intensive experience with this drug. I sub- jected the drug to the most thorough and penetrating clinical scrutiny. 81-280---68-pt. 8-12 PAGENO="0178" 3270 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Every possible means was taken to determine the true action of this drug and to avoid bias on the part of myself or the patient. Dr. O'Brien suggests that my patients were badly neglected and that I had lost interest in them until I suddenly presented them with a wonder drug. All of my patients with rheumatoid arthritis con- tinually receive the most personalized attention from me, regardless of what drugs or therapies I have been or am employing. No change whatsoever was made in our approach or routine management. As I have previously stated, most of these patients have at various times been subjected to one or another type of clinical experimentation. In accordance with my own scruples and ethics, and with the law, I did explain to each patient that he was undertaking a new experi- ment, and often this was done in the presence of a spouse or a near relative, and the patient was then required to sign an appropriate release form. Dr. O'Brien would lead you to think that some poor miserable arthritic had staggered into my examining room, discouraged and de- pressed by my indifference to his disease activity, and that I suddenly burst into the examining room, wildly elated and exclaiming to the patient that I had found a wonder drug and that the patient was about to be miraculously cured. Such an ugly implication is dangerous at worst and naive at best. The fact is that our whole setup was geared to achieve the greatest objectivity in our evaluation of this drug. Of course, as stated previ- ously, I informed the patient fully that an experimental drug trial was to be initiated, but that no patient should feel in any way coerced into joining in this trial, because I think that a patient must give informed consent. I think if there was any bias in our study, it was as a result of this informed consent of the patient, which tended to eliminate the timid and the weak of heart, but this is now required by law and a necessary part of any drug trial. Under such circumstances, the subjective response of the patient, in my opinion, is about equally divided between some 20 percent on the one hand who want very much to have a good result and therefore get an unrealistic benefit from the drug, and about 29 percent on the other end of the spectrum who, because of their great fear of the nature of experimentation, would like to have the drug discontinued as soon as possible and tend to report minor or imagined ill-effects, or even tend to minimize possible good ~effects. Only long-term trial with these patients can effectively bring their results into true perspective. Achieving this true perspective can be greatly aided and solidified by the liberal use of placebos, both single-blind and double-blind, as well as by the gradual but systematic reduction or withdrawal of other effective therapies, most notably the corticosteroids, or cortisone. Likewise, evaluation of side effects of a drug can only be determined in patients on the basis of long-term observation. These side effects must be carefully appraised, keeping in mind at all times the safety of the patient, but weighing and balancing out as far as possible the need for truth and knowledge about the nature of the drug under investigation. In my opinion, it is wrong to suddenly thrust at a patient a double-blind study without some prior preliminary trial of the drug. Such an early doublerblind trial i~ bound to have the built-in problem of the patient's first experiences with the good an4 PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3271 bad effects of a drug, and these will undoubtedly color his own responses to the investigator's questionnaire. In my opinion, such a study is far more valuable if the patient is allowed to be on the drug for a sufficient time to familiarize himself with it and to become casual and unconcerned, and then the application of either single-blind or double-blind studies will have much greater validity. Finally, I would like to add here-and I do not want Dr. O'Brien to take any offense at this statement, but I must say it-that many rheumatologists would disagree vigorously with his seemingly cavalier statement that no therapy influences the course of the disease. Fur- thermore, such a statement could have an extremely demoralizing effect on hundreds of thousands of rheumatoid arthritics throughout this country and the world. The evaluation of rheumatoid arthritis is extremely difficult in all its aspects. Even the diagnosis is often a tenuous one. Our methods of measuring good effects and bad effects leaves much to be desired, and I am sure Dr. Mainland would be the first to agree; in fact, I think he has already reported elsewhere this general opinion about eval- uating therapy in rheumatoid arthritis. Parenthetically, I can say that we sat on a panel discussion with several noted rheumatologists in Japan-Dr. Joseph Hollander from Philadelphia and Dr. William Kuzell from San Francisco. This was organized by the Japanese as a panel for evaluating therapy in rheumatoid arthritis. Dr. Kuzell was asked his opinion, and he said the best way to measure it was to say to the patient: How do you feel? Dr. Hollander went to the trouble of describing a palpometer, which is a mechanical device for squeezing on a patient's joint to see at what point it would cause pain. Now, one of the criteria that the Mainland group used was tenderness of a joint. Now, this is tenderness in San Francisco and in New York and in Miami and so on, and each examiner is squeezing that joint. You cannot make me believe that the one in Miami knows how hard the one in New York is squeezing a joint, too, so that there can be real objective comparison of tenderness. If Dr. Holiander feels the need to develop a palpometer2 I think you can readily appreciate that determining with any exactitude the tenderness of a joint is a very difficult thing. We have great difficulty in knowing truly how much, if any, influ- ence we have produced on any given disease, and this is about equally true of rheumatoid arthritis, or perhaps a little more so. One could probably say that insulin has no influence on the basic course of diabetes, and there would be a certain amount of truth in this. But no one would say, do not give the diabetic insulin. How can we say that a patient who has active inflammatory disease in his joints has not had his basic disease altered when the inflammation has been reduced or eliminated by certain types of therapy? Dr. O'Brien even referred to cortisone as having a powerful anti- arthritis effect. Now, "antiarthritis" means that it acts against inflam- mation within the joint. If he thinks that cortisone can abolish the inflammation in the joint, he must concede that this has to have some basic influence on the course of the disease. Even if the eventual outcome of the disease has not been influenced~ we still cannot say that it has not been retarded, or its harmful effects minimized or reduced. I think that today you do not see the extremely PAGENO="0180" 3272 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY severe, advanced crippling of the arthritic that we used to see 20 years ago. I think this is eloquent testimony itself that our therapies are effective in `at least partially influencing the course of the disease. We have patients under our care whose disease we regard as static, but whenever we attempt to reduce or withdraw certain therapies, the disease process flares up and accelerates intensively. No single therapy benefits every patient with rheumatoid arthritis, not even aspirin, and, yes, not even corticosteroids. Certainly it has never been suggested, hinted, or implied that indomethacin benefits every case of rheumatoid arthritis. Senator NELSON. Are there any statistics as to longevity of `rheuma- toid arthritics now vis-a-vis 20 years ago? Dr. ROTHERMICH. I do not believe so. I think that this is a very difficult thing, because of its long term nature. `Senator NELSON. No statistics? Dr. ROTHERMICH. Yes, it is very difficult, because patients with rheumatoid arthritis do tend to live an awfully long `time; in fact, you might say in some cases too long `because of their prolonged suffer- ing. But-to compare ltngevity-I do not think this has been done. Finally, the members of this subcommittee sho'uld know that emi- nent, highly competent, and highly respected rheumatologists from all over the world have reported favorably on their results with judo- meth'acin in rheumatoid arthritis and have indicated the important adjunctive place of this drug in its overall management. Numerous congresses on rheumatic diseases have been conducted iti various parts of `the world, and these eminent rheumatologists (who are held in highest esteem and often closely affiliated with the American Rheuma- tism Association) in paper after paper have reported favorable results in what they consider to be controlled trials of the drug for extended periods of time. `Most rheumatologists would be dismayed (and large numbers of patients with rheumatoid arthritis would be bitterly disappointed) if they were to be deprived of the clinical and therapeutic benefits of indomethacin on the basis of a few brief-trial negative reports. I wish to thank you, Senator Nelson, and all of the members of the subcommittee for the opportunity of presenting this statement and having it included in the hearing records. If I can be of any further assistance or service to the subcommittee, I shall be glad to cooperate as fully as possible. Senator NELSON. Doctor, we were very pleased to have you come to present your informed viewpoint `based upon your long experience. Mr. GORDON. Dr. Rothermich, I have several letters here written by you to the Merck Co. which were secured from the files of the Food and Drug Administration. I would like to read one of them. This is from you to Merck Co. It says: Few improvements were noted in the peripheral arthritis group at dosage levels of 150 mg daily. Most of the peripheral arthritics `are now being carried on a daily dose of 300 mg daily, but a significant number were benefited to a striking degree to 200 mg daily. The greatest deterrent to increasing `dosage to an effective level is the appearance of cerebral toxicity. This manifests `itself clinically in excruciatingly severe headaches, dizziness, lightheadedness, disturbances of sensorium, a feeling that the head is floating away or even separating from the body, feeling of detachment from reality. `The higher the dose, the more severe the symptoms. PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3273 Here you say that most of your patients-these are your words~- most-are being carried on dosage of 300 mg. On the other hand, the upper limit of approved dosage is 200 mg. Now, it seems to me that no doctor could repeat your experiences. In other words, what I am questioning is can your studies be used as proof of efficacy for this drug? Dr. ROTHERMICH. What is the date of that letter, sir? Mr. Goi~ooN. Your letter is dated June 12, 1963. Dr. ROTTIERMICH. This is the point I have made in my report to the JAMA. On long-term trials, we came to realize that patients experi- enced cerebral side effects worst when they suddenly had the drug thrust on them in high dosage, and we realized that there were certain times of day when they were more likely to have cerebral side effects than others. We also came to realize that if we began at a very low dose and built it up, they were far less likely to have any significant cerebral side effects. Mr. GORDON. But you still cannot go over 200 mg. now. That is the approved dosage. You cannot go above that, but you went beyond it in your trial. You went up to 300 mg. and 400 mg., too. My point is this: The studies that you made cannot be used as proof of efficacy of that drug, because nobody can duplicate that dosage today. Dr. ROTHERMICIUI. No, I said that in my report to the Journal of the American Medical Association, too~ Mr. GORDON. Yes, I know that. Dr. ROTHERMICH. That the dosage I used should not be used clini- cally and therefore physicians could not expect as high a degree of improvement as I had reported-this is stated in that article. Mr. GoRDoN. I have it right here. Dr. ROTHERMIOH. You will see it right in the first part, if the synop- sis, right at the bottom, that they should not use this high a dosage, that if they used it in smaller dosage and gradually increased it to tolerance, they would then begin to get effects which were not dis- cernible at the early stages. This was proven repeatedly to us by patients, both on single-blind and on what we call double-blind study, although the statistician for the JAMA refused to allow us to use that term. We felt it was inadequate. But we did feel, as we developed greater experience with the drug, we came to realize that there was a significant number of patients who were getting benefit from indomethacin. Now, what we were trying to show in our studies, and this was for the benefit of the profession, we felt obligated to report to them as fully as possible. We were trying to show what the maximum dosages were and what would happen if those maximum dosages were ex- ceeded. We put six patients in the hospital, at the university, and sub- ~ected them to enormous single-dose trials, as much as 350 milligrams in one dose in the morning, and we made intensive studies on them throughout the day, using all kinds of parameters of study, because we felt we had to know what happened to a human with increasing dosage and where therapy was jeopardized by toxic effects. Now, we were impressed early in our studies by the cerebral side effects, and I emphasized this: that since then we have learned that we can mitigate øç minimize by certain techniques of therapy, by PAGENO="0182" 3274 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY always giving the drug on a full stomach or with milk at bedtime, as we had recommended in the JAMA report; that we avoid a morning dose; and that we avoid having the patient take it in association with caffeine ingestion, because we feel this aggravates the tendency for the cerebral side effects. We also did learn that there is a certain idiosyncratic reaction, that some patients are exquisitely sensitive to this. I had one patient develop this in very bad form on 25 mg., whereas many patients can take much more and get no side effects. Did I answer your question? Mr. GORDON. Not exactly. Dr. ROTHERMICIT. Well, what do you want me to say? Mr. GORDON. You are aware that 200 mg. is the maximum dosage approved by the FDA? That we can agree on. Dr. RoTHE1~MIOll. Yes. Mr. GORDON. You also stated that most of your patients were on 300 mg., which was above the Food and Drug Administration limit, and that it cannot be duplicated today. Then I asked you whether this could be used as proof of efficacy, given the present limitation by the Food and Drug Administration on dosage. I do not think I got a clear answer from you. Dr. RoTH1~nMIdn. I thought I answered quite clearly. I said that we got a remarkably high percentage of good and excellent results, but that in many of these cases the dose was at levels in excess of what should be used in general practice, and that physicians could not expect a comparable high percentage of good effects because they would necessarily have to use smaller doses. Mr. GolwoN. Let me read another excerpt from one of your letters. This is a letter from you to Merck & Co., dated October 12, 1963, in which you state: Inclocin has an excellent beneficial effect in some cases of peripheral rheu- matoid arthritis but only a good effect in a large percentage and there is a complete failure or ineffectiveness in a *distressthgly high percentage of such cases. Does that add to what you said before? Dr. ROTHERMICH. No, I think it simply amplifies it. I think, yes, I would say today that indomethacin will prove of significant clin- ical-because of the statistician, I have to avoid the word "signifi- cant"-that it will prove to be of appreciable clinical benefit, worth- while for the physician to give his patient, in something over 50 percent of the patients-about 50 or 55 to 60 percent, in that area, on the limited dosages we have. Mr. GORDON. This is Indocin as against nothing. How about Indocin as against aspirin? Dr. ROTTIERMICH. Now, I think this brings out a point that I appre- ciate. Many physicians around the land have a sort of all-or-none atti- tude toward treatment of rheumatoid arthritis. They give the patient this drug and if it is not beneficial, they stop it, and then they give him that drug. We do not believe in this, and I have said in other papers that combinations of the~apy are vastly important in rheumatoid arthritis-that aspirin will contribute, let us say, 10- to 15-percent benefit; Indocin may add another 20-percent benefit; small doses of a corticosteroid may add another 30-percent benefit. Even giving paren- PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3275 teral injections of gold may add another. So that the cumulative benefit from small amounts of all of these drugs will give the patient a 70- or 80-percent total benefit. Do you see? Did I answer that? Mr. GORDON. Yes. Mr. Chairman, I ask that this correspondence as well as Part 2 of Dr. Rothermich's article which appeared in the March 28, 1966 issue of JAMA be placed in the record right after the testimony of T)r. Rothermich. The chart appeai~ing on page 126 of the 1966 JAMA article indicates that most of the patients were on daily doses well above the permitted level.1 Dr. ROTHERMICH. Senator Nelson, I am not objecting that it be put in there, but I believe that the date should certainly be emphasized; 1963 was a long time ago. Senator NELSON. I don't know if it is particularly relevant at this stage, because that was before we had much clinical experience with it, right? Dr. ROTHERMICH. Right. Mr. GROSSMAN. Doctor, I would like to ask you one question. On page 6 of your testimony, concerning your report in modified form, you say, in the first full paragraph: The fact is that Medical Journal editors are generally assuming more and more of an authoritarian position and demanding modification of practically every article or report submitted to them. These modifications are based on recommendations from editorial boards and reviewers who, no doubt, are themselves quite human and fallible. How do you see your role? You talked before about doing things for the benefit of the profession. What do you see as your role in seeing to it that, for example, reports are not published in modified form? If they say they are only going to publish it in a modified form, why would you not say, then, do not publish it if you are going to leave out significant aspects of it? Do you not have some responsibility there? Dr. ROTHERMICH. This is a question that I find difficult to answer. I cannot quite agree with the increasing authoritarian position as- sumed by medical journal editors, and I find that at times they are extremely arbitrary. But, you see, they have total power of veto; and if you want to get some information to the profession, you may find it necessary to modify to some extent. Now, if you feel it is going to be modified substantially, then I think you are honorbound not to agree to its publication, But when I agreed to the publication by striking out the word "blind," I did go to great lengths to explain in the article for the benefit of the statistician- reviewer, that I was doing this, so I felt that my position was tenable. Does that answer your question? Mr. GROSSMAN. I think so. As far as you are concerned, there is no control over the various journals to see that this is not done, except for the particular physician who writes the article. Otherwise, nobody checks to see what he leaves out or what lie does not? Dr. ROTHERMICH. No, I th1nk when the article is submitted to the medical journal, the editor submits it to several different reviewers. These reviewers may be all academicians, for example, who are not patient oriented and know little or nothing about the practice of 1 See information beginning at p. 3282, infra. PAGENO="0184" 3276 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY medicine. They may be laboratory-oriented physicians or they may be statisticians. I once submitted to the editor of Arthritis and Rheumatism an article dealing with my extensive study of the incidence and preva- lence of rheumatoid arthritis in criminal ançl insane populations. We examined 20,000 insane and 4,400 criminals in the Ohio penitentiary to determine if they had rheumatoid arthritis. I submitted this and was told that this was referred to some prison psychiatrist, and he took exception to certain parts of it and wanted to have these deleted. I refused, and the article was not published. The editor subsequently apologized to me and said that he was bound to follow the reports of his reviewers and his editorial board. He subsequently agreed that he would publish it as a brief report without any editorial changing of it. I had to condense it, then, so that it would fit in length with the qualifications of "brief reports." Mr. GROSSMAN. My point is only this: It seems there should be two responsibilities. One rests with the individual anthor of the piece, to make sure that his piece is honorable, that it goes to the points, and does not leave anything out; and secondly, that these medical journal editors, whoever they are-I happen to know that we are giving them, if they are nonprofit organizations certain tax advantages and other advantages-these editors should at least own up to these things and make sure we are getting the full story. Dr. ROTHERMIOII. I am sure that these medical journal editors are highly conscientious men, and they strongly believe, some of them, for example, in the infallability of the double-blind study, which I have today tried to show you is not infallible. Mr. GROSSMAN. Then we are wholly dependent on the individua' author's integrity. It comes to a point where he says, I will not let you print my material. Dr. ROTHERMIOH. Yes. Then he might just as well go hide in a closet. Mr. GROSSMAN. He may have to. Dr. ROTHERMIOJI. You see, this is the problem now. Mr. GROSSMAN. Thank you. Senator NELSON. Thank you, Dr. Rothermich, for coming in today. We appreciate having you here. Dr. ROTHERMIOH. Thank you. (A supplemental statement was subsequently submitted by Dr. Rothermich and follows:) SUPPLEMENT TO STATEMENT OF NORMAN 0. ROTHERMIOH, M.D. Finally, I should leave with the committe a clear-cut, concise statement of my present views and attitudes regarding indomethacin, and to emphasize the objectivity of this (as not something suddenly thought up for the benefit of this committee), I will simply quote from the invitational lecture which I gave before 1,200 Yugoslavian doctors at their Symposium on Rheumatic Diseases in Ljubljana, Yugoslavia on Friday, April 2G, 19G8. "Uonclusions.-After six and one-half years of clinical experiences, I continue to regard indomethacin as a valuable adjunct to the treatment of rheumatoid arthritis. It may be considered as a treatment of choice in ankylosing spondylitis, chronic gouty polyarthritis and psoriatic arthritis and may be beneficial in some other miscellaneous rheumatic diseases, such as osteoarthritis (especially of the hip) and in some eases of fibrositis. Cerebral and gastric side effects are cer- tainly not uncommon, but with prophylactic attention to dosage and method of administration and with reasonable vigilance on the part of both the physicial' PAGENO="0185" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3277 and patient, these should not prove harmful or a deterrent to clinical trial with the drug. As with all drugs, certain peculiar idiosyncratic effects may be expected, but only rarely. No one should make the mistake of thinking that indomethacin is the final word or the cureall for rheumatoid arthritis, but to many of these unfortunate patients it is a godsend and the physician should be prepared to offer such patients this possible benefit. At the same time, he should certainly not ignore the basic fundamental approach to the treatment of rheumatoid arthri- tis with increased rest, physical therapy, aspirin or other salicylates and atten- tion to any other diseases and malfunctions in the body which may be con- tributing to or worsening the arthritis." Lastly, I should also offer to Senator Nelson and the subcommittee my own recommendations regarding the development of a new drug in the field of rheu- matic diseases, as follows: 1. Thorough and intensive basic pharmacologic studies in animals and pre- liminary trials in paid human volunteers. 2. Cautious initiation of therapeutic trials in patients by one or a few experi- enced clinical rheumatologists, beginning with very low doses and gradually increasing to therapeutic levels. 3. After achieving a satisfactory baseline, the rheumatologist should then introduce single-blind trials with placebos and also initiate attempts at reducing other therapies or eliminate them entirely, if possible. 4. If the drug seems promising from these preliminary investigations (which should last from six months to a year), then controlled double-blind cross-over trials should be initiated by those already studying the drug and also by other qualified groups who may be interested. 5. If these studies continue to indicate promise of therapeutic effectiveness of the drug, then it should be given to a large number of rheumatologists for con- trolled therapeutic trials over a prolonged period. Again at least six months to a year. 6. If at the end of these studies the drug shows continued therapeutic effec- tiveness and the side-effects can be considered reasonably acceptable and not unduly hazardous to the patient, the drug can then be released for sale and general prescription by the medical profession. It is my opinion that the public is well protected by the surveillance presently exercised by the Federal Food and Drug Administration in the development of clinical drug trials. It is not within my province to make any comment regarding drug advertising. (The supplemental information submitted by Mr. Gordon follows:) [From Clinical Pharmacology~ and( Therapeutics, vol. 6, No. 1, June 5, 1964, pp. 25-~O} A CLINICAL TRIAL OF INDOMETHACIN IN RHEUMATOID ArrrHRJTIs* (Indomethacin, a new nonsteroidal compound, was tested as an antirheumatic drug in 97 patients. Beneficial effects were recorded as excellent in 6, good in 23, and fair in 12. The drug was discontinued in 60 patients, and 6 others were lost to follow-up. The most common reason for discontinuation of the drug was gastrointestinal effects.' Peptic ulcer developed in 6 patients.) (By Albert M. Katz, M.D.. Carl M. Pearson, M.D., and Joseph M. Kennedy, M.D., Los Angeles, Calif., Division of Rheumatology, Department of Medicine, U.C.L.A. School of the Health Sciences, and the Wadsworth Hospital, Veterans' Administration Center.) Indomethacin (Indocin) is a nonsteroidal compound, 1- (p-cblorobenzoyl) -5- methoxy-2-methylindole-3-acetic acid, which possesses significant antipyretic properties and analgesic effects in animals.11 Toxicologic studies in animals showed effects which were similar to those demonstrated by many other anti- inflammatory agents. These included fluid retention, gastric irritation, and ulcer- ative lesions of the gastrointestinal tract.3 510 Since indomethacin is active when given orally, and because it possessed certain potentially advantageous clinical properties, its value as an antirheumatic agent was tested in man. *Received for publication, June 5, 1964. NoTE-Numbered footnotes at end of article, p. 3282. PAGENO="0186" 3278 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TESTING PROCEDURES The majority of patients included in this series bad one of the rheumatic clis- eases, in mest cases rheumatoid arthritis. Criteria for admission included: 1. Continuing difficulty with current regimen of treatment or the need for large doses of corticosteroids. 2. The ability of the patient to return frequently to the clinic, at least 2 con- secutive weeks originally. 3. Freedom from significant complicating disease. 4. A reasonable measure of reliability of the patient's observations of his symptoms. 5. Stage III of ARA classification (although a few stages II or IV are in- cluded)8 if rheumatoid arthritis was present. The patients were first examined weekly, then biweekly, and later monthly. Evaluation was made of the amount of pain, tenderness, effusion, range of motion of the joints or other structures involved, general well-being, the presence or absence of fever, and possible side effects. Almost all patients were on other medications at the time indomethacin was first administered. Medications were continued at the same dose level so as not to influence the evaluation of the effect of the indomethacin. In some cases, however, the dose of other drugs, such as cortisOne, was reduced when the indomethacin was found to be of benefit. Some patients were evaluated in a study in which they received either indomethacin or an identically appearing placebo. After one week on one treatment, the drug was changed without the patient's knowledge to the opposite substance. The dosage of indomethacin ranged from 100 mg. to 400 mg. daily, given in the form of 25 or 50 mg. coated tablets in the most convenient divided dose schedule for the patient. Four hundred milligrams was given as 100 mg. four times each day, 300 mg. as 100 mg. three times daily, etc. In the beginning, patients were instructed to take the medication with meals but, as gastrointes- tinal side effects became evident, they were instructed to take it after meals. Antacids were used prophylactically in a number of subjects in the later phases of the study. Periodic laboratory examinations, which included complete blood count, erythrocytic sedimentation rate, uringlysis, stool guaiac, serum bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), and serum uric acid, were performed. Other examinations were made as indicated. The test drug was immediately discontinued if any potentially serious com- plications developed, or if annoying side effects became more incapacitating than the disease under treatment. If no benefit was noted after a suitable period of time. usually about 2 weeks, the trial was concluded. Each patient was seen by one of the three authors. Every patient started on the drug is included in this report; 97 in all, 52 females and 45 males. Age ranges from 10 to SI, with the majority between 30 and 50. RESULTS The effects of indomethacin on clinical signs and symptoms were rated by com- parison with the therapeutic regimen of aspirin that nearly all of the patients had been receiving immediately prior to the trial. The major benefit was a de- crease in joint and muscular pain and stiffness. A significant number of patients also experienced a marked decrease in the duration and intensity of morning gel, or the elimination of it altogether. The response was considered fair if it was judged to be as effective as a therapeutic amount of aspirin, good if it greatly surpassed aspirin, and ewceUent if it completely relieved symptoms. The advan- tageous clinical effects noted in 41 patients who tolerated the drug for a period of 3 months or more are noted in Table I. Borderline cases were always listed in the less favorable category. Among the 97 subjects to whom indomethacin was administered, 41 were benefitted, the drug was discontinued for one reason or another in 50 patients, and 6 were lost to follow-up. PAGENO="0187" COMPETITJVE PROBLEMS IN THE DRTJG INDUSTRY 3279 TABLE I-DEGREE OF BENEFICIAL EFFECTS IN 41 PATIENTS TREATED WITH INDOMETHACIN Disease Excellent Good Fair 3 Rheumatoid arthritis (71) 14 10 Rheumatoid spondylitis (6) 1 2 Reiter's syndrome (4) Gout, chronic (5)~ 1 Osteoarthritis (4) 1 2 Acute gout(l) 1 Psoriatic arthritis (1) 1 Causalgia (1) 1 Erythema nodosum (1) I Scleroderma (2) Adiposa dolorosa (1) Total (97) 6 23 12 Note: Figures in parentheses total treated in each category. In 71 patients with rheumatoid arthritis, Improvement was excellent in 3, good in 14, and fair in 10. Ten of the 37 subjects with rheumatoid arthritis who stopped taking the drug had noted improvement. This response was not graded, however, because of the short duration of drug administration in most of these patients. Excellent results also were noted in one patient with erythema nodosum, one with acute gout, and one with both osteoarthritis and rheumatoid arthritis. If there were beneficial effects, they were almost always noted within the fLrst 24 to. 48 hours, usually after the first or second dose of indomethacin. The 41 patients who responded favorably have been treated from 3 to 12 months. The dose has ranged frosu 100 mg. to 400 mg. clailiy, and for the most part the beneficial effect does not seem to be dose-related. Rarely have we noted greater improvement when the dose was increased in a patient who had not responded to a lower dose. Indomethacin was evaluated in 17 patients, of whom 12 were started on the drug and 5 on placebo. After one week, the drug and placebo were exchanged without the patient's knowledge. Six of the 17 patients were clinically unaffected by either agent, although 2 stated that they were "benefited" at a time they were taking the placebo. Three of the 5 patients receiving placebo followed by drug benefited from the change. All 8 subjects who received the drug (with benefit) followed by placebo experienced severe exacerbations within 24 hours of the change. One patient bad a severe exacerbation lasting 4 days, after which he was symptomatically the same as when taking indometbacin. Once again he was given the drug, but derived no further benefit. The experience in this case casts some doubt upon the validity of accepting an exacerbation which occurs after a drug has been discontinued or replaced by a placebo as proof of the drug's efficacy. Six patients out of 8 had exacerbations of symptoms on a trial discontinuation of the drug, In most cases the exacerbation that followed substitution of the placebo for the drug exceeded in severity the clinical state prior to indomethacin treatment. In 5 of the 44 cases the indomethacin appeared to become less effec- tive with the passing months. This, of course, may have been the result of altered activity of the disease. Two patients were unable to take the medication during the day because of lightheadedness, but were able to sleep uninterrupted and had no morning gel when taking indomethacin before sleep only. Both had previously awakened frequently to "loosen up" and had considerable morhing stiffness and pain. One patient with psoriasis and arthritis had a remission of the dermatitis coincident with that of the arthritis and an exacerbation of both when placebo was substi- tuted. In most cases existing effusions did not change perceptibly. The erythrocytic sedimentation rate was unaltered despite clinical improvement. PAGENO="0188" 3280 COMPETITIvE PROBLEMS IN THE DRUG INDUSTRY ADVERSE EFFECTS There were substantial adverse reactions in the study~ Thirty-seven of the 97 patients (37 percent) found it necessary to discontinue the medication after a short period because of adverse effects (Table II). Thirteen patients experienced neither benefit nor side effects, despite a stepwise increase in dose to 400 ing. daily. Six patients did not return. TABLE Il-SIGNIFICANT ADVERSE EFFECTS FROM INDOMETHACIN IN 97 TREATED PATIENTS Other Light- Disease Number Headache Peptic gastroin- headed- Mixed Othe r I Total Percent treated ulcer te~tinaI ness and symptoms symptoms dizziness Rheumatoid arthritis 71 5 6 6 8 4 3 32 45 Rheumatoid spondylitis_ - 6 1 1 Reiter's syndrome 4 I I Osteoarthritis 4 1 1 Scleroderma 2 1 Adiposa dolorosa ~ ~::T.TTT.T.T.._~.~_~____-_--_------- Total 8 6 7 9 4 3 37 11 each: ankle edema, abnormality of glucose tolerance, and urticaria. The major reasons for discontinuation of indomethacin were, in order of fre- quency, gastrointestinal symptoms, lightheadedness, giddiness, headache, and psychic changes (Table II). In almost all cases the adverse effects were evident within hours or a few days. Occasionally, gastrointestinal symptoms did not develop for a week. Nine patients had to stop taking the drug because of lightheadedness, giddi- ness, loss of equilibrium, inability to concentrate, and dissociation of mind and body. No neurological signs were evident, although a majority of the patients bad Wscontinued the drug before they were examined again. One subject had a syn- copal attack and fell, sustaining minor injuries. Four patients who were still taking indomethacin had similar symptoms which, however, were mild and transient. Seven patients had bothersome gastrointestinal complaints which necessitated discontinuation of the drug, and another 5 had transitory symptoms but were able to continue with the medication as the symptoms lessened. The symptoms included epigastric burning, nausea and vomiting, diarrhea, and melena. Peptic ulcer developed in 6 of the 97 patients (6 per cent). In each case the drug was stopped immediately. Three of these patients were also taking small doses of prednisone (5 to 10 mg. daily), but each had been on a corticosteroid preparation continuously for several months at least, often in the higher dosage range, with- out epigastric distress. In one patient, a 60-year-old woman with advanced active grade IV rheumatoid disease, who was on prednisone 7.5 mg. per day and indo- methacin 250 mg. per day, a prepyloric ulcer perforated into the lesser omental sac 4 months after treatment with indomethacin, with only 4 or 5 days of mild epigastric symptoms. Four of the 6 patients who developed ulcer did so very rapidly after receiving indomethacin. Epigastric distress usually began after the first two or three doses. In one patient, a prepyloric ulcer was demonstrated 48 hours after the start of treatment and 24 hours after the onset of symptoms. Only 1 of the 6 patients had a prior history of ulcer, which was known to have healed. Antacids were not given routinely since this was not part of our protocol in the early phases of study. Antacids, however, were used in most of the patients late in the study. Headache developed in 13 patients, 8 severe enough to discontinue the drug. There was no apparent pattern as to location, although the bifrontal type was the most common. Both steady and throbbing headaches were encountered. Al- though most patients with headaches had an accentuation of symptoms shortly after each dose, 2 reported partial relief of their headaches after each dose of medication and an accentuation of headache proportional to the length of time between medication. Three subjects were given ergotamine tartrate with caffeine without relief of headache. Urticaria developed in one patient on two separate occasions following ingestion of indomethacin. However, she had had urticaria once previously without known PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3281 cause. A patient with rheumatoid arthritis had ankle edema on two separate trials of indometbacin. LAIIORATORY FINDINGS Almost all patients had a large number of laboratory examinations before treatment was begun. There was the expected high percentage of moderate anemia and elevated erytbrocyte sedimentation rates., Other pretreatment lab- oratory abnormalities included moderately increased Bromsulphalein retention in 5 patients with rheuwatoid arthritis, elevated SGOT levels (3 patients), elevated serum alkaline phosphatase (1 patient), and elevated serum uric acid (4 patients). A not unexpectedly high percentage of patients with reversed al- bumin/globulin ratio was also found. Complete blood count, urinalysis, and erythrocytic sedimentation rate were alt performed routinely and repeatedly in follow-up. With two exceptions, no pattern of change was noted that could not be attributed to chance or spontaneous varia- tion in disease activity. Other laboratory examinations performed randomly in the follow-up period, which showed no abnormalities, were: serum creatinine (19 determinations), serum uric acid (23 determinations), albumin/globulin ratio (21 determinatIons), serum bilirubin `(17 determinations), cephalin flocculation (18 determinations), and thymol turbidity (22 determinationS). Five of 51 patients bad gualac-positive stools. Of these, 2 had melena without radiologically demonstrable cause and 3 had peptic ulcer. One subject with diabetes mellitus noted increased glycosuria after starting indomethacin. The patient was then studied on a constant dosage of aspirin, with and without indomethacin. While on indomethacin, the glucose tolerance curve appeared to be more abnormal; on 200 mg. of indomethacin daily, there was 0.5 per cent to 2.0 per cent glycosuria, whereas it was negative to 0.5 per cent before medication. Other abnormalities were noted in 2 patients with rheumatoid arthritis while on treatment, but neither had control determinations for the specific abnormality. One had a serum SGOT of 106 and a serum pyruvic oxaloacetic transaminase (SGPT) of 123 after 2 weeks of treatment. Two weeks after discontinuation of the drug, the SGOT was 37 and SGPT was 46. Indomethacin was then adminis- tered for 5 days, after which the SGOT was 53 and the SGPT 56. The patient bad no clinical signs that could be related to the changes and had symptomatic relief of the arthritis. The second patient was found to have a serum alkaline phosphatase of 25 KIng-Armstrong units (normal 2.9) 3 weeks after starting indomethacin. Bilirubin and transaminase were normal. The drug was discon- tinued and over the next 6 weeks the alkaline phosphatase slowly fell to normal. DISCUSSION The discovery of a new class of compounds with antirheumatic effects is a significant advance. Indomethacin is not related chemically to the salicylates, pyrazalones, or corticosteroids, and yet In many respects it seems to operate like them. The way in which indomethacin induces symptomatic relief is unclear. The compound possesses antipyretic, analgesic, and perhaps "anti-inflammatory" effects, although specific histologic evidence on the latter point is so far lacking in man. The dramatic effect of indomethacin in cases of acute ~ suggests ac- tions resembling those of the corticosteroids. In the rheumatic diseases indo~ metbacin is, in some respects, nonspecific in its action, since symptomatic relief is obtained in a variety of conditions; rheumatoid arthritis, gout. Reiter's disease, ankylosing spondylitis, osteoarthritis of the hip, and other condi- tions.' 10 So far, it has not been possible for us to select the patients who will respond to indomethacin. Our observations seem to indicate that indomethacin does not specifically alter the basic rheumatoid process or that of other diseases which have been treated. Synovial effusions have generally persisted~ and the sedi- mentation rate and titer of rheumatoid factor have not decreased significantly. Where these have improved, in a few cases, the change probably was a result of the natural course of the underlying disease. The incidence of adverse effects from indomethacin is unfortunately high. An- noying headache and gastrointestinal irritation come soon after the drug has been given. We have found no satisfactory way of overcoming them. The more serious problem of peptic ulcer aligns .indomethacin with other established antirheumatic agents. Most of the ulcers in our series were noted in the latter PAGENO="0190" 3282 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY months of the study; hence, we were not as cautious with the use of prophylactic antacids or other measures as we otherwise might have been. Early in the series we carefully checked stools for blood with no positive results. It should be emphasized that this study was conducted completely with the use of a now obsolete compressed tablet which was subsequently shown to have a variable dissolution rate and erratic absorption.2510 When a new formulation of indo- methacin was used, and a smaller daily dose employed, the incidence of toxic and adverse effects was said to have been reduced.° The discovery of a new type of antirheumatic agent is notable. However, indo- methacin is by no means the Ideal agent because of the large number of patients who do not respond favorably and because of large number of adverse effects which it induces. It is hoped that related substances may prove to be effective antirheumatic agents and free of serious adverse effects. SUMMARY Indomethacin, a new nonsteroidal compound, was tested in 97 patients. Results were excellent in 6, good in 23, and fair in 12. The drug was discontinued in 50 patients, and 6 others were lost to followup. The most common reason for discon- tinuation of the drug was gastrointestinal side effects, which includes 6 cases of peptic ulcer. Although the ratio of adverse to beneficial effects is high, the sig- nificant and symptomatic relief which many rheumatoid and other rheumatic patients experience suggests the possibility that a related drug may be found with a more acceptable therapeutic ratio than that of indomethacin. This study was supported by a grant from Merck Sharp & Dohme, Inc. References 1. Boland, E. W.: Non-specific anti-inflammatory agents, California Med. 100: 145-155, 19434. 2. Cantwell, N. H. R. : Personal communication. 3. Hart, F. D., and Boardman, P. L.: Indomethacin: A new non-steroid anti- inflammatory agent, Brit. M. J. 2: 985-970, 163. 4. Norcross, B. M.: Treatment of connective tissue diseases with a new non- steroid compound (Indomethacin), Arth. - Rheumat. 6: 290 (abst.), 1968. 5. Percy, J. S., Stephenson, P., and Thompson, M.: Indomethacin in the treat- ment of rheumatic diseases, Ann. Rheumat. Dis. 23: 226-231,1964. 6. Rothermich, N. 0.: Indomethacin: A new pharmacologic approach to the management of rheumatoid disease, Arth. & Rheumat. 6: 295 (abst.), 19433. 7. Smyth, C. J., Valayes, B. B., and Amorosco, C.: Indomethacin in acute gout using a new method of evaluating joint inflammation, Arth. & Rheumat. 6:299 (abst.), 1963. 8. Steinbrocker, 0., Trager, C. H., and Batterman, R. C.: Therapeutic criteria in rheumatoid arthritis, J.A.M.A. 140: 659-662, 1949. 9. Wanka, J., and Dixon, A. St. J.: Treatment of osteoarthritis of the hip with indomethacin: A controlled clinical trial, Ann. Rheumat. Dis. 23: 288-94, 1964. 10. Wanka, J., Jones, L. I., Wood, P. H. N., and Dixon, A. St. J.: Indoinethacin in rheumatic diseases: A controlled clinical trial, Ann. Rheumat. Dis. 23: 218- 225, 1964. 11. Winter, C. A., Risley, B. A., and Nuss, G. W.: Anti-inflammatory and anti- pyretic activities of indomethacin,, 1-(p-chlorobenzoyl)-5-methoxy-2-methyl- indole acetic acid, J. Pharmacol. & Exper. Therap. 141: 369-376, 1963. THE COLUMBUS MxDICAL CENTER. Columbus, Ohio, June 12, 1963. NELSON H. REAVEY OANTWELL, M.D., Ph. D., Merck $harp i Dohme Research Laboratories, Division of Merck ~ Co., Inc., West Point, Penn. DEAR DR. OANTWELL: Our ~interest in the therapeutic effects of Indosnethacin has been centered largely on Rheumatoid Arthritis, both peripheral and spinal. In reviewing and analyzing our data, I have come to the conclusion that 61 pa- tients have had sufficient trial to be included in our study. Of these, 49 were of the peripheral and 12 of the spinal variety. A goo.d (decisively beneficial) effect was PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 32S~ obtained in 45 (in all of the spinal) and only a fair (indecisive) effect was obtained in 10. No benefit was noted in 6. The duration of treatment was sufficiently long to permit good clinical observation, being between 12 and 18 months in at least 22 of the patients. As you know, placebos were used, both in single and double blind and 128 relapses were produced by substituting placebo. As regards dosage, the spondylitics uniformly required less than the peripherals and the daily dose for them varied from as low as 50 mg. to 200 ing. with an average of about 125. In the peripheral arthritis, the average therapeutic dosage level was about 200 to 250 mg. daily. However, in many cases, the dose was taken up to 300 and higher and at least 6 patients received 400 mg. daily for at least one week. Few improvements were noted in the peripheral arthritis group at dosage levels of 150 mg. daily. Most of the peripheral arthritics are now being carried on a daily dose of 300 mg. daily but a significant number are benefitted to a striking degree on 200 mg. daily. The greatest deterrent to increasing dosage to an effective level is the appearance of cerebral toxicity. This manifests itself clinically in excruciating severe head- aches, dizziness, lightheadedness, disturbances of sensorium, a feeling that the head is floating away or even separating from the body and feelings of detach- ment from reality. The higher the dose, the more severe the symptoms but there was some variation in individual susceptibility. A few individuals experienced considerable toxicity at levels of 100 mg. daily whereas, a goodly number could take 300 mg. a day without any adverse symptoms. However, the usual appearance of symptoms was at the range of about 200 to 225 mg. although cerebral toxicity occurred in over half of our patients, that is 31 out of 61. In 80% of these, the toxictty could be adequately ameliorated or abolished by reduction in dosage. We did not run a specific questionnaire regarding an antecedent history of migraine but a prom!- nent history of headache was present `in only about 8 to 10. I trust the above will provide you with the information you desire. If however you desire additional information, please let me know. Yours truly, NORMAN 0. ROTHERMICH, M.D. COLUMBUS MEDICAL CENTER RESEARCH FOUNDATION, INC., Columbus, Ohio, July 3, 1963. NELSON H. REAVEY OANTWELL, M.D., Ph. D., Merck sharp ~ Dohme Research Laboratories, Division of Merck ~ Co., Inc., West Point, Pa. DEAR NELSON: Enclosed is the Indomethacin questionnaire whicl~ you asked me to fill out from our work. As you know, we have interested ourselves almost exclusively in the benficial effect of Indomethacin on rheumatoid arthritis and have used it only Sporadically and in a random way on other rheumatic dis- orders. We have chosen to exclude the latter groups since they have not been formally organized and analyzed. From the nature of the questionnaire, you must understand that all of our patients have been treated for a greater or less period of time with 150 mg. or less and hence are included on the questionnaire but in a s4gniflcant number of these, `the dose was raised to a much higher level to achieve a satisfactory result. Consequently, the number listed under unimproved should not be looked upon as the total number of Indomethacin failures. Furthermore, the number experi- encing headache is given as that number which occurred at the dosage range of 150 mg. or less. As you know, we had a considerably higher incidence of cerebral toxicity at higher dosage levels. These data are well explained in my previous report to you several weeks ago. The one case of bleeding was probably from a diverticulum and not ulcer and furthermore is not included among those who experienced gastrointestinal symptoms since his only symptom was that of weakness and faintness'. We are in the process of trying to develop satisfactory control techniques for determinations of Indomethacin blood levels. I don't see how you can possibly refute the finding of a zero blood level in every instance where blood was drawn 24 hours after the preceding dose. We hope to resolve this question. PAGENO="0192" 3284 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY As you know, we are also keenly interested in whatever effects, if any, Indo- methacin may have on tryptophane and serotonin metabolism and how this may relate to the disease of rheumatoid arthritis. Best wishes always. Sincerely yours, NORMAN 0. ROTXIERMICH, M.D. INDOMETHACIN QUESTIONNAIRE, JUNE 19, 1963 Nanie of Investigator: Norman 0. Rothermich, M.D. 1. How many patients have been treated with 150 mg or less? 60 a. Number who experienced relief of pain? 40 b. Number who experienced relief of swelling & inflammation? 40 c. Number who had definite over-all improvement? 40 d. Numiber unimproved? 20 2. How many of the above patients experienced headache? 15 3. Of those who had headaches a. bow many had to discontinue the drug because of it? ~_-__ 8 b. how many became tolerant of the headache and continued on the drug? 3 c. how many had relief of their headache at a lower dosage? 4 4. How many of the patients experienced gastrointestinal symptoms (ab- dominal distress, nausea, vomiting, etc.) ? 3 a. How many bad to discontinue the drug because of these symptoms?__ 0 b. How many developed a definite ulcer or bleeding? 1 5. How many of your treated patients have a. chronic rheumatoid arthritis? 48 spondylitis? 12 b. Arthritis or inflammatory disorders other than chronic rheumatoid arthritis? 6. Does acute inflammatory disease respond better than chronic disease?~__ No NORMAN 0. ROTHERMICH, M.D. COLUMBUS MEDICAL CENTER RESEARCH FOUNDATION, INC., Columbus, Ohio, October .9, 1962. NELSON H. REAVEY CANTWELL, M.D., Ph. D., Merck ~Sharp c~ Dohme Research Laboratories, Division of Merck c~ Co., Inc., West Point, Pa. DEAR NELSON: A special report to ~you is In order regarding the appearance of an adverse effect of the new drug, MK-615, now under investigation. This effect is an entirely symptomatic one and as yet not measurable by any objetive meth- ods. The patient complains of a distressing lightheadedness, a feeling of "the hQad being in outer space", a feeling of the head being foggy and a feeling of difficulty in concentration or in cerebration. There may or may not be an associated ~violent headache and in a few cases, the headache was so violent that it was predomi- nant or alone. In a few instances, these symptoms have been so severe as to be totally incapacitating and even proRtrating. The physical findings at this time are not remarkable. The ocular fundi are negative and there is no papilledema. The neurologic examination is' likwise negative in all other respects. In a few instances, the electroencephalogram has shown no decisive or characteristic changes. Other laboratory studies are not changed significantly during these episodes. The spinal fluid has not been studied. In general, this adverse effect appears to be a dosage related phenomenon and in most cases, does not appear until 250 mg. daily has been reached. HowE~ver, there is a considerable variation in individual susceptibility to this effect. Some patients have been on 300 mg. or more daily for some time without any adverse effects. Some patients have felt this effect at dosages as low as 150 mg. daily. It is definitely reproducible in the same patient at approximately the same dosage levels. There appear to be no residuals from this adverse effect. Symptoms dis~ appear usually within 24 to 48 hours after `discontinuing the drug. The anti- rheumatic effects of the drug are not reduced by this effect. As a matter o'f fact, the antirheumatic effect may be very striking at these higher dosage levels. In some severe artbritics, it has been impossible to control the arthritis witho'ut pro~ ducing these adverse effects. As of this date, 16 patients have had toxic effects out of a total of 49 patients receiving the drug. No other ill-effects of the drug have been noted. Yours truly, NORMAN 0. ROTHERMICH, M.D. PAGENO="0193" COMPETITIVE PROBLEkIS IN THE DRUG INDUSTRY 3285 Pun COLUMBUS MEDICAL CENTmn, Oal'umbus, Ohio, October 12, 1963. NELSON H. REAVEY OANTWELL, M.D., Ph. D., Merck Sharp c~ Dohmc Resea'rch Laboratories, Division of Merck ~ Co., Inc., West Point, Pa. DEAR DR. CANTWELL: The results of our experiences with the capsular form of `Indocin' are contained in detail on the enclosed summary tables. There can be no doubt that `Indocin' does have clinically observable antirheu- matic effect. This effect is uniformly consistent at comparatively low dosagd levels in the rheumatoid spondylitie. It is in this particular disease that phenyl- butazone and derivatives have been particularly effective but it would appear that `Indocin' is equally effective at a slightly lower `losage level and, of course, without any of the life-threatening adverse effects which so often complicate therapy with the former eompoun4s. In other words, it is my belief that In rheumatoid spondylitis, `Indocin' can do as much for the patient as phenyi~ butazone but do it with comparative safety. In the peripheral rheumatoid arthritis, there is considerable variation from one patient to the next and sometimes in the same patient from one time to another in the ability of `Indocin' to exert a consistently and significantly bene- ficial effect. There is no doubt that higher dosage levels are required than in the case of the rheumatoid spondylitic. As higher dosage levels are approached, it is to be expected that the incidence of cerebral toxicity goes up proportionately and this, in my opinion, represents a not insignificant disadvantage to the drug for it reduces the number of arthritics who can be benefited by the drug and also reduces the degree of `benefit in a given arthritic because it necessarily puts a ceil- ing on maximum maintenance dosage. This is particularly frustrating because I am personally convinced that this cerebral toxicity does not threaten the life of the patient nor does it `leave any permanent residuals. In fact, there is usually prompt subsidence of the cerebral toxic symptoms within comparatively few hours (usually 12 to 24) after the drug has been discontinued. Most of the time, the drug can be resumed at a lower dosage level witho'ut a recurrence of the cere- bral toxicity. It is quite apparent from the chart that we have been able to carry some patients on a comparatively high maintenance dose and, of course, this im- plies that these patients did not have enough cerebral toxicity fo'r them to wish to be taken off the drug or have it reduced in dosage. On the other hand, some patients have developed disahling cerebral toxicity usually in the form of severe vertigo, lightheadedness or violent headaches Ga comparatively low doses. One patient tried on three sepa'rate occasions to t'ake a 25 mg. capsule but just on the one dose develo'ped such a violent headache that he could not continue it. On th'e other hand, another patient had been on 50 mg. and h.s. for `at least a year when his vertigo and lightheadedness had increased to a disabling degree and required him to discontinue the drug tem- porarily. One other patient developed a violent toxic reaction after only one week of therapy and had to `be confined to be'd, more or less continuously, for four or five days. One patient while on a ladder working became dizzy and fell off suffering a fractured `arm. Another busy executive `became so dizzy and lightheaded that he feared crossing the street against all traffic. It would seem worthwhile to list the various manifestations which I have chosen to lump together under the designation of cerebral toxicity: 1. Headache. 2. Vertigo (usually not true room-spinning). 3. Lightheadedness. 4. Feelings of fogginess in the head. 5. Sometimes difficulty in concentration. 6. Occasional feelings of unreality. 7. Marked stimulation with resultant insomnia. Very similar in des. `signation to caffeine effect. 8. In higher doses, some ataxia and even personality change, more toward a paranoid state, were observed. It is ~y belief tha't the capsule Is superior to the tablet only in that it permits for a more consistently reliable rapidity of absorption whereas the tablet form varied greatly in its rate and degree of absorption. However, it cannot be said that `the capsule has reduced the incidence of cerebral toxicity. At the same time, "Indocin" is notably free of other toxic effects. A few patients complain of some stomach pain but these were rarely consistent and reproducible. There were no deleterious effects on the formed elements in the peripheral blood including the red and white corpuscles and platelets. There were no alterations of 81-280-68-pt. 8-13 PAGENO="0194" 3286 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY any of the chemical elements of tfle blood. Notably, we could not find any con- sistent elevation of the BUN. All liver function studies remained normal during therapy and there were no evidences of any ill-effects on the kidneys or lower urinary drainage structures. No cardiovascular effects could be detected. The drug did not have any reproducible effect on the Latex Fixation Test nor wa~ there any significant effect on the Sedimentation Rate regardless of the clinical response. No effects on the skin were observed and there were no changes in the lower bowel or the bowel habits. The drug had no apparent effects on appetite or on muscle strength. In summary, "Indochin" would appear to be an excellent therapeutic vehicle for treating rheumatoid spondylitis. In the very few cases where it was tried, it seemed to have a beneficial effect on acute attacks of gout. It did not seem to influence materially cases of generalized chronic fibrositis or acute localized periarticular fibrositis nor did it have any beneficial effect on back problems, especially posterior cervical fibrositis. In one case of chronic gouty arthritis, it has proved to `be dramatically but consistently beneficial to a very high degree over a period of nearly two years. "Indochin" has an "excellent" beneficial effect in some cases of peripheral rheumatoid arthritis but only a "good" effect in a larger percentage and there is complete failure or ineffectiveness in a distressingly high percentage of such cases. In most of these latter cases, it was our feeling that the failure was due largely to the inability to break through the therapeutic ceiling maintained by the cerebral toxicity. I hope the enclosed summarized data will be helpful to you.j' Cordially yours, NORMAN 0. ROTHERMICH, M.D. [From Journal of the American Medical Association, vol. 195, No. 13, Mar. 28, 1966, ~p. 124-128] AN EXPENDED STUDY OF INDOMETHACIN* II. CLINICAL THERAPY (By Norman 0. Rothermich, M.D.) A new antirheumatic drug, indomethacin, was evaluated over a long period of observation (42 months maximum). Clinically satisfactory results listed as both good and excellent were obtained in a high percentage of patients with ankylosing spondylitis, gouty polyarthritis, psoriatic arthritis, and other miscellaneous benign (nonfatal) rheumatic diseases. In rheumatoid arthritis, indomethacin pro- duced good and excellent results in a lesser, though appreciable, percentage of eases and may be regarded as another valuable drug to be added to the overall program of therapy in this notably difficult disease. As indicated in the previous report, the experimental nature of this study required that in some cases the dosages be increased to and beyond tolerance. Therefore, therapy in private prac- tice may not yield as high a percentage of favorable results as indicated in this report. The present treatment of rheumatoid arthritis still leaves much to be desired. Virtually all therapeutic agents which are believed to have beneficial effect in this disease have limitations on their utility and efficacy because of harmful side effects, usually dose-related. The development of an antirheumatic agent with little or no clinical hazards would be very desirable. In a previous publication,1 it was reported that indomethacin was not hazardous, except for the possibility of gastric-ulcer formation. Previous reports have indicated that indomethacin produces significant bene- fit in certain rheumatic diseases.2345 These reports were based largely on corn- tRetained in committee files. From the Department of Medicine, Ohio State University Hospital, and the Columbus Medical Center Research Foundation, Columbus, Ohio. Reprint requests to 1211 Dublin Rd. Columbus, Ohio 43212. 1 Rothermich, NO.: A Report of 42 Months Experience With Indomethacin: I. Clinical Pharmacology, JAMA, to be published. 2 Noreross, B. M.: Treatment of Connective Tissue Disease With a New Nonsteroidal Compound (Indomethacin), Arthritis Rheurn, 6 :290 (June)1 1963. ~ Smyth, C. J.; Valayos, E. E.; and Amoroso, C.: Inclomethacin in Acute Gout Using a New Method of Evaluating Joint Infiamation, Arthritis Rheunm 6 :299 (June) 1963. Rothermich, N. 0.: Indomethacin: A New Pharmacologic Approach to the Manage- ment of Rheumatic Disease, Arthrstis RheRm 6 :295 (June) 1963. ~ Hart, F. D., and Boarciman, P. L.: Indomethacin: A New Nonsteroid Anti-inflammatory Aigent,Bret Med J 2:965-970 (Oct 19) 1963. PAGENO="0195" COMPETITIVE PROBLE~dS IN THE DRUG INDUSTRY 3287 paratively short-term observations. The present report will describe clinical experiences with indomethacin which began in November 1961. Our attention was given mainly to its effects on patients with rheumatoid arthritis, but other rheumatic diseases were also treated. Because this was the first trial of indometh- acm in the human, small amounts were given initially and effective dosages were not reached until late January 1962. For this reason, the present report deals with experiences during a 42-month period from Feb. 1, 1962, to Aug. 1, 1965. Materials and Methods The treatment sample comprised 216 patients and 234 patient-trials. This does not include 2~ patients on whom therapy was begun but for one reason or another became "dropouts." These will be discussed later. It is noteworthy that 26 patients have been on continuous therapy for 30 months or more, the longest being 42 months. In the treatment sample, there were 147 females and 69 males, and all were adults with the exception of three children ages 9, 11, and 13 years. There were 117 patients with probable, definite, and classical rheumatoid arthritis as defined by the Committee on Diagnostic Criteria of the American Rheumatism Association (ARA) ; all cases of "possible" rheumatoid arthritis were listed under nonspecific polyarthritis. There were 22 cases of ankylosing spondylitis and 14 cases of chronic gouty polyartbritis (ie, the chronic polyarthritis having characteristics similar to rheumatoid arthritis, but associated with a negative latex titer and a high serum uric acid level and occurring in an indivdual who has been diagnosed as having gout). In addition, there were 15 cases of osteo- arthritis, 29 eases of fibrositis, and 19 cases of other miscellaneous rheumatic diseases as follow: 10 "possible" rheumatoid, 3 juvenile rheumatoid, 2 psoriatic arthritis, and 1 each of Reiter's disease, pseudogout, villonodular synovitis, and Tietze syndrome. In the initial trials, patients were selected with moderately severe rheumatoid arthritis which was fairly well controlled with the standard basic program of therapy consisting of increased rest, physical therapy, salicylates, and sedation, as well as small doses of corticosteroids and sometimes gold or phenylbutazone therapy or both. The first step was to discontinue administration of all thera- peutic agents except salicylates and corticosteroids, or as many as possible con- sistent with the patient's continued good management and control of the disease process. Indomethacin therapy was initiated in small doses and gradually in- creased according to the patient's ability to tolerate higher levels. At the same time, a gradual reduction of corticosteroid therapy was begun. If and when corticosteroid therapy could be discontinued entirely, gradual reduction of salic- ylate therapy was attempted. In some cases all therapeutic agents were with- drawn and control of the disease was continued at the same level on indomethacin alone. (Withdrawal of salicylates was for experimental purposes and is not to be construed as recommended clinical procedure.) The evaluation of clinical results was based on those factors described in a previous report.6 Greatest emphasis was placed on the patient's own gradation of his disease from 0 (no symptoms or disability) to 4+ (severe pain, morning stiffness, and total disability) based on his past experience with his disease. In addition, a separate evaluation of disease activity and disability was made by the physician. It is believed that accuracy and objectivity of such gradations can be greatly enhanced and made more secure by liberal use of placebo substitution and by quantitation of the steroid and aspirin requirements of the individual. When used by a clinician interested in the management of rheumatoid arthritis, these criteria can often be as accurate and precise as the many criteria which have more formalized physical and arithmetical indices. The well-recognized decisively beneficial effects of corticosteroids (and to a much lesser degree of aspirin) provide an excellent base for reference in therapy of rheumatic diseases. Any new agent therefore must be able to reduce materially or eliminate the need for corticosteroids in an appreciable number of cases. After such elimination, therapy may be further evaluated by the ability to reduce the dose of or discontinue salicylate therapy. These have been important criteria in our evaluation of a favorable response to indomethacin. In all cases listed as having had an excellent response to indomethacin, either of these two or the clear-cut, unequivocal placebo relapses have been a required criterion. 6 Rothermich, N. 0.: Clinical Experiences With Indomethacin In Rheumatic Diseases, Proceedings of the Eighth Congress 01 the Japan Rheumatism Association, Okayama, Japan, 1964, pp. 159-163. PAGENO="0196" 3288 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In "fresh" cases of rheumatoid arthritis where corticosteroid therpay had not been previously used, a patient was rated as having good or excellent response to indomethacin if evidences of active synovitis, the jelling phenomenon, and painful disability, as indicated by the patient's symptoms and the physician's observa- tions, receded under active drug therapy and promptly exacerbated when placebo was substituted. In some patients, the placebo trials were made several or more times in order to establish with certainty the relapsing character of the disease under placebo influence. In cases other than rheumatoid arthritis, such as spon- dylitis, psoriatic arthritis, and chronic gouty polyarthritis, therapeutic evaluation was based on control of disease activity on indomethacin alone, with relapses precipitated by placebo substitution. Occasionally, patients would suspect placebo substitution by a change in side effects. For this reason from the statistician's viewpoint, the placebo trials in this report (and probably in most clinical drug reports) cannot be considered as true "blind" studies. Usually there was enough delay in this awareness to permit the therapeutic assessment. Furthermore, the appearance of side effects is often capricious and inconsistent; thus further limit- ing the patient's ability to detect placebo. In some of these cases, adequate control had previously been achieved by the use of phenylbutazone, and effectiveness of inclomethacin could be measured by its ability to replace such therapy. Placebo substitutions were made in 86 of the patients. In 70 of these, there was decisive clinical relapse on placebo; this was verified on repeated trials in 55 patients. In most instances, placebo was introduced whenever a patient seemed to be established and well-controlled on indomethacin therapy. In addition, at times when an adverse reaction appeared, a placebo was substituted to determine if the adverse reaction was actually due to indomethacin or some other cause. Occasionally, in a patient whose therapeutic response to indomethacin could not be determined with any reasonable accuracy or whose disease continued to pro- gress even though be was on other antirheumatic medications as well, a placebo was administered to observe if actual worsening of disease occurred while admin- istration of other medications was continued in exactly the same dosage. In 21 instances, neither the patient nor the physician was informed of the placebo sub- stitution, and in one such case a striking effect was observed and charted (Fig 1). >- F- Li > Li C') Li C') .~z Li Li Li 0 Li z x I- 0 0 z FIGURE 1 1. Placebo trial on a 40-year-old woman with severe psori- atic arthritis. Note profound relapse on receiving placebo and partial loss of disease control on day 7 with reduction in dosage. O-OLEFT HAND ----OTHER JOINTS © CODEIN REQUIRED PLACED 0 INDOMETHACIN UIll~ nriJ PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3289 Ressi~Zts The therapeutic results in rheumatoid arthritis are shown in Table 1. The good and excellent results combined totaled 88 out of 117 (75%). The patients are categorized according to the diagnostic criteria of the ARA into classical definite and probable. It is noteworthy that in the classical group, which is notoriously resistant to treatment the percentage of favorable results was surprisingly high (65%) As might be expected this was appreciably lower than the 82% in the combined groups categorized as definite and probable The dosage range was approximately the same In the three different groups; in all patients where no side effects were encountered, the vast majority received a maintenance dose between 100 and 200 mg. In the 88 patien'ts who obtained a good or excellent result, 69 had been receiving a maintenance dosage of corticosteroids at `the time indomethacsin therapy was begun, and 44 of these were able `to reduce the cortico- steroid dosage by 25% or more categorized as follows: 3 patients, a `dose reduc- tion of 25%; 8 patients, 331/~%; 10 patients, 50%; 4 patients, 75%; and 19 patients, 100% (discontinued). TABLE 1-RESULTS IN 117 PATIENTS WITH RHEUMATOID ARTHRITIS ` Diagnosis ` Number of patients - Results -- Excellent Good Poor1 Classical 55 18 19 18 Definite 35 14 14 , 7 Probable 27 16 7 4 Total 117 48 40 29~ Equivocal or no benefit. In ten patients with rheumatoid arthritis administration of the drug had beea discontinued for one reason or another for an appreciable period of time A second and clinically distinct trial of indomethacin therapy was made in these patients The results were the same in both trials in six of the patients but in two the first trial obtained a good result and the second a poor result whereas in two others the exact opposite held true. fliustrative case reports CASE 1-A 37 year old white woman has had classical rheumatoid arthritis for eight years in an extremely active progressively disabling form Several years ago, on large doses of aspirin, she developed a huge gastric ulcer. On a trial of gold therapy, there was `mild improvement but toxicity developed. On corticosteroid therapy, `there was definite improvement, but this therapy was withdrawn for ohecure reasons and she bad a severe relapse Chioroquine phos phate produced severe toxicity and phenylbutazone aggravated the ulcer When first brought into this study in December 1962 the patient was a stage IV class IV with total disability and the arthritis was in a very active destructive phase Treated with small doses of corticosteroid, enteric-coated aspirin, and cautious doses of phenylbutazone, the arthritis was somewhat controlled. Indomethacin therapy was begun and with gradually increasing doses, the arthritis became fairly stable and of questionable activity despite reduction `and eventual elimi- nation of all other medications, including salicylates (Fig. 2). After 14 months of indomethacin therapy, the ulcer was reactivated but it healed on treatment while the drug therapy was continued. The patient is now up and about, takes care of her entire household, and occasionally even goes to dances. The total duration of indom&thacin therapy was 25 months and the patient had received no other medication for the last ten months. PAGENO="0198" 2. Disease activity in patient with classical rheumatoid arthritis. Note elimination of all therapy except indomethacin with continued reasonably good control of disease, and the gastric ulcer appearing and healing on continued high-dosage indomethacin therapy. 0 LTJ L~J 0 0) z 0 0) `-`4 PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3291 In the benign rheumatic diseases other than rheumatoid arthritis, the results are even more encouraging as indicated in Table 2, and the average effective main- tenance dose was lower, being only 100 mg. or less in 72% of the cases. Out of 22 cases of spondylitis, there were only three treatment failures, and three such failures were also seen in 14 cases ot' chronic gouty polyarthritis. In the cases of osteoarthritis, the results were not quite so spectacular, with a good or excel- lent result in ten out of 15 cases. In the cases of fibrositis, the results were even less favorable, but still impressive with a good or excellent result in 55%. There was a high percentage of benefit in the miscellaneous group of disorders which comprised for the most part those cases with chronic polyarthritis of an indeter- niinate nature which would otherwise have qualified as "possible rhienmatoid arthritis," according to the ARA classification. Also in this miscellaneous group and deserving of special mention are two cases of severe psoriatic arthritis (Ic, cases having the clinical characteristics of rheumatoid arthritis and active psoriasis but with a negative latex titer) in which there was a dramatically beneficial effect on the arthritis, but no effect whatever on the psoriasis. TABLE 2.-RESULTS IN 99 PATIENTS WITH MISCELLANEOUS RHEUMATIC CONDITIONS Diagnosis Number of patients -~-- Excellent Results --- Poor 1 Good Rheumatoid spondylitis Gouty arthritis Fibrositis 22 14 29 15 10 12 4 1 4 3 3 13 Osteoarthritis 15 4 6 5 Miscellaneous 19 10 4 5 Total 99 51 19 29 I Equivocal or no benefit. In eight patients, a repeat clinically distinctive trial of therapy was made and the result was the same in five eases, ~hule in three, the results changed from poor to good. The following case is an illustration of indomethacin effectiveness in. a patient with nonrheumatoid arthritis. CASE 2.-A 56-year-old white man developed a very severe, dIsabling poly- arthritis five years previously. He was in continuous pain, unable to work and having extreme early-morning stiffness. He had been known to have gout, and serum uric acid determinations were quite high (10-12 mg/100 cc). As a result of treatment with salicylates, corticosteroids, colchieine, and phenylbutazone, there was considerable improvement in his arthritis iut he was still left with occasional joint pain and tenderness and some early-morning stiffness. Indo- methacin therapy was begun in January 1962 and gradually administration of all other antirheumatic drugs was discontinued (Fig. 3). In later months, relapse occurred apparently associated with failure of the uricosuric drug. A change in the uricosuric drug again brought the serum uric acid level to normal and re- mission was again achieved with administration of indomethacin alone. The patient is well with no indications of rheumatic disease, although relapses occur whenever be is given placebo. The total duration of indomethacin therapy was 42 months, and the patient has received no other medication except probene- cid and then sulfinpyrazone (Anturane) for the past 38 months. PAGENO="0200" FIGURE 3 0 0 t~4 ci ci rJ2 w w U) Lu C') 0 Lu Lu 0 Lu 0 PT. (3~ 50 GOLJTY LATEX NEG.. SUA~sl2.0mgm. v E$RUI1mm. LI INDO MET HACIN mg ASPI RIN PHENYL BUTAZONE mg PROBE NEC ID gm COLCHICINEj 3. Disease activity in patient with chronic gouty polyarthritis. Before indomethacin ther- apy, phenylbutazone, colchicine, and aspirin were given with only fair disease control. Note the prompt r&apses with each placebo trial. SUA= serum uric acid. PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3293 Comment Indomethacin is effective in the control of certain cases of rheumatic diseases The high percentage of good and excellent results in nonrbeumatold benign rheumatic diseases would suggest that it is the treatment of choice The imtial dose may be 25 mg once or twice daily. In this group of diseases, it is seldom necessary for the physician to exceed a total daily dose of 100 mg or 125 mg at the most. However, even with low dosage the physician must be on guard for the occasional patient who might develop gastric upset or even ulceration as well as the unusual patient who is highly susceptible to cerebral side effects En rheumatoid arthritis indomethacin is also effective producing a good and excellent result in an appreciable number of cases and because of its limited hazards, it should be included among the therapeutic weapons to be used in the treatment of this difficult disease However it should not be inferred that in domenthacin replaces or eliminates the need for a sound basic therapeutic pro- gram for the patient with rheumatoid arthritis which should include increased rest, salicylates, physical therapy, and other `adjunctive or supportive measures. The patient with rheumatoid arthritis who is not responsive to the basic pro- gram of therapy may have this supplemented by the cautious prescribing of indomethacin beginning with a dose of 25 mg two or three times daily, best given after meals and at bedtime with a glass of milk. The daily dose may be increased in increments of 25 mg at perhaps weekly intervals. If disease activity persists, the physician would be justified in increasing the total daily dose to 150 to 250 mg daily according to tolerance As the higher dosage of indomethacin is approached the physician must increase his caution regarding the possible development of gastric ulcer and in, some patients must be prepared to cope with the distressing symptoms of headache, lightheadedness, and disturbances of sensorium. If the i heumatoid arthritic process continues to remain actively painful and disabling the physician may cautiously add to the overall program such therapy as gold and low-dosage corticosteroid therapy as recommended in previous reports.78 "Dropouts" In accordance with the suggestion of Mainland and Sutcliffe,° an explanatory note is appended regarding patients who were dropped from the study. Twenty-three patients who began therapy, for one reason or another, became dropouts. They are grouped in four main categories: (1) Five patients were simply lost to followup for inexplicable reasons. Some were doing well `and some were not doing so well. (2) There were four patients in whom the original diagnosis was determined to be incorrect. (3) Six patients were finally deter- mined to be impossible to evaluate, despite the liberal use of placebo. Some of these at one time were considered to yield excellent results and at another time, seemed to `be therapeutic failures. However, while `honest and objective appraisal was attempted, retrospectively it was decided that there was too much uncer- tainty regarding their evaluation to permit conclusions in one `direction or another. (4) Eight patients were receiving the drug for so brief a time that no conclusions could possibly be' warranted. Most of these were too disturbed at the prospect of experimentation,, after they had to sign "release form." Two others unexpectedly had to move out of town within a week after therapy was started. Generic and Trade Names of Drugs Indomethacln-Indocin. Phenylbutazone-Butazolidin. Chloroquine phosphate- Aralen Phosphate. Prednisone-Deltasone, DeZtra, Meticorten, Pceracort. Probenecld-Benemid. Sulfinpyrazone-Anturane. RothermiOh, N. 0.: Local Steroid Injection Therapy in Rheumatic Diseases, Postgrad Med `30 :283-292! (Oct) 1961. ~ Rothermic~h, N~ 0.: Corticosteroid Therapy in Rheumatoid Arthritis, Postgrad Med 36 :117-128 (Aug)' 1964. Mainiand, D., and Sutcliffe, M. I.: The General Problem of Droj~outs, AR4. Coop Olin Committee Bull 18 :6 (Dec 7) 1964 PAGENO="0202" 3294 COMPETITIVE PROBLEMS EN THE DRUG INDUSTRY Senator NELSON. We will recess until tomorrow morning at 10 a.m. (Upon the direction of the chairman, the letter by Mr. T. 0. Cron, Assistant Commissioner for Education and Information, FDA, sub- sequently dated, follows:) 1 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND Dnuo ADMINISTRATION, Washington, D.C., May 3, 1968. Hon. GAYLORD NELSON, Chairman, Subcommittee on Monopoly, Select Committee on S~mall Business, U.S. Senate, Washington, D.C. DEAR SENATOR NELSON: You will recall that Dr. Robert McCleery of our Bureau of Medicine testified before your Subcommittee yesterday and noted that an article in Pageant magazine misrepresented the safety and effectiveness of Indocin (indoinethacin). While Dr. McCleery was testifying, Merck & Co., manu- facturers of the drug, distributed a statement of rebuttal. Three major points were made in the company's release: (1) that the FDA had never discussed this matter with the company; (2) that the company neither encouraged publication of the article nor supplied testimonial letters on un- approved claims; and (3) that `the company did not see the text before it ap- peared in print. For the record, the Pageant article was indeed discussed with the Merck man- agement, including its President, on November 11, 1966. I was present at that meeting. Prior to that, our Agency received letters from the company's Vice- President for Public Relations and its Administrative Vice-President about the article and its creation. In addition, both Vice-Presidents had `acknowledged to us in writing that Merck had supplied "case histories" (another term for testimonials) to the authors of the magazine article. Finally, the letter from Merck's Vice-President for Public Relations enclosed an internal memorandum written to the Administrative Vice- President, dated June 17, 1966, which demonstrated that the company's public relations staff had seen the Pageant article and had not registered disapproval. This was, of course, before the July publication date of the magazine. I hope this letter is helpful to the work of the Subcommittee. Sincerely yours, THEODORE 0. CEON, Assistant Commissioner for Education and Information. (Whereupon, at 2:35 p.m., the subcommittee recessed, to' reconvene at 10 a.m., Friday, May 3, 1968.) 1 See p. 3370, Infra. PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FRIDAY, MAY 3, 1968 U.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BusiNEss, Washi'ngton, D.C. The subcommittee met, pursuant to recess, at 10 :10 a.m., in room 318, Old Senate Office Building, Senator Gaylord P. Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson, Scott, and Hatfield. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; Elaine C. Dye, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. The hearings of the Subcommittee on Monopoly will open. We will hear testimony this morning from representatives of Merck & Co., who will be introduced by the distinguished and very able Senator from New Jersey, Mr. Case. Senator, I understand you will introduce the representatives of this very fine company, which is located in your State. STATEMENT OF HON. CLIFFORD P. CASE, A U.S. SENATOR FROM THE STATE OF NEW JERSEY Senator CASE. Thank you, Mr. Chairman. It is indeed located in New Jersey, and I guess a lot of other places, too, but we claim it as a citizen. Also, as a citizen of Rahway, N.J., we claim it as a citizen of my hometown. That makes it a special pleasure and privilege to present to you this distinguished citizen of my town, represented by its chief executive and several of its leading scientists. Two of the witnesses are constituents, New Jersey residents and personal friends of mine: Mr. Henry Gadsden, president of Merck & Co. on my right, and Dr. Max Tishler, who is president of Merck, Sharp & Dohme research laboratories division. As a matter of fact, Dr. Tishler and I were remembering that 31 years ago, when I first ran for public office in the Common Council of the great city of Rah- way- Senator NELSON. That is at the head of the Boy Scouts. I remember that. Senator CASE. Senator, you are so disarming. He opened his door to me when I was ringing doorbells in the ap- proved fashion and seeking votes. So if he is a good friend, I think we have good reason to be. 3295 PAGENO="0204" 3296 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Did you check the vote in that precinct? Senator CASE. This vote was 10 to 1. This was a good, solid, Ameri- can precinct. I am glad to say it is more or less in the State, sir. The other two witnesses, Mr Chairman, are Dr Karl Beyer, senior vice president for research, and Dr Douglas Lawrason They are from the State of the senior Senator from Pennsylvania, `tlso on the Senate Small Business Committee, who is here this morn ing. Senator ScoTr I will give you as much time as you want to say some thing nice about me, although you may defer Senator CASE If it is all right, Mr Chairman, I shall defer this until the Senator runs again. I have to go over to another committee, unfortunately. Senator NELSON He would rather have you say something mce when it counts, I am sure Senator CASE Well, I have this other committee and I have to do my duty there The committee has been examining Merck products in ltR hearings Now I understand it is Merck's turn I am glad that they asked for an opportunity to testify and that the committee found it possible to schedule them so *soon after the other witnesses had testified. I am pleased to present these witnesses, representative of a company and an industry which occupy an important and valuable role in the life and growth of our State and our Nation Thank you very much, Mr Chairman Senator NELSON Thank you very much, Senator Case The committee is very pleased to have you appear here this morning and present these distinguished citizens from your State Senator CASI' Thank you Senator NELSON How did you wish to proceed, gentlemen ~ You have a number of witnesses here Do you have any particular schedule you want to follow ~ INTRODUCTORY REMARKS OP HENRY W GADSDcEN, PRESIDENT, MERCK & C~, INC, RAIlWAY, N J, ACCOMPANIED BY LLOYD N CUTLER, SPECIAL COUNSEL, WASHINGTON, D C Mr GADSDEN Mr Chairman, I would like to make a few opening i emarks and introduce Dr Tishler, who will proceed to introduce Dr Beyer, and then Dr Lawrason, who did the clinical investigation Then I shall return, as the final witness, to present a statement with reference to the company's marketing, advertising, and promotional activities, which, in our opinion, have fairly presented this drug and have positioned it appropriately in the minds of the physicians Shall I proceed? Senator NELSON Your biographical sketch will be printed at this point. Please proceed. (The biographical sketch of Mr Gadsden follows ) BIOGRAPHICAL SKETCH OF HENRY W GADSDEN PRESIDENT MERCK & Co INC Henry W Gadsden became president of Merck & Co Inc on January 15 1965 after directing all the company's production marketing and research activities for nearly a decade as executive vice president PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3297 Before becoming executive vice president and a director of Merck in 1955, he served as vice president and then administrative vice president Mr Gadsden had been a vice president and director of Sharp & Dohme Incorporated when the latter company merged with Merck in 1953 Mr Gadsden is a director of the Campbell Soup Company New Jeisey Bell Telephone Company and the New Jersey State Chamber of Commerce He is a member of the Board of Directors' of the Pharmaceutical Manufacturers Association and secretary treasurer and a director of the PMA Foundation He is a trustee of the Committee for Economic Development; New Jersey State Safety Council Inc and Seeing Eye Inc Born in New York City April 16, 1911, Mr. Gadsden was graduated from Yale University in 1933, receiving a B.S. degree in economics. He was first associated with Bankers Trust Company in New York City (1933-34) and then with the managoment consulting firm of R. A. Lasley, Inc. (1934-37), also in New York. He joined Sharp & Dohme in Philadelphia in 1937 At Sharp & Dohme, after two years as an analyst in sales research, Mr. Gadsden became assistant to the executive vice president in 1939 director of production and engineering in 1946 vice president in 1949 and a director in 1952 During World War II be served as executive officer of the Philadelphia Ordnance District of the U.S. Army, rising to lieutenant colonel. Returning to Sharp & Dohme in 1946, he served in a civilian advisory capacity as district chief of the Philadelphia Ordnance District from 1948 to 1955. He is a former vice president and director of the American Ordnance Association. Mr. Gadsden formerly served as a director of the First Pennsylvania Banking and Trust Company; Provident Mutual Life Insurance Company; the Institute for Cancer Research, Philadelphia; and the Philadelphia branch of the American Cancer Society He was formerly a trustee of Lankenau Hospital Philadelphia Overlook Hospital Summit N J Episcopal Academy of Philadelphia and Short Hills Country Day School. A resident of Short Hills New Jersey Mr Gadsden is married to the former Patricia Parker of Philadelphia. They have four sons: Christopher H., born in 1946 Thomas P born in 1949 William F born in 1955 and Robert W born in 1956. The family formerly resided in Gladwyne, Pennsylvania, from 1949 to 1955. Mr. GADSDEN. Mr. Chairman, I wish first to express my appreciation and that of my associates for this opportunity to appear before the committee during the 5 days set aside for the examination of various aspects of indomethacin. As you know, this drug was discovered by Merck scientists and is marketed by the company, for the management of certain arthritic disorders, under the trademark of "Indocid" abroad and "Indocin" in the United States. We felt it urgently important that we present our testimony now, Mr Chairman, because although the committee's intent may have been to focus on FDA actions relating to Indocin, the announcement of the hearings suggested a primary concern with the product and the be- havior of our company. The FDA has regulatory authority over all prescription drugs anc1 a broad responsibility to protect the public interest as such drugs are developed, tested, and used. But, in practical terms, the agency cannot be held ultimately responsible for the safety and effectiveness of any specific drug product or for the integrity with which it is brought to the attention of physicians. In the final analysis, it is we who are responsible for both. It' is our purpose to present to the committee and place on the record our assessment of Indocin. In the process, we will also present a record of our performance. With me today from the company are Dr. Max Tishler, president of our Merck Sharp & Dohme research laboratories; Dr. Karl H. Beyer, Jr., our senior vice president for research; and Dr. F. Douglas Lawra- PAGENO="0206" 3298 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY son, our vice president for medical affairs. You have statements of their background before you, as you have mine. Let me simply say that they are scientists whose research contributions and professional distinction are internationally recognized. Also present with us today are two distinguished independent rheumatologists, who are prepared briefly and informally to discuss their own experience with Indocin and their own perception of its place in the management of arthritic disorders. I make this distinc- tion, Mr. Chairman, because I want to emphasize the conditions under which they are here, lest these conditions be misunderstood. To make the record absolutely clear: when we heard about this inquiry into Indocin and decided that we should ask for an oppor- tunity to testify, we asked Dr. Smyth and Dr. Cala'bro if they would be willing to appear and use a few minutes of the time allocated to us. They have performed clinical investigations on Indocin under grants from Merck to defray the costs of the work. We offered to pay their expenses in coming to Washington. We are not paying them an lion- orarium for their appearance here. We would not and could not pay them for their testimony. We asked them to accompany us only be- cause we believed it would be helpful to the committee to hear the views of practicing rheumatologists who have studied Indocin in patients. We are also accompanied today by Mr. Lloyd Cutler as our Wash- ing counsel. As I said at the outset, I will submit a closing statement with refer- ence to what we think is the very responsible conduct of the company in the presentation and positioning of the product. May I now introduce the president of the Merck Sharp & Dohme research laboratories, Dr. Max Tishler, whose curriculum vitae is sub- mitted for the record. He is recognized as one of the great industrial research directors in the Western World. Rather than summarize his long list of achievements and honors here and abroad, I shall mention only two. Dr. Tishler is a life trustee of Tufts University and a mem- ber of the National Academy of Sciences. Among its approximately 800 members, I understand the Academy has admitted less than 30 from industry. Dr. Tishler. Senator NELSON. Doctor, the committee welcomes you and the other representatives of your distinguished company. We have always fol- lowed the policy on this committee, and I am sure we will continue to do so, which I have announced a nun~ber of times from the Chair, that we would permit any company from the drug industry to come before this committee upon its request. We desire to maintain a balance in the testimony, and I think at least a half dozen times from this chair, I have publicly invited both the companies and the Pharmaceutical Manufacturers Association to appear. So we welcome you here today. I think I should say to you that you may have based some of your viewpoints about the hearings upon what you have read in some of the medical publications and trade press as well as on statements by the PMA, and you might very well have come to the conclusion that this committee has not intended to receive balanced testimony. In fact, as I read the statements going out in a fair percentage of the medical publications, those that are supported by advertising and those that are not, I do not recognize that I have attended the same hearings that these reports have covered. I say the same thing about the statements PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3299 I read coming from the association of which you are a member, the Pharmaceutical Manufacturers Association. So, I wish you to know that your company is welcome to come before this committee at your request at the earliest possible date we can schedule. That has been said repeatedly for every company in the country. I have, and I am sure the committee has no abjection, made this statement because we intend to give to the industry an opportunity to respond to anything that is said at these hearings. We have made that position clear from the very beginning, and, as I understand it, your request to appear came a very short time ago and we scheduled it as you desired, forthwith. That has been our practice in the past and is our intent for a11 future hearings. Senator ScoTr. Mr. Chairman, may I congratulate the chairman on the promptness in which this company has been given an opportunity to reply to a good many statements, many of which are derogatory to it and some of which, I am sure from having looked over some of their statements, they are prepared to rebutt. I am aware that medical journals take one point of view on the matter and that the American press generally may be able to report only what it hears in this room and what the chairman or I or other members of the committee say. I do regret that there appears to be some effort to try this case in the press before it has been heard fully in the hearing room. I have not been entirely sympathetic to the position of the American Bar Association in its effort to inhibit the press in its reporting of crime news, but I think it is a crime in itself for the press to put any witnesses under a shadow before he testifies, and it is wrong to do this. I had read in a book once that you should never criticize the press, and I am now doing the worst thing that any politician should do, but I am doing it, I think, under this rather intensive provocation. My criticism, however, is not directed as much to the press-and I hope they will give the same three-column treatment to your testimony as they gave to your opposition yesterday-but my criticism is funda- mentally to the fact that the Food and Drug Administration, which often comes in to us to make recommendations, whom we listen to with a great deal of care, nevertheless seemed with altogether too much eagerness yesterday to have launched themselves into a series of attacks on this company, and the merits of this will develop as we hear all the testimony. But I do not like the fact that Mr. Goodrich's testimony was so timed yesterday as to carry more than the implication of a threat in saying, as reported in the press, that decisions whether to recommend prosecu- tion to the Justice Department now rests with him, the clear implica~ tion being that if you gentlemen and your company do not behave yourselves or if you give him too much trouble, you will pay for it. Dr. McCleery, as acting director of the FDA's Division of Medical Advertising, criticizes the advertising practices as seriously misleading. I am going to examine the entire testimony when we are through, with a particular eye on the credibility of Government witnesses and the motivation of Government witnesses and the timing of the appear- ance of Government witnesses for the purpose, apparently, of influenc- ing or affecting the testimony of subsequent witnesses. I have been a member of the bar for more than 40 years, and I think I know slanted testimony when I see it. I think I know timing when I see it, and I PAGENO="0208" 3300 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY think I know the use of the press to create an impression before all the evidence is in when I see it. I am glad to see that the press is making copious notes of this. I expect to be probably criticized in various columns as the tool of the interests, but after 26 years, I am able to bear that burden, also. I do not know any of you gentlemen, I never met you until this morning, and I am only interested in the fact that you shall have a fair oppor- tunity to appear and to be heard. If you are wrong, I will condemn you just as cogently and incisively as my statement is critical of the apparent effort of a Government agency to gain a certain degree of publicity for its activities, a certain indecency, in my opinion, in rush- ing to the assault here where your testimony has not been heard. It might have been better if they waited to comment on your testimony. I appreciate the chairman's giving me an opportunity to say this. Your drug may be a good drug, it may be a bad drug. It may cure or alleviate some of the arthritic disorders; it may not. I hope it will, `because I have one of them. But right or wrong, I am pleading simply that, as `the chairman has said, we have hearings fairly balanced-and he has been most careful here to see that you are properly brought in. But I plead for the same treatment in the press. I cannot expect it in the planted stories among the columnists, because we all do that. I cannot say non mea culpa. Every politician on `the Hill is busy planting his views with some columnist; I have done it myself. So this is not said out of piety, but it is said out of recognition of the facts of life. Recognizing these facts, I conclude simply `by pleading once more for the most careful and fairest presentation of the testimony before the committee. As the chairman has so well demonstrated, he has con- cern for that. I also plead for the same kind of presentation in the press. I do not think that either Senators or newspapermen really know whether indomethacin is a good drug or not. So let us all join together, press and public and `the Government, to find out whether the patient is receiving the kind of thoughtful care from the drug indus- try and from the medical profession, which we hope he is, which I personally believe he is, and let us keep the patient's concern in mind. Thank you very much. Senator NELSON. Thank you, Senator. I think `I should comment on what the distinguished Senator from Pennsylvania has said. One, as to the FDA rushing to the assault before the company has been heard, I would like to say that it is partly my fault. The FDA has not appeared before this `committee at any hearing except at the request of the committee. We have requested the FDA to appear on specific problems. After having listened to all the FDA witnesses, having read their testimony very carefully before I came to the hear- ings and having talked to the witnesses, I think the testimony of these officials has been very carefully prepared and judiciously presented, in balance, and that they have presented their honest opinions. I must say they have been most persuasive in my listening to their testimony as well as listening to `those who disagree with FDA. I have, been tremen- dously impressed with the quality of the witnesses and the quality of their testimony. In any event, they came at the request of the committee. We did not ask the Merck `Co. to appear ahead of FDA and for the FDA to come to rebutt them. The purpose of the hearing is to learn about problems in the industry. PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3301 As to the press, given the fact that you conduct a 2 or 3 or 4 hour hearing covering very long and complicated testimony, and the fact that the reports of the press must necessarily be condensed because there is not that much space in the paper, I think that the press has done a balanced job of reporting. We have had a series of hearings here, the nature of which is to study what appear to be problems in the industry that are of public concern As to publicity of the industry, I do not think there is any doubt in the world that ~ percent of the inches in the press are favorable to the drug industry There is only a tiny percentage that is unfavor able That part that has been unfavorable with regard to drug pricing is unfavorable because it appears on its face to be an inexplicable pric ing structure We have heard from the industry in great detail, and I for one am not persuaded that it has given an adequate explanation of why a drug like prednisone should sell in competitive bidding in New York City, and to the Defense Supply Agency, and the Veterans' Administration, and hospitals for 45 cents a hundred and in the retail market for $17 90 a hundred, while the Medical Letter, a distin guished publication, says that at least 22 versions of the drug with this vast price range are of equivalent therapeutic value This is a matter of important public concern When you have two drugs of equal value, one selling for 45 cents a hundred to one group and the other for $17 90 a hundred to pharmacists, that is news, and I would have considered the press quite biased if they had not printed it. The other aspect that has been news is that the same company selling at $17.90 to the pharmacists are themselves offering their drug in the competitive marketplace at $1 20 a hundred, and at the same time, companies that are selling it for $1790 a hundred to the pharmacists in the retail marketplace in America are selling it for one fourth that in the marketplace in Bern, Switzerland, and elsewhere These are matters of news, and I do not think the press has been biased, frankly, in reporting this rather interesting and significant variance in the price structure. Senator SCOTT. None of which I read in this morning's press2 Mr. Chairman. I was not referring to that. I am not making any prejudg- ment. I wonder if the fact that these witnesses are due to appear had anything to do with the fact that the only news in the paper this morning consists of attacks upon the witnesses before they have been heard. I would be doing less than my duty, even at the peril of a politician being critical of the press, if I did not `say that I expect as a member of this committee a `balanced reporting of what goes on here, and I think balanced reporting does not include `an assault on the witnesses before they have been heard by quoting, after 4 hours of testimony, simply those statements which reflect on one company Senator NELSON. I would like to continue on this point. As to the FDA, I would want the Senator to know that there is no fault that rests with them. If there is any fault `at all, it rest's with the chairman of this subcommittee, because I decided upon the order in which they would `appear. Senator Scorr. You did not write the story. Senator NELSON. No, but I thought that perhaps you thought that the FDA volunteered to come in, `as you put it, in the indecency to rush to the assault before the company was heard. I `am only saying 8i-280-68-pt. 8-14 PAGENO="0210" 3302 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY that I was the one who requested them to appear on that day, and it does not reflect on the FDA. I `think you have a particular problem here. You have congressional committees which conduct hearings. They conduct hearings about problems that exist in the country, and it is these problems that the press report. If there are no problems in the industry, we do not expect the press to spend all its time oil research to discover what the industry did that was good. We had exactly the same situation when I introduced the first legis- lation for minimum tire safety standards and for uniform auto safety standards, both of which subsequently became part of the law of the land. I had people in `my own State, where we have a very distinguished auto company, American Motors, `and some distinguished tire com- panies who attacked me as being antiauto and antitire industry. I am not antiauto industry or antitire industry. I think they are great industries, just as the pharmaceutical manufacturing industry is a great industry and has made a great contribution to the country. But the fact was that there was something wrong in the industry and when the hearings were conducted, `and the stories on the front page repor'ted that there were defective and inadequate tires on the market, I think the press was right in reporting these facts. Everybody knows that the auto industry has made a great contribution to this country, but that does not mean that the auto industry is perfect, `any more than the pharmaceutical manufacturing industry is perfect or the legal profession, of which I am a member, is perfect, or any other field is perfect. The point that I make, and I do not think it has been made clear in the press and t'he drug industry, is that we are going to hear all viewpoints. We want to hear all viewpoints. We want `a balanced record. We have been attacked by the Pharmaceutical Manufacturers Association for not hearing all viewpoints, I guess because you cannot hear all viewpoints at once. We have leaned over backward to tell the companies involved that they can testify any time they wish as soon as we can schedule a place and time. We have told the PMA the same, and it has come three times `and has presented many wi'tnesses. Other individual witnesses have to wait in line. If the industry would prefer that they, either PMA or the com- panies, not have a preferential chance, which I think they are entitled to because we are talking about their business, the committee might very well proceed to listen to individual witnesses for the next 3 years, because we have had that many requests from individual doctors all over the country. Senator Scorr. Of course, if you tried that, you would have trouble with me, `as you know. Senator NELSON. My point is that we want balance and all view- points here. I say to you, representing the company, that if at any time in these hearings, you think there is `a viewpoint that has not been heard from `the industry standpoint, let the committee know and you will be heard. If I slip up on it, Senator Scott certainly will not. But I want that well understood from the beginning. The other aspect I would like to mention is that whenever you con- duct a hearing of this kind, members of the committee ask to explore the problem. The fact that you might cross-examine a witness or di- PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3303 rect-examine a witness or raise a tough question that sounds preju- dicial does not mean anything at all. This is the way to explore an issue to get full information. If you have the information, the record will show the answer. This committee does not make medical judgments. We are trying to get the best professional witnesses we can find, and I think we have had some of the best in the country, as we intend to have, to conduct further hettrings with the best witnesses we can find. Mr. GADSDEN. Mr. Chairman, may I make a comment, please? Senator NELSON. Surely. Mr. GADSDEN. As will be evident in the subsequent testimony, while we disagree most deeply with some of the conclusions and statements of the Food and Drug Administration, we nevertheless, credit them with speaking out of sincere conviction. This is the way they saw it, but we do believe that they just happened to be in error as to their conclusions. Senator NELSON. I think the FDA has very distinguished scientists and administrators and that they are sincere, just as I am sure you are. But that is the purpose of the hearing. If there is a difference in view- points, we want to hear yours so that, on balance, the record can be read and people can make a judgment about where the truth lies, whether it is on one side or the other or somewhere down the middle. We have had distinguished medical witnesses here-you are aware of this-from your own industry, from within the companies who will disagree vigorously about the interpretation of some kind of study, about the interpretation of the same set of facts. That is bound to be the case because medical science is still an art to a considerable degree. So there are bound to be differences of opinion. We want to hear all the best opinions we can get, both from those who feel one way and those who differ with them. Mr. GADSDEN. Should Dr. Tishler proceed, sir? Senator NELSON. I assume, Dr. Tishler, that if we have some ques- tions while you are testifying, you will have no objection to inter- ruptions? STATEMENT OP MAX TISHLER, PH. D., PRESIDENT, MERCK SHARP & D0HME RESEARCH LABORATORIES, DIVISION OP MERCK & Co., INC., RARWAY, NJ. Dr. TISHLJ~R. I have no objection. Senator NELSON. We have your statement and your biographical data. They will both be included in full in the record. If there is something, while you are reading, that you would like to extemporize on or elaborate on that would have taken too much time to write out in detail, you may feel free to do so. If there is anything you would like to eliminate, feel free to do so, but your statement as submitted will go in the record in full, and anything you wish to change in the course of your testimony, you may. Dr. TISHLER. Senator, I plan to read my statement. (The biography of Dr. Tishler follows:) PAGENO="0212" 3304 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BIOGRAPHY OF MAX TISHLER Pu P PRESIDENT MERCK SHARP & DOHME RIDSEARCH LABORATOI~IES DIVISION MEMBJ3IR BOARD OF DIRECTORS MERCH & Oo INC RAHWAY NJ Dr Max Tishler who heads the $57 million a year research program of Merck & Co., Inc. is not only President of the Merck Sharp & Dohme Research Labora- tories but also one of the nation's leading scientists in his own right. . When he was persuaded by the late George W. Merck to leave an academic career at Harvard to join the Merck laboratories, there were no antibiotics, no steroids, and only two vitamins commercially available. Dr. Tishler has con- tributed significantly In all of these and other fields of medicinal, chemistry, having received more than 100 patents and published more than 100 papers. In 1953 he achieved national recognition with his election to the National Academy of Sciences In 1937 when Dr Tishler became a member of the Merck research staff it numbered fewer than 100 persons Today he heads an organization totaling nearly 1 800 including representatives of some 35 diverse disciplines (In addi tion, 500 persons are engaged in research and development in other divisions of Merck) At niajor research centers in Rahway N J and West Point Pa and several experimental farms, Dr. Tishler directs extensive research programs in human and animal health. Major discoveries made in the Merck Sharp & Dohme Research Laboratories since Dr Tishler assumed leadership in 1956 include drugs for the treatment of heart disease hypertension rheumatoid arthritis and other inflammatory dis eases, and mental depression; and animal health products for control of economi- cally significant diseases of poultry and livestock. In addition to membership in the National Academy of Sciences his honors include election to the American Academy of Arts and Sciences in 1965 the 1964 Chemistry Lecture Award of the Royal Swedish Academy of Engineering Sciences (Stockholm, Sweden); Rennebohm Lecturer, University of Wisconsin School of Pharmacy (1963) the Julius W Sturmer Memorial Lecture Award Philadel phia College of Pharmacy, (1964); the 1963 Chemical Industry Award of the American Section of the Society of Chemical Industry the 1961 Industrial Re search Institute Medal; the 1960 Honor Scroll Award of the New Jersey chapter of. the American Institute of Chemists;. and the Merck Board of Directors Sci- entific Award (1951). He has received honorary D.Sc. degrees from Tufts Uni- versity (1956), Bucknell University (1962), and the Philadelphia College of Pharmacy and Science (1966) and an honorary D Eng degree from Stevens Institute of Technology (1966). He is also a member of the honorary societies, Phi Beta Kappa and Sigma Xi. Funds from the Merck Board of Directors Award established the Annual Max Tishler Visiting Lectureship at Harvard and the Max Tishler Annual Scholarship at Tufts. Born October 30, 1906, in Boston, Dr. Tishler was educated at Tufts University where he received his B.S. degree in chemistry, graduating magna cum laude. In 1929 he became Austin Poaching Fellow at Harvard University and after receiving the degrees of M.S. in 1933 and Ph.D. in 1934, he became Research Associate with the late Professor Elmer P. K~hler, aud in 1936, Instructor in Chemistry. Joining Merck in 1937 as a research chemist, he served successively as Sec- tion Head of Process Research (1941-44) and Director of Developmental Re- search (1944-53) During this period Dr Tishler led the Merck teams which first synthesized hydrocortisone and developed commercial syntheses for vitamin B-2 pantothenic acid and vitamin K-i He also headed the development of production processes for penicillin streptoniycin cortisone and hydrocortisone His work in sulfa drugs included discovery of sulfaquinoxahne the first effective drug against eoccidio~as a costly disease of poultry and he developed a number of practical syntheses of amino acids which furthered research in nutrition. In collaboration with Dr. Selman A. Waksman, Rutgers' Nobel laureate, he isolated the first actl.nom:ycin in crystalline form. In recent years, related actinomycins have found use in the treatment of certain types of cancer. He also collaborated with Dr. Waksman on a book entitled ~treptomycin, and with Harvard's Dr. James B. Conant on Chemistry of Orgasio Compounds, a textbook. In 1954, he became Vice President for Scientific Activities, and In 1956 was PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3305 named to head the Merck Sharp & Dohme Research Laboratories as Vice Pres~- dent and Executive Director, being named President in 1957. He was elected to the Board of Directors of Merck & Co., Inc. in 1962. Dr. Tis'hler is active in educational affairs and serves on a number of scientific advisory committees affiliated with the U.S. gorvernment, with the numerous professional societies of which he is a member, and with the pharmaceutical industry. Dr. Tishler and Mrs. Tishler, the former Elizabeth M. Verveer, reside in West- field, New Jersey, ~and are the parents of two sons, Peter Verveer and Carl Lewis. CURRENT AFFILIATIOSS (UNLESS OTHERWISE NoTED) Civic National Research Cbuncil of the National Academy of Sciencies: Member, Advisory Committee on Tropical Medicine; member, Committee on Role of Patents in Research. Educational Columbia University: Member, Scientific Advisory Committee, International Institute for the Study of Human Reproduction. Harvard University: Member, Visiting Cbmmittee (School of Public Health); member, Visiting Cbmmittee (Department of Chemistry). University of Pennsylvania: Associate Trustee (Science); member, Physical and Biological Sciences Board. Rutgers University: Member, Advisory Committee, School of Medicine. Tufts University: Life Trustee; member, Executive Committee; vice chair- man, Educational Policy Committee; member, Development Committee of Board; consultant, Modernization of Chemistry Department; member, Administrative Board, Tufts-New England Medical Center; chairman, Visiting Committee (Chemistry); member, Board of Advisors, School of Dental Medicine Program. Union Junior College: Trustee. The Fund for Overseas Research Grants and Education: Member, Board of Directors. The Weizmann Institute of Science: Member, Board of Governors. Indvstry Industrial Research Institute: Member, Advisory Editorial Board. "Research Management"; former member, Board of Directors (1902); member Awards Committee. Pharmaceutical Manufacturers Association: Member Research and Develop- ment Section. Professional Agricultural Cthemicai Society of Japan: Member. American Association for the Advancement of Science: Fellow. American Chemical Society: Member; former chairman, Organic Chemistry Division (1953-54); former coundillor, North Jersey Section; member, Com- mittee to Study Chemistry in Industry (Project of Committee on Chemistry and Public Affairs). American Institute of Chemists: Fellow; former councillor (1959-61). Association of Harvard Ohemists: Member; past president (1964). "Ohemical & Engineering News": Member, Advisory Board. Chemical Society (London) : Fellow. Chemical Society of Japan: Member. Directors of Industrial Research: Member. New York Academy of Sciences: Fellow. "Organic Syntheses": Former member, Editorial Board (1954-59); former Editor-in~Chief (1959). "Separation Science": Memiber, Board of Editors. "Industrial Research": Member, Editorial Advisory Board. Society of Chemical Industry: Honorary Vice-President (1968-69) ; member, Executive Committee (1963-08); former Chairman (1966), American Section; Chairman, Nominations Committee (1908). Swiss Chemical Society: Member. Dr. TISHLEB. My scientific colleagues and I welcome and appreciate the opportunity to tell this committee about the development and introduction of indomethacin. You will forgive me, Mr. Chairman, PAGENO="0214" 3306 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY if I talk about the Merck Sharp & Dohme research laboratories with pride. But it is pride in others: in the achievements of my fellow scientists, a~rid in the consistent philosophy of a management that be- lieves that the two most important ingredients of research are quality and integrity. The pharmaceutical industry laboratory, Mr. Chairman, is orga- nized to bring together scientists of widely different disciplines, `all needed to carry a program from the conceptual stage through clinical investigation. They comprise men from at least 35 separate disci- plines-from chemists to pharmacologists, pathologists, biologists, physicists, engineers, and physicians, who are joined together to seek solutions to medical problems. In our society, pharmaceutical research laboratories have almost unrivaled capacity for such collaborative research in medicine. This is the way our laboratories are organized at Merck, which con- siders research to be the vital heart of the company. To the best of our knowledge, there is no sizable company `outside the pharmaceutical industry that over the years spends a higher percentage of its own revenues-excluding government support-for research and develop- ment. Our budget for this work is the largest published of any pharma- ceutical concern in the free world-$57 million this year, of which less than 2 percent comes from government. We have 2,300 people engaged in this work, of whom more than 500 have advanced academic degrees. Last year they published nearly 150 research papers in scientific journals. Senator NELSON. Are you saying that $57 million is the figure that you identify as a cost accounting factor for research in your company? Dr. TISTILER. Yes, it is. Senator NELSON. Some times we have had trouble trying to get figures on how much is research, because company officials say it is difficult to separate it out, and I suppose it is. Mr. GADSOEN. I am not aware of your previous discussion on this point, Senator. I would assume that perhaps the problem had to do with the cost accounting principles of allocation to a specific project. However, under our system, we can tell you how much is spent for research throughout the company, and this is the figure to which Dr. Tishier is referring. Senator NELSON. When you refer to 2,300 people engaged in this work, just so I have it clear in my mind, I am not sure how you dis- tinguish research from something else, but does this involve quality control, too? Dr. TISHLER. No, this does not involve quality control. If you would like a breakdown on the type of research I am referring to, we have exploratory research, fundamental research, basic research, develop- mental research, and applied research-five categories of research. It is broken down into these categories. Most of the research is directed toward investigating, searching for new therapeutic agents, trying to find the limitations and scope of therapeutic drugs, developing the processes to make the products, doing all the physical things that are part of the controls that we have to set up for the situation. Senator NELSON. You have refined these categories a bit since 1 have been in school. It was pure and applied research in those days. PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3307 Dr. TISHLER. We have good reasons for breaking it into five cate- gories. Senator NELSON. I am sure you do. Mr. GADSDEN. I would have to tell you that this is Merck terminology, and what this means to us may not be the same as what it might mean in another research establishment. Dr. TISHLER. That is correct. Shall I proceed? Senator NELSON. Please go ahead. Dr. TISHLER. It is the quality and integrity of research that counts, not its quantity. To illustrate this point, it would be relevant, I believe, to give the committee a brief description of how Merck got into the long and difficult war against rheumatoid arthritis, a war in which indomethacin is one more significant advance. Thirty-five years ago, a few years before I came to the company, hardly more than a young lecturer from the Harvard Chemistry Department, some Merck scientists became interested in helping to iso- late the active ingredient of the yellowish outside layer, or cortex, of the adrenals-those two tiny glands that sit on top of each kidney. An insufficiency of this ingredient-even then thought to be a steroid hormone-causes Addison's disease, a normally fatal illness. What was the basis for Merck's interest in this field? There was little or no commercial reward at the end of the road. Only 800 Americans were then known to have Addison's disease, and they were kept quite healthy on adrenal extracts. The only possible reward for the effort appeared then to be scientific and medical. The active ingredient of the adrenal cortex was believed to be vital to life. My colleagues were not looking for a commercial drug to cure a specific disease. They were chiefly seeking knowledge to cure ignorance, which is the greatest enemy of human health. If this seems sententious, it is also practical. In 1933, when George Merck established the pioneer laboratory in our industry, he was per- suaded that the long-range success of both our research and the com- pany itself would depend primarily on our ability to make funda- mental and lasting contributions to human health. This has been our philosophy and our practice ever since. It took more than a decade of failures, however, to synthesize corti- sone, which had been isolated earlier from the adrenal cortex. The first complete synthesis was achieved in 1944 by a 26-year-old Merck chemist, Dr. Lewis H. Sarett, who had come to us from Princeton 2 years before. Four more years were required to produce enough corti- sone to try it in Addison's disease. It was suqcessful for this use, but there was little interest on the part of clinical investigators in explor- ing uses in other diseases. Then came the historic letter from Dr. Philip Hench, the great rheumatologist of the Mayo Clinic, explaining a scientific hunch and asking for some of this scarce chemical to try on a carefully studied bedridden rheumatoid arthritis patient. We sent Dr. Hench a single gram of cortisone for his patient. On September 28, 1948, a few days after treatment started, the patient rose from her bed and walked out of the clinic. From his scientific hunch, from one gram of cortisone and one well-studied patient, Dr. Hench made the epic discovery that won him the Nobel Prize. PAGENO="0216" 3308 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Several years after he made medical history by using cortisone in rheumatoid arthritis, Dr. Hench told a Senate committee: The work of investigators in scientific research is different from that in any other field that I know of. Frequently they are dealing with ideas for which there are no words. Thoughts are chemical processes, and there are times when a chemical process can be felt without any appropriate words. So that the only way you can really judge the quality of the members of any research organization is, in my opinion, by what they do-by their fruits. Dr. Hench was referring to our laboratories. Some of what my col- leagues there have done is told in a booklet, "By Their Fruits," which I would like, Mr. Chairman, to submit for the record.1 Senator NELSON. Yes, it will be received. Mr. GADsDEN. Is this the appropriate way? Senator NELSON. Just leave it at the desk here. Senator Sco~r'r. Mr. Chairman, I have to leave for the time being. May I have your permission to submit a statement at the end of the testi- mony if I decide to do it? Senator NELSON. Yes, it will be printed in the record.2 Senator Scorr. I shall try to get back. Senator NELSON. Thank you, Senator. Please proceed, Dr. Tishler. Dr. TISHLER. This booklet I submitted, Mr. Chairman, describes the contributions, up through 1963, of our company's scientists to some of the landmarks in chemical medicine. These accomplishments have become part of medical history, but let me remind you that in 1933, while I was still a graduate student at Harvard-and this was not so long ago-there were no vitamins; no sulfas; no antibiotics; no antihypertensives; no antidepressants; no corticosteroids; no polio, measles, or mumps shots; no blood plasma; no anticoagulant therapy; no controllers of gout; and no broadly effective diuretics. Today, these words are part of the layman's language and the tools of our physicians. The work of Merck scien- tists played a key role in progress in the research and development in these fields. Therapy in these fields has had an impact on the world around us. Anyone who has been a member of the Merck scientific team during any part of this period is proud of our contributions to these advances which have helped to wipe out or reduce the terror of whole categories of disease and have contributed dramatically to the extension of man's lifespan * * * a gift of years that has been called the greatest technological achievement of the 20th century. One of the drugs of which my colleagues and I are most proud is indomethacin. It is recognized by our peers in the world of science and medicine as a creative masterpiece. At least a hundred first-rate, technically trained men and women in more than 20 different dis- ciplines at Merck made contributions to this research and development achievement over a period of a decade. They have been rewarded in the only way that counts. Upward of a million people have been able, as a result of indomethacin, to lead happier, more productive, and less painful lives. This is what research at Merck is all about. I Retained in committee files. 2 See statement, p. 345i, Infra. PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3309 In 1959, Mr. Chairman, an attempt was made to measure the con- tributic~ns of industrial laboratories to the growth of fundamental knowledge. A study of the basic research articles printed in scientific journals during the course of 1 year was published in the weekly magazine, Science. Merck stood fifth on the list, right behind General Electric, Bell Telephone, Du Pont, and American Cyanamid. They averaged a third more papers than did we, but they also averaged over 30 times our financial resources. But if my colleagues have reason for pride, they also have reason for discouragement I am not referring only to disparagement of oui work, though this is sometimes heartbreaking. I am referring to the painful slowness with which we and our counterparts in other pharma- ceutical laboratories and our collaborators in the great research orga- nizations of government, universities, and medical schools around the world are able to push back the frontiers of ignorance. For most illness, such as the degenerative diseases,, we have not yet found either the cause or the cure. While we can discover drugs like indomethacin which improve the health and well-being of patients, we are still fighting our way through the dark, and we are often terribly discouraged. Biomedical knowledge is almost half a century behind that of the physical sciences in the accumulation of knowled~e of the kind and depth that leads to major discoveries. The situation stems from the complexity of life. In the human body research is dealing with some- thing like 100,000 or more biochemical processes. When you add to this the tremendous genetic complexities of the human being, the most con~'plica'ted hybrid on this planet, you can see how difficult it is to make a statistical analysis of his chemical and emotional reactions. The number of unknown variables with which we have to cope is well beyond our present comprehension. We still can and do make signi- ficant progress, but it is clear that if research is really to conquer disease, we must never lose sight of our central task the accumulation of more and more `basic knowledge. This `will require patience on the part of all, including the Congress, which has been so generous in re- cent years with appropriations for basic research in medicine Turning again to rheumatoid arthritis: in few other fields of medi- cine is our basic knowledge more deficient than it is in rheumatoid arthritis. Though indomethacin has given relief to many patients who suffer from this disease, there is still a deep dissatisfaction con nected with this achievement. It is a dissatisfaction, too, for the medi- cal profession and for the millions of victims of rheum'ttoid arthritis and related diseases. Neither we nor anybody else has found either the cure, or for that matter, the cause or causes of these diseases. All we have discovered are better ways to relieve painful suffering and return invalids to productive lives. This is important. But we still have before us the challenge to finish `the job-namely, to cure and prevent the diseases themselves. We now want to concentrate on the specific stage of our long research effort in this field-that of indomethacin-~that now interests you and your committee. To tell you about this program, I would like to call on Dr. Karl Beyer, Jr., senior vice president for research of our laboratories. He is a distinguished scientist with an international repu- tation. He has both an M.D. degree, and a Ph. D. degree in physiology. He is a past president of the American Society for Pharmacology and PAGENO="0218" 3310 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Experimental Therapeutics, which in its 60 years has honored oriiy one other scientist from industry with this post. He is a member of the Drug Research Board of the National Academy of Sciences, and among his other honors will be the Distinguished Service Award of the University of Wisconsin, which he will be awarded in Madison 2 weeks from today. Thank you very much. Senator NELSON. Thank you very much, Dr. Tishler. We appre- ciated having your testimony. We shall be pleased to hear from Dr. Karl Beyer, and we are pleased that my alma mater has seen fit to honor you with a distinguished service award, which is eloquent testimony to your qualifications. Dr. BEYEJI. Thank you, sir. Senator NELSON. Dr. Beyer, we have your biography and state- ment, both of which will appear in the record in full. You may proceed in any way you wish. (The biographical data of Dr. Beyer follows:) BIOGRAPHY OF KARL H. BEYER, JR., M.D., Pu. D., MERCK SHARP & DOHME RESEARCH LABORATORIES, WEST POINT, PA. GENERAL INFORMATION Born June 19, 1914, Henderson, Kentucky; married; two daughters. SPECIALIZATION Pharmacologist and Physiologist, with principal research interest being in the fields of renal pharmacology, metabolism of drugs in the body and enzymo- logic studies on secretory mechanisms of cells. EDUCATIONAL RECORD B.S.-1935: Western Kentucky State College. Ph.M.-1937: University of Wisconsin. Ph. D. in Physiology-1940: University of Wisconsin. M.D.-1943: University of Wisconsin. CAREER SUMMARY Instructor in Chemistry: Western Kentucky State College, 1935-36. Instructor in Physiology: University of Wisconsin Medical School, 1939-43. Assistant Director of Pharmacological Research, Sharp & Dolime, 1943-44. Director of Pharmacological Research, Sharp & Dohme, 1944-50. Assistant Director of Research, Sharp & Dohme, 1950-56. Director of Merck Institute for Therapeutic Research, West Point, Pa. 1956-58. President of Merck Institute for Therapeutic Research, 1961-~66. Vice President for Life Sciences, Merck Sharp & Dohme Research Labs., West Point, Pa., 1958-66. Senior Vice President, Research-Merck Sharp & Dohnie Research Labs., West Point, Pa., 1966-. MEMBERSHIPS Fellow in the American College of Physicians (F.A.C.P.). Fellow in American Association for Advancement of Science. Fellow in The New York Academy of Sciences. Fellow in The Royal Society of Medicine. Member of the American Chemical Society; American Physiological Society; Society for Experimental Biology & Medicine; Philadelphia Medical Society; Philadelphia Physiological Society; American Society for Pharmacology & Exper- imental Therapeutics (Secretary, 1959-61; President, 1964-65; Past-President, 1965-66) ; Federation of American Societies for Experimental Biology (President, 1965-66); Canadian Pharmacological Society; Association of American Medi- cal Colleges; The American Therapeutic Society; Society of Toxicology; Amer- PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3311 ican Society of Nephrology; Council on Circulation & Renal Section, American Heart Association; International Society for Biochemical Pharmacology; Board of Trustees, Biological Abstracts (Treaurer, 1965- ); Drug Research Board, National Academy of Sciences, 1964- ; Editorial Committee, Annual Review of Pharmacology; Editorial Board, Journal of Olinical Pharmacology & Experi- mental Therapeutics; Committee on Biological Handbooks; National Society for Medical Research Board, 1964- ; Who's Who in America; The Newcomen So- ciety in North America. AWARDS The Merck Scientific Award (1959). The Gairciner Foundatioa Award (1964). Modern Pioneers in Creative Industry Award, Natl. Assoc. of Mfgrs. (1965). Modern Medicine's Award for Distinguished Achievement (1967). American Pharmaceutical Association's Foundation Award in Pharmacody- namics (1967). OTHER AFFILIATIONS Lecturer in Physiology: Jefferson Medical College. Lecturer in Pharmacology: Temple University Medical School. Lecturer in Pharmacology: Graduate Medical School, UniverSity of Pennsyl- vania. Special Lecturer in Pharmacology: Woman's Medical College. PUBLICATIONS (OVER 150 PUBLICATIONS, INCLUDING THESE LISTED) "Sympathomimetic Amines: The Relation of Structure to Their Action and Inactivation" (Physiol. Rev. 26: 169, 1946). "Functional characteristics of Renal Transport MechanismS" (Pharmaeol. Rev. 2 : 227, 1950). `Pharmacological Basis of Penicillin Therapy" (Chas. C. Thomas, Publisher, Springfield, Ill., 1950). "Factors Basic to the Development of Useful Inhibitors of Renal Transport Mechanisms" (Arch. Int. Pharmacody., 98: 97-117 (May) 1954). "The Mechanism of Action of Chlorothiazide" (Ann. N.Y., Acad. Sci., 71: 363, 1958). "Newec Diuretics in Progress of Drug Research" (E. Jucker, Ed., Basle, 2, pp. 9-69,1960). "Effect of Drugs on Active Transport", in "Enzymes & Drug Action" (Ciba Foundation SymposIum, 1962. Ed. J. L. Mongar and A. V. S. deReuck; Pub. by J. & A. Churchill Ltd., London, England.) "Physiological Basis for the Action of Newer Diuretic Agents" (Pharmacol. Rev. 13: 517-562 (Dec.) 1961). "Fetal Malformations" (Arch. Env. Health 5: 94-96, 1962). "The Effect of the New FDA Regulations on the Drug Industry" (Clin. Phar- macol. Therap. 5: 1-5, Jan.-Feb., 1964). "Method of Inhibiting Gastro-Intestinal Irritation" Patent No. 3,129,137 dated Apr. 14, 1964. "My Criteria for Acceptable Research in Pharmacology" (Am. J. Pharmaceu- tical Education 28: No. 5, Dec., 1994). "Renotropic Characteristics of Ethacrynic Acid; A Phenoxyacetic Saluretic- Diuretic Agent" (J. Pharmacol. Exp. Ther. 147: 1-22, 1965). "From Theory to Therapy" (Proc. Western Pharruacol. Soc. 8, 1965). "Perspectives in Toxicology" (Toxicol. & Appli. Pharmacol. 8: No. 1, Jan., 1966). "The Federation in Midpassage", Introductory Remarks. Fed. Proc. 25: No. 5. Sept.-Oct. 1966. STATEMENT OP KARL H. BEYER, JR., M.D., PH. D., SE~tIOR VICE PRESIDENT POR RESEARCH, MERCK SHARP & DiOHME RESEARCH LABORATORIES, DIVISION OP MERCK & CO., INC., RAHWAY, N.J. Dr. Bn~n~n. Thank you, Senator. As has been stated by Dr. Tishler, neither the cure for nor the etiology of rheumatoid arthritis is yet within the realm of knowledge of physicians and medical scientists. PAGENO="0220" 3312 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY However, the development of a multitude of useful medicinal agents over the past 20 year&-some of them, like indomethacin, for disease entities still beyond our capability for understanding-provides evi- deuce that one does not need to know all about a biological function to alter it beneficially. The development of indomethacin does not suggest that we have moved any closer to understanding the factors that precipitate or are involved in the rheumatoid process. What the successful application of the compound does imply is that, with the benefit of accrued knowl- edge and experience, Merck scientists were able to formulate a working hypothesis as to what initiated and sustained the inflammatory process; and also able to develop methodologies for the discrete examination in laboratory animals of the effects of candidate compounds on the basic factors of the disease. While the search for more potent corticosteriods continued in the early 1950's, a group of Merck scientists and biochemists started what was to be a 12-year search in another direction-to find a compound that was not hormonal in nature, but that would still provide the benefits of the steriods. Early in 1957 the attention of the scientists in this program turned to compounds with an indole nucleus. This was because an indole metabolite, serotonin, was thought to play a role in initiating and sustaining inflammation. A number of serotonin antagonists were synthesized by Merck chemists and made available for pharmacologic assessment as anti-inflammatory agents. The serotonin theory eventually proved to be wrong, but it did provide the first promising chemical lead in our nonsteriod program. The program began to achieve full focus later in 1957, when Merck scientists observed the first promising indole derivative after evalu~ ating hundreds of unsuccessful agents, but it did not live up to the expectation of Merck scientists and physicians and was dropped. In March 1961, another promising derivative was finally synthesized. That compound, too, was effective in preclinical studies, but even as clinical trials were being planned, our scientists developed another indole derivative, indomethacin, which appeared to have greater potency with less toxicity than any of the previous compounds. Before indomethacin could be studied in man, it had to undergo lengthy and comprehensive testing in animals. More than 100,000 animals were used during the nonsteroid anti-inflammatory program leading to the development of the compound. While animals themselves do not suffer from rheumatoid arthritis as a disease entity, we have been able to utilize a number of animal models to define, reproduce, and control in the laboratory fundamental phenomena involved in arthritic diseases. Through the capability of developing methodologies for the control of biological phenomena in animals, our ~harmacologists achieved the ability to' strip arthritis down to its essential elements of inflammation, swelling, `pain, and heat or fever, so that the action of potential com- pounds could be examined unfettered by the imponderables created clinically as patient, disease, and drug interact. Some examples of animal models to test for antiarthritic activity are the carrageenin assay, which helps in the assessment of a drug's ability to reduce inflammation, pain, and swelling; the granuloma cot- PAGENO="0221" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY~ ~ 3313~ ton pellet assay, for measuring a drug's ability to inhibit inflammation and fibroblast proliferation; and still other tests which provide an indication of' the analgesic and `anti-inflammatory. properties of compounds. . ` . . . . Additional control of these animal models is afforded by a com- parison of the dosage of the drug with the response Moreover, such dosage response relationships are further compared with those of com pounds commonly employed in the management of arthritic disorders. These comparisons are more than comparisons of potency, for we are able to compare the qualitative characteristics of the compounds as well. The sizable and comprehensive animal studies with indomethacin provided clinicians with demonstrative evidence of the safety arid efficacy of the compound, warranting tests in man The anti mflammatoiy activity of indomethacm was demonstrated in the cotton pellet granuloma inhibition test in mice in which granu loma inhibition was observed following both oral and local administra- tion It was also demonstrated in the inhibition of edema induced by injection of the irritant, carrageenin, into the hind paw of rats Fever-reducing activity was demonstrated by inhibiting the fever produced by injection of a bacterial endotoxin in both rabbits and rats, as well as yeast-induced fever in rats. In these and other tests, the potency of indomethacin was signifi- cantly greater than that of the anti-inflammatory compounds with v~ hich it was compared It must be noted, however, that these studies comparing indomethacin with other known compounds, though serv ing as valuable indicators to the clinical investigator, are based on phenomeiia measured in animals and are not directly translatable to disease in man. As part of the pharmacologic assessment, indomethacin was examined in the laboratory for its effect on the heart, the cardiovas- cular system, and autonomic reflex mechanisms, as well as for its effect on excretion, renal function, and animal behavior. Indomethacin did not affect any of these organ systems and processes. When methodology was needed to examine a specific effect, we devised it if it was not available. Just as the Porter-Silber test, for example, bearing the name of two members of our staff, has become standard procedure in steriod measurement, so `we devised new meth- odology to enhance reliability of metabolic studies with indomethacin. To do this required meticulous knowledge of the physiology of the animals employed in the studies and the synthesis of indomethacin compounds labeled with radioactive carbon. Such advances in meth- odology not only furthered our own indomethacin studies, but also contributed to the studies of scientists in other laboratories, since much of our methodolgy was published hi detail. Tests in several species to determine the metabolic fate of indometh- acm indicated that in the dog, the drug present in the plasma is essen- tially all unchanged indomethacin. In other animals, metabolism of the drug differs In the guinea pig, a significant amount of the drug is present in the plasma as a metabolite, with a small amount of indo- methacin present in the cerebrospinal fluid. The route of excretion de- pended on the species and not the dose or the route of administration. The influence of indomethacin and hydrocortisone on resistance to PAGENO="0222" 3314 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY infection was studied extensively in mice, rats, and rabbits, both be- fore and subsequent to the initiation of clinical trials. In the area of bacterial infection, in investigations in mice and rats, 10 different bacterial pathogenic microorganisms were used and the drug was given at several dose levels and treatment schedules. In con- trast to hydrocortisone, indomethacin produced no detrimental effects in any of the experimental infections, even when administered in amounts 80 to 330 times the threshold dose for anti-inflammatory activity. In the area of viral infection, indomethacin neither increased nor decreased resistance, in mice, to infections induced by the influenza A, Columbia SK, or the Eastern Equine encephalomyehtis virus. In contrast to the adrenal corticosteroids, indomethacin did not de- press antibody formation, which is a defense mechanism of the body against infection. These findings undoubtedly accounted, in part, for the contrasting effects of indomethacin and hydrocortisone on experi- mental bacterial infections, as mentioned above. Taking all observations into account, itwas held to be most probable that indomethacin would have no effect, beneficial or detrimental, on infections in man. The safety assessment of indomethacin in the laboratory has been the most extensive we have ever undertaken and has included acute, subacute, and chronic toxicity studies in mice, rats, guinea pigs, rab- bits, cats, dogs, monkeys, domestic pigs, and chickens. Chronic toxicity studies were continued for 26, 52, and 129 weeks in dogs; 35, 57, and 80 weeks in rats; 18 weeks in monkeys; 22 weeks in rabbits; and 27 weeks in guinea pigs. Acute and subacute toxicity studies were conducted in mice, cats, domestic pigs, and chickens. Reproduction studies included two-generation tests in mice, the recommended two-litter study in rats, and an established pregnancy test in rabbits. The only toxicity that could be clearly identified as a direct effect of indomethacin was the production of gastrointestinal lesions of the type reported in animals for aspirin, phenylbutazone, and the anti- inflammatory steroids. Where anti-inflammatory potency and gastro- intestinal irritation could be tested in the same species, the therapeutic ratio was as favorable for indomethacin as for phenylbutazone or the steroids. This type of potential side effect of antiarthritic dosages of aspirin, phenylbutazone, and steroids is well known to the physician. Of course, there were other side effects we could not foresee which have occurred in man, but they were primarily of the subjective, sen- sory type, such as headache and dizziness, which are not usually ob- served in animals, since animals cannot communicate with man. In the interest of time, I should like simply to condense the rest to say that the publications from our laboratories clearly disclose the results of the extensive animal studies carried on in the preclinical evaluation of indomethacin. They have not been challenged, even in the face of intensive invest%ation of the compound by other scientists. The details of these studies are found in an extensive monograph which was provided each investigator and the FDA before clinical studies were undertaken. Reports of animal data to FDA and investi- gators were updated regularly to reflect the findings of animal studies continuing after the preclinical phase had been completed and the human studies were underway. PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3315 No drug, to my knowledge, has received a more intensive preclinical assessment than indomethacin. Except for the sensory effects, the trans- position of the total preclinical assessment to experience in man has been gratifying. The critical clinical evaluation phase, and the professional review period following the discovery of a new drug, will be covered by my colleague, Dr. F. Douglas Lawrason, a certified member of the Amer- ican Board of Internal Medicine, and former dean of the University of Arkansas School of Medicine. May I introduce Dr. Lawrason? Senator NELSON. Thank you very much, Dr. Beyer, for your very valuable contribution to the discussion of this drug. As I think you perhaps know, I believe all of the witnesses, including the FDA, have commented upon the value of the drug in the treatment of rheumatoid arthritis and some other conditions. What they have differed on is the interpretation of some of the tests that have been made and the place that Indocin has in the medical armamentarium. But if my memory is correct, there has not been any question in anybody's mind that it has a useful and valuable place in the treat- ment of rheumatoid arthritis and some other related conditions. Thank you very much. Dr. BEYIIR. Thank you, sir. STATEMENT OP F. DOUGLAS LAWRASON, M.D., VICE PRESIDENT FOR MEDICAL AFFAIRS, MERCK SHARP & DOHME RESEARCH LABORATORIES, DIVISION OF MERCK & CO., INC., RLAHWAY, N.J. Senator NELSON. Dr. Lawrason, the committee appreciates having you here today. You did submit, I think, a biographical sketch. Dr. LAWRASON. That is correct. Senator NELSON. Your full statement and biographical sketch will be printed as supplied to the committee by you. You may proceed to give your testimony as you see fit. (The biography of Dr. Lawrason follows:) CURRICULUM VITAE I. Name: F. Douglas Lawrason, M.D. II. Education: University of Chicago, 1937-40. University of Minnesota, BA., 1941. University of Minnesota Graduate School, M.A., 1944. University of Minnesota School of Medicine M.D., 1944. III. Internship and Postgraduate Training: Yale School of Medicine. New Haven Hospital, New Haven, Conn., Internship and Residency, 1944-4S. IV. Teaching or Research Experience: University of Minnesota, Assistant in Anatomy, 1942-44. Yale School of Medicine, Dept. of Internal Med. James Hudson Brown Memorial Res. Fellow, 1949. Yale School of Medicine, Dept. of Internal Med., Instructor in Medicine, 1950. Yale School of Medicine, Dept. of Internal Med., Assistant Professor, 1951. National Academy of Sciences, Washington, D.C., National Res. Council, Div. of Med. Sciences, Professional Associate, 1950-53. Univ. of North Carolina School of Medicine, Chapel Hill, NC., Asst. Prof. of Med. and Asst. Dean, 1953-55. PAGENO="0224" 3316 COMPI~TITIVE PROBLEMS IN THE DRUG INDUSTRY Univ. of Arkansas Medical Center, Little Rock, Ark., Prof. of Med., Pro- vost for Medical Affairs and Dean of th~ School of Medicine, 1955-61. Merck Sharp & Dohm'e Research Laboratories, West Point, Pa., 1961 to present. Research studies included- Research concerned with cancer and leukemia in inbred strains of mice, at the University of Minnesota. Investigation of new methods for the determination of plasma proteins and investigation concerned With salt and water ex- cretion as related to renal dynamics, at the Yale School of Medi- cine. Studies in experimental leukemia in inbred mice with particular reference to immunologic aspects and factors of resistance of transplanted tumors, at the University of North Carolina School of Medicine. As a United, States Naval Reserve Officer, studies in experimental anemia in swine, hematologic studies in animals exposed to atomb bomib radiation (Bikini) and hematologic follow-up studies in Japanese exposed to atomic bomb; done at the Philadelphia Naval Hospital and the Naval Medical Research Institute, Bethesda, Md. V. Medical Practice: Medical practice associated with various professional appointments listed. VI. Medical Publications: Lawrason, F. D. Studies of Leukemia and Mammary Cancer in Inbred Mice. Thesis for M.A. University of Minnesota, 1944. Kirschbaum, A., Lawrason, F. D., Kaplan, H. S., and Bittner J. J. Influ- ence of Breeding on Induction of Mannary Cancer with Methyl- cholanthrene in Strain Dba Female Mice, Proceedings of the Society for Experimental Biology & Medicine 55:141, 1944. Lawrason, F. D., Kirschbaum, A. Dietary Fat with Reference to the Spontaneous Appearance and Induction of Leukemia in Mice. Pro- ceedings of the Society for Experimental Biology & Medicine 56:6, 1944. Lawrason, F. D. and Cronkite, E. P. Incidental Finding of Megaloblas'tic- like Cells in Bone Barrow of One of Two Swine with Macrocytic Anemia and Chlorhydrin. Yale Journal of Biology & Medicine 29 :87, 149. Lawrason, F. D., Eltzholtz, A. C., Sipe, C. R., and Schork, P. K. Correla- tion between the Mean `Corpuscular Volume and Reticulocytosis in Phenylhydrazine Anemia in Swine. Blood 4:1256, 1949. Goodyer, A. V. N., Relman, A. S., Lawrason, F. D., Epstein, F. H. Salt Retention in Cirrhosis of the Liver. Journal of Clinical Investigation 29:973, 1950. Epstein, F. H., Lawrason, F. D., Relman, A. S., Goodyer, A. V. N. Studies in Salt Excretion *during Quiet Standing. Journal of Clinical Investigation 30 :63, 1951 Erslov, A. J., Iverson, `0. K., and Lawrason, F. P. Cortisone and ACTH in Hypopiastic Anemia. Yale Journal of Biology & Medicine 25:44, 1952 Wagner, R. and Lawrason, F. D. The `Production of Fever by Influenzal Viruses. IV. Effects of ACTH and Cortisone. Lawrason, F. D., Alpert, E., Mohr, F. L., and McMahon, F. G. Ulcera- five-Obstructive Lesions of the Small Intestine. Journal of the American Medical Association 1.9 :641-44, 1965 VII. Present position: Vice President for Medical Affairs, Merck, Sharp & Dohme Research Laboratories, West Point, Pa. Dr. LAWRASON. Mr. Chairman, members of the committee: My major responsibility is the clinical investigation of Merck drugs, as `a member of a team of 40 physicians who are devoting their careers to this work. The clinical investigation of indomethacin has been my responsibility. PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3317 In this statement, I have four points to make: First, indomethacrn is a useful drug for the treatment of at least four different forms of arthritic disease It is effective and safe as described to the medical profession Second, Merck answers to its own standards of research as well as to the regulatory judgment of this country and other countries throughout the world. Our standards are based upon several decades of notable accomplishments in medical research, and we give ground to no one as to the integrity of our standards and performance. Third, the validation of the merits of our work since our studies began in 1961 up to the present can be found in the collective judgment of several hundred investigators of recognized authority in this country and abroad Fourth, there does not exist in this world today a generally accepted test design for the study of drugs or of any other type of therapy in rheumatoid arthritis. If there were, we would be the first to use it. Mr. Chairman, I shall explain what we do in the study of drugs in rheumatoid arthritis. In addition, I want to point out what neither we nor others can do to study drugs in this field and why the studies conducted on indomethacin fully warrant its right to be available for physicians who wish to prescribe it for their patients The study of indomethacin in man dates back to 1961. At that time the cooperating clinics project of the American Rheumatism Associa tion was still in the primitive stages of its long effort to improve chrn cal design in this field We faced the task of studying a new drug shown in animal testing to possess anti inflammatory activity corn parable to steroids. The patients could not wait, nor would we wait for the design of a wholly satisfactory double blind study for rheumatoid arthritis We performed what was the best method of study in 1961, and what still remains the best method in 1968 We took the drug to a handful of expert physicians in rheumatology. They began with very low doses, gradually increasing them Under careful observation they determined the patients' positive or negative reactions When these men told us the drug worked-that it provided relief of pain and reduction in inflam mation-we accepted their judgment, both because of their knowledge and experience and also because it provided significant confirmation of the laboratory and animal work that had preceded it. After that we put the drug in the hands of additional specialists having particular expertise in a variety of arthritic disorders-rheumatoid arthritis, spondylitis, gout, osteoarthritis, musculoskeletal disorders, and so forth. As experience with the drug accumulated, we obtained the co- operation of investigators in more than 60 major medical centers in the United States and abroad. If the committee wishes, I will provide a list of these institutions for the record. Senator NELSON. If you would, please. (The document referred to follows:) 81-280 O-65----pt. 8-i5 PAGENO="0226" 3318 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY LIST OF INTERNATIONAL INSTITUTIONS WITh WHICH INDOCIN ® INVESTIGATORS (ORIGINAL NDA) ARE ASSOCIATED Buenos Aires Hospital, Argentina Sahlgren Hospital, Gutenberg, Germ- Institute of Rheumatology, Argentina any. Karolinska Institute, Stockholm, St. Erik's Hospital, Sweden. Sweden St. Stephen's Hospital, London, Eng- Marion General Hospital, Manila, land. Philippines Tokyo University Hospital Tokyo Medical Institute of Rheumatology, Japan.~ Bogota, Columbia Tokyo Women's Medical College, Tokyo, Military Central Hospital, Lima, Peru Japan. National School of Medicine, Mexico University of Florence, Florence, Italy. Norfolk and Norwich Hospital, England University of Frankfurt, Frankfurt, Osaka University Hospital, Japan Germany. Oslo University Hospital, Norway University Hospital of Cork, Cork, Okayama University Hospital Japan Ireland. Queen Elizabeth Hospital, Adelaide, University Hospital of Wurzburg, Australia Germany. Royal North shore Hospital, Australia University of Paris, Faculty of Medi- Royal Perth Hospital, England cine, Paris, France. Royal Prince Alfred Hospital, Australia University of Vienna, Austria. Royal Victoria Infirmary, England. Westminster Hospital, London, Eng- RheumatolO~ Foundation Hospital, land. Finland. Kyushu University, Japan. LIST OF DOMESTIC UNIvERsITIES AND HOsPITALS WITH WHICH INDOCIN® INVESTIGATORS ARE ASSOCIATED Arkansas University Medical Center. Tulane University School of Medicine. Boston University Medical School UCLA School of Medicine Buffalo University School of Medicine. UCLA Medical Center. Children's Hospital (University of University of California Medical Center. Iowa). University of Chicago School of Colorado University Medical Center. Medicine. Columbia University College of Physi- University of Miami Medical School. cians & Surgeons. University of Michigan School of Cornell University School of Medicine~ Medicine. Duke University Medical Center. University of Minnesota Medical School. George Washington School of Medicine. University of Oregon Medical School. Harvard Medical SchooL University of Pennsylvania School of House of the Good Samaritan (Boston). Medicine. Johns Hopkins University Medical University of Southern California Med- School. ical School. Long Island College Hospital. University of Tennessee College of Maryland University School of Mccl- Medicine. icine. UtS. Naval Hospital Newport, R.I. Massachusetts General Hospital. Utah University Medical School. Methodist Hospital (Brooklyn). Vanderbilt University School of New York University School of Medicine. Medicine. . Veterans' Administration Hospital Palo New York University Medical Center. Alto California Medicine University School of Veterans' Administration Hospital, Oklahoma University School of Philadelphia, Pa. Medicine. Washmgton University School of Oregon University MedIcal School. Medicine. Stanford University School of Medicine. Western Reserve University School of Texas University Southwest Medical Medicine. School. Yale University College of Medicine. PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3319 Dr. LAWRASON. At this point, several of the investigators employed a controlled-study method known technically as placebo substitution. This is a highly useful method of confirming drug action. it is a single-blind study. Here the patient is placed on various medications including placebo at different stages, but does not know when the dif- ferent drugs, which are identical in appearance, are being added or removed. These studies confirmed that the therapeutic response ob- tained on indomethacin was due to the drug, since the symptoms rapidly returned when the patient was given the placebo medication. In the 1961-65 period we are discussing, this method was not only sound but respected. Even though criticized earlier in these hearings, it still~-remains valid today. The skilled physician, deeply concerned over the patient's comfort and progress, soon learns the characteristic pattern of the fluctuations in the activity of the individual's disease. By his experience he easily recognizes an exacerbation of symptoms of the disease, and he is able to regain control with reinstitution of the effective therapy. To imply that these clinical investigators purposely choose to institute placebo at the point in the patient's disease when the patient is about to experience an exacerbation of his illness is sheer nonsense and is a reflection on the scientific integrity of the observer and also on his moral character. Mr. GORDON. May I interrupt here just a moment? Dr. LAWRASON. Yes, sir. Mr. GORDON. I do not like to be in a position of defending any previ- ous witness, but it seems to me that if a writer points out a flaw in an lnvestigative method, I do not t'hink he is thereby imputing dishonesty, is he? Dr. LAWRASON. I do not believe this was said, Mr. Gordon. I believe the implication was that one could give a placebo or an active com- pound, and then at the time one expected an exacerbation to occur or a remission, a change in the cyclic character of the disease, the investi- gator would change medication. This is what this refers to. Mr. GORDON. Yes, but it does not necessarily impute dishonesty, does it? Mr. GADSDEN. Even though I am not a doctor, I think the implied criticism of the single-blind study is that it is open to this kind of variation. If this criticism is implied, then I think Dr. Lawrason's comments are appropriate. Dr. LAWRASON. I would like to refer to Dr. O'Brien's testimony, in which he said that a study of this type-namely, the single-blind placebo-was designed in such a way that the bias is in favor of the drug. Mr. GORDON. That is a statistical bias, I would think. At least, that is the way I understood it. Dr. LAWRASON. He did not say "statistical." Mr. GORDON. Well, we are talking about statistics. As I said, I do not want to defend anybody, but my understanding is that the bias was a statistical bias rather than a personal bias. But I do not want to read meaning into his words. Let me ask you this: In referring to the 1961-65 period, are you implying that clinical trials using control groups were not used before 1961? PAGENO="0228" 3320 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr LAWRASON No, the double blind study is not new It has been used for many years However, the difficulties involved in rheumatoid arthritis includes the subjective character of the observations to be made It is extremely difficult to construct a valid control study under these conditions, where active therapy is usually in the background Mr GORDON Have you any idea how many years controlled trials have been in use? I am not saying double blind, necessarily, but controlled. Dr. LAWRASON. Are you referring to clinical controls? Mr. GORDON. Yes, well-controlled clinical trials. Dr LAWRASON This is nothing new I would hazaid `t guess of 20 years or more. Mr GORDON You may be interested to know that as `t result of some research, I discovered that well controlled clinical trials were con ducted in the 18th century, about 225 years ago it is in this book by Lind "On Scurvy," that discusses CL wonderful trial he did, and I am going to include it in the record at this point, with the permission of the chairman. It is a short description of this particular trial. (The article follows:) [From Lind's Treatise on Scurvy, edited by C. P. Stewart and D. Guthrle, University of Edinburgh Press, pp. i45~-i46] OF THE PREVENTION OF THE SCURVY As the salutary effects of the prescribed measures will be rendered still more certain and universally beneficial where proper regard as had to such a state of air diet and regimen as may contribute to the general intentions of preserva tion or cure; I shall conclude the precepts relating to the preservation of seamen, with shewing the best means of obviating many inconveniences which `attend long voyages, and of removing the several causes productive of this mischief. The following are the experiments. On the 20th of May 1~T47, I took twelve patients in the scurvy, on board the Salisbury at sea. Their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of their knees. They lay together in one place being a proper apartment for the sick in the fore hold and had one diet common to all viz water gruel sweetened with sugar in the morning fresh mutton broth often times for dinner at other times puddings boiled biscuit with sugar &c and for supper barley and raisins rice and cur rants sago and wine or the like Two of these were ordered each a quart of cyder a day Two others took twenty five gutts of eluoir vitriol three times a day upon an empty stomach using a gargle strongly acidulated with it for their mouths. Two others took two spoonfuls of vinegar three times a-day, upon an empty stomach; having their gruels and their other food well acidulated with it, as also the gargle for their mouth. Two of the worst patients, with the tendons in the ham rigid, (a symptom none of the rest bad), were put under a course of sea-water. Of this they drank half a pint every day, and sometimes more or less as it operated by way of gentle physic Two others had each two oranges and one lemon given them every day These they eat with greediness at different times upon an empty stomach They continued but six days under this course, having consumed the quantity that could be spared The two remaining patients took the bigness of a nutmeg three times a-day, of an electuary recommended by an hospital surgeon made of garlic mustard seed rad raphae balsam of Peru and gum myrrh using for common drink barley water well acidulated with tama rinds by a decoction of which with the addition of cremor tartar they were gently purged three or four times during the course. The consequence was, that the most sudden and visible good effects were per- ceived from the use of the oranges and lemons; one of those who had taken them, being at the end of six days fit for duty. The spots were not indeed at that time quite off his body, nor his gums sound; but without any other medicine, than a gargarism of elicoir vitriol, lie became quite healthy before we canw into Plym- outh which was on the 16th of ~une The other was the best recovered of any in PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3321 his condition; and being now deemed pretty weU, was appointed nurse to the rest of the sick. Mr GORDON So I might point out to you that a well controlled trial was conducted as far back as the 1700's. Mr. GADSDEN. I think the thrust of the remarks of the witness, Mr. Chairman, deals strictly with whether, in order to have a well con trolled test, it must be a double blind. Senator NELSON. Please go ahead. Dr. LAWRASON. When we take a drug such as indomethacin to the clinic, we go to the expert in the relevant discipline or specialty. We bring him in as an independent but full-fledged member of the research team. He collaborates in the planning and execution of the studies. Such experts are experienced investigators whose judgment is re- spected. They are independent in their actions and decisions. Their research is supported with grants for studies that often yield negative as well as positive results. I stress this relationship because we rely heavily on these investigators for the acquisition of objective observa- tions and data on the effectiveness and safety of our drugs. The experience and authority of the physicians who studied indo- methacin, and whose judgments provided the basis for the approval of the drug, is evidenced by the following facts. Two-thirds of the indomethacin investigators in this country were Board-certified in their specialty, which is an unqualified endorsement of their training and experience. Three-quarters of them had full-time appointments with a university or a teaching hospital. Over half of them were active members of the American Rheumatism. Association. I can say that the major investigations were carried out by some of the most eminent members of the American Rheumatism Association. I would like to emphasize that we also went to the best clinics and hospitals throughout the world. These institutions are under the direc- tion of distinguished rheumatologists. They came to the same conclu- sion regarding the effectiveness and safety of indomethacin as did the chemical investigators in this country. If the cumulative judgment of this body of men is taken into account, the committee and the Food and Drug Administration, and the physicians and patients using indomethacm can be assured that the value of the drug was confirmed in the clinical judgment of an outstanding group of physicians. The criticisms that have been voiced earlier in these hearings about the testing of this drug do not repre- sent the majority of experienced medical opinion. The clinical program was completed in the spring of 1964. We had collected a large amount of data from 150 investigators here and abroad. The massive amount of evidence supporting efficacy and safety was submitted to the FDA for evaluation. It contained well-controlled studies and met the requirements of the preclinical and clinical stand- ards of the day It showed indomethacm to be safe and effective for the uses claimed. The application was approved by the FDA in June of 1965, after approximately a year of review, for the four indicated conditions for which it is labeled and promoted in the United States (oday. Senator NELSON. Those four are rheumatic arthritis Dr. LAWRASON. Rheumatoid arthritis, gout, rheumatoid spondylitis, and osteoarthritis of the hip. PAGENO="0230" 3322 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Is it indicated for any other purpose? Dr. LAWRASON. In this country, it is not. Senator NELSON. Do you get a different reaction in patients in another country? Dr LAWRASON In some of the other countries some additional con ditions for which we believe it is effective and safe for use are allowed. The Food and Drug Administration in this country has not allowed such other indications. Senator NELSON. Which are the others? Dr. LAWRASON. Osteoarthritis in general, rather than specifically of the hip, and musculoskeletal disorders, which involve numerous dis- orders such as bursitis. Senator NELSON. Why does not the FDA allow you to make these claims in this country? Dr. LAWRASON. I believe their reason is that they feel we have not presented them with sufficient evidence of its efficacy. Senator NELSON. Have you presented these other countries with evi- dence of its efficacy? Dr. LAWRASON. We have presented them with a great deal of evi- dence. There are a great many double-blind studies ongoing and com- pleted, and we expect within a very short time to present to the FDA evidence that will be convincing to them for efficacy and safety in thesi two indications. Senator NELSON. Well, now, in how many countries do you sell this drug? M~r. GADSDEN. Perhaps I ought to answer that. I cannot be specific with reference to this drug, Mr. Chairman, but our drugs are sold in approximately 100 countries throughout the world. Senator NELSON. Is indomethacin sold in these 100 countries? Mr. GADSDEN. I know drugs of Merck origin are sold in 100 countries. I do not have at the moment information as to whether "Indocid," is the trademark which is used abroad, is sold in all of these countries. I would assume that it was sold in the great majority of them. Senator NELSON. What proof did you present to these other coun- tries that indomethacin is effective for the additional uses that you mentioned? Dr. LAWRASON. In the original application, there was substantial evidence of its efficacy in these other indications. Since then2 we have submitted a supplement to the NDA which provided additional evi- dence as to its efficacy and safety. This same evidence has been presented to other regulatory agencies in other countries. When reviewed by these other agencies, they have come to the conclusion that it is safe and effective in these indications and have `allowed it use. Senator NELSON. Do each of these 100 countries have an agency. of scientists who evaluate the information you supply and make a judg- ment? Mr. GADSDEN. May I respond to that, sir? Senator NELSON. Yes. Mr. GAD5DEN. The answer, as I think you might know, is that not all do have such an agency. It is the more developed countries, particularly of Western Europe that do, and even there not all of them. But I would agree with you if your point is that there are countries which do not have such regulatory control. PAGENO="0231" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3323 Senator NELSON. This puzzles me a little bit, not necessarily about this drug in particular2 but about any drug. If the country does not have a qualified scientific agency to make a judgment, then a drug can be advertised and sold for any purpose the company desires to sell it for, can it not, regardless of whether it is indicated or not? Mr. GADSDEN. I would have to agree that it could be, but I do not think a responsible company would do so, sir. Senator NELSON. We had the case here of chloramphenicol being promoted in Great Britain with no precautions being given in the ads at all. At the same time, the firm testified here that it agreed that all the specific precautions in the package insert required here were important and necessary and should be listed. Yet in Great Britain and other countries, the firm said it did not list these because the law of those countries did not require them. What I am getting at is the claims of the company that they follow a very ethical, high standard. Yet here is a clear-cut case where as soon as there are no regulations, they promote the drug for a purpose which is illegal in this country, and without any precautions, contrary to the best testimony of all the medical experts in America. Mr. GADSDEN. Sir, I do not want to be put in the position of talking about whether the conduct of a competitor was appropriate or not. But if you like, I have a statement here which I would be happy to read indicating that the British Pharmaceutical Association, working with the appropriate medical and regulatory bodies in England, concluded that-in advertising-it was undesirable to put such contraindications and warnings in the advertisement when it was a so-called reminder advertisement. I think that the earlier witness who was questioned on this, if my memory is correct, was perhaps not conversant with the subject of advertising. Senator NELSON. What is your definition of a reminder ad? Mr. GADSDEN. In this case, sir, this is one- Senator N]~SoN. In any case, what is, in your industry, the definition of a reminder ad? Mr. GADSDEN. I shall have to give you several definitions, sir. In the United States, the Food and Drug Administration has taken a very narrow definition of what is a reminder ad and we comply with that. In England, with the agreement of the British medical group and the appropriate governmental authority, it was stated that if there was no dosage indication which would be helpful to the physician in prescribing the product, that is a reminder ad. The editor of the Brit- ish Medical Journal said he considered it an insult to the intelligence of the British physician to include such material. Senator NELSON. So, that is different from the reminder ad in America, in which you cannot include any language indicating the usage of the drug; is that correct? Mr. GADSDEN. Yes. Senator NELSON. But you can in England and you need not put any warnings or precautions about its use in the ad; is that correct? Mr. GADSDEN. It is a broader definition in England, where the defi- nition of a reminder ad is any advertisement in which information with reference to dosage is eliminated. Senator NELSON. In this country? PAGENO="0232" 3324 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GADSDEN. No, sir; I said in Great Britain. Senator NELSON That is not a reminder ad in this country In other words, you usually do not put dosages in your ads any~ ay, do you, in this country or in any country~ Mr GADSDEN We frequently do, sir, in this country I think the basic point, which is perhaps going to crop up on several occasions, is that when you are an international company and doing business in a variety of countries, quite naturally your foreign subsidiaries must con duct themselves in accordance with the local practices, laws, and regu- lations of that country-which, in many cases, differ from the regula- tions in this country as promulgated by the Food and Drug Adminis- tration. Senator NELSON. How do you view the problem of a country that does not really have any agency for evaluating drugs at all ~ Mr GADSDEN Well, I think we get back to the statement of one of our scientific witnesses-I trust you will permit me to speak just for Merck & Co., because I am neither authorized nor competent to speak for anyone else-that we have our own internal code of ethics with reference to what is appropriate. When, in the opinion of our medical research group, it is concluded that a statement is appropriate to make in these countries, the medical research people have the authority to make the decision that it can and should be made. Senator NELSON What bothers me about that is that even in this country, there are disputes among the industry and doctors and the FDA about the promotion of drugs The argument on the part of those who think drugs are overprescribed is that it is the result of this type of advertising and promotion, despite the insistence of the FDA that package inserts contain certain warnings and contraindications and so forth. The consequence of the advertising, in any event, is that many drugs are widely overprescribed for nonindicated cases. At least, the testimony we have had on some drugs from experts is that this is the fact. So the result of the advertising and the promotion, even with FDA monitoring what is said in the package insert and in the advertising, is overprescription of many drugs for nonindicated uses If that is the case in this country where you have a regulatory agency, it cer tainly must be the case in those countries where you do not have one. It seems to me that there should be in that instance, very important internal restraints upon a company advertising in such a country Mr GADSDEN I would agree with you, sir But if you have a code of morals and ethics, you must adhere to it and not take advantage of the fact that you may not get caught somewhere. Senator NELSON But let me proceed with this If you have an underdeveloped country, or any country without a sophisticated scien- tific community and without a regulatory agency so that it cannot protect itself, what is your standard of guidance for advertising in that country ~ Mr GADSDEN Our standard of guidance, sir, is whatever has been approved by the scientists of Merck as the appropriate medical posi tioning of the product. Senator NELSON. Then you do not use the standard of what is approved by FDA in this country? Mr. GADSDEN. No, we do not. PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3325 Senator NELSON. So you feel that your company, or any company, ought to be able to decide on its own what the standard will be in a country which has no scientific community or regulatory agency at all ~ Mr GADSDEN No, sir, I do not think I have said that Senator NELSON That is exactly what you said, that you decide what the standard is Mr. GADSDEN. I beg your pardon, sir? Senator NELSON. Please repeat what you have said. Mr. GADSDEN. I said that in this malter, Merck & Co.-and I refer to `my earlier statement that I speak only for Merck & Co.-we have a code of ethics and principles. We assume responsibility for the posi- tioning of the product. This reference to this w'as made in Dr. Lawra- son's statement, I believe We hold our medical staff responsible They must approve what is said, whether it be in the United States or any country of the world. This, for Merck, is the restraint under which we operate Senator NELSON. I di'd not get the distinction between what you said and what I said I said you set the standard Mr. GADSDEN. Sir, may I paraphrase what I understood you to say? I think you said, if I understand you correctly, that it is appropriate for Merck or any other company, in countries where there are no regulating agencies, to say what it wants in advertising. Senator NELSON. To set your own standard, I think I said. Mr. GADSDEN. I am sorry, perhaps I misunderstood you. Senator NELSON That is what I intended to say In other words, you are saying that in another country where there is no scientific community to evaluate the evidence you have, a company sets its own standards without any outside control. Is that what you have said? Dr. LAWRASON. Mr. Chairman, may I just say that we do not set separate standards for different countries. We have a single `standard at Merck. Senator NELSON. You mean you run precisely the same ad in the Philippines that you run in the British Medical Journal? Dr. LAWR~SON. No, I am referring to how the drug can be used and what indications are to be cited-in other words, the claims made for the drug and which disease's it should be used for. Senator NELSON. I do not quite follow that. The FDA will not permit you to use it in this county for-what were `the indications? Dr. LAWRASON. Osteoarthritis. Senator NELSON. And that involves tendonitis? Dr. LAWRASON. No, sir; that was the musculoskelatal. Senator NELSON. And that involves tendonitis and bursistis. The FDA says you cannot use it because you have not submitted, `a~ far as they `are concerned, satisfactory evidence or proof of its efficacy, for those conditions. Dr LAWRASON That is correct Senator NELSON. Now you go to England and you advertise it for that purpose, and the British will say that it is all right for that purpose. Then, you may go to another country and they will say it is all right for all the purposes you use it for in America plus one other, but not two. Then you go to another country, that has no scientific eommumty, `and you claim that it is good for some other purposes and you advertise it and sell it for those purposes in that country if your PAGENO="0234" 3326 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY scientists and you come to the conclusion that it is useful for those purposes, would you not? `Mr. GADSDEN. Perhaps I should explain to you, sir, what is the procedure. In the internal workings of Merck & Co., a scientific and medical evaluation is made which ultimately results in an application for new drug approval. The thing I want firmly on the record, in case there is any question about it, `is that we do not sell abroad-I think I am right-anything for which approval has not been requested of the Food and Drug Administration in the TJrnted States Senator NELSON. I do not understand. Mr. GADSDEN. Well . . . if we are not willing to report it to the Food and Drug Administration, we are not going to say in an under- developed `country that it will cure something for which we are not requesting approval in `the United States. Senator NELSON I understand But if you request approval in the United States for its use for a certain purpose and the FDA says that so far as they are concerned, your scientific submission of evidence does not support its use for that purpose, and they turn you down, you still will sell it for that purpose in an underdeveloped country that has no scientific community at all? Mr. GADSEN. Yes, sir; we will. Senator NELSON. I am not `saying th'at some company may not make a mistake; it may turn out to be right and the FDA wrong. The prin- ciple that bothers me is there are l'ots of companies in this business that may not be as coiiscientious as Merck, and you will end up with all the companies supplying drugs to other countries that do not have drug `standards, so th'at a drug might be used for purposes that it should not be. We have had testimony here that drugs which could not be sold in this country because they did not meet U.S.P. standards were shipped overseas-not your company. I am just raising the question, because it seems to me that if that testimony was correct on subpotent drugs which could not go on the market here being sold in Sou'th America, I think it ought to be explored from the stand- point of some legislation. I do not t'hink anybody ought to have a license to put drugs on any market that do not meet a reasonable stand- ard in this country. Mr. GADSDEN. I agree with you. but I `think you yourself said earlier that there are differences in medical opinion, and this can result in the Food and Drug Administration's concluding in `all sincerity that they do not think the evidence complies with the law and regulations under which they operate, and yet in the opinion of t'he American scientists it is believed that there is substantial evidence. Senator NELSON. That is bound to be the case; there is no question about that. While I am on that point, it is agreed, as I understand it, that indomethacin is not indicated for use in children? Dr. LAWRASON. Indomethacin? Senator NELSON. That is right. It is not indicated for use in chil- dren; is that correct? Dr. LAWRASON. It is contraindicated in this country at the request of the Food and Drug Administration. Senator NELSON. Is it indicated in other countries for use in chil- dren? PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3327 Dr. LAWRASON. There are other countries that feel the indications for the efficacy and safety of the drug warrants its being used in children; that is correct Senator NELSON I think it is an interesting point just to put into the record at this stage on the question of uses of the drug in this country that in a study done by Modern Medicine of August 1, 1966- I will submit it for the record so I do not have to go through it all- it was found that within 1 year after it went on the market indo methacin was used in pediatrics by 9 4 percent, I believe, of pediatri cians who answered questionnaires, 94 percent of the pediatricians were using indomethacrn despite the fact that the I~ DA has not approved it for pediatric use in this country Mr CUTLFR Could you give us the date, Senator Nelson ~ Senator NELSON Yes, the results of the poll appear in the August 1, 1966, issue of Modern Medicine Mr CUTLER What was the date of the poll, sir ~ Does that show ~ Senator NELSON Well, let me see It was published August 1, 1966 It may be in here, but I do not see the date of the poli (The document referred to follows:) PAGENO="0236" How do physicians treat rheu- matoid arthritis today? Are there notable differences from region to region~ Between internists and physiatrists' Be tween large cities and small towns' Some of the answers are on the following pages. This report contains the most important portions of the analyses carried out on the basis of a questionnaire sent to all Modern Medicine readers. No attempt at this time is made to present or detail all of the analyses, or to comment on the significance of these analyses. It is the purpose of this report to present the findings with- out expression of either approval or disapproval. The fact that nearly 12,000 phy- sicians took time from their busy lives to answer this ques tionnaire on rheumatoid arthritis demonstrates a high degree of interest and provides considerable validity to the answers obtained in the questionnaire. Continued reader cooperation with future questionnaires will provide readers and editors with an interesting and revealing series of shared expe- riences. IRVING S. WRIGHT, M.D. Editorial consultant WYMAN E. JACOBSON, M.D. Associate Editor A Special Preprint fro,n MODERN MEDICINE August 1, 1966, pp. 75-90 Copyright 1966, Modern Medicine Publications, Inc. Printed in U.S.A. 3328 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MODERN MEDICINE S / Poll on Medical Practice RHEUMATOID ARTHRITIS PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3329 Poll /RHEuMATO1D ARTHRITIS 11,603 Respond to Questionnaire Of the 11,603 physicians who responded to the questionnaire, 5,694 (49.1%) reported that they had treated patients with rheumatoid arthritis within a period of thirty days. Of those reporting treatment, 50.1% were general practitioners, 28.2% internists, 5.5% orthopedic surgeons, 5.4% pediatricians, 2% surgeons, 1.1% physiatrists, and 7.7% other specialists (Fig. 1). Nearly eight out of ten physicians who treated patients with rheumatoid arthritis were either general practitioners or internists. An open end questionnaire was employed to eliminate or reduce to a minimum the fac tors which might cause an intrinsic bias or result in responses based on th~ correct answer rather than on the true prac tice of the~p~iysician Accuracy of the responses was consid ered best achieved by short recall-thirty days-which in most instances would not require review of patients' charts or lead to unreliable guesses. One-half of the physicians re- porting therapy treated no more than one new case and no more than four follow up cases of rheumatoid arthritis in a thirty day recall period Analysis of treatment Table 1 represents the analysis of treatments employed and of patients treated for rheuma- toid arthritis during the thirty-day period. The 5,694 physi- cians used an average of 2.72 methods of treatment and treated a total of 104,010 patients. Major categories of meth- ods used were systemic drug treatment, nondrug treatment, and external drug treatment in a small sample method of treatment was unknown or not clearly indicated. The cate- gories of systemic drugs included [11 analgesics and combi- nations, [21 adrenal steroid hormones and combinations, [3] gold, [4] nonsteroid anti-inflammatory drugs, and [5] a group of miscellaneous drugs, none of which was utilized to any large extent even when the agents were combined in sub- groups on the basis of chemical or pharmacological charac- teristics. PAGENO="0238" 3330 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 5.4~ ii Orthopedic surgery Pediatrics Physical medicine Surgery Others Fig. 1. Type of practice of physicians who treated rheumatoid arthritis during thirty-day period I (AL I 7-7 Internal medicine 28.2 I 2.0 I 1.1 PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3331 Poll /RHEUMATOID ARTHRITIS Table 1. Methods of treatment used for rheumatoid arthritis Number Percent of Percent of patients Category treatments of patients mentioned per mentioned mentioned treatment mentioned systemic drug treatment 87 1% 79 6% 6 13 Analgesics and combinations 25.9% 28.4% 7.37 Aspirin, salicylates, and salicylate compounds 24.1 26.8 7.43 Other or unspecified 1.8 1.6 6.43 Adrenal steroid hormones and combinations 22 2/0 16 2% 4 87 Cortisone and combinations 1 8 1 4 5 15 Prednisone and combinations 5 4 3 1 3 82 Prednisolone and combinations 1 9 1 4 4 73 Methylprednisolone and combinations 1 5 1 0 4 36 Triamcinolone and combinations 1 6 1 0 4 35 Dexamethasone and combinations 1 7 1 1 4 46 Hydrocortisone and combinations 0 5 0 3 4 55 Other corticosteroids or unspecified and combinations 6 6 5 9 6 03 Adrenocorticotropic hormone 1 2 1 0 5 13 Gold 55% 48% 590 Nonsteroid anti-inflammatory drugs 27.4% 22.1% 5.41 Indomethacin 17.3 14.3 5.56 Phenylbutazone 8.2 5.8 4.74 Chforoquine 1.9 2.0 6.97 Miscellaneous drugs 6 1 / 8 1°/ 8 96 Muscle relaxants 06 07 853 Tranquilizers and sedatives 06 07 868 / Vitamins 13 20 1039 Narcotics and combinations 0.3 0.3 8.14 Anabolic agents 0.1 0.2 9.71 Vaccines 0.3 0.5 10.20 PAGENO="0240" 3332 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Number Percent of Percent of patients Category treatments of patients mentioned per mentioned mentioned treatment mentioned Systemic drug treatment (cont) Antibiotics and chemotherapeutics 0 5 0 5 6 15 Coichicine and combinations 0 2 0 3 9 19 Probenecid and combinations 0 1 0 1 5 35 Nonadrenal hormones 03 0 4 9 56 Others 18 24 910 Nondrug treatment 11.5% 19.4% 11.33 Physical therapy 9.6% Heat 23 Rest 1.9 Exercise 13 Other or unspecified 3.8 Osteopathic manipulation 0 3 Surgery 10% Miscellaneous nondrug treatment 0.9% 16.9% 11.84 3.4 10.11 3.2 11.38 2.3 11.62 7.4 13.05 0.6 13.58 0.8% 5.46 1.7% 12.50 0.0 4.56 1.4 14.21 0.3 10.69 0.0 3.17 0.2% 6.42 1.2% 0.8% 4.60 100.0% 100.0% 6.71 (15494) (104010) * X-ray Diet Psychotherapy Other or unspecified External drug treatment Therapy unknown or unclear 0.1 0.6 0.2 0.0 0.2% Base PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3333 Analgesics and combinations Adrenal steroid hormones and combinations lndomethacln Phenylbutazone Nondrug treatment Miscellaneous drugs Gold Chloroqulne Analgesics and combinations Indomethacin Adrenal steroid hormones and combinations Gold Chioroquine i Miscellaneous drugs Nondrug treatment Analgesics and combinations Adrenal steroid hormones and combinations Indomethacin Phenylbutazone Miscellaneous drugs Gold 1 Gel~eraI practice J Intt mcli P011/ RHEUMATOID ARTHRITIS Fig. 2. Treatment of rheumatoid arthritis according to type of practice 65.0 54.8 I 23.9 15.9 I 14.6 Ia-I 178.2 51.1 50.6 Nondrug treatment 26.3 Phenylbutazone I 23.~ F; ii I I 46.2 67.2 42.. ii a I c i i e liic ~ry 39.0 19.8 I Orthü S U r 1151 I 1161 t 40 50 60 Chloroquine 0 10 20 30 PER CENT t 8 - 16 81-280 0 - 68 - p 70 80 90 100 PAGENO="0242" 3334 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Analgesics and combinations Adrenal steroid hormones and combinations 18.4 ft!L Nondrug treatment Indomethacin I Miscellaneous drugs 4 Gold 4.8 I Pedi trics S vi ________ Chloroquine I I I I I I 1.3 r ery Analgesics and combinations . Adrenal steroid hormones and combinations Indomethacin Nondrug treatment Phenylbutazone Miscellaneous drugs Gold Chloroquine 56.1 6.1 ~ 2.6J Nondrug treatment Analgesics and combinations Adrenal steroid hormones and conibinations Indomethacin I p5.4 I Physical medicine L 50.8 33.8 0.2 Phenylbutazone Miscellaneous drugs Gold I Chloroquine I fr' I 0 10 20 30 40 50 60 70 PER CENT 80 90 100 PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3335 P011/ RHEUMATOID ARTHRITIS Although the nonsteroid anti inflammatory drugs were prescribed more often than the other systemic agents, the three drugs included in this category- i ndomethaci n, phenylbutazone, and chloroqu i ne-are differ- ent enough to warrant individual consideration. The anal- gesics and combinations (primarily salicylates) accounted for more than one-quarter of all the treatments, the adrenal steroid hormones and combinations for slightly less than one- quarter and indomethacin for approximately one sixth In the nondrug treatment category, physical therapy was pre- scribed most often and accounted for about one tenth of all the treatments. The data on treatment were also processed in relation to the 104,010 patients receiving therapy. Some major differences were noted when the per- cent of patients mentioned was compared with the percent of treatments mentioned. Although the adrenal steroids were reported in almost one-quarter of the responses, these drugs were used in only one-sixth of the patients. The nonsteroid anti-inflammatory drugs were reported in 27% of the returns but used in only 22% of the patients, salicylates in one- fourth of the returns but in more than one-fourth of the pa- tients, physical therapy in one-tenth of the reports and one- sixth of the patients, and total nondrug therapy in one-tenth of the returns but one-fifth of the patients. In the data processing, medi- cations combining two or more of the major systemic drugs were included in the group in which the drug was consid- ered to have the strongest pharmacological action in the opinion of the medical editor. Thus, combinations of aspirin and adrenal steroids were included with the adrenal steroid hormones, since the predominant pharmacological action was considered to be due to the hormone. Methods of treatment by type of practice General practitioners and in- ternists utilized analgesics, adrenal steroids, gold, and indo- methacin to a greater extent than did the other specialists (Fig. 2). Among the 2,852 general practitioners who reported PAGENO="0244" 3336 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY treatment of rheumatoid arthritis during the thirty-day pe- riod 65% prescribed analgesics and combinations 548% adrenal steroid hormones and combinations, 53 1% indo methacin 23 9% phenylbutazone, and less than 20% any of the other single categories. Among the 1,606 internists, 8 out of 10 prescribed analgesics and combinations, 5 out of 10 indomethacin or adrenal steroid hormones, 2.5 out of 10 gold, and 2 out of 10 phenylbutazone or physical therapy. This is in sharp contrast to the 310 pediatricians, who relied primarily on analgesics and combinations (5 out of 10) but only infrequently prescribed i ndomethaci n, phenylbutazone, or gold. It is of considerable interest that the surgeons, or- thopedic surgeons, and physiatrists used adrenal steroids and indomethacin frequently (3 to 5 out of 10 physicians) but rarely used gold The internists used gold therapy much more often than did any of the other specialists. This analysis reveals major dif- ferences in treatment based on the type of practice, some of which are directly related to the nature of the specialty; ex- planations of other variations are less obvious. Fig. 3. Distribution of physicians by city size who treat rheu- matoid arthritis PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3337 Poll/RHEUMATOID ARTHRITIS Variations in treatment based on other factors The data were evaluated in re- lation to age of the physician, size of the locality in which the physician practiced, and the geographic location on a national basis. Of the 5,694 physicians who reported treat- ment of patients with rheumatoid arthritis, one-fifth were in cities of 500,000 or more population and one-sixth in com- munities of under 5,000 (Fig. 3). Physicians in smaller cities and towns prescribed indomethacin more frequently than did physicians in larger cities: 55% of physicians in areas of under 5,000 persons, but only 38% of those in cities of 500,000 people or more, prescribed indomethacin. On the other hand, physical therapy and surgery were employed more frequent- ly in the larger cities than in communities of under 5,000 population. The methods of treatment var- ied with the age of the physician, but only a couple features were rather prominent. Physicians age 65 years or older used gold only about half as frequently as did those age 64 or younger. Physicians 35 to 64 years of age used gold therapy with about the same frequency. Physicians under 35 years of age used adrenal steroid hormones less frequently than did the middle-aged and older physicians. However, the younger physicians used indomethacin and surgery considerably more often than did the physicians age 65 or over. Results of treatment Obviously, the most difficult evaluation is that related to the results of treatment. The questionnaire made no attempt to provide any more than a crude estimate by the attending physicians as to the nature of the response. Physicians were asked to estimate the per- centage of patients who apparently recovered, showed im- provement, and showed no improvement and in whom the condition was arrested. The results of this evaluation are shown in Table 2. Approximately two-thirds of the patients who were treated either showed improvement or apparently recovered. PAGENO="0246" 3338 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY . Mean average percent Apparent recovery improvement shown Condition arrested No improvement shown 5 60 19 16 Total (Base: 4,477) 100 Major changes in treatment from 1949 to 1966 In 1949, Modern Medicine at- tempted to evaluate the treatment of rheumatoid arthritis. Results of that survey were compared with those of the 1966 study (Table 3), though the two surveys were not comparable in question form. The 1949 questionnaire listed five specific types of treatment: drugs, vaccines, diet, physiotherapy, and orthopedic procedures. The obvious differences are in rela- tion to medications which were not available in 1949-name- ly, the adrenal steroid hormones and the nonsteroid anti-in- flammatory drugs. The analgesics and combinations accounted for approximately one-third of the treatments in both studies. Gold was used almost twice as frequently in 1949 as in 1966. The large miscellaneous group in 1949 included drugs only. Vaccine was used in 27% of the prescriptions in 1949 but in only 0.9% in 1966. Table 3 Comparison of drugs prescribed in 1949 and 1966 1949 1966 Percent Analgesics and combinations 32.7 29.7 Adrenal steroid hormones and combinations - 25.6 Gold Nonsteroid anti-inflammatory drugs 11.5 - 6.3 31.4 Miscellaneous 55.8 7.0 Total Table 2. Results of treatment of rheumatoid arthritis (esti- mated percentage of cases) 100.0 100.0 PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3339 Poll/RHEuMATOID ARTHRITIS Fig. 4. New cases and follow-up cases of rheumatoid arthritis treated during a thirty day period New cases treated Mean 1 2 3 4 5 6 7 8 9 10 All physicians 2 55 Physiatrists ~4.44 Orthopedic surgeons 40 Internists 2.61 General practitioners . . Surgeons 2.51 / Follow-up cases treated All physicians Physiatrists 9.78 4 j Internists 9.11 4 4 1~I Orthopedic surgeons 80~ ~ General practitioners * Surgeons 5.79 4 4 4 PAGENO="0248" 3340 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The physician and rheumatoid arthritis patient population The physiatrists had the largest mean average (4.44) of new cases during the thirty-day period. The orthopedic surgeons reported a mean average of 3.40 new cases, the internists 2.61, the general practitioners 2.59, and the surgeons 2.51 (Fig. 4). Although the mean average of new cases for all physicians was 2.55, the median average was 1.00, i.e., 50% of the physicians had more than one new pa- tient and 50% had less than one. The physiatrists also had the largest mean average (9.78) of follow-up cases of rheumatoid arthritis during the thirty-day period. The internists had a mean average of 9.11 such cases, the orthopedic surgeons 8.03, the general practitioners 7.47, and the surgeons 5.79 (Fig. 4). Although the mean average of follow-up cases for all physicians was 7.47, the median average was 4.00, i.e., 50% had more than four follow-up cases and 50% had less than four. The questionnaire and its validity The questionnaire on rheuma- toid arthritis (Fig. 5) was included in all copies of the March 14, 1966, issue of Modern Medicine. Four weeks after release Fig. 5. Doctors were asked these questions: 1. Do you attend patients with rheumatoid arthritis? Yes________ No________ 2. How many patients have you seen for the first time with rheumatoid arthritis during the past 30 days?_____________ (number) 3. How many patients have you seen on subsequent visits for rheumatoid arthritis during the past 30 days?_____________ (number) 4. How did you treat the patients you saw during the past 30 days? 5. What results have you experienced over the past year with your treatment of rheumatoid arthritis? (Estimate by per- centage of cases.) PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3341 Pofl/ RHEUMATOID ARTHRITIS Type of practice General practice 3,200 Internal medicine 1,784 Surgery 1005 Obstetrics and gynecology 776 Pediatrics 710 Eye, ear, nose, and throat 639 Neurology Allergy Cardiovascular disease Physical medicine Thoracic surgery Preventive medicine Plastic surgery Colon and rectal surgery 27.6 34.4 15.4 12.9 8.7 9.6 6.7 6.9 6.1 5.7 5.5 5.8 4.2 5.0 3.3 2.9 3.2 3.2 2.9 3.4 2.6 1.5 1.7 2.0 1.4 1.4 1.5 1.3 1.1 0.4 1.0 0.6 Total 11,603 Table 4 Type of practice of physicians replying to question naire compared with that of total U S physician population Physicians replying Total U.S. to questionnaire physicians Number Percent Percent Psychiatry Orthopedic surgery Radiology Anesthesiology Dermatology Urology Pathology 484 380 372 340 299 193 192 170 126 111 70 66 58 53 52 40 21 462 0.6 0.6 0.5 0.5 0.4 0.3 0.2 4.0 Gastroenterology Pulmonary disease Other 0.2 0.6 0.3 0.5 0.3 0.2 0.2 0.7 100.0 100.0 PAGENO="0250" 3342 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of the questionnaire, more than 11,800 responses had been received. Of these, 11,603 were satisfactory for data proces- sing and tabulation: 3,200 from general practitioners, 1,784 from internists, 1 005 from surgeons 710 from pediatricians, 380 from orthopedic surgeons, 70 from physiatrists, and 4,454 from physicians of other specialties (Table 4). Almost all responders, classi- fied according to their specialty or primary type of practice, are represented in about the same proportion in the survey as in the national distribution of the physician population (Table 4). Among the general practitioners, 89.1% reported treating patients with rheumatoid arthritis, among the inter- nists 90%, among the physiatrists 90%, and among the ortho pedic surgeons 82.9%. Table 5. Regional distribution of physicians replying to ques- tionnaire and of all physicians in the United States , Region Physicians replying to questionnaire Number Percent All physicians in U.S.~ Percent New England 722 62 66 Mid-East 2,291 19.7 23.0 South Atlantic 1,413 12.2 12.7 Great Lakes 1,816 15.7 18.0 Mid-South 481 4.1 4.8 Plains 955 8.2 7.2 Southwest 856 7.4 7.9 Rocky Mountain 549 4.7 3.8 Far West 1,793 15.5 15.5 Pacific ` 55 0.5 0.5 Unknown 672 5.8 - Total 11,603 100.0 100.0 *source: Buckley Dement . PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3343 Poll /RHEUMATOID ARTHRITIS The large size of the response the representative distribution by all types of practice, and the geographic distribution of the responders are considered evidence for reliability of the data in this report. With only minor variations, the return on this poll was highly com- parable to the distribution of all physicians by states and regions. Table 5 shows this comparison for regions only, but the analysis by the editors included comparison for all fifty states. Questionnaires are often con- sidered somewhat suspect. It is therefore important that the objectives of the questionnaire. which we have presented for your help and ultimate information be restated. The diagnos- tic and therapeutic measures used by physicians are known to vary considerably. The factors associated with these dif- ferences are not known. Teachers in medical schools do not know whether their instructions and recommended forms of treatment have been adopted by their students. Those plan- ning postgraduate training courses do not know what their prospective matriculates have been using in their own prac- tices. Neither the American Medical Association nor the Department of Health, Education, and Welfare can provide detailed information on the actual practices-and the prac- titioner does not know what his confreres are doing. The pur- pose of this project is to answer some questions regarding certain leading causes of death and disability. The editors will compile the information which you provide as the prac- titioners representing different types of practice, all age groups, and wide geographic distribution. The aim is to determine what is going on. These findings are not to be considered as en- dorsement or condemnation of any form of treatment. The editors of this section will operate with complete indepen- dence and detachment in this regard. If others see fit to use this material to strengthen their teaching programs, to read further information into the various forms of treatment which appear to be widely used, or to vent their opinions in the literature regarding these findings, this series will have served some useful purpose. PAGENO="0252" 3344 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. The point I was making is we continue to have cases arise of drugs being used for conditions in which they are not indicated. The dramatic one was brought out in the `testimony of several distinguished doctors, including Dr William Damashek of Mount Sinai Hospital, th'Lt chloramphemcol ~ as being used at least 90 percent of the time in nonindicated cases So, despite the warnings in the package insert, the promotion of the drug or some other factor was causing doctors to prescribe it widely, as the testimony showed, for head colds, minor infections, acne, hangnails, and toe infections. We have cases by the dozens in my files, and testimony of deaths caused by Chioromycetin. All of them resulted from the drug having been given when it was not indicated. All I am pointing out is that we continue to get this kind of evidence. This committee is inter- ested in the question of drug promotion `and promotion resulting in the use of drugs in cases which are nonindicateci. The questionnaire I referred to was sent on March 14, 1966 Mr GADSDEN Sir, I think you will appreciate that we `Lre at some disadvantage in trying to comment on this because we do not have it If you will permit me, I would not like the record to show this juxta position between indomethacin and chioramphenicol I am not qualified to talk about chioramphenicol. I am prepared to talk about indo- methacin. Senator NELSON. I did not use that example to compare them at all. I was just saying that pediatric use of Indocin is not indicated in this country, and in this poll, 9 4 percent of the pediatricians who re sponded, were using it on occasion for this purpose I am only point in~ out that we hear evidence time after time about drugs that are being used for nonindicated purposes. I think that part of the cause for such misuse is the dr'Lmatic and effective promotion of the drug Mr. GADSDEN. Well, sir, as you know, I will be the last witness. I am sure you will have some questions for me on what we have done in the way of promotion for "Indocin." Senator NELSON. Senator Hatfield has a question. Senator HATFIELD. Doctor, there are a couple or three questions that come to mind at this point First of all, as I understand your testi mony, you indicated that you submit to the FDA a great mass of material, pretests, research when you are submitting a new drug for approval Do you feel that the FDA is presently equipped, both with manpower and staff generally, to handle this type of responsibility ade- quately? Dr LAWRASON I believe that it is generally recognized that this is a terribly difficult job-evaluation of drugs, review of all the infor mation, the data that `is submitted on each new application. My opin- ion is that they need every support and every bit of help, scientific and medical help, they can get to review these applications Senator HATFIELD Now, this mass of material that you submit-I understand, for example, that they have what, a staff of 170 to review 2,000 or more applications ~ Can they adequately and effectively read and review all of this mass of material that you and each other drug house submits for this New Drug Application? Dr. LAWRASON. I believe the past 2 or 3 years have been rather difficult times for the agency because they have had a backlog which PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3345 they, I believe, have effectively reduced or are effectively reducing. I am not quite sure that the 2,000 you are quoting is an ongoing total amount that is constantly before them. Senator HATFIELD. I think the figure is about 2,600, the latest figure that I obtained on that. Do you think it is possible in terms- Senator NELSON. May I interrupt you? I think the record ought to show, Senator, that the 2,600 represents active IND's. Senator HATFIELD. These are applications. Senator NELSON. These are active IND's, I believe. Mr. GADSDEN. I do not have that figure. Just to amplify Dr. Lawra- son's remarks, Merck and the industry have, over the years, supported the FDA in their applications for additional funds and additional people, because we are appreciative of the problems which they have in trying to deal with very complex subject matter. Senator NELSON. Testimony on this subject is in the record as of yesterday or the day before. Senator HATFIELD. I would like to be sure that we have the exact figure in relation to whether it is NDA or IND at this place in the record. Do you think there could be a better system devised, such as perhaps utilizing outside consultants, or do you think it should just be a bigger bureaucracy? Of course, you realize I do not have much faith in the bureaucracy that exists there now. But are you indicating to me that we should just add more and more staff to an already rather inefficient operation? Dr. LAWRASON. Senator, I would hate to make suggestions on how to solve some of these problems of the Food and Drug Administration. Senator HATFIELD. Would you like to comment on the bill that I have introduced to take all this away from the FDA and put it in the competent hands of the National Academy of Sciences? Dr. LAWRASON. I would not want to. Senator HATFIELD. You would not care to? Dr. LAWRASON. No. Senator HATFIELD. I understand why perhaps you might not want to at this point. What would you say as to the second problem that bothers me? That is that you indicate, like your other colleagues in the industry, that you accumulate a mass of material to have the FDA review and study for these approvals, but what kind of continuing research do you have? What kind of continuing program is there to review the effects after a longtime use of these drugs? I have at no point found any. satisfactory evidence that there is such a continuing research by indus- try or of review by Government on the effects that might occur after- not the initial efficacy or the purpose for which it was originally taken, but the side effects or other things that can happen after long term use of the drug? Dr. LAWRASON. Senator, I can give you some figures on the extent of our continuing investigation of indomethacin which I think will be pertinent to these hearings. As you will recall, seven controlled studies, not all double-blind, were submitted with the New Drug Application. Since then, four additional double-blinds have been completed. There are now nine others ongoing in rheumatoid arthritis, with an additional four to six with other controls, other drugs. The total, PAGENO="0254" 3346 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY including these double blind studies, is 131 studies now ongoing in the various indications. We have 26 in rheumatoid arthritis, 21 in osteoarthritis, two in osteoarthritis of the hip, 22 in musculoskeletal disorders, and 60 others which involve the investigation of the drug as an analgesic and anti- pyretic for thrombophiebitis and so forth. Senator HATFIELD. What is the span of time in which these are contmuing? What is your general control period? Dr. LAWRASON. The general control period extends, for each study, anywhere from 2 weeks to 3 months. Senator HATFIELD But ~ hat about beyond that point ~ What if some one has been on some kind of drug for, let us say, 3 years, 2 years, or 5 years? Are there not effects, as has happened in the past, that did not show up maybe in the first few weeks or the first few months, or the first year, or the first 2 years? Dr. LAWRASON. We have a great deal of evidence for long-term study and treatment in patients. As a matter of fact, each of the two other physicians appearing today before~ the committee has had long- term studies going in patients for up to 5 years or more. Senator HATFIELD. Do you use primate centers to any degree in the long-term studies? Dr. LAWRASON. Only in toxicity. We have our major toxicity effort within our own group, within our own research laboratory. Senator HATFIELD. Have you thought about the possibility of utiliz- ing these primate centers to a greater extent on the basis of contract? Dr. LAWRASON. Yes. Senator HATFIELD. Because here you have a controlled situation. In many of these long-term effects, you cannot have a human control situation, but you can have an animal control situation in these primate centers. Dr. LAWRASON. You are very right, and we are considering it. As a matter of fact, we have had preliminary discussions with the primate center just outside of New Orleans. Senator HATFIELD. Let me ask you one other question. What kind of program or system is there for reporting side effects from the use of drugs? Every once in a while, I see something about a side effect, but I read it as something as a result of some individual having had some ill effects and having to initiate the reporting of that, and some physician more or less identifying the cause of it. Is there a system of reporting side effects by the drug manufacturers to the FDA and they in turn to the public, or what does exist in that way? Dr. LAWRASON. The system involves reporting of both side effects and adverse effects during the investigational stage of a new drug and after the New Drug Application has been approved. During the in- vestigational stage, we anticipate certain side effects even before we go into the clinic as a result of the preclinical information and labora- tory data that has been acquired. Anticipating these, we also watch for anything that is extraordi- nary. If it is extraordinary to the degree in which it is potentially life- threatening, we report it directly to the FDA. Once the application has been approved, any adverse effects that occur which are not cited in the package circular, or any that are extraordinary and new or of `I serious nature, we send this information in directly to the Food and PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3347 Drug Administration as an adverse reaction report. This is to be done, I believe, within 15 days of the time we acquire the information. Senator HATFIELD. This is by regulation? Dr. LAWRASON. By regulation. Senator HATFIELD. So that all pharmaceutical houses subscribe to or are required to follow this same procedure? Dr. LAWRASON. That is right. Senator HATFIELD. Do you think it is an adequate procedure? Do you thing it is an effective one at the present time? Dr. LAWRASON. I believe it is working fairly well; yes, sir. I think one of the problems, if I might say so, is the handling of massive amounts of data . . . we are talking about enormous amounts of in- formation. Senator HATFIELD. What I did understand you to say was the pe- riod of time that this system of reporting continues after the initial introduction of the drug? Dr. LAWRASON.- As long as the drug is registered as a new drug, it will continue on for years. Senator HATFIELD. You mean you are on a continuing research and accumulation of data and facts on the use of this drug all of the life of the drug? Dr. LAWRASON. It depends on which aspects of research with the new drug we are pursuing and how it relates to the reporting of ad- verse reactions, but the accumulation of data continues throughout the lifetime of the drug. Senator HATFIELD. Do you have a pill-the pill? You do not manu- facture the pill? Dr. LAWRASON. No, we do not. Senator HATFIELD. Well, in my opinion, that is something. Mr GORDON You mentioned the various studies that are going on Are these conducted, sponsored, or directed by your company ~ Dr. LAWRASON. Yes, sir; they are all sponsored-the double-blind studies, the ones I reported. They are all under IND's. Mr. GORDON. You talked about recent ones, the ones that are going on now. Dr. LAWRASON. That is correct. They are all established under the IND system and sponsored by us. Senator HATFIELD. Could I ask you one followup question, Doctor? Are you satisfied with the kind of reporting you are getting from physicians on their own experiences in the use of these drugs? What kind of conflict does a doctor face in possibly being fearful of mal- practice charges if he reports some of most, say, erratic kinds or the most undesirable kinds of re'ictions ~ Is there an inhibition on the part of the physician, or what kind of relationship do you have on that? Dr. LAWRASON. I would say that one o~ our greatest problems, as it is in most circumstances these days, is communication. However, we have established within our research group, at least, a good working relationship with physicians so that reporting and constant `surveil- lance of ongoing studies are handled as well as we possibly can. We are always attempting to improve this. Distance, time, these are fac- tors. We try to minimize any delay in communications with physicians. Senator HATFIELD. You are not really, then, fully satisfied with the kind of reporting which you now have from physicians? PAGENO="0256" 3348 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr LAWRAS0N I do not think ~e will ever be fully satisfied, sir Senator HATFIELD Do you think this present lack or, let us say, this underdeveloped reporting system th'tt exists now could become a source of difficulty for you in getting some real evaluations in some of these drugs? Dr. LAWEASON. They have in the past, but we have spent a great deal of time in examining the issues and rectifying the problems I would hope that they would not. Senator HATFIELD. There is no role of Government, then, that you see ~ Dr LAWRASON No, just that it is part of the requirement for ade- quate supervision and surveillance of the studies. Senator NELSON Please go ahead, Doctor Dr LAWRASON The commattee has heard much of the ARA Co operating Clinics project and of other approaches to the develop- ment of controlled studies. When the ARA project offered the oppor- tunity to have our new drug be the first agent employed in a complex study of this design, we were pleased. We consulted with the commit- tee and we supported its goals, even though all previous experience with such studies indicated that no agent of demonstrated anti inflamma tory and analgesic properties had ever successfully been differen tiated this way Mr GORDON I have been informed by Dr Donald Mainland of the Cooperating Clinics Committee, that they did a trial on hydroxy chloroqurne sulfate This was a 6 month trial using the same method as was used with Indocin, with aspirin permitted in accordance with the committee's practices. The trial showed clear cut differences be- tween the drug and placebo. Dr LAWRASON I am not a clinic witness Mr GORDON This does not fit in with what you were just saying You said there was no such study, or that this type of study had never shown any differentiation This particular study apparently did I just wanted to bring that to your attention. Dr LAWRASON Has this study been published ~ Mr. GoiwoN. I do not know. Dr. LAWRASON. We are referring to the fact that a similar study was carried out with cortisone almost 10 years ago. It showed that cortisone was no more effective than the placebo. I believe there was another study that has not yet been published, to our knowledge, and that this also failed to show a difference. Mr. GoiinoN. I also would like to read into the record the communi- cation I received from Dr Mainland on April 24, 1966, with respect to that type of study that they did. It says: In addition to review by the editor and referees of the Journal in which the report was to be published Dr~,, Mainland requested a manuscript of this repoi t be reviewed by Dr. Stanley Shor, who has been director of the Department o~ Biostatics of the American Medical Association * * * Dr Shor was very critical and very experienced in reviewing medical journal manuscripts as exemnlified by his report on the subject, "statistic evaluation of medical journal articles," volume 195, pages 41123 to 41128. Dr. Sho'r commented on April 18, 19436, on the indomethacin report as followa-- that is the CCC report- It is I think the type of analysis that should be kept as a reference by every clinic investigator Many times I am asked are there any studies that have been published that you think are really good In terms of drug trials Of coui se every PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3349 drug trial has its own bundle of proolems, and it Is not very useful to set up a step-by-step procedure which is to be used by all drugs in all cases. However, the analysis in this paper brings out so many important points which the usual clinical investigator is either not aware of or simply does not take into considera - tion that it should be required reading for all the people engaged in clinical trials. I particularly like your method of showing how observed differences could be misleading in the absence of controls. This is especially interesting in your dose response relationship near the end of the manuscript. I ask that this be included in the record at the proper place. Senator NELSON. Very well. Mr. CUTLER. Could we have a copy, Mr. Gordoil? Mr. GORDON. Certainly; I shall have it Xeroxed and give it to you. (The documents referred to follow:) [From Bulletin on Rheumatic Diseases, vol. 13, No. 2, October 1962, pp. 28:7-290] HYDROXYCHLOROQUINE SULFATE IN RHEUMATOID ARTHRITIS, A Six MONTH, DOUBLE-BLIND TRIAL1 This trial was conducted by the Cooperating Clinics Committee of the Ameri- can Rheumatism Association, under the chairmanship of Dr. Charles Ragan. In attempting to create an instrument that can promptly and reliably evaluate a new and apparently promising drug, the Committee is acutely aware of the danger of a controlled trial that is inadequately planned and loosely conducted. The pseudoscientific verdict of such a trial is more misleading than the impres- sion of a single experienced and critical clinician. A report 2 of the Committee's activities from 1958 through September 1961 describes the difficulties it met and the methods adopted to reduce them. Having gained experience in a pilot study ("dry run") and in a three month trial of hydroxychioroquine, the Committee decided to conduct a six month trial of the same drug, partly to obtain more experience and partly to learn more about the behavior of the drug. It recog- nized that there is considerable evidence that antimalarial compounds benefit certain types of rheumatoid patients to some degree under certain conditions; but it wished to know (1) whether a drug-placebo difference could be dem- onstrated on the available patients by the methods employed and (2) the magni- tude of such a difference. CRITERIA OF ADMISSION TO THE TRIAL The subjects were to be outpatients, of either sex and any ethnic group, with classical or definite peripheral rheumatoid arthritis (A.R.A. Criteria, 1958 Re- vision3) which had become manifest after the sixteenth birthday and had been present for at least one year before the trial. There were to be present at the beginning of the trial at least three clinically aetive joints, as determined by tenderness on pressure and/or pain on passive movement. Joint swelling was not used as a criterion of eligibility but was recorded and used In assessment of progress. Patients with certain specified diseases, such as polyarteritis nodosa, psoriasis, systemic scleroderma, ulcerative colitis and disseminated lupus erythematosus, were excluded, as were patients who, within the previous six months, had experi- enced pregnancy, childbirth, severe infection or a major surgical operation. Patients who were known or suspected to have ankylosing spondylitis were ex- cluded, but it was not obligatory to screen all patients by sacroiliac radiology. Previous therapies that excluded patients were antimalarials, systemic steroid or phenylbutazone therapy within the preceding two months, and gold therapy within the preceding year, unless a full course within the year had produced no obvious effect.4 1 From the Medical Statistics Unit and the Study Group on Rheumatic Diseases New York University Medical Center. Mailing address: 112 Blast 19th Street, Room 11O6 New York 1, N.Y. 2MainlancT, D., J. New Thaigs, 1 :197 1961. Ropes, M. W., et al.. Bull. Rheuma't. Dis., 9 :175, 1958. Probably in all clinical trials there are some implicit restrictions on the type of patient population to which the results can be generalized. Such restrictions are not easy to define and may be overlooked. In this trial, in which the primary objective was a study of the method of opeartion itself, it was desirable to obtain maximum, and willing, cooperation. Therefore it would have been unwise to insist that patients who appeared to be benefiting from another therapy he entered in the trial or to risk the placebo treatment of patients who, in the opinion of the clinic chief or clinIcal observer, ought to be available for steroid therapy whenever it might appear desirable. 81-280 O-68--pt. 8-17 PAGENO="0258" 3350 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THERAPY The prescribed dosage of drug or corresponding placebo was one 200 mg tablet four times daily. Assignment of drug or placebo by random numbers was per- formed at the Coordinating Center at New York University. ApproximatelY equal numbers of drug- and placebo-treated patients were studied at each clinical center During the trial systemic steroids gold and phenylbutazone or related drugs were not permitted, nor were antimalarials. Aspirin was permitted or prescribed at the discretion of the individual observers. METHODS OF EVALUATION Two initial examinations were made, one week apart, and on the second visit therapy was started. Thereafter the patients were examined six times at 28 day intervals (maximum permissible deviation, ±7 days). All observations on any one patient were made by the same observer. The following methods of assess- ment were used. 1. American Rheumatism Association functional classiflcal,5 with reference to the patient's usual occupation (recorded on each visit). Class I-able to carry on all usual activities without handicap. Class Il-able to carry on all usual activities despite handicap of dis- comfort or limited mobility of one or more joints Class Ill-able to perform few or none of the usual activities or self care. Class IV-largely or wholly incapacitated; bedridden or confined to wheel- chair, with little or no ability for self-care. 2. Duration of morning stiffness-estimated for an "average" or "typical" day (recorded on each visit). 3. Number of clinically active joints-determined by tenderness on pressure and/or pain on passive movement and/or swelling other than bony proliferation (recorded at beginning of trial again after 3 months and after 6 months). 4. Grip strength-determined by folded blood pressure cuff attached to mercury sphygmomanometer with patient s arm unsupported Read height of column maintained (not initial spurt) by squeezing Record mean of thiee read Ings on each hand (recorded on each visit). 5. Walking time-the time, recorded by stop watch, required to walk 50 feet as fast as possible (without running) from a standing start (recorded at begin- ning of trial, again after 3 months and after 6 months). 6. Erythrocyte sedimentation rate-Westergren method, one hour reading (obtained at beginning of trial, again after 3 months and after 6 months). 7. X-ray fllnas-postero-anterior, both hands (obtained at beginning and end of trial). 8. Observer's overall assessment-the observer's opinion at end of trial regard- ing the change in the patient's arthritis since the beginning of the trial, recorded as "better," "about the same" or "worse." 9. Patient's impressioi~-recorded at end of trial in the same terms as the observer's assessment. Undesirable signs and symptoms during the preceding four weeks were re- ported at each visit. The trial extended from December 1960 through September 1961. It involved 121 eligible patients from 10 clinics (7 to 20 per clinic), including 63 ort placebo and `58 on the drug. PATIENTS' CHARACTERISTICS AT BEGINNING OF TRIAL Table I shows the principal characteristics recorded. The distribution by. A.R.A. functional classes was: Class I-li; 11-68; 111-38; IV-4. Rheumatoid factor tests were reported as follows: positive-76; negative-18; doubtful-i not investigated recen.tly-26. In Table I the range of individual variation repre~ sents approximately the middle 90 per cent of the frequency distribution. In non of the characteristics was there any important difference between the placebi~ and drug-treated patients. 6 Stelnbrocker, 0., Traeger, C. H., anti Batterman, R. C., J.A.M.A., 140 :659, 1949. PAGENO="0259" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3351 TABLE I-PATIENTS CHARACTERISTICS AT BEGINNING Of TRIAL 141 males; 80 femalesj Median 90 percent Range Age(years) Duration of disease(years) Duration of morning stiffness (hours) Number of din. active'joints' Grip strength (mm. Hg):2 Males 53 6 2 23 95 31to72. fl/2to 21. 3~ to 7. 5to 54. 53to260. Females 96 44to237. 50-ft. walk (second) FSR(mm.inlhour) 14 40 9 to 34. 10to86. I Total possible joints (excluding hips): 66. 2 2 males and 2 females had maximum registrable strength, 260 mm. Hg. RESULTS The data from 8 of the 12:1 patients presented problems in the analysis; e.g., one patient had received phenyibutazone from a private physician during the trial, one had fractured her hip and one had disappeared entirely. After the analysis of the data from the remaining 113 patients, the 8 problem eases were incor- porated in such a way `as to avoid bias in favor of the drug. The effect on the main results was negligible. In some instances, however, specific figures were not available for the problem cases; therefore the results given below are from the 113 cases, 60 on placebo an:d 53 on the drug. In certain analyses some cases had to be excluded; e.g., 11 in the walking test because of inability to walk or absence of lower limb lesions, and 11 in the E.S.R. records because of unreliable laboratory work at one clinic. None of the omissions are due to defective reporting by observ- erg. All comparisons: cover the whole six months of the trial. NOTE: To avoid the statistical terni "significant," with its suggestion of "im- portance," drug-placebo differences are stated to be "adequately accounted for by individual variation" if they would occur in more than 5 per cent of ran:dosn assignments (such as were used in this trial) when there was no difference at all between treatments'. On the other hand, a difference is interpreted as being "as- sociated with the drug" if the frequency of occurrence in purely random as~ signments would be less than 5 per cent-2 or 3 per cent at most. Total group comparisons by individual indexes In Table II all the differences appear to favor the drug, `but all could be readily accounted for by individual variation. Moreover, the two groups differ very little in the average (median) amount of change, and the individual variation is high in both groups. TABLE 11.-TOTAL GROUP COMPARISONS BY 5 INDEXES Index Placeb o (60 patients) Drug (53 patients) - Num- ber Improved (percent) Median change 90 percent range - Num- her Improved (percent) Median change 90 percent range Duration of morning stiffness. 56 54 -3~ hour.. -3 to +43/2-- 53 66 ~~3% hour.. -43/b to +13/2 Number of din. active joints. Grip strength 50-foot walk ESR 60 56 54 49 62 70 46 45 ` -3 joints_ - +12 mm~ 0 seconds_ - +1 mm,, -19 to +16~ - -47 to +55~ -6 to +14~ - -34 to +34-- 53 51 48 42 70 86 50 64 -7 joints - +29 mm.~.. 0 seconds - -7 mm.~ -32 to +6. -17 to +123. -10 to +8. -37 to +55. $ubdivision by initial severity In four indexes (morning stiffness, number of clinically active joints, walk- ing time and E.S.R.) a much snore clear-cut drug-placebo difference was: found when the `data from patients who were more severely `affected at the beginning of the trial (a quarter to a third of the total patients) were examined separately (Taible III). In the first two of these indexes the differences were clearly asso- ciated with the drug. In grip strength, the patients who were stronger initially showed the greater' drug-placebo difference. PAGENO="0260" 3352 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 111.-COMPARISONS AFTER SUBDIVISION BY INITIAL SEVERITY Number of Percent Index Initial severity patients P D Median change in group exceedin? group median P D Median change in subgroup P D Duration of morning stiffness. 3 or more hours 22 18 -23-ihr 32 72 -l~4hours -3 hours Number of din active joints. 50 foot walk More than 28 joints More than 16 seconds 18 19 15 14 -10 joints -2 seconds 28 68 27 64 -6 joints -16 joints 0 seconds -3 seconds ESR Grip strength More than 55 mm 75 mm. Hg or more 17 13 34 36 -12 mm_ +22 mm - - 41 61 35 64 -11 mm.... -17 mm. +14 mm -- +34 mm. Overall assessment8 Three methods of overall assessment showed marked differences associated with the drug. 1. A.B.A. functional clas8es-Of the patients initially in Class II, only 9 per cent of 33 who were on placebo moved to Class I, whereas 50 per cent of 30 drug- treated patients did so. (P approximately 0.001.) Migration of Class III patients to Class II showed no influence of the drug. 2. Five point scoring system-Each patient was given a score of one unit for an improvement in any one of the five individual indexes and the scores were then summated. (When a patient could not score on one of the indexes, e.g., through in- ability to walk, an adjustment was made to bring his total possible score up to 5.) Scores of 3, 4 or 5 were counted as "improvement" (Table IV). Phis index had shown a drug~placebo difference in the three month hydroxychioroquine trial and is to be explored further as an overall measure. 3 Observers overall assessments-This was not a clinical impression in the ordinary sense because the observers had a summary of their month by month observations but perhaps it is the most comprehensive summing up of a pa tient s progress and it is free from treatment connected bias in a truly double blind trial The patients impressions of drug placebo differences consideied apart from the other data could have been accounted for by individual variation No patient went into remission during the trial X-'ray cerdenoe-assessment (by Dr Josephine Wells Columbia University) is not yet finished but an unselected sample of films from 50 patients has shown no drug-placebo difference. Undesirable signs and symptoms Table V shows that all the recorded phenomena occurred more frequently in drug-treated patients, but the placebo patients showed considerable frequencies that might have been attributed to the drug in a trial without placebo. No patient was removed from the trial because of these occurrences. IP=placebo; D=drugj TABLE IV-COMPARISONS BY ASSESSMENTS Parameter Placebo Drug Number Improved (percent) Number Improved (percent) Advanced from class Ito class I 33 9 30 50 Spolntscores Observers' assessments Patients' impressions 57 54 60 35 60 60 53 53 53 75 64 75 PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3353 TABLE V-UNDESIRABLE SIGNS AND SYMPTOMS Percentages represent patients (out of 60 placebo treated and 53 drug treated) who reported an occurrence on 1 or more visits after therapy startedi Sign or symptom Frequ ency (percent) Placebo Drug Pruritus Skin rash Headache Abdominal pain Tinnitus Nausea Dizziness Blurred vision Diarrhea Anorexia Stomatitis or sore tongue Vomiting Photoohobia Miscellaneous 38 32 48 47 37 38 35 20 20 30 15 15 10 63 58 53 53 49 47 45 43 43 40 38 30 23 13 75 Variables other than therapy-The samples were too small to provide sensitive tests of the relationship between the outcome of the trial and such variables as age, sex, duration of disease at start of trial, presence or absence of rheumatoid factor and differences between clinics. The data did not, however, suggest any close relationship between these variables and the improvement rates or drug- placebo differences. CONCLUSION5 REGARDING DRUG EFFECTS Three overall measures (functional class, observers' assessment and the five point scores) have shown differences in percentage frequency of improvement that were associated with the drug; and so also have certain individual indexes in patients who were severely affected at the beginning of the trial. "Associa- tion," however, does not imply causal relationship in a trial that cannot be main- tained completely double-blind. It is conceivable that observers, nurses or others might have guessed at the patients' therapy from side-effects and then, probably unconsciously, they might have affected the patients' responses to questions and tests. To detect such an influence, the number of undesirable signs and symptoms reported on the final visit were compared with the observers' overall assessments and with the five point scores'. No consistent relationship was found. Perhaps the test was too insensitive; but the magnitude of the percentage frequency differ- ences in Table IV, taken along with other workers' experience with antimalarials, leaves little doubt that the drug-placebo differences were largely cause-and-effect relationships. One must, of course, beware of accepting percentage differences found in samples of 50 or 60 patients as equivalent to what would be found in a study of much larger numbers of patients of the same kind and under the same condi- tions. The observers' figures for improvement were placebo-35 per cent, and drug-64 per cent, a difference of 29 per cent. Even if the patients in the trial were strictly random samples of their respective (placebo and drug) populations, all that the 29 percent could tell us would be that the true (population) differ- ence was probably somewhere between 15 and 40 per cent. SEROLOGICAL STUDIES Sera collected from all patients at the beginning and end of the trial were sent to the Rackham Arthritis Research Unit in Ann Arbor, Michigan, for serological, chemical and electrophoretic studies. Complete pairs of sera were available from 50 drug- and 52 piacr~bo-treated patients. We are grateful to Drs. George R. Thompson and Ivan F Duff for permitting us to summarize some of their results here prior to their own publication. Late~o agglutiaation tube test-Thirty-six drug- and 44 placebo-treated patients had positive tests initially. In 7 drug and 2 placebo~treated patients the tests became negative. When changes in titer of more than one tube up or down were examined, the following contrasts were observed: in the 50 drug-treated pa- tients, a fall in 10 and a rise in 3; and in the 52 placebo patients, a fall in 5 and a rise in 6. Although these differences could have been accounted for by individual variation, it should be noted that they are in agreement with results PAGENO="0262" 3354 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY reported for the sheep cell agglutination test following administration of chioro- quine87 and of gold.8 There was no obvious relationship between the latex teat results and the clinicians' overall assessments. Changes in serum albumin-Llectrophoretic analyses showed a rise in patients who were reported to he clinically better or unchanged, and a fall in those reported as worse. The difference could not be accounted for adequately by individual variation. The changes did not differ markedly between the two treatment groupe. Cha4iges in serum gamnu~ ~tobulin-There was a return toward normal in the drug-treated, but not in the placebo patients. PARTICIPATING CENTERS Lack of space prevents listing the 55 persons (clinic chiefs observers and nurse secretaries) who contributed to this trial The 11 participating centers were: Rackham Arthritis Research Unit, University of Michigan, Ann Arbor; National Institute of Arthritis and Metabolic Diseases and Georgetown Uni versity Medical Center, Bethesda and Washington, DO.; Massachusetts General Hospital, Boston; University of Illinois, Chicago; Southwestern Medical School, Dallas; University of California and Veterans Administration Hospital, Los Angeles; University of Tennessee, Memphis; Jackson Memorial Hospital, Miami; Presbyterian Hospital, New York; University of Pennsylvania, Philadelphia; and University of California, San Francisco. ACKNOWLEDGMENTS The project was supported by Grant A-3252 from the National Institutes of Health, U.S. Public Health Service, and by funds from The Arthritis and Rheu- matism Foundation for x-ray expenses. The Committee is indebted to Winthrop Laboratories for generous supplies of the drug (Plaquenil) and placebo, and for cooperation in the special labeling and dispatching of the compounds. The co-authors wish to express their indebtedness tot their former colleague, Miss Lee Herrera for her invaluable contributions to this work. She participated In all the activities of the project until October 1901 when she moved to California. DONALD MAINLAND, M.B., CH.B., D.Sc., MARION I. SUTCLTFFE, B.S. New York, N.Y. [From Bulletin on Rheumatic Diseases, vol. 10, No. 3, November 1965, pp. 38&-391] ASPIRIN IN RHEUMATOID ARTHRITIS, A SEVEN-DAY, DOUBLE-BLIND TRIAL- PRELIMINARY REPORT The time honored place of sa~licylates in the therapy of the rheumatic diseases as well as their postulated mode of action is being reappraised by many investi- gators today. This preliminary report of a therapeutic trial of aspirin points up effectively `the pitfalls, the tremendous problems and great effort involved in carrying out such clinical studies in order to obtain data which can be meaning fully interpreted Certainly salicylates are most useful compounds but contrary to the claims of some advertisers their true effectiveness and action has yet to be determined. Attention is called to Dr. Mainland's invitation for readers to submit questions and suggestions regarding this trial to him. -THE EDITOR. This trial was conducted by the Cooperating Clinics Committee of the American Rheumatism Association, under the chairmanship of Dr. Charles Ragan. After conducting double-blind trials on an antimalarial compound12 and a seven-day variability study3 on 499 patients without change in their assigned therapies, 6Freedm'an, A., and Steinberg, V. L., Ann Rheumat. Dii., 19 :243, 1960. 7Popert, A. J., Meijers, K. A. B., Sharp, J., and Bier, F., Ann. Rheunvat, Dii., 20 :18, 1961. 8 Research Subcommittee, Empire Rheumatism Council, Ann. Rheumat. Dii., 19 :95, 1960. 1 Mainland. D., J. New Drugs, 1 :197, 1961. 2 Mainland, D., and Suteliffe, M. I., Bull. Rheumat. Dis., 13 :287, 1902. Cooperating Clinics Committee of the American Rheumatism Association, Arth. and Rheumat., 8 :302, 1965. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3355 the Committee turned its attention to the scarcity of well-documented information on the clinical effects of aspirin. It decided to study the changes in manifestations of disease activity in patients who were continued on their previously assigned antirheumatic therapies, but were assigned strictly at random to aspirin in a fixed rather high dosage or to placebo, in approximately equal numbers, and were studied by the double-blind technique. In order to avoid excessive distress to patients, and a risk of breakdown of the trial, the period was restricted to seven days. CRITERIA OF ADMISSION TO THE TRIAL The patients were to be outpatients (or domiciliary hospital patients), of either sex and any ethnic group with classical or definite peripheral rheu matoid arthritis (A R A Criteria 1958 Revision 4) which had become manifest after the sixteenth birthday In addition to the 20 exclusions in the A R A Criteria, patients were not to be admitted if they had experienced severe infection or major surgical operation within one month before the start of the trial, or if they had a history of toxic reactions to aspirin. Patients who were known or suspected to have ankylosing spondylitis were to be excluded, but it was not obligatory to screen all patients by sacroiliac radiography. THERAPY The drug, acetylsalicylic acid, was administered in capsules, each Capsule containing 7.5 grains (approx. 0.5 gm.) and the prescribed dose of drug or corresponding placebo was 2 capsules 4 times a day for 7 days (total daily dose = 60 grains = 39 gm) Assignment of drug or placebo was performed by random numbers at the Biometrical and Coordinating Oenter. Except for these assignments, patients were allowed to be on any (or no) therapy for rheumatoid arthritis, but it was stipulated that, if possible, no change be made in the type of therapy during the two week preceding the trial or during the trial itself, and also that dosage changes, especially of corticosteroids, be minimal during the trial. Patients were be urged to refrain from aspirin and other salicylates during the week of the trial. Details of types and dosages of all therapies were recorded in the data sheets for use during analysis. The trial extended from April 5 through November 14, 1963. METHODS OF EVALUATION All observations at the initial and final examination (Day 1 and Day 8) were to be made by the same observer who was to have at least the rank of clinical fellow The maxunum allowable departure from the 7 day interval was ±1 day The following assessments were made in both examinations: 1. American Rivenmatism Association functional clctssiflcat'ion5 with reference to the patient's usual occupation. 2. Duration of morning stiffness-estimated for an "average" or "typical" day. 3. Grip strength-determined by folded blood pressure cuff attached to mercury sphygmomanometer, with patient's arm unsupported. Inflate initially to 20 mm. Hg. Read height of column maintained by squeezing (not initial spurt). Record three successive readings on each hand. 4. Walking time-the time required to walk a straight continuous distance of 50 feet as fast as possible (without running) from a standing start. ~5 Number of clinically active 2osnts-determlned by any one of the following tenderness on pressure, pain on passive movement, swelling other than bony proliferation. Recorded also were heat, redness, ankylosis (determined by clinical examination) and subcutaneous nodules. 6. Erythroeyte sedimentation rate-Westergren method; anticoagulant, 3.8% sodium citrate; one hour reading. 7. Patient's assessment-the patient's impression regarding his arthritis, recorded as "good," "fair" or "poor"; and as "better," "about the same" or "worse" in comparison with his condition one week previously. 8. Observer's overall assessment-recorded in the same terms as the patient's assessment, taking into account not only the impressions gained from the meas. urement methods (without referring to Day 1 data sheets), but any other available information. Ropes, M. W., et al., Bull. Rheumat. DIs., 9 :175, 1858. 5 Steinbrocker, 0., Traeger, C. H., and Batterman, R. C., J.A.M.A., 140 :659, 1949. PAGENO="0264" 3356 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Blood salicylate levels were determined on Day 1 and Day 8 at six clinics by the method of Brodie, Undenfriend and Coburn.° The interpretation of these data is complicated by the variability of the Intervals between the last dose of aspirin on Day 8, the time of clinical examination and the withdrawal of blood for salicylate determination. The more detailed report will include this topic. The data sheets called for the reporting of undesirable signs and symptoms, but no check list was provided. Expenditure of much time on this inquiry did not appear to be justified because no valid population estimate of frequencies could be made from a group that was partly selected by exclusion of salicylate reactors. PATIENTS' CHARACTERISTICS Prom the 492 patients who were entered in the trial, the data of 51 (28 on placebo and 23 on aspirin) were omitted from the analysis for the following reasons: ineligible by protocol, 19; drop-outs or late for final examination, 14; change in basic therapy, 15; change in observer, 3. If this had been a trial of a new drug it would have been necessary to handle the data from the drop-outs and late attenders in such a way as to avoid bias in favor of the drug. This hardly seemed necessary, at least in a preliminary report on experiences with aspirin. The remaining 441 patients were considered eligible in all respects, including the interval between assessments (9 were one day late, 1 was one day early). They were provided by 11 clinics (18 to 86 per clinic). Assigned to placebo: 223; assigned to aspirin: 218. Males: 131; females: 310. Median age: 53; range (middle 90 per cent) : 30 to 73. Median duration of disease: 7 years; range (middle 90 per cent) : 1-27 years. THERAPIES The basic therapies with numbers of patients assigned to placebo (P) and aspirin (A) were as follows: Corticosteroids (P, 59; A, 55); Sailcylates (P, 100; A, 93); Antimalarials (P, 14; A, 17); Miscellaneous, i.e., combinations of thera- pies and some patients who at the beginning of the trial were receiving no anti- rheumatic therapy (P, 50; A, 53). Phirty~one patients were receiving indo- methacin, usually along with another therapy. Except in the salicy'late group, all these patients were maintained on their basic therapies during the trial. In `order to permit a search for relationships between intake of the trial therapy and the outcome of the trial, patients were classified rather arbitrarily as "on schedule" if they met all the following criteria: (1) at least 32 capsules during the 5 days following the day of the initial examination; (2) at least 8 capsules on the day preceding the day of the final examination, or 6 capsules if the only dose missed was the breakfast dose; (3) at least 2 capsules on the day of the final examination. The 117 patients (28% of the P patients, 25% of the' A patients) whose reported dosage failed to meet one or more of these criteria were classified as "not on schedule." There was little difference in the proportions of these among the various therapy groups. The data were analyzed as a whole, and also in "on-schedule" and "off-schedule" groups separately. The results from the total 441 patients are shown here, because when a pronounced placebo-aspirin differ- ence in `outcome `occurred, it did so in spite of the incomplete dosage o'f some patients. COMPARISON OF AVERAGE CHANGES IN FIVE MEASURES OF DISEASE ACTIVITY Table 1 shows the placebo-aspirin contrast in patients who in the initial examination were recorded as having greater than zero `readings in the respec- tive measures of disease activity, because the inclusion `of initially "inactive" patients would tend to damp the contra'st between the two agents. To estimate how frequently the drug-placebo contrasts in the table would occur solely as the result `of the random assignments, the data were arranged in fourfold tables (placebo versus aspirin; improved versus not improved, i.e., deteriorated or unchanged), and the chi-square `test (with Yates' correction) was applied. In all measures ex'cept morning stiffness the differences would rarely occur in random assignment (P values from chi-square less than 0.01). In morning stiffness the P value `was 0.12; which means that, even if there were no difference 6 Hepier, 0. B., Manual of Clinical Laboratory Methods, Charles C. Thomas, Springfield, Illinois, 1953. PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3357 in the effect of placebo and aspirin on this measure of activity, differences as great as the observed difference, and greater, would have been produced by the randomization alone. These results, therefore, appear to have provided a clear demonstration of aspirin effect on all the measures except morning stiffness. TABLE 1.-COMPARISONS BY 5 MEASURES OF DISEASE ACTIVITY (Impr. (I.)=improvement. Deter. (D).=deterioration. N.C.=no change.~ Placebo Aspirin Measure of activity Num- Impr. N.C. Deter. Median Num- Impr. NC. Deter. Median ber in (per- (per- (per- change ber in (per. (per- (per- change group cent) cent) cent) group cent) cent) cent) Morning stiffness.. 198 33 23 44 0 184 41 32 27 0. Clin. active joints. 220 38 10 52 1 jt. D 216 56 9 36 1 jt. I. Grip strength: Male 61 31 0 69 15.5 mm. D~ - 58 64 0 36 5.5 mm. I. Female 152 38 1 61 7.5 mm. D. -. 153 59 2 39 7.5 mm. I. 5Qfoot walk 214 41 13 47 0 209 55 16 29 0.5 sec. I. E.S.R 214 30 5 65 3 mm. D 213 51 8 41 1 mm. I. Note: Patients excluded: (a) Reported absence of disease activity on initial examination: morning stiffness 55; joints 4; grip 10 males and 4 females. (b) Inability to perform test: walking 18; grip 1 male and 1 female. (c) Imperfect data etc.: morning stiffness 4; joints 1; grip 1 female; E.S.R. 14. Of particular interest was the question whether the salicylate group, about half of whom were suddenly deprived of their basic therapy for the seven days of the trial, showed a larger placebo-aspirin difference than did the other basic therapy groups-particularly a greater frequency of deterioration when On placebo than the corticosteroid group. All the basic therapy groups were analyzed with reference to this question, but no consistent difference could be found at- tributable to the salicylate deprivation in those who had been on that therapy at the beginning of the trial. It is possible, however, that the conditions of the trial were not suitable to demonstrate such an effect, owing to the variable and uncontrollable time intervals between the clinical examination and the preceding dose of aspirin. EXTENT OF CHANGE IN DISEASE ACTIVITY Table 1, showing overall percentage frequencies and averages, has restricted significance because: 1. A drug-placebo difference in the frequency of improvement may be large but of little practical value if the amount of the improvement is small. 2. The averages of the gains and losses, and the drug-placebo differences in these averages, are trivial; but in certain subgroups the differences may be large. (The records of voluntary aspirin consumption by placebo patients did not sug- gest that this was the cause of the small size of the differences.) 3. The lack of any conclusive drug-placebo difference in the effect on morning stiffness may have been due to the inclusion of subgroups that were not likely to show much change in a period of seven days. Much more informative are statements about the ranges of improvement or deterioration, and the Seven-day Variability Study has shown that these differ according to the initial (Day 1) level of activity. In that study those levels were divided, for each measure separately, into classes from A (the mildest) to J (the most severe), each class containing as nearly as possible 10 percent of the total 499 patients in the study. As examples, Table 2 shows the application of the Variability-Study classifi- eation to certain of the data in the present study. In addition to the display of the extent of change, the sub-classification provides a method for increasing the sensitivity of comparisons in drug trials. Thus, although the analysis of the total data showed no convincing drug-placebo difference in the morning stiffness change, the figures in Table 2 show that, when allowance is made for the amount of stiffness recorded on Day 1, the drug-placebo difference becomes more obvious. For example, of the patients who started with 5-25 minutes of morning stiffness, 26 percent of placebo patients reported an hour or more on Day 8, whereas only 5 percent of the aspirin patients reported that amount of deterioration. A later report will show the general application of this simple method of increasing the sensitivity of a trial. PAGENO="0266" 3358 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 2--EXAMPLES OF RANGE OF VARIATION WITH ALLOWANCE FOR SEVERITY AT INITIAL EXAMINATION IP=placebo; A=aspirin; VS==variability study; m.t.=more than; I.t=Iess thani Severity Class at nit. Exam. Num ber in group Impr ~to: nu Percentof mber in group Det'n. to: nu Percentof mber in group P A VS P A VS P A VS Morning stiff: A. zero 23 32 57 mt. 25 mm 22 6 9 B. 5-25 mm 19 21 20 zero 5 10 10 mt. 55 mm 26 5 10 I. 3.75-4.75 hr 17 18 19 It. 30 mm 6 11 5 m.t. 4.75 hr 53 1 721 J. 5 hr..all day 24 21 48 It. 2.75 hr 21 19 4 No. of din, active jts.: A.0-3 17 12 44 m.t.8 18 0 7 B. 4-5 13 9 36 It. 4 15 33 39 mt. 8 31 11 8 I. 30-36 14 24 45 It. 20 0. 8 9 mt. 36 36 25 24 J. 37-66 25 18 35 It. 25 4 6 9 P A VS P A VS Ill P A VS IV P A VS 11 55 36 9 17 71 29 36 81 17 3 121 1 86 12 2 125 94 6 205 0.5 96 4 80 9 86 5 67 12 88 152 5 94 1 5 100 7 100 17 12 88 From Pable 4 it would appear that the patients were somewhat more opti- mistic than the physicians regarding improvement in general and regarding the benefits of the trial therapy; and a similar observation was made in an anti- malarial trial It appears also however that the patients were more pessimistic regarding deterioration-that they were more ready to report change, in one or other direction, than the physiëians. (A more detailed examination of such contrasts is being made in the data from the Seven-day Variability Study.) TABLE 4.-OBSERVERS' AND PATIENTS' ASSESSMENTS Observers: Placebo Aspirin Patients: Placebo Aspirin Note: Improvement or deterioration implies change from one class to another. OVERALL A55E55MENP5 Table 3 shows the placebo-aspirin contrast in relation to the A.R.A. functional classification There appeared to be a slightly greater tendency to improve in the drug treated than in the placebo patients more especially in the less disabled patients; but it will be noted that numerous changes of class were recorded in the Variability-Study patients who were maintained for one week on their accus- tomed therapies. TABLE 3.-COMPARISONS BY ARA FUNCTIONAL CLASSES (P= placebo; A=aspirin; VS=variability studyj Class at initial examination Treat~ Number in Class at final examination (percent of N) ment class (N) I II Ill IV INumbers of patients: Placebo, 223; aspirin, 218J Changes Assessors and therapies Improved from initial to final examination (percent of pts.) Aboutthesame Worse 17 48 31 54 35 15 23 33 44 45 36 19 PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3359 FURTHER ANALYSES Many questions in addition to those discussed in this report have been applied to the data from this trial, such as the question of the interrelationships of cumulative effect, recency of last dose and amounts of aspirin consumed- an attempt to see whether the trial could give any clue to an "optimum" aspirin regimen However it seemed desirable at this stage to present an overall view as an invitation to readers to submit questions and suggestions that would help in the preparation of the more detailed report. PARTICIPATING CENTERS Lack of space prevents listing the 46 observers and about 16 study-secretaries who coptributed to this trial. (Study secretaries `did not contribute patient assess- ments as some of them did in the Seven-day Variability Study.) The 11 partici- pating centers were: Southwestern Medical School, Dallas; State University of New York, Downstate Medical Center, Brooklyn; University of Illinois, Chicago; University of California and V A Hospital Los Angeles Massachusetts General Hospital Boston Jackson Memorial Hospital Miami Rackham Arthritis Re search Unit, University of Michigan, Ann Arbor; N.I.A.M.D. and Georgetown University Medical Center, Bethesda and Washington, D.C.; Presbyterian Hos- pital, New York; University of California, San Francisco; University of Tennessee, Memphis. ACKNOWL~DOMENTS The Cooperating Clinics' program is supported by Grant AM-03252 from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, U.S. Public Health Service. The Coordinating Center is indebted to Mrs. M. 0. Blake, Mr. P. C. Miller and Miss A. C. Powell for assistance in the analyses; and to the Merck Company for its generous `and painstaking coopera- tion in the provision of drug and placebo Medical Statistics Unit, Room 1106, 112 East 19th Street, New York, N.Y. Prepared for the A.R.A. Cooperating Clinics committee by Donald Mainland, M.D., Ch.B., D.Sc., and Marion I. Sutcliffe, B.S., and revised 1y the Publications Subcommittee. Senator NELSON. Please go ahead, Doctor. Dr. LAWRASON. We doubt whether even the authors of this tentative, exploratory, and hopeful experimental design, with all of the complex statistical loose ends that remain to be tied up, would hold it up to the world as a finished and refined tool of bio~tatistics and control. Let me make it clear that we at Merck are in no way opposed to the intense desire of experts in rheumatology to take steps forward in clinical design. However, we do not accept the validity of the co- operating clinics study presented to this committee last week as a measure of the value of indomethacin in medical practice. We do not believe a wholly satisfactory double-blind study for demonstrating the effect of a drug in treating rheumatoid arthritis has yet been designed. From what we know today, no drugs used in rheumatoid arthritis get at the cause of the disease, nor do they appear to halt its ultimate progression. Thus we are talking about drugs which will only give relief of symptoms. Much of this can be determined only by the patient and his physician. At this state of our knowledge there are no really good objective measurements or tests. Those we have, at best, are very crude. The rheumatoid patient manifests no objective labora- tory parameters, such as the blood sugar of the diabetic, which the physician can point to and which enable him to know if the patient 1S improving. PAGENO="0268" 3360 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY As you know, aspirin has been the backbone of drug therapy in the rheumatoid patient for many years. Therefore it is natural that in- domethacrn would be compared with aspirin in rheumatoid arthritis, just as any new drug would be compared to an accepted standard therapy of the day Aspirin is guierally accepted by both the medical and lay public as safe Howevei, there is a great deal of history with aspirin which has never been written Only in recent years has this drug come under closer scrutiny In thinking about aspirin, one finds that it really is two drugs-the one that most people take for minor aches and pains in one-, two-, or three-tablet doses, and the second a drug which must be taken in massive doses up to 20 or more tablets (4 to 8 grams a day) to effect a therapeutic benefit in a disease such as rheumatoid arthritis In the case where only a few tablets are taken occasionally, as needed, there are few side effects Most people are able to tolerate aspirin in these amounts, but even with these small doses there are patients who experience gastrointestinal irritation However, when one approaches the therapeutic doses of aspirin needed to treat rheumatoid arthritis, there are definite side effects- some very similar to those with indomethacin-which need to be watched carefully by patient and physician Many patients either cannot tolerate these high doses of aspirin or just will not swallow that many tablets. On the other hand, most rheumatoid patients who can tolerate aspirin will take it whether it is prescribed or not If they respond to aspirin and the pain disappears, no further medication, no matter how effective, can make that pain disappear any further If motion of a joint is allowed up to its maximum by aspirin, then indomethacm, phenylbutazone, or the steroids are unlikely to increase that motion any further. If grip strength, swelling of a joint, and inflammation, for example, have improved in a patient who responds to aspirin, an additional drug, no matter how effective, would probably not provide further improvement in the physical status of the patient. Although we cooperated in setting up the cooperating clinics study, we did not participate in the design of the study-this was up to the committee However, I understand there were wide differences of opinion on the study design within the committee itself, particularly with respect to whether or not those patients who were to receive mdomethacin should continue to receive aspirin, in the amount the patients desired, as a basic background medication Obviously the majority of the patients included in the study were responsive to aspirin, and it was decided to allow them to continue to take it. Whether this was the right decision is a matter of opinion, but for the reasons I cited earlier I am not surprised that neither these patients nor the physicians could determine the effect of a second active drug that was being given on top of an already "treated" patient These studies may not have shown that indomethacin is an effective drug in rheumatoid arthritis by the rigid criteria used, but neither have they shown that it is ineffective. They show nothing as to the effectiveness of indo- methacin in patients who do not respond to aspirin or cannot) tolerate it in large doses. They do show that during treatment with indo- methacin many patients were able to decrease the amount of aspirin they were taking, and when indomethacin was discontinued some of PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3361 the patients experienced some degree of clinical relapse. Some statis- ticians would consider this to be evidence of activity, but the com- mittee chose not to accept these factors as criteria of effectiveness. The study has yet to be designed which all would agree is the ideal format for a controlled study of such agents. Some double-blind studies were included in our original indomethacin submission to the FDA, and you have heard testimony in criticism of their structure. Dr. Mainland has stated that his study is part of a continuing, long-range effort to eliminate the unreliable factors and variables. More recently we have been involved with the further development and design o~ double-blind studies. Many of these are being carried out. But here, too, it is impossible to say whether the principles underlying these studies will be generally accepted as satisfactory. During the coming years, I am convinced, controlled clinical meth- odology will be developed so that truly objective data will result. As physicians in medical research at Merck, this is our job and our effort is dedicated to this end. However, it should be recognized that the clinical sciences have not vet reached the scientifically controlled state that has been attained in the laboratory. The patient is not and can never be the exact counterpart of a highly inbred, genetically and environmentally controlled laboratory animal. If we had to do our clinical research over again with indomethacin, we would do it the samc way, by fi~rst going to the expert. We would subsequently supplement our basic clinical evaluation with the best double-blind control studies we could devise. This, in fact, is what we are doing today as we take a new anti-inflammatory drug to the clinic. But so long as we do not yet know of a wholly satisfactory double- blind method of proving effectiveness for drugs used to treat rheuma- toid arthritis, we do not believe there is any medical basis for postpon- ing the introduction of a drug experts believe to be valuable. The question of the safety of indomethacin has also been raised. It is important to distinguish between safety for use as contrasted with side effects experienced during use of the drug. The issue of safety deals with the potential threat of serious, life-threatening con- sequences. The issue of side effects deals with sometimes bothersome, sometimes annoying effects which are not in themselves `of serious potential. These issues have `been grouped together in the discussion of in- domethacin. In the resulting confusion, the major point-that most of the side effects of indomethacin are of a minor or manageable nature- has been lost. Many disappear in a short time with continuation of the medication or an adjustment of dose. Only 10 to 15 percent of all patients receiving the drug have to discontinue it because of side effects or reactions. In rheumatoid patients the incidence of patient intolerance appears to `be greater than in patients with other forms of arthritis. But this is not surprising. It is well known that patients with rheumatoid arthritis have a greater sensitivity or a lower threshold to the adverse effects of many drugs, for reasons which are not known. It should be pointed out also that most of such patients are on multiple drug therapy. This, together with the vagaries of the disease itself, often sets the stage for higher incidence of adverse drug effects. Sufficient clinical experience was accumulated with indometh'acin over the years of investigation before its ~pproval by. FDA to assure PAGENO="0270" 3362 COMPETITIVE PROBLEMS fl~ ~HE DEtJG INDUSTRY its safety for use as directed I can assure this committee that we would not have requested consideration for approval of this drug if we `had thought it was not safe. The final overall assessment of safety can only be assured after extensive experience. For example, aspirin and related compounds which have been used for over 50 years are even now being reassessed with regard to their potential long-term effects on the kidney. Information on the safety of indomethacin is outlined in the official product circular. So long as the physician is aware of the effects that have been reported-those that appear more frequently and those only rarely noted-we believe it can be prescribed with the proper assur- ance that the potential risks can be weighed against the benefits to be obtained. We are proud of indomethacin. We know through personal experi- ence what it means to many, many people. I am confident, looking ahead, that the scientific teams at Merck that produced indomethacin will develop further advances as they continue to search for the causes of these crippling diseases. I will be happy to answer your questions. Senator NELSON. Thank you, Dr. Lawrason. The committee ap- preciates very much your testimony for our record. Senator Hatfield? Senator HATFIELD I have just one question, Doctor On page 6, you were saying in the third full paragraph: We do not believe a wholly-satisfactory double-blind study for demonstrating the effect of a drug in treating rheumatoid arthritis has yet been designed. On page 10, in talking about your clinical research, you say: We will subsequbntly supplement our bask clinical evaluation with the best doubl&blind control studies we could devise. I do not quite understand what the hangup is on devising or having now `made effective double-blind `studies. Why is itso difficult? Why do we not have it now and why do you feel you can devise one that has not yet been done? Dr. LAWRASON. One of the problems of the studies `with rheumatoid arthritis involves the quantification of the subjective measurements; that is, measurement of response in the patient. We do not `believe, as I stated, that there is yet an ideal format for `design of a `double-blind, controlled study, Dr. Mainland and his group in the cooperating clinics point out themselves that their efforts in thi's direction and their studies with i'ndometha'cin are part of a long-term effort to design a truly controlled and adequate study. But we are also in the same process. In the 100 or more such studies that we `have developed over the past 2 years `and are ongoing now, not all are the same. We do not claim to `have the ultimate design. But `this is our purpose `and this is our job, to find the very best study design that can give objective measurements and results. Senator HATFIELD. How many drugs are tested by the double-blind study? How broadly used is this `technique? Dr. LAWRASON. Oh, this is a widespread control method, using the the double-blind. It is particularly effective in getting rid of physician or patient bias where measurement is in part subjective. Some diseases are easily `studied this way and some are not. PAGENO="0271" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3363 Senator HATFIELD. Should all the drugs be subjected to this kind of test before they are put on the market? Dr. LAWRASON. Yes, to the extent that they can. But in studying a diuretic, for example, the double-blind is really not necessary to deter- mine whether or not there has been a diuresis within a patient, increase in urine volume. Senator HATFIELD. What criteria do you use in determining when to use this double-blind study, on which drug, and when not to? Dr. LAwit~&soN. In those diseases where there are truly objective measurements-for the most part laboratory m~asurements, or objec tive signs within the patient of ch'aiiges that take place, whether it be with the electrocardiogram or other techniques-the double-blind is of only `ancillary `and confirmatory value. It is where observations are being made by the physician and patient, where pos~ible bias is inter- jected, that the double-blind serves the greatest purpose. Senator hATFIELD. Thank you, Mr. Chairman. Mr. CUTLER. Mr. Chairman, could I supplement that for a moment? When Dr. O'Brien was testifying, he construed the 1962 Drug Amend- ments as requiring double-blind studies to prove effectiveness in all future drugs. We have prepared a memorandum on the legislative history of the 1962 amendments, including both the term, "adequate and well-controlled," and the term, "substantial evidence." We would like to submit this memorandum for the record, if we could. It shows that Congress does not believe double~b1ind tests are essential for "substantial evidence"_that the Congress was well aware that for some diseases and drugs there were at that time no satisfactory double- blind tests. With respect to "substantial evidence," one of the very illustrations given at the time was the case of rheumatoid arthritis, where doctors continued to disagree as to which drug was the preferred drug, if any, for treating the disease. Senator NELsoN. That memorandum will be accepted for the record. (The document referred to follows:) LEGISLATIVE HISTORY OF THE DRUG AMENDMENTS OF 1962 MEANING OF "SUBSTANTIAL EVIDENCE" AND "ADEQUATE AND WELL-CONTROLLED INVESTIGATIONS" AS USED IN SECTION 505 (d) (s) OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT. Under the Drug Amendments of 1962, Section 505(d) of the Federal Food, Drug, and Cosmetic Act was amended to include a new "effectiveness" test with those Which a new drug application must pass' before it is approved. This `test is set forth in Section 505 (d) (5), Which provides that the Secretary shall issue an order refusing `to approve a new drug `application if he finds that: "[E]valuated on the basis of information submitted to him as part of the application and any other information before him With respect to such drug, there is a lack of substantial evidence that the drug Will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof. . . ." Sec. 505(d), Federal Food, Drug, and Cosmetic Act, as amended, 21 U.S.C. 355(d). PAGENO="0272" 3364 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRT If the Secretary finds that the above provision, and others, do not apply, "he shall issue an order approving the application." The 1962 Amendments also added the following definition of the term "substan- tial evidence": "[T]he term `substantial evidence' means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts quali- fied by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or the proposed labeling thereof." Ibid. There has been some discussion in these hearings about the meaning of the terms "substantial evidence" and "adequate and well-controlled investigations" which were introduced by the 1962 amendments. The testimony of Dr. William M. O'Brien has particularly focused upon these statutory terms. Dr. O'Brien, in his prepared statement at page 2, stated that: "The 1962. Kefauver-Harris amendments specifically stated that a manufac- turer must support claims of efficacy of a drug with `subtan'tial evidence.' The law defin:es this as `adequate and well oontro fled investigation by experts qualified by scientific training and experience `to evaluate effectiveness.' "I define the word control `as a standard of comparison for checking inferences in an experiment-in `other word's, in testing a drug one group is treated, and its response is compared to the response of an identical group which receives a standard `of `comparison-a standard treatment or a dummy (placebo). I believe this was the exact intent of Congress in the 1962 amendments. . . ." Furthermore, at page 5 of his prepared testimony, Dr. O'Brien stated that: "The only scientifically sound method for drug testing is the controlled double blind trial which eliminates both positive and negative bi'a's and uses a com- parison-either a placebo or a standard drug." Dr. O'Brien's views on the meaning of the pertinent statutory terms were underscored in his oral testimony before this committee, in response to a quetion by Mr. Gordon. "Mr. GORDON. Is it your opinion, then, as I understand it, that before a drug i's approved by the FDA, controlled double blind studies should be conducted by objective sources? Is that correct?" "Dr. O'BRIEN. Well, apparently it is not only my opinion but this is what the 1962 amendments said. . . Although Dr. O'Brien conceded in his oral testimony that the 1962 amendments did not specifically require double blind investigations, it is apparent that Dr. O'Brien reads the statutory terms "adequate and well-controlled investigations" as synonomous with, and only with, controlled double blind studies. Dr. O'Brien also concludes that "substantial evidence" can only be produced by controlled double blind studies. The words in the 1962 amendments of course do not state `so precisely what constitutes an adequate and well-controlled investigation. We submit that the lack of such `exactitude in the statute was deliberate, and that Congress intended flexibility in interpretation of the statutory terms. As this submission will show, Congress was well aware of several important points when it enacted the terms "substantial evidence" and "adequate and well- controlled investigations" in 1962. Throughout the legislative debate, it was clear `that these terms could have different content, depending upon the kind of disease under consideration. Rheumatoid arthritis received particular attention as a disease about which there is great dispute as to proper methods of diagnosis and treatment. The professional witnesses who testified in the Senate and House hearings did not suggest that there was any particular or exact way to measure the effectiveness of any particular drug. The entire course o'f the hearings in- stead established that a wide range of adequate and well controlled investiga- tions and of professional opinion about what they prove can exist with regard to any drug, and that the 1962 amendments were not intended to require an either-or choice between differing schools of thought. LEGISLATIVE HISTORY As introduced by Senator Kefauver on April 12, 1961, S. 1552 would have required the Secretary to refuse to approve a new drug application if he had insufficient information to determine whether the drug is "efficacious in use" under the conditions prescribed, recommended, or suggested in the proposed PAGENO="0273" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3365 labeling. 107 Cong. Rec. 5638. The original Senate bill did not consider the quantum of evidence necessary to establish sufficient information as to "effi- caciousness," nor did it consider the manner in which such evidence should be assembled for presentation to the Secretary. "SUBSTANTIAL EVIDENCE" During the Senate hearings on S. 1552, the issue of the amount of evidence which would be sufficient to allow the Secretary to determine "efficaciousness" was thoroughly considered. On July 19, 1962, after the Senate hearings on S. 1552, the Senate Committee on the Judiciary reported out a revised bill. At that time, the previous language regarding "efficacious in use" was amended to provide that the Secretary should refuse to approve a new drug if: "IT] here is a lack of substantial evidence (including clinical evidence), sup- ported by investigations of experts qualified by scientific training and experi- ence to evaluate the effectiveness of drugs, that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof . . ." The thorough debate on the issue of what would satisfy "substantial evi- dence" of effect resulted in a firm consensus, which is illustrated in the Senate Report. "The term `substantial evidence' is used to require that therapeutic claims for new drugs be supported by reliable pharmacological and clinical studies. When a drug has been adequately tested by qualified experts and has been found to have the effect claimed for it, this claim should be permitted even though there may be preponderant evidence to the contrary based upon equally reliable studies. There may also be a situation in which a new drug has been studied in a limited number of hospitals and clinics and its effectiveness estab- lished only to the satisfaction of a few investigators qualified to use it. There may be many physicians who would deny the effectiveness simply on the basis of a disbelief growing out of their past experience with other drugs or with the diseases involved. Again, the studies may show that the drug will help a substantial percentage of the patients in a given disease condition but will not be effective in other cases. What the committee intends is to permit the claim for this new drug to be made to the medical profession with a proper explana- tion of the basis on which it rests. "In such a delicate area of medicine, the committee wants to make sure that safe new drugs become available for use by the medical profession so long as they are supported as to effectiveness by a responsible body of opinion. "In his testimony supporting new authority for the Food and Drug Adminis- tration to pass on the effectiveness of new drugs before they are marketed, Sec- retary Ribicoff said that questions of `relative efficacy' are not here involved, and that the requested authority `would not require a showing of relatively greater efficacy than that of other drugs' (hearings, pt. 5, p. 2585)." S. Rep. No. 1744, 87th Cong., 2d Sess., p. 16. The views of Senators Dirksen and Hruska, in the same Senate Report, con- firm the view that substantial evidence can be less than preponderant evidence, and that room for minority opinions should exist. "We wish to augment the discussion of the effectiveness of drugs as now provided for in the majority report. Two quotations from the Senate hearings on S. 1552 are especially notable. Eugene N. Beesley, president of Eli Lilly & Co., and chairman of the Pharmaceutical Manufacturers' Association, in his testi- mony before the Senate Antitrust and Monopoly Subcommittee at page 1998 stated: "`Also, it is our understanding that the manufacturer would be required to provide only substantial evidence that a drug produces the effects claimed for it. He would not be expected to prove that scientific opinion was unanimous, or even preponderant, in supporting the effectiveness of a drug. Thus, if a number of tests by competent clinicians show that in well-conducted clinical trials a drug produced the claimed effect on their patients, the drug would not be barred simply because other tests did not produce the identical results with different patients. In other words, a drug should be made available for the benefit of those patients for whom the individual physician thinks it would be useful. "`In the entire realm of medical science nothing is more difficult and more subject to honest differences of competent opinion than the determination of the therapeutic merits of drugs in human beings. Experts have sharply opposed 81-280 0-68-pt. 8-18 PAGENO="0274" . . 3366 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY views concerning the proper treatment of many common diseases, and each school of thought has a strong champion. Many highly qualified physicians are con- vinced of the value of corticosteroid drugs in relieving rheumatoid arthritis; there are others who prefer aspirin; still others are proponents of a variety of other treatments . . .` "At the completion of Mr. Beesley's statement, Senator Kefauver agreed with Mr. Beesley's determination of effectiveness in the following language found on page 2007 of the printed hearings. "`You agree, as we have also recommended, that the Food and Drug Adminis- tration should pass upon whether a new drug is substantially efficacious for the claims made for it by the manufacturer, and that is the intent of the language in the bill although it may need some clarification Your language was sub stantial evidence not only that the drug is safe but also that it produces the results claimed." That is exactly what we had in mind in connection with that. "`Mr. BEESLEY. Mr. Chairman, I think we agree in the principle involved. The precise language of the statute is very important, bearing, of course, upon the interpretation that will be given to the statute, and the points which we have made here we think further clarify the statute and are exceedingly important to the way in which it will be administered. Senator KEFAUVER I would certainly accept as far as I am concerned your further statement on page 10: "`"Thus if a nuniber of tests by competent clinicians show that in well-con- ducted clinical trials a drug produced the claimed effect on their patients, the drug would not be barred simply because other tests did not produce the identical results with different patients," the key word's are "well-conducted clinical trials by competent clinicians." I agree with that. `t `Mr. BEESLEY. Mr. Chairman, the key words here from our point of view are "substantial evidence." What do we mean by efficacy? What do we mean by effectiveness of a drug? And that is the thought, the new thought, that we are producing there, which, may I submit, is exceedingly important. "Senator KEFAUVER. Substantial evidence is required in most Government pro- cedures and that is Inherent in what we have in mind with the bills.'" S. Rep. No. 1744, 87th Cong. 2d. Sess., pp. 57-58. After further consideration, on August 21, 1962, the Senate Committee on the Judiciary Issued a second part to its earlier report. At that time, the Senate bill was further amended to include the effectiveness test including the definition of "substantial evidence" that was ultimately enacted into law. The August 21, 1962, Senate Report further elaborated what was meant by substantial evidence The proposed committee amendment clarifies and strengthens the previously reported bill by restating and carefully defining the quality and quantum of evidence which the Secretary must find to exist as a basis for clearance of the drug or for withdrawal of a previously approved new-drug application. In the course of committee deliberations a distinction evolved, in this connection, be- tween two tests-the `proponderant evidence' tests and the `substantial evidence' test as now specifically defined. Under the former a claim would not be accepted under the new-drug section unless it represented the preponderant view of experts qualified by training and experience in the subject that the claim was supported. The committee recognizes that in the difficult area of drug testing and evalua- tion there will frequently, if not usually, be a difference of responsible opinion. The committee feels that the existence of such a difference should not result in disapproval of a claim of effectiveness if it is supported by substantial evidence defined in the manner set forth below and evaluated by the Secretary in the light of all the information available to him at the time. "As the result of subsequent study, a definition of `substantial evidence' has now been added to the bill concerning what would constitute such evidence. The amendment provides that `substantial evidence' means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. That is to say, a claim could be rejected if it were found (a) have the investigations were not `adequate'; (b) that they were not `well controlled'; (c) that they had been conducted by experts not qualified to evaluate the effectiveness of the drug for which the application Is made; or (d) that the conclusions drawn by such experts could not fairly and PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3367 responsibly be derived from their investigations." S. Rep. No. 1744, Part 2, 87th Cong., 2d Sess. p. 6. The Report of the House Committee on Interstate and Foreign Commerce' and the Conference Report2 do not elaborate further on the substantial evidence concept. The legislative history could not be more clear in establishing that Oongress understood the wide range of opinion that exists In the medical profession as to the effectiveness of any particular drug Thus Congress provided a definition of substantial evidence which allows the Secretary to find that a drug's effective- ness is supported by substantial evidence even if that evidence is, in volume, outweighed by opposing views. "ADEQUATE AND WELL-CoNTRoLLED INVESTIGATIONS" The issue of the manner in which an applicant should assemble evidence necessary to constitute "substantial evidence" was not directly in question dur- ing the hearings. The issue, however, was mentioned in debate as a necessary adjunct to the question of bow much evidence would be substantial. The Senate Judiciary Committee, in its second report, recognized that: "[Tin the difficult area of drng testing and evaluation there will frequently, if not usually be a difference of responsible opinion The committee feels that the existence of such a difference should not result in disapproval of a claim of effectiveness if it is supported by substantial evidence defined in the manner set forth below and evaluated by the Secretary in the light of all the information available to him at the time." S. Rep. No. 1744, Part 2, 87th Qong., 2d Sess. p. 6 (emphasis added). In the vast number of pages which the Senate hearings consume, there is only scant reference to the question of the correct methodology for testing drugs. The absence of long debate on this subject-is probably best explained by Secretary Ribicoff's observation that the amendments did not "contemplate and basic changes in the established pattern of testing the effectiveness of drugs." "Secretary Rinicor~'. Let me make it absolutely clear that we are not dealing here with what some have called `relative efficacy.' The claim has been made be- fore this subcommittee that the proposed amendment would enable us `to decide the relative or comparative efficacy of a new drug in terms of drugs already on the market,' or allow us to refuse clearance for a new drug merely because, in the Food and Drug Administration's opinion, it is `not the most efficacious drug for the purpose intended or was not as efficacious as one might ideally wish.' "The bill furnishes no basis for such apprehensions. The proposed amendments would merely require a showing that the new drug described in the application is safe for use and is effective in use, under conditions prescribed recommended, or suggested in the labeling thereof. This would not require a siiowing of rela- tively greater efficacy than that of other drugs. It would merely require that a drug claimed to be effective for a particular purpose has been demonstrated by sownd scientific procedures to be effective for that purpose. In short, it must live up to the claims made for. it. It should also be pointed out that this proposal does not contemplate any basic change in the established pattern of testing the effectiveness of drugs Testimony of Secretary Ribicoff before Senate Subcommittee on Antitrust and Monopoly, September 13, 1961, pp. 2585-2586 (emphasis added). The subject itself is extremely complicated, as the testimony of Dr. David P. Barr illustrated: "Every one who has tried to test drugs knows how extremely difficult it is to determine whether a drug is or is not effective, and the establishment of its effectiveness requires extensive facilities and team efforts which may require joint services of many participants, physicians, certainly, and pharmacologists, and others." Testimony before Senate Subcommittee on Antitrust and Monopoly, July 19, 1961, p. 259. That differences of opinion among responsible clinicians as to effectiveness and testing occur frequently was amply demonstrated in the course of the legisla- tive history. "The coniumittee recognized that legitimate difference of opinion may exist among responsible clinicians with respect to the effectiveness of a particular 1 HR. Rep. No. 2464, R7th Cong., 2d Sess. 2H.R. R~p. No. 2526, S7th Cong., 2d Sess. PAGENO="0276" 3368 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY new drug. Experience has shown that a majority of so~called experts `has often been wrong in initially condemning a new drug, just as new inventions in other fields are usually regarded with skepticism and often with hostility. The new ground for rejection of a new drug application is therefore expressed in terms of `a lack of substantial evidence,' evaluated on the basis of all the information be- fore him, that the drug will have the effect claimed for it. The term `substantial evidence' is defined in terms of the kind and quality of the investigations that must support the claims." Statement by Senator Eastland, 108 Cong. Rec. 16304 (August 23, 1962). "In the entire realm of medical science nothing is more difficult and more subject to honest differences of competent opinion than the determination of the therapeutic merits of drugs in human beings. Experts have sharply opposed views concerning the proper treatment of many common diseases, and each school of thought has strong champions. Many highly qualified physicians are convniced of the value of corticosteroid drugs in relieving rheumatoid arthritis; there are others who prefer aspirin; still others are proponents of a variety of other treatments." Testimony of Eugene N. Beesley before Senate Subcommit- tee on Antitrust and Monopoly, December 7, 1961, p. 1998. "Mr. BILa5LEY. . . . By `substantial' evidence we mean less than preponder- ant, or conclusive, evidence. "We mean that, where a reasonable number of clinicians have conducted tests which show that a drug has the claimed effects, FDA should permit the drug to be marketed even though other tests by other clinicians do not show the same effects. This is a case of difference of medical opinions, which, as Dr. Hussey had said, should .not be resolved by the fiat of any authoritarian body but by each physician in his own practice. "Senator KEFAUVER. All right. "Then we seem to be pretty well agreed all the way around, sir." Id., at p. 2012. Only at a few points in the hearings was there focus upon "controlled" investi- gations. When Dr. Charles May, Professor of Pediatrics at New York University, testified, the concept of a controlled examination was used to distinguish the facilities available to the individual physician. See Hearings before the Subcom- mittee on Antitrust and Monopoly, July 18, 1961, p. 204. The same distinction was emphasized by the testimony of Dr. Louis Goodman, Professor of Pharmacology at the University of Utah. See Id., at `pp. 217, 243. The one witness before the Senate hearings who stated that he had "often testified to the importance of double-blind controlled trials in clinical research" insisted that his statements did not constitute a demand for such trials on all new drugs. The witness, Dr. Louis Lasagna, asserted that: "The emphasis should be on scientifically acceptable evidence, of whatever quality and quantity required to give a reliable answer to the questions posed concerning the drug's effects." Hearings before the Senate Subcommittee on Antitrust and Monopoly, July 19, 1961, pp. 282-283. In discussing the subject of phraseology, Dr. Lasagna concisely stated a view which permeated the hearings: "I would hope that if such' a bill were passed, that there would be every opportunity for a flexibility of interpretation." Id., at p. 288. The legislative history also includes a statement by Dr. I. S. Ravdin introduced into the hearings before the House Committee on Interstate and Foreign `Com- merce. The statement was signed by a large number of doctors from all parts of the country, including Drs. Michael E. DeBakey and Paul Dudley White. The statement made the following points: "(1) Medicine is in part an uncertain science. There is at the present time no precise method for determining absolute efficacy or effectiveness. Such a determination must frequently be based upon medical opinion, and medical opinion is not always unanimous. "(2) Physicians very often have differing opinions about the usefulness of an agent in treating a particular disease. Many eminent physicians, for example, favor the use of the corticosteroids in the treatment of rheumatoid arthritis, but others believe that the corticosteroids are not the drug of choice for this purpose. "Under such circumstances, it is difficult, if not impossible, to determine the exact effectiveness of the corticosteroids in treating rheumatoid arthritis. . . Hearings before House Committee on Interstate and Foreign Commerce, August 20, 1962, p. 207. Perhaps the most complete discussion of the problems involved in the working of the substantial evidence standard and the methodology of investigating drugs PAGENO="0277" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3369 was by Dr Theodore Klumpp the President of Winthrop Laboratories befOrE' the House Committee on Interstate and Foreign Commerce Dr Klumpp testified that Despite advances in scientific techniques therapeutic representations and claims remain essentially matters of opinion Different schools of thought with respect to the proper treatment of various diseases are prevalent and sometimes completely contradictory Not infrequently it takes years and sometimes decades of widespread clinical experience to evaluate the true or relative merit of a drug in given conditions From such long experience a medical consensus generally emerges, but even then some qualified physicians refuse to go along with their colleagues. . At the present time there are sharply opposed views among experts concern ing the proper treatment of many common diseases Rheumatoid arthritis is such a condition There are highly qualified physicians who favor the use of oortico steroid drugs There are others who feel that the employment of the cortico steroids does more harm than good and that the only meritorious drug is aspirin Still others are proponents of respectively Butazolidin gold salts and anti malarial drugs such as quinacrine chloroqurne and hydroxychloroquine The use of pyramidon or large doses of vitamin D still has adherents and particu larly among clinicians in foreign countries The reaction of experts to any new drug offered for the treatment of rheumatoid arthritis will inevitably be condi tioned by the school of thought to which they happen to adhere By whose advice is FDA to be guided in the evaluation of a new drug for this condition'? [Dr Klumpp then considered similar problems with drugs for epilepsy mucous colitis and the common cold I The above specific illustrations are only a few of the many that can be cited to show that- (a) The determination of the effectiveness of a drug is always difficult and sometimes cannot be achieved except by the test of time and widespread use (b) Therapeutic representations are essentially matters of opinion (c) Differing schools of thought frequently exist concerning therapeutic issues and the school which favors one theory as to the nature and treatment of disease tends to be skeptical of the drugs advocated in opposing schools More over medical opinions as to effectiveness of a particular drug can differ widely among equally qualified physicians because of basic differences in opinion relating almost entirely to questions of diagnosis and preferred method of treatment, as well as differences as to the comparative efficacy of one member of a class of drugs in relation to others or the mode of action of a particular drug in the complex body mechanism Hearings at pages 232-235 CoNCLusIoNS The legislative history of the 1962 amendments establishes quite clearly that Congress did not intend substantial evidence to mean a preponderance of evi dence Nor did Congress expect the medical profession to arrive at single con clusior~s about drugs and treatments Rather than enacting standards which would require exact proof and which could leave no room for minority opinions Congress explicitly favored concepts of flexibility which could accommodate the range of responsible professional opinions. Had Congress disagreed with Secretary Ribicoff's view that the amendments would not change the established pattern of testing drugs, there would have `been more discussion on the subject of the methodology of drug testing But Congress did not take issue with the Secretary s assessment of `the law and the legislative history shows that Congress intended to maintain flexibility in the area of drug testing just as it so intended with the concept of substantial evidence The substantial evidence standard itself as enacted requires a comparable openness with regard to differing opinions in the area of what constitutes adequate and well controlled investigations It may well be that certain drugs for some kinds of diseases are better investigated with some techniques than with others A substantial difference of opinion might exist about which methods of testing should be applied in different circumstances It would be wholly inconsistent with the clear and unambiguous intent of Congress with respect to the substantial evidence standard to conclude that only certain kinds of tests could produce such evidence when there is a body, however small, of reliable professional opinion to the contrary. An "adequate" test for one situation might be inadequate in others; the kinds of controls possible in one instance might be impossible of achievement or less meaningful in aonther and even the qualifications of PAGENO="0278" 3370 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY persons performing clinical investigations can be matters for honest differences of opinion. The substantial evidence standard itself concedes that room must be left open for well-founded differences of opinion. That standard would become rigid, and precisely what Congress expressly intended to avoid, if one point of view about the proper methods of testing drugs were allowed to dominate and exclude other points of view. As long as a sound professional difference of opinion about the merits of different methods of drug investigation exists with regard to par- ticular drugs, it is clear from the legislative history of the 19~2 amendments that a single view, especially one which seeks exact answers in inexact areas, cannot properly be considered the "only scientifically sound method for drug testing." Senator NELSON. I have a letter that I received from the Department of Health, Education, and Welfare, signed by Theodore Cron. Mr. Cutler has a copy of this letter as does the press I will ask to have it put into the record at the appropriate place after yesterday's testimony Mr. `GADSDEN. I might ask, are we going to revert for a moment to-you are putting Mr Cron's letter into the record ~ I am asking the privilege now or later of talking on the substance of what is going in the record Senator NELSON. All right. The appropriate place for this, I would assume, is after yesterday's testimony.' If you would like to comment on it now, I will ask that your comments `be placed in the record after this letter. Mr. GADSDEN. Yes, sir. Senator NELSON. Or, if you wish to submit something later that you will prepare, you may do so. Mr. GADSDEN. I would like to comment here, and then we can decide into `what degree of detail you want to go, sir. First, I think it is important to record that `at the time of the release of indomethacin by the Food and Drug Administration, I, as the chief executive officer of the company, issued an order that und'er no cir- cumstances were we to seek any lay publicity in connection with it-its benefits, or anything else. I assume, lest we have any confusion here, that you are alluding to the same Mr. Cron letter which I have in front of me~ Senator NELSON. It has no date. Mr. GADSDEN. The first sentence begins "You will recall that Dr. McCleery." Senator NELSON. Yes, that was delivered here this morning at about 10:45.1 am referring to that letter. Mr. GADSDEN. I would like to make a statement on that, sir. A free-lance `writer and TV fellow, Mr. Goldman, called our director of public relations, Mr. Fletcher. Mr. Goldman said his wife had suffered from tennis elbow and had been unable to play `and that her doctor prescribed "Indocin" and it worked miraculously. He had checked around and found a lot of doctors who were using it effectively, and said he was going to write a story about it. He was upset with the company, namely Merck & Co., for not telling people about the drug, and he asked the company for background materials, which we sent him. . He was told that tennis elbow is not an approved claim, and he was also told why the company had elected not to publicize the drug. `See p. 3294, supra. PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3371 Several weeks ensued Mr Goldman did not visit the company 01 talk with anyone in the company about the drug or the story `he was writing. Then he called Mr. Fletcher again, said his story was essent- ially finished, said he had a lot of anecdotes to liven it up, and asked if the company could provide addition~i anecdotal material to per- sonalize it still further. Mr. Fletcher supplied him with four or five letters from our files, deleting the names of the correspon~dents. They dealt with approved claims. There is, as I understand it-and I will check it if this is material- an attribution of a nonapproved claim in the article This was not among the cases supplied to him by Merck & `Co. Senator NELSON. What is an approved claim? Mr GADSDEN The four that were enmnerated earlier, sir, which have to do with various aspects of arthritis. Senator NELSON. What is an approved claim? Mr. GADSDEN. When we make a submission to Food and Drug, as we discussed earlier, we request-iet us call them indications. Perhaps that is a more precise term than "claims," meaning for what disease conditions use of the drug is indicated The FDA must approve these indications The thrust of the criticism is that we were seeking through lay publicity to publicize and popularize the use of this drug for con ditions-indications--~which had not been approved. Senator NELSON. I see. Mr. GADSDEN. I will continue, sir, if I may. We were altogether unprepared for the appearance of this Pageant' article, with the name of the drug as the title of the article, and a subtitle that enumerated its value for a number of conditions for which we had no claim. Senator NELSON. That will go into the record immediately follow- ing this letter so that they will both appear in the appropriate place in the record. Mr GADSDEN Counsel reminds me, sir, that contrary to the state ment that is contained in the letter which has gone into the record, Mr. Fletcher did not see the article until after it was printed. Mr. Cumi~. Also', Mr. Chairman, the article itself, as I understand it, refers to one letter which the author says he got from Merck relat- ing to the use of the drug for an unapproved claim. No such letter was furnished by Merck. Senator NELSON. Thank you. Aga:in, thank you, Doctor. Dr. LAWRASON. Before introducing the two.~ outside witnesses, Dr. Oalabro and Dr. Smyth, the two physicians, who will summarize their views and the views of physicians who are treating patients with arthritic disorders, I have with me an even broader representation of medical opinion concerning the values and limitations of indomethacm that we hereby submit to you with the request that it be made part of the official record. Senator NELSON. Would you identify what it is? Mr. CiJTLER. It is' this green folder which you should have up there, Senator Nelson. ` Dr. LAWRASON. This exhibit, Mr. Chairman, consists of letters and telegrams from distinguished rheumatologists and experienced physi- PAGENO="0280" 3372 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cians across this country and `around the world. I want to tell YOU how they came to us. When we learned that this committee was planning to hold hearings on indomethacin, we asked a number of investigators who we knew had worked with indomethacin to give us, so we could give to you, their frank `appraisal o'f the drug. Their names and positions and reputations speak for themselves, and also bespeak the fact they would support no drug and no drug company if the facts did not war- rant support. We are submitting here every communication we have received, exactly `as it came to us. When the committee examines this documentation, it will find it represents the full range of medical and scientific opinion. Some investigators have found indom,ethacin very useful, some have found it useful in some conditions and not in others; some have found it only marginally useful. This sample of professional judgment o'n the part o'f physicians using indomethacin in their practice reinforces our conviction that when properly used, it is a safe and effective drug that benefits hun- dreds of thousands of patients. I would like to ask your permission that these letters and telegrams be put in the record. Senator NELSON. You want it in the record at this point? Dr. LAWRASON. Yes, sir. Senator NELSON. They will `be put in the record at this point. (The documents referred to' follow:) RECEIVED FROM DR. F. DUDLEY HART, WE5TMIxIsTim HosPITAI~, ENGLAND In the light Of your extensive experience in the managemen,t of diseases for which indomethacin is indicated- (1) Do you consider that the introduction of ind'olnetihacin has contributed to the management of your patients? Yes. (2) Do you find that indomethacin enables you to obtain results in some of your patients `that were difficult to obtain prior to its introduction? (3) If `so, can you define those areas in which the drug has been most helpful? (a) In `acute gout, I would rate it the drug of first choice. Good as are the pyrazoles, we find their acti'on slightly slower, and in `this disease `a quick re- sult is all-important. Our order of preference is indomethacin first, phenyl- butazone and o'xyphenbuljazone second and colehicine third. (b) In ankyl'osing spo'ndylitis, although aspirin is suitable for the mild cases, taken as required, if larger regular `anti-inflammatory dosage is necessary, few men doing active wo'rk, as are 80% of those attending our clinic, can (or will) take such dosage, and much perfer indomethacin or the pyrazoles. We consider the last two equally effective, but the real hut rare danger of `blood dyseraslas with the pyrazoles now leads us to try indo'methacin first, and only proceed to the pyrazoles if results are unsatisfactory. We try fiufenamic acid next, as we find it less effective. (c) We find indomethacin helpful in half our cases of rheumatoid arthritis, and consider its anti-inflammatory action less than that of the corticosteroidis or eor'tic'otrophin, but greater than that of the other non-steroidal anti-inflamma- tory agents. The trial and erro'r method which is necessary in the treatment of rheumatoid arthritis must leave some choice to the patient, who finds large num- bers of aspirin tablets tedious to take in many instances, and they will not, and do not, take them. We start with aspirin and only go on to other drugs if ther- apeutic results are poor to `toxic effects troublesome. A number of patients with rheumatoid arthritis prefer indomethacin and do better on it than any other agent. Because of the unwanted endocrine effects, we use co'rticosteroids only in small dosage in selected patients. (d) We find indomethacin a useful drug in Reiter's disease. (e) In osteoarthrosis of cervical spine and hip, we find indomethacin a useful substitute for the pyrazoles, which, though very useful, have the danger of causing blood dyscrasias, though rarely. This is the main reason for preferring indomethacin to the pyrazoles, for in most other respects the drugs are equally effective in the same group of disorders. PAGENO="0281" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3373 LOVELACE OLINIC, Albuquerque, N. Mea~., April19, 1968. Dr. MAX TISHLER Merck Research Laboratories, Merck ~ Co., Inc., Rahway, NJ. DEAR DL PISHLER: I understand that there are to be hearings very soon In Washington regarding the efficacy of certain drugs which have been marketed in recent years. Among these I understand that Indocin is one to be considered. I should like to state that I have used Indocin since it first became available, even before it was marketed and that in selected instances I feel that this is a very notably effective and safe drug. I feel that its indiscriminate use, just as the in- discriminate use of any medication without adequate reason, is unwarranted. However, in my opinion, it is the drug of choice in such cases as rheumatoid spondylitis and degenerative arthritis involving the spine and hips especially. Its use in gout is according to literature, very definitely an appropriate measure and with less drastic effects than some of the other medications that are avail- able for treatment for this acutely painful process. My own experience is no extensive enough with this particular problem to warrant comment. I feel that much of the "poor publicity" which has surrounded Indocin is a result of its indiscriminate use in many instances where it has not been war- ranted. In my own experience, it is not nearly as effective in peripheral rheuma- toid arthritis as it is in the other instances mentioned above. So far as its toxicity is concerned, I feel that the serious problem has to do with gastrointestinal irrita- bility, the symptoms of which are quite readily apparent and if both doctor and patient are aware of this problem, serious trouble can be easily avoided. I have not yet run into any other significant toxic reactions to this drug that would in- dicate any serious effects on health. I feel that from the standpoint of all available information in the literature that merits consideration there is adequate information regarding this drug, that further investigatioi~a1 procedures would be a waste of time and a waste of money and would deprive certain patients from the use of a drug that has very definite value to them. Very truly yours, C. M. KEMPEE, M.D. RR,HARD W. PAYNE, M.D. Oklahoma City1 Ohio., April 20,1968. DEAR DR. PISHLER: I hear that there is some movement afoot to curtail the use of Indocin. If this news is correct, I would like to put myself on record as finding Indocin indispensable in my practice of rheumatology. The agent has a relatively low order of serious side effects and is of undoubted value in the practical long- term management of many patients with various types of arthritis. While there are double-blind studies which question the efficacy of Indocin- I am equally prone to question the validity of such studies that I have seen, including my own. After 6 yrs. experience with Indocin I have no doubt that it is a valuable therapeutic agent in a group of diseases notoriously difficult to treat. That we don't know exactly how it produces its beneficial effects is no fault of the drug. MEMORIAL HOSPITAL, Charleston, W. Va., April20, 1968. MAX TISHLER, Ph. D., Merck Research Laboratory, Merck cI Co., Inc., Rahway, N.J. DEAR DR. TISHLER: It is my understanding that you and your associates will be appearing before a Congressional Hearing very shortly to engage in dialogue and data gathering regarding indomethacin and its clinical benefits in the treat- ment of particularly rheumatoid arthritis, as well as the double blind method of drug evaluation. I thought that you might, therefore, be interested in some of my personal conclusions regarding these two issues based upon my experience with double blind study using Indocin and placebo, as well as experience with indoinethacin prescribed to rheumatoid arthritis patients these past three years. Regarding the double blind method in evaluating drugs for rheumatoid arthri- tis, I think there is universal agreement that this is still not the answer to evalua- tion of drugs for this disease, but it is the best we have available at this time. In the first place, rheumatoid arthritis is so variable from day-to-day, week-to- week, and month4o-month that any change short of virtual remission of the dis- ease must be submitted to the mathematical probability wherein the results PAGENO="0282" 3374 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY are trends and not conclusive evidence. Secondly, in the measurement of ac- tivity of disease in rheumatoid arthritis there is also apparent universal agree- ment that there is still no satisfactory means of doing this. Lansbury's criteria, measurement of the inflammation of the joints, the swelling, mobility, general w~1i-being of the patient, etc., all have a certain subjective element and a wide standard deviation. Typical example is the objective measurement of the knuckle circumference or the knee circumference. This requires no judgment on the part of the patient; however, in order to arrive at a probable accurate mathematical figure, the measurement of his joint must be done by the same person at each observation and several times each observation, even then, the other variables of swelling of the extremities due to causes not related to rheumatic disease are never determinable. This same problem can be applied to all the other objec- tives and are certainly applicable to the subjective measurements for rheumatic activity But I repeat that this is all that we have at this time and I eagerly search the literature and discuss with my colleagues any daveiopments in this area. Regarding Indocm and its effectiveness-Indocin is presented as an anti inflammatory drug and is ranked with aspirin, phenylibutazone, adrenocortical steroids and lesser anti-inflammatory agents. Whether antimalarials are actual anti-inflammatory in the sense of these drugs has never been really determined I think organic gold salts are not considered primarily anti-inflamatory. Of all these drugs, gold in my impression and the impression of the literature has been the one that has stood the test of time and double blind study as being probably causative in the induction of remission in rheumatoid arthritis. Thus, indometha- cm, an anti-inflammatory drug, cannot offer the promise of remission, but rather a reduction in pain and swelling, and perhaps a delay of the destructive conse- quences of sustained synovitis. This latter has not been proven even for aspirinS and definitely has not been proven for steroids. Steroids may prevent ankylosis and result in a mobile destroyed joint, which is more amenable to surgical therapy. Perhaps a good and consistent use of other anti-inflammatory drugs like Indocin would do the same and have this benefit. My colleagues in West Virginia, realizing my interest in rheumatology and my experience with the use of Indomethacin have asked me-what do I think of the drug? I tell them at this point that indomethacin is a definite anti-inflammatory drug and it is as good as the other anti-inflammatory agents mentioned above. The next question is-why should I use it above the others? I refer them to the serious side effects of phenylbutazone and adrenal steroids, which brings us down to the discussion as to whether it should be used in addition to or rather than salicylates; and this apparently is the issue that has appeared in the literature. I then say that effective salicylate therapy demands the continuous administration of sub-tinnitis dosage of the drug and this means that the patient must be experi- encing from time to time tinnitis as well as diaphoreasis, cerebral symptoms, etc., and requires a dosage from 12 to 18 tablets a day. I submit that the problem of getting the patient to take that number of tablets every day for years is in some cases insurmountable; but the same can be accomplished with approximately 6 capsules of Indocin a day. This is then the current pragmatic feeling on my part regarding the use of indomethacin in the spring of 1968. We are currently in the process of retrospective analysis of patients treated 18 months or more with all the above drugs, singly or in clusters, including indomethacin. These are in the hands of our biostatistician and will be made available when completed. Very truly yours, DANIEL HAMATY, M.D., F. A. C. P. MEDICAL COLLEGE OF VIRGINIA, Richmond, Va., April22, 1968. MAX TISHLER Ph D Merck & Co., Inc., Rahway, N.J. DEAn DR. TISHLER: It has recently come to our attention that in the near future inquiries will be held concerning the efficacy of Indocin (Indomethacin). Indocin is no panacea in the treatment of rheumatoid arthritis but it definitely has a place in its treatment and in the treatment of other rheumatic disease such as gout, osteoarthritis, and ankylosing spondylitis. The management of rheumatic arthritis involves a treatment program of some complexity No rigid set plan of drug therapy should be followed A program PAGENO="0283" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3375 which proves beneficial in one patient may not in another. If one medication proved effective in all patients, there would be no needfor the long list of avail- able medications. If one method of approach does not prove effective, another should be pursued. Aspirin or some other salicylate preparation should be given initially in essentially all cases of rheumatoid arthritis. If after several weeks no clinical improvement is experienced, another agent should be added. We frequently use Indocin as the second agent and will continue to use it in this capacity. Also, we have found the drug to be helpful in selected cases of osteoarthritis, acute gouty arthritis, and ankylosing spondylitis. Sincerely, DUNCAN. S. OWEN, Jr., M.D., Assistant Professor of Medicine, Division of Connective Tissue Disease. MEDICAL COLLEGE OF VIRGINIA, Richmond, Va., April 22, 1968. Dr. MAX TI5HLER, Merck Research Laboratories, Merck ~G Co., Inc., l~ahway, N.J. DEAR DR. TIsHum: It has come to my attention that there will be a Con- gressional Hearing regarding the efficacy of Indoniethacin (Indocin) m the treatment of rheumatoid arthritis and related rheumatic disorders My personal feeling about this drug is that it has a definite place in the treatment of rheuma toid arthritis and in certain cases has a very beneficial result There have been certain side effects which prohibit its use but none have been of a serious nature in my experience. Many investigators state that "double blind" and "double blind crossover" studies are the only ways to properly evaluate the effect of .a drug. It is my feel- ing this does not always hold true in the case of rheumatoid arthritis. Patients with rheumatoid arthritis will vary as to their physical abilities throughout the period of day's time and the natural history of rheumatoid arthritis with remissions and exacerbations are two factors which make the double blind study difficult to evaluate in this disease. If there were a more realistic method of evaluating efficacy or lack of same in the rheumatic diseases this would be most helpful. Yours sincerely, ROBERT IRBY, M.D., Associate Professor of Medicine, Medical College of Virgin4a, Richmond, Va. HOLBROOK-HILL MEDICAL GROUP, Tucson, Ariz., April 22, 1968. MAX TI5HLER, Ph. D., Merck Research Laboratory, Merck d Co., Inc., Rahway, N.J. DEAR DR TISHUiR Dr Richard Smith telephoned me this morning asking me to write to you regarding my impressions about Indocin and my thoughts about double blind studies for evaluation of agents for treatment of rheumatoid arthritis. First, in regard to Indocin, our group did conduct a clinical trial to study efficacy and toxicity before Indocin was marketed. These studies were limited prmarily to rheumatoid arthritis and unfortunately, did not show consistent results. There were a few patients who `felt that Indocin gave them much more relief than other analgesics or anti infiamatory compounds but we did not feel that the drug altered the course of the disease. We continue to use Indocin in a limited number of patients where they feel it has been of help to them Unfortu nately, a number of our patients were unaible to tolerate the drug. In regards to double blind studies with rheumatoid arthritis, it has been most difficult in our experience, to get a true assesment as to its efficacy. This is prob- ably due to the fact that we have such a wide variation, not only in disease activity `and extent, but also in patient variability in age, personality, motivation, PAGENO="0284" 3376 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY etc. We are now in the process of trying to improve our methods of evaluation through a system of gross measurements, correlating the subjective with the objective findings. Trusting this is the information you desire, I am Sincerely, DONALD F. HILL, M.D. THE UNIVERSITY OF IOWA, Iowa Uity, Iowa, April22, 1968. flr. MAX TISHLRR Merck Re8earch Laboratory, Merck, sharp ~ Doh~ne, Rahway, N.J. DEAR DR. TISHLER: I ~n~i enclosing `two of the Bulletins that we have written giving our experience with indomethacin.1 You will notice that the last one was written in 1965. Since that time we have continued to use indomethacin, particularly in rheuma- toid arthritis, and are of the same opinion, namely, that this drug is a safe and effective anti-inflammatory medicament in the management of rheumatoid arthritis. Over the years we have used this drug only in conditions in which we could make a definite diagnosis, and from our past experience knew that it would be effective. These conditions were rheumatoid arthritis, gout, Reiter's disease, and a few cases of degenerative arthritis. We have not prescribed this drug in the conditions that are difficult to accurately diagnose, or in which we are limited only to the patient's response. These include low back pain, fibrositis, painful `shoulder, and pains in elderly individuals which are, unfortunately, classified as osteoarthritis. Most physicians are very impatient and think that an anti-inflammatory drug should relieve or cure a chronic ailment such as rheumatoid arthritis in a short period of time. We have found many patients who were on adequate treatment but still continued to have mild degrees of synovitis. The swelling caused by the synovitis results in pain which is difficult to control. When these people are given indomethacin, in addition to the treatment they are receiving, the synovitis gradually decreases, and improve clinically. This, however, may take several weeks rather than a few days. By the same token when we see a new rheumatoid we usually start them on salicylates and if we cannot hold them with this drug, we usually add indomethacin. A high percentage of the patients that we have do well, but a few continue to show intermittent exacerbations and must be given other drugs as well, including steroids, or gold, etc. If one of our patients has been on steroids, we will add inclomethacin in an attempt to reduce the dose of steroids to a safe level. As you know, we believe that rheumatoid arthritics should not receive more than a total of 8 mg. of prednisone, or its equivalent in other steroids, per day. Indomethacin has helped us reduce the steroid dose and prevent many of the side-effects caused by the steroid. Since 1965, our usual dose of indomethacin is 75 mg. per day. With this dose we see fewer side effects than we reported in the enclosed Bulletin. At times we may give 100 or 125 mg., but cut back as soon as the patient has dizzyness, muzziness, or other irrelevant effects. In our hands, indomethacin is a very safe drug. I was surprised to hear `that a Oongressional Committee is investigating indomethacin. I suppose this has been started because of `the some of the recent reports on the double blind studies. It is in these studies that one finds many of the loosely defined syndromes being treated, as well as rheumatoid arthritis. Most `of these studies depend on the patient's own response to the `drug given for a short period of time, usually about two weeks. It is difficult to determine `the effect of indomethacin in the ill-defined syndromes. Even in rheumatoid `arthritis we have seen severe and relentless progression of the disease despite every `type of heroic therapy that we try. It is a well known fac't that individuals with a high titer of the rheumatoid factor will have progression despite anything that you do. It is not unusual to see an individual with `a very high titer have break- down of the joints in the wrists and fingers, even though they are getting adequate physical therapy, adequate dos'es of salicylates, steroids, indomethacin, and/or gold. On the other hand, people who have a low titer may have a remission for long periods of time with little or no destruction of joints. In any double blind study, one has both types of patients, and therefore any drug will not work in 1 RetaIned In committee files. PAGENO="0285" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3377 some arthritics and will appear to be an excellent drug in others. We are very conscious of this as we try to separate these two groups and select the severe ones as candidates for prophylactic surgery (synovectomy, etc.). In conclusion, our group at Iowa feel that we could not treat rheumatoid arthritics adequately without indomethacin. Sincerely yours, W. D. PAUL, M.D. - PAUL Youxa, M.D., Asheville, N.C., April 22, 1968. Dr. MAX TISHLER, Merck Research Laboratory, Rahwa~y, N.J. DEAR Dn. TISHLER, I have been in the full time practice of rheumatology as a private practitioner since 1958. I believe that I am one of the very few physicians in the country who is in this position of making a full time professional activity out of the treatment of arthritis. Over half of my practice consists of patients with rheumatoid arthritis and I am treating approximately 300 such patients all the time for the last five to ten years. I have been actively engaged in the evaluation of new drugs for the treatment of arthritis and was doing this in practically all of my patients in the period of 1960 to 1963. I discontinued these endeavors in 1963 because of the enormous amount of paper work which was generated by the law which was passed in 1962 where you had to prove that you were taking the same precautions we had been taking all the time. During the period of 1960 to 1963 I was engaged in the evaluation of 18 different drugs in the treatment of arthritis on some 3000 patient/drug combinations. I have been quIte familiar with the work of the committee on coopera- tive clinics of the A.R.A. since 1960. It ~sas at my suggestion that the OCO en- gaged in the study of variability in rheumatoid arthritis in about 1963. I am personally acquainted with well over half of the physicians involved in the CCC studies and I am quite familiar with their drawbacks and limitations. I am not particularly enthusiatic about the use of Indocin in rheumatoid arthritis because I feel that this has only analgesic and anti-inflammatory effect and prefer to use compounds such as gold and the anti-malarials for the long term treatment of this disease. However it is beyond any reasonable doubt that Indocin does give effective relief of the symptoms of rheumatoid arthritis and in some patients this is the most effective remedy of its type on the market. Probably aspirin would do just as good a job if patients could take 30 aspirin a day, but in my experience most patients cannot take 12 aspirin a day on a regular basis whereas many can take Indocin. It is ridiculous to argue that Indocin is no better than aspirin when many patients cannot take aspirin. With respect to the recent questions that have been raised by the CCC trials of Indocin, I would like to say that under the circumstances of these trials the types of patients used would not very well demonstrate the effect of Indocin. Due to the nature of the disease, rheumatoid arthritis, Indoein is most effective in patients who have not developed joint deformities and secondary complications of the disease due to anatomical damage. If this study had been confined to patients without deformity and with most of their symptoms being due to the pure inflam- matory effects of arthritis `there would be in my mind, absolutely no question but that Indocin would have been shown to be an extremely effective drug for re- lief of inflammatory symptoms due to rheumatoid arthritis. For physicians who are thoroughly and professionally acquainted with the nature of rheumatoid arthritis it is not necessary to do the "double blind" studies in order to tell whether a drug is effective or not. It certainly is necessary to do this type of study in order to tell whether one drug Is more effective than another drug in a similar type of patient. In conclusion, I would like to state that the recent questioning of the value of Indocin in rheumatoid arthritis merely illustrates the ignorance of the people asking the question and the lack of familiarity with the nature of the disease, rheumatoid arthritis, and the proper precautions to be evaluated in judging therapeutic efficacy. PAGENO="0286" 3378 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It would be a great disservice to the public at this time to raise any question which could lead to the withdrawal of Indocin for treatment of patients with rheumatoid arthritis. The drugs we have to use in treating rheumatoid arthritis are not as good as we would like to have but there are some patients who desperately need each and every one of them. ARTHUR DOBKIN, M.D. Akron, Ohio, April22, 1968. Dr. MAX TISHLER, Merck Research Laboratories, Merck c~ Co., Inc., Rahway, N.J. DEAlS DR. TI5HLEB: I ~am one of a few physicians in this metropolitan area who have been interested in and practicing Rheumatology for a number of years. I have used one of your drugs, Indocin, ever since it was released several years ago. In my experience with this drug, I find that it has a useful place in the therapy of arthritis I fully realize that it has no curative effects never theless, I have found "Indocin" to be beneficial in a selected and limited number of arthritis patients. It has been effective in relieving the symptoms of a number of patients with Rheumatoid Arthritis, Gouty Arthritis, as well as Osteoarthritis and Rheumatoid Spondylitis. "Indocin", like many other medications now used in Arthritis, none of which are curative, will therefore have a place in the treatment of the Rheumatic Diseases in selected cases-at least until such time as newer and more effective medications are available. MAYO CLINIc, Rochester, Minn., April 22, 1968. MAX TIsHI~ER, Ph. D., President, Merck Bharp d Dohme Research Laboratories, Ralvway, N.J. DEAR DR. TISHLER: It is my understanding that a congressional hearing is soon to be held in which the efficacy of indomethacin may be challenged I do not know the basis for this contest but if the opportunity presents itself, I would be pleased to have you convey my opinion that indomethacin has served a use- ful function therapeutically. The record clearly shows that it has been adequately tested on an experimental basis prior to its introduction for clinical usage and that widespread clinical trial has indicated an acceptable risk of occasional intolerance on the part of certain patients. It should be noted, however, that all known anti-inflammatory drugs seem to have a tendency to gastrointestinal bleeding but that this does not seem to be an overriding interference to `the use of anti-inflammatory drugs in general. As a matter of fact, the public interest would not be served by the elimination of anti inflammatory drugs I feel further that the medical profession has been amply instructed in the proper usage of indomethacin. The challenge to indomethacin on any basis with which I am familiar is in my opinion unwarranted and probably prejudicial. Sincerely yours, H. F. POLLEY, M.D. VETERANS' ADMINISTRATION CENTER, Los Angeles, Calif., April 22, 1968. Dr. MAX TISHLER, President, The Merck Foundation, Merck c~ Co., Rahway, N.J. DEAR DR. TISHLER: It is my understanding that there will be a congressional hearing soon to consider, among other things, `the current' controversy that has been brought forth regarding the antirheumatic efficacy of indomethacin. I would assume that this is somehow related to the results of more recent double- blind evaluations with indomethacin in rheumatoid arthritis (RA). It is my opinion that while double-blind studies are ohviously useful in evaluating new agents, they are also extremely difficult, particularly in such a capricious disease as RA. To this point, I might add that there are few (if any) double-blind trials with other antirheuniati'c agents that are entirely satisfactory. PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3379 ~)ven more appalling are the apparent expectations of many investigators con- ducting short-term studies in RA that indomethacin would provide objective functional improvement. This is a clinical misconception since all antirheumatic agents are at best palliative. By providing effective relief of joint pain and inflammation, drugs allow patients to undertake therapeutic exercise and other supportive measures. These provide objective improvement. Yet, such measures receive scant mention and do not appear to be an integral part of the reported double-blind studies of indomethactin in RA. In spite of these controlled trials, many physicians have the impression that indoniethacin benefits certain patients with RA. As Henley has recently pointed out in the Bulletin of the Rheumatic Diseases (18, 483, 1967), there may be a sub-group of patients with RA that are controlled by indomethacin, a finding that would not be evident when such patients are included in a general drug trial. To my knowledge, this hypothesis has not been tested. The result of our long-term evaluation of indomethacin in ankylosing sponcly- litis (AS), a form of rheumatoid disease affecting young men, has recently appeared in the journal Arthritis and Rheumatism (11,56, 1968). In this trial of indomethacin averaging 33 months in 28 AS patients who re- ceived an average daily dosage of 1(X) mg., the response to the drug was good in 21 patients, fair in 5 and poor in 2. Of the 28 patients, 21 improved to AR,A functional class I Before the use of indomethacm only one of the 28 was so rated Joint symptoms followed temporary withdrawal of the drug in all but four of the 28 patients. These symptoms were promptly relieved when indomethacin was again taken by the patients. Olearly, our report parallels the experience of others, such as Bilka, Hart, Kass, Pohi, Rothermich and De Seze, that indomethacin is an essentially safe and effective drug in suppressing the articular manifestations of AS. I sincerely hope, despite the current controversy and confusion, that investiga- tive pursuits of indoinethacin will continue. Only then can we more fully under- stand the role of this extremely useful and valuable antirheumatic agent. Best wishes. Very truly yours, JOHN J. CALABRO, M.D. Chief, Rheumatology section, Wadsworth Hospital. ST. Louis UNIvERsITY, ScHooL OF MEDICINE, ~t. Louis, Mo., April32, 1968. MAX TI5HLER, Ph. D. Merck Reseairch Laboratories, Merck c~ Co., Inc. Rahway, N.J. DEAR DR. TI5HLER: I understand that indocin is u)nder Federal scrutiny in re- gard to its effectiveness in rheumatoid arthritis. Since I am presently perform- ing a double blind study with this drug in the treatment of rheumatoid arthritis, I would like to offer the foilowinct comments. The therapy of rheumatoid arthritis as you know is very difficult Fortunately we have many drugs available today which help the practicing physician control this crippling illness in most patients Many times we find it necessary to use several medications in the same individual because of a lack of any specific drug which will perform to the degree of satisfaction we desire. Some of these `drugs are rather toxic, thereby obviating their routine usefulness. By combining drugs like indocin with `some of the more toxic medications, we are thus able to effectively use some of the latter preparations in smaller dosages and, conse- quently, `avoid some of their complications. This would be particularly true of the steroids, the "cortisone-like" drugs. Also, when used alone, indocin may offer significant relief so that the addition of' other antifiammatory drugs may not be necessary. Despite the fact that indocin's value in rheumatoid arthritis has been ques- tioned recently, it is my opinion that this medication certainly has a place in the therapy of rheumatoid arthritis. I do not administer indocin as a drug of first choice; `however, I do believe it offers a significant advantage to approximately fifty percent of rheumatoid patients. Evaluation of any drug for the treatment of rheumatoid arthritis is extremely difficult. Double blind studies, such as thos'e `being performed at the present time, seem to be the appropriate method of determining a drug's effectiveness. If a PAGENO="0288" 3380 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY sufficient number of patients are studied, satisfactory answers should result from such studies. The difficulty in evaluating a drug for the treatment of rheu- matoid arthritis arises because of the many pacients who will improve with placebo therapy. Also, objective manifestations of improvement are frequently very difficult to measure with any degree of accuracy in rheumatoid arthritis. If there is doubt about indocin in the treatment of rheumatoid arthritis, I be- lieve that double blind studies should give the most reliable information in its efficacy. `Sincerely yours, JACK ZUCKNER, M.D., Associate Clinical Professor, Director, Section of Arthritis. PITTSEURGH, PA., April 22, 1968. MAX TISHLER, M.D., Merck Reseairch Laboratory, Merck c~ (Jo., Inc., Ralvway, N.J. DEAR DR. TISHLER: This is in reply to an inquiry from Dr. Richard Smith concerning our findings and results in the clinical therapeutic use of Indo- methacin (In'docin). Although we have not employed double-blind controls, our extensive experience in the management of patients with rheumatic disease has indicated to us over the years that through close clinical observation of our patients under treatment we have generally arrived at conclusions concerning clinical effectiveness of therapeutic agents which closely approximated those reported in controlled thera- peutic trials. Our own experience over an extended period of time has indicated a significant degree of effectiveness of Indocin as an anti-inflammatory agent in a considerable proportion of patients with rheumatoid spondylitis, gouty arthritis, osteoarth- ntis of the hip, and some pa:tients with rheumatoid arthritis. The incidence and character of side effects have likewise corresponded with those described in the literature. In conclusion, we feel that Indocin in appropriate clinical situations offers a useful addition to our therapeutic armamentarium. Sincerely yours, H. M. MAROOLIS, M. D. JAMES H. BARR, Jr., M. D. BERTRAND L. STOLZER, M. D. CARL H. EISENBEIS, JR., M. D. BURTON IT. POLLOCK, M. D. UNIvERsITY OF MIAMI, Miami, Fla., A pril 22, 1968. Dr. MAX TISHLER, Merck Research Institute, Merck t Co., Inc. Rahway, N.J. DEAR DR. TISHLER: I understand that your company is under investigation by the Subcommittee on Monopoly, chaired by Senator Nelson, in reference to the drug, Indocin. `In our University Clinic we use Indocin, quite effectively, for pain relief in the milder cases of rheumatoid `arthritis. Certain patients, particularly males, have better response to Indocin with less side effects than when given large doses of aspirin or mild narcotics. Business men are able to get pain relief with- out drowsiness. We use Indocin for lowering the dosage of Prednisone. Thus, I think, Indocin is a' useful adjunct in the treatment of various arthritics. Sincerely yours, DAVID S. HOWELL, M.D., Professor of Medicine, Director, Arthritis Division. PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3381 ~ Los ANGELES,. CALIF., April 22, 1968. Dr MAX TISHLER Merck Researck I4boratorieS Merck c~ Co hw Rahwa'y NJ DE~u~ DR TISHLER It is my understanding that there are to be some congreS ~iona1 hearings related to the use o1~ rndomethaern in the treatment of rheuma told arthritis. We are all cognizant of the difficulties involved in the evaluation- even double blind studies-of inciomethacin or `any drug in a disease such as rheumatoid arthritis which is characterized by exacerbations, remissions and the emotional component. However, I have found indomethacin to be a very use- ful drug in the treatment of rheumatoid arthritis particularly in milder cases or in patients where one is reluctant to use corticosteroids as patients in the older age group and in those with diabetes osteoporosis etc Furthermore in the concomitant use of indomethacin with corticosteroids the dosage of corticoster oids has been reduced in some patients. Indometbacin has also been a very useful drug in the treatment of other types of rheumatic disease i e episodes of acute gouty arthritis bursitis and osteoarthrltis In degenerative arthritis of the hips-for which we have so little to offer therapeutically-I have seen dramatic results from the use of indomethacin. Sincerely yours, NATHAN E. HEADLEX, M.D., Associate (itinical Prof essor of Medicine, U.S.C. School of Medicine. UNIVEBSITT OF COLORADO MEDICAL CENTER, Denver, Cob , Apr~1 22,1988 Dr MAX TISHLER Merck Research Laboratories, Merck ~ Co Inc Rahway NJ DEAR DR TISHLER I undeistand that hearings currently in progress, under the chairmanship of the Honorable Gaylord Nelson, are considering the drug Indomethacin (Indocin) and its value in the management of patients with rheumatoid arthritis. I first undertook clinical investigation of this non cortisone anti inflammatory agent in 1963 and first published our clinical studies of this drug in 55 rheumatoid patients in 1965 in the journal Arthritis and Rheumatism These clinical mvesti gations were based upon the best objective measurements of rheumatic activity and at that time It was concluded that Indomethacin suppresses joint inflam mation and improves function but may require up to 2 to 4 months to obtain maximum therapeutic effects With three additional years of experience with this drug in more than 100 patients under rigid clinical ~bservatlon and using similar methods of evaluation I am still of this opinion To state how frequently favorable therapeutic effects occur based upon objec tive tests, and bow often this drug is clinically beneficial is difficult, but In my opinion, between 20 to 25' percent do show objective changes; an additional 20 to 30 percent repQrt subjective benefits. Among the toxic reactions reported with the use of Indomethacili the frequency of peptic ulceration has been of major concern to critical clinical observers An analyses of more than 700 patients treated with Indomethacin at the University of Colorado hospital and its clinics indicates that this complication seldom occurs These patients bad previously received other anti inflammatory and analgesic drugs including aspirin corticosteroids and phenylbutazone The incidence of peptic ulcers during the Indometbacin period of therapy was actually less than during similar periods of other anti inflammatory anti rheumatic agents In my experience the occurrence of peptic ulceration is not a major obstacle to the clinical use of this d~rug in patients with rheumatoid arthritis In my five years experience based on the practical use of Indomethacin and a careful analysis of the results in all of our patients treated by a staff experi enced in the management of patients with rheumatoid arthritis in this University Hospital I am of the opinion that Indomethacin benefits some patients with rheumatoid arthritis At present no reliable tests are available to predict which 81-280---68-pt. 8-19 PAGENO="0290" 3382 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY patients with this chronic disease which is marked by spontaneous remissions and exacerbations, will respond favorable to this drug. Until more potent and less toxic anti-inflammatory agents are made available for clinical use, I strongly recommend that Indometbacin continue to be available for use in this most crippling of all arthritic conditions. I would not discard a valuable tool although it might have a sharp edge. Sincerely yours, CHARLEY T. SMYTH, M.D., Prof essor of Medicine, Head, Division of Rheumatic Diseases. NORTHWESTERN UNIVERSITY, Chicago, Ill., April ~2, 196'8. Dr. MAX TI5HLER, Merck Research Laboratories, Merck c~ Co., Inc., Rahway, N.J. DEAR DR. TISIILER: As you know, we have been engaged during the last year in evaluating the efficacy of Indocin in patients with generalized osteo- arthritis. In addition, we have used Indocin in the treatment of patients with other forms of arthritis particularly those of rheumatoid arthritis. Although we do not have the results from our osteoarthritis study tabulated as yet, I would like to recall for you some of the difficulties that emerge from this type of work. First, the cause of these types of arthritis is unknown. This means that one must utilize the symptoms the patient shows as clues concerning the response of the patient to treatment. It is not possible to state that a given causative feature has or has not been altered or changed by the treatment program. Such a state- ment concerning drug evaluation would of course be the best evidence for deter- mination of an effective program. This difficulty is further compounded by the variability of the course of these illnesses. It is very difficult to interpret the exact response of the patient to a drug or to no drug. Therefore, to properly reach a conclusion about the efficacy of a drug requires a careful assessment of a number of signs and symptoms present in the disease and sufficiently large number of patients who are being evaluated. Although gold treatment for rheumatoid arthritis has been used for almost four decades, it was only in the last few years that a carefully controlled drug study on the efficacy of this compound was completed by a group of British workers.1 Even here considerable difficulty was encountered. I do not take the view that proper assessment is impossible but it certainly is difficult. I think that it can be said that Doctor Mainland reached similar conclusions in his careful assessment of role of Indocin in rheumatoid arthritis. He did find it had a beneficial effect although no greater than aspirin. He also points out the real problems that beset any one who does drug evaluation studies. In ordinary practice in our clinic we have been impressed by patients' response to Indocin in rheumatoid arthritis and other forms of arthritis, including estee. arthritis. We use the drug to help provide relief for patients who require addi- tional medication besides aspirin. It would be a tragic event if the demands for precision outstrip the methodology available. In our present state of ignorance one must accept less than optimal tneasure of effect. However, one constantly must try to improve the state of the art. Sincerely yours, FRANK R. SCHMID, M.D., Associate Professor of Medicine, Chief, Arthriti.s-Conneotive Tissue Section~ TUCSON, ARIZ., April ~2, 1968. MAX TISHLER, Ph. D., Merck Research Laboratory, Merck $harp c~ Dohme, Ralw~ay, N.J. Dsi&n DOCTOR Tisnum: This Is a testimonial letter in regard to Indomethacin (Indocin). 1Annals of Rheumatic Diseases, 19 :95-117, 20 :315-884. 1961. PAGENO="0291" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3383 My experience with this medication began with investigational studies starting in 1961, before this drug was released. Subsequently, Indomethacin (Indocin) has become a most valuable medication in the treatment of various forms of rheumatic diseases. Approximately one-half of my patients are receiving Indocin. Cordially yours, HARRY E. THoMPsoN, M.D. COLUMBUS MEDICAL CENTER RESEARCH FOUNDATION, Columbus, Ohio, April 92,1968. MAX TI5HLER, Ph. D., Merck Research Laboratories, Merck c~ Co., liw., Rahway, N.J. DEAR DR. TISIILER: It is my understanding that you have been invited to appear before a Congressional hearing under the Honorable Gaylord Nelson to diSCUSS the relative merits and clinical value of indomethacin, which is marketed under the brand name of Indocin. Since I originally introduced this drug to humans in November 1961, and have had as long and profound clinical experience with the drug as any physician in the world, I feel constrained to offer some comments. It may be proper at this point to identify myself to you. As you may or may not know, I have been on the medical faculty of the Ohio State University for more than twenty-eight years and since 1960, have held the rank of Clinical Professor of Medicine. In addition, I am the Founder and Director of the Columbus Medical Research Foundation. I am also senior physician director of The Columbus Medical Center, which is a group-practice clinic of specialists in Diagnosis and Internal Medicine, with a heavy preponderance of rheumatic dis- eases. Three of the eight physicians (including myself) sub-specialize in the field of Rheumatology to the extent of having more than fifty percent of their practice devoted to that field. We have approximately five-hundred patients with rheumatoid arthritis on continuing active treatment and we regard Inclocin as an important part of their overall drug-therapy program. Not all patients with rheumatoid arthritis are benefited by Indocin, `but the same can be said about all other antirheumatic drugs, even including cortisone- derivatives and aspirin. However, more than half of patients with rbetunatoid arthritis receive decisive benefit from Indocin and are able to continue taking the drug without undue adverse effects; its record in this respect is superior to aspirin and second only to the benefits derived from cortisone-derivatives.. In over half of the patients who do benefit from Indocin the benefits are strik- ing and decisive and the drug is regard as indispensable to the patients continued well~being and disease-control. This variable, limited, and to some degree unpre- dictable response of Indocin in rheumatoid arthritis has led to opposite extremes of reaction in the minds of some physicians. Because It is not effective in consid- erably less than one hundred percent of the patients, some physicians call it a total failure, deny any value to it, and think it should be abandoned. Other physicians regard the striking benefits in some patients as proof that Indocin is a panacea and can be used to the exclusion of all other antirheumatic agents. Both of these extremes of viewpoint are ill-founded and unwarranted. The fact is that Indoein is an excellent adjunct in antirheumatic `therapy and should be given a trial, beginning in low doses, in those patients with rheumatoid arthritis who have failed to respond to the so-called basic or conservative program of increased rest, physical therapy, salicylates and so forth. Evaluation of drug efficacy in rheumatoid arthritis is a most difficult, pro- foundly complex and often unrewarding endeavor, best carried out by an experi- enced clinician-rheumatologist who has not only some acumen and scientific orientation, but also patience, understanding, empathy and a keen insight into the complexities of the rheumatoid personality, as well as the rheumatoid disease. Unfortunately, there are no satisfactory criteria for evaluating rheumatoid disease activity with uniform and reliable consistency. The use of the "single- blind" placebo, by an experienced clinician, in a patient who has been on the drug under evaluation for some period is probably the most reliable method of approach to the problem and enables the clinician to evaluate the drug by PAGENO="0292" 3384 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY observing the patient's clinical response to the unknown substitution of placebo and to the unknown resumption of the active drug. Where emphasis is needed or where any doubt exists, the placebo trial can be repeated on a number of occa- sions in the same patient. The use of a placebo can also help the clinician to decide if the appearance of adverse effects or side reactions is drug~related. Oftentimes it is found that an adverse effect, thought to be drug-induced, was in truth the result of the patient's apprehension at taking part in an experimen;t. In theory, the "double-blind" technique is the most desirable form of evaluation, but the non-clinician and the statistician fail to appreciate the numerous, often insurmountable difficulties in applying a "double-blind" study to a group of human patients. It is understandable that those who have done most of their work with testing in laboratory animals would want to carry-over this same methodology to the human, but it is becoming increasingly apparent from the re- ports of such statistician- an.d laboratory-oriented sources that the pitfalls of the "double-blind" study are manyfold and seem to increase exponentially with the increasing application of further controls and safeguards. Nevertheless, it may be advantageous for an experienced clinician to institute a "double-blind" study during the course of a therapeutic trial of a new drug, and derive important data from it. In my many years of clinical experience with Indocin, I have used a number of "double-blind" trials, but I have not regarded them as having as much value to inc as the hundreds of "single-blind" placebo trials which I carried out. The results of both, however, served further to convince me of the therapeutic effi- cacy of Indocin in the majority of patients with rheumatoid arthritis. The Merck Company is to be congratulated for having labored so diligently to produce yet another effective drug for the treatment of this dread disease. I appreciate the opportunity to have developed the earliest clinical experiences with Indocin. However, the most important thing which I personally think makes your compan~y especially deserving of commendation is the wholesome, objective, scientific atmosphere which all of the representatives of your company created and maintained throughout all my studies on Indocin. At no time were any pressures exerted on me in any manner or in any direction which could possibly have influenced my objective approach or created any prejudice or bias in my work or even in my thinking. At all times I felt completely free to report favorably or unfavorably and to state that in my opinion Indocin was good, bad or Indifferent. `In fact, at several stages I was hyper-critical of the drug and even now emphasize that It Is not the last word in rheumatoid arthritis therapy, that improvements can probably be made with derivatives of the drug, that cerebral side-effects are a definite limitation, both in dosage ceiling and In mow universal application of the drug. In this atmosphere I have developed the conviction that Indocin is a valuable drug and should not be denied to those patients with rheu- matoid arthritis in whom it can and will produce decisive benefits. Yours truly, NORMAN 0. ROTHRRMrOH, M.D. l3nowx, N.Y., April 22, 1968. Dr. MAX TISELER, Merck Reaearck Laboratories, Merck t~ Go., Inc., Rahway, N.J. DEAR DOCTOR Tisnnnx: I am aware that there has been a discussion In the Oongress through their appointed Oommittees to evaluate the evidence with regard to the therapeutic efficacy and the place in our pharmalogic armamen- tarium of Indomethacin. The studies that we have performed and our current studies indicate that Indo- methacin has an anti-inflammatory action, and through this anti-inflammatory action, a potent analgesic effect In the treatment of Inflammatory connective tissue disease, particularly the Inflammation associated with traumatic osteo- arthritis. It appears to be of use In some patients with acute and chronic rheu- matoid arthritis. Of course Its effect in acute gout is well known. The problem with Indomethacin has been the variable response to the drug. This is extraordinarily unusual, but offers a challenge as to the difference be- tween this anti-inflammatory compound and the other which are available. Cer- tainly, further research with Indomethacin and Its analogues is warranted, and we are currently actively engaged In this research. The question of the design of the studies for Indomethacin efficacy has been a challenge to us. A double blind study of Indomethacin against a sugar placebo PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3385 would produce no results since patients would be left for prolonged periods of time without medication, and if they were unfortunate enough to have the sugar placebo to continue in the study. In addition, there would be a discrepancy in the results between the possible carry over in the Indomethacin study which might have a greater effect with Indomethacin and a much less effect with the placebo. It would seem that an active medication would be indicated in the placebo capsules. We believe that aspirin answers this need. With all of these considerations taken into account, I believe that a final evaluation with regard to Indomethacin efficacy should be postponed until all of the data from the studies that are now being carried out is collected. This will not only be more valuable with regard to Indomethacin, but will encourage further studies with Indomethacin analogues which are so important in the future. Cordially, JEROME R0T5TEIN, M.D., F.A.U.P., F.C.C.P., Head, Rheumatic Disease Unit. LOUISVILLE, Ky., April 22, 1968. Dr. MAX TISHLER, Merck Research Laboratories, Merck M. Co., Inc., Rahway, N.J. DEAR DR. TISHLER, This is a letter attesting to the efficacy of Indocin in my practice of rheumatology in Louisville, Ky. This drug has been extremely effective in all of my patients with anklylosing spondylitis. As you well know, this is a very debilitating disease, which affects young men in their prime, and can be ruinous economically if the disease is not checked. In every one of my patients with anklylosing spondylitis, the disease has been checked either partially or completely. All of them are fulfilling, at present, useful lives. Indocin has further more been effective in selected cases of osteoarthritis. In gout, Indocin has been very effective with minimal side effects. In rheumatoid arthritis, the drug has not been as effective as I would like, and I utilize it very little in these individuals. For any sort of blind study to be done in individuals afflicted with these crip- pling diseases, I would consider it inhumane as well as immoral to deny benefits to a selected group of patients. It would be my feeling, at present, that Indocin is a very effective drug in the conditions named, and there should be no question in its' efficacy in those individ- uals not only in suppressing their disease, but keeping them useful, productive citizens in our society. If there is any further information you may require please contact me. Cordially, FRANK W. LEHN, M.D. BOMBAY, April 22, 1968. We had previously published the results of our experience with Indomethacin in rheumatoid arthritis and still feel that this drug represents a definite ad- vance in treating many rheumatic diseases. Our experience confirms it to be a potent anti-inflammatory, analgesic and antipyretic agent, without many of the severe side effects of corticosteroids and butazones. We have used Indo- methacin successfully in many cases who had not responded satisfactorily to aspirin and butazones. In rheumatoid arthritis, there is no doubt that require- ments of corticosteroids can be substantially reduced and in a significant per- centage of cases, these can be eliminated gradually. Side effects such as head- ache, giddiness and gastrointestinal irritation have occurred in about 40% of patients but it is not always necessary to discontinue therapy. Such side effects can be managed in the usual manner. We have not come across any case of blood dyscrasia, liver or renal damage. K. K. DATEY, M.D., F.R.C.P. Honorary Professor of Medicine, Seth G.S. Medical College and King Edward Memorial Hospital; and Director, Department of Cardi- ology, King Edward Memorial Hospital, Bombay. I PAGENO="0294" B38f COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BRUSSELS, April22, 1968. Q.-In the light of your extensive experience in the management of diseases for which Indomethacin is indicated, do you consider that the introduction of Indomethacin has contributed to the management of your patients? A-Yes--in osteoarthritis of the hip, in Bech;terew's disease and in rheumatoid arthritis in association with gold therapy. Q.-Do you find that Indomethacin enables you to obtain results in some of your patients that were difficult to obtain prior to its introduction? A.-Yes-in osteoarthritis of the hip and Bechterew's disease because the toxicity of Indomethacin on long-term treatment is lower than the toxici;ty of ether available drugs. Q.-If so, can you define those areas in which the drug has been most helpful to you? A.-Osteoarthrltis of the hip and spondylitis rhizomelica. Prof. Dr L. J. Michotte. BOMBAY, April 22, 1968. I have been using indomethacin in the form of capsules as well as suppositories since the last five years. In my experience, indomethacin has proved to be a valuable drug for treating rheumatoid arthritis and allied disorders. A number of my patients who had not responded to salicylates, phenylbutazone or oxyphenbu-. tazone were maintained satisfactorily on indomethacin. I have studied the drug's steroid-sparing properties carefully and am convinced that the dosage of cortico- steroids can be gradually reduced in a large percentage of cases. I have also tried the drug for prolonged periods in Still's disease where it works most satisfactorily and has excellent tolerance. Indomethacin suppositories have been used in my department in 16 patients for almost two years continuously. Patients having gastrointestinal problems with capsules can be managed remarkably well on indomethacin suppositories. M. M. DE5AI, M.D. M.R.C.P., F.C.PJ~., Honorary Associate Prof essor of Medicine, Topiwala National Medical College and B.Y.L. Nair Hospital; Physician In-charge, Department of Rhenmatic ~ Collagen Diseases, B.Y.L. Nair Hospital, Bombay. RHEUMATISM RESEARCH UNIT, CANADIAN RED CROSS MEMORIAL HOSPITAL, Taplow, Maidenhead, Berks, April 22, 1968. Dr. MAX TISHLER, President, Merck, ~harpe Dohme Research Laboratories, Rahway, N.J. DEAR DR. TISHLER, Dr. Carl Pearson of Los Angeles has let me know that there are to be some Congressional hearings in relation to Indomethacin (In- docin). I regret that I shall not be able to come over, but instead he suggested that I might write you in general terms about our experience with this drug both here and at the Royal Postgraduate Medical School. We have not performed any controlled trials, so that what follows is the result of clinical observation. I feel that this drug is useful in certain patients with rheumatoid arthritis and has about the same potency as aspirin. It is, however, more expensive and we therefore tend to use it when patients cannot tolerate aspirin and sometimes to wean them off steroid medication. This we have been able to do satisfactorily. It seems useful also in ankylosing spondylitis, and we have used it there in such cases who have developed intolerance to phenylbutazone. It appears to be of some value in osteoarthritis of the hip. I have not used it in gout. We have used Indocin in over 30 children in the first two decades with chronic polyartliritis and it has seemed quite useful here, except perhaps in the youngest children, in whom it has induced vomiting. In general we have not bad a great deal of trouble with side effects, apart from headache. We have had one case with perforation of the stomach and two with melaena. Two of our patients have had a rather odd reaction mentally which has ceased on stopping the drug. Since, however, we have had no control series, it is difficult to evaluate these complications, since, as you well know, some such effects occur even on placebo. We t)iink, however, that these were probably related to the drug. 0 PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3387 I hope this is the information you require. Yours sincerely, E. G. L. BYWATERS, F.R.C.P., (Professor of Rheumatology, University of London, Hon. Director, Medical Research Council Rhe'u,matism Research Unit). (Telex received In New York from Milan] APRIL 22, 1968 Dr. M. TI5HLER, Rahway: Prof. D. Gigante-Director of Rheumatological Tnstltute of University of Rome-stated today-The introduction of Indomethacin has greatly contributed to the management of patients with rheumatic disease. Corticosteroids still remain the most effective drugs for the treatment of many rheumatic patients. However Indomethacin has enabled me to treat effective a large number of these patients because of its marked anti-inflammatory properties which are generally not accompanied by the occurrence of serious nide effects. Indomethacin has been most helpful in t:he treatment of the following dis- oases-gout, degenerative disease of the hip and Ankylosing Spondilitis. It has been also very effective in a great number of patients with rheumatoid arthritis. Copy of above statement signed by Gigante will be airmailed. [Message received In New York from Milan] APRIL 23, 1968. Dr. MAX TISHLER, Rahway: Following statement by Prof. C. B. Ballablo, Director of Rheumatological Insti- tute of the University of Milan-"Without doubt the introduction of Indometha- cm has contributed to the management of my rheumatic patients. In degenera- tive disease of the hip Indomethacin gives excellent results which were not pos- sible to obtain with any other medication. The rheumatic diseases which in my experience can be treated most effectively with Indomethacin alone or sometimes in association with other medications are ankylosing sponylitis and gout. Indomethacin is of some help in the treatment of some rheumatoid arthritis patients especially males." Copy of above statement signed by Ballabio will be airmailed. [Telex received from Hoddesdon In New York] APRIL 23, 1968. Dr. M. TISHLEE, I2alaway: Indomethacin contributes to the management of rheumatoid arthritis. It onables some patients to be controlled who have not previously been controlled. Watson Buchanan Head of the Centre of Rheumatuc Diseases, Glasgow. Regards, H0DGKINS0N. BuENos AIRES. Tishler Dr. Romanowicz report head of Rheumatology Rheumatic Disease ?Center, Rawson Hospital answer first question yes Indocid is of great utility, second, yes, third, rheumatoid arthritis arthrosis gout ankylosing spondylitis unspecific arthritis. MASANTL CAPE TOWN, April 23, 1968. Question: In the light of your extensive experience in the management of dis- eases for which Indomethacin is indicated, do you consider that the introduction of Indomethacin has contributed to the management of your patients? Answer: Yes. PAGENO="0296" 3388 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Question: Do you find that Indomethacin enables you to obtain results in some of your patients, that were difficult to obtain prior to its introduction? Answer: Definitely yes. Question: If so, can you define those areas in which the drug has been most helpful to you? Answer: Resistant cases of rheumatoid and osteoarthritis gout. Dr. R. A. ASHERSON. STATEMENT ON INDOMETHACIN BY Dx. SELWYN Nm~soN This statement is made on the un~~rstaflhdiflg that no use Is made of it which is likely to be unethical or embarrassing to the writer. Indomethacin is a valuable addition to the range of preparations available for the treatment of rheumatic diseases. All drugs used in the long term management of rheumatic diseases are likely to cause unwanted effects in some patients and Indomethacin Is no exception. Most if not all of the toxic effects of Indomethacin are rapidly reversible and also are obvious to the patient. In the choice of treatment of rheumatic diseases the clinician takes into account the properties of the drug and his experience of Its effectiveness in vari- ous conditions, its toxicity and the incidence and reversibility of possible unwanted effects. He also takes into account the contra-indications having regard for the expected effect of tha drug on a patient suffering from other dis- orders related or unrelated to the primary condition being treated. The approach to the prescribing of Indomethacin can be based on a positive or negative assessment of the patient's needs. Experience with Indomethacin has demonstrated its very great effectiveness in gout, rheumatoid arthritis, osteoartbritis and ankylosing spondylitis. It is also very useful in certain mis- cellaneous non-specific painful disorders of the musculo-skeletal system e.g. Bursitis, "fibrositis" etc. This might be termed the positive approach. As Indomethacin has a different chemical composition from other non- steroidal anti-inflammatory drugs it can be used where other preparations have been tried and found wanting. Indomethacin can be used in preference to other anti-Inflammatory drugs where there has been a previous toxic effect on the bone marrow caused by another preparation. It is also valuable in the presence of reduced cardiae reserve as it does not cause retention of salt and fluid. (`Translation] Dr. Pedro M. Catogglo, Director of the National Institute of Rheumatology, National Institute of Rheumatology, Martinez de Hoz y Marconi-Ramos Mejia, Pcia. Bs. As., Rep. Argentina: (1) Question: In the light of your extensive experience in the management of diseases for which indomethacin is Indicated, do you consider that the intro- duction of indomethacin has contributed to the management of your patients? Answer: Yes (2) Question: Do you find that indomethacin enables you to obtain results in some of your patients that were difficult to obtain prior to its introduction? Answer: Yes (3) Question: If `so, can you explain those areas in which the drug has been most helpful to you? Answer: Rheumatoid arthritis, acute inflammatory exacerbations in arthrosis,. periarthritis, and in acute gout and rheumatoid spondylitis I have little ex- perience. Comments: (1) In the last few months we have used suppositories more fre- quently, (2) We often made the association with ASA, corticoste:roids or anti- malaric drugs (In R.A.) ______ (`Translation] Dr. Raul Houssay, Rheumatologist of the Department of Rheumatology, Ward 20, Rlvadavia Hospital, Sanchez de Bustamante 2560, Buenos Aires, Rep. Argen- tina: PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3389 (1) Question: In the light of your extensive experience in the management of diseases for which indometbacin is indicated, do you consider that the intro- duction of indomethacin has contributed to the management of your patients? Answer: Indomethacin contributes to the management of rheumatic patients for its analgesic action and when the effective dose is well tolerated. (2) Question: Do you find that indomethacin enables you to obtain results in some of your patients that were difficult to obtain prior to the introduction? Answer: Indomethacin enables me to obtain good results in some patients in which the necessary doses of other drugs for the obtention of satisfactory analgesic and anti-inflammatory effects are not tolerated. (3) Question: If so, can you explain those areas in which the drug has been most helpful to you? Answer: (a) OsteoarthritiS. Arthosis of the hip, (b) Rheumatoid spondylitis, (c) Nonarticular rheumatisms (painful shoulder, bursitis, fibrositis, etc.), (d) Rheumatoid arthritis: Indomethacin is effective in some patients with R.A., especially if it is administered in combination with other medications. Indo~ methacin is useful for the treatment of morning stiffness. [Translation] Dr. Osvaldo Hflbscber, Rheumatologist of the Department of Rheumatology, Ward 20, Rivadavia Hospital, Sdnchez de Eustamante 2560, Buenos Aires, Rep. Argentina: (1) Question: In the light of your extensive experience in the management of diseases for which indomethacin is indicated, do you consider that the introduction of Indomethacin has contributed tto the management of your pa- tients? Answer: Yes; in some patients. Indometbacin has analgesic and anti-inflam- matory action. It can be administered for a long time without important danger. (2) Question: Do you find that indomethacin enables you to obtain results in some of your patients that were difficult to obtain prior to its introduction? Answer: Yes. In some patients the addition of indomethacin to the previous treatmeiit or its substitution, enables the physician to obtain a better management of the patients. In other patients indomethacln has no action. (3) Question: If so, can you explain those areas in which the drug has been most helpful to you? Answer: (a) In rheumatoid arthritis: generally associated to other drugs. Without doubt it has a steroid sparing effect. The use of suppositories at bed- time improves the morning stiffness of the patients, (b) In osteoarthritis with inflammatory signs, (c) In rheumatoid spondilitis, (d) Lower action in fibrositis, tendinitis and other unspecified conditions, (e) No experience in acute gout. [Translation] Dr. Armando Maccagno, Head of Clinics, Rheumatic Diseases Center, Ward 14, Rawson Hospital. Buenos Aires. Republica Argentina: (1) Question: In the light of your extensive experience in the management of diseases for which Indomethacin is indicated, do you consider that the intro- 4uction of Indomethacin has contributed to the management of your patients? Answer: Yes (2) Question: Do you find that Indomethacin enables you to obtain results in some of your patients that were difficult to obtain prior to its introduction? Answer: Yes (3) Question: If so, can you explain those areas in which the drug has been most helpful to you? Answer: Rheumatoid arthritis, Rheumatic spondUitis, Intermittent hydrar- *hrosis. Arthrosis: Only in the first and second period. In period 3 I prefer surgical treatment. In gout I have not much experience; in these patients I prefer phenilbutasone &ecause it has urlcosuric effect. Only when phenilbutazone is ineffective I use Indomethacin. PAGENO="0298" 3390 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I think that the combination Indomethacin-Dexamethasone is very effective because Indomethacin has a steroid sparing ~ffect and the action of both drugs is potentiated. [Translation] Dr. Osvaldo Garcia Morteo, Head of Rheumatology, Rheumatological Depart- ment, Ward 20, Rivadavia Hospital, Sanchez de Bustamante 2560-Buenos Aires-Rep. Argentina, Secretary of the Argentine Society of Rheumatology: (1) Question: In the light of your extensive experience in the management of diseases for which indomethacin is indicated, do you consider that the intro- duction of iridomethacin has contributed to the management of your patients? Answer: In some rheumatic conditions the introduction of indomothacin has~ contributed to the management of the patients. In some patients with rheumatoid arthritis it has been able the use of lower doses of corticosteroids and some- times it was possible the withdrawal of these drugs. In patients with acute inflammatory exacerbations may be a good approach. (2) Question: Do you find that indomethacin enables you to obtain results in some of your patients that were difficult to obtain prior to its introduction? Answer: Yes. Some patients have a therapeutic response not obtained previ- ously with other anti~rheumatie drug. Is useful in rheumatoid spondilities and ln~ some inflammatory conditions of the soft tissues. Irregular results were obtained in acute gout. Sometimes indomethacin is ineffective. (3) Question: If so, can you explain those areas in which the drug has been most helpful to you? Answer: Its possibility of long time administration made of indomethacin,, a drug which is useful in the treatment of R.A. and osteoarthritis. The adminis- tration of indomethacin, when the patient goes to bed produce an improvement of morning stiffness. Indomethacin is better tolerated when is administered by rectal route than by oral route. [Translatiois] Dr. Ana Porrini, Rheumatologist of the Department of Rheumatology, Wardl 20, Rivadavia Hospital, Sanchez de Bustamante 2560, Buenos Aires, Rep. Argentina: (1) Questions: In the light of your exte~isive experience in the management of diseases for which indomethacin is indicated, do you consider that the intro- duction of indomethacin has contributed to the management of your patients? Answer: Yes. (2) Question: Do you find that indomethacin enables you to obtain results In some of your patients that were difficult to obtain prior to its introduction? Answer: Yes. (3) Question: If so, can you explain those areas in which the drug has been most helpful to you? Answer: (a) In R.A.: Sometimes alone, associated to a basic plan of treat- ment which includes ASA, exercises and resting. Sometimes it is possible the reduction of steroid drugs. (b) In Osteoarthritis. (c) In Rheumatoid spondilitis: In my opinion, phenilbutazone is the selecteft drug in this condition but, however, I think that indomethacin is more useful in this case. (d) In non articular rheumatic conditions: specially tendinitis of the shoulder and dorsal and lumbar fibrositis. (e) In gout: In acute gout the results were not satisfactory; in these patienta there were important side effects attributable to the use of high doses. Good results were found in some patients with chronic gout. OAPETOWN/KAAPSTAD, Apri' 2.f, 1968. I have not had the facilities to conduct controlled studies of Indomethicin, but from 1964 I have had an extensive experience with this drug in the Arthritis Clinic of the Teaching Hospital of the University of Cape Town as well as in? private practice. PAGENO="0299" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3391 Side effects were common at the outset because the dosages recommended proved to be too large. Moreover side effects were for the most part unpleasant but were not danger signals. The possible exception in gastero-intestinal com- plications which are in the first place rare and in the second place it is difficult to establish a cause and effect relationship. More often than not such patients were receiving other anti-rheumatic preparations as well e.g. Salicylates. Indomethicin has proved of value the treatment of Gout, Osteo-Arthritis and Rheumatoid Arthritis. In the last named it is especially useful as a steroid spar- ing agent. T. J. Dxx, M.D. WIESBADEN, 2~.4.1968. Re Indomethacin. Dr. MAX TI5HLER, Präsident der Merck ~iharp u. Dohm Vis. Laboratories Rahway, N.J. DEAR Dx. TI5HLER: Since 1964, indomethacin has been tested clinically and prescribed regularly at the clinic for rheumatic diseases in the Kaiser-Friedrich Spa Wiesbaden. Indomethacin is indicated in rheumatic and related diseases. In antipyretic therapy indomethacin has proved to be a valuable drug for sup- plementing already established anti-inflammatory agents. Indomethacin was shown to be useful in certain cases and forms of rheumatoid arthritis, arthrosis deformans, Bechterew's disease (rheumatoid spondylitis) after the other, non- hormonal anti-inflammatory agents had failed. Our experiences are confined to rheumatic and related diseases. The drug, which has meanwhile become a fre- quently used standard preparation, was not given in other indications. Very truly yours, Dn. MIEHLKE, Chief-of-Staff. BALTIMORE, MD., April 23, i968~ Dr. MAX TISHLER, Merck Research Laboratory, Merck c~ Co., Inc., Rahway, N.J. DEAR Dx. TI5HLER: I understand that there are to be hearings on the drug Indocin before a senate subcommittee in the near future. My letter is to let you know that I have found Indocin very helpful in a limited number of arthritics who have not responded to other medication, such as aspirin, Butazolidin and Tt~ndearil. There are a small number of people with rheumatoid arthritis who do extremely well on Indocin, and if they respond, they respond to doses of 75 mg. a day or less. Although there is a great deal of emphasis placed on so-called double-blind studies of antirheumatic drugs by the American Rheumatism Association and its Study Group, I have found that this type of study is not essential to determining whether a drug has a beneficial effect in a rheumatoid arthritic who has been under my care for a long time. To quote Dr. Fuller Albright, under whom I had the privilege of working for one year in 1941-42 in Boston, one patient well studied is worth 100 patients poorly studied. My patients with rheumatoid arthritis are well studied and well followed and I can tell when they receive benefit from a drug. I believe that Indocin is a valuable addition to our therapeutic armamentarium in mahaging patients with this disease. I have also found it of value in a few patients with ankylosing spondylitis who have failed to respond to Butazolidin. Very sincerely, HARRY F. KLTNEFELTEB, M.D. BUFFALO, N.Y., April 23, 1968. Dr. MAX T~SHLER, Merck Research Laboratory, Merck ~ Co., Inc., Rahway, N.J. DEAR Dx. TI5HLER: In view of the impending Congressional hearing concerning the results of Indocin (Indomethacin) treatment of arthritis, I believe that the conclusions of "clinically" oriented rheumatologists and their numerous patients are just as importar~t as the results of "double blind" studies which have been PAGENO="0300" 3392 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1~eported by "statisticians" or "full time" physicians who treat a small number of patients with rheumatic diseases. While I admit that "double blind" studies are desirable, there are many possible errors that are not included in the statisti- cal analysis of these studies and the results are used only to depreciate the poten- tial values of the drug under test. This is especially true in the case of patients with rheumatoid arthritis, where the disease process is extremely variable from clay to clay, or week to week status; where short term evaluation of drug effect is inaccurate (in a few weeks) ; when patients are allowed to use a variable amount of aspirin; and where only objective measurements of joints are the decisive criteria. In the majority of rheumatoid patients in any one study, whether "double blind" or "uncontrolled," irreversible changes that determine size of joints, range of motion, and discomfort, have already occurred and do not im- prove particularly in a period of a few weeks. Such changes are not due to the active inflammatory process of the disease but are the result of long continued disease. The resultant "mechanical" disturbance of joint components cannot be corrected by anti-inflammatory drugs, whether they are salicylates, anti-malarials, phenylbutazone, or indomethacin. However, the statisticians and the "purists" decry the lack of objective measurements of improvement and completely disre- gard the subjective response of the patient. I will admit that none of the anti- inflammatory drugs mentioned above, have the prompt, dramatic response as the cortico~sterolds but they do not have the serious toxicity associated with their "long term use." After more than 20 years of experience in the exclusive treatment of rheumatic patients, I do not subscribe to the conclusions of Short & Bauer that 50% of rheumatoid patients improve with the most conservative treatment. Another fre- quently quoted "double blind," "cross over" `trial with an anti-malarial drug, which was regarded as a masterpiece of drug testing and demonstrated the un- questionable response to the drug, is no longer considered as a "drug of choice" by most clinical rheumatologists. This decision has been determined by the nebu- lous response of most patients both subjectively and objectively, plus the pos- sible occurrence of irreparable eye damage which was impossible to determine during the short period of the study. I have used Indometbacin in the therapy of the rheumatic diseases in more than one thousand patients in the past 6 years. In my experience, it has been an effective drug in the majority of these patients and has contributed one more effective drug to the treatment of various rheumatic conditions, which have been a most difficult problem, not only to the physician, but more importantly to the patient. On the basis of carefully controlled animal experiments in the laboratory and also by reduction of fever and inflammation clinically in the patient with acute arthritis, there can be no dispute that Indomethacin is a potent anti-inflam- matory drug. There is no question throughout the world that Indomethacin is one of the most effective drugs in relieving such conditions as acute gouty ar- thritis, acute tendonitis, ankylosing sipondylitis, and degenerative (osteoarthritis') joint disease of the hip. The only dispute has centered about the question of re- sponse in patients with rheumatoid arthritis, which even the "statisticians," the "purists" awl the "reviewers" admit is subject to remissions and exacerbations, difficult to evaluate, and that Indomethacin is at least comparable to phenylbuta- zone and aspirin. Indometha'cin is of benefit to a variable degree in at least 66% of the patients in my experience. Subjective response has been better maintained with this drug than with either phenylbutazone or salicylates in the chromic arthritic patients (either rheumatoid or degenerative joint disease). The majority of these patients have continued to use the drug (many since 19t2) for more than 3 years, which I believe in itself is a testimonial that the drug is effective. Many of this group have been challenged with a placebo or have voluntarily discon- tinued the drug, even replacing it with a high salicylate dose. However, they have reported a prompt flare of their symptoms and have resumed Indomethacin therapy in practically all instances. The drug has produced functional improve- ment in many patients, even in patients with mechanical damage to their joints. In early rheumatoid patients With inflammation and joint swelling, I frequently observe decrease (and even complete subsidence in some patients) of the joint inflammation. The results of long term administration in this group of patients will be published in the proceedings of the 2nd Laurentian Conference on Rheu- matology (Nov. 1966) which I understand is in press at this time. It has also, been my experience that 50% of rheumatoid patients on corticos- teroid therapy have been able to reduce the steroid when Indomethacin has been added to their therapy. Toxicity remains within tolerable limits in my experience PAGENO="0301" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3393 and I have not encountered any unusual new reactions with its continued use. Side effects on the gastro-intestinal tract, headaches, dizzyness, or a feeling of confusion continue to be the common complaints in my experience. Sincerely yours, BERNARn M. Noncnoss, M.D. MINNi~PoLIs, MINN., April 23, 1968. MAX TISHLER, Ph. P., Merck Research Laboratories, Merck ~ Co., Inc., Rahway, N.J. DEAR Dn. TI5HLER: I am writing this letter to place on record my opinion that Indom'ethacin is an effective anti-rheumatic agent. Although, my own clinical research published in 1964, plus a fairly extensive experience with Indomethacin since then does not indicate a major anti-inflammatory effect in rheumatoid arthritis, the drug is useful in many such patients. But without doubt indo- methacin is of great benefit in patients with ankylosing spondylitis. Baiter's disease, psoriatic arthritis, and acute gout. It's benefit in these later patients is so unequivocal that a double-blind trial is, I `believe, unnecessary and likely redundant. The few negative reports should not out weight the preponderant positive evidence of the usefulness of this drug. Sincerely, PAUL J. BILKA, M.D. LoUIsvILLE, Ky., Aprit 23, 1968. Dr. MAX TISHLEX, Merck Research Laboratories, Merck, Inc., Rahway, N.J. T)RAR DR. TISHLEE: I have been asked to comment on the evaluation of drugs in rheumatoid arthritis, and the question of effectiveness of indomethacin. I am enclosing a reprint `of one of my papers published in the J.A.M.A. Although my remarks related to the difficulty in assessing the effects of drugs in rheuma- toid `arthritis were written with special regard to eorticosteroids, I think they remain pertinent to the present queation. (See `bottom of page 1254 under heading "Rationale `of Procedure" and top of page 1254 as marked.) Ooncerning ind'omethacin, my feeling is that this compound is effective in acute gouty arthritis and ankylosing spondylitis. Response in rheumatoid arth- ritis is not predictable without clinical trial but certain rheumatoid patients seem to derive benefit. I hope this information will be useful. Sincerely, DAvID H. NEUSTADT, M.D., Associate Clinical Professor of Medicine, Chief, Section on Rheumatic Diseases, University of Louisville School of Medicine. [From J.A.M.A., July 11, 1959, p. 1254] RATIONALE OF PROCEDURE There is no completely reliable plan or method of evaluating a new agent in rheumatoid arthritis that is not associated with certain shortcomings. To control all variables that come into play in a chronic disease of unknown origin subject to spontaneous fluctuations is a problem which has recently received well- deserved attention. Short-term ojservations may be misleading. However, if one omits patients from a study who received a drug for short periods, one may be accused of in- fluencing the final statistical results. Also there may have been some important reason for withdrawing the drug early in the study. Double-blind and random selection studies are considered by some to disclose results of greater scientific precision than the older and more conventional type of evaluation study. However a double-blind technique also carries with it certain disadvantages that may compromise Its value. In conducting studies with a relatively inactive drug (slowly acting agent), such as an antimalarial agent or a gold salt, a double-blind' stndy can be carried out. When employing a corticosteroid which has powerful suppressive capacity, abrupt withdrawal and PAGENO="0302" 3394 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY placebo substitution is immediately noticed by the majority of patients. Sud- den discontinuance also is not without danger because of the possibility of producing a marked degree of adrenal insufficiency. This hypoacirenal state can become an acute and serious medical emergency. Also random selection introduces a number of patients who may ~e unreliable and are not suitable for testing. Thus, it is almost impossible to carry out such a program without both in- fluencing patients and introducing added difficulties. For these reasons patients were carefully screened to include only those with well-esta~blished rheumatoid arthritis of over one year's duration and to exclude hyperreactors, unreliable patients, and hypersensitive ones. OCHSNER CLINIO, New Orleans, La., April 23, 1968. Dr. MAX TISIILRIS, Merck Rcsearck Laboratory, Merck d~ (Jo. Corp., J2ahway, N.J. DEAR Dn. TTSflIER: Recently it has come to my attention that a Congressional body was considering a recommendation that Indocin be removed from the open market and reclassified so that additional double blind studies could ~e carried out in attempting to establish its role in the treatment of arthritis. I had the opportunity to prescribe Indocin in the earlier days when it was available in ta~blet form, and, of course, was not impressed by the results that we obtained. When the new physical changes were made, and it was furnished in capsule form, I gained the impression that it offered symptomatic relief and in some cases favorable objective changes in a significant number of arthritic patients. At least 95% of my practice deals with arthritic patients; I have had oc- casion to prescri~be for these sufferers for many years and have now placed Indocin as a valuable drug adjunct in the therapeutic armamentarium. Patients whom I see comprise a group that I have had an occasion to watch for many years and, as I have maintained in the past, it is only after observing arthritic patients over a minimum of a three year span am I able to gain some insight into what pattern the disease may follow. Realizing this, I appreciate that drug response varies from patient to patient. My personal conclusions are that Indocin is of definite symptomatic benefit in a large group of patients with arthritis. Gouty patients obtained significant releif from their acute gouty pan when Indocin is administered and the chronic gouty arthritic who is una~hle to take aspirin medication or Butazolidin will frequently be very thankful because Indocin relieves them of their chronic, nag- ging joint aches. They can continue to take Indocin without it interfering with uricosuric drugs or where geographcial location makes it unable to obtain blood counts that must ~e used to guide treatment with Butazolidin. This also is an economic factor when repeated lab studies must be carried out in patients who are given an agent such as Butazolidin. Ankylosing spondylitis and osteoarthritis of the spine frequently cause patients a considerable amount of pain and incapacitation and Indocin has proven very helpful for these patients, and it is my opinion that it has kept many of these people on the job or in schooL Other types of non-specific rheumatism, such as bursitis, tendinitis, and giant cell arteritis, also seem to respond symptomatically and the patients are thankful for having such an agent avai1a~ble. In rheumatoid arthritis the drug gives a certain number of patients a signifi- cant amount of subjective relief, allowing them to carry out the arthritis ex- ercises and other basic parts of their treatment. Here, too, I feel that the com- fort obtained allows them to carry on with their daily obligations and lead a more normal life. It seems to offer an adjunct to aspirin medication, which is our pest antirheumatic drug, and does not seem to interfere with other agents, such as gold salts. It also has allowed me to reduce the quantity of adrenal steroids that some patients seem to require to remain functional. I have watched patients use Indocin long enough that occasionally they are under the impres- sion that the drug is no longer giving them any beneficial effect and they dis- continue its use on their own, or request permission to discontinue it, and more often than not they find that resuming the drug does give them an added benefit. I find that the symptomatic response to Indocin is often unpredictable for the rheumatoid arthritic patient. PAGENO="0303" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3395 The toxic effect of the agent is appreciated, but to date I do not recognize that it is any more irritating to the stomach than Butazolidin or aspirin and the ~other annoyances, such as headache, dizziness, etc.,, are transient and disappear once the drug has been reduced. I am familiar with the published articles that question the value of Indocin, ~but I do not feel that double blind studies necessarily reflect the true value ~of a drug for stages of these diseases change, and only by watching patients ior many years can we evaluate a drug response. In my mind and those of my associates, this drug is of value for the arthritic patient and we would feel that it would do the patients an injustice to remove it from the market at this time, and in my own mind I question how long double ~b1ind studies would have to be carried out before they would be effective and meaningful. It seems that any double blind study would take at least ten years and the evidence against the drug does not validate such a move. Yours truly, THOMAS E. Wzass, M.D. LoUIsvILLE, Kx., April 23,1968. Dr. MAX TThHLE*R, Merck Research Laboratories, Merck c~ (Jo., Inc., Rahway, N.J. Dnan DL TISHLEB: It has come `to my attention that a congressional committee is investigating the drug Indocin (indomethacin). I should like to state that there are mhny clincial Indications for its use, certain situations where it is the drug of choice and that these comments are ~borne out by experience with a variety of disease entities. Sincerely, WILLIAM P. PEAK, M.D. HENRX FORD HOSPITAL, Detroit, Mich., April 23, 1968. ~Dr. MAX TISHLER, Merck Research Laboratories, Inc., Rahway, N.J. DEAR DOCTOR TISHLER: I have learned the Nelson Committee is investigating the efficacy of Indocin. In view of these developments, I thought you might be interested in our comments. It has been our experience that Indocin is both antlinflamn~atory and anti- rheumatic. It has been a useful adjunct In the management of patients with osteroarthritis, rheum'atoid arthritis, ankylosing spondylitis, and gout. In some instances of hypercortisonism, it has been a useful antirheumatic agent when steroids were withdrawn. Although the antirheumatie and anti-inflammatory effects of Indocin may be unpredictable, Indocin has been a welcome addition to our armamentarium. Sincerely yours, JOHN W. SIGLER, M.D., Chief, Division of Rheumatology. Naw YORK, N.Y. April 23, 1968. Dr. MAX TISHLER, Merck Research Laboratories, Merck c~ Co. Inc., £ahway, N.J. DEAR Du. TIsHLnn: I have been informed that the Nelson Committee is con- sidering Indocin, and one of the points under consideration is that it is no more effective than Aspirin in the treatment of rheumatic disease. To date, I have administered Indocin to more than four hundred patients. I have also had the occasion to compare the results of Indocin with a number of Aspirin preparations. I was doing a double blind test on various preparations of Aspirin and a number of patients were taken off of Indocin to be included in this Aspirin study after two weeks without medication. These patients, after finishing the Aspirin study and another two week period without medication, were again returned to the Indocin. I was aware at the time that there had been a question raised as to whether Indocin was more effective than Aspirin. I, therefore, was Interested PAGENO="0304" 3396 COMPETITPIE PROBLEMS IN THE DRUG INDUSTRY in the clinical comparison and, in my opinion, Indocin is definitely superior t& Aspirin in tI~'e treatment of various forms of rheumatic disease. It, of course, does not control every case but it does help a great many where Aspirin fails to do so. I am also fully acquainted with the Mainland report, and I think the criteria used are unre~listic and do not give a real evaluation of the drug being studied. Sincerely yours, WILLIAM B. RAwLS, M.D. ARTHRITIS REHABILITATION CENTER, Washington, D.C., April 23, 1968. Dr. MAX TISHLER, Merck Research Laboratories, Merck ~ Co., Inc., Rahwcty, N.J. DEAR Docron TIsHLi~a: I am writing you about our experiences with Indometha- cm when used as a therapeutic agent in the management of patients suffering: from rheumatoid arthritis. First, let me say that our practice is limited to the diagnosis and treatment of patients with arthritis and rheumatic diseases, that we register over one hundred new cases of rheumatoid arthritis every year and that we have not less than two hundred eases of that condition under close observation at all times. I have checked my, Diagnosis File and find that since I first opened an office in 1937, a diagnosis of rheumatoid arthritis has been made in 2,043 patients. Against the above background, it is my opinion that Indomethacin is an ex- tremely valuable agent in the management of this potentially disabling condition' and that it has been an important addition to our medical armamentarium. Thus, we have found patients who did not respond to aspirin, phenyl'butazone or oxyphen:bntazone, who did respond to Indomethacin. By "rbspon'd", I mean that the patients would note less pain and stiffness while the physician would observe lessening of the swelling and increase in the motion of involved joints. Furthermore, patients who have originally shown response to aspirin or one of the other drugs, may later become resistant to that drug and then respond ta Indometbacin. * Of course, the reverse is also true and `some patients who respond to aspirin and phenylbutazone or oxyphenbutazone will not respond to Indomethacin and some of those who do respond to Indomethacin will later become resistant to it. I confidently hope that the day is not too far off when we will have a "cure" for rheumatoid arthritis. However, no "cure" is known today, and we must there- fore use every therapeutic modality available in our fight against this chronic and too often devastating disease. Any drug which will help retard the con- dition-even if only for a time-is one to be used as long as it brings about relief. In this context, Indometbacin `has earned it~ place as an agent which should be available to any physician treating rheumatoid arthritis. Very sincerely, DARRELL C. GRAIN, M.D. THE LANKENAV MEDIcAL BUILDING, Philadelphia, Pa., April 2~., 1968. Dr. MAX TI5HLER, Merck Research Laboratories, Merck ~ Co., Inc., Rahway, N.J. DEAR Docron TISHLER: I have been recently advised of the question which has been brought up regarding the efficacy of Indocin. I would like to have the privilege of speaking to this. Indocin has been extremely helpful in my practice in the management of a multiplicity of problems. I have a large pure rheumatologic practice. A rough estimate of my experience with Indocin would include approximately thirty rheumatoid spondolytics, perhaps 200 rheumatoid artbritics and innumerable osteoarthrities and gouts. I am amused by the remarks I recently read regarding the need to do double blind studies with Indocin. There can `be' absolutely no equivocation as to the efficacy of Indocin in a host of rheumatic disease. After fifteen years of a practice limited to rheumatology one cannot make mistakes PAGENO="0305" COMPETITIVE PROI3LEMS IN THE DRuG INDUSTRY 3397 of this type. This is so emphatically evident in the rheumatoid spondolytiC that I consider this observation though it may not be effective an enormous joke however misleading the public medical lay is dangerous and grave enough a situation to prompt me writing you Indocin is certainly not effective in all, in fact a much smaller percentage of my patients than I had hoped and it has some unhappy side effects which require careful observation but it must be perfectly evident that I would find it very difficult to practice rheumotology without this valuable arm I should be happy to provide statistics if you care for them Very truly yours ERNEST M. BROWN, Jr., M.D. MAYO CLINIC, Rochester, Minn., April 24, 1968. MAX TI5HLER, Ph. D., President, Merck sharp ~ Dohme Research Laboratories, Rahwav NJ DEAR DOCTOR TI5HLER: It has been brought to my attention that the matter of the effectiveness of indomethacin may be questioned at a future congressional hearing on drugs. As a rheumatologist, I have bad considerable experience with the use of indomethacin in patients with a wide variety of rheumatic diseases and I would be most distressed if this drug were not available for use in appro- priate rheumatic diseases. I have found that many patients derive helpful relief of rheumatlè symptoms from indomethacin, relief which often has not been ob- tainable with other simple analgesic medications. As is the case with all of the anti-rheumatic medications, there are some side effects resulting from the use of indomethacin but in my experience proper regulation of dosage and proper observation of the patient has enabled the use of indometbacin without undue risk considering its beneficial effects Sincerely yours EMMERSON WARD M D ORTHOPEDIC AND ARTHRITIS CENTER, Oklahoma City April25 1968 Dr MAX TISHLER Merck Research Laboratories Merck c~ Co., Inc., Rahwa/y, N.J. DEAR DOCTOR TI5HLER: This letter is written regarding our work with indo- methacin We first began using this drug in 1961 At that time a double blind study was carried out with mdomethacin on patients with rheumatoid arthritis It was directed by Dr Richard Payne who is in charge of our drug evaluation studies Recently we have completed a study again using the double blind tech nique on the use of indomethacin in patients with osteoarthritis The results of the first study have been published (Payne R W Treatment of Rheumatoid Arthritis with Indomethacin Jour of Oklahoma State Medical Association 553- 587 December 1965) The results of the study on osteoarthritis have just been completed and the paper is now at the publishers The difficulty in evaluating drugs in the treatment of any form of arthritis is well recognized We have felt that indomethacin is useful in a small but signifi cant group of patients. This would be in the neighborhood of one patient out of four or five Tbe ones who fail to respond of course get no results but those who do respond may develop very desirable effects which, in some instances would eneour~ge a natural remission of the disorder If more details are needed regarding our work with indomethacin please advise Sincerely yours WILLIAM E. I5HMAEL, M.D. [Cable received in New York from Sao Paulo] S~o PAULO, April 25,1968. Mezey Reyour cable following are Dr. Cobra's statements addressed to Dr. Max Tishler quote in the light of my extensive experience in the management 81-280---68-Pt. 8-20 PAGENO="0306" 3398 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of diseases for which indomethacin is indicated I have found that: indomethacin has highly contributed to the better management of our rheumatic patients, senso lato, when administered within certain dosage limits, 25 to 75 milligrams orally per day or 100 mg. per day by rectal use. Above these limits there is a high increase in the incidences of side effects which limit the advantage in the use of the drug. Indomethacin represents a valuable advance in the sense that it facilitated the compensation of certain chronic infiamatory syndromes and permitted the reduc- tion of doses of other drugs such as phenylbutazone and steroids thereby reducing many of their side effects. Indomethacin alone; i.e., without being associated with other drugs or with other therapeutic measures does not seem useful to us `because in most of the cases the necessary doses surpass the limits described above. Indomethacin has shown itself efficient as an Adguvant E. "compensation" ~treatment of patients with rheumatoid arthritis anylosing spondylitis and chronic gout arthritis as well as in the painful stage of osteoarthritis. Summarizing: As a drug used alone indomethacin is efficient only in large doses but with a consequent high incidence of side effects. Indocmethacin repre- sents a drug of decisive efficacy when in moderated doses it is combined with other drugs. Original statement being mailed today. [Cable received in New York from Mexico] Mnxico, ApriZ 25,1968. iDa. K. 0. MEZEY, Merck: Robles Gil reply as follows: 1 Since Indomethacin is drug that frequently allow treating patients in best way, 2 Indomethacin produces response in patient on whom previous treatment did not produce therapeutic response and permits the reduction of other drug such as corticosteroids. 3 Principal Indomethacin indica- tion are rheumatoid arthritis. Degenerative articular problems gout. Memo follows. IBARRA. THE UNITED NEWCASTLE UPON TYNE HOSPITALS, Newcastle Upon Tyne, April 25,1968. ~Dr. R. HODKINSON, A! edical Unit, Merck f~harp c~ Dohme Limited, Hoddesdon, Hertfordshire. DEAR DR. HODGKINSON, I understand that the United States Senate is currently reviewing some aspects of the drug industry, including the status of Indometh- acm. I have knowledge of articles published in non-medical journals, namely the Wall Street Journal and the Sunday Times, which have contained references ~to Indomethacin. In my opinion, these articles were inadequate and inaccurate in many aspects, as they failed to mention the properly conducted and controlled clinical trails which were done in 1962 and 1963, and which demonstrated the value of Indomethacin in the management of rheumatic disorders. In fac't, Indomethacin was subjected to both the most prolonged and careful scrutiny that any drug had ever received prior to its introduction to clinical usage. Controlled trials and a considerable amount of subsequent clinical experience have fully justified the place of Indomethacin in Rheumatology. I also feel that unjustifiable emphasis has been placed on side effects which are common to every drug used in medical practice, and in my opinion, the careful administration of Indomethacin constitutes one of the safest and most effeCtive ,methods of drug treatment in the management of numerous rheumatic conditions. In particular Indomethacin is virtually exempt from `the risk of haematopoietic, hepatic and renal side effects which complicate the use of many other drugs in rheumatology. If you feel it would be helpful to produce this letter and the appended state- inent of my views on the usage of Indomethacin in rheumatology, you have my permission to do so. Yours sincerely, MALCOLM THOMPSON, M.D., M.R.0.P., Uonsaltant Pivysician. PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3399 Carefully controlled clinical trials have shown Indomethacin to be effective in ~the treatment of- Osteoarthritis Rheumatoid arthritis Ankylosing spondylitis Acute gout Capsulitis of shoulder Lumbar disk lesion with sciatica In my experience, Indometha!ln has either been the agent of choice or the only agent suitable on many occasions, in the treatment of the above listed conditions. Dr. LAWRASON. In order to give the committee, Mr. Chairman, the benefit of the expert testimony of men who have thorough and exten- ~sive study of this drug, it is my pleasure to present to you first, Dr. John J. Calabro, who is associate professor of medicine at the University of California at Los Angeles School of Medicine and chief of the rheumatology section at Wadsworth Hospital, VA Center, in Los Angeles. It should be noted that Dr. Calabro has been, since 1963, the official representative to the National Society for Medical Research for the American Rheumatism Association. Senator NELSON. We appreciate your coming here today, Doctor. Do you have a statement? ~STATEMENT OF rOHN J. CALABRO, M.D., ASSOCIATE PROFESSOR OF MEDICINE, DEPARTMENT OF MEDICINE, UCLA SCHOOL OF MEDI- CINE, CENTER FOR THE HEALTH SCIENCES; AND CHIEF, RHEU- MATOLOGY SECTION, WADSWORTH HOSPITAL, VETERANS' AD- MINISTRATION CENTER, LOS ANGELES, CALIF. Dr. CALABRO. I have a letter directed to you, Senator Nelson, and 1dated April 23. I would like to begin first by submitting my credentials, my curricu- lum vitae. I am full-time associate professor of medicine at UCLA School of Medicine and, in that capacity, chief of the rheumatology section of an affiliated hospital, Wadsworth Hospital, VA Center, Los Angeles. I do not engage in the private practice of medicine. I am a full-time teacher and clinical investigator in the field of rheumatology. (The curriculum vitae of Dr. Calabro follows:) CuRRICULUM VITAE, JOHN JAMES CALABRO, M.D., MAY 1968 PRESENT POSITIONS (SINCE OCTOBER 1967) thief, rheumatology section, Wadsworth Hospital, Veterans Administration Center, Los Angeles, Calif. 90073. Associate professor of medicine, Department of Medicine, UCLA School of Medicine, Los Angeles, Calif. 90O~24 Born: Buffalo, New York-May 18, 1924. Marital Status: Married-July 9, 1967-Mrs. Josephine (PugUsi) Calabro. Medical Licensure: New York (75896) October 5, 1954, New Jersey (196498) June 4, 1958, California (G-14611) May 6, 1968. Military Service: July 1944-June 1946 USNR, PhM 3/c. Education: B.S., 1947, Canisius College, Buffalo, New York; Postgrad. Biology, September 1947-June 1948, Canisius College, Buffalo, New York; M.D~, 1952, "cum laude" Georgetown University, School of Medicine, Washington, D.C. Graduate Medical Education: Rotating intern, July 1952-June 1958 Mercy Hospital, Buffalo, New York; Junior Assistant Medical Resident, July 1953- June 1954, Georgetown University Hospital, Washington, D.C.; Senior Assistant PAGENO="0308" 3400 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Medical Resident, July 1954-June 155, Georgetown University, Washington, D.C. Chief Medical Resident, July 1955-June 1956, Fourth (Harvard) Medical Service, Boston City Hospital, Boston, Massachusetts; Chief Medical Resident, July 1956-April 1957, Jersey City Medical Center, Jersey City 4, New Jersey; Visiting Clinical Fellow in Arthritis, April-June 1957, Hammersmith Hospital, London, England, Juvenile Rheumatism Unit, Taplow, England (under Prof. B. G. L. Bywaters); Clinical and Research Fellow, in Medicine (For study of Arthritis), July 1957-January 1959, Massachusetts General Hospital, Boston, Massachusetts. Previous Academic Positions: Instri~ctor in Biology, Sept. 1947-June 1948, Canisius College, Buffalo New York; Assistant in Medicine, July 1954-June 1955, Georgetown University School of Medicine, Washington, D.C.; Instructor in Bacteriology, July 1954-June 1955, Georgetown University School of Medicine,. Washington, D.C.; Assistant in Medicine, July 1955-June 1956, Harvard Medical School, Boston, Massachusetts; Instructor in MedicIne, July 1956-June 1957, Seton Hall College of Medicine, Jersey City 4, New Jersey; Visiting Fellow in Arthritis, April-June 1957, Postgraduate Medical School of London, London,. England; Research Fellow in Medicine, July 1957-June 1958, Harvard Medical School, Boston, Massachusetts; Instructor in Medicine, July 1957-June 1958, (on leave of absence), Seton Hall College of Medicine, Jersey City, New Jersey; Assistant Professor of Medicine, July 1958-June 1962, Seton Hall College of Med- icine, Jersey City, New Jersey; Associate Professor of Medicine, July 19432- October 1967, New Jersey College of Medicine (formerly Seton Hall College of Medicine), Jersey City, New Jersey. Past Hospital Appointments: Director, Division of Rheumatology, July 1966 to October 1967, Veterans Administration Hospital, East Orange, New Jersey 07019; Assistant Attending Physician in Medicine for Rheumatic Dis- eases, January 1967 to October 1967, Newark City Hospital, Newark, New Jersey 07107; Assistant Attending Physician in Medicine for Rheumatology, April 1960 to October 1967, B. S. Pollak Hcepital, Jersey City, New Jersey 07304; Attending Physician in Medicine, Chief, Arthritis Clinic, July 1958 to October 1967, Jersey City Medical Center, Jersey City, New Jersey 07304; Consultant In Rheumatology, April 1963 to October 1967 U.SPH Service Hospital, Staten Island, New York. Scientific Societies: Diplomate, National Board of Medical Examiners, June 25, 1953; Certified, American Board of Internal MedIcine, 1963; Fellow, American College of Physicians; Associate Fellow, American College of Car- diology; American Medical Association; Association of American Medical Col- leges; American Association for the Advancement of Science; American Medical Writers' Association; American Heart Association; New York Academy of Sciences; American Rheumatism Association; Southern California Rheumatism Society; Horseshoe Club of England; The DiGamma Society of Canisius College. Special Activities: American Rheumatism Association.: Member, Education Committee, 1961-1962; Member, Committee on Exhibits, 1962-1963; 1964-pres- ent; Representative to National Society for Medical Research, 1963-present. The Arthritis Foundation: Delegate, Interchapter Medical & Scientific Com- mittee, 1959-1967. National Association of Broadcasters Scientific Advisory Panel, Member, 1965 to present. Member, Editorial Board (Rheumatology Con- sultant), International Journal of Industrial Medicine and Surgery, 1967. South- ern California Chapter, The Arthritis Foundation, Member, Medical and Scienti- fic Committee, 1967; Chairman, Education CommIttee, 1967; Chairman, Post- graduate Seminar for SCGP Society, April 20, 1967. Awards and Honors: (1) Ganlsius College, 1947: Graduation honor for excellence in philosophy. (2) New York State, 1947: War service scholarship. (8) Georgetown Medical School: Gold medals for highest academic stand- ing in Bacteriology and Obstetrics & Gynecology. Honorable mention in Medicine, Oncology and Psychiatry. Cahill medal for highest academic standing in Surgery. Pediatric Thesis Award. C. V. Mosby Co. Award for highest academic standing in Senior Year. (4) The Arthritis Foundation, New Jersey Chapter, May 1967: The Robert Wood Johnson Humanitarian Award presented "For his dedication to the betterment of his fellow man and his devoted service to juvenile arthritis patients." This award is made anni~ally to a native or resident o~ New Jersey who has made an outstanding contribution toward the better- PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3401 ment of his fellow man in the fields of medicine, social service or community activity. BibliographY_PUbliCatiOuIs: 1. Calabro, J. J.: Celiac disease. Olin. Proc. Children's Hospital, Wash- ington D.C. 8:154-165 (July) 1952. 2. Calabro, J. J.: Hiccups. Am. J. Nursing. 55:1365-1366 (November) 1955. 3. Calabro, J. J.: A therapeutic approach to rheumatoid spondyiltiS. GP 22:88-95 (July) 1960. 4. Sponzilli, E., and Calabro, J. J.: Gonococcal arthritis in the newborn: Report of a case and review of the literature. JAMA. 177:919-921 (Septem- ber 30) 1961. 5. Calabro, J. J.: The feet as an aid in the differential diagnosis of arthritis. Atti del X Congresso della Lega Internazionale contro il Rheu- matismo, Rome, Italy 2:209-211 (September) 1961. 6. Nosenzo, C. J., Calabro, J. J., Primack, A., and Heimer, R.: The inhibi- tion of complement fixation in rheumatoid arthritis Atti del X Congresso della Lega Internazionale contro ii Rheumatismo, Rome, Italy 2:758-759 (September) 1961. 7. Calabro, J. J.: A critical evaluation of the diagnostic features of the feet in rheumatoid arthritis. Arthritis Rheum. 5:19-29 (February) 1962. 8. Calabro, J. J., Nosenzo, C. J., Catsoulis, B., and Traugott, F.: Juvenile rheumatoid arthritis: Protean manifestations. Postgra. Med. 31 :475-477 (May) 1962. 9. Calabro, J. J.: Arthritis of the temporomandibular joint, J. New Jersey State Dent. Soc. 38:404-407 (May-June) 1962. 10. Levey, G. S., and Calabro, J. J.: Tiet~e's syndrome: Review of the world literature and report of two cases. Arthritis Rheum. 5:261-269 (June) 1962. 11. Calabro, J. J.: Hereditable multiple polyposis syndromes of the gastro- intestinal tract. Am. J. Med. 33:276-281 (August) 1962. 12. Levey, G. S., Carey, J. P., and Calabro, J. J.: Polymyalgia rheumatica A separate rheumatic entity? Arthritis Rheum. 6:75-77 (February) 1963. 13. Scudese, V. A., and Calabro, J. J.: Vertebral Wedge Osteotomy for correction of rheumatoid (ankylosing) sponclylitis. JAMA. 186:627-631 (November 16) 1963. 14. Sharp, J. T., Calkins, E., Cohen, A. S., Schubart, A. F., and Calabro, J.J.: Observations on the clinical chemical and serological manifestations of rheumatoid arthritis, based on the course of 154 cases. Medicine. 43:41-58 (January) 1964. 15. Calabro, J. J.: Clinical aspects and medical management of chronic arthritides. J. Am. Phya Ther. Assoc. 44:584-591 (July) 1964. 16. Edwards, M. H., Calabro, J. J., and Wied, M. B.: Patients' attitudes and knowledge concerning arthritis. Arthritis Rheum. 7 :425-434~ (August) 1964. 17. Calabro, J. J., and Luczynskl, B. W., Jr.: Flebre y exantema en arthritis reumatoidea juvenil. Ray. Med. Chile, $uppl. 6:53-55 (December) 1964. 18. Calabro, J. J., and Marchesano, J. M.: Medical management of juvenile rheumatoid arthritis. Bull. Rheum. Dis. 15:378-381 (May) 1965. 19. Calabro, J. J., and Mody, R. B.: Management of ankylosing spondylitis. Am. J. Occupat. Ther. 19 :255-258 (September) 1965. 20. Calabro, J. J., and Marchesano, J. M. : Tietze's Syndrome. GP33: 101-105 (January) 1966. 21. Calabro, J. J.: Current comment: Juvenile rheumatoid arthritis. Arthritis Rheum. 9 :82-87 (February) 1966. 22. Edwards, M. H., Calabro, J. J., Avedon, B. M., Arje, F. B., and Berry- man, D. L.: Therapeutic recreation for the patient with ankylosing spondy- litis. Arch. Phys, Med. & Rebab. 47:77-83 (February) 1066. 23. Calabro, J. J., atid Mody, R. B.: Management of ankylosing spondylitis. Bull. Rheum. DIs. 16:408-411 (April) 1966. 24. Calabro, J. J.: Artrite reumatoide juvenil-aspecto corrente. Rev. Brasileira Reumat. 10:9-19 (May) 1966. 25. Calabro, J. J., and Marchesano, J. M.: Tietze's syndrome: Report of a case with juvenile onset. J. Ped. 68 :985-987 (June) 1966. 26. Calabro, J. J.: Juvenile rheumatoid arthritis. In Arthritis and Allied Conditions. Edited by J. L. flollander. 1355 pp. PhiladelphIa: Lea, 1966 Pp. 220-235. 27. Calabro, J. J., and Amante, C. M.: Ankylosing spondylitis. J. Wads- worth General Hosp. 10 :103-112 (Nov.-Dec.) 1966. PAGENO="0310" 3402 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 28. Calabro, J. J., and Marchesano, J. M.: Fever associated with juvenile' rheumatoid arthritis. N. Eng. J. Med. 276:11-18 (January) 1967. 29. Calabro, J. J.: Management of ankylosing spondylitis. The Physician's Panorama 5:9-12 (Feb.) 1967. 30. Calabro, J. J., and Marchesano, J. M.: Medical Intelligence. Current Concepts. Juvenile rheumatoid arthritis. N. Eng. J. Med. 277:696-699 (Sept.. 28) 1967. 31. Calabro, J. J., and Marchesano, J. M.: Medical Intelligence. Current Concepts, Juvenile rheumatoid arthritis (Concluded.) N. Eng. J. Med. 277:746-749 (Oct. 5) 1967. $2. Calabro, J. J.: Cancer and arthritis. Arthritis Rheum. 10:553-567 (Dec.) 1967. 33. Classification of juvenile rheumatoid arthritis. New Eng. J. Med., 277:1374 (Dec. 21) 1967. 34. Calabro, J. J., and Amante, C. M., Indomethacin in ankylosing spondy- litis. Arthritis Rheum. 11 :56-64 (Feb.) 1968. 35. Calabro, J. J., and Marchesano, J. M.: Rash associated with juvenile' rheumatoid arthritis. J. Ped. 72:611-619 (May) 1968. 36. Calabro, J. J., and Marchesano, J. lvi.: The early natural history of juvenile rheumatoid arthritis. A 10-year follow-up study of 100 cases. Med. Clin. N. Amer. 52:567-591 (May) 1968. 37. Calabro, J. J.: An appraisal of the medical and surgical management of ankylosing spondylitis. Clin. Orthrop. & Related Research. 1968 (in. print). 38. Calabro, J. J.: Role of salicylates in juvenile rheumatoid arthritis. In-Proc. Conf. on Chronic Administration of Salicylates. New York City,.. June 1966. Ed. by Dr. Ronald W. Lamont-Havers. Public Health Service Bull. 1968 (in print). 39. Calabro, J. J.: The diagnosis of juvenile rheumatoid arthritis. Pediat. Dig. To be published, 1968. 40. Calabro, J. J.: Letter to the editor. Canad. Med. Ass. J. To be pub- lished, 1968. 41. Calabro, J. J., and Amante, C. M.: A long-term evaluation of indo- methacin in ankylosing spondylitis. Excerpt Medica. To be published, 1968. Bibliogi~aphy, abstracts: 1. Calabro, J. J.: The feet In rheumatoid arthritis. Arch. Interam. Rheum.. 2:249-250 (June) 1959. 2. Calkins, E., Sharp, J. T., Cohen, A. S., Schubart, A., and Calabro, J. J.: Some observations on the clinical, chemical and serologic manifestations of' rheumatoid arthritis based on a study of the course of 150 cases. Arch.. Interam, Rheum. 2:208 (June) 1959. 3. Cohen, A. S., McNeil, M., Sharp, J. T., Schubart, A., Calabro, J. J., and C~a1kins, E.: X-ray examination of the spine of patients with rheumatoid' arthritis and spondylitis: a correlation with serologic and clinical manifesta- tions of disease. Arch. Interam. Rheum. 2:222-223 (June) 1959. 4. Calabro, J. J., Nosenzo, 0. J., and Traugott, F.: The feet in rheum~toid~ arthritis. Abstracts, T~welfth Annual Scientific Assembly, A.A.G.P. 10 :334k (March) 1960. 5. Calabro, J. J.: The feet as an aid in the differential diagnosis of arthritis. Arthritis Rheum. 5:435-436 (October) 1960. 6. Calabro, J. J., Nosenzo, C. J., and Traugott, P.: Arthritic feet. Abstracts,. Thirteenth Annual Scientific Assembly, A.A.G.P. 11 :294-296 (April) 1961. 7. Edwards, M. H., Murphy, F. J., Osborne, P. J., Calabro, J. J., and Nosenzo, C. J.: Serologic screening for rheumatoid factor In a health depart- ment laboratory Arthritis Rheum. 4:413-414 (August) 1961. 8. Calabro, J. J., Lo Presti, P. J., and Nosenzo, 0. J.: The antirheumatic effect of salicylate, salicylamide-(2-cthoxyethyl)-ether and sucrose placebo in patients with rheumatoid arthritis. Arthritis Rheum. 5:286-287 (June) 1962. 9. Edwards, M. H., Calabro, J. J., and Wied, M. K.: Patient's attitudes and knowledge concerning arthritis. Arthritis Rheum. 5:643-644 (December) 1962. 10. Calabro, J. J., and Luczynski, K. W. Jr.: Observations on the fever and rash of juvenile rheumatoid arthritis. Arthritis Rheum. 6:265 (June) 1963 11. Calabro, J. J., and Marchesano, J. M.: Prognosis in juvenile rheumatoici~ arthritis. Arthritis Rheum. 8:434 (June) 1965. PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3403 12. Calabro, J. J., and Marchesano, J. M.: Patterns of onset and course of juvenile rheumatoid arthritis. Proc. XI Intern. Congress on Rheuma. 11 :243- 244 (December) 1965. 13. Oalabro, J. J., Marchesano, J. M., and Abruzzo, J. L.: Idiopathic hy-~ pertrophic osteearthropathy (pachydermoperiostosis) : Onset before puberity.. Arthritis Rheum. 9 :9496 (June) 1966. 14. Ruderman, J. E., Marchesano, J. M., Abruzzo, J. L., and Calabro, J. 3.: A comparative radiologic study of the cervical spine in adult and juvenile' rheumatoid arthritis. Arthritis Rheum. 9:537-538 (June) 1966. 15. Calabro, J. J., and Marchesano, J. M.: Rash associated with juvenile rheumatoid arthritis. Arthritis Rheum. 0:850 (December) 1966. 16. Amante, C. M., and Oalabro, J. 3.: Rheumatoid factor in ankylosiug spondylitis. Arthritis Rheum. 10 :263 (June) 1967. 17. Amante, C. M., and Calabro, 3. J.: Prognosis in ankylosing spondylitis. Excerpta Medica, Intern. Congress Series No. 143:1-76-77, (Oct.) 1967. 18. Calabro, 3. J., and Amante, 0. M.: Indomethacin in ankylosing spondy- litis. Excerpta Medica, Intern. Congress Series No. 143 :1-77 (Oct.) 1967.. 19. C~tlabro, 3. J., and Marchesano, 3. M.: Monarticular onset juvenile rheumatoid arthritis: A 10-year followup. Arthritis Rheum. 11: (June) 1968. 20. Calabro, J. 3., and Amante, C. M.: Prognosis in ankylosing spondy- litis. Arthritis Rheum. 11: (June) 1968. Scientific exhibits: (Each exhibit has been shown at the Annual Meeting of the American Medical Association, Clinical Session of the American Medical Associa- tion, Annual Meeting of the American Academy of General Practice, and the Annual Meeting of the Medical Society o'f New Jersey) 1959-1960: Wax moulage exhibit: "The feet in rheumatoid arthritis." Por- tray's clinical and radiologic features of feet of patients with rheumatoid arthritis, with special reference to heel and metatarsal lesions. (Cala'bro, 3. 3., Nosenzo, C. 3., and Traugott, F.) 1960-1961: Wax moulage exhibit: "Arthritic feet." Utilizing the clinical and radiologic features of arthritic feet in the differential diagnosis `of arthritis, in- cluding psoriatic a'rthropathy, rheumatoid arthriti's, acute gouty arthritis, dia- betic neuropathic join't disease and chronic tophaceous arthritis. (Calabro, 3. J,, Nosenzo, C. J., and Traugott, F.) 1961-1962: Ectocbrome transparency exhibit: "Juvenile rheumatoid art'hritis.'~ Ectochrome illustrations demonstrating the protean manifestations of juvenile rheumatoid arthritis. (Oalabro, 3. J., Catsoulis, E~, Nosenzo, C. J., and Traugott, F.) 1963-1964. Wax moulage exhibit: "The foot a's an aid in the differential di- agnosis of arthritis." (Calabro, J. J., Nosenzo, C. 3., Luczynski, E., Jr., Abruzzo, 3. L., Mody, R. E., and Traugott, F.) Award: AMA Honorable Mentiton. 1964-1965: Ectochrome tranparency exhibit: "Tietze's Syndrome." (Oalabro, J. J., Marchesano, J. M., Mody, R. E., Ruderman, 3. E., Abruzzo, 3. L., and Trau- gott, F.) Award: AMA Certificate of Merit. Presentations of papers at national or international meetings: June 2-6, 1959 (Washington, D.C.): Second Pan-American Congress on Rheu- matic Diseases, in conjunction with the 23rd Annual Meeting of the American Rheumatism Association. Delivered paper on "The Feet in Rheumatoid Arthritis." Co-authored two other papers, one on "Some Obser'c4ition on the Clinical, Ohemi- cal and Serologic Manifestations on Rheumatoid Arthritis. Based on a Study of the Course of 150 Cases." and "X-ray Examination of the Spine of Patients With Rheumatoid Arthritis and Spondylitis: A Correlation with Serologic and Clinical Manifestations of Disease." Septem'ber 4-7, 1961 (Rome', Italy): 10th International Oongress of Rheuma- tology. Delivered paper on "The Foot as an Aid in the Differential Diagnosis of' Arthritis." September 13-15, 1962 (London, England): Salicylates: An International Sym- posium. Sponsored by the E~npire Rheumatism Council, with the support of the' Nicholas Research Institute, Ltd.: Held at the Post Graduate School of London. Discussor of therapeutic role of aspirin in rheumatoid arthritis.. June 13-14, 1963 (Atlantic City, New Jersey): Annual Meeting of the Amer- ican Rheumatism Association. Oo-chairman of arrangements. Delivered paper' on "ObserwLtion on the Fever and Ra~sh of Juvenile Rheumatoid Arthritis." October 15-19, 1963 (Santiago, Chile): Third Pan-American Congress on Rheu- matic Diseases. Delivered paper on "The Protean Manifestations of Juvenile Rheumatoid Arthritis." PAGENO="0312" 3404 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY October 1-3, 1964 (Princeton, New Jersey): Conference on Gout and Purine Metabolism. Sponsored by the American Rheumatism Association, the National Institutes of Arthritis and Metobolic Diseases, and the Arthritis Foundation. Participant in clinical discussions. June 17-18, 19fi5 (Philadelphia, Pa.): Annual meeting of the American Rheu- matism Association. Delivered paper on "Prognosis in Juvenile Rheumatoid Arthritis." December 5-11, 1905 (Mar Del Plata, Argentina) : XIth International Congress of Rheumatology. Delivered paper on "Patterns of Onset and Course of Juvenile Rheumatoid Arthritis." Arthritis Foundation Travel Grant. June 6-10, 1966 (New York, N.Y.): Second International Symposium on Popu- lation Studies of the Rheumatic Diseases. Spensored by NIH and the Arthritis Foundation. Secretary of the Council on Diagnostic Criteria for Juvenile Rheu- matoid Arthritis. Member of Committee on Diagnostic Criteria for Ankylosing Spondylitis. June 13-14, 1966 (New York, N.Y.): International conference on Chronic Administration of Salicylates. Sponsored by NIH and the Arthritis Foundation. Delivered paper on "Role of Salicylates in Juvenile Rheumatoid Arthritis." June 16-17, 1966 (New York, N.Y.): Annual Meeting of the American Rheu- matism Association. Delivered paper on "Idiopathic Hypertrophic Osteoarthro- pathy (PachydermOperiostoSiS) Onset Before Puberty." December 2-3, 1966 (Cincinnati, Ohio): 12th Interim Scientific Session of the American Rheumatism Association. Delivered paper on "The Rash Associated With Juvenile Rheumatoid Arthritis." June 15-16, 1967 (New York, N.Y.): Annual Meeting of the American Rheu- matism Association. Co-author of paper entitled "Rheumatoid Factor in Anky- losing Spondylitis." Chairman of one concurrent session. Oct. 22-26, 1967 (Mexico City, Mexico): IV Pan-American Congress of Rheu- matology. Delivered two papers, one on "Indomethacin in Ankylosing Spondylitis," the other on "Prognosis in Ankylosing Spondylitis." Chairman of session on juvenile rheumatoid arthritis and Reiter's syndrome. November 13-20, 1967 (Rome, Italy) : International Clinical Symposium, spon- sored by Rome University in coorperation with the National Academy of Clini- ~ians. Delivered several talks entitled "Situations in Rheumatology." Dr. CALABRO. In my two-page letter dated April 23, I have summar- ized my experience and knowledge of the drug indomethacin and its role in patients with various rheumatic diseases. My first comment pertains to recent reports of double-blind studies of indomethacin in rheumatoid arthritis. Conclusion of such studies have led to some controversy concerning the efficacy of this drug as an antirheumatic agent in patients with rheumatoid diseases. It is my opinion that, while double-blind studies are obviously useful in evalu- ating new agents, they are also extremely difficult to interpret, particu- larly in such a capricious disease-I am sure this has been stressed throughout the hearings-as rheumatoid arthritis. To this point, I might add-and I do not think this has been stressed-that there are few, if any, double-blind trials with other antirheumatic agents in rheumatic arthritis that are entirely satisfactory. These would include adrenocorticosteriods, gold compounds, antimalarials, phenyibutazone, and the well-known salicylates-drugs that are generally accepted in the care of rheumatoid patients. Even controlled crossover techniques of drug testing can be faulty. In that regard, I would like to point to a publication that appeared in the Canadian Medical Association Journal on .June 3, 1967. This is an article by a rheumatologist, T. D, Kinsella, and coworkers, Mac- Kenzie, Kim, and Johnson. The title of this article, and I will submit this for the record, from the Journal of the Canadian Medical Associ- ation, is "Evaluation of Indomethacin by a Controlled, Crossover Tech- i~iique in 30 Patients with Ankylosing Spondylitis." (The document referred to follows:) PAGENO="0313" COMPETITIVE PROBLEMS IN. THE DRUG INDUSTRY 34O5~ [From Canadian Medical Association Journal, vol. 6, June 8, 1967, pp. 1454-14591 EVALUATION OF INDOMETHACIN BY A CONTROLLED, CROSS-OVER TECHNIQUE IN 30~ PATIENTS WITH ANKYLOSING SPONDYLITIS* T. D. KINSELLA, M.D., F.R.C.P. [C],** K. R. MACKENZIE, M.D., PH.D.,t S. 0. KIM, M.D4 AND L. G. JOHNSON, M.D., F.R.C.P.[CJ,~ MONTREAL A clinical evaluation of indomethacin employing a controlled, cross-over tech- nique with an inert placebo was undertaken in 30 patients with ankylosing. spondylitis. Patients were studied for the frequency and dose relationship of side effects and for the subjective response of morning stiffness, chronic spinal pain, acute exacerbations of pain and peripheral arthralgia. Objective evaluation assessed measured change in movements of the cervical and lumbar spines, In chest expansion and in the range of movement of involved peripheral joints. Evaluation of the results indicated that a significant number of patients experi- enced side effects in the form of headache and dizziness while receiving indo- methacin in doses above 150 mg. per day. Many other side effects reported by the patients were not found to occur at a statistically sigiaificant leveL The signifi- cance of pulmonary infections encountered in three patients was reviewed~ Relief of chronic spinal pain and peripheral arthralgia occurred in 14 and 16~ patients, respectively (p <0.05). Relief of morning stiffness and acute exacerba- tion of pain, and increase in the range of movement of any of the segments of the spine or the involved peripheral joints were not significant (p >0.05). Based on the results of this study, it is suggested that the role of idomethancin in the management of ankylosing spondylitis be re-evaluated and that the daily therapeutic dose of this drug which has been heretofore recommended be decreased. Indomethancin is a non-steroid anti-inflammatory drug which has been reported to be of therapeutic value In a variety of rheumatic diseases.'~ Among the latter, ankylosing spondylitis has been reported to respond particularly well.57 Because a large group of patients with ankylosing spondylitis previously studied8 was available at Queen Mary Veterans' Hospital, a detailed controlled, crossover trial with indomethacin and a placebo was conducted on some of these patients to assess further the therapeutic efficacy of this agent. MATERIALS AND METHODS All patients in this study conformed to the criteria proposed by Kellgren for the diagnosis of ankylosing spondylitis. Forty-eight patients were chosen at random as possible candidates; all of the latter were specifically advised of the side effects which were known to occur with indometbacin. Table I illustrates the eventual composition of the series. Only those patients who had clearly defined and persistent symptomatbology were started on therapy. All patients were continued on their previous forms of medication, and these are indicated~ in Table II. *From the Department of Medicine (Arthritis Service), Queen Mary Veterans' Hospital Montreal, Quebec. **Pormerly consultant in Medicine, Queen Mary Veterans' Hospital, Montreal. f Consultant in Arthritis, Que6n Mary Veterans' Hospital. ~ Canadian Arthritis and Rheumatism Society Clinical Fellow; Clinical Fellow (Ar- thritis), Royal Victoria Hospital, Montreal. Formerly Senior Consultant in Arthritis, Queen Mary Veterans' Hospital, Montreal; Director, Division of Rheumatology, McGill University Clinic, Montreal. Reprint requests to: Dr. K. ii. Mackenzie, Royal Victoria Hospital, 687 Pine Avenue- West, Montreal 2, Quebec. Presented at Second. Laurentian Rheumatology Conference, International Symposium on Non-steroid Anti-inflammatory Compounds. Saint Marguerite, P.Q., Canada October 20-22, 1966. N0TE,-Numbered footnotes at end of article, p. 8412. PAGENO="0314" :3406 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 1.-Composition of stndy Patients Originally chosen for study 48 Started on medication 138 Lost to study: Failed to cooperate 5 Developed side effects 3 Oompleted study 30 1 10 omitted-inability to cooperate or lack of consistent, well-defined symptoms. TABLE 11.-DISTRIBUTION OF TYPES OF MEDICATION EMPLOYED (OTHER THAN INDOMETHAC1N) IN 30 PATIENTS WITH ANKYLOSING SPONDYLITIS Type of medication Daily dosage range (mg.) Number of patients 1 A.S.A.2 Phenylbutazone Steroids a ~l,200 >1,200 ~400 >400 ~5 12 9 10 0 3 ~None >5 0 5 I Total exceeds 30, since some patients employed more than 1 type of medication. 2 A.S.A.=acetylsalicylic acid. 2Steroids expressed in equivalents of prednisone. The range of the duration of illness in these patients was from 13 to 26 years, with a mean of 20.1 years. Capsules of indornethacin (25 ing.) and the placebo for oral use, and rectal suppositories of indomethacin (100 mg.) and the placebo were provided in identical forms. One suppository of the appropriate form was used at bedtime during the first six days of the first period of assessment. This ~procedure was not repeated during the second period of assessment, since it was felt that the patients would have become aware that substitution or "cross-over" had taken place. The dosage schedule for capsule therapy was 25 mg. twice a day for two days, then 25 mg. four times a day for two days, then 50 mg. three times a day for two days and then 50 mg. four times a day. Although indometha- cm and placebo were assigned in a random manner, patients were advised to modify the daily dose, depending upon the occurrence and severity of the side -effects experienced. Reassessment was carried out by the same physician at three, six, nine and 12 weeks after the start of therapy. Cross-over to either indomethacin or placebo was carried out at the end of six weeks, but the assessing physician was not aware of which substance the patient had received. All medication was dis~ pensed in the clinic by one physician who also assessed the frequency and severity of side effects, modification of the dosage schedule was recommended to the pa- tients by this physician when it seemed appropriate. All medication which had not been consumed during each three-week period of assessment was returned by the patients to this physician, who then provided a further supply of a known amount of the appropriate medication. Assessment of the therapeutic response was based upon both subjective and objective evaluation of the patients. The subjective evaluation was based on patients' opinions, which were graded as to whether the following showed "no change", were "worse" or "improved"; (a) duration and severity of morning ~stiffness, (b) severity of chronic pain in some or all segments of the vertebral -column, (c) frequency and severity of acute exacerbations of pain, and (d) frequency and severity of peripheral arthralgia. Objective response was as- sessed by the following measurements: (1) movement in the cervical and lumber spines as shown by the range of forward fiexion and lateral fiexion, extension and rotation, (2) maximal chest expansion, (3) degree of tenderness on "punch" palpation of the sacroiliac joints and (4) range of movement of the involved ~peripheral joints. The following criteria were employed to designate objective improvement: increase of at least 15° in each of two of the four basic move- snents in the cervical and lumbar spii~es, respectively; a sustained increase of at least one-half inch in chest expansion, improvement in the range of movement -of two or more peripheral joints, or of at least 25% in a single peripheral joint. Laboratory tests were done on each patient a't each clinic visit in order to assess PAGENO="0315" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3407 both the side effects and the ability of indomethacin to suppress the various lab- oratory indices of Inflammation. The following tests were performed routinely by conventional methods: complete urinalysis, complete hemogram including erythrocyte sedimentation rate (~lSR-Wlntrobe), blood urea nitrogen (BUN), serum creatinine, serum alkaline phosphatase, serum glutamic oxaloacetic trans- aminase (SGOT), serum protein paper electrophoresis, latex test for rheumatoid factor,1° and antinuclear factor (ANF-LE-Test, Hyland). When Indicated, chest film, barium meal, electrocardiogram, urine culture and antibiotic sensitivity (if any), and serum protein Immunoelectrophoresis were also done. Statistical -evaluation of the results was carried out by the chi-square test according to the method of McNemar, using one degree of freedom. ~ TABLE 111-30 PATIENTS ON INDOMETHACIN AND P LACEBO: FREQUENCY OF SIDE EFFECTS Indomethacin Placebo Type of side effect S Number Percent Number - Percent ~CNS: Headache Dizziness Depression "Feeling inebriated" Miscellaneous Gastrointestinal: Anorexia and nausea Symptoms of peptic ulcer Skin eruption Anemia Elevated alkaline phosphatase Elevated SGOT 15 150 12 140 2 6 5 16 3 2 10 7 23 ii 36 3 10 6 20 3 10 1 3 7 3 1 2 2 7 9 0 2 1 1 23 10 3 6 6 23 30 0 6 3 3 I Significant at the 0.05 level. 2 Decreased hearing, blurred vision and drowsiness-i each. RESULTS Twenty-seven patients completed six-week courses of both indomethacin and placebo, while one patient completed three-week courses of each. Two patients whose initial six-week course consisted of indomethacin and who experienced 5a severe clinical relapse during the first three weeks of placebo administration were subsequently restarted on indomethacin without the knowledge of the assessing physician. These 30 patients represent those who were assessed by the previously described clinical and laboratory parameters. Three additional patients who were lost to the study had received indomethacin only (Table I). Dose tolerated The maximum daily dose of indomethacin tolerated without incapacitating side effects by 15 (50%) of the 30 patients was six capsules (150 mg.) per day, and by five others (16%) was four capsules (100 mg. per day). Thus, only 10 patients (34%) tolerated eight capsules (200 mg.) per day; in comparison to the placebo this was a highly significant difference (p=0.0O15). $ide effects Three patients who had received only indomethacin were forced to withdraw from the study (Table I). All of these patients experienced severe central nervous system reactions, principally headache and dizziness. One of these also developed ~extensive right middle and lower lobe pneumonitis which required hospitalization. The occurrence of a pulmonary infection was also noted in two other patients while they were receiving indomethacin. Of the 30 patients who completed the study, 24 (80%) developed some form of side effect, as demonstrated either clinically or in the laboratory. Thus only six patients (20%) experienced no side effects while receiving indomethacin. On the other hand, 18 patients (60%) experienced some form of side effect while receiving placebo and 16 (53%) of the entire group experienced one or another of the side effects on both indomethacin and placebo. Viewed in this respect, there was no significant difference in the total number of side effects experienced on indomethacin or placebo (p> 0.05). The types and frequency of the various side effects are listed in Table III. It will be noted that reactions involving the central nervous system occurred with the greatest frequency, particularly those manifesting as headache and dizziness. PAGENO="0316" 3408 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY With respect to both of these symptoms there was a significant difference between the two treatment groups, the ~ values being 0.027 and 0.015 respectively. A similar difference was not found between `the two treatment groups in regard to other complaints referable to the central nervous system, or indeed to any of the other side effects noted in Table III. It should be noted that four patients whose gastrointestinal symptoms were severe were investigated by means of a barium meal, but in none of these patients was peptic ulceration demonstrated. Sabjective response The results of subjective evaluation of the response to both drugs are depicted In Fig. 1. It will be seen that significant levels of response were noted with respect to relief of chronic spinal pain and peripheral a'rthralgia, the actual p values being 0.05 and 0.01, respectively. However, there was no significant difference in the responses of morning stiffness and of acute exacerbations of pain. P4orn~n~ stiffness ~w p > 0.05 ~ IP4DOMETHACU( ~J PLACEBO Chroqic. pain p.< 0.05 Acute exacerbations .~.. P > 0.05 Peripheral arthralgia < 0 ~ (29 patients) p 0 10 20 30 Number of Patier~ts Fig. 1.-S-Subjective response to therapy in 30 patIents with ankylosing spondylitis.. Objective response Fig. 2 illustrates' the results of objective evaluation of both drugs with respect to the cervical and lumbar spines, chest expansion, and sacroiliac and peripheral joints. It can be seen `that in none of these parameters was there a significant difference between the two forms of therapy (p> 0.05). Two additional findings should also `be noted: first, the very small numbers of patients who demonstrated any subsequent variation in the measurements initially recorded; and second, the lack of correlation between the subjective and objective assessment of the peripheral joints. TABLE V-EFFECT OF INDOMETHACIN AND PLACEBO ON LEVEL OF ESR AND ALPHA-2 GLOBULIN Number of Decreased to normal by: patients Indomethacin Placebo Elevated ESR Elevated alpha-2 globulin 25 26 1 6 (p>0.05) 1 8 (p>0.05) 2 3 1 Significant at the 0.05 level. PAGENO="0317" 3409 Peripheral joints (29 patients) Os COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY * Cervica~ spine Chest expansion p > 0.05 1NDOHETHACIN ~J PLACEBO p > 0.05 Lumbar spine p >0.05 Sacro~-iliaC joints p >0.05 P > 0.05 - 10 20 30 Number of Patients Fig. 2.-Objective response to therapy In 30 patients with ankylosing spondylitis. Laboratory results No abnormal results were encountered before or during both forms of treat- ment with respect to the serum antinueleoprotein test, latex fixation test, creati- nine and BUN. Similarly, none of the patients exhibited a significant difference in the total white blood cell or differential counts on either drug. It should be noted that two of the three patients who developed a pulmonary infection ~vere able to react with a neutrophiic leukocytosis (range: 11,000 to 21,000 per c.mm.) while the third showed no such response. Abnormal urine was noted intermittently in eight patients (27%) while taking .indoinethacin and in 10 patients (83%) while taking a placebo; of the total of 18 patients there were four who had an abnormal urinalysis while receiving both indomethacin and placebo. Thus, 14 patients (47%) in this group showed abnormalities in the urinary sediment. These abnormalities were cbaracteriz~d by minimal proteinuria and microscopic pyuria and were usually not associated with dysuria. Their rate of occurrence could not be related to the administration of indomethacin (p> 0.05). The development of anemia (a fall of hemoglobin of greater than 1 g. %) was noted in six patients (20%) while receiving Indomethacin and in two patients (6%) while receiving placebo (Table III): this was not significant at the 0.05 level (p> 0.05). It should also be noted that an anemia of less than 13 g. % (range: 9-13 g. %) was present in six other patients before the administration of either drug and remained stable throughout the period of observation. Two patients who complained of symptoms suggestive of peptic ulcer also developed anemia. Investigation of these patients failed to demonstrate occult blood in the stool or, by barium meal examination, an upper gastro-intestinal tract ulceration. Elevation of the ESR was found at some time during the study in 25 (88%) of the 30 patients, but in only eight, of whom six were receiving Indomethacin ~and two placebo, ilid the ESR return to nournial (p > 0.05) (Table IV). By PAGENO="0318" 3410 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY serum protein electrophoresis the alpha-2 globulin was found elevated at some time during the study In 26 (86%) of the 30 patients; in the majority of pa- tients the elevation was slight. The level of the alpha-2 globulin returned to~ normal values in eight patients (26%) while receiving indom.ethacin and in three patients (10%) while receiving placebo (p > 0.05) (Table IV). Eight (26%) of the patients demonstrated a slight elevation of the serum gamma globulin on paper electrophoresis and none of these showed a significant change in this~ value during the period of observation. No significant difference at the 0.05 level (p> 0.05) was noted with respect to the few patients who developed on abnor- mal elevation of the level of the serum alkaline phosphatase and glutamic oxaloacetic transaminase (Table III). DISCUSSION The relative value of any medication must be assessed with respect to poten- tially harmful side effects and the degree of both subjective and objective thera- peutic benefits derived from it. The present study was undertaken to assess these factors as they applied to indomethacin in the treatment of ankylosing spondylitis. In the majority of instances the rate of occurrence of side effects in the present group of patients with spondylitis wa's not shown to be significant by statistical analysis. It is probable that the many "placebo reactors" in this group resultedJ because the patients were specifically cautioned regarding these side effects at the onset of the study and because, during the course of the study, con- siderable attention was directed both to their occurence and to their possible dose relationship. Accordingly, we do not feel that sufficiently unbiased data were ob- tained from this portion of the study to warrant extensive extrapolation. Although the data were not shown to be statistically significant, note should be taken of the three patients who developed pulmonary infections while receiv- ing inclomethacin. In one patient, resolution occurred only after three weeks of' antibiotic administration and withdrawal of indomethacin. In two of these pa- tients a brisk leukocyte response was noted in the blood while in the third, the individual with the prolonged course who did not respond to antibiotics, no leukocytosis was detected. Since some experimental studies with indomethacin13 do indicate an enhanced susceptibility to infection in animals the recent report by Phelps and McCarty n of decreased leukocyte mobility in the presence of indomethacin should prompt close re-evaluation of the incidence of infection in patients receiving this drug. Abnormal urinalyses were noted intermittently in 14 patients (47%) durIng this study. Although apparent interference with normal renal function has been reported with indomethacin administration,14 there was no statistical evidence in the present group of patients that the abnormal urinalyses were related to indomethacin therapy. Similar abnormalities have been previously reported by~ and are a recognised accompaniment of ankylosing spondylitis.15 The observations relating to the subjective and objective therapeutic respenses~ to indocmethaein provided more definitive data than those relating to the side effects. Prom the point of view of subjective evaluation, only the rellef~ from. chronic spinal pain and' from peripheral arthralgia were found to be statistically significant responses. The failure of indomethacin to relieve morning stiffness in the spine and, In particular, to decrease the frequency and severity of acute exacerbations of spondylitis in this group of patients is in distinct contrast with the results reported in previous studies which did not employ a controlled, cross. over technique.' From the point ,of view of subjective response, therefore, indomethaeln provided only minor benefit in the management of this group of spondylitis patients. In none of the objective parameters of assessment was there a significant Im- provement with the administration Qf indometliacin. It should also be noted that the subjective improvement reported' In peripheral arthralgia was not sub- stantiated by Objective assessment of the involved peripheral joints. These data clearly demonstrate the failure of Ind~methacin to produce objective improve- ment in the ranges of movement of the spinal and peripheral joints in this group of patientewith ankylosing spondylitis. It was considered possible that the very poor objective responses which were noted did not accurately reflect the anti-Inflamniatory potential of idomethacln, since, as has been previously indicated, the mean duration of illness in this group of patients was 20.1 yearg. In other words, it was possible that extensive Im- mobilization of the vertebral column by ligamentous ossification and apophyseal joint fusion would prevent an `objective display of Improvement In the various' ranges of movemeht. Accordingly, an attempt was made to reassess thedata with PAGENO="0319" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3411 this possibility in mind by comparing the radiological changes in the vertebral column with the observed clinical responses. As might be anticipated, it was virtually impossible to re-evaluate these data without introducing bias. The only definitive data which could be salvaged in this regard related to the cervical spine; employing the previously defined criteria for improvement, it was found that of 21 patients with no functionally significant radiological changes of ligamento'us ossification and/or apophyseal joint fusion only one patient improved with indomethacin and none with placebo. On the other hand, of the remaining nine patients who were judged to have functionally significant radiological changes, three improved on idomethacin and one while on placebo. These observations would, therefore, suggest that the failure of these patients to demonstrate objective improvement was not due to mechanical re- striction of the cervical spine but rather to failure of indomethacin to decrease or abolish active inflammation. It should also be noted that the latter conclusion is supported by the data which demonstrated the inability of indomethacin to pre- vent acute exacerbations and to relieve morning stiffness. The laboratory tests (DSR and alpha-2 globulins) employed to assess the anti-inflammatory effect of indomethacin showed no significant change during this study. Once again these data correlate well with the other parameters used to asses's indomethacin in this group of patients. Although indomethacin has been reported to have both anti-Inflammatory and analgesic properties,1° ~ the results' of this study would indicate that on anky- losing spondylitis the main effect in indomethacin is as an analegisic, since the only significant responses observed were relief of chronic spinal pain and of peripheral arthralgia. The failttre of indomethacin to decrease morning stiffness and the frequency an'd severity of acute exacerbations, to improve the restricted movements in the spinal and peripheral joints, or to suppress the elevated ESR and alpha-2 globulin levels would also indicate that the anti-inflammatory prop- erties of indomethacin in chronic but active ankylosing spondylitis are minimal. CONCLUSIONS The majority of patients in this study were unable to tolerate the recommended daily therapeutic dose of up to 200 mg. per day of indomethacin. When 15 pa- tients (50%) received a dose in excess of 150 mg. per day and five others (.16%) a `dose in excess of 100 mg. per day there was a high incidence of side effects. Accordingly, we would suggest that the maximum daily therapeutic dose of indomethacin be reduced below 150 mg. per day. It would also appear that if a beneficial therapeutic response does not occur with a dose between 100 mg. and 150 mg. per day, the probability that such a response will occur with higher doses is slight. When the frequency and severity of indomethacin-related side effects, par- ticularly those involving the central nervous system, are considered in conjunc- tion with the apparent lack of an anti-inflammatory effect of indomethacin, the role of this agent in the routine management of ankylosing spondylitis should be questioned. Since in our experience8 a satisfactory therapeutic program for ankylosing spondylitis can be achieved with physical measures, maintenance doses of acetylsalicylic acid and intermittent administration of phenylbutazone, we can discern no preferential role for indometbacin in such a program. In order to further evaluate the role of indomethacin in the management o~f patients with ankylo~sing spondylitis, we would suggest that a cross-over study comparing phenylbutazone and indo'methacin might provide more definitive data than were obtained in the present study. It would also seem appropriate to conduct such a study in a group of patients with spondylitis having a shorter duration of illness, so that objective assessment of the anti-inflammatory effects of the drugs would not be obscured by anatomically restrictive changes in the spine. Appreciation is expressed' to Dr. William Dorlan of Merck Sharp & Dolme of Canada Limited, Montreal, for his generous support and encouragement, and to Dr. F. Robert MacDonald, Associate Radiologist at the Royal Victoria Hospital, Montreal, tor his evaluation Of the radiological examinationjs of this group of patients. PAGENO="0320" ~3412 COMPETITIVE PROBLEMS IN THE DRUG. INDUSTRY REFERENCES ~ Hart, F. D. and Boardman, P. L.: Brit. Med. J., 2: 965, 149613. ~ Wanka, A. and Dixon, AL St.J.: Ann. Rheum. Dis., 23: 288, 1964. ~ Smyth, C. J., Velayos, E. E. and Amoroso, C.: Acta Rheum. Scancl., 9: 306, 1963. Kelly M.: J. Amer. Geriat. Soc., 14i: 48, 1966. 5 Smyti~, C. J. and Godfrey, R.: Arthritis Rheum., 7i: 345, 1964 (abstract). f° Calabro, J. J. and Mody, R. B.: Bull. Rheum. Dis., 16: 408, 1966. `~ Hart, F. D.: Brit. Med. J., 2: 1281, 1965. 8 Klnsella, T. D., MacDonald, F. R. and Johnson, L. G.: Canad. Med. Ass. J., 95: 1, 1966. Kellgren, J. H.: Bull. Rheum. Dis., 18 :291, 1962. ~° Singer, J. M. and Plotz, C. M.: Amer. J. Med~, 21: 888, 1056. ~1 Maxwell, A. E.: Analyzing qualitative data, John Wiley & Sons Inc., New York, 1961, p. 26. ~° Merdk Sharp & Dohme, Research Laboratory, Westpolnt, Pa.: Unpublished data. 13Phelps, P. and McCarty, D. J.: Suppression of crystal-induced synovitis in canine joints by indomethacin: demonstration of inhibition of leukocytic motility. Paper presented at the annual meeting of the American Rheumatism Association, Denver, Colorado, June 17-18, 1966. ~ Wanka, J. et al.: Ann. Rheum. DIs., 23: 218~ 14964. 15 Copeman, W. S. C., editor: Textbook of the rheumatic dIseases, 3rd ed., B. & S. Livingstone Ltd., EdInburgh, 1964, p. 526. 16 Sunshine, A. et al.: Clin. Pharmacol. Ther., 5: 699, 1964. ~ Winter, C. Ai., Risley, B. A. and Nuss, G. W.: J. Pharmacol. Exp. Ther., 141: 369, 1963. Dr. CALABRO. This article requires comment, since rarely does any one study violate so many basic tenets of a drug evaluation. For in- stance, Senator Nelson, as part of the drug trial of indomethacin, all patients continued to take their previous medication, such as aspirin, phenyibutazone, or adrenocorticosteroids. In fact, some patients were even receiving two of these other drugs simultaneously. Now, how do we test a drug if we allow patients to sta~y on another worthwhile and effective antirheumatic agent at the same time ~ But even before undertaking the study-and this is an inherent difficulty of many crossover studies-unnecessary bias was introduced. All 30 patients, the investigators point out "were specifically advised of the side effects which were known to occur with indomethacin." In fact, the patients were so `well advised that half developed indo- methacin side effects while on placebo. In table III of their report, 60 percent of the patients had side effects-not ordinary side effects, but indomethacin side effects-while they were receiving placebo. Predicta~bly, such a poorly conceived and biased study produced in- conclusive results. However, even more appalling-for me as a clinical rheumatologist responsible for the care of patients with rheumatoid spondylitis-even more appalling than their obvious errors of metho- clology are the apparent expectations by Kinsella and associates that indomethacin would provide "objective functional improvement." Now gentlemen, this is a clinical misconception, since antirheumatic agents are at best palliative. By providing effective relief of joint pain and inflammation, drugs then allow the clinician to utilize important supportive measures, such as therapeutic exercises imd other forms of physical therapy. To illustrate this point, Senator Nelson, if you had rheumatoid arthritis of the right wrist, and I were to give. y~u an antirheumatic agent, be it corticosteroids or for that matter indomethacin, these drugs could relieve the inflammation and pain in your wrist joint. But if this effect required a number of weeks or a number of months, you would then end up with a joint that would have some restricted mo- tion. No drug in the world is going to bring that motion back. The only measures that will correct this deformity, of course, are well- prescribed, regulkrly performed therapeutic exercises. I might ask all of you gentlemen to analyze closely the double-blind studies reported by Dr. Mainland and more recently analyzed by Dr. PAGENO="0321" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3413 O'Brien, in order to question the role of so-called physical measures in these short-term studies. What about these physical modalities that I have just made reference, to? Were such physical measures, as thera- peutic exercises, standardized in the 11 clinics that were part of the cooperative clinic study of indomethacin? Actually, there was no men- tion of these in Dr. Mainland's paper. Again, you must realize that no drug will restore motion unless such impaired and limited joints are put through physical measures to increase ranges of motion, and this is obviously an important adjunctive part of the care of tl~e rheu- matoid patient. I will stress again: Antirheumatic drugs do nothing more than re- move joint pain and inflammation, and function is restored through supportive measures, such as physical therapy and so on. Now, in spite of the results of the various ~double-blind and con- trolled trials that you have heard much testimony on, many physicians still have the impression that indomethacin benefits certain patients with rheumatoid arthritis. And, you have heard various statistics quoted, anywhere from 25 to 65 percent of rheumatoid patients may be benefited. But as Dr. Healey, a noted rheumatologist from Oregon, has pointed out in the Bulletin of Rheumatic Diseases in December 1967-there may be a subgroup of patients-be it small or large (what- ever it is) who may be benefited `by indomethacin, a finding that would certainly not be evident if all such patients are included in a general statistical evaluation. What is unique to those patients who do respond to indomethacin? And, to my knowledge, and I quote Dr. Healey, "This hypothesis has not been tested." Earlier Senator Hatfield had asked about long-term evjluatious of indomethacin in various rheumatic disorders. Dr. Charley Smyth, from Denver, Cob., will tell us shortly about his experience with indo- methacin in rheumatoid arthritis. I have already submitted to you, Senator Nelson, a reprint of our long-term evaluation of indometha- cm in ankylosing spondylitis. This is a form of rheumatoid disease affecting young men. It usually begins between ages 15 and 35. Unlike rheumatoid arthritis, it affects the small (apophyseal) joints of the back-but may also involve the peripheral joints, such as the knee and hip. In many ways, therefore, it is similar to rheumatoid arthritis. In this indomethacin trial that I have submitted, averaging 33 months, and which is still continuing, actually intq its seventh year, there were 28 ankylosin~ spondylitis patients who received an average daily dosage of 100 milligrams. The response to the drug-using three subjective criteria and three objective criteria, including the erythro- cyte sedimentation rate (ESR) as follows: The overall therapeutic rating of all parameters proved to be good in 21 of 28 patients (75 percent), fair in five, and poor in two. (See table I.) Of the 28 pa- tients, three of five patients who had previously been in functional class III improved to class II and two to class I; 21 patients eventu- ally were in the most favorable functional class `I, Senator, where only one patient was so rated before the start of incbomethacin. These functional designations are according to the scheme for long- term drug evaluations devised by the American Rheumatism Associa- tion, whereby functional class I means the patient is able to carry on all the usual activities cf daily living. and oc~ rtj~, and class II means that he may be able to perform in these activities despite joint 81-280-68-pt. 8-21 PAGENO="0322" 3414 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY limitation or handicaps. Class III means that the patient has difficulty maintaining self-care and occupation, while class IV refers to patients who are bedridden or confined to a wheelchair. I would like to stress that I wish we had better measures for drug testing. While we have used this classification, and it is as effective as any we have today, it was devised in 1949. The Therapeutic Criteria Committee of the American Rheumatism Association are continuously devising techniques that might sharpen our therapeutic studies of new drugs even more. I might add that in this study joint symptoms followed temporary withdrawal of the drug in 24 of the 28 patients- Senator NELSON. You are talking about your study? Dr. CALABRO. Yes, this has now appeared in the journal, Arthritis and Rheumatism, in February 1968. Senator NELSON. Did you ask to have this printed in the record? Dr. CALABRO. Yes. Mr. CUTLER. It is attached to Dr. Calabro's letter. Senator NELSON. It will be printed in the record at the conclusion of Dr. Calabro's statement. Dr. CALABRO. Return of joint pain was then promptly relieved when indoinethacin was again taken by the patients. Actually, we could repeat this withdrawal performance periodically. Clearly, our report of indomethacin in spondylitis parallels the experience of others, such as Bilka from Minneapolis, Hart of London, and European investigators such as Koss and Pohl, and Rothermich, whom you heard yesterday, that indomethacin is effective in ankylosing spondyiltis. That indomethacin has antirheumatic effects in disorders other than ankylosing spondylitis is also apparent, as judged by numerous reports of its usefulness in the management of the majority of patients with gout-Dr. O'Brien puts it up to 80 percent of gout cases in his publica- tion appearing in early 1968 (Clinical Pharmacology and Thera- peutics) -and osteoarthritis of the hip. I might refer to an additional followup publication, since Mr. Gor- don has referred to the Katz, Pearson, and Kennedy article of January- February 1965 (Clinical Pharmacology and Therapeutics), but neglected to mention that at the end of that report it was clearly stated that these therapeutic trials were done with an outmoded indomethacin tablet that was never released. He also neglected to mention that Dr. Pearson, the senior investigator-and I would like to submit this also for the record-has since pubiished on the indomethacin capsule, in May-June 1966, Clinical Pharmacology and Therapeutics, the same journal that Dr. O'Brien has his January-February 1968 publication in Pearson, having now used the capsule, has reported greater success in rheumatoid patients, but most notable was the reduction of adverse side effects, from 37 percent in their initial study to 12 percent in their continuation series, with no serious complications. Finally, again, Mr. Gordon points to a poll on use of indomethacin in medical practice. We should mention very clearly that this is a poll on the treatment of rheumatoid arthritis. It is true that 8 percent of the pediatricians were using indomethacin. The comment is then made, "Unlike the internists, of whom over 50 percent were using indometha.. cm, this is in sharp contrast to the 310 pediatricians who relied pri- PAGENO="0323" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3415 manly on analgesics and combinations thereof, five out of 10, but only infrequently prescribed indomethacin, phenylbutazone, or gold." If you look even more critically at this report, you will note that 18 percent of pediatricians were using adrenocorticosteriods for the care of patients with juvenile rheumatoid arthritis. This is a most disturb- ing situation in young children, because steroids have many more hazards in the child than in the adult. For instance, it will suppress growth in height and weight. It may cause thinning of the bones, notably in the spine, which may then go on to vertebral fracture. Pseudotumor cerebri may also occur in children. I have recently published all of the notable side effects of steniods that are unique to children. This data can be found in two parts, in the September 28 and October 5 issues of the New England Journal of Medicine in 1967. We should also note that the pediatricians elected to use simple anal- gesics in half of their rheumatoid arthritis children. Accordingly, they are using agents that do not have the needed antirheumatic effect. How do they expect to get at joint inflammation with simple analgesics? How do they expect to restore joint motion without first alleviating joint pain and inflammation? I sincerely hope, despite the current controversy and confusion, that investigative pursuits of indomethacin will continue. Only then can we more fully understand the role of this extremely useful and valuable antirheumatic agent. I have now been working with this agent-this is my seventh year. While I have only published reports of its usefulness in ankylosing spondylitis, I have used it in other disorders. Such data is certainly not scientifically organized and should not be presented, especially since none of it has been published. But I have also watched the growing literature on indomethacin very critically, and I have tried to present my estimation and fair appraisal of this most needed antirheumatic agent. There are many conditions in the rheumatic disease field for which we have few agents. You may remember that yesterday, Mr. Gordon, we listed all of the agents we might use in rheumatoid arthritis. We listed, I think, five or six. For ankylosing spondylitis, a not uncommon disease, we can list only three agents. Besides indomethacin, there is phenylbutazone, which has its toxicity. The original report of phenyl- butazone in spondylitis cited a 37-percent incidence of side effects.1 X-ray therapy to the spine has now been generally abandoned because of the increased risk of ]eukemia. Court Brown, reporting in the British Medical Journal (2:1327-1332, 1965), cites 49 cases of chronic myelo- genous leukemia due to radiotherapy. This has increased the hazard of leukemia from X-ray therapy in the spondylitis patient to some 10 times that of the population at large. Leukemia cases did not occur only after the forth, fifth, or sixth years after stopping radiotherapy, as we initially believed, but are occurring even now 14 and 15 years after radiotherapy was stopped. I need indomethacin to treat my patients with ankylosing sponclyli- tis, as indeed we need it for those patients with rheumatoid arthritis who do not respond to more conservative measures. Indeed, indo- 1 See Toone, B. C., and Irby, W. R.: "Evaluation of Phenylbutazone (Butazolidin) in the Treatment of Rheumatoid Spondylitis: Report of 50 Cases." Ann. mt. Med., 41: 7O-78~, PAGENO="0324" 3416 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY methacin is a valuable agent in the treatment of acute gouty attacks of arthritis, as it is in patients with osteoarthri'tis of the hip. Senator NELSON. Thank you, Doctor. I think the testimony does not differ from what the FDA witnesses said yesterday about the use of indomethacin, except that you went into considerably more detail. You suggested that the committee evaluate `these tests. The commit- tee does not feel competent to evaluate these tests. That is why we call in experts like you and who may well differ with each other. We feel that is the best way to find out what the truth is. Dr. CALABRO. I hope I have made it apparent that most rheumatolo- gists are unhappy about the methods we have for evaluating antirheu- matie agents. As a matter of fact, Dr. Carl Pearson, professor of medicine at UCLA, as well as myself and three other investigators have just received an enormous gran't aimed at the pharmacology and testing `of drugs in arthritis. I am afraid to even mention the amoun't. Senator NELSON. From where? Dr. CALABRO. From the NIH, for $3.5 million for 5 years. This grant was awarded Dr. Pearson to study the pharmacology of drugs-but more important, to ascertain newer techniques and tools by which we might better objectively evaluate current ñrugs, or newer drugs, used in the various rheumatic disorders. I hope `that thi's represents `at least the beginning of the type of support that many investigators will ob~ viously' need in order to evaluate the long term efficacy of an'tirheu- matic drugs. Clearly, we need a drug like `indo'methacin, and 1 hope to test indo- methacin with our newer methods of objective evaluation as these be- come available. Senator NELSON. Thank you very much, Doctor. We appreciate your coming to testify today. (The letter and supplemental information submitted by Dr. Calabro follow:) APRIL 23, 1968. Hon. GAYLORD NELSON, Chairman, Subcommittee on Monopoly, Senate Committee on Small Business, U.S. Senate, Washington, D.C. DEAR SENATOR NELSON: In anticipation of my participation in the congressional hearing of your committee on May 3, 1968, the following summarizes my experi- ence with the drug indomethacin and the role it has in the management of pa- tients with rheumatic diseases. Recent reports of double-blind studies o'f indomethacin in rheumatoid arEh'ritis (RA) `have caused considerable controversy concerning the efficacy of this drug as an antirheumatic agent. It is my opinion that while double-blind studies `are obviously useful in evaluating new agents, they are also extremely difficult, par- ticularly in such a capricious disease `at RA. To this point, I might `add that there are few (if any) double~blind trials with other antirheumatic agents that are entirely satisfactory. Even more appalling `are the apparent expectations of many investigators conducting short-term studies in RA that indomethacin would provide objective functional improvement. This is .a clinical misconception since all antireheumatic agents are at best palliative. By providing effective relief of joint p'ain `and in- flamation, `rugs allow patients to undertake therapeutic exercise and other sup- portive measures. These provide objective improvement. Yet, such measures re- ceive scant mention and do not `appear to be an integral part of the reported double-blind studies of iiidomethacin in RA. In spite of these controlled trials, many physicians have the impression that indomethacill benefits certain patients with RA. As Healey has recently pointed out in the Bulletin of the Rheumatic Diseases (18, 483, 1967), there' may be a sub-group of patients with RA that are controlled by indomethacin, a finding that PAGENO="0325" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3417 would not be evident when such patients are included in a general drug trial. To my knowledge, this hypothesis has not been tested. The result of our long-term evaluation of indomethacin in ankylosing spondy- litis (AS), a form of rheumatoid disease affecting young men, has recently appeared in the journal Arthritis and Rheumatism (1156, 1968). In this trial of indornathacin averaging 33 months in 28 AS patients who re- ceived an average daily dosage of 100 mg., the response to the drug was good in 21 patients, fair in 5 and poor in 2. Of the 28 patients, 21 improved to ARA functional class I. Before the use of indomethacin, only one of the 28 was so rated. Joint symptoms followed temporary withdrawal of the drug in all but four of the 28 patients. These symptoms were promptly relieved when indomethacifl was again taken by the patients. Clearly, our report parallels the experience of others, such as Bilka, Hart, Kass, Pohi, Rothermich and De Seze, that indomethacin is an essentially safe and effective drug in suppressing the articular manifestations of AS. That indometbacin has antirheumatic effects in disorders other than AS is also apparent, as judged by numeriotis reports of its usefulness in the manage- ment of the majority of patients with gout and osteoarthritis of the hip. I sincerely hope, despite the current controversy and confusion, that investiga- tive pursuits of indomethacin will continue. Only then can we more fully under- stand the role of this extremely useful and valuable antirheumatic agent. Best wishes. Very truly yours, JOHN J. CALABRO, M. D., Chief, Rheun'uttoiog~i Section, Wadsworth 1Io~pitai, Associate Professor of Medicine, UCLA School of Medicine. [From Arthritis and Rheumatism, vol. Li, No. 1 (February 1968), pp. 56-64] INDOMETHACIN IN ANKYLOSING SP0NDYLITIS (By John S. Calabro and Clemente M. Amante) (From the Division of Rheumatology, Department of Medicine, New Jersey College of Medicine. `Supported In part by Grant 2A-5148 from the National Institutes of Flealth, United States Public Health Service. `John J. Caiabro, M.D. F.A.C.P.: Formerly Associate Professor of Medicine and Diregtor, Division of Rheumatology. New Jersey College of Medicine, Medical Center, Jersey City. Currently Associate Professor of Medicine, UCLA School of Medicine, and Chief, Rheumatology Section, Wadsworth Hospital, VA Center, Los Angeles, Calif. 90073. Clemente M. Amante, M.D.: Fellow in Medicine, New Jersey College of Medicine, Medical Center, Jersey City.) Among the more promising newer drugs used in the treatment of rheumatic diseases, indomethacin occupies an important place. This nonsteroidal, anti-in- flammatory indole compound became available for clinical trials in November, 1961. Studies since then have variously evaluated its potential effectiveness in rheumatoid arthritis'9 Rei,ter's disease, ~ psoriatic arthritis, 1-1-0 anklyosing spondylitis, 1 5-10_12 gout,~34 rheumatic fever 15 and degenerative joint dis- ease. A number of studies 14 have pointed out that the best results with indomethacin were obtained with low dosages, and that even then, the incidence of side effects, such as dizziness, headaches and gastroentestinal disturbance, was unfortunately high Rothermich 117 has recently shown that even using dosages as low as 25 mg. daily, the physician must be on guard for the occasional patient who may develop gastrIc upset or even ulceration, or the unusual patient who is highly susceptible to cerebral side effects. It is well established now that with indomethacin, as with all antirheumatic drugs, dose-related side effects' may appear either early in treatment or when the drug is taken over a long period of time. 817 While our early experience with the drug yielded extremely variable results in peripheral rheumatoid `arthritis, far more predictable and satisfactory disease suppression was noted in ankylosing spondylitis (AS). Since then, and after reporting some preliminary results,58 we have maintained 28 AS patients on indo- NOTz.-Numbered footnotes at end of article, p. 3424. PAGENO="0326" 3418 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY inethacin in a clinical study that i~ now in its fifth year. A battery of laboratory tests was done before and periodically during this drug trial. Thus, we were able to Conibifle a long-term threapeutic evaluation of indomethacin with a continuous monitoring of possible side effects. MATERIALS AND METHODS The patient group. Only patients with active AS were selected for this study. They were 25 men and 3 women who attend the arthritis clinics of the Jersey City Medical center. They have been treated with indomethacin for periods ranging from 5 to 52 months, or for an average of 33 months (Table 1). On alalysis in April, 1967, the age of the Patients averaged 41 years, ranging from 20 to 58 years. The duration of disease averaged 19 years, ranging from 3 to as long as 36 years. Time mean age of the patients at disease onset was 24 years. The longest inter- val between onset and diagnosis was 25 years in one man, but the average inter- val proved to be 9 years. r1~he mode of onset was ifl:sidiOUs in iS patients and acute in 10. Initial involvement was found to be axial (spinal) in 14 patients, peripheral in 13 and systemic (with recurrent iritis) in one. Of 14 patients with axial onset, 12 had lumbar, one had dorsal, and one had cervical involvement. Of the 13 patients with AS of PeriPheral onset. 6 had involvement of the hi!), 4 of the knee. 2 of the shoulder, and one of the heel. Serial x-rays have disclosed bilateral sacroiliitis, apophyseal irregularities, and some degree of vertebral demineralization or squaring in all 28 patients. Three i~atients have associated ulcerativ.e colitis and two lTave regional enteritis. Major systemic manifestations in these 28 patients before the indomethacin trial included iritis in 6 patients, aortic insufficiency in 2, angina in 2, while one patient each had vasculitis and cauda equina involvement (Table 2). Per- sistent EKG :abiiormi~alities, chiefly in the form of conduction disturbances, were iioted iii 10 patients. Prior to the trial with indomethacin, one patient was in functional class I, 21 in class II, 5 in class III, and one in class IV (Table 1) ~ Previously of the 28 patients, 15 had taken aspirin (daily dosage 1.5 to 6.0 Gm.), 9 had re- ceived ihenylbutazone (100 to 300 mg), one oxyphenbutazone (300 mg.), while 3 had taken various types and amounts of adrenocorticosteroids. Indoniethacin dosage. The initial dosage of indom.ethacin administered to each patieat was 100 mg. daily, with 25 mg. capsules given after meals and at bedtime. Daily maintenance dosages were then adjusted to the lowest possible required for individual suppression of active articular disease. Adjunctive inca surc.s. such as physical therapy. were encouraged. But no medication other than the test drug was admhuistered except in one patient who was gradually being weaned from adreiiocorticosteroicls. The study design. Each patient was evaluated huitially, and again at weeks two, six and 12, and then at three-month intervals. At the initial visit, a (le- tailed work-up. including history, physical examination, x-ra ys, electrocardio- grain and a battery of laboratory studies, was performed on each patient. The patient's functional status was then assessed by means of the ARA Steinbroeker criteria.~ At each follow-np visit, careful histories were taken and physical examina- tions were performed omi all patients. In addition four parameter~ of disease activity were selected for initial and contimied assessment. The pa raineters were: 1.) joint pain, 2) duration of morning stiffness. 3) onset of fatigue and 4) joint mobility including spine ex- tension all(1 fiexiomi chest cage expan~i(ii amid range of motion of peripheral joints. To serve as a control phase, temporary withdrawal of indomethacin was carried out in all patients after they had been maintained on the drug for a period of at least three months. The drug was promptly readministered puce active di~ea se had recurred. Laboratory studies performed before indomethacin administration and each timae we saw the patients included serum SOOT, SGPT, alkaline phosphatase. cephalin flocculation. thymol turbidity, total biliruhin, total rurotein and A/G rstio, BUN. uric acid, paper electrophoresis, latex fixation and blood glucose. Of the last S patients admitted to the trial, serum studies included only a BUN, SOOT, uric acid, paper electrophoresis and latex fixation test. PAGENO="0327" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3419 Other studies performed initially and on each follow~up visit on all 28 pa- tients included a Westergren ESR, hematocrit, WBC and differential counts, urinalysis and a stool guiaiac test. At follow-up, patients were asked to report any adverse reactions to the drug. Upper 0-I series were performed on only those patients who had gastro~ intestinal complaints. X-rays of axial and involved peripheral joints and electro- cardiograms were performed yearly. An ophthalmologic evaluation including slit lamp examination was conducted on all 25 patients who had received indo~ methacin for more than one year. Evahtation of findings. Therapeutic assessments done at the end of the trial consisted of evaluation of: 1) ARA functional class, 2) the four selected param- eters, singly and collectively, 3) calculation of average maintenance dosage, 4) the withdrawal phase of the trial, 5) ESR values, (~) systemic manifestations, and 7) adverse reactions to the drug. The four selected parameters were ra:ted as improved when joint pain decreased in intensity, duration of morning stiffness diminished by at least one-half hour, onset of fatigue decreased by at least two hours, and the total range of joint motion increased by 25 per cent or more. We also devised an over-all therapeutic rating scale, whereby improvement in three or four of these selected parameters was graded as good, in one or two as fair, and in none as poor. PAGENO="0328" 3420 -J C-) 0 0 U- 0 CI, C,, 0 C,, a- U- 0 0 C.) E C,, -ø II E CC) IcC = .~ ~ E ~ - cC)g~ C,, a. COMPETITIVE PROELEMS IN THE DRUG INDUSTRY E ~ ii ~ .~ .. CC). E CO +++II+I+t +I++I+++I+++I++t+II it:: I++++++I+ II++I+I+++Iil++I++I +++++ I +++ + I ++ I + I ++++++++ I ++ +++++++ I + +++++++++++++++ I ++ I 000) CCJ - C~ CC) CC) CC) ~.. 00(00)0)0.4CC) ~ CC) U)0.4 0.4 ~ CC) - ~CC~J CC) CC) - -~ N. ~ - C') CCC -CC) 00 0) 00CC) ~ 0) 00~ U) CC) N- - CC) ~ N- CC)0) ~ (`4 N. 0)0) (`4 N-CO 0-40.4 CC) u~ C)CC)CC) CO C) CC) 0-400 (0 CC) CC) 0-4 0-40.4~ CC) ~ CC)C'4 CO CO - - - - - - >_ --- - >_ 0)0)0)000)0) - -~ CC) N. N. 000)0)0)00 ~CO 0)C'4 ,.~0o -.(0CO (0CC) 00-CO CC~ 0) C) CC)COCO~COCOLC) CO LC~~~22 2~OE~LL~ PAGENO="0329" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 3421 TABLE 2-SYSTEMIC MANIFESTATIONS OF ANKYLOSING SPONDYLITIS DEVELOPING DURING INDOMETHACIN TRIAL AVERAGING 33 MONTHS Numberot Numberof Systemic manifestations cases before cases during indomethacin indomethacin trial trial Iritis 1 6 3 Angina pectoris 2 0 [KG conduction changes 10 4 Aortic insufficiency 2 1 Foot and ankle ulcerations 0 1 Vasculitis 1 Cauda equina lesion 1 0 Total 22 9 11 patient had 3 bouts of iritis during the indomethacin trial, but had had recurrent iritis before this trial while receiving other antirheumatic agents. Two other patients experienced their first bquts of aitis while receiving inclqrpe~Ia~qip. RESULTS Indomethacin proved an effective suppressive agent of the articular manifesta- tions of AS in the present study, as judged by the foijowiug: 1. After treatment for an average period of 33 moi~tths, 21 of our 28 patients were in the most favorable functional class j,~9 as ~ompared with only one of 28 before utilization of indomethacin (Table 1). Of 5 patients in functional class III before the drug trial, 3 improved to class II, and 2 to class I. 2. Analysis of each of the four selected parameters revealed a decrease in joint pain in 25 of 28 patients (89 per cent), a decrease in the duration of morning stiffness in 22 (79 per cent), delay in the onset of fatigue in 17 (61 per cent), and an increase in joint mobility in 17 patients (61 per cent) (Table 1). Joint pain and morning stiffness diminished promptly after indometbacin was started, usually in 48 hours, or within one to 7 days. Alleviation of fatigue and improvement in joint mobility was less dramatic, taking from one week to 3 months, and occurring on the average within 4 weeks. After an average treatment period of 33 months with indomethacin, the over-all therapeutic rating of all four parameters was good in 21 of 28 patients (75 per cent), fair inS (18 per cent) and poor in 2 (7 per cent) (Table 1). 3. The average daily maintenance of indomethacin required for suppression of articular disease was 100 mg., the lowest was 25 mg. and the highest 200 mg. (Table 1). Only 7 patients needed more than 100 mg. daily, 5 with active hip or other peripheral joint disease, 2 because of marked axial (spinal) involvement. 4. When indometbacin was withdrawn, severe axial pain and morning stiffness recurred on an average within 48 hours in 24 of the 28 patients. Symptoms were promptly alleviated in all 24 patients when inclomethacin was readministered. Of the remaining four patients, two (Table 1, patients no. 25 and 28) did not respond to the drug and therefore exhibited no symptoms when indomethacin was withdrawn. Two patients (patients no. 15 and 17) had achieved remission. 5. The average Westergren ESR values for all 28 patients decreased during the drug trial from 3. mm, to 26 mm. (Table 1). The p value obtained from Student's t table is statistically significant at the <0.01 level after testing the average paired differences against zero for the ESR values before and after inclomethacin. ESR values were normal (15 mm. or less) initially and remained so in 8 patients (29 per cent). Eight other patients (29 per cent) attained normal ESR values by the end of the trial. Thus, normal ESR values were noted in 16 patients (58 per cent) while on indomethacin (Table 1). Only 4 patients had marked ESR values after the trial. Response to indometh- acm was good in 2 patients, fair in one and poor in one (Table 1). 6. While articular manifestations of AS were generally controlled with in- domethacin, certain systemic manifestations of the disease were not (Table 2). During long-term maintenance on indomethacin, iritis occurred in 3 patients, and multiple recurrent ulcerations of the left foot and ankle in one patient. The mur- mur of aortic insufficiency developed in one patient, while EKG conduction disturb- ances developed in 4 patients. Cauda equina involvement of three years' dura- tion in one patient, manifested by nocturnal incontinence, poor stream and dim- inished bladder and rectal sensation, did not improve with indometbacin. PAGENO="0330" 3422 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Despite suppression of articular symptoms In all but two of the 28 patients, serial x-rays of axial and involved peripheral joints disclosed progressive changes in the majority of patients. 7. A total of 13 side effects, often transient and usually observed during latter months of indomethacin administration, occurred in 8 patients on maintenance dosages of 25 to 200 mg. daily (Table 1). Each of the 4 patients receiving the daily maximum of 200 mg. had adverse reactions. Headache was noted in 4 of the 8 patients. Of the 4 patients with headache, one also had nausea, and another nausea and diarrhea. Two patients had dizzi- ness, one of whom also had nausea. Two other patients had nausea, one of whom also had diarrhea. All side effects disappeared spontaneously even though the drug was continued at the same dosage, except for 2 patients whose symptoms persisted until the daily maintenance of indomethacin (200 mg.) was temporarily reduced. Side effects did not reccur in these 2 patients when 200 mg. dosages of indomethacin were reinstituted at a later date. Upper 01 series, performed on the 5 patients with gastrointestinal side effects, revealed no abnormalities. Overt gastrointestinal bleeding did not occur, despite the intermittent presence of positive stool guaiac tests in 6 patients. There was no evidence of any ocular, renal, hepatie or bematopoietic side effects. There appeared to be no increased susceptibility to infection. Jndomethacin was discontinued in three patients. It was withdrawn in one patient (patient no. 25) with regional enteritis and active foot and heel involve- mnet because his response to indomethacin was poor, after having been tried on three different occasions over a six-month period. It was discontinued in another patient (patient no. 28) because of a poor response after 5 months on the drug. Both patients have been more adequately controlled with 300 mg. phenylbutazone daily. Indomethacin was temporarily discontinued in a man with associated ulcera- tive colitis (patient no. 18) when the patient developed multiple recurrent ulcerations of the left foot and ankle after he had taken 200 mg. of the drug daily for 36 months. But Indomethacin was resumed three months later after two biopsies of the lesion proved negative for vasculitis. The ulcer has now healed. DISCUSSTON Our most striking observation about indomethacin is the clear-cut benefit it seems to provide in ankylosing spondylitis. When indomethacin is used in other rheumatic disorders, such as rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome or juvenile rheumatoid arthritis, one cannot predict if a patient will benefit from its use.14~10-12 But as demonstrated in this study, and as suggested by other reports,1'8'4'6'9 indornethacin seems to be almost consistently effective in ankylosing spondy- litis. Despite this enthusiasm about indomethacin, it must be kept in mind that this drug, like other antirheumatic agents, does not specifically alter the under- lying disease process. Thus, while articular manifestations of ankylosing spon- dylitis are suppressed with indomethacin, systemic features appear not to be affected. The disease activity of most rheumatic disorders is usually reflected in the erythrocyte sedimentation rate (ESR), but this relationship does not seem to be as precise in ankylosing spondylitis as in rheumatoid arthritis.20 A possible correlation between disease activity and the ESR was suggested in this study, when more than half or 16 of the 28 patients either maintained or achieved a normal ESR value paralleling a favorable therapeutic response. This finding has not been reported previously. In most cases, ankylosing spondylitis tends to be relatively stable for long periods, so that the symptomatic effects of a single drug can be evaluated by using the patient as his own control. Consequently, when indomethacin was tem- porarily withdrawn, articular manifestations usually recurred within 48 hours, and were then promptly alleviated when indomethacin was resumed. Therefore, we agree with Kass ~ that it is not necessary to utilize complicated therapeutic experiments in a disease such as ankylosing spondylitis. But, since we did not use a double-blind crossover approach, including a placebo and other antirheu- matic agents, we cannot report any objective comparisons between indomethacin and other drugs useful in AS. Furthermore, we were convinced at the beginning of this study that the long-term administration of a placebo to patients with active disease and its attendant distress and discomfort cannot be justified ethi- PAGENO="0331" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3423 cally. Wallace and Ragan2t bad similar convictions about the use of placebo in patients with active rheumatoid arthritis. Despite the fact that the world literature now abound$ with warnings of the potential side effects of even small doses of indomethacin, none of our 28 patients were forced to discontinue the drug because of side effects. Indomethacin was stopped in 3 patients, in 2 because of a poor therapeutic response, and in the other only temporarily, when he developed infected foot and ankle ulcerations which proved later not to be due to the drug. Nevertheless, our findings support the view that side effects are most frequent among patients receiving larger amounts of the drug,'4 while they are also in agreement with the concept, stressed by Rothermicb,17 that cerebral side effects may occur on low dosages in susceptible individuals. All 4 patients on the highest daily indomethacin maintenance dosage of 200 ing. experienced adverse reactions to the drug, while 4 other patients receiving small daily dosages of 25 to 100 mg. developed headache and dizziness. Most drug reactions disappeared spontaneously, except in 2 patients whose side effects persisted until the dosage of indomethacin was reduced. The rather late occurrence of most side effects, though briefly mentioned else- where,3' has not been stressed prior to this investigation. Annoying headache or gastrointestinal upset were not seen soon after patients were started on indomethacin. In fact, the 13 side effects observed in 8 of our 28 patients usually occurred only after months and even a year or more of indomethacin administra- tion. In any case, close attention to minimal individualized dosages needed for disease suppression appears to reduce the occurrence of potential side effects. This has alsoi been the experience of Boardman and Hart.22 In conclusion, despite the fact that indometbacin has been found of consider- able therapeutic usefulness, we do not mean to give the impression that we are treating patients merely with drugs. On the contrary, we cannot emphasize sufficiently the overriding importance of treating the entire disease, particu- larly with physical, recreational and rehabilitative measures. All of thes~e are intrinsic parts of the overall management of the patient w ith ailkylosing spondylitis.'8 ACKNOWLEDGMENTS We are indebted to Dr. Rustom B. Mody, former Fellow in Rheumatology, for his early assistance in this study to Dr. Bertram W. Charap of the Mt. Sinai Hospital in New York City for ophthalmologic studies and to Mr. John Wykert of Science & Medicine Publishing Co., Inc., New York, for his assistance in the preparation of this manuscript. The indometbacin used in this study was supplied by Dr. Nelson H. Reavey Cantwell of Merck Sharp and Dohme, Research Laboratory, West Point, Pennsylvania. 5UMMARY Indomethacin was found to be highly effective in the management of 28 patients with ankylosing spondylitis in a clinical trial that is now in its fifth year. As judged by selected criteria, including joint pain, duration of morning stiffness, onset of fatigue and joint mobility, the response to the drug was good in 21 patients, fair in 5 and poor in 2. After receiving indomethacin for n average period of 33 months, 21 of the 28 patients were classified in ARA functional class I. Only one patient had been so classified prior to the drug trial. Joint symptons followed temporary withdrawal of the drug, but were promptly relieved when indomethacin was again taken by the patients. However, willie articular manifestations of ankylosing spondylitis were suppressed by indo- methacin, systemic features were not. Therapeutic maintenance doses of thdomethacin were carefully individualized. While the average daily dosage proved to be 100 mg., four patients with marked peripheral and axial joint involvement required 200 mg. daily. A battery of laboratory tests accompanied the entire period of the drug trial. These tests revealed no ocular, renal, hepatic or bematopoietic changes due to the use of indomethacin. Cerebral and gastrointestinal side effects, generally mild and usually transient, occurred most often after prolonged administration of the drug. Of the eight patients who experienced 13 side effects, 4 were taking 200 mg. of indomethacin daily. Side effects persisted in 2 of these 4 patients until their maintenance dosage was reduced. Otherwise all side effects disappeared spontaneously while the drug continued to be taken. PAGENO="0332" 3424 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EEFERENCES 1 Rothermich, N. 0.: An extended study of indomethacin. J.A.M.A. 195: 1102, 1966. 2 Norcross, B. M.: Treatment of connective tissue disease with a new non-steroidal com- pound (indomethacin). Arthritis Rheum. 6: 290, (Abstr), 1963. Katz, A. M., Pearson, C. M., and Kennedy, J. M.: A clinical trial of inclometbacin in rheumatoid arthritis. Clin. Pharmacol. Ther. 6 : 25, 1965. Hart, F. D., and Boardman, P. L.: Indoniethacin and phenylbutazone: A comparison. Brit. Med. J. 2: 1281, 1965. ~ Bilka, P. J., Woliheim, F., and Williams, R. C., Jr.: Indomethacin-a new antirheumatic agent. Minnesota Med. 47: 777, 1964. Thompson, M., and Percy, J. S.: Further experience with indomethacin in the treatment of rheumatic disorders. Brit. Med. J. 1 : 80, 1966. 7 Smyth, C. J.: Indomethacin in rheumatoid arthritis. A comparative objective evaluation with adrenocorticosteroids. Arthritis Rheum. 8: 921, 1965. Wanka, J., Jones, L. I., Wood, P. H. N., and Dixon, A. St. J.: Indomethacin In rheumatic diseases: A controlled clinical trial. Ann. Rheum. Dis. 23: 218, 1964. Pitkeathly, D. A., Banerjee, N. R., Harris, R., and Sharp, J.: Indomethacin in In-patient treatment of rheumatoid arthritis. Ann. Rheui~. Dis. 25: 334, 1966. 10De S~ze, 5., Ryckewaert, A., Kahn, M. F., and Solnica, J.: Résultats d'un essai contrôl~ de lindomdthacine en rhumatologie. Rev. Rhum. 32: 769, 1965. 11 Kass, E.: Indomethacin in ankylosing spondylitis. Acta Rheum. Scand. 11: 205, 1965. ii Pohi, W.: Zur inedikamentlisen Therapie der Sponclylitis ankylopoetica. Med. Kiln. 61: 921, 1966. ii Boardman, P. L., and Hart, F. D.: Indomethacin in the treatment of acute gout. Prac- titioner 194: 560, 1965. 7~ Smyth, C. J., Velayos, B. E., and Amoroso, C.: Influence of new antiinflammatory drug, indomethacin in acute gout. Acta Rheuni. Scand. 9 306, 1963. 10 Vignau, A. I., Correa, B. T., Guasch, J. L., Schuster, A. C.. Patri, A. M., Vaisman, S. B., and Mortimer, B. A., Jr.: The effects of indomethacin on rheumatic fever. Arthritis Rbeum. 8: 501, 1965. ~° Wanka, J., and Dixon, A. St. J.: Treatment of osto-arthrltis of the hip with indometha- cm: A controlled clinical trial. Ann. Rheum. Dis. 23: 288, 1964. 17 Rothermieh, N. 0.: An extended study of indomethacln. J.A.M.A. 195: 531, 1966. 18 Calabro, J. J., and Mody, H. B.: Management of ankylosing spondylitis. Bull. Rheum. DIs. 16: 408, 1966. ~° Steinbrocker, 0., Traeger, C. H., and Batterman, H. C.: Therapeutic criteria in rheuma- told arthritis. J.A.M.A. 140: 659, 1949. i° Boland, B. W.: Ankylosing spondylitis. In Hollander, J. L., ed.: Arthritis and Allied Conditions, 7th edItion. Philadelphia, Lea & Febigr, 1966, p. 633. 21 Wallace, S. L., and Ragan, C.: The problem of therapeutic evaluation in rheumatoid arthritis. Arthritis Rheum. 1 : 20, 1958. ~ Boardman, P. L., and Hart, F. D.: Side-effects of indomethacin. Ann. Rheum. DIs. 26: 127, 1961. *Dr. LAWRASON. Mr. Chairman, the second presentation to the com- mittee will be from a man with long experience in the problems of management of rheumatoid arthritis and other arthritic disorders, a man who has addressed himself to drug evaluation and a, leader in the professional society, the American Rheumatism Association. I would like to present Dr. Charley Smyth, a professor of medicine and head of the Division of Rheumatic Diseases at the University of Colorado School of Medicine. Incidentally, he is also past president of the American Rheumatism Association. Senator NELSON. Doctor, we appreciate your coming here today and your patience in Waiting SO long to testify. Your curriculum vitae will be printed at this point. Please proceed. (The curriculum vitae of Dr. Smyth follows:) CURRICULUM VITAE, CHARLEY J. SMYTII, M.D. Born: Mart, Texas, February 7, 1909. Education: University of Michigan, AB Degree, 1931; University of Michigan, MS Degree (Pathology), 1938; Jefferson Medical Ool'lege of Philadelphia, M.D. Degree, 1935. Internship: University of Michigan Hospital, 1935-1936. Residency: University of Michigan Hospital, Medicine, 1936-1938; Pathology, 1938-1939; Fellowship, Arthritis, 1939-1940. Professional appointments: Assistant Physician-Rackham Arthritis Research Unit, University of Michigan, 1939-1941; Medical Director-Wayne County General Hospital, Eloise, Michigan, 1941-1949; Assistant Director, Graduate and Postgraduate Medical Education, Univ. of Cob., 1949-1950; Director, Graduate and Postgraduate Medical Education, University of Colorado, 1950-1954; Editor, Rheumatism Reviews for American Rheumatism Assn., Part time 1956-1958. PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3425 Present position: Professor, Internal Medicine, University of Colorado, in charge of Rheumatic Disease Section, 1967-present. Academic appointments: Instructor, Internal Medicine, 1939-1942, University of Michigan, Ann Arbor, Michigan; Instructor, Internal Medicine, 1949-1950, Wayne University, Detroit, Michigan; Assistant Professor, Internal Medicine, 1949-1950, University of Colorado; Associate Professor, Internal Medicine, 1950- 1967, University of Colorado; Professor, Internal Medicine, 1967-present, Uni- versity of Colorado. Certification of specialty board: American Board of Internal Medicine, 1950. Hospital appointments: Consultant, Internal Medicine, Fitzsimons General Hospital, 1950-present; Consultant, Internal Medicine, Denver Veterans Admin- istration Hospital, 1950-present; Consultant, Internal Medicine, St. Joseph's Hospital, Denver, 1953-present; Consultant, Internal Medicine, St. Luke's Hos- pital, Denver, 1953-present; Consultant, Internal Medicine, General Rose Me- morial Hospital, Denver, 1953-present; Consultant, Internal Medicine, Mercy Hospital, Denver, 1953-present; Consultant, Internal Medicine, Presbyterian Medical Center, Denver, 1953-present. International, national, State and county organizations: Committee appoint- ruents, Board of Directors and Executive Committee, Arthritis F'ounciation (Na- tional), Vice President La Lingue Internationale Contre Le Rheumatisme, 1965- present. Professional society memberships: Governor for Colorado, American College of Physicians, 1960-present; American Society Internal Medicine, Committee on Academic Membership, 1965-present; Board of Directors and Executive Commit- tee, Rocky Mountain Chapter, ArthritIs Foundation, 1950-present; Central Society for Clinical Research, 1939-present; American Federation for Clinical Research, 1942-present; American Rheumatism Association, 1940-present (Pres- ident 1960); American College of Physicians, Fellow, 1951-present; Society Experimental Biology and Medicine, 1942-present; American Therapeutic So- ciety, 1958-present; Colorado Society of Internal Medicine, 1952-present (Presi- dent 1957-1958)~; American Society of Internal Medicine, 1957-1968 (Trustee 1967-present) ; Denver County and Colorado State Medical Society and the American Medical Association, active member, 1949-present; American Society of Clinical Rheumatology, 1960-present (President 1964). Honorary scientific societies: Sigma Xi, Michigan, 1939; Alpha Omega Alpha, Jefferson Medical College, 1935. STATEMENT OP DR. CHARLEY J. SMYTH, PROPESSOR OP MEDICINE; AND DIRECTOR, DIVISION OP RHEUMATIC DISEASE, UNIVERSITY OP COLORADO MEDICAL CENTER, DENVER, COLO. Dr. SMYTH. Senator Nelson, it is an honor. I am deeply grateful for this opportunity to present my views concerning the results of treating arthritic patients with indomethacin. My major responsibilities include the care of patients seeking relief of pain and disability in two large weekly arthritis clinics at the Colorado General Hospital. In addition, I see and examine, as a con- sultant, patients in the Denver Veterans Hospital, the Fitzsimons Army Hospital, and other unfortunate victims with various types of arthritis in other hospitals in Denver. I estimate in an average week, I pass judgment and recommend treatment upon 75 to 80 individuals affected with one form or another of arthritis. In the 30 years that I have worked with arthritic patients I have dealt firsthand with many new compounds. The most exciting and promising was cortisone, introduced in 1949. I witnessed the phenom- enal rise and slow decline in its popularity as the sad ill effects of its long-term use made their appearance in the clinics, on the hospital wards, and, unfortunately, at the autopsy table. Therefore, it was with great interest that I and many other of my colleagues in clinical investigations treating rheumatic diseases began studies with the promising new compound indomethacin in 1963. PAGENO="0334" 3426 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It had clearly been demonstrated in experimental animals. It looked as though it were more powerful than cortisone or any of the other then commonly used drugs in the treatment of arthritic patients. It soon became apparent that this drug quickly controlled the pain and inflammation of gouty joints. After treating 30 patients with acute gout and observing uniformly favorable results with minimal side effects we reported our experiences in Stockholm, Sweden, before the European Congress on Rheumatic Diseases in 1965. Other critical clinicians throughout the world have since confirmed these early stud- ies, and today there is general agreement that this drug is as effective and as safe as any other in the treatment of acute attacks of gouty arthritis. Our next effort in the area was to investigate patients with rheu- matoid arthritis of the spine. Dr. Calabro has told you of his investi- gation of this variety of arthritis affecting healthy young men in which the disease attacks mostly the spine. The results were excellent, and the drug was well tolerated. Many of these patients were confined to bed, but returned to gainful employment within weeks after the beginning of therapy with this new compound. Other investigators have made similar observations, and today there is no debate about the value of indomethacin in patients with rheumatoid arthritis of the spine. There is still some controversy about the use of indomethacin in rheumatoid arthritis. This is the great crippler and one of the com- monest of the rheumatic diseases. It is in this type of arthritis that the clinical investigator has the greatest difficulty in evaluating drugs, or indeed the effect of any procedure. I refer primarily, Senator, to the procedure called synovectomy that the orthopedic surgeons are now doing; that is, taking out joint mem- branes for this disease. We have had great trouble in deciding whether these procedures are really justified or not. They are being done throughout the world without any proof that they are actually bene- ficial to the patient. So the course of this disease, as you already have heard, fluctuates up and down, notoriously rises spontaneously and suppresses spon- taneously, whether you treat the patients or do not treat them. Further- more, it has been expressed repeatedly before your committee that there is no satisfaction or sense of security in the methods of testing either a surgical procedure (synovectomy) or a new drug that is handed to the clinician with the question: Is this or is this not an effective agent in this capricious, fluctuating illness? Our group undertook this difficult problem of attempting to evalu- ate rndomethacin in 1963. We devised a series of objective test&-not including the patient's symptom response-with the aim of express- ing a reliable opinion. These studies were based upon the best objective measurements available and conducted by an experienced clinician. To control our data further, we included periods of therapy using placebo capsules, during which neither the patient nor the doctor knew whether his patient was actually taking the real drug or a "dud" pill. In 1965 we published our experiences with 55 patients with rheumatoid arthritis treated with indomethacin. In that report we stated, "Indo- methacin suppresses joint inflammation and inproves joint function, but may require up to 2 to 4 months to obtain maximum therapeutic PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3427 effort." With 3 additional years of experience in treating more than 100 rheumatoid patients under the same rigidly controlled conditions of objective evaluation, I am still of this same opinion. As I have previously stated, but a point that must be emphasized, the course of rheumatoid arthritis varies continuously with spontan- eous flareups and remissions. Therefore, it is extremely difficult to obtain completely reliable data concerning the `benefit of any drug or procedure. We are continuously altering our objective tests, and we have recently devised a skin temperature device in which we will put a thermester, which registers joint temperature, directly on the skin over the joint to critically measure skin temperature to see if this can be a more objective measure of gaining reliable information in this area of clinical drug testing. Now, if I were to express an opinion abont the frequency with which responses occur in rheumatoid arthritis, recognizing fully these limitations which all of us agree to, I would say that 20 to 25 percent of rheumatoid patients treated with adequate doses of this drug do show objective improvement; an additional 20 to `30 percent report symptomatic relief. I think it should be stressed that when a reliable investigator ad- ministers this drug to his patients, the result's in indomethacin response are definite; you do not need the statistician to tell the experienced clinician that his patient is better. For this reason I am convinced, as are many other reliable observers who care for rheumatoid patients, that indomethacin is effective in some cases when other agents have failed. It is claimed by some observers who have appeared before this committee that peptic ulcers are common in rheumatoid patients treated with this drug. I would stress that this is true of any effec- tive anti-inflammatory agent. In other words, if aspirin or any other commonly used antirheumatic drug is taken, it is potentially ulcero- genic or potentially an ulcer-forming agent. My colleagues at the University of Colorado and I have analyzed on our own initiative, because of our interest in the scientific question: Is indomethacin ulcer- ogemc? We have analyzed now 299 patients treated with indomethacin at the University of Colorado Medical Center during the past 5 years. As a control, we took 65 rheumatoid patients in the same clinics who had received aspiriil or other commonly used antirheumatic drugs. This statement I would like to emphasize and bear down upon, because I th'ink that it is the first comparative study that has ever been re- ported. There was no difference in the frequency of peptic ulcers in these two groups of patients. These studies do not support the view that indomethacin is ulcerogenic. In the final analysis, it is the arthritic patient himself who decides if any drug is worth taking. If he does not ~et relief from his joint aches, pains, and stiffness, from a prescription, his physician hears about it on the next visit. It is not the advertising campaign of the drug manufacturers that convinces the practitioner of the virtues and safety of a new drug. His judgment of the benefits and reliability of a drug is based upon his own personal experience gained from listening to and examining his patient. Senator NELSON. Are you referring to all drugs? Dr. SMYTH. I did not say so, sir. I could broaden that if you wish me to say so. PAGENO="0336" 3428 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Oh, no. You said that, "It is not the advertising campaign of the drug manufacturers that convinces the practitioner of the virtues and safety of a new drug. His judgment of the benefits and reliability of a drug is based upon his own personal experience gained from listening to and examining his patient." Dr. SMYTH. I think I will qualify that to arthritic drugs, sir. Senator NELSON. Thank you. Dr. SMYTH. As I look at indomethacin from the vantage point of 5 years of practical e~perience, coupled with my knowledge of the many reports from other parts of the world, this drug has established a place in the treatment of arthritic patients. Furthermore, it has achieved a reasonable degree of both patient and physician acceptance in large-scale clinical use, which, in the final analysis is the only true test of any therapeutic agent or procedure. I ~vOuld be handicapped in the management of many arthritic patients without this drug. (The attachment to Dr. Smyth's statement follo~vs:) MnDronrlc-AN AliT AS 1Vhi~L AS A ScIENcE In spite of the truly miraculous advances in the sciences of chemistry and pharmacology that synthesize and bring from the laboratory to the doctor new drugs for trial, there are still some faQtors that are unique in determining the true value of a new drug in a human being. The practice of medicine is not a pure science; it is both an art and a science. In men and women with arthritis of rheumatoid type there is no simple magic test that gives us yes and no answers. Unfortunatel~r, as of now, this is not so. Judgment or medical opinion in weighing the effectiveness or the lack of it with a drug like Indomethacin is based upon experience and previous responses using other, better understood anti-rheumatic agents. Dr. SMYTH. I am extremely grateful to you, Senator Nelson, for permitting me the opportunity to appear before your committee. Th~tnk you very much. Senator NELSON. Doctor, the committee appreciates your taking the time to come here and testify. As to your ]ast sentence, I hope you do not have the impression that we ha\re had witnesses from the FDA and elsewhere who said that indomethacin should not be in the marketplace. Dr. SMYTIT. This is my impression, from the testimony of FDA and others included, that this drug should not be used, medical evidence notwithstanding. Senator NELSON. You mean it is your opinion that testimony has been presented that this drug should not be available to the public? Dr. SMYTH. Yes. Senator NELSON. No; I thought in the last sentence, there was an indication that you believed that witnesses before this committee rec- ommended that the drug be taken off the market. Dr. Si~rrrH. Senator, these remarks have been prepared in Denver. They appear exactly as printed. Senator NRLSON. I though you had the impression that some of the witnesses were saying this drug did not have any value. But, the gen- eral consensus, as I understood it from the witnesses who have testified today and on previous days, is that this drug has an appropriate place in the physician's armamentarium. Mr. GORDON, Doctor, I just want to ask one question. PAGENO="0337" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3429 I read an article by you in a magazine called Consultant, issue of April 1967. It is entitled, "Treating Rheumatoid Arthritis, What Is Most Apt To Succeed?" You discuss steroids and the value of short-term treatment. You discuss phenylbutazone as a drug for the management of rheumatoid arthritis, the antimalarials, gold, orthopedic surgery. But except for mentioning indornethacin in passing, you do not discuss that at all. Why? Dr. SM~rH. There is a limit to which you can go in an article of that type. It is very restricted, was highly edited by the editor of this journal, Consultant. I just did not have enought time to amplify my opinions about indomethacin in that brief report. I think my presenta- tion today before this committee explains my position much more fully than I was able to do at the time this article was written. Mr. Goiuiox. Thank you. Senator NELSON. Thank you, Doctor. Mr. GADSDEN. Is it your wish that I should continue? I will be the final witness for Merck. Senator NELsON. Please proceed. STATEMENT OF HENRY W. GADSDEN, PRESIDENT, MERCK & CO., INC., RARWAY, NJ.; ACCOMPANIED EY LLOYD N. CUTLER, SPECIAL COUNSEL, WAS}IIN~TON, D.C. Mr. GADSDEN. Thank you, sir. I would like again to express my appreciation for my associates and myself for the early opportunity to get this on the record. I would like first to explain why I plan to focus my remarks before the committee on advertising and promotion. I am a layman, and it seems appropriate that the medical and scientific issues of interest to you should, be discussed by the most highly qualified professionals. I do not feel that I could add anything to the profile of "Indocin" that has been drawn today by Dr. Beyer and Dr. Lawrason. On the other hand, the philosophy that animates our advertising and promotion is not only a subject of continuing concern to me, but also one for which I can properly accept a very direct responsibility. As president of Merck, I wear many hats-one as chairman of our new products committee. That committee, as one of its major respon- sibilities, seeks to make sure that the marketing profile of a drug corresponds in every respect to its medical profile. It is Merck's policy to avoid the possibility of including any ques- tionable statement or theme in any of our advertising or promotion. The mere fact that any point is validly challenged, in or out of the company, leads us immediately to change or remove the point under discussion. I have repeatedly made this policy clear to my associates, as the following excerpts from my memorandum of May 1966 to top executives of the company will make clear: We seek to convey through both the parts and the whole of each advertisement a factual message which Will be useful and Interesting. Never must the ad seek to Obscure a blemish for the sake of over all appeal. * * * We seek to provide sharper focus and greater perspective so that the reader, viewer, or listener will make his own decision. These principles are so cardinal to the success of our operations as to warrant periodic re-emphasis. * * * Please take this occasion to re-indoctrinate all of your people who have a responsibility for our advertising, and follow this up with reminders at appropriate intervals. 81-280-68-pt. 8-22 PAGENO="0338" 3430 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY More specifically, our internal procedures require that every piece of advertising and promotion must have the approval of a physician and a lawyer, who are responsible for its medical accuracy and con- formity with law. When it concerns a new product, it also undergoes final review by the new products committee. The safeguards are necessary and proper. But I would not have you think that I conceive of advertising and promotion primarily in negative or restrictive terms. Properly carried out, it serves an altogether good and socially valuable purpose. Through the process of discovery we have described for you, making a drug available is only the first long step toward the objective of having it used by those patients who need it. This objective can be attained only if physicians are aware of the availability of the drug, know what it can do, what its limitations are, and what undesirable effects may accompany it. Furthermore, we believe that this informa- tion should reach the physician as quickly as possible. The public interest would be poorly served if patients were denied the benefits of a good drug simply because its availability was not known. Merck's experience with Benemid, a product for the treatment of gout, illustrates how marketing decisions can have social value. When we introduced Benemid in 1951, we felt that it was a major product because it forestalled attacks of gout instead of merely giving relief after an attack. Sales did not approach anticipated levels for years, apparently because there were simply not sufficient cases of gout. We continued to inform physicians about it, however, in the belief that gout was more prevalent than sales indicated. The past 8 years have justified this belief. The estimated number of cases of gout under treatment has risen from fewer than 350,000 in 1959 to approximately 1 million in 1966. Obviously, the incidence of gout has not increased threefold since 1959. Mr. GORDON. Is this due to your advertising? Mr. GADSDEN. As I am going to say, Mr. Gordon, in the next sen- tence, we would like to take partial credit for increasing the awareness of the symptoms of gout. Recognition and subsequent treatment of gout have increased-due in part, we believe, to our communications program. I have described the precautions we take with our advertising. Nevertheless, an occasional advertisement does run into trouble with the FDA. I think the reasons can be found primarily in the changing regulatory climate, and in the turnover of officials responsible for interpreting and applying the advertising regulations. As official attitudes have become increasingly critical of the motives and methods behind the advertising of prescriptiQn drugs, more and more companies have been embroiled in disputes with the FDA. However, questions of interpretation to one side, Merck hopes and believes that the agency shares our belief that responsible and effec- tive promotion is a necessity. It is particularly necessary in the case of a drug which offers the possibility of benefits to patients suffering from conditions for which there is as yet no fully effective or satis- factory method of treatment. Arthritic disorders represent just such a condition. Some patients obtain little or no relief from drugs which are available; side effects limit the benefits others may obtain. The availability of a new drug which can help those who cannot obtain relief from other measures becomes important. PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3431 As Dr Donald F Hill stated in his presidential address to the American Rheumatism Association in June 1961 Our patients come to us discouraged Arthritis is a discouraging disease Too many of our patients aie further discouraged by what the doctor tells them Too many of them hear him say There is not much we can do for you Our failure to keep up with, and apply, the latest treatments and medical information in arthiitis may not have final and fatal results but if it means the difference between a useful and productive life or a life as a cripple the point may be lost on the patient' It is true that a company promotes a drii~ in order to sell it But such a statement is an oversimplification which ignores the full facts A drug sells because it is promoted, and because physicians are fanul iar with it, and finally because they have found that it fills a real need in their practice That Indocin does fill such a need in medical practice has been amply demonstrated The purpose of clinical investigation is to assure safe and effective medicines Added evidence that we have provided such a medicine in Indocin is to be found in the high refill rate of prescrip- tions for this drug. Because it is a useful drug, it deserves appropriate promotion We have promoted Indocin in many ways, but have consistently sought to follow the principle of supplying accurate and useful infor mation in a manner complying with our understanding of the regulations When Indocin was first made available in this country, we had accumulated experience based on nearly 5 years of investigation by more than 300 physicians in the United States and abroad, as well as extensive experience gained from overseas marketing. Our best knowl- edge was incorporated into our promotional materials. The initial promotion pieces very clearly stated that in patients with rheumatoid arthritis, ankylosing spondylitis, arthritis of the hip, and gout-the four indications for which the safety and effectiveness of Indocin had been established-overall improvement considered to be excellent or good had been reported in 65 percent of those patients This not only established the usefulness of the drug to the physician but, equally, it advised him that the drug had limitations and could not be considered effective in all patients Furthermore, prominently presented in these promotional pieces was a table showing the incidence of adverse reactions It not only listed those adverse reactions the physician could expect to encounter, but what their prdbable incidence would be. And it also included the statement: In about 10 to 15 percent (of the patients) adverse reactions may be of a severity requiring dosage reduction or discontinuance of therapy After the introductory phase of our promotional efforts, and as physicians became more familiar with the drug, our themes were varied, but our presentations continued to include the limitations of the product In many of the advertisements the negative aspects 0± the drug actually consume the bulk of the text As my scientific colleagues have stated, many, if not most, distin guished rheumatologists believe that the use of objective measurements alone in arthritic disorders fails to take adequately into account the 1 Progress for the Patient Hill Donald F M 1D Arthritis and Rheumatism vol iO No 5 (October 1067) PAGENO="0340" 3432 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY disease process involved. And even more importantly, the use of these measurements alone ignores the subjective benefits enjoyed by the patient. No claim has ever been made that Indocin has any effect on the basic disease processes involved in arthritic disorders, The only claim made has been that in some 65 percent of the arthritic patients who are placed on Indocin, their stiffness, swelling, tenderness, and pain-which are manifestations of their disease-are relieved. These are the reasons that these patients seek medical help, and the relief of these symptoms is an important benefit to the patients and a source of satisfaction to the physicians who have prescribed the drug. There is nothing new about the purely statistical approach---as opposed to the clinical approach-to the measurement of the effective- ness of a drug such as Indocin in conditions such as arthritic disorders. Few physicians would dispute that the corticosteroids can provide dramatic relief to many arthritic patients in whom all other measures have failed. Yet in 1960 the following statement appeared in the journal, Annals of Interna~1 Medicine: Reports of the Medical Research Council and Nuffield Foundation and the Empire Rheumatism Council indicated no significant difference in results of treatment between two groups of patients, one on cortisone and the other on aspirin. HOwever valid these results statistically, purely functional therapeutic effects of steroids iii certain individual patients were still impressive. Since none of these drugs affected the disease fundamentally, the question was whether cortisone had not in some instances enabled the patient to "get more out of life," though happiness is not a scientific quality. The education of the physician is long and intensive. I think it is fair to say that to succeed in the practice of medicine, much more than in most professions, one must be able to make valid judgments of cause and effect. On the basis of his training and experience, the physician tries a drug in a patient. On the basis of his observation of the effect the medicine produces, he decides whether to continue it. His attitude toward the drug, and certainly toward the promotion relating to it, is continuously watchful and thoughtful-just as it is toward his patient. For example, the physician must evaluate the history of the patient's complaints, determine the significance of his findings on physical examination, and assess the results of laboratory tests before he can arrive at a diagnosis. Equally, he must be critical of the results he obtains from any therapeutic regimen. And if for any reason he is not, you can be sure that his patient will be. I wonder if any of you gentlemen on the committee or its staff ever have suffered from a recurring pain? Speaking as one who has, I venture the opinion that you could not be deceived-certainly not for long-about whether a drug gave you relief. Well, the patient with arthritis comes to his physician for relief. If he does not receive it, he will want an explanation~ or else he will seek relief elsewhere-regard- less of the drug advertising his doctor may be exposed to. To suggest that a physician is uncritical is completely to ignore the realities of the situation. Promotion may assure a physician's interest in a drug, but promotion cannot substitute for results. There is no doubt in my mind that when physicians feel there is a need for a new drug in their practice, promotion can induce them to try one that offers promise. It is equally certain, however, that promo- 1 "Thirteenth Rheumatism Review": Annals of Internal Medicine, vol. 53, No. 7, Dec. 30, 1960, p. 49. PAGENO="0341" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3433 tion cannot persuade them to continue prescribing the drug unless they themselves find that it fills a real need in their practice. Indeed, the history of medicine is replete with examples of drugs whose early promise was not fulfilled, and whose sale's were equally unsatisfactory. Senator NELSON. I would like to make the `point, however, that chlor- amphenicol is one item which was heavily promoted, arid the promo- tion was very effective; there is no question about that. The promo- tional activities were effective and there were disastrous results because the drug was prescribed and used for nonindicated cases. `That is part of the issue on which we have been conducting hearings here. Certainly the doctors got dramatic results. One of the distinguished physicians testified-I think it was Dr. Dameshek-that he had a patient who h'ad been taking chioramphenicol prescribed for a cold. 1-us patient told him that the doctor told her to take it borne, put it on the bathroom shelf, and take it every time she had a cold. It sure wiped out the cold for all time, but it killed `her, too. T'his is one dramatic case where the promotion of the drug resulted in a vast overprescription of the drug, which caused Dr. Goddard to say before this committee, "I am at my wits end" as to how to persuade doctors not to use this drug for nonindicated cases. rFhat i's wha:t the hearings are about, the effectiveness of the promo- tion of drugs. Here is a case where the promotion has been fantastically effective, with disastrous results for many, many patients. I have scads of letters in my office from people about relatives who have died from taking this drug. One doctor prescribed it because he had been told by a detail man that there were no `side effects. He prescribed it for his son for a minor infection. The child developed aplastic anema and died. Well, the evidence is that promotion is effective and very often doc- tors do not pay any attention to the precautions that are written in the labeling and that very effectively, in their advertising, drug compa- nies manage with the cleverest advertising agents in America, to kind of skip over the side effects. We had testimony on the advertising of your drug on this exact point. Yesterday we heard testimony that in JAMA, the language used was that Indocin was "(a) drug of choice." Mr. GADSDEN. Yes~ sir. Senator NELSON. Well, everybody knows that the phrase "drug of choic&' are words of a~rt in the medical field and that they have a very special meaning and that to put the word "a" in brackets does not pre- vent doctors from thinking that it is "the" drug of choice. I think it is misleading. But in any event, I have seen example after example of the very clever wording which is aimed at playing down side effects, playing down contraindications, and expanding claims for a drug's use. I am not criticizing your company especially. I think every `single company I have looked at that uses ads does not tell the story as ac- curately in the ad as they tell it in the package insert which has to be approved by FDA. Mr. GADSDEN. Senator, if I may respond-you can understand, I imagine, my continued sensitivity to perhaps the inadvertent reference to chioramphenicol within the context of our discussions about in- PAGENO="0342" 3434 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY domethacin. So I would like to read something to that point into the record. Senator NELSON. The reason I referred to it is that your language was in the most general kind of terms as were used for chloramph.eni- col or many other drugs. Qhloramphenicol happens to be one of the dramatic examples heard before the committee, standing unrefuted by the company or anybody else that I know of, of the wide misrepre- sentation of a drug because of the type and intensity of promotional activities. Mr. GADSDEN. But I think there is a differentiation between the point that I was making, which related to effectiveness-the patient and the physician cannot be fooled over an appreciable period of time by an effective drug-and the issue which you raised about whether the physicians did or did not pay attention to whatever might have been known about the safety of chloramphenicol. Senator NELSON. Well, I would suggest that they were not fooled in this case over any period of time about an ineffective drug. It was a dramatically effective drug, but was being used for the wrong pur- pose. It no doubt had an effect on infections, but it also may cause fatal aplastic anemia. It was just being incorrectly used. Mr. GADSDEN. With your permission, may I make a statement on this point? Senator NELSON. Yes. Mr. GADSDEN. Chloramphenicol is an extremely potent antibiotic drug with a propensity to cause aplastic anemia which often results in a fatality. Indomethacin has no adverse effect even remotely ap- proaching this condition. Chloramphenicol, although uniquely valuable for some infectious diseases such as typhoid fever and staphylococcus infection, can often be replaced in the case of other infectious diseases by different antibiotics with less severe side effects. Indomethacin, on the other hand, does not have greater adverse effects than most of the other drugs available for treating certain classes of arthritic disease. Moreover, patients suffering from arthritic diseases do not uniformly respond to the same drug. While it may be that aspirin has fewer adverse effects than indomethacin in the massive doses needed to treat rheumatic disorder, although this has not been proved, there are many arthritic patients who cannot tolerate aspirin or who do not respond to it. Dr. Hodges estimated the number who cannot tolerate aspirin at 25 percent. Many such patients do respond to indomethacin and do not suffer greater adverse effects than those caused by other, alternative treatments. Dr. Hodges has summarized for you the many severe side effects that result from the corticosteroids, the butazones, the antimalarials, and gold salts, and you can see that indomethacin compares favorably with any of these alternatives. Accordingly, any suggested parallel between indomethacin and chloramphenicol is, in my opinion, extremely farfetched. Senator NELSON. Has anybody suggested a comparison? Mr. GADSDEN. Sir, I am paraphrasing. Senator NELSON. I have not suggested a comparison? Mr. GADSDEN. I apologize for my undue sensitivity. PAGENO="0343" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3435 Senator NELSON. I want to make it clear for the record that I was responding to a statement in your testimony that had nothing to do with indomethacin in particular, or any drug in particular. The sentence was: "It is ec~ually certain, however, that promotion cannot persuade them"-that is, the doctor-"to continue prescribing the drug unless they themselves find that it fills a real need in their practice." Part of these hearings is directed to the question of the promotion. The point I was making is that you, again, persuade them by promo- tion to use a drug in their practice that is effective for the purpose for which they use it but should, for the sake of safety, be used with much greater discretion. That is my comment. I was not comparing it with indomethacin at all. Mr. GAD5DEN. There is one other point that you made, Senator. Referring to the quote which did, in fact, appear in our ads-this was a factual quote from a recognized authority. Senator NELSON. Which quote? Mr. GADSDEN. The one about "a drug of choice." In fact, the actual quote says, "the drug of choice." Under AMA editorial policy, they do not permit you to say "the" drug of choice; so if you check our advertisements, you will find that we ran both advertisements. In the JAMA, we said "a drug of choice"; in the others, we used the language of the quote itself, which is, "the drug of choice." I would furthermore like to call your attention to a quotation of 1967 from the recognized publication, New Drugs, as published by the AMA. It says that because "Indocin" has produced relief in acute attacks within 48 hours, and because it lacks the untoward effects of Colchicine, some physicians consider it to be the drug of choice for these attacks. Shall I proceed, sir? Senator NELSON. Yes, go ahead. Mr. GAD5DEN. Mr. Chairman, Indocin has demonstrated its ability to fill this need in the practice of physicians, both in this country and around the world. If it did not fill a need, the past 3 years of ex- perience with it would have clearly demonstrated this fact. I do not challenge the sincerity of some who have said that in our promotional efforts we made some errors. Language is not a perfect method of communication, and it may well be the words and phrases that we used in the belief they meai~t one thing may have been inter- preted by some physicians to mean something else. Such are the com- plexities of semantics. But this was never done purposely, and when- ever any possibility of misunderstanding was called to our attention, we moved promptly to correct it. If we have made errors, they were only minor ones, and to the degree that they existed they were hemmed in by the total emphasis given to the relative effectiveness, safety, and limitations of the drug. We responded immediately to negative comment by the FDA, and the advertisement which they complained of has not appeared since November 166. We took this action primarily from a prudent desire to cooperate with the Agency. We hope that upon the completion of the computer tabulations of our entire patient data, we can discuss with the Agency the renewed use of such claims as "Extends the margin of safety." Senator NELSON. What does the phrase, "Extends the margin of safety," mean? PAGENO="0344" 3436 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GADSOEN. In the context in which this was discussed, in the ad- vertisement and as positioned by our scientists and medical personnel based upon their own knowledge and primarily that of clinical investi- gators, when compared to the drugs which have been mentioned here before, butazones and corticosteroids, it says that more patients can be treated with Indocin with fewer side effects. Senator NELSON. That is what "extends the margin of safety" means in this case? Mr. GiUSDEN. Yes, sir. Senator NELSON. Please continue. Mr. GADSDEN. Indocin has established its place in medical practice because it has demonstrated effectiveness in many patients with cer- tain arthritic disorders, at the same time being relatively safe for most patients to take over the long periods of time they must remain under treatment. In closing, I would like to make one general point. Merck has been making and marketing a lot of drugs for a long time. It has been a point of pride with us-and an essential element in our success-to provide good, reliable information on these drugs and their proper use. The record will show that out batting average has been very high. And the people who have benefited from them are, I submit, the best evidence of the social values of our products and the way we market them. Mr. Chairman, thank you again for the opportunity of appearing before you. If you have any further questions, my associates and I are at your disposal. Senator NELSON. Thank you, Mr. Gadsden, for your very thoughtful contribution to these hearings. I believe the minority counsel has a question. Mr. GROSSMAN. Yes, Mr. Gadsden. I would like to ask you about the article that appeared in Pageant. I think that the company issued a release yesterday, `but I would like to get it clear for the record, be- cause that matter did not go into the record. I would like to know first of all, and I think you can make a general statement if you wish, but first, is it true that Merck & Co. in no way initiated that article or paid for it in any way and that these people were completely acting on their own. Is that correct? Mr. GADSDEN. We neither initiated nor paid for nor stimulated it, nor did anything except what I referred to in my earlier testimony. Mr. GROSSMAN. So in other words, for the record, so that we have it clear, there was no dealing with Pageant magazine or with the authors of the article? Mr. GADSDEN. No, there was not. Mr. GROSSMAN. May I ask you, is soliciting material from you com- mon procedure among individuals who write these articles ~ Do you think there is any way of controlling this? Is it an abuse that industry can handle? Mr. GADSDEN. I think we are into an area here which is very difficult, if I may be presumptuous, for you or for us on what to say or what not to say. In other words, we have a free press in the United States. You have recognized scientific writers who quite naturally wish to in- form the public upon what they consider interesting developments. We have to toe a very close line as between deciding that we will withhold PAGENO="0345" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3437 information from the press com~letely and thereby run the risk that what is printed is completely misleading, as contrasted to using our best judgment as to what we should supply in the interest of a balanced presentation. Mr. GROSSMAN. What are your general feelings about articles that reach beyond the doctor, such as this one; in other words articles di- rected at the general public? Mr. GADSDEN. This is the type of article to which I am referring. So that we may be completely clear, when I say "science writers," I am referring to science writers for lay publications as contrasted to pro- fessional journals. Mr. GROSSMAN. I agree with your point about the freedom of the press. I am just getting a general impression of what you think about this. Mr. GADSDEN. Well, I guess I am fairly pragmatic on this subject. Regardless of whether we think it is appropriate or inappropriate, the fact remains that the public ha~ become increasingly interested in any- thing to do with health. There have been any number of articles. I think that within the restraint under which we must place ourselves- one is that we must dbviously comply with the food and drug regula- tions and other laws of the land-within our interpretation of that, we should attempt to see that what appears in print is as factual as possible. Mr. GROSSMAN. One other question in a different area. There has been some testimony and some inference that there is no truly inde- pendent research being done, in the sense that there is an inherent con- flict of interest, almost, in that you have firms to do your clinical re- search and report their objective findings. I wonder what comments you might have on idea that, for example, the Government might select that specific consultant for the company, the company would pay for it, and submit the findings to the FDA for approval? Mr. GADSDEN. First, as temperately as possible, I would like to resent the implication that a company such as Merck either could or would attempt to doctor the results. Mr. GROSSMAN. That is not my question. Mr. GADSDEN. I realize that. I just want to get that on the record, if you will permit me, because we have been in business for a long time and we could not risk our reputation this way, even if we could "buy results." Now, some of the previous witnesses before this committee have raised a question as to the integrity of the drug companies or the clinical investigators, who in the main are connected with acad.mic institutions. Well, on their behalf and gratuitously, I resent it for them, too. Also, one of your witnesses before this committee raised some rather serious doubts in his testimony about whether civil servants would assume the responsibility of making a decision if there were a gain-risk balance, and someone had to assume the responsibility. Mr. GROSSMAN. I think this is the FDA's decision. Mr. GADSDEN. I think what I am suggesting is that we are pretty soon in a never-never land. There may be a fourth party, but I cannot identify it at the moment. Questions have been raised as to whether the pharmaceutical companies can do it, or whether it can be ap- PAGENO="0346" 3438 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY propriately done under grant by academic people; now we have finally completed the circle by saying that, in the opinion of at least one witness, there is question as to whether someone who is a Government employee will assume this degree of responsibility. I am frankly lost with this kind of, if I may, sophistry. In our opinion, the procedures which have been described by my scientific colleagues have, in fact, yielded very good results, This is what I referred to in my statement. We are in the happy position-in regard to these products which Dr. Tishler has described, starting with the vitamins and bringing it up to date-that there have been very rare occasions when the initial positioning of a Merck product had to be seriously modified based upon experience in the marketplace. Mr. GROSSMAN. Thank you. Senator NELSON. Thank you very much, Mr. Gadsden. If you have any additional pertinent material which you have neglected to give us for the record today, the record will be open for another week. If at any time in the course of these hearings, you wish to make any contribution concerning any issues raised before the committee we shall be pleased to have your material. Mr. GADSDEN. Thank you for that opportunity, Senator. Even before these hearings, in the telephone conversations which I had with Mr. Gordon-I think that Mr. Cutler has had subsequent ones-we asked for the opportunity, if it seemed appropriate, to file supplemen- tary statements based upon testimony that was given between the time we prepared our statements and our presentation `here, because we had to do this on very short notice and we compressed it within a limited period of time. (Subsequent correspondence and supplemental statements were sub- mitted `by Merck & Co., Inc., and follow:) MERCK & Co., INC., Rahway, NJ., May 14, 1968. Hon. GAYLORD NELSON, Chairman, $ubcommittee on Monopoly, select Committee on Small Business, U.S. Senate, Washington, D.C. Dear SENATOR NELSON: I am enclosing several supplementary statements for inclusion in the record of the hearings of your Subcommittee relating to `Indocin'. We appreciate your willingness to permit us to file these supplementary state- ments and your recognition that we could not deal in our prepared statements with the testimony of witnesses who immediately preceded us. We believe that the testimony we presented on May 3 and the statements of Dr. Hodges, Dr. Rothermich, Dr. Calabro, and Dr. Smyth constitute a sufficient response to most of the testimony of the academic witnesses who testified on April 23 and 24. We have prepared, however, and submit herewith supplementary material bear- ing on two aspects of Dr. O'Brien's testimony: an internal memorandum by Dr. Hiirwitz of the FDA, apparently overlooked by Dr. O'Brien, which revises the views Dr. Hurwitz expressed in an earlier memorandum that was critical of the clinical studies with `Indocin' and that was quoted from at length by I)r. O'Brien; and a statement of Merck's policies and procedures in the support of clinical investigation. In connection with the May 1-2 hearings, we are also submitting supplementary material related to the testimony of Dr. Jennings and Dr. McCleery of the Food and Drug Administration, who dealt primarily with the content of our labeling and advertising and with our performance in promoting `Indocin'. Implicit in Dr. Jennings' and Dr. McOleery's testimony were suggestion's that the Company and its executives acted on the basis of motivation to overstate claims, minimize adverse effects, expand use of the drug beyond allowed claims, and resist efforts of the Food and Drug Administration to enforce proper stand- ards of communication to doctors. PAGENO="0347" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3439 It is difficult to present objective evidence in rebuttal of these subjective impu- tatioris We would remind the Subcommittee however that there is a common sense and e'~sentia1 logic in our position that any such motivation would mcvi tably damage our reputation with the doctor and the patient and would be detri mental to our business interests in the long run Since our business is uniquely dependent on what the health professions thmk of or character and reputation it would make little sense for us to engage in this kind of conduct-and we do not do so. . As I said in my direct testimony it is not the Food and Drug Administration that is ultimately responsible for the safety and effectiveness of our products including the information we give to the doctor about them. It is we who must bear that responsibility and who must suffer the consequences of failure This is the way it should be, and this is the way the Food and Drug Administration should want it to be. We would appreciate your placing these materials in the record at the end of the testimony of Dr 0 Brien Dr Jennings and Dr MeCleery respectively and request that this letter be placed at the end of the Merck testimony on May 3 Sincerely, H W GADSDEN President SUPPLEMENTARX STATEMENT OF MERCK & CO INC IN RFSPONSE TO PORTIONS OF TESTIMONY BY WILLIAM M. O'BRIEN, M.D., ASSOCIATE PROFESSOR OF PREVENTIVE AND INTERNAL MEDICINE UNIVERSITY OF VIRGINIA SCHOOL OF ME~I0INE TUESDAY APRIL 23 1968 BEFORE THF MONOPOLY SUBCOMMITTFE SENATE SELECT COMMITTEE ON SMALL BUSINESS I his statement is filed pursuant to permission granted by the Chairman of the Subcommittee to comment on testimony by witnesses who appeared before the Subcommittee on April 23 and 24 and May 1 and 2 with regard to this Com- pany's performance in the development and marketing of its product `Indocin'. This supplementary statement covers two points (a) Dr. O'Brien was permitted, at the Committee's request, to review Merck's indomethacin New Drug Application file at the Food and Drug Administration including FDA s internal memoranda relating to the application Dr 0 Brien quoted extensively from a January 25 1967 memorandum of David Hurwitz M D of the 1~ ood and Drug Administration (Page~ 4538-40) Dr 0 Brien failed to mention that the document quoted from was primarily concerned with a review by Dr. Hurwitz of a supplement to the original New Drug Application, filed in May 1966 to cover additional indications Dr 0 Brien quotes the document as if it dealt only with the approval of the original New Drug Application. As Dr. Hodges pointed out in his testimony (pp. 4668-70), Dr. O'Brien also appears to have overlooked a subsequent memorandum of Dr. Hurwitz dated August 167, in which he, after further review of the data, substantially reyised the opinions expressed in his memorandum of January 25, 1907. We have ap- pended to this statement a copy of Dr. Hurwitz's August 1967 memorandum, and request that it be placed in the record at this point. (b) In his testimony on April 2-~ Dr 0 Brien appeared to cast doubt on the integrity and reliability of clinical investigators selected by Merck and other pharmaceutical companies and on the method of their selection To complete your record we are setting forth below Merck s policy and pro cedure in the selection of investigators (Copies of this statement were at the 1 equest of the Subcommittee staff submitted prior to Merck s appearance on May 3, 1968, but were not made a part of the record.) MERcK's POLICY AND PROCEDURE IN THE SELECTION OF INvESTIGATORs After careful review of preclinical evidence of safety and pharmacological activity of a new therapeutic compound it may be cleared for clinical study The Company s medical and scientific staff then must decide whether they wish to carry the compound into the clinical investigative process. If they do, a plan for PAGENO="0348" 3440 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the clinical program is developed and the clinical objectives-based on the phar- macological and toxicological data derived from animal studies-are established. Clinical protocols are then prepared. These outline the broad design of the pro- posed clinical studies and convey the basic information on toxicology and phar- macology with which clinical investigat&rs must be familiar in order to study the drug in man. In developing the protocols, we consult with clinical phar- macologists, biostatisticians, and selected investigators. In this process, we strive for the best possible study design, reconizing at the same time that the new drug can only be studied within the scope of presently available methodology as well as the availability of patients, volunteers, and clinical research facilities. Once the clinical plan has been completed and submitted to the FDA, clinical studies are inittlated in Phase I-which probes the basic pharmacology and metabolism of the drug in man. These studies are carried out only by expert clinical investigators in a few selected clinical laboratories, normally not more than five. These tire almost always in university-affiliated medical centers and are carried out in carefully selected individuals. If Phase I studies provide evidence of safety and pharmacological activity, the clinical program is expanded to include a half dozen or more expert investi- gators in the field of medicine where the drug promises to be useful (Phase II). An antihypertensive drug, for example, is taken to specialists in cardiology who have had experience in the investigation of such drugs. By this time the appropriate dosage range for the drug is fairly well estab- lished, and the effects of the drug can be studied in various disease states where it is expected to have a beneficial effect. This additional experience, involving studies in depth, adds greater assurance of safety and efficacy and provides the basis for expansion of the studies Into Phase III. The final phase (III) provides still greater evidence of safety and therapeutic benefit which can then be well delineated in the clinical indications for use of the drug. These studies are carried out by carefully selected physicians ex- perienced in the field of stud3r concerned. These are selected by our medical staff based upon knowledge of their prior work in the field, their prior work for us, and in some instances on the recommendation of Phase I and II investigators. A primary purpose is tO obtain a deeper insight into how the drug will respond in the hands of physicians generally. During all three phases, the studies are well controlled. The more sophisti- cated and complex double-blind studies are undertaken particularly during the Phase III stage. These studies serve as much as possible to eliminate bias and the elusive clinical variables which are ever present. It must be recognized, however, that although data from such studies tend to appear more convincing, their validity may also be subject to question. In most fields of medicine, it has yet to be proved that aU relevant factors have been accounted for in the control design, and thus we must avoid total reliance on what may be simply a tidier version of an imprecise appraisal of a drug. The first and ultimate responsibility for drawing conclusions with regard to safety and efficacy of a drug lies within the medical staff and the research organization of the Conmpany sponsoring the studies. We do not and cannot delegate this repsonsibility to a `third party. Financial assistance in the form of grants-in-aid is given to the investigator to cover the expenses incurred in carrying out his research. For the most part a contractual relationship is established between the Company and the university or institution where the work is being carried out. Grants are made on a sound budgeting basis~ Clinical research grants are never based on the condition that a certain number of case reports be submitted or that only positive data be pro- vided. Our records clearly show that studies supported by grants frequently fail to support the objectives set forth in the clinical protocol, either because of a shortcoming in the drug itself or failure to anticipate one or more of the numerous variables which arise during the clinical study and result in negative data. Most grants-in-aid cover the following costs: Laboratory, technical, clerical, hospital, and bed costs; supplies, mtaerials, and overhead. If there are indirect costs assigned to a project as part of `the investigator's overall research budget, these too are covered. Should the investigator request that special studies be done-such as radioisotope work, or metabolic balance studies demanding the special facilities of metabolic ward-these are financed to cover all direct and indirect costs. It is difficult to generalize about the costs of clinical research in the conduct of studies with new drugs. One cannot, for example, correlate the number of PAGENO="0349" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3441 patients or case reports per study with the cost. Where a minimum amount of laboratory work is required and the patients may not be seen by the physician more than three or four times during the course of the study, the cost of studying 50 patients may not be more than $5,000. On the other hand, studying six patients for six weks In the hospital or in a metabolic ward, at the rate of possibly $100 a day, may cost $25,000 or more. Costs vary with the degree of patient or hospital care needed, the extent of laboratory work, and the number of individual technical or professional tests to be done. Today, when hospital, laboratory, and research costs are skyrocketing, and when the expense of conducting clinical research on a new drug may extend over a period of three to five or more years, the cost of clinical investigation has become substantial. Indomethacin studies extended over a period of three and one-half years, from November 1961 to NDA approval in lune 1965-and Indeed a large program still continues. It is rare for a clinical research program involving a new drug to cost less than a half million dollars. Most are closer to one million dollars before an NDA has been achieved. Even after NDA approval, there are aspects of clinical re- search which may be pursued for years thereafter. It should be pointed out that a sponsor would be fosiish-in this developing age of clinical science-to undertake `to "pay" an investigator for positive data which cannot be substantiated. This could not be done with responsible clinicians. In any case, the cost of conducting medical research is already `so high that to add a factor of cost to this by trying to buy data which could not be confirmed would be not only `bad ethie~ and bad research but also bad business. A well- established research enterprise such as ours, with it~ scientific and medical reputation at stake and investing very heavily in obtaining clinical data, has much more to lose than to gain from this inaccurate data. It is the policy of the Company to seek out the best and most experienced clinical investigators it can find to evaluate its new drugs or to explore new uses of existing drugs. In 1967, we invested to $2,000,000 in the clinical investiga- tive phase of our research effort, supporting the work of several hundred inves~ tigators here and abroad. Although averages are not always meaningful or as accurate as one might wish in describing such a program, we estimate our "average" clinical reserach grant to have been approximately $5,000 during 1967. This compares with the average for an NIH clinical grant of perhaps ~15-25,000 during the same year . . . it is recognized, of course, that the NIH grants are more broadly based and for a longer term. But there are other comparisons that can be made with NIH grants as well. Like the NIH grantee, the Merck grantee is free to and encouraged to publish his data, whatever they may be. Like the NIH grantee, the Merck grantee is committed only to the accomplishment of a study, not to results. Like the NIH grantee, the Merck grantee is drawn from a cross-section of the nation's and the world's resources in the health sciences. The excellence of the performance and the quality of the data depend not so much on the sponsoring institution as on the state of the nrt and the state of the science in a given field. Thus, clinical reserach supported by Merck is and will be quali- tatively similar to research supported by Federal funds. At the same time, both companies such as Merck and Federal agencies such as NIH have a responsibility to do what they can to help strengthen the resources for better and ever better research, including clinical research. The key thing, from the Company's point of view, and the key message it would wish to communicate to a Committee of Congress that has interested itself in this question, is that the objective of the Company is quality performance in clinical reseraeh yielding reilable data. This represents an ever-present goal. We do not suggest that we are universally successful in achieving this goal; to attain such a level in any human endeavor is perhaps impossible. But our record has been good. Indeed, there is no other course for a responsible company to take. We are dealing with products related intimately to man's aspiration for health and free- dom from pain and suffering. All such products have a great capacity for good or for harni. In the final analysis, we are responsible for our drugs and have noth- ing to gain and everything to lose by performing inadequately in our own labora- tories, or by permitting sloppy performance by outside investigators, or by know- ingly-in our evaluation of preelinical and clinical data-ignoring and neglecting the facts as they bear on the safety and effectiveness of a new drug. PAGENO="0350" 3442 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [Copy made by Merck from facsimile] INDOCIN IN RHEUMATOID ARTHRITIs (By David HurwitR, M.D., Metabolic & Endocrine Div./ODS) Since its introduction in March of 1965, indocin has enjoyed wide public ac- ceptance as an anti-arthritic agent. Early pharmacologic studies had indicated an unprecedented potency when the drug was used to control inflammation in various animal models. It was hoped, at that time, that Indocin would have a high therapeutic ratio and thus offer a significant advantage over corticosteroids with their multipilicity of serious adverse reactions. Unfortunately indocin has shown a similar propensity to cause a wide variety of serious and sometimes fatal reactions, and its clinical usefulness has been limited by its toxicity. This toxicity has been well documented and is now well-appeciated by the medical profession, and Indocin has taken its place along side aspirin and phenylbutazone as another useful agent in a group of poorly understood diseases not amenable to any definitive therapy. At no time, however, was the actual efficacy of Indocin questioned. It was ap- preciated that the drug worked considerably better in acute inflammatory con- ditions like gout than in the chronic arthritides such as rheumatoid arthritis, hut the drug was believed efficacious in the latter condition. Several new studies published in the first quarter of 1967 in major scientific and medical journals now dispute the usefulness of this drug in rheumatoid arthritis. Chief among them in an exhaustive clinical study carried out by the Cooperating Clinics Com- mittee of the American Rheumatism Association in association with Dr. Donald Mainland, a well-known biostatistician. This exhaustive study involved 141 patients treated for a three-month period and required ten months to be com- pleted. Indomethacin was compared in a double-blind fashion with a placebo, the patients being allowed free use of aspirin as needed. Although many different parameters were measured and studied by sophisticated statistical techniques, the authors were unable to find any statistically significant differences in those parameters between Indocin and the placebo medication. In the same month, Donnelley et al. published a similar study in the British Medical Journal. The British authors used a double-blind crossover study coin- paring Indocin with a placebo, and they also were unable to establish any sta- tistically significant difference between Indocin and placebo. In neither study were there any serious reactions to the medications. In a third article by Pinals and Frank no differences was found between Indo- methacin and aspirin in the treatmeiit of rheumatoid arthritis. This study was a double-blind crossover type and was not as thorough or as well planned as the previous two studies. The authors arrived at the conclusion that Indocin and aspirin have no significantly different effect 011 the parameters measured which is justified by the results of the experiment, but they seem to have missed the obvious conclusion that no therapeutic effect was demonstrated for either of the medications. The measured parameter, while not varying significantly between the Indocin-treated group and the aspirin treated group, also did not vary sig- nificantly within each group at two weeks and four weeks. The lack of inclusion of base line data adds a further difficulty to the interpretation of this paper. In contrast to this study, however, the Mainland and the Donnelly studies were well-planned, well-controlled, and seemed to be products of rigorous, thoughtful research. Indocin's potential toxicity would niake its use in rheumatoid arthritis unac- ceptable if indeed it has no efficacy for this condition. Therefore it was deemed necessary to review the original studies establishing efficacy in this disease. A search of 100 volumes of the NDA revealed six acceptable controlled studies, five of them double-blind the other single-blind. All of these studies claimed efficacy for Indocin but they vary in quality. As a whole, they would seeni to indicate efficacy in this condition; results are summarized in the table, below. In comparing the old studies to the new ones, it is obvious the latter are better- controlled and use more sophisticated methods of evaluation. Because of the extremely variable nature of the disease and the consequent difficulty in evaluat- ing modes of therapy, it is impossible to say that the new studies outweigh the old, particularly in view of the large mass of testimonial data indicating efficacy. While testimonial studies are not in themselves adequate to allow approval of a drug by the FDA, they certainly cannot be disregarded as meaningless when the ultimate usefulness of the drug and its success is determined by individual PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3443 patient reaction to the medication. We are therefore faced with the dilemma of a drug whose efficacy has been seriously questioned by excellent studies but which enjoys solid acceptance by the medical community and the patients it treats. At the present time, then, it would seem wise to consider Indocin as probably effective in rheumatoid arthritis pending further studies in this area. The drug is at the present time safe for use in this condition since in the dosages commonly employed there is very little risk of a serious adverse reaction. This author has recommended in the summary of the most recent supplement submitted by Merck, Sharp & Dohme that further studies be carried out to determine the efficacy of Indocin in rheumatoid arthritis. PAGENO="0352" TABLE l.-INDOCIN REVIEW-CONTROLLED BLIND STUDIES FROM ORIGINAL NDA Author Date Volume Number of patients Type Results Comment Hart, F. D., and Boardman, P. L. 1965 (British Medical Journal, 11 :1281, 1965). Percy, J. S., Stephenson, P., 1964 Thompson, M. (Ann. Rheum. Dis.) (23:226, May 1964). Wenka, J., Jones, L., Wood, P., 1964 Dixon, A. Ward J. R. 1965 Smyth, C. J 1965 Bode, J. J 30 30 30 30 47 80 18 Double-blind crossover comparison (1) Little difference between drugs in with Phenylbutazone 56 days. therapeutic or adverse effects; (2) Indocin had greater effect on reduction of joint swelling; (3) no serious reactions. 24 Double-blind crossover sequential (1) No significant difference between comparison with Phenylbutazone. drugs in patient preference or grip strength; (2) Phenylbuta- zone had lower incidence of ad- verse reactions (none serious in either group). 22 Double-blind crossover comparison (1) Patients preferred Indocin but no with placebo 6 weeks. measurable difference in grip strength; (2) no significant re- actions, Studies: (1) 29; 2 studies double-blind crossover com- (1) Indocin group had less tenderness (2) 40. parison with placebo. In study No. and morning stiffness; (2) Indo- 1, unlimited and irregular use of as- cm group had significant de- pirin and steroids was permitted. crease in pain, morning stiff. Study No. 2, all patients on fixed ness, swelling, tenderness; (3) aspirin and prednisone, dosage 4 no significant reactions, months. 55 Single-blind variable time several lndocin effective in several param- weeks to several months. eters as compared to placebo. 27 total, 15 on Indo- Double-blind 3 months (1) Indocin group had decrease joint cm. tenderness and pain, no differ- ence in parameters; (2) no serious reactions. Data not included with study (has been published with adequate data). Data incomplete as regards grip measure- ment or preference, it would be desirable to see how parameters were measured and actual figures; without these we are unable to tell if the patients improved. The ARA Committee has noticed a feelins of well-being in patients on Indocin; ig this the case here? No objective benefit was noted in the single measured param- eter-grip strength. (1) Results variable, uncontrolled use of aspirin and prednisone in study No. 1 make it invalid. (2) data scant, inadequate placebo effect (nil); validity of statistics, questionable dos- age of other medications unspecified (Study No. 2). (1) Well-developed response criteria; (2) large, unwieldy amount of data; (3) poorly controlled, variable dosage and length of administration; (4) results only suggestive to efficacy. (1) Did patients use olber medications dur- ing this long study? TABLE 11.-I NDOCI N-NEW STUDiES QUESTIONiNG EFFICACY (1) No difference between indocin (1) No baseline data; (2) neither drug had and aspirin; (2) no serious reac- any clinical effect which mal~es results finns. difficult to interpret; authors did not discuss this point; (3) 5 tatients on steroids. Donnelly, P., Lloyd, K., Camp- 1967 30 Double-blind crossover comparison (1) No statistical significant difference (1) Well-designed study, well-controlled; bell, H. (British Medical with placebo 1 month. between Indocin and placebo; (2) (2) used aspirin in all patients but amount Journal, January 1967). some delay in onset of fatigue on was recorded and evaluated statistically. Indocin but not statistically signifi- cant; (3) no serious reactions. Mainland et al. (Clin. Pharm. and 1967 141 Double-blind comparison with placebo (1) No statistically significant differ- Therapeutics, January 1967). 3 months. ence between Indocin and placebo; (2) no serious reactions. Use of aspirin reduces sensitivity of experi- ment and may mask small differences between placebo and Indocin. Pinals, R. S., Frank, S. (NEJM 1967 March). 0 L~i H H 0 Cr2 H 0 Cr2 H 24 Double-blind crossover comparison with aspirin 2 months. PAGENO="0353" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 3445 SUPPLEMENTARY STATEMENT OF MERCK & CO., INC. IN RESPONSE TO PORTIONS OF TE!STIMONY BY JOHN JENNINGS, M.D., ACTING DIRECTOR, OFFICE OF MARKETED DRUGS, BUREAU OF MEDICINE FOOD AND DRUG ADMINISTRATION, GIVEN ON WEDNESDAY, MAY 1, 1968 BEFORE THE MONOPOLY SUBOOMMI1'1~EE SENATE SELECT COMMITTEE ON SMALL BUSINESS This statement is filed pursuant to permission granted Merck by the Chairman of the Subcommittee to comment on `testimony by witnesses who appeared before the Subcommittee on April 23 and 24 and May 1 and 2 during hearings inquiring into this Company's performance in the development and marketing of its product "Indocin". On May 1, Dr. Jennings, testifying for the Food and Drug Administration, described the negotiations between the Agency and the `Company that led to two package circular revisions in the fall of 1966. (Pages 4690-4704) The general impression we receive from Dr. Jennings' testimony is that the Food and Drug Administration tried from July 15 forward to get the Company to add additional warnings, contraindications, and adverse reactions to the package circulars on "Indocin", but that the Company was reluctant, even recalcitrant, in doing so. It is implied that the Company should have voluntarily made the requested changes long before it did so. Thus, "By regulation, these changes could and should have been put into effect by the firm at the earliest possible times, without awaiting approval from the FDA." (Page 4690) On the other hand, there is in the same testimony an implied criticism of the Company for proceeding voluntarily without FDA approval when it did change the package circular. "Rather than wait for all the recommended labeling changes to be worked out with us, interim revisions of the labeling were put into effect by the company without our advance approval." (Page 4694) Dr. Jennings concludes that our letter `to doctors transmitting the volunteered package insert changes was "promotional literature" in which the original intent to war physicians of additional hazards was "completely lost." (Page 4695) His concluding testimony on this subject could leave the impression `that the Agency was struggling with the massive problem of a recalcitrant firm unwilling to convey to the doctor important new information on hazards of its drug. This impression is not justified by `the actual facts. We submit below a brief review of our communications with the Food and Drug Administration during the spring and summer of 1966 on revisions in the package insert for "Indocin." These are summarized from our internal memos and records of correspondence with the Agency. 1. April 6, 1966. Telephone call to our Dr. Shaffer from Dr. O'Gra'dy, FDA investigational Drug Branch. This call dealt with the Company's IND on "Indocin" covering studies in indications not in the then-approved NDA. Dr. O'Grady reported that the Adverse Reaction Bureau, FDA Bureau of Medicine, thought there was an increasing number of side effects associated with the use of "Indocin". Dr. Shaffer told Dr. O'Grady that from our review of reported adverse reactions, the incidence of such reactions was not increasing but decreas- ing with more widespread use of the drug. A request was made to discuss the entire investigational program with Dr. O'Grady. 2. April 7, 1966. Dr. Shaffer telephoned Dr. O'Grady for a date for conference. This was tentatively set for April 15, `but later in the day changed to April 18. FDA was asked whether it had adverse reaction data from sources independent of Merck. 3. April 19, 1966. Conference between FDA and Company medical representa- tives. Although the conference related primarily to the investigational studies for added claims, the FDA representatives reported their opinion `that the current package insert should be revised to reflect current adverse information reports, including some data they had that we did not have. The Company medical representatives felt Merck should make a complete review of the labeling and 81-280 0-68-pt. 8-23 PAGENO="0354" 3446 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY see whether the data available to us suggested the need for package circular revisions. 4. May 2, 1966. As a follow-up to the April 19 conference our Dr. Shaffer telep'honed Dr. Seife and asked if he would provide us with the type and number of adverse information reports they had received through the FDA Adverse Reaction Reporting Program. Dr. Seife called back the same day and gave us this information, characterizing the reports with regard to the role "Indocin" may have played. He promised to keep us informed as additional reports came in to FDA. 5. May 5, 1.966. Letter from Dr. Ruskin of the FDA Division of New Drugs, primarily relating to the pending NDA on an "Indocin" formulation. it "recom- mended that revised labeling be submitted supplemental to your approved appli- cation for the capsule form to contain the most recent reports of adverse reactions which are not in the current `labeling. . . ." In this letter Dr. Ruskin requested that a statement be added in boldface type to the warning section of the labeling that this was not an innocuous drug and should not be used for other than recommended indications, and not be used in women of childbearing age. "We recommend that these labeling revisions be discussed with the New Drug Fiur- veillance Branch. . . ." (Italic added.) 6. May 27, 1966. Our Dr. Shaffer `telephoned Dr. Seife of the New Drug Sur- veillance Branch to arrange for the requested discussion. We suggested a meeting on June 6, but Dr. Seife was "occupied with another problem" and said he "would like to arrange for such a conference before the end of June." It was left that Dr. Seife would let us know when he was available. Additional adverse information FDA had received from March 24 through May 5 was communicated in this conversation 7 July 1 1966 Our Dr Shaffer telephoned Dr Seife of FDA to ask about the proposed meeting Dr Shaffer learned that Dr Seife was out of town and that Dr Jennings Acting Director of the Drug Surveillance Branch should be called Dr Shaffer called Dr Jennings and learned that the matter had been reassigned to him. He said he would discuss with Dr. Ruskin the May 5 letter we had from Dr. Ruskin, but that if any urgent changes in labeling were necessary, these could be made without submitting a new drug application supplement for FDA approval. Dr. Shaffer told Dr. Jennings that "in order to avoid subsequent changes requiring reprinting etc., we requested an opportunity to discuss labeling revisions with them as requested by the Ruskin letter of May 5, 1966." Dr. Jennings asked that we "check back with him in about one week." 8 July 15 1966 Conference in Washington between FDA and Company medical representatives. Dr. Seife was to enter the hospital for surgery and our labeling matter had been assigned to Dr. Standard. A summary of major labeling changes prepared by Dr Seife was reviewed in detail. Dr. Seife told us the reconvmendations outlined during this discussion would be sent to us in the form of a letter. 9. August 4, 1966. Dr. Shaffer wrote `to Dr. Jennings as follows: "As you know, we met with Dr. Seife, Dr. Bryan, and Dr. Standard July 15 to discuss proposed revisions of the `Indocin' Package and Direction Circulars. It was our understanding that Dr. Seife's proposed revisions would be submitted to us by letter. We would appreciate receiving this communication so we may prepare an appropriate revision based both upon your proposals and our evaluation of the available data." (Italic added) 10. August 22, 1966. No further communication from FDA had been received. On this date, the Merck Sharp & Dohme Division Counsel advised that, since we were willing to accept a number of the FDA recommended changes, we should make the changes voluntarily, notify the FDA, and mail the revised circular to physicians. 11. $eptember 2, 1966. We submitted a supplemental NDA containing the added contraindications, precautions, and adverse reaction information, stating in the transmittal letter to the FDA: "We feel it important that these changes be placed into effect at the earliest possible time." The majority of the FDA's suggestions were adopted. We gave our reasons in that letter for not adopting all of them. Our letter ended with the following paragraph: "We appreciated the opportunity to discuss suggested changes in the Indocin labeling with your staff. We believe that the revised labeling submitted with this supplemental application accomplishes the mutual goal of providing the physician with the most useful information about this drug. To accomplish this goal, we have taken the position that the labeling should be unencumbered by a listing of PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3447 every report ~f an adverse reaction if, in our best judgment, there does not appear to be a reasonable relationship to the drug. An attempt has been made to provide the physician with some guidance as to the relative frequency with which the listed adverse reactions may occur. We are following the clinical experience with this drug closely and will make further labeling revision if and when indicated." 12. t~eptember 30-October 6, 1966. No reply to our September 2 letter had been received from the Food and Drug Administration. On September 30, we started our mailing to doctors, and on October 6 notified the FDA that the revised circular had "just been mailed." Enclosed in the letter was the circular, the transmittal letter and the envelope which contained in large red letters, "Do Not Discard Before Reading-Drug Safety Information." The revisions were noted in boldface type so that they would not be missed by the readers. Although the letter sent out to doctors was clearly marked as noted above, and the enclosed revised insert was made easy for the physician to read, and the body of the letter conveyed what it was intended to convey, it did contain first and last sentences that tended to give it a promotional overtone. In retrospect, we think it should not have had those sentences in it. We do not do everything perfectly, and did not do so here. Nevertheless, we think that the essential intent and message of the letter was clear, and that Dr. Jennings' categorical opinion that original intent was completely lost (page 4695) is overstated During the course of these discussions with the FDA, we found ourselves involved in differences of medical opinion about the implications of the reports of adverse reactions and side effects of the drug. In terms of telling physicians about them, we were of the opinion that placing before them a mass of detail, much of it repetitious, would tend to obscure the really important warnings. As to the reports themselves and their significance, there were not unnatural differences of opinion. Our medical staff felt, and still does, that nothing es- sentially new was emerging from these reports, that the increasing number of reported reactions reflected the increasing use of the drug rather than an in- creasing incidence of reactions, and that as more experience was gained what was emerging was an expected refinement of the original essential pharmacologic profile. The Food and Drug Administration people appeared to think differently. It did not-and does not now-follow that they were right in this opinion. A good example of this difference of opinion is our view of the value and proper `use of the drug in cases of juvenile rheumatoid arthritis. Dr. Jennings, during his testimony, refers to reports of deaths in children associated with the use of indomethacin. He disposes of a number of these cases as probably not due to the drug, but reserves opinion as to several. There is a considerable differ- eice between a drug's being possibly linked to a death, and definitely related to it. The FDA is understandably cautious and has consistently singled out pediat- ric age groups as a patient population bearing risks `beyond the adult group. From the beginning, because the FDA did not accept our pediatric data, our domestic package circular included a specific contraindication against the use of `Indocin' in children of pediatric ages. During our discussion's with the FDA in the spring and summer of 1966 about the revision of our labeling, the FDA itself did not request us to include any statement in the circular referring to fatalities in children. The only differ- ence between us at that time was whether the existing contraindication of `In- docin' for children was sufficient, or whether it should be strengthened by the addition of a phrase at the beginning of the circular stating "Not for Use in Children." We did not believe then `and we do not believe now that this addition was necessary or desirable. In the light of the FDA's desire for more emphasis, we did italicize the portion of the circular containing the specific contraindication for use in children, so that it would come even more prominently to the attention of doctors. Moreover, we added an additional paragraph, printed in boldface type in the revised circular, calling attention to the fact that `Indocin' could mask the existence of infection and reminding physicians that it should be used with caution in patients with existing infections. In our scientific opinion, the reported deaths in children were related more to the existing complications of a serious infection in these patients than to the fact that they were children. FDA insisted in meetings that followed the events summarized above that we make a further amendment adding a specific statement at the beginning of the circular that the drug should not be prescribed for children, and it requested for the first time that we refer in the contraindications to reports of severe reac- tions, including fatalities, in a few cases of severe juvenile rheumatoid arthritis. PAGENO="0356" 3448 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Although we did not agree with this medical judgment, we did include these statements because of the FDA's insistence. In the judgment of our medical staff, `the total prohibition of `Indocin' in Juveniles suffering from acute rheumatoid arthritis is not warranted. Acute juvenile rheumatoid arthriti.s is a serious and often hopeless disease. If treated with corticos'teroids:, very serious effects-including loss of calcium in the bones and the disturbance of the endocrine system-can frequently. result. In those children who do not respond to aspirin or cannot tolerate it, we believe it is medically preferable to treat them with `Indocin' than to risk corticosteroids or to leave them untreated The FDA does not agree with us and for that reason we have always contraindicated Indocin for this purpose in the United States But many doctors do administer the drug successfully to children in Europe The matter presents a question of refined medical judgment but it is one on which you will find much responsible opinion on our side It must be accepted as a truism that the FDA is at all times in a position to bring great pressure on us to adopt every detail of what they want For our part, we wish to cooperate as much as possible with the Agency. Good relations with it are essential for us. Subsequently, when at Dr. Goddard's request we met on. November 11, 1966, with him and his staff to discuss our labeling and advertising of `Indochin', we reviewed the differences of opinion about the controversial points and the trans- mittal letter to doctors As a result of the meeting even though our respective medical staffs continued to be in disagreement on a number of issues we chose to abide by FDAs wishes and sent out a further revised circular contain ing all the changes FDA requested including the different typographical and position treatment of the contrarndications in children This revised circular was transmitted to doctors in December 1966 with a letter which made reference to nothing but the changes in the insert. Both the circular and the letter were worked out with the FDA. Neither in these meetings nor subsequently was there any recalcitrance on our part. In our opinion, sincere disagreements in medical opinion cannot be equated with recalcitrance. We were deeply concerned `at the time at What seemed to be imputations to us of bad motives and lack of integrity. We argued against such imputations most vehemently. But we worked out this particular problem on the basis of a full and frank discussion of where we and `they stood on the matter. Perhaps it is fair to say that the Company and the FDA must share the respon sibility for the time it took to issue the first revised circular. The job could have been done faster if we and the FDA officials concerned had been able to arrange more frequent meetings and to obtain prompt decisions. With respect to the wording of the first transmittal letter to doctors, we must and `do accept sole responsibility. ________ SUPPLEMENTARY STATEMENT OF MERCK & CO., INC. IN RESPONSE TO PORTIONS OF TESTIMONY BY ROBERT S McCLEFRY M D ACTING DIRECTOR DIVISION OF MEDICAL ADVERTISING, BUREAU OF MEDICINE FOOD AND DRUG ADMINISTRATION GIVEN ON THURSDAY, MAY 2, 1968 BEFORE THE MONOPOLY SUBOOMMI1~EE SENATE SELEOT COMMITTEE ON SMALL BUSINESS This statement is field pursuant to permission granted Merck by the Ohairman of the Subcommittee to comment on testimony by witnesses who appeared before the Subcommittee on April 23 and 24 and May 1 and 2 during hearings inquiring into this Company s performance in the development and marketing of its product Indocin This supplementary statement covers portions of the testimoni of Dr McOleery on May 2 PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3449 We do not agree with the allegations of fact charges and conclusions contained in Dr McCleery s testimony on a number of detailed aspects of our advertising of Indocin such as his extensive discussion of the reference in our advertisement to an article by Hart and Boardman in the British Medwal Journ~al of Octther 18 1963 We have presented to the Food and Drug Administration detailed factual and legal responses to these charges. In our view, the advertising statements the Company used did not misrepresent the status of the drug, intentionally or otherwise. In any event, the criticized statements have not appeared in any Merck advertisement since 1966. As Mi Goodrich testified before your Subcommittee this matter is now pending before him for a decision on whether fur her legal proceedings should be recom mended While the matter is in this status-and since the issues involved require lengthy analysis and interpretation of the criticized quotations the scientific data on which they were based and the articles from which they were taken-we believe it would be inappropriate to comment on the issues in this forum We do feel however that we should note our exception to one specific point `tbout our advertising raised by Dr McOleery since it suggests knowing misrepre sentation on our part. In commenting on an advertisement in the July 18, 1966, edition of the Journal of the American Medical Association, he said that the advertisement ". . . featured the claim of one of the participants in a Merck- sponsored symposium. This is attributed to Dr. Englund-they featured a claim, quoting from him at this symposium that [he] had had 500 patients on the drug for, three years, when Merck's own records would have told them this was not true." (Page 4733) The advertising to which he referred contained this statement I have had some 500 patients on indomethacin now for about three years I find it an extremely helpful drug I think there are certain areas where it will be without question [a] drug ot choice One of these is osteoarthritis of the hip This quotation was taken from a statement made by Dr DeWitt W Englund in response to a question from the chairman of an international symposium `~n Non Steroidal Anti Inflammatory Drug Therapy in Rheumatic Diseases conducted September 26-28, 1965, in New York City, by the Excerpta Medica Fou~'~°~'n. We do not believe that Dr. McOleery's criticism of the Company for using the statement "when Merck's own records would have told them this was not true" is warranted. Merck could properly have relied on Dr. Englund's recorded and published statement as the factual observation of an eminent and leading rheu- matologist. Our records did show that Dr. Englund had treated at least 500 patients by that time The information was contained in Merck s first quarterly report to the FDA after the approval of the New Drug Application on June 10 1965 It was sent to the Agency about the middle of September 1965 and should also be in its records In another portion of his testimony Dr McCleery described his understanding of our connection with a lay article about the drug in Pageant magazine (Pages 4716-20) We consider this also to be fundamental because according to Dr McCleery, it led the FDA to conclude that this Company "might not be scrupulous in its advertisinng to the medical profession." We are therefore setting forth in detail what took place with regard to the Pageant article: 1. On February 15, 1966, Mr. Robert P. Goldman, who has been a science writer since the late 1940's, telephoned John E. Fletcher, Director of Public Relations for Merck stating that while in France his wife had been given a prescription for Indocin for the treatment of tennis elbow Mrs Goldman and her doctor felt that the treatment had been successful When Mr Goldman inquired of the doctor as to the source of the drug he was surprised to learn that it had been originated by an American company namely Merck Mr Goldman chided Mr Fletcher about the fact that there had been no publicity about the drug He said he planned to write an article about indomethacin and asked the company to pro vide him with some background material on it. 2. Oii February 17, 1966, Mr. M. T. Noar, a member of the Company's public relations staff, at the request of Mr. Fletcher, sent Mr. Goldman appropriat~~ background information, including a "backgrounder" containing medically and scientifically authenticated information about the drug, its genesis, and the disease conthtionq for which it is approved a package circular relevant papers by scmeatists from Merck and other laboratories and a bibliography 3 Sometime within the next month Mr Goldman called Mr Fletcher stating that he would like to have some human interest stories to increase readability PAGENO="0358" 3450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and asked whether we had any letters. Mr. Near, at Mr. Fletcher's request, sent Mr Goldman six letters from patients who had voluntarily written to the Com pany. Identification of the individuals and their physicians was `blocked out in the copies `sent to Mr. Goldman. a The first letter dated August 1965 from San Diego Cahforma dealt with osteoarthri'tis of the hip joint (an approved claim). `b. The second letter, dated December 14, 1965, related in the patient's language to arthritis (there wa's no reason to suppose it othbr `than `rheuma- toid-an approved claim). c. The third letter, dated December 24, 1965, from Morganton, North Carolina, related to os'teoarth'ritis of the hip (an approved claim). d. The fourth letter, dated January 6, 1966, from Williamstown, Massa- chusetts, related in the patient's language to arthritis (`there was no reason to suppose it other than rheumatoid-an approved claim). e. The fifth letter, dated January 10, 1966, on the letterhead of the Enterprise Oity School District, related to rheumatoid arthritis (an approved claim). S f. `The sixth letter, dated October 4, 1965, contained the following para- graph: "I am not too sure whether I `have bursitis, tendonitis, or just plain arthritis, and also, my doctors don't know. However, I do know that I had to give up playing golf and I do know that after these few days'that I have `been taking your wonderful capsules, that I am going to play golf again, and soon." 4. On April 14, 1965, Mr. Goldman wrote Mr. Fletcher stating that' he had done the piece on `Indocin' and `that it would probably appear in Pageant in July, with the magazine to be on the stands `about June 16, 1966. According to hi's records, Mr. Fletcher also received a telephone call in mid-May from Mr. Goldman - in which the latter said that `he thought his `story would appear in a summer issue of Pageant. 5. On the morning of June 15, 1966, while driving to work, a member of the Company's public relations staff heard a radio commercial about a story on `Indocin' in Pageant. He stopped by a newsstand and purchased the magazine in which the article appeared. This was the first time anyone from `the Company had seen it. 6. On June 21, 1966, a copy of the article was `sent to Mr. Oron, then Director of Public Information and Education of the Food and Drug Administration, together with a copy of an internal memorandum explaining the `article's origin. 7. Nothing was heard from `the FDA about the article or our part in it until a speech was delivered by Mr. William W. Goodrich, Assistant General Counsel of the Food and D'rug Administration, `before the Pharmaceutical Advertising Club in New York on October 20, 1966, in which he criticized the Pageant article and gave his version of the Company s role in it This chronology of events demonstrates that: 1 The Company did not stimulate or cause publication of the article it responded to a request for information from a recognized science writer. 2. Approved claims were named in all of the letters supplied to Mr. Goldman by Merck. No case histories on unapproved claims were submitted. No testi- monials on unapproved claims were submitted. In one single letter the patient reported that he and his doctors did not know whether he had tendonitis, `bursitis, or arthritis-arthritis being an approved claim. 3. Merck did not see the text of the article before it appeared in print; it first saw the article when the July issue was purchased from a newsstand on June 15, 1966. 4 Analyc~is of the article shows that of the nine personal experiences recited by the authors, only four are attributable to the Company. Of these four, three involve approved claims only. The fourth mentions "bursitis." Although the article purports to quote extracts from this fourth letter, the quotations are not accurate and they changed the letter's meaning by omitting the reference to arthritis, an approved claim. 5. The C~'mpany voluntarily made the facts known to the FDA shortly after the published article came into Merck's hands. 6. The FDA did not discuss the Pageant article with Merck or seek to vertify Merck's role with respect to it prior to the time Mr. Goodrich made a public speech attacking the article and the Company on October 20, 1966. Senator NELSON. If you have a supplementary comment, it will be printed in the record at the appropriate place. PAGENO="0359" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3451 Mr. GADSDEN. Thank YOU. - (The subsequent correspondence and statement of Senator Scott follows:) U.S. SENATE, COMMITTEE ON THE JUDICIARY, Washington, D.C., May 9, 1968. Hon. GAYLORD NELSON, 17.6. $enate, Washington, D.C. DEAR `GAYLORD: You will recall that at the Monopoly Subcommittee hearing of Friday, May 3rd you granted me permission to submit a statement at the end of that day's hearings. A copy of that statement is enclosed. I would like to have it printed in the permanent record of the hearing of May 3, as if delivered personally, immediately following Mr. Gadsden's final remarks and just prior to your statement recessing the hearing. Cordially, HUGH SCOTT, U.S. Senator. STATEMENT OF HON. HUGH Sco~ru, A U.S. SENATOR FROM THE STATE OF PENNSYLVANIA Mr. Chairman, it is entirely clear that today's hearings, requested by Merck & Co., have provided a substantial step forward in dispelling the pall of con~u- sion that has accumulated on these issues during the last two weeks. The value of taking testimony from the party most directly involved in a problem was demonstrated today. The testimony indicates that there is essentially no problem regarding the safety and effectiveness of this drug as it has been determined by a broad group of highly qualified experts. It is also apparent from the testimony that the Food and Drug Administration had ample evidence regarding safety and efficacy to support its action of licensing this drug. No insurmountable problem exists with the way in which the Company pre- sented product information to the practicing physician except as a matter of semantics-of subtle differences of opinion on the interpretation of words, judg- ments, and impressions during a time when the Food and Drug Administration itself has been groping with the problem of how to regulate the flow of informa tion to the medical profession Such differences as exist can more appropriately be resolved by conference rather than by public charges or legal threats It would appear that the interests of physicians and patients would thus be better served After reading the statements and discussions of the hearings on this product, I am more regretful that the circumstances have led to a condition where a good Company, a good performance, and a good drug have so lamentably been charac- terized by headlines suggesting danger and deceit. The events of the past two weeks only reinforce the need to reexamine the structure of the hearings them- selves so that the parties concerned can appear at the outset and provide a factual `base against which criticisms can be leveled or improvements proposed. Fair balance has become a watchword in the drug field today. The planning and timing of Congressional `hearings might well be so devised as to bring more balance in the final impression left with the public at large. (A subsequent statement and supplemental information submitted by Senator Nelson follows:) STATEMENT BY SENATOR GAYLORD NELSON, CHAIRMAN OF THE MONOPOLY `SUBCOMMITTEE The Monopoly Subcommittee of the Senate Small Business Committee to date has held five days of public hearings on indometbacin, which is manufactured and sold under the trade name of Indocin by Merck & Company. Of our witnesses, 3 were independent physicians from the academic field, 3 from the Food and Drug Administration, 6 from (or on beha'lf) of Merck & Company, and one, a practic- ing physician who evaluated the drug for Merck. `The testimony highlighted five problems which are very important to the health and. welfare of our people. These are: (1) drug evaluation: (2) what is meant or should be meant by "substantial evidence of safety and efficacy ;" (3) the use of euphemistic, soft and unclear language in drug warnings; (4) overpromotion PAGENO="0360" 3452 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of drugs and (5) false and misleading advertising I shall discuss these problems in order As I stated in my opening statement on April 23 the FDA does not engage in the clinical testing of drugs It approves new drugs solely on the basis of infor mation supplied by the pharmaceutical industry. This raises the question of whether it is sound practice for a firm which has a financial interest in marketing a drug, to direct, arrange, and finance its evaluation. It also raises the question of whether it is possible for an evaluator to maintain objectivity when he is dependent on funds from the company. Is it a good idea for a physician who is testing a drug to send his data to the company for a statistical analysis while at the same time asking for additional financial support? Is it a good idea to send a rough draft of proposed results to the firm while at the same time asking for additional money'? Wouldn t it be rather difficult to tell a firm that its product is unsatisfactory especially when a grant for your department at your medical school has been suggested? These are actual cases and I am placing into the record several letters which illustrate the points raised here. (The letters follow:) STATE UNIvERsITY OF IOWA, Iowa City, Iowa, April 18, 1963. NELSON H. REAVEY CANTWELL, M.D., Ph. P., Merck sharp c~ Dohmc Research Laboratories, West Point Pa DEAR DR CANTWELL I received your letter this morning and want to thank you for suggesting a grant for the rheumatology section at the University of Iowa Since you were here we have started a number of new patients on indomethaem (the LX capsules) At least three of the patients complained of severe epigastric distress within 30 minutes after taking the capsule Therefore in the next few subjects we started them out on 1 capsule twice a day increasing 1 capsule daily until they reached the maximum 6 capsules and believe it or not we encountered no distress This is the method we will follow for the time being with our fingers crossed. The fifteen year old patient with generalized psoriasis and psoriatic arthritis returned for a check-up and is under excellent control on a total dose of 150 mg. per day She goes to school daily and is able to walk much better than she has at any time during the past year Another woman (age 45) was admitted with gen eralized psoriasis and psoriatic arthritis Before she was admitted to the hospital she was started on terrific doses of steroids which did not control either the pain ful hands or the skin eruption The dermatologist started her on 42 mg Triam cinelone and a few days later we began the indometbacin 2 tablets at first then increasing daily until she reached the maximum of 300 mg By the time that we reached the maximum dose she had little or no pain in her hands was able to make a partial fist and began to feel much better This morning we have her down to 16 mg Triamcinelone She is able to be up and about has no fe~ er the skin lesion is receding rapidly and she can actually close her fingers and grasp objects. We started another psoriatic arthri.tic who has been on steroids for over five years to determine whether or not we can reduce the steroid dose. Under separate cover I am sending you another batch of the monthly Bulletins in case you need s'ome of these. I have had several calls from Iowa physicians asking me about the drug and two of them have sent patients to us so that we could evaluate them and give them indomethacin. Again I want to thank you for your kindness and will see you in June Sincerely yours, W. D. PAUL, M.D. PAUL J BILKA M D Minneapolis, Minn., May 8, 1963. NELSON H REAVEY CANTWELL M P Merck sharp c~ Dohnie Laboratories, West Point, Pa. DEAR NELSON: I have decided to make a preliminary analySis of the patients on the Indocin tablets. Since I started the higher dosage' schedule, beginning last summer, there are 63 patients who have been treated from up to eight months, and it certainly looks like we are getting a better result using the minimum dosage PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3453 of 100 mg a day, with the vast majority getting 150 mg per day as the minimal dosage. 15 patients had no help 17 patients recorded slight help (that is less than 25%). 20 patients had sigrnficant help (25 to 50%) 11 patients report great improvement (over 50%) I have not yet analyzed all of the laboratory data, so I cannot give an accurate statement as yet, however certain things are apparent and might be of interest at this time: 18 patients reported severe headache; all but six were able to continue the medication at lower dosage levels or by adding Benadryl; 8 patients reported severe gastrointestinal upset. One patient (Mr. Jensen) had a history of a DU, but the pretest X-ray was negative. During the third month of 200 mg per day, he developed an active PU. He was continued on the medication in the same dosage and X-rays two and four months later show the ulcer healed Another patient (Mrs Rose) with a known active DII was started on Indocin 150 mg per day and was continued on this for two months because of the marked relief she obtained At this time however her 01 symptoms increased the X ray showed the still active DII and the Indocrn was stopped A third patient (Mr Rardin) with a known history of a PU and with signs of activity was given a two month trial of Indocrn 75 mg per day His ulcer symp toms also increased on the medication and the X-ray showed an active PU. All of the other patients had negative X-rays. I will start going over the charts for the detailed analysis of the laboratory data and will let you know of the results. The work with MK715 is too early to make any comments on except that it seems at least as potent as 615 in the two to one dosage ratio. I am enclosing the laboratory charges for March and April Again would you have this made out to St. Barnabas Hospital, Arthritis Research. I shall soon be enlarging the facilities for out patient caie at the Kenny Insti tute and we will be in a position to utilize extra funds for our project there If Merck can make an additional contribution of $3000 toward this work it will be useful and appreciated Sincerely, PAUL J. BILKA, M.D. THE COLUMBUS MEDICAL CENTER Columbus, Ohio, May11, 1964. NELSON H. REAVEY OANTWF4LL, M.D., Ph. P., Merck ~Sharp ~ Dohme Research Laboratories Division of Merck c~ Co Inc West Point Pa DEAR NELSON The enclosed letter is from a very fine patient a 45 year woman who is a Ph P and teaches at Dennison University She is quite intelligent im inensely cooperative and completely un neurotic I thought you would be interested in her very vivid and articulate description of the adverse symptoms which she encountered with Indomethacin. I would emphasize that these do not alarm me nor indicate any evidence of organic damage but I am afraid they will offer some practical problems in marketing this drug. Needless to say, I am very grateful for all of your kind efforts in regard to my trip to Japan. I'll look forward to seeing you on my return. I think we must get together and plan on publishing some of the data which we have collected. Best regards always. Sincerely, NORMAN 0 ROTHERMICH M D P S I sent a copy of Dr Shepard s letter to Elmer PAGENO="0362" 3454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CLEVELAND METROPOLITAN GENERAL HOSPITAL, Cleveland, Ohio, June 27, 1963. NELSON H. REAVEY OANTWELL, M.D., Merck Sharp ~ Dohme Research Laboratories, West Point, Pa. DE~1~ Dn. CANTWELL: This is in answer to our telephone conversation. As I mentioned to you in my letter of 26 January, we have treated 51 patients with acute rheumatic fever. I have discussed the whole situation with Dr. Mortimer and our plans. for analysis are as follows. Dr. Mortimer is presently analyzing the data and in September Dr. Correa, who participated in the study in Chile, will come to the United States to spend six weeks here going over the data and preparing it for publication. It is possible that we will have a rough draft before that time and if we do we will forward it on to you. In addition, Dr. Correa is going to bring with him the serum specimens that we collect once a month from these individuals. In October I am going to Chile to collect further specimens from the study group. The final analysis of the effect of the drug on valvular heart disease will be completed in January. One of the problems that we will face will be adding the final evaluation of the effect of the drug on valvular heart disease to the analysis of the effect of the drug on the acute phase symptoms. It is my feeling that the two should go together since there is no indication that the drug would or should be effective on valvular heart disease and it is not likely that a second publication will be justified. We are in the process of training two technicians to help us complete the laboratory work. In going over our financial situation, we will require the money remaining in the original proposed budget to complete this work in an adequate fashion. With best personal regards, Sincerely yours, CHARLES H. RAMMELKAMP, M.D., Professor of Medicine. DUKE UNIvERsITY MEDICAL CENr]n~, DEPARTMENT OF MEDICINE, Durham, N.C., July ~9, 1963. Dr. NELsON H. REAVEY CANTWELL, Merck Sharp ~ Dohme Research Laboratories, West Point, Pa. DEAR DR. CANTwELL: I enclose your completed questionnaire with an attached sheet listing a few further observations. We do not plan on making any further formal report of our findings this year. The protocol sheets are available to you at any time, of course. I would emphasize as I did prior to accepting MK615 for use that the data here are in no way to be interpreted as representing a controlled study. Our patients come from distant towns usually and are often under the simultaneous care of a local physician whose prescriptions are seldom known to us. We simply report what we have noted in our particular and transitory clinic setting. We need a further supply of both 25 mg and 50 mg capsules of MK615, if these are available. I share with you an impression that these are well tolerated. Sincerely yours, GRACE P. KE1U3Y, M.D., Rheumatism Clinic. PAUL J. BILKA, M.D., Minneapolis, Minn., July 9, 1962. NELSON H. REAVEY CANPwELL, M.D., Merck Sharp d Dohme Research Laboratories, West Point, Pa. DEAR DR. CANTwELL: I have made a preliminary analysis of 50 patients with rheumatoid arthritis who have received MK-615 for at least one week. As I am sure it will take some time before I can complete the clinical evaluation forms on each patient, I thought you might be interested in my impression of the drug at this time. Of the 50 patients 22 recorded no help or else obtained the same degree of help as from the placebo. Nineteen patients recorded slight hclp in the range of 10 to 25 percent improve- ment. PAGENO="0363" CQ~MPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3455 Eight patients reported significant help which I quantitated, at 25 to 50 percent ielief of symptoms One patient reported great help, that is, more than 50 percent improvement. Eleven patients who were on medication for at least 3 weeks had the laboratory data which you suggested: There was no evidence of new ulceration or aggravation of previous X-ray findings of the upper (II. tract. Urinary tract disturbance was evident in 4 patients: One had a transient 4 plus albuminuria and 3 showed a few casts. One of these patients who is severely hypertensive had a BUN of 36 which fell to 30 two weeks after stopping the MK 615; no prior BUN was recorded. Some evidence of liver function disturbance appeared in 7 of these 11 patients: The BSP was elevated in 4; the Cephalin floe was 3 or 4 plus in 5 patients; the alktase was elevated in 4 Unfortunately I did not do base lme values in meet of these patients therefore it is impossible to say if these were the result of thn~ medication in as much as most of these patients were on other dru~s such as small doses of steroids, gold, chioroquin or were recently on Butazolidin. How- ever one patient might be worth indicating in detail and I have enclosed this work sheet that was filled out by Dr. Schultz at the University. One other patient had a normal ceph floe before therapy. The symptomatic disturbances were relatively minor: One patient reported nausea after a single 10 mg dose, repeated on 2 occasions; one patient said her stools were somewhat loose while on the medication for one month; one patient reported mild itching and orythema with 2 trials of the drug (75 mg a day for 3 days and again on 30 mg for one week); three patients were slightly stimulated mentally and even felt a little jittery on the medication. What this all adds up to is difficult to say. Certainly many of the patients were grateful for the added relief the medication seemed to offer even if it was not in the great degree such as with steroids The apparent evidence of hepatic charige~ might be a cause of concern. I would appreciate your ideas concerning extending this study or changing the procedure. I am just about out of the medication and will conclude the study if you wish. I am enclosing some statements from the laboratories where the test procedures were done on these patients. There may still be a few coming in yet so I will send them later. Sincerely, PAUL J. BILKA, M.D. UNIVERSITY OF UTAH, COLLEGn OF MEDICINE, DEPARTMENT OF. INTERNAL MEDICINE, Sa't Lake CIty October15 1963 NELSON H. REAVEY CANTWELL, M.D., Ph. D., Merck $harp ~ Dohnie Research Laboratories, West Point, Pa. DEAR NELsoN: It was pleasant to meet with you again and learn first hand of the current status of MK61S. Your offer of assistance in the statistical analysis of our data is greatly appreciated. The data summary sheets are completed and will be forwarded to you under separate cover, along with detailed information as to the method of acquiring and computing the scores on each patient. The relative weight of each parameter will be described. For your information and use, we are submitting a summary of our experiences with indomethacin in a double blind crossover and long-term evaluation study. All of the patients in- cluded in the double blind study fulfilled the following criteria: 1. A diagnosis of either definite or classical rheumatoid arthritis, using the A.R.A. classification. 2. Active disease as evidenced by swelling and tenderness and/or the necessity of corticosteroids to control symptoms. Most of the patients have had moderate to severe disease with continuous activity for greater than five years. The patients were paired as closely as pos- sible in regard to age, sex, duration of disease, severity of disease and stage and class of disease. One of each pair, chosen at random, was started on indo- methacin, with the other member of the pair being started on placebo. This was done in such a way that neither the patient nor anyone involved in the evaluation of the patient's response knew which medication the patient was receiving at any time. All patients were started on a dose of 200 mg. a day in four divided doses. At the end of one month, the parameters for evaluation were measured PAGENO="0364" 3456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY again and the other form of the drug given. After one month on placebo and one month on indomethaein all patients were started on known drug for the long term evaluation All of the examinations were repeated at monthly intervals or as close thereto as possible With the long term evaluation dosage of indo methacin was varied according to the patient's response and/or side effects. The following parameters of disease activity were evaluated at each visit The patient 5 evaluation of the amount of pain he had had in the previous month graded on a scale of no pain slight pain moderate or severe pain The number of aspirin taken the duration of morrnng stiffness the amount of cor ticosteroids or other medication. A cuff compression test of hand grip and a ring size of each finger were taken each visit. Swelling and tenderness of the shoulders, elbows, wrists, fingers, toes, ankles, knees and hips were evaluated according to the following scales swelling was graded 1 for slight synovial thickening 2 for swelling that changed the contour of the joint 3 was swelling that obliterated the normal joint contour 4 was the presence of a demonstrable effusion Tenderness was graded 1 for the patient says it hurts when pressure is applied 2 the patient says it hurts and winces 3 the patient tries to with draw from the stimulus It was possible for the same observer to evaluate the patients greater than 90% of the time Sub totals of the swelling the tenderness the grip strength the ring size the duration of morning stiffness the amount of pain the number of aspirin and the milligrams of prednisone or equivalent were obtained for each visit The difference between the individual parameters and its base line was obtained so that a negative score indicated worsening of the arthritis whereas a positive score indicated improvement In the marameters of swelling, tenderness and number of aspirin (300 mg. tablets) a change of 1 was reflected as a change of 1 in the score. A change in the amount of prednisone was scored as the number of milligrams times two. The duration of morning stiffness, a change of 1/2 hour was scored as a change of 1. The grip strength was scored as the change in total score of both hands divided by 20 or in other words a change of 20 mm of mercury was scored as a change of 1 The sub totals of the changes in each parameter were then totalled to determine a numerical figure for improvement or worsening of the arthritis By inspection of the changes in the total score of arthritis we have evaluated the response to indomethacin as good, fair and none. A good response was considered a re- sponse of clearly significant improvement, while on indomethacin, with little or no response while on placebo. A grade of fair was given when there was moderate but definite improvement while on indomethacin, again with little or no response to placebo. The grade none represents either worsening of the arthritis while on indomethacin, or no difference between response to placebo and indomethacin. We had 31 patients who started the double blind study. Of these, 4 were unable to complete the double blind part of the study because of uncontrollable side effects. The side effects requiring cessation of the study were nausea, vomit- ing and headache in 2 patients nausea and headache in 1 patient and dizziness with nausea and headache in 1 patient Thus in the short term double blind experiment 68% of the patients had a favorable response 19% had no de monstrable response; and only 13% had side effects requiring stopping the medication. The long-term evaluation study has now been under way for ten months, with observations on patients ranging from seven months to ten months in length. Of the 27 patients finishing the double blind part of the study, 2 were with- drawn before long-term evaluation could be done. One of these was for side effects of the drug, specifically nausea and vomiting, and one patient with a history of bronchial asthma expired with an episode of asthma refractory to all treatment. Of the 25 patients left in the study 15 had a good response 9 had a fair re sponse; and 1 showed no response. Of this group, 8 patients have had to stop taking Indocin because of side effects that exceeded the benefit they were re ceiving These side effects were dizziness in 5 patients nausea and dizziness in 1 patient; severe refractory ulcer-type symptoms in 1 patient; giddiness and mental fuzziness in another In addition to the double blind study, we have used `Indocin' in 12 additional patients. Two of these patients had progressive systemic sclerosis; 1 has the fibrositis syndrome; and 1 has an unusual form of hereditary degenerative joint disease. The remaining 8 patients have a diagnosis of either definite or classical rheumatoid arthritis, and were started on the known drug because of severity of the disease process Four of these were hospitalized because of their arthritis at PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3457 the time `Indocin' was started. Of this group, we have had a good response in 9 patients ; a fair response in 2 ; and 1 patient had side effects that required cessa- tion of the drug before any effect could be noted. Of this group, 5 patients have required stopping `Indocin' because of side effects, even though the response had been fair or good. In our work with Indocin we have found that headache while not an infre quent side effect has not been particularly difficult to control responding either to antihistammes or to reduction in dosage of Indocm The dizziness nausea and ~ omiting however have been refractory to most efforts at control with the ox ception of stopping Indocin Using antacids anti emetics etc has had no effect in stopping this complication. We have found in a few patients that stopping the drug for a period of time, and then re-starting it, has been successful. We have made frequent checks of blood chemistry and hematological studies, and have found no disturbance with hematopoesis or hepatic or renal toxicity. We have had several patients on `Indocin' develop peptic ulcer disease, and have had two epi- sodes of massive upper G.I. bleeding. However, in the 2 patients with upper G.I. bleeding, `Indocin' has been continued after their acute episode and these patients are now 9 months and 4 months post-hemorrhage with no symptoms, or only min- imal symptoms remaining All of the patients who have developed ulcers have also been on corticosteroids The possibility of obtaining fewer side effects with as good or better results from the use of the capsule form of Indocin has been of interest to us As we dis- cussed with you we would be anxious to try the capsules also in a double blind crossover fashion, similar to our study with the tablet form. To~run such a study with the number of patients we would have available would require 90 bottles of 25 mg. `Indocin' capsules, and 00 bottles of placebo capsules. Anticipating the number of patients who will respond favorably to this, and in whom we would like to continue the capsules past the double blind study, we would need approx- imately 400 bottles of 25 mg. capsules to carry these patients for a total of six months. We feel that there would be certain other studies that should be pursued in the use of Indocin These would include correlation of blood level with thera peutic effect and with side effects or toxicity Because of the peculiar mental reactions we have had, we would feel that an attmept to correlate electroence- phalographic findings with blood level and with effect should be done We would like to receive, some of the bulk `Indocin' so that its effect in experimental modeLs of arthritis could be pursued shortly Ultimately the determination of Indocin s place in the therapeutic armamentarium of the rheumatologist should be done. Several of these things will require more detailed planning before they can be accomplished. However, the capsule double blind study and use of the bulk drug in experimental models of arthritis could be accomplished as soon as we can re- ceive the necessary drug. From our experience with your drug `Indocin', we feel that you have developed an agent that has a definite place in the treatment of rheumatoid arthritis, even though we have had considerable disappointment in the amount of side effects We would feel that with further work maybe the difficulties might reasonably be expected to be overcome Although it is still too early to tell we have noticed in 4 or 5 patients a tendency for the development of remission of their disease `ictivity Whether they are truly going into remission remains to be seen but the evidence suggesting that they are Is there. We can discuss the necessary financial support for a double blind study using capusules when the decision is reached to initiate the study. Very truly yours, JOHN R. WARD, M.D. STANFORD UNIVERSITY SCHOOL OF MEDICINE, STANFORD MEDICAL CENTER, DEPARTMENT OF MEDICINE, Pa'o AZto, Ca2if., August 22, 1963. NELSEN H REAVEY CANTWELL M D Merck $harp c~ Dohme Research Laboratories West Point Pa DEAR DR CANTWELL I am sorry I haven t answered your previous request for information about Indoinethacin For various reasons I have not put our results together yet but will do so in the nst too distant future This was our first effort at drug evaluation, and I am afraid we have been somewhat inefficient in maintaining precise up-to-date evaluations of the patients. Though all the necessary information is In their charts, we have not extracted it all as yet. PAGENO="0366" 3458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Our impression of the drug remains good. It is clearly not the answer to rheumatoid arthritis and has not been helpful in those few instances of connec- tive tissue disease where we have tried it; but in a significant number of patients it is of decisive benefit when other medications have failed. I am writing to you about a financial question. We have obtained a modest amount of laboratory information on our patients which the patients were guaranteed would not be charged to them. The day of reckoning. is approaching with the hospital when they insist that I settle accounts. I am therefore writing to ask what mechanism you would propose that we employ to obtain the money from you to meet these expenses? Many thanks for your consideration. Sincerely, ITAI~s~rED R. HOLMAN, M.D. SCRIPPS CLINIC AND RESEARCH FOUNDATION, La Jolla, Calif., April 29, 1963. ELMER ALPERT, M.D., Merck Sharp c~ Dohme Research Laboratories, West Point, Pa. DEAR DR. ALPERT: I thought I would drop you a little progress note as to what we are doing with the MK-615 that you sent to us, and at the same time, ask if you could send me some more. With the full realization that our clinic material Is too limited in numbers for a large double blind study, we have been merely using MK-615 in the manage- ment of some of our patients and recording our impressions of it. Today I can merely tell you that we have seen no untoward effects from it although our top dose has been only 250 mgs as per your suggestion. We have also found that patients tolerate MK-615 together with ASA dose of 4 grams a. day without signs of salicylate intoxication. I can also say that the persons on MK-015 seem to be doing quite well although it does not, seem to be holding one 40 year old lady. Finally, regarding our equilibrium dialysis study with MK-615 we have found that MK-615 does, indeed, bind to the same site on albumin that is bound by the I~ labeled Urokoh. As you recall, sodium salicylate also binds to this site but we think that MK-615 has a stronger bond than does sodium salicylate. Meantime, with your generosity I would greatly appreciate some more 50 mg MK-615 tablets so that we may continue our few patients on it. Very sincerely yours, RICHARD S. FARE, M.D., Head, Division of Allergy and Immunology. NEW BEDFORD, MASS., February 18,1964. N~soN H. R. CANTWELL, Ph. D., M.D. Merck Sharp ~ Dohme Research Laboratories, West Point, Pa. DEAR NELSON: I am sending to you the initial MK-015 Clinical Evaluations as I originally submitted them. Under comments, where previously no comments had been made on any of the forms, I have brought my data up to date to the time when each patient discontinued the medication. As you may see from these comments, I failed to note any beneficial effect on either a decrease in steroid dosage or any relief which may have been obtained from these patients who all were suffering from some allergic disorder. My initial impression after evaluating the original data therefor held it does not seem to be of any benefit in allergic diseases. I might note that I have had four allergic patients with bursitis in whom I took the liberty of trying this drug and had beneficial result in all four. I was patiently waiting the recurrence of my own gout to see if it would be of benefit but fortunately or unfortunately depending upon your point of view, I myself have not had the chance to evaluate it per- sonally. Because of the poor data I did obtain, I saw no reason to go ahead and use the capsule form of M-615 and have not done so. If you feel there is a dramatic dif- ference in the therapeutic benefit, which I would doubt, I could try a group of selected patients on this if you so desire. Edward Joyce was in to see me and informed me that you are considering a topical preparation of this which may help in dermatological disorders. I indicated PAGENO="0367" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3459 to him that I would be willing to carry out a clinical trial if you felt this was promising. As far as compensation for the work done, I feel a grant of $1500.00 would be fair if you so see fit. I am sorry you have been too busy to come in to this area. I will be at the Amer- lean College of Allergy meeting in Miami the first of March. If you have that in your plans I will be happy to see you then. Best regards from Elaine. Hope all is well with you. Very truly yours, PAUL CHISRvINSKY, M.D. MINNEAPOLIS, MINN., Jane 24,1963. NELSON R. CANTWELL, M.D., Merck Sha'~p & Dohme Laboratories, West Point, Pa. DEAR NELSON: I have gone over the data on the 63 patients I reported to you earlier this. month and have extracted the information you recently asked about. 1. 40 patients have been on 150 mg or less of Indocin per day. 20 of these re- ported no or slight help and 20 reported significant (25% to 50%) or great (more than 50%) help. - 2. 15 patients had 200 mg per clay and 7 reported no or slight help and 8 reported significant to great help. 3. 8 patients had more than 200 mg per day. 5 reported no or slight help and 3 reported significant or great help. 4. All patients had rheumatoid arthritis. 5. There was a definite increase in GI symptoms and especially headache with increase in dosage. There was very little headache on 100 mg or less per day. Gastric irritation seems to be an increasing problem. 6. I have had little experience with non-rheumatoids so far, but 1 patient with Reiter s disease had an excellent response 1 patient with chronic gout had a good response and 1 patient with Scieroderma had slight help 7 Regarding headache and migraine the very day you called the first patient I asked the question of stated that she had been a frequent sufferer of migraine before developing her arthritis. She had been free of headache until it recurred with Indocin. However, she stated this headache was different from what she remembered her migraine was like. I haven't had the opportunity to put the ques- tion to all patients, but several have denied previous migraine, yet 3 have admit- ted to prior migraine. 8. 39 of the 63 patients have been on Indocin for 2 months or more, some over 8 months. It is my plan to carry as many on long-term therapy as tolerate and benefit from the drug. New patients are being constantly added as I presume is your desire. Sincerely, PAUL J. BILKA, M.D. PAUL J. BILKA, M.D., Minneapolis, Mina., August 29, 11?62. NELSON H. REAVEY CANTWELL, M.D. Merck $harp ci Dohme Research Laboratories, West Point, Pa. DEAR DR. CANTWELL: During the last month I have been carrying on a new trial with MK-615 using the higher douage range which you suggested. A pre- liminary analysis of 22 patients indicates rather significant improvement in the results using this higher dosage. All patients have rheumatoid arthritis, and the majority have been on the lower dosage trial. The results after 2 to 4 weeks therapy are as follows: Four patients report no significant improvement. Five patients report 10 to 25 percent subjective improvement. Twelve patients report 25 to 50 percent improvement. One patient reports marked, or over 50 percent improvement. There have been 2 complaints of nausea caused by the higher dosage and one patient who had a previous active duodenal ulcer, and also is on 0.6mg beta dexamethasone per day developed an active PU on 100mg MK-615 per day. One other patient complained of headaches. I have not, as yet, analysed the labora- tory data, but will do this shortly when I fill out the regular investigative forms. I thought, however, that you would be interested in these preliminary findings. Sincerely, PAuL 3. BILKA, M.D. PAGENO="0368" 3460 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DUKI~ UNivI~RsITy MEDICAL CENTER, DEPARTMENT OF MEDICINE, Durha~m, NfJ., Deoembcr 10, 1963. Dr. NELSON H. REAVRY CANTWELL, Merck sharp cG Dohme, West Point, Pa. DEAR DR. CANTWELL: Enclosed are the original data sheets for patients who received Indocin tablets. You will note that some are continuing on capsules. Another 24 patients started on capsules since August 1963, and these data sheets are retained here at present. The presently enclosed sheets represent for the most part those patients covered in the June 1963 summary which I sent to you. Sincerely yours, GRACE P. KEBBY, M.D., Rheumatism Clinic. DUKE UNIVERSITY MEDICAL CENTER, DEPARTMENT or MEDICINE, Durham, N.U., December 8,1963. Dr. NELSON H. REAVEY CANTWELL, Merck sharp c~ Dohine Research Laboratories, West Point, Pa. DEAR DR OANTWELL I am sorry to have missed seeing you at the recent Boston meeting However I do want to mention two patients in regard to Indocin one for your own information and one to raise a question re contraindication to use of Indocin. A 19 year old CF with unequivocal SLE manifesting most strikingly as acute nephritis with good renal function was admitted in October while I was out of town. Because she was not sufficiently critically ill to require immediate ACTH or steroids, my colleagues started her on Indocin, 50 mg per day increasing over about one week to 150 mg per day at which time I first saw her on return to town An originally normal BUN rose slightly in the first few days and then to 47 mg% by the time I first saw her On the chance that this was the phenomenon you have noted with Indocin in the presence of pre existing renal disease Indocin was discontinued The BUN returned to normal over the next few days A young WM with chronic rheumatoid arthritis, on phenylbutazone, was admitted recently to the VA hospital here with UI symptoms Two gastric ulcers near the cardia were demonstrated He was to be discharged this past weekend with ulcers healing well and promptly, to come to the Rheumatism Clinic at Duke for the first time either this Thursday Nov 12 or Nov 19 referred specifically for Indocin However recalling the report at the June meeting of pa tients with previous peptic ulcer/developing multiple gastric ulcers, I question whether Indocin may not be contraindicated in this patient. If it is at all possible to have your comments on any further information concerning the UI tract during Indocin therapy prior to this patient s scheduled first visit to the clinic I shall most appreciate having them He has to travel 150 miles from his home doing his own driving despite severe rheumatoid arthritis. Had I realized that I would be unable to get your comments in Boston I would not have suggested such an early appointment for the patient Following our recent telephone conversation I sought and obtained permis sian from NIH to use up to $3600 from my research grant for the proposed work with Dr. Luscher. I am therefore proceeding with my plans as related earlier. I also contacted Dr Stead to ask if funds of the sort you proposed were per mitted by the department. He wa's entirely agreeable and felt that such uncom- mitted funds offered greater latitude in opportunity to work and visit in other laboratories, as well as provide enjoyable contact with the commercial firm. From my awn point of view the added advantage of being able to conserve my NIH funds in greater part for the operations in my own laboratory which would continue on a limited scale in my absence Therefore I am free to accept any research funds from Merck if you still feel as before that the type of informal report sent you last June on our experiences with Indocin constitutes a valid basis for such funds This type of informal report on our experience can continue to be furmshed although as I recounted earlier formal reports from here will never be proper due to the long distances our patients travel making closer supervision impossible In answer to your inquiry as to institutional and depart mental requirements in addressing funds the funds from Sandoz three years ago were addressed as follows', and this would be the preferred method now: PAGENO="0369" COMPETITIVE PROBLEMS IN THI~ DRUG INDUSTRY 3461 Name of Payee: Anna H. Hanes Research Fund, Department of Medicine, payable to Dr. Grace P. Kerby. Street Address Duke University School of Meclieme Olty: Durham, N.O., 27706. Sincerely yours GRACE P. KEnnY, M.D. UNIVERSITY OF OREGON MEDICAL SCHOOL, DEPARTMENT OF PHARMACOLOGY, Portland, Oreg., February 25, 1964. Dr. NELSON H. REAVEY CANTWELL, Merck ~1uirp c~ Dolvme Research Laboratories, West Point, Pa. DEAR DR CANTWELL Herewith are the special ease reports for 11 cases who have had trial of the Indocin capsules The number of the cases are from 3518 to 3528 For the record I am retaining the additional case record forms that you sent and numbered from 3529 to 3567 These unused forms will be used for any additional cases that are placed on "Indocin" capsules. However, if you wish these blank case forms returned, I can do that. As you know, I sent you a copy of the individual case records for all the patients (21 cases) who have received both the tablets and the capsules of "Indocin", I am currently writing this up as a short report for possible pub- lication as a research note in CURRENT THERAPEUTIC RESEARCH. When I complete this short note, I shall forward you a copy for your inspection. I hope that your case reports for the capsules are coming in satisfactorily and you can get off the material to the FDA. Good Luck! With best wishes, NORMAN A. DAVID, M.D. Professor of Pharmacology. STATEMENT OF SENATOR NEL50N-Resumed One of our witnesses Dr Donald Mainland a medical doctor ~and one of the most famous biostatisticians in this country, has recommended that the evaluation of drugs be taken entirely out of the hands of the pharmaceutical industry, an idea which merits study. Even if the drug firms continue to do animal, and to some extent clinical studies, approval for marketing by the FDA should be based, at the very least, on studies under its direction. Perhaps it may be a good idea to establish a national drug institute, the purpose of which would be to evaluate drugs in house and/or by contract In other words it seems reasonable that there should be an independent careful and scientific evaluation of a drug to secure FDA s approval We are studying this problem and may be pr~pared to propose legislation in this field sometime soon The second problem is FDA s requirements for evidence of safety and efficacy The statute requires substantial evidence of safety and efficacy which means "evidence consisting of adequate and well-controlled investigations." On Decem- ber 7, 1964, the medical officer in charge of the New Drug Application for Indocin stated in her summary that "There is a paucity of controlled studies in this massive NDA." On March 15, 1967, Dr. David Hurwitz, M.D. of the FDA's Bureau of Medicine in referring to claims of efficacy in osteoarthritis of the joints, other than the hips and muscular skeletal disorders, found that "136 out of 137 studies are deficient in technique and incapable of standing up to critical exam- ination; it is unfortunate that the company and its investigators do not use the more sophisticated investigative techniques that have been evolved to evaluate new drugs Dr Hurwitz also stated that In view of the wide spread acceptance of Indocin and its seeming benefit in Rheumatoid Arthritis, it is an unwarranted conclusion to say at this time that the drug is of no usefulness in this disease. However, since these excellent studies by Cooperating Clinics Committee and by Donnelly et al. in the British Medical Journal cast considerable doubt on the efficacy of Indocin, further studies of equal or better quality and of longer duration are in order to determine the place of this drug in the physician's Armamentarium. This re-evaluation is particularly necessary given the toxicity of Indocin which renders the drug totally unfit for use if a significant therapeutic benefit cannot be established." The question then arises whether a "significant" therapeutic benefit has been 81-280 0-08-pt. 8-24 PAGENO="0370" 3462 COMPETITIVE PROBLEMS IN THE DRUG INDUSTItY established for rheumatoid arthritis, which presents the largest potential market for indomethacin, Indocin). Perhaps an answer can be found in Dr. Hurwitz's memorandum of August 25, 1967, in which he stated that: "At the present time, then, it would seem wise to consider Indocin as probably effective in rheumatoid arthritis pending further studies in this area." The word "probably" should be emphasized. How can we reconcile the FDA medical officers' opinion that there is a "paucity of controlled studies" and that the drug is "probably effective" with the statu- tory requirement of substantial evidence of efficacy? How can we reconcile the requirement of "substantial evidence" of safety with the opinion of an FDA `medical officer that "* * * Indocin has shown a similar propensity to cause a wide variety of serious and sometimes fatal reactions, and its clinical usefulness has been limited by its toxicity." The American Medical Association's New Drugs, 1967 edition, states that: "Central nervous system effects (.headaebes, usually severe in the morning; vertigo; light headedness; mental confusion) occur during the early weeks of therapy in about 20% to 30% `of patients taking indomethacin. Drowsiness, con- vulsions, depression and psychic disturbances such as depersonalization have also been reported. * * * Indomethacin should be regarded as being potentially ulcer- ogenic. It may produce single (or) multiple ulceration of the esophagus, stomach duodenum or small intestine. Cases of perforation and hemorrhage, a few of them fatal, have been reported." I am inserting at this point a summary of side effects reported by Merck's investigators. (The summary follows:) SIDE EFFECI's-INDOCIN "The patient complains of a distressing lightheadness, a feeling of being in outer space, a feeling of the head being foggy and a feeling of difficulty in con- centration or in cerebration. There may or ma~ not be an associated violent headache and in a few cases, the headache was so violent that it was predominant or alone. In a few instances, these symptoms have been so severe as to be totally incapaciting and even prostrating" (Oct. 9, 1962). Dr. NORMAN 0. ROTHERMICH, Colum~bus Medical Center, Research Foundation, Inc., Columbus, Ohio. "The greatest deterrent to increasing dosage to an effective level is the appear- ance of cerebral toxicity. This manifests itself clinically in excruciatingly severe headaches, dizziness, lightheadedness, disturbances of sensorium, a feeling that the head is floating away or even separating from the body and feelings of de- tachment from reality" (June 12, 1963). Dr. NORMAN 0. ROTHERMICH. "As higher dosage levels are approached, it is to be expected that the incidents of cerebral toxicity goes up proportionately and this, in my opinion, represents a not insignificant disadvantage to the drug for it reduces the number of arthritics who can be benefited by the drug. . . . on the other hand some patients' have developed disabling cerebral toxicity . . . on comparatively low dosages" (Oct. 12,1963). Dr. NORMAN 0. ROTHERMICH. "I am sorry to report but I am sure ~you should know, that we saw rather severe dermatitis in one patient after' taking four tablets (100 mg) of MK-615 over a 24 hour period. We sincerely hope we will have better results to report in the future" (Apr. 24, 1962). Dr. H. M. MailGous, ______ Pittsburgh, Pa. "We had 31 patients who started the (short term) double-blind study. . 13% had side effects requiring stopping medication." "In our work with Indocin we have found that heachache while not an infrequent side effect, has not been particularly difficult to control, responding either to antihistamines or to reduc- PAGENO="0371" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3463 tion in dosage of Indocin." "We have had several patients on Indocin develop peptic ulcer disease, and have had two episodes of massive upper 01 bleeding." "We feel that there would be certain other studies that should be pursued in the use of Indocin. These would include correlation of blood level with therapeutic effect and with side effects or toxicity. Because of the peculiar mental reactions we have had, we would feel that an attempt to correlate eleotro-encephalographic findings with blood level and with effect should be done." "We have had con~ siderable disappointment in the amount of side effects" (Oct. 15, 1963). Dr. JOHn~ fl. WABD, College of Medicine, University of Utah, Salt Lake City, Utah. "I would be very anxious to receive further information from you concerning other clinical experienèes with Indocin. Our experience to date with the material you supplied us has been limited because of the significant incidence of head- aches and gastrointestinal complaints. This has made me reluctant to use it in a number of instances where I might wish to have done so. I would therefore greatly appreciate any further data you have relating to this drug that might influence our use of it" (Jan. 9, 1968). Dr. KURT J. ISSELBACKER, Harvard Medical School, Massachusetts General Hospital, Boston, Mass. "Toxic Manifestations: Only 6 of the 27 failed to show some evidence of toxic- fty, but in 2 others showing GI toxicity and 1 with~ rash the medication was continued. Only 1 of the 6 males showing `excellent' therapeutic response showed clinical toxicity-GI pain" (Jan. 2, 1964). Dr. WM. C. KUZELL, San Francisco, Calif. "I believe you have an excellent skeletal analgesic but I am worried about the headache, nausea and emesis and mental confusion" (Mar. 20, 1963). Dr. HAROLD M. ROBINS, Delaware Avenue Medical Center, Buffalo, N.Y. "In brief, the acute data indicate that indoinethacin is approximately as effec- tive as aspirin in the control of fever, joints and other acute manifestations" (Sept. 4, 1963). Dr. EDWARD A. MORTIMER, Jr., Cleveland Metropolitan General Hospital, Cleveland, Ohio. "Dr. Gum continues to find that Indocin is an interesting and effective agent in rheumatoid arthritis. The incidence of headaches, however, is between 85% and 100%. This is causing him real concern. He commented that this would also seriously impair any presentation to FDA. *. * * Dr. Burch . . . refuses to do further clinical investigations and is not too happy that any of his staff continues to do them" (May 6,1963). Memo R. R. Robert to Dr. N. H. R. Cantwell on "Progress of Study of Indocin" Merck Co. "The side effects occur in about ten percent of the patients and in nearly one- half of this group, the drug had to be discontinued. The side effects are nausea, headaches and lightheadedness" (Oct. 3, 1963). Dr. W. D. PAUL, University Hjspitals, University of Iowa, Iowa City, Iowa. "We also discussed with Dick Rebert we definitely feel that you should set up a double blind on the drug. . . ." "It is with some disappointment that we are reaching the conclusion that the effect of the drug is largely subjective and PAGENO="0372" 3464 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY would most clearly be assigned to the category of analgesics rather than anti- phlogistic agents according to our present experience (Oct 1 1963) Da R W PAYNF McB rule Clinic Inc Oklahoma City Okia In the fall of 1962 I submitted data on the tablet form of Indocin on the government forms I have no additional data My results were generally unsatis factory and so I discontinued use of the drug (Jan 7 1964) Dr. JOSEPH E. GIAN5IRACU5A, ~an Jose, Calif. `I don t believe I will continue to use Indomethacin until some other reports are available from people in this country the only possible use that I think we might make of it sometime would be in the treatment of acute gout.. . . I think a study of Indomethacm compared with Placebo might be something the house officers might like to undertake sometime in the future We have no plans at this time" (Jan. 9, 1964). Dr. J. W. HOLLINOSWORTH, school of Medicine, Yale University, New Haven, Conn. "I have learned that two other patients on Indocin have developed peptic ulcers, one with perforation necessitating operation. This now, in our series of approximately 100 patients, makes at least six, and perhaps seven, ulcers. Cer- tainly this agent is ulcerogenic to a degree that will make it difficult to continue to advise its use" (July 9, 1963). Dr. CARt M. PEARSON, School of Medicine, University of California Medical Center, Los Angeles, Calif. My incidence of headaches in this group has been about 33% I have discon tinued the drug as soon as headaches occur because I have not known bow to evaluate this from a toxic point of view. Until we know more about its causes, I don't think we should continue it in the presence of headaches" (June 21, 1963). Dr. EDWARD E. ROSENBAUM, ______ Portland, Oreg. "However, the incidence of side effects that we have more recently encoun- tered seems to us to be at the present time too great to have this medication used as therapy in general office practice" (June 11, 1963). Dr. CARL M. PEARSON. STATEMENT OF SENATOR NELSON-RESUMED In the December 17 1965 issue of Medical World News Dr Charley J Smyth is reported to have claimed that indomethacin is the most promising antirheu- matic agent since cortisone. Yet, less than two years later in an article in the April 1967 issue of Consultant with the title, "Treating Rheumatoid Arthritis: What's Most Apt to Succeed?" Dr. Smyth mentions indomethacin only in passing. Steroids phenylbutazone antimalarials gold treatment and surgery are dis cussed but not indomethacin Dr Smyth s explanation to the Subcommittee is that space was limited Would it not be reasonable to assume that if space is limited the most important items would have been included and the ma~ginal ones left out9 Doctors Calabro and Smyth presented their personal views of the drug on behalf of the manufacturer The only independent doctor who had the oppor tunity of inspecting the NDA file was Dr 0 Brien of the University of Virginia Medical School. His judgment was that although there was considerable testi- monial evidence, there was relatively little scientific evidence. Dr. L. A. Healy in the article which Senator Scott has kindly put into the record stated that "In a chronic disease such as rheumatoid arthritis, which is marked by spontaneous remissions and exacerbations where both the patients and physicians naturally are hoping for improvement, the subjective impression of the efficacy PAGENO="0373" . COMPETITIVE PROBLEMS IN ~EIE DRUG INDUSTRY ~465 of any drug is inadequate to judge its value. It is apparent that more reliable information on effectiveness of indomethacin can be obtained from the third group, the controlled studies." Four independent well controlled studies have shown that indomethacin is not more effective in rheumatoid arthritis than is aspirin which is still the drug of choice according to the AMA. The third problem is the use of euphemistic language in warnings and con traindications when strong language is required The reviewing medical officer recommended that the following wording be included as a contraindication Indocin should not be administered to children This is clear and strong, but this essential warning ended up as follows: "Since the experience with Indocin in children is limited, it is recommended that this drug should not be administered to pediatric age groups until the indica- tions for use and dosage have been established There is quite a difference in clarity and conciseness between the version recommended by FDA s medical officer and the one adopted by the firm and finally approved by the FDA The result was that the message did not get through In a poll by Modern Medicine which was reported in its August 1 1966 issue almost 10% of the pediatricians who reported treatment of rheumatoid arthritis prescribed indomethacin during a thirty day period in the first year of its marketing life During this time (first year of Its marketing life by July 1966) five deaths in children being given this drug were reported Up to the beginning of 1968 9 deaths in children were reported A stronger warning wa~ adopted laterat the insistetice of the FDA. Why didn't the FDA insist on a strong warning in the first place? The reason given by Dr. Hodges was that there wasn't enough data to show that it was dangerous or safe for children. Yet, even though the statute insists that sub- stantial evidence of safety and efficacy should be presented for uses of a drug, it appears that the FDA modified the requirements and used soft warnings for children because the drug was tested in only 55 children and there was not enough evidence to show lack of safety and efficacy The fourth problem is that of the overpromotion of Indocin Here is a drug with very limited uses and yet it is reported that it has a wholesale sales volume of over $40 million per year and is one of the 200 most frequently prescribed drugs The New Drug Application for Indocm was originally approved for use in only the following 4 conditions: (a) Rheumatoiçl arthritis. (b) Rheumatoi4 (ankylosing) spondylitis. (o) Degenerative joint disease (osteoarthritis) of the hip. (d) Gout. The most frequently occurring illness is Rheumatoid Arthritis, for which, according to AMA's NEW DRUGS, aspirin is the drug of choice, and Indocth should be used only when aspirin fails or cannot be used. The FDA testified that Indocin is being used beyond its approved indications and that some physicians regard the drug as a general purpose analgesic anti pyretie anti inflammatory agent and the 1966 promotion of the drug featured this effect. The fifth problem is that of false and misleading claims which the FDA testi fled have been made for this drug and which necessitated a remedial Dear Doctor" letter and a Bureau of Medicine recommendation of prosecution under the Food and Drug Act. I am also inserting at this point a staff memorandum dealing with Merck's advertisement of Indocin in the British Medical Journal of 196T-68. (The memorandum follows:) MEMORANDUM To Senator Gaylord Nelson chairman Monopoly Subcommittee From Benjamin Gordon staff economist Subject Comparison of ads for Indocin in the British Medical Journal and the Journal of the American Medical Association 1967-68 None of the advertisements for Indocin in the British Medical Journal (BMJ) in the years 1967-68 included any prescribing information Some of these ads say Detailed information is available to physicians on request Others do not even make this reference to indicate the desirability of obtaining information on the drug prior to prescription and administration. PAGENO="0374" 3466 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRr The ads quote from papers favorable to Indocin. But, they do not, at any time, mention warnings,, precautions, contraindicatfóns, or side effects. Not one of these ads refers to deaths of children from Indocin-a subject which is required to be mentioned in all ads run in the U.S. None of the ads warns against use / of the drug in pregnant women or people suffering from peptic ulcer. The fact that Indocin may cause reactions of the central nervous system, gas- trointestinal reactions, skin reactions, blood disorders or eye-ear problems .as reported by Merck's clinical investigators, is not even mentioned. But, because of FDA regulations with respect to advertising, all U.S. ads do carry these warn- ings. Furthermore, almost every ad which h'as appeared in the BMJ in the last 18 months has promoted Indocin for bursitis and other muscular problems for which the FDA has not approved claims in this country. Thus, although Merck is not allowed to promote Indocin for these conditions in the U.S., the firm is ac- tively promoting it for them abroad If the scientific clinical evidence of the value of Indocin in the treatment of bursitis is not sufficient to recommend it for consumption by `Americans for this purpose, is there any reason to believe that it would benefit the British people? Thus, by praising Indocin, and pointing to its benefits, but by failing to call attention to the drug's negative aspects, Merck is presenting an unbalanced pic- ture to the British Medical profession STATEMENT OF SENATOR NELSON-RESUMED In summary, FDA's criticism of Merck with respect to Indocin is as follows: 1. Merck made a promotional letter out of a remedial letter to doctors. An additional letter had `to `be sent out at the insistence of the FDA to correct the first one. 2. Merck used an older article as a testimonial when a more recent but less favorable article was available well before the ad was created and published. In addition, the second `article favored a competitive product to a great extent: 15 patients preferred phenylbutazone: 10 found them equally effective; and one preferred indomethacin. 3. Claims of effectiveness were based on dosages far in excess of the upper approved safe limit when the drug was marketed in this country in capsule form. 4 Promotion over the first year of Its approved marketing improperly presented the drug to the medical profession-both as to the range of its effectiveness and margin of safety. The testimonial letters submitted by Merck & Company for the hearings record reflect in general a lack of enthusiasm for the potentialities and safety of Indocin and appear to confirm the testimony of the Food and Drug Administration, with respect to the limitations of Indocin and the unwarranted claims made for it in its advertising and promotion. Some significant statements from Merck's submissions follow: Dr. Kemper: Drug of choice rheumatoid spondylitis' and degenerative arthritis. Not nearly as effective in peripheral rheumatoid arthritis .as in others. Dr. Hamaty: "Regarding .the double blind method in evaluating drugs for rheumatoid arthritis . . . it is the best we have available at this time." Dr. Duncan S. Owen, Jr.: "Indocin is no panacea in the treatment of rheu- matoid arthritis but it definitely has a place in its treatment. * * *" And what is the place? Dr. Owen says that aspirin should be given first "in essentially all cases of rheumatoid arthritis. If after several weeks no clinical improvement is expe- rienced, another agent should be added. We frequently use Indocin as the second agent and will continue to use it in this capacity. Also, we have found the drug to be helpful in selected cases of osteoarthritis, acute gouty arthritis, and ankylosing spondylitis." Dr. Donald F. Hill: "u * * our group did conduct a clinical trial to study efficacy and toxicity before Indocin was marketed These studies ~ crc limited primarily to rheumatoid arthritis and, unfortunately, did not show consistent results. There were a few patients who felt that Indocin gave them much more relief than other analgesics or anti inflammatory compound but we did not feel that the drug altered the course of the disease. We continue to use Indocin in a limited number of patients where they feel it has been of help to them. Unfor- tunately, a number of our patients were unable to tolerate the drug." PAGENO="0375" * COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3467 Dr. Arthur Dobkin: "I have found `Indocin' to be beneficial in a selected and limited number of arthritis patients." Dr. Jack Zuckner: "If there is a doubt about Indocin in the treatment of rheumatoid arthritis, I believe that double blind studies should give the most reliable information in its efficacy." Dr E G L Bywaters I feel that this drug is useful in certain patients with rheumatoid arthritis and has about the same potency as aspirin. It is, however, more expensive and we therefore tend to use it when patients cannot tolerate aspirin and sometimes to wean them off steroid medication. . . . It seems useful also in ankylosing spondylitis and we have used it there in such cases who have develoiped intolerance to phenylbutazone. * * *" Dr. Harry F. Klinefelter: "~ * * J have found Indocin very helpful in a limited number of arthritics who have not responded to other medication, such as aspirin. Butazalidin and Tachearil. There are a small number of people with rheumatoid arthritis who do extremely well on Indocin, and if they respond, they respond to doses of 75 mg. a day or less." In addition Mr Gadsden during the course of his testimony made the follow ing statement: "I would furthermore like to call your attention to a quotation of 1967 from the recognized publication, NEW DRUGS, as published by the AMA. It says that because `Indocin' has produced relief in acute attacks within 48 hours, and because it lacks untoward effects of Coichicine, some physicians consider it to be the drug of choice for these attacks." The complete paragraph from the AMA 1967 (publication from which the excerpt was taken and which presents a more limited picture of the drug's uses is as follows: "Indomethacin produces anti-inflammatory effects in patients with gout and may be as effective as phenylbutazone in its promptness of action an the degree of relief it provides Because it has produced relief in acute attacks w ithm 48 hours and because it lacks the untoward effects of colchicme some clinicians consider it to be the drug of choice for these attacks however controlled trials are needed to determine how its effectiveness compares with that of colchicine Indomethacin may 8e useful as a supplement to colchincine in the management of severe cases of gout. Whether it is useful as a prophylactic agent in gouty arthritis remains to be established." [From the Medical Letter, vol. 10, No. 10, May 17, 1968] INDOMETEACIN (IND0CIN) Indomethacin (Indoein-Merck) is widely used as an anti-inflammatory anal. gesic drug in the treatment of rheumatoid arthritis and spondyhtis osteo arthritis and gout (Medical Letter Vol 7 p 89 1965) Enthusiastic reports of its effectiveness followed the introduction of the drug in 1965 but many of the reports published since that time have been much lets enthusiastic, some even questioning whether the drug was more effective than placebq. In the mass of conflicting studies of indomethacin, not many have been con- trolled and very few of the controlled studies have been so designed as to give clear answers about the usefulness of the drug. Frequently other drugs were used simultaneously and doses varied widely. The numerous uncontrolled studies have generally ignored the variable course of rheumatic disorders and the effectiveness of placebos in many patients. On the basis of both published reports and their own experience, Medical Letter consultants believe that indomethacin is a useful drug, but that its usefulness is limited by its frequent and sometimes severe side effects. Rheumatoid arthritis.-Indomethacin appears to have about the same anti- inflammatory and analgesic effectiveness as aspirin in patients with rheumatoid arthritis (R S Pinals and S Frank New Eng J Med 276 512 1967) Aspirin is better tolerated by most patients and it remains the drug of first choice for rheumatoid arthritis. Indomethacin is not as hazardous as the corticosteroids, gold, or phenylbutazone (Butazolidin), however, and it is worth a trial in patients who cannot tolerate aspirin. Some investigators have observed additive effects when indomethacin was given along with aspirin; other investigators have observed no additive effects (The Cooperating Clinics Committee of the Amer. Rheum. Assn., Clin. Pharmacol. Ther., 8:11, 1967). PAGENO="0376" 3468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Rheumatoid (ankylosing) spon4ylitis.-Although adequate trials are lacking, indomethacin appears to be a~ effective as phenylbutazone in ankylosing spoIl dyhtis For patients in whom aspirin is ineffective some clinicians prefer in domethacrn to phenylbutazone because its side effects while frequent are not likely to be as serious as they may be with phenylbutazone many deaths from blood dyscrasias have followed prolonged or repeated u~e of that drug Gout -Indomethacin is often effective in the treatment of acute gouty arth ntis (P L Boardman and F D Hart Practitioner 194 560 1965) with some reports indicating that it acts more rapidly than colehicine or phenylbutazone Some clinicians prefer a brief course of phenylbutazone, and consider both drugs preferable to colehicane because of the frequency and severity of gastrointestinal side effects with colchicme Trials comparing indomethacin with phenylbutazone are too few to permit a confident choice between the drug~ Osteoart1i~ritis -The manufacturer claims that indomethacin as effective in osteoarthritis of the hip While the evidence is not conclusive one controlled short term trial does support this claim (J Wanka and A St J Dixon Ann Rheum Dis 23 28$ 1964) Present evidence does not adequately support the results of early studies showing the drug to be effective in other joints affected by osteoarthritis Ad'verse effects -The incidence of adverse effects has varied In different studies from a few per cent to about three quarters of the patients Gastric side effects have been less frequent with the cap~,ule formulation which replaced the early tablet formulation Most of the studies have shown a high incidence of such side effects as headaches vertigo and gastrointestinal disturbances including nausea and vomiting Peptic ulceration has occurred sometimes with bleedmg and cholestatic )aundice has been reported Mental depression has also been reported (M Thompson and J S Percy Brit Med J 1 80 1966) There have been a few reports of leukopenia thrombocytopenia and agranulocytosis A number of deaths have been associated with the use of Indomethacin some of them the result of ulceration and bleeding Both the incidence and the severity of side effects have usually been dose related Indomethacin may interfere with resistance to infection particularly in children (J C 3acobs JAMA 199 932 1967) or may activate latent infections For the persent Indomethacin should not be administered to children Dosage -The manufacturer recommends an initial dosage of 50 to 75 mg a day with gradual increases up to 200 mg a day Because of the high incidence of adverse effects at 200 mg many clinicians limit dosage to 100 to 150 rig a day. Conclusion -Indomethacin appears to be no more effective than aspirin in the treatment of rheumatoid arthritis; all Medical Letter consultants agree that aspirin is the drug of choice and that indomethacin should be used only in patients who cannot tolerate aspirin. There is some belief that the combina- tion of indomethacin and aspirin may~ be beneficial in a few patients with rheumatoid arthritis not satisfactorily controlled on aspirin alone and that a trial of the combination in such patients is worthwhile Indomethacin appears to be as effective as phenylbutazone in the treatment of ankylosing spondyhtls and is probably less hazardous It is also effective in acute gouty arthritis and it may be helpful in the treatment of osteoarthritis of the hip Despite frequent minor side effects and occasional serious effects indomethacin appears to be less hazardous for long term use than corticosteroids gold or phenylbutazone [From the Medical Letter, vol. 7, No. 22, Oct. 22, 19651 INDOCIN Indomethacin (Indocin-Merck) is a nonsteroid indole derivative offered for the treatment of rheumatoid arthritis ankylosing (rheumatoid) spondylitis osteoarthritis and gouty arthritis Like other drugs used in arthritis-aspirin phenylbutazone and the corticosteroids-indomethacin has analgestic and anti inflammatory effects The drug is not free of serious side effects and its effective ness is much more limited than many of the early claims would indicate never theless it appears to be a useful addition to the group of drugs available for the treatment of arthritic disorders Rheumatoid arthritis and spondylitas -In a number of clinical trials, mostly uncontrolled about 40 to 50 per cent of patients with rheumatoid arthritis showed some improvement when given indomethacin In one study doses of 150 to 200 mg of indomethacin daily were found to be effective in most patients with mod- PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3469 erately severe rheumatoid arthritis, though they had little effect when the dis- ease was severe (A. M. Marmont et al., in International Symposium on Non- Steroidal Anti-Inflammatory Drugs, Amsterdam, Excerpta Medica Foundation, 1965, p. 363) . In ankylosing spondylitis, indomethacin has appeared to relieve pain more consistently than in other types of arthritis (F. D. Hart and P. L. Boarciman Brit Med ;r 2 965 1963) How it compares with aspirin and phenyl butazone in the treatment of s~ondylitis is not yet known Indomethacin has been used in combination with prednisone in a number of studies on patients with rheumatoid arthritis The use of indomethacin permit ted reduction of dosage of the steroid with all the patients in some studies with fewer than half in others The side effects of corticosteroids are much more sen ous than those thus far observed with mdomethacin and the combination, with reduced dosage of steroids, is well worth a trial where steroids cannot be elimi- ~ nated altogether. It is not yet known whether indomethacin can be safely and effectively used in combination with such other anti-rheumatic drugs as phenyl- butazone, gold salts and chioroqulne. Gouty arthritis.-In the treatment of acute gouty arthritis with indomethacin, many patients have shown improvement within about 48 hours (P. L. Boardman and F. D. Hart, Practitioner, 194:560, April, 1965). How the drug compares in effectiveness with colchicine and phenylbutazone can be determined only by better controlled trials than those so far reported The usefulness of indomethacm corn bined with a uricosuric agent such as probenecid (Benemid-Merck) in the treat ment of chronic gouty arthritis is being investigated Osteoai thritis and other conditions -In uncontrolled trials mdomethacm has been reported to be effective in relieving pain in osteoarthritis. A valid judgment of its usefulness must await further trials. It is not recommended by the manu- facturer for such acute musculoskeletal disorders as bursitis, tendinitis, an~ synovitis. Adverse effects.-Adverse effects, often severe, and requiring discontinuance of the drug in many patients, are common, and a few fatalities have been at- tributed to indomethacin. Among the most frequent adverse effects are headache, dizziness gastrointestinal disturbances (nausea anorexia vomiting diarrhea bleeding and ulceration) and psychic disturbances Whether significant hemato logic renal hepatic or neurologic reactions occur is not clear A fuller assessment of adverse effects ~ ill be possible only after longer use indomethacm appears to be too hazardous to be substituted for aspirin when that drug is effective but it may prove less hazardous than other anti arthritic drugs Precautions and contraindications -The manufacturer warns that indometh acm is contraindicated in patients with active peptic ulcer gastritis ulcerative colitis and regional ileitis Whether it crosses the placental barrier is not yet known, nor are its effects on the human fetus; therefore, indomethacin should not be used in pregnant women. The manufacturer also warns that there has been insufficient experience to warrant its use in children. Because of the frequency of dizziness, lightheadedness, and feelings of detachment, patients on indomethacin should be cautioned against operating motor vehicles or other machinery climbing ladders etc and the drug should be used with great caution in patients with psychological difficulties epilepsy or parkinsonism since it sometimes aggravates these conditions Doiage and administration -The recommended initial dose is 25 mg twice daily with gradual increase as needed Good response is often obtained with 100 mg daily divided into four closes Further improvement rarely occurs when the dose is increased above 150 or 200 mg a day. The drug should be given with food to reduce gastric irritation. Conclusion.-Early clinical trials indicate that indomethacin is a useful addi- tion to the group of drugs available for the treatment of rheumittoid arthritis and ankylosing spondylitis. Its place in the management of acute gouty arthritis and osteoarthritis is less clear; properly controlled trials are needed. In the treatment of rheumatoid arthritis aspirin is still the drug of first choice (see The Medical Letter Vol 7 p 75 1965 for a discussion of the side effects of aspirin) When effective doses of aspirin are not well tolerated indomethacin may be used with lower doses of aspirin or if necessary substituted for it before resort is had to corticosteroids In patients already on corticosteroids reduction of the steroid dosage and a decrease in steroid side efrects can often be achieved by the addition of indomethacm If gastric ulceration occurs with either aspirin phenylbutazone or cortico- steroids indomethacin cannot be considered a safe substitute since it too causes gastric ulceration. In such cases, gold salts or chioroquine can be tried; these also have serious side effects, but they do not cause gastric ulceration. PAGENO="0378" 3470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (From New Drugs, 1967, pp. 539-542] INDOMETHACIN [INDOCIN] CH3O_(\fl-~-.-~_CH2C 0 OH 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid ACTIONS AND USES Indomethacin is a new type of nonsteroidal chemical compound that has anti- inflammatory, antipyretic, and analgesic properties. Present clinical experience indicates that this drug is as effective as the saucy- lates in patients with rheumatoid arthritis. However, its use is not necessary when salicylate therapy is effective. Although aspirin is still considered the drug of first choice, indomethacin may be tried If aspirin ceases to be beneficial or is no longer tolerated. Doses of aspirin may be taken in between regular doses of indomethacin if necessary. When given alone indoniethacin is more effective ir~ active rheumatoid arthritis than in the inactive burnt out type In about two4hirds of the patients pain tenderness, and stiffness decrease and ambulation increases in two to three days. However some clinicians have found that maximal benefits are not obtained until indomethacin has been given for a month or more. With prolonged adminis- tration, 10% to 15% of the patients who responded initially must stop taking indomethacin because of its untoward effects. It has been reported that indomethacin reduces joint swelling and edema in some patients with rheumatoid arthritis. However, results have been equivocal in the few studies in which ob)eetive measurements of )olnt size were made The erythrocyte sedimentation rate was not affected. When given alone indomethacui is less effective than the corticosteroids in the treatment of rheumatoid arthritis When given concomitantly however the dose of the steroids often can be halved and in some patients completely withdrawn. Thus indomethacin may be especially useful in patients who have been receiving long-term therapy with corticos1~eroids. However, the hazards Of combined therapy with steroids and indomethacin have yet to be fully evaluated. Indometkacin has been particularly useful in the treatment of mild to moderate osteoarthritis of the hip joint, a condition that is resistant to all other anti- inflammatory agents. It also appears to relieve the pain of ankylosing spondylitis as effectively as does phenylbutazone. Indomethacin produces anti-inflammatory effects in patients with gout and may be as e~ective as phenylbutazone in its promptness of action and the degree of relief it provides. Because it has produced relief in acute attacks within 48 hours, and because it lacks the untoward effects of coichicine, some clinicians consider it to be the drug of choice for these attacks however controlled trials are needed to determine how its effectiveness compares with that of colchicine. Indomethacin may be useful as a supplement to coichicine in the management of severe cases of gout. Whether it is useful as a prophylactic agent in gouty arthritis remains to be established. This drug should not be used in children until the indications for use and appropriate dosage have been established. ADVERSE REACTIONS Central nervous system effects (headaches, usually severe in the morning; vertigo; light-headedness; mental confusion) occur during the early weeks of therapy in about 20% to 30% of patients taking indomethacin. Drowsiness, con- vulsions4 de~ession, and psychic disturbances such as depersonalization have also been reported. Generally, these effects are dose-related and are less likely to appear if the daily dosage is 100 mg. or less given in divided amounts. The symptoms may occur within the first few hours after administration or may be PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3471 delayed for two or three days ; they frequently disappear with continued' use but, if they are severe, the drug shouki be discontinued. Gastrointestinal reactions (nausea, indigestion, epigastric burning, stomatitis, diarrhea~', which have been observed in about 25% of the patients, often are transient and can be minimized by giving the drug after meals and with milk at bedtime. These symptoms are severe enough to require discontinuing the drug in less than 10% of the patients but, even in these, the adverse effects may not recur when administration of the drug is resumed. Indomethacin should be regarded as being potentially ulcerogenic. It may pro- duce single or multiple ulceration of the esophagus, stomach, duodenum, or small intestine. Cases of perforation and hemorrhage, a few of them fatal, have been reported. Some patients with a history of peptic ulcer have tolerated the drug without experiencing gastrointestinal symptoms or having evidence of an active ulcer; other patients have developed ulcers after having taken the drug for 1~/2 to 3 years. Since most patients who developed ulcers had received doses of 150 to 300 mg. a day, dosage may well be a contributing factor. Occult bleeding and resulting anemia may occur In the absence of an ulcer, and persistent indigestion may be a symptom of this. Although measurements indicate that the occult blood loss associated with indomethacin is less than that produced by clinically equiva- lent doses of aspirin hemoglobin determinations should be made regularly and the drug should be discontinued if any evidence of gastrointestinal bleeding develope. Leukopenia, purpura, and thrombocytopenia may develop. Agranulocytosis has been reported rarely, but its relationship to indomethacin administration has not been established. Reports of jaundice and hepatitis have also appeared. Dermatologic or hypersensitivity-type reactions (pruritus, urticaria, rash, angioneurotic edema, loss of hair, acute respiratory distress) and reactions affect- ing the eye or ear (tinnitus, blurred vision, orbital and periorbital pain) have occurred infrequently. No significant alterations in the glucose tolerance test, electrolyte balance, or kidney function have occurred after administration of indomethacin for periods as long as three years. However, more long-term studies are needed to completely assess the effects of its prolonged use. PRECAUTIONS Patients who require larger dosages of indomethacin must be observed more closely for the possible occurrence of toxic effects. The patient may accept the untoward effects of indomethacin if he is told of their possible occurrence. Indomethacin, like aspirin, should be administered on a regular schedule and not used indiscriminately in the treatment of rheumatoid arthritis. ~Indomethacin is contraindicated in patients with active peptic ulcer, gastritis, regional enteritis, or ulcerative colitis, and it should be used wth caution in patients with a history of these disorders. These patients may tolerate the drug if small doses are used. Indomethacin also should be used with care in patient~ who have epilepsy, parkinsonism, or emotional or psychiatric problems, since the drug may aggravate these conditions. Because of the possible occurrence of central nervous system effects, patients being given indomethacin should avoid activities requiring mental alertness, judgment, or physical coordination (e.g., driving a car, operating dangerous machinery), particularly during the early weeks of therapy. Indomethacin is contraindicated in patients with asthma who are sensitive to aspirin. It is now known that indomethacin can mask the signs and symptoms which usually accompany infectious `disease. Therefore, the physician must be aware of this possibility to avoid delay in the treatment of an infection, and should use the drug with caution in the presence of existing, controlled infections. No teratogenic effects have been demonstrated in animal studies. However, it has been shown that indomethacin does cross the placental barrier. Thus', the possibility of risk to the fetus must be weighed against the expected therapeutic benefits if indomethacin is considered for administration to a pregnant woman. A few deaths in children with severe juvenile rheumatoid arthritis who were receiving indomethacin with other drugs have been reported; in two of these cases, death was attributed to intercurrent infections of possibly unrecognized severity. Clinical studies have been insufficient to establish any recommendation for the use of indomethacin in infants and children and, at the present time, the drug is considered to be contraLndicated in infants and children because safe conditions for `use have not `been established. PAGENO="0380" 3472 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PHARMACOLOGY In man, indomethacin is absorbed promptly following oral administration, and peak plasma levels occur within two hours. About 90% of a single dose is excreted in 24 to 48 hours; approximately two thirds of this amount is excreted in the urine as the glucuronide and the remainder is excreted in the feces DOSAGE AND PREPARATIONS Ronte of adnnni,'tration -Oral Dosage -To minimize adverse reactions, small doses of indomethacin are given initially when necessary the size of the dose is then gradually increased until an effective level is reached. In rheumatoid arthritis, ankylosing .spondylitis, and degenerative joint disease of the hip the initial dose is 25 mg two or three times daily If the patient does not respond, this dose is increased at weekly intervals by increments of 25 mg. a clay until a satisfactory response is obtained or `until a daily dose of 150 to 200 mg is reached larger closes are not recommended If adverse reactions occur the drug should be discontinued or successive adjustments in dosage should be made until the best possible response is obtained After an acute phase or exacerba tion of rheumatoid arthritis is controlled the dose of indomethacin should be reduced to a satisfactory maintenance level No reports on its occasional inter mittent use for short periods are available When mdomethacine is added to a regimen of corticosteroid therapy it is often possible to reduce the dose of the steroid by as much as one half or to ~iseontinue it entirely. However, this reducti'on `should be made gradually in order to avoid the effects of `steroid withdrawal. Acu'te attacks of gout may be controlled with a dosage of 50 mg. three times a day until the attack subsides. During the intervals between attacks, a dose of 25mg. twice a day may be sufficient. Preparations.-Oapsules 25 mg. ~uppiied by.-Merck Sharp & Dohme [In'docin]. Year of introduction: 1965. Evaluated for N.D. 1966. Reviewed: 1967. [From New Drugs, 1966, pp. 531-534] INDOMETHACIN [IND0cIN] CH3O- E_-_l_CH2COOH 1-(p-chlorobenzoyl)-5-methoxy-2-methyllndole-3-acetic acid ACTIONS AND USES Indomethacin is a new type of nonsteroidal chemical compound that has anti- inflammatory antipyretic and analgesic properties Present clinical experience indicates that this drug is as effective as the sah cylates in patients with rheumatoid arthritis However its use is not necessary when sahcylate therapy is effective Although aspirin is still considered the drug of first choice indomethacin may be tried if aspirm ceases to be beneficial or is no longer tolerated Doses of aspirin may be taken in between regular doses of indomethacin if necessary When given alone indomethacm is more effective in active rheumatoid arthritis than in the inactive burnt out type In about two thirds of the patients pain tenderness and stiffness decrease and ambulation increases In two to three days PAGENO="0381" COMPETITIVE PROBLEMS IN THE DflIJG INDUSTRY 3473 However some clinicians have found that maximal benefits are not obtained until indomethacin has been given for a month or more. With prolonged adminis- tration, 10% to 15% of the patients who responded initially must stop taking indomethacin because of its untoward effects. It has been reported that ~ indomethacin reduces joint swelling and edema in some patients with rheumatoid arthritis. However, results have been equivocal in the few studies in which objective measurements of joint size were made. The erythroeyte sedimentation rate was not affected. When given alone indomethacrn is less effective than the corticosteroids in the treatment of rheumatoid arthritis When given concomitantly however the dose of the steroids often can be halved and in some patients completely with drawn Thus indomethacin may be especially useful in patients who have been receiving long term therapy with corticosteroids However the hazards of com bined therapy with steroids and indomethacin have yet to be fully evaluated Indomethacin has been particularly useful in the treatment of mild to moder ate osteoarthritis of the hip joint a condition that is resistant to all other anti inflammatory agents. It also appears to relieve the pain of ankylosing spondylitis as effectively as does phenylbutazone. Indomethacin produces anti-inflammatory effects in patients with gout and may be as effective as phenylbutazone in its promptness of action and the degree of relief it provides. Because it has produced relief in acute attacks wihin 48 hours, and because it lacks the untoward effects of colchicine some clinicians consider it to be the drug of choice for these attacks however controlled trials are needed to determine how its effectiveness compares with that of colchicine Indomethacin may be useful as a supplement to coichicine in the management of severe cases of gout Whether it is useful as a prophylactic agent in gouty arthritis remains to be established ADVERSE REACTIONS Central nervous system effects (headaches, usually severe in the morning; vertigo; light-headedness; mental confusion) occur during the `early weeks of therapy in about 20% to 30% of patients taking indomethacin. These symptoms may occur within the first few hours after administration or may be delayed for two or three days; they frequently disappear with continued use and are revers- ible when the drug is discontinued. Generally, these effects are dose-related and are less likely to appear if the daily dosage is 100 mg or less given in divided amounts. Gastrointegteuti reactiOfl8 (nausea indigestion epigastric burning stomatitis diarrhea) which have been observed in about 25% of the patients often are transient and can be minimized by giving the drug after meals and with milk at bedtime. These symptoms are severe enough to require discontinuing the drug in less than 10% of the patients but even in these the adverse effects may not recur when administration of the drug is resumed. Indomethacin should be regarded as potentially ulcerogenic, although the available evidence on this point is contradictory. Some patients with a history of peptic ulcer have tolerated the drug without experiencing gastrointestinal symp- toms or having evidence of an active ulcer; other patients have developed ulcers after having taken the drug for 11/2 to 3 years. Since most patients who developed ulcers had received doses of 150 to 300 mg. a day, dosage may well be a contribut- ing factor Occult bleeding and resulting anemia may occur in the absence of an ulcer; persistent indigestion may be a symptom of this. Although measurements indicate that the occult blood loss associated with indomethacin is less than that produced by clinically equivalent doses of aspirin hemoglobin determinations should be made regularly and the drug should be discontinued if any evidence of gastrointestinal bleeding develops. No significant hematologic reactions or alterations in the glucose tolerance test electroylte balance, or liver and kidney function have occurred after administra- tion of indomethacin for periods as long as three years. However, more long-term studies are needed to completely assess the effects of its prolonged used. Other adverse effects reported infrequently are edema; psychic reactions such as depression; angioneurotic edema; drowsiness; tinnitus; blurred vision; and dermatologic reactions such as pruritus, urticaria, and rash. Indomethacin should be discontinued if these reactions occur. Leukopenia has been reported in a few patients PAGENO="0382" 3474 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PRECAUTIONS Patients who require larger dosages of indomethacin must be observed more closely for the possible occurrence of toxic effects. The patient may accept the un- toward effects of indomethacin if he is told of their possible occurrence. Indo- methacin, like aspirin, should be administered on a regular schedule and not used indiscriminately in the treatment of rheumatoid arthritis. Although `there is no definite evidence that indomethacin causes peptic ulcers, it is contravindicated in patients withY active ulcers. In addition, because of its potential for causing bleeding in the gastrointestinal tract, the drug should be used with caution if the're is a history of ulcer, regional ileitis, gastritis, or ulcer- ative colitis. Patients with these conditions may tolerate the drug if small doses are used. Indomethacin also should be used with care in patients who have epilepsy, parkinsonism, or emotional or psychiatric problems. Since the drug may cause aggravation of these conditions. Because of the possible occurrence of central nervous system effects, patients being given indomethacin should avoid activities requiring mental alertness, judgment, or physical coordination (e.g., driving a car, operating dangerous ma- chinery), particularly during the early weeks of therapy. No teratogenic effects have `been demonstrated in annual studies. However, it has been shown that indomethacin does cross the placental barrier. Thus, the possibility of risk to the fetus must be weighed against the expected therapeutic benefits if indome'thacin is considered for administration to a pregnant woman. Clinical studies have been insufficient to establish any recommendation for the use of indomethacin in infants and children. PHARMACOLOGY In man, indomethacin is absorbed promptly following oral administration, and peak plasma levels occur within two hours. About 90% of a single dose is excreted in 24 to 48 hours; approximately two `thirds of this `amount is excreted in the urine as the glucuronide and the remainder is excreted in the feces. DOSAGE AND PREPARATIONS Route of Administratjon.-Oral. Dosage.-To minimize adverse reactions, small doses of indomethacin are given initially; when necessary, the size of the dose is then gradually increased until an effective level is reached. In rheumatoid arthritis, ankylosing spondylitis, and degenerative joint dis- ease of the hip, the initial dose is 25 mg. two or three times daily. If the patient does not respond, this dose is increased at weekly intervals by increments of 25 mg. a day until a satisfactory response is obtained or until a daily dose of 150 to 200 mg. is reached; larger doses are not recommended. If adverse reactions occur, the drug should be discontinued or successive adjustments in dosage should be made until the best possible response is obtained. After an acute phase or exacerbation `of rheumatoid `arthritis is controlled, the dose of indomethacin should be reduced to a `satisfactory maintenance level. No reports on its occa- sional intermittent use for short periods' are available. When indomethacin is added to a regimen of corticosteroid therapy, it is often possible to reduce the dose of the steroid by as much as one half or to discontinue it entirely. However, this reduction should be made gradually in order to avoid the effects of steroid withdrawal. Acute at'tacks of gout may be controlled with a dosage of 50 mg. three times a day until the attack subsides. During the intervals between attacks, a dose of 25 mg. twice a day may be sufficient. Prepavations.-Capsules 25 mg. $upplied by-Merck Sharp & Dohme [Indocin]. Year of introduction: 1965. Evaluated for N.D. 1966. PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3475 [From the Washington Post, Jan. 21, 1967] FDA Is PROBING MERCK DIvISIoN FIRM COULD FACE CRIMINAL PROSECUTION OVER AD FOR ARTHRITIS DRUG (By Morton Mintz) The maker of Indocin, a drug widely prescribed for arthritic disorders, has appeared at a closed hearing to show cause why the company should not be criminally prosecuted for an Indocin advertisement The firm Merck Sharp & Dohme a division of Merck & Co Inc confirmed that an informal hearing was held recently by the Food and Drug Administra tion's district office in Philadelphia. The company said comment on the sub- stance of the discussion would be inappropriate. The advertisement appeared several times last year in the Journal of the American Medical Association. Its headline said Indocin (indomethacin) "extends the margin of safety in long-term management of arthritic disorders." CITED BY FDA COUNSEL That headline was cited last October by William W. Goodrich, FDA's chief counsel, in a speech in Manhattan. "There is not yet enough experience to suppOrt the claim for greater long-term safety," he told the Pharmaceutical Advertising Club. "To the contrary, the longer the drug is used the more side effect information appears Goodrich mentioned Indocin in the course of criticizing promotions of the "Big Eight" prescription drugs~-a group of drugs and antibiotics, including indomethacin, that entered the market in 1965 and within 12 months had become among the 200 drugs most frequently prescribed. Like most new drugs, the official said, Indocin was asserted to be safer and more effective than existing products in the same therapeutic group. But as experience has accumulated, he said, "more side effects have been noted and more warning information has been required." In response to an inquiry, FDA said it knows of 16 deaths and 303 side reactions among Indocin patients. ASSOCIATION WITH DRUG Seven of the dead were children the agency said Only one of these deaths was said to have had a clear cut association with Indocin In another the association was regarded as questionable. In the remainder, it was regarded as dubious, because the children had had severe illnesses and had been treated with other medicines. The nine adults bad had long-standing rheumatoid arthritis and were, FDA said, in an age group over 50. The deaths of three of them were said by FDA to have had a "possibly clear-cut" relation with Indocin. Such a relation was doubted in the others, all of whom had had major, pre-existing complications. In another complaint about the AMA Journal ad for Intlocin, Goodrich told the Advertising Club that the ad quoted "authoritative sources, without the full impact of the actual articles." He pointed to a claim of usefulness for Indocin in arthritis of the spine ("anklosing spondylitis"). The claim is supported by a reference. A physician who checked it out. Goodrich said, would find that the reference was to a 2-inch abstract of a speech made in 1964. In addition, Goodrich said, the ad failed to cite this statement in the abstract: "Excellent results have also been obtained in some cases of rheumatoid arthritis there have been some striking failures as welL" A third complaint made by the agency counsel was that the ad "omits some very important warning information that is required" in the authorized prescrib- ing instruction-the brochure enclosed with every package of a drug. In West Point, Pa., a Merck, Sharp & Dohme spokesman said: It is our judgment based on the facts of Indocin use that this new anti arthritic agent does not suffer from certain disadvantages such as the production of hormonal side effects and certain blood clyscracias which do occur with some of the other agents previously available. In thi.s way it has extended the margin of safety in the long-term management of arthritic disorders." Since the Goodrich speech FDA has refused to comment on the closed hearing or on the possibility of prosecution. Except where data are requested by Congress, PAGENO="0384" 3476 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the agency customarily makes no disclosure to the medical or lay public when it calls and holds such hearings or takes certain other steps against drug ads that it considers misleading. POSSIBLE ACTIONS In the pending case, FDA's Philadelphia office could recommend anything from concurrence with a company position that it had done nothing wrong to prosecu- tion A recommendation for a criminal proceeding could be vetoed at headquarters in Washington or by the Justice Department if the case were to be sent there Goodrich disclosed in his October speech that a few days earlier Indocin s maker had mailed a new revised brochure to the profession with new cautionary information in heavy print The fatalities among Indocin patients were men tioned neither in the brochure nor in the accompanying Dear Doctor letter signed by Dr Frederick K Heath ~ ice president for professional communica tions. Displayed on the envelope however was a prominent box saying Safety/Drug Safety Information." Generally, Dr. Heath blended an alert to "important changes" in prescribing instructions for Indocin with statements marked by a promotional tone. His letter said that "144,000,000 patient days of therapy in 99 countries" bad been accumulated with Indocin since its introduction about 16 months earlier. He also said that Indocin has become next to aspirin the most frequently prescribed antirheumatic drug The characterization of indomethacin as an antirheumatic drug is no longer allowed by FDA In addition the agency found the letter inadequate and insisted on a new one ~s hich the manufacturer mailed in December Above the Dear Doctor saluta tion the words Drug Safety Information were printed in deep blue Promotional plugs for Indocin were absent In addition to directing attention to new precautions Dr Heath s December letter emphasized that Indocin "should not be prescribed for children because safe conditions for use have not been established." That same warning appears three times in boldface type in the new prescribing circular enclosed with the letter. Also in boldface the circular says that severe and even fatal reactions ha~ e occurred in a few cases of severe juvenile rheumatoid arthritis in children who received Indocin along with other drugs The precaution in the October circular about the use of Indocin in children was found by FDA to be too mild ARTICLE CRITICIZED The Goodrich speech also contained criticism of an article by freelancers Phyllis and Robert P Goldman in the July Pageant The title was INDOCIN the trade name of the drug. The FDA counsel said the article featured Indocin for bursitis trick knee tennis elbow and a host of other less common disorders characterized b~y pain and swelling in and around the joints.'" The only support for these claims Goodrich said ~as user testimonial'~ which, according to the article, were made available to the writer by the sponsor of the drug [From the Washington Post, Mar. 19, 1967] FDA BEGINS A RFSTUDY OF ARTHRITIS DRUG SOME AUTHORIZED CLAIMS FOR INDOCIN ARE NOW IN DOUBF (By Morton Mintz) The Food and Drug Administration is reevaluating a drug that has been taken mainly for arthritic disorders by millions of persons here and abroad. The drug is Indocin (indomethacin). In the United States FDA-authorized instructions to physicians prescribing the drug indicate that it is useful in rheumatoid arthritis arthritis of the spine degenerative joint disease of the hip and gout It is one or more of these authorized claims that the FDA is now ree~ aluating The FDA disclosed its action yesterday in response to a Washmgton Post query about articles in three prestigious medical journals about Indocin s efficacy against rheumatoid arthritis Two of the reports indicate that aspirin is as PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3477 effective as Indocin; the third indicates the drug to be no more effective than a placebo, a pill containing an inert substance. The reports raise questions not only about the agency's handling of Indocin, which was a1pproved in June, 1965, but also about the law's strict requirement that "substantial evidence" of efficacy be demonstrated. Merck & Co., the manufacturer, said Thursday that Indocin's safety and efficacy were established "by more than 300 clinical investigators" and by "a wealth" of experience. The three journal reports were prepared by experts who performed well- controlled clinical investigations. And only selected patient groups got Indocin; other groups got aspirin, Indocin and aspirin, or aspirin and/or a placebo. These were highly sophisticated double-blind studies. Neither patients nor physicians knew what was being administered until a code was broken at the end of the trials. Some patients were crossed over, that is, switched without disclosure from one group to another. But Merck said some of the studies in behalf of Indocin it had submitted to the FDA also were double-blind. It also protested that Indocin worked with some rheumatoid arthritis victims with whom aspirin failed; and that in the other diseases for which Indocin is approved it allows successful control while aspirin does not. VALUES IRREGULAR In addition, the relative valpe of drugs in rheumatoid arthritis is hard to measure objectively, Merck said. Many patients are relieved of pain by aspirin; investigators are unwilling to substitute a placebo for test purposes, the company said. Last October, Merck revised its prescribing brochure and mailed a copy accompanied by a letter to the Nation's practicing physicians. The letter cited "new cautionary information" but made no mention of fatalities. By December, FDA knew of 329 adverse reactions, including seven deaths in children and nine in elderly persons. It termed the relation to Indocin clearcut in one fatality, "possibly clearcut" in three others and highly questionable in the rest. The October Merck letter said that "144,000,000 patient days of therapy" had been accumulated with indomethacin, and that it "has become, next to aspirin, the most frequently prescribed antirheumatic drug." The characterization of Indocin as "antirheumatic" was later disallowed by the FDA. DEATHS CITED In November, a jolting warning letter was sent Canadian physicians by the Food and Drug Directorate, the FDA's north-of-the-border counterpart. The letters told of several indomethacin deaths in children and of a number of un- expected adverse reactions. These included "not uncommon" and sometimes severe effects on the central nervous system, and blood diseases and blurred vision. In upper case, The Canadian government letter said in capitals "That Indo- inethacin Should Not Be Used in Children . . ." In addition, doctors were warned that the drug "can mask the signs and symptoms of an infectious process or activate a latent bacterial infection." In Washington, the FDA called in Merck. In December the company sent out a 2-paragraph letter which warned against Indocin use in children and called attention to the enclosed prescribing brochure which had again been revised to emphasize that warning. Several months before the FDA approved Indocin in 1965, warnings against its use were published in the Medical Journal of Australia by physicians who "de- tailed an imposing list of side effects." SUGGESTION'S ROLE The double-blind study, reported in the British Medical Journal last Jan. 14 involved 28 persons for 10 weeks. Although side effects "occurred more often with indomethacin" than with a placebo, the report inferred that "suggestion played a large part in determining both the incidence and variety . . ." The authors were three Welsh physicians, Phelim Donnelly, Kenneth Lloyd and Hubert Campbell. The New England Journal of Medicine study, published March 2 by Drs. Robert S. Pinal~ and Sumner Frank of Boston, was done on 24 patients for a month. Two 81-280 0-68--pt. 8-25 PAGENO="0386" 3478 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY on Indocin, including one also taking aspirin, dropped out with "intolerable side effects." Another dropped out for an unrelated reason. Among the remaining 21 one third preferred aspirin and one third indometha cm; one-third was unable to detect a difference. The physicians rated Indocin superior in five patients and aspirin in six. 10 WERE THE SAME No difference was found in 10. "Side effects did not differ in frequency or sever- ity," but headache was noted more commonly with indomethacin and auditory symptoms with aspirin, they said. The study reported in the January-February Olinical Pharmacology and Thera- peutics was sponsored by the American Rheumatism Association and was done by biostatistician Donald Mainland, primarily to establish objective standards for judging rheumatoid arthritis~drugs. No significant differences were found among patients taking Indocin and others taking a placebo Patients in both groups were allowed to take as much aspirin as desired. Merck cited this in asserting that the study does not show that the relative effectiveness of Indocin and aspirin used separately. [From the Washington Post, May 21, 1968] DRUG AD EXPORTS POSE A PROBLEM (By Morton Mintz) In Animal Farm, the satirical fable by the late George Orwell, all the animals were equal, but only for a time. Then some animals asserted themselves to be more equal than others. A parallel may exist in the attitudes businessmen in one country take toward citizens of another when it comes to advertising pre scription drugs. American pharmaceutical companies hold a commanding position in the non- Communist world, and in promoting drugs it might be presumed that they would treat doctors abroad the same as doctors here If a promotional claim is pro hibited in this country because it might mislead a physician (and kill, injure, or at least exploit his patient), the same claim presumably would not be made in other countries. But that this is not always the case is suggested by a recent disclosure concerning Abbott Laboratories of North Chicago, Ill. In March 1967 this firm ran an advertisement in the Journal of the Amerwan Medical Association for Enduron, Abbott's trade name for a thiazide diuretic called methyclothiazide The ad claimed that in removing excess fluids Enduron caused a lesser depletion of potassium than rival prescription products. This claim was deemed by the Food and Drug Administration to be misleading Under pressure by the FDA, the company then sent a letter individually to every pre- scribing physician in the Nation acknowledging `that the loss of potassium with Enduron was not seen by experts as significantly different from the loss with other thiazide diuretics. But a year later-in April, 1968-substantially the same claims were being made to physicians in Canada for the same product, which there is called Duretic. One ad in which this occurred was published in the Canadian Medical Associa- tion Journal by Abbott Laboratories Limited. Whether the claims which the parent company had repudiated were carried in other publications and in other countries, a spokesman in North Chicago refused to say. Other incidents raising ethical questions in the same ballpark have cropped up in hearings held by the Senate Monopoly Subcommittee and troubled its chair man Sen Gaylord Nelson (D Wis) A recent one concerned indomethacin a rheumatoid arthritis drug which Merck & Co sells in the United States as Indo- cm and elsewhere as indocid In this country the FDA has refused to let Merck claim that the drug has been demonstrated to be safe and effective in certain additional methcal conditions But these same medical conditions are freely promoted as appropriate for Indocid in about 100 other countries. To be sure, a few of these are highly developed Western nations which, it might be fairly argued, could have effective drug regulation if they do not now have it. What especially bothered Nelson, however was that in countries with no regulation and no significant scientific community, drug promotion can be entirely free-wheeling, with resultant over- prescribing at the expense of the health and pocketbooks of innocent patients In such countries, Nelson asked Merck president Henry Gadsden, "What is your standard of guidance for advertising?" PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3479 Gadsden said that his firm's standard "is whatever has been approved by the scientists of Merck as appropriate," and for which evidence has been sub- mitted to the FDA, even if the agency has not been persuaded by that evidence. Nelson did not remind Gadsden of FDA testimony the day before that the agency's counsel was considering whether a criminal prosecution of Merck for misleading advertising of Indocin in the United States should be recommended to the Justice Department. Instead, the Senator said in regard to drug promo- tion in less-developed countries, ". . . there are lots of companies in this business that might not be as conscientious as Merck . . ." Surely a difficult and delicate problem is posed. Americans may be uneasy about how American firms promote medicines abroad; they may doubt the wis- dom of applying the adage about doing in Rome as the Romans do. But they cannot lightly try to arrogate unto themselves power to tell other countries what to do. Maybe other countries could require as a condition of import that adver- tising and promotion conform to United States requirements. Maybe it's a prob- lem for the World Health Organization. Maybe even there is no solution. [From the Washington Post, Mar. 3, 1968] LETTER MISLEADING, DRUG FIRM ADMITS (By Morton Mintz) For the second time since May, Geigy Pharmaceuticals has conceded that it engaged in a prescription-drug promotion that the Food and Drug Administration criticized as "potentially misleading." A promotional letter to physicians, the company said, "presented only favorable information" about Persantine, which is used in long term therapy of patients with the intense chest pain known as angina pectoris. Actually, the firm acknowledged, "there is a substantial body of opinion that does not support the claimed effectiveness" of Persantine, the Geigy brand of dipyridamole. This is one of the drugs marketed before 1962 for which claims of usefulness have been neither approved nor disapproved by FDA, pending an efficacy review by the National Academy of Sciences. The promotional letter for Persantine claimed that several studies document its effectiveness "in extending walking distance and generally increasing exercise tolerance." The claim was backed up with an enclosure-a reprint of a study reported last March in the Journal of Chronic Diseases. The claim was knocked down in September, the Geigy Chemical Corp. division has recognized, by a report in the Journal of the American Medical Association. There, telling of a six-month, so-called double-blind study that was designed to eliminate possible bias, two researchers said: "The study failed to detect a statistically significant difference between the improvement in patients receiving dipyridamole and the improvement in patients receiving a placebo," or inert, dummy pill. This conclusion was relayed by Geigy in a "corrective letter" sent individually on Feb. 15 to each of the country's prescribing physicians. Geigy went on to recall that the AMA's Council on Drugs had said last year in its primary publication that double-blind studies comparing dipyridamole with a placebo "have shown equivocal results . . . the drug has not been shown to be effective in the long-term treatment of angina pectories "Our future promotion will express the range of expert medical opinion on the effectiveness of Persantine when any segment of that opinion" is cited in promo- tional material, the company said. The earlier case involved two Geigy prescription drugs used to lower blood pressure. They are Hygroton (chiorthalidone), which the FDA said was mis- leadingly advertised in MD Medical News Magazine, and Regroton, (chlorthali- done plus reserpine), which was advertised in Circulation Magazine in a way also condemned by the agency. In the earlier case the firm sent its first "corrective letter." Various firms have sent a total of 21 of them since February, 1967. Had they not been sent, FDA was prepared in each case to seize interstate shipments and announce the action in a press release. Senator NELSON. We are adjourned subject to call of the Chair. (Whereupon, at 1 :55 p.m., the hearing adjourned subject to the call of the Chair.) PAGENO="0388" PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TUESDAY, SEPTENBER 17, 1968 TI S SENATE, MONOPOLT SUBCOMMITTEE OF THE SELECT CoMMrr'rEE ON SMALL BusINEss, Washington, D C The subcommittee met, pursuant to call, at 9 40 a m, in room 318, Old Senate Office Building, Senator Gaylord, P Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Elaine C. Dye, research assistant; and William, B Cherkasky, legislative director, staff of Senator Nelson Senator NELSON Today the Monopoly Subcommitee of the Senate Small Business Committee resumes hearings first begun in May 1967 as part of its study of the pharmaceutical industry Our primary concern, during the next 4 days of hearings,1 will be to explore the impact of the drug manufacturers' salesmen, commonly called detail men, upon the prescribing practices of the physician. A study which appeared in the Canadian Medical Journal in April 1968, the American Medical Association's study conducted some years ago, and testimony before our subcommittee indicated that oral state- ments by drug manufacturers' detail men, who contact physicians directly, are the most potent force in promoting the use of drugs Mr William Goodrich, FDA's Chief Counsel, feels that the FDA has authority over the claims made by detail men under the labeling pro visions of the Food, Drug, and Cosmetic Act The American Law Division of the Library of Congress has a different opinion which I shall insert at the appropriate place in the written proceedings of these hearings.2 While section 502 of the act (21 U.S.C. 352) gives the FDA author- ity over written advertisements, it is not clear whether or not FDA has authority over oral representations. In any case, it would be ex- tremely difficult, if not impractical, to monitor what thousands of detail men say to physicians Hence, it is difficult to avoid the conclusion that the representations of the detail men, the most important source of information for the physician, are outside the practical application of our food and drug laws How, then, is the public to be protected? Can salesmen, representing commercial drug interests, be expected to act in the interests of the public? ~ Testimony for September 18, 19, and 2~, 1968, appears in Competitive Problems In the Drug Industry,, Part 9. 2 See p 3517 infra 3481 PAGENO="0390" 3482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY How can we insure that the information the physician receives on drugs via word of mouth conforms with the FDA's requirements on package inserts and printed advertisements of these same drugs ~ These are some of the questions we hope to consider over .the next several days. Today, we shall direct our attention to the drug Indocin. On May 3, Mr. Henry W. Gadsden, president of Merck, testified as follows: (Merck) seeks to make sure that the marketing profile of a drug corresponds in every respect to its medical profile. * * * J~ is Merck's policy to avoid the pos- sibility of including any questionable statement or theme in any of our advertising or promotion. * * * Our internal procedures require that every piece of advertising and proniotion must have the approval of a physician and a lawyer, who are responsible for its medical accuracy and conformity with the law. * * * Testimony by the FDA indicated that these statements by the Presi- dent of Merck were not in accord with reality. In fact, the FDA's Bureau of Medicine recommended prosecution of Merck for false and misleading advertising. It was obvious that Merck's journal advertisement, submitted by the FDA as exhibits, made claims beyond those authorized in the package inserts. In addition, the Merck Co., according to FDA's testimony on May 2, turned a "Dear Doctor" remedial letter into a promotional piece. FDA then directed Merck to send a second letter to correct the first. This kind of activity on the part of any drug company should not be tolerated by the FDA, and it is difficult, indeed, to conclude that Indocm's marketing profile, as Mr Gadsden put it, corresponded in every respect with its medical profile. What have the detail men been telling doctors about Indocin? I suspect that neither the FDA nor any of us here know. We do know, however, that Merck's promotional instructions to their, detail men suggested uses not approved by the FDA and this is the subject of today's hearing. On May 20, 1968, I sent the following letter to the Commissioner of the Food and Drug Administration I am enclosing a number of instruction bulletins on Indocin sent to Merck and Company's detail men, apparently by the district supervisor in one of the firm's sales regions. Without attempting to interpret the law, it appears that these instructions seek to promote use of Indocin which you have not authorized. It would be greatly appreciated if the relevant officials in your agency would examine these bulletins and send me their comments on the accuracy of the claims made and the effect on medical practice of the selling techniques recommended. Your cooperation is greatly appreciated. On June 17 I received an answer from the FDA, which I shall put into the record in its entirety at this point (The information referred to fo1lo'~ s ) DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washington, D.C., June 17, 1968. Hon. GAYLORD NELSON, Chairman, Subcommittee on Monopoly, Select Committee on Small Business, U.S. Senate, Washington, D.C. DRAB SENATOR NELSON: This is in reply to your letter of May 20, 1968, enclos- ing a number of bulletins addressed to Western District Sales Associates of Merck Sharp and Dohme, Division of Merck and Company, Inc. PAGENO="0391" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3483 The Bulletins titled "Profit Improvement Promotional Program-'Indocin,'" are in memorandum form. Their form and, contents would suggest that they are internal communications that are not intended to be distributed beyond the con- trol of the firm. These instructions to the detail force for increasing sales of Indocin recom- mend methods typical in the promotion of a variety of products with no public health implications. We regard the instructions as seriously misleading. While there is considerable repetition (which in itself is a promotional tool) throughout the bulletins, the latter can be grouped for comparison into two time periods. For example, Indocin Bulletins 83, 84, 87, 88, 93 and 95 are dated be- tween July 12 and August 4, 1965 (the period of introduction of the drug) ; and Indocin Bulletins 23, 66, 74, 80 and 85 are dated between April 5 and September 27, 1967. The 1965 bulletins suggest generally to the detail men that they promote use of Indocin beyond approved indications, and play down side effects and other warn- ings present in the labeling. Some examples of passages from the bulletin are: Unwarranted Ea~tension of Indications when there is Heat. . . Redness. .. Swelling. . . and Pain in the muscles or joints. .. `Indocin' is usually effective." ". . treatment of the misery inflicted by arthritic diseases." "Available to relieve pain, reduce fever tenderness and swelling, and increase joint mobility in patients with rheumatic disorders ". . . Just Plain musculoskeletal Aches and ~$tiffness.. In connection with the above Bulletin 87 contains this admission "In fact, our guys are using a real expanded claim for `Indocin' on inflam- mation They are consistently telling their doctors that [as above] Deemphasis of ~8ide Effects, etc. "Therapy with `Indocin' is safer . . . a remarkable record of safety." Side effects . . . are usually minor and seldom constitute a problem. Usually they can be controlled by simple adjustment of dosage." "With an extended margin of safety." In relation to severity of side effects: "Bothersome is probably as severe an adjective as we can use to describe these effects because in most patients they are tolerable, and transient." The discussion of contraindications omits reference to the fact that Indocin is not recommended for use in children. Special Note Most reprehensible and significant in indicating the firm's disregard of the patient is the following passage: "... it is obvious that `Indocin' will work in that whole host of rheumatic crocks and cruds which every General Practitioner, Internist, and Ortho- pedic Surgeon sees everyday in his practice." As you knew, there were a series of events that occurred between 1965 and 1967 which involved our dealing with the firm regarding their advertising and promotion of Indocin. Merck was cited in regard to Indocin advertising, con- ferences were held with the firm's management in 1966 and the Assistant General Counsel of the Department spoke publicly regarding the misleading nature of an Inclocin advertisement appearing in the Journal of the American Medical Association, and elsewhere. With such notice, the firm did take action to correct its forms of promotion which are subject to our control. Notwithstanding such notice however we find in 1967 Indocin bulletins The expansion of indications for open-ended uses, "Wherever there is pain. inflammation, and swelling in or around the joint with a resultant limita- tio:~ of motion [The remainder of this sentence mentions the approved indications but in context the listed indications are examples only and do not overcome the suggestion for expanded uses.] The continued minimization of side effects and warnings, "Most of the adverse reactions which occur with `Indocin' are common with any antirheu- matic drug. They usually are transient, easily controlled, and often disappear on ~continued treatment." Also, "Gastric irritation can be minimized by giving the dose of `Indocin' after meals." While the foregoing comments are examples of things in the bulletins that have been given prominence by repetition or other emphasis, we believe that the PAGENO="0392" 3484 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY full misleading character of the promotional drive can be assessed only by coii- sidering the full text of the bulletins The setting of substantial quotas and re ports of sales suggest that the promotional scheme was successful The extent to which the sales instructions were followed or what extrapolation the Merck detail men may have given to the bulletin instructions in their oral presentations is of course unknown to us But we do know that Indocin ha~ been promoted for conditions outside the approved labeling We have no reason to doubt that the promotional instructions contributed to prescribing of the drug for un- approved uses. We appreciate your making the bulletins available to us for examination. Please let us know if we may be of further assistance. Sincerely yours, PAUL A. PUMPIAN, Director Office of Legislative and Governmental ~crvwes Senator NELSON But let me quote a few passages from this letter The 1965 bulletins suggest generally to the detail men that they promote use of Indocin beyond approved indications, and play down side effects and other warnings present in the labeling. * * * As you know, there was a series of events that occurred between 1965 and 1967 which involved our dealing with the firm regarding their advertising and promotion of Indocin Merck was cited in regard to Indocin advertising con ferences were held with the firm s management in 1966 and the Assistant Gen eral Counsel of the Department spoke publicly regarding the misleading nature of an Indocin advertisement appearing in the Journal of the American Medical Association, and elsewhere. With such notice, the firm did take action to correct its forms of promotion which are sub)ect to our control Notwithstanding such notice however we find in 1967 Indocin bulletins The expansion of indications for open ended uses * * * The continued minimization of side effects and warn ings. * * * The setting of substantial quotas and reports of sales suggest that the pro- motional scheme was successfuL The extent to which the sales instructions were followed, or what extrapolation the Merck detail men may have given to the bulletin instructions, in their oral presentations, is, of course, unknown to us. But we do know that Indocin has been promoted for conditions outside the approved labeling. We have no reason to doubt that the promotional instructions contributed to prescribing of the drug for unapproved uses We will hear now from the witness Our witness this morning is Dr Robert S McCleery, Acting Deputy Director, Bureau of Medicine, Food and Drug Administration of the TI S Department of Health, Education, and Welfare Dr McClerry, we appreciate your appearance here this morning very much, and you may proceed to present your statement. I assume that you would have no objection to interruptions for questions from time to time. Dr. MCCLEERY. No, sir. Senator NELSON. Please go ahead, Dr. McCleery. STATEMENT OF DR ROBERT S McCLEERY, ACTING DEPUTY DIREC TOR, BUREAU OF MEDICINE, FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY DR B HARVEY MINCHEW, ACTING DIRECTOR, BUREAU OF MEDICINE, FDA, HARRY CHADDUCX, DEPUTY DIREC TOR, DIVISION OF MEDICAL ADVERTISING, BUREAU OF MEDI CINE, FDA, WILLIAM W GOODRICH, GENERAL COUNSEL, FDA, AND MORTON M. SCHNEIDER, ASSISTANT DIRECTOR, OFFICE OF LEGISLATIVE AND GOVERNMENTAL SERVICES, FDA Dr MOCLEERY Mr Chairman, on May 2, as you mentioned, I appeared before you at your request to discuss our experience with the PAGENO="0393" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3485 advertising of Indocin that had come to our attention Later, you made available for our review and comment a number of sales bulletins on Indocin These bulletins appear to have been sent to Merck detail men by the district supervisor in one of the firm's sales regions Their form and contents suggest that they are internal communications to the detail ing force, not intended for distribution beyond control of the firm. I would like to add here, Mr. Chairman, for the record, that the following comments are based on the assumption that these are indeed statements by responsible officials of the company, and all I have to say hereafter will be based on that assumption Senator NELSON You are referring to the instructions ~ Dr MCCLERRY Right Senator NELSON Just so the record will be clear at this stage, a detail man sent the bulletins to us At the top it says, "To all western district associates from H Glassner," who is the district manager of that area, and it is these bulletinb upon which we raise the questions- Dr MCCLEERY Right Senator NELSON (continuing). With the FDA, and it is on these bulletins- Dr. MCCLEERY. That we are making comments. Senator NELSON (continuing) That you are m'iking youi comments Dr MOCLEERY Yes, sir, that is correct Before dealing with specific features of the instructions to Merck detail men, I should point out that the methods recommended in the bulletins for increasing sales of Indocm seem typical of methods used to promote a variety of products which ordinarily do not have such serious public health implications, as does a drug like Indocm And on the whole we regard these sales bulletins as seriously misleading. Senator NELSON Doctor, may I interrupt a moment ~ If the detail man did, in fact, follow the instructions in the bulletins, he would be making some claims for this drug that were not approved by the FDA, is that correct Dr MCCLEERY I ~ould say yes Senator NELSON And if the doctor got his information and relied upon the detail man, he would then be using this drug for purposes not approved by the FDA, is that correct ~ Dr MCCLEERY If he were not only influenced by some of the state ments here, but derived a large part of his basis for judgment on the drug, that is why we are saying that they were misleading. Senator NELSON. You say seriously misleading in your statement. Dr MCCLEERY I did The extent to which the sales instructions were followed or what extrapolation the Merck detail men may have given to the instructions in their oral presentations are unkno~ n to us As to the effect of the instructions on medical practice, there seems little reason to doubt that they would contribute to the prescribing of In docin for unapproved uses Mr Chairman, we found that the bulletins could be grouped for comparative study into two time periods Six bulletins, dated between July 12 and August 4, 1965, were i epresentative of the group of instruc tions issued during the period of the introduction of Indocin to the marketplace Six other bulletins, typical of the second group, were 4~ PAGENO="0394" 3486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY dated between April 5 and September 27, 1967. This latter group was after we had had discussions with the company's top management about its promotional methods. There was, nevertheless, considerable repe- tition of the faulty sales concepts throughout the instructions for these two time periods. In general, the 1965 bulletins, represented by bulletins that we se- lected out of the total that you submitted to u~, bulletins Nos. 83, 84, 87, 88, 93, and 95 suggest to detail men that they promote the use of Indocin beyond approved indications, and play down side effects and other warning information present in the then approved Indocin labeling. I offer now for the record a copy of the Indocin package labeling that was in effect at the time the 1965 instructional bulletins were sent out to Merck detail men. Senator N~L8ON That will be printed in the record at this point (The information referred to follows:) PAGENO="0395" COMPETiTIVE PROBLE1\Ih IN THE DRUG INDUSTRY 3487 A.H.F.S. Category: 92:00 Ph. 262301 INDOCIN® (INDOMETHACIN) II.4DOCIN* ~indomethacin) is a new "anti- Rheumatoid (Ankylo8ing) Spondylitis rheumatic" drug that has anti-inflamma- INDOCIN frequently produces marked re- tory, analgesic, and antipyretic activity. ~ lief of pain and improved motion of the has a unique chemical structure which dif- spine within 3 to 10 days. ferentiates it from the salicylates, corti- Degenerative Joint Disease costeroids, phenylbutazone-like compounds, ~Osteoarthri1is) of the Hip and colchicine. Unlike corticosteroids, it has no effect on pituitary oradrenal function. INDOCIN has provided relief of pain and increased range of motion in patients with INDOCIN is an effective anti-inflamma- . . degenerative joint aisease 01 zne nip. tory agent that is suitable for iong term as -well as short term use in adult patients of Gout all ages. It has been found' effective to ro- In acute attacks of gout the response to* lieve pain; reduce fever, swelling, and ten- IND0cIN is usually rapid and often dra- derness; and increase mobility In patients matic. Marked reduction of pain may be *with rheumatic disorders. obtained wi1~hin 2 to 4 hours. Tenderness and heat subside within 24 ~o 36 hours, and INDICATIONS, swelling decreases over a 3 to 5 day period. INDOCIN has been found effective In the During the interval phase of gouty ar- treatment of: thritis, indomethacin together with ade.. Rheumatoid arthritis quate doses of a uricosuric agent may pro' Rheumatoid (ankylosing) spondylitis vide relief of pain and prevent the recurrence Degenerative joint disease (osteoarthri- of acute attacks. tis) of the hip Gout CONTRAINDICATIONS In these conditions INnociN may often replace other commonly used agents such As with other anti-inflammatory agents, as corticosteroids, salicylates, phenylbuta- INDOCIN may mask the signs and symptoms of peptic ulcer. INDOCIN itself may cause zone-like compounds, and coicnicine. . . peptic ulceration or irritation of the gas- Rheumatoid Arthritis trointestinal tract. For these reasons it In many patients with chronic rheuma- should not be given to patients with active toid arthritis INDOCIN produces a significant peptic ulcer, gastritis, or ulcerative colitis, decrease of pain and stiffness within 48 and should be used with caution if there is hours, while in other patients treatment a. history of these disorders. In 4 patients must be continued longer before significant with i:egional enteritis treated for up to one subjective relief or objective evidence of month, and one patient treated for 6 months, : decreased joint swelling and tenderness INDOCIN was well tolerated. However, in occurs. Treatment with INDoCIN should be view of the paucity of data, this drug continue4 for at least a month before con- should not be given to patients with re- cluding that It has not produced significant gional enteritis until additional evidenceS benefit. of gastrointestinal tolerance is available. When a response to INDOCIN has been. Reproduction studies in mice, rats, and obtained, the daily salicylate requirements rabbits showed no `ciTect on fetal develop- can usually be reduced and often stopped. ment or the reproductive cycle, although in Also, if patients have been receiving cor- rats there was some decrease in fetal vi-' * ticosteroids, the steroid dosage often can ability. Studies in mice demonstrated that be gradually reduced by 25 to 50 per cent, INDocIN creases the placental barrier. Since and in some patients it can eventually be the effects of lunociN on the human fetus `completely discontinued. In such instances cannot be predicted with certainty from the steroid dosage should be reduced slowly, animal studies, the safety for use In preg-' In acute rheumatoid arthritis, or in acute nant patients has not been established. * flares of chronic rheumatoid arthritis, Since the experience with IND0CIN in INDOCIN will usualLy produce prompt Im- children is lImited, it Is recommended that provement with relief of pain, tenderness, this erug snould not be administered to swelling and stiffness. psdlatrlc age groups until the Indications *Reglstered trademark of Merek * Co,~ INC. for use ana dosage have been established. PAGENO="0396" 3488 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY INDOCIN® (Indomethacin) WARNING developed ulcerative colitis and another regional ileitis while receiving IND0cIN. Patients who suffer from dizziness, light- When INDOCU~ was given to patients with headedness, or fedlings of detachment on pre-existing ulcerative colitis, there was an INDOCIN should be cautioned against oper- increase in abdominal pain. ating motor vehiciles or other machinery, Other adverse effects that have been in- climbing ladders, etc., if these symptoms* frequently reported include drowsiness, tin- are present. . . nitus, mental confusion, depression and IND0CIN should he used with caution in other psychic disturbances, blurred vision, patients with psychiatric disturbances, epi- stomatitis, pruritus, urticaria, angioneu- lepsy, or parkinsmxiiizm, since it may, in rotic edema, skin rashes, and edema. some instances, .aWTavate these conditions. Extensive laboratory examinations have been made during treatment with IND0cIN. PRECAUTIONS AND ADVERSE A slight usually transient, increase in BUN REACTIONS . has. been reported in some patients. Al- The most frequent adverse reactions asso- though two investigators have reported ap- elated with INDOcJDS are headache, dizzi- parent changesin renal function, the relia- - ness, llghtheadedneN, and gastrointestinal bility of the techniques used was uncertain. disturbances such as nausea, anorexia, vom- The preponderance of evidence Indicates * lUng, epigastric distress, abdominal pain or that It-moclN does not have an adverse diarrhea. The central nervous system effects effect on renal function. Nevertheless, renal * are often transient and frequently disap- function should be checked periodically in pear with continueil treatment or with a patients on long-term therapy. Patients reduction of dosage.. The severity of these with pre-existing renal disease have re- * effects may, on occasion, require stopping / ceived INoociN without difficulty. * thm~apy. . . A few cases of leukopenia have been re' The gastrointestinal effects may be mini- ported in patients with rheumatoid ar- inized by giving the drug immediately after thritis; l~ukopenia is not uncommon in this meals or with food. . disease. Studies in normal subjects with radio. Transient elevations in alkaline phospha- active chromate-ta~eed red blood cells mdi. tase, cephalin-cholesterol flocculation, and eats that large doses of indomethacin (50 thymol turbidity tests have been observed mg. four times a clay) produce less fecal In some patients and, rarely, elevations of blood loss than average doses of aspirin SGOT values. The relationship of these (600 mg. four times a day). Notwithstand- changes to the drug, if any, has not been lug, INDoCIN may cease single or multiple established. ulceration of the slesriach, duodenum, or Unlike steroids, IND0cIN has not been small intestine. Them have been reports of associated with an increased incidence of severe bleeding and ef perforation with a infections. few fatalities. Patiests may also develop As with any new drug, patients should be gastrointestinal bleeding with no obvious followed carefully to detect unusual mani- ulcer formation. If gastrointestinal bleeding festations of drug sensitivity. occurs, INDOCIN shoi~L be discontinued. In S many patients with peptic ulceration a his- DOSAGE AND ADMINISTRATION tory' of a previous ulem was present or they limociN is available as 25 mg. and 50 mg. were on concomitant steroids, salicylates, capsules for oral use. or phenylbutazone. The possible potentia- In chronic disorders treatment should be tion of the ulcerogenie effect of these drugs started with a dosage of 25 mg. two or three cannot be ruled out at present. In some times a day. Starting therapy with low patients there was no history of a previous doses, with gradual increases when aeces- * ulcer and other drugs a3:~ not being given. sary, will produce maximum benefit and As a result of obvious or occult gastroin- minimize adverse reactions. Always give testinal bleeding some patients may mani- INDoCIN with food or immediately after feat anemia. For this reason periodic meals to reduce gastric irritation. hemoglobin determinatlisms are recommended. Dosage Recommendations for: Rare reports where it ~ not known 1 Rheumatoid arthritis and rheumatoid whether the effects can be attributed to the drug include bleedinj from the sigmoid (ankyboszumg) spon y tics colon, either from a di'merticulum or without Initial dosage: 25 mg. two or three times a known previous pat&sstogic condition, and a day. If the response is not adequate, in- perforation of pre-ezhting sigmoid lesions crease the daily dosage by 25 mg. a a ou (diverticulum, carcisarna). In other rare weekly intervals until a satisfactory response eases a diagnosis of gastritis has been made is obtained or a dosage of 150 to 200 mg. a while Iwoocmw was balag given. One patient day is reached. If a satisfactory response Is PAGENO="0397" COI\IPETIT1VE PROBLE1\IS IN THE DRUG INDUSTRY 3489 INDOCIN® (Indomethacin) not obtained wlth 200 mg. a day, larger indole-3-acetic acid. It has the following doses probably will not be effective, structural formula: If adverse reactions develop as the dosage CH3O ,` Is increased, decrease to a tolerated level CH2COOH and maintain at that dosage for 3 to 4 weeks. If an adequate response has not then been obtained, gradually increase the daily N " ~ dosage by 25 rug, at about weekly intervals to150to~00mg.aday. C=o For patients with acute rheumatoid ar- thritis or with acute flares of chronic rheuma- toid arthritis, increase the dosage daily by 25 mg. until a satisfactory response is ob- tamed or a total daily dosage of 150 to 200 - mg. is reached. If adverse effects develop as the dosage is increased, it should be reduced ci to a tolerated level for 2 or 3 days and then AInflamm~ory Action gradually increased by 25 mg. every few In laboratory animals, Ir~nociN is a po- daVs as tolerated. After ithe acute phase is tent anti-inflammatory compound.. Results under control, it is often possible to reduce of granuloma inhibition tests in rats receiv- the daily dosage of IND0CIM gradually to~ ing the compound either orally or by local 75 to 100 mg. - application indicated activity about 85 Reduction of steroid dosage: Use of times that of phenylbutazone. Given orally, INDocIN often will permit a gradual reduc- the compound was about 4 times as active tion of steroid dosage by 25 to 50 per cent. as hydrocortisone. When given in effective In some patients steroids can be slowly dis- doses to intact rats, indomethacin, unlike continued over a period of several weeks or anti-inflammatory steroids, did not affect months. The usual precautions should be the size of the adrenals or thymus, or retard observed in withdrawing steroids. gain in body weight. Its anti-inflammatory activity does not depend upon activation of 2. Degenerative Joint Disease (Osteoarthritis) the adrenals, since it was fully active in of the Hip adrenalectomized rats. Initial dosage: 25 mg. two or three times a Theanti-inflammatoryactivityofluDOciu day~ If the response is not adequate, in- was also demonstrated by its ability to in- crease the daily dosage by 25 rug. at about hibit edema formation induced by subplan- weekly intervals until a satisfactory response tar injection of carrageenin in rats. By this is obtained or a dosage of 150 to 200 rug. a test, the relative potency of indornethacin day is reached. If a satisfactory response is was: 30 times aspirin, 20 times phenylbuta- not obtained with 200 mg. a day, larger zone, and 2 times hydrocortisone. INr)ocIM doses will probably not be effective, does not possess antihistarninic or antisero- tonin activity, since it did not affect edema If adverse reactions develop as the dosage induced by injection of egg white, serotonin, Is increased, decrease to a tolerated level or yeast. Combinations of indomethacin and maintain at that dosage for 3 to `I and a steroid were more effective than corn- weeks. If an adequate response has not then parable doses of either drug alone in inhibit- been obtained, gradually increase the daily tog granuloma growth or edema formation. dosage by 25 mg. at about weekly intervals Antipyretic Actiritj~ to 150 to 200 mg. a day. * Iserocmr Is an antipyretic in laboratory 3. Gout animals. In rabbits it was about 21) times as To control acdte attacks: 50 mg. three potent as phenylbutazone and 10 times as times a day until all signs and symptoms potent as aminopyrine. Its duration of ac- subside. Definite relief of pain has been re- tionwasmuchlonger than that of aminopy- ported within 2 to 4 hours. Tenderness and rifle and comparable to that of phenylbuta- zone. In rats indoniethacin appeared to be heat usually subside in 24 to 36 hours, and about 10 times as potent as phenylbutazone. swelling gradually disappears in 3 to 5 days. The antipyretic activity of INDocz~i has To prevent acute attacks: During the inter- been confirmed clinically by observations in val phase of gouty arthritis the dosage may patients with Hodgkin's disease, acute be reduced to as little as 25 mg. twice a day, rheumatic fever, and a variety of other given with an adequate dose of a uricosuric acute febrile conditions. agent such as probenecid. Analgesic Activity CHEMISTRY AND PHARMACOLOGY Laboratory tests designed to detect mild analgesic activity indicate that indo- * The chemical name for indomethacin is rnethacin is more potent than aspirin or 1-(p-chlorobenzoyl) .5-methoxy -2- methyl- aminopyrine. PAGENO="0398" 0 0 : ( PAGENO="0399" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3491 Dr. MOCLEERY. The approved package labeling-package insert- includes the allowable claims and the required precautionary and warning information which is to be included in advertisements and promotional labeling of a prescription drug like Indocin. As you will see, the Indocrn package insert limits the use of this drug to four indications (a) rheumatoid arthritis, (b) rheumatoid (ankylosing) spondylitis, (c) degenerative joint disease (osteoarthri- tis) of the hip, and (d) gout. This labeling indicates that Indocin will relieve pain, reduce fever, swelling and tenderness, and increase mobility in patients with rheumatic disorders. indocin is a potent drug and, as the package insert shows, it has many side effects, con- traindications, precautions, and warnings that must be heeded for its safe and effective use. For these, and other, reasons, it was not approved for use in all rheumatic disorders, but only for those rheu- matic disorders I have named. The Indocin Bulletin No. 83, dated July 12, 1965, is typical of the group of instructions sent out during that time period. So that your committee may consider the bulletins as a group, I am including copies of the group as exhibit B for the record. These were sent out to Merck detail men. Senator NELSON. They will be printed in the record at this point. (The information referred to follows:) BULLETIN No. 83, JULY 12, 1965 To: All Associates Western District. From: H. Glassner. Subject: `Indocin.' One of the reasons a real Senior Salesman like John Brekke consistently writes over $300,000 a year is that the physicians in his territory ~elieve him. Physicians believe John because he tells them a concise, clear story that meets their needs, their wants, their desires, or allays their anxieties. Here is John Brekke's story on `Indocin'. I'll bet he leads them with this. "Doctor, I'm certain that in your busy practice no day passes without several patients seeking your help from the misery inflected by painful, reddened, swollen, feverish joints-the classic signs of inflammation. It is true that short term therapy with `Decadron' has offered dramatic relief to many of these patients. However, today, with `Indocin', a new compound which is not a steriod- you can offer these patients new hope, new vistas of relief from their pain and an extended margin of safety. More than 300 clinicians both here and abroad have concluded that when there is heat-redness-swelling-and pain in the muscle or joints-'In- docin' is usually effective. `Indocin' is .indomethacin-a modification of the naturally occurring amino acid tryptophan. `Indocin' is chemically unique. `Indocin' is not an aminopyrine derivative like phenylbutazone nor is `Indocin' a steroid. `Indocin' relieves stiffness, reduces swelling, alleviates tenderness, decreases fever, and above all soothes pain. The advantages of `Indocin' are these: 1. Therapy with `Indocin' is safer. Clinical investigation in thousands of advanced cases has shown `Indocin' to have a remarkable record of safety. 2. Therapy with `Indocin' is rapid in onset of action. In many cases- particularly in acute flare ups of gouty arthritis-relief of pain is evident in 2-4 hours. Usually on therapy with `Indocin' tenderness and heat subside in 24-48 hours and swelling is reduced in 3-10 days depending upon the severity of the condition being treated. 3. Furthermore, unlike steroids, tolerance to `Idocin' has not been reported. 4. The dosage schedule with `Inclocin' is simple and uncomplicated. Usual- PAGENO="0400" 3492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ly 1-25mg capsule of `Indocin' 2-3 times a day taken with meals-does the job. If necessary 1 capsule per day may be added at weekly intervals up to a maximum dose of 8 capsules per day. In acute gout, where speed of relief is urgent, 2 capsules of `Indocin' ti.d. may be given until the flare up is controlled. 5 Unlike toxic aininopyrine derivatives or steroids the side effects of therapy with Indocin are usually minor and seldom constitute a problem Usually they can be controlled by simple adjustment of dosage. Like all new agents today therapy with Indocin is contraindicated in pregnancy Other than that the only contraindications to therapy with Indocin are ulcerative colitis active peptic ulcer and gastritis These are not unusual since as you know doctor, even aspirin causes some gastric complaints. `The other side effects are not serious. Some patients on therapy with `Indocin' may experience headache, dizziness, or lightheadedness, and even some minor G.I. disturbances. This effect can be minimized by giving `Indocin' with meals. Headaches usually disappear after the patient has had a cup `of coffee. Doctor, clearly `Indocin' represents a giant step forward in the safe and effective treatment of the mitsery inflicted by arthritic diseases I m certain you have in your practice ten or more patients who right now -today-would welcome the dramatic relief Indocm can afford Would you like some starter doses `of `Indocine' for those patients whom you want to start on `Indocin' therapy today? `Indocin' is now stocked at the phar- macies in this area. You may prefer to call your prescriptions in right now rather than bother or have the patient come in." There's a detail that `clearly should convince the physician that Whenever the problem is oppressive joint pain associated with heat, red- ness, tenderness and swelling. When the muscles around an inflamed joint are in spasm causing a limitation in motion. Whether the tentative diagnosis is osteoarthritis of the hip gout rheuma toid arthiritis, rheumatoid spondylitis, or just plain muscoskeletal aches and stiffness. For short term use in acute conditions or long term use in chronic diseases Indocin will afford relief to three out of four natients effectively-with an extended margin of safety-with fewer tables-at less cost-with less doseage adjustment-and therefore fewer problems for both the physician and his patient than any other currently availa~ble product. Unless you've got a better story put together I would suggest you consider using this one. It will sell `Indocin'. BULLETIN No 84 JULY 14 1965 To All Sales Associates in the Western District From: H. Glassner. Subject Indocin Top salesmen reach peak sales ability by training their instincts to think of advantages and benefits Such men react naturally instantaneously and instinctively with maximum selling power to the physicians needs desires wants or fears Some trainers call this the hot button approach You call on a busy physician. He is thinking about his patients' problems. Only when you give him a glimpse of some advantage he does not now enjoy will he listen. Charlie Mitchell has done just that with his approach on Indocin With many years of experience on a regular territory and now with over eighteen months of experience in a specialist-hospital territory Charlie has learned the need for personalizing each presentation Here are three attention getting hot button individualized approaches he is planning to use For the G P Doctor, you do agree that in the treatment of' chronic rheumatoid dis- eases-aspirin is too weak for optimal effect PAGENO="0401" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3493 You no doubt also will agree that the arninopyrine derivatives such as Butazolidin and the steroids like Prednisone are too risky for long term use. Yet, until now, aspirin, aminopyrine derivatives, and steroids have been the only major agents available for relieving pain and reducing disability in a whole host of rheumatic problems Now today Indocin -a new non steroidal anti inflammatory agent which approaches the potency of the steroids~-equal' or surpasses the effectiveness of Butazolidin-~but which in therapeutic doses has a safety index corn parable to aspirin is Available to relieve pain. Reduce fever tendencies and swelling and increase joint mobility in pa tients with rhenmatic disorders. For the physician who is presently prescribing Darvon. Doctor, you no doubt agree that pain and disability are the most common complaints of patients with rheumatoid problems. Would not a drug that can control long term pain in such patients yet in therapeutic doses be as safe as aspirin fill a real need? Indocin -a new non steroidal anti inflammatory agent has a potency equal to or greater than Butazolidin-which as you know is an aminopyrine-like synthetic Indocin usually controls acute arthritic pain within one to two hours However Indocin is more than just an ordinary analgesic like aspirin or Darvon because `Indocin' has anti-inflammatory activity which is almost equal to full dose steroids For the conservative therapeutic nihilist. Doctor, it is true that no patient ever dies from chronic rheumatoid ar- thritis-but they do become cripples who live a very limited life. The burden of crippling disability imposed by chronic rheumatoid ar- thritis can now be lifted in three out of four patients on therapy with `In- docin'. No matter what approach you use-no matter what story you tell-make certain that when you leave the office the physician agrees that Whenever the problem is oppressive joint pain associated with heat red ness tenderness and swelling- When the muscles around an inflamed joint are in spasm causing a hmita tion in motion- Whether the tentative diagnosis is osteoarthritis of the hip gout rheu matoid arthritis rheumatoid spondylitis or just plain muscoskeletal aches and stiffness- For short term use in acute conditions or long term use in chronic dis- eases- `Indocin' will afford relief to three out of four patients effectively- with an extended margin of safety-with fewer tablets-at less cost-with less dosage adjustment-and therefore fewer problems for both the physician and his patient than any other currently available product Go get it!!! BULLETIN No 87 JULY 20 1965 To: Mr. Gordon R. Klodt. From: H. Glassner. Subject: `Indocin' Profit Plan Objectives. Surely you jest. The `Indocin' Profit Plan Objectives for the Western District have just arrived. Your ouija board has a definite short circuit. The figures you forwarded are so ridiculously low that they are a rank insult to the hottest, sellingest district in the country Only because these figures will appear on the official R-300 and R-317 reports beginning with July 1965 are we even bothering to forward them to our associates since we intend to smash them We realize these dollar objectives were calculated by determining the per centage of sales in each territory of Decadron Tablets and Injection Deca gesic Benemid and O~lBenemid Apparently the same percentages were then used in determining the percentages of the total objectr~ e for each territory on Indocin Apparently you next built the territory objectives into the Field Man ager Group objective and then the district total Yet even though your approach PAGENO="0402" 3494 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY was rational, I'll Bet You the Price of a Bottle of Your Favorite Booze that the Western District Beats this Objective by at Least 50% This Year. Heck, Gordon, `Indocin' is the hottest product we've had come down the pike in many a moon. Our guys are primed at fever pitch. Competition is running scared. Results on recalls look great. The only questions we are getting regularly are easily handled such as: Does `Indocin' affect prothrombin levels? The answer, of course, is "No." Does `Indocin' affect glucose tolerance? The answer, again, of course is "No." `Indocin' can be safely used on the diabetic patient. In fact, our guys are using a real expanded claim for `Indocin' on inflam- mation. They are consistently telling their doctors that- Whenever the problem is oppressive joint pain associated with heat, red- ness, tenderness, and swelling- When the muscles around an inflamed joint are in spasm causing a limi- tation in motion- Whether `the tentative diagnosis is osteoarthritis of the hip, gout, rheu- matoid arthritis, rheumatoid spondylitis, or just plain musculoskeletal aches and stiffness- For short-term use in acute conditions, or long-term use in chronic con- ditions- `Indocin' will afford relief to 3 out of 4 patients effectively- With an extended margin of safety- Probably with fewer tablets- Therefore, at less cost- With less dosage adjustment- And, therefore, fewer problems for both the physician and his patient than any other currently available product. For these reasons-we intend to really roll up the `Indocin' bonus credit points this year. We'll be laughing at you when we make our year's objective by Octo- ber 30. BULLETIN No. 88, JULY 21, 1965 To: All Western District Sales Associates. From: H. Glassner. Subject: `Indocin.' Jim Blake is kind of new. He is a pharmacist, so he has developed a very healthy respect for what drugs will and won't do. I suppose he just doesn't know any better than to sit down and prepare a detail that puts side effects in their proper perspective. Here is how he is handling the side effects on `Indocin'. "Chemically, `Indocin' is indomethacin. The only similarity in structure between `Indocin' and steroids or phenylbutazones is that all three are or- ganic compounds. After that, the similarity ceases. The ability of both the steroids and phenylbutazones to relieve inflamma- tion is unquestionable. However, both of these agents cause undesirable- and, in the case of phenylbutazones-even hazardous side effects. So, doctor let's examine the relative lack of side effects of `Indocin'. In six out of ten patients on `Indocin', you need anticipate no adverse qffects whatsoever. In two out of three of these ten patients, some bothersome effects might oc- cur. Bothersome is probably as severe an adjective as we can use to describe these effects because in most patients they are tolerable, and transient. Reports of changes in the white blood count of patients on therapy with `Indocin' have been exteremely rare. In most cases, it has been impossible to implicate `Indocin' as the causative agent. Unlike phenylbutazone, patients on therapy with `Indocin' do not require weekly or bi-weekly blood counts. Unlike `steroids, therapy with `Indocin' does not depress adrenal function, decrease resistance to infections, or present withdrawal problems. The percentage of patients experiencing side effects, which are listed in this chart, needs some explanation. Originally, our studies on `Indocin' were done with tablets. For some unknown reason, the tablets did not disintegrate properly and absorption was erratic. Now, commercially, `Indocin' is being marketed as a capsule. In capsule form, `Indocin' has not caused as high a percentage of even these minor reactions. These charts, however, do include the side effects experienced with the earlier tablets which are not even avail- able on the market. Therefore, the incidence of adverse reactions which you PAGENO="0403" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3495 probably will experience in your patients will be somewhat lower than these figures indicated here. You will note that gastrointestinal disorders head the list. This irritating effect can be markedly reduced by taking `Indocin' after meals. Headaches are next in frequency. These headaches are mild and are readily relieved by caffiene. Usually a cup of coffee does the job. Lightheadedness and dizziness occurs occasionally with `Indocin' as with almost any other medication. For the most part, these effects are very mild and very transient. Diarrhea accounts for less than 2% of all reactions. You will also note that the incidence of peptic ulcer is less than 1.5%. Since it is estimated that 7 to 7.5% of all arthritic patients have ulcers-Probably Because of the Large Amounts of Aspirin and Steroid Which These Patients Have To Take Over Long Periods of Time-It is hard to construe this effect of `indocin' as being a true side effect. In summary, doctor, six out of ten patients on `Indocin' probably will experience no adverse reaction. Two out of three of these ten patients may experience some mild adverse effects which are transient and tolerable. And, only one out of ten of these patients will probably experience side effects severe enough to warrant a reduction of dosage. On the basis of these complete figures-you will agree that `Indocin' does Extend All the Margin of Safety-in the management of arthritic disorders." With a complete and candid explanation on side effects such as this, it is difficult to see how any physician can refuse to believe that Whenever the Prob- lem Is Oppressive Joint Pain Associated With Heat, Redness, Tenderness, and Swelling- When the Muscles Around an Inflamed Joint Are in Spasm Causing a Limitation in Motion- Whether the Tentative Diagnosis Is Osteoarthritis of the Hip Gout Rheumatoid Arthritis Rheumatoid Spondylitis or Just Plain Musculo skeletal Aches and Stiffness- For Short Term Use in Acute Conditions or Long Term Use in Chronic Conditions- Indocin Will Afford Relief to Three Out of Four Patients Effectively- With an Extended Margin of Safety- Probably With Fewer Tablets- and, Therefore, Less Cost- With Less Dosage Adjustment- and, Therefore, Fewer Problems for Both the Physician and the Patient Than Any Other Currently Available Product. Tell `Em Again, and Again, and Again. Tell `Em Until They Are Sold and Stay Sold! BULLETIN No. 93, JULY 28. 1965 To: All Western District Sales Associates. From: H. Glassner. Subject: Profit Improvement Promotional Program `Indocin', August, 1965. All reports indicate that this one is a Real Winner. Our dollar volume on `Indocin' in June was basically the automatic shipments. Therefore, these figures are of limited value in assessing individual sales performance as regards repeat orders. Instead, please rely on the weekly tabulations in Angel Town Topics to measure your rate of progress on `Indocin'. Pick up ten or fifteen new prescribers each week on `Indocin' and you'll move to the top of your group. Obviously, `Indocin' sales greatly Exceed all initial sales forecasts. New revised projections are being developed at West Point These will be more in line with actual sales experience. Sometime prior to the end of August, your revised 1965 objective on `Indocin' will be forwarded to you. My guess in that our original objective will be tripled. Mr. Klodt just hates to lose any bet. The best way to beat this-or any other objective-is to continue to sell H- out of `Indocin'. It is imperative to do this because time is going to run out. One and probably two additional red-hot items are scheduled for release by October 1. Obviously, these new products will also require and get our all-out effort at the time of PAGENO="0404" 3496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY their release. In addition, it is reported in trade journals that both Upjohn and Parke Davis are reaching the final stages of research on anti-inflammatory products of their own. Those, as I understand it, are nonsteroidal. Obviously, this leaves no time to procrastinate on `Indocin'. We must estab- lish `Indicin' firmly during the next sixty days-or it will be too late! In August here s what we have to work with RD. value 150 Indocin 25 mg -21 s (3150 tablets) $225 50 Indocin 25 mg (3 x 6) (900 tablets) 63 150 Indocin Detail Folders 35 150 Indocin Folder Index Cards 15 150 Indocin Dosage Cards 9 Add to this figure the cost of having you make 139 to 140 presentations on In docin' this month, plus the cost of journal ads and direct mail necessary to support your efforts in your territory. Then, as a businessman-ask yourself how many dollars in `Indocin' sales You need to get back to make enough profit to plow $32.0 million in to Research to give You new products. Before you make any call on Indocin in August ask yourself these questions 1 Why am I calling on this physician ~ 2 What is he presently using in lieu of Inclocin'? 3 What hits his hot button fear effectiveness safety price etc 4 Just what am I going to tell him today that will make it imperative for him to Prescribe Indocin Today'? After you have made that call ask yourself just one question to measure your own effectiveness 1. Based on what I ju~t did in that office . . . How many tablets of `Indocin' is that physician likely to prescribe this month'? Let's face it! `Indocin' is a superior therapeutic agent. The documented F&DA approved claims indicate thet `Indocin' relieves the pain, reduces the stiffness, tenderness and fever-and increase joint mobility in patients treated with Indo cm when the diagnosis has been acute and chronic rheumatoid arthritis osteo arthritis of the hip ankylosing sj~ondy1itis and acute and chronic gout These clinical entities are the toughest most resistant most prolonged rheumatic lesions the specialist is likely to encounter Since Indocin is known to convey effective relief from the pain and infiamma tion of these most difficult lesions and to do this with an extended margin of safcty it is obvious that Indocin will work in that whole host of rheumatic crocks and crucls which every General Practitioner Internist and Orthopedic Surgeon sees everyday in his practice For these entities he is presently prescrib ing steoids aminopyrme like butasones aspirin or limited analgesics like Darv on and the almost worthless muscle relaxants. Remember, until `Indocin,' the physician who wished to use medication had only four classes of drugs a~ai1able to him: 1. Aspirin or simple aspirin-like analgesics which only relieve pain. 2. Steroids which only relieve inflammation. 3 Butasolidin or other aminopyrine derivatives which are too dangerous for prolonged use. 4. Muscle relaxants which rarely work and, at best, only temporarily relieve. Today Indocin effectively does all of these things with just one tablet Indo cm is anti inflammatory Indocin is analgesic Indocin breaks up the pain- spasm-pain cycle, thus increasing joint mobility. Yet, `Indocin' is neither a steroid nor an aminopyrine derivative-but rather a unique new chemical entity which affords an extended margin of safety in the long-term management of arthritic disorders. Run scared! Get a sense of urgency into every presentation. When you do, you will convince the physician that- Whenever the problem is oppressive joint pain associated with heat, red- ness tenderness and swelling When the muscles around an inflamed joint are in spasm causing a limita tion in motion.... Whether the tentative diagnosis is osteoarthritis of the hip gout rheu matoid arthritis rheumatoid spondylitis or just plain musculoskeletal aches and stiffness For short term use in acute conditions or long term use in chronic condi tions PAGENO="0405" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3497 Indocin will afford relief to 3 out of 4 patients effectively With an extended margin of safety probably with fewer tablets and therefore at less cost with less dosage adjustment and there fore, fewer problems for both the physician and the patient than any other currently available product. You've told this story now, probably 130 times. The physician, however, has heard it only once. So, go back and tell it again and again and again and again, until it is indelibly impressed in his mind and he starts-and continues-to pre- scribe `Indocin.' Let's go! ______ BULLETIN No. 95, AUGUST 4, 1965 To All Western District Sales Associates From: H. Glassner. Subject: Profit Improvement Promotional Program-'Indocin.' Bill Benedict brought back from the meeting in Chicago a group of the most common questions you have been asked about `Indocin.' Unfortunately, we do not have all of the answers. As you get questions-shoot them in and we'll try our best to get you an answer you can use. 1 What is the mode of action of Indocin'? Where does it work'? Indocin exerts its anti inflammatory-analgesic and antipyretic effects at the tissue level How it works is not yet clear since chemicalLy Indomethacin represents the first of a whole new group of compounds 2 How can an analgesic cause headache'? This phenomenon also is not yet clear The direct central action of Indo cm is very slight It is presently postulated that Indocmn may exert some peripheral vaso dilatory effect . . . which causes a mild headache-type cen- tral reflex. 3. Will `Indocin' work in any musculoskeletal inflammatory reaction? Yes. However, in submitting the original claims for an approved N.D.A. it was obviously important to demonstrate both the effectiveness and safety of `Indocin' in the toughest and most resistant cases. These are the only cases that top notch investigators will follow Indocm works effectively in those resistant cases Other specific claims such as bursitis fibrositms etc will be forthcoming Indocmn works in these entities From the point of view, of daily clincal practice, the physican himself will expand the uses to suit his practice Indocin however is a broad spectrum anti inflammatory agent which is specific for inflammatory lesions of the musculoskeletal system. 4. Is `Indocin' indicated for bronchial asthma? No. Bronchial asthma is an acute or chronic allergic disease. While there is. lots of inflammation present . . . it takes a specific anti~allergic agent such as `Periactin' or `Decadron' to work effectively in bronchial asthma. 5. Why is the maximum dose of `Indocin' only 200 mg./day? That is all it takes to get the job done. Going beyond that limit does not appreciably increase the effectiveness of `Indocin' and does seem to increase the severity of the side effects one may anticipate 6 Does Indocin alter the pH of body fluids or urine'? No Indocin has no affect on the pH of blood or urine 7 Can Indocin be safely administered to a diabetic'? Yes Indocin has no effect on glucose metabolism or glucose tolerance in either the normal patient or a diabetic patient 8 Can Indocin be safely administered to a patient who is taking anticoagu lants? Does it affect prothrombin time? `Indocin' has no affect on prothrombin time. `Indocin' can be safely admin- istered to a patient who is also taking anticoagulants. 9. Will antiacids interfere with absorption of `Indocin' from the G.I. tract? No. Antiacids may be administered concomitantly with `Indocin.' 10 When will reprints on Indocin be available'? As soon as the papers are published in journals of wide circulation probably within the next three to six months It is becoming evident that the greatest mistake we can make with Indocmn is NOT to remind the physician that-- PAGENO="0406" 3498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Whenever the Problem is Oppressive Joint Pain Associated With Heat, Redness, Tenderness, and Swelling. When the Muscles Around an Inflammed Joint Are in Spasm Causing Limitation of Motion. Whether the Tentative Diagnosis is osteoarthritis of the Hip, Gout, Rheu- matoid Arthritis, Rheumatoid, Spondylitis, or Just Plan Musculoskeletal Aches and Stiffness. For Short-Term Use in Acute Conditions or Long-Term Use in Chronic Conditions. `Indocin' Will Afford Relief to 3 Out of 4 Patriots Effectively. With an Extended Margin of Safety. Probaibly With Fewer Capsules. And, Therefore, Less Cost. - With Less Dosage Adjustment. And, Therefore, Fewer Problems for Both the Physician and the Patient Than Any Other Currently Available Product. This Is a Big One. Keep Sellin' It! BULLETIN No. 23, APRIL 5, 1967 To: All sales Associates. From: H. Glassner. Sub)ect Profit Improvement Promotional Program Indocin April Promotion During 1966, the Western Region with 10.8% of the nations manpower, con- tributed 10.3% of the nation's total volume on Indocin. That was not very good. Now for the first two months of 1967, we have contributed only 10.1% of the nation's total volume on Indocin. That is even worse. While for two months of 1967, the nation had a 32.6% increase in Indocin salee, the Western Region had only a 25.0% increase. For the two month period we are 0.6% behind our Profit Plan Objective on Indocin. District rankings, giving equal weight to percent of objective attained and per- centage incease over 1966 sales follow. Remember 66.6% of objective is par. Percent of Percent . District Total sales quantity of objective attained plus/minus 2 months of 1966 Perttula's Pirates $105, 285 Westmoreland's Wranglers 71, 999 Benedict's Bombers 92,875 Waddle's Warriors 124,867 Feudin Hatfields 63, 151 McCabe's Maulers 70,224 Lundahl's Lumberjacks 89,892 Region 72. 7 73. 3 67. 8 69. 2 60.6 60.8 56. 8 66. 0 35. 3 31, 2 31. 3 21. 6 24. 6 20. 9 12. 0 25. 0 Nation 32. 6 Top three and low three volumes among our regular representatives for the two month period were turned in by; 1. Joe Powell, $18218. 2. Rich Mazziotti, $16331. 3. Bud Iverson, $13002. 68. Roger, Hillman, $4406. 69. Dan Taylor, $3225. 70. Fred Mansho, $3027. Tabulations of two month. sales on Indocin, ranked by the percentage of objective attained, for all regular territories is attached. The Tools During April you will be working with the following assortment: 75 Indocin 25mg (3x6)-1350 Capsules $98 25 Indocin 25mg-21's---525 Casules 37 50 Indocin Folder Index Cards 296~ 5 Total PAGENO="0407" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3499 So far in 1967, Joe Powell has gotten almost a 70 fold return on his monthly Indocin promotional assortment. What is your return on the investment of promotional material which you have made? The Plan Our objective in April and every month in 1967 is to narrow the gap between your sales and the top sales in the Region. This can best be done by "Selective Detailing"-bringing the right product to the right physician with the right theme The theme must be one that allays his fears, or makes his therapy more effective, safer, or more economical. Indocin is an easy product to be selective about. Sales and Marketing Research studies show that general practitioners and internists prescribe more than 90% of all the nonsteroidal anti-inflammatory, anti-arthritic agents used. Therefore, in April. . . . pin point your shots. Select no more than 30 general practioners and/or internists for a hard hitting detail on Indocin. Let's be realistic. By this time most physicians have seen, read, or heard about the report in the New England Journal of Medicine and/or the Wall Street Journal. The general practitioner and internist in private practice is a mature, prag- matic individual. He realizes that his patients can not afford the luxury of "Ivory Tower" thinking. The arthritic he sees in his daily office practice demands prompt relief of pain. The arthritic he sees in daily office practice demands an anti-inflammatory agent that will relieve swelling and increase joint mobility so that he can become productive. The private practitioner realizes that the arthritic he sees in daily practice will probably be taking medication on a chronic basis. He wants a prepara- tion that can be taken for the long term with as few hazardous side effects as possible. Indocin is an effective anti-inflammatory agent that is suitable for long term as well as short term use in adult patients who are not pregnant. Indocin has been found effective in relieving pain; reducing fever, swelling, and tenderness; and increasing mobility in patients with rheumatoid arthritis, rheu- matoid spondylitis; osteo arthritis of the hip and gout. Indocin is much more than a simple analgesic It is a unique chemical entity unrelated to aspirin steroids colchrine or phenylbutozine Let's stand on our little old two feet this month and sell the benefits of Indocin. When some hard nosed physician brings up one of the recent controlled studies reported in the Wall Street Journal . . . Rich Mazziotti stops him cold by opening the Indocin literature to the bibliography and simply asking "Doctor, can all of these physicians of impeccable reputation really be wrong? "Doctor, can your own experience with Indocin in your own practice thes~ past 33 months really be wrong? Take off the kid gloves. If he wants to use aspirin as base line therapy, let him use it Ohances are the patient is already taking aspirin He has come to the physician because aspirin alone is not affording satisfactory optimal effects When aspirin alone is not enough Indocin is the logical prescription of choice. District Managers report that because Edecrin was on primary promotion in March, most of you still have a supply of the leave detail piece sent for use in March. It is a good one. Use it in A4pril to show general practitioners how to maximize the benefits of Indocin for their patients. If you do this effectively, your pockets can swell with extra bonus bucks. Let's go back down to selling Indocin again. PAGENO="0408" Group: Lachman $7,887 79 Lockett 9,235 73 Putnam 8, 450 70 Lewine 8,100 70 Tonkyro 8,633 67 Groos 10,475 60 Total 71,999 ~ Perttula s group Mazziotti 16 331 91 Woolley 11160 83 Houts 10 101 71 Number2626 8,456 71 Wolfe 7,136 70 Washington 5,662 69 Mustard 6,017 69 Mickelson 7,930 66 Edwards 9,638 66 Hammang 8,311 66 Brekke 11,914 62 Total 105, 285 73 Waddle's group: Powell 18,218 83 lverson 13,002 77 Bentley 10,118 71 Smith 10,482 69 Pies 10 890 62 Hart 7 053 65 Cargile 8 144 64 Ginger 11,588 63 Hilliker 12,045 62 Yarborough 8,632 61 Kohls 8,199 58 Total 124 868 69 Benedict's group: Brown 8,846 77 Nordquist 5,109 72 Alfano 9,282 70 DuBois 9,469 69 Solari 7,182 68 Lazarus 4 159 68 Lawing 9,052 67 Vitt 7 846 6u Strinz 6,315 66 Benedict's group-Continued Richardson $6,908 64 Blake 8,870 64 Filler 8,584 64 Total 92,876 68 Lundahl's group: Walker 7,892 64 Collins 6, 110 64 Knight 6,835 63 Doody 7,510 62 Nolan 5,796 60 Locke 9,018 Hydeman 9,392 58 Harris 5, 817 54 Peper 9,061 52 Stewart 8, 579 52 Lanciotti 5, 006 51 Wessells `7,879 50 Total 89,893 57 McCabe's group: Mele 7,335 74 Gray 12,851 66 Chalmers 7 984 66 Ayala 7 365 61 Chazankin 4 985 61 Callan 9, 184 60 Kearney 5 557 57 Hillman 4 406 53 No. 2720 6, 197 51 Total 70,225 61 Hatfield's group: Furr 4,456 65 O'Brien 8,456 64 Burgess 7,052 63 Allen 8,600 63 Pederson 5,910 60 Mansho 3 027 59 Koberstein 9,446 57 Baker 4 196 52 Taylor 3 225 _62 Total 63 151 61 Region total 618,955 66 3500 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY INDOCIN JANUARY THROUGH FEBRUARY 1967 Volume Percent Volume Percent BULLETIN No. 66, JULY 17, 1967 To: All Western Region Sales Associates. From: H. Glassner Subject: Profit-Improvement Promotional Program, `Indocin'. PAST PERFORMANCE For five months of 1966, with 10.8% of the national manpower, the Western Region has contributed 10.7% of national sales on `Indocin'. While the nation was 22.6% ahead of the same period in 1966, this region was 24.7% ahead. At the end of five months, we were running about 2.5% ahead of our Profit Plan for `Indocin'. These figures, of course, include the orders that were dated in April and May. However, package sales for June indicate we are again increasing sales of `Indocin'. It appears the bad publicity we had early in the second quarter is now behind us. PAGENO="0409" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3501 The standings, by district, for five months follow: - Percent of District Amount objective attained Percent plus/minus 1966 1. Westmoreland's Wranglers $187, 687 95 2. Perttula's Pirates 274, 432 93 3. Benedict's Bombers 253, 019 91 4. Waddle's Warriors 334, 788 91 5. Feudin' Hatfields 173, 145 81 6. McCabe's Maulers 182,489 77 7. Lundahl's Lumberjacks 240,614 74 Region 86 Nation During the months of July and August, you will be working with the following assortment: 125 Indocin 25 mg (3 X 66)-2250 capsules $140 50 `Indocin' 25 m.g.-21's-1050 capsules 70 50 Indocin Folder Index Oards 539L 10 2 Indocrn Permanent Detail Piece 612L 20 250 Indocin Telephone Pads 30 50 Indocin How to Use Leaflets? 10 Total 280 Joe Powell is making an average monthly assortment return $60 for every $1 he expands in promotional material. What is your batting average? THE 1'LAN A recent report from Sales & Marketing Research on the reputation and usage of various drugs in severe rheumatoid arthritis points the way to increased opportunities In this study physicians identified any patient with severe rheumatoid arthritis as one afflicted with pain and crippling so severe he could not perform his usual activties often needed to be cared for by others and had objective evidence of severe disease. The survey found the following attitudes among general practi- tioners and internists relative to severe rheumatoid arthritis: 1. `Indocin' held only 19% of the severe rheumatoid arthritic market. 2. `Indocin' was the second most often prescribed product in this market. 3 Eight out of ten physicians questioned sometimes use Indocin in the treatment of severe rhematoid arthritis, yet seldom used it as the first drug they prescribed. 4 Almost five out of ten physicians questioned do not use Indocin as either the first or the second drug to treat severe rheumatoid arthritis 5 Two other products aspirin and Darvon have 48% of the severe rheumatoid arthritic market 6 Eighteen per cent of the physicians questioned treated all of their severe rheumatoid arthritic patients with aspirin Yet G I side effects were eon sidered as a bad characteristic of avpirin more frequently than of Indocin 7 Only aspirin had a better reputation for efficacy and few side effects thtn did Indocin Darvon has a more favorable reputation for fewer side effects but a less favorable reputation for efficacy than does `Indocin'. 8. Butazones, corticoids, and gold salts, hold 33% of the severe rheumatoid arthritic market. Yet, these more potent products have a less favorable repu- tation among physicians using them for efficacy and side effects than does Indocin Obviously we have done a good job of selling Indocin for long term manage ment of chronic rheumatoid arthritis Now we must convince our physicians to use Indocin for short severe flare ups 36.9 30.8 30.1 26. 8 25. 1 15.0 10.3 24.7 22.6 Top three sales volumes in the region for five months on Indocin were turned in by 1 Joe Powell $46 024 2. Rich Mazziotti, $36,560. 3. Dean Hilliker, $35.884. THE TOOLS PAGENO="0410" 3502 COMPETITIVE PROBLEMS IN `THE DRUG INDUSTRY There is room for continued growth of `Indocin' in the treatment of severe rheumatoid arthritis_where pain and crippling are so severe that the patient cannot function normally. This growth can come from two areas: 1. From the many physicians who prescribe therapy which is "more potent" than therapy with `Indocin' (i.e. butazones, steroids, and gold) before trying `Indocin', and 2. From those severely afflicted patients who are not adequately controlled by aspirin or Darvon, i.e. when pain-killers no longer give adequate control or when they only kill pain without reducing inflammation or improving joint mobility. . . . `Indocin' should be tried promptly or even tried first. Remember, and make sure your physicians realize that `Indocin' is an effective anti-inflammatory agent that is suitable for short-term as well as long-term use in adult patients. Rememher, and make sure your physicians realize that unlike aspirin and DarvQn `Indocin' has been found effective in not only relieving pain but reducing fevej'~ swelling, and tenderness . . . and increasing joint mobility in the sympto- matic treatment of rheumatoid arthritis. Remember, also, and be sure your physicians realize that for patients with acute, severe rheumatoid arthritis, or acute flares of chronic rheumatoid arthritis, the total daily dose of `Indocin' may be increased by one capsule per day until a satisfactory response is obtained or a total daily dose of six to eight capsules a day is reached. We have not really scratched the surface on this one yet. Let's start digging this month. INDOCIN, JANUARY THROUGH MAY 1967 Pertulla's group: Mazziotti 36, 560 100 Wootley 27,587 100 Mustard 17,359 98 Edwards 29,358 98 Washington 15,939 95 Groos 22,290 91 Mickelson 22,247 91 Wolfe 18,725 90 Houts 26,030 89 Hammang 22,697 88 Brekke 31,365 80 Group 274,432 93 46,024 103 32,743 101 29,955 96 32,130 9 35,884 9 25,524 84 19,119 86 21,486 83 30,876 83 22,767 79 21,895 75 334,788 - - 91 22,886 98 27,175 98 18,607 95 `25585 95 13,579 93 25,031 89 18,847 88 24,775 87 23,783 87 18,797 86 Volume Percent Benedict's group-Continued Vitt 19,958 83 Lazarus 10,325 83 Group 253,019 91 Lundahi's group: Collins 18,943 98 Walker 22, 593 90 Locke 25,379 81 Doody 20, 018 81 Hydeman 24,858 76 Knight 16, 863 76 Nolan 14,771 75 Stewart 22, 708 68 Lanciotti 13, 053 67 Harris 16,875 66 Peper 22,992 65 Wessells 21 006. 65 Group 240,614 74 18, 577 92 21,725 87 33,357 84 19,175 78 15,056 75 12,536 75 23,836 74 17,330 70 10,807 63 Group 182,489 77 12,703 91 16,695 83 21,884 83 21186 83 21,009 82 15,208 78 7,845 74 22,885 74 9,276 73 173,145 81 Region 1,649,075 86 Volume Percent Westmoreland's group: Lachman $19,936 98 Putnam 23,413 95 Lockett 24, 007 92 Tonkyro 24,020 91 Lewine 21,053 89 Adams 27,512 78 Group 189,687 95 McCabe's group: Mele Chalmers Gray Ayala Kearney Chazankin Callan Nylund Hillman Waddle's group: Powell Pies Smith Iverson Hilliker Bentley Hart Cargile Ginger Yarborough Kohis Group Benedict's group: Brown Lawing Strinz Alfano Nordquist DuBois Solari Blake Filler Richardson Hatfield's group: Furr Pederson Allen Burgess O'Brien Baker Mansho Koberstein Taylor Group PAGENO="0411" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3503 BULLETIN No. 74, SEPTEMBER 5, 1967 To: All Western Region Sales Associates. From: H. Glassner. Subject: Profit Improvement Promotional Program, `Indocin.' "If it doesn't work in a week, forget it." Now that's a clever slogan. It really should say, "If it does work in a week, you had better really forget it." Here are some direct quotes from the current package circular for Butazolidin. 1. "Important Note. Butazolidin brand of phenylbutazone, cannot be con~ sidered a simple analgesic and should never be administered casually. Each patient should be carefully evaluated before treatment is started and should remain constantly under close supervision of the physician 2. "Contraindications. Butazoildin, brand of phanyibutazone, is contrain- dicated in the presence of edema and in cases in which there is danger of cardiac decompensation Now, how many older patients . . . the patients with most of the aches and pains . . . the real crocks and cruds seen in everyday daily practice . . . just how many of these patients do not have some degree of cardiac decompensation or some degree of edema? Yet, the term "contraindication" has medico-legal connotations. This part of the country has the highest rate of malpractice suits and, therefore, the highest rate of malpractice insurance. Why add fuel to the fire? 3. "Precautions. Patients receiving Butazolidin, brand of phenylbutazone, should remain under close supervision of the physician and should be warned to report immediately `the recurrence of fever sore throat lesions in the mouth, or black or tarry stoolsi. Specifically, it is recommended that periodic visits with the physician include: a. Verbal and physical examinations for indications of toxic reactions. b. Check of patient's weight to determine significant water retention. c. Oomplete blood counts at weekly intervals during the early phase of therapy and at intervals of two weeks thereafter to guard against the possibility of blood dyscrasia." A complete blood count costs at least $7 to $10. That makes therapy much, much too expensive. Let's take the kid gloves off and start slugging it out. Let's stress the balance between efficacy and safety of `Indocin'. Our literature doesn't say anything about complete blood counts under precautions or contrain- dications. The annoying G I side effects of Indocin can be easily nunumzed by simple dosage adjustment, taking the dosage with food, milk, or antacid. Let's get back to selling `Indocin'. Be certain that every physician understands that Wherever there is pain, inflammation, and swelling in or around the joint with a resultant limitation of motion as there is in rheumatoid arthritis, ankylosing spondylitis, acute attacks of gout, or osteoarthriti's of the hip- Whether the condition is acute or chronic... Therapy with `Indocin' usually- Relieves pain, reduces inflammation, and increases joint mobility on a simple dosage regimen that is relatively safe often dramatically rapid in effect, and usually most economical. `Indocin' is a great drug. Promote it like it was. BULLETIN No. 77, SEIPTEMBER 11, 1967 To: All Western Region Sales Asseciates. From: H. Glassner. Subject: Profit Iniprovenient Proinotioaal Pro gra'ia, `Indocin.' Let's dare to compare. In the management of inflammatory lesions of the musculoskeletal system where there is pain, inflammation, and limitation of motion-as there is in rheumatoid arthritis, osteoarthritls of the hip, ankylosing spondylitis, and acute gout-what choice does the physician really have if he does not prescribe `INDO- CIN'? PAGENO="0412" 3504 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Sure he can use aspirin But the patient has probably already used aspirin before he visits his physician. Furthermore, no less an authority than Dr. Howard Polley at the Mayo Clinic has said I wouldn t put Indocm in the category of aspirin I think it is more potent. But, if indomethacin is as good as aspirin, that is a pretty good claim in my view. That is a recommendation for indomethacin If he is a gambling sole-and almost no physician ever likes to gamble with his patient's welfare-he can prescribe Butazolidin. However, the current edition of the Goodman and Gilman, on pages 338-339, states the following about Butazolidin. Phenylbutazone is poorly tolerated by many patients Some type of side effect is noted in 10% to 45% of patients, and medication may have to be discontinued in 10% to 15% Nausea vomiting epigastric discomfort and skin rashes are the most frequently reported untoward effects from phenylbutazone. . . ." Its use should `be restricted to short-term therapy of not more than one week during any one treatment period. Even then the incidence of disturbing side effects is about 10% He can prescribe steroids, the most potent anti-inflammatory compounds pres- ently available. But there is general widespread agreement among qualified clinicians that steroids. 1. Should never be the initial agent used to treat rheumatoid arthritis. 2. Should be used only after a conscientious and unhurried trial of conservative measures fails to `achieve satisfactory results. 3. Should not constitute the only measure of treatment. If he wants just analgesic effect Darvon will work just as well as aspirin but Darvon has little or no anti-inflammatory `activity. Its use is purely palliative. At `best, treatment covers only one symptom. Let s be rational Do yourself and your physicians a favor Before you do any thingelse, as soon as you get into the office, make sure that he realizes that When there is pain inflammation and limitation of motion in or around a joint `as there is in rheumatoid arthritis, ankylosing spondylitis', `acute gout or osteoarthritis of the hip, Whether the condition is acute or chronic, For short-term or long-term use, Therapy with `Indocin' usually Relieves Pain, "Reduces Swelling, and Improves Joint Mobility on a flexible dosage regimen that is usually effective usually safe and alway'~ economical Remember the product credit value of Indocin is now 10 If your Indocin sales are just average, you have automatically increased your income by $22 per month. Now, every extra bottle of 1000 `Indocin' that you sell is worth an extra $2.80 in incentive payments. Go get it. BULLETIN No 80 SEPTEMBER 13 1007 To All Sales Associates in the Western Region From H Glassner Subject Profit Improvement PromotIonal Program Indocin If you are a timid sole if you are a cautious Indocin detailer you can still find some Powerful Sel'ling Sentences right in the F&DA approved package circular. How about using these'~ In acute rheumatoid arthritis or in acute flares of chronic rheumatoid arthritis prompt improvement with relief of pain tenderness swelling and stiffness will usually occur." In many patients with chronic rheumatoid arthritis Indocin produces a significant decrease in pain and stiffness within forty eight hours Indocin has anti inflammatory analgesic and antipyretic activity It has a unique chemical structure which differentiates it from the salicylates corticosteroids phenylbutazone like compounds and cholchicine L nlike cortico steroids it has no effect on pituitary or adrenal function Use one use two or use em all But be sure he understands that PAGENO="0413" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3505 Whenever there is pain inflammation and limitation of motion in and around a joint-as there is in rheumatoid arthritis, ankylosing spondylitis, osteoarthritis of this hip, and gout whether the condition is acute or chronic whether therapy is to be long-term or short-term therapy with `Indocin' relieves pain, reduces inflammation, and improves joint mobility on a flexible dosage schedule that is usually effective, usually safe, and quite economical Remember if your sales of Indocin are just average the new product credit value for Indocin gives you an automatic $22 per month increase in incentive payments plus the opportunity to earn $280 extra for every bottle of 1000 Indocin you sell over your present average sales BULLETIN No. 85, SEPTEMBER 27, 1967 To: All Western Region Sales Associates. From: H. Glassner. Subject: Profit Improvement Promotional Program, `Indocin.' Don 1~pperson is brand new He hasn t even been assigned to a territory vet He is still waiting to go to West Point to complete his Basic Training He doesn t know any better than to spend enough time putting a hard hitting story on Indocin together and then deliver it with conviction enthusiasm and force He is temporarily working in a vacant territory Howard Perttula brought the following detail back after working with Don just two days Try it It might put you in the top ten before Don gets assigned By that time, he should be crowding our Top Ten Club. The selling time for this detail is less than three (3) minutes. "Doctor, in the management of pain, inflammation, and limitation of motion associated with musculoskeletal diseases, there are many choices of therapy. Basically, at one end of the continuum is Aspirin . . . at the other and are steroids. In between these two extremes you can choose between phenylbutazone and Indocin Indocin is chemically unique It is not a steroid It is not an aminopyrine derivative Therefore it is distinctly different from phenylbutazone Indeed unlike phenylbutazone when Indocin is used for prolonged therapy the patient does not need to pay for periodic complete blood counts * Most of the adverse reactions which occur with `Indocin' are common with any anti-rheumatic drug. They usually are transient, easily controlled, and often disappear on continued treatment. Yet, `Indocin' is not a simple analgesic. `Indocin' is a potent analgesic with pronounced anti-:inflammatory properties which frequently affords prompt relief of acute rheumatoid arthritis and increased joint mobility within forty-eight (48) hours. In fact, the action of `Indocin' is often so rapid that when it is used in an acute attack of gout, a marked reduction of pain often occurs within two to four hours Whenever the patient s problem involves pain inflammation redness swelling and limitation of motion in or around the joint as in rheumatoid arthritis, osteoarthritis of the hip, ankylosing spondylitis, or gout- whether the condition is chronic or acute, whether therapy is to be short or prolonged, Indocin usually provides a reduction in swelling relief of pain Since most rheumatoid arthritic patients who present themselves to you with such problems are having an acute flare-up of their disease, you can maximize the benefits of `Indocin' by starting the patient on one or two capsules of `Indocin' three times a day. . . pushing the dose to a maximum of six capsules until relief is obtained and then gradually tapering the patient off to the usual maintenance dose of two or three capsules a day. Gastric irritation can be minimized by giving the dose of `Indocin' after meals PAGENO="0414" 3506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Doctor, will you use `Indocin' in the management of these arthritic dis- orders either after Aspirin or before Steroids, so your patient can benefit from `Indocin' that much `sooner?" Remember, every bottle of 1000 `Indocin' that you sell, over your normal average, is now worth an additional $2.80 in incentive payments. Pile it in! Dr. MCOLEERY. This Bulletin No. 83 advises the detail man to tell the physician: Doctor, I'm certain that in your busy practice no day passes without several patients seeking your help from the misery inflicted by painful, reddened, swol- len, feverish joints-the classic signs of inflammation. The bulletin goes on to promote Indocin for "pain in the muscles" It urges the detail man to "convince" the physician that Indocin should he used "when the muscles around an inflamed joint are in spasm caus- ing a limitation in motion" and for "just plain musëoskeletal [sicj aches and stiffness * * ~" The unwarranted claims I have just mentioned appear repetitively in other bulletins of this same introductory time period. We regard these claims as outside the limits of indications in the approved label- ing and therefore seriously misleading. In this connection, Bulletin No. 87, July 20, 1965, contains this statement of admission: In fact, our guys are using a real expanded claim for "Indocin" on inflamma- tion. They are consistently telling their doctors that * * * They repeat the quotes similar to the ones I mentioned just above. Senator NELSON. So in the drug company's own bulletin this sen- tence is a confession that they are making claims over and above those approved by the FDA, is that not correct? Dr. MCCLEERY. Yes, it is correct that that is what these bulletins say. Senator NELSON. Please go `ahead. Dr. MOCLEERY. It appears quite clear that the detail men were being told to influence physicians to use Indocin for unapproved uses. But the instruction to Merck detail men did not stop with the pro- motion of unapproved uses. The detail men were given slanted infor- mation to deemphasize side effects and other warnings. Mr. Chairman, in the interest of saving the committee's time I will not recount all of the information in the Indocin package insert on contraindications, precautions, adverse reactions, and other warnings. In the composite, all of this information suggests that Indocin must be used cautiously, if at all, and with the expectation that serious side effects may occur. Notwithstanding all of the warning advice in the package insert, the bulletins representing the period July 12 to August 4, 1965, in- structed Merck detail men to convince physicians that "therapy with Indocin is safer." The implication was that Indocin is even safer than aspirin. The physician was told that the drug is contraindicated in pregnancy but nothing was said in the `bulletins of instructions about its being contraindicated in children. The instructions stated that the only contraindications are pregnancy, ulcerative colitis, active peptic ulcer, and gastritis. This was false. The instructions went on to say: The other side effects are not serious. Some patients on therapy with Indocin may experience headache, dizziness or lightheadedness, and even some minor G. I. disturbances. PAGENO="0415" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3507 What the instructions did not disclose here were many serious side effects listed in the package insert. One such was that- Indocin may cause single or multiple ulceration of the stomach, duodenum, or small intestine. There have been reports of severe `bleeding and of perforation with a few fatalities. Some other side effects listed in the package insert are drowsiness, tinnitus, mental confusion, depression and other psychic disturbances, blurred vision, stoma'titis, pruritis, urticaria, angioneurotic edema, skin rashes, and edema. In Bulletin No. 88, issued July 21, 1965, it `was suggested that the detail men use this sales approach: So doctor let s examine the relative lack of side effects of Indocin In six out of ten patients on "Indocin," you need anticipate no adverse effects whatsoever. In two out of three of these ten patients, some bothersome effects might occur. Bothersome is probably as severe an edjective as we can use to describe `these effects because in most patients they are tolerable, and transient. Mr. Chairman, as you know from our testimony last May there were a series of `events that occurred `between 1965 and 1967 which involved our dealing wi'th Merck regarding its advertising and promotion of Indocin. The Assistant General `Counsel, Food and Drugs Division, of the Deparment of Health, Education, and Welfare spoke publicly in October 1966 regarding our opinion as to the misleading nature of an Indocin advertisement which appeared in the Journal of the American Medical Association and elsewhere Conferences were held with Mr Henry W Gadsden and his associates in the Merck managa ment in November 1966. Senator NELSON. So there is not any requirement on the part of the American Medical Association that th'e drug company make claims in their `advertising in compli'ance wi'th approved indications by the FDA? Dr MOCLEERY I don't believe that their code of approval of ad ~ ertising copy includes the requirement that it conform to the package insert They do have their own code, which they follow And they state in each journal that it is applied to all advertising submitted to the journal before an ad is approved Senator NELSON Do you mean to say that the American Medical Association, the AMA Journal, knowing `the claim made in an ad in their medical journal goes beyond approved claims by the FDA is still willing `to accept `that `ad? Dr. MCCLEERY. I would not want to say that the staff of the journal is aware of the information in the package inserts or that they are not, or why they make the judgments they do Senator NELSON. So far as you know, they do not require as a matter of advertising policy that the company inserting an ad comply with FDA approved regulations as to that drug ~ Dr MOCLEERY So far as I know they do not, but I do not know just what their standards precisely might be. Senator NELSON. Are you aware of the fact that any number of times ads have been put in the AMA Journal which made claims be- yond approved indications `by the FDA? Dr. MOCLEERY. I am aware, Mr. Chairman, that on quite a number of occasions we have felt the necessity to charge ads as false or mis- PAGENO="0416" 3508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY leading in our view that have appeared in the Journal of the American Medical Association. Senator NELSON. But I don't suppose I could expect you to comment on it, but it would seem to me that the great and distinguished medical profession ought to have the integrity to throw out any ad by any drug company that misleads the doctois If there is anything a doctor ought to be able to rely upon, it is the official publication of the Amen can Medical Association I would assume that every doctor would say to himself that this is the distinguished leadership of the medical professions speaking to us, and what we say in their journal is honest, and I think it is an incredible disgrace that the AMA Journal wouldn't lay down a rule that any ad you put in here has got to comply with the FDA regulations It shocks me, and I am ashamed of the leader ship of this great profession respecting this kind of business mislead- ing the doctors Please go ahead Dr MCCLEERY Having given the Merck organization notice of our views of the status of their advertising and promotion of Indocin under the Federal Food, Drug, and Cosmetic Act, the firm did take action to correct its journal advertising Notwithstanding, we find in Merck instructional bulletins dated be tween April 5 and September 27, 1967, continued suggestions for open ended uses and continued minimization of side effects The bulletins, addressed to all associates western district, still bear the name of the same individual who apparently issued the bulletins back in 1965 There is nothing we see in the 1967 bulletins that suggest the firm had changed its basic philosophy and methods of promotion of Indocin from those employed in 1965 Mr Chairman, we have applied the principles of the advertising and labelmg regulations in evaluating the Indocin bulletins apparently issued to Merck detail men in 1965 and 1967 Against these principles, we regard the bulletins as false or misleading in many details Other features of the bulletins which appear worthy of mention reflect disquieting attitudes of the firm's employees toward the medical profession and to the patient Some of the statements in point in the bulletins are * * * it is obvious that Indocin will work in that whole host of rheumatic crocks and cruds which every General Practitioner Internist and Orthopedic Surgeon sees everyday in his practice Tell em again and again and again Tell em until they are sold and stay sold' For these entities [ rheumatic crocks and cruds ] he [the doctor] is presently prescribing steroids, aminopyrine-like butazones, aspirin, or limited analgesics like Darvon and the almost worthless muscle relaxants You ye told this story now probably 130 times The physician however has heard it only once So go back and tell it again and again and again and again until it is indelibly impressed in his mind and he starts-and continues-to prescribe Indocin Let s go Let s stand on our little old two feet this month and sell the benefits of Indocin Take off the kid gloves If he wants to use aspirin as base line therapy let him use it Chances are the patient is already taking aspirin He has come to the physician because aspirin alone is not affording satisfactory optimal effects Now every extra bottle of 1000 Indocin that you sell is worth an extra $280 in incentive payments Go get it Pile it in~~t Mr Chairman, if you ha~ o ~ny questions I will be glad to answer them to the extent possible PAGENO="0417" COMPETITIVE PROBLEMS iN THE DRUG INDUSTRY 3509 Senator NELSON. There was one other quote in Bulletin 74 referring again, referring this time to older patients and calling them "The real crocks and cruds." Now that quote is: Now, ho'w many older patients, the patients with most `of the aches and pains, the real crocks and cruds seen In everyday and daily practice, just bow many of these patients do not have some degree of cardiac decompensation and some degree of edema? For a great and distinguished company to be referring to elderly citizens as "the real crocks and cruds" gives you some idea of the level of their attitude toward the patients. And apparently the attitude of the detail men and all the rest of them. The approved package labeling which I have here is dated effective May 19~5; is that correct? Dr. MCQL.EERY. Yes, sir. Senator NELSON. Is a copy of the package labeling sent by the firm to all the detail men? Dr. MOCLEERY. Presumably so. It is required. We have no way of knowing for certain the intimate detail. Senator NELSON. But the FDA does require that that be done? Dr. MOCLEnRY. With every sample of drug that the `detail man is given to give to doctors, there is required to `be a package insert. Senator NELsON. So, then, the 1965 instructional bulletins to detail men were issued after the package labeling had been in effect, is that not correct? Dr. M0CLEEnY. Yes, sir. Senator NELSON. Do you have a listing of all o'f the unapproved claims made by the company in the various bulletins examined? Dr. MCCLEERY. I don't have one before me. We have made one, and I have mentioned a number of them in my testimony. I think that that attitude is perhaps exemplified best in the early period of enthusiasm, which might be understandable if not condonable, in the period when a new drug comes on the market. However, it is less understandable in the year 1967, long after that introduction, and after our contacts on the principle of proper promotion of Indocin had led to agreement between the Commissioner ai~d the top officer of Merck. I think the bulletins in 1967 are much more impressive in the way they express the value and indications of Indocin, and also what uses are suggested in this language, presumably by a regioiial sales manager, to develop copy for oral assertion by individual detail men to the doctor. This is much more subtle than the kind of language in the introductory pe- riod, but I think it is also quite instructive of the problem. I would be glad to point out one or two instances of what I mean if you wish. Senator NELSON. Please go ahead. Dr. MC'CLEERY. You had made reference just a moment ago to a statement in Bulletin 74 dated September 5, 1967, on the "real crocks and cruds." In the same bulletin in which that statement is made, there is a reference on the second page which runs through, in a very subtle way, the whole pattern of promotion by this method in the time period of 1967. I will quote from it, Mr. Chairman. On page 2 it says- Senator NELSON. Is that September 5, 1967, Bulletin 74? Dr. MOCLEERY. Yes, sir; on page 2. It says: "Wherever there is pain, inflammation and swelling in or around the joint with a resultant limitation of motion as there is in rheumatoid arthritis, rheumatoid 81-280---88-pt. 8-27 PAGENO="0418" 3510 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (ankylosing) spondylitis, acute attacks of gout, or osteoarthritis of the hips." On the surface, when this goes by quickly, it sounds like it is entirely within the indications described `by the approved package labeling. But the fact of the matter is that it is an open-ended state- ment of indications, because it says "Wherever there is a pain, inflam- mation and swelling" use this drug, and the only limitation, and it is not a real limitation, is in bringing in the proper indications by the state- ments "as there is in rheumatoid arthritis." This is not a limiting state- ment. It only says wherever there is inflammation use Indocin, and there is inflammation in rheumatoid arthritis, and so forth. This runs through the whole time period of 1967. Senator NELSON. And that statement I read to you previously about the older patients, that is: Now, how many older patients, patients with most aches and pains, the real crocks and cruds seen in everyday practice, just how many of these patients do not have some degree of cardiac decompensation or degree of edema? What is that in there for, cardiac decompensation and some edema? Dr. McCu~aiy. Well, there are competitive drugs which are men- tioned throughout the bulletins of this time period. The characteristic of this time period is competitive selling, giving the detail men infor- mation which may or may not be proper about the dangers or effective- ness of competitive drugs. One of the competitive drugs does have warnings in its labeling about the possibility of causing edema. There- fore, they are saying that this would limit the value of the competitive drug in this particular class of patient. There is some truth in that. Senator NELSON. Is it common that you may end up with muscular soreness and tenderness as a consequence of the edema? Dr. MCCLEERY. That would be `difficult to answer, Mr. Chairman. As far as the patient is concerned, he might feel that he had aches in his muscles, because of the swelling, and very likely wouldn't himself localize it to muscle, but just to his lower extremity. We said in our testimony that there was some slanting of information and I would like, if you wish, to describe what we meant by that statement. Senator NELSON. Yes, if you would, please. Dr. MaCLEERY. I mentioned `that the need to sell a product by one company in competition with somewhat similar products by other companies creates the need to draw limits of value between it and its competitors' products. This is going on a great deal during this time period. One of the drugs which has to be discussed, in this competitive way, for the treatment of rheumatoid `arthritis and other inflammatory diseases, is plain aspirin. The bulletin of July 7, 1967, Bulletin No. 66, on page 2, is an example of a description of the value of aspirin in comparison with Indocin. It says: From those severely afflicted patients who are not adequately controlled by aspirin or Darvon, i.e., when pain killers are no longer giving adequate con- trol- I `am sorry, it says- when pain killers no longer give adequate contrel or when they only kill pain without reducing inflammation or improving joint mobility, Indocin should be tried promptly or even tried first. PAGENO="0419" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3511 It goes on to say on the same page: Remember and make sure your physician realizes that, unlike aspirin and Darvon, Indocin has been found effective in not only relieving pain but reducing fever, swelling and tenderness, and increasing joint mobility in the symptomatic treatment of rheumatoid arthritis. Now, it is very likely true that few doctors would be misled. by this description of the effects of aspirin. I don't know how many might be, but in some real sense that is beside the point. The description here is an inaccurate description of the value of aspirin. It puts it in an unfair light in competition, because it puts aspirin together with Darvon, which is not an anti-inflammatory agent, and makes it appear that aspirin also is not an anti-inflammatory agent-that it is only good for the relief of pain. And when it no longer does that one simple thing, then you should turn to Indocin, or even maybe turn to Indocin first, because it implies, if it doesn't directly say, that aspirin only kills paid without reducing inflammation or improving joint mobility. This is not true of the salicylates, of which aspirin is a member. It is not at all true that unlike aspirin, Indocin has been found effective in not only relieving pain but reducing fever, swelling, and tenderness. Aspirin and other salicylates will also, as has been shown in double- blind studies, reduce not only pain, but fever, swelling, and tenderness. They have reduced swelling in the joints. They have improved joint mobility in double-blind studies. This is a more subtle, much less bla- tant, approach than the 1965 bulletins, but nevertheless, in our view, slanted and misleading. There are many other examples. Senator NELSON. You did say a few moments back that you had in going through the bulletins extracted from them all of the claims that were made beyond FDA-approved claims? Did I understand you to say that? Dr. MCCLEERY. Yes. We have really enumerated most of those, the most important and significant ones in our testimony as far as unap- proved indications are concerned. Senator NELSON. If there are any others that you didn't list in your testimony- Dr. MOCLEERY. Yes, I have another one in Bulletin 77, Septem- ber 11, 1967, which is headed on page 1 by the statement: "Let's dare to compare." Senator NELSON. Pardon? Dr. MaCLEERY. "Let's dare to compare," and I should mention that this, I feel, reflects a normal and even laudable urge on the part of com- panies to compete. That is not what we are faulting in this time period, but only describing that this characterizes the nature of the 1967 bulletins. This one again happens to be on aspirin and salicylates, and it started off by saying, "In the management of inflammatory lesions of the musculoskeletal system, where there is pain, inflammation and limitation of motion," again parenthetically, "as there is in rheumatoid arthritis." It then repeats the proper list of indications. But it is always this combination of the very subtle enlargement created by mentioning inflammation, and whenever there is swelling, "as there is" in the list of indicationed illnesses. This runs all the way through. Then it turns to an authority that is well known in the field of arthritis and rheumatism, Dr. Howard Polley, of the Mayo Clinic. PAGENO="0420" 3512 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY But first it suggests, in the language of the bulletin here for the detail man: Sure you can use aspirin, but the patient has probably already used aspirin before he visits his physician. FurthermOre, no less an authority than Dr. Howard Polley of the Mayo 01mb has said, "I wouldn't put Indocin in the category of aspirin. I think it is more potent. But if Indocin is as good as aspirin, that is a pretty good claim in my view. That is a recommendation for indomethacin." Now there is a break in the quote of Dr. Policy's opinion. The impli- cation of this quote is, if it were indeed used by a detail man to a doctor, that Dr. Polley is saying that, since indomethacin is as good as aspirin, he would recommend Indocin instead of aspirin. I don't know if that is his view. Whether it is or not, it isn't the view of experts in the field in general. I haven't had a chance to locate this statement by Dr. Policy. Senator NELSON. You say there is a break in the quote. You mean there was something more said by Dr.-what is his name? Dr. MCOLEERY. Polley. Yes, but I don't mean to imply anything more than to describe that there is a break in the quote. I am not suggesting that they have broken it at any particular point for any particular reason. Senator NELSON. You don't know what the full quote is? Dr. MCCLEERY. No, sir. I don't know where it came from, where he said it or anything like that. The bulletin goes on to say that- If be [the physician] is a gambling soul- And again I have to break the quote and make a parenthetical state- ment. I don't know whether this is a Freudian slip, but constantly the language used here spells soul "s-o-l-e." I assume he means "soul." The quote goes on to say- If he is a gambling sole, and almost no physician ever likes to gamble with his patient's welfare. He can prescribe Butazolidin if he is a gambling sole. Senator NELSON. He can prescribe what? Dr. MaCLEERY. Butazolidin, a competitive product. Senator NELSON. That purports to be a quote from whom? Dr. MCCLEERY. I was quoting from this Bulletin No. 77, Septem- ber 11, 1967. Senator NELSON. What about contraindications? The July 12 in- structional bulletin says, Other than *that (pregnancy) the only contraindications to therapy with Indocin are ulcerative colitis, active peptic ulcer, and gastritis. Now, that isn't a correct statement, is it? Dr. MaCLEERY. Will you ask that again, please? I don't mean the whole question. Senator NELSON. In the July 12 instructional bulletin they say, Other than that (pregnancy) the only contraindications to therapy with Indocin are ulcerative colitis, active peptic ulcer, and gastritis. Is that a correct statement? Dr. MCOtEERY. The statement that you are repeating from the bulletin is an incorrect statement in reference to the full range of contraindications as contained in the package labeling. PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3513 Senator NELSON. Since you have inserted the package labeling~ that includes the full range of contraindications. Are there several more in addition to these here? Dr. McCn~ERY. No, sir; there aren't several more. We mentioned one by name in our testimony, and that was that the drug is contra- indicated in children. That is not mentioned. There is another inflam- matory disease of the intestinal tract which is contained in the package labeling as a contraindication and is somewhat similar to the ones that you were naming, called regional enteritis. That is not on this list. That is the other contraindication. Senator NELSON. Of course the children-it covers a vast number of people in any event. Dr. MOCLEERY. Yes, I mentioned it was contraindicated in children. * Senator NELSON. Then the next sentence said, These are not unusual signs as you know, Doctor, even aspirin causes some gastric complaints. Isn't the intent of this sentence to play down the warning of the previous sentence? Dr. MOCLEERY. I would think so. Senator NELSON. In Bulletin 84, July 14, 1965, it states: Indocin equals or surpasses the effectiveness of Butazolidin. Is that correct? Dr. Mc~CLEERY. If I may, I would like to avoid trying to give a definitive answer to that. The evidence of comparative studies of these two products are unknown to me. I do not know if they exist to an extent that would permit someone to make meaningful comparative claims against another product. Senator NELSON. Continuing to quote from Bulletin 84, July 14, 1965, and this is the excerpt form the statement: "In therapeutic doses has a safety index comparable to aspirin." Is that correct? Dr. MOCLEERY. I would have to say that in my understanding of what I feel are the views of people that I have read who work in this field, aspirin, as varied within the dosages used, is really safer. But you are asking me a question, Senator, that I am not really an expert in. `Mr. GORDON. Do you know of any studies which indicate-perhaps you have already answered this-that Indocin equals or surpasses the effectiveness of Butazolidin? On what do they base that statement? Dr. MCCLEERY. I don't know what they base the statement on, but I must say I am not an expert in the field of these drugs. There are studies I have read, but I am not prepared to make a statement that would be-I am perhaps more reluctant to do it than the statements we are reading were reluctant to make the claims. I know of none that prove this. Senator NELSON. On page 2 of the bulletin it is stated: Lightheadness and dizriness occur occasionally with Indocin as with almost any other medication. For the most part these effects are very mild and very transient. One of the leading physicians who evaluated Indocin for Merck, Dr. Rothermich, wrote to Merck on June 12, 1~63: The greatest deterrent to increase in dosage to effective level is the appearance of cerebral toxicity. This manifests itself clinically in excruciatingly severe headaches, dizziness, lightheadedness, disturta'nce of sensorium, a feeling that PAGENO="0422" 3514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the head is floating away or even separating from the body, and a feeling of detachment from reality. Does this comment of evaluation by Dr. Rothermich compare with your own claim? Dr. MCOLEERY. The statements that you are reading are opinions of Dr. Rotherinich that I haven't seen. They are similar to the kinds of experiences reported with Indocin, and which are included within the package labeling. Senator NELSON. So they have played down in their instructional bulletin the effects that are described and required in the labeling, is that correct? Dr. MCCLEERY. Well, it seems that they have a dimunition of the impact of the ideas which are being described. Senator NELSON. On page 3 of the Bulletin No. 66 dated July 7, 1967, we find, you have mentioned this yourself previously: Indocin should be tried promptly or tried first. Now, in the AMA's 1967 edition of New Drugs, page 540, we find the following statement: Present clinical experience indicates that this drug is as effective as the salicylates in patients with rheumatoid arthritis. However, its use is not neces- sary when salicylaite therapy is effective. Although aspirin is still considered the drug of first choice, inclomethacin may be tried if aspirin ceases to be beneficial or is no longer tolerated. Is the statement by the AMA Journal representative of the view- point of the FDA? Dr. MOCLEERY. It squares with my own personal understanding of the view of men who are experts and have written on comparative drug trials. In the approved labeling of the drug Indocin, there are no such comparative claims of this sort. It is the kind of view that I was trying to express awhile ago. It is a most common view of the experts in the field that the salicylates are still the drug of first choice to use. They give much of the same benefits that Indocin does if not to all patients. Senator NELSON. I want to thank you very much, Dr. McCieery. We appreciate your very fine statement and you and your staff asso- ciates coming here this morning to testify. Does anybody have anything they wish to add to the statement? We will resume hearings, then, again tomorrow morning at 9:30. Thank you. (Additional instructions from H. Glassner to All Western District Associates, undated, follow:) To: All western district associates From: H. Glassner Subject: Indocln The "Indocin" release meeting was great. However, several of you have asked for a concise Product Information Outline from which you can build your own presentation. Here are the "must know" facts on `Indocin'. Put the words `together so they sound like you. Remember, however, no presentation is a good presenta- tion unless it creates prescription specification. What is Indocin? Indocin is an entirely new "anti-rheumatIc" drug that affords ANTI-IN- FLAMMATORY ANALGESIC-AND ANTIPYRETIC ACTIVITY. The unique chemical structure of `Indocin' differs entirely form salicylates, corticosteroids, coichicine and phenylbutazone. PAGENO="0423" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3515 Wha~t is Indocin for? Indocin is effective in the management of both short-term and long-term--acute or chronic inflammatory lesions of the musculoskeletal system including: Degenerative joint disease of the hip (osteoarthdtls); Gout; Rheumatoid spondylitis; and Rheumatoid arthritis. What wili Indocin do? When inflammation is causing pain and limitation of motion, therapy with `Indocin' will usually: Promptly relieve pain; Reduce fever, swelling, and tenderness; and Increase joint mobility. What are the advantages of Indocin? Indocin is rapid and effective in action. Relief of symptoms is prompt. (a) In most patients with chronic rheumatoid arthritis, `Indocin usually re- lieves pain and stiffness within 48 hours. (b) In acute rheumatoid arthritis, or arthritic flares of musculoskeletal pain- `Indocin' usually relieves pain, swelling, and tenderness, and fever within 48 hours. (c) In acute attacks of gout, `Indocin' is dramatic. Marked reduction of pain is common within two to four hours. Tenderness and heat subside within 24 to 36 hours, and swelling decreases in 3 to 5 days. In degenerative joint disease-particularly osteoarthritis of the hip-'Indoein' takes a bit longer to work but has clinically provided RELIEF OF PAIN AND INCREASED RANGE &F MOTION. In~doein has an ea~tended margin of safety Although `Inclocin' is second in potency only to the steroids-'Indocin' has a wide range of safety. (a) Chemically, `Indocin' is related to tryptophan, a naturally occurring amino acid. Unlike Butazolidin, it is not an aminopyrine derivative. Therefore, `Indocin' does not have the well-documented poisonous effects of aminopyrine and related compounds. (b) `Iiiidoein' has no effect on pituitary or adrenal function. Therefore, the well known and well documented side effects of steroids such as birsutism, psy- chic disturbances, etc. are not problems in patients on therapy with `Indocin', Broad applicability Because `Inclocin' has an extended margin of safety, it can be safely used on any adult patient. Because `Indocin' works even in stubborn, long-standing, degenerative joint disease (osteoarthritis of the hip), it undoubtedly will be dramatically, excitingly effective in routine rheumatoid complaints. What is the dose of Indocin and how it is supplied (a) Indocin is available as a 25mg. blue & white capsule. The cardinal rule in dosage with Indocin is start low and go slow. In chronic arthritides, the starting dose of `Indocin' is 1 capsule b.i.d. or t.1.d. If response is inadequate, this dose may be increased by 1 capsule daily at weekly intervals. The new dose is continued until adequate response is obtained or until a maximum of 8 capsules per day is reached. In acute arthritis, the starting dose of `Indocin' is 1 capsule b.i.d. or t.i.d. If re- sponse is inadequate, one additional capsule per day may be added each day until an adequate response is obtained or until a maximum of 8 capsules daily is given. In acute gout, the recommended dose of `Indocin' is 2 capsules t.id. This dose may be increased to a maximum of 8 capsules per day if necessary. In chronic gout, 1 capsule b. i. d. may be given with `Benemid' to minimize the possibility of subsequent attack. What are the precautions of Indocin therapy? Unlike Butazolidin, reports of changes in the white blood count in patients on therapy with `Inclocin' have been extremely rare. In most reported cases, it has been impossible to implicate Indocin as the causative agent. Therefore, unlike Butazolidin, we do not recommend weekly or bi-weekly blood counts in patients being treated with `Indocin'. Periodic, simple hemoglobin determinations may be made by the physician on routine office visits. PAGENO="0424" 3516 COMPETITIVE PRQBLEMS~ IN T11~ DRUG INDUSTRY In about six out of ten patients, no adverse reactions of any kind will occur. In about three ~ut of ten patient~, very mild transient and tolerable reactions will possibly occur. These reactions would include mild nausea, mild headache, mild dizzine~ss, and the other n~inor nuisance effects, Usually, these effects will dis- appear with continued therapy even without dosage adjustment. In only one out of ten patients were reactions severe enough to justify dosage reduction or discontinuance of therapy. Learn these facts well enough to handle objections. Then, on every call make sure you leave the physician's office with him completely convinced that- Whenever, the problem is oppressive joint pain associated with heat, red- ness, tenderness, and swelling; When the muscles around an inflamed joint are in spasm causing limita- tion in motion; Whether the tentative diagnosis is osteoarthritis of the hip, gout, rheuma- told arthritis, rheumatoid spondylitis, or ji~st plain musculoskeletal aches and lumbago; or For short-term use in acute conditions or long-term use In chronic conditions~- Indocin will afford prompt relief to three out of four patients-more effec- tively-with an extended margin of safety-at less cost-with fever tablets- less dosage adjustment-and, therefore fewer problems to the patient and to his physician than any other currently available agent. Go get it. This is a big one. H. GLASSNER. To: All western district associates. From: H. Glassner. Subject: Indocin. Here is the biggest potential volume product we have released since `Decadron'. Automatic shipments are in the stores and in the jobbers. Voluntary, repeat orders are pouring into the Branch. Advise your customers that 12 x 100 `Indocin' are packed in a compact, easy-to-handle shipping carton. This should become the basic unit of sale. Each time you ship a carton of 12 x 100 `Indocin' you put $84.00 more on the bottom line. At 6%, that puts a little better than a brand new $5.00 bill in your pocket, If you haven't already done so-complete the fourth book of Programmed Instruction. Then, build a detail. Your Field Managers will be testing you on the Information contained in Book No.4. No matter what else you say, repeat and repeat and repeat this theme until it is indelibly impressed in the physician's mind. Learn it cold. Believe it fervently. Communicate it effectively. Whenever the problem is oppressive joint pain associated with heat, redness, tenderness, apd swelling. When the muscles around an inflamed joint are in spasm causing limitation of motion. Whether the tentative diagnosis is osteoarthritis Of the hip, gout, rheumatoid arthritis, rheumatoid spondylitis, or just plain musculoskeletal aches and stiffness. For short-term use in acute conditions or long-term use in chronic diseases. Indocin will afford prompt relief to three of four patients. More effectively-with an extended margin of safety-at less cost-with fewer tablets-less dosage adjustment-and, therefore fewer problems for both the patient and the physician than any other currently available product. Let's not make the mistake of trying to teach the physician to diagnose. ~Indocln' is for relief of pain due to Inflammation. Let him decide when to use `Indocin'. However, encourage him to use it early when it will do the patient the most good. Get hot on this one. We're gonna lead them. H. GLASSNER. (The American Law Division opinion previously referred to follows:) PAGENO="0425" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3517 THE LIBRARy or CONGRESS, LEGISLATIVE REFERENCE SERVICE, Washington, D.C., May 7, 1968. To: Senate Subcommittee on Antitrust and Monopoly (attention Mr. Gordon). From: American Law Division. Subject: Does Food and Drug Administration have authority over oral state- merits of drug manufacturer's representatives who contact physicians directly. No specific authority is conferred on the Food and Drug Administration to deal with the matter in question. The Food and Drug Act deals, in pertinent part, with labels and labeling. A drug shall be deemed to be misbranded in several situations set forth in the law. See 21 U.S.C. § 352. We have located three court decisions involving prosecutions under the Food and Drug Act for oral represen- tations which apparently were misstatements respecting the product to which they relate. None of these, however, were concerned with statements to physi- cians. In U.B. v. Hohensee, 243 F. 2d 367 (1957) the evidence was sufficient to sus- tain the conviction of the defendant who subsequent to shipment of harmlessly labeled food products in interstate commerce to pre-arranged towns, went to such towns to give lectures and distribute literature promoting the use of such prod- ucts to promote health. The case of Nature Food Centres, Inc. v. UJg. 310 F 2d 67 held that defendants selling drugs identified on attached labels as dietary sup- plements could not meet branding requirements of Federal Food, Drug, and Cos- metic Act through sale of "lecture notes" concerning the drugs where some of the drugs were destined for sale at stores where notes were not available and, even at halls where lectures were delivered and drugs were available, notes were obtainable only upon payment of additional price In UJ~. v. Article of Drug, etc. 362 F. 2d 923 the court held that the evidence supported the finding that the drug company claimant adopted as its own representation a radio broadcaster's claim that vitamins were efficacious for prevention and treatment of human disease, and that claimant intended its products to be used for general purposes recom- mended by broadcaster, as asserted by the government which charged misbrand- ing in that claimant's catalogs failed to contain adequate directions for use. These three cases involving oral statements would appear to have but limited application, if any, to the quetsion presented. It seems to us that there is no clearly defined authority for the exercise of control by the Food and Drug Administration over oral statements of manufacturer's representatives to physi- cians in all situations. HUGH P. PRIoR, Legislative Attorney. (Whereupon, at 10:35 a.m., the subcoimnittee recessed to reconvene at 9:30 a.m., Wednesday, September 18, 1968.) PAGENO="0426" PAGENO="0427" APPENDIXES APPENDIX I [From Annals of the Rheumatic Diseases, vol. 25, 1966, pp. 334-339] INDOMETHACIN IN IN-PATIENT TREATMENT OF RHEUMATOID ARTHRITIS (By D. A. Pitkeathly, N. R. Banerjee, R. Harris, and J. Sharp, Devonshire Royal Hospital, Buxton) Indoinethacin has been used in the treatment of rheumatic disease for over 3 years. Preliminary reports of the effectiveness of the drug were encouraging (Rothermich, 1963; Norcross, 1963) Katz, Pearson, and Kennedy (1963) also found the drug to be beneficial but treatment had to be discontinued in over 20 per cent of patients because of side-effects. Hart and Boardnian (1963) showed that thdomethacin produced a measurable reduction in swelling of the proximal interphalangeal joints in patients with rheumatoid arthritis and that, when a placebo and the drug were used alternately, significant rebound effects commonly occurred with the commencement of placebo treatment. Side-effects, principally headache, dizziness, clyspepsi a, and mental disturbances, were frequent being observed in over 50 per cent. of patients treated with a dose exceeding 200 mg. A trial of the drug by Wanka, Jones, Wood, and Dixon (1964) showed that indomethacin was effective when compared with a placebo, and a comparative trial against plienylbutazone by Percy, Stephenson, and rfhompsoli (1964) showed that 200 ing. indomethacin was approximately equivalent to 300 mg. plienylbuta- zone daily, although a decidedly higher incidence of side-effects occurred with indomethacin. During this period *of development of the drug it was supplied in tablet form and the doses used ranged from 150 to 400 rag. daily. Wauka and others (1964), using this preparation and range of dose, reported one ease of intestinal haemor- rhage and one of perforated gastric ulcer. L5vgren and Allander (1964) used a similar dosage iii eighteen patients with rheumatoid, arthritis, six of whoimi had a previous history of peptic ulcer but had negative barium meals immediately before treatment; five patients developed peptic ulcers, two of these having no previous history, and three of the five had severe bleeding. During the past 2 yCars indomethacin has been supplied in capsule form and the manufacturers have recommended an initial dose of 50 rag. daily, gradually increasing to a maximum of 1~0 rag. The incidence of side-effects was stated to have fallen from 50 to 10-30 per cent of all treated Patients (Today's Drugs, 1964) as a result of using capsules and more conservative dosage, and Clark (1964) reported satisfactory improvement iii many Patients of a large grOfl~) with rheumatoid arthritis using this scale of dosage. Recently hart and Board- man (1965) have compared 75 mg. indomethacin (Tally with 300 rag. phenylbiita- zone daily, in out-patients with rheumatoid arthritis. A double-blind crossover trial was carried out, each drug being given for a period of 28 days. No significant differences were found iii tile relief of symptoms although there was a greater reduction of morning stiffness with plienylbutazoime. There were no significant differences iii streiigth of grip or in improvement in ring sizes of proximal imiter- phalangeal joints, but indomethaein tended to have a greater effect on the latter. The preference of patiemits was in favour of phenylbutazone. The incidence of side-effects of indomethacin in this short-term trial are not stated. but in long- terni studies on patients with rheumatoid arthritis, ost co-arthritis, and ankylo- sing spondylitis, the authors found that 37 per cent of the patients developed side-effects of drug treatment. The present study has beemi carried out to evaluate indomethacin in a dose of 50 to 100 rag. ~R tile in-patient trea.tment of patients with rileuniatoidi arthritis. Salicylates are currently the mainstay of drug therapy while the patient is being 3519 PAGENO="0428" 3520 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY treated with rest in bed and splintage followed by graded exercises. It was our aim to decide if indomethacin could effectively replace salicylates under these circumstances. Hajnal, Sharp, and Popert (1959) have drawn attention to the considerable effect of "spontaneous improvement" in hospitalized patients. In addition to rest in bed and splintage, other features such as increasing familiarity with hospital environment and in the case of strength of grip, practice in the use of the appa- ratus, contribute to the improvement shown. This must be dissociated from the effect of drug therapy before the value ~of a new drug can be assessed. PATIENTS STUDIED AND METHODS EMPLOYED 34 women and eight `men with classical and definite rheumatoid arthritis (1958 A.R.A. Criteria-Ropes, Bennett, Cobb, Jacox, and Jessar, 1959) were studied. Before entering the trial each patient spent one week settling into the hospital routine. During this period analgesia was provided by soluble aspirin and was maintained at the pre-admission dose provided that this did not exceed 4 g. daily. If the patient was already on corticosteroids, the dose was maintained at the pre- admission level during the first week and throughout the trial. Patients were excluded from the study `if they had known peptic ulceration or seyere dyspepsia or were intolerant of aspirin, or if the grip test could not be adequately performed by reason of severe anatomical deformity of the bands or if the strength of grip exceeded 300 mm. Hg. The patients were allotted alternately to indometbacin or soluble aspirin on entry. The first drug was given for a 2-week period and then the other drug was administered for a further 2 weeks, so that half the patients received indo- methacin followed `by soluble aspirin, and the other half received soluble aspirin followed by indomethacin. The soluble aspirin was `specially coloured and flavoured and the patients were unaware of the identity of the tablets. It was given in a dose of 4 g. daily throughout the 2-week period. Indomethacin was given in a dose of 25 mg. twice daily for 2 days, followed by 25 mg. three times daily for 6 days and then 25 mg. four times daily for the remaining 6 days. Of the 42 patients, 38 completed the study. Two patients were withdrawn while taking soluble aspirin, one because of severe deafness and the other on account of repeated vomiting. One patient developed profound dizziness on indomethacin and the drug had to be withdrawn. The fourth patient was given an incorrect dose of indomethacin during the second week of treatment `and was therefore excluded from the analysis. Of the remainder, twenty patients had commenced the trial taking soluble aspirin and eighteen patients had started with indo- methacin. Five of those starting on solube aspirin were taking prednisolone with a mean daily dose of 9 mg.; seven ~f those `starting on indomethacin were taking prednisolone with a mean daily dose of 10mg. Clinical assessment.-Assessments were carried out on the first day of the trial and thereafter at weekly intervals until the completion of the study. As far as possible the patients were assessed at the same time of day throughout and the daily physiotherapy was not given until the assessments bad been made. Strength `of grip of both hands were recorded weekly. Swelling of the proximal inter- phalangeal joints was measured using jeweler's rings. These rings were labelled from A to Z with Intermediate half-sizes; the diameter of `size A was 0.476 in. and the increase In diameter from size A to B was 0.015 in. The patients were questioned concerning headache, dizziness, and dyspepsia, `and any other side- effects were noted. At the end of the study the patients' preference for one drug or the other was recorded. PAGENO="0429" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3521 ANAYSIS OF RESULTS The mean strength of grip at the commencement of the study and at weekly intervals throughout the trial was calculated for each series of patients (Table I). TABLE 1.-MEAN VALUES FOR WEEKLY ESTIMATIONS OF STRENGTH OF GRIP (MM. HG) FOR PATIENTS STARTING ON SOLUBLE ASPIRIN AND INDOMETHACIN Starting drug Soluble Indomethacin aspirin Numberofcases 20 18 Grip (mm. Hg): Initial 145.65 159.28 Week 1 1163.90 2194.11 Week 2 `173.60 2194.50 Week 3 Week 4 2183.80 2188.30 `199.17 `202.06 1 Aspirin. 2 Indomethacin. Improvement was most marked during the first week of treatment with both drugs and in this week the average improvement was almost twice as great in those starting on indomethacin as in those starting on soluble aspirin. In the second week the indomethacin group-although then on a slightly higher dosage, having changed from 25 mg. three `times daily to 25 mg. four times daily-showed on average no improvement in mean strength of grip but the value in the soluble aspirin group continued to improve, so that after 2 weeks the difference had narrowed considerably. During the second half of the study both groups showe4 some further average improvement, which was again more steady in those start- ing on aspirin, who were now on indomethacin; over the whole of the second fortnight those now on soluble aspirin showed only half the improvement of the other group. The total improvement after 4 weeks was virtually identical in the two groups. * * * * * * * TABLE IV.-SIDE EFFECTS ATTRIBUTABLE TO SOLUBLE ASPIRIN AND INDOME THACIN IN 42 PATIENTS Side effect ~ Drug ----------~------ Soluble Indomethacrn aspirin Headache Dizziness Deafness Dyspepsia Vomiting Diarrhea Rash Sweating 10 17 3 4 6 0 10 10 3 1 3 0 0 1 1 1 * * * * * * * PAGENO="0430" 3522 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Patient Preference.-This is shown in Table V. All three patients who were withdrawn from the trial because of severe side-effects on one drug completed 2 weeks of treatment on the other drug and are shown as preferring that drug. TABLE V.-Patient Preference Number Preference: or cases For soluble aspirin 21 For indomethacin 13 None 7 Total 41 DISCUSSION The anti-inflammatory action of indomethacin has been demonstrated convinc- ingly under experimental conditions. Winter, Risley, and Nuss (1963) showed that the drug had a powerful effect in inhibiting granuloma formation in rats. In addi- tion, inflammatory oedema induced by carrageenin was suppressed. Boris and Stevenson (1965) found that indomethacin was the most powerful of a group of five anti-inflammatory agents in inhibiting the inflammatory reaction induced by carrageenin in rats, the others being flufenamic acid, mefenamic acid, oxyphenyl- butazone, and phenylbutazone in order of decreasing potency. Under clinical con- ditions, Hart and Boardman (1963) confirmed this anti-inflammatory action using 150-300 mg. of the drug daily. In view of the high incidence of side-effects with this range of dose we wished to study the effect of indomethacin in a dose not exceeding 100 mg. daily in the in-patient treatment of rheumatoid arthritis and to compare it with soluble aspirin in a dose commonly used in these patients. Studies had already been carried out by Hart and Boardman (1965) and Thomp~ son and Percy (1996) and the drug was found to have considerable therapeutic value in patients with a variety of rheumatic diseases. In recent years salicylates have been shown convincingly to have anti-inflam- matory properties in experimental animals. Spector and Willoughby (1963) showed that systemic sodium salicylate has an inhibitory effect en the volume of exudate in turpentine-induced pleurisy in the rat and causes a non-specific sup- pression of the action of many substances that increase vascular permeability. Kelemen (1963) studied acute inflammatory oedema in rats using 1~" serum albumin. He considered that there were two components to the inflammatory response. One was inflammatory swelling which was diminished by salicylate. The other, a possible tissue component, preceded visible swelling, persisted after the oedema had disappeared, and was unaffected by salicylate. In view of this work on salicylates in experimentally-induced inflammation, it must be borne in mind that doses of 4 g. daily in patients with rheumatoid arthritis may have anti- inflammatory activity of the same order of magnitude as that shown by indo- methacin in low dosage. In this study we have used strength of grip and improvement in swelling of the proximal interphalangeal joints measured by jeweller's rings tO assess the weekly improvement throughout the trial period. Analysis of mean strength of grip during periods of treatment with soluble aspirin and inclomethacin has shown that drug effect was approximately one half of the effect attributable to spontaneous improvement. It has also been shown that indomethacin had a greater effect than aspirin in improving strength of grip and that this difference was just significant at the 5 per cent level. On the other hand, there was no difference between the two drugs in their effect in reducing swelling of the proximal inter- phalangeal joints and most of the improvement which occurred was the result of spontaneous improvement. There was a greater preference of patients for soluble aspirin than for indo- methacin in this triaL The incidence of headache during soluble aspirin treat- ment was surprisingly high, so that the patient preference can hardly be due to indom~thacin headaches unless these were qualitatively different from the headaches reported during aspirin treatment. Greater pain relief from aspirin in the dosage used may have been important. Hart and Boardman (1963) stated that indomethacin had no analgesic action in the mouse or rat using methods then in use. The manufacturers claim, as a result of controlled clinical studies, that 50 mg. inclomethacin is equal in analgesic effect to 600 mg. acetylsalicylic acid. If this is so, then the analgesia produced by aspirin in this study was much greater than that produced by indomethacin. PAGENO="0431" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3523 The high incidence of side-effects of indomethacin reported in the literature has made physicians cautious. Headache and dyspepsia were ~ti1l fairly frequent in this study despite the low dosage employed and the slow build-up of the drug. On the other hand, the incidence of side-effects except headache differed little from that occurring with 4 g. soluble aspirin daily. There is little doubt that side- effects would have been reported less frequently with both drugs if patients had not been asked about specific symptoms. No serious complications such as gastro intestinal hemorrhage occurred, but the trial was of short duration and patients with severe dyspepsia or known peptic ulcer were not admitted to it. It is to be noted that, in the studies of Hart and Boardman (1965) and Thompson and Percy (1966), cases of neurological disturbance and gastro-intestinal bleeding were reported and that these side-effects could be present after many months of treatment. SUMMARY A cross-over trial of indomethacin and soluble aspirin has been conducted in in-patients with rheumatoid arthritis. The indomethacin was increased from 50 to 100 mg. during the treatment period, but the dose of soluble aspirin was main- tained at 4g. daily. A method of analysis has been used which dissociates drug effect from other factors which may lead to the improvement with time usually observed in hospitalized patients regardless of medication. This has re-emphasized the im- portant contribution of these factors. Comparison of the two drugs has shown that strength of grip improved to a greater extent during indomethacin treatment and that this result was just significant at the 5 per cent level. Decrease in swelling of proximal inter- phalangeal joints was very similar during treatment with the two drugs but 21 patients preferred soluble aspirin, whereas thirteen preferred indomethacin, and the remaining seven had no preference. It is concluded that indomethaci should net replace aspirin in the routine treatment of in-patients with rheumatoid arthritis. However some patients appear to do better with indomethacin and it may therefore be useful in selected cases. We wish to thank Professor J. H. Kellgren for advice and criticism in the prep- aration of this paper. Miss P. Bier performed the statistical analysis and we are greatly indebted to her. REFERENCES Boris, A., and Stevenson, R. H. (1965). Arch. mt. Pharmacodyn., 153, 205. Clark, G. M. (1964). Art hr. and Rheum., 7,300. Hajnal, J., Sharp, J., and Popert, A. T. (1959). Ann. rheum~ Dis., 18, 189. Hart, F. D., and Boardman, P. L. (1963). Brit. med. J., 2,965. (1965). Ibid., 2, 1281. Katz, A. M., Pearson, C. M., and Kennedy, J. J. (1963). Arthr. and Rheum., 6, 281. Kelemen, E. (1963). In "Salicylates: An International Symposium sponsored by the Empire Rheumatism Council with the support of the Nicholas Research Institute, Ltd. Post-graduate Medical School of London, 1962", ed. A. StJ. Dixon, B. K. Martin, M. J. H. Smith, and P. H. N. Wood, p. 148. Churchill, London. Lövgren, 0., and Allander, B. (1964). Brit. med. J., 1, 118. Norcross, B. M. (1963). Art hr. and Rhet~m., 6,290. Percy, J. S., Stephenson, P., and Thompson, M. (1964). Ann. rheum. Dis., 23, 226. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A. (1959). Ibid., 18, 49. Rothermich, N. 0. (1963). Art hr and Rlveum., 6,295. Spector, W. G., and Willoughby, D. A. (1963). In "Salicylates: An International Symposium sponsored by The Empire Rheumatism Council with the support of the Nicholas Research Institute Ltd., Post-graduate Medical School of London, 1962", ed. A. St.J. Dixon, B. K. Martin, M. J. H. Smith, and P. H. N. Wood, p. 141. Churchill, London Thompson, M., and Percy, J. S. (1966). Brit. med. J., 1, 80. Today's Drugs: Indomethacin (1964). Ibid., 2,429. Wanka, J. Jones, L. I. Wood, P. H. N., and Dixon, A. StJ. (1964). Ann. rheum. Dis., 23, 218 Winter, 0 A., Risley, B. A., and Nuss, G. W. (1963). Fed. Proc., 22, 543. PAGENO="0432" 3524 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY APPENDIX II [Reprinted from Annals of Internal Medicine, vol. 49, No. 1, July, 1958, printed In ILS.A.} RHEUMATOID SPoNDYLrrIs: MANIFESTATIOItS AND MANAOEMENT* (By Aaron M. Lefkovits, M.D., F.A.C.P., and J. R. Thomas, M.D., Memphis, Tenn.) Rheumatoid spondylitis is one of the most common arthritic diseases affecting young and middle aged men during their most productive years and, with the exception of trauma, is probably one of the most common causes of backache in this segment of the population. its importance as a cause of morbidity and dis- ability in young men is attested to by the numerous articles which appeared in the medical literature during the war years and thereafter. However, despite this keen interest, the disease in many patients is unrecognized during its early stages and is allowed to progress until irreversible deformities develop before the correct diagnosis is made and proper management for its control is instituted. It appears, therefore, that some aspects of this disease need further clarification, especially in regard to its earlier recognition and to the institution of proper and effective therapeutic measures. METHODS The records of 267 patients in whom the diagnosis of rheumatoid spondylitis was made were carefully reviewed. Some of the available data pertient to this study are indicated in table 1. With few exceptions, all patients were examined and treated by one of us (A. M. L.). Since this study was made at a Veterans Ad- ministration hospital, where the majority of patients are males, all these patients were of that sex. The diagnosis of rheumatoid spondylitis in every instance was made on the basis of the history, physical findings and radiographic evidence. Roentgenographic examination included A-P and lateral views of the lumbo- sacral, dorsal and cervical spines. Whenever indicated, special inclined views of the sacroiliac joints and oblique views of the lumbar and cervical spines were ob- tained. Blood studies included the following determinations: hemoglobin, white blood cell count, erythrocyte sedimentation rate and, in a few patients, C-reactive protein, total serum proteins, albumin, globulin and A/G ratio. The results are shown in table 2. Treatment consisted of physiotherapy, irradiation of painful areas of the spine, instruction in breathing and postural exercises, measures of rehabilitation, dietetic management, correction of static factors, braces, aspirin, and, in a few patients, hydrocortisone and Butazolidin. During the later period of this study only those patients were treated with irradiation of the spine who failed to respond to the other measures. TABLE 1.-CLINICAL FEATURES Number of patients Percent Eamily history of arthritis Trauma Subjective complaints of arthritis in peripheral joints Objective signs of arthritis in peripheral joints Radiographic changes in sacroiliac joints Radiographic changes in hip joints Calcification of ligaments Osteoporosis 25 of 201 66 of 229 166 of 264 113 of 266 267 of 267 41 of 267 89 of 267 64 of 267 12. 4 28.8 62. 8 42. 4 100. 0 15. 3 33. 3 23. 9 *Recelved for publication June 4, 1957. From the General Medicine and Rheumato1ogy Section of the Medical Service, Veterans Administration Hospital, Kennedy Division, Memphis, Tennessee. Requests for reprints should be addressed to Aaron M. Lefkovits, M.D., Chief, Section on General Medicine and Rheumatology, Veterans Administration Medical Teaching Group Hospital, Park Avenue and Getwell Street, Memphis 15, Tennessee. PAGENO="0433" COMPR~flTIVE I~ROBL~MS IN TE~E DRUG INDUSTRY 3525 TABLE 2.-LABORATORY DATA Hemoglobin White Blood Cell Count E.S.R. (Wintrobe Method) Gm. % >14.5 No. of pts 117 Percent 45.7 >13.5 70 27 >10.0 <10.0 >10, OOfi 60 9 57 23.4 3.5 21.8 >5,000 <5,000 190 14 72.8 5.3 >10 per hr. <10 per hr. 209 46 81.9 18 Pos. C-RP - Neg. Total Serum Protein Normal Abnormal Albumin (Normal 3.0-4.5 gm. %) Normal Decreased Globulin (Normal 2.3-3.6 gm. %) Reversal A/G Ratio Normal Elevated No. of pts 23 3 35 0 32 2 25 9 7 OBSERVATIONS The age of onset (figure 1) of the disease varied from the second to the sixth decade; the youngest patient was 17 years and the oldest 54 years at the onset of the disease. The period of observation (figure 2) varied from a few months to as long as nine years. The greatest number, 153 (57.4%), were in their third decade at the time of onset of the disease (table 3). In 201 patients the presence or absence of arthritic disease in the family was recorded; of these, 25 (12.4%) gave a history of `~arthritis" in some other member of the family. Trauma was given as a precipitating factor by 66 (28.8%) of 229 patients. Subjective com- plaints of peripheral joint involvement were present in 166 of 264 (62.8%); ob- jective signs of peripheral joint involvement in 133 of 266 (42.4%) ; and sciatic radiation in 63 patients (23.5%). All patients had radiographic evidence of sacroiliac involvement. Calcification of the vertebral ligaments was present in 89 patients (33.3%), and osteoporosis in 64 patients (23.9%). Forty-one patients (15.3%) had hip joint involvement. These data are recorded in table 3, and graphs. Rheumatoid Spondylitis FIG~ 1. 81-280-68-pt. 8-28 PAGENO="0434" 3526. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 70 160 40 120 100 ~ 80 ~6 60 z 40 20 FIG. 2. TABLE 3.-AGE AT ONSET AND DURATION OF OBSERVATION Age at onset Number of patients Duration of observation o umber f patients Less than 20 71 Lest than 6 months 168 21 to 30 31 to 40 41 to 50 51 to 60 152 37 6 1 More than 1 year More than 2 years More than 3 years More than 4 years Morethan5years More than 6 years More than 7 years More than 8 years More than 9 years 41 17 11 10 4 5 6 2 3 Total number of patients 267 267 MODE OF ONSET The onset of the disease in the majority of the patients was insidious, generally over a period of several months or even years, and progression of the disease was interrupted by pain-free periods lasting several weeks or months. With each relapse, however, the symptoms were generally more severe and the duration of each episode was longer; ultimately the symptoms became more or less constant. Thus, there was a gradual increase in the severity of the patient's complaints. In a small number of patients the course of the disease was progressive and developed fairly rapidly, although they continued to have periods of exacerbations and remissions. The most common symptoms at the onset of the disease were stiffness and aching in the low back in the morning on awaken- ing which would persist for half an hour or longer. With activity, the back would "limber up" and the aching and stiffness would gradually disappear toward the late forenoon, only to return toward the end of the day or during the night while the patient was lying In bed, awakening him. The severity of the backache varied considerably In different patients. Characteristically, it awakened the patient two or three hours after falling asleep. The patient would then get off the bed and walk about for one-half hour or longer to obtain relief; then he would return to bed, only to be awakened again in two or three hours, to repeat the process of walking to obtain relief. Patients whose disease was more severe repeated this process two to three times nightly, so that their rest and sleep were markedly disturbed and, as a result, their general well-being suffered, their appetites became poor, and they lost weight. In some patients numbness of the lower extremities accompanied the aching and stiffness in the low back, and they "had to rub" their lower extremities to obtain relief. Rheumatoid Spondylitis Total No.of Patients 267 6rno. j 2 3 4 ~ 6 7 8 9 Dvrotion of Observation in Years PAGENO="0435" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3527 In many patients the disease began as "catches, like pinching of a nerve" in one or the other hip region, at times radiating anteriorly to the iliac crests or abdomen. A few patients complained, of weakness, or a sensation of "giving way" of the hip, alternating from one to the other hip. Itadiation of pain to the buttocks, groins or along the posterior or, less often, the lateral aspect of the lower extremities to the knees or ankles occurred in some patients and, in a few, tingling in the toes on walking. In some, the backache was aggravated on coughing, sneezing, lifting weights or on any movement of the spine. The aching in the back at times was so severe that it seemed to "double up" the patient. A few subjects stated that the backache was accompanied by a tightness or "knot" in the abdomen, spasmodic contractions and .rigidity of the abdominal musculature. Patients with involvement of the dorsal spine complained or soreness or migratory sharp pains in the chest during respiration and yawning, and had varying degrees of impaired chest expansion. The complaints were generally worse after periods of inactivity and, in some patients, during incle- ment weather. A few patients dated the onset of aching and stiffness in the low back to a time when they were treated in a hospital for some other ap- parently unrelated disease, such as gunshot wound, tonsillitis, etc. Three patients had been explored surgically for herniation of the nucleus pulposus at other institutions prior to our observation. A small number of patients had been believed to be psychoneurotic before the nature of their complaints was rec- ognized, the correct diagnosis made and proper therapy instituted. In contrast, a few patients had only minor complaints referable to the spine, despite well developed deformities and advanced radiographic changes. These patients were generally older men in whom the disease was accidentily discovered while they were in the hospital for the treatment of an unrelated conditon, such as hyper- tension, coronary artery disease, pulmonary emphysema, etc. Careful questioning of these pateints revealed that in the past they bad bad only temporary discom- fort in the back, consisting of aching and stiffness which did not interfere with the pursuit of their occupation or customary activities. PHYSICAL FINDINGS There was considerable variation in the objective findings. In the milder cases, during `the early stages of the disease, no abnormal physical findings were noted and, as a rule, no abnormalities were seen on the radiograms. These were diag- nosed on subsequent admissions to the hospital when definite objective abnormali- ties were found and radiographic evidence of the disease developed. In these in- stances we found the various leg and spinal maneuvers, particularly Lasègue's, Patrick's Gaenslen's and Ely's, and extent of chest expansion, of great help in arriving at the correct diagnosis.' Patients in whom the disease was more ad- vanced presented some or all of the following manifestations in different degrees of severity: flattening of the lumbar spine, with partial or complete obliteration of the normal lumbar lordotic curve and exaggeration of dorsal kyphosis; flat- tening of the chest and impaired chest expansion; tenderness on pressure or per- cussion over the sacro-iliac joints and vertebral column; varying degrees of atrophy of the muscles of the spine; rigidity and impairment of some or all spinal movements; anterior fixation of the cervical spine; forward crouching deformity of the entire vertebral column, the so-called "poker spine"; and "en masse" movement of the entire spine. One patient had such marked anterior flexion and rigidity of the vertebral column that the longitudinal axis of the head was parallel to the floor. Several patients who had involvement of the hip joints bad a characteristic waddling gait, walking with slightly flexed knees, forward-bent body `and hyperextended neck, the upper extremities swinging in a plane posterior to that of the body as they shifted the pelvis from side to side with each step. `Lasègue's Maneuver: Flexing the extended lower extremity upon the abdomen and noting the angle of flexion at which the pain In the low back is reproduced. Patrick's Maneuver: With the patient In the supine position, the leg and thigh are flexed and the lower extremity Is abducted and externally rotated at the hip. Gaenslen's Maneuver: Hyperextenslon at the hip of the extended lower extremity while the opposite lover extremity is forcibly held by the patient in the knee-chest position. Ely's Maneuver: With the patient in the prone position, the leg is flexed on the thigh and the lower extremity Is hyperextended at the hip. Chest Expansion: The circumference of the chest is measured at the level of the nipples at the end of full Inspiration and expiration. PAGENO="0436" 3528 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY LABORATORY DATA Nine patients (3.5%) had less than 10 gin. % hemoglobin; 130 patients (52%) had mild to moderate decrease of hemoglobin concentration, and 117 patIents (45%) had normal levels of hemoglobin. The white blood count was more than 10,000 per mm.8 in 57 patients (21.8%) ; the highest count was 16,400; 14 patients (5.3%) had counts of less than 5,000 per mm.3; the lowest count was 3,200; 190 patients (72.8%) had normal white cell counts. The erythrocyte sedimentation rate was normal in 46 (18%) and abnormally elevated in 20~ patients (81.9%); the highest level was 54 mm. in one hour. The C-reactive protein was determined in 26 patients; it Was positive in 23 (88.4%) and negative In three patients. The total serum protein level `was normal in all 35 patients in whom it was deter- mined. The levels of the albumin and globulin fractions were determined In 34 patients. The level of albumin was normal in 32 and below normal in two l)a- tients; the globulin fraction was normal in 25 and abnormally elevated in nine patients; the highest level of globulin was 4.9 gm.%. The albumin-globulin ratio was reversed in seven patients (table 2). RADTOGEATHIC CHANGES It is generally known that the subjective manifestations of rheumatoid spondylitis may make their appearance long before definite evidences of the disease are seen in the radiograms pf the sacro-illac joints and/or of the spine. This interval may vary from a few months to a few years. A still greater cliffi- culty is the recognition and correct interpretation of the early radiographic changes caused by the disease in the sacro-iliac joints, and particularly in the small diarthroidal joints of the vertebral column, namely, the apophyseal, the costovertebi'al and costrotransverse articulations. The differentiation of these minor change.s from the normally `occurring variations in the size, shape and direction of the articular facets is extremely difficult. We have obtained con- siderable help from inclined views of the sacro-iliac joints taken with the x-ray tube tilted at an angle of approximately 35°, and oblique views of the lumbar and cervical spines. The inclined views of the `sacro-iliac joints render clearer visualization of their margins and joint spaces, so that minor changes could be differentiated more readily from the normally occurring variations. All patients had radiographic evidence of involvement of the sacro-iliac joints. These changes were varied: narrowing or widening of the joint spaces, irregular and indistinct joint margins, at times serrated edges, partial or complete oblitera- tion of the joint spaces, spotty osteoporosis and irregular sclerosis of the adjacent sacrum and/or Ilium. Similar abnormalities were noted in the apophyseal joints of the lumbar spine and the cervical spine. Adequate or correct recognition of such changes in the dorsal spine was rarely possible because of interference by overlapping rib shadows. Calcification of spinal ligaments was recognized in 89 patients (33.3%). The degree and extent of calcification also varied markedly; in some, it was present only In two or three isolated areas of the spine irregularly spaced; in others, it involved all the ligaments, produced the characteristic "bamboo effect," and transformed the entire spine into a rigid column. The hip joints were involved in 41 patients (15.3%); the abnormalities consisted of varying degrees of narrowing of the joint spaces, erosions of the cortices of the head of the femur and acetabulum, spotty osteoporosis, and irregular areas of sclerosis in the head of the femur and acetahulum. In a few patients the margins of the symphysis pubis showed considerable irregularity and spotty osteoporosis of the adjacent bones. Irregularities of the lower margins of the ischia, spotty sclerosis and osteoporosis of the adjacent bones were also occasionally present. Osteoporosis of the entire spine was noted in 64 patients (23.9%). TABLE 4-RESPONSE TO THERAPY Number of pat~ents * Response Percent good or excellent None Fair Good Excellent Physiotherapy Radiation: 1 course - - - - 2 courses 3 courses Total 95 116 42 7 , 4 13 1 0 21 17 8 1 52 57 23 3 18 29 10 3 73. 7 `74. 1 `78.5 `85,7 260 18 47 135 60 75.0 Mean, 75.5 percent. PAGENO="0437" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3529 ASSOCIATED AND INTERESTING MANIFESTATIONS Three patients presented the triad of Reiter's syndrome, i.e., urethritis, iritis and arthritis involving both the spine and some of the peripheral joints. One patient had complete ankylosis of the temporomandibular joints and was unable to separate his jaws sufficiently to permit the intake of solid food. The condyles of the mandible were resected. Ankylosis recurred several months later; it was then relieved by arthrotomy and replacement of the condyles by Vitallium prostheses. Thirteen patients (4.5%) had iritis or iridocyclitis; six of these had involvement of the peripheral joints also. Five patients (1.8%) bad psoriasis; all had involvement of the peripheral joints also. Thirty-six (13.5%) had various forms of anomalies of the spinal column; these are indicated in table 5. DIAGNOSIS Rheumatoid spondylitis is easily recognized in patients In whom the disease is well developed, During its early stages, however, the diagnosis is often difficult. When objective manifestations of the disease, or corroborative radiographic changes, are lacking, the fatigability, weight loss and inconstant pain in joints or muscles of the spine are usually ascribed to psychogenic factors. Since there are no specific diagnostic tests, it is often impossible to arrive at the correct diagnosis until characteristic signs of the disease or abnormal radiographic changes appear. We found the following of considerable value in diagnosing the disease: (1) aching in any part of the back in a young man which occurred often during the night and induced him to get off the bed to "limber up"; (2) careful evaluation of results of leg and spinal maneuvers, and particularly the flexibility or rigidity of the spine on body movements; (3) meticulous examina- tion of x-rays of the sacro4liac joints, and especially of the inclined views of these joints. The laboratory data were of limited value in diagnosing the disease. The erythrocyte sedimentation rate and C-reactive protein were elevated in the majority of patients. The hemoglobin level was slightly to moderately decreased in approximately half of the patients. TABLE 5.-Associated and interesting manifestations Router's syndrome 3 Iritis 13 Psoriasis Anomalies of vertebral column: Transitional lumbosacral joint 15 Spina bifida occulta 8 Spondylolysis 6 Spondylolisthesis 3 Miscellaneous 4 MANAG~MBNT Seven patients were asymptomatic at the time of observation and needed no therapy. The remaining 260 patients were treated with a variety of therapeutic measures. The complaints and findings of each patient were carefully considered prior to outlining his therapeutic regimen. Boards were placed under the mattress to prevent sagging of the bed, and the patient was advised to use no pillow under his head while lying in the supine position. Pillows were used until the head when the patient was lying on his side; they were also used until the lumbodorsal spine while lying in the supine position, or at some level under the trunk while lying in the prone position, provided such positioning of the pillow added to his comfort. State factors such as tilting of the pelvis, inequalities in the length of the lower extremities or weak feet were corrected by construction of heel lifts, metatarsal bars, a~ch supports, etc. Dental care wa~ given. Instruction in deep breathing and in exercise to correct postural abnormalities and to strengthen the muscles of the back and abdominal wall was given. Appropriate dietetic manage- ment was prescribed, i.e., patients who were underweight were given a high Calorie and high protein diet (approximately 3000 calories containing 100 to 150 gm. of protein daily), and overweight patients were placed on a reducing diet (800 to 1,200 calories). Dry or moist heat (infrared, diathermy, hydrocollator pack) was applied locally to the painful regions of the spine and to the involved peripheral joints. Ultrasound was applied in some instances, Occupational and corrective therapy was employed. When present, synovial fluid was aspirated in peripheral PAGENO="0438" 3530 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY joints, and hydrocortisone, 25 to 50 mg., was injected intra-articularly whenever this was deemed advisable. Aspirin, 0.3 to 1 gm. at four-hour or longer intervals, was used to control pain whenever needed. A few patients who complained of se- vere pains in the chest and abdomen of radicular distribution, or had spasm of the abdominal and intercostal muscles, were given hydrocortisone orally (50 to 100 mg. daily in divided doses), or phenylbutazone (400 to 600 mg. daily) for short pe- riods of time. Radiation therapy ~ was administered with the Maximar 250 Ky or the Picker 200 Ky unit to painful areas of the spine through one to five portals in doses of 150 to 200 r as measured on the skin or air on alternate days for a total dose of 600 to 750 r to each area. The size of the portals over the sacro-iliac joints was 10 by 12 cm., and over the spine, 6 by 12 to 6 by 15 cm. The following factors were employed: Filter-Thoreaus No. 2 or 0.5 mm. Cu and 1 mm. Al. HVL-1 or 2 mm. of Cu. If symptoms persisted, a second course of radiation therapy consisting of 450 to 600 r through each of two to five portals was given at an interval varying from six weeks `to several months. A few patients were given a third series, several months later, consisting of 300 to 450 r through each of one te three portals. No serious toxic reactions were observed from irradiation. A number of patients complained of nausea and occasional vomiting, and a few had a moderate degree of leukopenia. The leukopenia was temporary. The nausea and vomiting were relieved by Dramamine in doses of 50 mg,, or Bonamine in 25 mg. doses. Most patients whose radiograms showed osteoporosis were placed on a so-called "osteoporotic regimen" for a period of three weeks. This regimen consisted of the following: (1) high calorie, high protein diet; (2) ascorbic acid, 100 mg. orally, daily; (3) depo-testosterone, 25 mg. intramuscularly, three times weekly; (4) stilbestrol, 1 mg. orally, daily; (5) vitamin B12, 100 ag intramuscularly, three times weekly. Sixty-three patients were fitted with braces (Taylor, three-point, Knight or von Wersowitz) to support the lumbodorsal spine. Plaster body casts with wedging or turn-buckles were employed in a few patients in an attempt to correct extreme forward-crouching deformities. Three patients had arthrodesis or arthroplasty of one or both hip joints. One patient had bilateral artbroplasty of the temporomandibular joints to relieve ankylosis of these joints, and one patient had arthrotomy and synovectomy of the left sternoclavicular articulation. The nature of the disease in the light of presently held views was explained to the patient, with assurance of its generally benign character and eventual "burn- ing out" of activity. The patient was encouraged to maintain an o~ptimistk out- look. Emphasis was placed on the importance of maintainin~g good posture to prevent the development of deformities, of continuing muscle strengthening and breathing exercises, of the use of physiotherapeutic measures at home, and of the necessity of avoiding overexertion and upper respiratory tract or other in~ections. He was also advised to shift his position at sufficiently frequent intervals to prevent too great a "jellying" effect, to avoid bending over or liftiflg heavy ob- jects, to bend his knees as in stooping, instead of bending his spine, when lifting objects off the floor, tying shoelaces, etc., and to avoid postures or activities that aggravated his discomforts. An attempt, not always successful, to rehabilitate the more severely affected patients was ms~de by giving them vocational guidance and a~si~tance in c~ang~ng tQ an Qcoup~ttion which did not involve standing or $it~ing ~er pr~lo~ged perio~s, qr a~'duqus physical exertion, RESULTS It was difficult to evaluate the results of therapy correctly in terms of arrest of the disease, or the extent of relief of the subjective complaints. Duration of hos~ pitalization could not be used as an indicator because many of our patients re- ~naiiied in the hospital for reasons other than their complaints referable to the spine. In estin~at1ng the ~feect of therapy, we relied ~eneral1y on the ~egree of lessening of subjective complaints, especially decrease or d~sappearanc~ of aching and stiffness, and extent of freedom of ~ody movements. The degree of improve- ment was expressed as: (1) excellent: complete relies of subjective complaints and ability to resume re~~lar occupation; (2) good: eonsiderab~e r~ltef of subjec- tive cQmplaiutS and ability to carry om~it body mpveinents with relative freedom; (~) fair: some decrease of aching and $iffness; (4) no effect. Tbe results are indicated in table 4. 2Radiotberapy wa~ ,adn~lnl5tered under the supervision of Dr. Ralph Bramuid, Dr. Walter Mendel and t~r. Benjamin Greenbei~g. PAGENO="0439" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3531 It is seen that "good" or "excellent" response was noted in 70 of 9 patients (73.7%) who were not given irradiation therapy, and in 125 of 165 patients (7J~T%) who were given one to three courses of irradiation. There is therefore ~-itiE significant difference between the two groups. We must emphasize, however, ~--~ that the comparison is not valid because: (1) irradiation was only one of several therapeutic measures employed in the management of our patients, and (2) we did not evaluate separately the efficacy of physiotherapeutic measures apart from irradiation therapy. Our aim was to employ a therapeutic regimen which would expeditiously bring about a satisfactory remission of the disease and maintain this remission as long as possible. DISCUSSION During the course of this study we were impressed by thevariability of the subjective manifestations and the general lack of correlation, between subjective complaints, clinical manifestations, alleged disability and theroentgen manifesta- tions, especially during the early stages of the disease. We became aware of the influence of the expected gain to be derived from the persistence of complaints in regard to awards of disability compensation in many of `our veteran patients. Nevertheless, the diagnosis could be made with certainty in most of these patients. We found the following clinical features to be of value in diagnosing the disease during the early stages: (1) the complaint of aching and stiffness in any part of the lumbodorsal spine, occurring during the night, awakening the patient two to three hours after he had fallen asleep, and necessitating his getting off the bed and walking around in order to "limber up" and obtain relief; (2) the repetition of this process two to three times nightly; (3) the occurrence of stiffness and ach- ing in any part of the lumbodorsal spine on awakening in the morning, but "lim- bering up" upon resumption of activity; (4) reaction of the patient to the per- formance of the various orthopedic maneuvers. We were also impressed by the difficulty in correctly interpreting the earliest radiographic changes and their differentiation from the normally occurring vari- ations in the margins of the sacro-iliac and apophyseal joints. We also became aware of the difficulties in estimating the extent of relief obtained separately from physiotherapy and from irradiation. This difficulty was partly due to the fact that the relief of subjective complaints occurred not infrequently two to four weeks after completion of irradiation therapy. In our experience, the best results were generally obtained from the combination of physiotherapy, irradia- tion, postural and miiscle exercises, the judicious use of aspirin and correction of static factors and of established deformities by orthopedic procedures. $U~MA1~N The clinical features and roen~enqg~ap~ilc signs in 267 patients with rheu- matQid spondylitis are d~crib~d. The di6lculties in diagnosis encountered during the early stages of the disease are discussed, and metho~s found helpful by the authers in 4iagn~siug the ~J~en~e duri~ig its early ~t~ges ~tre described. ~anage- ment of the disease is discussed, and results of therapy in this series of cases are tabulated. SUMMAJ~IO ~N INTE~LINGUA Es describite manifestationes clinic e le constatationes roent~enqgraphic in 267 patientes mascule con spondylitis rheuniatoide. Le cliag~iose e ie tractamento es discutite. Le etates del patientes al tempore del declaration del morbo variava inter le secunde e le sexte decennio. A judicar per le gravamine~ ~ubject1ve del patientes, affection de articulation peripheric esseva presente in 166 ex 264 casos (i.e. 62,8%). Signos objective de affection de articulation peripheric esseva pre- sente in 113 ex 266 cases (i.e. 42,4%). In le majoritate del casos, le declaration del morbo esseva insidiose. Le grados de severitate del dolor dorsal variava con- siderabilemente in c1i1~ferente patientes. In 63 cases (i.e. 2~3,5%) illo esseva aceompaniate de radiation sciatic e de paresthesias. In le casos characteristic, le patientes esseva eveliate perdolor~s dersal duo a tr~s horas poet addormir se. Alicunes habeva dolor~ose contractiones del musculos abdominal e acute dolores migratori in le thorace durante le respiration. Le constatationes physic variava grand~m~nte in differente pattentes. Observa- tiones frequente esseva applatation del thorace e del spina lumbar, oblitteration del curva lordotic, exaggeration de cyphosis dorsal, dysfunction del expansion del thorace, rigi~11tate con movimento "como massa unite" del spina integre, e dys- PAGENO="0440" 3532 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY function del movimentos spinal. Le niveleo de hemoglobina esseva infra b norma in 55% del patientes. Le numeration leucocytic esseva normal in 72,8%. Le sedi- mentation erythrocytic esseva anormalmente accelerate in 209 casos (i.e. 81.9%). Vistas oblique del articulationes sacro-iliac facilitava grandemente le recognition de precoce alterationes radiographic causate per le morbo. Le alterationes radio- ~graphic in be articulationes sacro-iliac e apophysee consisteva de restriction o allargation del spatios articular, de irregular o pauco distincte margines articular, e de obbitteration partial o complete del atriculationes. Evidentia radiographic do affection sacro-iliac esseva trovate in omne le casos. Calicification de liga- inentos vertebral esseva presente in 89 casos (i.e. 33.3%), osteoporosis in 64 (i.e. 23.9%). Tres paUente~ exhibiva be triade del syndrome de Reiter. Un patiente habeva ankylosis complØe de ambe artlculationes temporamendibular. Dece-tres (i.e. 4.5%) habeva i~itis o iridocyclitis. Cinque habeva psoriasis. E. 36 (i.e. 13.5%) habeva anormalitates del columna vertebral. Le tractamento utilisava vane mesuras therapeutic. Factores static esseva corrigite. Le patientes esseva instruite in como respirar e como executar oxen- citios postular. Un appropriate regime dietetic esseva prescribite. Cabor humide o siclesseva applicate al region doborose del ~olumna vertebral e del afficite articu- bationes peripheric. Fluido synoviad esseva aspirate ab be articulationes peripheric. Hydrocortisona (25 a 50 ing) esseva injicite in le articulationes. Esseva utilisate therapia occupational e corrective. Aspirin (0,3 a 1 g) essèva administrate pro subjugar be dolores. Alicunes del patientes recipeva diurnemente doses oral de hydrocortisona (50 a 100 mg) o de phenylbutazona (400 a 600 mg). Patientes con osteoporosis recipeva regimes osteoporotic. Sexanta-tres esseva equipate con apparatos orthopedic. Canto sexanta e cinque recipeva inter un e tres cursos de roentgenotherapia profunde per intei un e cinque portales dirigite a areas doborose del columna vertebral. Esseva administrate 600 a 750 r a omne portal in le prime curso, 450 a 600 in be secunde curso, e 300 a 450 r in le tertie curso. Cento vinti-cinque (i.e. 75,7%) obteneva bon o exeellente responsas ab be irradia- tion. Le mebior resultatos esseva effectuate per be combination de physiotherapia, irradiation, exercitios postural emuscubar, uso judiciose de aspinina, e correction do factores static e dc establite deformitates per inesuras orthopedic. BIBLIOGRAPHY 1. Boband, E. W., and Present, A. J.: Rñeumatoid spondylitis, 3. A. M. A. 129: 843,1945. 2. Hench, P. S., Sbocumb, C. H., and Polley, H. F.: Rheumatoid spondylitis. Questions and answers, M. Olin. North America 31: 879, 1947. 3. Hart, D. F., Bagdanovitch, A., and Nichol, W. D.; The thorax in ~nkybosing spondybitis, Ann. Rheum. Dis. 9: 116, 1950. 4. Baker, L. D.: The diagnosis and care of Manie-Strtimpell arthritis, Postgrad. Med. 15: 428, 1954. 5. Toone, E. S., Jr.: The treatment of rheumatoid spondybitis, Am. Pract. 2: 530, 1948. 6. Pobley, H. F., and Sbocumb, C. H.: Rheumatoid spondylitis: a study of 1,035 cases, Ann. Int. Med. 26: 240, 1947. 7. Mowbray, R., Latner, A. L., and Middlemiss, 3. H.: Ankybosing spondylitis, Quart J. Med. 18: 187, 1949. 8. Hart, F. D., Robinson, K. C., Abbchin, F. M., and Maclagan, N. F.: Ankybosing spondylitis, Quart 3. Med. 18: 217, 1949. 9. Roijeston, 1. L.: The early radiological diagnosis of ankylosing spondylitis, Bnit. J. Radiol. 20: 288,1947. 10. Oppenheimer, A.: The apophyseal intervertebral articulations roentgenobogi- cally considered, Radiology 30: 724, 1938. 11. Borak, J.: Significance of the sacroibiac findings in Manie-Stniimpelb spon- dybitis, Radiology 47: 128, 1946. 12. Golden, R.: Diagnositic roentgenology, 1956, The Williams and Wilkins Co., Baltimore, p. 543. 13. Boband, E. IV., and Shebesta, E. M.: Rheumatoid spondylitis, correlation of clinical and roentgenobogical features, Radiology 47: 551. 1946. 14. Guest, C. M., and Jacobson, H. G.: Pelvic and extrapebvic osteopathy in thenmatoid spondylitis, Am. 3. Roentgenol. 65: 760, 1951. PAGENO="0441" COMPETITIVE PROBLEMS IN THE DRUG INDtISTRY 3533; APPENDIX III SOHERING CORP., November ~, 1961~ ~1f1~IATLOED NELSON, ~ Se~te, Washington, D.C. DEA~s SENATOR NELSON: In the course of the July 24, 1967, hearings before the Subcommittee on Monopoly of the Senate Select Committee on Small Business, you referred to the "research. . . done by the National Institutes of Health with prednisone," and interrogated Mr. W. H. Conzen, President of Schering Corpora- tion, concerning the report you had received from the NIH as to its expenditures in that regard. You stated that you had been informed by NIH that they spent a total of $2,114,000 in intramural research on prednisone and prednisolone in the years 1953 through 1967, and that, in addition, NIH had submitted to you a record of expenditures totaling $14,384,144 in extramural research grant obligations for the period from 153 through 1967. You further stated (Transcript, p. 1032) : "This involved 639 grants from the period 1953 through 1967. These grants were not, I understand. exclusively to do research in prednisone and prednisolone, but in each of these 639 grants, research was done on prednisone and prednisolone, and that totaled $14,384,144." You asked that the listing of the intramural research expenditures and the table of the extramural research obligations be printed at the conclusion of Mr. Conzen's testimony. The interpretation given to these statements by the press throughout the country Is typified by the following: "Senator Nelson of Wisconsin pointed out that some 60 million dollars had been spent on prednisone research and development grants by the National Institutes of Health. So much for the claim, that in this instance private industry carried the ball" (Times Herald, Carroll, Iowa). "Nelson also took issue with Schering's claim of its contributions as the dis- coverer and developer of prednisone. He cited figures that the National Insti- tutes of Health has spent some $60 million in development and research grants on the drug" (The Washington Post, Washington, D.C.). To clarify this matter, our Research Vice President requested NIH to furnish us information on this subject. We are now in receipt of its response, a copy of which we are enclosing. We ask that it, together with this communication, be incorporated into the record of the proceedings so that the latter may be more precise and complete. Very truly yours, IRVING H. Junow, 1/ice President and General Counsel. DEPARTMENT OF HEALTH, EDUCATION, AND WELF'ARE, PUBLIC HEALTH SEIIVICE, NATIONAL INSTITUTES OF HEALTH, Bethesda, Md., October 4, 1967. DEAR Dn. GIBSON: This is in response to your recent inquiries concerning references made to NIH support of research on prednisone and prednisolone before the Senate Select Committee on Small Business Subcommittee on Monopoly, chaired by Senator Gaylord Nelson. We are enclosing a copy of the material supplied to the Committee in response to their request. There are several points which need to be reemphasized, although they were fully explained by Senator Nelson during the hearing on July 24. As you will see in the attached document, the research reported (both intramural and extra- mural) covered prednisone and prednisolone for the fiscal years 1953 through 1967. The intramural funds reported were spent entirely on prednisone or prednisolone research. The footnote on the extramural research data (which was read into the hearing record by Senator Nelson, according to a member of his staff) reads as follows: "Extramural obligations overestimate funds devoted to prednisone ancli prednisolone since all grants in which prednisone and/or prednisolone were named were counted in the total." As far as the method of compiling the information is concerned, the Division of Research Grants, together with the Science Information Exchange, conducted a hand search of research projects either through the "Notice of Research Project" or through the Public Health Service Index for fiscal years 1953-1965. PAGENO="0442" 35~34~ COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A punch card run produced the data for FY 1966 and 1967. Projects included here are ones for which prednisone or prednisolone played a sufficiently prominent role to be included in the summary research protocol. We felt that we had no basis for attempting to prorate the amount of the grant award among its various elements. Therefore, we chose to explain the limitations of the data in the above-quoted footnote. Your inquiries raise several other matters which are of some concern to us. The first is the matter of the misquoting of Senator Nelson in the Washington Post on July 25. We regret that our response to the Senate Committee has become embroiled in this controversy~, but We arO cert5in that you were not intending to involve or bla~ne the NIH in any way for the error of the Washington Post or the fact that this error Was picked up b~ other newspapers. A second matter of concern to us was the statement in your letter of August 14: "I particularly would question the purpose of the large sums expended in recent years after the activity of the drugs in question had been quite thoroughly explored by many laboratories throughout the world." A review of our Research Grant Indexes indicates a shift of emphasis in recent years in projects involving these agents from subjects primarily within the purview of the National Institute of Arthritis and Metabolic Diseases or the National Institute of Allergy and Infectious Diseases to those more within the purview of the National Cancer Institute. This corresponds to our experience in our own intramural program as well, with the National Cancer Institute being the only Institute with increasing in-house research in recent years directly related to prednisone and prednisolone. We believe that this shift of emphasis may account for the level of expenditure which you questioned. We welcome this opportunity to clarify our position with respect to this matter, and hope the attached information will meet your needs. Sincerely yours, JAMEs A. SHANNON, M.D. Director. ESTIMATED NIH RESEARCH EXPENDITURES FOR DIRECT OPERATIONS 1 2 RELATED TO PREDNISONE AND PREDNI- SOLONE, FISCAL YEARS 1953-56 Fiscal year NCI NIAMD NINDB 1953 0 $15,000 0 1954 0 50,000 $18,000 1955 0 40,000 18,000 1956 $10,000 30,000 10,000 1957 57,000 20,000 10,000 1958 13,000 10,000 0 1959 74,000 10,000 0 1960 19,000 0 0 1961 29,000 0 0 1962 11,000 0 0 1963 84,000 0 0 1964 231,000 0 0 1965 394,000 0 0 1966 409 000 0 0 1967 552 000 0 0 Total 1,883,000 175,000 56,000 Total NIH3 2,114,000 1 Include contracts. 2 Funds spent for purchase of drugs for the treatment of NIH Clinical Center patients not included. a NIAID, nones PAGENO="0443" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3535 NIH EXTRAMURAL RESEARCH GRANT OBLIGATIONS, FISCAL YEARS 1953-67 1 1954 1955 1956 1957 1958 1959 1960 - 1961 1962 1963 1964 1965 1966 1967 Total $156,237 12 327,711 12 394,817 18 350,554 15 326,554 21 655,725 37 783,502 44 930, 866 52 1,134,729 56 1,229,653 68 1,338,872 60 1,384,401 60 1,683,464 69 1,695,827 61 1,991,232 254 14,384,144 6 I Extramural obligations overestimate funds devoted to prednlsone and prednisolone since all grants in which pre dnisone and/or prednisolone were named were counted in the total. for fiscal year 1967. incomplete data. Note: Total intramural and extramural, $16,498,144. 0 FIscal year ~ -~- Total funds Number of grants