PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4971 COMPANY CIBA Dome duPont Eaton Laboratories Endo Laboratories Flint Laboratories Glenwood Hoechst Ives Laboratories NO. ISSUES 11 7 6 10 6 3 4 7 3 2 2 10 9 8 7 12 Total... Total... Total... Total... Total... Total... PRODUCT 1. Doriden 2. Ismelin 3. Regitine 4. Ritalin 5. Ser-Ap-Es 1. Pminet 1. Syimnetrel 1. Furadantin 1. Percodan 2. Valpin 1. Choloxin 1. Butazolidin 2. Hygroton 3. Pertofrane 4. Preludin 5. Tofranil 1. Patoba 1. Lasix 1. Isordil NO. PAGES 18 21 6 23 19 87 3 7 7 3 2 5 6 20 21 16 14 23 94 12 36 2 Total... 12 Total... 9 Total... 2 Total... 98 81-280 O-69--pt. 11--44 PAGENO="0002" 4972 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY NO. ISSUES NO. PAGES Key Pharmacal 1. Nitroglyn 9 Total... 9 Lakeside Laboratories 1. Cantil 6 Total... 6 Lederle Laboratories 1. Aristocort 6 12 2. Artane 6 12 3. Declomycin 6 12 4. Diamox 4 4 5. Hydromox 7 14 6. Pathibatnate 10 20 Total... 74 Lilly, Eli, & Co. 1. Aventyl 10 28 2. Dymelor 12 39 3. Darvon 12 24 Total... 91 McNeil 1. Butiserpine 11 11 2. Butisol 11 22 Total... 33 Massengill Company 1. Oberdrin-LA 9 Total... 9 Mead-Johnson 1. K-Lyte 4 8 2. Mucomyst 5 20 3. Peri-Colace 11 11 4. Quibron 3 6 5. Vasodilan 12 48 Total... 93 99 PAGENO="0003" 4986 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMERICAN FAMILY PHYSICIAN 1966 COMPANY DRUG NO. ISSUES NO. PAGES Abbott 1. Compocillin 5 10 2. Erythrocin-Sulfas 7 18 3. Surbex-T 1 1 Total... 29 Armour 1. Chymar 1 2 2. Chyinoral 2 4 3. Pentritol 1 6 Total... 12 Cole 1. Indo-Niacin 3 Total... 6 Endo 1. Hycoinine 2 4 2. Valpin 12 12 Total... 16 Fesler 1. Trichotine 5 Total... 5 9~z~ 1. Butazolidine-Alka 6 6 2. Persantin 7 10 3. Pertofrane 2 14 4. Preludin 4 8 Total... 38 Hankskraft 1. Zymenol 5 Total... 5 Lederle 1. Peretinic 6 Total... 6 Massengill 1. Obedrin-LA 6 Total... 6 113 PAGENO="0004" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4987 DRUG NO. ISSUES NO. PAGES COMPANY McNeil Mead-Johnson Neisler Ortho Parke-Davis Pfizer Roche 1. Butigel-Zyme 4 4 2. Butiserzapide 11 20 3. Butiserpine 5 5 4. Parafen-Forte 12 12 5. Tylenol 9 19 Total... 60 1. Trind 8 8 2. Vasodilan 4 32 . Total... 40 1. Rynatan/Rynatuss 3 6 2. Dainite-KL 5 Total... 5 11 1. Delfen 3 3 2. Ortho-Novuni 10 Total... 22 25 1. Benadryl 7 7 2. Benylin 7 7 3. Cosanyl 3 3 4. Carbrital 12 12 5. Initia 5 5 6. Myadec 7 7 7. There-Camber 11 Total... 11 52 1. Bonine 2 4 2. Daric:xi 3 3 3. Diabinese 3 Total... 11 18 1. Libriuiu 8 8 2. Yalium 5 5 Total... 13 114 81-280 O-69-pt. 11-45 PAGENO="0005" CONTENTS V Article: "To Label or Not to Label," from the Journal of the American Page Medical Association, vol. 194, P. 1311, December 1965 4644 Report: Excerpts From "Proceedings of the AMA House of Delegates," November 1966 4647 Brochure: "Advertising in the Annals of Internal Medicine__Exhibiting at the Annual Sessions" 4730 Chart: Annals of Internal Medicine advertising income, 1964-1968 4733 Letter to Benjamin Gordon, staff economist, :Select Committee on Small Business, U.S. Senate, from Dr. Edward C. Rosenow, Jr., executive director, American College of Physicians, dated April 7, 1969, re adver- tising in Annals of Internal Medicine 4734 Memorandum to Dr. Robert S. Long, president, ASIM, from W. R. Ramsey, dated March 11, 1969, re American Society of Internal Medi- cine finances, 1963-1969 4741 Correspondence between Benjamin Gordon, staff economist, Select Com- mittee on Small Business, U.S. Senate, and Mac F. Cahal, J. D., execu- tive director and general counsel, American Academy of General Prac- tice, with accompanying material 4778 Article: "Vive La Difference!" from American Academy of General Prac- tice, January 1965 4780 Article: "Phenacetin and the Nephrologists," from American Academy of General Practice, June 1965 4779 Article: "Drug Removal," from American Academy of General Practice, September 1967 Article: "Another Look at Immunizations," from American Academy of General Practice, April 1969 4779 Charts: American Family Physician income and expense analysis, January 1961-November 30, 1968 4781 APPENDIXES I. Article: "The Image of the Drug Industry, as Seen by Town and Gown"-results of a questionnaire with regard to the phar- maceutical industry and products are presented-by Drs. W. J. Hagood, Jr., and J. A. Owen, Jr., from the Virginia Medical Monthly, vol. 94, February 1967, pp. 110-114 4789 II. Article: "Teaching the Evaluation of Drug Advertising to Medical Students," by D. R. H. Gourley, Ph. D., from the Virginia Medi- cal Monthly, vol. 93, August 1966, pp. 459-461 4793 III. Letter, dated April 22, 1969, to Dr. :W. J. Hagood, Little Retreat Clinic, Clover, Va., from Senator: Gaylord Nelson, chairman, Monopoly Subcommittee, with accompanying NAS-NRC studies 4795 IV. Article: "Fatal Circulatory Collapse in Premature Infants Receiving Chloramphenicol," by L. E. Burns, M.D., J. E. Hodgman, M.D., and A. B. Cass, M.D., from the New England Journal of Medicine, vol. 261, No. 26, December 24, 1959 4799 V. Article: "Safe and Effective Chioramphenicol Dosages for Pre- mature Infants," by J. E. Hodgman, M.D., and L. E. Burns, M.D. from American Journal of Diseases of Children, vol. 101, February 1961 4804 VI. Article: "i3acterial Meningitis," by P. F. Wehrle, A. W. Mathies, J. M. Leedom, and D. Ivler, from Annals New York Academy of Sciences, 1967, pp. 488-498 4812 VII. Article: "Management of Bacterial Meningitis," by P. F. Wehrle, M.D., A. W. Mathies, Jr., M.D., Ph. D., and J. M. Leedom, M.D., from Clinical Neurosurgery, Chapter IV, vol. 14, pp. 72-85 - -- 4820 VIII. Article: "Antibiotic Antagonism in Bacterial Meningitis," by A. W. Mathies, Jr., J. M. Leedom, D. Tyler, P. F. Wehrle, and B. Portnoy, from Antimicrobial Agents and Chemotherapy, 1967, pp. 218-224 4829 IX. Article: "Ampicillin in the Treatment of Acute Suppurative Menin- gitis," by F. F. Barrett, M.D., W. A. Eardley, M.D., M. D. Yow, M.D. and H. A. Leverett, from the Journal of Pediatrics, Septem- ber 1966, vol. 69, No. 3 4834 PAGENO="0006" VI CONTENTS X. Article: 11fl* Influenzae Meningitis: A Controlled Study of Treatment With Ampicillin," by L. D. Thrupp, J. M. Leedom, D. Tyler, P. F. Wehrle, J. F. Brown, A. W. Mathies, and B. Portnoy, from Post Page Graduate Medical Journal, December 1964, Pp. 119-125 4844 XI. Article: "Experience With Ampidillin in Bacterial Meningitis," by A. W. Mathies, Jr., J. M. Leedom, L. D. Thrupp, D. Ivier, B. Portnoy, and P. F. Wehrle, from Antimicrobial Agents and Chemotherapy, 1965, pp. 610-617 4850 XII. Excerpts of affidavits submitted to the Food and Drug Administra- tion from various physicians re prescribing of drug Thalidomide based on information given by detail men 4857 XIII. A study of pharmaceutical advertising in selected medical journals, prepared by the Education and Public Welfare Division, Legisla- tive Reference Service, Library of Congress 4863 HEARING DATES* February 19, 1969: Morning session 4297 February 20, 1969: Morning session 4321 February 26, 1969: Morning session 4351 February 27, 1969: Morning session 4371 March 13, 1969: Morning session 4477 March 18, 1969: Morning session 4583 Afternoon session 4675 March 25, 1969: Morning session 4709 March 26, 1969: Morning session 4753 sThe 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 Apr. 23, 24, and May 1, 1968, appears in pt. 7 of these hearings; the testimony for May 2, 3, and Sept. 17, 1968, appears in pt. 8 of these hearings; the testimony for Sept. 18, 19, and 25, 1968, appears in pt. 9 of these hearings; the testimony for Dec. 11, 17, 18, 19, 1968, and Jan. 23, 1969 appears in pt. 10 of these hearings. PAGENO="0007" COMPETITIVE PROBLEMS 1N THE DRUG INDUSTRY WEDNESDAY, FEBRUARY 19, 1969 U.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMITTEE SMALL BUSINESS, Wa8hington,D.C. The subcommittee met, pursuant to notice, at 10 a.m., in the caucus room, Old Senate Office Building, Senator Gaylord Nelson (chairman of the Subcommittee) presiding. Present: Senators Nelson, McIntyre, and Dole. Also present: Senator Byrd of Virginia. Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; Jay Cutler, acting minority counsel; and Elaine C. Dye, clerical assistant. Senator NELSON. The committee is pleased to welcome this morning the Senator from Virginia, Senator Harry Byrd, who will at this time introduce one of his distinguished constituents as the first witness this morning. Senator Byrd. STATEMENT OP HON. HARRY P. BYRD, JR., A U.S. SENATOR PROM THE STATE OP VIRGINIA Senator BYRD. Thank you, Mr. Chairman, Senator McIntyre. I appreciate the committee giving me the opportunity to present this morning to the committee, a splendid, outstanding citizen of Virginia, Dr. William J. Hagood, Jr., from Clover in Halifax County. For the benefit of my New Hampshire friends I might say that Halifax County is near the border of North Carolina. It is one of the larger counties of our State, and Dr. Hagood, along with his cousin, Dr. Warren Hagood, his uncle, Dr. James D. Hagood, practice medi- cine and operate a medical clinic in Halifax County. These are Virginians, all three, who have the confidence of the people of their area. Dr. William J. Hagood, Jr., who will speak this morning, is well known throughout the State. He is public spirited. He takes a keen interest in the problems of the people of our State. I might say that his partner, and his uncle, Dr. James D. Hagood, is the senior member of the Virginia Senate. He is the president pro tempore of the Virginia Senate. He is chairman of the senate finance committee. He has been elected to the Virginia Senate more times than Carl Hayden was elected to the U.S. Senate, and he is equally as beloved in our State, and in the Virginia Senate, as was Senator Hayden in the U.S. Senate. 4297 PAGENO="0008" 4298 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY So it is a privilege and a pleasure to present to this distinguished committee a very fine Virginian, and one in whom the people of Vir- ginia have great confidence, Dr. William J. Hagood, Jr. Senator NELSON. Thank you, Senator Byrd. Dr. Hagood comes from a part of your State where my wife has so many relatives, it is almost a mathematical certainty that one of them was a patient of the Hagood Clinic. Senator BYRD. I might say, Mr. Chairman, that we in Virginia are very proud of the fact that Mrs. Nelson is a native of Wise County in our State. Senator NELSON. Thank you, Senator Byrd. First let me mention that Senator Tom McIntyre is a new member of the Senate Small Business Committee, and a new member of the Monopoly Subcommittee, and, as chairman, I am pleased to have him join us this morning in these hearings. This morning the Senate Small Business Committee's Monopoly Subcommittee resumes its hearings on problems in the drug industry. Our first witness was to be Dr. Philip R. Lee, Assistant Secretary for Health and Scientific Affairs with the Department of Health, Education, and Welfare. I should have said the "former" Assistant Secretary because Dr. Lee's resignation became effective just this past Monday. Dr. Lee has resigned from his post with HEW to accept the position of chancellor at the University of California Medical Center in San Francisco and he was asked to report to the university immediately. We are, of course, disappointed that he is unable to be with us in person. However, Dr. Lee has submitted his statement for the record and it will be printed in the record in full. This statement has been distributed to the press. (The statement of Dr. Lee follows:) STATEMENT BY PHILIP R. LEE, M.D., ASSISTANT SECRETARY FOR HEALTH AND SCIENTIFIC AFFAIRS, U.S. DEPARTMENT OF HEALTH, EDuCATION, AND WELFARE Mr. Chairman, last September 25th, I had the honor of appearing before the Subcommittee to report on some of the interim findings and recommendations of the Task Force on Prescription Drugs. At that time, we had not reached our findings on the principal charge to the Task Force-to determine whether it is both necessary and feasible to include prescription drugs as a benefit in the Medicare program. We have now completed our studies and the answer to both questions is an unequivocal yes. To reach this conclusion, the Task Force needed and obtained detailed infor- mation about the manufacture, distribution, promotion, prescribing, and use of prescription drugs in this country and abroad. We have made this information widely available in a series of five interim reports and four background papers, entitled "The Drug Users," "The Drug Makers and The Drug Distributors," "The Drug Prescribers," and "Current American and Foreign Programs." A fifth background paper, "Approaches to Drug Insurance Design," and a final summary report are in press and will be released very shortly. Mr. Chairman, I am pleased to submit these reports for the Subcommittee's records. These reports say a great deal about the use of prescription drugs in our society. Most central to our mission, however, was their use by the elderly. We found that our 20 million citizens age 65 and older spend nearly three times as much each year for prescription drugs as the average for all Americans. We found that a significant number of these drugs are used over long periods of time in the treatment of serious chronic conditions. At the same time, we found that for many of the elderly, their incomes, assets, protection through health insur- PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4299 ance, and the relief they obtain through income tax deductions are simply inadequate. These and other findings point directly to :the need for a Medicare drug insur- ance program, and we have spelled out in great detail the alternatives for the development of such a program. The recommendations of the Task Force related to the Medicare program are now under study in the Departmnt, and I expect that the Secretary will reach a decision on this within the next few weeks. He has not yet had the opportunity to review many of the other recommendations of the Task Force. In reaching our conclusions, Mr. Chairman, the members of the Task Force were not unaware of the sensitive social and economic issues that are involved in the marketing of prescription drugs. We were aware of the significant price differences between brand name drugs arid their generic name counterparts, and of questions that have been raised about their relative efficacy. We also had to consider the profusion of available drugs, including large numbers of combination products and so-called "me-too" drugs, and whether Federal funds should be used to support the market for these and other non-essential drugs. In other words, we had to decide whether the scope of benefits in a Medicare drug program could be restricted without~ reducing the quality of health care and without depriving physicians of access to valuable therapeutic agents. Although these and other aspects of the Task Force investigations were all related to the question of including prescription drugs as a Medicare benefit, many of them have much wider significanëe. One of them that is of particular concern to me, has to do with the explosive growth of drug research, develop- ment, promotion, and marketing, and the profound effect this has had upon the use of drugs, and indeed, upon the entire practice of medicine. In our lifetime, the pharmaceutical industry has become an increasingly complex research and development enterprise. Beginning with research at the turn of the century related to epinephrine and other sympathomimetic drugs, we can trace a continuing series of developments, including vitamins, insulin, the sulfonamides, analgesics, antibiotics, steroids, antimalarials, tranquilizers, antihistamines, and the growing battery~ of modern chemotherapeutic agents and biologicals. Drug development, produétion, and sales in the last thirty years have raised the drug industry in the United States from a $300 million to a $5 billion-a-year operation. The striking growth in the availability of increasingly potent and dramatically effective drugs has done much to increase the effectiveness of the physician in lengthening life and alleviating suffering. At the same time, it has made the pharmaceutical industry, the makers and sellers of drugs, among the most in- fluential members of what has been called "the health team." Its influence has been brought about not only as a result of epochal advances in biology, phar- macology, chemistry, and medicine, but also because of profoundly significant changes in the scope and methodology of drug promotion. Much has been said in these hearings and elsewhere about the use of advertis- ing and promotion to create a market for new drugs and maintain markets for older ones. The Task Force has expressed similar concerns. Substantially less interest has been aroused, however, by the efforts of industry to mold the attitudes of medical students, medical faculty members, professional organiza- tions, and those who are responsible for large-scale purchase of or reimbursement for prescription drugs, including both public and private agencies. This problem was highlighted by the recent decisions on the part of students at two medical schools, Western Reserve and Harvard, to return drug industry gifts. These actions clearly reflected the concern of these students about the involvement of the drug industry in programs of medical education and informa- tion, because the drug industry is engaed here not only in educating but in selling. It is through his early medical training that the physician-to-be forms attitudes about the use of drugs, their relative merits, and the function of drug manufac- turers as sources of reliable information. In many medical schools it is not unusual for representatives of drug firms to take part actively in physician training as lecturers, consultants, and simply as sources of information. The medical student, under these circumstances, naturally associates drugs with their suppliers as well as with their chemical and clinical properties. And here, Mr. Chairman, is the point at which the strategy of names begins to take on great importance. For it is during his training that the student begins to associ- ate useful medicinal drugs with their trade names as well as, and often in place of, their geueric names. PAGENO="0010" 4300 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It is also important to note the extent to which those who are responsible for the teaching of pharmacology and pharmacy are supported by the pharmaceuti- cal industry. All indications are that the major drug houses provide financial sup- port to departments of pharmacology, schools of pharmacy, and individual sci- entists engaged in teaching and research that is very considerable indeed. Through grants, contracts, fellowships, guest lectureships, and unrestricted sup- port, many in academic medicine have developed very close ties to the drug mak- ers for necessary support which amounts to millions of dollars each year. That this academic-industrial relationship has been productive, there is no doubt. But there can also be no doubt that the medical profession, our medical students, and the public have the right to an honest and open accounting of this relationship. In the case of the American Medical Association, for example, it would appear that more than half of its total revenue is derived from the pharmaceutical advertising carried in various AMA publications. The effect of the very substantial involvement of the pharmaceutical indus- try in the practice of medicine, Mr. Chairman, finds its ultimate expression in the drugs prescribed by physicians. Last year, over a billion prescriptions were filled in the United States at a retail cost of over three billion dollars. Each of these prescriptions represented a tacit assurance by the physician that the patient was receiving the most appro- priate drug that could be prescribed-the most appropriate in terms both of performance and cost. Yet I wonder bow many physicians were really prepared to give that assurance. The problem is not a simple one for the physician or his patient. There are now more than 7,000 prescription drugs available in this country. This therapeu- tic arsenal includes some 1,200 generally available drugs and 6,000 combina- tions, most of them marketed in a number of different dosage forms. In the past twenty years there have been 715 new single chemical entities mar- keted. Duplicate single products have numbered 1,407; compounded products 3,840; and new dosage forms 1,820. Thus a total of 7,782 new products and new dosage forms have been marketed in the last two decades alone. How does the physician respond to this profusion of new products? Of the 1.1 billion prescriptions written last year, 67 percent were written for 200 drugs and 85 percent for 500 drugs. Among the 200 most frequently prescribed drugs are 119 single chemical entities and 81 combination products. The development and use of fixed drug combinations, as we have noted in our reports, has become increasingly popular within the past twenty years, but the widespread reliance on their use has generated sharp criticism. The Council on Drugs of the American Medical Association has long held the prescribing of such fixed drug mixtures to be irrational, and you will recall that near the outset of your own hearings, a noted authority on infectious diseases said: "A careful review of fixed branded combinations on the market, including com- binations of penicillin and sulfonamides, penicillin and streptomycin, tetracycline and antifungal agents, and tetracycline and novobiocin, does not substantiate the claims that the combination is superior to one of the agents used separately. The combinations are expensive, deny the physician flexibility in dosage, are pri- marily promotional devices, and have the inherent problem that the patient undergoes the risk of serious adverse reactions to two or more drugs rather than a single defined agent. The physician cannot determine which component is causing trouble if a bad reaction is encountered. I personally believe that we would do much better without these preparations."' The National Academy of Sciences National Research Council has completed a careful evaluation of the 2,824 drugs marketed between 1938 and 1902, the year in which the Food, Drug and Cosmetic Act was amended to require that drugs marketed be both safe and effective. The NAS-NRC has taken a similar position with respect to a number of the fixed drug combinations. The actions by the Academy and the Food and Drug Administration are sure to rouse the ire of industry, but more importantly they should make many of the physicians who have been prescribing drugs now described as ineffective question their own obser- vations with respect to these drugs. One of the consequences of the introduction of safe and effective drugs is bet- ter health and well-being for many people. Another consequence is drug-induced IKunin, Calvin M.: Statement in U.S. Senate, Subcommittee on Monopoly Select Com- mittee on Small Business, "Compefitivc Problems in the Drug Industry" U.~. Government Printing Office, Washington, D.C., 1907. PAGENO="0011" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4301 disease, or what Moser2 has called diseases of medical progress. His recent book includes 27 chapters describing a host of problems from discoloration of the teeth, to drug dependance and death. A search of the medical literature during a recent four-year period revealed 178 citations on the untoward effects of iron; in less than three years, 03 articles on the effect of tetracyclines on teeth; and in a four and one-half year period, 112 articles on the adverse effects of LSD. Attention is now being directed to many of these problems. In one recent study, of 830 patients with chronic illness admitted to the medical wards of a hospital for treatment and rehabilitation, approximately 35 percent reported at least one adverse reaction to drugs administered during their hospital stay. This incidence of adverse drug reactions is considerably higher than the 5-20 percent reported in earlier studies of hospitalized patients.3 It should also be noted that 80 percent of the reactions observed were moderate or serious. Studies of adverse `drug reactions on an' outpatient or ambulatory basis are, of course, far more difficult. In recent years several computer based systems have been developed that will permit study of this problem as well as the pre- scribing habits of physicians. At the University of Southern California a study of prescribing patterns has identified four types' of inappropriate prescribing: (1) Inappropriate drug quantities by single prescription; (2) inappropriate amounts of individual drugs in patients' possession that result from multiple prescriptions; (3) inappropriate concurrent prescriptions; and (4) inappro- priate drugs for specific disease entity.4 One example of the kind of problem uncovered in this study was the patient who received over 100 prescriptions for trannquilizers and hypnotics over a~ nine-month period. She received the prescriptions from her regular clinic and from a hospital emergency room. Neither facility `has access to the other's medical records. At the end of the nine months, the patient had over 1,100 fifty-milligram capsules of chlorpromazine, 2,000 ten-milligram tablets of trifluoperazine, and' 650 two hundred-milligram capsules of amobarbital theoretically in her possession. The potentials for abuse in such a situation are obvious. Another kind of problem more subtle and more difficult to assess has recently been discussed in an excellent editorial in' the New England Journal of Medicine.3 This is the duress imposed by the attitudes of the medical profession and society. The physician knows he will be more severely criticized if he fails to treat a curable condition than if he overtreats a dozen that require little or no treat- ment. As the editorial stated. "Actions speak stronger than words, but strong words scold inaction. Treat- ment, moreover, is gratifying to both doctor and patient in proportion to its specificity, incisiveness and magnitude. Under conditions when choice is possible, operation is preferred to pills, pills to diet, diet to nothing at all. The patients' desires, the doctors' peace of mind, the opinion of the medical profession, and the societal attitudes press for vigorous treatment. Is it therefore any surprise that the physician who has to choose between over- and under-treatment almost invariably `opts for the former?" The editorial concluded: "Basic to ~good treatment are the physician's in- tegrity and education. The shape of the therapeutic structure erected on these two foundations is determined by the interaction between individual and cir- cumstances. It is a complex process which pharmaceutical advertising in- fluences but usually does not dominate, and constraints placed on this factor alone will improve therapeutics but little. A better appreciation of the principles of medical therapy is required by society at large, and the necessary educa- tional process must involve everyone-those who give, those who receive, those who intermediate, and the many who ,choose to write about what's wrong with medicine. When one man treats another, the exchange involves not only a whole patient, but also a total physician." Mr. Chairman, I have tried to describe and diagnose, if you will, a malady that affects physician, patient, and the public generally. If the diagnosis is accurate a prescription is in order. One of the basic ingredients of this prescription must be education. In pharma- cology, the major problem is that the; subject is taught early in the medical cur- 2 Moser, H. H.: Diseases of Medical Progress, Springfield, Illinois, Charles C. Thomas. 3Bo~da, `~: T., Sloan, D., and sack, H.: "Assessment of Adverse Reactions Within a Drug Surveillance Program," JAMA 205 :644-647, August 26, 1968. Maronde, Robert, M.D., Professor of Medicine and Pharmacology School of Medicine, University of Southern California: Personal Communication. 5Editorial: "Treatment by the Whole: Individual," New England Journal of Medicine 280 :271-272, January 30, 1069. PAGENO="0012" 4302 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY riculum as a basic science when it really is a clinical science as well. As a re- sult, the clinical uses of drugs do not receive the attention they deserve. The situation was very well stated by the President of the American Medical Association in a recent address: "Certainly there needs to be a recognition by all elements concerned with medical education that pharmacological principles should not and cannot be limited to a single or conservative series of courses given fairly early in the curriculum of the modern medical student, which almost universally now in- eludes 4 years of medical school and 4 more years of internship and residency. "The goal of pharmacologic teaching is not a theoretical one. It is not limited to action at the molecular level. It must in part be practical and it should in- clude information concerning safe and effective use of drugs. A key principle is that all drugs are potentially toxic. The student as well as the practicing phy- sician must remain continually aware of the possibility that any drug may do harm as well as good. Such continual awareness comes only from repeated ex- posure to pharmacologic education." And he stated: "It is my belief, which I share with many other people who are concerned with this problem, that ideally students should be educated in pharma- cology in such a way that as physicians they will have the basic tools for con- tinued learning about new drugs and new developments in therapeutics that will appear during their years of active practice. Furthermore, they should be educated so that during the years of practice they will be oriented to the con- tinuing education of pharmacologic experts in medical schools and not to the advertising of pharmaceutical manufacturers." In its background paper, "The Drug Prescribers," the Task Force reported on steps taken at a number of medical schools to bridge the gap between pharma- cology as a basic and clinical science. At Harvard University, for example, students are offered an elective seminar on advanced pharmacology in the fourth year which employs a case history ap- proach to drug therapy in which emphasis is placed on problems of drug inter- action and adverse drug reactions. I understand that twice as many students apply for admission to this course as can be accepted. At Columbia University and the University of Florida, clinical pharmacology is now being taught in the third and fourth years in addition to the basic sci- ence course. A number of other schools have begun or are plannng to offer similar courses. The Task Force has recommended that a course in clinical pharmacology be in- cluded as part of the regular medical curriculum in all schools and that Federal support be provided where the need is apparent. Perhaps even more important than the urgent need to improve the educational opportunities in our schools of the health professions is the need to improve educational programs and sources of drug information for interns, residents, and practicing physicians, for unless the physician is prepared to go on learning for as long as he practices medicine, there is little hope that he will be able to deal effectively with the obstacles to rational prescribing. Information on prescription drugs reaches the physician from many sources: medical journals; journals of prescribing such as The Medical Letter and Ph arm acology for Physicians; drug compendia; formularies; textbooks; in- dustry advertising; drug samples; detail men; and postgraduate education. Surprisingly few of these sources, however, provide the objective, current, and comparative data that the physician needs in order to make sound thera- peutic judgments. You may recall, Mr. Chairman, that when I last appeared before the Subcommittee, I spoke of the need to support the efforts of State and local medical societies, in cooperation with medical schools and other health institutions, to provide regularly scheduled postgraduate seminars of current developments in drug therapy. I also discussed the Task Force recommendations about establishments of a comprehensive drug compendium and support for a journal of prescribing. These are recommendations which I felt should be of tremendous interest to the medical profession, and so on November 7, 1968 I sent a letter to all of the Nation's 306,000 physicians describing our recommendations to provide better drug information and asking for their comments. I am pleased to submit a copy of my letter for the record. Wilbur, Dwight L.: "Pharmacology and the Practicing Physician," Proceedings of the Western Pharmacology Society 10:5-11 (1968). PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4303 During the first several weeks, through December 4, we received 3,307 replies. Of these 2,554 contained comments and 753 were simply requests for copies of the Task Force reports. Since that time we have received several hundred more replies which we have not fully tabulated, but the nature `and direction of the response did not appear to differ from the early replies. Of those with comments, 1,709 or 66.9 percent were favorable to the recom- mendations overall, 529 or 20 percent were clearly negative, and 316 or 12.4 percent could not be judged either favorable or unfavorable. On the specific issues discussed in the letter, the responding physicians indi- cated as follows: 1,621 physicians commented on our proposal for a comprehensive drug compendium. Of these, 1,246 or 77 percent were in favor and 375 or 23 per- cent were opposed. 1,419 replied to the recommendation for a journal of prescribing. 858 of them or 60 percent were favorable and 561 or 40 percent were opposed. 1,138 commented on the expansion of~ undergraduate training in clinical pharmacology. 751 or 66 percent were in favor and 387 or 34 percent were opposed. 1,070 physicians discussed our proposed support for continuing education courses in drug therapy. 789 or 74 percent were in favor and 281 or 26 percent were opposed. What do these replies mean? First, they indicate the serious thought that many physicians have given to the problems involved in obtaining objective and reliable prescribing information. Beyond that, any judgments must be tempered with caution. This was not a survey in any,: statistical sense and it i's therefore impossible to say that it does or does not represent the thinking of the entire medical community. But these replies clearly do show that a significantly large number of physicians are finding it difficult to live with the traditional ways of obtaining drug information. Much more can be done, Mr. Chairman. For example, medical centers could establish drug information centers, staffed on around-the-clock basis very much like the existing poison control centers, to provide rapid access and complete information on the use of drugs as well as on the handling of adverse reac- tions. The National Library of Medicine is now developing through the Lister Hill Biomedical Communications Center, a plan for a communications network that would put such information at the physician's fingertips. The potential of this program, not only as a source of up-to-date drug information, but as a mechanism for continuing education, must not be overlooked. In order to assess the impact of various kinds of information, programs of drug utilization review should be undertaken. These should help to identify thoughtless or harmful prescribing and to promote more rational therapeutic decisions. The Department of Health, Education, and Welfare, which already has a substantial stake in this problem, has not supported nearly enough re- search in the past, and to help remedy the situation I have established an Interdepartmental Committee on Drug Utilization Review. This committee will review and coordinate the Department's research efforts in this area. Education is important but it is not enough. Another basic essential is forceful but reasonable Federal drug regulation. Some in the medical profession, includ- ing those in academic medicine, have tended to disparage the Food and Drug Administration, and in the past, some of this may have been justified. Even today, despite the dramatic gains of the past few years, more remains to be done. Experience, some of it tragic, has made it very clear that the Food and Drug Administration needs to be strengthened in the public interest and for the benefit of the medical profession and the pharmaceutical industry. Critics of the FDA, friend and foe alike, agree that it needs a broadened scientific capability, that its scientific base is considerably less than that of the pharmaceutical industry it is charged to regulate. To meet this need, the Task Force has recommended establishment of a drug research center within the FDA which would provide additional opportunities within the agency for the kinds of drug research which underlie its regulatory mission. The Task Force has suggested in its Fifth Interim Report a number of examples of research that could be undertaken by such:a center. Education of the physician and the regulation of industry are but two ele- ments; the third is a far better understanding on the part of society of the principles and problems of medical therapy. I believe that one of the most effective means of achieving better public understanding has been Congressional hearings such as these. They have generated wide public in'terest and they PAGENO="0014" 4304 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY have provided a means of determining the extent to which those of us In public service are discharging our responsibilities with wisdom, integrity, and energy. I believe that Congress needs to be provided with greater staff resources and funds for special studies in order to fulfill its obligation to society. Legis- lation and appropriations are but two key Congressional functions. Oversight of the Executive Branch is of equal importance. Another essential for better public understanding is better public information. These hearings and the reports of the Task Force on Prescription Drugs have aroused considerable concern about the use and cost of prescription drugs, thanks to the efforts of but a few dedicated journalists. But these are matters which vitally affect all Americans and they deserve much broader public discussion. It is important for those outside of the medical profession to look Inside, at us. But it is equally important that we in the profession critically appraise our own activities and our own responsibilities. We should demand, for example, to know how much support our medical societies obtain from sources outside of the profession, particularly how much comes from the drug industry. We should be interested in knowing where the support for publication of drug studies comes from. Certainly every study done under a Federal grant is identified as such. Should we want to know less about funding of such studies by private sources? In conclusion, Mr. Chairman, I would like to state my conviction that the problems facing the medical profession in the use of prescription drugs must be solved by doctors themselves. We can benefit greatly from the attention that has been drawn to the problems of drugs in our society. But I doubt that any solution that comes from outside of the profession, or that lacks the understanding and support of physicians can produce the changes that are urgently needed in medical education, prescribing practices, and the protec- tion of the American people. But there is growing evidence thaf physicians-and medical students-are deeply concerned, and I expect that this concern will be evidenced in support of measures both public and private to help assure that the medical profession- not the makers and sellers of drugs-will retain its critical responsibilities in this area. Thank you, Mr. Chairman. Senator NELSON. I would like, at this time, to pay tribute to Dr. Lee. During his tenure of office with HEW he proved to be a very able and dedicated public servant. He will be sorely missed. We have had many occasions to call upon his services and he never failed to respond promptly and to cooperate fully. He has been present at a good many of our hearings, and his good counsel has added im- measurably to the study we are conducting. Our thanks and best wishes go with him as he undertakes his new duties. Today's witness will be Dr. W. J. Hagood of the Little Retreat Clinic in nearby Virginia. Dr. Hagood is in private practice and is one of several physicians who requested an opportunity to appear before the subcommittee. The Pharmaceutical Manufacturers Asso- ciation also asked us to extend an invitation to Dr. Hagood and we are happy to do so. We have a biographical sketch of Dr. Hagood which will be printed in the record prior to Dr. Hagood's statement. (The biographical sketch of Dr. Hagood follows:) BIoGR~uIcAL DATA Name: William Joseph Hagood, Jr. Born: Victoria, Virginia, January 6, 1918 Education: Harlan High School, Harlan, Kentucky Eastern State Teachers College, Richmond, Kentucky (Bachelor of Science) MedIcal College of Virginia, Richmond, Virginia (MD) 1943 PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4305 Fraternity: Phi Chi (Medical) Internship: Medical College of Virginia Private Practice: Associated with Dr. James D. Hagood and Dr. Warren C. Hagood in General Practice at the Little Retreat Clinic, Clover, Virginia Medical Activities: Member, Medical Society of Virginia, 1946- Member, American Medical Association,: 1946- Member, American Academy of General Practice, 1949- President, Halifax County Medical Society, 1949 Member, State Board of Medical Examiners, 1949-1954 Chief of Staff, Halifax Community Hospital, 1956 President, Virginia Academy of General Practice, 1961-1962 Special Consultant in General Practice to Medical College of Va., 1962- Member, Medical Education Advisory Committee of State Council of Higher Education, 1962 Alternate Delegate, American Academy of General Practice, 1962-1964 Delegate, American Academy of General Practice, 1963-1965 Member, Radiation Advisory Board, Virginia, 1965 Member, Advisory Committee on Regional Medical Programs, Va., 1966- Vice-Speaker, Congress of Delegates, American Academy of General Practice, 1965-1967 Speaker, Congress of Delegates, American Academy of General Practice, 1967- Civic Activities: Member, Lions Club President, Lions Club Zone Chairman, Lions International County Chairman, United Fund, Halifax County, Virginia Member, Parent's Advisory Committee, Bridgewater College, Bridgewater, Virginia, 1966-1968 Member, Executive Board of the Piedmont Area Council, Boy Scouts of America, 1967- Military Activities: Army of United States, Dec. 1943-March 1946 Battalion Surgeon, 84th Infantry *Campaigns: Rhinelandç Ardennes, Central Europe Decorations and Citations: Purple Heart, European African Middle Eastern Service Medal, Meritorious Service Unit Plaque, Bronze Star Medal, Com- bat Medical Badge, Rank, Captain. Hobbies: Raising roses, Writing, Public Speaking Religious Activities: Denomination, Southern Baptist Member, Clover Baptist Church Deacon, Clover Baptist Church Sunday School Teacher, 1950- Vice Moderator Dan River Baptist Association 1952 Moderator Dan River Baptist AssOciation, 1953-1954, 1956-1959 Member, Virginia Baptist General Board, 1957-1962 Member, Executive Committee, Virginia Baptist General Board 1957-1963 Chairman, Committee on New Baptist Building, Virginia Baptist Board, 1958-1962 Vice-President, Baptist General Association of Virginia, 1962-1963 President, Baptist General Association of Virginia, 1964-1965 Member, Committee on Boards, Southern Baptist Convention, 1963, 1968 Member, Faculty Christian Focus Week: Bluefield College, Virginia, 1961 Campbell College, Buies Creek, N. C., 1962 Chowan College, Murfreesboro, N. C., 1964-1966 Averette College, Danville, Va., 1967-1968 Married: Aileen Brilihart, Troutville, Virginia Children: Dianne 23, R.N., married Jon A. Lucy and living in Gloucester Point, Va. Nancy 21, Senior, Bridgewater College, Bridgewater, Virginia Jean 15, 9th Grade Mark 12, 7th Grade PAGENO="0016" 4306 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Doctor, you may proceed to present your state- ment in any fashion you see fit, either reading it or if at any time you wish to extemporize on any aspect of your statement, you are cer- tainly free to do so. Your statement will be printed in full in the record as well as whatever extemporaneous remarks you make. I trust you have no objection that if a question occurs to us from time to time during the course of your statement, we ask it. Dr. HAGOOD. No, sir. Senator NEI50N. Thank you, Dr. Hagood. We appreciate your tak- ing time from your busy practice to make your contribution toward these hearings we have been conducting for almost 2 years now. STATEMENT 01' DR. WILLIAM 3. HAGOOD, FR., PRIVATE PHYSICIAN, LITTLE RETREAT CLINIC, CLOVER, VA. Dr. HAGOOD. Thank you, Senator Nelson and Senator McIntyre. I appreciate very much the opportunity of you letting me appear before your subcommittee, and also I wish to thank you again for letting me change the date because of a conflict in schedule. I would like the record to state that I am appearing as a private citizen. This statement I make this morning is my own. I do not repre- sent any organization. I do not own any stock in any drug company. In fact I am not beholden to any drug company in any manner at all. I am William J. Hagood, Jr., M.D., of Clover, Va. I am a general practitioner, and while there are some people who would like to be- lieve that the GP has no business in the airy goings-on of political Washington, I think to the contrary we have something very impor- tant to contribute. I am grateful to you for letting me come, and I earnestly hope my being here will be helpful. I said I live in Clover. You can get there from here by going south 100 miles to Richmond, the site of the Medical College of Virginia. That is where I got my academic medical education the same years a certain nurse trained there who later married the distinguished chairman of this committee. From Richmond you turn south and west on Route 360 for another 100 miles; there you'll find Clover, a tobacco farming community, near Danville, in south-central Virginia. In Clover my uncle, Dr. J. D. Hagood, started the Little Retreat Clinic that has served that farming community for over four decades. I've been in practice there 23 years and now operate the clinic with my cousin, Dr. Warren C. Hagood, who has been there 15 years. We are, as I guess the foregoing suggests, small operators, if you compare us with some of the larger institutions that have presented their testimony here previously. We are professionals who continually strive to give the public in our area the best in medical care using as aids to accomplish this these two things-continuing education and the best of physical facilities. Our clinic is completely equipped for the type of service Warren and I wish to offer the public, and that is comprehensive and continu- ing medical care. We have modern X-ray equipment that we use care- fully and regularly. We have a. laboratory sufficient and adequate for our needs. My associate and I da.ily sta.ke our reputations on the results handed us by our laboratory technician. She does blood counts, throat and urine cultures, cholesterol and uric acid levels, et cetera. Warren and I have over 150 diabetics in our practice and this techni- PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4307 cian tells us what any given one's blood sugar level is 20 minutes after she takes the specimen. We have four identical and completely equipped examining rooms, with the best diagnostic aids available, down to the point of having pushbutton adjustable examining tables. A room has been set aside and especially equipped to test vision, hearing, and to do electrocardiograms. Another room is equipped with a hospital bed, oxygen, ultrasonic and diathermy equipment. Warren and I have some convictions that are evidenced by printed signs and lack of printed signs, that is, we have conspicuously posted "No Smoking" and there is a conspicuous absence of "Colored only" and "White only" signs. In all modesty, I doubt that many patients in large cities have more modern or comfortable or more effective medical care facilities than ours. You, Mr. Chairman, or anyone is welcome to inspect our clinic at any hour where Warren and I give daily a 24-hour service to our patients. `We have no medical specialists staffing our clinic. But we have, and we use, every necessary specialty in medicine available to us. In sur- rounding cities we can call upon urologists, orthopedists, psychiatrists, dermatologists when needed. We have surgeons, internists, obstetri- cians, gynecologists and a pediatrician at our community hospital just 17 miles away. And we use them. We have built up over the years, a good relationship with these people. Of course, our primary reason for doing this is about 15 percent of our patient's problems require services we are not trained to supply. A second, important reason for our regu- lar contact with them is that they teach us. They show us how we can better diagnose conditions we might otherwise miss or misidentify. They educate us to handle what we can handle and equally important, they help us to recognize situations we cannot adequately meet. A third reason is we teach them about our medical way of life. These three reasons mold both groups of physicians into a useful team whereby Warren and I can deliver comprehensive and continuing medical care. Essentially, then, what we have in Clover is a group practice with- out walls. We look isolated. We are not. As a matter of fact, we are very much in touch. Back in the days when artificial kidneys were experimental curiosities the life of one of our patients was threatened by a mounting potassium level in his bloodstream. Smith `Kline & French made a service item, an exChange resin, that would attack and reverse this lethal trend in our patient. Four hours and twenty minutes after a phone call to Smith Kline & French in Philadelphia this drug was delivered to the front door of the Halifax Community Hospital, South Boston, Va. The patient recovered thauks to the drug. The cost to the patient, nothing. This was a service item Smith Kline & French made available to the medical profession gratis. They didn't even ask for a report on the results of their drug. Unfortunately some of the witnesses who have testified before your committee have left the impression drug companies have doctors as prisoners. In my experience, it is the companies who are captives of the doctors. The drug companies do what doctors want them to do; and that is, doctors want good drugs, successful firms have produced them, and those pharmaceutical houses have been justly recognized for their performance by the repeated prescribing of their reliable drugs. To be sure, there have been drugs manufactured and marketed by reputable drug houses that were not what they had been represented 81-280-69--pt. il-2 PAGENO="0018" 4308 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY as being. Laws have been passed by the most reliable governmental deliberative body in the world, the Congress of the United States, and some of those laws were not what they had been represented as being. Fortunately, drug houses and Congress, each in its own time, have removed no good drugs and no good laws from the people. And I need not remind you of the time record or the batting average. My point is, both institutions are good but not perfect, and both need constant attention in order to get the desired results. Let me tell you what enters into my consideration in choosing a drug for my patient. To do so, I must again illustrate how unrealistic it is to pretend it is drug companies alone that make up my mind for me. Senator NELSON. May I interrupt for a second, Doctor. Dr. HAGOOD. Yes. Senator NELSON. I don't think we have had any testimony that I can recall before the committee that asserted that drug companies alone make up the minds of all doctors in prescribing the drugs. But the testimony has been that it is a variable situation in which some doctors rely much too heavily upon the advertising and the promotion of the companies. It has not been that we have had witnesses saying all doctors rely upon the drug companies to make up their minds. Dr. HAGOOD. It was my feeling that this was alluded to, as I read through some of the proceedings of this. For instance. On page 570 of the Nelson hearings there is a statement there by Dr. Cluff; on May 15, 1967, there was a statement by Dr. Holloman; Dr. Carstenson on May 17, 1967, made the statement that led me to make this state- ment. Dr. Modell in June 1967 and Dr. Magee on page 492 of the Nelson hearings, and these were the statements from which I drew this.1 Senator NELSON. Did any of those witnesses in their statements, state that drug companies are the only influence on doctors, for all doctors on all drugs that they prescribed. Dr. HAGOOD. To my knowledge they did not say that drug com- panies alone do this. Senator NELSON. That was the reason I was raising this. You see, so many of the medical publications, throwaways supported exclu- sively by' drug advertising, other publications supported heavily by drug advertising, would take excerpts from statements and then draw a broad conclusion from them which caused doctors to believe that witnesses before the committee, distinguished witnesses, were saying that all doctors are simply victims of the propaganda of the drug com- panies and all doctors rely solely upon drug company promotion `and advertising for `their prescribing practices. I am not aware of any testimony to that effect. Please go ahead. Dr. HAGOOD. I am, I suspect, no more an avid reader than most G-P's; that is to say I read, regularly and rather fully, two or three na- tional medical journals. In addition, I am active in my local and State medical societies. I am a member of the AMA. I belong to the Ameri- can Academy of General Practice. A look at any one of the dozens of programs of AAGP in promoting postgraduate education shows the 1 See hearings, "Competitive Problems in the Drug Industry"; testimony of: Dr. Clufl~, pt. 2, pp. 559H580; Dr. Holloman, pt. 1, pp. 4-54; Dr. Carstenson, pt. 1, pp. 228-2~7~ Dr. Modell, pt. 1, pp. 283-305; Dr. Magee, pt. 2, pp. 486-499. PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4309 extent of information offered me from that source. Indeed, member- ship in that association requires each meniJber to complete every 3 years 150 hours of approved postgraduate. education. The fact that over 31,000 general practitioners are part of AAGP shows we GP's are indeed interested in, and are obtaining, the professionally organized and administered postgraduate education some of your witnesses have in effect suggested does not go on. I am not operating in a vacuum, you see. In addition to all the more formal types of communication I've just touched upon I have the valuable, indeed, invaluable guidance of my fellow physicians. Everyone in the profession is informed speedily when a new pharma- ceutical becomes available, thanks in a large measure to efforts of drug companies who produce them. We all agree, certainly, not all new drugs are destined to become essentials of medicine. Personally, I would rarely want to have the distinction of being the first physician to use any new drug the day it reached the pharmacy; nor do I want to be the last. In deciding whether, and when, to try a new drug, I find it most helpful to have the advice of my professional friends. There are, of course, publications aimed at providing early guidance on the new drugs. The Medical Letter is a well-known source. I am proud today I am a charter subsCriber to that letter, and I still retain volume I, No. 1, in my office, near my desk and close at hand. I think of the letter as a source of useful opinion, and that is saying a great deal. But, at the same time, Mr. Chairman, it is no Bible, and its au- thors do not, I am sure, want anyone to think it is one. Many doctors consider the Medical Letter to be entirely too negative, if not nihilistic, and I think it does have a certain pontifical, academic ring about it. I am afraid doctors who spend their entire day seeing patients tend to be a little annoyed at what appears to be ivory tower pronounce- ments from on high. Senator NELSON. Could you tell me in what way-I am not a reader of the Medical Letter, of course-in what way it is negative or nihilistic. Dr. HAGOOD. Their conclusions are rather tersely drawn, and they are very forthright in saying that this is good, this is not good, and in doing this there is this feeling out in the practicing profession, there we use drugs and we know, to begin with, there is a large ele- ment of the placebo effect, for one instance. We also know that there are differences in patient reactions to drugs. In fact, in my own prac- tice I know that there are families, if you please, in which I can use certain drugs and that there, are other families that I cannot use these drugs, and this is one of the reasons for this. Someone in one of those families has had a reaction to a drug, and this becomes known in the family. So when the same condition comes up in another member of this family, and maybe this is a first drug of choice and I would like to prescribe this, and if I mention this drug, why they immediately say, "No, sir, Doctor, I am just not going to take this because this made my aunt so sick we thought she was going to die," or she had a rash or something of that sort.: As a result, why, we use another drug or fortunately we have other' drugs that we can use. Nevertheless, as you read the Medical Letter you find that this thing is somewhat cut and,dried. PAGENO="0020" 4310 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY As I said, I read this letter, I take this into my consideration, but again I have to make my own decisions based upon the situation as it arises daily in my office. Senator NELSON. Thank you. Dr. HAG0OD. May I proceed? Senator NELSON. Yes, sir. Dr. IJAGOOD. I suspect they are not entirely unique in this regard; 1 imagine practical politicians feel the same way toward those proud theoreticians of political science who make profound analyses of poli- tics but who have never actually taken the risk of running for office. What I am saying, gentlemen, is there is a whole ranges of sources of information, impressions, and advice operating side by side with commercial sources. To pretend the doctor has only drug companies' opinions to look at is to ignore reality. The fact is we have a great many coiumunication channels, all of them of value, and none of them unleavened by others. So long as drug therapy is heavily sub- ject to professional judgment rather than solely to hard science, this multichannel approach will be the best one overall. The last thing we need now and in the future is a monolithic concept of therapy, which says this drug, in this patient, in this dosage, is the alpha and the omega of therapy. That approach, I am positive, has no basis in either medicine or science. Senator Nr1~soN. May I interrupt for a moment? Dr. HAGOOD. Yes, sir. Senator NELSON. I don't think anybody before this committee has suggested one monolithic approach. Do you know of any? Dr. HAGOOD. No; I do not and I certainly hope its does not arise. Senator NELSON. Thank you. Dr. HAGOOD. This leads me-may I proceed? Senator NELSON. Yes, sir. Dr. HAGOOD. This leads me to comment on the concept of a single drug compendium, that has been discussed before this Subcommittee. \Ve have, of course, the Physicians' Desk Reference, and I must say that book, as good as it is, is becoming a bit large for my desk. It is not perfect, but I find it outrageous it is condenmed because it is "just advertising" as some have said. Of course, the material in it is paid for by drug companies. But what of that? Currently, meaning 1969, isn't every syllable in it written in conformance with labeling require- ments of the Food and Drug Administration? Where can you show me evidence entries violate FDA-approved descriptions of drugs? Surely, if any do, FDA has ample power to correct the matter. But on what basis is the PDR to be brushed aside? Gentlemen, I am not here to glorify that book, or any other. But I will tell you this; the current edition of PDIR has an estimated circula- tion of 450,000. That is 318,500 more than the combined estimated circulation of this country's three official compendia of standards; U.S. Pharmacopeia, National Formulary, and Homeopathic Pharmacopeia of the United States. That book, the PDIR, is one doctors use more than any other. Take that one away, and you will have removed a working reference. Is it inadequate? Fix it. Is it incomplete? Expand it. But look at it. It now contains entries on nearly 2,600 drugs. It is now 1,415 pages long, 2 inches thick, and weighs 3 pounds, Di/2 ounces. Yes, I weighed the 23d edition on my baby scales when it was delivered PAGENO="0021" COMPETITIVE PROBLEMS IN: THE DRUG INDUSTRY 4311 to my office January 19. Fortunately, the PDR won't triple its weight this year, as does a newborn its first year of life, but the book will add three-quarters of a round during the year as the four quarterly sup- plements are glued in. The prospect of one immense book that fully describes all drugs in PDR plus several thousands of others is not attractive to me in the least. Such a book may be an interest to some- body; but not to me. I am a practicing physician, not a librarian. I need to know a great deal about less than a hundred drugs, not 2,000, as there are now in PD1R, and certainly not the 6,000 of 7,000 that would be found in an encyclopedia of the sort being described. Unless you make your compendium more valuable and practical than the PDR, your compendium will be replaced by a private tome that does this. So you are asking for competition now. Maybe your compendium will force the PDR to, become even better. I say this be- cause in the day-to-day active medical practice the doctor wants cor- rect, practical information that ~S concisely stated. And please-no fine print because one can't underline passages that need emphasis without blotting out print. You may force the physician to keep a copy of your compendium in his office, but you will never force him to use it unless it fits his needs better than other available sources. The sine qua non your new book must offer, practicability in practice. My final note on the compendium is-I don't know what you will have published, but you must leave the ultimate choice of the drug, the dose of the drug, and the source of the drug to the; physician who is charged morally, ethically, professionally, and legally to treat the patient. If he assumes the full responsibility of treating; any patient he must be free to pre- scribe the drug he wants. Senator NELSON. May I interrupt a moment there, Doctor? Dr. HAGOOD. Yes, sir. Senator NELSON. So far as I know, no witness before this coimnittee has suggested that the ultimate choice of the drug not be left to the physician. What puzzles me is that we have had several witnesses who put in this sentence which to me leaves the implication that somebody before this committee, or the committee itself, is suggesting that the responsibility for prescribing a drug be taken away from the physi- cian. There has been no such testimony before this committee, and it has not been the position of anybOdy on this committee. Dr. HAGOOD. I said this for emphasis, Senator Nelson, because I certainly hope this would never be given any serious consideration before this committee. This is a thing that must remain with the physician. Senator NELSON. We have not, as I said, heard any testimony to this effect. The Pharmaceutical Manufacturers Association in some of its propaganda has left that im~ilication, because I received a number of letters from practicing physicians who raised the same point. I just wanted to assure you that nobody before this committee has made that suggestion, and nobody on the committee has made that suggestion. Dr. HAGOOD. Thank you. May I proceed? Senator NELSON. Yes, sir. Dr. HAGOOD. Mr. Chairman, I have related in brief some of the more formal influences upon my prescribing practices. Now if I may, I should like to relate some other, secondary but real factors no physi- cian concerned about medicine and people over the long range can corn- PAGENO="0022" 4312 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY pletely ignore. These influences are somewhat analogous to a precinct, county, or township that repeatedly delivers the vote. About 13 years ago a 3-year-old child was brought to me, the daugh- ter of a man I know who farms near Clover, and who has a good old- fashioned farming family-a large one. This little girl had a sore ankle. We puzzled over it for a few minutes; it is not unusual to find the young child in a large family is more used to listening than talk- ing, and this one was one of those who wouldn't say much about her problems. The thought struck me she might have an early case of osteo- myelitis. I X-rayed the leg, did other tests and soon determined she did indeed have an infected bone. I put her on a drug called Signemycin.1 Now it is important in acute osteomyelitis to begin treatment promptly with an effective drug, prescribed in adequate dose and con- tinued past the point of clinical healing. The infection is found in the bone and if unchecked, it spreads quickly, killing bone tissue as it pro- ceeds, causing immense pain, leaving wrecked bones and destroyed joints in its wake. I had some Signemycin in the office, and I gave what I had to the child. I wrote her a prescription for some more. Knowing her family's situation, I felt sure between cost of raising six other children and problems they were having with their farm, they would be hard put to bear the cost of this necessary cost of therapy. Wben the detail man from J. B. Roerig and Co. came around, I ex- plained the problem to him. I made it clear, eventually, this farmer would pay for the drug, but right now it would be difficult. I asked him if he could do something for this child. As it turned out. Roerig supplied gratis the entire amount estimated to retail at $350.00. That was a lot of money 13 years ago. Fortunately. the little girl responded beautifully. I have a whole series of X-rays that show the gradual regression of the infection. I would like to show you the child now; she is now 16 and she has an interest in miniskirts, but for this experience, she might not other- wise have. Gentlemen, I will not ignore memories like that, and I hope you don't think I should. When I began practice 25 years ago, chronic osteornyelitis was fairly common. The resultant death of bone, t.he painful involvement and destruction of joints, the formation of large quantities of pus, and the unpleasant outlook all made for an exceptionally ugly situation. The antibiotic era has made chronic osteomyelitis an uncommon disease; it has the prompt and effective cure of acute osteomyelitis almost routine. I can't forget things like that. Call it hearts and flowers if you wish. It is human to thank, and I thank the drug companies that discover these drugs. I am even more appreciative to find when the situation warrants, the best of them are more than willing to provide their prod- ucts at a loss. This is responsible behavior, and it goes unheralded, ex- cept, of course. by the patient who benefits from it. Another hind of example I mention is Aureomycin, made by Lederle Laboratories, the first tetracycline. I remember two things in particular about Aureomycin. The first., it caused a lot of my patients to vomit; and, it cost wholesale $1.50 per capsule when it was first introduced. 1 See App. III, pp. 4795-4799. infra, with reference to Signemycin. PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4313 Whether there was a causal relationship between these two points I leave to your judgment. I used to tell my patients every time they failed to keep one down they were throwing $1.50 in the basin, that helped them keep it down. Anyway, it wasn't long before the drug firms manipulated the tetra- cycline molecule and other tetracyclines came along. They corrected the two objections; very few people vomit the newer ones, and, through competition, the price is down to less than a tenth of what it was. Senator NELSON. May I interrupt a moment? Dr. HAGOOD. Yes, sir. Senator NELSON. You see, this committee has been conducting hear- ings about what we consider to be some problems that need public discussion involving the drug industry and the medical journals and profession. The committee has not, of course, at any time taken the position that the drug industry has not made a great contribution to medicine. I think everybody on the committee, I think every witness we have had for 2 years, is willing to concede that the drug industry has made a great contribution to medicine, and that it is a very imporLant industry. But any time hearings are conducted involving an industry, the position of the industry usually is "we have done great things you aren't giving us credit for and you shouldn't expose to public view critical aspects." This happened to me when I introduced the tire and automotive safety legislation. The auto companies and others attacked me as criticizing a great industry. It is a great industry and we were criticizing it because the tire companies and auto companies were put- ting purposely, knowingly, rather unsafe tires on the highway, and still are. So the fact that we raise these questions about some practices that we consider improper does not mean we are making a general indictment of the drug industry.; We have raised questions on pricing practices which the industry can't answer. You mention on page 10 of your statement: I am even more appreciative to find when the situation warrants, the best of them are more than willing to provide their products at a loss. Then you mention tetracycline on page 11. I assume you are aware that Pfizer, Lederle, Bristol, Squibb, and Upjohn were found guilty in a criminal case of conspiring to fix prices, and that they just made an offer of settlement, a free offer of their own, of settlement of $120 million to the people they cheated for ten years. Itwas a criminal conspiracy; it was cheating. They were gouging the public and, of course, they could afford to give any doctor who asked for it for a patient, such as yours, free tetracycline because they were cheating the people so badly that it didn't cost them any- thing. This is the kind of thing that we have been exposing. I don't think you, or even the drug companies themselves, could defend price- fixing and price-gouging of the public, could you? Dr. HAGOOD. Senator Nelson, may I go back for just a moment there? I read this piece in the paper you are referring to now, I guess it is 2 weeks or something ago. It was not my impression from the re- lease that I read that these people had been found guilty of this. They had offered to set aside $120 million of dollars to pay off any claims that may be forthcoming by the 6th of March in this situation but it PAGENO="0024" 4314 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY was not my understanding that they had been proven guilty of this, and that they had purposely and willfully cheated. Senator NELSON. That was the finding, December 1967, guilty of criminal conspiracy to fix prices. Guilty on three counts. It was a jury trial. This isn't the only one, hut they were found guilty. This is the point I would like to make with you, Doctor. This corn- mittee is conducting hearings on practices which we think, as they evolve, are inexcusable and the public is entitled to know them. That doesn't mean that a company doesn't also do some good research, but the posture taken by the Pharmaceutical Manufacturers Association in the propaganda they spread so effectively because they have vast amounts of money to do it, is that this committee is making a general indictment of doctors, a general indictment of the medical profession, a general indictment of the medical journals. That is not the case at all. We are raising those questions in those areas where there is an important public issue, and whereas a company is entitled to credit for research and healthful discoveries, they are entitled and should receive criticism when they gouge the public, and that is what these hearings are all about. Thank you. Dr. HAGOOD. Now that I have used the words Signemycin and tetra- cycline I wifi express myself on the subject of generic versus brand name. I will continue to prescribe brand name drugs until I can be assured a generic drug is as effective, no more toxic, as convenient to give and is cheaper than the brand name drug. And these assurances must be present batch after batch after batch. Furthermore, I prefer these assurances be arrived at by a nongovernmental source or a source com- posed of representatives from the medical profession, the pharmaceu- tical industry and the Federal Government. As far as price is concerned I am not knowledgeable enough to make a firm statement other than to say I don't believe you are going to set a price that will produce more than ephemeral satisfaction to the pub- lic. Doctors, hospitals, and drugstores have always been targets of dissent and they always will be because they represent sickness, bad health, unhappiness-something no one wants. True-many patients are grateful and probably the majority are at times. Nevertheless, nobody cares to be associated with any part of the medical profession any longer than absolutely necessary. Yet, when they are involved with the medical profession they expect good results. And results leads to the much discussed subject of equivalency. To me, equivalency boils down to who is involved. If the drug is made by what I consider a reputable drug house I will accept it. If it is made by a drug firm unfamiliar to me but vouched for by my local pharma- cist I have known for 15 years I wifi give it serious consideration, then decide whether I will accept it. The third point on generic versus brand name drugs concerns the flame of the drug. I would prefer to reduce confusion of drug names so a specific drug is known by the same name with the drug manufac- turer's name following it. This suggestion opens up discussion for many other problems, such as, patent rights, royalties, profits, et cetera. And again, I am not knowledgeable in these areas-but would it be reasonable to allow the initial manufacturer to name the drug with PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4315 the approval of the organization that inspects his facilities and ascer- tains his quality control is what it should be?' Senator NELSON. Let me say, Doctor, that is a proposal that other distinguished witnesses made as a suggestion to the committee. We have introduced legislation to that effect, and I think every dis- tinguished person from the medical or pharmacy field who has appeared before the committee endorses this concept as suggested by you. I suspect that the drug companies will oppose it, but because brand name domination of the marketplace is their method of extend- ing the patent long beyond the time a patent expired, but I think good prescribing practices according to professional witnesses before the committee would support the concept you suggest here. Dr. HA000D. Thereafter, other firms manufacturing this drug would use this approved name followed by the~ secondary manu- facturer's name. This would serve as an incentive to research. I realize this may well give the primary manufacturer a sales advantage which could be offset by changing the 17-year patent rights period. Regardless of what is done this section of our incomparable free enterprise system, the drug industry, must be protected, preserved and promoted; else a disservice will have been done not only to Americans but the entire population of this globe. Finally, let me say a word about promotional efforts of drug firms, which are, I am told, very costly, and which, no doubt, involve a degree of waste. I have every confidence in the earnestness of those who would reduce the cost of drugs by reducing this effort, but here again, as with the PDR, we have an established tool, the detail man, who in my opinion is not as effective as he could be. In 1964 I had the privilege of addressing the public relations sec- tion of the Pharmaceutical Manufacturers Association. At that time I said the caliber of a physician's practice of medicine will be no larger than his continuing education effort. Time is limited. There- fore, every learning tool and every avenue through which learning can be projected must be large caliber to be effective. Please, don't send out any small bore detail men. I still believe the detail man has a minor but important place in the well balanced continuing education program of the practicing physician. Those detail men I spend time with bring information about drugs-sometimes new drugs of major import, sometimes ones I will elect to forget, and he brings it in person. So I can challenge him and his company. So I can ask for and receive additional infor- mation, quickly. I don't know whether elimination of detail men would bring a significant reduction in drug cost, but I do know it I Dr. Hagood subsequently submitted the following: "On transcript page 5567, Senator Nelson interrupted, then stated my, point `had been made in several previous `testimonies. He was referring to my statement: I'd prefer to reduce confusion of drug names so a specific drug is known by the same name with the drug manufacturer's name following it. And that's true. However, I don't believe I made my innovation, to this often repeated point, clear to the Senator. The innovation is this: allow the initial manufacturer to name the drug with the approval of the organization that inspects his facilities and ascertains `his quality control is what it should be. An example of this innovation, follows. "Ciba discovers a drug `that will cure hemophilia. Ciba consults with the organization that inspects Ciba's manufacturing process of the drug and they agree to name the drug Hemophiliam. Thereafter, the drug is officially called Hemophiliam wi'th Ciba's name following-thun-He'mophiliam Ciba. Under the current patent laws Ciba would be the sole producer of this drug for 17 years. At the expiration of the 17 years other companies could produce the drug. However, the drug would be called Hemophiliam and~ the secondary manufacturer's name would follow the drug name. Now the drug could be prescribed Hemophiliam Ciba, Hemophiliam Lilly, Hemophiliam Abbott, etc." PAGENO="0026" 4316 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY would be a costly step in terms of the loss of communication. Inci- dentally, I doubt that elimination of the detail man would reduce cost of drugs to patients as much as the cost of merchandise to all Americans would be reduced if there could be a 50-percent reduction in shoplifting. Senator NELSON. May I interrupt again, Doctor? Dr. HAGOOD. Yes, sir. Senator NELSON. We have here a bit of conflicting testimony on detail men, although I would guess from memory that most witnesses have taken the position you have, critical of detail men and some have testified that they made a valuable contribution. I notice in the Virginia Medical Monthly, volume 94 of February 1967 on page 113, in an article' written by you, you stated that: If the ideal detail man exists he is clearly outnumbered by his imperfect brethren who reportedly interrupt the office routine, parrot stereotyped encomiums, hawk their wares in a truculent manner and talk without listen- ing. This confrontation destroys one thing the physicians want, an opportunity to learn valuable information. Dr. HAGOOD. What you have said exists in that paper but this is not the entire story there. I am searching here for the-there were other statements in there. In fact 80 percent of the group of people that I interviewed by questionnaire felt very kindly toward the detail man. They wanted to see him continued. Many of them said that his service could be improved, but to say this was a typical state- ment that has been made by the group is not entirely accurate. Senator NELSON. I was not trying to suggest that. I was quoting your statement, not the statement of the people you polled. This was a quotation, as I understand it, from your article. It is on page 113 in an article written by you and John 0. Owen, Jr., of Charlottesville. In the right-hand column, the bottom one third, this is on page 113. This is a statement which I assume you and Dr. Owen agreed upon in evaluating the detail man. Dr. HAGOOD. This, I must accept the responsibility for, because my name is attached to this. I would say this simply in the way of explanation, that the writing of this was largely done by Dr. Owen because at that time I was engaged in some other activities, and I simply said to him, "Jolm, if you write this you will have to do it yourself because I am busy at this time." He did send me copies of this for my comments and any corrections, and I must say that this statement here does not now reflect my feeling toward this. Had I, if I had my druthers, I would have done it differently, but neverthe- less I wrote it, my name is signed to this. I will have to accept responsibility, but I `feel differently. Mr. GORDON. Dr. Hagood- Dr. HAGOOD. Yes, Mr. Gordon. Mr. GORDON (continuing). I notice you quoted a figure of 85 per- cent of the rural physicians giving the detail man a strong vote of confidence. Now, in the same paper that the Chairman was discussing we are coming now to the younger doctors, 37.5 percent of the residents, had unfavorable opinions of detail men, and only 3 percent were fav- orable, and about 60 percent neutral. 1See app. I beginning at p. 4789, infra. PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4317 in your survey of residents, interns and students only 9 percent of respondents were favorably disposed to the advertisements of the drug industry and 52 percent expressed gross dissatisfaction with advertisements. Dr. HA000D. Mr. Gordon, let me explain, this paper is written from questionnaires, two questionnaires. One, the general practitioner, myself, sent out to a group of 200 rural general practitioners. A separate questionnaire, made by Dr. Owen, was circulated among the house staff and the medical students of the University of Virginia, and this is his portion of this paper there. Mr. GORDON. But it is rather interesting to see how the rural practitioner differs from those at the university, the "Town and Gown" as you have named the article, the great disparity, the great difference in attitude toward the detail man. Would you say it is rather interesting? Dr. HAGOOD. This is certainly interesting. I would think that the comment in the first paragraph of the coiument should be brought out here, which says "it would be imprudent to attempt multiple interpretations of the responses to two different questionnaires dis- tributed to two different and heterogeneous groups with such a variable percentage of replies." Senator NELSON. Fine, Doctor. Go ahead. You were at the top of page 14. Dr. HA000D. Yes. We must be realistic in viewing this form of communication. Obviously his basic function is to sell. Obviously he is not there to extol the competition's product any more than one would expect Republicans or Democrats to praise the opposition. The doctor isn't so foolish as to assume such things, and because of that the detail man is identified in the physician's mind as a biased, albeit honest, source. To be successful, the detail man must appreciate the fact he is seen with a bit of doubt, and he must therefore, if anything, be overly conscious of the need for honesty. A show of ignorance, of deception or fraud, and he may permanently damage his company in the doctor's view; and he certainly will be making his last visit to my office. Going back to the 1964 talk I made to PMA people, I told them 80 percent of doctors practicing in rural areas in Virginia answering my questionnaire said they favored continuing use of detail men by drug companies. That questionnaire was mailed to 200 doctors in rural settings in Virginia. I received returns from 80 doctors in 55 counties, who had practiced medicine from three to 61 years in corn- munities, varying in size from open rural country to a town of 4,200. in general, I believe drug company promotions, and their repre- sentatives, are both helpful and reliable. Imperfect, of course. But their function is not withOut real value, and I know of no workable or less costly alternates. Lacking better substitutes, I suggest we concentrate on improving them, rather than deploring them. Mr. Chairman, again I thank you for allowing me, a general prac- titioner from rural Virginia, to tell you my views on some of the knotty problems facing this committee. I earnestly suggest you hear more from practicing physicians from all over America. By practicing physicians I mean those who make their living daily by fee for service. That is where the action is. The National Center for Health PAGENO="0028" 4318 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Studies said during the 1-year period from July 1966 to June 1967, an estimated 71.8 percent of all physician visits took place in the physician's office. This figure is growing because this represented an increase of 10 percent over the 1957-58 study year. A further breakdown of NCHS figures shows general practitioners accounted for 64 percent of office visits and 85 percent of house calls. Patient visits to all physicians totaled 831.1 million. That many millions of visits to doctors doesn't impress one until it is related to a concern of this committee. Mr. Chairman, every one of those visits to a physician represents at least one prescription writ- ten or reffiled. And that means if all these prescriptions were written at once and distributed to the population of these United States each man, woman, and child would each have four prescriptions in their hand. Senator NELSON. Are you saying there that every patient receives a prescription for a drug? Dr. 1HIAGOOD. I am saying this represents a prescription or a refill prescription. This is my assumption. Senator NELSON. That everybody who visits a doctor gets a pre- scription for a drug or a reffil. Dr. BIAGOOD. No, I was trying to relate this figure to something that was of concern to this committee, so that I simply used this to empha- size the number of patient visits to doctors throughout this country. Senator NELSON. But you weren't saying that every patient who comes to your office gets prescribed a drug? Dr. BIAGOOD. No, I was not saying that. Senator NELSON. I want to thank you very much, Doctor, a.gain for taking the time from your busy practice to come here. Just so that you won't have any misunderstanding about how this committee is proceeding, we have made it clear from the first day that, on every issue raised of any consequence before the committee, that the committee would invite the viewpoint, every viewpoint, as to that issue raised. That is what we have been following. A number of times the PMA has made attacks on the committee saying the witnesses are handpicked, the committee is unfair, the viewpoints aren't being heard, and that is a gross misrepresentation. It shocks me to see how often the PMA representing this great distinguished industry would intentionally propagandize in this fashion. Our position has been that first preference goes to the drug com- panies on any issue raised which concerns them. We have invited every drug manufacturer in America, publicly several times, to appear be- fore this committee on any aspect of these hearings they wished. Very few of them have volimteered. We have invited them all repeatedly. We have invited every company who is criticized before this com- mittee, immediately, as soon as we could arrange it, to have an oppor- tunity to appear to discuss the criticism that is made of them. I don't see how we could be more fair than that. We have made it clear that we will hear the viewpoints of all med- ical organizations in this country, and including the Academy of Gen- eral Practitioners because I happen to think it is a. very important as- pect of the practice of medicine in this country. You may be assured there is not a single viewpoint group of any significance at all that won't be amply heard. If they think that the PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4319 time assigned to them isn't adequate we will welcome them back again. We are inviting them all. We have been attacked because some of them haven't been invited before others. But if we are going to hear wit- nesses over a period of 2, 3, 4 years, as I am sure you appreciate, you can't hear them all at once. You have to hear them in some order or another. But I want you to leave here knowing that the general practitioners are going to be amply heard, including the American Academy of General Practitioners, all other majOr medical organizations, and any distinguished individuals who have something to contribute to it, as well as the PMA, which we have already heard, and have told they can come back again. I want to assure you that the hearings here are not stacked in any way. There are now nine volumes printed, and any organization that has been involved, any medical organization, any medical journal, any industry, any company or any individual can read those hearings and if they wish to respond to something on it they can send in their state- ment on it or they can ask for hearing time and in due time they will be heard, so these will be balanced hearings, and that is one of the rea- sons you are here today. Dr. HAGOOD. Thank you, sir. Senator NELSON. Thank you very much, Doctor. Counsel had one question on the advertising of the drug companies. Mr. Goi~uoN. In your statement, on page 14, you stated: "A show of ignorance, of deception or fraud, and he may per- manently damage his company in the doctor's view; and he certainly will be making his last visit to my office." You are referring to detail men here. In an article' by Dr. Gourley of the University of Virginia entitled "Teaching the Evaluation of Drug Advertising to Medical Students," which appeared in the Virginia Medical Monthly in August of 1966, we find that students were particularly impressed with the number of quoted references which were not available even in a good medical library- Senator NELSON. Was this in the advertising? Mr. GORDON. The advertising, yes. But when they really got around to looking into it, they found that they couldn't even find 95 percent of the references. Now, how is the practicing physician going to know whether he is really being had or whether they are proper references when he sees this advertising or even when a detail man gives you a whole line of references. Dr. HA000D. Mr. Gordon, the only way I can answer this is from a personal standpoint. Advertising in itself means very little to me, and as far as checking on the references that are quoted in the advertising material, I don't recall ever once looking into this because I use other sources from which I have fOrmed my opinion, and, of course, I have stated those in my statement here. Senator NELSON. Again, thank you very much, Doctor, we appre- ciate your taking time to come here. Senator McIntyre. Senator MCINTYRE. Thank you. ~ See app. II beginning at p. 4793, Infra. PAGENO="0030" 4320 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY I just want to say, Doctor, I read your statement last night and Ii found it to be most readable and I consider it an excellent statement. overall. I am not sure that you are representative of the average doc- tor, but I certainly was impressed with it as a probative argument. I think tha.t your decision to enter in the medical profession was probably a loss that the legal profession had to sustain. Thank you very much. Dr. HAGOOD. Thank you, Senator, you are most kind. I would like to make a statement if I might, please, sir. Senator NELSON. Yes. Dr. HAGOOD. First of all, I want to thank you for the opportunity of coming before this group. To me this represents, and this gives very positive evidence of, the great country that we have here. That an individual from a little hamlet in our country can come before a corn- mitte~e of the Senate of the United States of America and state his views. I thank you very much for this. Senator NELsoN. Thank you, too, Doctor. I think, it being my experi- ence in committees of Congress, that almost all chairmen, given tha time, are willing to hear all the viewpoints and try to get all the view- points although sometimes some people around the country have an impression we don't. But again thank you very much. Dr. HAGOOD. Thank you. (Whereupon, at 11:10 a.m., the committee was adjourned, to recon~ vene at 10 a.rn., Thursday, February 20,1968.) PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, FEBRUARY 20, 1969 11.5. SENATE, MONOPOLY Strl300MMIrrEE OF THE SELECT `COMMIrEEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to notice, at 10:10 a.m., in the Cau- cus Room, Old Senate Office Building, Senator Gaylord Nelson (chair- man of the subcommittee) presiding. Present: Senator Nelson. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist Jay Cutler, acting minority coun- sel; and Elaine C. Dye, clerical assistant. Senator NELSON. Our witness this morning is Dr. Robert Moser, chief, Department of Medicine, Walter Reed General Hospital. Doctor, the committee is very pleased to have you come and present your testimony this morning. You have submitted your biographical background, which will be printed in the record. (The biographical sketch of Dr. Moser follows:) CURRICULUM VITAE, ROBERT H. MOSER, COLONEL, MO, USA Born: Trenton, N. J., 16 June 1923. Married to former Stella Neeson~ - 2 sons: Steven, age 19'; Jonathan, age 16 College: Loyola College of Baltimore, 1940-1942 Villanova College, 1942-1943 (B.S.) Medical School: Georgetown University, 1944-1948 (M.D.) Internship: District of Columbia General Hospital, 1948-1949 Residency: Internal Medicine; Fellow in Pulmonary Disease, D.C. General Hosptal, (Dr. Sol Katz) 1949-1950 Assistant Resident, Georgetown University Hospital, 1952-1953 Resident in Cardiology, Brooke General Hospital (with Colonel Weldon Walker), 1956-1957 Associate Professor of Medicine, Baylor University College of Medicine, 1958-1959 Fellow in Hematology, Salt Lake City Hospital (with Dr. Maxwell M. Win- trobe), 1959-19~30 Military: U.S. Navy, December 1943-July 1948 U.S. Army, July 1948 until present Chief, Department of Medicine, U.S. Army Hospital, Salzburg, Austria, 1953-1955 Chief, Department of Medicine, U.S. Army Hospital, Wurzburg, Germany, 1955-1956 Physician to the American Delegation "Foreign Ministers Meeting," Geneva, 1956 4321 PAGENO="0032" 4322 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Assistant Chief, Department of Medicine, and Director of Education, Brooke General Hospital, 1957-1959 Assistant Chief, Department of Medicine, and Director of Education, U.S. Army Tripler General Hospital, 1960-1964 Medical Flight Control Team-"Project Mercury"-participating in all suborbital and orbital missions, May 1959 until termination of program Command and General Staff College-1964 (Fall Associate Course) Chief, Department of Medicine, William Beaumont General Hospital, Jan- uary 1965-June 1967 Chief, Department of Medicine, Brooke General Hospital, June 1967-July 1968 Chief, Department of Medicine, Walter Reed General Hospital, July 1968- Certiflcation-s: Certified in Internal i~Iedicine, 1955. Organization~s.~ (1) American Medical Association (2) Fellow, American College of Physicians, 1961- (3) American Therapeutic Society, 1964- (4) Assn. Mil. Phys. 1966- (5) Bexar County Medical Society 1968 Journal Activities: Book reviewer for Military Medicine, 1960- Author of monthly column, "Diseases of Medical Progress" for "Clinical Pharmacology & Therapeutics" Journal 1962- Author of monthly column "Of Tomes and Tangents" for "Medical Opinion & Review" Journal-July 1966- Contributing Editor-"Medical Opinion & Review" 1966- Editorial Board-"Mffltary Medicine", Jan. 1967- Book Review Editor (Editorial Board)-"Archives of Internal Medicine." `Jan 1967- Author of bi-monthly column "The Training Scene" for "The House Physi- cian Reporter", Sep 1967- Consulting Editor of the Medical Annals of the District of Columbia Oct 68- Committees: (1) Consultant In Internal Medicine to Queen's Hospital, Honolulu, 1960- 1964 (2) Member, Advisory Panel of the Registry of Adverse Reactions, Council on Drugs, AMA, 1960-1967 (3) Consultant to AMA Council on Drugs publication "New Drugs," 1966- 1967 (4) Consultant in Internal Medicine to "Medical Tribune," 1966 (5) Consultant in Internal Medicine to Manned Spacecraft Center, Project Gemini, NASA and Member of Medical Evaluation Team, Project Gem- ini-1964 until completion of project (6) Consultant in Internal Medicine to Manned Spacecraft Center, Apollo Project-1967- (7) Appointed to AMA Council on Drugs, March 1968 (8) Appointed to Editorial Board, Medical Opinion & Review, April 1968 (9) Appointed Editor of American Lecture Series in Medical Writing and Communication, Chas. C. Thomas Pub. Co., 1969 Teaching Aj~Uiatian~s: Associate Professor, Baylor University College of Medicine, 1957-1959 Clinical Professor-Georgetown Univ Sch of Med 1968- PuBLIcATIoNs 1. Diseases of Medical Progress, 0. S. Thomas & Co., Springfield, 1960. 2. Diseases of Medical Progress, 2nd Ed., Edited by Col. R. H. Moser and 12 co-authors. C. S. Thomas & Co., Springfield, 1964. 3. "Steroid-Induced Adrenal Insufficiency Aggravated by Severe Medical ill- ness," Amer. J. Med. Sci., 239, Mar 1960. 4. "Back Door" Digitalis Intoxication: Review and Report of a Case, U.S. Armed Forces Med. J. 11:391-402, Apr 1960. 5. "Renal Biopsy" 11:307-317, U.S. Armed Forces Med. J., Mar 1960. 6. "Malignant Carcinoid: Report of a Case Confined by Percutaneous Hepatic Biopsy," Texas State J. Med., (Jul) 1960. 7. "An Atlas of Sternheimer-Malbin Staining Technique in Examination of Urinary Sediments" What's New 218 (Summer) 1960 and 226 (Oct-Nov). PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4323 8. "Diseases of Medical Progress-Report", Olin. Pharm. & Ther. 2:446-522, (Jan) 1961. 9. "The Man in the Loop" Hawaii Med. J. 23 :109-113, (Nov-Dee) 1963 (Editorial) 10. "On Speaking to Patients," Ann. Tnt. Med. 51, (Sept) 1964. 11. "Congenital Inclusion Body Hemolytie Anemia Associated with Epilepsy and Disordered Pyridoxine Metabolism," Blood 24, (Aug) 1964. 12. * "Of Plagues and Pennants," Mu. Rev.! 45:71-84 (May) 1965. 13. "Are Drug Hazards Overstressed," Issues 1 :1-14, (Dee) 1964. 14. "Man in Space," Southwestern Med. 1:45-48 (Feb) 1966. 15. "Hypertension and Hypercalcemia," Ann. Tnt. Med. 64:378-381, 1966. (co-author) 16. "Malaria," Southwestern Med. 47 :213-219 (Aug) 1966. 17. "The Modern Aspect of Leprosy," Texas Medicine J. (Aug) 1966. 18. "Non-Spherocytic Hemolytic Ane'mia in Pyruvic Kinase Deficient Erythro- cytes" (co-author) pending publication. 19. "Percutaneous Renal Biopsy in Chimpanzees" Am. J. Vet. Res. VoL 28, No. 126, 1631-1634, Sep 1967 (co-author) 20. "Evidence for a Reservoir of Red Blood Cells in Man" by M. C. Nusynowitz, R. L. North, R. H. Moser (submitted to J. Olin. Invest.) 21. "To the Physician-Soldier"-commencement address to Medical Field Serv- ice School, August 1967. 22. Diseases of Medical Progress, 3rd Ed. Edited by Col R. H. Moser and 12 co-authors. 0. S. Thomas & Co., Springfield (pending publication) 2~J. Urinary Sediment Handbook, Clay-Adams, Inc., September 1968. 24. "latrogenic Disorders" Medical College of Virginia Quarterly 3(2) :91-100, 1967. 25. "ATP Metabolism in Pyruvate Kinase Deficient Erythrocytes" by Jeremiah J. Twomey, Floyd B. O'Neal, Clarence P. Alfrey and Robert H. Moser Blood, Vol XXX, No. 5, November 1967. 26. "Iatrogen Disorders" Animals and Clinical Pharmacologic Techniques in Drug Evaluation edited by Peter E. Siegler, M.D. and Hohn H. Moyer, III, M.D. Year Book Medical Publishers, Inc., Chicago, 1967. 27. Moser, R. H.: "Tatrogenic Disorders," in Proger, S.: The Medicated So- ciety, New York, The Macmillan Company,: 1968. 28. "Hereditary Chronic Nephritis Complicated by Nephrotic Syndrome." Arch Int lIed, 122:156 (August) 1968 (Co-author) 29. Moser, R. H.: "The New Ethics" in Kutscher, A. H.: But Not to Lose, New York, Frederick Fell, Inc., 1968 (In press) ~0. "Prospective Epidemiology Studies," Drug Information Bulletin, p. 92, July/September 1968 31. Editorial, "A Proposal from the Periphery," Military Medicine, 133:849 (Oct) 1968 32. "More . . . On Speaking to Patients" Medical Arts and Sciences, Vol 21, 2d Qtr, 1967 Senator NELSON. I have read your statement and I think it is an excellent presentation. It makes a very fine contribution to the comrn mittee's deliberations. : You may present your testimony in any way you see fit. If you find it best to read it, you may. If you wish to extemporize on any particu- lar point, just feel free to do so. I assume that you have no objection to us interrupting with questions, as they might occur to us. STATEMENT OP Bit. ROBERT H. MOSER, OHIE~', DEPARTMENT OP MEDICINE, WALTER REED GENERAL HOSPITAL, WASHINGTON, D.C. Dr. MOSER. Thank you, Senator Nelson. Senator NELSON. Please speak into the microphone so they can hear in the back of the room. *Awarded "Military writing achievement" by Military Review. 81-280-69-pt. 11-S PAGENO="0034" 4324 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. MOSER. At the outset, I would like to state that I am not a clinical pharmacologist. My subsequent remarks, sir, represent my per- sonal opinion as a practicing internist interested in the drugs I pre- scribe. I am not speaking for the U.S. Army Medical Department, nor for the AMA Council on Drugs, of which I am a member. My interest in drugs has centered primarily around the problem of adverse effects of drugs, drug interactions, and related areas. Most of the comments I am about to make are quoted or paraphrased from sections of books, chapters of books, and papers I have written on this subject in the course of recent years. The physician and his patient are the beneficiaries of the most dra- matic expansion of medical capability in the long history of our art. But the rapid proliferation of medical knowledge has not been entirely bemgn. Our reverses have been minor when contrasted to our advances, but negative effects cannot be ignored or derogated. Pertinent to this evolution of medical capability has been the im- provement in quantity and quality of drugs. In the early days new drugs came in a trickle. There was time for the physician to become familiar with their virtues and idiosyncracies. Soon the trickle became a stream and there was less time for study and reflection. The stream has now become a torrent; it is impossible for the physician to keep pace. One might say his little black bag runneth over. It has been stated that drug-induced adverse effects are the price we must pay for more effective and better medicaments, and there can be no quarrel with this statement; it is the high price we are haggling about. The thalidomide disaster indicated how expensive it can be. By last count there were 2,625 amelic and phocomelic children born in West Germany-these were children with extremity deformities- between 1958 and 1962. About 1,000 of these deformed children will be obliged to remain under regular prosthetic care and supervision for the rest of their lives; about 100 with the most serious deformities will remain under medical supervision the rest of their lives. For- tunately between 80 and 90 percent of the deformed children were in school by the end of 1967, and 60 to 70 percent were attending regular schools. From the financial aspect, the Health Ministry of West Germany has spent $2.8 million in research, treatment, rehabilitation, and de- veloping facilities for the deformed children. This sobering catastrophe had the effect of catalyzing international concern about adverse effects of drugs, a sentiment of rather amor- phous configuration before thalidomide. It is true that each year a mere handful of important new drugs ultimately emerge from the profusion of products offered to the phy- sician. But it takes time and experience to sort out nuggets from gravel. Senator NELSON. May I interrupt you, Doctor, for just a moment? Dr. MOSER. Yes, sir. Senator NELSON. In 1968, according to the statistics our committee has, there were 101 new drugs introduced, of which only 14 were new chemical entities, and of these five new single drugs and two bio- logicals had any significance. Do you have any comment to make PAGENO="0035" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4325 about the great profusion of new drugs,: such as 101, of which only 14 were new entities? What is the value of the other 90 or so drugs coming into the mar- ketplace? Dr. MosER. That's rather difficult to answer, sir. The problem is that when a new drug emerges it is extremely difficult to figure out what its ultimate place is going to be, and it does take time to sort them out. It takes considerable clinical study before one can be sure that this drug is indeed going to be a valuable contribution. It is a bit more than the average physician can do without the help of some fine investigators. I hadn't thought about 14 specific drugs, but I would assume that is a fairly good average of what we would get each year. The effective new agents do represent a handful. Senator NELsoN. What about those 87 new drugs which are simply the same chemical entities that are already in the marketplace now introduced as new drugs in some other combination? What is the pattern historically of the value of these new combinations? Dr. Mosi~ii. Well, again, I think it is hard to generalize. I would suspect that many such drugs come out as a result of competitive drug manufacture. I don't know if combinations ever represent any signifi- cant contribution. Chlorothiazide when it first came out was super- ceded by hydrochlorothiazide. This was offered as a better drug, but ultimately it turned out to be quite similar. I can't cite specific instances, but I:think there are many cases where these combination drugs add very much to our ability to take care of patients. Senator NELSON. Thank you. Dr. MOSER. To continue, once the physician does manage to figure out which of the new drugs are indeed valuable agents-and this is not easy-the pressure may come from patients and often from one's own peers, this pressure to try a new, unfamiliar compound-that has been effectively merchandised-is an additional force to be con- sidered in the therapeutic capability of the individual physician. Yet I have observed an expanding spirit of skepticism and dis- content with empiricism in therapeutics. I find more and more that modern practitioners demand drugs that have proper credentials. And this has precipitated a virtual renaissance in drug investigation. The demands of the clinician to know more about drugs are being met by increasing capaibility in the laboratory. New insight and ap- preciation of the complexities of drug effects have come from several diverse avenues of investigation. Percutaneous biopsy, which is a tech- nique using a needle where one can get a piece of tissue from the lung, liver, and so forth, and examine it on a microscope, electron microscopy, and immunofluorescent techniques have-~which are techniques that can be used to identify specific substances within tissues that have been taken with biopsy, have resulted in dramatic revelations; the mysteries of intracellular morphology and physiology in the living organism has begun to yield. Often, we are able to observe the specific site of drug action within the cell and subcellular structures. In other areas techniques continue to be perfected for assay of blood any tissue levels of drugs, intern'ie- diate products, enzymes, and hormones and thus we have come to learn more of the wonders and hazards of contemporary therapeutic agents. PAGENO="0036" 4326 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The prdblems of adverse drug effects are many. Reduced to simplest elements, when drug A is introduced into the body, ultimately it or its intermediate products will be carried in blood and body fluids to bathe virtually all cells of the organism. The effects of drug A become perceptible only when the function of certain organs is modified, by whatever mechanism, and this may be either beneficially or detrimentally, to the point of producing clinically perceptible changes, and it is by these phenomena that we learn to characterize the nature of drug A. Yet as we focus attention upon the anticipated response of a specific organ (or organs), we are inclined to forget that drug A is also in contact with other tissues of the organism. Effects in these areas are not in immediate evidence, but subtle often nefarious influences may be at work, which become manifested clinically, at a much later date. Such long-range effects may never be correlated with the antecedent administration of our drug A and if one were to add drugs B, C, D, E, F, and so forth, one begins to appreciate the endless combinations and permutations. The identification of a significant adverse reaction follows a long but familiar pattern. First, scattered unsubstantiated reports-and these may come by hearsay, anecdote, word of mouth, in the cloakroom at the hospital-are encountered, hinting that a certain drug has caused a certain undesirable effect. Then begins the tedious process of painstaking retrospective analy- sis. Many suspected cases must be scrutinized, and perhaps, ultimately the suspected culprit-the provocative drug will be revealed. To depart from the text, there are several mechanisms wherthy this is done. The most familiar, of course, is the FDA gathering of their forms 1639 where any physician, who encounters an adverse re- action may complete the form and send it to the FDA where it will be plugged into their computer system. The AMA Council on Drugs also collects similar types of reports from private physicians throughout the country, which again will be introduced to their computer. And if physicians in the North, South, East, or West~ all unrelated and un- known to each other, seem to report the same kind of reaction occur- ring with a specific drug, then the wheels are set into motion for the beginning of an investigation. Senator NELSON. May I interrupt you a moment? Dr. MOSER. Yes. Senator NELSON. How effective is the reporting system, that is, what percentage of the doctors around the country who discover a side ef- fect from using a drug, report it to the FDA or AMA Council on Drugs? Dr. MOSER. Senator, if you will bear with me, I will get to that toward the end. At this point one must follow with a meticulously controlled pro- spective study which will involve provocative testing in animals and often in men, before we can prove that indeed it was the suspected drug that causes this difficulty. It is a tedious, frequently unrewarding proc- ess. But it is the only valid technique currently available to medicine. This is a shadow world of pathophysiology, where relation of cause to effect is at best difficult to assess. I need only cite the stifi raging PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4327 controversy over analgesics and renal disease to demonstrate this dif- ficulty, and there are other problems. Perhaps the most careful, definitive study of adverse drug reactions is being conducted by Dr. Nelson Irey of the recently established Reg- istry of Tissue Reactions to Drugs. In reviewing the firsl 509 cases discussed in the new registry, Dr. Irey cited four principal areas of difficulty in his investigations. Senator NELSON. Who established the Registry of Tissue Reactions to Drugs? Dr. Mosi~n. This was a joint effort, as I understand it, sir. The reg- istry is sponsored by AMA, Food and Drug Administration, PMA, and NIH. But the organization operates independently, and Dr. Irey is an outstanding scientist. They were in the old Army Institute of Pathology, and at the present time they are in interim headquarters, and I am told that they will occupy a wing at the new Armed Forces Institute of `Pathology on the campus at Walter Reed when that build- ing is completed. That is where the new headquarters for the Armed Forces Medical Museum will be. Dr. Iiey told me several months ago that that is where they ultimately will keep their registry. So it is a very independent organization. I think it is a fine study. Dr. Irey cited in one of his publications four principal areas where he is having difficulty identifying these types of reactions. One, there is incomplete time relationship between the drugs and the disease. Second, in most instances there is a multiplicity of drugs admin- istered (this makes it difficult to pin down which drug or drugs is involved). Often there is a lack of objective means of demonstrating a correct relationship between the drug and the reaction. And, finally, there is a limited number of reaction patterns of the body to the entire range of physical, chemical, and biologic causes of disease. In other words, the body has a restricted nunTher of ways in which it can respond to harmful stimuli regardless of their source whether it is bacteria or a drug or a climatic condition, et cetera. The liver, for example, can only respond in a limited number of ways. Very frequently it is extremely difficult to say whether a drug or a virus has been the cause of a specific liver dysfunction, such as hepatitis. Thus, following the appropriately rigid criteria demanded by the registry, it was observed that in only 8 percent could a specific drug be definitely called the causative factor. In 40 percent it was con- sidered to be "probable"; in 32 percent "impossible"; and in 15 percent, "coincidental." In 4 percent there was no apparent relationship. The contribution of drug interactions to this complex milieu will be discussed later. The widely quoted adverse reaction studies of Cluff and associates at the Johns Hopkins Hospital has pointed up dramatically, the "ice- berg" nature of this problem. This was an intensive prospective assault on the question, conducted by highly motivated house officers; 714 such patients with adverse drug reactions were discovered during a 3-month period at the Hopkins. Cluff has stated that 13.6 percent of patients acquired an adverse drug reaction during the period of hospitalization, and the other re- sults that he found were also rather astonishing. PAGENO="0038" 4328 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Are you saying 13 percent of all patients admitted? Dr. MOSER. That is right; 13 percent of the patients who were in the hospital came in with an adverse reaction or acquired one while in the hospital. Now, 4 percent of these patients were admitted to the general medical services with an adverse reaction. This was the cause of the mission, 4 percent. This was the admitting diagnosis. Of this particular group 30.4 percent acquired another drug reaction during the course of hospitalization. The Oluff team observed a 4.2-percent incidence of reactions among patients who were receiving six to 10 drugs while in the hospital, 24.2 percent with 11 to 15 drugs, 40 percent m patients who were receiving between 16 and 20 drugs, and astonishingly, 45 percent of patients suffered adverse reactions who were receiving 21 or more drugs in the hospital. Now, this may seem like a lot of drugs but anytime this fact has been studied, it is found that many patients are receiving between 8 and 12 drugs while they are in the hospital, and this is a fair repre- sentation of the drugs being given to individual patients in fine uni- versity hospitals. Now, in the Cluff study, antimicrobial agents (antibiotics), and car- diac drugs were implicated most often, accounting for 21.2 percent of all reactions each, or 42.4 percent of the total. Hypnotics, another word for sleeping medication, and sedatives, produced 13.0 percent re- actions; insulin, 8.9 percent; and antihypertensive drugs, 8.2 percent. The clinical manifestations of adverse drug reactions were: gastro- intestinal, 35.6 percent; neuromuscular reactions (muscle aches and pains) 15.8 percent; metabolic disturbances, 13 percent; cardiovas- cular disturbance, 11.6 percent; skin rashes, 10.3 percent; hematologic, 4.9 percent; renal, 3.4 percent, and multiple systems (this would be heart, liver, kidneys, combinations of systems) were involved in about 2.7 percent. And, finally, pulmonary (that is, lung) and other mis- cellaneous types of reactions accounted for 1.4 percent each. About 7 percent of aU~ adverse reactions observed during this 3- month period of study were life threatening or fatal, and five deaths in this series were attributed to adverse drug reactions. Over two-thirds of the in-hospital adverse reactions were detected within 4 days after the causative drug had been started. Allergic re- actions usually developed between the fifth and 10th day, and some came on in an accelerated fashion. Nausea, vomiting, or diarrhea were the most common manifestations, and these occurred most fre- quently in women. Adverse reactions were more common in patients over 50; whites suffered more than blacks; women more than men. The average duration of hospitalization for patients with adverse drug re- actions was 20.8 days. This is in contrast with 14.3 days for patients on the medical wards. This is a significant increase. In another well-known study of adverse drug reactions performed by five cooperating medical school hospitals in the Philadelphia area, namely, Halmernann, Jefferson, Temple, Penn, and Women's 772 adverse drug reactions were reported during a 24-month period of study. In this study dermatologic and allergic reactions were the most corn- mon and accounted for 65 percent of all case reports. Penicillin was PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4329 suspected in 101 reactions; phenobarbital and digitalis preparations in 21, and aspirin in 20. In this study the overall incidence of adverse reactions was .49 per- cent of all hospitalized patients for the first year of the study, and .41 percent for the second year. And, incidentally, it was during this Greater Philadelphia study that the first demonstration of a positive Cöombs test in patients taking cephalothin sodium was detected. The differences in incidence of adverse reactions between the Cluff study, the Schimmel report (in which 10 percent of hospitalized pa- tients suffered adverse drug reactions) the Greater Philadelphia pro- gram, and others, may be related to techniques of data gathering and definition of what constitutes an "adverse drug reaction." For example, the Philadelphia group and Koch-Weser at the Mas- sachusetts General Hospital required that for admission to their proto- col, a reaction must be "severe enough to be commented upon in the progress notes." And those familiar with the terse and often sparse progress notes written by the busy house officer might consider this to be a chancy qualification. Of course, this was not a determinant in the Cluff and Schiminel studies where the incidence figures of adverse reactions was much higher. Finally, Cluff and Schimmel utilized a prospective method while other groups used a retrospective method. In other words, they set out to seek reactions on the wards while the others waited for them to occur and be reported. The problems of adverse reactions to placebos or spontaneously occurring symptoms due to nondrug causes cannot be entirely dis- counted, especially when one is evaluating minor reactions to drugs. However, I feel it is equally safe to assume that for every ~patient who becomes sufficiently ill with an adverse drug effect to trek to emergency room or physician's office, there are perhaps 10 who will not. This is my own estimate. Senator NELSON. In other words, are you saying that about One- tenth, one out of 10 cases of drug reactions are reported? Dr. MOSER. No, not quite that. One out of 10 drug reactions are severe enough to bring them to clinical attention, to come to a doctor's office or to come to a clinic. And I think it is fair to say that with non- drug-induced illnesses it may be the same.But I think the point is that adverse drug reaotions represent illnesses just like other diseases, and the same ground rules apply. Probably one out of 10 come to clinical attention, and that is a fair guess. The reasons are plentiful: The reaction may be mild, one may fear loss of time from the job, et cetera (the same reasons that one doesn't go to see a doctor for a non-drug-related disease). At the present time there are man~y studies underway throughout the country to gather more meaningful data on this subject. And I will comment upon these later. Let's approach the problem from still another aspect. What is known of the role played by drugs in predisposing the organism to attack by micro-organisms or degenerative disease? One example is the effect of long-term corticosteroids in predisposing the leukemia or lymphoma patient to systemic fungus infections. PAGENO="0040" 4330 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY We have heard a great deal in medical literature about the so-called "opportunistic organisms." I consider this a semantically poor euph- emism, but that's not the point. It is important to our thesis to mention the fungus Gandida aibican.s. This is one of a group of saprophytes. A. saprophyte is an organism that is normally found in the gut and usually does no harm; it is of limited pathogenicity under normal circumstances. Candida may emerge as a systemic infection and seed into man organs during or following broad spectrum antibiotic therapy wit or without concomitant cort;icosteroids or immunosuppressive drugs. This phenomenon has been related to suppression of susceptible in- testinal bacteria with disruption of the normal ecologic balance. Every- one's intestinal tract exists in a state of balaiice between various groups of micro-organisms. We acquire these as soon as we begin to live; (literally), and they exist in symbiosis with the host throughout life. However, when one gives antibiotics occasionally this balance will be disrupted, and organisms that are not killed by this particular anti- microbial agent may gain ascendency. They will proliferate and often they will escape the intestinal confines, and if one is also receiving corticosteroids or immunosuppressive drugs, this occurs at a time when the normal defense mechanisms (to resist infection) are all but para- lyzed, and one can get a systemic infection with fungus. Another example is the devastating influence of prolonged- Senator Nri~soN. Is there any drug that is effective against the fungus? Dr. MOSER. Yes. There is amphotericin B which is a fairly effective systemic fungicide agent. Another example is the devastating influence of prolonged corti- costeroid therapy upon the elderly patient who is somewhat immobi- lized by cardiovascular disease or arthritis. In these individuals accel- erated demineralization is encouraged through the antianabolic effect of corticosteroids. In other words, the corticosteroids will actually accelerate the normal tendency of the bones to lose calcium and some of their protein matrix. And again this is a classic demonstration of exac- erbration, or making more severe, a degenerative process induced by a drug. In this situation we start; with one disease, and our treatment for it produces another disease. Let's modify the question again. What is known of the effects of drugs upon a previously diseased organ, with limited capability to metabolize or detoxify or otherwise cope with a drug given to treat another illness? Now, I have mentioned the phenacetin controversy. The discussion here revolves around the status of analgesic compounds in the provocation of a variety of interstitial kidney infection and destruction of papillary tips of the kidney in a normal organ. This is a longstanding controversy in which some of the analgesic drugs are thought to be able to cause specific disease of the kidney. But this discussion is about what they do in a normal kidney. And I ask what effect does phenacetin or aspirin or caffeine have upon a sick kidney, already poorly disposed to resist assault from either microorganisms or nephrotoxic drug? Mr. GORDON. May I interrupt here for a moment? Dr. MosER. Yes. Mr. GomoN. This is the APO tablets? PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4331 Dr. MOSi~R. Yes. Mr. GORDON. These are also sold overthe counter without a prescrip- tion? Isn't that right? Dr. MOSER. Most of them have had phenacetin removed, according to my information. I think there may be a few companies that still pro- duce it, but I think most of the APC's have the phenacetin removed. Now, I want to say that this is a far from settled business. I don't mean to sit here and tell you that I know the answer to this problem, because many fine people have devoted a lot of time to trying to work this out. I don't want to take a stand on this because I really don't know. Let us say that there is perhaps an increased mcidence of inter- stitial nephritis and papillitis in patients who have taken a variety of analgesic compounds. What the specific agent (or agents) is I don't really know. I would like to go on to discuss now the phenomenon of delayed excretion of drugs or their active intermediate products (which we call metabolites), by an organ which is already diseased. In this situa- tion the unanticipated high blood levels introduce a whole new spec- trum of toxic effects. And what happens to the diseased kidney of itself, if the drug which it has been reticent to excrete, happens to be specifically toxic to the kidney and then.becomes superconcentrated in the countercurrents of the kidney medulla. All this means is that in the lower part of individual kidney units (in the lower part of the nephron) where there is exhaberant water absorption, any product that is coming through the kidney will be concentrated in this particular portion. And I pose the thought that in the event that the drug which with we are dealing happens to be nephrotoxic, the kidney may suddenly be receiving a very concentrated dose of this particular drug. It is an interesting area. Or, consider the patient with a subclinical liver disease-a mild cir- rhosis, if you will. What happens when he is given halothane or chlor- promazine or phenylbutazone, drugs known, occasionally, to be unkind to the normal liver? What happens when it is given to a previously diseased liver? One could cite many examples wherein an organ with marginal function may be further insulted by a drug administered, most inno- cently, to treat another ailing system? The thought remains a continu- ing source of uneasiness in all drug therapy. The mechanisms of adverse drug reactions have been a subject of many taxonomies, and I have selected one feasible classification as modified from a paper by Long, and he lists seven classifications: Hypersensitivity or allergy; idiosyncrasy; immunological injury; enzyme induction (which means acceleration of the metabolism of a drug), enzyme potentiation (or inhibition of drug metabolism), car- cinogenesis (which means cancer), teratogenesis and mutagenesis, which mean the induction of congenital conformities. I don't feel it is pertinent to this presentation to delve in depth into the mechanisms of drug interactions or specific physiologic mecha- nisms that cause adverse reactions. However, a few general remarks may facilitate understanding of some of the problems that beset the practitioner in his effort to employ drugs effectively. PAGENO="0042" 4332 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PHARMACOGENETICS Perhaps the most fascinating new dimension in drug reactions was the identification of a relationship between enzyme systems and drug effects. In 1959, Vogel introduced the term "pharmacogenetics" into clinical medicine. This was defined as "the study of genetically determined variations that are revealed solely by the effects of drugs." The genetic aberration results in the absence or insufficiency of cer- tain specific enzyme systems. This mechanism, the revelation of smol- dering enzyme insufficiencies, has already been cited as one major ex- planation of the extraordinary human variability in response to con- ventional doses of conventional drugs. Here we are discussing the effects of a single drug (A) upon a patient with congenital or inborn disorder of a specific enzyme or enzyme system. And I leave you to ponder the possibilities of what might happen if the drug (A) inhibits or stimulates enzymes respon- sible for the metabolism of Drug B or C. We will discuss this later in more detail, but I would like to cite a few notable examples of the phenomenon of pharmacogenetics. The historical and classical prototype is the hemolytic anemia-this is a variety of anemia where the red cells burst-suffered by some members of certain ethnic groups, specifically Mediterranean basis dwellers, rare Scandinavians, and Negroes, individuals who have a quantitative or a qualitative deficiency of a critical enzyme that resides in red blood cells. Brisk rupture of these blood cells may follow ex- posure to many common therapeutic agents, and among these are cer- tain antimalarials, certain sulfonamides, aspirin and perhaps a dozen other so-called "oxidant" type drugs. Even our old nemesis, the medi- cal student's friend, the notorious Fava bean, continues to kill a few Sardinian children each year by triggering a catastrophic hemolytic anemia on the same basis. And I might add whimsically that the excitement generated by the discovery that drugs could be employed to delineate specific enzyme insufficiency syndromes has done a great deal to increase the status of drug research as a respectable means of earning a livelihood. It is very respectable to do basic research in enzymes. Now that the drugs have been discovered to unmask such enzyme disorders, a lot of people are becoming interested in drug research. The cause of this red cell destruction is a genetically transmitted defect that results in various degrees of deficiency, quantitative or qualitative, of this enzyme. These patients are clinically normal. They have no apparent, either by appearance or by physiologic testing, abnormality of their red cells, until one of the provocative drugs is given, and then they will develop a brisk anemia. Deficiency of this important red cell enzyme is somewhat of a prob- lem in the chloroquine-primaquine antimalarial prophylaxis program in Southeast Asia. Soldiers known to suffer the clinical manifestations of this disorder are restricted from duty in endemic malarious areas, because we don't want to give them the chloroquine or primaquine tablets. . And there are dozens of other fascinating pharmacogenetic dis- orders, and new ones continue to emerge. If one reflects for a moment PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4333 upon the multitude of known enzyme systems as well as those suspected. or latent or subclinical, but not as yet identified, one could predict that many* drug effects that are now classified as idiosyncratic or even allergic will gradually be herded in the fold of pharmacogenetic dis- orders or perhaps enzyme insufficiencies that are acquired as the result of disease. DRUG INTERACTIONS One of the more complex, fascinating, and disturbing areas of phar- macology which has direct pertinence in any discussion of adverse drug effects is "drug interactions." Efforts to establish a feasible classification continue as new mechanisms, are discovered. Dr. Hart- shorn defines drug interaction `as-and this is the best definition I could find-"The phenomenon which occurs when the effects of one drug are modified by the prior or concurrent administration of another-or the same-drug (s). Drug interactions may arise either from `alteration of the absorption, distribution, biotransformation, or excretion of one drug by another or from combination of their actions or effects." He makes a distinction between interaction and drug incompatibil- ity. He reserves the latter form for reactions which occur either in the bottle as one mixes two drugs or in the syringe before they are given to a patient. Dr. Irey has also been involved `in interaction and he lists another classification of interaction in categories. 1. Interaction with other drugs or themselves. This is an induction process. 2. Then `there may be interaction with endogenous physiologic chemical agents. And the example here is monoaminoxidase inhibitors and epinephrine. 3. Interaction of the drug with components of the diet, as in the `administration of MAOI drugs with tyramine as one would get in cheddar cheese. 4. Interactions with chemicals used in diagnostic tests or the results of such tests. And an example of this would be the oral contraceptives which may modify the glucose tolerance tests. Two of the more fascinating aspects of drug interactions have to do with enzyme induction `and enzyme inhibition, and I would like to discuss these briefly, in turn, just to illustrate the magnitude of the problem. ENZYME INDUCTION . Many drugs, when taken over a period of time, can cause `a marked acceleration of their own metabolism or can accelerate the metabolism of other drugs being administered concomitantly or subsequently. This effect is mediated through stimulation of drug metabolizing enzymes in the liver. This process is calle.d "enzyme induction," and it has be- come an extremely important . aspect of drug toxicity. Induction can lead to an escalating requirement for maintenance doses of a given drug, each of which can be acutely toxic. . Fortunately, most drugs do not involve enzyme induction, but it must be conceded that not all drugs have been subjected to this rather difficult and time-consuming type of testing. Nor is it known if all individuals are susceptible to' enzyme induction by a specific drug. And this brings us to another aspect of this effect. Not oniy may a PAGENO="0044" 4334 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY drug accelerate its own metabolism, but it may affect others. The ad- ministration of drug A may stimulate hepatic enzymes which ac- celerate the metabolic breakdown of drug B. If this phenomenon is not appreciated and anticipated, it may result in lower than expected blood levels of drug B. I would like to show a. slide a.t this moment to illustrate this point, if I may. The point is this. Here we have a patient who comes to see a doctor. The diagnosis is made, and the patient is started on a conventional dose of this drug. He is given one gram a day. Over a period of time over the next few days the patient gets the desired therapeutic effect, and the patient is going quite well. However, by the fourth day the patient is seen by another doctor or by the same doctor and is then given drug B for some other complaint. Now, drug B happens to be a drug capable of causing mduction of drug A. In other words, it accelerates its metabolism, and the blood level of drug A rapidly falls off. So you see we have now a lack of effect. The patient comes back to the original doctor and says, "Doc- tor, I am certainly not getting the same response that I got from that drug (A) you gave me." But she neglects to tell him that she is also taking drug B,; so he increases the dose of the first drug (A). After a few days she gets back up to the same therapeutic level, and then for one reason or another drug B is stopped, and this was the drug which was inducing and accelerating the metabolism of drug A. It is gone and suddenly we have a patient who becomes toxic from drug A~ And if the physician does not know about this mechanism, he will become very confused and may think that the drug is no longer effective. And this is why enzyme induction is dreadfully important to us. The cardinal principle involved is that individual doses of drugs may be required that are quite toxic in an effort to maintain blood levels that were achieved with much lower does earlier in the course of drug therapy. And the corollary is equally as important. One may consider that a drug is ineffective, when the actual fact is that the blood levels are too low, despite the administration of proper doses. ENZYME INHIBITION Now, the next phenomenon, one that is more familiar to physicians, that is antithetical to the concept of enzyme induction and accelerated drug metabolism. This is inhibition of the metabolic breakdown of one drug by another with a potentiation of its effect. And we have another slide to illustrate this. Now, here we have exactly the reverse situation. The patient comes in and is given drug A (drug A becomes more notorious as we pro- ceed) and gets a therapeutic effect as anticipated. At this particular time drug B is given by someone else. Drug B in this situation, rather than accelerate the metabolism of drug A, as occurred previously, now inhibits the metabolism. Therefore, drug A remains in the blood stream longer than was anticipated, begins to accumulate, and suddenly the patient develops toxic effects from drug A. PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4335 The physician at this point scratches his head and says, "1iVell, this patient may be unusually sensitive to this drug." So he drops the dose to half. And within a few days the blood level is back down, and the patient has lost the toxicity desired. A few days later drug B is stopped and inhibition of the first drug ceases. Now the physician is giving this patient an inadequate dose and the loss of therapeutic effect becomes evident. The importance is realization of the fact that two drugs can modify the effect of one upon the other. It is a fairly common occurrence, can cause great consternation in any physician, if he does not appreciate this phenomenon. And we are just beginning to appreciate the complexities of drug interactions. There are several other mechanisms involved, and I will not go into them in any great detail. Occasionally disease of the excretory organ, such as the kidney, can be made worse by a drug. This may cause inhibition of the excretion of another drug, and then drug B (the second drug), will persist in the blood for longer than anticipated periods of time. Another mechanism is the physical displacement of drugs from blood protein (carriers). Most drugs are bound by circulating pro- teins, and therefore are relatively ineffective. They only become effec- tive when released from their protein binding sites, and this is again calculated into the dosage requirements. But if you give a second drug that bumps the first drug off of its protein binding site, you will then have more of the free drug A circulating, and in this situation you can get toxicity. DRUG EXCRETION A few words about drug excretion seem appropriate. A prototype drug involved in this problem of excretion is phenylbutazone, which is an antiarthritic drug. When given in conjunction with a aceto- hexamide, a popular antidiabetes drug, the phenylbutazone will inhibit the excretion of the acetohexamide and one can get a higher than anticipated level of the latter. This can cause very low blood sugar levels and occasionally in an elderly patient can cause some hypoglycemic shock. A drug that is known to inhibit the excretion of penicillin, through blocking kidney reabsorption, is probenecid. This is a drug normally used to accelerate uric acid excretion. Now, this is a beneficial effect. In this situation we frequently employ penicillin with probenecid, specifically to maintain higher blood levels of penicillin than normal. This is frequently used in patients who have bacterial endocarditis with resistant micro organisms. RESIDUAL DRUG EFFECTS Residual drug effects remain another enigmatic area. For example, reserpine, an antihypertensive drug, continues to exert its influence in certain patients for several weeks after it has been discontinued. And it may cause unpredictable responses to general anesthesia. If the anesthesiologist is not very careful, he may get into some difficulty in the process of inducing anesthesia. It is a fine drug, but one must know that it may cause these responses. In another area, elevated levels c~f iodine bound to protein were found to persist for 7 years in the sera of women who had received PAGENO="0046" 4336 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY iophenoxic acid, an agent used to take X-ray pictures of gall bladders And babies born several years after their mothers had ingested this dye had extremely high levels of protein bound iodine, although they did not have any clinical manifestation of hyperthyroidism. These agents may lie dormant in fat depots for many years, ap- parently innocuous but in curious contradiction to the usual tendency of the organism to rid itself of foreign substances. One might ask what other drugs are stored for prolonged periods. Do they exert adverse effects? One might summarize the complex prob- lem of drug interactions with this final diagram. This is a Venn diagram that I think summarizes the total picture. It is a little hard to see, but the point can be made. Here we have drug A at the top, drug B at the bottom. We have an enzyme system as it is involved in the metabolism of drug A and drug B, and finally we have the organ that is going to respond, the organ we are trying to treat with this combination. It is not just a simple matter of two circles, drug A and drug B acting upon the end organ. They are involved quite intimately with each other, with the enzyme system and with the end organ. And one could add on a whole sequence of circles that would intersect at various levels if you wanted to add enzymes B aand C which may be involved in the interaction. And all organs of the body are going to be involved. The physician is dealing with this, the middle of this complex situation, and therefore when drugs are being given it is not just a simple matter. It can be a rather complex business. WHAT DOES ALL THIS MEAN? Now that we have seen something of the broad introductory area of drug-induced diseases and drug interactions, a logical question might be, what will be the ultimate effect of these new therapeutic endeavors? And the answer must lie somewhere in the interface be- tween philosophy and physiology. The evolution of man is a continuing source of wonderment to stu- dents of physiology. Through the centuries of evolutionary meta- morphosis, each challenge thrown at man by his environment was met by gradual genetic modulation that enabled him to survive. The species have arrived at the current state of advanced physiologic capability, admirably adapted to its environment. We can dig diamonds at 9,000 feet in 123 degree heat and 100 per- cent humidity; we can spend a lifetime niinmg tin at 14,900 feet elevation; we can hike across the pole, and we can float weightless for 14 days in space. But in the past few decades we have devised methods unprecedented in the entire previous experience of the species to challenge the adapt- ability of the organism. We have designed molecules unique to human physiology and insinuated them into blood and tissue by techniques that are also unique physiologic experiences. Intravenous, intramuscular and subcutaneous injections, positive pressure inhalation, rectal administration, and agents facilitate passage of molecules through intact skin-all are unfamiliar modes of gaining access to the body. Add radiation-by X-ray, beta ray, gamma ray and neutron, plus oxygen under greatly increased barometric pressure, and some other PAGENO="0047" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4337 modalities that I have doubtlessly forgotten-and one `begins to ap- preciate the magnitude and genius of man's conspiracy to bypass the conventional avenues for introducing new environmental factors to the physiology of man. In the past we only had to cope with naive nature and misubtie environment. And they were confined to the gastro-intestinal tract, lungs, and occasionally the abraided skin, as avenues of access for alien materials to get at the core of man. The implications of these ingenious tactics of assault, these strange manmade chemicals and emanations upon the beleagured human mechanism are fascinating to contemplate. One could speculate that this incredibly resilient physiologic engine of ours is sufficiently ad- vanced in design `to be able to cope with `all environmental transgressors. We have evolved defenses at all `levels from the simplest reflex to the most complex immune reactions to meet the daily challenges of environment. And we have done very well in the matter of self- preservation. Yet it is quite evident that some of these unprecedented therapeutic intrusions overtax the ability of the body to accommodate-and it will react with displeasure, if not violent rejection. And, of course, this is the heart of our thesis-drug-induced diseases. CONCLUSIONS Adverse Reaction Reporting At this juncture I feel obliged to reiterate that these observations I am about to make are my own and do not necessarily reflect the opinion of the Army Medical Department or the AMA Council on Drugs. Drug-induced disorders will be with us forevermore. They cannot be swept under the rug either by clinician or drug producer. My own naivite in the world of commercial enterprise is revealed by my admis- sion t'hat I think a fine new `drug will become known to the profession on the basis of its merit. I am embarrassed when this noble commodity is demeaned by merchandising techniques, however subtle or artful, better suited to less vital products of commerce. I do not feel that drugs shOuld be propagandized to the medical profession. The pressure of commercial competition is not conducive to objectivity in the presentation of drug detailmen or in published advertisements. I feel that these factors add to the confusion in the already difficult problems of evaluating the efficacy and/or adverse effects of new drugs. The requirement for an impartial agency that can provide current, reliable and objective data about the characteristics of new drugs, and alert the physician to their beneficial effects and toxic hazards is abundantly evident. Senator NELSON. We have had testimony similar to your statement about the advertising and promotion of drugs. On the other hand, we have had claims by some doctors and the industry th'at promotion by detailmen is the most effective way of informing the American medical profession that the drug does exist. Are you satisfied-I take it you are, from your statement-that if PAGENO="0048" 4338 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY there was not this wide drug promotion by advertising in medical journals and by promotion by detailmen that the medical profession would discover the drug and its merits and its appropriate uses just as well. Dr. Mosi~ii. Yes I do. And I will speak to that as we progress. I will briefly summarize some of the efforts that have been made in this area. Both AMA and the FDA became immersed in the busi- ness of trying to obtain data on adverse drug reactions. The AMA had a potential information source of over 7,000 hospitals and 250,000 physicians. How many reports were received? The total as of Decem- ber 1968 was 8,733. Senator NELSON. From what date to what date? Dr. MOSER. I think the study actually began in the early 1960s with the registry on blood dyscrasias and is still going on. At times the quality and the accuracy of these reports was appalling. However, the original registry on blood dyscrasias fed information back to the profession in the form of semiannual tabulations. And these provided much helpful information. For example, knowledge of chlora.mphenicol and dipyrone toxicity was documented and f a- cilitated through this mechanism. Senator NELSON. We had rather extensive testimony here by a number of distinguished experts on the misuse or the use of chloram- phenicol for nonindicated cases. Testimony, unrefuted thus far at least by any witnesses, including the drug industry was that anywhere from 90 to 99 percent of the patients who received chloramphenicol received it for nonindicated cases. Now, if the toxicity of chloramphenicol was documented, why was there a failure to convey this information adequately to the medical profession? Dr. MOSER. I can't answer that, Senator. I think the informabion has been abundantly available from many sources. I am familiar with Dr. Best's report that received fairly wide dissemination in the Journal of the AMA and there has been informa- tion in the the Medical Letter. Virtually every publication that has come out in recent years has carried admonitions about careful selec- tion of indications in the use of chloramphenicol. It is difficult for me to understand how this information is not very broadly used. And I would be inclined to think-at least let's say I hope, that this misuse of chlormaphenicol is limited to a very few physicians. The actual indications are quite restricted and if the drug is used without proper indication, it is very bad. It is dreadful. I can't answer your questions as to why it continues to be used without proper indication. Senator NELSON. Well, if the testimony and the information we have is correct, approximately 4 million people are prescribed chlo- ramphenicol annually. We have had estimates here from-I am not attributing this estimate to any one of these people-Dr. Dameshek from Mount Sinai, Dr. Best, Dr. Lepper, and two or three others, that anywhere from perhaps 10,000 or 15,000 to 20,000 out of the 4 million received this drug for an indicated case. This seems to me to involve a tremendous amount of misprescribing; if it is 4 million, the other 3,900,000 shouldn't have received it at all. Have you followed, have you noticed, the advertising in the medi- cal journals of chlormaphenicol? PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4339 Dr. MOSER. No, sir. I must confess that for the last several years I have not been reading the journal advertisements. Senator NELSON. If a doctor opens up Goodman & Gilman, or any such source of information, and reads any `article on the use of chloramphenicol, he will probably find that the specific limited indi- cations of its use are listed very carefully, The package inserts that go with the medicine, which probably most doctors don't see because it goes to the pharmacist, lists the indicated uses and precautions and dramatic side effects in certain instances. What I am curious to find out, if all this information is available, why has it been so widely misprescribed, if the testimony of these doctors is correct? Dr. MOSER. Of course I cannot answer that, but one partial explana- tion resides in the fact that the average physician, in `the course of a lifetime, may never see a case aplastic anemia. The incidence has been quoted at from 1 in 20,000 to 1 in 100,000 administrations of chloram- phenicol. The rationale, as far as I can figure it, is that a physician may say, this is so rare it just isn't going `to happen to me. And chloramphenicol is a good drug. It is quite an effective drug. In fact, it is one of the most effective oral antibiotics tha't we have. Unfortunately, it has this potentially `devastating complication. I suspect that a physician will be tempted to prescribe this drug when it is not absolutely indicated because he just hasn't seen a case (aplastic anemia) himself. And there is a great tendency in medicine to rely on one's experience. This is dangerous; that is why we have the medical literature. Senator NELSON. I think there is a problem with that statistic from the California study, which was about I in 20,000, I believe, nobody knows what percentage of cases are reported. Obviously, if a doctor uses it for acne, sore throat, headaches, upper respiratory problems, gum infections, hangnails, all of which are specific cases for which it has been used, and aplastic `anemia results, which it has in all of these cases, he is not going to report it when he is liable in a lawsuit for the damage done. And there have been some very dramatic law- suits in the past and many on the way now. We have `testimony from doctors here that nobody is going to report that themselves. So when you say 1 in 20,000 it may be 10 or 15 or 100 times that figure. The figure is high, but even so, even though the testimony is that it is an `excellent drug, it is for such a limited number of indica- tions that if you just read it once, you wouldn't use it as a broad spec- trum `antibiotic for which it obviously is being used. Dr. MOSER. I do not feel that chloramphenicol should ever be used outside the hospital. It is a drug that should be used on inpatients for the treatment of very specific infections. Senator NELSON. Thank you. Dr. MOSER. Now, getting back to the discussion of the compilation of adverse reaction data, the AMA Registry continued to gather and tabulate its information until 1964, when it was decided that the data should be transferred to computer storage. And unfortunately this conversion never came to fruition. Also `an'ticipated plans for free com- munication between the AMA and the FDA programs also never achieved a working reality. Through both programs it has been eet~- mated that roughly 1 percent to 2 percent of adverse re,n,etioiiq th~ t, 81-280-69-pt. ii-4 PAGENO="0050" 4340 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY were occurring in the United States were being reported. The FDA continues to receive reports from about 85 hospitals, mostly military and Federal, throughout the country. The AMA Registry continues to receive reports from interested physicians who detect adverse reactions. At the present time, the coun- cil on drugs of the American Medical Association is in the process of devising an elastic prototype program that will enable hospitals of every size and mission to establish ongoing studies on adverse drug reactions and drug utilization practices. As a working member of this committee, I can assure you that prog- ress is being made. If such machinery can be established-and we have every reason to believe that it will be-and the data gatherin made painless for the physician, yet pertinent to the statisticians, an we begin to help physicians learn more about drugs, this will cer- tainly be worth the effort. At this point I would like to say a word about the hospital pharmacist. In this schema-and that's the one that we are devising for the AMA council to begin to do drug utilization studies-the hospital pharmacist will play an essential role. Under optimal circumstances, he should be integrated into the therapeutic team as an active mem- ber. While I feel it is inappropriate to have pharmacists participate in patient care decisions-an area which should remain the exclusive prov- ince of the physicians-pharmacists should serve as therapeutic ad- visers. The treatment of a patient includes too many variables beyond drug therapy. Social and psychologic perturbations, in addition to physiologic disruptions, add up to escalate the problems of "treat- ment" to a plane beyond consideration of drug therapy per se. Nevertheless, the pharmacist has a vital role. In our hospital, phar- macists are active members of the therapeutic agents board and the drug utilization and adverse drug reactions committee. Teams of pharmacists visit all wards of the hospital twice each week and contact individual ward officers to inquire about adverse drug reactions that have occurred. The pharmacists then complete the FD 1639 form from information derived from the patient's chart and from direct com- munication with the responsible ward officer. The FDA forms are reviewed by our drug utilization and adverse drug reactions committee, whch consists of one physician and three pharmacists; the pertinent data is presented at the next meeting of the therapeutic agents board, and then copies of FD 1639 are forwarded to the FDA and to the Army Surgeon General's Office. In the future it is anticipated that our hospital, the Drug Utiliza- tion and Adverse Reactions Committee, will conduct drug utilization studies and ultimately drug efficacy studies. In addition, the pharmacists-and this is the case at Walter Reed- maintain a ready file of FDA adverse reactions reports as a rapid information source for physicians. They also maintain current files of books and journals-available to physicians for immediate infor- mation on drugs, including efficacy, interactions, and toxicity. Thus the pharmacist, with his special interest in pharmacology, has become an essential, permanent member of the therapeutic team. A logical question at this juncture might be, "What is the source of drug information utilized by most prescribing physicians ?" PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4341 And I would like to preface my remarks by saying that I look upon all these statistics with some concern. The validity of a response by a given physician to this type of question from my personal observation is not necessarily candid. In one famous national survey sponsored by the Pharmaceutical Manufacturers Association, the principal sources of drug information utilized by physicians was investigated: 61 percent said that they received the information from the Physicians' Desk Reference, a publication distributed free by the pharmaceutical industry; 37 percent of physicians said they received their information through personal experience and knowledge; 27 percent through journals and medical periodicals, and 19 percent from detail men. Other sources consisted of colleagues, consultants, medical society meetings, medical literature textbooks. Compendia and drug reference books were the source utilized by 10 percent. Senator NELSON. Didn't any doctor attribute his information to a drug ad? Dr. MOSER. I assume that that was, sir, included in the 27 percent who said their information came from journals and medical period- icals. This was my assumption. It may not be valid. Response to the question of the relative frequency with which sources of drug information were used: The Physicians Desk Refer- ence was used by 82 percent; the Medical Letter by 2 percent, the Merck Manual by 2 percent. And there were 19 percent of the physi- cians in this group who had never heard of the Medical Letter. One could quote many other studies done by private organizations which usually reveal that the principal source of drug information is derived from publications or visits that have their source material derived from the commercial drug industry. On the 5th of February of this year, I had the privilege of partici- pating in a meeting that was concerned with the problem of continuing education of physicians with regard to drugs. This meeting was held under the auspices of the Drug Research Board of the National Academy of Sciences in conjunction with the Food and Drug Admin- istration and the regional health medical program of HEW. They had gathered about a hundred distinguished scientists from many disciplines representing clinical medicine, pharmacology, sociology, and psychology. They were a conscientious, perceptive, dedicated group of men and women. From 9 o'clock in the morning until 10:30 that night we ham- mered away at the problem. It was quite reminiscent of other similar sessions I have attended in the chambers of the American Medical Association, Council on Drugs in Chicago and several other meetings throughout the country in recent months of equally concerned groups. And the theme was always the same. We have a problem: There is urgent need to improve our methods of transmitting drug information to prescribing physicians at all echelons of medicine. And invariably at this point the discussion falters and usually founders on the matter of methods. Some have suggested a drug compendium, a sort of grand formulary that would contain authoritative, current information about all drugs that a contemporary physician might seek. This, they say, would be a PAGENO="0052" 4342 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY significant first step. I feel a drug compendium would just be another big book that would gather dust on the shelf, standing next to several other unread tomes containing authoritative current information on drugs. Others have championed the concept of a cadre of therapeutic con- sultants, a group of well-trained, practical-minded, clinical pharma- cologists based at university teaching centers who would size up the needs of their local area and assist physicians or local hospitals in establishing practical programs on clinical pharmacology and therapeutics. Still others have suggested periodic medical examination with successful passage being a requisite for relicensure. I have personally favored the program I mentioned earlier, of activating or revitalizing therapeutics boards in hospitals of all sizes by initiating a program of continuing drug utilization surveillance. This would be a hospital committee that would undertake periodic review of therapeutic practices by individual members of the staff as a means to improve therapeutic practices. Senator NELSON. What would you do about the doctor who is not hospital affiliated? I think we had testimony that. over one-third of the doctors in New York City have no hospital affiliation. And then you have t.housands and thousands of others in rural areas or in cities who have no hospital affiliation. What is their source of information? Dr. MOSER. Well, the cadre concept that has considerable appeal would bring such men into this program. The clinical pharmacologist who is based at the imiversity hospital would work not only with the local hospitals but actually get out in the community and visit these physicians. Or, he will train others who will go out and do that sort of thing. Physicians who are not hospital affiliated are a very difficult group to reach. I suspect that a personal type of approach would be the only way that they could be reached. Another possibility would be that therapeutics agents boards in regional hospitals-and I am speaking of small hospitals of 75- to 100- beds. Such local hospitals could periodically invite these unaffiliated men in for sessions where they could give them information on con- temporary advances in therapeutics. I think these are all difficult things to do, and this unaffiliated group is indeed the hardest to reach. I feel that all too often these individuals have been unduly singled out for criticism; I think that many of them are superb clinicians who do a very fine job. Many of my own acquaintances are men who are almost obsessive, compulsive readers. They keep themselves cur- rent because they know they are isolated, and these represent a sig- nificant proportion of American practitioners. I think what we are talking about is a minority, and I don't know how we can reach them. You can lead a horse to water but it is very hard to make him read. Senator NELSON. What single objective source is there in the litera- ture for a doctor to refer to? Dr. MOSER. I will get to that. Each of the plans that I have mentioned have their merits and its failings, as we have been discussing. The basic need is to motivate the PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4343 busy physician to learn more about the drugs he is using. And this is the heart of the problem. As I said, I feel that most physicians practice rational medicine. As a group they are intelligent, empathetic indi- viduals, dedicated to the welfare of their patients. And I think we are speaking of a noisy but certainly an important minority. In this same breath, I feel obliged to emphasize that effective drug therapy represents only one facet of the problem of postgraduate medical education in the United States. Admittedly, a proper knowl- edge of drugs is terribly important, but what about information about new diagnostic techniques, new physiologic principles, even new dis- eases and syndromes. The proliferation of medical information is not confined to therapeutics alone. If one were to solve this far broader problem of total continuing medical education, the enlightened use of therapeutic agents would fall into place. Now, several months ago, in my column "Tomes and Tangents," which I write each month for the journal, Medical Opinion and Re- view, I outlined such a plan for continuing postgraduate medical edu- cation which I consider practical and feasible. Mr. Cumi~. I was just wondering, would the availability of the price information be helpful to the physician on drugs? Dr. MosER. I don't quite understand-in what context? Mr. CUTLER. In the context of prescribing medicines in the hospital, if he knew the cost of the individual drugs, price of one drug as op- posed to another. Dr. MOSER. Are we talking about physicians in the hospital or out- side of the hospitals? Mr. CUTLER. In either instance. Dr. MOSER. I think it would be a factor, but I don't think it would be the sole factor. I think the most important thing that makes a doctor select a drug is will that drug work for him. Now, if you show me two drugs; one is cheaper than the one I use now, better, and you can prove to me that the cheaper drug is just as good as the other, I will certainly switch. But if you come and say that these drugs are the same, but you cannot document this to me, I will not go for the cheaper drug. And I think this is common sense. Senator NELSON. Your hospital has a formulary, doesn't it? Dr. MosER. Yes. Senator NELSON. And you have a formulary committee and your hospital buys drugs on bids, I take it. Dr. MOSER. Yes. Senator NELSON. So that answers the question raised by minority counsel in the seuse of cost to the patient, because all, I think all of the leading hospitals that use a formulary, have their own pharmacist and pharmacologist and their own clinical experience to draw upon and decide whether or not they are therapeutically equivalent and then accept the bids. And they may very well select the lowest bid or will select it, I assume, if they decide it is equivalent to all the rest of them. I think the question raised by minority counsel refers to the fact that a practicing physician who isn't practicing with the use of a formulary in a hospital doesn't have that advantage. He does not know what the price is probably, or doesn't have the backup of a formularly committee that has evaluated the use of the drug. PAGENO="0054" 4344 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I think that is the point that he is making. Dr. MOSER. Well, I am certainly not qualified to speak from the aspect of a physician in private practice because this is not my area, but it would seem quite logical that a physician who is working in a community would know what the prices are on the drugs that he uses arid have some feel for competitive pricing. But again, I am speaking with lack of personal experience. Senator NELSON. That really doesn't help the physician in private practice in many instances because brand name identification is such that the only drug being prescribed is the brand name version. To use the example of prednisone, the market is dominated by Meticorten and is usually the one that the doctor prescribes. The Medical Letter listed 22 versions of this drug which were tested and then using the advice of their clinicians around the country concluded that they were all equivalent. The price range was from Meticorten at $17.90 a hundred tablets to the pharmacist to Paracort at $17.88 a hundred to Merck's $2.20 to $1.80 to others at 59 cents. But you very seldom find the lower priced drugs in the drugstore because no one writes that on the prescription. They write Meticorten. That is the problem here. So the patient is paying up to $33 to $40 for 100 tablets when he ought to be getting it for maybe $2. That is the kind of problem I think minority counsel was raising. Dr. MOSER. Sir, if that physician was getting the Medical Letter, he would know that, you see. Senator NELSON. That's one of the problems, of course. The Medical Letter, from all the expert testimony we have, is a superb source of information, but I think the circulation is about 35,000 out of over 300,000 physicians. Dr. MOSER. That is true, and I am about to comment on this matter. This column that I spoke of, details this program of continuing postgraduate medical education, which I would really like to stress. This may not be the proper platform for this particular discussion. Senator NELSON. Yes, it is. We have had testimony along that line previously and it is the right forum. Dr. MOSER. I think all of us interested in medical education feel very strongly about this. The subject of therapeutics simply cannot be divorced from the big picture. It is perhaps the most essential aspect, but it must be included in the broad concept of continuing postgradu- ate medical education, which represents the most significant problem facing medicine today. Senator NELSON. The lack of it? Dr. MOSER. Sir? Senator NELSON. The lack of adequate postgraduate education. Dr. MOSER. I think that continuing postgraduate medical education should be a prime concern of all American physicians and all educators. Let's get back to the subject of what sources does the average physi- cian have to find out about new drugs. As I said before, it is my conviction that every physician who treats patients should subscribe to the Medical Letter. For $14.50 a year-less for House officers-one can obtain current, unbiased, candid information on new drug efficacy and toxicity. This publication arrives about twice a month. It can be read and digested in about 15 minutes. It comes in looseleaf form and can be PAGENO="0055" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4345 filed with ease and the data retrieved with facility. Index issues arrive about four times a year. In addition, I would suggest that every pre- scribing physician own "Drugs of Choice" by Walter Modell, which comes out every other year, or "Current Therapy," by Howard Conn, which comes out every year, and one good current pharmacology text. Sometimes in 1969, the comprehensive "American Medical Associa- tion Drug Evaluation" book will be available. This should serve as a most valuable adjunct to the physican who desirees to learn about drugs and should quell all dialog about the compendium. Of course, I would be delighted if everyone purchased a copy of my third edition of "Diseases of Medical Progress." But with this cluster of books within pivot-and-reach distance of his prescription pad, any physician will possess all the basic tools he needs to keep abreast of new drug developments and revised concepts of old drugs. Gentlemen, drug information is abundantly available. The problem resides in kindling the initiative-in firing up the enthusiasm to get physicians to reach for that information. Our remarkable therapeutic arsenal is a tribute to the commercial drug industry and the devoted chemists and pharmacologists of our medical schools. But neither AMA, FDA, nor the industry can solve the problem completely. For the past 15 years, in lectures and articles my plea has been directed to the physician on the firing line, the doctor who prescribes the drug. It is farthest from my intention ever to suggest therapeutic timidity or homeopathy. Our predecessors in medicine had limited diagnostic and therapeutic resources. The complement of nostrums in their little black bag was austere, but those drugs were regarded as old familiar friends. Some were worthless, others were dangerous; some were impure and unstand- ardized to the point of unpredictability. The few effective drugs were trusted allies whose strengths and weaknesses were well known. The practitioner of the past attempted to compensate for lack of material resources with meticulous attention to his patients, personal charm, kindness and above all, a pervading equanimity. His lonely hours of private hell, when he was tormented by his inability to come to grips with most of the severe illnesses that he encountered, constitute a long, bleak chapter in medical history. The modern physician is afforded rare glimpses of this agony when faced wih terminal malignancy or severe degerenative disease or irreversible neurologic illness. Modern pharmacology has brought this unhappy era to an end, and today we enjoy the privilege of fine, power- ful, well standardized therapeutic weapons. Now we must work to create an atmosphere of rational caution and critical evaluation, where each physician will pause before putting pen to prescription pad and ask himself, "Do I know enough about this drug to prescribe it? Does the possible benefit I hope to derive from this drug outweigh its potential hazard ?" I do not preach nihilism but rather therapeutic rationalism. Thank you. PAGENO="0056" 4346 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (The attachments to Dr. Moser's statement follow:) TABLE NO. 1.-SOURCES WHICH SERVED AS THE FIRST NOTICE TO DOCTORS OF THE AVAILA~LITY OF NEW DRUGS CONFERENCE ON CONTINUING EDUCATION FOR PHYSICIANS IN THE USE OF DRUGS Source Percent of doct ors naming as fi rst source- Caplow and Raymond Ferber and Wales Coleman, et al. Detail men Medical journals: Articles Advertisements Direct-mail advertisements Colleagues Medical meetings Others Number of doctors answerIng 31 19 6 16 14 ` 7 ~ 38 25 19 6 ~` 8 52 9 22 10 ~ 3 100 100 99 182 328 87 Sources: Caplnw, T., and Raymond,J.J. Marketing 19:18-23 (July) 1954 Ferber, R., and Wales, H. G.: `The Effectiveness of Pharmaceutical Promotion, Urbana, II." 1958, P. 22. Coleman, J. S., Katz, E., and Menzel, H. "Medical Innovation" A diffusion study, Indianapolis, the Bobbs-Merrill Co., Inc., 1966, p. 59. TABLE NO. 2.-SOURCES WHICH LED TO FIRST USE OF A DRUG Source Percent of doctors namin g source Coleman and others Ferber and Wales Gaffin Detail men Medical journals: Articles Advertisements Direct mail advertisements Colleagues Medical meetings Others Total Number of doctors answering 5 2 42 2 14 28 8 1 21 28 18 13 4 16 1 41 15 26 ~ 2 9 100 100 100 87 328 1, 011 1 Some doctors named more than 1 source. Percentages have been adjusted to 100 percent 2 This includes professional journals (21 percent) and periodicals published by drug companies (21 percent). Sources: Coleman, J. S., Katz, E., and Menzel, H.: "Medical Innovation: A diffusion Study," Indianapolis, The Bobbs, Merrill Co., Inc., 1966, p. 59. Ferber, R. and Wales, H. G.: "The Effectiveness of Pharmaceutical Promotion," Urbana, III- 1958, p. 24. "Attitudes of U.S. Physicians Toward the American Pharmaceutical Industry," Chicago, Ben Gaffin & Asso- ciates, Inc., 1959, p. C-13. TABLE No. 3.-What is the most important source of drug information? Percent Detail men 68 Medical meetings - Journal advertisements 32 Direct mail advertisements 32 Collea~ies 24 Journal articles 20 Senator NELSON. I would like to ask just one general question about drug combinations which have come into wide use. We had testimony-and I will just quote a statement or two-from Dr. Calvin Kunin, of the University of Virginia Medical School, before this subcommittee in part 2, page 731 of these hearings: A careful review of ftxecl-branded combinations on the market, including com- binations of penicillin and sulfonamides, penicillin and streptomycin, tetra- cycline, and antifungal agents and tetracycline and novobiocin, does not PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4347 substantiate claims that the combination is superior to one of the agents used separately. These combinations are expensive, deny the physician flexibility in dosage, are primarily promotional devices, and have the inherent problem that the patient undergoes the risk of serious adverse reaction to two or more drugs rather than to a single defined agent. The physician cannot determine which component is causing trouble if a bad reaction is encountered. I personally believe that we would do much better without these preparations. Then, as you know, the National Academy of Sciences under the Kefauver Act of 1962 has under review all of the drugs manufactured prior to then, and they have been making recommendations on vari- ous combination drugs that have been in the marketplace for a long time suggesting their-recommending their removal. On Panalba, which is a combination of tetracycline, phosphate com- plex, and novobiocin sodium, evaluation "ineffective as a fixed com- bination," and then some "comments from the panel report. It does not seem rational to expose a patient to the hazards of two drugs when the beneficial effects are no greater than those resulting from the use of one. Again, it has not been shown each active ingredient makes a contribution to the effect of the combination claimed." I am not reading the whole statement. The last sentences are: A large number of papers purporting to demonstrate clinical efficacy of this combination were reviewed. No control studies were located and most consisted of reports of a few patients treated, with variable results. It is the considered judgment of the panel that this combination has no place in rational therapeutics and should not be marketed. This particular drug is among the top 200 most prescribed drugs. I think the National Academy of Sciences as of now has recommended removal of six of these combinations and is continuing its studies. Do you have any comment from your experience or studies to make on the question of the developing, expanding production of combination drugs? Dr. Mosrin. Well, Senator, I guess the only thing that ever started the use of combination drugs was the simplicity of delivery where the patient takes one pill instead of two. But I am familiar with Dr. Kunin's statement, and I think this is reflected throughout the profession. You immediately hamstring yourself when you put two drugs in a fixed dosage together, and it is just not widely done in hospitals where I have been. I don't recall having used a drug combination in the last 5 years. Senator NELSON. Does your formulary carry any fixed combinations? Dr. MOSER. It carries one, to my knowledge. This is a combination of triameterene and hydrochiorothiazide. Senator NELSON. You don't prescribe them yourself? Dr. Mosnrt. No, I don't; because I like to adjust my doses, and I am not permitted by the fixed combination. And I think most phy- sicians feel the same way. One prefers the elasticity that comes with being able to adjust dosages. Also, they are more expensive. Senator NELSON. You mentioned a few moments ago what you considered an adequate source of information for physicians in pre- scribing drugs including the Medical Letter and some text and other sources. If the National Academy of Sciences is correct, and if your judgment about the use of them in your own practice is correct, on what basis do you suppose these drugs are so widely prescribed? PAGENO="0058" 4348 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In other words, what source of information is the physician using, because they are widely prescribed and widely sold, and Panalba is one of the top 200-if all of these sources of information are so readily available to the physician, how do you account for the fact that these fixed combinations are so widely used? Dr. MOSER. Well, I think it is because of the fact they are propa- gandized to the profession. I think that the detail men are well trained in the techniques of sales. They are very pleasant individuals who have time and give a very straight forward pitch. Their presentations are not cluttered by having to give you comparisons with other drugs. And I think there are other very effective means of promoting drugs. Drug advertisements are skillfully done and present a very straight- forward approach. In the very same journal you occasionally find a very colorful, well done advertisement, and tucked away somewhere in bowels of the text will be an article that says exactly the reverse. But the advertisement is brief and simple, and it takes too long to read the drab article. It is very easy to flip the pages and come up with this attractive, arresting advertisement. It is just a matter of good salesmanship. I think our problem is to encourage physicians to take the same amount of time that they do in listening to the detail men or reading these advertisements to read the Medical Letter or Modell or any of the other sources of drug information that are abundantly available. I think this is the problem, and it doesn't make sense to me that a physician would not utilize these sources of information. I suspect we just have not told them about it. 1 think we have to educate physicians that there are good information sources available. As I say, you can read the Medical Letter in 15 minutes. And this is a very worthwhile investment in time; One will learn about drugs. The time will `be spent expeditiously. Mr. GORDON. Doctor, throughout your paper you use only the official or generic names. Why didn't you use brand names? Why did you use only generic names? Dr. MOSER. 1 guess it is because I am stubborn. I find it a challenge to try to get people to use generic names. I find that the trade names are used simply because they are more euphemistic. With the TJSAN committee now working very hard to create the generic names that have less than 25 syllables, we will begin to see a greater use of generic words. I think it is more personal than anything else. I encourage all of my staff to use generic names unless a trade name represents the sole available drug form and is only known by that name. But it is just a personal idiosyncrasy, 1 guess. I just like the intellectual drill. Senator NELSON. Dr. Modell and all others who have testified on this point before the committee have advocated the use of generic names in prescribing. It has been suggested before this committee on several occasions that all prescriptions that go to the patient should include the generic name. And, of course, if the doctor desires, he can indicate the brand name, too, unless there was some reason the patient, the doctor felt, shouldn't know what drug he was receiving. The reason advocated for that was, in addition to good prescribing practice, the fact that there is such a multiplicity of brand names that nobody can keep up with them. PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4349 I asked a doctor who appeared before the committee whether he recognized a few brand names of thalidomide, none of which he rec- ognized, none of which he would be expected to recognize. In the case of thalidomide, long after its harmful effects were known all over the world, it was still in the marketplace in South America and Spain and other places under brand names even though the profession knew it should not have been used. If it had said thalidomide, it wouldn't have been used. And many suspect that it is still on the shelves and in medicine caibinets around the world yet, simply because there is no identification. Would you advocate the concept that the generic name be required on the label, with the doctor's choice as to whether he wants the brand name on, too ~ Dr. MOSER. Yes, sir. I believe that. I think that prescriptions should be so written, unless the physician has a specific desire for the trade name product, based on his own experience or knowled~e. And there are a few instances where physicians that I know, certainly feel quite strongly that they want a definite trade name; this product they feel is superior to another. I frequently challenge them to provie it, be- cause often it proves to be more visceral than scientific. But for the most part we do order in generics. Our hospital pharmacist will notify us if someone does order by trade name and the pharmacist does not carry it. He will call the physician and notify him about substituting another drug. My personal reaction is that we should use generic names, and if you desire to specify a company, it should be put in parentheses next to the generic name on the prescription pad. I think this would solve the problem of trying to remember hundreds of trade names. Senator NELSON. Well, Doctor, I want to thank you very much for your very valuable and thoughtful contribution to these hearings. We appreciate your taking time from your activities at Walter Reed Hospital to come here and testify today. Dr. MOSER. Thank you, sir. Senator NELSON. Thank you very much. (Whereupon, at 11:45 a.m. the hearing was adjourned.) PAGENO="0060" PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WEDNESDAY, FEBRUARY 26, 1969 U.S. SENATE, MONOPOLY SUBCOMMITTEE OP THE SELECT COMMITrEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to notice, at 10:20 a.m., in the Cau- cus Room, Old Senate Office Biñlding, Senator Gaylord Nelson (chair- man of the subcommittee) presiding. Present: Senator Nelson. Also present: `Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist'; `Jay Cutler, acting minority coun- sel; and Elaine C. Dye, clerical assistant. Senator NELSON. Today we resume our hearings on the drug chlor- iunphenicol-widely advertised under the Parke, Davis brand name of Chloromycetin. The drug is known to cause serious blood dyscrasias, including ~plastic anemia. Though it is a valuable drug when properly used, all expert witnesses agree that it is indicated for use in an extremely lim- ited number of cases-whe,n the disease is serious, when no other drug is effective, and when the organism involved is susceptible to chloramphenicol. In 1967, over 4 million people were administered this drug, though expert testimony before this committee is that 90 to 99 percent of these patients received it for nonindicated cases. That means that over 31/2 million persons were being needlessly exposed to the threat of serious side effects. As a result, many thousands have tragically and unnecessarily con- tracted blood diseases including aplastic anemia. The widespread publicity given to this situation by these hearings resulted in a dramatic drop in the use of this drug in capsule form dur- ing the first 9 months of 1968~~~~from 31.9 to 9.5 million grams-a decrease of 70 percent over the comparable period in 1967. Injectables decreased from 7.3 to 2.9 million grams, a decrease of 60 percent. However, it is alarming tO note that use of capsules has again in- creased during the last 3 months of 1968-from 3.6 to 4.9 million grams, an increase of 36.7 percent, as compared with the last 3 months of 1967. It is interesting to note that the use of the injectable form, usually con- fined to hospitals, went down during this 3-month period from 1.6 mil- lion to 500,000 grams, a decrease of 68 percent. The purpose of these hearings is to continue to focus attention on this serious problem. No other example that has' come before this committee more dramat- ically demonstrates the ineffectiveness of the medical leadership of the Nation on drug education when measured directly against the pow- 4351 PAGENO="0062" 4352 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY er and persuasiveness of drug company promotion and advertising. Every medical journal, every reputable drug reference, and every authority on this drug has repeatedly cautioned against misuse of chioramphenicol. Yet, against the combined authorative voice of the whole medical profession, drug company promotion has carried the day hardly drawing a deep breath. If this does not alarm the AMA, I fear that nothing ever will. Our witness this morning is Dr. Paul F. Wehrle, chief physician, children's division, pediatrics and communicable diseases service at the University of Southern California School of Medicine. It that correct ~ Dr. WEmun. In the Los Angeles County General Hospital. Senator NELsoN. Doctor, the committee appreciates very much your taking the time from your busy schedule to appear before the conmiittee~ today to testify. Your biographical sketch has been presented to the committee and will be printed in full in the record, prior to your statement. (The biographical sketch follows:) CuxuIculuM VrrAE-PADI FRANCIS WEHRLE Birthdate: December 18, 1921. Birthplace: Ithaca, New York. High School: Tucson Senior High School, Tucson, Arizona, 1937-1940, Coilge: University of Arizona, 1940-1943 and summer session, 1946, B.S. (Zoology) 1947. Tulane University of Louisiana, School of Medicine, M.D. 1947. University of Illinois Graduate School, Chicago, Course in Virus Techniques- 1949, no degree. Johns Hopkins University, Baltimore, Immunochemistry-1954, no degree. Internship: Scott and White Hospitals, Temple, Texas, 1947-1948. Residency: University of Illinois', Research and Educational Hospitals (Pedi- atrics) 1948-1950. Positions Held: 1950-1951: (1) Assistant Medical Superintendent, Chicago Municipal Contagious Disease Hospital Jan. 1950-June 1951. (2) Clinical Instructor in Pediatrics University of Illinois, College of Medicine July 1950-une 1951. 1951-1953: (3) S.A. Surg (R) Public Health Service Epidemiology Intelligence Service, Communicable Disease Center, Atlanta, Georgia, July 1951-July 1953. (Promoted to Surg. (R) Inactive, 1958). (4) Research Associate, Dept. of Epidemiology and Microbiology, Uni- versity of Pittsburgh Graduate School of Public Health, Sept. W51-July 1953. (5) Lecturer in Public Health Administration, Duquesne University, Pittsburgh, Pa., 1951-1953. (6) Staff Assistant for Allocation of Gamma Globulin, National Re- search Council, National Academy of Sciences, Washington, D.C. 1953. 1953-1955: (7) Research Associate, Poliomyelitis Laboratory Department of Epi- demiology, Johns Hopkins University, Baltimore, Maryland, July 1953-June 1955. (8) Attending Pediatrician, Baltimore City Hospitals July 1953-June 1955. (9) Staff Assistant, Hepatitis Program, Committee on Sterilization of Blood and Blood Products, National Research Council National Academy of Sciences, April 1955-56. PAGENO="0063" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4353 1955-1959: (10) Assistant Professor of Pediatrics, State University of New York, Upstate Medical Center, Syraëuse, N.Y. July 1955-May, 1959. (11) Assistant Medical Director City Hospital, Syracuse, N.Y., July 1955-April 1961 and Associate Attending Physician, Syracuse Memorial Hospital. (12) Poison Control Officer, City of Syracuse, Department of Health, January 1957-April 1961. (13) Acting Chairman, Department of Microbiology, State University of New York, Upstate Medical Center, Syracuse, N.Y., October 1959-April 1961. 1961-1968 (14) Hastings Professor of Pediatrics, University of Southern Cali- fornia School of Medicine, Los Angeles, April 1, 1961 to present. (15) Head Physician, Communicable Disease Service, Los Angeles County General Hospital. (16) Chief Physician, Children's Division (Pediatrics and Communi- cable `Disease) July 1, 1964to present. (17) Lecturer, Epidemiology-Infections Disease and Tropical Medi- cine, University of California at Los Angeles Schools of Medicine and Public Health, 1966 to present. Military Service: U.S. Navy 1942-45 (much of this time in various training programs, no over- seas service). U.S. Public Health Service 1951-1953. Present rank is Surg. (R) Inactive. Specialty Board Certificate: American Board of Pediatrics 1953. Personal Data: Married 1944, 4 sons. Professional Societies: American Academy of Pediatrics American Association for the Advancement of Sciences American Association of Immunologists American Association of University, Professors American Epidemiological Society American Federation for Clinical Research American Pediatric Society American Public Health Association (Fellow) American Society for Microbiology California Medical Association Infectious Diseases Society of American International Epideini'ological Association Los Angeles Medical Society Los Angeles Academy of Medicine Los Angeles Pediatric Society, (President 66-67, Vice President 65-66) Sigma Xi Society for Pediatric Research Western Society for Pediatric Research Western Association of Physicians Southwestern Pediatric Society Organizations and Activities: (a) TJ.2.U. and Hospital: Member of Faculty Senate, U.S.C. (1962-1967) Member of Faculty Executive Committee, U.S.C. School of Medicine 1961-present) Member, U.S.C. Computer Advisory Committee (1963-65) Member, Admissions Committee, U.S.C. School of Medicine 1962-68 Member, General Hospital' Attending Staff Board of Directors (1962- present) Secretary, Research Committee, Los Angeles County General Hospital Attending Staff (1963-present) Member, Internship Advsiory Committee, Los Angeles County General Hospital (1964-present) Consultant, Staff of Hun'tington Memorial Hospital, Pasadena (1968- present) Consultant, Staff of Children's Hospital of Los Angeles (1968-present) Member, Milk Commission, Los Angeles County (1968-72) PAGENO="0064" 4354 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (b) Local Medical Organizations: Chairman, Public Health Committee Los Angeles Pediatric Society and Southern California Chapter of the Academy of Pediatrics (1963-66) 1Jice President, Los Angeles Pediatric Society, (1965-66). President, Los Angeles Pediatric Society, (1966-67). Member, Executive Committee, Southern California Chapter of Acad- emy of Pediatrics (1962-63) Member, Infectious Disease Committee, Los Angeles Tuberculosis and Health Association (1962-64) Chairman, Los Angeles Virus Club (1963-64) Scientific Advisor, Los Angeles County Medical Association Sabin Polio Vaccine Program (1962-63) (c) State Organizationss Consultant to the California State Health Dept. 1. Ad Hoc Advisory Committee on Phophylaxis of Poliomyelities (1962- 1964) 2. Epidemiology, in Water Reclamation (1962-1967) 3. Air Pollution Medical Studies Unit (1962-1967) Member, State Hospital Advisory Board, State of California (1965-69) (d) Other Universities: The Johns Hopkins University: Consultant to Health Resources Evalua- tion Program, Peru (Division of International Development) 1962-63. (e) 1Vationa~: 1. Consultant, Human Resources and Development, Agency for Inter- national Development, U.S. State Dept. (1963-ii~67) 2. Member, Environmental Hazards Committee, Academy of Pediatrics (1962-1967) Chairman (1968 to present) 3. Member, Air Pollution Training Committee, Division of Air Pollution, United States Public Health Service, Washington, D.C. (1962-1966) 4. Member, Advisory Committee on Immunization Practices to the Sur- geon General, U.S. Public Health Service (1964-1968) 5. Member, Program Area Committee on Child Health, American Public Health Association (1963-1967), Chairman, (1967 to present). 6. Member, Committee on Infections Within Hospitals, American Hos- pital Association (1964-present). 7. Consultant, to the Commanding General, Sixth U.S. Army (1965- present). 8. Member, Subcommittee on Epidemiologic Use of Hospital Data, sub- committee of the U.S. National Committee on Vital and Health Statistics 1965-present). 9. American Red Cross, Vaccine Immune Globulin Consultant Com- mittee (1964-present) 10. Member, Committee on Diagnostic Standards in Respiratory Dis- ease, American Thoracic Society, Medical Section of the National Tuber- culosis Association (1965-present) 11. Consultant in Pediatrics & Infectious Diseases, Long Beach Naval Hospital (1968-present) 12. Member, Drug Efficacy Study Panel National Research Council, National Academy of Science (1966-1968) 13. Member, Epidemiology and Disease Control Study Section, Division of Research Grants, U.S. Public Health Service, National Institutes of Health, Bethesda, Md. (1967-present) PUBLICATIoNs 1. lVehrle, P. F. and Lapper, M. H.: Aureomycin Treatment of Pertussis, J. Fed. 39 :435-441, October 1951 2. Lepper, M. H., Wehrle, P. F. and Blatt, N.: Treatment of H. Influenza Meningitis, Am. J. Dis. Child. 83:763-768, June 1952. 3. Hammon, W. MeD., Coriell, L. L., Wehrle, P. F. and Klimt, C. R. and Stokes, J. Jrs.: Evaluation of Red Cross Gamma Globulin as a Prophylactic Agent for Poliomyelitis. III. Preliminary Report of Results Based on Clinical Diagnosis, J.A.M.A. 150 :757-760, October 25, 1952. 4. Lapper, Mark H., Dowling, Harry W., Wehrle, P. F., Blatt, N. H., Spies, H. W. and Brown, M.: Meningococcic Meningitis, Treatment with Large Doses of Penicillin Compared to Treatment with Gantrisin, J. of Lab. & Clin. Med., 40 :891-900, December 1952. PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4355 5. Lepper, M. H., Blatt, N. H., Wehrle, P. F. and Spies, El. W.: Treatment of Bacterial Meningitis of Unusual Etiology and Purulent Meningitis of Unknown Origin, A.M.A. Am. J. Dis. Child., 85:295-302, March 1953. 6. Hammon, W. McC., Coriell, L. L., Wehrle, P. F. and Stokes, J. Jr.: Evalua- tion of Red Cross Gamma Globulin as a Prophylactic Agent for Poliomyelitis, IV. Final Report of Results based on Clinical DiagnosIs, J.A.M.A. 151 :1272-1285, April 11, 1953. 7. Perlstein, M. A~, Andelman, M. B., Rosner, P. C. and Wehrle, P. F.: In- cidence of Hypertension in Poliomyelitis, Pediatrics 11 :628-633, June 11953. 8. Maclachlan, W. W. G., Crum, H. E., Kleinschmidt, R. F., Wehrle, P. F.: Psittacosis, Am. J. Med. Sci. 226:157-163, August1953 9. Hammon, W. MeD., Coriell, L. L., Ludwig, E. H., McAllister, R. H., Greene, A. E., Sather, G. E., and Wehrle, P. F.: Evaluation of Red Cross Gamma Globulin as a Prophylactic Agent in PoliOmyelitis, 5. Re-Analysis of Results Based on Laboratory Confirmed Cases, J.A.M.A. 156:21-27, September 4, 1954. 10. Wehrle, P. F.: The Epidemiology of Poliomyelitis. Study of an outbreak in Payson, Utah, 1951. California Med. 82 :314-318, 1955. 11. Wehrle, P. F.: The Risk of Poliomyelitis Infection Among Exposed Hos- pital Personnel. Pediatrics 17:237-246, February, 1956. 12. Hammon, W. MeD., Coriell, L. L., Ludwig, E. H., McAllister, R. H., Sather, G. E., Greene, A. E. and Wehrle, P. F.: Effect of Passive Immunity on Infection with the Poliomyelitis Viruses, Poliomyelitis. Papers and discussions presented at the Third International Poliomyelitis Conference, pp. 159~-166, I. B. Lippincott Co., Philadelphia, 1955. 13. Wehrle, P. F.: The Diagnosis and Management of Oral Infections, Pediatric Clinics of North America, 3:871-884, 1956. 14. Wehrle, P. F., Feldman, H. A. and Kuroda, K.: Effect of Penicillins V and G on Carriers of Various Streptococcal Groups in a Children's Home, Pediatrics, 19 :208-216, 1957. 15. Wehrle, P. F., Feldman, H. A., Mou, T. W. and Shields, F.: Penicillin V Therapy of Scarlet Fever and Acute Streptococcal Pharyngitis. Clinical and Serological Response, Antibiotics Annual, 1956-57, Medical Encyclopedia, Inc., New York. 16. Wehrle, P. F., Hammon, W. MeD., Coriell, L. L. and McAllister, R. M.: Spread of Poliovirus Infection During an Epidemic of Unusual Severity. Am. J. Hyg. 65:386-403, 1957. 17. Duffy, P. E., Portnoy, B., Mauro, J. and Wehrle, P. F.: Acute Infantile Hemiplegia Secondary to Spontaneous Carotid Artery Thrombosis, Neurology, 7:664-666, September, 1957. 18. Wehrle, P. F., Reichert, R., Carbonaro, 0. and Portnoy, B.: Influence of Prior Active Immunization on the Presence of Poliovirus in the Pharynx and Stools of Family Contacts of Polio Cases, Pediatrics, 21 :353-361, 1958. 19. Wehrle, P. F., Aronovitz, G., Parkman, P. and Zechnich, R.: Poliovirus Neutralizing Antibody Levels in Pediatricians and Pre-Clinical Faculty Mem- bers, A.M.A. Am. J. Dis. Child., 95:341-348,1958. 20. Portnoy, B., Draper, T. and Wehrle, P. F.: Intramuscular Tetracycline Phosphate Complez: Serum Concentration and Local Tolerance in Infants and Young Children, Antibiotics Annual, 11957-58, p. 386-390, Medical Encyclopedia, Inc., New York. 21. Wehrle, P. F.: Mumps, Current Therapy, W. B. Saunders Co., 1959. 22. Wehrle, P. F.: Recent Development in the Epidemiology of Poliomyelitis, Bull. of the Chicago Med. Soc., 61 :60~-66, July 26, 1958. 23. Wehrle, P. F. and Hammon W. McD.: Absence of Active Immunization Against Infectious Hepatitis. Follow: up study after administration of gamma globulin, J.A.M.A., 167:2062-2065, August 23, 1958. 24. Berger, S. H., and Wehrle, P. F.: Kanamycin Serum Levels in Infants and Children. Bull. N.Y. Acad. Sd., 76:136-139, 1958. 25. Goldstein, G. and Wehrle, P. F.: The Influence of Socioeconomic Factors on the Distribution of Hepatitis in Syracuse, N.Y., Am. J. Pub. Health, 49 :473- 480, 1959. 26. Berger, S. H., Bergstrom, W. H. and Wehrle, P. F.: Renal Clearance of Kanamycin in Children, A~ntibiotics Annual 1958-59, pp. 684-686, Medical Ency- clopedia, Inc., N.Y. 27. Wehrle, P. F., Judge, M. E., Parizeau, M. P., Carbonaro, 0., Miller, M. and Zinberg, S.: Disability Associated with ECHO Virus Infection. N.Y.S.J. of Med., 59:3941-3945, 1959. 81-280 O-69--pt. 11-5 PAGENO="0066" 4356 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 28. Wehrle, P. F.: Clinical Problems Associated with Enterovirus Infection. Bull. Chicago Med. Soc. Vol. 62, No. 39, March 26, 1960. 29. Willie, C. V., Harris, Virginia G. and Wehrle, P. F.: The Epidemiology of accidental poisoning in an urban population. I. Selection of the population sample and interviewing techniques. American J. Pub. Health, 50:1705-09, 1960. 30. Wehrle, P. F., Day, P. A., Whalen, J. P., Fitzgerald, J. W. and Harris, Virginia G.: The epidemiology of accidental poisoning in an urban population II. Prevalence and distribution of poisoning. American J. Pub. Health, 50 :1925-33, 1960. 31. Wehrle, P. F., DeFreest, L., Penhollow, J. and Harris, Virginia: The Epidemiology of accidental poisoning in an urban population. III. The repeater problem in accidental poisoning. Pediatrics, 27:614-620, 1961. 32. Wehrle, P. F., Hagan, F. and Carbonaro, 0.: Transmission of Polioviruses. I. Spread of naturally-occurring poliovirus Type I in a partially immunized school population. Pediatrics, 27:748-54, 1961. 33. Wehrle, P. F., Hagan, F. and Carbonaro, 0.: Transmission of Polioviruses II. Spread of attenuated poliovirus Type III in a partially immunized school pop- ulation. Pediatrics, 27:755-61, 1961. 34. Wehrle, P. F., Carbonaro, 0., Day, P. A., Whalen, J. P., Reichart, R., and Portnoy, B.: Transmission of polioviruses. III. Prevalence of polioviruses in pharyngeal secretions of infected household contacts of patients with clinical disease. Pediatrics, 27:762-64, 1961. 35. Day, Paul A., Osborn, Winifred, Mesibov, W., Rodidoux, H. and Wehrle, P. F.: Dimethoxyphenyl penicillin: A study of its use as a prophylactic agent in the newborn nursery and in the treatment of infectious diseases in pediatric patients. Monograph prepared under the auspices of the State University of New York, edited by Paul A. Bimn, M.D., 1961. 36. Day, P. A., Osborn, Winifred, Weinberger, H. L., Mesibov, W. R., Obidoux, H., and Wehrle, P. F.: The Clinical Efficacy and Prophylactic Use of 2,6 Di- methoxyphenyl Penicillin in Children and Newborn Infants. American J. Dis. Child., 102:785-792, 1961. 37. Wehrle, P. F.: Acute Respiratory Disease. Bull. of Wadsworth General Hospital, 5:3-10, 1961. 38. Wehrle, P. F.: Hospital Acquired Staphylococcal Infections. Medical Bull. Children's Hospital of Los Angeles, 1961. 39. Wehrle, P. F., and Portnoy, B.: Viral Infection of the Respiratory Tract, Current Therapy, pp. 104-1i06, ed. H. F. Conn, W. B. Saunders Co., Phula., 1962. 40. Wehrle, P. F.: Recent Developments in Poliomyelitis Prevention. The Bul- letin L.A. County Medical Society, 10, October 4, 1962. 41. Wehrle, P. F.: Control of Accidental 1~oisoning. Pediatrics Digest, 5 :19-24, 1963. 42. Nation, N. S., Pierce, N. F., Adler, S. J., Chinnock, R. F. and Wehrle, P. F.: Human Hyperimmune Globulin in the Treatment of Tetanus. Calif. Med. 98 :305-6, June 1963. 43. Wehrle, P. F.: Poliomyelitis Prevention. Analysis of L.A.C.1I1.A. Program. Bull. Los Angeles County Med., Vol 93, No. 11, pp. 16-18, June 6, 1963. 44. Oelsner, T., Massey, F. Portnoy, B., and Wehrle, P. F.: Acute Respiratory Disease and Air Pollution in Los Angeles. Arch. Env. Health, 8:182, 1964. 45. Wehrie, P. F.: Management of Acute Viral Central Nervous System Disease. Rounds of the Teaching Staff (Wadsworth V.A. Hospital, Los Angeles), 7:431-434, No. 1, 1963. 46. Wehrle, P. F.: Treatment of Influenza. Pediatric Therapy edited by S. Gellis and B. M. Kagan, W. B. Saunders, Philadelphia, 1964, pp. 568-569. 47. Portnoy, B., and Wehrle, P. F.: Respiratory Disease of Viral Etiology. Current Concepts of Chest Diseases, Vol. III, No. 2, September 1963. 48. Wehrle, P. F.: Viral Central Nervous System Disease, GP, 28:116-123, 1963. 49. Wehrle, P. F., Leedom, J.M., Portnoy, B., Pierce, N. F., and Cowper, H. H.: Safety of Sabin Oral Poliovaccine Strains, Los Angeles County 1962-63, J.A.M.A. 186:821-826, November 1963. 50. Pierce, N. F., Portnoy, B., Leeds, N., Morrison, R. L., and Wehrle, P. F.: Encephalitis Associated with Herpes Simplex Infection Presenting as a Temporal Lobe Mass. Neurology, 14 :708-713, August, 1964. 51. Ivler, D., Thrupp, L. D., Leedom, J. M., Wehrle, P. F., and Portnoy, B.: Ampicillin in the Treatment of Acute Bacterial Meningitis Antimicrobial Agents and Chemotherapy Conference, 1963, Antibiotics Annual, 1963, pp. 335-345. PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4357 52. Portnoy, B., Leedom, J. 1VI., Hanes, B., and Wehrle, P. F.: Factors Affecting ECHO 9 Virus Recovery from Cerebrospinal Fluid. Amer. J. Med. Sd. 248:521- 527, No. 5, November 1964. 53. Wehrle, P. F.: Meningitis, Acute, Bacterial. Current Therapy, W. B. Saun- ders Co., Philadelphia, pp. 24-25, 1965. 54. Wehrle, P. F.: Food Service Management on Communicable Disease Serv- ices. American J. Dietetics, 46 :465-467, No. 6, June 1965. 55. Wehrle, P. F.: Mumps. Current Diagnosis, W. B. Saunders Co., 1966, pp. 21-22. 56. Wehrle, P. F.: Current Immunization Methods and Precautions. Calif. Med., 101 :153-159, 1964. 57. Wehrle, P. F.: Lampton, A. K., and Portnoy, B.: Prevalence and Type of Muscle Weakness Associated with ECHO 4 Infection (in preparation). 58. Thrupp, L. D., Leedom, J. M., Tyler, D., Wehrle, P. F., Brown, J. F., Mathies, A. W., and Portnoy, B.: H. influenza Meningitis: A Controlled Study of Treatment with Ampicillin. Post-Grad. Med. J. (supp), 40 :119-125, December 1964. 59. Hammer, D. I., Portnoy, B., Massey, F. M., Wayne, W., Oelsner, T., and Wehrle, P. F.: The Relationship of Symptoms to a Single Air Pollutant During A Selected Twenty-Eight Day Period. Arch. Env. Health, 10 :475, March 1965. 60. Wehrle, P. F.: Immunization Agents and Their Utilization in Our Modern Society. Proc. of First Annual Immunization Conference, U.S. Public Health ServiceS Published by Communicable Disease Center 1964, pp. 16-23. 61. Portnoy, B., Leedom, J. M., Hanes, B., Kunzman, E. E., Pierce, N. F., and Wehrle, P. F.: Aseptic Meningitis Associated with ECHO virus Type 9 Infec- tion: With Special Reference to Variability by Sex and Incidence of Paralytic Sequelae. California Med., 102 :261-267, April 1965. 62. Ivier, D., Leedom, J. M., Thrupp, L. D., Wehrle, P. F., Portnoy, B., and Mathies, A. W.: Naturally Occurring Sulfadiazine Resistant Meingococci. Anti- microbial Agents and Chemotherapy, pp. 444-450, 1964. 63. Wehrle, P. F.: Immunization Against Viral Diseases. Calif. Med. 103 :79- 86, August 1965. 64. Wehrle, P. F.: Influenza. Current Ped. Therapy, Ed. by Gellis and Kagan, W. B. Saunders Co., Philadelphia, 1965, pp. 750-751. 65. Wehrle, P. F: Salmonellosis. Current Ped. Therapy, Ed. by Gellis and Kagan, W. B. Saunders Co., Philadelphia 1965, pp. 715. 66. Wehrle, P. F. Landry-Guillain-Barre-Strohl Syndrome. Present Concepts of Etiology and Management. Bull. Los Angeles Neurological Society, (in press). 67. Wehrle, P. F.: Communicible Disease Control in Schools. Ped. Clinics of North America, 12 :985-993, No. 4, November 1965. 68. Leedom, J. M., Ivler, D., Mathies, A. W., Phrupp, L. D., Portnoy, B., and Wehrle, P. F.; Importance of Sulfadiazine Resistance in Meningococcal Disease in Civilians. N. Eng. J. of Med., 273:1395-1401, No. 26, Dec. 1965. 69. Tyler, D., Leedom, J. M., Mathies, A. W., Fremont, J. C., Thrupp, L. D., Nortnoy, B., and Wehrle, P. F.: Correlates of Sulfadiazine Resistant in Men- ingococci Isolated from Civilians. Antimicrobial Agents and Chemotherapy- 1965 pp. 358-365, 1966. 70. Mathies, A. W., .Leedom, J. M., Thrupp, L. D., Tyler, D., Portnoy, B., and Wehrle, P. F.: Experience with Anpicillin in Bacterial Meningitis. Antimicro- bial Agents and Chemotherapy-1965, pp. 610-617, 1966. 71. Thrupp, L. D., Leedom, J. M., Ivler, D., Wehrle, P. F., Portnoy, B., and Mathies, A. W.: Ampicillin Levels in the Cerebrospinal Fluid During Treatment of Bacterial Meningitis. Antimicrobial Agents and Chemotherapy-1965, pp. 206- 213, 1966. 72. Wehrle, P. F. and Mathies, A. VT.: Psittacosis, Cat-Scratch Disease and Inclusion Conjunctivitis, Tice Practice of Medicine, Publ. VT. F. Prior Co., 1966, pp. 509-516. 73. Wehrle, P. F.: 1) Available Vaccines Against Measles, Procedings St. Louis Immunization Conference, United States Public Health Service, Com- municable Disease Center, April 21, 1966. 2) The Future of Immunization. 74. Wehrle, P. F.: Current Recommendations for Poliomyelitis Immunization, Los Angeles County Medical Association Bulletin, pp. 14-15, August 18, 1966. 75. Wayne, W. S., Wehrle, P. F., and Carroll, R. E.: Oxidant Air Pollution and Ath1et~c Performance. J.A.M.A., 199 :151 154, No. 12, March 20, 1967. 76. Wehrle, P. F.: Therapy for Acute Central Nervous System Infections, Proceedings of Research Conference, National Institute of Child Health and PAGENO="0068" 4358 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Human Development and the University of Texas, Cherry Hill, Pennsylvania, June 11, 1966, pp. 295-302. 77. The Prevention of Mental Retardation Through Control of Infectious Disease, Edited by H. F. Eichenwald, PES, Pub. #1692, 1968. U.S. Government Printing Office #0-271-454. 78. Wehrle, P. F.: Immunization Against Poliomyelitis, Joint Meeting of Council on Environmental Health, American Medical Association and Com- municable Disease Center, Atlanta, Georgia, October 17, 1966, Archives of Environmental Health, Vol. 15, October 1967, pp. 485-490. 79. Wehrle, P. F., Mathies, A. W., and Leedom, J. M.: Management of Bac- terial Meningitis, Proceedings of the International Congress of Neurosurgeons, October 18-21, 1966, San Juan, Puerto Rico, Published by Wilkins and Wilkins, Clinical Neurosurgery, Vol. 14, pp. 72-85. 80. Wehrle, P. F., Mathies, A. W., Leedom, J. M., Ivler, D.: Bacterial Men- ingitis, Presented at Conference on Comparative Assessment of the Broad Spec- trum Penicillins, The New York Academy of Sciences, New York City, Decem- ber 12 & 13, 1966. N.Y. Acad. Sd., 145:488-498, 1967. 81. WehrTe, P. F.: The Role of Education in the Control of Hospital Infec- tions, Presented at the American Hospital Association Conference on Environ- mental Control in Hospitals, Chicago, Illinois, December 16, 1966. Infection Control Bull., Published by Medical Plastics, Inc., Minneapolis, Minn., American Hospital Products, February, 1967. pp. 929-938. 83. Wehrl, P. F., Leedom, J. M., and Mathies, A. W.: Treatment of Men- ingococcal Menginitis Modern Treatment, Harper and Row, Publishers, Vol. 4, No. 5, September, 1967. 83. Wehrle, P. F.: Editorial, Youth Also Pays, Arch. Environmental Health, Vol. 14, pp. 377, March 1967. 84. Wehrle, P. F.: Vaccines on the Horizon. Presented at the 4th Annual National Immunization Conference, March 28-30. 1967, San Antonio, Texas. Published by the National Communicable Disease Center, Atlanta, Georgia. 85. Leedom, J. M., Ivler, D., Mathies, A. W., Thrupp, L. D., Fremont, J., Wehrle, P. F., and Portnoy, B.: The Problem of Sulfadiazine Resistant Menin- gococci. Antimicrobial Agents and Chemotherapy, 1966, pp. 281-292. Published 1967 by the American Society for Microbiology. 86. Wehrle, P. F.: Hemophilus Influenzae Infections, Current Pediatric Therapy, 1967-68, Edited by Gellis, S. and Kagen, B. M., W. B. Saunders Com- pany, Philadelphia, 1967, pp. 765-767. 87. Wehrle, P. F., Ivler, D., Leedom, J. M., Mathies, A. W. and Portnoy, B.: Variables Important in Survival From Pneumococcal Meningitis. Presented at the International Symposium on Antibiotics, June 27th, 1967, Vienna, Austria. Published by the International Congress of Chemotherapy. B 1/5 pp. 27-34. 88. Wingert, W. A., Wehrle, P. F.: Respiratory Infections: Epidemiology, Recognition; Prevention and Treatment. Sinusitis; Pneumonia. Ambulatory Pediatrics, Edited by Green, M. and Haggerty, R. pp. 884-890, 909-918. W. B. Saunders, 1968. 89. Mathies, A. W., Jr., and Wehrle, P. F.: Management of Bacterial Men- ingitis in Children, Pediatric Clinics of North America, W. B. Saunders Co., February, 1968. pp. 185-195. 90. Mathies, Allen W., Leedom, John M., Ivler, Daniel, Wehrle, Paul F., and Portnoy, Bernard: Antibiotic Antagonism in Bacterial Meningitis. Antimicrob. Agents and Chemotherapy, 1967. 91. Wehrle, P. F.: Approaches to New Schedules of Immunization. Presented at the Fifth Annual Immunization Conference, National Communicable Disease Center, held in San Diego, California. March 14, 1968. In press NCDC. 92. Wehrle, P. F.: T~e Immune Response With Reference to the Use of Multiple Immunizations. Presented at the 97th Annual Session of the California Medical Association, San Francisco, California, March 27, 1968. In press, Cali- fornia Medicine. 93. Egeberg, Roger 0., Frasier, .S. P.. and Wehrle, P. F.: Student Health Organization: A Faculty Appraisal, Medical Opinion & Review, Vol. 4, No. 11, November, 1968. 94. Wehrle, P. F.: Meningitis, Communicable and Infectious Diseases, Edited by Franklin H. Top, Sr., 6th Edition, Chapter 37, pp. 374-390, C. V. Mosby Co., Saint Louis, 1968. 95. Wayne, Walborg, Wehrle, P. F.: Oxidant Air Pollution and School Absen- teesim. Archives of Environmental Health, DREW, P118, in press. PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4359 96. Leedom, J. M., Wehrle, P. F., Mathies, A. W., Ivier, D., and Warren, W. S.: Comments about the Role of Gentamicin in the Treatment of Meningitis in Neonates, Adapted from discussion presented at Gentamicin Conference, Chicago, Illinois, October 31, 1968, at the University of Illinois College of Medicine. (In press). PUBLIOATIONS RESULTING Fno~r COMMITTEE WORK FOR VARIOUS ORGANIZATIONS (Member of Committee, Collaborator or Editor) 1. The Student Health Project 1966; University of Southern California, 1967 2. Standards of Child Health Care: American Academy of Pediatrics, 1967 3. Guide for Services for Children with Eye Problems; American Public Health Association, 1968 4. Guide for Children with Communicative Disorders; American Public Health Association, 1968 5. Guide for Children with Cerebral Palsy; American Public Health Associa- tion, 1968 6. Tuberculosis Programs for Children; American Public Health Association (In Press) 7. Working Conference on Smallpox (Report); Office of International Re- search, N.I.H. Bethesda, 1968 8. Control of Infections Within Hospitals; American Hospital Association (In Press) 9. Use of Hospital Data for Epidemiologic and Medical Care Research; Report of Subcommittee on Epidemiologic Use of Hospital Data of National Center for Health Statistics (Submitted for final review) 10. Conference on the Pediatric Significance of Peacetime Radioactive Fallout; American Academy of Pediatrics, Lee E. Parr, Editor, Pediat. 41: Part 2, 165-378, 1968 11. Diagnostic Standards for Respiratory Disease; American Thoracic Society- National Tuberculosis and Respiratory Disease Association. (In Press) Senator NELSON. You may present your statement in any way you see fit, and if at any time you wish to extemporize on any aspect of your statement and elaborate on it, we will be pleased to have you do so. I assume you have no objection to questions during the course of your testimony. Dr. WEHRLE. No, sir; I do not. Senator NELSON. Thank you very much, Doctor. Dr. WEHRLE. Would you like to have me simply read the statement as- Senator NELSON. That is probably the best way to approach it, and then any aspect of it that you would like to elaborate on, just feel free to do so, so that we get the best possible explanation in the record. STATEMENT OP DR. PAUL F. WEHRLE, CHIEF PHYSICIAN, CHIL- DREN'S DIVISION, PEDIATRICS AND COMMUNICABLE DISEASE SERVICE, LOS ANGELES COUNTY-UNIVERSITY OP SOUTHERN CALIFORNIA MEDICAL CENTER Dr. WEHRLE. Several important antibiotics have been developed since the licensure of chioramphenicol in 1949. Controlled studies have shown that the newer drugs have equalled or surpassed chioram- phenicol in efficacy against most of the infections for which this drug had been used previously. At the present time, the only clear indica- tions for the use of chloramphenicol appear to be in typhoid fever and in severe salmonellosis. Senator NELSON. May I interrupt there just a moment? Do you know how many cases of typhoid fever occurred- PAGENO="0070" 4360 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. WEHRLE. Approximately 400 cases each year recently. There were 398 cases dunng the last year for which figures are available. Senator NELSON. Is there any estimate on the number of cases of severe salmonellosis? Dr. WEHRLE. Severe salmonellosis is very difficult to estimate. If one takes another totally different disease, measles, in years past where we had good data on cases reported to health departments and cases actually occurring by sample surveys, the reporting of measles is about ten percent. So that if you assume that salmonellosis is recorded in the same proportion as measles in contrast to the actual extent in the pop- ulation, this would mean then that with 18,000 approximately reported in 1967, that this might be 181,000 or maybe 200,000. Senator NELSON. Of severe cases? Dr. WEHRLE. Well, here again, one has all gradations, and the 18,000 probably iepresents the most severe portion of what must be a much larger number. In salmonellosis chloramphenicol may be particularly advantageous in d~bilitated patients with bacteremia, localized soft tissue or bone infections. It should be noted that even in these conditions other drugs are often effective. Occasionally, serious diseases due to other organisms which are found to be susceptible in vitro to chlora.mphenicol but resistant to less toxic drugs may be treated with chloramphenicol. It should be empha- sized that this latter situation is an unusual occurrence. Until recently in pediatrics, chloramphenicol was considered the drug of choice for Hemophilus influenza infections, particularly in meningitis due to this organism. During the last few years, reports from our institution and others clearly indicate that Ampicillin, one of the newer penicillins, is at least as effective and is substantially safer. Consequently, we have not used chloramphenicol in the treat- ment of this condition in our hospital since the completion of our con- trolled evaluation in 1966. Senator NELSON. Which hospital are you referring to? Dr. WBma~. This is formerly the Los Angeles County General Hospital. It is now known as the Los Angeles County-University of Southern California Medical Center. Senator NELSON. How large a hospital is that? Dr. WEHRLE. It is a hospital of over 2,000 beds. It cares for approxi- mately close to 200,000 inpatients per year, and the total inpatient and outpatient load is nearly a million patient visits per year. Senator NELSON. Counting both outpatients and- Dr. WEm~. Counting both outpatients and inpatients. It is in my understanding the largest acute hospital in the world. Senator NELSON. Do you have any statistics on how many times during the past year or for any recent year chloramphenicol has been prescribed for children within your hospital? Dr. WEHRLD. The use in children has been reduced substantially during the last 5 years, and at the present time, the use in children is negligible. This drug is used in our hospital most frequently on the obstetrical service and on the surgical services. Senator NELSON. Are there any rules or practices followed within your hospital in the use of the drug; that is, if a prescription is written for the drug, does it have to be countersigned by anybody? PAGENO="0071" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4361 Dr. WEHELE. If the prescription is written for this drug, the attend- ing physician in charge of that service ~ expected to approve its use. In the Children's Division, we use it for cases of typhoid, which is seen most frequently among people who visit in Mexico and from Mexicans who develop the disease in Los Angeles County. For severe sal- monellosis, we also use it. We rarely use it for other conditions on our service. Senator NELSON. I am sorry I didn't follow you. You said if it is prescribed by whom, the attending physician must approve? Dr. WEHRLE. The system that we have in our hospital is very similar to the system in other large teaching hospitals. The attending physician, whether he be a member of the full-time faculty or whether he be a well-qualified physician in practice in the community and our clinical faculty is in charge of his particular service in the hospital. Prescription orders written by the intern or the resident must be done with the approval of the attending physician on that service. Senator NELSON. Is any record kept in your hispital of the use of chioramphenicol and the indications for which it was used? Dr. WEHRLE. The Therapeutics Committee did this for a period of time. The usage of chloramphenicol has fallen substantially, and after monitoring it on a very careful individual basis for several years, this practice was delegated to the chief of each service about, I guess, 3 or 4 years ago. Senator NELSON. Do you have any records which the hospital has kept over the past half dozen years on the use of chloramphenicol? Dr. WEHRLE. Yes; I have figures that were supplied to me by Mr. Stanley Seibert, our chief pharmacist, on the usage of chioramphen- icol. If you would like a copy of these- Senator NELSON. Yes; I would like to see that. Dr. WEHRLE. These records, I : believe, are of particular interest, and if I may, I would like to call your attention to two things. First I would like to call your attention to two things. First I would call your attention to the fact that 250 milligram capsules are recorded in the first column on the left so that one must devide by four in order to determine the number of grams. Usage for the preparations in the intermediate three columns is negligible. In the column on the far right chlora~mphenicol for parenteral use is recorded in grams. Senator NELSON. The far right column is grams? Dr. WEHRLE. The far right column is grams. The far left is 250 milligrams individual capsules. The two features these figures show very clearly are, No. 1, the peak usage of this drug was achieved in the 1958 through 1960 period when staphylococcal disease was a major problem and before the time when the semisynthetic penicillins were available to any extent or were well known. Senator NELSON. Is that Ampicillin? Dr. WEHRLE. This was Methicillin that came out first. Senator NELSON. It is Ampicillin that is used now? Dr. WEHRLE. Ampicillin came out later. I believe that Ampicillin was made available in 1963, I believe. Am I correct? Does anyone know? I believe it was around 1963, possibly 1964. The peak usage then was back sometime ago at a time when we didn't have many of the kinds of drugs that we have at the present time. PAGENO="0072" 4362 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The other thing that I would point out is the sharp decline in the last several years, a progressive decline from 157,000 capsules in 1963 down to last year with some 32,000 capsules, which represents about 8,000 grams. I would call your attention to the fact that the 8,000 grams in cap- sules is roughly equivalent to the 8,000 grams used in the parenteral form. These two are approximately equal at this time. I would further point out that our hospital is one that is set up and designed expressly for the care of the desperately ill individual, and it is our responsibility to care for all patients in Los Angeles County that are deemed hazardous in terms of infectious problems for other hospitals in that area. We have the Communicable Disease Service. Senator NELSON. What percentage of chloramphenicol is admin- istered in your hospital by capsules vis-a-vis injectables, do you know? Dr. WEHRLE. Parenteral use is equivalent to the capsule use in terms of numbers of grams of drugs dispensed. This would indicate to me that relatively little of this is used for the treatment of outpatients. Senator NELSON. Very little of what? Dr. WEHRLE. Very little of the drug is going into patients who are ambulatory and treated in our outpatient program. The reason for this is that this drug is well absorbed. It is well tol- erated by the gastrointestinal route and consequently after the initial serious, desperate illness is over, the physician is likely to change to the oral use of the drug while the patient is still in the hospital simply to save the discomfort of injection and the additional nursing time necessary for injection. Senator NELSON. This chart will be printed in the record at this point. (The chart follows:) CHLORAMPHENICOL PURCHASES OF LOS ANGELES COUNTY-UNIVERSITY OF SOUTHERN CALIFORNIA MEDICAL CENTER-UTILIZATION OF CHLORAMPHENICOL PRODUCTS Year Chloramphenicol 250 mg capsules Chloramphenicol solution 0.5 g./2 cc. Chloramphenicol palmitate 125 mg.14 cc. Chloramphenicol 1.0 g. I.M. Chloramphenicol sodium succinate 1 gm.f1O cc. 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 25,104 35,792 27,600 64,800 118,700 182,400 271,800 330,300 395,200 79,000 104,200 157,900 147,600 131,700 119,600 93, 600 32,400 348 8,320 15,548 5,490 10,250 18,580 32,340 16,520 (1) (`) (1) (`) (`) (`) 20 (`) (`) 598 1,800 2,278 4,026 4,896 6,048 7,272 8,352 8,768 1,800 2,007 1,598 2,016 1,008 1,440 480 48 (1) (1) 106 4,800 1,500 16,600 24,882 26,000 23, 200 3,000 4,250 7,000 4,000 4,000 5,000 4, 500 1,000 (1) (1) (`) (1) (`) (`) (`) 200,220 355, 000 127,000 25,802 36,494 42,924 46,000 35,000 23, 188 8,000 1 Data not available. Senator NELSON. Please go ahead, Doctor. Dr. WEHELE. The continued widespread usage of chioramphenicol, often for what are apparently minor illnesses, or illness for which another drug is of at least equal or greater effectiveness, is difficult to understand in view of the mounting evidence of serious toxicity. While the specific toxicity of this drug to newborn infants can be controlled PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4363 by reducing the dosage-this is the gray baby syndrome-no method of predicting or preventing bone marrow depression has yet been found. The California Medical Association study, published more than 2 years ago, indicated a fatal outcome attributed to this drug in one of each approximately 20,000 patients treated with chloramphenicol. The continued pattern of frequent usage, despite the availability of other drugs of equal or greater effectiveness, appears to be due to at least five factors. Senator NELSON. May I interrupt for a moment. I have been cu- rious about the statistics in the California study in that we have had witnesses, doctors, testify that in a case where the doctor discovers that it was administered for a nonindicated case he obviously isn't going to report it because he's subject to a lawsuit. I don't know how they extrapolated or how they got this figure, one in 20,000, from the study. How accurate an estimate do you think this record represents? Dr. WEHRLE. I think this is certainly subject to error in each direc- tion. I think this is the best estimate that anyone has come up with to date, but it should be regarded as an estimate and one that may be inaccurate and presents only part of the picture in each direction. I simply don't know whether this is iii the center or whether this is to one extreme, the high extreme or the low extreme. I simply don't know. Senator NELSON. Are there any other blood dyscrasias that result as a result of administration of chloramphenicol? Dr. WEHRLE. I think it should be recognized that this is based on fatal episodes, and this is a death certificate type of reporting. I would not-let me back up one moment. There are other kinds of problems that do occur. For example, in patients treated in the controlled evalu- ation when we were comparing chlorarnphenicol and Ampicillin in the treatment of meningitis, about 10 percent of the patients who received chlora.mphenicol had some evidence of marrow depression in terms of development of anemia or some lowering of the white count. One of these patients developed a severe granulocytopenia; in other words, a very marked depression of the bacteria-fighting cells of the blood. He developed a staphiocci pneumonia, presumably as a conse- quence, which was an extremely serious infection. This was fortunately controlled by the use of the Methicillin. Now, I have no idea in these one of 20,000 patients whether there are additional patients who may have died of asepsis secondary to marrow depression with the use of this particular drug. On the other hand, there is no way of knowing how many of these patients may have had a suppression of the marrow for presently unknown and unrelated reasons. Senator NELSON. Is it possible that they may have had some bone marrow depression which they lived with a good many years without dying, of course, and not being reported in the statistics? Dr. WEHRLE. I think this quite possible; yes. Senator NELSON. Did I understand you to say that the one in 20,000 figure was based on death certificate- Dr. WEHRLE. This was a survey of deaths or fatalities, and I am not certain whether this was from the vital statistics approach or a survey approach. Senator NELSON. Well, obviously then, if these statistics were based on deaths as a consequence of aplastic anemia, they certainly don't PAGENO="0074" 4364 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY include any statistics of those physicians who didn't report that it was caused by chioramphenicol. Dr. WEIIRLE. This is certainly correct, and I think some of the problems in death certificate reporting are well known to the members of your committee. The death certificate reporting is as good as we have for many kinds of problems, but still such reporting is still not entirely accurate by any means. Senator NELSON. You may proceed, Doctor. Dr. WEHRLE. The five factors which may be at least in part respon- sible for the continued usage are: 1. The initial availability at a time when widespread staphylococcal disease was occurring and the preferred drugs, the newer penicil- linase resistant penicillins, were not yet available. 2. Its preferred role by most pediatricians for the treatment of Hemophilus meningitis and other serious illnesses for many years. Just parenthetically, it is apparent that a drug that can effectively treat a condition that is 100-percent fatal if untreated is a most im- pressive drug and develops an aura quickly that may spread to many other conditions. 3. The excellent diffusion, both in vitro and in vivo. This charac- teristic gives impressive zones of inhibition in the usual hospital bacteriology laboratory, whereas another antibiotic with smaller zones of activity may be equally effective clinically. Mr. Go1u~oN. Doctor, may I go back to No. 2. Do you think the pediatricians throughout the country are generally aware that Ampi- cillin is better for Hemophilus meningitis? Dr. WEHRLE. I think there has been a considerable change in most hospitals around the country in the use of this drug for this condition. Dr. Martha Yow in Houston has published on a number of occa- sions. There have been several Canadian hospitals that have reported their experiences with this drug, in Toronto particularly. One of the Boston hospitals has reported experience with this particular drug. My associates and I have made several reports, and I think have the largest experience with this particular drug. But I think as in any- thing else the physician's admonition of don't be the first to take up the new, nor the last to discard the old holds here. A change has taken place over the last 2 or 3 years and I think the acceptance of Ampicillin has made a profound difference in the consumption of chioramphenicol by pediatricians around the country. Mr. GORDON. Would you know whether the manufacturers of Am- picillin are pushing that particular drug for this particular use with as great vigor as Parke, Davis pushed their drug? Dr. WEHRLE. It is my impression that people who make Ampicilirn are most anxious to sell it wherever they can. Mr. GORDON. Your hospital did a study of relative efficacy between Ampicillin and chloramphenicol. Was it for this disease only or for what? Dr. WEHELE. This was the main and I think the most important one of the antibiotic controls of the control studies that we have done in recent years. We have done others, but this one I think is the one that bears directly on this problem. Mr. GORDON. Can we get a copy of that? PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4365 Dr. WEHRLE. Yes, sir. I will have to mail you one. I seem to have forgotten my copies. The references are attached to the last page of my bibliography. We have also included the Houston studies, reference No. 6, by Barrett, Eardley, Yow, and Leverett; and the studies from our institution are items Nos. 3, 4, 5, 7, and 8.' The first two references pertain to Drs. Burns, Hodgman, and Cass, and Drs. Hodgman and Burns concerning the problem with the gray baby syndrome in young infants who receive this drug in what we now consider excessive dosage. Those are also from the Los Angeles group. In addition to the laboratory studies that I just mentioned where the extreme diffusibility of this drug is clearly evident, item 4 points out- Senator NELSON. May I interrupt for 1 second. I have a question. Dr. WEHRLE. Yes. Senator NELSON. You say, "whereas another antibiotic with smaller zones of activity may be equally effective clinically," are you referring to the situation whereas chloramphenicol may be very effective, an invitro study may indicate that another antibiotic with a smaller zone of activity, as you put it, may be just as effective? Is that what you are referring to? Dr. WEHRLE. Yes, sir. This is exactly what I mean. In other words, chloramphenicol is a drug that does diffuse very beautifully through tissues, into the eye, for example, into ~joints, areas such as this. It also diffuses very well through culture media used to test for antibiotic sus- ceptibility. Consequently, two drugs that may have the same activity in tube dilutions where you have the drug already diluted may be different, on an agar plate where diffusion plays a part in determining the disk or zone size. So consequently, chloramphenicol, a drug that diffuses very beauti- fully, gives very impressive rings where the bacteria don't grow around the disk containing this particular antibiotic, whereas one that diffuses very poorly, like polymyxin, for example, may have the same tube activity, yet the zone is very difficult to see. It is a very small zone. Now, this can mislead the hospital bacteriologist on occasion unless experienced in this problem, and can certainly mislead the physician if the physician stops and looks at the plates from the laboratory on his way to the patient's bedside. Senator Nm~soN. Haven't clinical studies indicated over the past few years those instances where, say, Ampicillin would be as effective as chloramphenicol though less toxic? Dr. WEHRLE. I personally feel so; yes sir. 4. A continuing aggressive advertising and detailing program, sug- gesting that the physician can "trust" this drug. This has continued to perpetuate the habit, established in earlier years, of prescribing this drug for both major as well as minor problems. 5. The availability of both oral and parenteral dosage forms which are comparatively free from minor gastrointestinal and local reaction. I think it is annarent that a physician is interested in the welfare of his patient. This drug is so well tolerated by the intravenous route as well as by the oral route that in fact, I think, has often influenced the physician's judgment in prescribing it. ~ See apps. IV-XI, pp. 4799-4857, infra. PAGENO="0076" 4366 COMPETITIVE P OBLEMS IN THE DRUG INDUSTRY The problem of continuing substantial usage of a potentially haz- ardous drug despite decreasing indications poses a problem with no easy solution. There are several possible avenues of approach and per- haps one or a combination of several may help place the future usage of this drug in a position more consistent with its indications. These are: 1. Limiting of availability to the hospital pharmacy. This drug could still be made available from such pharmacies to the occasional ambulatory patient for whom it might be indicated. The obvious dis- advantages to this restriction are a likelihood of increased drug cost to the patient and considerable inconvenience to at least some of the patients, since in the rural areas particularly there are more neighbor- hood pharmacies than there are hospitals. The obvious inference to the physician with such a limitation would be that he should think of alternates if it were to be considered hazardous enough to require dis- pensing only by the hospital pharmacy. Regardless of these obvious disadvantages, this approach would seem preferable to the use of regis- try numbers on prescriptions as is the case with narcotics. 2. Restrictions on advertising and detailing of this product. Despite changes in recent years, the notice of hazards is often in smaller type and in a less conspicuous location than is the statement regarding real or presumed benefits. Advertising should be restricted to illnesses for which the drug is preferred by a responsible group. Misleading illustrations, such as the bronchoscope, should be avoided. Such illustrations imply that chlor- amphenicol is useful for a variety of respiratory illnesses. Senator NELSON. May I interrupt a moment there? Dr. WEH.RLE. Yes. Senator NELSON. I have seen a number of those ads in which the bronchoscope is pictured. Are there any respiratory illnesses for which chloramphenicol is indicated? Dr. WEHRLE. In my opinion, none whatsoever. I think we have less toxic drugs for these infections at the present time. Senator NELSON. Is it indicated for any of the virus infections? Dr. WEm~E. Absolutely not. Senator NELSON. It would seem to me, at least, that the FDA ought to prohibit the use of the picture of the bronchoscope which obviously indicates to the physician the area in which the drug is effective. Dr. WEHRLE. This, in my opinion, would be a great step forward. Physicians should indicate gross violations in claims by pharma- ceutical house representatives, whose position is obviously dependent on sales of this particular drug. Such representatives have been well known to suggest antibiotic X for influenza. And by "antibiotic X," I do not mean chloramphenicol specifically but I mean any antibiotic that the particular representative is interested in selling. I would also point out that there are extremely ethical detail people who present the facts very clearly and very fairly. There are people who tend to deviate, and I personally feel strongly that it is the respon- sibility of the physician to indicate such violations very clearly to the pharmaceutical house and as well perhaps to the FDA. 3. Improving data regarding hazards, and publicizing this informa- tion to the medical profession. Methods of improving both hospital and death certificate information should be considered. Individual physician reporting for infectious diseases has failed and it not likely PAGENO="0077" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4367 to be more effective for reporting drug reactions. Oniy the more severe drug reactions would be discovered from hospital and death reporting, but these instance are, of course, our greatest concern. The greater attention currently devoted to hospital organization and toward de- partmental program and function by the Joint Commission on Ac- creditation of Hospitals provides substantial assurance that hospital sources of information may be improved. 4. Surveillance of local or regional usage patterns of particular drugs. Given the authority and personnel to do so, the Food and Drug Administration might be able to detect factors which- influence exces- sive usage of a drug in a region or in a local area. This approach appears to deserve study, as it may give a better insight as to why well- motivated and skillful physicians continue to persist in particular patterns of behavior after the factors establishing those patterns have ceased to operate. Comparative usage figures of an antibiotic such as chloramphenicol for several areas during a widespread influenza out- break might be particularly revealing and may also be helpful in designing appropriate methods of approach. Senator NELSON. Is it indicated for influenza~? Dr. WEHRLE. Absolutely not, butT think that this point might give a hint as to where the problem really is. One of the things that I would love to know, for example, is where the drug is going in Los Angeles, just as a matter of curiosity to see what types of physicians are using it and for what purposes. I think that one of the responsibilities that medicine has is in terms of the education and the assistance of the members of the profession. And I would feel very strongly that such information would be most helpful to guide efforts on the part of either the Food and Drug Ad- ministration or the post graduate programs in medical education in many of the schools and hospitals. The staff in many of the hospitals is providing guidance, and indications as to drug usage. I would not restrict this to chloramphenicol. I think that these would be data that would be very helpful to those charged with the responsibility of post graduate education of physicians. Senator NELSON. How would you find those statistics? Dr. WEHRLE. These could be collected in several ways. The easiest way would be to simply look at the distribution of a drug in a com- munity, and you know pretty well the physicians in the neighborhood and what pattern of practice they have. And if the usage is eight times or 10 times or 20 times as high in East Los Angeles as it is in San Gabriel or if you see other widespread differences in pattern, then 1 think it would be possible to be more selective in terms of who is prescribing and for what general kind of conditions. This would give a lead for the first time as to where the drug is going within a community. Senator NELSON. Well, mechanically, how would you collect it; how - much is sold to the pharmacist in the area and how it was dispensed, that sort of thing? Dr. WEHRLE. I would think that data on sales from pharmacies should be kept by the pharmacist. He's got to keep track of his stock and how much is going in and how much is going out. And I see no reason why such figures could not be made available. Senator NELSON. But then you'd only be guessing, unless you did some survey about how it was used, wouldn't you? PAGENO="0078" 4368 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY `Dr. WEHRLE. That is correct. But I think this gives at least a picture as to whether this is a uniform problem or a prc~b1em restricted to par- ticular areas. It may be that most of the Nation's chloramphenicol is going into particular portions of ten of the major cities or maybe it is predominantly a rural problem for the practitioner who does not, because of one of several reasons, get into the medical center to see what is happening. This technique is at least a step toward finding out where the prob- lem really is. I simply don't know drug usage patterns even in Los Angeles. In conclusion, the widespread usage of chloramphenicol, a drug with limited and decreasing usefulness, has continued during a period of substantial publicity and resulting greater awareness of its hazards. This poses a problem in designing the proper method of reducing usage without the establishment of unduly burdensome restrictions. Several methods of approach to this problem are suggested which may also have application for other particularly hazardous drugs in the future. Senator NELSON. Your primary suggestion was, as I recall it, the same as Dr. Dameshek's, and perhaps some others, before the commit- tee that it only be dispensed in a hospital or through a hospital phar- macy, is that correct? Dr. WEHRLE. This is the easiest one I think to accomplish. There will be obvious objections to this, and I have indicated some of my concerns. But I think this would be the most workable of several dif- ferent approaches. As far as the usefulness of this and hampering its use by such a route, I would point out that about equal quantities of the drug have been used for some time in the oral and injectable forms in our hos- pital which would again indicate that the great bulk of this is going into hospitalized patients for inpatient use. Senator NELSON. We've had some of the doctors, including one at the FDA, who expressed the view that most of the injectables are used in hospitals. We hope to have some statistics on that tomorrow. But at least that is what I was advised by a couple of different doc- tors. And if that is the case, that would explain the statistics of the past year-that is, the dramatic drop in the use in both capsule form and injecta~ble, and then in the first 6 months of 1968 versus the first month of 1967. And then for some reason, and this may be the reason, capsule use in the last 3 months of 1968 increased from 3.6 million to 4.9 million grams, that is, 1968 over 1967, a 36-percent increase of 1968 over the last 3 months of 1967, whereas in injectable form it went down during this 3-month period from 1,600,000 grams to 500,000 grams, If, in your hospital, it was 50-50, that was typical of hospital administration, then something else has to account for the increase of the capsule use elsewhere. Dr. WEHRLE. That is correct. And I wondered and speculated a bit about this. Now, if there is no artifact in these figures, in other words, if the producers of chioramphenicol are not getting large numbers of grams approved for next year's use, something like that, then I would think that it is most interesting that this is happening during the respiratory disease season and during the influenza outbreak, first the Hong Kong variety and currently the B which is beginning arise in some areas. So I think that this would indicate the need to at least PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4369 explore item 4 in the suggestions to find out where this drug is really going. I would also like to urge you to think very carefully about the state- ment that most injectabies are used in hospitals. There are some con- spicuous drugs which don't follow this pattern. I cite particularly benzathine penicillin. Benzathine penicillin is one with a very long action. Intermediate doses provide low levels of ~penicillin for a period of 2 weeks approximately and larger doses for a period of about a month. This is a most popular drug for outpatient use in the treat- ment of streptococcal pharyngitis and in the prevention of rheumatic fever for the short and the longer periods respectively. Senator Nri~soN. I was using the injectable cases applying solely to chloramphenicol. Dr. WEHRLE. I would certainly agree. Senator NELSON. I suppose there is some confusion about it. We liave had testimony here from people like Dr. Lepper, Dr. Best, Dr. Dameshek and others, all of whom have stated it is widely overused, and I think Dr. Dameshek said it only ought to be administered in hos- pitals. If, in fact, it is used for the purposes, the limited purposes in- dicated, that is, in general that the disease must be very serious, no other antibiotic is effective, and chloramphenicol is effective against a particular organism, if that is the case, then you have, you probably have a patient who is or ought to be in the hospital. And hospital administration conforms much more consistently to the indicated use than outside the hospital. I believe the testimony was that Johns Hopkins, for quite some time, has simply had a rule that anytime it is prescribed, it has to be countersigned by the head of the service or someone else. This is a difficult state to get to, but in any event, my statement, based on conversations with some of the doctors, referred only to chloramphenicol as to injectables. Dr. WEHRLE. Yes. Senator NELSON. We had testimony from the doctors I just men- tioned and some others, all of whom estimated that chloramphenicol was much more widely used than it should have been and their esti- mates were that 90 to 99 percent of the chloramphenicol administered was in their judgment administered for a nonindicated case. Do you have any judgment or view on the administration of chloramphenicol in this respect? Dr. WEHELE. Yes, sir. I think 1 would like, though, to qualify this very carefully by indicating that it is difficult for a physician in one particular field to be completely comfortable about all of the indica- tions and concerns that people in other fields have. Now, the best estimate that I can come up with concerns an extrap- olation of the pattern of usage in our particular institution. We might approach this from the standpoint of current usage and consider this drug to be used predominantly in inpatients. If we begin by indicating that the average of 1967-1968 usage was some 27,000 grams, about half parenteral and half oral, in the 798,000 patient visits to our hospital during the single year,: this would work out to approximately 35 milligrams per patient visit. Obviously, relatively few patients are receiving this drug. Now, if you further restrict this to only inpatients; these would aver- age 188,000 patients for each of these 2 years. If all chloramphenicol PAGENO="0080" 4370 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY used were in inpatients, this would average approximately 140 milli- grams per inpatient, that is per patient who was actually admitted to the hospital and remained for some time. Applying these data to the nearly 30 million hospital inpatients in the United States last year, as reported in the August 1968 issue of the Journal of Hospitals, published by the American Hospital Association, one would come to a total of approximately 2 million grams, about 1 million parenteral, about 1 million oral, for these 30 million patients admitted to hospitals all over the United States, including ours, providing our yardstick applied to the other hospitals. This figure takes account of the decreas- ing utilization in our hospital during recent years. Now, if you further recall that this figure is based on a hospital that cares for more seriously ill, more long-neglected, more difficult to treat and referred patients than the average hospital in the United States, the figure of about 1 million oral and 1 million parenteral grams usage would be in my opinion a high level or a conservative level as far as total usage goes. Senator NELSON. Do I understa.nd you to be saying that if the same yardstick that is applied for the use of chloramphenicol in your hospi- tal were applied to all hospitals in the United States, that would mean &0 million patients in all hospitals; is that correct? Dr. WEHRLE. That is correct. Senator NELSON. 30 million patients in all hospitals, during a single year would receive, would be administered 2 million grams, is that correct? Dr. WEHIWE. This is correct, about half of which would be oral, about half of which would be parenteral. Senator NELSON. In 1967, total number of grams used in the country was 42,800,000. In 1968, it dropped to 17,500,000. In 1967 and even in 1968, far and away most of the drug was being prescribed outside the hospital. Dr. WEHRLE. Yes, sir. I would certainly agree. It looks as though the usage in the profession as a whole around the country is running approximately tenfold, at least tenfold higher than we are currently. Senator NELSON. You mean in the whole profession? Dr. WEHRLE. Pardon? Senator NELSON. Who is using it tenfold higher, that is the average use in medicine in general is tenfold higher Dr. WEHRLE. Yes. Senator NELSON (continuing). And in your hospital? Dr. WEHRLE. Yes, sir; this is correct. This is what it would appear here. Obviously there are at least 10 times as many grams being mar- keted in respect to the numbers of patients admitted to other hospitals than to ours. Senator NELSON. And this is despite the qualitative figure in terms of your patient, that is, that you have a high percentage of seriously ill patients, is that correct? Dr. WEHRLE. This is correct, yes. Senator NELSON. Well, thank you very much, Doctor, for your most valuable testimony. We appreciate your taking time to come here and appear before the committee. It has been most helpful to us. We will recess until tomorrow morning at 10 o'clock. (Whereupon. at 11:15 a.m., the subcommittee adjourned, to recon- vene at 10 a.m., Thursday, February 27, 1969.) PAGENO="0081" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, FEBRUARY 27, 1969 U.S. SENATE, MONOPOLY SuBooMMIrri~E OF THE. SELECT COMMITI'EE ON SMALL BUSINESS, Wa~shington, D.C. The subcommittee met, pursuant to recess, at 10:10 a.m., in the Caucus Room, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; Jay Cutler, acting minority coun- sel, and Elaine C. Dye, clerical assistant. Senator NELSON. Our witness this morning is Dr. Herbert Ley, Commissioner of Food and Drugs. Dr. Ley, the committee appreciates your taking time to come here this morning and present your testimony. You may proceed to present it in any fashion you desire. And if at any time you wish to elaborate on anything in your prepared text, feel free to do so. We may have some questions from time to time. Go ahead, Dr. Ley. STATEMENT OF DR. HERBERT L. LEY, JR., COMMISSIONER OF FOOD AND DRUGS, CONSUMER PROTECTION AND ENVIRONMENTAL HEALTH SERVICE, PUBLIC HEALTH SERVICE; ACCOMPANIED BY DR. B. HARVEY MINCHEW, ACTING DIRECTOR, BUREAU OF MEDICINE, FDA; AND WILLIAM W. GOODRICH, GENERAL COUN- SEL, OEFICE OF GENERAL COUNSEL, HEW Dr. LEY. Mr. Chairman, I appreciate the opportunity of appear- ing before your committee today to discuss the current status of the antibiotic, chioramphenicol. Approximately 1 year ago, we came before you to discuss FDA's actions and intentions in regulating the interstate distribution of this drug. Today, I would like to report on the steps we have taken and the results of these actions. Shortly after the hearing in February of 1968, we notified the Parke, Davis Co. which markets the antibiotic under the trade name Chioromycetin, that substantial revision in the labeling would be necessary. The new labeling was completed and approved in April 1968. Senator NELsoN. In preparing the new label, who does the original preparation? Dr. LEY. The original preparation in this particular case was done 81-280 O-69-pt. 11-6 4371 PAGENO="0082" 4372 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY by the Bureau of Medicine's staff and then subsequently discussed with the firm. The firm had themselves prepared another draft so that actually the preparation was bilateral in this case. Senator NELSON. What is the normal practice? Dr. LET. The normal practice, Senator, is for the firm to initiate the labelmg change. Senator NELSON. Arid if my recollection is correct, the firm prepares the labeling and at some stage the FDA reviews it, but ordinarily the FDA does not approve it prior to its being used? Dr. LET. That is correct, Senator. Senator NELSON. In this particular case your department- Dr. L~r. May I make one minor correction? Senator NELSON. Yes, sir. Dr. LET. The labeling must be approved by FDA before it is used to accompany packages of the drug. Senator NELSON. What about the indications and precautions and description of uses that are put in advertising? Dr. LET. The advertising claims and promotional claims need not be precleared by the FDA. However, they are based on labeling which is, and must be cleared by the agency before the labeling may be used as a basis for the advertisement or promotion. Senator NELSON. Referring to that aspect of the advertising which lists the warnings and the precautions, does that have prior approval? Dr. LET. The body of information from which the warnings and precautions in an advertisement comes must have approval. Recent ads and the only current ad for this product features the entire package insert language for warnings and precautions. Senator NELSON. On chloramphenicol, you mean? Dr. LET. Yes, sir. Senator NELSON. Is this a special case? Dr. LET. This as it has evolved is a special case. With other drugs the manufacturer may prepare a brief summary which summarizes information in the package insert. That was not done in the case of this drug in any of the advertisements that were created after the committee hearing last year. Senator NELSON. What about other ads where they are, of course, required to insert a warning and the precautions. Is that the language of the manufacturer, or is it language specifically approved by the FDA for all drugs? Dr. LET. In the case where specific warning statements are featured in the package insert and reproduced in the advertisements, that lan- guage must be approved by the agency. Senator NELSON. But if they write an advertisement, do they have to include the warnings and precautions as are included in the package insert? Dr. LET. They must include these. Senator NELSON. You may proceed. Dr. LET. The revised labeling included a carefully worded indica- tions section expressed in restrictive terms. It included an estimate of the incidence of fatal anlastic anemia, based on a report made Jan- uary 1, 19G7, by the California Medical Association and State depart- ment of public health. It also states the desirability of hospitalizing patients being treated with chioramphenicol to facilitate observation during therapy. PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4373 Senator NELSON. The figure used on the incidents of aplastic anemia from the California study-I'm not exactly clear from my memory how that study achieved the statistics. It was the opinion, I believe, of Dr. Wehrle, who testified yesterday, that these statistics were gathered prom death certificates. Is that correct? Dr. LEY. If I may, Senator, I would like to outline the details of the California study leading to the determination of two separate risk incidents of aplastic anemia following chloramphenicol adminis~ tration, and I'm referring specifically to the summary at the beginning of the California report. The California group chose from death certificates filed in Califor- nia for an 18-month period all those who were related to hematologic disorder. They then separated from these patients who had aplastic anemia and subsequently those that had fatal aplastic anemia. From this culling- Senator NELSON. These were all death certificates? Dr. LET. These were all death certificates. That was the basic source of information. From this culling they uncovered 10 patients who had received chioramphenicol who died from aplastic anemia. This gives a numerator figure. For the denominator the total number of patients in California who had received chloramphenicol over the same period, they then made a survey of physicians and pharmacies to determine the usage. And they estimated that 220,000 patients had received chloram- phenicol over the corresponding period. There is one other computation which is critical here in arriving at the risk figure which the California group published in the determina- tion of the average dosage per patient of chloramphenicol, I read di- rectly from the report. "If the risk is calculated on the average dose of 4.5 grams during 1965, the risk is one in 40,500." Senator NELSON. Would you please start that sentence over again. Dr. LEY. "If the risk is calculated on the basis of an average dose of 4.5 grams per patient"-that was my insert-"during 1965, the risk"-and I insert "of aplastic anemia developing"-"is one in 40,500." The next sentence, "If the risk is calculated on the basis of an average dose of 7.5 grams-I insert "per patient"-"it"-the risk-"is one in 24,200." These were the two figures of risk identified by the California group which bracketed in their opinion the probability of the chloramphen- icol-receiving patient developing aplastic anemia. Senator NELSON. Well, doesn't this extrapolation made from these statistics have a built-in conservative factor; that is, you find 10 cases reported to have died from aplastic anemia. How often are you going to have cases in which the drug was prescribed for a nonindicated case and the physician simply isn't going to report that this was the case? Dr. LEY. There is a possible bias here in the initial failure to report a death due to aplastic anemia. It could introduce a bias as you sug- gest. Death certificates are now required in all of our States and must indicate a specific diagnosis, primary diagnosis as the cause of death. The group chose those death certificates in which physicians had en- tered the diagnosis, aplastic anemia, as the cause of death. Now, it is possible that they may have been some death certificates that did not include this information. That is a possibility in the study. PAGENO="0084" 4374 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Well, the statistics in the California report would be 10 more cases out of two hundred and some thousand and you've doubled the incidents. Dr. LEY. That is correct, sir. Senator NELSON. Please go ahead. Dr. LEY. Cautionary information is included regarding use of the antibiotic in pregnancy and lactation. Leukemia is listed as an addi- tional adverse reaction. On May 7, 1968, following approval of the new labeling, we sent a "Dear Doctor" letter to every physician in the country calling atten- tion to the proper indications for use and the strengthened warning about the hazards of this drug. The letter was also sent to all hospital administrators. The revised labeling was included with the letters, along with a facsimile of our Drug Experience Report form. Physi- cians were requested to report any adverse reactions associated with the use of chloramphenicol. I'd like to submit for the record a copy of this letter and the enclosures. Senator NELSON. Thank you. Those will be included in the record. (The information follows:) PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4375 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FOOD AND DRUG ADMINISTRATION WASHINGTON. D.C. 20204 May 7, 1968 Dear Doctor: Serious and often fatal blood dyscrasias are known to occur following the administration of chloramphenicol. Prominent warning to this effect has been part of the approved labeling for this drug since 1952, and this information has been disseminated in the medical and lay press, including editorials in the Journal of the American Medical Association. Because the amount of chloramphenicol distributed exceeds that to be expected if the drug were prescribed only for its valid indications, the Food and Drug Administration believes that chloramphenicol is often prescribed for conditions for which it is not indicated, including trivial conditions such as acne, the common cold, and simple infections. Fatal reactions have been associated with use in these conditions. To enlist your aid in ending the over-prescribing of this drug, the Food and Drug Administration asks that you carefully study the following "box warning' the substance of o~hich has been and will continue to be part of the recently revised labeling of this drug: WARNING Serious and fatal blood dyscrasias floes of the throaf; or as a prophy- (aplastic anemia. hypoplastic one- lactic agent to prevent bacterial mia, thrombocytopenia. and granu- infections. locytopenia) are known to occur after the administration of chioram- phenicol. In addition, there have Precautions: It Is essential that ade- been reports of aplastic anemia quate blood studies be made during attributed to chloramphenicol which treatment with the drug. While later terminated in leukemia. Blood blood studies may detect early dyscrasias have occurred after both peripheral blood changes, such as short term and prolonged therapy leukopenia. reticulocytopenia, or with this drug. Chloramphenicol granulocyfopenia. before they be. must not be used when less poten. come irreversible, such studies can. tially dangerous agents will be not be relied on to detect bone effective, as described in the "mdi. marrow depression prior to develop. cations" section. It must not be ment of aplastic anemia. To faciii. used in the treatment of trivial tate appropriate studies and obser. infections or where it is not mdi- vation during therapy, it is desirable cated, as in colds, influenza, infec- that patients be hospitalized. PAGENO="0086" 4376 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To clarify further the status of this drug in the therapy of infectious disease, the indications for use have been stated in the recently revised labeling as follows: The revised labeling suggests that patients being treated with chlorarnphenicol be hospitalized where indicated to facilitate observation during therapy. It also includes cautionary information regarding use in preg'nancy and lactation, and the listing of leukemia as an additional adverse reaction. An estimate of the incidence of fatal aplastic anemia is included based on a report to the California State Assembly and Senate by the California Medical Association and State Department of Public Health, January 1, 1967. 1. ACUTE INFECTIONS CAUSED BY SUSCEPTIBLE STRAINS OF SAL- MONELLA TYPHI Chioramphenicol is a drug of choice.° It is not recommended for the routine treatment of the typhoid "carrier state", INDICATIONS: IN ACCORD WITH TIlE CONCEPTS IN THE "WARNING BOX" AND THIS INDICATIONS SEC- TION, CHLORAMPHENICOL MUST BE USED ONLY IN THOSE SERIOUS INFECTIONS FOR WHICH LESS POTENTIALLY DANGEROUS DRUGS ARE INEFFECTIVE OR CONTRA- INDICATED. HOWEVER CHLORAM- PHENICOL MAY BE CHOSEN TO INITIATE ANTIBIOTIC THERAPY ON THE CLINICAL IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS BELIEVED TO BE PRES- ENT; IN VITRO SENSITIVITY TESTS SHOULD BE PERFORMED CONCUR- RENTLY SO THAT THE DRUG MAY BE DISCONTINUED AS SOON AS POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS ARE IN- DICATED BY SUCH TESTS. THE DECISION TO CONTINUE USE OF CHLORAMPHENICOL RATHER THAN ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY IN VITRO STUDIES TO BE EFFEC- TIVE AGAINST A SPECIFIC PATHO- GEN SHOULD BE BASED UPON SEVERITY OF THE INFECTION, SUSCEPTIBILITY OF THE PATHO- GEN TO THE VARIOUS ANTIMICRO- BIAL DRUGS, EFFICACY OF THE VARIOUS DRUGS IN THE INFEC- TION, AND THE IMPORTANT ADDI- TIONAL CONCEPTS CONTAINED IN THE "WARNING BOX" ABOVE: 2. SERIOUS INFECTIONS CAUSED BY SUSCEPTIBLE STRAINS IN ACCORDANCE WITH THE CON- CEPTS EXPRESSED ABOVE: a. Salmonella species b. H. influenzae, specifically men- ingeal infections c. Rickettsia d. Lymphogranuloma-psittacosis e. Various gram-negative bacteria causing bacteremia, meningitis, or other serious gram-negative infections f. Other susceptible organisms which have been demonstrated to be resistant to all other ap- propriate anti-microbial agents. 3. CYSTIC FIBROSIS REGIMENS In the treatment of typhoid fever some authorities recommend that chlorampheni eol be administered at therapeutic levels for 810 days after the patient has becnme afebrile to lessen the possibility of relapse. PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4377 The revision of the labeling of chloramphenicol was approved by a special com- mittee of experts in hematology, infectious diseases and other medical fields convened by the Food and Drug Administration on February 26, 1968. A copy of the revised labeling is enclosed for your attention. To assist us in further evaluation of this problem, the Food and Drug Adminis- tration requests that you report to us any adverse reactions associated with the use of chloramphenicol. A facsimile of our Drug Experience Report (FD 1639) is reproduced on the reverse side for your information. If you wish a supply, please write to the Food and Drug Administration, Bureau of Medicine, Washington, D.C. 2O2O~. Sincere~y yours, "Commissioner of Food and Drugs Enclosure: Revised Labeling PAGENO="0088" 050 WELFARE DRUG EXPERIENCE REPORT 1 BUDGET BUREAU NO 57-00004 1~ TIENT INITIALS ANO IDENTIFICATION NUOIRER J.IUC1CISIQNNOIFHOFDAHSP00101 1 i~ ~ ~.... ~ ~::t:~:..::.~i .. i. ......:.~ lbs LICAUC Li NEGRO Li ORIENTAL ~ AMENCUN Li oro~o OD~E CF000CTIONNARC lioopllst, otP)(N000 If ,spoofio~f Ph}S1CISM 10 0. ADDRESS OF SOURCE (Gil's Stops), City, Slots, ~td Zip CCdP.) AOVER SE REACTION(1I) AND ASO FORRI OLE ASSOCIATION WITIITIIC DRUG(S) INVOLOED 2 OUTCOME OF REACTION TO L1ALIIIIIWITIOSCIIUELAE Li RECOVERED Li STILL UNDER TREATMENT Li DIED (Gil's dRo ,tod E0055) ORDER OF SUSI'IC ION (RIROIIIRF100PPI List NDA C? IND NO.) MANUFACTURERS DOSAGE ( TOTAL ROUTE ( ill, dEl DURATION 0 ECTIQ IIM8 YANT ItOO)P 818 OATA RT STUDIES (CZ1OIEIIILSbC?CIIC?y,At topsy, X-Rsy, SIC.) CLINICAL LAS: POSE ATTAChE 0 Li NOT DONE RIOPSY/AUTOPST: ~ DONE Li ATTACOED Li NOT DONE IOUS OR ENVIRONMENTAL FACTORS (loElCds hoosshold ptCdUCfs, Iodottolsl ~od SgI'ICISIICISI EhPOICSIS) LIVES Liso (b) IF PREGNANT I~. MAT THE SOURCE OF TRIS REPORT 0 ERELEASED TO ROE ARMED FORCES 000ITT "~ WEEDS OF GESTATION INSTITA E 0 P OLO Li V ES Li NO FOR FDA USE ONLY FOR MFS USE ONLY TWO ORMORE DRUGS Li DRUGN000SED ACCORDING TOLARELING LiORUG WUTDATED Li OCE000SAGE Li DRAG MISLUOELEO Li CONTAMINATION OF DOUG Li OTCER DRUG MISUSE ISPSCIIF) FORM FD-1639 (R.o 8/67) Uss Od21IICOOI SRSSI If osEssss,y. PAGENO="0089" ci 0 0 w t~j t!j ci ci CI) PAGENO="0090" 4380 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 8. Precaution should be used in therapy during lactation because of the pos- sibility of toxic effects on the nursing infant. 9. The use of this antibiotic, `as with other antibiotics, may result in an overgrowth of nonsusceptible orga- nisms, including fungi. If infections caused by nonsusceptible organisms appear during therapy, appropriate measures should be taken. ADVERSE REACTIONS: 1. Blood Dyscrasias The most serious adverse effect of chloramphenicol is bone marrow de- pression. Serious and fatal blood dyscrasias (aplastic anemia, hypoplas- tic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol. An irreversible type of marrow de- pression leading to aplastie anemia with a high rote of mortality is char- acterized by the appearance weeks or months after therapy of bone marrosv aplasia or hypoplasia. Pe- ripherally, pancytopenia is most often observed, but in a small number of cases only one or two of the three major cell types (erythmcytes, leuko- cytes, platelets) may be depressed. A reversible type of bone marrow depression, which is dose related, may occur. This type of marrow depression is characterized by vacu- olization of the erythroid cells, re- duction of reticulocytes and leuko- penia, and responds promptly to the withdrawal of chloramphenicol. An exact determination of the risk of serious and fatal blood dvscrasias is not possible because of lack of accurate information regarding 1) the size of the population at risk, 2) the total number of dmg-associated dyscrasias, and 3) the total number of non-drag associated dyscrasias. In a report to the Califomia State Assembly by the Califomia Medical Association and the State Department of Public Health in January 1967, the risk of fatal aplastic anemia was estimated at 1:24,200 to 1:40,100 based on two dosage levels. There are reports of aplastic anemia terminating in leukemia ,attributed to ehloramphenicol. Paroxysmal noctumal hemoglobinuria has also been reported. 2. GastroIntestinal Reactions Nausea, vomiting, glossitis and stoma- titis, diarrhea and enterocolitis may occur in low incidence. 1. Neurofoxic Reactions Headache, mild depression, mental confusion, and delirium have been described in patients receiving chlor- amphenicol. Optic and* peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drag should be pramptly 4. Hypersensitivity Reactions Fever, macular and vesicular rashes, acigioedema, urticaria ,and anaphyla'xis may occur. Hersheimer reactions have occurred during, therapy for typhoid 5. "Gray Syndrome" Toxic reactions including fatalities have occurred in the premature and newborn; the signs and symptoms associated with these heactions have been referred to as the "gray syn- drome". One case of "gray syndrome" has been reported in an infant bum to a mother having received chlor- ampheniccsl during labor. One case has been reported in a 3 - month infant. The following summarizes the clinical and laboratory studies that have been made on these patients; (1) In most cases therapy with chloramphenicol had been insti- tuted within the first 48 hours of life. (2) Symptoms first appeared after 1 to 4 days of continued treat- ment with high doses of chlor- amphenicol. (1) The symptoms appeared in the following order; (a) abdominal distension with or without emesis; (b) progressive pallid cyanosis; Ic) vasomotor collapse, fre- quently accompanied by irregular respiration; (d) death within a few hours of onset of these symptoms. (4) The progression of symptoms from onset to exitus was acceler- ated with higher dose schedules. (5) Preliminary blood serum level studies revealed unusually high concentrations of chlorampheni- cal (over 90 meg/mI. after re- peated doses). (6) Termination of therapy upon early evidence of the associated symptomatology frequently re- versed the process with com- plete recovery, DOSAGE AND ADMINISTRATION DOSAGE RECOMMENDATIONS FOR ORAL CHLORAMPHENICOL PREPARATIONS The majority of micro-organisms sus- ceptible to chloramphenicol will respond to a concentration between 5 and 20 meg/mI. The desired concentration of active drag in blood should fall within this range over most of the treatment period. Dosage of 50 mg/kg/day di- vided into 4 doses at intervals of 6 hours will usually achieve and sustain levels of this magnitude. Except in certain cirrumstances (e.g., premature and newborn infants and individuals with impairment of hepatic or renal function) lower doses may not achieve these concentrations. Chlor- amphenicol, like other potent drags, should be prescribed at recommended doses known to have therapeutic ac- tivity. Close observation of the patient should be maintained and in the event of any adverse reactions, dosage should be reduced or the drag discontinued, if other factors in the clinical situation permit. Adults-Adults should receive 50 rag.! kg/day (approximately one 250 mg. capsule per each 10 lbs. body weight) in divided doses at 6-hour intervals. In exceptional cases patients with in- fections due to moderately resistant orga- nisms may require increased dosage up to 100 mg/kg/day to achieve blood levels inhibiting the pathogen, but these high doses should be decreased as soon as possible. Adults with impairment of hepatic or renal function or bath may have reduced ability to metabolize and excrete the drag. In instances of impaired metabolic processes, dosages should be adjusted accordingly. (See discussion under "Nesvborn Infants.") Precise con- trol of concentration of the drag in the blood should be carefully followed in patients with impaired metabolic processes by the available microtech- niques (information available on re- quest). Children-Dosage of 50 mg/kg/day divided into 4 doses at 6-hour intervals yields blood levels in the range effective against most susceptible organisms. Severe infections (e.g., bacteremia or meningitis), especially when adequate cerebrospinal fluid concentrations are desired, may require dosage up to 100 mg/kg/day; however, it is recom- mended that dosage be reduced to 50 mg/kg/day as soon as possible. Children with impaired liver or kidney function may retain excessive amounts of the drag. Newborn Infanfs-(See section titled "Gray Syndrome" under "Adverse Re- actions.") A total of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces and maintains concen- trations in blood and tissues adequate to control most infections for which the drag is indicated. Increased dosage in these individuals, demanded by severe infections, should be given only to main- tain the blood concentration within a therapeutically effective range. After the first two weeks of life, full-term infants ordinarily may receive up to a total of 50 mg/kg/day equally divided into 4 doses at 6-hour intervals. These dosage recommendations are extremely import- ant because blood concestration in all premature infants and full.term infants under two weeks of age differs from that of other infants. This difference is due to variations in the maturity of the metabolic functions of the liver and the kidneys. When these functions ace immature, (ox seriously impaired in adults), high con- centrations of the drag are found which tend to increase with succeeding doses. Infants and Children with Immature Metabolic Processes-In young infant: and other children in whom immature metabolic functions are suspected, dose of 25 mg/kg/day will usually pro. duce therapeutic concentrations of thi drag in the blood. In this group par. ticularly, the concentration of the drag in the blood should be carefully followec by microtechniques. (Information avails ble on request.) April 1968 Fond and Drug Administration / U.S. Department of Health, Education, and Welfare / Washington, D.C. 20204 PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4381 Dr. LEY. As a result of this letter, we received approximately 275 letters or notes from physicians. Most important, we received 22 ad- verse reaction reports, as follows-and if I may, let me read them- five cases of aplasti.c anemia, fatal; three cases of pancytopenia, fata; three cases of pancytopenia, persistent (not fatal); four leukopenia, transient, recovered; one nosebleed and paresthesias, recovered; two cases anemia, recovered; three cases aplastic anemia, still under treat- ment; and one case of erythema multiforme, recovered. At the time the "Dear Doctor" letter was mailed, we also contacted various professional publications-Medical Tribune, Medical World News, AMA News, and the journals of every State medical society- asking their cooperation in publicizing the proper use of the drug and the hazards associated with its use. The labeling revisions and the warning letter also were widely publicized in the general news media. Senator NELSON. Doctor, did the FDA do a specific check of all the State society journals and the AMA and various other medical jour- nals to see what they did say and do about this. Dr. LEY. We did not do a specific check of all State society journals. I have here, if the Senator wishes, a listing of all journals to whom we supplied this information which can be made available for the record, if you choose. Senator NELSON. This is a list of the journals thwt you requested? Dr. LEY. Yes, sir. Senator NELSON. Do you have any list of the journals that responded to the request positively? Dr. LEY. We have not, sir, as of this date doublechecked all of these journals to determine whether or not they did make specific references to the letter and material which we provided them. In some of the more widely distributed medical publications, the letter and the enclosures received considera~ble publicity, and I am speaking of "AMA News," "Medical World News," "Medical Tribune," and so forth. Senator NELSON. They did that? Dr. LEY. They did indeed feature it, and we have copies of the ar- ticles that appeared in those publications which we would be pleased to submit for the record. Senator NELSON. Including JAMA? Dr. LEY. I will have to check with the staff to determine whether "JAMA" is included in that list or not. We were unable to find any reference within "JAMA" itself. How- ever, "AMA News," which is published by the AMA as a weekly news magazine, did feature the item significantly. Advertisements for chloramphenicol-particularly the "reminder" ads which include no warning information-were also of concern in connection with the excessive use of this drug. On April 25, 1968, Dr. James, L. Goddard, then Commissioner of Food and Drugs, sent Parke, Davis & Co. a letter requesting them to discontinue such reminder advertisements and reminder labeling for chloramphenicol. With your permission, I would like to submit a copy of this letter for the record. Senator NELSON. You are talking solely about reminder ads of the kind such as "when it counts, Chloromycetin?" Dr. LEY. Yes, sir. Senator NELSON. You requested the discontinuance of this kind of ad and the company complied with the request? PAGENO="0092" 4382 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LEY. That is my belief; yes, sir. Senator NELSON. None of these reminder ads are being run on Chlor omycetin any longer? Dr. LEY. The only ad copy of which we are aware today is this ad copy here which carries that same front page that you illustrated there- but is accompanied by the full prescribing information including the warning in the label. Senator NELSON. Well, doesn't the company, in many instances~ achieve the same results it was seeking to achieve with the reminder ads for all those who don't bother to read the fine print? Dr. LEY. The first page of this spread carries an additional state' ment, "See following page for prescribing information." If a physician is to use the drug, unless he has had experience with the dosage in the past, he would usually refer either to the information in the advertise ment or to the Physicians~ Desk Reference, which carries exactly the same information. So that he would be reading the warning and all of the other information. I cannot however, guarantee that he does this Senator NELSON. But if the FDA felt it was important enough to stop the company from using the reminder ad as it stands alone-such as the example here-it seems pretty obvious to me that the purpose sought in the ad is to get the benefit of the reminder ad since many people might not carefully read the fine print. Isn't there a problem though in that the indications for the use of chioramphenicol have been changing rapidly in the past half dozen years? And I think, if I re- member correctly the National Academy of Science Report-it does not specifically list chloramphenicol as the drug of choice in any case. Dr. LEY. It does not carry the words, "The drug of choice" in any case in the present labeling-a drug of choice, yes, with typhoid. Senator Niii~soN. Pardon? Dr. LEY. There is the wording, "a drug of choice" for typhoid fever Senator NELSON. So here you have a situation in which the testi- mony of all the experts appearing before the committee-unrefuted by the company or any other witnesses-is that chloramphenicol con- tinues to be widely prescribed for nonindicated uses. Some of these nonindicated uses were, I would guess, indicated uses prior to, say, Ampicillin and some of the newer drugs. So that when a practicing physician who has been using the drug 5 or 6 years, prior to the re- vised judgment of what its indications are-sees the 1abelin~ in the ad, he just doesn't bother to read it-since he may have read it many times years ago. So isn't thiE, then, really, in effect, a~ reminder ad with the same effect on that physician-why read this fine print again for the 10th time? Dr. LEY. I acknowledge that the physician may not read the fine print. However, that same physician was exposed to a letter from Dr. Goddard the text of which specifically highlighted the significant and important changes in the labeling. Again, I cannot guarantee that the physician read the letter. But the combination of the letter and the considerable publicity given after your hearings of last year in "Medical World News," "AMA News," and "Medical Tribune," I think must have had an effect of reeducating the physician concern- ing the indications of use for this drug. Senator NELSON. Well, there is no question but that the statistics demonstrate a dramatic drop in the use of the drug, comparing the PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4383 first 6 months of 1967 vis-a-vis the first 6 months of 1968. And, of course, you have and are presenting the statistics of what happened the last 3 months of 1968 versus the last 3 months of 1967 when there was a dramatic increase in the use of the capsule form as contrasted with the injectable which went down. The point, it seems to me, still is that it is* widely misprescribed for nonindicated uses, and every conceivable effort has been made to as- sure that it will not be used for nonindicated uses. In the wording of the package insert, FDA, including Dr. Goddard and yourself, takes the position of the use of the drug should be limited to hospitals. The committee has had a number of distinguished experts who took that position. Yet FDA `has not been prepared to confine it to hospital use. If it were administered only in hospitals, there is no question but that there would be much more significant control, and a more significant factor in educating `the doctor about the precautions of this drug. But since the FDA isn't prepared to do that, and since it continues to be prescribed widely for nonindicated cases, it seems to me that FDA ought to be doing every thing else within its power to stop it. And it seems to me this use of the reminder ad with the fine print attached still promotes the drug for nonindicated cases. You really ought to consider whether `this type of ad-even with the fine print- can be justified. (The information previously referred to follows:) DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washington, D.C., April 25, 1968. Dr. AUSTIN SMITH, Parke Davis ~ Co., Detroit, Mioh. Di~&R DR. S~1ITH: Under the existing regulations pertaining to advertisements for prescription drugs, producer sponsored advertisements have been permitted an exemption from the requirement of providing a statement of information in brief summary relating to side effects, contraindications `and effectiveness if an advertisement contains no information as to indications or dosage recoin- mendations. In the case of Chioromycetin, we are aware of your use of so-called reminder advertisements for that product which contain no "Brief Summary." Taking into account the recent disclosures regarding the broad use of chloram- phenicol and the urgent need to bring warning information regarding the drug to the attention of physicians by every means feasible, I am asking that your firm immediately discontinue using so-called reminder advertisements and re- minder labeling in the promotion of chioramphenicol, whether or not any such promotion is entitled to exemption under the reminder advertising or reminder labeling provisions of the existing regulations. While we believe that we could require prior approval of chloramphenicol advertisements under the terms of section 1.105 (j) of the regulations, I would prefer not to consider proceeding under that concept at this time. Will you please let me have your comments as soon as possible concerning your willingness to meet the above request. Sincerely yours, JAMES L. GODDARD, M.D., Commissioner of Food and Drngs. PAGENO="0094" 4384 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Chioromycetin (chioramphenicol) PARKE-DAVIS when it counts PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4385 [From Thejournal ofthe American Medical Association,Jan. 22, 1968, pp. 162-163] may be i nd Ic ated ~ are short-term and prolonged administration of the drug. Among in certain severe the reactions reported are blood dyscrasias as mentioned in the warning. When, during the course of therapy, blood counts show unusual deviations which may be attributable to respiratory infections i:~e;~~0:: tinued. Also reported are certain gastrointestinal reactionx resulting in glossitis and stomatitis, which are indications to Because of its wide antibacterial spectrum and its ability to diffuse stop the drag On rare occasions, superimposed infection by into infective foci, CHLOROMYCETtN may be of value in the treat- Candida albicans may produce widespread oral lesions of the ment of selected severe respiratory tract infections due to suscep- thrush type. Diarrhea and irritation of perianat tissues have tible microorganisms. However, as with any antibacterial agent, the been reported Pseadomembranous enlerocolilis has been administration of CHLOROMYCETIN must be adjunctive to the over- reported in a few patients Hypersensitivity reactions all therapeutic approach to this family of diseases. Appropriately manifested by angioneurotic edema and vesicular and treated, good results can be expected in bacterial pneumonia and maculopapular types of dermatitis have been reported in empyema, in bacteria! complications of bronchiectasis and chloramphenicol-sensitive patients. Urticaria and vesicular bronchitis; all of which are severe disorders often chronic and lesions have been observed They are usually mild in character difficult to eradicate, and ordinarily subside promptly upon cessation of treatment. The decision to choose CHLOROMYCETtN from among a group of Febrile reactions have been reported. antibiotics suggested by in vitro studies to be potentially effective against a specific respiratory tract pathogen(s) should be guided by A reaction of the Jarisch-Herxheimer type has been reported severity of infection, relative susceptibility of the pathogen(s) to the following therapy in syphilis, brucellosis, and typhoid fever. various antibacterial drugs, relative efficacy of the various drugs in Typhoid fever patients have exhibited a shock-type reaction this family of infections, and the important additional concepts con- characterized by circulatory collapse attributed to sudden d' th "`b" release of endotoxin. Neurotoxic react:ons, including optic and peripheral neuritides, headache, mild depression, "dazed Patients with respiratory tract infections usually become afebnile in feelings," internal ophthalmoplegia, mental confusion, and 18 to 72 hours on recommended doses; roentgenographic clearing delirium have been reported. Symptoms of peripheral neuritis may be slower, or decreased visual acuity call for prompt withdrawal of the Neoptastic, fungal, and mycobacterial disease as a cause of persist- antibiotic and the possible use of large doses of oral or ing respiratory disease should be ruled out by appropriate means. parenteral vitamin B complex. When prolonged high dosage is necessary, toxic side effects may occur which call for dosage reduction or discontinuance of chloramphenicol therapy. Adults and children with impaired liver or kidney __________________________________________________________ function, or both, may retain excessive amounts of the drug. ____________________ 5 chd I th the d rn wth mf t 1 have resulted from high concentrations of the drug in the premature and newborn age groups. One case of "gray syndrome" has been reported in an infant born to a mother Chioromycetin havmg received cNorarnphenmoi dunng taboc The foPowing Del I d f m I I d g d t o d dos ge ppe bhl mph ~i h db t dw th th f 4P8Y~w th he package inserts of CHLOROMYCETIN products for systemic use. of life (2) Symptoms first appeared after 3 to 4 days of ~onsult the appropriate package insert, continued treatment with high doses of chloramphenicol. (3) The symptoms appeared in the following order: (a) abdom- Warning: Serious and even fatal blood dyscrasias (aplastic inxl distention with or without emesis; )b) progressive pallid anemia, hypoplastic anemia, thrombocytopenia, granulocy- cyanosis; (c) vasomotor collapse, frequently accompanied topenia) are known to occur after the administration of by irregular respiration; and (d) dealh within stew hours of chloramphenicol, Blood dyscrasias have occurred after both onset of these symptoms. (4) The progression of symptoms short-term and prolonged therapy with this drug. Bearing in from onset to exilus was accelerated with higher dose mind the possibility that such reactions may occur, chlor- schedules~)5) Preliminary blood serum level studies revealed amphenicol should be used only for serious infections caused unusually high concentrations of chloramphenicol after by organisms which are susceptible to its antibacterial effects. repealed doses. (6) Terminxtion of therapy upon early Chloramphenicol should not be used when other less poten- evidence of the associated symptomatology frequently bully dangerous agents will be effective. ft must not be used reversed the process with complete recovery in the trealment of trivial infections such as colds, influenza, : p t' - " r `n bo `f r r xli ns or infections of the throat; ores a prophylactic agent to ore- ` p vent bacterial infections. The use of this antibiotic, as with other antibiotics, may result Precautions: It is essential that adequate blood studies be in an overgrowth of nonsusceptible organisms, including m d d g f atm t w th th d g Wh I blood t d e m y f g C I dbb iv I ~ bi I e t I I If ew or during therapy, the drug should be discontinued and appro- studies cannot be relied on to detect bone marrow depression ~ prior to development of aplastic anemia. Monitoring of liver and kidney function should be accom- plished during therapy in patients with existing liver or ~HLOROMYCETIN, an antibiotic having Iherapeutic activity against kidney disease. i wide variety of organisms, must, in accordance with the cont,dpIs Supplied: CHLOROMYCETIN is available in a variety of forms the "warning box" above, be used only in certain severe infections, including Kapseals° of 250 mg. ~ontraindicatIons: Chloramphenicol is contraindicated in individuals with a history of previous sensitivity reaction to it, must not be used in the treatment of trivial infections such as colds, nfluenza, or infections of the throat; or as a prophylactic agent to irevent bacterial infections. PAGENO="0096" 4386 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY when it counts CHLOROMYCETIN® Kapseals® (CHLORAMPHENICOL CAPSULES) DESCRIPTION Chloramphenicol is an antibiotic that is clinically useful for, and should be res~d fur seeions infections caused by organisms sus- ceptible so its antimiceobial effects when less potentially hazardous therapeutic agents ace ineffective ue consraindicoted. Sensitivity testing is essential to determine its indicated use, but maybe per- formed concoreensly with therapy initiated on clinical impression that one of the indicated conditions mists (see "Indications" section). ACTIONS AND pHARMACOLOGY Isivitso chloramphenicol meets mainly a hacteriossatic effecton a wide range of gram-negative and gram-positive bacteria and is active irs vitro against rickettsias, she lymphogranuloma'psittacosis group and Vibsio cliolesae. Is is particularly active against Salmonella typhi and Hemopliilss irsfluesoae. The mode of action is through interference orinbibition of protein synthesis in insacscells and in cell-freesystemo. Chloramphenicol administered orally is absorbed rapidly from the intestinal tract. In controlled stoodiro in adult volunteers using she recommended dosage of 30 mg/kg/day, a dosage of 1 gm. every 6 hours foe 8 do ses tvas gisen. Using she microbiological assay method, the average peak scram level was 11.2 meg/mI. one hour after she first dose. A cumulative effect gave a peak rise so 18.4 meg/mI. after she fifth dose of 1 gm. Mean scram levels ranged from 8-14 mcg./ml. over the 48-hour period. Total urinary rocre sion of chloramphenicol in these studies ranged fmm a low of 68% to a high of 99% over a three-day period. From 8 to 12% of the antibiotic excreted is in the form of free chloramphenicol; the remainder consists of microbio- logically iosacsise mesabolites, principally the conjugate with gb- curonic acid. Since she gburaronide is excrete d rapidly, most chloramphenicol detected in she blood is in the mierobiobogically active free form. Despite the small proportion of unchanged drag excreted in the urine, the concentration of free chboramphenicol is relatively high, amounting to several hundred meg/mI. in patients receiving divided doses of SO mg/kg/day. Small amounts of active drug are found in bile and frces. Chboramphenicol diffuses rapidly, bus its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest coocentrasions are found in brain and cerebeospinal fluid. Chboramphenicol corers cerebeospinal fluid even in the absence of m eningeal inflammasioo, appearing in concentrations about half of those found in the blood. ,Measurable level sate also detected in pleural and in ascisic fluids, saliva, milk and in the aqueous and vitreous humors. Transport across the placen- ral barrier occurs svith somewhat loiter concentration in rued blood of newborn infants than in maternal blood. INDICATIONS IN ACCORD WITH THE CONCEPTS IN THE "WARNING BOX" AND THIS INDICATIONS SEcTION, CHLORAMPHEN- ICOL MUST BE USED ONLY IN THOSE SERIOUS INFEC- TIONS FOR WHICH LESS POTENTIALLY DANGEROUS DRUGS ARE INEFFECTIVE OR CONTRAINDICATED. HOWEVER, CHLORAMPHENICOL MAY BE CHOSEN TO INITIATE ANTIBIOTIC THERAPY ON THE CLINICAL IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS BELIEVED TO BE PRESENT; IN VITRO SENSITIVITY TESTS SHOULD BE PERFORMED CONCURRENTLY SO THAT THE DRUG MAY BE DISCONTINUED AS SOON AS POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS ARE INDICATED BY SUCH TESTS. THE DECISION TO CONTINUE USE OF CHLORAMPHENICOL RATHER THAN ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY IN I'ITRO STUDIES TO BE EFFECTIVE AGAINST A SPECIFIC PATHOGEN SHOULD BE BASED UPON SE- VERITY OF THE INFECTION, SUSCEPTIBILITY OF THE PATHOGEN TO THE VARIOUS ANTIMICROBIAL DRUGS, EFFICACY OF THE VARIOUS DRUGS IN THE INFECTION, AND.THE IMPORTANT ADDITIONAL CONCEPTS CON- TAINED IN THE "WARNING BOX" ABOVE: 1. Acute infections caused byssosceptible strains of Salsetisetellit typhi Chloramphenicol is a drug of choice.' It is not recommended for the routine treatment of the typhoid "carrier state." `In she s,rasmrxi of ,yphoid feces some au,hoeisies eeecmmrod hoe chloe omphenicol he odmiois,rsed or shesopeusic rant foe 0.10 do ys ohee she posirus has become ufebsile so rtiss she pussibiiiiy of ,eiupsr. 2. Serious infections caused by susceptible strains in accordance with the concepts expressed aboves a. Salmonella species b. H. ixfluerinae, specifically meningeal infections c. Ricketesia d. Lymphogranuloma.psittacosis group e. Various gram-negative bacteria causing bacteermia, meningitis or other serious gram-negative infections Other susceptible organisms which have been demonstrated tube resissa us so all other appropriate anti-microbial agents. 3. Cystic fibrosis regimens CONTRAINDICATIONS Chboramphrnicol is consraindicated in individuals wish a history of previous hypersensitivity and/or toxic reaction suit. Is muss not be used in she treatment of trivial infections or xvhrrr it~~iiidièated, ~1~'colcis, influenza, infections of the throat; orasaprophybactic ijOi8so prevent bacterial infections. PRECAUTIONS I. Baseline blood ssodirs should be folloxved by periodic blood studies approximately every two days during therapy. The drag should be discontinued upon appearance of mesicubocytopenia, leukopenia, sheombocysopenia, anemiu, or any other blood srady findings attributable so chloramphenicob. Hoo~evrr, is should be noted shot such sradirs d onus rxc lode she possible later oppearance of she irreversible type of bone morrow depression. 2. Repeated courses of she drag should be avoided if as all possible. Treatment should not be continued longer than required so produce cure wish little or no risk of relapse of she disease. 3. Concurrent therapy xvish other drugs shot may cause bone marrox depression should be avoided. 4. Excessive blood levels may result from administration of she recommended dose so patients svish impaired liver or kidney func- tion, including shot due so immature metabolic processes in she infant. The dosage should be adjusted accordingly or, preferably, she blood concentration should be determined as appropriate intervals. 5. Tb err are no studies so establish she safety of this drag in pregnancy. 6. Since ebboramphenicol readily crosses she placental barrier, caution in use of she drug is particularly important during preg- nancy as term or during labor because of potential tonic effects on she feras (gray syndrome). 7. Precaution should be used in therapy of premature and full-term infants so avoid "gray syndrome" toxicity. (See "Adverse Reactions.") Scram drag levels should b ecarefully followed during therapy of she neo'born infant. 8. Precaution should be used in therapy during lactation because of she possibility of toxic effects on she nursing infant. 9. The use of this antibiotic, as xsish usher antibiotics, may result in anoveegrooth of nonsuscepsible organisms, including fungi. If infections caused by nonsuscepsible organisms appear during therapy, appropriate measures should be token. WARNING Serious and fatal blood dysceasias (aplastic anemia, hypu- plastic anemia, theombocytopeOia, and granulocylopenia) are known so occur after the admioistratiun of chtoram- phenicol. In addition, there hate been reports of aplastic anemia attributed to chloramphmnicol which later termi- nated in Irukemia- Blood dyscrasias hose occurred after bush short term and prolonged therapy with this drug. Chboram- phenicol must nut hr used when less potentially dangrrous agents will be effective, as described in the "Indications" see- ~Thihdqbtd~ made during trratmmnt with the drug. While blood studies may detect early peripheral blood changes, such as leuko- pmnia, reticulocytopenia, or geanulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marross deprestion peioe to deselopment of aplassic anensia. To facilitate appropriate studies and observation during therapy, it is desirable that patients he hospitalired- PAGENO="0097" ADVERSE REACTIONS 1. Blood Dyscrasias The most serious advesseeffect of chloramphenicol is bone marrosv depression. Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol. An irreversible type of m arrow dopeession leading to aplastic anemia svith a high rate of mortality is characterized by the appearance sveeks or months after therapy of bone maccow aplasia or hypoplasia. Periph- erally, pancytopenia is most often observed, but in a small number of eases only one or two of the three major cell types (eeythrocytcs, leukocytes, platelets) maybe depressed. A reversible type of bone marrow depression, which is dust related, may occur. This type of marrow depression is charactenard by var- uolization of the eryshcoid cells, reduction of reticulocytes and leuko- peniu, and responds promptly to the withdrawal of chloramphenicol. Anexactdeterminationofthreiskofseeiousand fatalblooddyscrasias is not possible because of lack of accurate information regarding 1) the size of the population at risk, 2) the total number of drug-associated dysceasias, and 3) the total number of non-dflug associated dyscrasias. In a report to the California State Assembly by the California Medical Association and the State Department of Public Health in January 1967, the risk of fatal aplastic anemia was estimated at 1:24,200 to 1:40,500 based on twa dosage levels. There have been reports of aplastic anemia attributed to chloram- phroicol sshich later terminated in leukemia. Parosysmal nocturnal hemoglobinuria has also been reported. 2. Gastrointestinal Reactions Nausea, vomiting, glossitis nod stomatitis, diarrhea and entero- colitis may occur in low incidence. 3. Neurotoxic Reactions Headache, mild depression, mental confusion and delirium have been dcsceibed in pati rots receiving chlocamphenicol. Optic and peripheral neuritis have been reported, usually follawinglong-teem therapy. If this nccnrs, the drug should be promptly withdrawn. 4. Hypersensitisity Reactions Fever, maculac and vesicul areas hes, anginedema, oetieaeia and anaphylanis may occur. Heexheimer reactions have occurred daring therapy for typhoid fever. 5. "Gray Syndrome" Tonic reactions including fatalities have occurred in the premature and nesvborn; the signsand symptoms associated with these reactions have been referred to as the "gray syndrome". One case of "gray syndrome" has been reported in an infant born to a mother having received chloramphenicol daring labor. One case has been reported in a 3 month infant. The follosving summarizes the clinical and labo- ratory studies that have been made on these patients: (I) Inmost cases therapy with chloramphenicol had been instituted svithin the first 48 hours of life. (2) Symptoms first appeared aftee 3 to 4 days of continued treatment svith high doses of chloramphenicol. (3) The symptoms appeared in the follosving order: (a) abdominal distension svith or without emesis; (b) progressive pallid cyanosis; (c) vasomotor collapse, frequently accompanied by irregular (d) death within a few hours of onset of these symptoms. (4) The progression of symptoms from onset to coitus was accelerated with higher dose schedules. (5) Preliminary blood serum level studies revea led unusually high concentrationsofchloeamphenicol(over9O meg/mI. of see ccpeated doses). (6) Termination of therapy upon early evidence of the associated symptomutology frequently reversed the process with complrtr recovery. DOSAGE AND ADMINISTRATION DOSAGE RECOMMENDATIONS FOR ORAL CHLORAMPHENtCOL PREPARATIONS The majority of microorganisms susceptible to chloramphenicol svill respond so a concentration betsveen 5 and 20 meg/mI. The desired concentration of active drug in blood should fall svithin this range over most of the treatment period. Dosage of SO mg/kg/day divided into 4 doses at intervals of 6 hours svill usually achieve and sustain levels of this magnitude. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4387 Encept in certain circomstances (e.g., premature and newborn in- fants and individuals scith impairment of hepatic or renal function) losser doses may not achieve these concentrations. Chloramphenicol, likeothee potent drugs, should be prescribed at recommended doses known to has'e therapeutic activity. Close observation of the patient should be maintained and in the event of any adverse reactions, dosage should be reduced or the drug discontinued, if other factors in the clinical situation permit. Adults Adults should receive 50 mg/kg/day (approximately one 250 mg. capsule per each 10 lbs. body weight) in divided doses at 6-hour intervals. I nesceptional cases patients with infections due to moder- ately resistant organisms may require increased dosage up to 100 mg/kg/day to achieve blood levels inhibiting the pathogen, but these high doses should be decreased as soon as possible. Adults with impairment of hepatic or renal function oe both may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted accordingly. (See discussion under Ness'born Infants.) Precise control of concentration of the drug in the blood should be carefully followed in patients with impaired metabolic processes by the available miceotechniques (information available on request). Children Dosage of 50 mg/kg/day divided into 4 doses at 6-hour intervals yields blood levels in th ecange effective against most susceptible organisms. Severe infections (e.g., bactreemia or meningitis), especially when adequate cerebrospinal fluid concentrations ace desired, may require dosage up to 100 mg/kg/day; however, it is eecommended that dosage be reduced to 50 mg/kg/day as soon as possible. Chil- deco svith impaired liver or kidney function may retain excessive amounts of the drug. Newborn Infants fSee section tilled "Gray Syndrome" under "Adverse Ifleoelions.") A total of 25 mg/kg/day in 4 equal doses at6-liose inseevals usually produces and maintains concentrations in blood and tissues adequate to control most infections foe which the drug is indicated. Increased dosage in these individuals, demanded by severe infections, should be given only to maintain the blood concentration svithi nathera prod- cally effective range. After the first two weeks of life, fall-teem infants oedinaeily may receive up to a total of 50 mg/kg/day equally disided into 4 doses at 6-hour intervals. These dosage recommenda tions are esteemely important because blood concentration in all premature infants and full-term infants under two weeks of age differs from that of other infants. This difference is due to variations in the maturity of the metabolic functions of the liver and the kidneys. When thesefunutiunsure immatuer(orseriouxlyimpuiredioadults), high concentrations of the drag are found which tend to ioveruse with succeeding doses. Infants and Children with Immature Metabolic Processes In young infants and other children in whom immature metabolic functions ace suspected, a dose of 25 mg/kg/day will usually pro- dare therapeutic concentrations of the drug in the blood. In this group particularly, the concentration of the drug in the blood should be carefully follosved by microtechniques. (Information available on request.) PACKAGE INFORMATION Kapseals No. 379, Chloromycetin (chloramphenicol capsules), each contain 250 mg. chloramphenicol, supplied in packages of 16 and 100, and Roll-Pak° of 100. Capsules No. 477, Chloromycenin (chloramphenicol capsules), each contain 50 mg. chloramphenicol, supplied in packages of 25 and 100. Capsules No. 480, Chloromycetin (chloramphenicol capsules), each contain 100 mg. chloramphenicol,supplied in packages of 25 and 100. Oral Suspension Chlocomycetin Ichlocamphenicol) Palmitate, each 4cc. represents 125 mg. chlocamphenicol, (each cc. contains chloe- amphenicol palmitate equivalent to 31.25 mg. chloramphenicol with 0.5% sodium beozoate as preservative), in bottles of 60cc. Chloramphenicol Palmitate is hydrolyzed to chloramphenicol before absorption. Resulting blood concentration is similar to that produced by the oral administration of chloramphenicol. CHLOROMYCETIN, brand of chloramphenicol, Reg. U.S. Pat. Off. Parke, Davis & Company, Detroit, Michigan 48232 PARKE-DAVIS 81-280 0-69-pt. 11-7 PAGENO="0098" 4388 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Please go ahead. Dr. LEY. In a letter dated May 1, 1968, the firm notified us that it had discontinued all "reminder advertisements" in March of 1968, with the exception of those ads that were too far along in the publica- tion process to be cancelled. Dr. L. M. Lueck, of Parke, Davis, also said in this letter that the distribution from Detroit of all "reminder" pieces-such as rulers, pencils, and calendars-had been discontinued. He said this practice also was being discontinued in the field as rapidly as possible. Since that time, ads for the drug have carried essentially the full disclosure information from the package insert of the dangers and side effects associated with the use of chloramphenicol and the "box warning" that is part of the labeling. On June 27, 1968, we issued a revision of the prescription drug ad- vertising regulations applicable to "reminder" advertising which took into account our experience with chloramphenicol. Under these regula- tions, if the Commissioner finds there is evidence of a significant in- cidence of fatalities or serious side effects associated with the use of a particular drug, he can, by notifying the firm forbid the use of "reminder" advertisements that omit warning information. On March 12, 1968, we met with representatives of Parke, Davis `and the Pharmaceutical Manufacturing Association to determine whether the advertisement which appeared in the Reader's Digest is- sue of February 1968 "was caused to be disseminated" by the drug firm. This a.d, in our view, recommended the drug for uses that were not warranted and seriously understated the hazards, side effects, and contraindications. As a result of the meeting, we learned that the idea for this ad originated with the advertising agency handling the public relations program for PMA. The copy was reviewed and approved by PMA. Parke, Davis was subsequently asked to review the copy and to give permission for the use of the names of Dr. Payne and Dr. Burkholder. Funds for the advertising program which included this ad were con- tributed `by approximately 100 members of PMA. Dr. Goddard ac- cepted the explanation that PMA, not Parke, Davis was responsible for the ad. Senator NELSON. May I interrupt for a moment. We discu~sed this at great length with Dr. Goddard in the spring of 1968 and I raised the point that it didn't seem rational to permit Parke, Davis as a contributing membei of the PMA to sort of duck its responsibility since it was the advertising firm and PMA that paid for the ad with Parke, Davis, in fact, reviewing the ad. There is a further question-as a member of the PMA any member company must have imputed to it responsibility for whatever the corporation is that they really own and control. If that is not the case, then any company can escape responsibility for an ad, which really violates FDA rules and regulations, by simply saying, well, it was the advertising firm and the PMA; although they all run the PMA, in this way they escape responsibility. I thought it was a very inappropriate ruling on the part of FDA. My question is, What is the policy as to future situations such as this? Will the `company `be held accountable or will they be excused? PAGENO="0099" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4389 Dr. LEY. I would like to ask our General Counsel, Mr. Goodrich to respond to this question, if I may, Senator. Mr. GOODRICH. When we were here last spring we did have this conversation about imputing the responsibility to the company Dr. Goddard and I concluded that before making any recommendations we should get PMA and Dr. Smith, the president of Parke, Davis, in to find out what the relationship was. The facts that we developed are as stated in this statement. It is possible legally to argue that mere membership, contribution to this PR fund is the causing tof the dis- semination of the ad, but this would be a very difficult point to make in a criminal case, and Dr. Goddard accepted the explanation on this ad. In the future, of course, we are going to try to avoid this sort of thing. We expressed both to Parke, Davis and to PMA our displeasure with this ad, and you had done the same thing. I do not think it will occur again, and it has not in the future advertisements of this type which appeared after this ad in the Reader's Digest. Senator NELSON. Well, I suppose as lawyers we may have a differ- ence of opinion as to what may or may not be difficult to prove. Mr. GOODRICH. Right. Senator NELSON. I would think it would be almost automatic if the facts are as stated here, where the company itself, and 99 or so other associates own the PMA; it is their creature; next, all the ads are paid for by contributions to the PMA, it has no independent status of its own at all, then the ad is reviewed by Parke, Davis, and it makes broader claims than the FDA would approve. I don't think there would be any question in the world but what the firm would be as- signed a responsibility for that ad in any kind of a lawsuit. You may, of course, differ on that. My concern would be, at least, that they be notified that in any future case you: will try it. Mr. GOODRICH. Right. Senator NELSON. You will try a lawsuit and then find out what the law is. Mr. GOODRICH. That was done. Senator NELSON. You did try it? Mr. GOODRICH. That we have told them that this kind of practice in the future would be considered for possible prosecution. Senator NELSON. I see. All right. Please continue. Dr. LEY. Let me turn now to another problem associated with chioramphenicol. In May 1968, after reviewing all the blood-level data in our files on chlorampheniool for parenteral use, we concluded that chioramphenicol sodium succinate injection produced lower blood levels than the oral preparations. We suspended certification of chior- amphenicol succinate pending resolution of the question about the therapeutic effectiveness of these lower blood levels. Certification was resumed in September 1968, as will be explained shortly when I discuss revision of the labeling of parenteral forms of chloramphenicol. Senator NELSON. May I interrupt for a moment? Dr. LEY. Certainly. Senator NELSON. As I recall it, the issue was raised a year ago in December; is that correct? Dr. LEY. September 1967. PAGENO="0100" 4390 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELsoN. Yes. The question raised was that the other chlor- amphenicols in the marketplace did not achieve the same blood level at the same time as Parke, Davis' chloramphenicol, is that correct? Dr. Lny. That is correct, sir. Senator NELSON. Is there a.ny clinical evidence at all that demon- strates that one blood level has a better therapeutic aspect than the others? Dr. LEY. There is no evidence of this sort currently in our files. I would like, if I may, to trace the history of that particular incident because it might be valuable in further discussion here this morning. Senator NLr~soN. Fine. Dr. LEY. In October of 1966, the date the chloramphenicol patent protection expired, several other firms petitioned us to approve cer- tification for competing brands of chloramphenicol. In retrospect, the decision that was made at that time was in error. The staff of scientists at FDA considered that with a drug which could be synthesized, such as chloramphenicol can, which can be analyzed carefully and accu- rately, that permitting marketing on the basis of purely chemical standards of purity, identity, et cetera, would provide a product which was comparable in every respect to the original product in the market- place. This assumption was subsequently found to be false. At this point, when we recognized the blood levels from the later competing manufacturers of the product were at variance, in that they appeared more slowly than the blood levels from the Parke, Davis product, we faced the question of whether we could clearly define a blood level as being effective for this condition or that condition. The decision which we finally made in December of 1967, Mr. Chair- man, was a decision that each one of the competing firms could have one or the other of two choices. Either they could demonstrate by test- ing in human substance that the blood level which their product pro- duced was equivalent to the same blood level of the Parke, Davis prod- uct which was supported by adequate clinical data in the past, or as their second choice, they could collect and submit to us clinical data demonstrating the efficacy of their product even though it had a lower blood level. None of the manufacturers elected to ta.ke the second course; all chose the first course of action. So that at this point in time, the three manufacturers of chloramphenicol who are currently marketing their product all have blood levels which are essentially identical when tested in human substance. Senator NELSON. So there is no positive clinical evidence that one blood-level achievement in x period of time is more effective than another. Dr. LEY. The information of this sort is extremely rare, and there are several studies in progress at the moment that might eventually prove that a lower dosage of chioramphenicol would be effective in treating, let's say, typhoid fever than the dosage which was first given in the literature, but these data are not yet in. This is the extent to my knowledge-and I'll have to ask Dr. Minchew to be absolutely cer- tain-of the type of data that are available linking blood levels with clinical efficacy for this product. Is this correct? Dr. MINOHEW. Yes. Senator NELSON. Because the claims made by the PMA at that time, you know, were that this just proves the case that generics or that PAGENO="0101" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4391 the brand names are better, and so forth, when, in fact, it didn't prove anything except they achieved different blood levels. You could have, I suppose, a situation where the companies that came in last were, in fact, companies who discovered the drug and then along came another company that achieved a higher blood level 17 years later. Without some clinical tests, it doesn't prove anything one way or another; is that correct? Dr. LEY. That is the position we have taken. I believe it is a sound one. Senator NELSON. Mr. Gordon. Mr. GORDON. Mr. Chairman, I have just one question. Concerning the succinate form of chloramphenicol, am I correct that the intramuscular and the subcutaneous forms are effective only through the intravenous route? Dr. LEY. We came a little later to this point in discussing the Academy recommendations. Let me say that current labeling for the succinate labeling that is currently being distributed with new suc- cinate entering the market, limits in its indication the use of succmate through the intervenous route. The instramuscular and subcutaneous routes are not recognized on the basis of clinical `data submitted to us as appropriate routes for administration of succinate form at this point in time. Mr. GORDON. Are there any drugs on the market now of chloram- phenicol which is labeled intramuscular and subcutaneous? Dr. LEY. Material which was distributed into the market prior to the revision of the labeling still contains in the package for that prod- uct labeling which was prepared under the old set of guidelines before we received the Academy comments. The other means of getting in- formation on succinate; namely, the Physicians' Desk Reference, and current package inserts which may be requesed from the firm by physicians, are all revised to include the intravenous route only. Mr. GoRDoN. If you have a mislabeled drug on the market, you gen- erally recall it, don't you? Dr. LEY. This is a question that depends upon the particular cir- cumstances. If there is an immediate and clear-cut hazard in the taking of such a drug by a patient, let's say contamination, super- potency or subpotency, the drug itself would be recalled. In this case, we do not question the drug itself. It is the insert that accompanies the drug which has been modified in the subsequent period since this drug was put into warehouses, pharmacies, and so forth. Mr. GORDON. What happened with the products of the smaller com- panies that were on the market when there was mislabeling? Dr. LEY. That was not simply a question of mislabeling. That was a question in which our laboratory tests demonstrated that the product of the smaller companies, without exception, as nearly as we could determine, had a drug on the market, irrespective of the labeling, which was not capable of performing in a comparable fashion to the original reference product, the Parke, Davis product. That was a defective drug. Mr. GORDON. Are you speaking of the injeotables? Dr. LEY. No, I am speaking of the oral in that case. Mr. GORDON. We are now talking about the succinate form, the injectables. PAGENO="0102" 4392 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Dr. LEY. All right. Mr. GORDON. How were the smaller companies treated? Dr. LET. There is only one other firm besides Parke, Davis which is marketing succinate at this point in time. That firm's application for approval of the product was submitted-do you remember the exact date that came in? Dr. MINOHEW. It was in, I think, late 1967. Dr. LET. Approximately late 1967-and approved following the receipt of the Academy recommendations on the succina.te product. All labeling for that product is the new labeling revised along the lines of the Academy recommendations. Senator NErsoN. Please proceed, Doctor. Dr. LET. As a part of the overall review of drug efficacy being con- ducted for FDA by experts selected by the NAS-NRC, the Panel on Anti-Infective Drugs has been studying the various dosage forms of chioramphenicol. On August 9, 1968, we received reports from the Academy giving the results of this study. I submit copies for the record.1 These reports showed that the Panel on Anti-Infective Drugs: (1) Endorsed the warnings that FDA required in the ltheling of chioramphenicol. (2) Emphasized the toxicity of the antibiotic. (3) iRecommended the use of less hazardous agents where they could be expected to accomplish the desired therapeutic effect. FDA reviewed the Academy reports and agreed with them. We also reviewed, in the light of these reports, the labeling we had developed in May for the various chioramphenicol preparations and concluded that: (1) The labeling of chloramphenicol capsules was consistent with the Academy's recommendations. (2) The labeling of chloramphenicol palmitate oral suspension was consistent with the recommendations. (3) The labeling for parenteral forms of chloramphenicol re- quired further revision. The panel had noted the higher and pref- erable blood levels obtained by intravenous use, compared with intramuscular administration. It also recommended a change to the oral chloramphenicol as soon as possible since these gave bet- ter blood levels. The new labeling reflecting these recommenda- tions, was approved on September 3, 1968. I submit a copy of the revised labeling for the record.' The Academy reports also discussed the effectiveness, or probable or possible effectiveness, of chioramphenicol in treating a variety of spe- cific conditions for which it had been promoted-such as various sur- gical infections, respiratory tract infections, and urinary tract infec- tions-but none of these are listed specifically in the drug's current labeling, which is oriented to causative organisms rather than sites of infection. Senator NELsoN. Do I understand, then, that this kind of ad, which shows a bronchoscope, is now prohibited? Dr. LEY. That ad is no longer running. We would not look with favor upon such an ad. Senator NELSON. Was there any valid medical reason for using the `See information, pp. 4407-4470. PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4393 bronchoscope associated with chloramphenicol at any time in the his- tory of this drug? Dr. LEY. This is difficult to say. In the 1950's perhaps this might have been a very reasonable correlation, bronchoscopy, severe pulmo- nary infection, lung abcess, and chioramphenicol. We have very care- fully looked at this and the similar cystoscope ad, and although the text is absolutely word-for-word as stated in the package insert, we feel at this point in time that that type of visual display with that copy is inappropriate. Senator NELSON. The drug has never been indicated, has it, for any upper respiratory diseases? Dr. LEY. No, sir. It is not so indicated now. However, in the very early days in antibiotic therapy, chloramphenicol, tetracycline, and so forth, were widely used for many infections. That was in the late 1940's and early 1950's. Times have changed. Senator NELSON. It is well known in the scientific community that if the ad were ever justified, it was many, many years ago, is that correct? Dr. LEY. We believe that statement is correct. Senator NELSON. And this ad was run on February 5,1968? Dr. LEY. I'm aware of that. It has since terminated. Senator NELSON. So this ad was run many years after any conceivable claim could have been made for this kind of indication? Dr. LEY. I would agree. Senator NELSON. Fine. Dr. LEY. The same orientation, I might add, will be used for other antibiotics as labeling is revised to carry out efficacy recommendations of the National Academy. The rational choice of an antibiotic should be predicated on the judgment of the prescribing physician as to the causative organism. It also should take into consideration the possible adverse effects of an antibiotic as well as its established efficacy. The current package insert for chloramphenicol, as I indicated a moment ago, illustrates this approach. The indications section is basically ori- ented to causative organisms and the labeling also highlights the seri- ous adverse effects of the drug. I know that the committee is specifically interested in the overall use of this antibiotic. After the hearing before this committee last Feb- ruary, the issuance of the FDA "Dear Doctor" letter, and the discon- tinuance of "reminder" advertising for the drug, the quantities of chloramphenicol certified dropped materially. In calendar year 1968, we certified for all dosage forms for systemic use slightly less than half as much as in 1967. This is still, in our opinion, more than is needed for all of the ap- proved uses of the drug and we are exploring further measures that may be in order. Senator NELSON. Yesterday, Doctor Wehrle-I hope my memory is correct-in making some judgment about the use of chloramphenicol and using the statistics from his hospital and extrapolations from there, concluded that of the 30 million hospitalized patients annually, if the same standards for use were applied as were established for his hospital, about 2 million grams a year would be used on hospitalized patients. I am sure you are aware this was formerly Los Angeles Gen- PAGENO="0104" 4394 COMPETITIVE PROBLEMS~ IN THE DRUG INDUSTRY eral, now `associated with the university. I think it is the largest hospi- tal in the United States. He made the further point that they had a much higher incidence of very serious illness in that hospital than the ordinary hospital had. So they would use more of the drug on the average per patient than most hospitals would. Anyway, his conclusion was, extrapolating from their usage and the controls they have established over usage, that about 42 million grams, or slightly over, were used in 1967. Dr. LEY. That is correct. Senator NELSON. Then it dropped to 17, is that correct? Dr. LEY. Our figures on certification for systemic forms of therapy- that would be parenteral and oral capsules-are approximately, within a few hundred thousand, 20 million grams certified for last year. Senator NELSON. Versus 42 million grams for 1967? Dr. LEY. Yes, sir. Senator NELSON. Do you have any statistics that might be in any way comparable to Dr. Wehrle's showing how many grams of chlor- amphenicol would be indicated if it were confined to its proper use? Dr. LEY. This is a very difficult question to answer, Senator Nelson. We have put considerable thought on this particular question within the past several weeks. We have certain focal points that we can be reasonably certain of. For example, the fact that there were in 1967, 396 cases of typhoid fever in this country which would be suitable candidates for therapy. There were reported-and this is just a small fraction of the total-18,120 salmonellosis severe enough to warrant the attention of physicians. Senator NELSON. May I interrupt for just one second? Dr. LEY. Yes, sir. Senator NELSON. Dr. Wehrle's extrapolation from that was, assum- ing that 10 percent of those were reported, you get a figure then of 180,000 cases that might indicate its use. Is that, in your judgment, a reasonable estimate? Dr. LEY. This would be a rough estimate of the nature of salmo- nellosis in this country that conceivably could need therapy. We included in the labeling a strong insistence of the Cystic Fibrosis Association, a specific use of the drug in cystic fibrosis regimens. There are according to the foundation 7,000 such children and young adults who may require continuous ant.ibiotic prophylaxis to prevent serious infection and death in this rather tragic disease. Senator NELSON. That doesn't mean that chloramphenicol is indi- cated for all 7,000, does it? Dr. LEY. Not necessarily, Senator, although the drug is preferred in many of these infants and children because of the problems of giving multiple drugs and because the risk of death due to infection is very high in this group. But if we take these figures, we have a total of 396, 180,000, and 7,000, which would be roughly 190,000, 200,000 patients. Senator NELSON. And as I recall it, estimates were that in 1967 about 4 million people were administered chloramphenicol, is that about correct? Dr. LEY. This is based upon the assumption of an average dose per patient and the total certification. The total certification does not nec- PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4395 essarily represent sales for the same time period, although the two are closely related over a longer time span. Senator NELSON. I would assume that is the case, since in June of 1968, you certified zero, which we assume meant that it was still used in the United States, but that some had been left on the shelf. Dr. LEY. That is correct. The California data indicated that on the average in the patients who have received chloramphenicol there are a very small amount of the drug was given, approximately four to four and a half grams. However, in treatment of typhoid fever and salmonellosis, a very typical total dosage for an adult would be a total of 50 grams of the drug, approximately 4 grams per day over an ex- tended period of 10 to 12 to 14 days. Senator NELSON. Was that a small number of people percentage- wise? Dr. LEY. That is a small number of people. In terms of salmonella infections, amounts in the order of 30 grams over a period of a week would be typical. The estimates of how many people received the drug are based, to my best knowledge-and Mr. Gordon, I think is well aware of this-on dosage levels of the order of 4 grams per patient. * Senator NELSON. Pardon me? Dr. LEY. The estimate of the number of patients receiving the drug is made on the basis of an average : dose of about 4 grams per patient. Senator NELSON. It was my understanding 9.5. Dr. LEY. 9.5? Senator NELSON. I may be wrong about that. My memory was 9.5. There is a significant difference. Mr. GORDON. The California study showed that the average dose was 9.55 grams. Senator NELSON. I suppose none of these statistics are very firm. Dr. LEY. They're not. Senator NELSQN. I notice some dosages are as low as 4 grams and you have cited instances of 30 and 50. In any event, a very large num- ber of people are receiving it? Dr. LEY. However, I would point out, Senator, that if you take a dosage for the material certified last year, for example, and if you accept for the systemic form of therapy an average dose of 10 grams, the number of patients who would be treated by that amount would be somewhat less than the 4 million figure. I would be between 1 and 2 million on the basis of last year's certification. Senator NELSON. And the year before that? Dr. LEY. The year before that would be close to 4 million. Senator NELSON. Doesn't that dramatic drop indicate that it was being more widely used in 1967 for nonindicated cases than in 1968? Dr. LEY. I cannot draw any other conclusions, Senator. We know from discussions between our staffs, Mr. Chairman, that you are interested in a month-by-month listing of the quantities of the drug certified. I submit such a listing for the record. Senator NELSON. It will be printed in the record. (The information follows:) PAGENO="0106" 4396 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TOTAL CHLORAMPHENICOL CAPSULES CERTIFIED FROM 1966 TO PRESENT ON A MONTH-BY-MONTH BASIS Month [In grams] 1966 1967 1968 1969 January February March April May June July August September October November December 3, 323, 275 4, 566, 323. 0 1, 045, 900. 0 248, 575 2,817,750 4,954,775. 0 2,855, 325. 0 2,064,525 5,109,650.5 256,900.0 2,329,800 3,938,725.0 513,475.0 2,437,920 2,120,100.0 259,950.0 2,050,675 2,371,955.0 0 1,024,975 2,599,725. 0 `1,702,250.0 1,797,800 4,206,550.0 2,618,927.5 2,049,925 2,026,219.0 291,150.0 2, 704, 875 2 1, 836, 925. 0 3 1, 992, 466. 0 3,371,675 1,779,900.0 1,927,561.0 (5, 805, 702 0 1, 023, 307. 0 Month 1966 1967 1968 1969 January February March April May June July August September October November December 502,503 430,307 36,475 1,981,253 1,321,105 934,244 215, 752 842,420 715,779 728,666 1,534,408 1,325,461 796,4565 651,646.0 562,053.0 894,380.0 620,122.0 748,484.0 48, 809. 0 646,709.0 753,732.0 533,007.0 583,898.0 481,300.0 385,635 0 602,619 525,680 191,116 341,655 (1) (1) 125,707 2275,328 92,883 319,686 98,990 Annualtotal 10,568,373 7,320,596.5 2,959,299 1 Certification of chloramphenicol injection temporarily discontinued while FDA evaluated blood-level studies for drug. 2 Includes initial certification of injectable of chloramphenicol from firms other than Parke, Davis. TOTAL CHLORAMPHENICOL ORAL SUSPENSION CERTIFIED FROM 1966 TO PRESENT, ON A MONTH-BY-MONTH BASIS [In grams] January February March April May June July August September October November December 265, 913 560, 754. 0 688,969 181,980.0 87,195 361,434.4 362, 633 628, 000. 0 270,233 0 769, 466 682, 066. 3 88,875 274,841.0 378 583 0 0 80,145.0 891,126 0 451,450 0 454,680 0 Annualtotal 31,778,897 35,510,847.5 14,487,211.5 `Includes certification of generic chloramphesicol for Rachelle Laboratories. 2 Certification of generic chlsramphenicol discontinued because of low blood levels. 3 Includes certification of generic chloramphenicol for McKessen Laboratories. ~This includes initial certification of a total of 3,441,852 grams of chloramphenicol from firms other than Parke, Davis. TOTAL CHLORAMPHENICOL INJECTIONS CERTIFIED FROM 1966 TO PRESENT, ON A MONTH-BY-MONTH BASIS [In grams] Mosth 1966 1967 1968 1969 674,721.0 0 271,162.5 131, 310.0 272,216.0 266,640.0 Annual total 4, 709, 123 2, 769, 220. 7 1, 616, 049. 5 PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4397 TOTAL CHLORAMPHENICOL OPTHALMIC AND OTIC VIALS CERTIFIED FROM 1966 TO PRESENT, ON A MONTH-BY- MONTH BASIS [In gramsj Month 1966 1967 1968 1969 January February March April May June July August September . 1,833 1,931 2, 591 1, 806 4, 971 1,102 1, 448 6, 542 2, 513 1,796.2 2,028.5 2, 039. 8 6, 530. 0 2, 292. 0 1,215.5 1, 540. 0 4, 105. 7 809. 0 1,023.7 3,431 1,735.5 2, 540. 3 4, 906. 9 2,760. 9 678.3 1, 842. 9 1,327. 0 704. 7 October 1,099 1,936.0 666.0 November 1,152 2,104.0 1,507.0 December 3, 092 1, 313. 0 4, 110. 0 Annual total 30, 080 27, 709. 7 23, 803. 2 TOTAL CHLORAMPHENICOL OINTMENT CERTIFIED FROM 1966 TO PRESENT, A MONTH-BY-MONTH BASIS [In gramsj Month 1966 1967 1968 1969 January February March April May June July August September October November December 1,378 9,244 5,265 3,440 7, 093 6, 977 6, 385 6, 760 3,511 2,625 10, 800 2,603 3,328.9 1,639.0 8,463.6 3,409.2 4,687. 6 9,440. 3 15, 583. 5 17, 008. 8 22,605.5 11, 540. 0 12,856. 0 18,259.0 18,409.8 11,334 897.0 9,239.9 6,823.6 5, 904. 9 6,912. 4 13,714. 0 14,657. 0 11,097.5 5,894. 0 875. 0 5,711.0 Annual total 66, 081 128, 821. 4 100, 136. 1 Dr. LEY. In January 1969, we decided to again convene our ad hoc committee on chioramphenicol. It had been approximately a year since this advisory group had last met. We wanted the committee's evaluation of the steps taken in regard to chloramphenicol during this time, as well as its consideration of additional measures for the future. The meeting took place on February 20, 1969. After reviewing the certification figures for 1968, the committee con- cluded that the publicity concerning chloramphenicol had had signif- icant impact upon its use. The committee took note of the increase in the number of capsules certified in the last quarter of 1968, but noted also the sharp drop that occurred in January of 1969. Senator NELSON. May I ask a question at this points, Dr. Ley? Dr. LEY. Certainly. Senator NELSON. There was, as you know, a dramatic increase in the use of capsules, chloramphenicol capsules, in the last 3 months of 1968 over the last 3 months of 1967. Our statistics from your agency are that it increased from 3.6 million grams in the last 3 months of 1967 to 4.9 million grams in the last 3 months of 1968, which is a 36.7 percent increase. Are thse figures correct? Dr. LEY. I believe the figures `are correct, Senator, but there is an additional factor which must be considered in making such a compar- ison. This is noted in footnotes with the material which we have PAGENO="0108" 4398 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY submitted for the record, and I believe the same data was also provided at an earlier request from a member of your staff. In 1967, beginning on the month of October, certification of generic chloramphenicol was discontinued because of the low blood level that I previously mentioned, and during the month of December no chlor- amphenicol at all was certified for any manufacturer until we resolved this question of equivalency among the oral products. Senator NELSON. I had forgotten that. I do recall now. How does the last 3 months of 1968 compare with the last 3 months of 1966. Dr. LEY. They were considerably lower in 1968 than in 1966. I would have to do a quick addition here. It is approximately 3 million grams for 1968 and for the last 3 months of 1966-then this is not a good comparison because in the month of DecenTher of 1966 the generic manufacturers appeared on the scene-but the total for the months of October and November of 1966 is 6 million grams for those 2 months alone without the generic. Mr. GORDON. May I interrupt here? Dr.LEY. Certainly. Mr. GORDON. What percentage of the total did the small manu- facturers contribute? As I understand it, it is a very, very small percentage Dr. LEY. It was a small proportion for the entire period. There were certain months immediately after the small manufacturers began to apply for certification in which they represented a significant part of certification for a single month. I think the significant point here is that if we go so far as to exclude the month of December altogether, the total for October and November of 1966 is 6 million grams. For Octo- ber, November, and December of 1968, it is 3 million grams. I think that the comparison of 1966 and 1968 again demonstrates-four, I'm sorry. Senator NELSON. 4.9. Dr. LEY. Four. I'm sorry. Senator NELSON. 4.9, isn't it? Dr. LEY. Right. Mr. GORDON. And you think that the small companies made up that 36.7 percent- Dr. LEY. We have more detailed information on the graphic- Senator NELSON. Are you saying that nobody manufactured in December of last year? Dr. LEY. There were no certifications of chloramphenicol in the month of December 1967. Senator NELSON. For any company? Dr. LEY. Oral capsules. Senator NELSON. Oral? Dr. LEY. Oral capsules. Senator NELSON. How much in injectables? Dr. LEY. Half a. million grains, roughly. Four hundred eighty-one thousand grams of injectables in that month. Senator NELSON. This had nothing to do with FDA. It was just a question of Parke, Davis not submitting any batches for testing in December for capsules. Dr. LEY. I'm afraid, Senator, it did have something to do with the FDA. Tjntil we reached our eventual decision on the 20th of December, we chose not to certify any that month. PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4399 Senator NELSON. I see. That was action of the FDA then? Dr. LET. That is right. Senator NELSON. So then I would guess that you have to conclude from this that you just about have to measure year versus year rather than particular months, although at certain times of the year, there is a rise in the number of certifications which I assume is associated with the incidence of the cases for which it may be indicated; is that correct? Dr. LET. Yes. Senator NELSON. Please go ahead. Dr. LEY. The committee saw no need for any further labeling changes in the warning section or in the indications for use of the drug. A number of other suggestions which had been made in the past for controlling the use of this antibiotic were also considered by the committee. This includes such steps as restricting the use of the drug to hospitals, requiring a procedure of countersigning prescriptions, or licensing the drug as a narcotic. The committee was unanimously opposed to such restrictions. Neither did the committee consider it advisable to add warning information on the labeling provided the patient. The commitee did, however, recommend the exploration of further means of emphasizing to the medical community the proper uses for this drug and its possible adverse effects. On the basis of the committee's recommendations and our own con- sideration of this matter, we have started, or will promptly initiate the following actions: 1. We have asked the American Medical Association for assis- tance in communicating at the county medical society level infor- mation as to the misuse of chloramphenicol, the limited areas of its proper usefulness, and the grave hazards associated with the drug. 2. The AMA News has agreed to give further publicity to the chloramphenicol problem in an early issue. 3. Both the American Hospital Association and the Joint Com- mission on Accreditation of Hospitals will be asked to support and encourage the broader use of pharmacy and therapeutic com- mittees in hospitals, a point that Dr. Wehrle made in his testi- mony to you yesterday. 4. The AMA Council on Drugs has proposed that these com- mittees exercise more effective control over drug use and improve the reporting of adverse reactions. We intend to fully support the council in this recommendation. 5. We have received the Parke, Davis promotional material, noting the discontinuance not only of the "reminder" ads, but also of a group of ads headlined to promote the drug for respiratory and urinary infections, which we discussed here earlier. 6. We have checked the detailing piece used by Parke, Davis in the promotion of the drug and it is in conformity with the package insert. In summary, Mr. Chairman, I believe we have made considerable progress in dealing with an exceedingly difficult problem. I intend to make every possible effort in the months ahead to assure that this progress continues. I thank you for your time and attention, and if there are any ques- tions,I will be happy to answer them. PAGENO="0110" 4400 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. The only statistics we have as of now showing the reduction in the use of the drug are statistics of 1967 versus 1968. If I interpret what you have said correctly, it still is the judgment of the FDA, or of you, that it is still more widely prescribed than it should be; is that correct ? Dr. LEY. This is my belief Senator. Senator NELSON. Now supposing next year-as the president of Parke, Davis predicted last ,June, that once the hearings were for- gotten, the use would rise again-suppose that occurs, what steps does the FDA intend to take? Dr. LEY. At that point in time, I would be forced to reconsider this whole matter. I wish in the coming year to place very strong pressures on additional means of communicating the facts relating to the adverse reactions to chloramphenicol to the people who prescribe the drug. And I hope to be able to elicit the help of such groups as the AMA in this effort. Assuming that this does take place, fine. If it is not possible to obtain assistance from this group, I think we in FDA are going to have to consider our own means of getting significant information of this sort before the medical profession-possibly including still another letter. But I would say that we should give the steps I've outlined here a trial to see what they are capable of doing, because I do not believe these steps have ever been taken before. Senator NELSON. I suppose one of the problems here is, or has been from the beginning, to actually bring this matter of the indicated uses directly and forcefully to the attention of the prescribing physi- cian in such a way that he ends up being persuaded. We had some testimony here on one occasion from a very fine doctor who knew what chloramphenicol was used for but did not realize at the moment that the National Academy of Sciences had revised the indicated uses. In other words, there were substitutes, and so forth, and he wasn't quite aware of that. I think this is part of the problem that one might use this over a period of years. We have had some testimony on its use among the pediatricians to the effect that, because of the historical factor, they know about the drug and they use it. Then the indicated uses change for v~arious reasons and that fact isn't brought home to them. How are you going to bring it home to the physicians of the country that the National Academy of Sciences now says it is not "the" drug of choice for any condition? How do you get that home to them? Dr. LEY. I think it can be covered in two separate ways; each will have its impact, and yet ~`ith both. I cannot assure you that every physician will receive the message. We have plans scheduling an inter- view between the AMA News and myself in the near future. I wish to feature in that interview not only the types of adverse reactions which have been reported to us over the past several years, but also the appropriate indications for use. And I think we can even support the estimates that have been given by several previous people who have appeared before you, that as nearly as we can tell the drug is appropriately called for perhaps in roughly 10 percent of the patients who receive it. Senator NELSON. In your judgment that statistic still stands? PAGENO="0111" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4401 Dr. LJEY. That statistic is as good an estimate as we can make, and I believe your prior witnesses here could get no better statistic. We have not been able to find anythinp~ closer ourselves. Senator NELSON. If I understand you correctly, about 90 percent of the people receiving chioramphenicol are getting it for nonindicated cases. Is that what you are saying? Dr. LEY. Nonindicated cases under present labeling, that is correct. Senator NELSON. And that is in 1968 as well as 1967? Dr. LEY. It is too early, Senator, to really make this judgment. The course of aplastic anemia is a protracted one. We would normally not receive the report until the patient's death which may be a year after the initiation in the fatal cases. Senator NELSON. Let me understand this. The question of whether or not somebody died from aplastic anemia may not have anything to do with others who received it for an indicated case? You might receive it for a sore throat or infected gums or acne, without getting aplastic anemia, and it is still prescribed for a nonindicated case? Dr. LEY. That is correct. Yet, we have to enter the data system at some point and the only point available to us to enter it is the terms of the adverse reactions reported to us. In other words, we see the adverse reaction reports. In looking over the adverse reaction reports, it is our best judgment at this point in time that about 10 percent of the patients reported as having reactions of a whole spectrum of types receive the drug on appropriate indications. The indications are also outlined telegraphically in the reports. Now, if we are to see any change with time in the incidence of aplastic anemia as a result of your committee hearings last year and the increased interest this year, it will take us at least a year because of the delay in reporting such tests to have any evidence statistically of a change in incidence of aplastic anemia. That was the point I was trying to make earlier. Senator NELSON. Of course, the only study tha.t has been called to the attention of the committee is the California study which heaven knows is skimpy enough when you are dealing with a factor of 10 deaths and trying to extrapolate from them. The other factor, of course, is that literally tens of thousands of people may receive chlor- amphenicol for a nonindicated case, and get no reaction at all, and that statistic is nowhere to be found. I don't suppose it would be possible. Dr. LEY. Dr. Best in his review several years ago of serious side reactions, I believe, arrived at the same figure of appropriate usage of 10 percent, 10 percent of the patients who were reported to him as having reactions had been given the product on the basis of what would be an acceptable indication. Senator NELSON. I was thinking it was 1 percent, but I believe it was Dr. Weston, the pathologist, who thought that 99 percent received it for nonindicated cases. And :as I recall his testimony from a year ago, he had never seen a case in which death resulted from aplastic anemia in which the drug had been given for an indicated case, not one. Well, now, what concerns me is getting the information out. It is perfectly understandable that doctors become acquainted with the drug at some period in history-there are thousands of drugs-and they may not have reason or have gotten around to keeping up on the changes for its use. PAGENO="0112" 4402 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY Now, the National Acade1ny of Sciences has made their report. As I understand it, FDA agrees with that report. Dr. LET. We have not only agreed, but we have taken definite action with reference to this product. Senator NELSON. The literature will certainly carry references about this. There will be some news here and there in the medical journals. But the fact is one reason for advertising is to promote the drug. Gen- eral Motors made a public announcement calling back 4,900,000 cars on the ground that it is a public hazard. This is a matter of public health. Shouldn't Parke, Davis be required now to say it is a different bail game; there are other drugs, this is not the indicated drug, the drug of choice in any disease, and run ads in the medical journals say- ing that? This is what General Motors did. And we all agree, all the experts agree, and you do, that it appears that 90 percent of the people are getting this drug for nonindicated cases. It is no greater tragedy to die from an automobile accident than from this drug unnecessarily. General Motors has made the front page announcement. That is what the law requires. Why shouldn't Parke, Davis be required now to advertise what the fact is? For whatever purpose the ads were valid in the past, they aren't now, and it is not the drug of choice for any disease and it ought to be called to the attention of t.he medical profession by ads in all the journals. Why shouldn't that be done? WTe aren't willing to restrict their practice, saying they can only use it in the hospitals, but a lot of doctors should be told about this. Well, you aren't doing that. Just make them tell the truth. What is wrong with that? Dr. LEY. We have essentially through our own letters last year said, look, to the physician recipient, the indications of this product have changed. It is a different ball game. Parke, Davis has not said this. And I'd have to turn to the General Counsel to see if there is any way that FDA could be instrumental in arriving at such a statement from Parke, Davis. I have doubts whether we could. Mr. GooDmon. Well, I think we have required them to do that in this very ad. If you will read the box warning, it does tell them that the ball game has changed, that the indications have changed, that the warnings are stronger, and we have, by telling them to discontinue the reminder ads, required that this message go with all promotional material. Now, we do not have the specific authority of the Automobile Safety Act to require notification of defects, but this went to every physician in the United States a.nd keeps going in every ad used, in the detailing piece and in the Physicians' Desk Reference. So I believe we've done more than just say, just modified the labeling in terms of indications. The indications were written in a very special way in a box form, and the side effects and hazards were emphasized both in wording and in outlay and display. Senator NELSON. Well, we are talking, of course, about two different things: One is the package insert, that aspect of the fine print in the ad that you require, and the other is to counteract the history of a whole page stating, "when it counts." Mr. GooDRICH. That was the purpose of the letter to every physician in the United States, and rather than have Parke, Davis send it out we sent it out. We made sure it went not only to every physician but PAGENO="0113" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4403 to every hospital administrator, and we have followed that up by fol- lowing the promotion to make sure that those defects which we have outlined in the statement did not appear, such as that cystoscope and the headline series on respiratory infections, serious urinary tract infections, that now the message on chioramphenicol be oriented to its use only on the basis of an identified causative organism, not to be used where another less potentially hazardous product is available, and not to be used except in these specific indicated cases. This is the kind of message I think you are talking about that should be sent to the physician, and since we send it ourselves, first-class mail, with a notice on the front of the envelope, we think we communicated that to the physicians. They need to be told again, and as Dr. Ley's statement says, we are planning to try to communicate with them through the AMA at their local county medical society meetings to see if we can't emphasize this, tdo. Senator NELSON. But the test is the result? Mr. GOODRICH. Right. Senator NELSON. The testimony still is that 90 percent of the people receive it for a nonindicated case. It really wouldn't have done any good for General Motors to have announced that a whole lot of these cars have this defect, including a carburator that might induce lethal gases from the exhaust into the car, had a story on that, and that is all. It would have about the same effect as what the FDA is saying to the doctors. Some people would notice it and do something about it and most would not. And most apparently haven't done aything about this. Mr. GOODRICH. Well, there's been a substantial reduction in the use of the drug. I think we have started by agreeing with that. Senator NELSON. Correct. Mr. GOODRICH. And our point was that while some progress, some very good progress had been made,much remains to be done, and we've suggested a program of going at it. Senator NELSON. What I am getting at is, whether or not it is adequate. Now, it is a fact that it is no longer the drug of choice in any case. At one time it was the drug of choice in certain circumstances. And millions and millions of dollars were spent to demonstrate that it was the drug of choice. Apparently as a consequence of this kind of promo- tion, it was much more widely used than its indications warranted. This is a matter of public health. It is a matter of life and death to anybody who gets it for a nonindicated case and dies. Why shouldn't Parke, Davis be told that they should now run an ad in all journals saying "here is what the National Academy of Sciences now says-it is not the drug of choice for any disease, and here is specifically how to use it?" They got to the doctors in promoting it. Why shouldn't they get to the doctors in depromoting it, is my question? Mr. GOODRICH. That was the point of the statements in the indica- tions sections: "Chioromycetin must be used only in those serious infec- tions for which less potentially dangerous drugs are ineffective or contraindicated." Senator NELSON. Even the package insert doesn't tell the case. Why shouldn't the package insert say right at the top, this is no longer the 82-280 O-69--pt. ii--8 PAGENO="0114" 4404 CO~PETITIVE PROBLEMS IN THE DRuG INDuSTRY dru.g of choice for any disease in this country? It doesn't say that. I know what happens. I have had doctors say, "who reads these package inserts !" In the first place, they don't see them. They all go to the pharmacists. They see them if they get a free drug. So they really aren't seeing the ad anyway but they do see that ad in the medical journals. So, what you are really saying is we've gotten reasonably tough about the package insert which never goes to the doctor who prescribes it. I don't think this is fair to the consuming American public. Mr. GOODRICH. We have put into the record a copy. of the package insert which is a detailing piece that goes with the free samples. We've also put into the record the ads. Now, if that is not satisfactory, then it is not satisfactory, but that is what's been done. Senator NELSON. Well, I don't think it is satisfactory because I think we have to go by the test of results. All the distinguished wit- nesses, including Dr. Goddard and Dr. Ley, and all the other experts who have testified have said in public that about 90 percent of the peo- ple are getting this drug for nonindicated cases. And Dr. Goddard sat in that witness chair and said "I am at wits end," to quote him pre- cisely, "on how to stop the use of this drug." Well, I'm not at my wits end. I'll give you some suggestions. I think they ought to have to run an ad saying this is what it is now indicated for. I would think in the package insert, which most physi- cians don't really see, it should say right at the top in a box, quote: Not the drug of choice in any case. Here is what it is to be used for: Never to be used except in a case where the disease is serious; never to be used except when no other antibiotic will do the job, and never to be used unless the organism involved is susceptible to chioramphenicol. Not a whole lot of print, just concise and to the point. And then in the ad that goes in the paper, I would think you ought to print at the top, exactly what I've said. You know, if we had accomplished our purpose with what we had done a year ago, what Dr. Goddard did, I think there would be no argument, but we haven't. We've come a long way. There is no question about that. We have reduced the usage from 42 million grams to 20, but we are talking about people who are going to unnecessarily die. And I think that we ought to tell every doctor in America, in ads and package inserts, that here is the present status of the recommended use of the drug. Are you., for example, going to send out the "Dear Doctor" letter saying here is what the National Academy of Sciences says-not the drug of choice? Dr. LEY. This is a perfectly satisfactory option for us to consider, and I will weigh this very carefully. We have, Senator, also embarked on another effort which is broader in scope than this but very similar. Early this month, we cosponsored a. conference with the NIH on the continuing education of physicians in which Dr. Dowling chose chloramphenicol as a. beautiful example of the difficulty in updating the physicians' knowledge on drugs. His remarks were very similar to your own a few moments ago. He pointed out that there are a variety of influences operating on the physician. None of these are perfect. Public interest, newspaper publicity, to some extent the labeling, all are important in molding his reaction. However, the response which he indicated here is attractive in terms of the decrease in certification PAGENO="0115" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4405 over the past year, is one which must be continually pressed for by new means and more effective means of communication between us and the community at large. Senator NELSON. Well, now, I hope you will consider a "Dear Doctor" letter. I know that there will be those who get it for headaches and acne and flu and die from it, but these people are entitled to the most vigorous protection possible. Then it seems to me the advertising should contain what the National Academy of Sciences now says and with which the FDA agrees-this ought to be boxed in a very prominent place. I know enough from political advertising about how to cover up the warts and exaggerate the good qualities, but it would seem to me the FDA ought to require a very prominent place in the whole medical journal advertising. This is new. It is not the drug of choice. Now, why shouldn't that be considered? You can approve the advertising. All you are doing is saying tell the doctors what the National Academy of Sciences says. Dr. LEY. This is a possibility to consider that has wider ramifica- tions than merely this product. There are at present, and will soon be many more, examples of drugs whose indications are being drastically revised by the Academy's action and review. I think that the problem of communication of such changes of appropriate indication for the older class of drugs marketed between 1938 and 1962 is a very impor- tant problem for us to consider. How may we get this information, not just for chloramphenicol, but for the entire spectrum of drugs marketed between 1938 and 1962 effectively before the physician population of this country? It is a difficult problem, one that we have been looking at and exploring possible avenues of approach. We do not have an answer as of this time. Senator NELSON. I am sure it is a difficult problem. I'm sure you know how much more difficult a problem it is than this committee does. But I am concerned that we vigorously pursue it. And it does seem to me that the medical profession is entitled now to be told what the National Academy says. I am not critical-nobody conceivably could be critical of a practicing physician who doesn't know what the National Academy of Sciences now says. How is he going to know that? And the continuing education problem is certainly a tough one. I think the friends I have in the medical profession are very conscien- tious people. Some have a complicated, difficult problem to keep up on all these matters. But it seems to me in a case like this the situation is clear, though the FDA has done a lot, there is more it ought to do in terms of the advertising and the packaging insert and notifying the doctors, otherwise I think we'll have the tragedy of a rising use of the drug again. We will have more at the end of next year and we will still be talking about it at the end of next year. I wonder if perhaps you would take a look, when it is printed, at Dr. Wehrle's testimony, in which he made a suggestion about trying to find out just where geographically chioramphenicol is being used, for what purpose, and what doctors are prescribing it. He thought that you could perhaps set up some sample areas and do a survey of how much is being used in this area and what are the reasons for its use. PAGENO="0116" 4406 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I don't know whether you would consider that a useful enterprise or not, but it might very well be. I don't know whether you have the facilities to do that, but perhaps they may be available in NIH or HEW. I believe it would be valuable because nobody seems to be able to tell us, you know, what the variations are, nor why. Dr. Wehrle raised the question yesterday, for example, whether or not chloramphenicol was prescribed widely or not at all or in fair amount during the flu epidemic? Does anybody know that? Dr. Li~nr. No. This is a q~uestion we asked our consultants and they had no firm answer at this time. Senator NELSON. I wish you would take a look at it. It may well be that you could get some helpful information. It isn't indicated for influenza, is it? Dr. LEY. No, sir, it would not be indicated for influenza under any condition. Mr. GORDON. Coming back to the Reader's Digest of February 1968, you stated the ad recommended the drug for uses that were not warranted and seriously understated the hazards, side effects, and contraindications. Could anything have been done along these lines to make the Reader's Digest perhaps rmn a remedial ad? Dr. LEY. This is a question I would like to turn over to our General Counsel. Mr. GOODRICH. We have no direct authority to require any type of remedial ad. We have required some by persuasion, if you might call it that, where we had a choice of taking action against the company or its drug, but we would not have authority over Reader's Digest at all. Mr. GoiwoN. How about moral or ethical authority? Couldn't you, for example, approach the Reader's Digest and say, look, this is a false and misleading ad. How about correcting it for the sake of the public welfare? Mr. GOODRICH. Sure, that could be done. Mr. GomoN. That wasn't done, though, was it? Mr. GOODRICH. That was not. Mr. GORDON. Thank you. Senator NELSON. I want to thank you, Dr. Ley, for your very valu- able testimony. I wouldn't want you to feel that because we might have had some differences that I do not think the FDA in the past- since Dr. Goddard's administration and yours-hasn't been doing a superior job. Dr. LEY. Thank you, very much. Senator NELSON. Thank you, Doctor. (The supplemental information submitted by Dr. Ley follows:) PAGENO="0117" 6. QuantItative Formula Estobliohod (Non.Ptop~iototyi Nonto of Aotioo lng!odionts (in otdot shoot tobol) Chlorarnphenicol Attoottt (pot tobi.t, pn~ ni., 0.5 Gm./2 cc. vial 7. Dosogo Foon (tobtots, ott.) ampoule 0. Root. of Adnt. (O~ol, oft. Whot, too d.tg opplicotion diffocont ,o~ttos of odnivictcotion, sopototo fotns shoold bo osod.) parenteral 9. Th.top.otin Cloitttc-Attoch 10 lob.), ond 10 pockogo insotto (if nod) to ociginol Foon A bk,.) ond copy to dcphcoto Ponn A (ohits). 10. List of )itOtOtttc. tofoconoos tnost pocfln.nt to on ooolctotlon of ho offsotinonoss of Oh. dtccg On. oh. pcctpos.s fon nthlch it is off.t*d in th. lob.), tho pockog. ins.tt, ot boochoto. Apptooinotoly S to 10 boy f.tonooo no. toqoostod, if onoiloblo. (Attoch 10 copiss to otigitot Foon A (bios) ond I copy to dopiioote Fotn A (ohito).) 1. Tho oppikont is inoitod, if ho so docitos, to sobnit oty onpo blishod nototiol hot is pootinont to ho onolootion of ho dnog by ho Aoodottty- Rncoonch CoUncil. This soppinnontoty ,,totonioi ohocid be pocbogod ocith Fonno A (ohits). A sing). oopy of this motstioi ist.qccesf.d. 12. iv this spots, plooso list ond dosctibo bti.tly ch. soppi.tt.ntony nototioi hot is sc bttt)tted ocith Fot,tt A (ohito). COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4407 NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL Division of Medical Sciences DRUG EFFICACY STUDY Form A (To be submifed in dup)icate by opp)icanf) 6D307~ ~ 2. Dote Otiginolly Appnon,d December 3. 1953 3. Co OTt 0 Chloromycetin Solution Parke, Davis & Company ,Toseoh Camoau at the River: Detroit. Michiman 1. NDA N,,nb.n~___. 4. BnondNovo_____ 5. Appliconts Non. PAGENO="0118" 4408 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Panel on Anti-Infective Drugs (1111 INDICATIONS I. Staphylococcal infections, by implication of the discussion on the first page of the insert, may be an indication: "in a survey of experimental and clinical experiences of susceptibility of staph- ylococci to chloramphenicol, it was found that the incidence of chloramphenicolresistant staphylococci appears unrelated to fre- quency or to intensity of use of this antibiotic. Development of resistance to chloramphenicol can be regarded as minimal for staph- ylococci and many other species of bacteria." EVALUATION: Possibly effective. COMMENTS: Although chloramphenicol was useful for the treatment of some staphylococcal diseases during the mid-1950's, it now seems to be rarely indicated. Its major trial was in the staphylococcal pneumonias accompanying the influenza epidemic of 1957. Its effective ness was somewhat less than expected, even for sensitive strains. The statement concerning resistance is not true in the opinion of the Pane (see below). In the description of invitFp work just before the sen- tence quoted above, there is no reference to the transfer of episomal particles carrying chloramphenicol resistance. The advent of better agents for staphylococcal disease relegates this drug to a very rarely needed alternate choice. DOCUMENTATION: 1. Bloomer, W.E., S. Giamruona, G.E. Lindskog, and R.E. Cooke. Staphylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:265-274, 1955. 2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 3. Hausrnann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 4. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 5. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of transmis- sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965. 6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 7. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. II. Rickettsial diseases: epidemic and murine typhus, Brill's disease, scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox. PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 4409 EVALUATION: Effective, but COMMENTS: That chloramphenicol is effective in the diseases listed is well established, except in rickettsial pox, a condition so in- frequently seen that few data are available. However, if the warning is to be taken seriously--"chloramphenicol should not be used when other less potentially dangerous agents will be effective'---the tetracyclines, which have been shown to be as effective as chloram- phenicol, should be considered the choice and chloramphenicol used only if toxicity to these or failure to respond has occurred. The duration of therapy recommended appears adequate. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chloramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer. J. Med. Sci. 219:627-638, 1950. 3. Ley, H.L., Jr., T.E. Woodward, and J.E. Smadel. Chloramphenicol (chloromycetin) in the treatment of murine typhus. J.A.M.A. 143:217-219, 1950. 4. Murray, E.S., G. Baehr, G. Shwartzman, T.A. Manderbaum, N. Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and J.C. Snyder. Brill's Disease; clinical and laboratory diagnosis. J.A.M.A. 142:1059-1066, 1950. 5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E. Smadel. The treatment of Rocky Mountain spotted fever with chloromycetin. Ann. Intern. Ned. 29:656-663, 1948. 6. Smadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Leuthwaite. Chloramphenicol (chloromycetin) in the treatment of tsutsugamushi disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949. III. Typhoid fever. EVALUATION: Effective, but . . COMMENTS: Chloramphenicol has often been listed as the drug of choice in typhoid fever. It is not clear that ampicillin has changed this claim, but if they were of equal activity, the claim of "drug of choice" would have to be revised because of the toxicity warning. There is no mention of the carrier problem and relapses of positive stool cultures DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chioramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of typhoid fever. I. Combined therapy with cortisone and chioram- phenicol. Ann. Intern. Med. 34:1-9, 1951. PAGENO="0120" 4410 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IV. Other salmonelloses. EVALUATION: Possibly effective. COMMENTS: Because of variability of clinical course with each species and the large variety of species, there is little reason to presume that a generalization is possible. In a condition of short symptorna- tic duration like gastroenteritis, the use of the drug is most diffi- cult to evaluate. The variable courses of the systemic forms do not allow the assurance of effectiveness that has been derived for typhoid fever, which is more uniform. These differences between typhoid and the other salmonelloses illustrate the difficulty of generalization from one species to the next. It is likely that localized salmonella infections, such as osteomyelitis, empyersa or other diseases should have a therapeutic trial with chlorarnphenicol. The treatment of carriers with positive stool cultures should not be recommended and the insert should so state. Although the stools may be negative while the drug is continued, there is no evidence that the carrier state is terminated more frequently than would occur otherwise with a similar passage of time. Obviously, the inability to define drug effectiveness in salmonelloses also applied to other drugs, such as ampicillin; hence, a reliable comparison between drugs is not possible. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 56-58. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. V. Urinary tract infections. EVALUATION: Effective, but . . COMMENTS: As specified in the insert, outcome of treatment of urinary tract infections is influenced by anatomic factors, but these have little importance in the choice of drug except that, in situations in ~hich cure is unlikely, the use of toxic agents is probably not justi- fied. The susceptibilities of the organisms involved are of prime importance (chloramphenicol does not work any better against chloram- phenicol-susceptible organisms than other agents work against organisms susceptible to them). Hence, when organisms are susceptible to less toxic agents, chloramphenicol should not be used even if it is effective i~ vitro unless the others have failed. It is unusual for chloramphen- icol to succeed when other agents with satisfactory in vitro activity have failed. Of the three species singled out, Escherichia ~ is often treatable with other chemotherapy, but chloramphenicol may be a secondary choice. Streptococcus fecalis infections are probably better treated with other agents, such as penicillin and streptomycin or erythromycin. Various Proteus species are different in their susceptibility to different drugs; hence, the generalization "Proteus species" should be avoided. Proteus morgani, vulgaris, and rettgeri PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4411 are often susceptible only to chloramphenicol. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 105- 108. Antibiotics Monographs No. 8. New York: Medical Encyclo- pedia, Inc., 1958. VI. Surgical infections: postoperative wound infections. EVALUATION: Possibly effective. COMMENTS: Postoperative wound infections have a variety of etiologic agents, but ococcus aureus is the single most common. Chlor- amphenicol is effective against many of these agents, but is not the most effective against the Staphylococcus. For this reason, plus the toxicity warning, it is not the first choice in most infections unless an organism is isolated against which chloramphenicol is most active in vitro, or other preferred drugs cannot be given or have been inef- fective. DOCUMENTATION: Most favorable report is reference 1 (Altemeier). 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chlorornycetin) and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Nauss. Staphyloccal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 8. Waliman, 1.5., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. VII. Surgical infections: cellulitis. EVALUATION: Possibly effective. COMMENTS: Cellulitis (other than postoperative) is most often caused by streptococci or staphylococci for which chloramphenicol is not the most effective drug. For this reason, plus the toxicity warning, it is not the first choice unless an organism against which chloramphenicol is the mos.t active has been isolated, or the preferred drug cannot be given or has failed. PAGENO="0122" 4412 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DOCUMENTATION: Same as for Indication VI. VIII. Surgical infections: infected sinus tract. EVALUATION: Possibly effective. COMMENTS: Chloraniphenicol may be useful in some instances in which the organisms have been shown to be sensitive only to it. Many sinus tract infections are caused by tuberculosis and actinomycosis. Chior- amphenicol is not indicated in tuberculosis, and other agents are preferred in actinomycosis. Some sinus tracts associated with fistulas from viscera, including intestines, may be predominantly infected with fecal flora. In these, chloramphenicol may be the single most effective agent. When other agents appear equally effective in laboratory testing they should be tried first. There is rarely great urgency in treating sinus tract infections with antibiotics. The specific organisms for which chloramphenicol has been proved effective therapy (in this condition) should be listed. DOCUMENTATION: 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromyceti and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. * Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., C.N. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103: 532-542, 1959. 8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955. 9. Woodward, T.E., and C.L. Wissernan, Jr. Chloromycetin, pp. 122- 124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia Inc., 1958. IX. Surgical infections: peritonitis or intra-abdominal abscesses from ruptured intestines, diverticula, or appendix. EVALUATION: Possibly effective. PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4413 COMMENTS: These infections are often caused by mixed flora from the intestinal content . In the acute stage of peritonitis, a drug often must be selected empirically for surgical preparation or immediately postoperatively. Judged by statistical probability chloramphenicol is a good choice in such a situation. It should be given parenterally, however, because oral therapy in these infections is probably inap- propriate. In other less acute complications listed in the insert, chloramphenicol should be shown to be the most effective agent against the organisms isolated before it is used, or other less toxic agents should have failed or be contraindicated. The specific causative organisms for which chloramphenicol has been proved effective therapy (in these conditions) should be listed. DOCUMENTATION: Same as for Indication VIII. X. Respiratory tract infections. EVALUATION: Possibly effective. COMMENTS: This heading is ambiguous. The package insert should list specific organisms (and the site of respiratory infection) for which chloramphenicol has been proved effective therapy. In general, the etiology of these conditions is varied and chloram- phenicol is the best agent for only a few. In streptococcal, pneumo- coccal, and staphylococcal diseases of the respiratory tract, other drugs are preferable. Chloramphenicol should be used only in Kiebsiella infections and perhaps other necrotizing pneumonias caused by E. coli or related organisms when they are shown in vitro to be resistant to ampicillin, cephalothin, and kanamycin. Hempphilus influepz~ infec- tions of the respiratory tract respond well to ampicillin; hence, chloramphenicol is best used only when ampicillin is not tolerated or fails. DOCUMENTATION: - 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 63-72. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. XI. Meningeal infections. EVALUATION: Probably effective. COMMENTS: The three most common causes of meningitis are the meningo- cocci, pneumococci, and Hemophilus influenzae. All are susceptible to chloramphenicol, as are many staphylococci and the gram-negative aerobic rods that often infect newborns. Moreover, it is true that the drug does get into the spinal fluid well. As a drug of choice PAGENO="0124" 4414 COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY for empiric use, however, it is probably not first, because it is likely to be less effective in pneumococcal disease than is penicillin. Although many believe it is first choice in Hemophilus infections, tetracycline is probably as good and ampicillin is, too. It is likely that this claim (drug of choice in H. influenzae meningitis) is no longer justified. In menigitis of the newborn kanamycin is preferred as the drug of choice for empiric treatment. In older patients, when a diagnosis has been made and the organisms shown to be more susceptiblE to chloramphenicol than to other agents, it may be the drug of choice. As indicated, in the insert, initial treatment should be parenterally administered. The package insert should list the specific organisms for which chloramphenicol has been proved effective therapy in meningitis. DOCUMENTATION: 1. Parker, R.T., N.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E. Woodward. Therapeutic range of chloramphenicol in purulent men- ingitis. Antibiot. Ned. Clin. Ther. 1:192-200, 1955. XII. Brucellosis. EVALUATION: Effective, but . COMMENTS: Chloramphenicol, like other drugs, is capable of control- ling symptoms of acute brucellosis, but the relapse rate is high. It does not appear to be superior to the less toxic tetracyclines. DOCUMENTATION: 1. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of.brucellosis. Amer. J. Med. Sci. 219:627-638, 1950. 2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The University of Minnesota Press, 1956. 464 pp. 3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Raby. The beneficial effect of chloromycetin in brucellosis. J. Clin. Invest. 28:968-976, 1949. XIII. Bartonellosis. EVALUATION: Probably effective. COMMENTS: Chloramphenicol is reported to be an effective antibiotic in these infections. Of the references suggested by the manufacturer (see Documentation below): two are reports of studies involving a total of 25 patients whose bartonellosis was treated with chioramphen- icol with good success, and two are textbook discussions of bartonel- losis and its treatment. Of the latter discussions, one feels that the effectiveness of chloramphenicol is best documented, the other feels that other agents are probably as good. PAGENO="0125" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4415 DOCUMENTATION: 1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and .J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.) Philadelphia: W.B. Saunders Co., 1960. 2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with chloromycetin. Antiobiot. & Chemother. 1:92-99, 1951. 3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever, Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott, Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia: W.B. Saunders Co., 1963. 4. Urteaga, B.O., and E.H. Payne. Treatment of the acute febrile phase of Carrion's disease with chloramphenicol. Amer. J. Trop. Med. 4:507-511, 1955. XIV. Relapsing fever. EVALUATION: Possibly effective. COMMENTS: Treponema (Borrelia) recurrentis infections in experimental animals are susceptible to chloramphenicol. On a weight basis, how- ever, penicillin G is more active. In human infections, no direct comparison has been made, and, although chloramphenicol has been used successfully, penicillin should be tried first if it is tolerated. DOCUMENTATION: 1. Hirschboeck, N.M. Use of chloramphenicol in relapsing fever. Amer. J. Trop. Med. 3:712-713, 1954. XV. Granuloma inguinale. EVALUATION: Effective, but . . . COMMENTS: It has been reported that chloramphenicol caused the disappearance of Donavan bodies more rapidly than either tetracycline or streptomycin. Relapses after chloramphenicol have seemed to be less than 107. Although chloramphenicol may be slightly better than tetracycline, the latter may be, preferred for toxicologic reasons. DOCUMENTATION: 1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and N. Zises. Five-year study of antibiotics in treatment of granuloma inguinale. Amer. 3. Syph. 36:186-191, 1952. 2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol in the treatment of gonorrhea and granuloma inguinale. Amer. 3. Syph. 36:264-268, 1952. XVI. Plague. EVALUATION: Effective, but PAGENO="0126" 4416 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMMENTS: All forms of plague have been shown to respond to chlor- amphenicol when it is given in large doses early in the disease. There is no clear evidence that it is superior to tetracycline or s treptonycin. DOCUMENTATION: 1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E. Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and terramycin in the treatment of pneumonic plague. Amer. J. Med. 14:284-293, 1953. XVII. Ornithosis. EVALUATION: Possibly effective. COMMENTS: In embryonated eggs and experimental animal infections, chloramphenicol is less effective than the tetracyclines. Results of therapy of human infections have been variable and relapses have been frequent. The role of the drug in this disease is not well established. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. GENERAL COMMENTS The "Warning" section appears justified in view of the seriousness of aplastic anemia. Tissue distribution appears to be favorable. The distribution into the cerebrospinal fluid is good, as pointed out in the insert, and is reasonably good into brain tissue, which is important when cerebrit accompanies meningitis. The distribution into bile is not as high as that of the tetracyclines and some of the penicillins. The very small amount in the feces is of interest as is the fact that the fecal con- tent is higher when the palmitate has been given. The penetration into the eye is a plus factor for this drug. Trans- placental transfer was shown by chemical methods which may not measure the active drug. Emphasis should be put on the recommended dose, because a smaller dose is often given, particularly postoperatively. The fate of the drug when the metabolic mechanisms are disturbed should remain as stated. As to blood dyscrasias, it should be mentioned that frequent blood counts do not necessarily assure that aplastic anemia can be prevented In fact, it may occur after the drug has been stopped. PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4417 The roles of organisms other than candida and staphylococci in resistance and superinfection have been demonstrated, particularly Pseudomonas and some other gram-negative aerobic rods that are re- sistant. This should be pointed out in the section discussing resis- tance. Intravenous administration of chloramphenicol produces a rapid peak in blood levels and is preferred over oral or intramuscular admini- stration in critically ill patients. Because the oral form is so highly absorbed, as soon as the patient can take it, there is little reason to continue the I.V. use. This buffered solution is recom- mended for intravenous use only. It may be less ambiguous if there were a specific package insert that eliminated the references to the succinate and the intramuscular form. The lag in the use of the succinate is probably of little clinical im- portance, but if the insert were designed specifically for this form of the drug there could be little difficulty in making clear that there is a little lag in hydrolysis with a somewhat lower level of antibacterial activity at 15 mm. Only the paragraph on page 3 (con- cerning ampoule No. 258) is needed in this insert. ApprOV~ by CM1i~ The Drug Efficacy Study of the National Academy of Sciences - National Research Council has requested that the following qualifying addendum be conveyed with their reports to the ultimate recipients of these reports "Drugs of identical chemical composition (so-called generic drugs) formulated and marketed by numerous individual firms under generic or trademarked names have been evaluated for efficacy as a group without consideration of `therapeutic equivalence.' In the event that no evidence for pharmacological availability or therapeutic efficacy in man can be presented for any of the indications claimed for the use of any of the drugs in the attached listing, their classifications of effectiveness may need to be modified if regulations of the Food and Drug Administration require such proof." PAGENO="0128" 4418 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL Division of Medical Sciences DRUG EFFICACY STUDY Form A (To be submitted in duplicate by appticanf( 1. NSA N,,t,be, 6D3l5~j~Oj~)2 Dote Otigically A~~,0,~d...~Februarv 20, 1959 ~. t, OTt ~ 4. t,c,d Na,,. Chloromycetin Sodium Succinate Steri-Vial, 1 Gm. 5. Applicants Nan,e Parke, Davis & Company aed Add,e,, Joseph Campau at the River; Detroit, Michigan 6. Quantitative Formula Estabtish.d tNee.Fnepcietanyt Nam, at Aetine legnedi.ets tin atden shace, on tebet( Anaccet (pen tablet, pet tnt., Chloramphenicol Sodium Succinate 1 Gm. base/vial 7. Dosage Fete (tabtets, etc.t steri-vial 8. teute of Ad,,. (Otet. etc. Whene a eeoc d~ccg applicetian ecee diffenent eactes at adeinisteatian, sepenate tot,,, shccctd be ccsed.( parenteral 9. Thenapeutie Ctaiens-Attach tO tcbet, and 10 package inseCs (it cued) a atiginet Fan,, A (btuet and 1 eapy a duplicate Fete A (cehite). 15. L,st at tcteeetcae tet,eeeees nest pentitneet a an eenlccatiae at the effsetiee,ess at the decg ten the pcnpas.s fan sehleh It is affen.d Inc the abet, the paek.a. iesent, en b,aehune. Apptaeintately 5 to 10 key netenences ate tequested, it ecaileble. (Attach 10 eapies a etiginat Fete A )btue( end 1 copy to duptieate Pane A lohitet .1 11. The applccant is incited, if he sO desites, to subecit any cnpcc bushed etatctiat that is pe~tieent a the snalccatia, at the dtug by ths Acadsey- teseanch Cauneil. This suppleeentc,y eete,ict shanld be packaged acith Fate A lahitel. A siegts copy at this mateniat is e.qusstsd. 12. tn thcs space, please list and desc,ibe bniefly the suppleeente,y aate,ial that is scbeitted aith Fate A lahitel. PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4419 Panel on Anti-Infective Drugs (III) INDICATIONS I. Staphylococcal infections, by implication of the discussion on the first page of the insert, may be an indication: "in a survey of experimental and clinical experiences of susceptibility of staph-. ylococci to chloramphenicol, it was found that the incidence of chioramphenicol-resistant staphylococci appears unrelated to fre- quency or to intensity of use of this antibiotic. Development of resistance to chloramphenicol can be regarded as minimal for staph- ylococci and many other species of bacteria." EVALUATION: Possibly effective. CONMENTS: Although chloranphenicol was useful for the treatment of some staphylococcal diseases during the mid-l950's, it now seems to be rarely indicated. Its major trial was in the staphylococcal pneumonias accompanying the influenza epidemic of 1957. Its effective- ness was some~hat less than expected, even for sensitive strains. The statement concerning resistance is not true in the opinion of the Panel (see below). In the description of in vitro work just before the sen- tence quoted above, there is no reference to the transfer of episonial particles carrying chloramphenicol resistance. The advent of better agents for staphylococcal disease relegates this drug to a very rarely needed alternate choice. DOCUMENTATION: 1. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staphylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:265-274, 1955. 2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. .1. 4:287-294, 1953. 3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 4. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 5. Lepper, M.H., P. Tiliman, and R. Devetsky. Patterns of transmis- sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965. 6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 7. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427,. 1955. II. Rickettsial diseases: epidemic and murine typhus, Brill's disease, scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox. 81-280 O~-69-pt. 11-9 PAGENO="0130" 4420 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EVALUATION: Effective, but . COl4NENTS: That chloramphenicol is effective in the diseases listed is well established, except in rickettsial pox, a condition so in- frequently seen that few data are available. However, if the warning is to be taken seriously--"chloramphenicOl should not be used when other less potentially dangerous agents will be effective'-- - the tetracyclines, which have been shown to be as effective as chloram- phenicol, should be considered the choice-and chloramphenicol used only if toxicity to these or failure to respond has occurred. The duration of therapy recommended appears adequate. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chloramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Knight, V., F. RuizSancheZ, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer. .J. Med. Sci. 219:627-638, 1950. 3. Ley, H.L., Jr., T.E. Woodward, and J.E. Smadel. ChloramphenicOl (chloromycetin) in the treatment of murine typhus. J.A.M.A. 143:217-219, 1950. 4. Murray, E.S., G. Baehr, G. Shwartzman, T.A. Manderbaum, N. Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and .J.C. Snyder. Brill's Disease; clinical and laboratory diagnosis. J.A.M.A. 142:1059-1066, 1950. 5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E. Smadel. The treatment of Rocky Mountain spotted fever with chloromycetin. Ann. Intern. Med. 29:656-663, 1948. 6. Smadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Leuthwaite. Chloramphenicol (chloromycetin) in the treatment of tsutsuganushi disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949. III. Typhoid fever. EVALUATION: Effective, but . COMMENTS: Chloramphenicol has often been listed as the drug of choice in typhoid fever. It is not clear that ampicillin has changed this claim, but if they were of equal activity, the claim of "drug of choice" would have to be revised because of the toxicity warning. There is no mention of the carrier problem and relapses of positive stool cultures. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chloramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of typhoid fever. I. Combined therapy with cortisone and chioram- phenicol. Ann. Intern. Med. 34:1-9, 1951. PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4421 IV. Other salmonelloses. EVALUATION: Possibly effective. CO?IMENTS: Because of variability of clinical course with each species and the large variety of species, there .is little reason to presume that a generalization is possible. In a condition of short symptoma- tic duration like gastroenteritis, the use of the drug is most diffi- cult to evaluate. The variable courses of the systemic forms do not allow the assurance of effectiveness that has been derived for typhoid fever, which is more uniform. These differences between typhoid and the other salmonelloses illustrate the difficulty of generalization from one species to the next. It is likely that localized salmonella infections, such as osteomyelitis, empyema or other diseases should have a therapeutic trial with chloramphenicol. The treatment of carriers with positive stool cultures should not be recommended and the insert should so state. Althoughthe stools may be negative while the drug is continued, there is no evidence that the carrier state is terminated more frequently than would: occur otherwise with a similar passage of time. Obviously, the inability to define drug effectiveness in salmonelloses also applied to other drugs, such as ampicillin; hence, a reliable comparison between drugs is not possible. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wissernan, Jr. Chloromycetin, pp. 56-58. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. V. Urinary tract infections. EVALUATION: Effective, but . . COMMENTS: As specified in the insert, outcome of treatment of urinary tract infections is influenced by anatomic factors, but these have little importance in the choice of drug except that, in situations in which cure is unlikely, the use of toxic agents is probably not justi~ fied. The susceptibilities of the organisms involved are of prime importance (chloranphenicol does not work any better against chloram- phenicol-susceptible organisms than other agents work against organisms susceptible to them). Hence, when organisms are susceptible to less toxic agents, chioramphenicol should not be used even if it is effective in vitro unless the others have failed. It is unusual for chloramphen- icol to succeed when other agents with satisfactory in vitro activity have failed. Of the three species singled out, Escherichia ~]*j is. often treatable with other chemotherapy, but chloramphenicol may be a secondary choice. Streptococcus fecalis infections are probably better treated with other agents, :such as penicillin and streptomycin or erythromycin. Various Proteus species are different in their susceptibility to different drugs; hence, the generalization "Proteus ~p~cies" should be avoided. Proteus mor~app, v~4garis, and rettgeri PAGENO="0132" 4422 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY are often susceptible only to chloramphenicol. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wissenan, Jr. Chloronycetin, pp. 105- 108. Antibiotics Monographs No. 8. New York: Medical Encyclo- pedia, Inc., 1958. VI. Surgical infections: postoperative wound infections. EVALUATION: Possibly effective. COMMENTS: Postoperative wound infections have a variety of etiologic agents, but ! ylococcu~ ~ is the single most common. Chlor- amphenicol is effective against many of these agents, but is not the most effective against the Staphylococcus. For this reason, plus the toxicity warning, it is not the first choice in most infections unless an organism is isolated against which chloranphenicol is most active in vitro, or other preferred drugs cannot be given or have been inef- fective. DOCUMENTATION: Most favorable report is reference 1 (Altemeier). 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetii and aureonycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphyloccal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959 8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. staphylococcal pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955. VII. Surgical infections: cellulitis. EVALUATION: Possibly effective. COMMENTS: Cellulitis (other than postoperative) is most often caused by streptococci or staphylococci for which chloramphenicol is not the most effective drug. For this reason, plus the toxicity warning, it is not the first choice unless an organism against which chloramphenicOl is the most active has been isolated, or the preferred drug cannot be given or has failed. PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4423 DOCUMENTATION: Same as for Indication VI. VIII. Surgical infections: infected sinus tract. EVALUATION: Possibly effective. COMMENTS: Chioramphenicol may be useful in some instances in which the organisms have been shown to be sensitive only to it. Many sinus tract infections are caused by tuberculosis and actinomycosis. Chlor- amphenicol is not indicated in tuberculosis, and other agents are preferred in actinoniycosis. Some sinus tracts associated with fistulas from viscera, including intestines, may be predominantly .infected with fecal flora. In these, chloramphenicol may be the single most effective agent. when other agents appear equally effective in laboratory testing, they should be tried first. There is rarely great urgency in treating sinus tract infections with antibiotics. The specific organisms for which chloramphenicol has been proved effective therapy (in this condition) should be listed. DOCUMENTATION: 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetin) and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults. Brit. Ned. J. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, N.H., P. Tillrnan, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Ned. 103: 532-542, 1959. 8. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955. 9. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 122- 124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. IX. Surgical infections: peritonitis or intra-abdoniinal abscesses from ruptured intestines, diverticula, or appendix. EVALUATION: Possibly effective. PAGENO="0134" 4424 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY COMMENTS: These infections are often caused by mixed flora from the intestinal content . In the acute stage of peritonitis, a drug often must be selected empirically for surgical preparation or immediately postoperatively. Judged by statistical probability chlorampheniCOl is a good choice in such a situation. It should be given parenterally, however, because oral therapy in these infections is probably inap- propriate. In other less acute complications listed in the insert, chloramphenicol should be shown to be the most effective agent against the organisms isolated before it is used, or other less toxic agents should have failed or be contraindicated. The specific causative organisms for which chloramphenicOl has been proved effective therapy (in these conditions) should be listed. DOCUMENTATION: Same as for Indication VIII. X. Respiratory tract infections. EVALUATION: Possibly effective. COMMENTS: This heading is ambiguous. The package insert should list specific organisms (and the site of respiratory infection) for which chloramphenicol has been proved effective therapy. In general, the etiology of these conditions is varied and chloram- phenicol is the best agent for only a few. In streptococcal, pneumo- coccal, and staphylococcal diseases of the respiratory tract, other drugs are preferable. Chloramphenicol should be used only in Kiebsiella infections and perhaps other necrotizing pneurnonias caused by E.coli or related organisms when they are shown invitr~q to be resistant to ampicillin, éephalothin, and kanamycin. ~ infec- tions of the respiratory tract respond well to ampicillin; hence, chioramphenicOl is best used only when ampicillin is not tolerated or fails. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wissernan, Jr. Chloromycetifl, pp. 63-72. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. XI. Meningeal infections. EVALUATION: Probably effective. COMMENTS: The three most common causes of meningitis are the meningo- cocci, pneumococci, and ~~pphilus influenzae. All are susceptible to chioramphenicol, as are many staphylococci and the gram-negative aerobic rods that often infect newborns. Moreover, it is true that the drug does get into the spinal fluid well. As a drug of choice PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4425 for empiric use, however, it is probably not first, because it is likely to be less effective in pneumococcal disease than is penicillin. Although many believe it is first choice in Hemophilus infections, tetracycline is probably as good and ampicillin is, too. It is likely that this claim (drug of choice in H. influenzae meningitis) is no longer.justifjed. In menigitis of the newborn kanamycin is preferred as the drug of choice for empiric treatment. In older patients, when a diagnosis has been made and the organisms shown to be more susceptible to chloramphenicol than to other agents, it may be the drug of choice. As indicated, in the insert, initial treatment should be parenterally administered. The package insert should list the specific organisms for which chloramphenicol has been proved effective therapy in meningitis. DOCUNENTP~TION: 1. Parker, R.T., N.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E. Woodward. Therapeutic range of chloramphenicol in purulent men- ingitis. Antibiot. Ned. Clin. Ther. 1:192-200, 1955. XII. Brucellosis. EVALUATION: Effective, but . . COMMENTS: Chioramphenicol, like other drugs, is capable of control- ling symptoms of acute brucellosis, but the relapse rate is high. It does not appear to be superior to the less toxic tetracyclines, DOCUMENTATION: 1. Knight, V., F. Rui~-Sanchez, andW. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer. J. Med. Sci. 219:627-638, 1950. 2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The University of Minnesota Press, 1956. 464 pp. 3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Baby. The beneficial effect of chloromycetin in brucellosis. J. Clin. Invest. 28:968-976, 1949. :111. Bartonellosis. EVALUATION: Probably effective. COMMENTS: Chloramphenicol is reported to be an effective antibiotic in these infections. Of the references suggested by the manufacturer (see Documentation below): two are reports of studies involving a total of 25 patients whose bartonellosis was treated with chloramphen- icol with good success, and two are textbook discussions of bartonel- losis and its treatment. Of the latter discussions, one feels that the effectiveness of chloramphenicol is best documented, the other feels that other agents are probably as good. PAGENO="0136" 4426 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DOCUMENTATION: 1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.) Philadelphia: W.B. Saunders Co., 1960. 2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with chloromycetin. Antiobiot. & Chemothbr. 1:92-99, 1951. 3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever, Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott, Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia: W.B. Saunders Co., 1963. 4. Urteaga, B.O., and E.H. Payne. Treatment of the acute febrile phase of Carrion's disease with chloramphenicol. Amer. J. Trop. Ned. 4:507-511, 1955. XIV. Relapsing fever. EVALUATION: Possibly effective. COMMENTS: Treponema (Borrelia) recurrentis infections in experimental animals are susceptible to chloramphenicol. On a weight basis, how- ever, penicillin G is more active. In human infections, no direct comparison has been made, and, although chloramphenicol has been used successfully, penicillin should be tried first if it is tolerated. DOCUMENTATION: 1. Hirschboeck, N.M. Use of chloramphenicol in relapsing fever. Amer. .1. Trop. Med. 3:712-713, 1954. XV. Granuloma iriguinale. EVALUATION: Effective, but . . COMMENTS: It has been reported that chloramphenicol caused the disappearance of Donavan bodies more rapidly than either tetracycline or streptomycin. Relapses after chloramphenicol have seemed to be less than 1O7~. Although chioramphenicol may be slightly better than tetracycline, the latter may be preferred for toxicologic reasons. DOCUMENTATION: 1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and N. Zises. Five-year study of antibiotics in treatment of granuloma inguinale. Amer. J. Syph. 36:186-191, 1952. 2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol in the treatment of gonorrhea and granuloma inguinale. Amer. 3. Syph. 36:264-268, 1952. XVI. Plague. EVALUATION: Effective, but . . PAGENO="0137" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 4427 COMMENTS: All forms of plague have been shown to respond to chlor- amphenicol when it is given in large doses early in the disease. There is no clear evidence that it is superior to tetracycline or streptomycin. DOCUMENTATION: 1. McCrumb, F.R., Jr., S. Mercier, J. Robic, N. Bouillat, J.E. Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and terramycin in the treatment of pneumonic plague. Amer. J. Med. 14:284-293, 1953. XVII. Ornithosjs. EVALUATION: Possibly effective. COMMENTS: In embryonated eggs and experimental animal infections, chloramphenicol is less effective than the tetracyclines. Results of therapy of human infections have been variable and relapses have been frequent. The role of the drug in this disease is not well established. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. ENERAL COMMENTS The `Warning" section appears justified in view of the seriousness of aplastic anemia. Tissue distribution appears to be favorable. The distribution into the cerebrospinal fluid is good, as pointed out in the insert, and is reasonably good into brain tissue, which is important when cerebritis accompanies meningitis. The distribution into bile is not as high as that of the tetracyclines and some of the penicillins. The very small amoUnt in the feces is of interest as is the fact that the fecal con- tent is higherwhen the palmitate: has been given. The penetration into the eye is a plus factor for this drug. Trans- placental transfer was shown by chemical methods which may not measure the active drug. Emphasis should be put on the recommended dose, because a smaller dose is often given, particularly postoperatively. The fate of the drug when the metabolic mechanisms are disturbed should remain as stated. As to blood dyscrasias, it should be mentioned that frequent blood counts do not necessarily assure that aplastic anemia can be prevented. In fact, it may occur after the drug has been stopped. PAGENO="0138" 4428 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The roles of organisms other than candida and staphylococci in resistance and superinfection have been demonstrated, particularly Pseudomonas and some other gram-negative aerobic rods that are re- sistant. This should be pointed out in the section discussing resis- tance. Intravenous administration of chloramphenicol produces a rapid peak in blood levels and is preferred over oral or intramuscular admini- stration in critically ill patients. However, because the oral form is so highly absorbed, as soon as the patient can take it, there is little reason to continue the I.V. use. It would be less ambiguous if there were a specific package insert that eliminated the references to the buffered I.V. and the intra- muscular form. The delay in achieving peak blood levels in the use of the succinate form is probably of little clinical importance, but if the insert were designed specifically for this form of the drug there could be little difficulty in making it clear that there is a little lag in hydrolysis with a somewhat lower level of antibacterial activity at 15 mm. Approveci by k~! Chairman The Drug Efficacy Study of the National Academy of Sciences - National Research Council has requested that the following qualifying addendum be conveyed with their reports to the ultimate recipients of these reports: "Drugs of identical chemical composition (so-called generic drugs) formulated and marketed by numerous individual firms under generic or trademarked n~s have been evaluated for efficacy as a group without consideration of `therapeutic equjvalence*~ In the event that no evidence for pharmacological availability or therapeutic efficacy in man can be presented for any of the indications claimed for the use of any of the drugs in the attached listing, their classifications of effectiveness may need to be modified if regulations of the Food and Drug Administration require such proof." PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4429 NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCL Division of Medical Sciences DRUG EFFICACY STUDY Form A (To be submitted in duplicate by applicant) * NDA ~ 2. Data Oiginally Appoooed O~~OhPV 5, 1951 3. Cc ~ OTt D * Bnond Nonoe- Chioromycetin Palmitate oral Sunpensli~in * Apphcont's Na,na~Parke, navis ~ Ccampany _~ - andAddntss_..IQ~~P~L~t the River; Detroit. Michigan 6. QuantitatIve Formula eblished )Noo.Pcoptietacy Noon. of Adios togradlants (in ocden shoucn an label) Atttoant (pen tablet, pen ni., hioramphenicol Palmitate 125 mg./4 cc. Dosage Poem (tablets, etc.) suspension foote of Adco,. (0,cl, etc. Whtnt a ncou dnag opplicatio,c cacaos oral d~ff,nant nodes of od,ninistnofion, sepanate fonone shoald be csed.( Thetapecctic C(abcc-Attach 0 labels aod 10 package insects (it aced) to onigina( Fontn A (blat( and 1 copy to daplicot. Pen,, A (ohits). List at titenetccee cetseectats meet pettiocent to en eoali',tlan of the .ffaatinenass of the doug foe the pccpos.s fcc mhlah It (s affec.d In the tab.), the package insect, oc boachcne. Appnoai,noteiy 5 to 10 bay teftnancts one naqoestad, if anailabie. (Attach 10 copies to aniginol Fanno A (bias) end 1 copy to daplicatt Font, A )unhite).t Theappl~cantisincited,,fhesodas,nes,tasab,,,t onyccnpabiished cnatnnia) that is pontictt,ctto the ocaloalian of the dncg by the Aaad.nty- Restoncf, Cococil. Th,s sappitnttotony tnatan.al sliocld be packaged onith Fono A )mh(te(. A single copy of this tnaten(a( Is raqcc.stad. In this space, please list and desaniba bciafy the scppletttsttacy mafani~) that is scbntitted acith Fanm A (oohite). PAGENO="0140" 4430 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Panel on Anti-Infective ~ (nfl INDICATIONS I. Staphylococcal infections, by implication of the discussion on the first page of the insert, may be an indication: "in a survey of experimental and clinical experiences of susceptibility of staph- ylococci to chloramphenicol, it was found that the incidence of chloramphenicol-resistaflt staphylococci appears unrelated to ire- quency or to intensity of use of this antibiotic. Development of resistance to chloramphenicol can be regarded as minimal for staph- ylococci and many other species of bacteria." EVALUATION: Possibly effective. CONItENTS: Although chloramphenicol was useful for the treatment of some staphylococcal diseases during the mid-l950's, it now seems to be rarely indicated. Its major trial was in the staphylococcal pneumonias accompanying the influenza epidemic of 1957. Its effect~ ness was somewhat less than expected, even for sensitive strains. `1 statenent concerning resistance is not true in the opinion of the P~ (see below). In the description of in vitro work just before the SE tence quoted above, there is no reference to the transfer of episom particles carrying chloramphenicol resistance. The advent of bette: agents for staphylococcal disease relegates this drug to a very rar needed alternate choice. DOCUMENTATION: 1. Bloomer, W.E., S. Gia~ona, G.E. Lindskog, and R.E. Cooke. Staphylococcal pneumonia and enpyema in infancy. J. Thorac. Surg. 30:265-274, 1955. 2. Carmichael, D.B., J~. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Ned. J. 4:287-294, 19~ 3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. 1. 2:845-847, 1956. 4. Kanof, A., B. Epstein, B. Kramer, and I. Nauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 5. Lepper, N.H., P. Tillmau, and R. Devetsky. Patterns of transmi~ sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965 6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 7. Wallrnan, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. II. Rickettsial diseases: epidemic and murine typhus, Brill's disease, scrub-typhus, Rocky Mountain spotted fever, and rickcttsial pox. PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4431 EVALUATION: Effective, but . COMMENTS: That chloramphenicol is effective in the diseases listed is well established, except in rickettsial pox, a condition so in- frequently seen that few data are available. However, if the warning is to be taken seriously--"chloramphenicol should not be used when other less potentially dangerous agents will be effective:'--- the tetracyclines, which have been shown to be as effective as chloram- phenicol, should be considered the choice and chloramphenicol used only if toxicity to these or failure to respond has occurred. The duration of therapy recommended appears adequate. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chioramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer. J. Med. Sci. 219:627-638, 1950. 3. Ley, H.L., Jr., T.E. Woodward, and J.E. Srnadel. Chioramphenicol (chioromycetin) in the treatment of murine typhus. J.A.M.A. 143:217-219, 1950. 4. Murray, E.S., C. Baehr, G. Shwartzman, T.A. Manderbaum, N. Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and J.C. Snyder. Brill's Disease; clinical and laboratory diagnosis. J.A.M.A. 142:1059-1066, 1950. 5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E. Smadel. The treatment of Rocky Mountain spotted fever with chloromycetin. Ann. Intern. Ned. 29:656-663, 1948. 6. Smadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Lcuthwaite. Chloramphenicol (chloromycetin) in the treatment of tsutsugamushi disease (scrub typhus). 3. Clin. Inyest. 28:1196-1215, 1949. III. Typhoid fever. EVALUATION: Effective, but . . COMMENTS: Chloramphenicol has often been listed as the drug of choice in typhoid fever. It is; not clear that ampicillin has changed this claim, but if they were of equal activity, the claim of "drug of choice" would have to be revised because of the toxicity warning. There is no mention of the carrier problem and relapses of positive stool cultures. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureonycin and chloramphenicol: use in typhus, typhoid and brucellosis. 3. Clin. Invest. 28:1052.1053, 1949. (abstr.) 2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of typhoid fever. .1. Combined therapy with cortisone and chloram- phenicol. Ann. Intern. Med. 34:1-9, 1951. PAGENO="0142" 4432 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IV. Other salmonelloses~ EVALUATION: Possibly effective. CO~1MENTS: Because of variability of clinical course with each species and the large variety of~species, there is little reason to presume that a generalization is possible. In a condition of short symptoma- tic duration like gastroenteritis, the use of the drug is most diffi- cult to evaluate. The variable courses of the systemic forms do not allow the assurance of effectiveness that has been derived for typhoid fever, which is more uniform. These differences between typhoid and the other salmonelloses illustrate the difficulty of generalization from one species to the next. It is likely that localized salmonella infections, such as osteomyelitis, enpyema or other, diseases should have a therapeutic trial with chloramphenicol. The treatment of carriers with positive stool cultures should not be recommended and the insert should so state. Although the stools may be negative while the drug is continued, there is no evidence that the carrier state is terminated more frequently than would occur otherwise with a similar passage of time. Obviously, the inability to define drug effectiveness in salmonelloses also applied to other drugs, such as ampicillin; hencE a reliable comparison between drugs is not possible. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chioromycetin, pp. 56-58. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. V. Urinary tract infections. EVALUATION: Effective, but . COMMENTS: As specified in the insert, outcome of treatment of urinary tract infections is influenced by anatomic factors, but these have little importance in the choice of drug except that, in situations in which cure is unlikely, the use of toxic agents is probably not justi- fied. The susceptibilities of the organisms involved are of prime importance (chioramphenicol does not work any better against chloram- phenicol-susceptible organisms than other agents work against organisms susceptible to them). Hence, when organisms are susceptible to less toxic agents, chloramphenicol should not be used even if it is effecti'~ in vitro unless the others have failed. It is unusual for chloramphen- icol to succeed when other agents with satisfactory in vitro activity have failed. Of the three species singled out, Eseherichia coil, is often treatable with other chemotherapy, but chioramphenicol may be a secondary choice. St~ptococcus fecalis infections are probably better treated with other agents, such as penicillin and streptomycin or erythrornycin. Various Proteus species are different in their susceptibility to different drugs; hence, the generalization "Proteus species" should be avoided. Proteus rnor~gani, vul~aris, and rettgeri PAGENO="0143" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4433 are often susceptible only to chloramphénicol. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 105- 108. Antibiotics Monographs No. 8. New York: Medical Encyclo- pedia, Inc., 1958. 1. Surgical infections: postoperative wound infections. EVALUATION: Possibly effective. CONMENTS: Postoperative wound infections have a variety of etiologic agents, but ~~phyj~occus aureus is the single most common. Chior- amphenicol is effective against many of these agents, but is not the most effective against the Staphylococcus. For this reason, plus the toxicity warning, it is not the first choice in most infections unless an organism is isolated against which chioraruphenicol is most active in vitro, or other preferred drugs cannot be given or have been inef- fective. DOCUMENTATION: Most favorable report is reference 1 (Altemeier). 1. Altemeier, W.A., and W.R. Culbertson. Chioramphenicol (chloromycetin) and aureoniycin in surgical infections. J.A.M.A. 145:449-457, 1951.. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, C.B., Jr. Fatal bacterial endocarditis dua to staphylococcus aureus. U.S. Armed Forces Ned. J. 4:287-294, 1953. 4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J.. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphyloccal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococ.cal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 8. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. 1. Surgical infections; cellulitis. EVALUATION: Possibly effective. COMMENTS: Cellulitis (other than postoperative) is most often caused by streptococci or staphylococci for which chloraruphenicol is not the most effective drug. For this reason, pius the toxicity warning, it is not the first choice unless an organism against which chiorampitenico]. is the most active has been isolated, or the preferred drug cannot be given or has failed. PAGENO="0144" 4434 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DOCUMENTATION: Same as for Indication VI. VIII. Surgical infections: infected sinus tract. EVALUATION: Possibly effective. COMMENTS: Chioramphenicol may be useful in some instances in which the organisms have been shown to be sensitive only to it. Many sinus tract infections are caused by tuberculosis and actinornycosis. Chior- amphenicol is not indicated in tuberculosis, and other agents are preferred in actinomycosis. Some sinus tracts associated with fistula from viscera, including intestines, may be predominantly infected with fecal flora. In these, chloramphenicol may be the single most effecti. agent. When other agents appear equally effective in laboratory testi they should be tried first. There is rarely great urgency in treating sinus tract infections with antibiotics. The specific organisms for which chioramphenicol has been proved effective therapy (in this condition) should be listed. DOCUMENTATION: 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromyce and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giaminona, G.E. Lindskog, and R.E. Cooke. Staph- ylocca). pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. *.i. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Ned. .3. 4:287-294, 1953. 4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults. Brit. Med. .3. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lopper, N.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965 7. Martin, C.M., C.N. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103: 532-542, 1959. 8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. .3. 2:1423-1427, 1955. 9. Woodward, T.E., and C.L. Wissenian, Jr. Chloromycetin, pp. 122- 124. Antibiotics Monographs No. 8. New York: Medical Encycloped Inc., 1958. IX. Surgical infections: peritonitis or intra-abdominal abscesses from ruptured intestines, diverticula, or appendix. EVALUATION: Possibly effective. PAGENO="0145" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4435 COMMENTS: These infections are often caused by mixed flora from the intestinal content . In the acute stage of peritonitis, a drug often must be selected empirically for surgical preparation or immediately postoperatively. Judged by statistical probability cliloramplienicol is a good choice in such a situation. It should be given parenterally, however, because oral th~rapy in these infections is probably map- propriate. In other less acute complications listed in the insert, chioramphenicol should be shown to be the most effective agent against the organisms isolated before it is used, or other less toxic agents should have failed or be contraindicated. The specific causative organisms for which chloramphenicol has been proved effective therapy (in these conditions) should be listed. DOCuMENTATION: Sane as for Indication VIII. X. Respiratory tract infections. EVALUATION: Possibly effective. COMMENTS: This heading is ambiguous. The package insert should list specific organisms (and the site of respiratory infection) for which chioramphenicol has been proved effective therapy. In general, the etiology of these conditions is varied and chloram- phenicol is the best agent for only a few. In streptococcal, pneurim- *coccal, and staphylococcal diseases of the respiratory tract, other drugs are preferable. Chloramphenicol should be used only in Klebsiella infections and perhaps other necrotizing pneumonias caused by E.coli or related organisms when they are shown in vitro to be resistant to ampicillin, cephalothin, and kanamycin. Hemophilus influenzae infec- tions of the respiratory tract respond well to anipicillin; hence, chloranphenicol is best used only when ampicillin is not tolerated or fails. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 63-72. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. XI. Meningeal infections. EVALUATION: Probably effective. CO~-~NTS: The three mast common causes of meningitis are the meni.ugo- cocci, pncumococci, and Hemophilus influenzae. All, are sueceptible to chioraniphenicol, as are many staphylococci and the gram-negative aerobic rods that often infect newborns. Moreover, it is true that the drug does get into the spinal fluid well. As a drug of choice 81-280 0-69-pt. ll-lO PAGENO="0146" 4436 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY for empiric use, however, it is probably not first, because it is likely to be less effective in pneumococcal disease than is penicillin. Although many believe it is first choice in Ilemophilus infections, tetracycline is probably as good and ampicillin is, too. It is likely that this claim (drug of choice in H. influenzae meningitis) is no longer justified. In menigitis of the newborn kanatnycin is preferred as the drug of choice for empiric treatment. In older patients, when a diagnosis has been made and the organisms shown to be more susceptihi to chloramphenicol than to other agents, it may be the drug of choice. As indicated, in the insert, initial treatment should be parenterally administered. The package insert should list the specific organisms for which chloraraphenicol has been proved effective therapy in meningitis. DOCUMENTATION: 1. Parker, R.T., M.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E. Woodward. Therapeutic range of chloramphenicol in purulent men- ingitis. Antibiot. Ned. Clin. Ther. 1:192-200, 1955. XII. Brucellosis. EVALUATION: Effective, but . COMMENTS: Chloramphenicol, like other drugs, is capable of control- ling symptoms of acute brucellosis, but the relapse rate is high. It does not appear to be superior to the less toxic tetracyclines. DOCUMENTATION: 1. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer J. Med. Sci. 219:627-638, 1950. 2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The University of Minnesota Press, 1956. 464 pp. 3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Raby. The beneficial effect of chloromycetin in brucellosis. J. Clin. Invest. 28:968-976, 1949. XIII. Bartonellosis. EVALUATION: Probably effective. COMMENTS: Chloramphenicol is reported to be an effective antibiotic in these infections. Of the references suggested by the manufacturer (see Documentation below): two are reports of studies involving a total of 25 patients whose bartonellosis was treated with chlor;implien- icol with good success, and two are textbook discussion~; of barioinl- losis and its treatment. Of the latter discussions, onu fcels thai the effectivenoss of chlorampltenicol is best docunsnt~d, the other feels that other agents are probably as good. PAGENO="0147" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4437 DOCUMENTATION: 1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.) Philadelphia: W.B. Saunders Co., 1960. 2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with chioronycetin. Anti~biot. & Chemother. 1:92-99, 1951. 3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever, Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott, Eds. Cecil-Loeb Ttxtbook of Medicine. (11th ed.) Philadelphia: W.B. Saunders Co~, 1963. 4. Urteaga, B.0., and E.H. Payne.~ Treatment of the acute febrile phase of Carrion's disease with chloranphenicol. Amer. J. Trop. Med. 4:507-511, 1955. XIV. Relapsing fever. EVALUATION: Possibly effective. COMMENTS: Treponema (Borrelia) recurrentis infections in experimental animals are susceptible to chloramphcnicol. On a weight basis, how- ever, penicillin G is more active. In hurna~i infections, no direct comparison has been made, and, although chioramphenicol has been used successfully, penicillin should be tried first if it is tolerated. DOCUMENTATION: 1. Hirschboeck, M.M. Use of chloranphenicol in relapsing fever. * Amer. J. Trop. Med. 3:712-713, 1954. XV. Granuloma inguinale. EVALUATION: Effective, but . . COMMENTS: It has been reportedthat chloranphenicol caused the disappearance of Donavan bodies more rapidly than either tetracycline or streptomycin. Relapses after chloramphenicol have seemed to be less than l07~. Although chlorarnphenicol nay be slightly better than tetracycline, the latter may be preferred for toxicologic reasons. DOCUMENTATION: 1. Greeublatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and M. Zises. Five-year study of antibiotics in treatment of granulorua inguinale. Amer. J. Syph. 36:186-191, 1952. 2. Robinson, R.C.V., and T.L. Wells. Intramuscular cliloramphenicol in the treatment of gonorrhea and granuloma inguinale. Amer. J. Syph. 36:264~268, 1952. XVI. Plague. EVALUATION: Effective, but PAGENO="0148" 4438 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMMENTS: All forms of plague have been shown to respond to chlor- amphenicol when it is given in large doses early in the disease. There is no clear evidence that it is superior to tetracycline or s treptomycin. DOCUMENTATION: 1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E. Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and terramycin in the treatment of pneumonic plague. Amer. J. Med. 14:284-293, 1953. XVII. Ornithosis. EVALUATION: Possibly effective. COMMENTS: In embryonated eggs and experimental animal infections, chloramphenicol is less effective than the tetracyclines. Results of therapy of human infections have been variable and relapses have been frequent. The role of the drug in this disease is not well established. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. GENERAL COMMENTS The "Warning" section appears justified in view of the seriousness of aplastic anemia. Absorption after oral administration is good, in that 75-9O7~ of a dose can be accounted for by metabolic products found in the urine. Tissue distribution appears to be favorable. The distribution into the cerebrospinal fluid is good, as pointed out in the insert, and is reasonably good into brain tissue, which is important when cerebrit: accompanies meningitis. The distribution into bile is not as high as that of the tetracyclines and some of the penicillins. The very small amount in the feces is of interest as is the fact that the fecal con- tent is higher when the palmitate has been given. The penetration into the eye is a plus factor for this drug. Trans- placental transfer was shown by chemical methods which may not measure the active drug. Empahsis should be put on the recormuended dose, because a smaller dose is often given, particularly postoperatively. The fate of the drug when the metabolic mechanisms are disturbed should remain as stated. As to blood dyscrasias, it should be mentioned that frequent blood coui do not necessarily assure that aplastic anemia can be prevented. In PAGENO="0149" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4439 fact, it may occur after the drug has been stopped. The roles of organisms other than candidá and staphylococci in resistance and superinfection have been demonstrated, particularly Pseudomonas and some other gram-negative aerobic rods that are re- sistant. This. should be pointed out in the section discussing resis- tance. Appro',~ ~r (,) C1~a1rLafl j\-kU~ The Drug Efficacy Study of the National Academy of Sciences - National Research Council has requested that the following qualifying addendum be conveyed with their reports to the ultimate recipients of these reports: `tDrugs of identical chemical composition (so-called generic drugs) formulated ~nd marketed by numerous individual firms under generic or trademarked names have been evaluated for efficacy as a group without consideration of `therapeutic equivalence.' In the event that no evidence for pharmacological availability or therapeutic efficacy in man can be presented for any of the indications claimed for the ~ of any of the drugs in the attached listing, their classifications of effectiveness may need to be modified if regulations of the Food and Drug Administration require such proof." PAGENO="0150" 4440 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY - NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL Division of Medical Sciences DRUG EFFICACY STUDY Form A ITs be submitted in duplicate by applicant) 1. NDA Nunb,,. ~.6D3l5,m (`1ol'i~.) 2. Dut, O~iginniiy App,n,,d .~eptember 20, 1963 3. 8~ oic 0 4. Otund Nun. Chioromycetin Sodium Succinate - Infant, 250 mg. 5. Appiknnts Nnne Parke, Davis & Company Add,,ss .Toseph Campau at the River; Detroit, Michigan 6. Quantitative Formula Estabtish.d tNsn-P,,p~i.tmyi Nan, at Attin~ Ingmdistts Ii, ~ shun, un tnb,tl Aenunt IF" tabi,t, p,n tel.. chioramphenicol Sodium Succinate 250 mg. base/vial 7. Dss,g. Fnnm ltabi.ts. ,tu.l ster~-via1 8. Rnut, *8 Adm. lOnnI, .tt. Wh.e. a n.e des,g nppiknLnnnnn.es diff,e,nt nnutes nt ndnieistnntine. s,pntnt. fntees shnuld b. us,d.l parenteral 9. Thetnp.utis Clnims-Attnth 10 lnb,ls ned 15 penbng. iesnets lit us,dl tn neigient Fnem A lbiu,l ned t unpy tu dupi~uut. teem A lehitsi. 10. List *8 titsentun, nnt.e.eet, mast p.ntittset te nn nun iuntinn at the .C.atin.esssnt tfa dnug fat th, puepns.s tnt nhlnh is nffstsd in th. t,b.t, th, puabng. les,nt. en bnenhue.. Appen*etnt.iy 3 a 10 b,y nst~e,euns nec n.qu.stsd. if nnniiabi,. tAttnuh tO unpi,s a neigieni Face A Ibtuet ned 1 nnpy ta dupiiunts Fete A Inhitsi.) 11. The nppiiunet is ieait.d, it h, sa d,sin.s, a submit ney cuepu blish,d mntneint that is psntie.nt ta th. *nnluntiae at the deug by th. Aundsety- R,s,nnuh Cnueail. This suppi,eaetney entetini shnuid bs pnuknged niih Facet A tnhitsl. A siegi. unpy of this ,ent,ni,t tst.qu.st.d. 12. te this spnu,. pl.ns. list ned dssunib, beisfy the suppiseecetany ent,nint that is sub'ttittsd atith Facet A chits). PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4441 Panel on Anti-Infective Dr~gs (]~~I~ INDICATIONS I. Staphylococcal infections, by implication of the discussion on the firs.t page of the insert, may be an indication: "in a survey of experimental and clinical experiences of susceptibility of staph- ylococci to chloramphenicol, it was found that the incidence of chloramphenicol-resistant staphylococci appears unrelated to fre- quency or to intensity of use of this antibiotic. Development of resistance to chloramphenicol can be regarded as minimal for staph- ylococci and many other species of bacteria." EVALUATION: Possibly effective. CONMENTS: Although chloramphenicol was useful for the treatment of some staphylococcal diseases during the inid-l950's, it now seems to be rarely indicated. Its major trial was in the staphylococcal pneiirnonias accompanying the influenza epidemic of 1957. Its effective- ness was somewhat less than expected, even for sensitive strains. The statement concerning resistance is not true in the opinion of the Panel (see below). In the description of ~_y~itro work just before the sen- tence quoted above, there is no reference to the transfer of episomal particles carrying chioramphenicol resistance. The advent of better agents for staphylococcal disease relegates this drug to a very rarely needed alternate choice. DOCUMENTATION: 1. Bloomer, W.E., S. Ciamoona, G.E. Lindskog, and R.E. Cooke. Staphylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:265-274, 1955. 2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 4. Kanof, A., E. Epstein, B. Kramer, and L Mauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 5. Lepper, M.H., P. Tiliman, and R. Devetsky. Patterns of transmis- sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965. 6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 7. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. II. Rickettsial diseases: epidemic and murine typhus, Brill's disease, scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox. PAGENO="0152" 4442 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY EVALUATION: Effective, but . C0~1ENTS: That chioramphenicol is effective in the diseases listed is well established, except in rickettsial pox, a condition so in- frequently seen that few data are available. However, if the warning is to be taken seriously-- "chloramphenicol should not be used when other less potentially dangerous agents will be effective'---the tetracyclines, which have been shown to be as effective as chlorain- phenicol, should be considered the choice and chloramphenicol used only if toxicity to these or failure to respond has occurred. The duration of therapy recommended appears adequate. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chloramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute ~nifestations of brucellosis. Amer. J. Med. Sci. 219:627-638, 1950. 3. Ley, H.L., Jr., T.E. Woodward, and JE. Smadel. Chioramphenicol (chloromycetin) in the treatment of murine typhus. J.A.M.A. 143:217-219, 1950. 4. Murray, E.S. G. l3aehr, G. Shwartzman, T.A. Manderbaum, N. Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and J.C. Snyder. Brill's Disease; clinical and laboratory diagnosis. J.A.M.A. 142:1059-1066, 1950. 5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E. Srsadel. The treatment of Rocky Mountain spotted fever with chloromycetin. Ann. Intern. Med. 29:656-663, 1948. 6. Smadel, J.E., T.E. Woodward, H.L~ Ley, Jr., and R. Leuthwaite. Chloramplienicol (chi~'romvoet:n) in the treatment of tsutsugamushi disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949. III. Typhoid fever. EVALUATION~ Effective, but . COMMENT'~ Chtoramphenicol has often been listed as the drug of choice in typhoid fever. It is not clear that ampicillin has changed this claim, but if they were of equal activity, the claim of "drug of choioe" would have to be revised because of the toxicity warning. There is no mention of the carrier problem and relapses of positive stool cultures. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycim and chloramphenicol: use in typhus, typhoid and brucellosis. J. Clim. Invest. 28:1052-1053, 1949. (abstr.) 2. Smadel, J.E., H.L. Ley, Jr.; and F.H. Diercks. Treatment of typhoid fever. I. Combined therapy with cortisone and chlorate- phenicol. Ann. InLern. Med. 34:1-9, 1951. PAGENO="0153" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4443 IV. Other salmonelloses. EVALUATION: Possibly effective. COM~1ENTS: Because of variability of clinical course with each species and the large variety of species, there is little reason to presume that a generalization is possible. In a condition of short symptoma- tic duration like gastroenteritis, the use of the drug is most diffi- cult to evaluate. The variable courses of the systemic forms do not allow the assurance of effectiveness that has been derived for typhoid fever, which is more uniform. These differences between typhoid and the other salmonelloses illustrate the difficulty of generalization from one species to the next. It is likely that localized salmonella infections, such as osteomyelitis, empyema or other diseases should have a therapeutic trial with chloramphenicol. The treatment of carriers with positive stool cultures should not be recommended and the insert should so state. Although the stools may be negative while the drug is continued, there is no evidence that the carrier state is terminated more frequently than would occur otherwise with a similar passage of time. Obviously, the inability to define drug effectiveness in salmonelloses also applied to other drugs, such as ampicillin; hence, a reliable comparison between drugs is not possible. DOCUMENTATION: I. Woothrdrd, T.E., and C.L. Wieseman, Jr. Chloromycetin, pp. 56-58. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. V. Urinary tract infections. EVALUATION: Effective, but . CONMENTS: As specified in the insert, outcome of treatment of urinary tract infections is thfiuenced by anatomic factors, but these have little importance in the choice of drug except that, in situations in which cure is unlikely, the use of toxic agents is probably not justi- fied. The susceptibilities of the organisms involved are of prime importance (chioramphenicol does not work any better against chloram- phenicol-susceptible organisms than other agents work against organisms susceptible to then). Hence, when organisms are susceptible to less toxic agents, chloramphenicol should not be used even if it is effective in vitro unless the others hzvc failed. It is unusual for chloramphen- icol to succeed when other agents with satisfactory in~vi.t.~o activity have failed. Of the three species singled out, Escherichia c:~j, is often treatable with other chemotherapy, but chloramphenicol may be a secondary choice. Streptococcus fecalis infections are probably better treated with other agents, such as penicillin and streptomycin or erythromycin. Various Proteus species are different in their * susceptibility to different drugs; hence, the generalization "Proteus species" should be avoided. Proteus morgani, vulgaris, and rettgeri PAGENO="0154" 4444 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY are often susceptible only to chloramphenicol. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 105- 108. Antibiotics Monographs No. 8. New York: Medical Encyclo- pedia, Inc., 1958. VI. Surgical infections: postoperative wound infections. EVALUATION: Possibly effective. COMMENTS: Postoperative wound infections have a variety of etiologic agents, but St~p lococcus aureus is the single most consnon. Chlor- amphenicol is effective against many of these agents, but is not the most effective against the Staphylococcus. For this reason, plus the toxicity warning, it is not the first choice in most infections unless an organism is isolated against which chioramphenicol is most active in vitro, or other preferred drugs cannot be given or have been inef- fective. DOCUMENTATION: Most favorable report is reference 1 (Altemeier). 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetin) and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giamniona, G.E. Lindskog, and R.E. Cooke. Staph- ylococcal pneumonia and empyeraa in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U~S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann~ W., and A.J. Karlish. Staphylocioccal pneumonta in adults. Brit. Med. 3. 2:845-841, 1956. 5. Kanof,A., B. Epatein~ B. Kramer, and I. Mauss. Staphyloccal pneumonia and cmpyema. Pediatrics 11:385-392, 1953. 6. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., CJ1. Kimin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. IT. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 8. Wa?lman, 1.8., BC. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Ned. 3. 2:1423-1427, 1955. VII. Surgical infections: cellulitis. EVALUATION: Possibly cffective. COMMENTS: Cellulitis (other than postoperative) is most often caused by streptococci or staphylococci for which chloramphenicol is not the most effective drug. For this reason, plus the toxicity warming, it is not the first choice unless an organism against which chloramphenicol is the most active has been isolated, or the preferred drug cannot be given or has failud. PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4445 DOCUMENTATION: Same as for Indication VI. VIII. Surgical infections: infected sinus tract. EVALUATION: Possibly effective. COMMENTS: Chloramphenicol may be useful in some instances in which the organisms have been shown to he sensitive only to it. Many sinus tract infections are caused by tuberculosis and actinomycosis. Chlor- amphenicol is not indicated in tuberculosis, and other agents are preferred in actinomycosis. Some sinus tracts associated with fistulas from viscera, including intestines, may be predominantly infected with feca]. flora. In these, chloramphe.nicol may be the single most effective agent. When other agents appear equally effective in laboratory testing, they should be tried first. There is rarely great urgency in treating sinus tract infections with antibiotics. The specific organisms for which chloramphenicol has been proved effective therapy (in this condition) should he listed. DOCUMENTATION: 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetin) and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, D.B., Jr. Fatal bacterial endocardit.is due to staphylococcus aureus. U.s. Armed Forces Med. J 4:287-294, 1953. 4. Hausmann, W,, and A.J K~r]li~h. Staphyloccal pneumonia in adults. Brit. Med. .1. 2:845~847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and empyema. Pediatrics ll~385-392, 1953. 6. Lepper, M.II., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal prieumo~ia complicating influenza. A.M.A. Arch. Intern. Med. 103: 532-542, 1959. 8. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. 9. Woodward, T.E.~, and C.L. Wisseman, Jr. Chloromycetin, pp. 122- 124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. IX. Surgical infections: peritonitis or intra-abdominal abscesses from ruptured intestines, diverticula, or appendix. EVALUATION: Possibly effective. PAGENO="0156" 4446 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMMENTS: These infections are often caused by mixed flora from the intestinal content . In the acute stage of peritonitis, a drug often must be selected empirically for surgical preparation or immediately postoperatively. Judged by statistical probability chloramphenicol is a good choice in such a situation. It should be given parenterally, however, because oral therapy in these infections is probably inap- propriate. In other less acute complications listed in the insert, chloramphenicol should be shown to be the most effective agent against the organisms isolated before it is used, or other less toxic agents should have failed or be contraindicated. The specific causative organisms for which chloramphenicol has been proved effective therapy (in these conditions) should be listed. DOCUMENTATION: Same as for Indication VIII. X. Respiratory tract infections. EVALUATION: Possibly effective. COMMENTS: This heading is ambiguous. The package insert should list specific organisms (and the site of respiratory infection) for which chloramphenicol has been proved effective therapy. In general, the etiology of these conditions is varied and chloram- phenicol is the best agent for only a few. In streptococcal, pneumo- coccal, and staphylococcal diseases of the respiratory tract, other drugs are preferable. Chloramphenicol should be used only in Kiebsiella infections and perhaps other necrotizing pneumonias caused by E. coli or related organisms when they are shown in vitro to be resistant to ampicillin, cephalothin, and kanamycin. ~~ilus influenzae infec- tions of the respiratory tract respond well to ampicillin; hence, chloramphenicol is best used only when ampicillin is not tolerated or fails. DOCUMENTATION: 1. Woodward, T.E., and C.L~ Wisseman, Jr. Chloromycetin, pp. 63-72. Antibiotics Monographs No. 8~ New York: Medical Encyclopedia, Inc., 1958. XI. Meningeal infections. EVALUATION: Probably effective. COMMENTS: The three most common causes of meningitis are the meningo- cocci, pneumococci, and Hemophilus influenzae. All are susceptible to chioramphenicol, as are many staphylococci and the gram-negative aerobic rods that often infect newborns. Moreover, it is true that the drug does get into the spinal fluid well. As a drug of choice PAGENO="0157" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4447 for empiric use, however, it is probably not first, because it is likely to be less effective in pneumococcal disease than is penicillin. Although many believe it is first choice in Hemophilus infections, tetracycline is probably as good and ampicillin is, too. It is likely that this claim (drug of choice in IL influenzae meningitis) is no longer justified. In menigitis of the newborn kanamycin is preferred as the drug of choice for empiric treatment. In older patients, when a diagnosis has been made and the organisms shown to be more susceptible to chloramphenicol than to other agents, it may be the drug of choice. As indicated, in the insert, initial treatment should be parenterally administered. The package insert should list the specific organisms for which chloramphenicol has been proved effective therapy in meningitis. DOCUMENTATION: 1. Parker, R.T., M.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E. Woodward. Therapeutic range of chloramphenicol in purulent men- ingitis. Antibiot. Med. Clin. Ther. 1:192-200, 1955. XII. Brucsllosis. EVALUATION: Effective, but . . COMMENTS: Ch~ orar~phenicol, like other drugs, is capable of control- Hog symptoms of--acute bruceilosis, but the relapse rate is high. It does not appoa~ to be superior to the less toxic tetracyclines. DOCITh~NT~TION: 1. Knight, V., F. ~.`iiz-Sanchez, and W. McDermott~ Chloramphenicol in the treatment of the acute manifestations of brucellosis. Amer. J. Med. Sci, 219:627-638, 1950. 2. Spink, W.W, The Nature of Brucellosis. Minneapolis: The University of Minnesota Press, 1956. 464 pp. 3. Woodward, T.E., J.E. Smadel, LA. Holbrook, and W.T. Raby. The beneficial effect of chloromycetth in brucellosis. J. Clin. Invest, 28:968-976, 1949. XIII. Bartonellosis. EVALUATION: Probably effective. CONMENTS: Chioramphenicol is reported to be an effective antibiotic in these infections. Of the references suggested by the manufacturer (see Documentation below): two are reports of studies involving a total of 25 patients whose bartonellpsis was treated with chloramphen- icol with good success, and two are textbook discussions of bartonel- losis and its treatment. Of the latter discussions, one feels that the effectiveness of chloramphenicol is best documented, the other feels that other agents are probably as good. PAGENO="0158" 4448 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DOCUMENTATION: 1. Bartonellosjs, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.) Philadelphia: W.B. Saunders Co., 1960. 2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with chloromycetin. Antiobiot. & Chemother. 1:92-99, 1951. 3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever, Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott, Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia: W.B. Saunders Co., 1963. 4. Urteaga, B.O., and E.H. Payne. Treatment of the acute febrile phase of Carrion's disease with chlorampheniàol. Amer. .1. Trop. Med. 4:507-511, 1955. XIV. Relapsing fever. EVALUATION: Possibly effective. CONMENTS: Tr~ponenia (Borrelia) recurrentis infections in experimental animals are susceptible to chloramphenicol. On a weight basis, how- ever, penicillin C is more active. In human infections, no direct comparison has been made, and, although chloramphenicol has been used successfully, penicillin should be tried first if it is tolerated. DOCUMENTATION: 1. Hirschboeck, M.M. Use of chloramphenicol in relapsing fever. Amer. J. Trop. Med. 3:712-713, 1954. XV. Granuloma inguinale. EVALUATION: Effective, but . COMMENTS: It has been reported that chloramphenicol caused the disappearance of Donavan bodies more rapidly than either tetracycline or streptomycin. Relapses after chloramphenicol have seemed to be less than 10%. Although chloramphenicol may be slightly better than tetracycline, the latter may be preferred for toxicologic reasons. DOCUMENTATION: 1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and M. Zises. Five-year study of antibiotics in treatment of granuloma inguinale. Amer. J. Syph. 36:186-191, 1952. 2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol in the treatment of gonorrhea and granuloma inguinale. Amer. 3. Syph. 36:264-268, 1952. XVI. Plague. EVALUATION: Effective, but . . . PAGENO="0159" * COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4449 COMMENTS: All forms of plague have been shown to respond to chlor- amphenicol when it is given in large doses early in the disease. There is no clear evidence that it is superior to tetracycline or s treptomycin. DOCUMENTATION: 1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E. Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and terramycin in the treatment of pneumonic plague. Amer. J. Med. 14:284-293, 1953. XVII. Ornithosis. EVALUATION: Possibly effective. COMMENTS: In embryonated eggs and experimental animal infections, chloramphenicol is less effective than the tetracyclines. Results of therapy of human infections have been variable and relapses have been frequent. The role of the drug in this disease is not well established. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71. Antibiotics ~kv~.ographs No. 8. New York~ Medical Encyclopidia, Inc., 1958. GENERAL CO~NTS The warning section appears justified in view of the seriousness of aplastic anemit. Tissue distribution appears to be favorab1e~ The distribution into the cercbrospinal fluid is good as pointed out ~.n the insert, and is reasonably good into brain tissue, which is important when cerebritis accompanies meningitis. The distribution into bile is not as high as that of the tetracyclines and some of the penicillins. The very small amount in the feces is of interest as is the fact that the fecal con- tent is higher when the palmitate has been given~ The penetration into the eye is a plus factor for this drug. Trans- placental transfer was shown by chemical methods which may not measure the active drug. Emphasis should be put on the recomoended dose, because a smaller dose is often given, particularly postoperaçively~ The fate of the drug when the metabolic mechanisms are disturbed should remain as stated. As to blood dyscrasias, it should be mentioned that frequent blood counts do not necessarily assure that aplastic anemia can be prevented. In fact, it may occur after the drug has been stopped. PAGENO="0160" 4450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The roles of organisms other than candida and staphylococci in resistance and superinfection have been demonstrated, particularly Pseudomonas and some other gram-negative aerobic rods that are resistant to chloramphenicol. This should be pointed out in the insert in the section discussing resistance. Intravenous administration of chloramphenicol produces a rapid peak in blood levels and is preferred over oral or intramuscular admini- stration in critically ill patients. Because the oral form is so highly absorbed, as soon as the patient can take it, there is little reason to continue the I.V. use. This succinate solution is recom- mended for intravenous use only. The unique feature of the succinate is the delay in achieving peak concentrations of active drug because of the hydrolysis required. The material (about Steri-Vial 148) on page 2 of the insert points out the unique features of the design for the infant and instructions for each route. The instructions and dose recoranendations are good. In this case, the insert pertains to the one preparation and is also good from that point of view. Approved by _______________ Chair~n The Drug Efficacy Study of the National Academy of Sciences - National Research Council has requested that the following qualifying addendum be conveyed with their reports to the ultimate recipients of these reports: "Drugs of identical chemical composition (so-called generic drugs) formulated and marketed by numerous individual firms under generic or trademarked n~s have been evaluated for efficacy as a group without consideration of `therapeutic equivalence.' In the event that no evidence for pharmacological availability or therapeutic efficacy in man can be presented for any of the indications claimed for the use of any of the drugs in the attached listing, their classifications of effectiveness may need to be modified if regulations of the Food and Drug Administration require such proof." PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY 4451 NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCiL Division of Medical Sciences DRUG EFFICACY STUDY - FormA (To be submitted in duplicate by applicant) 1. NDA Number 6n3O2~ (LLSS) 2. Onto Originally Approtmd December 8, 1950 3. Ba OTC 0 4. Brand ~ Chioromycetin, 50 mg. & 100 mg. Capsules, 250 mg Kapseals 5. Applicants Nanre Parke, Davis & Company and Addr.ss .Toseph C~npau at the River; fletrnil-, M~u'h~gun 6. QuantItative Formula itabtishad tNan.Pnapd.t,ty) Nanc. af Actin. tngr.dlsnte (in order sharon on lab,l) Amount par tabl.t, p.r ni., 1. Chloromycetin, 50 mg. Capsule Chloramphenicol 50 mg./capsule 2. Chioromycetin, 100 mg. Capsule Chloramphenicol ` 100 mg./capsule 3. Chloromycetin, 250 mg. Kapseal Chloramphenicol 250 mg./kapseal Desage Farm (tablsts, dc.) capsules crnuyu~~ t. Rout, at Ade. (Oral. dc. Wham a naro drug application cooers different routes at adrmini,tratign, separate tormnc chould be used.)___~_~~ oral I. Thsrap.otic claims-Attach 10 labels and 10 package incamls lit used) to original Form A lblunl ond I copy to duplicats Farm A (ohite). I. List at Ilteretune rater mast partin.nt to on ecaluetlan of thn *ff.ctiosn.ss at th. drug fan the parpae.s for rohlch it Is affared In the lab.) tha peckags Ins.mt, or brochure. Approarmatnly 5 to 10 k.y noterencns oma raqu.it.d. it ocailabla. (Attach 10 copies to original Farm A tblu.) and 1 copy to duplicat. Form A )mhit.).) * Thu applicont is innit.d, ,t ha so dssrrss, to submit any unpublished rtotcrial that is pertinent to lbs ecaluclion at th. drug by the Aced.my- Research Council. Thrs supplementary mot.riul should be pachagnd mith Form A )cnhitsl. A slngl. capy at this material Is r.qu.st.d. * In this space, please (ret and descmibn bniefy the supplementary material that is submitted mith Farm A (mhit.). 81-280 11329 81-280 O-69-pt. 11-11 PAGENO="0162" 4452 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Panel on Anti-Infective Dr~gs (II~ INDICATIONS I. Staphylococcal infections, by implication of the discussion on the first page of the insert, may be an indication: "in a survey of experimental and clinical experiences of susceptibilit.y of staph- ylococci to chloramphenicol, it was found that the incidence of chioramphenicol-resistant staphylococci appears unrelated to fre- quency or to intensity of use of this antibiotic. Development of resistance to chloramphenicol can be regarded as minimal for staph ylococci and many other species of bacteria." EVALUATION: Possibly effective. COM~1ENTS: Although chloramphenicol was useful for the treatment 0: some staphylococcal diseases during the mid-l950's, it now seems t( be rarely indicated. Its major trial was in the staphylococcal pmeumonias accompanying the influenza epidemic of 1957. Its effeci ness was somewhat less than expected, even for sensitive strains. statement concerning resistance is not true in the opinion of the I (see below). In the description of in vitro work just before the tence quoted above, there is no reference to the transfer of episor particles carrying chloramphenicol resistance. The advent of bett agents for staphylococcal disease relegates this drug to a very ra~ needed alternate choice. DOCUMENTATION: 1. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staphylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:265-274, 1955. 2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Ned. J. 4:287-294, l~ 3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 4. Kanof, A., B. Epstein, B. Kramer, and I. Nauss. Staphylococca pneumonia and empyema. Pediatrics 11:385-392, 1953. 5. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of transm: sion of staphylococci. Ann. N.Y. Acad. Sd. 128:404-427, l96~ 6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asiai influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 7. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococca. pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955. II. Rickettsial diseases: epidemic and murine typhus, Brill's disease scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox. PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EVALUATION: Effective, but . 4453 COMMENTS: That chloramphenicol is effective in the diseases listed is well established, except in rickettsial pox, a condition so in- frequently seen that few data are available. However, if the warning is to be taken seriously--"chloramphenicol should not be used when other less potentially dangerous agents will be effective'---the tetracyclines, which have been shown to be as effective as chloram- phenicol, should be considered the choice and chloramphenicol used only if toxicity to these or failure to respond has occurred. The duration of therapy recommended appears adequate. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureonycin and chloramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of brucellosjs. Amer. J. Med. Sci. 219:627-638, 1950. 3. Ley, H.L., Jr., T.E. Woodward, and J.E. Smadel. Chloramphenicol (chloromycetin) in the treatment of murine typhus. J.A.M.A. 143:217-219, 1950. 4. Murray, E.S., C. Baehr, G. Shwartzman, T.A. Manderbaum, N. Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, andJ.C. Snyder. Brill's Disease; clinical and laboratory diagnosis. J.A.M.A. 142:1059-1066, 1950. 5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E. Smadel. The treatment of Rocky Mountain spotted fever with chloromycetin. Ann. Intern. Med. 29:656-663, 1948. 6. Sraadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Leuthwaite. Chloramphenicol (chloromycetin) in the treatment of tsutsugamushi disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949. III. Typhoid fever. EVALUATION: Effective, but . . COMMENTS: Chioramphenicol has often been listed as the drug of choice in typhoid fever. It is not clear that ampicillin has changed this claim, but if they were of equal activity, the claim of "drug of choice" would have to be revised because of the toxicity warning. There is no mention of the carrier problem and relapses of positive stool cultures. DOCUMENTATION: 1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and chioramphenicol: use in typhus, typhoid and brucellosis. J. Clin. Invest. 28:1052-1053, 1949. (abstr.) 2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of typhoid fever. I. Combined therapy with cortisone and chioran- phenicol. Ann. Intern. Med. 34:1-9, 1951. PAGENO="0164" 4454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IV. Other salmonelloses. EVALUATION: Possibly effective. COMMENTS: Because of variability of clinical course with each specie and the large variety of species, there is little reason to presume that a generalization is possible. In a condition of short symptoma- tic duration like gastroenteritis, the use of the drug is most diffi- cult to evaluate. The variable courses of the systemic forms do not allow the assurance of effectiveness that has been derived for typhoi fever, which is more uniform. These differences between typhoid and the other salmonelloses illustrate the difficulty of generalization from one species to the next. It is likely that localized salmonella infections, such as osteomyelitis, empyema or other diseases should have a therapeutic trial with chloramphenicol. The treatment of carriers with positive stool cultures should not be recommended and the insert should so state. Although the stools may be negative whul the drug is continued, there is no evidence that the carrier state is terminated more frequently than would occur otherwise with a similar passage of time. Obviously, the inability to define drug effectivene in salmonelloses also applied to other drugs, such as ampicillin; hee a reliable comparison between drugs is not possible. DOCUMENTATION: h Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 56-58. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. V. Urinary tract infection~. EVALUATION: Effective, but . . COMMENTS: As specified in the insert, outcome of treatment of urinar tract infections is influenced by anatomic factors, but these have little importance in the choice of drug except that, in situations ir which cure is unlikely, the use of toxic agents is probably not justi fied. The susceptibilities of the organisms involved are of prime importance (chloramphenicol does not work any better against chloram- phenicol-susceptible organisms than other agents work against organic susceptible to them). Hence, when organisms are susceptible to less toxic agents, chloramphenicol should not be used even if it is effect ~n vitro unless the others have failed. It is unusual for chloramphe icol to succeed when other agents with satisfactory in vitro activity have failed. Of the three species singled out, Escherichia ccli is often treatable with other chemotherapy, but chloramphenicol may be a secondary choice. Streptococcus fecalis infections are probably better treated with other agents, such as penicillin and streptomycir or erythromycin. Various Proteus species are different in their susceptibility to different drugs; hence, the generalization `Proteus species" should be avoided. Proteus morgani, vulgaris, and rett~eri PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4455 are often susceptible only to chloramphenicol. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chioromycetin, pp. 105- 108. Antibiotics Monographs No. 8. New York: Medical Encyclo- pedia, Inc., 1958. 1. Surgical infections: postoperative wound infections. EVALUATION: Possibly effective. COMMENTS: Postoperative wound infections have a variety of etiologic agents, but Staphylococcus aureus is the single most common. Chlor- amphenicol is effective against many of these agents, but is not the most effective against the Staphylococcus. For this reason, plus the toxicity warning, it is not the first choice in most infections unless an organism is isolated against which chioramphenicol is most active in vitro, or other preferred drugs cannot be given or have been inef- fective. DOCUMENTATION: Most favorable report is reference 1 (Altemeier). 1. Altemeier, W.A., and W.R. Culbertson. Chioramphenicol (chioromycetin) and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951. 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph- ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953. 4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults,~ Brit. Med. J. 2:845-847, 1956. 5. Kanof, A~, B. Epstein, B. Kramer, and I. Nauss. Staphyloccal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965. 7. Martin, C.N., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959. 8. Wallman, I.S., R.C.' Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. Surgical infections; cellulitis. EVALUATION: Possibly effective. COMMENTS: Cellulitis (other than postoperative) is most often caused by streptococci or staphylococci for which chloramphenicol is not the most effective drug. For this reason, plus the toxicity warning, it is not the first choice unless an organisni against which chloramphenicol is the most active has been isolated, or the preferred drug cannot be given or has failed. PAGENO="0166" 4456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DOCUMENTATION: Same as for Indication VI. VIII. Surgical infections: infected sinus tract. EVALUATION: Possibly effective. CONNENTS: Chloramphenicol may be useful in some instances in which the organisms have been shown to be sensitive only to it. Many sinus tract infections are caused by tuberculosis and actinomycosis. Chlor amphenicol is not indicated in tuberculosis, and other agents are preferred in actinomycosis. Some sinus tracts associated with fistul from viscera, including intestines, may be predominantly infected wit fecal flora. In these, chloramphenicol may be the single mbst effect agent. Wrien other agents appear equally effective in laboratory test they should be tried first. There is rarely great urgency in treatin, sinus tract infections with antibiotics. The specific organisms for which chloramphenicol has been proved effective therapy (in this condition) should be listed. DOCUMENTATION: 1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromyc and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951 2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30: 265-274, 1955. 3. Carmichael,-D.B., Jr. Fatal bacterial endocarditis due to staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953 4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults. Brit. Med. J. 2:845-847, 1956. 5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal pneumonia and empyema. Pediatrics 11:385-392, 1953. 6. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of trans- mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 196 7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103: 532-542, 1959. 8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955. 9. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 122- 124. Antibiotics Monographs No. 8. New York: Medical Encyclope Inc., 1958. IX. Surgical infections: peritonitis or intra-abdominal abscesses from ruptured intestines, diverticula, or appendix. EVALUATION: Possibly effective. PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4457 COMMENTS: These infections are often caused by mixed flora from the intestinal content . In the acute stage of peritonitis, a drug often must be selected empirically for surgical preparation or immediately postoperatively. Judged by statistical probability chloramphenicol is a good choice in such a situation. It should be given parenterally, however, because oral therapy in these infections is probably inap- propriate. In other 1e~s acute complications listed in the insert, chloramphenicol should be shown to be the most effective agent against the organisms isolated before it is used, or other less toxic agents should have failed or be contraindicated. The specific causative organisms for which chloramphenicol has been proved effective therapy (in these conditions) should be listed. DOCUMENTATION: Same as for Indication VIII. X. Respiratory tract infections. EVALUATION: Possibly effective. COMMENTS: This heading is ambiguous. The package insert should list specific organisms (and the site of respiratory infection) for which chloramphenicol has been proved effective therapy. In general, the etiology of these conditions is varied and chloram- phenicol is the best agent for only a few. In streptococcal, pneumo- coccal, and staphylococcal diseases of the respiratory tract, other drugs are preferable. Chioramphenicol should be used only in Klebsiella infections and perhaps other necrotizing pneumonias caused by E. coli or related organisms when they are shown in vitro to be resistant to ampicillin, cephalothin, and kanamycin. Hemophilus influenzae infec- tions of the respiratory tract respond well to ampicillin; hence, chloraraphenicol is best used only when ampicillin is not tolerated or fails. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 63-72. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. CI. Meningeal infections. EVALUATION: Probably effective. COMMENTS: The three most common causes of meningitis are the meningo- cocci, pneumococci, and Hemqphilus: irtfluenzae. All are susceptible to chioramphenicol, as are many staphylococci and the gram-negative aerobic rods that often infect newborns. Moreover, it is true that the drug does get into the spinal fluid well. As a drug of choice PAGENO="0168" 4458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY for empiric use, however, it is probably not first, because it is likely to be less effective in pneumococcal disease than is penicillin. Although many believe it is first choice in Hemophilu~ infections, tetracycline is probably as good and ampicillin is, too. It is likely that this claim (drug of choice in H. influenzae meningitis) is no longer justified. In menigitis of the newborn kanamycin is preferred as the drug of choice for empiric treatment. In older patients, when a diagnosis has been made and the organisms shown to be more susceptibi to chloramphenicol than to other agents, it may be the drug of choice. As indicated, in the insert, initial treatment should be parenterally administered. The package insert should list the specific organisms for which chloramphenicol has been proved effective therapy in meningitis. DOCUMENTATION: 1. Parker, R.T., M.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E. Woodward. Therapeutic range of chloramphenicol in purulent men- ingitis. Antibiot. Med. Clin. Ther. 1:192-200, 1955. XII. Brucellosis. EVALUATION: Effective, but . COMMENTS: Chloramphenicol, like other drugs, is capable of control- ling symptoms of acute brucellosis, but the relapse rate is high. It does not appear to be superior to the less toxic tetracyclines. DOCUMENTATION: 1. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol in the treatment of the acute manifestations of.brucellosis. Amer. J. Med. Sci. 219:627-638, 1950. 2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The University of Minnesota Press, 1956. 464 pp. 3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Raby. The beneficial effect of chloromycetin in brucellosis. J. Clin. Invest. 28:968-976, 1949. XIII. Bartonellosis. EVALUATION: Probably effective. COMMENTS: Chloramphenicol is reported to be an effective antibiotic in these infections. Of the references suggested by the manufacturer (see Documentation below): two are reports of studies involving a total of 25 patients whose bartonellosis was treated with chloramphen- icol with good success, and two are textbook discussions of bartonel- losis and its treatment. Of the latter discussions, one feels that the effectiveness of chloramphenicol is best documented, the other feels that other agents are probably as good. PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4459 DOCUMENTATION: 1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.) Philadelphia: W.B. saunders Co., 1960. 2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with chloromycetin. Antiobiot. & Chemother. 1:92-99, 1951. 3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever, Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott, Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia: W.B. Saunders Co., 1963. 4. Urteaga, B.0., and E.H. Payne. Treatment of the acute febrile phase of Carrion's disease with chloramphenicoi. Amer. J. Trop. Med. 4:507-511, 1955. XIV. Relapsing fever. EVALUATION: Possibly effective. COMMENTS: ~ponema (Borrelia) ~çurrentis infections in experimental animals are susceptible to chloramphenicol. On a weight basis, how- ever, penicillin G is more active. In human infections, no direct comparison has been made, and, although chloramphenicol has been used successfully, penicillin should be tried first if it is tolerated. DOCUMENTATION: 1. Hirschboeck, M.M. Use of chloramphenicol in relapsing fever. Amer. J. Trop. Med. 3:712-713, 1954. XV. Granulorua inguinale. EVALUATION: Effective, but . . COMMENTS: It has been reported that chloramphenicol caused the disappearance of Donavan bodies, more rapidly than either tetracycline or streptomycin. Relapses after chloramphenicol have seemed to be less than 107,. Although chioramphenicol may be slightly better than tetracycline, the latter may be preferred for toxicologic reasons. DOCUMENTATION: 1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and M. Zises. Five-year studyof antibiotics in treatment of granuloma inguinale. Amer. J. Syph. 36:186-191, 1952. 2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol in the treatment of gonorrhea and granulorna inguinale. Amer. J. Syph. 36:264-268, 1952. XVI. Plague. EVALUATION: Effective, but PAGENO="0170" 4460 COMPETITIVE PROBLEMS IN THE DRuG INDIJSTRY COMMENTS: All forms of plague have been shown to respond to chior- amphenicol when it is given in large doses early in the disease. There is no clear evidence that it is superior to tetracycline or streptomycin. DOCUMENTATION: 1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E. Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and terramycin in the treatment of pneumonic plague. Amer. J. Med. 14:284-293, 1953. XVII. Ornithosis. EVALUATION: Possibly effective. COMMENTS: In embryonated eggs and experimental animal infections, chloramphenicol is less effective than the tetracyclines. Results of therapy of human infections have been variable and relapses have been frequent. The role of the drug in this disease is not well established. DOCUMENTATION: 1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71. Antibiotics Monographs No. 8. New York: Medical Encyclopedia, Inc., 1958. GENERAL COMMENTS The Warning" section appears justified in view of the seriousness of aplastic anemia. Absorption after oral administration is good, in that 75-90% of a dose can be accounted for by metabolic products found in the urine. Tissue distribution appears to be favorable. The distribution into the cerebrospinal fluid is good, as pointed out in the insert, and is reasonably good into brain tissue, which is important when cere- britis accompanies meningitis. The distribution into bile is not as high as that of the tetracyclines and some of the penicillins. The very small amount in the feces is of interest as is the fact that the fecal content is higher when the palmitate has been given. The penetration into the eye is a plus factor for this drug. Trans- placental transfer was shown by chemical methods which may not measure the active drug. Emphasis should be put on the recommended dose, because a smaller dose is often given, particularly postoperatively. The fate of the drug when the metabolic mechanisms are disturbed should remain as stated. As to blood dyscrasias, it should be mentioned that frequent blood counts do not necessarily assure that aplastic anemia can be prevented. PAGENO="0171" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4461 In fact, it may occur after the drug has been stopped. The roles of organisms other than candida and staphylococci in resistance and superinfection have been demonstrated, particularly Pseudomonas and some other gram-negative aerobic rods that are re- sistant. This should be pointed out in the section discussing resis- tance. Intravenous administration of chloramphenicol produces a rapid peak in blood levels and is preferred over oral or intramuscular admini- stration in critically ill patients. However, because the oral form is so highly absorbed, as soon as the patient can take it, there is little reason to continue the I.V. use. This package insert is identical in every way with that for Chloro- mycetin Palmitate Oral Suspension, Log 2263. This preparation is the straight drug without palmitate. The dose recommendations are accurate. ~p~ro~ea by Chairman The Drug Efficacy Study of the National Academy of Sciences - National Research Council has requested that the following qualifying addendum be conveyed with their reports to the ultimate recipients of these reports: "Drugs of identical chemical composition (so-called generic drugs) formulated and marketed by numerous individual firms under generic or trademarked nemes have been evaluated for efficacy as a group without consideration of `therapeutic equivalence.' In the event that no evidence for pharmacological availability or therapeutic efficacy in man can be presented for any of the indications claimed for the use of any of the drugs in the attached listing, their classifications of effectiveness may need to be modified if regulations of the Food and Drug Administration require such proof." PAGENO="0172" 4462 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY SPC~M EN FOR INTRAVENOUS ADMINISTRATION CHLOROMYCETIN® (CHLORAMPHENICOL) SODIUM SUCCINATE [~ARKE.DAVIS I WARNING $erlous and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, Ihrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol. In addition, there have been reports of ~lastic anemia attributed to chloramphenicol which later terminated in Iukemia. Blood dyscrasias have occurred after both short term and pro- longed therapy with this drug. Chloramphenicol must not be used when Isss potentially dangerous agents will be effective, as described in the 14tndications" section. It must not be used in the treatment of trivial infec :~fl5 or where it is not indicated, as in colds, influenza, infections of the ~oat; or as a prophylactic agent to prevent bacterial infections. Precautions: It is essential that adequate blood studies be made during beatment with the drug. While blood studies may detect early peripheral mood changes, such as leukopenia, reticulocytopenia, or ~ranulocytopenia, bfore they become irreversible, such studies cannot be relied on to detect bene marrow depression prior to development of aplastic anemia. To ~Cilitate appropriate studies and observation during therapy, it is desirable that patients be hospitalized. IMPORTANT CONSIDERATIONS IN PRESCRIBING NS4ECTABLE CHLORAMPHEN1COL SODIUM SUCCINATE. 1. Chloramphenicol sodium succinate must be hydrolyzed to its microbiolog- ically active form and there is a lag in achieving adequate blood levels com- pared with the base given intravenously. 12. The oral form of chloramphenicol is readily absorbed and adequate blood levels are achieved and maintained on the recommended dosage. 3. Patients started on intravenous chloramphenicol sodium succinate should be changed to the oral form as soon as practicable. 4. Chloramphenicol sodium succinate is recommended for intravenous use only. Use of this product by the intramuscular route in emergency situations has been described, but this route is not recommended, because lower blood levels are attained and there is a lack of evidence that it is effective when ~lven by this route. DESCRIPTION O~Joramphenicol is an antibiotic that is clinically useful for, and should be reserved for, serious infections caused by organisms susceptible to its anti- mIcrobial effects when less potentially hazardous therapeutic agents are Ineffective or contraindicated. Sensitivity testing is essential to determine its inditated use, but may be performed concurrently with therapy initiated on clinical impression that one of the indicated conditions exists (see "Indications" section). HH PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4463 CHLOROMYCETIN (CHLORAMPHENICOL) SODIUM SUCCINATE ACTIONS AND PHARMACOLOGY In vitro chloramphenicol exerts mainly a bacteriostatic effect on a wide range of gram-negative and gram-positive bacteria and is active in vitro against rickettsias, the lymphogranuloma-psittacosis group and Vibrio cholerae. It is particularly active against Salmonella typhi and Hemophilus inf/uenzae. The mode of action is through interference or inhibition of protein synthesis in intact cells and in cell-free systems. Chloramphenicol administered orally is absorbed rapidly from the intestinal tract. In controlled studies in adult volunteers using the recommended dosage of 50 mg/kg/day, a dosage of 1 gm. every 6 hours for 8 doses was given. Using the microbiological assay method, the average peak serum level was 11.2 mcg./mI. one hour afterthe first dose. A cumulative effect gave a peak rise to 18.4 mcg./ml. after the fifth dose of 1 gm. Mean serum levels ranged from 8-14 mcg./ml. over the 48-hour period. Total urinary excretion of chloramphenicol in these studies ranged from a low of 68% to a high of 99% over a three-day period. From 8 to 12% of the antibiotic excreted is in the form of free chloramphenicol; the remainder consists of microbiologically inactive metabolites, principally the conjugate with glucuronic acid. Since the glucuronide is excreted rapidly, most chloramphenicol detected in the blood is in the microbiologically active free form. Despite the small proportion of unchanged drug excreted in the urine, the concentration of free chloramphenicol is relatively high, amounting to several hundred mcg./mI. in patients receiving divided doses of 50 mg./kg./day. Small amoUnts of active drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid. Chlor- amphenicol enters cerebrospinal fluid even in the absence of meningeal inflammation, appearing in concentrations about half of those found in the blood. Measurable levels are also detected in pleural and in ascitic fluids, saliva, milk and in the aqueous and vitreous hUmors. Transport across the placental barrier occurs with somewhat lower concentration in cord blood of newborn infants than in maternal blood. INDICATIONS IN ACCORD WITH THE CONCEPTS IN THE `WARNING BOX" AND THIS INDICATIONS SECTION, CHLORAMPHENICOL MUST BE USED ONLY IN THOSE SERIOUS INFECTIONS FOR WHICH LESS POTENTIALLY DANGEROUS DRUGS ARE INEFFECTIVE OR CONTRAINDICATED. HOWEVER, CHLORAM- PHENICOL MAY BE CHOSEN TO INITIATE ANTIBIOTIC THERAPY ON THE CLINICAL IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS BELIEVED TO BE PRESENT; IN VITRO SENSITIVITY TESTS SHOULD BE PERFORMED CONCURRENTLY SO THAT THE DRUG MAY BE DISCONTINUED AS SOON AS POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS ARE INDICATED BY SUCH TESTS. THE DECISION TO CONTINUE USE OF CHLORAMPHENICOL RATHER THAN ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY IN VITRO STUDIES TO BE EFFECTIVE AGAINST A SPECIFIC PATHOGEN SHOULD BE BASED UPON SEVERITY OF THE INFECTION, SUSCEPTIBILITY OF THE PATHOGEN TO THE VARIOUS ANTIMICROBIAL DRUGS, EFFICACY OF THE VARIOUS DRUGS IN THE INFECTION, AND THE IMPORTANT ADDI- TIONAL CONCEPTS CONTAINED IN THE "WARNING BOX" ABOVE: PAGENO="0174" 4464 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CHLOROMYCETIN (CHLORAMPHENI~OL) SODIUM SUCCINATE 1. Acute infections caused by Salmonella typhi Chloramphenicol is a drug of choice. It is not recommended for the routine treatment of the typhoid carrier state". 2. Serious infections caused by susceptible strains in accordance with the concepts expressed above: a. Salmonella species b. H. influenzae, specifically meningeal infections c. Rickettsia d. Lymphogranuloma-psittacosis group e. Various gram-negative bacteria causing bacteremia meningitis or other serious gram.negative infections f. Other susceptible organisms which have been demonstrated to be resistant to all other appropriate anti-microbial agents. 3. Cystic fibrosis regimens CONTRAIN DICATIONS Chloramphenicol is contraindicated in individuals with a history of previous hypersensitivity and/or toxic reaction to it. It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, influenza, infections of the throat; or as a prophylactic agent to prevent bacterial infection. PRECAUTIONS 1. Baseline blood studies should be followed by periodic blood studies approxi- mately every two days during therapy. The drug should be discontinued upon appearance of reticulocytopenia, Ieukopenia, thrombocytopenia, anemia, or any other blood study findings attributable to chloramphenicol. However, it should be noted that such studies do not exclude the possible later appearance of the irreversible type of bone marrow depression. 2. Repeated courses of the drug should be avoided if at all possible.Treatment should not be continued longer than required to produce a cure with little or no risk of relapse of the disease. 3. Concurrent therapy with other drugs that may cause bone marrow de- pression should be avoided. 4. Excessive blood levels may result from administration of the recommended dose to patients with impaired liver or kidney function, including that due to immature metabolic processes in'the infant. The dosage should be adjusted accordingly or, preferably, the blood concentration should be determined at appropriate intervals. 5. There are no studies to establish the safety of this drug in pregnancy. 6. Since chloramphenicol readily crosses the placental barrier, caution in use of the drug is particularly important during pregnancy at term or during labor because of potential toxic effects on the fetus (gray syndrome). 7. Precaution should be used in therapy of premature and full-term infants to avoid "gray syndrome" toxicity. (See "Adverse Reactions.") Serum drug levels should be carefully followed during therapy of the newborn infant. 8. Precaution should be used in therapy during lactation because of the possibility of toxic effects on the nursing infant. *ln the treatment of typhoid fever some authorities recommend that chloramphenicol be administered at therapeutic levels for 8-10 days after the patient has become afebrile to lessen the possibility of relapse. - - PAGENO="0175" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4465 CHLOROMYCETIN (CHLORAMPIIENICOL) SODIUM SUCCINATE 9. The use of this antibiotic, as with other antibiotics, may result in an over- growth of nonsusceptible organisms, including fungi. If infections caused by nonsusceptible organisms appear during therapy, appropriate measures should be taken. ADVERSE REACTIONS 1. Blood Dyscrasias The most serious adverse effect of chloramphenicol is bone marrow depres- sion. Serious and fatal blood dyscrasias (apiastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the admin- istration of chloramphenicôl. An irreversible type of marrow depression leading to aplastic anemia with a high rate of mortality is characterized by the appear- ance weeks or months after therapy of bone marrow aplasia or hypoplasia. Peripherally, pancytopenia is most often observed, but in a small number of cases only one or two of the three major cell types (erythrocytes, leukocytes, platelets) may be depressed. A reversible type of bone marrow depression, which is dose related, may occur. This type of marrow depression is characterized by vacuolization of the erythroid cells, reduction of reticulocytes and leukopenia, and responds promptly to the withdrawal of chloramphenicol. An exact determination of the risk of serious and fatal blood dyscrasias is not possible because of lack of accurate information regarding 1) the size of the population at risk, 2) the total number of drug-associated dyscrasias, and 3) the total number of non-drug associated dyscrasias. In a report to the California State Assembly by the California Medical Associa- tion and the State Department of Public Health in January 1967, the risk of fatal aplastic anemia was estimated at 1:24,200 to 1 :40,500 based on two dosage levels. There have been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia. Paroxysmal nocturnal hemoglobinuria has also been reported. 2. Gastrointestinal Reactions Nausea, vomiting, glossitis and stomatitis, diarrhea and enterocolitis may occur in low incidence. 3. Neurotoxic Reactions Headache, mild depression, mental confusion and delirium have been de- scribed in patients receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn. 4. Hypersensitivity Reactions Fever, macular and vesicular rashes, angloedema, urticaria and anaphylaxis may occur. Herxheimer reactions have oôcurred during therapy for typhoid fever. 5. "Gray Syndrome" Toxic reactions including fatalities have occurred in the premature and new- born; the signs and symptoms associated with these reactions have been referred to as the "gray syndrome". One case of "gray syndrome" has been reported in an infant born to a mother having received chloramphenicol during labor. One case has been reported in a 3 month infant. The following sum- marizes the clinical and laboratory studies that have been made on these patients: PAGENO="0176" 4466 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY CHLOROMYCETI N (CHLORAMPHENICOL) SODIUM SUCCINATE (1) In most cases therapy with chloramphenicol had been instituted within the first 48 hours of life. (2) Symptoms first appeared after 3 to 4 days of continued treatment with high doses of chloramphenicol. (3) The symptoms appeared in the following order: (a) abdominal distension with or without emesis; (b) progressive pallid cyanosis; (c) vasomotor collapse, frequently accompanied by irregular respiration; (d) death within a few hours of onset of these symptoms. (4) The progression of symptoms from onset to exitus was accelerated with higher dose schedules. (5) Preliminary blood serum level studies revealed unusually high concentra- tions of chloramphenicol (over 90 mcg./ml. after repeated doses). (6) Termination of therapy upon early evidence of the associated sympto- matology frequently reversed the process with complete recovery. ADMINISTRATION Chloramphenicol, like other potent drugs, should be prescribed at recommended doses known to have therapeutic activity. Administration of 50 mg./kg./day in divided doses will produce blood levels of the magnitude to which the majority of susceptible microorganisms will respond. AS SOON AS FEASIBLE AN ORAL DOSAGE FORM OF CHLORAMPHENICOL SHOULD BE SUBSTITUTED FOR THE INTRAVENOUS FORM BECAUSE AD- EQUATE BLOOD LEVELS ARE ACHIEVED WITH CHLORAMPHENICOL BY MOUTH. The following method of administration is recommended: Intravenously as a 10% solution to be injected over at least a one-minute in- terval. This is prepared by the addition of 11 cc. of an aqueous diluent such as water for injection or 5% dextrose injection. The "Infant Size" package (Steri-Vial No. 148) contains 250 mg. This should be reconstituted with 2.75 cc. of diluent. DOSAGE Adults Adults should receive 50 mg./kg./day in divided doses at 6-hour intervals. In exceptional cases patients with infections due to moderately resistant organisms may require increased dosage up to 100 mg./kg./day to achieve blood levels inhibiting the pathogen, but these high doses should be decreased as soon as possible. Adults with impairment of hepatic or renal function or both may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted accordingly. (See discussion under Newborn Infants.) Precise control of concentration of the drug in the blood should be carefully followed in patients with impaired metabolic processes by the available microtechniques (information available on request). Children Dosage of 50 mg/kg/day divided into 4 doses at 6-hour intervals yields blood levels in the range effective against most susceptible organisms. Severe infec- tions (e.g., bacteremia or meningitis), especially when adequate cerebrospinal fluid concentrations are desired, may require dosage up to 100 mg./kg./day; however, it is recommended that dosage be reduced to 50 mg./kg./day as soon as possible. Children with impaired liver or kidney function may retain exces- sive amounts of the drug. PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4467 CHLOROMYCETIN (CHLORAMPHENI~OL) SODIUM SUCCINATE Newborn infants (See section titled "Gray Syndrome" under "Adverse Reactions.") A total of 25 mg./kg./ day in 4 equal doses at 6-hour intervals usually produces and maintains concentrations in blood and tissues adequate to control most infections for which the drug is indicated. Increased dosage in these individuals, demanded by severe infections, should be given only to maintain the blood concentration within a therapeutically effective range. After the first two weeks of life, full-term infants ordinarily may receive up to a total of 50 mg/kg/day equally divided into 4 doses at 6-hour intervals. These dosage recommendations are extremely important because blood concentration in all premature infar~s and full-term infants under two weeks of age differs from that of other infants. This difference is due to variations in the maturity of the metabolic functions of the liver and the kidneys. When these functions are immature (or seriously impaired in adults), high concentrations of the drug are found which tend to increase with succeeding doses. Infants and Children with Immature Metabolic Processes In young infants and other children in whom immature metabolic functio:~ are suspected, a dose of 25 mg/kg/day will usually produce therapeutic con- centrations of the drug in the blood. In this group particularly, the concentraV~n of the drug in the blood should be carefully followed by microtechniqu (Information available on request.) PACKAGE INFORMATION Steri-Vial No. 57, Chloromycetin (chloramphenicol) Sodium Succinate provides the equivalent of 1 Gram chloramphenicol in a rubber-diaphragm-capped vial. Available individually and in packer units of 10. CHLOROMYCETIN, brand of chloramphenicol, Reg. U.S. Pat. Off. CA4f~ PARKE, DAVIS ~1b~ & COMPANY 121 865000 A DETROIT, MICHIGAN, U.S.A. - Aug. 1968k 81-280 0-69-pt. 1l-12 PAGENO="0178" 4468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FOR INTRAVENOUS ADMINISTRATION CHLORAMPHENICOL SODIUM SUCCINATE, STERILE, UIISIIPI WARNING Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the administration of chloramphenicol. In addition, there have been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia. Blood dyscrasias have occurred after both short term and pro- longed therapy with this drug. Chloramphenicol inust not be used when less potentially dangerous agents will be effective, as described in the `Indications" section. It must not be used in the treatment of trivial infec tions or where it is not indicated, as in colds, influenza, infections of the throat; or as a prophylactic agent to prevent bacterial infections. Precautions: It is essential that adequate blood studies be made during treatment with the drug. While blood studies may detect early peripheral blood changes, such as leukopenia, reticulocytopenia, or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia. To facilitate appropriate studies and observation during therapy, it is desirable that patients be hospitalized. IMPORTANT CONSIDERATIONS IN PRESCRIBING INJECTABLE CHLORAMPHENICOL SODiUM SUCCINATE 1. Chloramphenicol sodium succinate must be hydrolyzed to its microbiolog- ically active form and there is a lag in achieving adequate blood levels com- pared with the base given intravenously. 2. The oral form of chloramphenicol is readily absorbed and adequate blood levels are achieved and maintained on the recommended dosage. 3. Patients started on intravenous chloramphenicol sodium succinate should be changed to the oral form as soon as practicable. 4. Chloramphenicol sodium succinate is recommended for intravenous use only. Use of this product by the intramuscular route in emergency situations has been described, but this route is not recommended, because lower blood levels are attained and there is a lack of evidence that it is effective when given by this route. DESCRIPTION Chloramphenicol is an antibiotic that is clinically useful for, and should be reserved for, serious infections caused by organisms susceptible to its anti- microbial effects when less potentially hazardous therapeutic agents are ineffective or contraindicated. Sensitivity testing is essential to determine its indicated use, but may be performed concurrently with therapy initiated on clinical impression that one of the indicated conditions exists (see `Indications" section). - DSA-HH PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4469 ACTIONS AND PHARMACOLOGY In vitro chloramphenicol exerts mainly a bacteriostatic effect on a wide range of gram-negative and gram.positive bacteria and is active in vitro against rickettsias, the lymphogranuloma-psittacosis group and Vibrio cholerae. It is particularly active against Salmonella typhi and Hemophilus influenzae. The mode of action is through interference or inhibition of protein synthesis in intact cells and in cell-free systems. Chloramphenicol administered orally is absorbed rapidly from the intestinal tract. In controlled studies in adult volunteers using the recommended dosage of 50 mg/kg/day, a dosage of 1 gm. every 6 hours for 8 doses was given. Using the microbiological assay method the average peak serum level was 11.2 mcg./ml. one hour after the first dose. A cumulative effect gave a peak rise to 18.4 mcg./mI. after the fifth dose of 1 gm. Mean serum levels ranged from 8-14 mcg./mI. over the 48-hour period. Total urinary excretion of chloramphenicol in these studies ranged from a low of 68% to a high of 99°/~ over a three-day period. From 8 to 12% of the antibiotic excreted is in the form of free chloramphenicol; the remainder consists of microbiologically inactive rnetabolites, principally the conjugate with glucuronic acid. Since the glucuronide is excreted rapidly, most chloramphenicol detected in the blood is in the microbiologically active free form. Despite the small proportion of unchanged drug excreted in the urine, the concentration of free chloramphenicol is relatively high, amounting to several hundred mcg./ml. in patients receiving divided doses of 50 mg/kg/day. Small amounts of active drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid. Chlor- amphenicol enters cerebrospinal fluid even:in the absence of meningeal in- flammation, appearing in concentrations about half of those found in the blood. Measurable levels are also detected in pleural and in ascitic fluids, saliva, milk and in the aqueous and vitreous humors. Transport across the placental barrier occurs with somewhat lower concentration in cord blood of newborn infants than in maternal blood. INDICATIONS IN ACCORD WITH THE CONCEPTS IN THE `WARNING BOX" AND THIS INDICATIONS SECTION, CHLORAMPHENICOL MUST BE USED ONLY IN THOSE SERIOUS INFECTIONS FOR WHICH LESS POTENTIALLY DANGEROUS DRUGS ARE INEFFECTIVE OR CONTRAINDICATED. HOWEVER, CHLORAM- PHENICOL MAY BE CHOSEN TO INITIATE ANTIBIOTIC THERAPY ON THE CLINICAL IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS BELIEVED TO BE PRESENT; IN VITRO SENSITIVITY TESTS SHOULD BE PERFORMED CONCURRENTLY SO THAT THE DRUG MAY BE DISCONTINUED AS SOON AS POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS ARE INDICATED BY SUCH TESTS. THE DECISION TO CONTINUE USE OF CHLORAMPHENICOL RATHER THAN ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY IN VITRO STUDIES TO BE EFFECTIVE AGAINST A SPECIFIC PATHOGEN SHOULD BE BASED UPON SEVERITY OF THE INFECTION, SUSCEPTIBILITY OF THE PATHOGEN TO THE VARIOUS ANTIMICROBIAL DRUGS, EFFICACY OF THE VARIOUS DRUGS IN THE INFECTION, AND THE IMPORTANT ADDI- TIONAL CONCEPTS CONTAINED IN THE "WARNING BOX" ABOVE: DSA-HH PAGENO="0180" 4470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1. Acute infections caused by Salmonella lyphi Chloramphenicol is a drug of choice.* It is not recommended for the routine treatment of the typhoid "carrier state". 2. Serious infections caused by susceptible strains in accordance with the concepts expressed above: a. Salmonella species b. H. Influenzae, specifically meningeal infections c. Rickettsia d. Lymphogranuloma-psittacosis group e. Various gram-negative bacteria causing bacteremia, meningitis or other serious gram.negative infections f. Other susceptible organisms Which have been demonstrated to be resistant to all other appropriate anti-microbial agents. 3. Cystic fibrosis regimens CONTRAINDICATIONS Chloramphenicol is contraindicated in individuals with a history of previous hypersensitivity and/or toxic reaction to it. It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, influenza, infections of the throat; or as a prophylactic agent to prevent bacterial infection. PRECAUTIONS 1. Baseline blood studies should be followed by periodic blood studies approxi- mately every two days during therapy. The drug should be discontinued upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or any other blood study findings attributable to chloramphenicol. However, it should be noted that such studies do not exclude the possible later appearance of the irreversible type of bone marrow depression. 2. Repeated courses of the drug should be avoided if at all possible. Treatment should not be continued longer than required to produce a cure with little or no risk of relapse of the disease. 3. Concurrent therapy with other drugs that may cause bone marrow de. pression should be avoided. 4. Excessive blood levels may result from administration of the recommended dose to patients with impaired liver or kidney function, including that due to immature metabolic processes- in the infant. The dosage should be adjusted accordingly or, preferably, the blood concentration should be determined at appropriate intervals. 5. There are no studies to establish the safety of this drug in pregnancy. 6. Since chloramphenicol readily crosses the placental barrier, caution in use of the drug is particularly important during pregnancy at term or during labor because of potential toxic effects on the fetus (gray syndrome). 7. Precaution should be used in therapy of premature and full.term infants to avoid "gray syndrome" toxicity. (See "Adverse Reactions.") Serum drug levels should be carefully followed during therapy of the newborn infant. 8. Precaution should be used in therapy during lactation because of the possibility of toxic effects on the nursing infant. Cm the treatment of typhoid fever some authorities recommend that chioramphenicol be administered at therapeutic levels for 8.10 days after the patient has become afebrile to lessen the possibility of relapse. - DSA-HH PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4471 9. The use of this antibiotic, as with other antibiotics, may result in an over- growth of nonsusceptible organisms, including fungi. If infections caused by nonsusceptible organisms appear during therapy, appropriate measures should be taken. ADVERSE REACTIONS 1. Blood Dyscrasias The most serious adverse effect of chloramphenicol is bone marrow depres- sion. Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia) are known to occur after the admin- istration of chloramphenicol. An irreversible ty~e of marrow depression leading to aplastic anemia with a high rate of mortality is characterized by the appear- ance weeks or months after therapy of bone marrow aplasia or hypoplasia. Peripherally, pancytopenia is most often observed, but in a small number of cases only one or two of the three major cell types (erythrocytes, leukocytes, platelets) may be depressed. A reversible type of bone marrow depression, which is dose related, may occur. This type of marrow depression is characterized by vacuolization of the erythroid cells, reduction of reticulocytes and leukopenia, and responds promptly to the withdrawal of chloramphenicol. An exact determination of the risk of serious and fatal blood dyscrasias is not possible because of lack of accurate information regarding 1) the size of the population at risk, 2) the total number of drug-associated dyscrasias, and 3) the total number of non-drug associated dyscrasias. In a report to the California State Assembly by the California Medical Associa- tion and the State Department of Public Health in January 1967, the risk of fatal aplastic anemia was estimated at 1 :24,200 to 1 :40,500 based on two dosage levels. There have been reports of aplastic anemia attributed to chloramphenico~l which later terminated in leukemia. Paroxysmal nocturnal hemoglobinuria has also been reported. 2. Gastrointestinal Reactions Nausea, vomiting, glossitis and stomatitis, diarrhea and enterocolitis may occur in low incidence. 3 Neurotoxic Reactions Headache, mild depression, mental confusion and delirium have been de- scribed in patients receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn. 4. Hypersensitivity Reactions Fever, macular and vesicular rashes, angioedema, urticaria and anaphylaxis may occur. Herxheimer reactions have occurred during therapy for typhoid fever. 5. "Gray Syndrome" Toxic reactions including fatalities have occurred in the premature and new- born; the signs and symptoms associated with these reactions have been referred to as the "gray syndrome". One case of "gray syndrome" has been reported in an infant born to a mother having received chloramphenicol during labor. One case has been reported in a 3 month infant. The following sum- marizes the clinical and laboratory studies that have been made on these patients: - DSA-HH PAGENO="0182" 4472 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (1) In most cases therapy with chloramphenicot had been instituted within the first 48 hours of life. (2) Symptoms first appeared after 3 to 4 days of continued treatment with high doses of chloramphenicol. (3) The symptoms appeared in the following order: (a) abdominal distension with or without emesis; (b) progressive pallid cyanosis; (c) vasomotor collapse, frequently accompanied by irregular respiration; (d) death within a few hours of onset of these symptoms. (4) The progression of symptoms from onset to exitus was accelerated with higher dose schedules. (5) Preliminary blood serum level studies revealed unusually high concentra- tions of chloramphenico) (over 90 mcg./ml. after repeated doses). (6) Termination of therapy upon early evidence of the associated sympto. matology frequently reversed the process with complete recovery. ADMINISTRATION Chloramphenicol, like other potent drugs, should be prescribed at recommended doses known to have therapeutic activity. Administration of 50 mg/kg/day in divided doses will produce blood levels of the magnitude to which the majority of susceptible microorganisms will respond. ASSOON AS FEASIBLE AN ORAL DOSAGE FORM OF CHLORAMPHENICOL SHOULD BE SUBSTITUTED FOR THE INTRAVENOUS FORM BECAUSE AD. EQUATE BLOOD LEVELS ARE ACHIEVED WITH CHLORAMPHENICOL BY MOUTH. The following method of administration is recommended: lntravenously as a 10% solution to be injected over at least a one-minute in- terval. This is prepared by the addition of 11 cc. of an aqueous diluent such as water for injection or 5% dextrose injection. The Infant Size" package (Steri.Vial No. 148) contains 250 mg. This should be reconstituted with 2.75 cc. of diluent. DOSAGE Adults Adults should receive 50 mg/kg/day in divided doses at 6-hour intervals. In exceptional cases patients with infections due to moderately resistant organisms may require increased dosage up to 100 mg./kg./day to achieve blood levels inhibiting the pathogen, but these high doses should be decreased as soon as possible. Adults with impairment of hepatic or renal function or both may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted accordingly. (See discussion under Newborn Infants.) Precise control of concentration of the drug in the blood should be carefully followed in patients with impaired metabolic processes by the available microtechniques (information available on request). Children Dosage of 50 mg./kg./day divided into 4 doses at 6-hour intervals yields blood levels in the range effective against most susceptible organisms. Severe infec- tions (e.g., bacteremia or meningitis), especially when adequate cerebrospinal fluid concentrations are desired, may require dosage up to 100 mg./kg./day; however, it is recommended that dosage be reduced to 50 mg./kg./day as soon as possible. Children with impaired liver or kidney function may retain exces- sive amounts of the drug. DSA-HH PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4473 Newborn Infants (See section titled "Gray Syndrome" under "Adverse Reactions.") A total of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces and maintains concentrations in blood and tissues adequate to control most infections for which the drug is indicated. Increased dosage in these individuals, demanded by severe infections, should be given only to maintain the blood concentration within a therapeutically effective range. After the first two weeks of life, full-term infants ordinarily may receive up to a total of 50 mg/kg/day equally divided into 4 doses at 6-hour intervals. These dosage recommendations are extremely important because blood concentration in all premature infants and full-term infants under two weeks of age differs from that of other infants. This difference is due to variations in the maturity of the metabolic functions of the liver and the kidneys. When these functions are immature (or seriously impaired in adults), high concentrations of the drug are found which tend to increase with succeeding doses. Infants and Children with Immature Metabolic Processes In young infants and other children in whom immature metabolic functions are suspected, a dose of 25 mg./kg./day will usually produce therapeutic con- centrations of the drug in the blood. In this group particularly, the concentration of the drug in the blood should be carefully followed by microtechniques. (Information available on request.) cA4f~, PARKE, DAVIS & COMPANY 121 852250 A DETROIT, MICHIGAN, U.S.A. DSA-HH Aug. 1968 PAGENO="0184" YM C-) = C,, ~x I.' ~_ ~ C, ~ C.) C#)~ C~)~ W 0W 4~ ~ ~ -~ ~ ~c: ~~=5 ui ~ m __ U, 0 z U) SJSSU! P'~ ~S ~1N `ad aw oc-ssocj AIJVO LII1OY lVflSf 1 UOi])atuJ OSOi]XSQ %~ 10 UOC3DO(Uf iOJ .iasr1y~ 55~ `l~°~ ]U5fl[1~ snoanbe Jo DI I I j)~)1~ `UOOflfOS %OI v aied~id nj ~ ~ C40/PJoqt)/ .401 0/(/t'$/PlJ "°N VSfl 3C~0~ U 3!qD!jAJ P0JlS~a cued W03 `~C SIAT3a CIJUd s0000L'DDld )U1 S~UIUJLM )DSO[DUZY ~`S ~P~'U~ DIJ S0ipn~s poo~q S flbS1)1 151J3 ~ S! ~l loDiuaqdwL'lolqD JO OSn asp Sp!M p~C~0S -S1~ Scj icssw SSIS1JDSAp pOO~q- )N1N5IV,~ uoudijasajcl ~flOqi1M ~3ui -SuadSIp S11C1140i(l MS~ ltJ~P5d-NO1LflV) C#)~ a 0 ~ f.~Z 5-. ~ C~1 I~-~ ~:ø< -~ ~ -~ "4 ~ U Sterile solution may he kept at room temperature for 30 days without signifl. cant loss of potency. A cloudy solution should not be used. WARNLNG-Keep out of thu reach of children. Patient: Room: PAGENO="0185" Not suitable for laboratory diagnostic use. To prepare a 10% solution, add 11 cc. of sterile aqueous diluent such as Water for Injection or 5% Dextrose Injection. USUAL ADULT DAILY DOSE--SO mg. per Kg. See package insert. I I :moo~J :lus!Snd nIna `dxa UIipl!q3 JO qaeoi otg Jo ~OO dOOM-IJNINHVM `pnsn oq IOU P1fl04S UOIInjOS Apnop y `ADun~od jo ssoj 3USD -!J!~~s InOqITAL sAstp oc soj ninInJadwnl WOOi 3n ~cIn.~j aci Atm UOLIUJOS DlP~2S m. ] CAUTION-Federal law prohibits dispens- ing without prescription. WARNING-Blood dyscrasias may be as- sociated with the use of chioramphenicol. It is essential that adequate blood studies be made. See enclosed warnings and pre. cautions. Parke, Davis & Company Detroit, Michigan 48232 U.S.A. cgs t;; i=_~ ~z ~ C)5t" Z4- ~ N ~ >-~c.~ ~ < ~. ~~=4 ~4-. ~ 0) ~ LI) ~ Q - - 0 ~ ~j5tt~ ~ ~I ~5 LI, in1, ~ -~ ~a ~!r U ~ 1; 4> -~z . io~ Z~1 ~ II CI St 0 C C 02 % Solution - Date prepared: PAGENO="0186" 4476 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Not suitable for laborato,y diagnostic use. To prepare a 10% solution, add 11 cc. of sterile aqueous diluent such as Water for Injection or 5% Dextrose Injection. USUAL ADULT DAILY DOSE- 50 mg. per Kg. See package insert. I I ~iis ~a UOISEIIdX3 ~6069ZCD °N ~°1 ~11 uasp~1qs JO IP~3J GqJ JO JOO dII)~-9NINHVM * ~pusfl aq sou pi~"~i° UOUDJOS ~pnop y `L)ua3od * JO SSO~ R1E39!UE!S 3n0q3!M sASp 0~ JOJ OJD3E -sudws wool ~e sda3~ sq IcEIU uOnnJOs apiass _-~~ FSN 6505-754-0280 CHLORAMPNENICOL SODIUM ~ SUCCINATE, STERILE, U.S.P. FOR INTRAVENOUS ADMINISTRATION Equivalent to I Gram of chloramphenicol, U.S.P. PARKE, DAVIS & COMPANY DETROIT, MICHIGAN 48232 U.S.A. Caution: Federal law prohibits dispensing without prescription Ci.) Warning: Blood dyscrasias may be associated with the use of chloramphenicol. It is essen- tial that adequate blood studies be made. See L enclosed warnings and precautions. - (Whereupon, at 11:45 a.m., the subcommittee adjourned.) PAGENO="0187" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, MARCH 13, 1969 U.S. SENATE, MoNopoLy SUBCOMMITTEE OF THE SELECT CoMMIrrui~ ON SMALL BUSINESS, Washington,D.C. The subcommittee met, pursuant to recess, at 10:10 a.m., in the Caucus Room, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee), presiding. Present: Senators Nelson and Hatfield. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; and Elaine C. Dye, clerical assistant. Senator NELSON. I regret that our: hearing yesterday had to be can- celled. Dr. Dale Console, who was to be our witness, was unable to come because of ill health. His work within the drug industry as for- mer medical director for E. B. Squibb and Company and his experi- ence in private practice make him especially well qualified to comment on the various matters which have been dealt with in the course of our continuing study of the drug industry. Dr. Console's biographical sketch and prepared statement, which was submitted to us, will be made a part of our hearing record. The questions I had planned to ask will be sent to Dr. Console, and his answers will be placed in the record immediately following his state- ment. (Dr. Console's biographical sketch, prepared statement, and supple- mental information follow:) BIOGRAPHY, A. DAr,n CONSOLE, M.D. Born: 1915. Training: B. S. Cornell University 1937. M.D. Cornell Medical college 1941 (Polk Prize for General Efficiency). Intern, Asst. Res., Resident Surgeon, New York Hospital 1941-1946. Resident Neurosurgeon, New York Hospital 1946-48 (John and Mary Markle Foundation Grant). Research Fellow in Psychiatry, Pennsylvania Hospital 1957-1958. Research Fellow in Psychiatry, Payne Whitney Clinic 1958-1959. (Psychiatric Division of Cornell-New York Hospital) Experience: Consultant to Surgeon General (Neurosurgery), Fort Dix. Asst. Clinical Professor of Surgery, (Neurosurgery), Cornell Medical College. Attending Surgeon (Chief of Neurosurgery), St. John's Hospital. Research Consultant, New Jersey Neuropsychiatric Hospital. Director of Research and Training, N.J. State Hospital at Marlboro. Psychiatric Consultant, Douglass College. Assoc. Medical Director and Medical Director, E. R. Squibb & Sons. Research Assoc. in Psychiatry, Cornell Medical College. 4477 PAGENO="0188" 4478 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Certification: Diplomate of the American Board of Surgery. Diplomate of the American Board of Psychiatry and Neurology (Psychiatry). Memberships: American Psychiatric Association. Society of University Surgeons. American Group Psychotherapy Association. New Jersey State and Mercer County Medical Societies. Alpha Omega Alpha. Publications: 15 Pa~ers dealing primarily with Hypertension and the Sympathetic Nerv- ous System. STATEMENT BY A. DAIu CONSOLE, M.D. INTRODUCTION Before presenting my prepared statement I should like to make some intro- ductory comments. I have prepared my statement with the understanding that representatives of the drug industry, the PMA and the AMA either have had or will have their days in court. The drug industry and its friends have demon- strated in the past that they are more than able to speak for themselves. I do not exect them to support my views of the problems. I feel no need to support theirs. I also wish to make it clear that I am not an academician. For almost ten years I have devoted 90% of my time to the private practice of psychiatry, and my contact with the so-called "white towers of medicine" has been minimal. During those ten years I have held only one academic position and that is a part-time one, Research Association in Psychiatry at Cornell Medical College. I speak for myself and myself only. The primary justification for my appear- ance here derives from a degree of expertise I gained during the six and one-half years I spent as Associate Medical Director and Medical Director of E. R. Squibb & Sons. LICENSING AND INSPECTION I have always found it curious that a process that started in late 1959 as an investigation of "administered prices in the drug industry" ended in 1962 with the passage of legislation that had no effect on drug prices. Actually no one w-ho was knowledgeable expected that the Kefauver-Harris Amendments of the Drug Act would affect prices and it seems clear that the late Senator Kefauver accepted the bill in its final form only because it was the best compromise he could get at the time. Even so he made a last-ditch effort to introduce a patent amendment and was defeated. The record is clear and it demonstrates that the attack on drug prices had two prongs. One of these was contained in the patent provisions. The other w-as directed against the allegation that generic equivalents are inferior and unreli- able drugs. In drafting S. 1552, Kefauver and his staff sought to increase price competition by encouraging generic prescribing. Realizing that they could not accomplish this unless assurance was given that any drug on the market had to meet standards of purity, safety, and efficacy determined by the FDA, they drafted Section 508. Let me quote some of the pertinent language: "Paragraph (b) pro- vides that no license shall be granted unless the applicant demonstrates that the establishment . . . meets such standards . . to insure . . . the purity, safety, and efficacy of the drug. . . . When the Secretary (of HEW) determines that the establishment no longer meets the standards, he shall revoke or suspend the license." The intent of the language is crystal clear, and it w-as emphasized in Kefauver's opening statement in the first session of the hearings on S. 1552. Referring to the licensing and inspection provisions, he said, "These provisions put real teeth into the Food and Drug Act. By realizing that any firm w-hich produces inferior drugs can have its license to do business suspended or revoked, the physician should gain assurance that any drug sold in the country, w-hether produced in this coun- try or abroad, whether made by large companies or small companies, and whether marketed under a brand name or generic name, is of adequate and acceptable qualitij" (emphasis mine). PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 4479 Perhaps Kefauver and his staff were naive in thinking that these provisions would effectively neutralize the mountain of propaganda produced by self-pro- fessed reliable drug companies and by the PMA. They may have been naive in believing that the average physician's prescribing habits could be changed that easily. In any case, the theory never has been tested. During `the process of leg- islative hocus-pocus, Section 508 disappeared and a toothless version appeared in its place. It calls for registration of name and place of business. The inspection provisions are so vague that they defy interpretation. It has taken some five years for other to recognize the need to put more teeth into the Food and Drug Act. I have studied the Interim Report and recommenda- tions of the Task Force on Prescription Drugs, published in August 1968, with great care. No one in my opinion has made so exhaustive a study of the many problems posed by the ethical drug industry and expressed the findings in such balanced and temperate language. Among its recommendations it urges consid- eration of a registration and licensing system and strict quality control. Recog- nizing that this might raise the prices of some drugs, it feels that the increased quality would offset any increase in prices. While I am not an economist, I share the view that was held by Kefauver and his staff, namely that, overall, increased price competition would tend to low-er prices and at the same time ensure the quality and efficacy of all drugs. The need to strengthen the existing law has also received support from an unexpected quarter. It has been the practice of Medical Tribune to commission a Professor of Governments, Joseph D. COoper, Ph.D. to write extensive series of articles on the FDA, Generic Equivalency, and other subjects of interest to physicians. The tenor of Professor Cooper's comments and the editorial policy of Medical Tribune are quite obvious: It would require a rather remarkable distor- tion to characterize either as hostile to the drug industry. For this reason alone, it is of interest that a series of articles on the FDA that appeared in mid-1967, Professor Cooper called for a system that he labeled "licensed self-regulation." In describing the system, he went on to say, "the power of this method of control lies in the fear of the company that part or all of its license might be revoked." One can almost hear the ghost of the late Senator Kefauver. I strongly urge that Congress give early consideration to licensing and inspec- tion provisions similar to those proposed in the original S.1552. If the 1962 legis- lation had contained these provisions we probably would not find ourselves in the generic equivalency mess that now exists. In any case, the search for adequate guidelines would have started five years earlier than it did. MONETARY REWARDS AND OBJECTIvITy In his letter inviting me to appear before `this Committee, Senator Nelson men- tioned "growing concern that the medical profession has forfeited too much responsibility for the continuing education of physicians to the pharamaceutical industry and that the increasingly close financial relationship between the indus- try and the profession may be contrary to the best interests of the medical pro- fession and the public." I, too, share this concern; I have shared it for almost 18 years. It is now- almost nine years since I appeared before the "Kefauver Committee" and said: "Unfortunately drugs are not always prescribed wisely, and while the physician and patient among others must share the responsibility for this with the pharma- ceutical industry, it is the industry that carefully nurtures and encourages the practice. .. . The pharmaceutical industry is unique in that it can make ex- ploitation appear a noble purpose. It is the organized, carefully planned, and skillful execution of this exploitation that constitutes one of the costs of drugs which must be measured not only in terms of dollars but in terms of the inroads the industry has made into the entire structure of medicine and medical care. With the enormous resources at its command, it has usurped the place of the medical educator and has successfully substituted propaganda for education." At another point in the same statement, I said, "The abdication of leaders and educators in medicine is disturbing. Postgraduate medical education is their province, not the pharmaceutical industry's." I am also disturbed, however, over the tendency to focus on financial rela- tionships. While I feel that this is important and requires attention and correc- tion, I am also convinced that we would be making a grave error if we decided that the total problem could be corrected simply by cutting financial ties. The well-known articles by Dr. Charles May: and Dr. William Bean cover the problems of "payola" and other financial entanglements. I believe I can accomplish more PAGENO="0190" 4480 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY if, instead of repeating what they have already said so well, I try to draw your attention to an area of equal importance; perhaps even of greater importance. The relationship that exists between the medical profession and the drug industry is an unhealthy one and in many ways a corrupt one. It is important to remember, however, that it is not only money that has the power to corrupt. Having spent more than six years in the business of influencing doctors and investigators, and some five years as a member of Fellowships and Grants Com- mittee, I can assure you that while large grants and other monetary rew-ards play an important role, that role is minor relative to other inducements and techniques that can be used to destroy objectivity. An incident that will always remain fresh in my memory will perhaps illustrate the point I wish to make. Sometime in 1956, when I was still a Medical Director, the lagging sales of one of our products led management to decide that the product needed a boost. The boost took the form of obtaining an endorsement from a physician who was a prominent authority in the field. We knew that the particular physician was being subsidized by another drug company and so management decided that it would be simple for me as Medical Director to `buy" him. I objected since I felt that the doctor was incorruptible and because I felt the product did not deserve endorsement. My business colleagues overruled me and I was left with a blank check to win his favor. I was free to offer him a large grant to support any research of his choice "without strings" or to retain him as a consultant with generous annual compensation. I was quite certain that the doctor would throw me out of his office if I approached him w-ith any of the techniques sug- gested by my colleagues. They all had the obvious odor of a bribe. I decided, therefore, to use a strategem that was more likely to be effective and that I thought (at the time) would be easier on my own conscience. I took the doctor to lunch, and after the usual two Martinis, I told hiiii exactly what had been going on and of my disagreement with my colleagues. In this manner we established a physician-to-physician relationship in which we were both deploring the questionable tactics used by the drug industry. Conversa- tion gradually shifted to the product and, to make a long story short, we got our endorsement almost as a personal favor. My travel expenses and the price of the lunch made up the entire cost to the company. I recall this out of a hundred similar incidents only because the doctor w-as, and still is, a highly respected authority. My attitude toward him still is one of profound respect and admiration, since I must confess that the device that gulled him would have fooled me had I been in his place. We are still human in spite of being physicians. As humans, we are vulnerable to all forms of flattery, cajolery, and blandishments, subtle or otherwise. The drug industry has learned to manipulate this vulnerability with techniques whose sophistication approaches perfection. It was this knowledge that led me to write a letter that appears in the record of the "Humphrey Hearing" (p. 2289). Referring to the methods that can be used to destroy objectivity I said, "Any employee of a drug firm who is worth his salt has an expert's appreciation of their power, a gourmet's taste for their subtleties, and the deft delicate touch that leads the doctor to hang himself." These techniques are used not only by physicians employed by a drug company but also by more experienced detailmen. I know of no effective way to deal with this type of hanky-panky that goes on every day between the medical profession and the drug industry. It seems impossible to convince my medical brethren that drug company executives and detailmen are either shrewd businessmen or shrewd salesmen, never philan- thropists. They make investments, not gifts. As further evidence of this manipulation of the physician's vulnerability, let me quote from the literature that was uncovered during the thalidomide scandal. A document written by the William S. Merrefl Company w-as sent to "special representatives" before Kevadon (thalidomide) w-as approved for mar- *keting. It set up minimum goals and objectives, including contacting teaching hospitals and the chiefs and senior members of hospital departments "for the purpose of selling them on Kevadon and providing them with a clinical supply." In the instructions the representatives were told: "Appeal to the doctor's ego- we think he is important enough to be selected as one of the first doctors to use Kevadon in that part of the country" ("Humphrey Hearings," p. 1918). I can assure you that even this simple device will open many doctor's doors. Let me hasten to add that during my time as Medical Director I w-orked with many physicians who were incorruptible. Many of them received large PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4481 grants but they produced studies that were models of objectivity. These were truly cooperative efforts in which both the drug industry representatives and the investigators were seeking the truth. There is no doubt in my mind that similar cooperative efforts exist today. On the other hand, during my time as Medical Director, I can remember only six to eight drugs that were truly exciting and interesting. I also remember a hundred humdrum concoctions and combinations that would bore any doctor to death. These, however, must also be studied and in trying to find "investigators" who are willing to do the job, one must scrape the bottom of the barrel. As a result, the drug industry doctor must rub shoulders not only with the giants in medicine but also with its dregs. In my 1960 statement I called the latter "stables" using the vernacular of the industry. Drug testing is a costly, burdensome, and often a boring chore. Those who do the work well should receive adequate compensation. Both because there are doctors who are incorruptible and because someone must pay for drug testing, I think it is wrong to damn monetary rewards in a `blanket fashion. I do believe, however, that clinical testing and the choice of investigators should be taken out of the hands of the drug industry. So long as we have a system that allows drug companies to buy the claims that will sell a drug, we have a potentially corrupt system. I am convinced that the public interest ~vill be best served when we devise a system that preserves anonymity between the drug company that has a pro- prietary interest in a drug and the investigator whose research results may or may not supply the claims that will sell the drug. During the writing of this statement I learned that many physicians who preceded me recommended a "Drug Institute" or a similar central agency. I do not believe the recommendation can be repeated too often. A central agency, supported both by federal funds and by fees paid by drug companies, should serve as an impartial intermediary between drug companies and clinical investi- gators. By preserving anonymity and by selecting investigators on the basis of their qualifications, we could raise drug testing to a level it has never known. Since I believe in the theory of the unconscious (as well as the existence of incorruptible physicians), I am convinced that any thing that falls short of this system cannot insure objectivity. The larger problem of destroying objectivity by appealing to the doctor's ego is as old as man. I do not intend to offer a solution. I think it iS important that we remain aware of its existence and of the fact that physicians are just as human as everyone else. Unfortunately, what I said on this matter in my statement of 1960 is as true today as it was then. "There are far too many physicians who must still be taught the difference between a free golf ball, the magnetic personality of a detailman, and a scientific fact as criteria for the evaluation of a drug." THE PHYSICIAN'S PRIVILEGES AND PREROGATIVES The ease with which objectivity can be destroyed is only one of many signs that the relationship between the drug industry and a considerable segment of the medical profession is contaminated. Both the AMA and individual physicians have demonstrated that they are quite willing to pull the drug industry's chestnuts out of the fire when they can, at the same time, serve their own interests. Both the AMA and the PMA have long paid lip service to the principle of upgrading the scientific Stature of the FDA. Yet each time this principle has been tested, either the AMA or the PMA or both have demonstrated that they are not prepared to practice what they preach. They have proposed instead glib anti-scientific solutions. The AMA probably represents the majority of the nation's more than 200,000 physicians. Whether it speaks for them is not clear. In any case, the cozy "you scratch my back and I'll scratch yours" relationship that exists between the AMA and the drug industry raises some serious questions. One of the first major confrontations between government and medicine (regarding drugs) came in the "Kefauver Hearings." At that time, to use the words of Dr. William Bean, ". . . the AMA in its fear . . . euchred itself into [an] astonishing posture . . ." It suggested a solution that made "every physi- cian his own Pasteur." Even after the bill became law, anti-science still reigned, and the AMA House of Delegates resolved that "the AMA attempt to have removed from the Kefauver-Harris Amendments those provisions which author- PAGENO="0192" 4482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ize the U.S. Food and Drug Administration to determine the effectiveness of drugs." Anti-science is still with us. Another major confrontation came in 1963 when the FDA, following the recommendations of a panel nominated by the prestigious National Academy of Sciences proposed banning the sale of antibiotics in combination with cold preparations intended for symptomatic relief. The response of the drug industry, the PMA, the APA, and individual physicians constitutes one of the most shocking episodes in the history of American medicine. Although it is docu- mented in the record of the "Humphrey Hearings" (pp. 1502-1530) and has been described by Morton Mintz in By Prescription Only, it has received little attention in the medical community. I had intended simply to mention this episode and give the references. During the preparation of this statement, however, it became clear that we were heading into another major confrontation between the FDA and the drug industry, which is almost exactly the same as the confrontation that took place in 1963. In the hope that it might help to prevent a repetition of the 1963 episode, it seems worthwhile to give some account of the genesis, the life and the death of the proposed ban. Sometime in 19f32 became concerned about the inclusion of antibiotics in mixed cold preparations intended for symptomatic relief and in throat lozenges and troches. Concern about these products had been expressed in the medical literature since 1953. The FDA finally decided that these uses of antibiotics were irrational and should be studied. It requested nominations for a panel of experts from the NAS and selected from the nominations a panel chaired by Dr. Harry Dowling, an internationally recognized expert on infectious diseases and antibiotics. The report and recommendations of the panel led Dr. Ralph Smith of the FDA to write to his superior recommending (as the law requires) publication in the Federal Register of a proposal to remove antibiotic containing cold preparations from t.he market. In his letter, Dr. Smith said, "the proposal is likely to be met by substantial industry opposition." This will probably stand as one of the greatest understatements of all time. I doubt that more than a handful of practicing physicians read the Federal Register and so the information reached physicians through other channels. These were accounts in the media controlled by the AMA, in throw-away journals that subsist on drug advertising, and in letters mailed to physicians by a large drug company. I have a clipping from the J.A.M.A. of November 23, 1963 which is typical of accounts that help to mold the opinions of the medical profession. It is too long to read it in its entirety, but I request that it be made part of the record. In it both the PMA and the AMA take turns labeling the proposed ban "unauthorized inter- ference with the practice of medicine . . . goveimment fiat . . . governmental dictation . . . regulatory fiat . . . (and) coercion." To expect the average physician to consider any issue dispassionately when presented in such inflammatory language is equivalent to expecting a bull to become reasonable by waving a red flag at him. The response of physicians w-as hardly surprising. One account (The Pinl~ Sheet September 16, 1963) stated that "over 100 letters of protest" were received by the FDA. Another account (John Troan, Tvashington Daily News, November 12, 1963) stated "about 1,000 physicians have filed protests with the FDA." This larger figure may reflect the difference that appeared in the month that separated the tw-o reports. It appears that only one physician, Dr. Joseph K. Ackerman, wrote to the FDA approving its proposed action. His letter appears in the record of the "Humphrey Hearings", (p. 1523) and I quote part of it: "The opinion of a minority of experts is of much greater value than the opinion of a majority of practitioners who have had an irregular and inadequate exposure to com- petent and objective pharmaceutical literature. Whether their opinion has the political leverage is another thing again." There w-as one other letter that supported the FDA position but it was sent to Medical World News rather than the FDA. I wrote the letter in response to a news article entitled "Curb on Cold Remedies Faces Fight" which appeared in the September 13, 1963 issue of that journal. The letter appears in the record of the "Humphrey Hearings", (p. 1523) and I quote it in part from that source. "If the drug industry is successful in urging medical leaders to lodge a formal protest against the proposed ban on antibiotic mixtures . . . the caduceous should be at half mast . . . If `thousands of physicians' have found these mix- tures useful, it should be easy to collect conclusive data demonstrating that PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4483 utility. The drug indus:try can answer the FDA's objections better by collecting and submitting those data than by blowing up an emotional storm over `inter- ference' with the physician's prerogatives . . . the real need is for data not protest." At the same time I sent a personal letter to one of the members of Dr. Dowl- ing's panel in which I exhorted him to stand fast and to urge the panel not to be swayed by irrational protest regardless of its volume. I pointed out that if the panel and the FDA capitulated they would set a precedent for an incredible policy, namely drug evaluation by mass protest and by testimonial. Subsequent events demonstrated that the majority of practicing physicians with "irregular and inadequate exposure" had the "political leverage" and pre- vailed. The FDA retreated and extended the period for filing comments for two months. Subsequently, it appears, both the FDA and the panel did capitulate and this bold, but rational, step toward sound medical practice came to naught. Capitulation in the face of voluminous and vehement protest is understandable, but nonetheless regrettable. It is incredible that testimonials and irrational pro- test can be so effective. If scientific data ever were presented I have no knowledge of such data. Even the AMA (in `the article quoted above) gave a pathetically weak and specious argument to justify the continued use of these irrational combinations of drugs. In defense of these products the AMA said: "It seems that many phsyicians in practice prefer to prescribe such a mixture of drugs because they believe that each drug in the mixture will have a specific desirable purpose." The AMA still dlings to the fiction that every physician is his own Pastuer. It would probably Prefer to forget that there was a time when it refused to accept advertising for drug combinations. The AMA also gave its usual glib solution as the answer to the problem of irrational antibiotic-cold preparations. According to the AMA the answer lies not in FDA action but in "education of physicians" and "labeling." If the ex- perience with chlorainphenicol is an example of what can be accomplished by physician education and labeling, it is high time we began to search for other solutions. The weight that should be given to the average practitioner's concept of the problem is reflected in one of the letters to the FDA quoted by John Troan. The latter came from a small local medical society and said: "We deeply resent this proposed usurpation of our prerogative to treat and diagnose our individual patients and our prerogative to err if that be the case." I have added the em- phasis because as a psychiatrist I have always found the Freudian slip that reverses the order of the terms diagnose and treat of special interest. I am still awed by the arrogance the latter expresses. According to the PMA and the AMA these views should be given the same or greater weight than that given to scientific evidence derived from controlled studies. Testimonials are still testimonials regardless of their numbers. The irra- tional does not become rational by virtue of volume. If the entire antibiotic combination episode is an illustration of how `the drug industry, the medical profession, and their chosen representatives the PMA, and the AMA seek to enhance the scientific stature of `the FDA and how they seek to promote sound medical practice, it leaves much to be desired. Curiously, all the sound and fury was over nothing since the proposed ban did not interfere with the physician's prerogative to prescribe as he chooses. It did proscribe the marketing of certain irrational mixtures, but the physician was still free to prescribe a cold preparation and to write a prescription for any anti- biotic of his choice in those cases where it was indicated. If the FDA cannot proscribe the marketing of irrational mixtures of drugs because that proscription infringes on the privileges of physicians, Congress and the people should re-examine those privileges. This is clearly an abuse of priv- ilege and should not be tolerated. According to a Supreme Court decision the people give privilege to professions and the people may take it away. The stage for the pending confrontation between the FDA and the drug in- dustry was set in 19G2 when Congress approved the efficacy provisions of the Kefauver-Harris Amendments of the Drug Act. At that time Congress had a clear choice between exempting drugs approved for safety only during the period be- tween 1938-1962, under a grandfather clause, or making the efficacy provisions retroactive. In choosing the latter course Congress gave the FDA a clear mandate to re-evaluate all such drugs for efficacy and unleashed forces of explosive potential. 81-280 0-69-pt. ii-i:~ PAGENO="0194" 4484 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Probably because the leaders of the FDA recognized this explosive potential they elected not to exercise the authority given them by Congress until 196G. At that time the FDA, under the inspired leadership of former Commissioner God- dard, accepted the assistance of the FAS-NRC and select panels began the long review. The findings and recommendations of these panels have begun to filter down and the FDA either has published or plans to publish its intention to ban the marketing of certain irrational combinations. The most recent decisions deal with irrational antibiotic mixtures. While these steps are rational they fail to make allowance for the irrationality of the drug industry, the AMA, and a seg- ment of the medical profession. The drug industry and its friends operate under a different set of rules which can be stated quite simply. Whenever a drug, through rational or irrational usage, has acquired a place in the Art of Medicine it is no longer subject to any scientific scrutiny. Morton Mintz caustically labelled this the "Hussey-Stetler Test of Time." Any attempt to subject a drug that is already on the market to sicentific scrutiny is met with howls of protest over interference with the privileges of physicians. If we accept this abuse of privilege we set scien- tific concepts of drug therapy back to the Middle Ages. The spectacle of the drug industry acting as the champion of the privileges and prerogatives of the physician would be amusing if it did not have such serious consequences. The drug industry is interested in encouraging irrational prescribing and thereby increasing sales volume, not the rights of the physician. In my statement of 1960 I said: "The incidence of disease cannot be manipulated and so increased sales volume must depend, at least in part, on the use of drugs unrelated to their utility or need or, in other words, improperly prescribed." Today I would go a step ftrther than I did in 1960. Probably the major part of the sales volume of many drugs (and especially combinations) is dependent on their being prescribed improperly or irrationally. We can only hope that the FDA and the panels will not be swayed as they were in 1963. We have bad more than enough of drug evaluation by mass protest. We have had more than enough of political leverage. We have had more than enough of irrational prescribing, and of anti-science. If there is such a thing as a science of medicine then let us behave as if we believe it. The pharmacologic action of drugs is a Science not an Art. Those who believe it is an Art should limit their prescribing to innocuous placebos whose activity does indeed depend on art. Unfortunately there are rumors that the FDA may be returning to the doldrums it was in for more than 30 years prior to Dr. Goddard's leadership. Dr. Goddard was a realist and recognized that the industry had to be dealt with as an adversary. To deal with the drug industry in any manner than as an adversary is noj only unrealistc; it is nonsense. IRRATIONAL PRESCRIBING rI'he Task Force on Prescription Drugs simply accepts the existence of irration- al prescribing. For obvious reasons it makes no attempt to answer the all-impor- tant question about the incidence of irrational prescribing. It does state: "We find that few practicing physicians seem inclined to voice any question of their com- petency in this field. We have noted, however, that the ability of an individual to make sound judgments under these quite confusing conditions is now a matter of serious concern to leading clinicians, scientists and medical educators." There are two quite different ways to practice medicine. One calls for precise, pinpoint diagnosis and the aiming of a handloaded rifle bullet at the center of the target. Unfortunately, this method is not always available; an overwhelming po- tentially fatal infection is an obvious exception, but this is the primary method taught in medical schools. The other method, which is not taught in medical school, seeks only some general categorization of the patient's illness, such as anemia, infection, or gastro-intestinal disorder and either letting loose a shotgun blast in the hope that one of the pellets will find the mark, or firing one or more rifle bullets in random fashion hoping, again, that one will reach the bull's eye. These are examples of irrational prescribing and unsound medical practice. This latter method of practice requires far less skill, much less time, and uses much more medication than sound medical practice. Because it is easier, it has more and more appeal as the physician becomes more hurried, more harried. and more confused. Because it uses more drugs, the drug industry encourages the practice in the "education" it gives in its advertising and promotion efforts. It is easier than you will believe to fall into the habit of thinking fever equals infection equals a prescription for chloramphenicol. Viewed in this light, the mis- use of chloramphenicol becomes more understandable since chloramphenicol is PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4485 one of the biggest shotguns of them all. As I said in my statement of 1960: "Too many physicians, pressed for time, would like to believe that medicine can be practiced with a clinical thermometer and a bottle of pills." There is nothing new or unique in this description of irrational prescribing. As far back as 1953 Dr. Maxwell Finland, an eminent authority on antibiotics, dealt with the problem in a scientific paper. Under the heading "Omnibiotics" Dr. Fin- land said: "The physician in practice, and many of his patients as well, are con- stantly on the lookout for some simple substance or formula which they can apply with universal success. The busy practitioner is particularly desirous of having some major weapon on which he can always rely to be successful in all types of infections, and would thus relieve him of the responsibility and trouble involved in the complicated or even simple diagnostic procedures" ("Humphrey Hearings" p. 1507). In addition to precision in diagnosis (and treatment), medical schools also teach the painful and anxiety provoking process of watchful waiting when the diagnosis is not clear and a laissez faire attitude when the complaint is not serious. Watchful waiting does provoke anxiety and requires much more con- tinuous attention to the patient's changing condition. Laissez faire leads many patients to object because they feel their complaint has not been taken seriously. In either case, only too often, the physician feels compelled to write a prescrip- tion, even though the prescription does more good for his anxiety or his conveni- ence than it does for the patient's illness. It also exposes the patient to the addi- tional hazard of drug induced illness which may or may not obscure the underly- ing cause of the original illness, and may or may not make the cure worse than the disease. Because it feels that rational prescribing and sound medical practice cannot be legislated, the Task Force leans heavily on education, at both the medical school and the post-doctoral levels, for a partial solution of the problem. While I can- not gainsay the value of education I am dubious about the effectiveness of physi- cian education in this particular area. I am forced to ask the question I asked in 1960. Since it is a long one, I will paraphrase it. Is it reasonable, I asked, to expect legitimate education to compete with modern methods of advertising and promoting drugs? My answer was then, and still is, an unqualified no. Education is not enough and I believe the experience with chloramphenicol, among other drugs, proves it. I agree that rational prescribing and sound medical practice cannot be legislated. We can, however, enforce legislation that exists and con- sider new legislation, if necessary, to choke off at least part of irrational pre- scribing and thereby contribute to sound medical practice. The irrational use of drugs has at least two facets. On one hand we must deal with single drug entities which have specific but limited use and, while they may be irrationally prescribed, are still the drugs of choice in some disorders. Chloram- phenicol and penicillin are examples' of drugs that have specific uses but are often improperly prescribed for disorders for which they are not indicated. On the other hand, we have irrational combinations of drugs which serve only to encour- age irrational prescribing. If the use of these drugs were limited to those occa- sional cases where they might by stretching reason, be indicated *they would wither on the vine and their sale would become unprofitable. Invariably the pur- pose of these drugs can be served equally or better by prescribing the ingredients separately in those rare cases where more than one drug is indicated. Antibiotic containing cold preparations and the combination of amphotericin B with tet- racycline are examples of combinations in this category. We cannot ban products in the first category. We will have to accept the mususe and abuse of these drugs until education or publicity or both reduce such improper use. We should, however, ban the marketing of irrational combinations even if it requires new legislation. We probably w-ill have to interfere with the privilege of the medical profession arrogates to itself but rational prescribing and sound medical practice must take precedence over the AMA's the PMA's or the individual physician's concept of privilege. Naturally it woul be preferable if the medical profession policed itself. If the AMA could cure itself of its phobia over government control it could serve a useful pui~pose in contributing to sound medical practice. So long as it adopts astonishing postures it invites regulatory control. Experience has demonstrated that the AMA is phobic and that neither the drug industry nor a considerable segment of the medical profession is prepared to police itself. Actually the AMA and the medical profession should serve as the first line of reserves behind the FDA in the battle to curb `the excesses of the drug industry. Instead of sup- porting the FDA, the AiMA and a segment of the medical profession have joined PAGENO="0196" 4486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY forces with the drug industry and as allies they wage war against a common enemy, the FDA. The combined efforts of the drug industry and its allies make the anti-regulatory forces so powerful that it is doubtful that the FDA alone can deal with them. Reform and tighter regulation of drugs (and especially com- binations) is clearly required. Firm action and support of the FDA by Congress, the people, and the leaders and educators in medicine is in order. In conclusion, let me quote Senator McCumber, who, arguing for the Food and Drug Act passed in 1900, said: "You cannot, for years, surround a people with crime and deceit and imposition on every side without it, in time, affecting the moral character of the people. Constant association with crime and deceit calls our senses to offenses of that nature." I do not believe that his language is anachronistic. We have come dangerous close to repeating the conditions he described. PRINCETON, N.J., March 26, 1P69. Hon. GAYLORD NrisoN, U.S. Senate, Washingtoa, D.C. DEAR SENATOR NEr~soN: Let me take this opportunity to express my regret that I was unable to be present at the hearing. Under separate cover I am sending you the answers to the questions raised by you and by Mr. Gordon regarding my prepared statement. Whereas my statement was, indeed, prepared and went through several drafts and revisions before it took on a form I was partially satisfied with, I have not used this method in answering the questions. I have simply sat with a typewriter and allowed myself to reminisce allowing the flow of one thought to lead on to the next. This gives the answers a random and sometimes even a repetitive quality. Nevertheless, it is essentially what I would have said had I been present at the hearing. I have added exhibits and source material which brings this part of my statement up to date. If there are questions that remain unanswered, or if the answers raise further questions or need clarification, please do not hesitate to let me know. Sincerely, A. DARE CONSOLE, M.D. DR. CONSOLE'S ANSWERS TO QUESTIONS SUBMITTED BY SENATOR NEr~soN Qnerfion. (a) How can legitimate education compete with the millions wpon miflions of dollars spent on advertising and prcnnotion, gifts and financial grants to physicians, financing of journal-s and meetings and gifts to students? Wouldn't you say that this is a rather uneven struggle? (b) What has been the role of the ~nedical organizations in, helping the doctors get scientific, un7iia~scd informa- tion? Answer. The struggle is indeed, an uneven one. As I pointed out in previous testimony, industry alone commands the resources necessary to make propaganda effective. How can legitimate education compete with the carefully contrived distortions driven home by the triphammer effect of weekly mailings, the regular visits of the detailman, the two page spreads, and the ads that appear six times in the same journal; not to mention the added inducement of the free cocktail party and the golf outing complete with three golf balls stamped with the name of the doctor and the company in contrasting colors? Drug advertising and promotion efforts encourage the doctor to believe that there is an easy way to practice medicine. They offer larger and larger shotguns which make pinpoint diagnosis, or for that matter any diagnosis at all a pedantic exercise and a troublesome inconvenience that only the less informed academician bothers with. The sound practice of medicine is a rigorous discipline. There are no short-cuts. There are no easy ways to achieve the necessary goals. There are no omnibiotics or shotguns Fthat eliminate the need to think, and to worry. The disparity between legitimate education and drug advertising and promotion is not only in the quantity of the blandishments the drug industry offers, but also in the quality of the piece of candy dangled in front of the physician's nose. With respect to the role played by medical organizations, it is difficult to generalize. There are thousands of such organizations ranging from county medical societies to the select clubs consisting almost exclusively of blue bloods. I have maintained my membership in the Society of University Surgeons pri- marily because it tends to fall in the latter category. Although I have been a PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4487 member for almost 20 years I have never known it to offer a program intended for drug promotion. This is in contrast to the New York Academy of Science from which I, among others resigned because it began to sponsor obviously biased "symposia" which were nothing more than grandiose promotion programs intended to push a particular product. So long as the average practioner is the captive of the drug industry, and I am convinced he is, and medical organizations are made up of physicians who are captive, it follows `that the organizations are in turn captive. The real question is not whether they are captive but rather the degree to which they are cap- tive. Those who publish a journal and derive income from drug advertising are probably even more captive that the average practitioner. Those who derive such income cannot deny that a conflict of interest exists. The AMA's contention that it is not a party in a tacit conspiracy wit'h t'he drug industry is not convinc- ing. Its denial fails to explain the astonishing, unscientific, pro-drug industry positions it has taken. It has given `shelter to the `drug industry under the cloak of immunity given to physicians, and the drug industry has been more than will- ing to accept the shelter since it gives the industry an ethical image while it uses the same profit-oriented tactics of any big busines. It pays well for the shelter by buying advertising pages. As I suggested in my prepared statement, the AMA is serving its own interests and the support it gives the drug industry is sec- ondary. In my opinion this is simply a definition of conflict of interest. I would not expect the AMA to put the drug industry's interests before its own. I wish to make it clear that I `have used the term propaganda to describe the drug indus- try's "education", in terms of one of Webster's definitions of propaganda; "any systematic, widespread, deliberate indoctrination, or plan for such indoctrina- tion; now often used in a derogatory sense connoting deception or distortion". As we speak of propaganda as opposed `to education I am reminded of recent reports in which the AMA, trying to keep its significant income derived from drug advertising tax free, has quoted Dr. Goddard to the effect that drug adver- tising is educational. I do not know the source of this quota'tion or whether the quotation is being used in or out of context. If it is accurate and in context, I can only say that I disagree with Dr. Goddard. The concept that the merchant who hawks his wares serves an educational: purpose is a travesty. Finally let me point out that I devoted a major portion of my 1960 statement to exploding the myth that drug advertising is educational. I enclose a mimeo- graphed copy of that statement which you may wish to make a part of the record of these hearings. Question. On page 3 of your statement you refer to your ecvperience in getting the endorsement for a particular product. Was the product worthy of an endorse- ment?iWhat form did the endorsement take? Answer. I have `deliberately kept t'his part of my statment vague since I would not want, under any circumstances, to reveal the name of the physician involved. I have said in my statement that I did not `believe the product deserved en- dorsement at the time of the incident. Since that time nothing has happened to change my opinion. I can add, that it was a combination product which as a fixed `combination was rarely, if ever indicated. The doctor involved was a vocal opponent of all such products and frequently men'tioned our product by name. The "endorsement" was actually an agreement on his part to discontinue this practice. I essentially promised that we would limit our claims, but over the year,s the promise was not kept. The doctor did not know that the mere fact th'at we could market it with any claims at all `had already led to widespread misuse. Question. When you were a drug company medical director, did you ever `instruct detail men in how to sell drugs? What kind of techniques of selling did you present to the detail mun? How effective were these techniques on the phy- sicians? Was the aim to make physicians prescribe more intelligently? Answer. `During my time in the drug industry I had a close ongoing relation- ship with detailmen. It was from one of them that I learned the simple maxim I drew atten'tion to in my 1960 statement; "If you can't convince them, confuse them". During my time I attended detailing "clinics" and "workshops" and I played an important role in introducing new products to the entire detail staff (I believe it was about 500 men at that time). The primary purpose of detailing (as is true of all advertising and promotion efforts) is to sell the company's products. Any and all other goals are second'ary. The company that has exclusive rights to a new drug that is truly useful is for- tunate, indeed. This is a rare occurrence and those companies (e.g. Smith, Kline and French) who have been in such a position even for `a few years `have PAGENO="0198" 4488 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY made a fortune. Even so SKF made a strong bid for the Miltown ma~rket in its detailing, advertising and promotion. Most often the new product is a duplicative "me too" that resulted from patent evading molecular manipulation, a combination that has, at best, an extremely limited market, or an uninspired drug that must compete with a host of com- petitive drugs already on the market. Not infrequently a drug that represents a real breakthrough is useful only in a very small nunTher of patients (simply because the disorder is a rare one) and there is always the temptation to increase its sales volume by extending the indications to include patients who do not need the drug. In teaching and instructing detailmen one must attempt to instruct and inspire them over a product that is, more often than not, uninspiring in order to increase sales volume to its maximum point. A detailman is a salesman and, as is true of any salesman, his enthusiasni about the product he is selling plays an important role in how many sales he makes. The members of my staff and I were only a part of the manpower used to whip up enthusiasm over a humdrum concoction. In addition, innumerable prizes ranging from cutting boards to sets of monogrammed glasses are given to those detailmen who reach or exceed a pre-set quota of sales. Since I was the confidant of many of the detailmen I learned that many of them had convinced, or confused, a doctor to prescribe one of our products by telling the doctor that *they were only one step away from winning a prize. It is my considered opinion, regardless of what may be said by even a majority of average practitioners, that detailmen are nothing more or less than extremely expensive parasites. The Task Force estimates that there are 20,000 detailmen employed by the drug industry. I estimate that the cost of maintaining a detail- man is somewhere near $20,000 per year. This is a minimum rather than a maximum estimate, and so we are speaking of an expenditure on the order of one half billion dollars. This amount is, of course, deducted as part of the cost of doing business when income tax is calculated. In brief, the public pays a large part of the expense for the support of the detail man and pays it twice. I went into psychiatry on the crest of the wave of psychopharmacology and so I am psychopharmacologically oriented. I use drugs when they are indicated and I use many of them. In almost 10 years of practice I have never seen a detailman and only about a half dozen have called my office trying to make an appointment. My refusal to see detailmen is based both on my experience in training them and on their confiding to me the methods they use to make a sale. I am not aware that my ability to practice psychiatry or my knowledge of the many drugs used in psychiatry have suffered by the absence of the detailman. I would rather take the advice of an uninvolved, impartial expert than be guided by the claims made by the merchant hawking his wares. I can express my overall opinion about detailmen best by paraphrasing Oliver Wendell Holmes; if all detailmen were dumped into the sea it would result in the betterment of mankind and detri- ment to the fishes. The primary purpose of the detailman is to make a sale even if it involves irrational prescribing and irrational combinations that contain a prophylactic ingredient furnish an ideal path to confusion. There are drugs whose merit is such that there is no need to mislead or confuse the physician. If the physician does any reading at all, he has no need for the detailman. If we could legislate the detailman out of existence this could well prove to be the most important piece of drug legislation enacted. The detailman is not the expert both the industry and the apologists claim he is. His detail is often "canned" or is at best a paraphrasing of what he has been told to say. A standard answer to a question he has not been drilled on is to be modest and claim he would not want to tell the doctor how to practice medicine (not much). Or the detailman tells the doctor that he will forward his question to the home office. In this case an expert does the confusing rather than the inexpert detailman. Question. Dr. Paul Low inger of Wayne State University recommended to the coin mitt ee that investigators working on a drug know who the other investigators are and the results of their work. This could save a lot of time by pointing out faifures and pi.tfaiir. What do you think of this idea? Answer. In any kind of large scale research, proper coordination of the research is almost as important as the research itself. My suggestion that a central agency act as an impartial intermediary between the drug company and the investigators was predicated on the assumption that the central agency would serve as a coordi- nator. So long as rights regarding publication are respected, failure to follow Dr. Lowinger's suggestion would be foolish. Question. The AMA testified before the Kefauver Committee (Pt. I, p. 87 Drug Industry Antitrust Act): PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4489 inevitably a useless drug will not be, used because of the training and experience of physicians because of their experience with this useless drug, if it is permitted to be marketed. "* * We feel that a profession fully knowledgeable in a free market economy will soon bring about the withdrawal from the market of a useless drug." What do yon think abont this? Answer. I believe this is much more a semantic exercise than a statement that requires refutation. In the first place, if we use the AMA's definition of utility, there is no such thing as a "useless drug". Milk sugar or any other ine.rt ingredient when put into the form of a tablet, a capsule, a solution for injection, or any other dosage takes on the properties of any placebo. Administered as a drug it can produce temporary relief in a host of disorders and even cure in disorders. that are self limited. It can also produce side effects that lead the patient to refuse to take the "medication". If we use a pharmacological definition, milk sugar is a useless drug. If, on the other hand, we use changes that may be observed in some patients by physicians who do not know that it is an inert substance, and especially if they have been preconditioned to expect beneficial effects, milk sugar becomes a useful drug. This is the yardstick used by the AMA. A combination of meprobamate and benactazine (Deprol) has been marketed as a useful agent in the treatment of depression for at least ten years. Most experts agree that it has no demonstrable value in the condition for which utility is claimed. Yet it has withstood the "Hussey-Stetler Test of Time" which the AMA, by its own admission, feels is the ultimate test of the utility of any drug. Vitamin B 12, especially in the forni of 1,000 microgram injections, has an extremely limited use. If its use were restricted to those patients who really need it I would guess that the amount now used in one year would be enough to treat patients with true Vitamin B 12 deficiency for almost one hundred years. The absurd limits to which average practitioners go is illustrated by my own experience with Vitamin B 12 during the time I was Medical Director. Because claims for its utility in many neurological disorders ranging from peripheral neuritis to trigeminal neuralgia and herpes zoster, as well as claims for utility in loss of appetite, underweight, poor growth, etc, were based purely on testi- monial evidence I refused to approve such claims in our literature on the drug. I answered the detailmen's immediate complaint by pointing out that our brand of Vitamin B 12 was therapeutically equipotent with any brand `on the market. If the doctor believed that it was indicated in any condition other than true Vitamin B 12 deficiency, our brand would meet the need as well as any other brand. For many months after I made this decision I received letters of complaint not only from detailmen but also from practitioners (who were probably told by detailmen that I would like to hear from them). `Our sales volume fell off, and there is adequate reason to conclude that many practitioners actually believe that the pharmacological effects of a drug are dependent upon the labeling that accom- panies a drug. This is true not only of labeling that makes claims but also of labeling that does not make claims. Many physicians obviously believe that a drug that is identical with competitive drugs becomes inferior by virtue of the fact that it makes fewer claims than the competitive products. This is one of the more obvious illustrations of the irrationality of practitioners and the irration- ality of their prescribing habits. The rapid rate of obsolescence of drugs is dependent not on the wisdom im- puted to the average practitioner by the AMA, but rather on his lack of wisdom. "Since so much depends on novelty, drugs change like women's hem-lines and rapid obsolescence is simply a sign of motion, not progress as the apologists would have us believe . . . with a little luck, proper timing, and a good promotion pro- gram any bag of asafoetida with a unique chemical side chain can be made to look like a wonder drug. The illusion may not last, but it frequently lasts long enough. By the time the doctor learns what the company knew at the beginning it has two new products to take the place of: the old one." Not infrequently the doctor never learns and the obsolete drugs remain on the market. Oral Mephenesin is a good example. The "Hussey-Stetler Test of Time" deserves the contempt that Morton Mintz heaped on it. The uncontrolled observations of average practitioners constitute testimonials and as such have zero validity in the scientific evaluation of a drug. Whether we multiply zero by 1,000, 10,000, or 300,000 the answer is still zero. The contention that the fate of a drug in the `market place is an accurate index of its value as a drug simply is not true. Actually my first exposure to the principle of the test of time and the market PAGENO="0200" 4490 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY place came at least five years before the AMA gave its incredible testimony in the "Kefauver hearings." The position taken by the AMA was criticized by several medical experts in- cluding Dr. Bean, Dr. Butler, and Dr. Goodman, among others. Perhaps the clearest (and the most humorous) description of the AMA's position is that given by a layman, Miss Barbara Yuncker, a reporter for the New York Post. I enclose a photostat of her article entitled "AMA Delirium" and have marked it Exhibit #5. I request that the entire article be made part of the record or that the portion bracketed in pencil be quoted as part of my statement. I believe it was in 1953 that Squibb arranged an exclusive licensing agreement with a German firm that gave us rights to market some of their products. They were asked to send me supporting data that would permit me to decide which products I could approve. The supporting data they sent were sales volume figures for various countries where the drugs were marketed and the advertising and promotional material found most successful. When I asked for scientific data consisting of laboratory studies and controlled clinical trials they behaved as if I were mad. I still find myself chuckling when I am reminded that the Germans did not use the terms advertising and promotion. All such material was labeled "propaganda" and one needs only to give the word a Germanic inflection to under- stand how it was used. The word is `obviously borrowed `from English and the Germans either did not know or did not care about the connotation the word has in English. They actually believed that the test of time and the marketplace plus the suggestive effect of their "propaganda" was an adequate basis for my evaluation of the drugs. Broken down to simple language this is exactly what *the AMA suggests. In this particular area I, in contrast to the average practi- *tioner, was an expert. `While it is shocking, it is probably true that the chances that an average patient will get the right drug, in the right `amount, at the right time is in the order of fifty percent. `Ineffective drugs, drugs that are not indi- cated, drugs `that are effective in disorders different from the patient's illness, unnecessary ingredients in combinations, and placebo doses are only some of the pit-falls. The unluckiest patient of all is the one who needs no `drug since, if he has a complaint it is almost impossible to get out of the average practitioner's office without a prescription. Question. Isn't it true that there have been dangerous drugs put on the mar- ket? And many of them have been taken off the market? Do you know of any case in the last ten years of the AMA urging that a drug be taken off the market because of lack of safety or efficacy? Answer. The list of drugs that are dangerous and have had to be taken off the market is long. Some of them unfortunately are still on the market and should be removed. Off hand I think of MER/29, Orabilex, and Marsalid in the first cate- gory. Parmate (tranylcypromine) is, in my opinion, in the second category. We may have reached the point where chioramphenicol is also in that category. If in the last ten years the AMA has initiated action to take a drug off the market because of lack of safety or efficacy that action has not come to my atten- tion. It has played an important role in fighting quackery (e.g. Krebiozen), but it seems to be determined to deny that quackery exists in the ethical drug industry. Question. (a) What Ia the role of testimonials in the advertising and promo- tion of drugs with respect to efficacy and safety? (b) How about reprints of articles in journals which subsist only on the pur- chase of reprints by the industry? (c) Do you know of cases when independent doctors signed their names to articles and letters written by the drug company? (d) How did you get testimonials (when you were a medical director)? (e) Did you pay for them? (f) Were they included under research or advertising? (g) Have you had any ecper'ience of distinguished physicians and scientists turning down a drug and then by sendin~g the drug to the "right type" of doctor, "proof" of the drug's usefulness was finally secured? (h) Is it a common practice for drug firms to purchase reports in favor of drugs? Answer. Before answering this question I wish to make it clear that I bear no malice tow-ard Squibb. Actually, I regret the need to implicate Squibb at all, but if my testimqny is to carry any weight I must choose between mentioning them or remaining silent. Since I interviewed innumerable physicians w-ho had served other companie~ as possible candidates for my staff, and had other dealings with PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4491 other drug firms I came to the belief that Squibb was, if anything, more ethical than most. In the enclosed mimeographed copy of my 1960 statement I have bracketed an excerpt beginning on page 7 and concluding on page 8. I request that this excerpt be quoted in my statement as a partial answer to your questions regard- ing testimonials. There were proof mills that would deliver data at so much per head and in entreme cases we used them. There were drugs that were declared useless after clinical trial by experts that subsequently became marketable using the testi- monials of less experienced physicians to prepare a New Drug Application. I have adequate reason to believe that other firms were less fastidious than we were and purchased favorable reports. I always felt that a bribe was degrading not only to the one who accepted the bribe but also to the one who offered it. The testi- mony regarding Henry Welch in the "Kefauver Hearings" is an extreme example of the lengths to which `some companies went. My 1960 statement made an oblique reference to the Welch affairs since it was made before the investigation exposed his activities. In retrospect the language is quite clear. As I recall, there were at least two journals that subsisted on purchases of reprints used for advertising and promotion. They may still exist. Drug studies are almost invariably included under research expense and I pointed out the absurdity of the practice in my 1960 statement. Question. Dr. Frederick Wolff estimated before this committee that out of $10 spent on drugs, $6 are spent unnecessarily. Dr. George Baehr of New York said that the $6 figure was too low-that more than, 60% of the drugs prescribed are not needed. Would you be willing to make an estimate? Answer. I know of no way to make an accurate estimate of the percentage of drugs that patients pay for unnecessarily. In so far as prescription drugs are concerned I would keep my estimate consistent with the answer I have already given, namely about 50%. I should not be surprised if an actual study yielded a higher percentage of unnecessary drug expense. Naturally if we include over- the-counter drugs the unnecessary medication expense would be much higher. I should like to amplify the comment that the antibiotic-cold preparation episode I described is being repeated by Upjohn and Squibb regarding Panalba and Mysteclin-F. I gave a reasonably detailed account of the 1963 episode be- cause I feared that the present confrontation would follow- the same pattern and that the final outcome might be the same. Recently Morton Mintz reported that Upjohn sent out 22,000 letters and that Squibb had put its detail staff to work on the problem. Just as I was intrigued by the report that Lederle sent out 7,500 letters in 1963, I find 22,000 equally intriguing. Why 22,000 out of more than 300,000 physicians? Obviously a process of selection was used in 1963 and a process of selection is being used now. We would have to be naive, indeed, if we concluded that these figures represent a random sampling of physicians and, it would constitute an incredible indict- ment of the medical profession as a whole if it were a random and representa- tive sample. If I were a drug company executive faced with this problem and had to decide how to get the most mileage out of the letters I would use a sim- l)le logical process. I have already said that a detailman is an expensive piece of property. Since his time is limted, it cannot be squandered and so drug companies try to develop a set of rules that will make it possible to use the detailmen's time most prof- itably. One of the indices used is a rating scale of the physician's prescribing habits. Squibb used a scale of four categories, and I doubt that other companies use a substantially different method. At one end of the scale is the non-prescriber or occasional prescriber. I would probably fall into this category since I write between 100 and 150 prescriptions per year. The infrequent attempts of de- tailmen to try to see me tends to confirm my position on the scale. At the other end of the scale is the "heavy prescriber". For our purposes we can accept the definition given in the AMA's Fond du Lac study that appeared in the record of the "Kefauver Hearings". A heavy prescriber is a physician who writes over 10,0 prescriptions per week! This is the prime target of the detailman and in this group w-e probably have the least discriminating physicians in the country. I find it difficult to believe that anyone can write that number of prescriptions and still ta1~e time `to discriminate. In this group we also have the physicians most likely to raise a howl of protest over the prospect of taking away one of their toys. This is the group to whom I w-ould send the letter and I feel reasonably certain that this was the group selected. The letters of protest come, not PAGENO="0202" 4492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY from a representative group, but from `the least discriminataing physicians and from the physicans least qualified to give an intelligent scientific appraisal of the problem. Again, if I were a drug company executive, and I had an adequate detail staff, I would choose Squibb's method over that of Upjohn. The detailman is best ac- quainted with the prescribing habits and the different ways the physicians in his territory think. He is best able to determine which is the most fertile ground in which the seed of discontent and protest can be planted. As I said in 1963, "the real need is for data not protest". I hope Commissioner Ley will pay some attention to this. One of the differences between the 1963 episode and the present confrontation is the lack of publicity given to the present confrontation in the throw-away news media. This is probably only a lull before the storm. I enclose with my statement Exhibit #6 which is quite typical of letters of protest and is the first pertinent article that has come to my attention. -I clipped it from the "Letters to Tribune" section of the March 24, 1969 issue of Medical Tribune. As usual the letter to the FDA does not contain a scrap of scientific data and is a tirade full of illogical irrelevancies. In his letter Dr. Johnson says, "The FDA was created as an agency to prevent the movement in channels of interstate commerce of adulterated and/or misbran4ed food, drugs, and cosmetics" (my emphasis). Apparently Dr. Johnson is not aware of the efficacy provisions of the 1902 leg- islation. The FDA's proposal to take Panalba and Mysteclin-F off the market, as I interpret the law, falls within the statutory authority given to the FDA. The interference with Dr. Johnson's concept of the practice of medicine is an unfortunate side effect of regulatory action. This is only one of some 3,000 letters the FDA is reported to have received. I expect we will see more of them. Actually I believe that the FDA could do a valuable public service by publishing a large random sample of the letters it has received. I feel that if the protesters are given enough rope they will hang themselves. Question. Isn't it strange that although the AMA's Council on Drugs has always been against the use of combinations, the AMA still accepts advertising for them!? How do you account for this? Answer. The answer to the question of the discrepancies that exist between the AMA's Council on Drugs, the AMA's advertising staff, and the AMA's edi- torial policy can be `found in the record of the Kefauver Hearings. Following the Ben Gaffin Survey, which is reported in the record, the AMA apparently came to the realization that there is gold in drug advertising and that i.t was giving up a significant source of income. The AMA Seal of Acceptance was dropped and as I recall the Council on Drugs no longer had any voice in advertising policy. The record of the Kefauver Hearings covers some 13,000 pages and while I have a reasonable knowledge of all of it, I cannot keep all of it always at my finger-dips. If my memory serves me, one of the members of the Council on Drugs who disagreed with the official position of the AMA in the Kefauver Hearings stated that the Council was not consulted even though the main issue was drugs. You probably are acquainted with the disparity Dr. Charles May exposed regarding the editorial and advertising policies of the AMA. Although the AMA carried a scientific article indicating that Norlutin produced masculization in female fetuses with sufficient frequency to consider its use unsafe, the advertising pages blithely continued to carry advertisements for Norlutin which made no mention of this danger. The schizophrenic policies of the AMA are strange and are not amenable to the laws of logic and reasonS Miss Yuncker's term "delirium" understates the diagnosis and prognosis. Delirium implies an acute transient dis- order. The AMA's disease is chronic and probably incurable. Question. What is the role of the Medical Director in allocating research funds? Does he determine what field is to be looked into? What criteria are used? sales needs or medical needs? Cam you tell vs something about the quantity and quality of the research undertaken? Answer. During the time I served as a member of the Fellowship and Grants Committee, the committee was composed of 4 members; the Vice-President for Research and Development, the Director of Laboratories, the Medical Director, and the Vice-President in charge of Promotion (sic). As I recall the budget avail- able for clinical research done by my staff was between $2~0,000 and $3~0,0O0. While I had virtually complete command of the funds allocated for clinical studies of drugs, I had little or no authority in the selection of the drugs to be ~tudied. If I recommended a clinical study it was almost invariably approved unanimously. I believe that the total Squibb Research and Development budget was in the order of $0000,000 throughout my tenure. Most decisions regarding the overall PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4493 Research budget were made by the Executive Management Committee of which I was a member. I had one of six to eight votes. Many research programs were instituted not because they promised a worthwhile drug, but because they prom- ised profit. Molecular manipulation came into its own during my time in the industry. In my opinion about 20 to 25% of the total Research and Development budget was spent on worthwhile projects. The actual dollar figures given by drug companies for "Research and Develop- ment" are probably accurate, but the term Research and Development covers a multitude of sins. Question. What kind of doctors did you get to perform your clinical investiga- tions? Did you have any experiences with so-called "proof" mills? (Can you name any?) Answer. As I indicated in my prepared statement the drug industry doctor must rub shoulders not only with the giants of medicine, but also with its dregs. I doubt that by experience was different from that of others who serve or served the same function. Since the uninspired concoctions outnumber the worthwhile drugs by at least 10 to 1 most of the contact is with a rather shabby lot. I would prefer to name no names. I did work with proof mills, but again I would prefer not to name them. When one views the scene groin inside the drug industry he witnesses strange occurrences. I remember clearly an occasion when we were making preliminary studies of a drug that was being produced in very small quantities by a laboratory operation. We sent a highly placed authority enough of the drug to treat two patients and were somewhat puzzled by the fact that he sent us favorable data on three patients. When, shortly thereafter, he :sent US laboratory data containing an item dated one day after the posit mark on the letter, we black-listed him. To put the incident in its proper context I must confess that black-listing him con- sisted of taking his name out of the file of reliable investigators who could serve as adequate guides to important decisions. His card was transferred to another file that indicated that he could be used as a proof-mill when and if we should have need for one. It was one of the most obvious illustrations of what the FDA has called "graphite data" (i.e. data derived from a pencil rather than from laboratory studies) that came to my attention. We did not report it to the FDA and the secret was kept "within the family". To the best of my knowledge, it still is. Question. Precisely what functionu does a drug firm's medical director perform in determini'ng what should or should not be said in advertising? (If the medical director doesn't have this responsibility, then who does?) Answer. About four years ago I prepared an essay entitled The Good Life of a Drug Company Doctor. It was intended for publication in a lay magazine and *in it I tried to give a distillate of my experience, in non-technical language, giving an account of both the advantages and disadvantages of such a career. In it I pointed out the doctor's function in the "review" and "approval" of ad- vertising copy as one of the disadvantages. "Drug companies boast that all advertising copy is reviewed or approved by the medical staff. Most require approval since review is pointless if the doctor has no voice in determining what is and what is not acceptable. This pos~es problems for the doctor. In the first place all advertising copy makes a mountain of paper, some of which is difficult to digest. Over-all the task is dull and boring. In addition, the doctor who does not apprOve the majority of copy that reaches his desk is not likely to keep his job. Yet over and again he is faced with ad- vertising that is obviously misleading and which he cannot approve in good conscience. The dilemma is best resolved by a bizarre process of reasoning. "Drug advertisements are never simple expositary statements; they are works of art. The artist who puts a house in his landscape does not have to draw in every brick of the wall or every shingle on the roof. A line here and there, proper shading and texture, and the mere suggestion of totality usually suffice. The eye and the mind of the viewer fill in the gaps in a manner that is predictable and therefore can be manipulated. A drug advertisement is a total composition sub- ject to the same rules. It allows considerable latitude in creating ambiguities. This, too, constitutes an obvious objection to a compendium since it would not permit this latitude. "The doctor who reviews advertising copy must learn to ask himself not whether the advertisement is misleading, but rather whether it can pass. An over-simplified illustration of what can and What cannot pass is furnished by a well known optical illusion. Two lines, exactly equal in length, can bemade to PAGENO="0204" 4494 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY appear unequal by placing arrow-heads that converge at the ends of one line and diverge at the ends of the other line. The misleading nature of this device and the predictable response are not important. If one line is labeled `effect of Drug A' and the other `effect of Drug B' it can pass provided' that the adver- tisement does not specifically state that the lines are unequal. Under these conditions the advertisement can be defended against any attempt to prove it false or misleading. Obviously that which cannot be proved false must be true and the truth cannot be misleading. The doctor who wishes to keep his job in the drug industry will find it mandatory to use this kind of reasoning. "In desperate situations what can pass can be stretched to almost infinite limits. The determining factors are the mental and verbal facility of the doctor or lawyer who must defend it. One can always escape under a smoke-screen of words and if worse comes to worse, he can admit to an `honest error' and challenge anyone to prove that there was any intent to mislead. Typical examples of these techniques are documented in the record of the Kefauver Hearings." As Dr. Goddard said in his article in Esquire: "High-priced lawyers will spend hours in conference with FDA officials, haggling over the wording of promo- tional material, engaging in semantic arguments as to whether a certain section of government regulations does or does not give FDA the right to limit the company's `freedom' in a certain area". About three and one half years after I deplored the type of advertising that leads to the chain reaction: fever equals infection equals a prescription for an antibiotic, I clipped the advertisement I have marked Exhibit #1 from the J.A.M.A. I believe it speaks for itself. To demonstrate the kind of advertising that apparently meets the new FDA requirements I have clipped tw-o advertisements from the March 19G9 issues of Medical Tribune. These are marked Exhibits #2 and #3. The difference between Exhibit #1 and #2 is only in the degree of sophistication used and that the FDA requirement for full disclosure and "balance" have been met. Nevertheless the basic technique of creating a short circuit between a sign, and symptom, a complaint, a catch-all syndrome, or a catch-all diagnosis and the name of a drug that can be written on a prescription pad is followed to the letter. Ex- hibit #2 is in extremely poor taste not only because the woman depicted in the photograph can be suffering from anything from simple exhaustion, to anemia, through chronic schizophrenia, and on to any chronic debilitating disease, but also because it is only slightly, if at all, removed from the crass television commer- cials that say she has "tired blood" and needs Geritol, or those that say she has the "blahs" and needs AlkaSeltzer. She needs careful diagnostic work-up and not a prescription for Valium t.i.d. or q.i.d. The advertisement is a total compo- sition deliberately intended to convey the impression that the "always weary" (a diagnositic category unknown to me) can be treated by writing a prescrip- tion for Valium. Exhibit #3 is even worse and probably represents the best in advertising and the very worst in drug advertising. Advertising becomes more effective as it makes a stronger appeal to the irrational unconscious needs of the reader. To imply that the extremely variable and complex psychodynamics that may lead to symptom formation or psychopathology in this critical period of many men's lives can conveniently be dropped into a wastebasket labeled "Torschlusspanik" and treated with Librium approaches criminal neglect. I know of no scientific evidence that supports this oversimplified diagnosis and recommendation for therapy. At the time when Dr. Fritz Freyhan (in the March issue of the American Journal of Psychiatry) is deploring the deficiencies in the training that even psychiatric residents get in psychopharmacology, and states that drug therapy cannot be divorced from an understanding of the basic principles of psychiatry, we have drug companies educating physicians about "Torschlusspanik." Signif- icantly these advertisements appear in the Medical Tribune and not in the Psychiatric News or the American Journal of Psychiatry of the same period. It seems that they are directed at the more unwary average practitioner. It gives him another name he can write on a prescription pad thereby increasing his concept of his own omnipotence and fostering the delusion that every hu- man problem can be solved with a prescription pad. A question that is frequently asked, and it is invaribly asked in a tone that conveys amazement and total disbelief is; "Do doctors actually prescribe on the basis of advertising?" This device was used frequently in the Kefauver Hearings and most witnesses avoided the question since an affirmative answer left one open to the accusation that he was questioning the intelligence and integrity of his colleagues. PAGENO="0205" COMPETITIVE PROBLEMS IN THII DRUG INDUSTRY 4495 I note that Dr. Annis, the AMA's official representative, conceded that the chioramphenicol-bronchoscope advertisement was a "Madison Avenue Trick." According to the New York Times Dr. Annis said you were calling doctors dolts by suggesting that they would prescribe a drug on the basis of what they had read in an advertisement. It is important to note that dolts is Dr. Annis' term and not yours. The same peculiar reversal was true throughout the Kefauver Hearings. The mere suggestion that doctors are: indeed influenced by advertising became an accusation (that they were incompetent bunglers, dolts, or both. I am not prepared to characterize the majority of my colleagues as dolts because I do not believe it is true, nor could I support such an accusation. I am willing, however, to state categorically that my colleagues are human and as human (the majority of them are influenced by advertising when they write a prescription. Most medical experts and advertising experts who have examined the question agree that advertising takes the form that is most effective. Ulti- mately advertising-and it does not matter whether it is drug advertising or advertising for any other product-4akes a form that is determined both by the rule of the survival of the fittest and a variation of Gresham's law. I have never found evidence that drug companies waste money on profitless gestures. To imply that the multi-millions spent on drug advertising is spent only because an occasional doctor will be influenced into writing a prescription is not only unrealistic; it is totally illogical. The common practice of distributing desk accessories (calendars, letter open- ers, appointment books, etc.) boldly imprinted with the name of one or more drugs is not motivated by the company's wish to waste money on useless gim- micks and gadgets. The mere fact that one of these accessories is on his desk influences the prescription the doctor writes even if the stimulus is sub-liminal. The notion that doctors study drug advertisements is absurd, and so I question the effectiveness of the "full disclosure" regulation. One "reads" advertisements by turning pages and Exhibits #1, #2, and #3 are examples of my total work of art description. If exhibits #2 and #3 are examples of "balance" then I have no notion of the definition of the word balance. The total effect of the imbalance in these ads is to negate completely any effect that full disclosure might have. Accepting the Task Force's penchant for understatement I still find it difficult to understand why, on one hand, the Task Force feels that rational prescrib- ing canno)t be achieved by rules and regulations, but seems to feel that good drug advertising can be achieved by these methods. It says, "The frequency of biased, inaccurate drug advertising has apparently been reduced since the en- forcement of new advertising regulations by the FDA began in 1967." I find the concept of unbiased advertising untenable since it is a contradic- tion. The concept of degrees of bias in drug advertising holds, for me, the same connotation as the standard joke about being "slightly pregnant." If Exhibits #2 and #3 are examples of the improvement in drug advertising, may heaven help us! The notion that "training and experience" imbue the physician with God-like qualities that make him immune to the effects of advertising is non- sense. Such a concept betrays a remarkable ignorance of the fact that (con- trary to the average patient's belief) the: physician is neither omniscient nor omnipotent. It also betrays an incredible ignorance of the psychology of adver- ti~sing. Just as advertising affects the personal purchases a doctor makes, it also influence the purchase orders he writes for his patients. It was the AMA that said :that drug advertisements are "reminders." Reminders of what? Question. We have seen, with respect to chioramphenicol, important differences in the advertising and promotion of identical products by the same company in the domestic and foreign markets. In other words, the efficacy and safety of the drug seems to vary with the person's nationality. (a) Do yon know of any other products to which this applies? (b) What do you think about it? (c) When you were in the industry, Who reviewed overseas advertising? (d) What criteria were used for domestic and overseas advertising? Answer. About four years ago I attended a professional meeting in Mexico. Because I was still entertaining the notion that I would write a book about the drug industry I decided to gather some ammunition. Marsalid had been taken off the U.S. m'arket some two years before because its danger outweighted its utility. Accompanied by an interpreter I went to a drug store and after some difficulty in giving Marsalid the proper Spanish inflection I was offered a bottle of the drug over the counter (a common practice in Mexico). Until about PAGENO="0206" 4496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1955 Squibb had only one Medical Director and his authority extended to the overseas market as well as the domestic market. This resulted in a constant source of friction between the Medical Division and the advertising and pro- motion department of the Overseas Division. The Overseas Division held not only the notion that the safety and efficacy of a drug varied with the patient's nationality, but also that the advertising and promotion of drugs depended on the nationality of the physician. Physicians in any of the countries south of the border were considered less sophisticated than U.S. physicians and a "simpler" approach had to be used. This simpler approach resulted in some rather remark- able distortions. There were many products that were sold south of the border that had become obsolete in the domestic market but I recall only one, an Elixir of Glycerophosphates that had magical tonic qualities south of the Rio Grande and was useless in the States. More frequently, the difference was in the claims made for the same drug. The real eruption occurred in about 1955 when, as I understood it, Parke- Davis had offered Squibb a license to market chloramphenicol in some of `Squibb's South American markets. (Parke-Davis apparently felt that Squibb had a firmer position in these markets and that they could realize more profit from royalties on Squibb's sales than on their own sales.) I was presented with the prospect of marketing chloramphenicol under the Squibb label making all the excessive claims for the drug and excluding a warning statement since it was not required in the countries in which sale is proposed. I refusdd to approve the tentative copy and made it clear that I would tender my resignation before I would approve the copy. Apparently my colleagues thought I was sufficiently valuable and instead of making a confrontation out of the issue they decided to use an end play. The Overseas Division appointed its own Medical Director who was in no way responsible to me. Curiously Squibb never did market chloram- phenicol, at least not to my knowledge. I do not know the reasons why. As I think back I recall one absurd proposal intended for the South American markets. It was proposed that we add to our injectible penicillin a substance that would produce the taste of garlic when it was absorbed. This, it was said, would impress the patient and would lead him to believe that he had, indeed, been given effective medication. The Medical Division did not approve it. Let me add that to anyone who believes in placebo medication and the mumbo-jumbo of the art of medicine the proposal has merit. It has no place in modern con- cepts of a science of therapeutics. To get the full flavor of the kind of jockeying that went on you must understand that during my tenure as Medical Director I used a philosophy of giving in on the smaller issues and reserving veto power on large issues backed up by a letter of resignation I carried in my pocket for almost two years. I still have it in my files and it shows obvious signs of wear. Question. Why did you leave Squibb? Answer. Since it is almost 12 years since I resigned I have had sufficient time to reconsider the decision. I cannot count the number of times the question has been asked nor the number of answers I have given. I believe that the best answer can be found in my unfinished essay on The Good Life of a Drug Company Doctor. Toward the end I said: "These are only some of the things a drug com- pany doctor must learn if he is to be happy in the industry. After all, it is a business, and there are many more things he must learn to rationalize. He must learn the many ways to receive the FDA and, failing in this, how to seduce, manipulate, or threaten the physician assigned to the New Drug Application into approving it even if it is incomplete. He must learn that anything that helps to sell a drug is valid even if it is supported by the crudest testimonial, while anything that decreases sales must be suppressed, distorted and rejected because it is not absolutely conclusive proof. He must learn to word a warning statement so it will appear to be an inducement to use the drug rather than a warning of the dangers inherent in its use. He must learn, when a drug has been found too dangerous for use in this country, he can approve its use in other countries where the laws are less stringent and people have less protection. He must learn, when a drug has been found useless on one side of the Rio Grande, it can be sold as a panacea on the other side and that he is expected to approve the claims made for it. He will find himself squeezed between businessmen w-ho will sell anything and justify it on the basis that doctors ask for it and doctors w-ho demand prod- ucts they have been taught to want through the advertising and promotion schemes contrived by businessmen. If he can absorb all this, and more, and still main- tain any sensibilities he will learn the true meaning of loneliness and alienation." During my tenure as Medical Director I learned the meaning of loneliness and PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4497 alienation. I reached a point where I could no longer live with myself. I had com- promised to the point where my back was against a wall and I had to choose between resigning myself to total capitulation or resigning as Medical Director. I chose the latter course. Actually I have never understood, completely, the reasons that Squibb did not fire me long before I resigned. While I had a magical touch with detailmen and came to be known as "Mr. Raudixin" because I engineered most of the investi- gation as well as the advertising, promotion and detailing of rauwolfla serpentina (which for many years was Squibb's biggest money maker) I was nonetheless a thorn in the side of most of my business colleagues. Part of my durability can be attributed to the fact that Squibb went through three different sets of manage- inent during the time I was with them. Nevertheless, at some time, the honeymoon would have ended and I certainly would have been fired. My successor has long since left Squibb and is in another drug company. For a time, I considered other drug companies but I rapidly learned that no one else would have me and that, even if they did, I would be jumping from the frying pan into the fire. One com- pany made it clear that the president made all final decisions including medical decisions. I could not envision myself as a yes man approving medical decisions made by a layman. Question. What do you recommend be done about irrational prescribing? Answer. This question stimulates a rush of many diverse thoughts. First, since I am neither a lawyer nor a legislator I cannot claim any competency in the draft- ing of legislation. Since I served as one of the many consultants used by Kefauver and his staff during the drafting of S. 15~2 I am influenced by the philosophy they adopted. Next, it has been many years since I became disenchanited (and from the tenor of Dr. Goddard's Esquire article I assume that, one of the reasons he left his posi- tion as Commissioner of the FDA, is that he, too, became disenchanted) with the notion that the drug industry can be restrained by legislation. To quote Dr. God- dard, "Operating on an undisclosed, multimillion dollar budget in dues paid by the companies * the PMA is able to present a united front to protect the Establishment's business interests against forays `by the public, Congress, or any of the federal regulatory agencies `~ *. The Drug Establishment functions with all the smoothness of an intricate Swiss watëh." Although I have studied drug industry practices for 18 years and have become inured to the point where nothing surprises me, I am still awed `by the amazing versatility the drug industry demonstrates. It seems impossible to write legisla- tion that does not contain loopholes through which the drug industry lawyers can slip. Although the 1962 legislation has resulted in some improvement in some areas, the brave new world it promised has not materalized. If the `slightest chink is left in the armor, the drug industry will widen it until a barge can be passed through it. The drug industry's manner of dealing with the full disclosure and balance requirements in drug advertising is an excellent example. It took 32 years to add to the primitive concepts of drug regulation, enacted in 1906, the concept of safety. At the time the opponents of the legislation claimed that a juridical definition of safety was impossible. The Elixir of Sulfanilimide tragedy salvaged the safety requirement. It:took another 24 years to introduce the concept of efficacy and again the opponents claimed that a juridical definition of efficacy was an impossibility. Had it not been for the thalidomide scandal the PMA and AMA lobbies might have won the point. A bill that had been butchered to death was partially resurrected and won unanimous approval. I do not believe that it `should be necessary to wait another quarter of a century, or for another tragedy to add to the concepts of safety and efficacy, the concept of rationality. We have reached a point where drugs, and especially combinations, must `be proved not only safe and effective but, also, rational. The opponents will claim that this too, is juridically impossible. My disenchantment with the effectiveness of legislation alone has not led me to the conclusions that attempts `to enact legislation with teeth is futile. On the con- trary I believe that there is greater need for carefully considered and extremely carefully worded restrictive legislation. Since this is not my province I can only offer guide lines based on scientific concepts and my limited knowledge of `the draftng of legislation. I have had enough experience (or perhaps insufficient experience) to comment that if we are not prepared to engage in a Gargantuan struggle. the proposal of effective legislation is a hollow gesture. We can and should try. PAGENO="0208" 4498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In the patent provisksis of the original 5. 1552, Kefauver proposed that a pat- ent application for "any molecular modification of any patented or unpatented drug or for any combination of two or more drugs" would not be granted a patent unless "the Commissioner (of patents) 0 * * determined that the change from the prior art made by the modification or combination would not have been obvious to a person having ordinary skill in the `art, and (B) the Secretary (of HEW) has determined that the therapeutic effect of `such a modification is sig- nificantly greater than that of the drug so modified or that the therapeutic effect of such drugs taken in combination is significantly greater than the therapeutic effect of such drugs when. taken separately". [My emphasis.] The legislation I have hi mind would simply substitute for patent application a new drug application and in place of granting a patent; granting a license to market. Like the efficacy provisions of the 1962 legislation I would make the legislation retroactive. In determining the definition of significantly greater therapeutic effect I would again `be guided by the definition of efficacy that ap- pears in the Kefauver-Harris Amendments of the Drug Act, "substantial evidence means evidence consisting of adequate and well-controlled investigations, incluci- ing clinical investigations, by experts qualified by scientific training and experi- ence to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly and responsibly concluded by such experts that the drug `will have the effect it purports or is represented to have under the conditions of use pre- scribed, recommended, or suggested in the labeling or proposed labeling thereof". In brief, the legislation I have in mind has already been written. Making it applicable to drug combinations requires changing a few words. I am not un- realistic enough to believe that such legislation could get past the PMA and AMA lobbies without a `Gargantuan struggle. Nonetheless it is required if we are going to `put teeth into the drug act. A valid objection that would be `raised is that prescriptions for two or more drugs would cost more. This is a moot point and we must weigh it against the fact that a combination such as `Achrocidin is prescribed for at least 10 patients who do not need it, for one who may need it and all patients pay for the anti- biiotic they may or may not need. The antibiotic constitutes the major part of the cost of the combination. The argument that rational prescribing would cost more than irrational prescribing is, in my opinion, inane and `I do not believe that it could survive in any fair debate over the issue Raising the question of the cost of drugs, I am reminded that I intended to clarify the question of whether licensing. inspection, and strict quality control would raise or lower the cost of drugs. The Task Force Report states: "Any company, large or small, brand name or generic name `producer, can institute and maintain an effective quality control program, and most companies have `apparently done so. The cost of such a program ha's been estimated to be about 2.4% of sales for a large company, but may be somewhat more for a smaller firm". The term "somewhat more" is vague but I believe we can satisfy it if we mul- tiply 2.4% by more than four times and `assume that strict quality control for a generic drug would raise its price by 10%. The Committee is aware that the spread between brand name and generic drugs can be in the order of ten times or more, but these are extreme examples. Let us take an average example with which I am well acquainted. Generic Sodium `Pentobarbital sells for `approxi- mutely $4 per thousands. In the catalogues seI~t to me (a copy of which is en- closed) by wholesale `houses the price has varied from $3.85 to $4.40. This is an umbrella price at which I can buy the drug in quantities of 1,000. The pharmacist probably pays less; he certainly does not pay mere. In the same catalogue the price of Nembutal (Abbott's brand name for the same drug) remains fixed at $17.00 per thousand. If we assume that the generic `bran'd is not qual'i'ty con- trolled an'd that the institution of quality control would raise the price by 10% we ~tlll have a figure of $4.40, or at most, $5.00 per thousand. Even an idiot can conclude that in a competitive market the $17.00 brand would `have to lower its price to meet the competition or be forced `off the market. It is conceivable that it could be reserved for the carriage trade sin'ce there are those people who auto- matically conclude that anything that cost.s more must be better. The physician who writes prescriptions for patients cannot and should not indulge in `this luxury. While the relative wholesale price of brand name drugs as compared with generic drugs is just as available to other physicians as it is to me, any attempt to translate these prices into the price the patient pays for his prescription PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4499 requires the application of an infinitely variable constan$t. I almost invariajdy wr~te generically (I must confess thsit about 50% of the time I am able to con- vince myself that writing Trifiuoperazine instead of Stellazine is a pedantic exercise that accomplishes nothing since only the patented version of the drug is available). Since I write relatively few prescriptions, I can take time in the 5~ minutes I see each patient to have him bring in the filled prescription and determine whether it has been filled by a brand name or a generic drug when I have prescribed generically and a generic brand is available, and inquire who filled it, and how much it cost. The pharmacists cost for 30 capsules of Sodium Pentobarbital is in the order of 12 cents whereas his cost for 30 capsules of Nembutal is about 52 cents. The most frequent practice is to fill a generic pre- scription for Sodium Pentobarbital with the brand name and to charge accord- in~gly.. Some pharmacists who fill it with the generic brand charge $1.15 indicating that they can meet the cost of overhead and make a profit by charging slightly over $1.00 to fill the prescription. When the prescription is filled with the brand name the price varies from $1.85 to $2.25 and he charges between $1.3t~ and $1.7~ to fill the same prescription for the same drug with the brand name version of the drug. To take another more extreme example, we can use imipramine (Tofranil). This is a commonly prescribed antidepressant. which is patented and no generic equivalent exists. I frequently write a prescription for 100 fifty milligram tablets. The umbrella price for me is $105/thousand. The pharmacist probably pays $100/ 1.~00O ($liO/100) or less. Yeit the patient's cost for a prescription for 100 tablets ranges from $15 to $20. These are figures given to me by my patients. Curiously the drug comes prepackaged in quantities of 100 tablets (which is part of the eeason I prescribe that quantity). The pharmacist needs only to affix a pre- scription label to the bottle; yet he charges from $5 to $10 for this service. I was pleased when I read the testimony of Dr. William S. Apple, Executive Director of the American Pharmaceutical Association, and found he among others, questioned the equity of the present mark-up system and recommended a fixed fee system. Until such a system becomes the standard practice of pharma- cists, the physician is completely in the dark and the actual price the patient will pay for `his prescription is unknown. I Strongly urge that a fixed fee system replace the variable and unpredictable system Of a mark-up which is subject to the whims of the individual pharmacists and is based on the concept of what the traffic will bear. A fixed fee system would bring order and sense into the price that patients pay for a prescription. It seems that the practices of pharmacists are fully as subject to investigation as the practices of the drug industry and the medical profession. All of the causes of the high price of prescription drugs cannot be laid at the doorstep of the drug industry. Question.. Do yon have any other suggestions besides legislation to solve the problem of irrational prescribing? Answer. Like Dr. Goddard I, too, am at my wits end in trying to come Up with a reasonable solution to the problem of irrational prescribing. As I have indicated., I believe new legislation regarding irrational combinations can serve as the first step. Beyond that I would tend to combine suggestions made by others at different times. Dr. Goddard spoke of Therapeutic Committees but was extremely fastidi- ous over the matter of interfering with the practice of medicine. I can understand his reluctance since he was in a very sensitive position. The antagonism of the average practitioner toward the FDA hardly needed fanning `by Dr.' Goddard. I do not know if some hospitals call their Formulary Committees Therapeutic Committees. Dr. Goddard's suggestion, as I understand it would model Thera- peutic Committees along the lines of Tissue Committees which, I believe, are essential if .a hospital is to get accreditation. There was a time (and to a much lesser extent there still is) when some surgeons made a practice of removing organs from the body, not because the organ w-as diseased and required removal but, rather, because the surgeon needed a fee. I do not remember the exact chronology but there was a time when un- necessary operations became a cause celebre which received much publicity. Whether the formation of Tissue Committees preceded or followed this I ani not sure. In any case, the function of a Tissue Committee is to examine the pathological reports on organs removed in surgery. The surgeon who makes more .than his share of honest errors soon comes to the attention of the Tissue Committee and he may be censured or even lose his hospital privileges if he continues to indulge in the practice. 81-280 0-69--pt. 11-14 PAGENO="0210" 4500 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Again, as I understand Dr. Goddard's suggestions, Therapeutic Committees would review the doctor's prescribing habits just as Tissue Committees review his surgical habits. The task will be much more difficult than reviewing patho- logical reports on organs but just as the uterus and the appendix are prime targets for Tissue Committees certain prescribing habits would similarly become prime targets of Therapeutic Committees. There is another suggestion made first (I believe) by Dr. Barbara Moulton who was formerly with the FDA. Dr. Moulton suggested a special category for drugs that were hazardous and tended to be over-prescribed. She suggested that a prescription for such a drug would not be permitted without the approval of a consultant. I believe the idea has merit and should be given further consideration. The FDA should be given authority to form a category of "Dangerous Drugs". Supplies and prescriptions for these drugs would be handled in the manner that now holds for narcotics. These would be target areas for Therapeutic Commit- tees but could also be spot checked by FDA inspectors. Since it is impossible to anticipate every contingency I would not insist on a consultation and allow emergency prescription when approval by a consultant or by a Therapeutic Committee would, because of time involved, not be in the best~interests of the patient. The doctor should know, however, that when he prescribes such a drug in an emergency and without approval, he may, if he cannot justify its emergency use, expose himself to censure, loss of hospital privileges, or in cases of repeated offenses, suspension of his license. Offhand I think of only two drugs I would place in that category, chlorampheni- col and .tranylcypromine (Parnate). There probably are others and there cer- tainly will be others in the future. I am dubious about the possibility that the medical profession would adopt this method of self regulation voluntarily and it is possible that irrational prescribing will have to become a cause celebre and that publicity might force its adoption. If Congress gave the FDA authority to form a category of "Dangerous Drugs" the remaining steps would almost cer- tainly have to follow. In summary, irrational prescribing can be reduced by legislation requiring that a drug combination be rational as well as safe and effective; by steps that would lead to the formation of Therapeutic Committees, by the creation of a class of "Dangerous Drugs", and by publicity, publicity, and more publicity. Question. What are your feelings regarding a Compendium? Answer. I know that the Committee and the FDA are enthusiastic about a compendium. I wish I could share the enthusiasm. The tenor of my prepared statement makes it clear that I would favor anything that leads to more scientific practice of therapeutics and takes the black magic out of medical practice. A compendium would be a step in the right direction. The task of preparing it would be monumental, and it would have to be encyclopedic in scope. My doubts are raised not by its scientific value but by the reception it would get from the average practitioner who needs it most. Like the Medical Letter it would be used by those who are already skeptical and have less need for it. I enclose a clipping from Medical World News dated January 31, 199 and which I have marked as Exhibit #7. When the President of the American Academy of General Practice was asked about the compendium hi~ reply (according to MWN) was he "* * * would not want a new drug compendium to be put out by the government because it w-ould be `garbaged up' by all the material the FDA requires". It is difficult to determine how one should respond to this statement of principle. We can hope that it expresses the views of an individual rather than the official views of the Academy over which he presides. The hope is probably a vain one since a negative response to a compendium is essentially the party line handed dow-n by the PMA and the AMA, and is the response one should expect if he has any knowledge of the thinking of the average practitioner. Probably the greatest fault of the average practitioner is his inability to understand and to admit the limits of his ow-n competence. The secure physician who is confident about the knowledge he does have is much more ready to admit that he does not know- everything, and that there are areas where he needs help. Such physicians would probably welcome a compendium that would help them to find their way through the drug jungle. As the average practitioner becomes more hurried, more harried, and more confused, the gap between w-hat he does know and what he does not know widens and his inability to admit the existence of such a gap increases. An admission that he does need a drug compendium becomes a tacit admission that up to this time he has been groping in the dark. PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4501 In addition, it is. important to be aware of the exalted position the physician has in the lives of his patients. While many patients have become disenchanted with the AMA, organized medicine, etc., most still cling to the impression that their personal physicians are both omnipotent and omniscient. This is under- standable since it insures that the doctor will be better able to help the patient in the time of his need. Unfortunately many physicians enter into the fantasy entertained by their patients and fulfill their own infantile wishes to be omnipotent and omniscient. The average physician is not about to step off the throne that makes him God. A compendium will still be a legitimate educational tool and it will have to compete with Madison Avenue tricks. It would be more likely to be successful if we could fill it with free gifts, gimmicks, and gadgets, and in the long run, we may have to learn Madison Avenue triëks which will give us some chance of beating the drug industriy at its own game. STATEMENT OF DR. DALE CONSOLE AT THE KEFAUVER HEARrNGS, 1960 I wish to introduce this statement by making my position clear. I am here by invitation and assume that invitation was extended to rue because it was felt that my experience as a former Medical Director in the pharmaceutical indus- try would enable me to assist this committee in its work. I am not here as a witness against the firm with which I was associated. Since I destroyed the records in my private file when I resigned from. the industry, I can offer nothing which can be construed as proof. I can offer a distillate of my experience and the opinions I have formed as a result of that experience. These are opinions and are intended to serve only as guides. There is a simple maxim, I learned from detailmen, which is known to most if not all in the pharmaceutical industry. "If you can't convince them, confuse them." This is a valuable tool in the industry and I have seen it in operation as a guide to detailing as well as to other forms of advertising and promotion of drugs. It operates in what Dr. Lasagna has so aptly called the "numbers racket" with its never-ending barrage of new products, confusing names, conflicting dosage schedules and indications, claims and counter claims. I have seen it in operation here in statements made by industry spokesmen. Part of that confusion arises from. the unqualified use of the term "drugs". Not all drugs are the same arid unless we understand this we cannot understand each other. For our purposes I would classify drugs roughly in four categories: 1. Effective drugs prescribed only for patients who need them. 2. Effective drugs prescribed for patients who do not need them. 3. Drugs from which all patients derive either no benefit or no more benefit than would be derived from an inexpensive substitute. 4. Drugs which have a greater potential for harm than for good. These are all products of the pharmaceutical industry and it should be clear that the cost of drugs cannot be measured by price alone. When a patient pays for a drug which he does not need or for one from which he derives no benefit the cost is excessive regardless of price. To assume that all drugs fall into the first category and to concentrate on lowering the price of a broad spectrum antibiotic pill from sixty cents to fifty or even to forty cents is to miss the point. If we include everything from research cost to the salary of the detailnian the total cost of creating, producing and selling drugs in the last three categories exceeds that of effective drugs properly prescribed. Unfortunately drugs are not always prescribed wisely, and while the physician and patient, among others, must share the responsibility for this with the pharmaceutical industry it is the industry which carefully nurtures and en- courages the practice. The incidence of disease cannot be manipulated and so increased sales volume must depend at least in part on the use of drugs unre- lated to their utility or need, or in other words, improperly prescribed. Human frailty can be manipulated and exploited and this is fertile ground for anyone who wishes to increase profit. The enormous sales of so-called tranquilizers are only a small part of the crop reaped from this ground. The pharmaceutical industry is unique in that it can make exploitation appear a noble purpose. It is the organized, carefully planned, and skillful execution of this exploitation which constitutes one of the costs of drugs which must be measured not only in dollars but in terms of the inroads the industry has made into the entire structure of medicine and medical care. With the' enormous resources at its PAGENO="0212" 4502 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY command it has usurped the place of the medical educator and has effectively substituted propaganda for education. It is generally accepted that after the average practitioner leaves medical school the drug industry represents the most potent influence determining many aspects of how he practices. In its desire to create a favorable image the industry confirms this when it justifies the enormous expense of advertising and promotion by claiming that it serves the purpose of postgraduate medical education. Now some of the effects of propaganda and education are identical, but to conclude that drug advertising and promotion in education is one of the many fallacies intro- duced into these discussions. Perhaps the committee will get a better understanding of this euphemism if we examine some aspects of it. Since I wish to describe practices which apply to many products and most if not all companies, I shall make my examples general and slightly hypothetical. Since I cannot name them all it would be unfair to brand the one named in the example. I can assure you, however, that the disguise is so thin and the practices so w-idespread that there will be no difficulty in finding adequate promotional material to document them. First an extremely simple example. While in medical school the physician is taught; when the patient has a fever, determine its cause, and then treat it accordingly. The drug brochure teaches: when the patient has a fever think of-and here the name of a company's antibiotic follows. (See Exhibit 1 re a thermometer and erythromicin.) There are many variations on this theme and often the symptom and name of the drug appear in bold colored type to elimi- nate the effect of any intervening words. One need only change the symptom [or sign] and the drug to multiply the examples. To help drive this valuable lesson home in one promotional program a free clinical thermometer was sent to physicians. The invitation is delightfully tempting. Too many physicians, pressed for time, would like to believe that medicine can be practiced with a thermometer and a bottle of pills. The authority of the w-ritten word driven home by repetition is often enough to tip the balance. The exercise of judg- ment takes far more time and uses less drug. If this is education then we should also include lessons on how to smoke an opium pipe. This approach is used only by the more naive since it does antagonize some physicians. It hardly does justice to the ingenuity of the more experienced drug house. A better approach is one which is used frequently in the promotion of so- called tranquilizers, but with minor variations spreads to many other drugs. Either in the course of legitimate investigation or in the search for a new promotion device it is found that a drug which is claimed to be effective in relieving anxiety, produces, in rats, specific objectively mensurable changes in a particular area of the brain. Now this is an interesting truly scientific finding but in the present state of our knowledge its significance is unknown. To the promotion people this lack of significance is unimportant since it is both in- triguing and impressive. It is presented in an advertisement or a brochure com- plete with accurate anatomical illustrations of the brain beautifully executed in vivid colors. This is coupled with the claim that the drug relieves anxiety. The usual response of the average practitioner who is not, and is not expected to be, an expert in neuro-physiology is to associate the two and to assume that they support each other. To the expert, however, any attempt to relate the claim and the ftnding is absurd since there is no known relationship between human anxiety and this finding. It is no more absurd to relate the claim to this finding than to the finding that the drug, when given to cats, makes their tails curl up and form a square knot. The latter is obvious, the former is not. Be- cause it is not, the impressive but irrelevant fact is carefully presented in vivid form. The clarifying facts are equally carefully omitted. The desired effect is achieved by encouraging false associations and the frequency with which this approach is used is adequate evidence of its success. This, too, is called education. Another example makes good use of the confusion technique. When the novelty of more potent vitamin pills began to wear thin, someone conceived of adding minerals and trace elements. Among these is zinc and since I am not an expert on zinc it may not be significant that I know of no evidence of zinc deficiency in man. If, however, one searches the literature long enough he will find that when chickens are deprived of zinc they cannot form a hard shell on the eggs they lay. When this curious fact is added to others similarly curious and mixed with some which are significant one ends up with an impressive array of "cvi- dence" for the rationale of the product being advertised and apparent reasons PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4503 why the doctor should prescribe this mixture of vital ingredients. Now let us look at only one of the facts which are carefully omitted. No mention is made of the fact that the zinc deficiency can only be produced by extremely careful and expensive purification of the diet. Every trace of zinc must be eliminated and if the chickens get only an occasional meal by random pecking in the barn- yard they obtain enough zinc to destroy the effect. In short, the deficiency is a laboratory artifact and has no counterpart outside the laboratory. Or stated differently, if one is to draw logical conclusions the zinc makes the vitamin pills invaluable for laboratory chickens provided, of course, that one is willing to go to the expense of purifying their diet. Here the physician is bludgeoned with a barrage of irrelevant facts he has iieither the time, the inclination, nor frequently the expert knowledge to examine critically. Multiply this by a dozen detailmen each selling a dozen products and backed by a dozen wizards in the home office who hold a dozen conferences trying to determine the best way to make nothing appear like a pot of gold. This, too, is called post graduate medical education. But let me turn to the practice which forms the backbone of all advertising and promotion of drugs. This is the use of the testimonial as scientific evidence of the efficacy of drugs. It was a practice in the Middle Ages for some people to wear suspended from the neck a cloth bag filled with asafoetida. The foul smell was believed to ward off plague. Apparently someone had observed that some people who used this medicinal fetish did not contract plague. Either it was not observed or not con- sidered important that some who did not use it also did not contract plague. Since it is considered unscientific the practice has long since been abandoned. But it flourished a long time simply because it gave some people a greater sense of security and made them feel better, at least until they contracted plague. While the practice has been abandoned the principle which determined it re- niains with us essentially unchanged. Since the beginning of time men have stumbled over the meaning of the simple fact that when something is done for or to a person, especially if that something has magical or emotional significance, that person frequently feels better. At the *present time it is better recognized but still poorly understood. It has been given the unfortunate title placebo effect. Similarly since the dawn of time men have stumbled over the error of attribut- ing to various agents the ability to ward off or to cure disease without taking into account what happens to those who do not get he benefit of the agent. This practice was not abandoned in the Middle Ages and one need only examine any current medical journal to find examples of it masquerading as science. Since the committee has had adequate exposure to the controlled study, the double blind, and the placebo, I shall not take the time to expand on this. Let me emphasize that no drug study is fool proof, but that the scientific validity of any study can be immeasurably increased by proper experimental design. (A drug trial which makes no allowance for placebo effect, and which fails to make accurate comparison with an untreated group is suspect, and the vast majority of reports on such studies are simply testimonials, not scientific evi- dence. A testimonial written by a doctor, even when it is given the additional cloak of respectability afforded by publication in a scientific journal, is still a testimonial. It has no more scientific validity than the opinion expressed by the woman who caught the largest tuna on record, that a certain brand of cigarettes are kind to the throat even when it appears in color on the back cover of a maga- zine. Yet the claims for the efficacy of an amazing number of modern drug products are based exclusively on this type of evidence. Testimonials are used not only to give apparent substance to the advertising and promotion of relatively worthless products, but also to extend the indica- tions of effective drugs beyond the range of their real utility. They appear either as complete reprints or as priceless quotations in advertisements or brochures. They convince too many physicians that they should prescribe these drugs. Now the true nature of these testimonials is well known to the industry and its own contempt for them is shown by its vernacular for sources from which they are easily obtained. These are called "stables". Still it is an important function, usually of the medical division, to send representatives with generous expense accounts to all `parts of the country searching out these sources. The burlesque is compounded `by calling the drug trials "scientific studies" and `by supporting them with grants which are charged to research cost.] PAGENO="0214" 4504 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (These are some of the techniques used in this travesty of medical education. While not all drug advertising and promotion is of this type, too much of it is. Some is educational but there is ample evidence to indicate that the industry is only too ready to depart from its self-professed role of the Knight in Shining Armor totally `dedicated to Science and the Healing Arts. These practices and others more vicious such as the subtle persuasion to use indiscriminately drugs (such a chloramphenicol) which are dangerously *toxic and indicated only in selected desperately sick patients suggest that dedication is primarily to profit, even at the expense of good medical care.] While the industry's practices and policies in advertising and promotion `are necessarily exposed for examination, this is not true in most other areas. Here the camouflage of euphemisms and self-proclaimed virtue is not so easy to pene- trate. Research is a good example. `While the industry spokesmen w-ould have us believe that all research is on wonder drugs or better medicinal products this is no more true than the eu- phemism of post-graduate medical education. They stress that there are many failures for each successful drug. This is true since it is the very essence of re- search. The problem arises out of the fact that they market so many of their failures. Between these failures which are presented as new drugs and the use- less modifications of old drugs (the addition of zinc to vitamins is a good exam- ple) most of the research results in a treadmill which moves at a rapid pace but goes nowhere. Since so much depends on novelty, drugs change like women's hem- lines and rapid obsolescence is simply a sign of motion, not progress as the apolo- gists would have us believe. There is an interesting relationship between research and `advertising and pro- motion. In many companies there is considerable `antagonism since the advertising people feel, with justification, that they are expected to do what research cannot. The perennial cry is "if research would give us a good drug we could turn out a really good promotion program". Actually they `do remarkably well with what they get. Lacking facts which are convincing *they invent fictions which are confusing. I am only slightly amused by the breast beating, statistics juggling, and com- parisons with the research costs of other industries. Even the statistics are suspect since I wonder how many cigarette companies charge the cost of paid testimonials to research rather than advertising. I doubt that there are many other industries in which research is so free of risks. Most must depend on selling only their successes. If an automobile does not have a motor no amount of advertising can make it appear to have one. On the other hand, with a little luck, proper timing, and a good promotion program a bag of asafoetida with a imique chemical side-chain can be made to' look like a wonder drug. The illusion may not last, but it frequently lasts long enough. By the time the doctor learns what the company knew at the beginning it has two new products to take the place of the old one. This, too, is well recognized' and in some companies calls for casuistry of a high order. In others it is simply called a "business decision". While I doubt that it actually does, with this advantage, the pharmaceutical industry can well afford to spend more on "research". For those who are interested in comparisons I would suggest examination, not of prices, but of the advertising and promotion of identical products by the same company in its domestic and foreign markets. This will proba~bly reveal the rather remarkable fact that the efficacy of some drugs varies according to the position of the Rio Grande. Now I am more aware than most of the worthwhile contributions of the industry, especially since it was my privilege to play a small part in some of them. I have no wish to minimize them, nor to deny the apologists their right to exaggerate them. To imply, however, that these contributions make up *the total, or even the major effort in research, or in other endeavors, is gross distortion. At this point let me remind you of an old French proverb which states "There are more buyers than sellers". The victim of exploitation is a victim only because in being exploited he serves some purpose of his own. A brief examina- tion of the other side of the coin gives a better understanding of the nature and scope of the problem. The physician is human and his medical degree does not change this. Since he likes to believe that he helps his patients the wish fulfilling phantasy of the PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4505 pill affects him as well as his patient. One need only observe the reactions of many physicians or being exposed to valid evidence de~unking a pill they have been using with the delusion of confidence. These vary from mild denial and disbelief to irate protest and one is reminded of the varied reactions of children on being told that there is rio Santa Claus or of adults on learning that TV quizzes are frauds. Keeping up with the voluminous medical literature is an enormous task, and the busy practitioner is forced to neglect it to an increasing degree as his practice increases. Many feel guilty about this. They can read the condensed and pre-digested pap of drug advertising and promotion in the same time it takes to throw it in the waste basket or get a five minute education in the latest advances in medicine from the detailman. It is not surprising that they enter into a folie a deuce and foster the delusion of advertising and ~promotion as postgraduate medical education. The patients contribute their share. Too many are unable to accept that the physician in spite of his limitations is still best able to determine the proper treatment. The best doctor is not necessarily the one who gives a shot for every complaint, and the more conservative physician who does not prescribe the latest drug reported in Coronet may be far more competent than the one who does. But fear of disease did not end with the plagues and patients still seek their bag of asafoetida. It is this anxiety which leads some to avoid black cats, and most to seek newer, stronger and more impressive magic from the doctor. Too many physicians respond to this pressure not by dealing with it directly but by trying to produce ~i. tangible symbol of the magic. To the pharmaceutical industry this is an open invitation to exploit both the patient and the doctor, and so it claims to have the magic all wrapped up in pretty packages and with a price tag which makes the magic all the more impressive. The simple fact that anxiety is virtually impossible to evaluate objectively and that it responds to almost any bag of asafoetida accounts for the market in the so-called tranquilizers. In modern times the anxiety is stirred up not by an epidemic of plague but by advertising and promotion, and the meteoric rise of one of these drugs was not deterred by the early appearance of two lengthy testi- monials, back to back, in the Journal of the American Medical Association. This leads one to wonder what motivates editors to accept these articles which do not merit publication. Since they do not accept every paper which they receive they cannot hide behind their usual protest against censorship. Perhaps they are unaware of the damage which can be done by the cloak of respectability they lend and how well they serve the interests of the pharmaceutical industry to whom these atrocities are like manna from Heaven. I do not know if paid advertising influences this. I have a better notion why public platforms ostensibly dedicated to the dis- semination of scientific information are turned over to drug companies to launch programs of obviously biased drug promotion under the guise of scientific sym- posia. Even the platform of a government agency has been perverted to intro- duce, on the flimsiest evidence, a new drug which later came under the fire of the Federal Trade Commission. In this case the abuse was so flagrant that it aroused effective protest from a small group of indignant merical educators. This latter phenomenon is so rare that one must wonder about the responsi- bility of the leaders and educators in medicine. Most face the problem~ with denial, complacency, or a sense of futility. Perhaps *this is understandable in the light of the fact that the industry alone commands the resources necessary to make propaganda effective. How can legitimate education compete with the philosophy of the opium pipe and the carefully contrived distortions driven home by the trip-hammer effect of weekly mailings, the regular visits of the detailman, the two-page spreads, and the ads which ~ippear six times in the same journal, not to mention the added inducement of the free cocktail party and the golf outing complete with three golf balls stamped with the name of the doctor and the company in contrasting colors. While I feel that restrictive legislation is necessary to curb the excesses this is a partial answer at best. In all areas relating to the healing arts vulnerability and the facility and temptation to exploit it are so great that self-imposed restraint has always been considered a necessary prerequisite. If the industry could prac- tice this instead of proclaiming virtue we would have the ideal solution. I am un- aware of any tendency in this direction and the internal problems in the industry PAGENO="0216" 4506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY are such that I see little hope for it. Rules of conduct are laid down but they are intended only `as public relations gestures and their force is apparent rather than real. The older, well established, conservative houses once did resist many of the abuses. However, the entry of newer, solely profit-oriented competitors has encouraged an ever-increasing substitution of the more profitable practice for the ethical, and all firms have found themselves under increasing pressure to adopt the practices in order to survive. One can no longer think of pharmaceutical houses as black or white. All are shades of gray and while some are almost black none to my knowledge is white. In this setting it is difficult to conceive of en- forcement of rules of conduct from within since one hesitates to throw stones when his own house is made of glass. Participation in intra-industry meetings will convince anyone of this. It is my conviction that unless sweeping reforms are instituted a truly ethical house cannot survive in the present competitive wrangle. The pressure for those reforms will almost certainly have to come from without. An intelligent program of education should l~elp but it is well to remember that it generally takes several years of intensive analytic treatment to signifi- cantly alter one's belief in and need for magic. The abdication of leaders and educators in medicine is disturbing. Post graduate medical education is their province, not the pharmaceutical industry's. Unfortunately, I can contribute far more to a definition of the problem than to its solution, and I am not unapprecia- tive of the potential of the adversary they face. There have, however, been en- couraging moves by courageous medical educators to ascertain and disseminate unbiased information on drugs. Unfortunately, the principal audience for this information consists of those who are already skeptical. There are far too many physicians who must still be taught the difference between a free golf ball, the magnetic personality of a detailman, and a scientific fact as criteria for the evaluation of a drug. It is of interest that the industry generally shrugs off these moves since experience has taught that they do not affect its best customers. Finally, I suggest with hesitation the consideration of a central agency em- powered to approve or to disapprove the sale of drugs on the basis of objective evidence of efficacy and to ban misleading and ambiguous advertising and pro- motion. I recognize that it will be virtualiy impossible to set up proper criteria but there are some areas where it is better to be guided by the dictates of good common sense rather than tortured legal constructions. It is a curious fact that as things stand now proof of the efficacy of a drug, to which some scientific rules can be applied, is governed essentially by the rule that anything goes if it cannot be shown that it probably will kill too many people who take it. On the other hand, a drug claim which is obviously misleading must be proved so by a process requiring the mental gymnastics of an insane philosopher. Surely a panel of experts, who can distinguish between privilege and license, charged with the responsibility for protecting medical care can make these decisions better than someone who has something to sell, `and who simply makes ~"business decisions". I cannot believe that a distraught mother whose infant lies desperately ill faces the same problem and emotions that she does in selecting a cereal from the Super Market shelves. While the physician is interposed between the patient and the drug industry there is a chain of responsibility and each member must accept his share. Drugs are a part of medical care and medical care has unique requirements. If the industry cannot exercise the necessary restraint it should not be free to exp~loit the privileges. It is this the industry fears most since so much of its sales volume is dependent on exploiting the privilege and since it recognizes the danger of being hoist by its own petard. I know of nothing more likely to generate the pressure necessary to persuade the industry to clean its own house. PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4507 EXHIBIT 1 [From the journal of the American Medical Association, Sept. 21, 1963] 0 sign symbol of of infection? therapy! Ilosone is better absorbed-It provides high, long-lasting levels of antibacterial activity-two to four times those of other erythromycin preparations-even on a full stomach. Ilosone is bac- tericidal-It provides bactericidal action against streptococci, pneumococci, and some strains of staphylococci. Ilosone activity is concentrated-It exerts its greatest activity against the gram-positive organisms-the offending pathogens in most common bacterial infections of the respiratory tract and soft tissues. Usual adult dosage: 250 mg. every six hours, In summary: Ilosone is an antibiotic indicated in infections caused Gastrointestinal disturbances not enunciated with hepatic effects by micro-organisms sensitive to erythromycin, especially strepto- are observed in a small proportion of individuals as a result of a cocci, staphylococci, and pneumococci. Even though llosone is local stimulating action of the medication on the alimentary tract. the most active oral form of erythromycin, the incidence of side- cutaneous manifestations of hypersensitivity may be observed effects is very low. Infrequent cases of drug idiosyncrasy, mani- occasionally; maculopapular skin eruption or urticaria has been tested by a form of intrahepatic cholestatic jaundice, have been noted in less than 0.5 percent of putients. In eotremely rare in- reported. There have been no fatal or definite residual effects. stances, anaphylaxis has occurred with erythromycin therapy. Ilosone® works to speed recovery Erythromycin Estolate . I ~ I Additional information available upon request. Eli Lilly and company, Indianapolis 6, Indiana, _____________ PAGENO="0218" 4508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EXHIBIT 2 [From the Medical Tribune, Mar. 6, 1969] \TaliUnr(diazepam) helps relieve psychic tension with associated depressive symptoms &ftttt ptttt~ibittg, pI,ts, tttttttttlt tttt~p!ttt, pttttdttttt itfttt- tttttitttt, tttttttttttyttftthitth ftflttt: Ittdk~titt,ts: Ttt'tittt tttd ttttti,ty ttttttt; ttttttttit pititttt tthkb ittt,~tt tf , tttitttttl fttttt,,; pty- th,tttttttitt ttttttt tt,tttif,tttd by ttttt,itttt, tttttittty, tpptttt- h,tttit,,, ftttigtttt, dttp,ttttttittt ty~ptttt,t tgiwltttt; ttttitttt, t-ttt,tttt, d,lfritttt, ttttt,ttttt tttdhtll tttit dttt tt t~ttt, tIttthtl ttitbd,tttt1; tdjtt~ttittt1y it, tkttl,tttl tpttttt d tt,,fly, tpttttt tt lttttI ptthtltgy, tptttidty tttttdbyttpptt~,ditttttdttthtttttit,ttiff- ditdttt(ttttfttlttthtt,tpy). c,~i,dlcttt,d: Kttttt, hyp,,,ttttititity ttt thtt dtttg. Cbildtttt ttt,d,t 6 ttttttt,ht ti tgtt. Attttt W~tt6ttgtt: Ntt ti ,th,, itt p,ytbtw p~tttt,t. Cttttitttt tgti,ttt httttt,dtttt pttitttt t,qttith~g tttt,plttttt tttttt,ttl Wbtt, t,t,d tdjtttttttitdyi,, ttttttt,ltit, &ttttd,ttt, ptt,tibility ti itt,ttttt, it, fttqttttttty ttd/ tttttity tf gttttd ttttl ttti:ttttttt tttty tttptfrtt ittttttttttd dtttttgt ti ttt.tt- dt,dttt~tttt1tditttitttt;bptttithdtltt,tybt ttttttittt,d ttith tttttptttttty ~ttti,, fttq ty ttd/t,t ttt,i~tftti:tttt.Adt-ittttgttitt1tttttttitgttttittt ti tkthtI tttd ,,thttt CNS dty tttttttt. Witbdttttl tyt,p- b.ttttt ttttttttd ftlltttitg tbttpt dittt~ttttttt. Ktttp tddit6t *p,ttttt i itidttlt tt,dtt ttt,,ftl tt,t'til- bttttttt tf thttitt ptttditpttitit,t tt htbittttittttttd dtptttdttttttt1,, p,tyttttty, 1tt6ttt ti tbild- bttttitgtgt,ittighpttttttitlbtfittgtitptttibltthtttttd. Pt,ttttt6tt,ts: if cttttbitttd ttith tthtt ptythttttpitt ttttitttttltttttt,tttidttttttt,ftllyphitgytftgttttt tt,pitytd. Uttti pt titttt ittditttttd ittpttittttttt,ttttiy dtpttttttd, tt ttith itt,ttt dtptttttittt, tttith tttiddtti dtttti,t. Obt,tttt tttttti pttt ttitttt it, itttptittd ,tt,ti htpttit f,,,,ttit,,. Li,,,it dtttgttttttttilttt tlf,t6tt itt ,ld,,lyttdd,biIi,tttttdttptttdtdtttttttittttttttttttdttittt. Sidtt Effttttst D,tttitttttt, ttt,tftttit,t, dipltpitt, hyptttttt- tit,t, tbtttgtt itt libidt, ttttttttt, fttigtt~, dtpttttittt, d0- t,th,it, jttttdkt, ,ki,, tttth, tnttit, tttttttipttittt, h,td i,ttttttitttttttt, thtttgttt it, tttiittttit,t, tht,,ttd tptttth, t,tttttt, ttttigt, t,,itttty t,t,t,tittt, bltt,,td ,`itittt. Ptttt- dtttitti t,tttit,tt t,tdt tt tt,ttt hypttttttitttd ttt, ttttti- ttty, htllttit,ttitt,t, i,,t,tttttd tt,tttdt tptttitity, i,ttt,ttt,it, ttgt, tltttp ditttt,btt,tttt, ttit,tttittit,t, htttt btttt tttptttttd; thttld thttt, tttttt, ditttt,,6t,tttt d,ttg. ittitt,d tttptt-tt tf ,tttttttptttit, jtttttditt; ptti t,~tt,t~ tdit blttd ttuttt ttd 1it~ ~~Roche ftt,,ttit,t tttttt tdtittbl, d,tt- L_J.~J.t~ttt,t,ttt itgitt,g-t,tt,tthttttpy. Psychic support for the "always weary" When psychic tension is the reason for chronic fatigue, Va1ium~ (diazepam) can help provide the right kind of support. In proper maintenance dosage, Valium calms the tense, tired patient while seldom dulling the senses or interfering with functioning. The patient thus may be better able to cope with stress, and retum to a more relaxed mental state with energy enough to enjoy the day. And whenever psychic tension. is the reason for insomnia, Valium n~ay be helpful. An h.s. dose added. to t.i.d. regimen can provide just the right amount of relaxation needed for natural sleep. PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4509 EXHIBIT 3 [From the Medical Tribune, Mar. 10, 1969] a victim of ~o~j~1u$pani11 **, PAGENO="0220" 4510 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Librium (chiordiazepoxide HCI) 5-mg, 10-mg, 25-mg capsules Torschlusspanik. For one patient, it may begin on the day somebody else gets the promotion he thought was "his." Suddenly, he realizes that he's gone as far as he's.going to in the firm-and that he's reached an age where ob-switching is both difficult and risky. With mounting panic, he takes stock of himself, How little, he reflects in dismay, he has actually accomplished in his life so farl And now-time seems to be running out.,. The intense anxiety typical of such a "middle-aged crisis" may not always be overtly expressed. In many individuals, anxiety may manifest itself as a functional complaint or through such anxiety-linked symptoms as insomnia and unexplained fatigue. Anxiety can also con- tribute to some of the organic diseases commonly seen in middle-aged men-diseases such as duodenal ulcer and hypertension. But no matter what form the patient's anxiety may take, it can usually be relieved with adjunctive Librium (chlordiazepoxide HCI). Librium has a prompt calming and antianxiety effect that helps reduce emotional pressures and relieve psychogenic symptoms. Feeling calmer and more in command of himself, the patient is often able to consider his problems more objectively and to cope with thedi more capably. For the anxious middle-aged patient, Librium: quickly relieves anxiety-Librium, by its prompt and reliable antianxiety action, usually helps relieve immediate emotional distress and encourages cooperation in required diagnostic and therapeutic procedures. helps improve response in psychophysiologic disorders-Librium, by reducing excessive anxiety and related symptoms, often proves a useful adiunct to primary therapy whenever anxiety contributes to or exacerbates gastrointestinal, cardiovascular, musculo- skeletal, gynecologic or dermatologic disorders. seldom impairs mental acuity on proper maintenance dosage-Librium, on proper maintenance dosage, generally relieves excessive anxiety without impairment of mental acuity; therefore, it is usually suitable for ambulatory patients. helps break the anxiety-insomnia cycle-Librium, in an additional h.s. dose, can help relieve the patient's anxiety-induced insomnia. has wide margin of safety- Librium, after more than eight years' use, continues to demonstrate an impressive record of safety. In general use, the most common side effects re- ported have been drowsiness, ataxia and cpnfusion, particularly in the elderly and debilitated, (See prescribing information,) Before prescribing, please coosolt complete product in- formation, a summary of which follows: Indications, lodicated when anoiety, tension and appre- hension are significant components of the clinical profile. Contraindications: Patients with known hypersens:l:vity to the drug. Warnings: caution patients about possible combined effects with alcohol and other CNS depressonts. An with all ctts-acting drugs, caution patients against hazardous occupations requirirg complete mental alertness leg., operating machinery, drivingl. Though physical and psy- chological dependence hove rarely been reported on recommended doses, use caution in administering tu addiction-prone individuals or those who might increase dosage; withdrawal symptoms lincludiog convulsionsl, 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 benefits be weighed against its possible hazards. Precautions: In the elderly and debilitated, and in chil- dren over sin, limil to smallest effective dosage initially 10 mg or less per dayl to preclude ataxia or overseda- ion, increasing gradually as needed and tolerated. Not recommended in children under six Though generally not recommended, if combination therapy with other psychutropics seems indicated, carefully consider in- dividual pharmacologic effects, particularly in use of potentiatieg drugs such as MAO inhibitors and pheno- thiazines. Observe usual precautions in presence of im- paired renal or hepatic function. Paradoxical reactions e.g., excitement, stimulation and acute ragel have been reported in psychiatric patients and hyperactive aggres- sive children. Employ usual precautions in treatment of anxiety states with evidence of impending depression; suicidal tendencies may be present and protective measures necessary. Variable effects on blood coagula- tion hove been reported very rarely in patients receiuieg the drug and oral anticoagulants; causal relationship has not been established clinically. Adverse Reactions: Drowsiness, ataxia and confusion may occur, especially in the elderly and debilitated. These are reversible in must instances by proper dosage odlustment, but ore also occasionally observed at the lower dosage ranges. In a few instances syncope has been reported. Also encountered are isolated instances of skin eruptions, edema, minor menstrual irregularities, nausea and constipation, extrapyromidal symptoms, in- creased and decreased libido-all infrequent and gen- erally controlled with dosage reduction; changes in EEG patterns low-voltage fast activityl may appear during and after treatment; blood dyscrosias lincluding agranu- locylosisl, aundice and hepatic dysfunction have been reported occasionally, making periodic blood counts and liver function tests advisable during protracted therapy. ~ARoche LABORATORIES Nutley. NemJet'enOSttO PAGENO="0221" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4511 PAGENO="0222" 4512 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EXHIBIT 4 [From the New York Times, Feb. 2, 19691 STUDENTS SEND BACK DRUG MAKER'S GIFTS One-third of the first-year medical students at Columbia University's College of Physicians and Surgeons said yesterday that their "dissatisfaction with the exploitative pricing and promotional practices of the American drug industry" had compelled them to return gift stethoscopes to Eli Lilly & Co. This follows a similar move announced Friday by 45 second-year students at Harvard Medical School. The Harvard students, returned to the Lilly com- pany a black bag and kit of diagnostic instruments-including a stethoscope. Robert S. Pynoos, spokesman for the protesting Columbia students, said his group had written a letter to Lilly in which they had expressed disapproval with "the motivation behind these gifts." The letter said in part: "Promotional programs of this sort are obviously intended to initiate the establishment of close ties between physician and phar- maceutical house, for mutual benefit." "Such a relationship" the letter continued, "relegates the needs of the patient to a role of secondary importance." Henry F. DeBoest. vice president of corporate affairs for Lilly, said yester- day that the medical instruments "have been offered with the prior approval of the medical schools." The gifts were "a mark of appreciation for their [the students] willingness to undertake the long, difficult road of an education as a physician." EXHIBIT 5 [From the New York Post, July 10, 1961] AMA DELIRIUM Speaking of the real and the unreal, we wish that we could get rid of the feeling that the American Medical Association is out of this world. We know better. But the miasma floating from the Senate Caucus Room as the mighty medics battle the Kefauver drug bill did little to clear our heads. Dr. Hugh H. Hussey, there to speak his piece as chairman of the AMA's Board of Trustees, is dean of a medical college and by all accounts a literate, gracious gentleman. Yet there he sat, through three long sessions, pursuing an argument which went roughly like this: It is better that a worthless drug be marketed than run the risk of a worth- while drug being lost so therefore the Food and Drug Administration shouldn't be given power to rule on drug usefulness because the AMA is doing it better in a program that will be working by 1963 and is the only wholly objective agency able to handle the chore since more than half its income comes from the drug industry, the job being one that cannot and should not be done because no company tries to market a worthless drug and FDA already has power to stop them and is making adequate and effective judgments now inasmuch as FDA is incompetent to evaluate at all because drug evaluation is a highly complex and technical matter requiring skilled teams of test designers, pharmacologists, clinicians and statisticians and therefore has to be left to the individual family doctor treating you and me. Is everythting clear? EXHIBIT 6 [From the Medical Tribune, Mar. 24, 1969] CHALLENGE TO FDA Editor, Medical Tribune: Below is a copy of a letter sent to Herbert L. Ley, Jr., M.D., Commissioner of Food and Drugs, Washington, D.C.: "1. The editorial from the MEDICAL TRIBUNE, January 30, 1969, is self-explana- tory. Mycolog is produced by Squibb. PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4513 [The editorial dealt with the inability of a dermatologist to obtain the separate ingredients of Mycolog for patch testing because this would require the formal- ities of a new-drug investigation.] "2. Mysteclin F i's produced by Squibb `and the FDA has requested Mysteclin F no longer be made available as a drug to be prescribed by physicians. "3. I need a license to practice medicine. The practice of medicine is many things to many people. "4. Congress never authorized the FDA to assume control of the medical pro- fession nor to direct physicians how to practice medicine. "5. As a practicing physician, there are many patients in whom I believe Mys- teclin F is the drug of choice. I assume the responsibility for each decision I make. I do not believe the reason given for removing Mysteclin F from the market is a legitimate one. . . `indiscriminate use of antifungal agents is to be avoided.' "6. The FDA was created as an agency to prevent the movement in channels of interstate commerce of adulterated and/or misbranded foods, drugs, and cos- metics. Your agency has no authority in the areas concerned with the practice of medicine. It only has supervisory control over t'he pharmaceutical industries, not the medical profession. "7. There is a big difference between pharmacology, pharmacological efficacy, and the practice of medicine and the medical uses of drugs. Drugs are used in the practice of medicine. Each patient is genetically different from every other pa- tient. Physicians are taught to think and act using the tools of medicine. Pharma- cology is but one subject of many taught to physicians. There has been no Con- gressional authority granted to the FDA to make comments about the medical profession and its actions. Your continued usurpation of granted powers must be recognized and stopped. Your continued intimidation of physicians and drug houses must be challenged and stopped. It must' be recognized that your primary concern is not the patient but your own self-preservation according to the best legal minds under the tutelage of Mr. Goodrich. Anonymity of responsibility is your biggest and most powerful weapon since the Supreme Court refuses to pass judgment on any specialized agency such as yours. Knowledge of this isolaton and freedom from legal recourse has made yOur department wicked and un- scrupulous. But who can do anything about it? "8. Not only am I and my patients to be your victims but you and your family too. By what authority do you presume to have "the right to tell physicians how to use drugs medically and when-except by usurping powers not granted you ?" JAMES H. JOHNSON, M.D., Chicago, Ill. EXHIBIT 7 [From Medical World News, J'a4n. 31, 1969] SOME PRACTICING PHYSICIANS REPLY Senator Nelson's subcommittee hasn't invited,' and therefore hasn't heard, testimony from the practicing doctors whose drug-prescribing competence has been so severely questioned by pharmacologists and other academicians. To get the other side, MWN has solicited reactions from the president of the American Academy of General Practice, the chairman of the AMA Council on Drugs, and an Oregon internist who says he has repeatedly, but vainly, tried to testify. The AAGP president, Dr. Maynard I. Shapiro of Chicago, expects to appear be- fore the subcommittee on a yet unspecified date. "I can't agree with the conten- tion that doctors are unable to prescribe drugs accurately on the basis of the information available to them," he says. "I'm confident I have knowledge of the drugs I prescribe. If some question is not answered by the material at hand- the package inserts, ads, and such-I make it my business to find out." He says his additional sources are journal club discussions, curbstone consultations with colleagues, and the companies. "If there `is something specific I want to know, I go to the professional services department of a drug company." Dr. Shapiro feels the doctor may already get too much information. "FDA requires every adverse reaction to be listed-like, for example, one skin lesion in 10,000 cases. This looks a little foolish to some of us in practice. Already the circulars are getting so long and detailed and the type is so tiny I'm afraid a lot of men are not reading them." PAGENO="0224" 4514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. Shapiro would not want a new drug compendium to be put out by the government because it would be "garbaged up" by all the material the FDA requires. He expects the AMA's forthcoming compendium to `be more useful. "It will not be a PDR. It will be a scientifically composed book with therapeutic and symptom information the government does not provide." Dr. Shapiro says it would be handy if the AMA volume would include cost in- formation. "But I have solved that problem. I keep a copy of the pharmacists' Red Book, which gives all costs, in my office desk drawer." The chairman of the AMA council, Dr. John Adriani of New Orleans, also believes that the information currently supplied doctors is sufficient for them to prescribe drugs safely. "But the doctor needs more information than what he gets from the package inserts, ads, and detail men," says Dr. Adriani. "The information put out by drug companies is all right for safety. But the `why' and `how' you've just got to go out and get yourself." Considerably more angry about the hearings is Dr. Clinton S. McGill Jr. of Portland, Oreg. "It seems very clear that Senator Nelson does not want anyone to tell the story from the private practitioner's point of view, or even to allow us to defend ourselves against the scurrilous attacks that are. now a part of the public record," Dr. McGill told a recent meeting of the Pharmaceutical Manufacturers Association. Dr. McGill accused the subcommittee of believing that "we doctors are simple boobs, so snowed under by drug advertising that we can't select the right therapeutic agents for our patients. "Anyone who has even casual acquaintance with medical literature knows that long before any important new product is ever marketed, there will be a number of articles on it in our professional journals. Next, it will be described in some detail in the JAMA section on new drugs. All of this, mind you, before the product is distributed." Dr. McGill defended the content of drug advertising and described detail men as "trained professionals who provide us with valuable information." He does not look with favor on government drug publications. "I am sure the physicians of this country have a great ideal more confidence in our own council on drugs than we would ever have, in a publication of the Department of Health, Educa- tion, and Welfare-at least as long as the present atmosphere exists." Senator NELSON. Beginning today, and continuing throughout the month of March, the committee hearings will be devoted exclusively to major medical associations and a medical consultant who was for- merly a professor of pharmacology. Our witnesses today are Dr. Blaise Alfano and Dr. John C. Krantz, Jr., of the Huntingdon Research Center, Inc. of Baltimore~ Md. He is professor emeritus of `the Department of Pharmacology of the University of Maryland. Our first witness this morning is Dr. Bli~ise Alfano, executive secre- tary of the American Society of Abdominal Surgeons. You have submitted a biographical sketch which will be printed in the record prior to your statement, Doctor. (The biographical sketch of Dr. Alfano follows:) BIoLoGICAL SKETCH OF Br~&IsE F. ALFANO, M.D. Date of Birth: September 14, 1923-Boston, Massachusetts. Boston Latin School: 1942 Harvard University, A.B., 1946: Accelerated course- (1942-1944 and summer of 1946) Degree awarded in 1952. Secretary-Treasurer, Harvard Student Council. Secretary to Philip Brooks House. Elected to 1946 Class Committee 1946 to date. 1946 Class Treasurer 1946 to 1956. U.S. Navy active duty 1943-1946: Ensign, USNR, Aleutian Islands Tufts Medical School: M.D. 1950. Internship: Cambridge City Hospital-July 1, 1950 to June 30, 1951. Surgical Residency: Cambridge City Hospital, July 1, 1951 to June 30, 1954. Chief Surgical Resident: July 1, 1953 to June 30, 1954. Instructor in Surgery: Tufts Medical School PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4515 Instructor Anatomy: Harvard Medical School, 1952. Advanced Surgery given at Massachusetts General Hospital by Harvard Medical School-1954. Hospitals: Senior Surgical Privileges at: Cambridge City Hospital, 1954 to 1964 Melrose-Wakefield Hospital-1954 to date New England Sanitarium and Hospital 1954 to date Winchester Hospital-1954 to date Surgical teaching staff at Cambridge City Hospital-1954 to 1964 Societies and Associations: American Medical Association. Massachusetts Medical Society. Middlesex East District Medical Society. Secretary, American Board of Abdominal Surgery. Executive Secretary, American Society of Abdominal Surgeons. Fellow, International College of Applied Nutrition. Founder-Diplomate, International Board of Applied Nutrition. American College of Gastroenterology. American Association for the Advancement of Science. Association of Medical and Allied Publications. Institute for Advancement of Medical Communication. American Medical Writers' Association. Medical Society Executives' Association. Phi Beta Pi (Honorary) Medical Fraternity. Board of Governors, International College of Applied Nutrition. Associate Editor, Journal of Applied Nutrition. Director of Publications, Journal of Abdominal Surgery. Executive Secretary, Clinical Congress of Abdominal Surgeons. Fellow, American Geriatrics Society. Leaders in American Science. Who's Who in the East. Secretary, Section on General Surgery, A.M.A. 1962-1965. Advisory Board-Middlesix County National Bank 1966. Official Observer, Apollo 8 Launch, December 21, 1968. Elected Chairman Advisory Board-Middlesex County National Bank- January 1969. Senator NELSON. Dr. Alfano, we are pleased to have you here today. You may proceed to present your statement in any way you desire. If you wish to depart from the text at `any~ time to elaborate on any aspect of your statement, feel free to do so. Your full statement will be printed in the record, as well as any other extemporaneous com- ments you wish to make. I assume if we have some questions from time to time, you will not mind being interrupted. STATEMENT OP DR. BLAISE P. ALPANO, EXECUTIVE SECRETARY OP THE AMERICAN SOCIETY OP ABDOMINAL SURGEONS, MEL- ROSE, MASS. Dr. ALFANO. Fine. I wish to thank Senator Nelson and the members of the Monopoly Subcommittee for this opportunity to speak before the committee. American medicine is known and acclaimed throughout the world as providing the highest level of medical care. This is so despite the statements of the detractors who quote the statistics of infant mor- tality. This is an area that needs improvement, to be sure, but the raw statistics do not necessarily indicate a weak spot in medical care; close evaluation most likely will reveal that other factors play a significant role. Senator NELSON. Let me interrupt, Doctor, On the point of infant 81-280-69-pt. 11-15 PAGENO="0226" 4516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY care. You note in those statistics and some reports indicate that the incidence is very high in those areas where the poorest people live. Is it not likely that the problem here is that there are poor people who cannot pay to get medical care? Dr. ALFANO. That is one of the problems, a socioeconomic problem. There is also an education factor involved. There are some people m the country who are fearful of hospitals. That still exists. Their care is rendered outside of hospitals. Senator NELSON. More so than people from other countries, who have a lower incidence of infant mortality? Why in this country? Dr. ALFANO. I believe you will find in those countries with a lower incidence of infant mortality, they have a higher mcidence of hospital deliveries and their prenatal care is, say, regulated. Most of these coun- tries, I believe Sweden and Norway, have a low incidence. Senator NELSON. `It does say something about supplying medical care in this country, then? It is a significant factor? Dr. ALFANO. It is not just medical care. I believe there are other factors besides medical care. If the doctors saw all these individuals, prenatally and through the delivery, we would find our incidence of infant mortality would be down. It would be the same or better than other countries. The fact is that the physicians do not have an oppor- tunity to care for these people. Therefore, you have a higher rate of infant mortality. Senator NELSON. Nonetheless, it does say something about the kind of care and delivery provided in this country-the richest country in the world. It indicates~ does it not, that this problem deserves the at- tention of the public? Dr. ALFANO. Yes. It certainly needs correction and attention, I would say, yes. I am not saying that we cannot improve our system of medical care. I believe we ca.n. Changes and improvements are occurring constantly as they have over the years. I do submit that legislation that disrupts the physician-patient rela- tionship, which is the basis of medical care, can cause deterioration of the system it purports to help. I refer to the proposal that ~vhen a physician prescribes a brand name drug the pharmacist may substitute a generic drug as he see fit, and the only determining factor is the price of the drug. Senator NELSON. May I interrupt for a moment, Doctor? Dr. ALFANO. Yes. Senator NELSON. Whose proposal it that? I am not aware of such a proposal. Dr. ALFANO. There was a proposal-I believe Senator Long had a. proposal. We have a iroposa.l now in Massachusetts that states a pharmacist can substitute a generic drug for a trade name drug. Senator NELSON. Committee counsel advises me that Senator Long's proposal only refers to the question of reimbursement; that is, that reimbursement under the medical programs would be solely at the price of the generic drug. It does not require that the doctor prescribe it, but the Government will not pay more than the price of the equiva- lent generic. Dr. ALFANO. I am sorry, I do not have that bill with me here. But as I recall, they do have a factor where there could be discussion- PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4517 not only, as you say, the price factor. But at any rate, we do have in Massachusetts a bill now pending that generic drugs be substituted for brand name drugs. This stems, as I believe, anyway, from legislation that has been submitted or talked about here in Washington. Senator NELSON. I will have to take another look at that proposal of Senator Long's. I am not aware that there is any proposal pending that- Dr. ALFANO. There was. I do not believe it is pending now. It was; in the previous Congress, I believe. I have not seen it for this Congress~ Senator NELSON. As I say, I do not remember specifically what that bill proposed. I do not believe there is any bill that just gives a blanket authorization to a pharmacist to substitute a generic for any brand name. I might be wrong, but I do not recall that there is such a proposal. There have been proposals that would require, as I said, reimburse- ment only at the generic cost. That, ultimately, I suspect, will become the law in public-funded programs, because of these dramatic cases of price variances of equivalent drugs. You may be familiar with the Medical Letter case on prednisone. The price varied from 59 cents for 100 tablets to $17.90 for 100 tablets of the brand name Meticorten. This is just to the druggist. The Medical Letter flatly asserted that in their chemical tests and in their consultations with clinics, they were all of therapeutic equivalence, and they listed 22 of them. I suspect the public is not going to use public funds very long to pay $17.90 a 100 plus the markup, when the drug is available at 59 cents. Would you think they would? Dr. ALFANO. No; I agree with you. But I do not believe that because you have a case or several cases, that should change the system. As I understand it-excuse me, Senator-the medical profession has a way of correcting this. You are speaking of Schering's product, I believe. Senator NELSON. Yes, sir. * Dr. ALFANO. They had 100 percent of the market. Now they have, what is it, 5 percent, or less than 5 percent of the market. Senator NELSON. They get a large percentage of the retail market, but they do not get very much of the general hospital market, the city of New York, institutional markets, Defense Supply or Vet- erans' Administration, because they get outbid all the time. The inter- esting thing about it, and this is true of all brand names, is that no one who testifies on this question ever explains the reasons behind this. After our hearings, Schering reduced the price on its Meticorten- prednisone-from $17.90 for 100 to $10.50. Parke, Davis reduced their price of Paracort-prednisone_later from $17.88 a 100 to $3.25 a 100. It is perfectly clear to anybody that Schering is gouging the public, but they can do it because doctors write the name, "Meticorten." If they write Meticorten, that is all the pharmacists can prescribe. At that time, they were selling to pharmacists for $179 a thousand. That was the equivalent of their $17.90 a 100. However, to New York City, they offered it at $12 a 1,000. They wanted the New York City bid and knew they would be in competition. That is $1.20 a 100 versus the $17.90 they were charging the pharmacist on the same day, across the street from city hall. New York City awarded the contract to Lannett, who bid $4.58 a 1,000, which is 45 cents a 100. PAGENO="0228" 4518 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Now, is there any reason in the world why any public program or any program ought to be paying $17.90 a 100 when it is available at 45 cents? ~\Te have the same company, Schering, selling for $17.90 to pharma- cists and bidding for the U.S. Defense Supply Agency at 82 cents a 100. Do you have any defense for that? Dr. ALFANO. No; I certainly cannot defend that type of action, Senator. What I was stating was, I think the physicians learn of this over a period of time. That is why Schering's portion of the market has dropped down considerably. Senator NELSON. It has been dropping as a consequence of some publicity here in Washington, I think. But it is not only Schering. Let me give you Ciba's reserpine. Ciba sells that to the pharmacists for $39.50 a 1,000. However, they bid to the Defense Supply Agency not $39.50, but $3.95 a 100. The winner if you can imagine this incredible figure, the bid 89 cents. Now, ~9 cents for a 1,000 versus $39.50. The only reason they can charge $39.50 in the retail marketplace is that they have used your publication and other medical publications to sell the brand name. So the doctor writes the brand name. The poor patient is getting gouged day in and day out. Defense Supply is buying both brand names and generics. Defense Supply is making a good choice of a drug. I do not think there is any question about that. Why should the public pay that price? This is what comes about, I think, from the continuous promotion of brand names, which you advocate in your statement, and which other doctors testifying before the committee have also. They have taken the drug company line on brand name and physicians become convinced that you have to use a brand name, then they become con- vinced that it has to be a certain brand name, like Meticorten. Thus, the public is constantly gouged. Quite frankly, I think the drug industry has brainwashed the medi- cal profession. Dr. ALFANO. I am sorry you do not have confidence in the members of the medical profession, but it is not the fact of brainwashing the physicians. Physicians have faith and confidence in a particular phar- maceutical firm. They have had experience over a period of time with thousands of doses of medication. They are not willing to take a chance with an unknown preparation. A manufacturer not known to you-how can you feel secure in prescribing this for your patient? Senator NELSON. This is the problem that troubles this committee. Every witness before the committee speaks with great admiration of the quality and integrity and scientific distinction of the Medical Letter, even the Pharmaceutical Manufacturers Association. Each wit- ness, when asked, answered, we have a high regard for it. Now, the Medical Letter here lists 22 brands of prednisone, Meti- corten at $17.90, American Pharmaceutical at $1.80, Bryant Pharma- cal, $1.65, Darby, 61 cents, Wolins Pharmaceutical, 59 cents. In their statement to the physicians over the country, they say the great price spread among the tablets purchased from different pharmaceutical companies suggest the desirability of prescribing by generic name and specifying at least for patients of little means that the perscription be filled with low priced prednisone tablets. Why would not the medical PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4519 profession rely upon the Medical Letter more than the claims of the advertisers in promotional shares? Which one would you put your confidence in-this Medical Letter or the particular name of the brand name company? Dr. ALPANO. I do not think it is a simple answer either way. Per- sonally, I would not use either one myself. You have to make your own judgments. I know one or two of those names. I know one of them is a distribu- tor, not a manufacturer. Therefore, they have gotten their particular drug that they are selling, I believe you said at 61 cents. They get it from somewhere else, somewhere along the line. But where is it from? I am afraid to give it to my patient until I know about it. I will say, yes; I can try a particular known drug, run an experi- ment with my patients, carefully watch them, see them more fre- quently. It requires more recordkeepin'g. Then I can determine for myself as far as the efficacy or the therapeutic equivalent of that drug that I experiment with or am trying versus the one I have been using regularly. If I find it works out, I am satisfied with the results, cost- wise, it is better, naturally, I would use the one that costs less and yet produces the same effect. I think that is logical to do. But not just because it has a price of 61 cents or $1 versus $17. I am not going to use it for price consideration primarily. Senator NELSON. On what basis would an individual doctor, for example, decide to continue to prescribe Meticorten at $17.90 per 100 when Merck sells at $2.20? That is a distinguished brand name company. Dr. ALFANO. I do not have the figures with me, but I will be glad to send them. But I believe Schering, which `had 100 percent of the mar- ket, is down to 5 percent or less, which is an indication that the medi- cal profession recognizes this factor of cost and has chosen other drugs than Schering's product. Senator NELSON. I think we had testimony on Meticorten a year ago as to its share of the market. I do not have it before me. You might be correct that that is the share of the world market. They have a much higher share than that of the retail market. When they have to bid in competition, they get beaten quite regu- larly, unless they lower the bids. It is the brand name retail market- place, where brand name predominates, which is the important ques- tion. I will check and see what share they have now. But, of course, they have had a lot of publicity in the past year on their price and they did redu'ce that price to $10.50. Dr. ALFANO. I believe the medical profession then is cognizant of this price differential and does not blindly follow, say, Meticorten, which has been advertised or so-called brainwashed. They do not use it indiscriminately or continually. They change products or companies who can provide a quality product at a lower price. I believe all physi- cians throughout the country would do that. Senator NELSON. Well, they certainly dominated the retail market- place for a long, long time when other equivalents were available. That is the point. On this whole field of pricing structure, which is what we are dis- cussing, let me give you another example. The defense continually made before this committe about the prices they charge-the witnesses PAGENO="0230" 4520 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY testify that they do a lot of research and use new drugs and so they are entitled to certain rewards and, of course, they get that in a 17-year patent. They are not entitled to anything after 17 years except fair and honest competition. But they do not get fair and honest competi- tion in the marketplace even after the 17 years. The doctors are in the habit, after 17 years, of writing the brand name and they continue to do so. I have had doctors say to me, when I explained the price differential, well, I have been writing Meticorten for x number of years and I suppose I will write it the rest of my life. That is the attitude of physicians, even though their patients could get it at one-thirtieth the price. Now, I would like to ask you a question on this point. How would you explain that Schering, who sells for $179 a 1,000 to the pharmacist here, sells it in Berne, Switzerland, for $43? In other words, $17.90 a 100 here versus $4.37 in Berne, Switzerland, after assuming the cost of packaging and shipping it overseas? Dr. Ai~r~o. Senator, first, I would like to say I am certainly not trying to defend the drug company, trying to justify some extremes in cost of drugs. I cannot explain various extremes in costs of drugs. 1 am not in the drug industry. I do not know these factors. Senator NELSON. Well, I do not want to be unfair to you. I ask because the pattern of your testimony, like the pattern of a number of other very distinguished physicians who defended the pharmaceutical manufacturers-take their line on brand name, on the cost of the services they get, on every single point the pharmaceutical manufac- turers make. Therefore, I think it is fair to raise the issue of the wide price differences with those who defend the arguments of the manufac- turers. That is what a good part of this hearing is about, the fact that the doctors say we cannot rely on anything but brand names. Strangely, the best hospitals in America, the Defense Supply Agency, and the Veterans' Administration, all buy large amounts of generics. They have their own pharmacologists, they take competitive bids. They find no difierences in those drugs versus the brand name drugs. Dr. ALFANO. I know, Senator, but if I had the facilities, if I had the setup that the Defense Department has for investigating drug firms and testing out the drugs, I could purchase a large number of drugs and use them because I have tested them. As I understand, they reject what is it, 40 to 50 percent of the drugs submitted to them. But they, I think, are the only Facility capable of testing as they do. There was another point I wanted to state. The patients in this country are not that naive. I have had patients come back and com- plain of the cost of a particular drug. They make known to the doctor the cost. The doctor, in turn, will make it his business to find out what the costs of these particular drugs is when patients come in. It is not that this is unknown to the doctor. He does not know the cost-I believe that is the history of Meticorten. He had no choice, he had to use the higher priced drug, but as qualified drugs, so to speak, came on the market, the doctors used them. That is why Schering's share of the market has dropped. Otherwise, it would be as high as it was in the beginning. If, as you say, the doctors are brainwashed, are creatures of habit where they are not thinking concerning the cost of drugs. PAGENO="0231" COMPETITIVE PROBLEMS IN', THE DRUG INDUSTRY 4521 Senator NELSON. With respect to the use of the phrase "brain- washed"-I only use it on the question of price and brand name. I am not using it any other way. In other words, all I am saying is the promotion is so effective that doctors become convinced that they should prescribe this particular brand, name, and that holds the price of that brand up. As an example you can take almost any drug you want in which there has `been a patent, it has been on the market a long time, `the patent runs out. That brand name still holds a very strong place in the marketplace at a very high price compared to other available drugs. For example, we can take dextroamphetamine. Smith Kline and French put out Dexedrine. They charge the pharmacist $22.60 for a 1,000 five-milligram tablets. They offer it to the Defense Supply Agency for $1. So. while they are convinced that because of their promotion, their brand name Dexedrine is going to `be, written by the doctor and there will be no substitute, they charge $22.60. When they want the Defense Supply Agency `business, they bid $1. That is incredible to me. In New York City, they did not bid, but the winning bid was 57 cents. So, New York is buying dextroamphetarnine at 57 cents for a 1,000. The poor customer in the retail market place i's paying $22.60 plus the druggist's markup, for Dexedrine, for the very simple rea- son that Smith Kline and French, through a vast program of pro- motion, has convinced the doctor to write Dexadrine. He writes it and his poor patient is paying $30 and $35 when New York City is buying it for 57 cents. That is what I am talking about when I say the companies have done a magnificent job of selling the brand name. Every witness who comes in to testify on the side of the company gives that line of argmnent. They never answer why it is that they are able, the same company, to charge $22.50 and then turn around and offer to sell it to the Government for $1 when they have competition. Dr. Ai~r~o. Certainly as I said before, I cannot speak for the drug company on their costs. But I can say that the drug-not that the drug company sells the drug. The drug sells itself. The doctors have used it and found it works and they know how it works. Therefore, they will continue to use it until they have another product that will come along that will do the job and cost less, but not use a drug be- cause it costs 10 cents versus a drug that cost $1. A doctor first must consider the condition he is treating and his patient. Secondarily, the cost factor comes into treatment, not primarily. Senator NELSON. Well, of course, to all~ the hospitals that have a formulary and to the Defense Supply and to all the rest, cost is a very important factor to them. Every major hospital in this country has its own therapeutics committee, sets up its own formulary. In that formulary, you will find brand name drugs and you find gen- eric drugs, lots of them. The formulary, as you know much better than I, is designed by the best clinicians, representing all aspects of the profession in the `hospital, along wth the pharmacist and so forth-a group evaluation of what drugs should be in the formulary. They do not pay anywhere nearly as much. In fact, you find the brand name companies bidding to the hospitals, just as they do to Defense Supply Agency, at a price way below what they are charging the pharma- cists, because the brand name does not do them any good with the PAGENO="0232" 4522 CO~ETITIVE PROBLEMS fl~ TI~ DRUG INDUSTRY Defense Supply Agency. The important question is, does the drug meet USP standards? Dr. ALFANO. I believe it is more than just TJSP standards on that. They have their own testing for drugs. Senator NELSON. They test on TJSP standards, I take it. Dr. ALFANO. I will not speak on that I understand there is a clinical evaluation of these products. They inspect the drug companies, the factories where they manufacture. Senator NELSON. I am not aware tha.t they do any clinical evalu- ation when they take bids on drugs. They analyze them on their own to see if they meet USP standards. Dr. ALFANO. It is my understanding that 44 percent of these drugs are rejected. That must mean they are rejected on substandard manu- facturing reasons. Senator NELSON. I would suspect they reject as many brand names as they do generic. The only test we have is the test of the FDA of 4,600 drugs, 2,600 of them generic, the other 2,000 brand name, for potency. Of the brand name drugs, 8.8 percent did not meet the IJSP potency test; 7.7 percent of the generics did not. So, in a miscel- laneous test of 250 manufacturers of 4,600 drugs on potency, the generic drag was better quality, met the standards slightly better than the brand name. What would be your observation about that? If that is the only test you went on, would you not be saying, you could not trust the brand name, I will gamble with the generics, because they meet the potency tests better? Dr. ALFANO. If that is the only test you go by. Was not that test rejected as not valid? The one you quoted? Senator NELSON. Dr. Goddard testified on that. Out of the 4,600, there was a mistake on something like half a dozen. Dr. ALFANO. I will have to send that in. I do not have it here. But as I understand, that is dramatically different from the original fig- ures you quoted. (Material not received.) Senator NELSON. Here is the testimony from Dr. Goddard. It has been in the record for a long time, unrefiited by anybody. You would imagine it would be refuted the next day by the pharmaceutical manu- facturers, if it were possible. In six samples involving five firms, after the review of the original data, they did concede that they had made an error. So they conceded six errors out of 4,600. It still would not change the percentage. The generic drug names met the standards of potency better than the brand name. Dr. ALFAN0. I believe there is something later than that. I could not give it to you now. Senator NELSON. No; there has been nothing later. The quote is- Dr. Goddard-"Now the other original findings I still say are correct. We stand behind these as long as it is understood that this is not a representative sample of the marketplace." That is, they were mis- cellaneous collection from 250 manufacturers. All I say is- Dr. ALFANO. What does he mean, not representative? Senator NELSON. Well, they did not try to take a representative sample. They were just drugs that were from 250 different manu- PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4523 facturers, with 2,600 of them generic drugs and 2,000 brand names. But it is the biggest and best test that we have, and it indicates that the generic drugs met the standard potency better. Now, do you have any evidence-we have had none by any repre- sentative before the committee-of tests showing that brand names are better? The only test we have is that the generics win. Dr. ALFANO. The only test, really, is in the field. You are working with patients, you are. prescribing drugs, you know it works. I do not think we can come up with anything better than that. After all, that is what we are working on, treating patients. If we come out with good results, fine. If you can show me that I can use another drug that costs less and is equivalent to the drug that I am using, which costs more, naturally, I will use the drug that costs less and does the job. But certainly, I am not going to go ahead and run experiments on my patients every day, say giving unknown drugs until I can evaluate them. It would he impossible for an individua.l physician to carry out this type of experimentation with many, many patients. He can do it over a period of time. Senator NELSON. Of course, it is not possible for an individual physician, as a practical matter, to make comparisons of the efficacy of a half dozen different drugs of the same compound, anyway. You get a testimonial. But you do not get scientific evidence. The doctor may very well conclude correctly, after experience, that this is a good drug and it works. He sees it work. That is his experience. That does not prove that another one does not work. It does not prove anything. It just proves that the one he is using, as far as he is concerned, does work. Dr. ALFANO. Well, in the final analysis, that is what counts, is it not, the confidence the doctor has in his particular treatment? That is very important, regardless of the benefits of other types of drugs and medications that are around. He is using a particular drug, and it is important that he have faith and confidence in that particular drug. How can I treat a patient when I do not have confidence myself in what I am giving this patient? I would be a nervous wreck. I would be out of practice of medicine inside of a week. Senator NELSON. Well, I submit that the classic example is the Medical Letter again. Dr. ALFANO. Well, I do not believe everyOne has that sort of faith in the Medical Letter. Senator NELSON. Pardon? Dr. ALFANO. I do not believe everyone has that blind faith in the Medical Letter. I do not subscribe to it, I do not have it, but my chief of medicine feels it is fine, but there are certain limitations to it. Senator NELSON. There are limitations to everything. The Medi- cal Letter had the drug prednisone tested chemically, and 22 all met USP standards. Then they consulted with their clinicians around the country, distinguished professional men. Dr. ALFANO. They do not say who they are, though. do they? Senator NELSON. Well, they list the editorial board, of course. Now, their advisory board is Dr. Gardner, professor of pediatrics, State University of New York, Upstate Medical `Center; Lewis S. Good- man, professor, head of the Department of Pharmacology at the Uni- PAGENO="0234" 4524 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY versity of Utah, College of Medicine; Dr. Lasagnia, associate professor of medicine, director of the Division of Clinical Pharmacology, Johns Hopkins Medical School; Dr. Lavietes, associate clinical professor of medicine, Yale University Medical School; Dr. Mark Lepper, professor of preventive medicine, University of Illinois Medical School; Dr. George E. Moore, clinical professor of~ surgery, State University of New York at Buffalo, director of Roswell Park Memori- al Institute; Maxwell Wintrobe, professor and head of Department of Medicine, University of Utah, College of Medicine; Dr. Robert Wise, professor and head of Department of Medicine, Jefferson Medi- cal College. They use other consultants. They consult with people who are in the field using this particular drug; then with the benefit of their chemical analysis and their consulting with clinicians, they come to a conclusion about the drug. Now, nobody has refuted this, including the company. The company testified. They have not refuted this. No one has refuted it. What I am saying to you is-certainly, you want to be sure that your drug is employed. But this committee~ as one part of the hearings, is concerned about the pricing structure of the drug industry and the fact that in the retail marketing place by their brand name identi- fication, they are able to charge an excessively high price which they cannot get from a general hospital or Defense Supply or Veterans' Administration. It is just a. clear cut case of gouging the public. In- credible gouging. They could not answer why they charged one-fourth as much in Berne, Switzerland, for their drug, after shipping it over, as they charged here. They said that the standard of living is lower over there. Then I pointed out that the standard of living is much lower in Mexico City and they charge three times as much in Mexico City. He said he would ask the comptroller of the company to look into that and write me. That was over a year ago. We have not heard yet. But~ in my view, this is a case of gouging the public by the drug companies, with the support of a lot of the medical profession who say, "Stick to the brand name." Now, it would seem to me that if I were practicing medicine, I would go get the best formulary from the nearest hospital, in other words, rely upon the judgment of the distinguished doctors at that hospital, and prescribe from their formulary. That would answer a lot of these questions. Dr. ALFANO. I do not believe you would wa.nt that, Senator. You want your physicians then to be herded into one group. Physicians are individuals. They. will decide what they feel is proper for their particular patients. I do not believe-you use the word "gouging". I am not going to try to justify variations in pricing, but I believe there are reasons why trade name drugs cost more than generic drugs. Trade name or ethical pharmaceutical firms provide services that we do not get from generic companies. In fact, most physicians do not know the generic companies. I believe I have in here in~ this statement some of the services rendered by the pharmaceutical firms. For example, the medical department of the drug company. You certainly would not want the American public and the medical pro- fession to go without the services of the medical department of a drug firm. We do not ha.ve medical departments in generic firms. Certainly, PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4525 that will cost money and if the generic firms had a medical depart- ment, their drugs would have to be up by that certain amount. Then if they had professional relations departments and other services that benefit the patient and the profession, the generic drugs, certainly, there would not be that wide difference in costs. Senator NELSON. Well, that exact position has been put to this com- mittee a number of times and I have responded with this question, `which has not been answered yet: What is the purpose of the patent? If they discover a new drug, the Congress has said you can have 17 years to charge any price you please. And when you consider that Schering was charging $17.90 for a 100 tablets and Wolins was selling at a price of 59 cents a 100, you can imagine what kind of profit they made. So they had 17 years. They know how much it costs for drug re- search, they know what their overhead is. They wanted to make a profit. It is the highest profit in America. So they had 17 years. `What justification at the expiration of the patent is there for charging a high price? They are able to do it, I submit, Doctor, because that brand name becomes so well know they can stick with the high price and gouge the public. Otherwise, `Wolins would be selling more of their product in the retail market, and so would American Pharmacal and Merck. So what answer is there? They have the patent. What else do they need? Dr. ALFANO. I cannot discuss patents and other types of things. I know nothing about that type of thing. I am just stating that ethical pharmaceutical firms do offer services which are of benefit to the pa- tient and to the profession which we do not get from generic firms. These costs, these services, do amount to a certain amount of money and this amount of money has to be applied to the drug as the patient purchases it. As to justifying extreme costs, I cannot do that and I do not intend to try to justify an extreme cost. I am only stating that we do have benefits from ethical pharmaceutical firms. Senator NJ~I~soN. On the question of whether anyone would rely upon or use a good hospital formulary, did I understand your answer to be that the doctor is an individualist and would not want to do that? Are you saying that you do not think the formulary system in our major hospitals is a good system, that the collective judgment of all the distinguished specialists and clinicians in that hospital is not better than the single judgment of a single practitioner? Dr. ALFANO. All hospitals do not have a formulary system. I am on three hospitals. None of them have formulary systems. They are all accredited community hospitals. I have not worked under a formulary system. There are problems with formulary systems where the physician is handicapped. Most physicians will not join the staff of a hospital where it is required that he use only the formulary system. He will jOin if~ he may use beside the formulary system drugs of his choice that possibly are not listed on the formulary system list. But what I understood you to say is the doctor is out in practice outside the hospital. He comes to the hospital and he has to be gov- erned by these drugs that, are listed by the hospital pharmacy or formulary system. That, I believe, would be objectionable. PAGENO="0236" 4526 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator ~ELSOX. I would not say he would have to be governed, by any means. All I am saying; for example, is "I am a doctor, I am trying to help my patient, trying to get the best drug. If I am a sole practitioner, I like to get the best sources of information possible. I would be happy to check with the hospital and say, what are you using for prednisone? I have been prescribing a brand sold to the druggist for $17.90, a.nd costing my patients, with the markup, $30 or $35. What do you use?" They say, well, we are using Merck's at $2.20, Wolins at 59 cents. What is your experience? Very good. We cannot find any difference. That is the sort of thing I would consider; that the collective judg- ment and practice and experience of that hospital might be very useful to me and I would be glad to get that information. But in any event, 88 percent of the a.ccredited hospitals in America use a formula.ry. None of them that I know of-that is, of those who testified-have a formulary in which it was compulsory under all circumstances that the doctor use the drug in the formulary. If he has a specific reason for desiring a particular brand name, he has that leeway. Dr. ALFANO. I do not believe they have any choice. The medical pro- fession would not stand for a closed type of system. They would not go for it. The patients are their prime concern, not the hospital pharm- ac.y or whatever it is in Senator NELSON. What happens is that as a matter of practice, most all the drugs prescribed in the hospital come right out of the formu- lary. The exception is rare, percentagewise. When the hospital in Atlanta went to a formulary 2 or 3 years ago, the doctors testifying here said they saved, I believe it was, a quarter of a million dollars and that they found the generics they used to be very good. Dr. ALFAN0. I think there are two different systems of formularies, though. There are some hospitals that you are required to use these particular drugs in. If you write a tra.de name, they will give the drug in stock for that drug. Then, there is a system whereby a formulary does exist and it is permissive as far as you may or may not use it, depending on how you feel concerning your patient at that time. Senator NELSON. I imagine there are. hundreds of them, so there is a great variety in their use. I only wanted to make the point that-of the doctors who testified here, those practicing in a hospital with a formulary-these doctors said that within their hospital any physician desiring a specific brand name, though it might not be in the hospital formulary, would be free to prescribe that particular brand. No one would quarrel with that. Dr. ALFANO. You may rightly ask how does the cost of the drug interfere with the physician-patient relationship-does a more costly drug improve this relationship? Of course not. But anything that shakes the confidence of the physician or patient interferes with this necessary relationship. A physician who writes a prescription for a particular medication knowing full well that the pharmacist will sub- stitute a generic drug in filling the patient's prescription does not have the confidence that the drug received by the patient will do the job. The doctor prescribed a known drug but the patient will take an unknown product. Will the generic drug have more of an effect than PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4527 desired, the same effect as the prescribed drug or will it provide less than the desired effect. Since the doctor is not sure that the medication received by the patient is doing the job properly he will have to see the patient more frequently. Thus the savings in the cost achieved by the use of the generic drug will be more than offset by the extra visit or visits Under our present system the physician prescribes a drug which is known to him and manufactured by a known reputable firm. More important however, the physician has personal knowledge and experi- ence with the particular product. He can advise the patient, anticipate results and accurately judge when he should see the patient again. The doctor has a working knowledge of the particular product. Under the present system of generic drugs the doctor can never gain a work- ing knowledge of the product. Under the generic system each time a patient has a prescription filled for the same drug he could receive a drug produced by a different manufacturer. Each of the products can react differently since each manufacturer has his own method of producing the finished product. This problem is compounded by the fact that it is not possible to iden- tify the manufacturer. Under these circumstances no physician can gain a working knowledge of a generic drug. The most significant point of all, I believe, is the fact that a chem- ically equivalent drug does not mean it is therapeutically equivalent. Senator NELSON. What evidence do we have of that specifically? Dr. ALFANO. Well, studies of Max Sadove, an anesthesiologist in Chicago. lie has done a study of the generic versus the trade-name drugs. Then there is a study of Pfizer on oxytetracycline. There is a difference which, I believe the FDA has confirmed. Senator NELSON. We have not been able to get any convincing evi- dence from the manufacturers or anybody else that drugs that met USP standards are not therapeutically equivalent. Dr. ALFANO. You have no evidence? Senator NELSON. The best Dr. ALFANO. Well, I will send you the material concerning these studies that there is a difference. (Material not received.) Senator NELSON. We have those studies. They have been refuted. Dr. ALFANO. When were they refuted? I do not recall seeing this. Mr. GORDON. In one of our earlier volumes, specifically volumes 1 and 2. Dr. ALFANO. Was it not the chloramphenicol, too, that there was a difference? Senator NELSON. That is the only drug we are aware of and there is no proof yet. Dr. Lee testified on that recently. There is no proof that the different blood level achievement of Chloromycetin versus the other chloramphenicols, indicates that one ~as any more efficacious, that there was any difference in therapeutic effect. There may be, but what happened was that in the tests, the brand name, Chloromycetin, achieved a higher blood level more quickly. The FDA took the other two, I believe, off the market because they did not achieve the same blood level. They wanted uniformity in bloOd level achievement. Dr. Lee says there is no evidence that either or any one of these was a more efficacious or a better drug than the other. They may find this to be so PAGENO="0238" 4528 COi~~tPETITIVE PROBLEMS IN THE DRUG INDUSTRY some day. All they had was a differeilt blood level achievement in a different period of time. Dr. ALFANO. There is a study on oxytetracycline, I think. I can send you a copy of that. (Material not received.) Senator NELSON. But the evidence was that there was no therapeutic significance to the difference. The following is a line of questioning of Dr. Lee, former Assistant Secretary of HEW, on this question of equivalency. Mr. GORDON. I have one nitpicking question. You say there are only two or three which demonstrate an initial lack of equivalency and one of them has no practical clinical importance. Are there two or three? Which is it? Dr. SILVERMAN. There are two. One of them, as you probably surmised, is chioramphenicol. The second one is tetracycline. In the article in this publication, the scientists that wrote this article pointed out quite clearly that although differences were detected, this was not of any clinical importance. Dr. ALFANO. That is tetracycline? Senator NELsoN. Yes. Dr. ALFANO. There is one on oxytetracycline, a new one. Senator NELSON. In any event, the USP, the formulary, and the FDA, can cite only one of two cases. Dr. Kiwc'rz. May I speak to this, because it is very apropos of this? Senator NELSON. Yes. Dr. KRANTZ. The Department of Defense a few years ago, after having bought these brand name items at low price as generics, brought me 19 of them that did not show complete therapeutlc efficacy. These are these drugs: Reserpine, thiopental sodium, tolbutamide, tedral, tobocurarine chloride, Warfarin, Heparin sodium injection, oxytocin injection, diphenylhydantoin sodium, digitoxin or digoxin, phenolsul- fonphthalein, pentaerythrityl tetranitrate, succinyicholine chloride (Anectine), bromsulphalein solution, sustained release tablets, meth- enainine mandelate (enteric coating), Dexamyl. Senator NJ~r~sON. We will check the record further. Counsel advises me that the task force on these drugs went into this and found out that- Dr. KRANTZ. They came to me for the purpose of finding pharma- cological data which would show the generic equivalency of these drugs. Senator NELSON. Were these drugs you cited here-I have not read `that report-were these drugs that did, in fact, meet USP standards? Dr. Kiw~rrz. Oh, yes; they put them through the USP test. This is very simple for them to do. Senator NELSON. Did they meet the USP standards or fail them? Dr. Kn~z. Met the USP standards but the diphenylhydantoin `did not control epilepsy. The meprobamate did not produce sedation. `The thyroid did not change the metabolic rate.' Senator NELSON. You are certain that these are cases where the drug met the USP standards, not failed the standard tests when `tested? Dr. IclLu~rz. The pharmacopeia standards are only standards of identity, purity, and also the rate of tablet disintegration. Senator NELSON. Potency? ~ See pp. 4555-4557 of Dr. ICrantz' testimony. PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4529 Dr. KRANTZ. Identity and purity. Senator NELSON. The coramittee is well aware of that, Doctor. What I am saying is did each one of the drugs named under test meet the U.S. pharmacopeia standard or did they fail to meet the standard? Dr. KRANTZ. I was so informed by the colonel who brought them to me, that they had met the pharmaco~eia standards. Senator NELSON. I would question it for this reason. We have dis- cussed this question with the Directors of the National Formulary and U.S. Pharmacopeia and they flatly state that they cannot find any cases, excepting one or two, in which `a drug met USP standards or U.S. Formulary standards and was proven not to be therapeutically eqivalent. Now, I will take these and recheck them, but this has been the testimony by the Director of the FDA, by the U.S. Formulary, the U.S. Pharmacopeia, and by a number of distinguished pharmacolo- gists. If they met the standard, there have been only one or two cases where that was proved not to be therapeutically equivalent. If there is further evidence of exceptions, of course, the committee would like to have it. Dr KANTZ. Well, this came from the Army source of supply in Philadelphia. The colonel came to see me in my laboratory about a year ago and asked me if we could develop pharmacologic tests which could prove their pharmacologic activity in addition to the fact that they had already proved their chemical identity. Senator NELSON. Dr. Lee testified for the Department of Health, Education, and Welfare on December 23 respecting the Task Force Report. Twill read what I said to him and what he said: Just on one point of your conclusion- that is the conclusion of the Task Force Report- that when drugs are chemically equivalent and meet all the chemical standards, they are therapeutically equivalent except in rare instances, as you are aware. We have had distinguished pharmacologists and elinicians appear before this Committee and give the same testimony I assume that when you refer to the fact that you have relied upon the literature, and clinicians, and past experi- ence and so forth, that that also involves the rather vast experience of the Defense Supply Agency, the Veterans Administration, and general hospitals and others who buy on competitive bidding. And on one occasion they get one brand of prednisone and one brand of another drug. Dr. LEIS. Tetracycline. Senator NELSON. And their experience over the years has been that if they meet the same standard and have the same chemical composition, that they are therapeutically equivalent; is that correct? Dr. LEE. That is correct. Because this is a highly charged and controversial area, the task force made a very extensive study. The task force study has been going on for well over a year. We consulted with the leading experts in the field; our staff reviewed the literature; we had the special studies carried out; we reviewed the experience of the Defense Supply Agency and other agencies who have had just the kind of experience that you have described. Our con- clusions really are based on a detailed examination of the information that is available today. Senator NELSON. Thank you. I have to go vote, but the committee counsel tells me that he cannot find anything in your material, Dr. Krantz, that says these drugs, in fact, met USP standards. Could you show him where that is? I will be back as soon as possible. (A recess was taken.) PAGENO="0240" 4530 CO~ETITflTE PROBLEMS IN THE DRUG INDUSTRY Senator NErsoN. We will resume the hearing. It was called to my attention during the recess that on our dis- cussion about hospital formularies, that all hospitals must have formulary committees to be eligible to collect for medicare patients. Dr. ALFANO. Committees, yes, but not formularies. You are talking about committees. A committee and a list are two different things. Senator NELsON. What is the purpose of having a formulary com- mittee if they do not select a group of drugs to fit the formulary? What is the point? Dr. ALFANO. Supposedly, they check all the drugs that do come into the hospital pharmacy, regardless of whether it is a generic or trade name. The formulary committee makes sure that the hospital does not have a drug within the walls of the hospital, the type of drug that may be harmful or cause problems that may be detrimental to the hospital. Senator NELSON. You are saying that under the medicare law, in your judgment, hospitals are not required to have a drug formulary in order to get medicare payments for medicare patients? Is that what you are saying the law is? I do not know what the law is. Dr. ALFANO. I do not believe it is a law that you must have a formulary committee-a formulary. I believe they do require the Joint Commission on Hospital Accreditation to have a formulary committee, but not necessarily a formulary. Senator NELSON. I am still puzzled about what the formulary committee would do if they did not devise a formulary for the hospital. Dr. ALFANO. A formulary is a list of drugs. If it is so restricted, you can only use this list of drugs within the hospital. The formulary committee reviews all drugs that come into the hospital and are used within the hospital. They will prevent a drug coming into the hospital that may be harmful and cause a. danger as far as the patients within the hospital or causa problems for the hospital corporation a.nd the staff. If I, as a doctor, want to come in with a drug that is not approved, not accepted, if we have no formulary committee, I could bring any drug I wanted to into the hospital. There is no protection, therefore, for the hospital and the hospital staff and the hospitalized patient. The forinulary committee will prevent that from occurring. Senator NELSON. Please continue. Dr. ALFANO. Thus when a physician has a patient on a generic drug produced by an unknown manufacturer he is conducting an experi- ment because he does not know how the patient will respond. The patient must be seen more frequently in order that the physician ~ evaluate the therapeutic effect. With a brand name product the physician over a period of time has obtained a working knowledge of the specific drug and does not have to see the patient as frequently as is required with an unknown product. From the patient's standpoint the substitution of a generic drug can have a profound effect upon the patient's confidence. For example, the physician orders a particular drug while the patient is hospitalized and upon discharge writes a prescription for continuation of the medication at home. The druggist substitutes a generic drug which may be a round red pill rather than the oblong yellow medication the PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4531 patient received in the hospital. What is the result? After discussion with the pharmacist the patient is not convinced that he received the proper medication. The next natural thing to do is to contact the physician in order to determine if the medication dispensed is in fact the one prescribed. Unfortunately the phy,sician cannot identify the generic drug by its shape, size, and color and must contact the pharma- cist to determine if an error was made or if the patient actually has the medication which was prescribed. If you were that partmcular patient I'm sure that your confidence would be thoroughly shattered. Senator NELSON. May I interrupt, Doctor? I would like to make the point that exactly the same thing happens all the time. As I said, 88 percent of accredited hospitals of America have a formulary. Every witness we have had from every major hospital has a formulary and uses generic drugs in the formulary. So to use your argument, the patient is in the hospital; the hospital gives him a generic brand drug. It is a little round red one. He gets out of the hospital, goes to the doctor and the doctor prescribes the little round yellow one and you shatter his confidence. Nonsense. Dr. ALFANO. I can only testify from my experience. In my experi- ence, if I prescribe a trade name drug, that is what the patient gets in the hospital. If I discharge the patient and the law requires that they substitute a generic drug, then they get a different one. Senator NELSON. All I am saying is it works both ways. All the major hospitals in America are using a formulary. In those hospitals, the doctors are using the drugs in their formulary with rare excep- tions. So the patient leaves the hospital, goes to another doctor, gets a little red pill instead of a little yellow one and his confidence is shattered. I must say even if it is shattered, it is shattered both ways. Dr. ALFANO. I do not believe the formulary system is the way you understand it, really. The physicians on the staff, the formulary coin- mittee will make up a formulary and the drugs of choice are listed on that formulary. It is not made up primarily as a cost limit for the hospital. Senator NELSON. Oh, it is a very important part of the cost. We have witnesses testifying to that. As I pointed out, one hospital saved a quarter of a million dollars a year. Dr. ALFANO. If you are stating the formulary is made up for cost reasons, I condemn that type of system. I think the patient is the primary consideration. Senator NELSON. I did not say that at all. All I am saying is the formulary is made up by a group of doctors representing the disci- plines practiced in the hospital. I am just repeating what the expert testimony is, that using the knowledge and experience of a group of physicians who make up a formulary. It is expected that the doc- tors will use it and they do use it. They do have a caveat that if the doctor insists, has some reason to use a particular brand or another, he is completely free to do so. But this is an exception to the rule, not the rule. So all I am saying is that in these hospitals, lots of patients are getting a generic drug. When they leave the hospital instead of getting a little round red one, they get a little round yellow one, a brand name. I simply submit that if it shatters their confidence one way, it shatters their confidence the other way. But I would be amazed if a great deal 81-280-69-pt. 11-16 PAGENO="0242" 4532 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY of shattering were going on. If there were, perhaps the hospital should be required to continue to use on that patient the same generic drugs, the same brand drugs, so that the patient's confidence would not be shattered when the doctor changes from a generic to a brand or from a brand to a generic. All I am saying is your argument is full of holes. It works both ways. Dr. ALFANO. I do not believe so, because you are talking about a formulary system. The staff has a formulary committee. The staff then submits the drugs they wish to use. You have a staff that have on the formulary the drugs they wish to use, the drugs they use on their patients, inside the hospital and outside the hospital. There is no other change, no other outside force that comes between them. The formulary system belongs to the staff and is controlled by the staff. Senator NELsoN. Correct. Dr. ALFANO. They have the drugs they wish on that. So it is not the same as you say, that they can have one drug in the hospital and another drug outside. The doctors on the staff submit the types of drugs they want on the formulary, because the formulary is derived primarily for the benefit of the patients and the staff, secondarily, for the cost. And I am sure-I do not have the figures, but if the hospital bought a large amount of a drug, a trade name drug or a generic drug, their prices or cost would be less than if they bought smaller amounts for, say, individual medications rather than a wholesale purchase. So there is a savings on both generic and trade name drugs. Senator NELSON. There is no question about that. All I'm saying is one of the purposes of the formulary is economic. That is one of the purposes. The fundamental, primary idea in the selection of any drug is to be sure that you have a quality drug that does what the drug is supposed to do. That is fundamental. There would not be anyone who would argue about that. Then another factor is the economics and it is an important factor, the difference between $17 a hundred and 59 cents is quite a bit. Any hospital that used a substantial number of drugs but did not develop a formulary to take competitive bids is a poorly managed hospital. When they design the formulary, they design it to be used. The testi- mony of the witnesses here is that it is used and it is the exception when a doctor insists that he wants to give Meitcorten or Paracort instead of Merck's prednisone or Wolin's. If he has a reason, he may. But that is the exception. So patients are going into hospitals and often going back to their own or another physician, who is not associated with that particular hospital. And this physician decides that he will prescribe Meticorten instead of Paracort and the little red tablet becomes a little yellow one and you have shattered the patient's confidence. That is all I am saying. It works both ways. So to use your argument, you just turn it around and use this one. It happens all the time. I wonder about how much shattering, but I suppose it happens. Dr. ALFANO. I know it happens. I recently spoke by telephone to a colleague at the Naval Air Station, Alameda., Calif., and asked if he had any problems with generic drugs versus brand name drugs. At the naval air station it is customary to use both brand name and generic drugs. He related one experience PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4533 that illustrates the problem. A patient was hospitalized in order to achieve a therapeutic blood level by a particular drug. Upon dis- charge, the patient was given a prescription for the drug and instructed on how to take the medication. The patient presented the prescription at the pharmacy and received the generic drug of the brand name prod- uct he received while in the hospital. A week later the patient returned to see the doctor. The patient stated he had not taken the prescription medication because it was different from the medication :he received as a patient in the hospital. The patient had to be readmitted to the hospital and treatment was started all Over again. It is quite obvious that there can be fatal consequences with interference to the physician- patient relationship. Senator NELSON. Let me ask a question. That is one example. Now suppose a patient had been `admitted to the hospital and had been get- ting a generic drug. He comes out of the hospital and the doctor pre- scribes a brand name drug. He goes to the pharmacy and sees the brand name drug as a little yellow one instead of a little red one. He refuses to take it. He has to go back to `the hospital. What are you proving? In one case, it was a brand name he got in the hospital and rejected the generic. In the other case, he got out and refused to take the brand name. What are you proving? That the brand name is better than the generic? Dr. ALFANO. I don't believe the practiàe is as you stated. The phy- sician doesn't change medication on the patient that way. A physician will use medication and carry it on to the point where if that medica- tion is not working any more, he will change the prescription and order a new medication. Senator NELSON. Are you saying in this case at the hospital, the doctor prescribed the brand name and the pharmacist illegally substi- tuted the generic name? Dr. ALFANO. No, this is a system here. They have both brand name and generic drugs. While in the hospital, evidently, the brand name was used and at the pharmacy, the generic drug was dispensed. It could be the other way around. Senator NELSON. Of course. But what does it prove? Dr. ALFANO. It proves that you must have consistency as far as the medication. A patient gets confused. I have seen it happen. Have you ever gotten medication, you get one type of medication, it is for a certain condition, and you go to a pharmacy and you have a different type of medication and it is foreign to you, that you do not question it? Do you feel, well, it is a different color and must be the same? It is irrational to say it is the same. Senator NELSON. I assume you could have some instances on six or seven drugs and they switch. But you are using the case where the patient goes to the hospital and is taken care `of in that hospital by the specialists, goes on back to a local physician in another city. The doc- tor there knows he is supposed to get prednisone, so he' writes a brand name that he likes. It is not generic. So the patient's confidence is shattered again. Dr. ALFANO. No, no, it isn't. It is understood. This is the patient- physician relationship that exists. There is no disturbance there. I write a prescription for a patient, tell the patient, you take it. They fill that prescription. You are talking about `another doctor's prescription? PAGENO="0244" 4534 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Yes, so his confidence is shattered. Dr. ALFANO. ~o, it is not. Senator ~ELSOX. There are tens of thousands of patients who go into hospitals and get a drug and go back to a doctor in their rural coimnirnities. The doctor has been notified that the patient is supposed to get this particular drug. He will be notified, most likely, in generic terms, that he should be getting, for example, prednisone. So the doctor will say, well, I will select Paracort. In the hospital, he got Meticorten. So he is upset. Or in the hospital, he got Wolins' generic. So he is upset. All I am asking is, what are you proving? Dr. ALFANO. You are trying to change this around, Senator, because the patient is treated by Dr. A in the hospital a.nd has a certain medi- cation. He goes home, Dr. B states, I will write a prescription for you to cover what you have been taking. Here is my prescription for the same medication made by a. different company. There is no confusion by the patient. They accept the fact. They have a new prescription. it is the same medication, made by a different manufacturer. There is no confusion. Senator NELSON. So he writes a prescription and all of a sudden, the patient loses his confidence because it is a different pill. But if the doctor explains to him, you have been getting a little round yellow one. Dr. ALFANO. The patient knows that. Senator NELSON. I know, but now I am going to prescribe one for you and it is going to be a little round red one. Don't let that upset you. Dr. ALFANO. if he knows it, he had better tell the patient that, because the patient will be. confused if he has a different type of nmdi- cation. This has happened in practice. This is not a theoretical type of problem. Senator NELSON. I am sure it happens, and I am sure the example I have given where the patient gets a generic in the hospital and he gets a brand name back in the town where he comes from and he refuses to take it and they have to put him back in the hospital, as far as I am concerned, that proves you should have continued to give him the drug under its generic name. Dr. ALFAN0. You have turned around what I was trying to say. Senator NELSON. Just applying the same logic to both situations. Please proceed. Dr. ALFANO. This same sort of thing would happen when a patient refiled a prescription and, in the meantime, thie pharmacist purchased the generic drug from a different company. Also, this would happen when the patient changed drugstores. In all cases, the extra physician visits required to reassure the patient and to reestablish the contact between the physician, patient, and the medication in use would do away with all the savings achieved by requiring the use of generic drugs. Confidence on the part of the patient in his physician is absolutely necessary for the physician-patient relationship, and vital to the patient's response to a course of treatment. A patient who loses confi- dence in his physician or is not secure in the medication received does not respond to the treatment, which results in a delay in returning to full productivity. A physician cannot adequately treat his patient if he does not have full confidence in the medication taken by the patient. The individual PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4535 physician has developed confidence and faith in a particular drug and in the manufacturer over a period of time. Experience with a drug which consistently produces the desired effect results in confidence. No amount of advertising in journals, by mail, at conventions, or per- suasion by the detailman can short circuit the process of developing confidence in a particular drug. The pharmaceutical firms know that, confidence on the part of the physician is essential for the existence of the company. As a result, these firms are constantly striving to prpduce quality medications and to improve their methods of production. A bad result with a drug or misleading information cutting corners, or a bad batch of `a particu- lar medication can be disastrous for a pharamaceutical firm. Each pro- prietary company is identified with every one of its brand-named drugs and puts its reputation on the line with each and every package that leaves the plant. A generic drug is anonymous. By inspection there is no way of telling what the drug is, let alone the manufacturer. The generic drug firm if it so desires can cut corners and if a bad result occurs, the attention is not focused on the manufacturer. There is no need for the generic firms to gain the confidence of the medical profession be- cause there is no way of identifying the drugs produced with the generic firm. Once there is product identification, the company is a brand-named firm and must have the confidence of the medical profession. Senator NELSON. Let me ask a question here. Again, what we seek to get in the evidence here-and we ask about this constantly-is what are the examples of adequacy or inadequacy of the generic drug versus brand name? We have been asking that for 2 years and really have not been getting any adequate answers. We get the assertion that you can't trust generics, you h'ave to have confi- dence, you have to stick to the brand name company. But, we just do not get any real evidence that this is, in fact, so. Dr. ALFANO. As I stated, I will send that report on oxytetracycline that has come out. (Material not received.) Senator NELSON. Conirnittee counsel tells me that that would not quite fit the circumstance, because that drug is only produced by one company, Pfizer. Dr. ALFAN0. I do not have the report. I cannot go discussing it. Senator NELSON. Is this Terramycin? If it is Terramycin, it is under patent to be produced by one company. Dr. ALFANO. As I have said, I do not have it, and I could not come up with the answers. But you could just, on chioramphenicol, `have one product and show that-as far as I know, there has been evidence to show that the generic product was not therapeutically equivalent to the trade name product. Senator NELSON. The FDA testified that that is not the case. I asked Dr. Ley who was here just last week. I asked him if FDA had any evidence that there was any difference in the therapeutic equiva- lency of the chloramphenicol they took off the market? He said there is no such evidence. They achieved a different blood level at a different period of time. That is all. Dr. ALFANO. What was that period of time? PAGENO="0246" 4536 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELsoN. It is in part 6 of our hearings. All I am saying is that there is no evidence that Dr. Ley knows about, and I guess he would know it, because they have asked us about every single brand of drugs-but they wanted to achieve the same blood level over the same period. So they set that standard. Dr. ALPANO. Was there any blood level? Senator NELSON. Oh, yes. Dr. ALFANO. I saw that thing in a generic product just in dissolving it. Over a half hour, it never dissolved. Senator NELSON. We have that both ways. We have as many brand names that do those things as generics. As I said, according to the only test we have had on potency that is big, the brand name companies did not meet the standards of the generics. Dr. ALFANO. I am saying here, Senator, once a generic name is identified, a generic drug is identified with a manufacturer, then it is essentially a brand name. It is identified. There is knowledge of this. I am not saying that the generic drugs are not worthy of being used or that type of thing. Senator NELSON. As I am sure you know, a number of purely ge- neric manufacturers manufacture compounds for the brand name companies. One of the distinguished companies is Strong, Cobb & Amer. Many brand name companies buy from Strong, Cobb & Amer. Dr. ALFANO. Oh, yes, but while they have no name of manufac- turer as to source, there is a question mark as far as the medical pro- fession is concerned, and there should be. Senator NELSON. All I am saying is that you hear the fiat assertion all the time that brand names are better and yet the only test to date says that generics are better. Dr. ALFANO. I am only Saying that generics with a known manufac- turer is a brand name. They do not have identification as you do with an ethical pharmaceutical firm. There are ways of identifying them with name. initials, and so forth. Senator NELSON. I assume the pharmacist knows whether it is Lannett, American Pharmical or Merck or anything else. He knows. There it is. It is a little label on his jar, manufactured by this com- pany. The tablets, except for one company, are not identified. The identity code is only used, so far as I know, by one company. All I say is we continue to hear these assertions from the people who come before us, but when I ask for examples, I do not get them. For example, let us take a recent case. This involves Parke, Davis. Have you heard of the TinnerhoZn-t case involving Parke, Davis & Co., a 1968 case which involved a brand-named vaccine, sold under the name of Quadrigen by Parke, Davis & Co. In 1968, the Court said: Evidence in action against manufacturer of vaccine for damages resulting from infant's having been injected with vaccine by physician established that vaccine was defective and that defect was proximate cause of infant's injuries. Since that time he has been retarded in his mental development, being clas- sified in the imbecile-idiot range. evidence established that there existed sufficient number of both unreal- istic and conflicting reports from field to have required manufacturer to take serious second look at its product before placing it on the market. PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4537 Then, in another case, the Court said: Of the severe reactions reported, the first apparent instance in which death resulted was in March of 1959. It does not appear that Parke, Davis made any effort to determine the cause of the high incidence of reactions, and only a cursory attempt was made to investigate the cause of a death attributed to the use of Quadrigen. This is just one brand name. We do nOt have such cases on a generic company. Were you aware of these cases Dr. ALFANO. No, Senator, I was not aware of that. Senator NELSON. This raises an interesting example, Doctor. I will wager that hardly anybody in the medical profession is aware of these cases. But if this had been a generic company, you would have seen the Pharmaceutical Manufacturers AssociatiOn grind out a load of propa- ganda attacking generics, reciting the deaths which resulted, saying it was a generic company, you cannot trust them, and all of the medical journals in the country would have run their stories. Because every time you make an attack like that, they get publicity. The case of chioramphenicol is an example. So you have an interesting case here of a distinguished brand name manufacturer. Nobody knows about these cases. Because you can bet your hat that the Pharmaceutical Manufacturers Association did not spend money to notify the medical journals, and the medical journals have a tendency, from my reading of them in general-some of them much worse than others-to more or less ignore such things when it involves a brand name company that advertises in the journal.' I think these are interesting cases and I shall put them into the record at the end of today's proceedings.' Dr. ALFANO. I believe the example of Parke, Davis, when it was known that chioramphenicol or Chloromycetin caused aplastic anemia, I believe the record shows that the medical profession reacted to the bad result or this complication of the drug. Their sales dropped off. It was reported that way. You will probaibly find that the medical pro- fession does not depend on outside agencies to get this type of informa- tion. The American Medical Association~ 1 `am sure, will list this result. Senator NELSON. On this I think you will find there is an interesting relationship. Part of the committee consideration here is to ascertain the relationship between the medical profession and the manufactur- ers. What I am saying is that they would have ground out the story in big press releases and announcements and all the medical journals would carry it, attacking and saying, here is another example why you can't trust a drug under its generic name. The doctor reads that and says, oh, oh, you have to stick with the brand name. This is a fantastic propaganda machine. `Dr. ALFANO. I do not believe a doctor chooses on that basis, really. At least, I hope not. Otherwise, we are in trouble in this country. Senator NELSON. You mentioned the case" of chloramphenicol. I believe that was the most tragic case of misprescribing of drugs prob- ably in modern history. But the organized medical profession `did not make a point of informing its members-those who were misprescib- ing. This committee conducted extensive hearings, and because of the vast publicity and the lawsuits started around this country, the 1 See information beginning at p. 4558, infra. PAGENO="0248" 4538 CO~ETITIVE PROBLEMS ~ THE DRUG INDUSTRY use of chioramphenicol dropped after our hearings. In the year 1968, it dropped from 40 million grams prescribed down to about 20. But the testimony before this committee by distinguished doctors and pharmacologists and authorities in the field is that about 90 to 99 percent of the patients receiving chloramphenicol are receiving it for nonindicateci cases, an incredible number. Dr. ALFANO. Ninety to 99 percent, is that? Senator NELSON. One of the witnesses testified that in his judgment, less than 1 percent of the people getting cliloramphenicol are getting it for indicated cases and that of every death he had ever seen from chloramphenicol, not one had received it for an indicated case. Dr. Dameshek, the distinguished hematologist who has written for the AMA on this question, testified that perhaps about 10 percent received it for indicated cases. Our files are filled with letters, two more last week-I get some every week-of cases of doctors prescribing chloramphenicol for non- indicated cases-acne, infected gums, flu, sore throat-the last one, a woman died from getting it for flu-hangnails, all kinds of things. How did it get that way? It got that way by some fantastic promo- tion in the medical journals in this country. That is what misled phy- sicians. They did not correct it. Dr. ALFANO. I have never seen it advertised for hangnail or flu or acne or that type of thing. Senator NELSON. No; it is just advertised-Chloromycetin, when it counts. Very cleverly over the years, it has been promoted-at least it ends up this way-for use as a broad-spectrum antibiotic for all kinds of things. I do not think the doctors promoted it. I think it is the company's promotion that was effective through their detail men, through their advertising, through their promotion. Or maybe somebody else has an explanation. The medical profession did not reform itself. The reduction in use has come about from the broad publicity this committee is getting. Last week, Dr. Ley testified that still about 90 percent of the patients are getting it for nonindicated cases. Dr. ALFANO. I am glad the committee has had a beneficial effect, but I believe we should not condemn the pharmaceutical industry or the PMA. I think it is a function of the medical societies, the medical organizations, to improve their continuing education programs. I believe you, through the committee, have probably functions in that regard. I do not believe you can condemn advertising per se as the cause of a problem `that exists probably based on something else. I am involved in continuing surgical education and there is a prob- lem as far as stimulating the individuals to participate in courses and methods of instruction. Senator NELSON. Well, what responsibility does the profession have? The fact is known. The medical journals, I suppost all of them-I do not know whether 1 have seen an ad in your journal on Chloromycetin, but I assume you have had them. I have seen them in all kinds of medical journals, including the AMA journal. Dr. ALFANO. It is a good drug. Senator NELSON. Yes, but the indication is~ Dr. ALFANO. It has uses. `Senator NELSON. But the indications are very, very fiinited. PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4539 Dr. ALPANO. I know, `but when you do use it as a lifesaving drug, you have nothing else to use. This is it. Senator NELSON. As you probably know, the National Academy of Sciences has said it is not the drug of choice for any case. But inchca- tions have been that it is only to be used if the disease is serious, if no other drug will do the job, and only if the disease will respond, the organism causing the disease will respond to this drug. But that is not the way it has been used. The AMA itself is aware that 90 percent of the people are getting it for nonindicated cases and they still accept big drug ads promoting the drug. You would think the AMA would require them to put a big box in the ad saying, "This is being widely misprescribed," that they would run headline stories saying, "Doctors are misprescribing this drug and killing people with it"-would you not? Or else refuse to take the ads on the ground that the promotion has resulted in the mis- use of the drug. What's the answer there? Dr. ALFANO. I don't believe they have substantiated these claims by individuals and when they have, the medical profession will do something. I don't believe they have gotten it down to that, that only 10 percent of the cases are prescribed right. This has not been proved. Senator NELSON. That is true. Dr. ALFANO. I am not aware that the medical profession is-but it should be working toward that end-coming up with the facts as far as they can to determine which way they should act concerning cer- tain drugs. Senator NELSON. Five of our witnesses, doctors2 stated `that it was their guess, their best guess, that it was about this way, based upon what they have seen, each of them having a wide experience with the drug. Dr. AL1~ANO. No, Dr. Dameshek; he is a hematologist. He would have the end result of a complication, not a wide use of that particular drug in his patients. I do not believe he would use it at all. Senator NELSON. When he sees a patient and 90 percent of them got the drug for nonindicated cases- Dr. ALFANO. That is retrospect, also. There is another problem in there. Looking back, you can get 10 doctors, a hundred doctors, you will not find they all agree 100 percent as to the course of treatment, type of drugs. Medicine has considerable variation in treatment and methods of treatment. You can have experts all disagreeing. Senator NELSON. That is correct. But when you get one of them testi- fying that in every death he had seen from aplastic anemia, not a single patient had received it for an indicated case-if you see all five of them testify along the same line, so they conclude as they look at people with aplastic anemia that if nine out of 10 of them are `getting it for a nonindicated case, that might give you a pretty good guess that where nine out of 10 people did get it for a nonindicated case, they just didn't get aplastic anemia. Dr. ALFANO. No, I would not say you can project it that way on just a small sampling of indications. At least, 1 would not accept it that way. Senator NELSON. Please go ahead. Dr. ALFANO. Awareness of the name of a manufacturer by the physician and indeed by the patient is in the best interests of the pub- lic. The manufacturer must produce a drug of the highest quality PAGENO="0250" 4540 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY possible because he knows that an inferior batch of one drug will adversely affect his entire line of products. He must protect his repu- tation as does any other manufacturer. In fact, the drug manufacturer is more vulnerable than other manufacturers because the word travels fast throughout the medical profession when something goes wrong. This is certainly in the best interest of the public. I would like to point out that the pharmaceutical firms provide services for the patients and medical profession which are essential for proper medical care. Generic drug firms do not provide these services. A vital and indispensable service offered by the ethical pharmaceu- tical firms is a medical department available 24 hours a day every day of the year. If a physician finds he has an untoward reaction caused by a particular medication he can call upon the medical department for assistance and advice. When a drug does not seem to have the de- sired effect the medical department is available to help solve the prob- lem. It must be remembered that the medical department has accumulated the reports of physicians from all section of the country representing the sum total of millions of doses for each medication. How can we overlook the importance of this one particular service for the sick of our country. We must not gloss over this service by stating we know and appreciate the contributions made by the pharmaceutical firms but comparisons show that the generic drugs are cheaper for the most part and therefore the patient has been gouged by the brand name drug firm. This price differential would not be as great if the generic drug firms offered the services of a medical department. I don't believe that this committee or the American public would tolerate the loss of the services of the medical departments of the ethical pharmaceutical firms. Indeed, this committee should insist that the generic drug firms provide the services of a medical depart- ment similar to the services provided over the years by the medical departments of the proprietary drug firms. The medical department is only one of many services provided by the pharamaceutical firms and these services cost money which is reflected in the cost of drugs. Another example is the professional relations department which will respond to a wide variety of requests made by the individual physician. Pharmaceutical firms are always ready to supply a rare drug or a drug in short supply for a single patient. A simple telephone call by a physician starts in motion the mechanism to bring to a patient the required lifesaving drug. The cost in man-hours expended for the benefit of one patient plus the other costs involved are not re- covered by the drug firms. It is a service. Senator NELsoN. Doctor, let me interrupt for one moment. It is all included in the cost of production like any other overhead cost. They put it in the price of the drug. It is a cost of operation, just as an advertisement is a cost of operation. They recover it from the drugs all right, otherwise it would not be the highest profit industry in this country. Dr. ALFANO. I know, but it is a service to the patient. The generic firms do not offer this to the doctor or the patient. Senator NELSON. I just want to say it is included in the cost of the drug. PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4541 Dr. ALPANO. Oh, sure, this accounts for part of the cost of the drug, right. Senator NELSON. Of course. Dr. ALFANO. A detail man is more than a salesman. In my area most of these men are registered pharmacists. The detail man provides the physician with information on new products plus a review of estab- lished drugs. True, he endeavors to have the physician use his firm's products. It's logical because without sales the firm would go out of existence. However, the detail man's first job is to inform the physician about the drug, how it works, the side effects, and contraindications. He must provide the research reports and reprints of clinical trials of the drug, answer questions and supply or obtain whatever addi- tional data the doctor may desire. A drug detail man is more than salesman, he is a professional who is well informed about drugs. A liaison between his firm and the individual physician, he is the man turned to by the hospital, the pharmacist, and the physician to obtain whatever is required either in drug information or services. Research at the rate of more than a million dollars a day is carried on by the pharmaceutical firms. Naturally, each company strives to come up with a product which will return the money spent for re- search. But this does not happen with predicted regularity. But all this is not lost because both the positive and negative results con- tribute to mankind. Pharmaceutical firms support continuing medical education. They support postgraduate programs by grants to pay for emminent speak- ers. The firms do not require that their products be mentioned or discussed in the post graduate programs. In fact, they made a point of stating that all they desire is a credit line indicating the company is sponsoring the program in part. They support continuing medical education because they know it is vital for the medical profession and the public. Certainly they are aware that a better informed profession will result in benefits to the entire pharmaceutical industry. The pharmaceutical firms provide almost unlimited quantities of new drugs to clinical investigators in order to determine the effectiveness and safety of the new product. Financial support is given to carry out the clinical trials of a new drug which entails the keeping of extensive records, almost constant laboratory examinations and close observation of the patient. After a drug has successfully passed the clinical trials, the drug firms support scientific exhibits which present the results of the clini- cal trials. It is in the interest of the pharmaceutical firm to support a scientific exhibit which is centered around one of its products. How- ever, a scientific exhibit is an excellent method of making known to the profession the existence of a new drug. Scientific exhibits use the generic name of drugs in the display material and mention the trade name and the manufacturer as a footnote. Most important, the physician who participated in the clinical trials is available at the booth to answer questions and to add whatever additional explanation may be needed. The scientific exhibit's purpose is to make known the existence of a new drug and the results of the drug with patients during clinical trials. PAGENO="0252" 4542 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Without scientific exhibits, published reports and reprints the benefits of a new drug could possibly take years before it reached the members of the medical profession, and also their patients. If the generic firms provided these services there would be little difference in prices between the generic drugs and the proprietary drugs. Senator NELsoN. May I interrupt a moment? I raise the question again of how you can assert that with confidence? If so, how can you explain that Schering can sell its drugs for $1.20 a hundred to New York City and sell it for $4.25 a hundred in Berne, Switzerland, but stayed in the marketplace until after these hearings at $17.90 a hundred? Why were they not selling it here at less than the price at which they were selling it in Berne, Switzerland. You say they have to have these prices in order to do all these services. Why do they not have to have that price when they sell to New York City, De- fense Supply, or Berne, Switzerland? Dr. ALFANO. As I said before, I cannot explain these extremes. I am talking about the average, the usual that is going on in medicine, not specifically isolated types of examples or a handful or whatever number of examples are available.This does not occur throughout the entire industry. Senator NELSON. Every single brand name drug that was patented has the same time-17 years. Every company sells it cheaper to New York City by far, than they do in the marketplace. Dr. ALFANO. What I am saying is, there is a difference. The cost is increased by these services. I am not trying to justify an extreme cost by these particular types of services. These services are provided by the ethical pharmaceutical firms and not provided by the generic firms. Senator NELSON. But this is continually asserted by the manufac- turers as the reason for their prices. All I point out is they get a patent. That is the only protection they are entitled to. Nobody else in Amer- ica who gets anything patented is able to stay in the retail marketplace once the patent runs out at an exorbitantly high price. For example, you have invented a new lawnmower, you are selling it at a high price because the patent ha.s been in effect and it is a good lawnmower. Then the patent runs out. You can't get by in the marketplace selling it in competition with other lawnmowers, because the consumer can make a judgment that another one is just as good at a cheaper price. But the consumer camiot make the same judgment on drugs. The drug com- panies know he cannot. The purchaser for New York City or the Defense Supply Agency, or the Veterans' Administration, that buyer can make the judgment and he does. And the drug company dramati- cally drops its price. So on the same day they are charging 30 times as much to the phar- macist, they are offering it for one-thirtieth as much because they know they have to compete with other brand names and the generics. In the retail marketplace, however, the buyer is not qualified to make any distinction at all. The doctor writes a brand name. }-Ie prescribes and the buyer, the patient., pays. These great discrepancies apply to all the drugs that I have looked at. Everybody comes in with the assertion that they have to have this price because they do all these services, but nobody ever explains how PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4543 they can make a profit of $1.20 and make a profit in Berne, Switzer- land, of one-fourth as much. I just say, to you, Doctor, and I do not want to be unfair to you because a number of other witnesses have said the same thing-I just say that in my judgment, your statement is not supported by the facts and what you are repeating is what the pharmaceutical manufacturers have been saying year after year. Most of the medical profession also has been saying this. Most of the medical profession has never heard what the industry charges in New York City or in Switzerland and London and Rome. We have checked all these cities. The physicians do not know what is being done over there. If they did, I think they would say to the companies, how do you explain that you are selling it cheaper, one-fourth as much, in another country and my patient has to pay four times as much? I have never heard a doctor say that. I, know why. He has not heard about it. But he has heard from the company at the rate of $4,000 or $5,000 advertising each year to each physician. So the company has convinced the physician. What you are saying to me-and I am not critical of you for it-is what nine out of 10 doctors say to me when they talk to me across the country. I had a meeting in Wisconsin with four doctors. One of them started to say to me, here's the reason why the firms have to charge more. I said, you just hold that for a minute, and I called another doctor aside and said, here is what he is going tO tell me, and I lined up all the arguments by the pharmaceutical industry. And we went back to the group and the doctor told me every one of these items. Because that is what he has heard from PMA. The evidence supports that every single one of the doctors and the pharmaceutical manufacturers said the same thing. Dr. ALFANO. I am telling you what I say did not come from the PMA. About 2 years ago, I wrote to the pharmaceutical firms asking for the services provided by these companies. If you wish, I could send a couple of suitcases of material down to you. This is what I got from being in the practice and being exposed to the services provided. I do not believe I have anything in here that comes from the pharma- ceutical manufacturers, at least that I received and put into this statement. Senator NELSON. I believe that a number of my good friends make the same argument. I am not saying there is anything illegal about that. I am just saying that the manufacturers have made what to the doctors have been a compelling, convincing case and the doctors be- lieve it. All I say is I do not think the doctors know the whole story, because when I have asked the doctors about these prices, they have never heard it before. They can't explain it. But the record can't stand without having these examples saying, why can they sell in Berne, Switzerland at $4.50 and sell here at $fT.90. I call that gouging. Dr. ALFANO. Have the companies not been in to explain the differ- ences in costs? Senator NELSON. Yes; when I asked Mr. Conzen-I had the whole list of foreign prices-he said, they charge less in Berne, Switzerland, because the standard of living is lower over there. But they charge more in Mexico City by three times than in Berne, Switzerland. When PAGENO="0254" 4544 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY I asked him about that, he said he did not know the answer and he would have to ask the comptroller of the company. I said you ask him and write me. That is a year ago and I have not heard. Dr. ALFANO. I do not believe the medical profession can answer these questions of cost and the differences, really. However, I have more faith in myself and my colleagues, that they will not knowingly write prescriptions for a high-priced drug when they know full well that there is an available drug that will do the job and cost a lot less. Senator NELSON. I am confident of that. I think the medical profes- sion is a profession of integrity, but they do not know these facts. That is the problem. So when the spokesmen of the medical profession say the drug companies do all these very fine things and the generic companies do not, therefore that shows the price differential--- Dr. ALFANO. It accounts for a proportion of that price. The price can't be equal when one is providing certain services and another is not. There have to be differences. What the difference is, I could not give you. That I do not know. Senator NELSON. But to make this unqualified defense all the time of the industry, not being able to explain-as a matter of fact, not knowing-that the company they are defending is selling at one- twentieth the price to New York City and the Veterans' Aciministra- tion, and one-quarter the price in Berne, Switzerland-I am just say- ing this argument does not hold water because they are charging a fraction of that price in other parts of the world and in the Defense Supply Agency. I see I have a rolicall vote. I will try to be back in a couple of minutes. (Short recess.) Senator NELSON. Please forgive me, Doctor. Will you proceed? Dr. ALFANO. A compendium which lists all prescription drugs un- der their generic names together with all the necessary prescribing in- formation and a supplement of the brand names, the suppliers and the prices at which the drugs are available at first seems to be a laudable endeavor. As I understand it, the compendium would list 7,000 drugs with 21,000 dosage forms. This type of listing would not be practical since it could not be easily used by the prescribing physician. For ex- ample, the PDR contains about 600 drugs and is more than 2 inches thick; the compendium would contain almost eight times the number of drugs listed in PDR and would be at least 16 inches high. Even if special paper were used the book would be 15 inches high because it would contain 10,000 to 12,000 pages. The compendium would not be used and the PDR would continue to be used by the busy physician. Why is it necessary to list all of the 7,000 prescription drugs when in reality physicians are in the habit of using a small number of drugs. ~\Then it becomes necessary to prescribe an infrequently used drug, the physician can obtain the required information from the appropriate reference material. Mr. GoRDoN. May I ask you a question at this point, Doctor? Dr. ALFANO. Yes. Mr. GoRDoN. You are a surgeon? Dr. ALFANO. Yes. Mr. GORDON. Can you give us an idea of the number of drugs, on the average, the abdominal surgeon prescribes in a year? PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4545 Dr. ALFANO. The number of drugs? Mr. GoiwoN. Number of different drugs. Dr. ALFANO. No; I could not. I have actually been out of practice the last 6 or 7 years, so I could not give it to you right from actual experience now. Mr. GoimoN. Could you give us an idea? Dr. ALFANO. A surgeon uses less drugs than, say, an internist or a general practitioner. Mr. GORDON. Would you say about 25 or Dr. ALFANO. Well, about 25 would be a reasonable number that are constantly being used-pain medications, infection, control of infection, that type of thing. Mr. GORDON. I see. Around 25. Dr. ALFANO. I could be way off on that. I am guessing. really. Mr. GORDON. What would be his principal source of information about toxic and dangerous properties of a new drug? Dr. ALFANO. On a new drug that he is using now? Mr. GORDON. Yes. Dr. ALFANO. We have had a survey in the past on why does a physi- cian, why does one of our members use a particular drug? What causes him to use that particular drug? Twenty-three percent stated an ar- ticle in the journal was the No. 1 reason they used- Senator N1n~soN. You are talking about surgeons? Dr. ALFANO. Members of the American Society of Abdominal Sur- geons, right. Senator NELSON. You are talking about your journal, or all articles in- Dr. ALFANO. No, no; any medical journal. Senator NELSON. Twenty-three percent, did you say? Dr. ALFANO. Twenty-three percent; yes, sir. Mr. GORDON. How about the rest? Dr. ALFANO. I have that, I am pretty sure. Do you want to know what influences a physician to use a particular drug? Mr. GORDON. No; the surgeons. Dr. ALPANO. The surgeons; yes. This was a survey sent to members of the American Society of Abdominal Surgeons. Senator NELSON. How many do you have? Dr. ALFANO. 9,000. Senator NELSON. How many responded? 9,000 responded? Dr. ALFANO. No. The questionnaire was sent to 1,500 surgeons and a total of 20.53 percent of the surgeons responded and completed the questionnaire. Senator NELSON. When was the survey coflducted? Dr. ALFANO. 1964. Senator NELSON. And what other sources did they use? Dr. ALFANO. Presentation at a medical meeting-at a meeting. It does not say medical meeting-presentation at a meeting, 19.8 percent. The detail man, 19.6 percent. Exhibits at a meeting, 11.6 percent. Recommendations from a colleague, 11.5 percent. Journal advertise- ment, 7 percent. Senator NELSON. Advertisement in a- Dr. ALFANO. In a journal. PAGENO="0256" 4546 COMPETITIVE PROBLEMS ~ TI~ DRUG INDUSTRY Senator NELSON. Medical journals in general, you are talking about? Dr. ALFANO. Yes; because a surgeon would get, say, the Journal of the American Medical Association. Mr. GORDON. What percentage is that? Dr. ALFANO. Seven percent. Advertising sent by mail, 4.6 percent. Miscellaneous, 2.5 percent. That first figure, journal article, exactly is 23.4 percent. Senator NELSON. This was a survey as to where they got their infor- mation or began to use a new drug, is that what you are talking about? Dr. ALFANO. Yes; the factors that influenced them to use a particu- lar preparation, what caused them to use this particular preparation, brand new, the first time they used it. Mr. GORDON. What percentage did you get for detail men? Dr. ALFANO. 19.6. Mr. GORDON. And the percentage of those learning from colleagues? Dr. ALFANO. 11.5 percent. Mr. GORDON. It could be, of course, that the colleague could well have secured his information from, say, the detail men or advertising or a journal. We just do not know. That does not mean too much, really. Dr. ALFANO. No, no, but this is-that is right, the colleague has to get the information originally from some particular spot. I would say it probably follows the same, though it would be a journal article or a presentation at a meeting or a detail man. Senator NELSON. Please continue. Dr. ALFANO. I suppose if a smaller listing of prescription drugs was undertaken it would be a duplication of the PDR and would serve no additional purpose but would create the problem of what drugs to list and who would make the selection. It appears that the American Medical Association's drug evaluations currently being developed would serve the purpose of the medical pro- fession because it would include the 500 most commonly prescribed drugs. It also would give a comparison of drugs within the same class. Information on the pharmacology of the drugs would be included in the AMA publication much of which is lacking in the package inserts. The proposed compendium would lack the pharmacology nec- essary to knowing all about a drug since the compendium, as I under- stand it, would be made up of the package inserts. Senator NELSON. We have had some testimony on the concept of a compendium. We have introduced legislation, but as to what the nature or makeup of a practical compendium would be, we have not really gone into it in any depth, nor have we received the advice of all the appropriate sources, the medical profession and organizations and the manufacturers and so forth. So I would guess when we have hear- ings on a compendium, if such a bill were recommended by the com- mittee, it would be one that was developed as a consequence of testi- mony from a broad number of authoritative sources. As to whether it would be package inserts or something else, I do not know and I would not want to form a firm opinion until I listened to the appropri- ate experts in the field. Dr. ALFANO. If it is the intent of the compendium to bring bef ore PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4547 the physician a list of the generic drugs and a price comparison then this could be done by a supplement to the AMA drug evaluations. However, if the intent of the compendium is to change the prescrib- ing habits of the medical profession then I don't believe that this can be accomplished by the compendium. The chairman of the Monopoly Subcommittee stated in invitation to speak before the committee that some witnesses have expressed concern about the dependence of medical organizations upon funds derived from the drug industry. I can speak for the American Society of Abominal Surgeons and state that the society does not depend upon funds from the drug industry. The society can function without any outside help. In 1961 drug advertising accounted for 7 percent of the cost of pub- lishing the Journal of Abdominal Surgery. In 1962 it was 8 percent; 1963, 17 percent; 1964, 21 percent; 1965, 28 percent; 1966, 49 percent; 1967, 61 percent; 1968, 41 percent. Senator NELSON. May I ask a question at this point? Dr. ALFANO. Yes. Senator NELSON. When was the journal founded? Dr. ALFANO. The first issue was February of 1959. Senator NELSON. We have the percentage figures here supplied by the Legislative Reference Division of the Library of Congress.1 Do you have the dollar figures? Dr. ALFANO. Yes. Senator NELSON. That is, the dollar figures of advertising? Dr. ALFANO. I have the net advertising income. Senator NELSON. What does that mean? Dr. ALFANO. That means the advertising income-for example, in 1961, it was $5,533 of advertising income. Subtracted was the commis- sions that went to the advertising agency plus our own space repre- sentative who gets a commission. Senator NELSON. So the figures you are going to give us now are the net, not the gross? Dr. ALFANO. Not the gross, billing, yes. For example, 1961, it was $5,533 as a gross. The net was $2,846. Senator NELSON. Could you give them to us for e.ach year? Dr. ALFANO. Yes. 1961, $2,646; 1962, $3,520; 1963, $8,657; 1964, $10,592; 1965, $15,214; 1966, $41,941; 1967, $55,734; 1968, $42,138. Senator NELSON. What was the figure for 1967? Dr. ALFANO. $55,734. Senator NELSON. Now, were these all net figures? Dr. ALFANO. Those are the net figures, yes. Senator NELSON. I see. Mr. GORDON. What percentage of your total income would that be? Dr. ALFANO. That is what I have over here-no, that was the per- centage of the cost of publishing the journal. I do not have the percent- age of the total income that I can give you. I gave you-these figures are the percentage of the total cost of publishing the journal. For example, 1968, the cost of publishing the journal was $103,850; that $41,000 represents 41 percent. 1 See Appendix XIII, "A Study of Pharmaceutical Advertising in Selected Medical Journals," pp. 4863-4998, infra. 81-280-69-pt. ii-17 PAGENO="0258" 4548 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Of the cost of publication? Dr. ALFANO. Right. Senator NELSON. I see. Then what's the other income from, subscriptions? Dr. ALFANO. Yes. Senator NELSON. Do these two factors constitute the total income, subscriptions and advertising? Dr. ALFANO. Yes, subscriptions, advertising, and there is a small amount from reprints of articles that are published in the journal. An author may wish to have a hundred or a thousand reprints, whatever he desires. There is a cost for that. The income from drug advertising allows a publication to publish more articles per issue and special features which benefits the profes- sion and the public. For example, I would like to have more advertis- ing income in order to develop a monthly feature on surgical anatomy and surgical technique. This is a very expensive endeavor since it requires the talents of medical artists and surgical anatomists. I hope that all will agree that this is a worthwhile endeavor. Mr. GORDON. Doctor, may I interrupt? When you say you would like to have more drug advertising to publish more articles, what you are really saying is you would like to have the public, the drug-consuming public, pay for this. Surgeons do very well financially. Why should they not pa.y through higher membership rates or higher subscription rates? Dr. ALFANO. Well, I have not tried that system. You mean assess the individuals who receive the journal higher amount? Mr. Gor~oN. When you say you want more advertising, you are really saying that you want the consuming public to pay for it. Dr. ALFANO. Well, the public, I am hoping, are the ones who benefit from the results of the journal, or from the journal itself. They are the ultimate ones to benefit from it. Mr. GORDoN. But it is pretty indirect. Senator NELSON. Please continue. Dr. ALFANO. A medical publication does not come in contact with the drug companies who advertise in the publication or the drug com- panies who are potential advertisers. A medical journal has a space representative who contacts the advertising agencies representing the drug companies. Thus, there are two independent companies between the medical journal and the drug company. The men and women engaged in medical publications have earned the respect and trust of their readers and that is really what counts regardless of what some out.siders may say in an attempt to undermine the integrity of medical publications and the sponsoring medical societies. Senator NELSON. In any event, does not the fact that a medical journal-any medica.l journal-that depends in substantial part on advertising by a drug firm, does it not really end up having, even un- consciously, a subtle effect upon the position the journal might take on the kind of promotion that is in the ad, or criticism of the industry itself? The publication is relying-it does not make any difference whether it is a medical publication or newspapers or what have you, when they receive substantial moneys from an important advertiser, is it not just potentially inherent in the case that they are going to be PAGENO="0259" COMPETITIVE PROBLEMS IN, THE DRUG INDUSTRY 4549 quite reluctant to be very critical of the one who is supplying the money that is important to the publication? Dr. ALFANO. I do not believe so. Not in medicine, sir. You can probably find it in other types of advertising, but in medicine, if there is a just criticism of the drug company or the entire industry, that criticism will be made regardless of the number of advertisers in the journal. Because this industry that is limited to 350,000 doctors; therefore, the profession is not a captive of the individual drug coin- panies or the industry. If there is a valid justified criticism, I believe every medical journal and every society would make it known and would not hesitate because they have `advertising or money coming in because of ads in their particular journal. I would never be afraid to put anything in the journal criticizing the drug industry. If I have something that is valid, I will put it in. Senator NELSON. Well, is it not just human nature, the nature of human beings, whether it is medical publication or any other, that if an important source of money is coming from a particular place, it creates a potential bias. It could be conscious or unconscious. I read some of these publications. I am not referring to yours-I have not read it, so I do not direct this at you at all. But I read quite a few of the publications that rely heavily upon drug company ad- vertising. Sometimes I cannot quite identify the hearing they are talking about because of the bias they put into the .stories. Actually they are these hearings. If you just look at them regularly, you will find a lot of bias in favor of the company. I suppose that is just natural. If that publication is critical and tough on an advertiser, who they think is doing something wrong, that advertiser is likely not to spend any money with them. I do not see how that is avoidable. So it just seems to me that medical journals and medical publica- tions are compromised by the substantial amount of money that they rely upon from an industry which needs independent critical evalua- tion from the medical profession all the time. I do not see how you avoid that. Dr. ALFANO. WTell, I believe the checks and balances-the American indivicltial is critical. They are critical individuals. If you have an association with a publication that tries to 15ut something over on its membership, that publication, that society will hear about it, because they have hundreds of thousands of members who are reading. They will not stand for something which they feel is iiot correct or proper. I do not think they can put something over on the members is what I am saying, because of money from advertising. Senator NELSON. There is no doubt in my mmd that as professions go, I am biased toward the medical profession. I was raised in a family with lots of doctors. I think there is not any profession that has a higher percentage of conscientious people in~ it. I think it probably has more conscientious people than any other profession because of the nature of the person who is inclined to select that profession in order to take care of the health of someone else. But that does not mean they are all perfect. We all know that. I happen to be a lawyer, but I think there is more dedication, a higher percentage of the people who are really dedicated, in the medical profession, doing good for other people, than there is in my profession, though we have a sub- stantial number of highly dedicated people, too. PAGENO="0260" 4550 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY So I would not raise any question about that. I think if a publication conscientiously misrepresented or defended a bad cause in the medical field, practically all individual doctors would be very critical of it. So I am not raising that question. I simply say that if you are a publication and you rely heavily upon an advertiser-in this case, it is drugs-you lust may omit criti- cizing them. You do not have to mislead by commission, you can mis- lead. by omission. I think it is true of almost every magazine or paper that relies heavily upon some industry for advertising. I do not see tough criticisms in various publications of the major advertiser in that publication, when it is a daily newspaper. They are pretty careful. If something breaks and they have to cover the news, maybe they do. But here is a case where the profession has the primary obligation to the public and its patients. And it is important that the profession at all times be vigorously, conscientiously evaluating all aspects of medicine, including the promotion of drugs and the use of drugs and advertising, policies and claims for drugs. The fact is that there are just endless examples of the drug companies making claims for their drugs that are not acceptable to the FDA. Dr. ALFANO. They do not a.ppear in journals, to my knowledge, that type of ad. They cannot. The journal must have the approved information. Senator NELSON. Counsel advises me that last year-within about the last year and a half-as a consequence of paid drug ads in publica- tions, medical publications, the FDA required 29 "Dear Doctor" letters-ui other words, 29 times in the last year and a half, because of misleading advertising, the FDA has required the company to write a letter to every single doctor in America correcting the mis- leading claim. That is quite a bit. But it appeared in the journals. Dr. ALFANO. These were ads that appeared in journals? Senator NELSON. In medical journals. Dr. ALFANO. Excuse me, the Medical Tribune is not a medical journal. Senator NELSON. I do not want to mislead you. Some of them were in these other publications which rely exclusively upon drug advertising. I recogi~1ze a dist.inction between a. publication that receives 100 per- cent of its money from drug advertising and one that receives 50 percent. But if they receive a large percentage, I think that they can- not really be independent and objective in the fashion they ought to be in order to protect the interests of medicine itself. Do you really? Dr. ALFANO. I believe the scientific medical journals, journals that are published by societies, they are published by these same individ- uals who you state are the most dedicated group in the country. I do not believe they would be influenced one way or the other by the amount of money that comes in by an ad. If they have something valid to sa.y in criticism of a particular company or of the industry, t.hey would put it in. Now, there are more than just scientific medical journals that carry the same ads. I am only speaking as far as the medical journals that are published by medical societies. Senator NELSON. Counsel advises me that 19 of the 29 "Dear Doc- tor" letters were based upon ads in medical journals. PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4551 Dr. ALFANO. I know, I have seen these "Dear Doctor" letters. I have received them and some of the criticism, they are not that im- portant as regards the patient and the result of the medication. There is a dispute between the FDA and the drug companies that I do not know that much about. But it does not seem that it makes that much difference. But these letters come out and, as you say, there were 19. But I am sure they do not affect the policy that the journal, if it is something vital, will certainly make it known in the next edition that they did publish an article that was misleading and they would make it known. Mr. GoRDON. Doctor, are you aware that certain criminal cases have been brought against drug companies for advertising in medical journals? Dr. ALFANO. I do not believe so. Which ones are you referring to? Mr. Goi~oN. Well, the criminal cases are Pree MT, Esidrix K, Esi- drix, and the civil case is Enduron. Dr. ALFANO. I do not know about those cases. Senator NELSON. I have another rollcall and I do not want to hold you over. We are late as it is. I think this is an important question, however. As I say, I do not think it is so much a question of reputable journals misleading intentionally. I do not think they do that. But the argument remains that you might omit to do something that you ought to do-I mean broadly, any journal; because that is the nature of human beings. I find it very hard to be critical of a good personal friend of mine because I like him. I overlook defects or something wrong with somebody I like, and so do you. And you end up in a posi- tion-that is, the medical journals end up-in a position, it seems to me, where just in the nature of the case, they compromise themselves and condone some of these things that they ought not to. Dr. ALFANO. There is no close relation between a journal and a drug company as such. As I stated, there are other individuals or com- panies that come between the journal and the drug company. Senator NELSON. But the financial relationship, when it reaches a substantial amount-is a close financial relationship. And if you are depending upon that and you would like to have more advertis- ing, or any of the rest of them would, I do not see how any publica- tion can avoid being compromised by it. It is the nature of the animal, I think. Dr. ALFANO. I disagree. I do not believe that this type of thing exists where they would knowingly withhold information which essen- tially is unethical for a medical publication or a man who is editor of a publication to withhold information. He must make known-what- ever he knows must be made known to his colleagues. Senator NELSON. I would not suggest that they willingly withhold, but maybe they fail to criticize. I think Chloroinycetin is a dramatic case in point. Now, many of the medical journals carried articles by distinguished authorities on the drug explaining and emphasizing that it is over- prescribed, was being widely misprescribed, at the same time they were receiving it, carrying lots of clever advertising promoting the drug. This is a terrible case, it is a terrible indictment of those in the pro- fession who misused the drug and the promoters of the drug. I would have a thought that every medical journal in America ought to have PAGENO="0262" 4552 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY front page, cover stories, and if necessary, a national meeting about it. I never saw that. It took the dramatic publicity from these hearings to do it. The medical profession should have done that. Of course, they will say, we ran an article a few years ago. We ran one another time. But the fact is the wide misprescribing continued and the leaders of the medical profession knew it and they did not stop it. Dr. ALFANO. These are the opinions of certain individuals. You mentioned Dr. Dameshek, that 10 percent only needed or it was neces- sary to use Chloromycetin. I say when this is substantiated and it is an absolute fact, you will find it in all the medical journals that x drug should not be used because it has more dangers than it has bene- fits. Until that happens, I do not believe that you should expect a journal or a society to arbitrarily take action against a particular drug, particularly the one you mentioned, which is known to be an ex- cellent drug, with its indications. Senator NELSON. There is not a medical organization or a leading distinguished authority in America who has doubted the drama of this situation-that it is being widely misprescribed. I have a file you could cry reading. I get letters every month. I have a file that high: "My daughter came home from college with a sore throat and got Chloromycetin and died." One from a husband last week with a 30-year old wife who had Chloromycetin for the flu and died. "My son had a hangnail and died"-"an infected gum, and died." Every single case nonindicated. Every single case. I did not see the profession or the journals screaming to the high heavens about it. I think it is an indictment. Dr. ALFANO. Did the profession get that information? I have not seen a letter come to our organization or the journal concerning these specific cases of misuse. However, you must remember, there are 831 million patient visits a year. Certainly there are going to be exceptions to good medical care out of that 831 million patient visits. But I do not believe because you have some examples that you have to condemn the whole professioi~ or the system. Senator NELSON. But when you have distinguished authorities say- ing in their judgment, 90 percent is for nonindicateci cases, one of them saying 99 percei~t in his judgment, nobody is refuting it. Maybe it is only 85 percent, maybe it is 95, but it is terribly high. And these pubhicatioi~s all take ads. Dr. ALFANO. It may be 89 percent in his case, it may be 1 percent to someone in practice out in the suburbs. I do not know what those figures are. Senator NELSON. There are certainly a number of doctors who never misprescribe at all. We know that. But this figure is awfully big and it dropped by half when the hearings started. I have imposed on you enough and I appreciate very much your tak- ing the time to come. I do not want to have you come back again. I thank you for your willingness to testify today. I will be back in about 10 minutes. (Short recess.) Senator NELSON. Dr. Krantz, I am sorry we have had some inter- ruptions. The Senate would be a lot better place if I were running it, but I am not. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4553 Our next witness is Dr. John C. Krantz, Jr., of Huntingdon Re- search Center, Inc., in Baltimore. Dr. Krantz is a professor emeritus of the Department of Pharmacology at the University of Maryland. Go ahead, Doctor. We are very pleased to have you here today and we apologize for being delayed so long in getting to your testimony. STATEMENT OP JOHN C. KRANTZ, JR., PH. B., HUI'TTINGDON E~SEARCH CENTER, INC., BALTIMORE, MD. Dr. KRANTZ. Senator, Mr. Counsel, every animal is capable of a cry characteristic of its species; man alone speaks. All along the tortuous road of ascent, articulate speech has been the sharp line of distinction between man and other primates. Speech gave him a history, speech enabled him to transmit knowledge, and speech has marched with a fidelity that is unwavering in the vanguard of advancing civilization. But when speech or any form of communication is unclear it may serve as the source of misunderstanding and mischief. In medicine, with the prescribing of drugs, it can be the difference between the "quick and the dead." St.. Paul, in his letter to the Church in Corinth, gave us the word, "Except ye utter by the tongue words easy to be un- derstood, how shall it be known what is spoken? For ye shall speak into the air." This thesis is a plea for simplicity in the nomenclature of drugs. I have been advocating this principle for four decades. Its first target was the preposterous use of the Latin titles in the official compendia and on prescriptions. I have witnessed the complete demise of this anachronism. For three decades I taught pharmacolOgy to medical students in the School of Medicine in the University of Maryland. It was extraor- dinarily difficult to have the student become familiar with two names and sometimes three or four for the same drug. It was more difficult to explain to an intelligent person why this cumbersome and confusing practice existed. This confusion did not prevail only with the student but also with trained physicians. My proposal is simple and would bury the so-called created generic name in the same cemetery with the Latin titles. I propose that a new drug be assigned a name by its manufacturer, approved by the FDA and/or USAN, with a suitable suffix, representing the manufacturer. For example: Benadryl-Parke, Davis-not diphenhydramine hydrochloride. Dramarnine-Searle-not, dimenhydramate. Isordil-Ives-not isosorbide dinitrate. Capla-Wallace-not mebutamate. Such a name then becomes the only name that the drug has other than the true chemical name that may appear in small print on the label. At the termination of the patent, other manufacturers could syn- thesize and market the product, using the assigned name without the originator's suffix. Thus, the names Benadryl, Dramamine, Isordil and Capla would be the equivalent of the generic name used today. This has happened in the case of aspirin. Manufacturers are free to market aspirin but, Aspirin-Bayer has withstood the ravages of time and competition. This leaves us still with the age old problem of PAGENO="0264" 4554 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "generic equivalency." The advocates of the purchase of generic named drugs, on the basis of economy, are only correct in a comparatively few cases. 1. The report of the study of this problem by the AMA asserts, "Except in a few cases, there is no economy achieved in the purchase of generic named drugs." Senator NELSON. May I interrupt there a second? Dr. KRANTZ. Yes. Senator NELSON. About a year ago, two drug chains, Peoples and C-ray's-I am going by memory here-I think representing about 300 drugstores, both announced that they were going to stock a line of generic drugs, that the manufacturer would be Strong, Cobb & Amer. Dr. KRANTZ. The Cleveland company? I think it is the Cleveland company; a very fine company. Senator NELSON. They have a good reputation, I understand. This is on price. The stores have announced that the average price of their generic drugs would be one-half the price of the brand names, on the average. So that is in direct contradiction to the AMA report. Is this a study that the AMA did about a year ago in December? Dr. KRANTZ. And published in their newsletters. Senator NELSON. I am going to have to take another look at it, but I think there were some fatal defects in it. They did some buying at drugstores and then announced a price. They made purchases at the retail level and ended up by saying that they did not gain anything in price. This is very simple to explain. Under all the laws of this country, if a doctor prescribes a~ generic name, the pharmacist can supply anything he wants, any brand. If ho prescribes a- brand name in some 40-odd States, there can be no sub- stitution. Maybe it applies in all States now, I do not know. But I think it is 42. Now, all that happens is that if you go to a drugstore, as the AMA, I understand did, and you ask for prednisone and the store is only carrying meticorten, you pay the same price as if you went into the store and asked for meticorten. So I was impressed by that study of theirs, really, because I think that was a fatal defect in it. I shall look at the record and be sure I am not mistaken in what I state here. If I am, I shall correct it. Dr. KRANTZ. Senator, if you follow this suggestion, you will elimi- nate all those worries. You will not have that problem any longer. Senator NELSON. WTell, I think the suggestion made-we have had some testimony along this line of simplification, and I think the sug- gestion you make here is a very simple one and might very well be exactly what ought to be done. Dr. KRANTZ. May I continue? Senator NELSON. Yes. Dr. KRANTZ (reading). 2. The purchase of generic-named drugs on price from manufacturers of unknown reputation involves the risk of an inferior or even an ineffective product. This is tantamount to throw- ing dice for the destiny of the patient. Senator NELSON. Might I say there, Doctor, we mentioned Strong, Cobb & Amer. I am not qualified to make any independent judgment of my own about the quality of any product put out by any company. PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4555 Strong, Cobb & Arner, I understand, sells to many companies and, from everything I have heard, has a fine reputation. Dr. KRANTZ. That is right. Senator NELSON. As to your item No. 2, what risk would there be to a pharmacist who announced, as Peoples & Gray's did, that we are going to stock `a brand of generics `by Strong, Cobb & Amer because we know that they are a distinguished company with good quality. Dr. KRANTZ. None whatsoever. Senator NELSON. Thank you. Dr. KRANTZ. You say I qualify this `by stating that unknown repu- tation. 3. There is no substitute for integrity and pharmaceutical expertise of the manufacturer. To be sure, the originator of the product would be the most likely source of a dependable, uniformly formulated and active product. Notice I say, most likely. To assert that skilled pharmaceutical scientists employed by reliable manufacturers cannot formulate ef- ficacious `and uniformly dependable dosage forms of medicaments is equivalent to saying that pharmacy and biopharm'aceutics do not exist. As a member of the Committee on Revision of the U.S. Pharm'a- copeia, I have also advocated the use of trade names in the mono- graphs. But there are those who stated if, for example, the title Capla- Wallace were used in an official compendium, the trade m'ark rights would be abrogated. I have recently read, the law pertaining to these matters and am of the opinion that this was an unfounded judgment. The advantages of this suggestion are as follows: 1. One name for each drug enhances safety and ease in prescribing. If we stop right after "safety," this justification is enough for doing this. 2. The manufacturer is always identified with the product. 3. The manufacturer stands to gain `by such `a process of simplifica- tirni by having `his name or insignia attached to the only name of the drug. Senator NELSON. Well, I would certainly agree that from the evi- dence we have had over the past 2 years from other distinguished wit- nesses, that the question of simplifying the names in identification of the drugs is an important question. I would certainly agree with you, based upon other witnesses, like you who have testified on this question, that it ought to be done. I do not know the best way to accomplish it, I am not certain in my own mind, but I think the present system is, as you say, very cumbersome and confusing. Well, I thank you very much. Mr. GounoN. Do you have that list of drugs you talked about before? Dr. KRANTZ. It is the only list I have. Senator NELSON. D'octor, what is the significance of-I have not had a chance to study it-the document you have submitted with the list of drugs? Dr. KRANTZ. Well, the statement was made `this morning that these generic-equivalent drugs are always, or generally, the therapeutic equivalent of the trade mark item. I simply stated that a colonel from the Army-I suppose it would be their purchasing agent- Mr. GoRDoN. Do you know his name? PAGENO="0266" 4556 CO~ETITIVE PROBLEMS fl~ THE DRUG INDUSTRY Dr. KRANTZ. No. I do not know his name, but. I have it in my records at home. It has been about a. year ago since he appeared. He came and told me one day that they had purchased a number of these items by price and they had not worked well in the patients. They have not given the required therapeutic results that they expected. So I delineated a series of tests that we could do on animals that would enable him, in turn, to be sure within a reasonable doubt that the item that he was purchasing would be tantamount to the trade mark item. At the present time, we are considering the same situation for the Maryland Hospital Association, which includes some 56 hos- pitals and spends roughlv $13 million a year on drugs. It is their contention that if they could buy with certainty a drug that was generically labeled instead of trade mark labeled, they may save some money. So if we apply these tests, I think we can assure them that they are, within reason, the therapeutic equivalent. Senator NELSON. I see no indication here of the test that was made on each of these drugs, if it was made, to determine whether it might be up to DSP standards. \T\Tho made that test? Dr. KRAXTZ. Some of these products are not in the Pharmacopeia, you see. Tedral, for example, one of them, is not an official product. Senator NELSON. Of those that are, where was the test made to see whether it met the DSP standards? Who made it? Dr. KRANTZ. I presume it was made by the laboratory of the Army procurement group, but I do not know. Senator NELSON. So you are not certain whether or not any of these drugs met DSP standards? Dr. KRANTZ. No; I did not have any of the drugs. Senator NELSON. I think that this is a crucial question. The testimony before the committee has been that if the drug meets DSP standards, it is their judgment that it is therapeutically equivalent and there has not been any significant evidence except as Perhaps to one drug, and that is a maybe, that if they met DSP standards, they were therapeutically equivalent. We do not know, then, whether the drugs you mentioned, met DSP standards? Dr. KRANTZ. I agree. Senator NELSON. WTe recognize, and I know you do, as an expert, that brand name companies and generic companies manufacture drugs and, for reasons of quality control, a certain percentage of them do not meet DSP standards. As I have said earlier in the hearing, the one big test made showed that generic companies had a better per- centage in meeting a potency test than did the brand name companies, by 1 percentage point. So these are not submitted, then, as part of that? Dr. KRANTZ. Oh, no, no. Senator NELSON. I see. Mr. GORDON. I might also mention that tolbutamide is not sold by the generic name. It comes only under the brand name of Orinase. It is manufactured by only one company, Dpjohn. Dr. KRANTZ. I thought the patent had expired. Mr. GORDON. Not yet. It will expire soon, but has not yet. As of now, only Dpjohn manufactures that. Dr. Kn~&x'rz. Dp to this time, and this was about a year ago, the patent had not expired on Miltown and EquaniL which was the same PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4557 drug, meprobamate. I asked the colonel about this, because I was interested in the inclusion of meprobamate in the pharmacopeia, because I was director of Scope Mr. GolmoN. I said that, with respect to tolbutamide, there is no other company making this but Upjohn. Dr. KRANTZ. You cannot be sure. Mr. GORDON. Is Tedral a brand name? Dr. KRANTZ. This is an asthmatic, remedy that contains amino- phyilin ephredrine and some other agents-I do not remember. Mr. GORDON. Is this a. brand name or a trade name? Dr. KRANTZ. A trade name. Mr. GORDON. So you have trade names on your list? Dr. KRANTZ. There is no other name. It is a mixture. Mr. GORDON. I still cannot understand what the significance of this list is. Dr. KRANTZ. Let me explain it to you very carefully and very slowly: Our laboratory engages in scientific research, developmental procedures, and so forth. This colonel from the Procurement Office of the Army in Philadelphia called and asked if he could have an appointment. 1-le came down and spent a whole afternoon with me and told me his problem was this: By Government mandate, he is forced to buy drugs on price. Now, we have bought these drugs that he has mentioned there and they have not, in the hands of our doctors, met the stand- ards, or met the clinical equivalency would be better-clinical equiva- lency-of the trademark product. Senator NELSON. May I interrupt there? Did your lab conduct the clinical tests, how many patients were involved, and where were they conducted? Dr. KRANTZ. I do not know this. This was in the Army. They were giving them to soldiers and people in veterans hospitals, I presume. Senator NELSON. So we do not know what kind of tests they con- ducted and whether it was a scientific, clinical test or not. We do not know whether the drugs met USP standards or not? Dr. KRANTZ. That is correct. It is simply an opinion. Senator NELSON. We do not know how many were generics and how many were trade names, either? Dr. KRANTZ. Well, I got the impression from him-this conversa- tion has been over a year ago, so it is not all clear in my mind-that there were several companies that were making these items prior ~o expiration of the patents. Now, I can readily see how most any com- pany could make something comparable to Tedral by simply mixing the ingredients. They know the formula, it is available, so they could call it most anything they wanted-psuedo-Tedral or anything of the sort. Senator NELSON. Of course, if it is under patent, they could not market it. Dr. KRANTZ. I doubt if it is patentable, a mixture of this kind. Senator NELSON. All right. Thank you very much, Doctor. We appreciate your taking the time to come here. I apologize for having delayed so long in getting you on. The committee will stand in recess until Tuesday, March 18, at 10a.m. PAGENO="0268" 4558 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (The supplemental information submitted by Senator Nelson follows:)' [From Federal Supplement, vol. 257-cases argued and determined in the U.S. District Courts-U.S. Customs Court-pp. 991-998] SHANE STROMSODT, a minor, by Robert M. Stromsocit, his guardian ad litem, Plaintiff, V. PARKE-DAVIS AND COMPANY, a corporation, Defendant. Civ. No. 3992 United States District Court, D. North Dakota, Northeastern Division- September 28, 1966, Product liability case involving defendant's ethical drug which allegedly caused injuries to infant plaintiff. The District Court, Ronald N. Davies, J., held that evidence established that defect in defendant's drug caused damage to brain and central nervous system of infant, that such defect constituted breach of implied warranty of merchantability, that defendant was chargeable with negligence in failing adequately to test product and adequately to warn of dangers inherent in its use and that infant was entitled to award of $500,000,00. Judgement for plaintiff. 1. Druggists ~1O Evidence established that competent, producing cause of damage to brain and central nervous system of infant was defect in defendant's ethical drug, a quad- ruple antigen with a prophylaxis against diphtheria, pertussis, tetanus and poliomyelitis, and that chronologically and etiologically, infant's condition was traceable directly to the drug administered to him. 2. Sales ~284(1) Defect in drug resulting in damage to brain and central nervous system of infant to whom drug was administered constituted breach of implied warranty of merchantability. 3. Sales ~255 Asserted lack of privity is not defense in North Dakota in an action by ulti- mate consumer against manufacturer of drug for breach of implied warranties, where, through advertising or other media of education and information, defend- ant manufacturer has persuaded medical profession to prescribe defendant's drug. 4. Druggists ~9 Finding that defendant drug manufacturer breached implied warranty of merchantability and that infant plaintiff's injuries were caused thereby did not preclude finding that manufacturer was also chargeable with negligence in fail- ing adequately to test product and adequately to warn of dangers inherent in its use. 5. Druggists ~1O Evidence established that adequate test performed prior to marketing of defendant's ethical drug would have disclosed product's potency instability as well as cause of greater incidence of reaction and that defendant was negligent in failing to adequately test product, in suit for damage to brain and central nervous system of infant resulting from defect in defendant's drug which was administered to infant. 6. Druggists ~9 Even though drug manufacturer met all of government regulations and requirements in production and marketing of drug, manufacturer still owed duty to warn of dangers which were inherent in use of drug and of which it knew or should have known in exercise of reasonable care. ~. Druggists ~9 For drug manufacturer to be liable for injuries caused by use of its drug on basis of its failure to warn of dangers which are inherent in use of drug and 1 See p. 4537, supra. PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4559 of which it knows or should know in exercise of reasonable care, danger must be reasonably foreseeable and injury must be proximately caused by failure to warn. 8. Druggists ~1Q Evidence established that defendant drug manufacturer knew or should have known that its ethical drug, a quadruple antigen with a prophylaxis against diphtheria, pertussis, tetanus and poliomyelitis might cause encepbalopathies in some users and that it was negligent in failing to give adequate warning of that danger, in action for damage to brain and central nervous system of infant resulting from use of drug. 9. Druggists ~ Even if case of encephalopathy was the first occurring after administration of defendant's ethical drug, that did not preclude finding that such as foreseeable by defendant and that defendant was negligent in failure to give adequate warning. 10. Dainages~132(3) Where plaintiff as a baby suffered convulsions following administration of defendant's defective drug and at time of trial, when plaintiff was seven years old, he walked unsteadily, lacked coordination, spOke but a few words, had none of basic childhood skills normally possessed by children of this age, plaintiff suffered permanent and irreversible injuries to his brain and central nervous system and plaintiff would in all probability be institutionalized shortly for inability of his parents to give him necessary care, plaintiff was entitled to award of $500,000. Melvin M. Belli, of Belli, Ashe, Gerry & Ellison, San Francisco, Cal., Mart R. Vogel of Wattman, Vogel, Vogel, Bright & Peterson, Fargo, N.D., Carlton G. Nel- son, and Jerome J. Mack, of Nelson & Mack, Grand Forks, N.D., for plaintiff. Harold D. Shaft, of Shaft, Benson, Shaft & McConn, Grand Forks, ND., for defendant. MEMORANDUM AND ORDER RONALD N. DAVIES, District Judge. This is a product liability case tried to the Court without jury, involving the ethical drug Quadrigen made by the Defendant, Parke-Davis and Company, con- taining four antigens: diptheria toxoid, tetanus toxoid, pertussis (whooping cough) vaccine and poliomyelitis vaccine. It was also described as a quadruple antigen with a prophylaxis against diphtheria, pertussis, tetanus and poliomye- litis. Jurisdictional requirements of 28 U.S.C.A. § 1332, have been met. The Plaintiff was originally shown as "Robert M. Stromsodt, guardian ad litem of Shane Stromsodt, a minor." By ex parte order entered by this Court April 1, 1906, leave was granted Plaintiff to amend the caption of the amei~ded coin- plaint to iaclude "and Robert M. Stromsodt, individually." The Defendant moved the Court to set aside this order, urging that it was given no opportunity to object to it and contending that the North Dakota Statute of Limitations had run as against any claim of Robert M. Stromsodt, individually. A ruling was reserved on this motion. To make certain that the issues are solidly joined in this cause, and that its ultimate resolution may not be attacked by reason of any real or fancied future claim to which the Defendant may think itself exposed, the Defendant's motion upon which ruling was reserved, must be and it is hereby granted. The Defend- ant's motion to dismiss the cause of action as to Robert M. Stromsodt, individ- ually, must be and it is hereby granted. for the reason that the complaint fails to state a cause of action as to Robert M. Stromsodt, individually. This case is order- ed captioned as it appears herein, that is, "Shane Stromsodt, a minor, by Robert M. Stromsodt, his guardian ad litem. Plaintiff, versus Parke, Davis and Company, a corporation, Defendant," and as so styled it will be adjudicated. In 1953 Parke, Davis commenced studies for the purpose of determining the feasibility of combining poliomyelitis vaccine with the company's trivalent anti- gen sold under the trade name "Triogen," containing diphtheria toxoid, tetanus toxoid and pertussis vaccine. Parke, Davis' product, Quadrigen, which has here- tofore been described, was finally developed and licensed March 25, 1959, and its manufacture authorized by the Department of Health, Education and Wel- fare (HEW). Commercial marketing of the drug under the trade name "Quadri- PAGENO="0270" 4560 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY gen" commenced in July of 1959 with Quadrigen having an expiration dating period of twelve months after manufacture, and six months after issue. On April 13, 1961, the Division of Biologics Standards (DBS) of the National Institutes of Health (NIH) issued a memorandum to manufacturers of mul- tiple antigen products containing pertussis and poliomyelitis vaccines that the products could contain no less than 14 units of pertussis potency (previously 12) and be labeled with an expiration date of six months after manufacture, and four months after issue. This change was necessitated when studies indicated a sig- nificant loss of pertussis potency in quadruple antigen vaccines after marketing. No comparable loss of pertussis potency had been found in triple antigen products not containing poliomyelitis vaccine. DBS then determined that some lots of inactivated poliomyelitis vaccine con- tained a live vacuolating agent (SV 40), from the monkey kidney cells on which poliomyelitis virus w-as grown. Resultantly, a memorandum was issued May 20th, 1961, requiring the subsequent lots of vaccines containing components grown on monkey kidney cells be free of live SV 40. On August 23, 1961, DBS issued a regulation or letter placing a new toxicity test requirement on all products containing pertussis vaccines; and on September 21, 1961, provided a new reference vaccine for the pertussis potency test which effected an additional increase in the potency requirement. The new toxicity test required additional treatment of the pertussis component. This treatment ad- versely affected the pertussis potency to the extent that the potency requirement could not consistently be met. Various articles appearing in medical literature indicated that the poliomyelitis component and the preservative being used might be the cause of the instability in multiple vaccines. Production and marketing of "Quadrigen" was finally halted in November, 1962. Shane Stromsodt was born in Grand Forks, North Dakota, May 24th, 1959. His mother's pregnancy and his birth were entirely normal and uneventful, accord- tag to her physician, Dr. John H. Graham. On August 26th, 1959, Shane was tak- en for examination to Dr. Graham's office; and on that date Quadrigen was ad- ministered to him intermuscularly. The infant seemed to suffier no ill effects, and his mother recalled no reaction which caused her any alarm. On October 1, 1959, some five weeks later, Shane was again taken to Dr. Graham's office, examined and once more Quadrigen was injected into the child's body, between four and five o'clock that afternoon. Mrs. Stromsodt bundled up the child and took him to the family car in which her husband, Robert, was waiting. She reached the car some five or ten minutes after Shane had received the Quadrigen, removed the blankets from about the child, and noticed a fine red rash on his face. The Stromsodts drove to their home where Shane was undressed, and the rash was noticed on his face and the upper part of his body. Mrs. Stromsodt gave Shane his bottle immediately after the family had had their meal. Shane promptly vomited the bottle's contents, something he had never done before. Mrs. Stromsodt laid the child on the bed and testified the baby bad a "seizure." She described his eyes as rolling back in his head, his heels and head dug in~to the bed, his back arched and his fingers grasping. Mrs. Stromsodt believes the convulsion may have lasted five minutes. Having no idea of what was happening, she watched Shane, and when the seizure was over, telephoned Dr. Graham. She described to the Doc- tor what had happened to Shane and added that she thought the baby had the measles. The Doctor, however, thought it was a reaction from' the shot given Shane and instructed Mrs. Stromsodt to watch him and to telephone next morn- ing if the child was no better. Shane seemed normal the next morning, and Mrs. Stromsodt did not call the Doctor nor see him again until November 4, 1959, when the baby was taken to Dr. Graham's office for a third shot. Shane slept most of the next two days following the initial seizure, but he had two more convulsive attacks after the first one, both of which were prior to November 4, 1959. When Shane was taken to Dr. Graham's office, November 4, 1959, Mrs. Strom- sodt recited his condition to the Doctor. She told him the baby had suffered from two "spells" since the last Quadrigen shot, that he had been sleeping more and "it seemed like he wasn't doing anything any more." In short, the child was not progressing normally. The Doctor concluded that Shane should not be given Quadrigen because of the severe reaction suffered by the infant following the October 1 injection of that drug, and thus, on his third trip Shane was given Triogen which contained diphtheria toxoid, pertussis vaccine and tetanus toxoid (DPT). Poliomyelitis vaccine was not given on this date. Shane continued to have difficulties which stemmed from the October 1st in- troduction of Quadrigen into his body and repeatedly had seizures until January, 1960. Mrs. Stromsodt testified the baby was making no progress. On January PAGENO="0271" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4561 13, 1960, the Stromsodts sought the advice of a specialist in pediatrics and took Shane to Dr. Samuel L. Pettit in Grand Forks. The Doctor prescribed phenobar- bital for the child and testified that he finally prescribed a conventional dosage of one-quarter grain phenobarbital three times a day for Shane, which amounts he continues to receive. When trial of this case began Shane was nearly seven years old. The record show he walks unsteadily, lacks coordination, speaks but a few words has none of the basic childhood skills normally possessed by children of his age and can neither read nor write. Uncontroverted medical testimony disclosed that he has damage to the brain and central nervous system. Shane is definitely, permanently and `irreversibly injured, and in all probability his parents shortly will be unable to give him the necessary care and the boy will have to be institutionalized. [1] A careful weighing of all the credible medical testimony in this case leads this Court to the inescapable conclusion that the competent producing cause of Shane `Stromsodt's condition was Quadrigen, and that chronologically and etiolog- i'cally Shane's condition is traced directly to the Quadrigen administered to him October 1st, 1959. Of the several theories under which the Plaintiff seeks to recover in this ac- tion, only two are sustainable and require discussion here. They are breach of an implied warranty and negligence. EREACH OF IMPLIED WARRANTY "The liability in negligence of a manufacturer or other supplier for damage caused by his product is `based on the supplier's failure to exercise reasonable care. Hence, negligence is a tort concept `based on fault. "Although the courts are occasionally confused a'bout the matter, warranty, on the other hand, is not a concept `based on fault or on the failure to exercise reasonable care. But this does `not mean `that warranty is necessarily contractual or nontortuous in nature. Liability in warranty arises where damage is caused by the failure of a product to measure up to express or implied representations on the part of the manufacturer or other supplier. Accordingly, an injured person is not required to prove negligence in a warranty-products liability ease. "This has `been concisely summarized as follows: "`There seems `to be some confusion in understanding `the nature of im- plied warranty liability. In the first place, `concepts of negligence and fault, as defined by negligence standards, have no place in warranty recovery cases. Proof of negligence is unnecessary `to liability for `breach of implied warranty and lack of it is immaterial to defense there'of. Since the warranty is implied [emphasis by court] either in fact `or in `law, no express representations or agreements by the manufacturer are needed. Implied warranty recovery `is based upon two factors: (a) The product or article in question has been transferred from the manufacturer's possession while in a "defective" state, more specifically, the product fails to be "reasonably fit for the partic- ular purpose intended" or of "merchantable quality," as these two terms, separate but often overlapping, are defined by the law; and (b) as a result of being "defective," the product causes personal injury or property dam- age.'" 2 Frumer & Friedman, Products Liability, Chapter 3, Sec. 16.01[1]. [2] None of `the experts called by either party `Could or would state `which par- ticular ingredient in Quadrigen caused `the damage to Shane Stromsodt Plain- tiff's witness, Dr. Ronald Okun, testified that there was evidence to show that pertussis en'dotoxin made the other components of Quadrigen more liable to cause an anaphylactic sort of reaction in a patient. Other evidence indicated `that the product was rendered defective by the instability of potency in the pertussis vac- cine. The evidence justifies the conclusion that the Plaintiff's injuries and dam- ages were caused `by a defect in `the Quadrigen, and `that `such defect constitutes a breach of the implied warranty of merchantability. [3] The asserted lack of privity is not a `defense in North Dakota `to a claim based upon breach of an implied warranty. See Lang v. General Motors Corpora- tion, 136 N.W.2d 805 (N.D.1965) Thi sapparently would be particularly true in actions by the ultimate consumer against a manufacturer for breach of implied warranties where "through advertising or other media o'f education and informa- tion defendant has convinced and persua'ded the medical profession to prescribe its drrig, since it is in the very competitive field of supplying drugs and medicines for the alleviation of human suffering as well as for its own pecuniary advan- tages." Bennett v. Richardson-Merrell, Inc., D.C., 231 F.Supp.150 PAGENO="0272" 4562 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY NEGLIGENCE [4] The finding that Parke, Davis breached the implied warranty of mer- chantability and that Plaintiff's injuries were caused thereby does not preclude a finding that the Defendant is also chargeable with negligence in failing ade- quately to test the product and adequately to warn of the dangers inherent in its use. The insert,1 under "Reactions", reads: "When given in accordance with suggested methods, local and systemic reactions following the administration of Quadrigen are usually mild. The incidence is usually no greater than is normally experienced with trivalent vaccine. Local reactions and fever of short duration may occur, however, and parents should be cautioned not to apply local treatment, such as wet dressings or heat. Any child who shows a febrile reaction should be kept quiet, should be offered water repeatedly and may be given one or more doses of aspirin as indicated. Occasionally, a residual induration or circumscribed nodule may persist for a week or more. "In instances of more marked reaction, the immunization may be coin- pleted with monovalent antigens or other combinations of antigens. "Local reactions have been known to be more severe when the child is in the incubative stage of pertussis. Encephalitic symptoms occasionally occur with acute pertussis though rarely with the use of the prophylactic vaccine. Such severe symptoms of the central nervous system include convulsions and lethargy. They may be followed by mental or lhysical manifestations, sometimes permanent, or even by death; but fortunately such reactions are extremely rare. "The poliomyelitis vaccine components of Quadrigen contains small amounts of penicillin and streptomycin used in culturing the virus. During the adsorption process most of the antibiotic content is removed. In fact, residual antibiotics in the adsorbed product are usually not demonstrable by ordinary laboratory technics. However, consideration should be given to the possibility of allergic reactions in individuals sensitive to these anti- biotics and they should be tested for sensitivity where this possibility exits. "The value and importance of maintaining continuing antibody levels in the infanct in relation to the possibility of provocation of paralytic poliomye- litis by injection are self-evident. In modern clinical practice the admin- istration of medication by hypodermic injection is generally accepted. and the hazard of thereby provokng poliomyelitis is increasing. If, however, basic immunity against poliomyelitis as evidenced by circulating antibody has been achieved, provocation is quite unlikely. Also, it should be noted that Quadrigen is considered less likely to provoke paralysis than is the trivalent product not containing poliomnyelitis vaccine. With products not containing poliomyelitis antigen the patient is at some risk following each injection. With Quadrigen. on the other hand, after the first injection, basic immunity is developing and risk is greatly decreased for subsequent inoculations. Furthermore. if current recommendations are followed, the course of immunization will be started during the first 6 months of life under the protection of passive maternal antibody. How-ever, the hazard of provo- cation in the face of an epidemic. particularly with the first dose of Quadri- gen, cannot be ignored and the physician should exercise discretion. as with any injectable." Clinical trials of Quadrigen prior to marketing were conducted by Dr. Clar- ence D. Barrett of Detroit beginning in 1956 and terminating in 1959. These tests used Quadrigen considered "fresh" in that the product was less than six months of age from the date of "pooling" of the poliomnyelitis component with the DPT fraction. The trials were designed to determine antibody response and the earliest age in infancy at which immunization against poliomyelitis, diph- theria, tetanus and pertussis would be started, using a multiple antigen against `Exhibit 46 is a tiny bottle of Quadrigen contained in a small cardboard box which included also Parke-Davis' insert showing what the product was designed to do. It is observed that the bottle itself contained no warning whatever, the cardboard box in which it was enclosed contained no warning whatever. The insert itself, a single sheet of paper containing in the main very small print, showed the nature of the product, when to immunize, dosage and administration, recall or booster doses, reactions and storage in- structions, and was printed on a sheet measuring approximately four by seven inches, in which were compressed approximately 1,444 words, excluding the reference list on the bottom of the reverse side. PAGENO="0273" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4563 all four diseases. No clinical reactions of any serious consequence were reported or observed. Quadrigen was then made available to selected members of the medical pro- fession who were requested to comment on their use of the product. These "field trials" indicated a marked increase in reactions among patients given Quadrigen over those being given DPT and poliomyelitis vaccine. Of the severe reactions reported the first apparent instance in which death resulted was in March of 1959. It does not appear that Parke-Davis made any effort to deter- mine the cause of the high incidence of reactions, and only a cursory attempt was made to investigate the cause of a death attributed to the use of Quadrigen. [5] It appears to this Court that adequate tests performed prior to marketing would have disclosed the product's potency instability as well as the cause of greater incidence of reaction, especially in view of the number and serious- ness of the reactions being reported. This w-as not a situation w-here an epi- demic existed or where need justified the risk of premature marketing since products were already available to the medical profession that satisfactorily accomplished that Quadrigen was designed to do. [6] Although all of the Government regulations and requirements had beeii satisfactorily met in the production and marketing of Quadrigen, the standards promulgated were minimal. The Defendant still owes a duty to warn of dan- gers of which it knew or should have known in the exercise of reasonable care. Love v. Wolf, 226 Cal.App.2d 378, 38 Cal.Rptr. 183. See also Ebers v. General Chemical Co., 310 Mich. 261, 17 NW. 2d 176; Brown v. Globe Laboratories, 165 Neb. 138, 84 N.W.2d 151; Gonzalez v. Virginia-Carolina Chemical Company, 239 F.Supp. 567 (DC, SC, 1965). [7, 8] The danger must be reasonably foreseeable and the injury must be proximately caused by the failure to warn. The Defendant knew or should have known that Qnadrigen might cause encephalopathies in some users and to warn of the danger. [9] Though this may have been the first case in which encephalopathy 2 oc- curred after the administration of Quadrigen, it does not preclude the finding of foreseeability and negligence. See Roberts v., United States, 316 F.2d 489 (3 Cir., 1963). The warning "Local reactions have been known to be more severe w-hen the child is in the incubative stage of pertussis" on the insert accompanying the product, not only would not have warned members of the medical profession, but might have misled them to believe that only in cases where the child was in the incubative stage of pertussis would encephalitic symptoms occasionally occur. There is no competent evidence in the entire record, medical or other, to show that Shane's condition arose out of or from any susceptibility or predis- position, nor that the child had any congenital disease or disorder or defect of any kind, nor that he had any allergy or idiosyncrasy, nor that heredity was a factor that might account for his present condition. This Court being of the opinion that the Defendant is liable both for breach of an implied warranty and for negligence, it becomes unnecessary to forecast whether the Supreme Court of North Dakota would apply Sec. 402 A of the Restatement of Torts in a situation such as is here presented. As pointed out in 2 Frumer-Freidman, Chapter 3, Sec. 16A [4] "Strict liability in tort in the products liability area is in its infancy. There- fore, the precise scope of the rule and the defenses thereto have not as yet been clearly defined. It is believed, however, that strict liability in tort is for the most part no different than strict liability in warranty, that similar results can be achieved under either theory. Comment in to § 402A of the Restatement of Torts seems to agree. It states: "`There is nothing in this sec:tion which would prevent any court from treating the rule stated as a matter of "warranty" to the user or consumer.' "But in the next sentence it is pointed out that, "`if this is done, it should be recognized and understood that the "warranty" is a very different kind of warranty from those usually found in the sale of goods, and that it is not subject to the various con- tract rules which have grown up to surround such sales.' "If a court does not require, inter alia, privity of contract, a sale, or notice of a breach of warranty, does it matter that the defendant is being held strictly liable in warranty rather than in tort? The answer seems obvious. 2 degenerative disease of the brain. 81-280-69-pt. 11-18 PAGENO="0274" 4564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY If a court imposes strict warranty liability irrespective of contract and sales rules, then strict liability in warranty and tort are synonymous." The Plaintiff has sustained the burden of proving, by a fair preponderance of the credible evidence adduced upon trial, that Parke-Davis has breached an implied warranty, and in addition, has been guility of tortious negligence. The verdict which this Court reaches, and the damages awarded, are supported by either one or both of these theories. [10] It is my conclusion that the sum of $500,000.00 constitutes a fair, just and adequate award to Shane Stromsodt, considering the totality of circumstances in this lawsuit. Counsel for the Plaintiff are directed to prepare and submit through the Clerk of this Court findings of fact, conclusions of law, order for judgment and judg- ment with the least practicable delay. [From Federal Supplement, voL 285-cases argued and determined in the U.S. District Courts-U.S. Customs Court-pp. 432-454] Enic R. TINNERHOLM, an infant under the age of fourteen years, by his Guardian ad Litem, Carl F. Tinnerholm, and Carl F. Tinnerholm, Individually, Plaintiffs, `V. PARKE, DAVIS & Co., Defandant. No. 62 Civ. 4006. United States District Court, S. D. New York-May 15, 1968 Action against manufacturer of vaccine for damages resulting from doctor's administration of vaccine to infant. The District Court, Tenney, J., held that evidence established that manufacturer breached its implied warranty and war- ranty of merchantability and manufacturer was guilty of negligence. That Court further held that plaintiffs were entitled to damages in the sum of $651,783.52 to reimburse father for loss of services and medical expenses incurred and for infant's loss of w-ages, future medical expense, and pain and suffering. Judgment accordingly. 1. Druggists ~1O Evidence established that release of endotoxin into fluid contained in vaccine injected into infant w-as cause of unusually high fever which, in turn, caused severe and permanent brain damage. 2. Druggists ~10 In action against manufacturer of vaccine for damages resulting from infant being injected with vaccine, plaintiffs need not disprove every possible ground of causation suggested by manufacturer nor must findings of court meet stand- ards of laboratorian. 3. sales ~42T Liability for "breach of warranty" arises where persons or property are dam- aged because of product's failure to live up to an express or implied represerita- tion by manufacturer or other supplier. See publication Words and Phrases for other judicial constructions and definitions. 4. Sales ~=`427 "Breach of warranty" is distinguished from negligence liability in that it is not based upon fault or upon failure of such manufacturer or supplier to exercise reasonable care. 5. Sales ~=26O An "express warranty" will arise where manufacturer, supplier or other seller positively represents a fact concerning goods he sells. See publication Words and Phrases for other judicial constructions and definitions. PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4565 6. Sales c~434 Allegation that vaccine was fit for use as immunizing agent against various ailments and was of good merchantable quality constituted an allegation of "implied warranty". See publication Words and Phrases for other judicial constructions and definitions. 7. Sales ~279 Warranty of "merchantability" is that thing sold is reasonably fit for general purpose for which it is manufactured and sold. See publication Words and Phrases for other judicial constructions and definitions. 8. Sales ~~273(1) Implied warranty of fitness for particular purpose is distinguished from merchantability warranty in that in merchantability warranty there is reliance on particular seller's skill and judgment. 9. Sales ~=~55 In action by New York residents against manufacturer of vaccine for damages resulting when infant was injected with vaccine, court was bound by New York law of warranty. 10. Sales ~255 Under New York law, doctrine of privity did not apply to action against manu- facturer of vaccine for damages resulting from infant's being injected with vaccine by physician. 11. Sales ~=~246 Even if sale is necessary in order to impose warranty liability, such require- ment was fulfilled in action against manufacturer of vaccine for damages result- ing from vaccine having been administered to infant by doctor. 12. Druggists ~=~1O Evidence in action against manufacturer of vaccine for damages resulting from infant's having been injected with vaccine by physician established that vaccine was defective and that defect was proximate cause of infant's injuries. 13. Sales ci~=z441(1) In action against manufacturer of vaccine for damages resulting from vaccine administered to infant, evidence established that manufacturer breached an im- plied warranty in manner that increased chances of party injected with vaccine of contracting an encephalopathy. 14. Sales ~=~441 (3) In action against manufacturer of vaccine for damages resulting from doctor's administering vaccine to infant, evidence established that manufacturer breached its warranty of merchantability. 15. Druggists ~9 Finding of implied warranty liability did not preclude court from finding manu- facturer of vaccine liable in negligence for damages resulting from doctor's administering vaccine to infant. 16. Federal Civil Procedure ~=2571 While finding of implied warranty liability would not preclude finding liability based on negligence, plaintiffs are limited to one recovery. 17. Druggists ~=1O In action against manufacturer of vaccine for damages resulting from doctor's administering vaccine to infant, evidence established that manufacturer was negligent in failing to adequately test its product, for releasing product for com- mercial distribution in face of certain danger signs emanating from test results, and in failing to adequately warn medical profession of risks inherent in its use. PAGENO="0276" 4566 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY 18. Druggists ~9 Where drug manufacturer develops new drug subsequently found to produce harmful side effects which manufacturer failed to discover in course of testing product, manufacturer is liable in negligence if drug in fact was inadequately tested or manufacturer failed to exercise due care in development of product prior to its release on market for commercial distribution. 19. Druggists ~9 Where it was well known that variations in temperature could have marked effects on safety and effectiveness of vaccine, and it was also know that many lots could not be shipped under refrigerated or storage conditions, it was incum- bent upon manufacturer of vaccine to subject their pre-release lots to those fore- seeable variations in temperature to which their product would be exposed prior to point of inoculation so as to insure that this exposure would not produce deleterious effects. 20. Druggists ~9 Although it would be negligence for manufacturer to disregard regulations established by National Institutes of Health in manufacture of its drug products, manufacturer could not exempt itself from liability in negligence for failure to exercise due care in area not covered by specific regulation. 21. Druggists ~9 Manufacturer of vaccine was negligent in using, as basis for its representation that vaccine yielded no greater local or febrile reactions than n-as experienced with former vaccine, a clinical study which lacked controls for diagnostic and reporting procedures and used vaccines which contained ingredient that had been in cold storage for two years. 22. Druggists ~1O In action against manufacturer of vaccine for damages resulting from doctor's administering vaccine to infant, evidence established that there existed sufficient number of both unrealistic and conflicting reports from field to have required manufacturer to take serious second look at its product before placing it on market. 23. Druggists ~9 Where products were already available to medical profession which satisfac- torily accomplished that which new vaccine was designed to do, there was no epidemic or need justifying risk of premature marketing. 24. Druggists ~1O In action against manufacturer of vaccine for damages resulting from doctor's administering vaccine to infant, evidence established that manufacturer n-as negligent in not adequately warning medical profession of dangers inherent in vaccine's use. 25. Druggists ~9 Drug manufacturer is under duty to warn medical profession of dangers in- herent in its biological drugs which, in exercise of reasonable care, it knew or should have known to exist. 26. Druggists ~9 Watering down substance of warning so as to give false assurance to medical profession that drug or biological can be safely administered, thereby minimizing danger which exists in use of product, amounts to inadequate warning. 27. Druggists ~9 Doctors have right to and in fact do rely on brochures sent to them by drug manufacturers regarding safety and use of their products. 28. Druggists ~9 Drug manufacturer who, after reporting results of its test to Food and Drug Administration, and on strength of those reports markets its products, discovers new harmful side effects produced by drug, yet fails to send out warnings of this new development to foreseeable users, is negligent. PAGENO="0277" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4567 29. Druggists ~9 Any significant increase found to exist in reaction rate of particular drug must be disclosed by manufacturer. 30. Druggists ~=9 Where manufacturer of vaccine had noted that study revealed that seven per cent of children inoculated with vaccine suffered fevers of 104 degrees and above, manufacturer was under duty to timely amend brochure included with its prod- uct in order to inform medical profession of information which would reasonably be expected to affect doctor's decision to use vaccine. 31. Druggists ~9 Manufacturer of vaccine marketed in 1959 was under duty to warn medical profession of possibility of allergic reaction. 32. Damages ~=~1 Under New York law damages are compensatory, not punitive. 33. Parent and Child ci~=~7(1) Father is entitled to recover for loss of injured child's services and for medical attendance and expenses. 34. Damages ~60 "Collateral source" doctrine has been severely limited in its application. 35. Damages ~60 Where liability for care of mentally defective infant may be asserted by state against infant and his father, doctrine of "collateral source" does not apply. Mental Hygiene Law N.Y. ~ 24 and subds. 5(b), 9(b). 36. Mental Health ~32 Where state has provided care for mentally defective infant, damages awarded father for past period of institutionalization are subject to lien of state and defendant may move to have lien determined. Mental Hygiene Law, N.Y. § 24 and subds. 5(b), 9(b). 37. Damages ~43 In absence of proof that nursing services performed by infant's mother were other than would normally have been rendered by mother to her child, damages for such services would not be awarded. 38. Damages ~133 Father was entitled to damages in amount of $2,500 for loss of services of infant who became mentally retarded as result of receiving vaccine at age of three months. 39. Damages ~32, 37, 43 Infant who became mentally retarded from being administered vaccine at age of three months was entitled to damages to cover future medical expenses, to reimburse him for future loss of wages, and to cover past, present and future pain and suffering. 40. Damages ~135 Evidence established that $160,000 would be fair amount to insure adequate future medical care for infant who became mentally retarded from administra- tion of vaccine at age of three months. 41. Damages ~133 Infant who became mentally retarded from administration of vaccine at age of three months was entitled to $50,000 as damages for loss of future earnings even though he would be confined to institution during most of his life and would not start work until age 21. 42. Damages ~132(3) Infant who as result of being administered vaccine suffered from high fever, underwent two spinal taps and craniotomy, was partially paralyzed and subject to seizures and was mentally retarded was entitled tO $400,000 as damages for pain and suffering. PAGENO="0278" 4568 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY Fuchsberg & Fuchsberg, New York City, Jacob D. Fuchsberg, Richard E. Shandell, New York City, of counsel, for plaintiffs. Costello, Ward, Tirabasso & Shea, New York City, Joseph M. Costello, New York City, David C. Dethmers, Detroit, Mich., of counsel, for defendant. TENNEY, District Judge. This product liability case. w-hich was tried to this Court without a jury, in- volves the ethical drug Quadrigen, made by defendant Parke Davis & Co., and administered to the infant plaintiff herein. Quadrigen contains four antigens: diphtheria toxoid, tetanus toxoid, pertussis (whooping cough) vaccine and poliomyelitis vaccine. The action has been brought on behalf of the infant plain- tiff by his father, and by the father individually, charging negligence in various respects and breach of an express and implied warranty. There is no dispute that the injuries suffered by the infant plaintiff are catastrophic. The plaintiff, Eric Tinnerhoim, was born on August 30, 1959, in Huntington Station, Long Island, New York. He was the third child born to his parents, the plaintiff Carl F. Tinnerholm and Mrs. Tinnerholm, the other two children then being five and four years of age. His birth was normal, as was his mother's preg- nancy, and at the end of the first and second months of his life he was taken to the family physician, Dr. Gerald Feinberg, for routine check-ups. The infant was apparently a big, healthy boy who ate and slept well and was active and alert. Some time between ii :00 AM. and noon on Saturday, November 28, 1959, Mrs. Tinnerhoim, by prearrangement, took Eric to Dr. Feinberg's office for his first immunization injection. She was informed that this immunization was not the usual 3-in-i that her other children had received, but that it was a 4-in-i which added poliomyelitis vaccine to the antigens with which she was already familiar. Eric suffered no immediate side-effects following the injection and continued in apparent good health through that Saturday and Sunday. On Monday he ap- peared extremely quiet and seemed to look toward the wall most of the day, although the parents apparently thought nothing of this at that time. On Tuesday morning, December 1, 1959, at about 4 :00 A.M., the child was found tangled up in his bedclothes and whimpering, but on being picked up and patted he quieted down and presumably went back to sleep. There was no indication of temperature at that time. However, some time later, between 6 :30 and 7:00 AM., the child was found by his mother huddled under the covers, lethargic and bathed in per- spiration. His temperature at that time n-as 108°, he was very white, his lips were blue, arid he was limp. While Mrs. Tinnerholm gave the child an alcohol bath, Dr. Feinberg was summoned by the boy's father. When the doctor arrived around 7:30 AM. he confirmed the 108° temperature which was shortly reduced to 106° by the alcohol bath. The doctor's examination further disclosed a small amount of emesis and some coughing. The remainder of the examination was negative. Eric was admitted to Huntington Hospital at 8 :45 A.M. where he was again examined by Dr. Feinberg, who found the child's neck supple, an absence of masses, and a negative Brudzinski.° Dr. Feinberg's original diagnosis was fever of unknown origin. Eric remained in Huntington Hospital until December 18th. during which period he was cared for by two pediatricians, Doctors Gordon and Kagan, and also examined by a neurologist, Dr. Sengstaken. Dr. Kagan examined the boy on the day of his admission to the hospital and found him to be pale, hyperpneic,3 the eyes dull and apathetic, with focal seizures and twitching of the right side. There was a dullness and loss of landmarks in the ears and some redness at the back of the throat. On the basis of his examination, Dr. Kagan believed that the boy had either a bacterial infection of the bloodstream (sepsis) or meningitis. However, subsequent laboratory testing ruled out both the sepsis and meningitis, for a spinal culture revealed clear fluid with only three cells, a normal finding, indicating the absence of infection. There was, however, an elevated protein content of 10 milligrams percent, indicating some abnormality attacking the brain. A repeat lumbar puncture ten days after admission again showed an absence of cells and a protein content of 56 milligrams percent, lower than the previous 100 milligrams percent, but still above normal. During this first hospitalization Eric developed recurrent seizures, and on the fifth day a flaccid paresis or paralysis of the right arm and leg was noted and which per- 1 An antigen is a substance which causes antibodies to be produced by the organism into which it is injected. 2 A Brudzinski is a neurological test which includes tile forward flexion of tile neck or the head on the neck, which, if done without resistance and without pain, indicates there is no meningeal irritation. Abnormally rapid breathing. PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4569 sisted until his discharge on December 18, 1959. Since that time he has been retarded in his mental development, being classified in the imbecile-4diot range. He is unable to stand or walk or talk, is incapable of toilet training, and in order for him to be able to sit he must first be propped up. There is a spasticity in posturing of the right upper limb and the right lower limb, indicating a spastic weakness of these extremities. He still suffers occasional seizures and has a mental age in the range of five months. Is it possible to determine, with reasonable medical certainty or reasonable medical probability, that something peculiar to Quadrigen was the proximate cause of the injuries suffered by the infant plaintiff? The question must be answered affirmatively. Dr. Charash, one of plaintiffs' experts, concluded that the child suffered a pertussis-vaccine encephalopathy,4 basing his conclusion on the temperal relationship between the immunization and the onset of illness; the unusual and spectacular sudden rise and subsequent rapid reduction in temperature; the appearance of unilateral seizures and weakness; the essen- tially extraordinary discrepancy between the very high protein and the absence of white cells in the spinal fluid; and the flatness of the fontanel. For the same reasons, he discounted the possibility of a viral encephalitis,~ one of the possible alternatives raised by defendant. Likewise, the suggestion that the infant may have developed a brain abscess from otitis media is not supported by the evidence. What was it, then, that was peculiar to Quadrigen that it can be stated, with reasonable medical certainty or probability, that it caused the injuries already described? In order to answer this question it is necessary to discuss in some detail pertussis and pertussis vaccine as incorporated in Quadrigen. Pertussis, or whooping cough, is a communicable respiratory disease caused by a bacterial organism. The disease may attack the brain to the extent that con- vulsions, high fever, and occasionally hemorrhages in the brain are produced. Sometimes this is accompanied by hemiplegia or paralysis of half the body, and not infrequently there is a resultant mental retardation. The disease is particu- larly dangerous for children during their first year of life, since little or no maternal immunity is passively transferred to the newborn. Immunity, how-ever, may be obtained through the injection of a vaccine. A vaccine, by introducting an antigenic factor into the body of the recipient, is intended to stimulate the production of antibodies, which antibodies confer protection against the disease. In the process, lymphocytes, a form of cell con- tained in the lymph glands, absorb the antigenic factor and produce an antitoxin against the particular disease. With some infectious diseases, such as diphtheria and tetanus, it has been possible in developing a vaccine to isolate the soluble toxin or poison excerted by the bodies of these bacteria, and to inactive this toxin with formaldehyde, thus converting the toxin into what is called a toxoid. This toxoid preserves the ability to immunize against the disease by stimulating the production of antibodies in the recipent, but it has lost its poisonous qualities. The pertussis organism, however, is a unique, very complex one containing many different factors. There is an exotoxin, an endotoxin, a protective antigen, a factor that gives the Schwartzman phenomenon,6 a factor sensitizing to his- tamine, yeast, protein extracts, vaccines and endotoxin, to infection by gram negative bacteria and by influenza, to X-rays, pressure, the stress of cold, and to a marked degree sensitizing to ceretonium, one of the important neuro-hor- mones of the brain. The exotoxin in the pertussis organism is thermo labile, i.e., it is destroyed by heat, and all vaccines with which we are concerned are heated during preparation and the thermal labile exotoxin destroyed. However, the endotoxins inside the cell are not destroyed by heat. It is this endotoxin, also called a lipopolysaccharide, to which febrile reaction following administra- tion of pertussis vaccine is usually attributed. In addition to the protective anti- gen already mentioned, there are some fourteen or fifteen different antigens, and nobody knows which, of all these antigens, is the one which stimulates production of the antibodies conferring protection against pertussis (whooping cough). By reason of the complexity and mystery of the pertussis organism it was impossible to isolate the toxin conferring protective activity and make a toxoid out of it, as in the case of diphtheria and tetanus. Therefore, it was necessary to administer the entire bacteria organism, treating it in some way by heat or otherwise to kill the organism but preserve the antigenicity. As a result, whereas there were practically no reactions to diphtheria or tetanus toxoids, there were Encephalopathy Is any degenerative disease of the brain. Encenhalitis is an inflammation of the brain. 6 The Schwartzman phenomenon is the production of ulcers on injection under the skin of a rabbit. PAGENO="0280" 4570 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY not uncommonly reactions to pertussis vaccine such as a swollen injection area and some fever. Occasionally, there was severe plain from the site of the injec- tion, and on rare occasions convulsions, high fever and the neurological sequelae of brain hemorrhage, hemip.legia and mental retardation, just as with the disease itself. The cause of these neurological manifestations following the use of pertussis vaccine is not definitely known either on a pathological, histological or clinical basis. These manifestations, however, were first brought to the at- tention of the medical profession in April of 1948. Thereafter there were devel- oped additional controls over the production of pertussis vaccine. Under the new regulations the encephalopathic type of reaction was minimized. The use of phosphate adjuvants made possible a decrease in the amount of pertussis in the formula; new maximum as well as minimum potency standards were set; and the toxicity of the pertussis component was reduced by extra heating and by the toxicity test. The potency test is performed by injecting groups of mice with varying dilutions of vaccine, and, then, after a period of time, challenging the mice with virulent organisms. The toxicity test was performed by injecting a group of ten mice of specified weight with a specified dose of vaccine and weighing the group at specified intervals. I will have further occasion herein to discuss in greater detail the matter of tests as to their adequacy in the present case. Mention has been made above of the use of phosphate adjuvants which permitted a reduction of the amount of pertussis in the formula. Today, at least in American vaccines, an aluminum salt is used as an adjuvant. An adjuvant serves as a depot or button which will slow the release of the antigen rather than having it released all at once when the vaccine is merely suspended in a liquid. When aluminum phosphate was first used, there was some apparent in- crease in toxicity and the amount of the aluminum phosphate was reduced ap- proximately one-half with a resultant substantial reduction in toxicity. There- after vaccines with the aluminum phosphate were no more toxic than other adsorbed vaccines. One other aspect of the manufacture of pertussis vaccine should be mentioned at this time. All vaccines packed in multi-dose vials require a preservative to keep them sterile (not to preserve their potency). In the development of pertussis vaccines until the development of polio vaccine the universal preservative used was Merthiolate. At the time there was no information that the Merthio- late affected the vaccine for better or for worse, but it has recently been dis- covered that Merthiolate acts as a stabilizer of the vaccine, that in its presence the vaacine tends to decrease in toxicity in storage at the same time that its potency is stabilized at a level at least for the first six months. In the early 1940's, there was developed the method of combining pertussis vaccine with diphtheria and tetanus toxoid into a combined antigen product colloquially known as "DDT". No apparent decrease in toxicity or reactivity was noted as a result of such combination. Defendant marketed such a product under the trade name "Triogen". After the Salk poliomyelitis vaccine had been developed, it was decided by do- fendlant to attempt to mix the polio vaccine with the "Triogen" in order to develop commercially a quadruple antigen product. In connection with the development of polio vaccine it had been learned that Mertliiolate had a deleterious effect upon the polio virus, caused by the action of released mercury ions. Eli Lilly & Company incorporated Versene within its vaccine, which prevented the re- lease of the mercury ions. However, Versene was incompatible with the aluminum phosphate used as an adjuvant by defendant in Triogen, and since defendant anticipated that it would want to develop a vaccine combining the polio vaccine with Triogen. it decided to use benzethoniurn chloride, or Phemerol which was defendant's trade name for this product. Unknown to defendant the benzethoniurn chloride had an unusual effect on the pertussis vaccine contained therein. It appears that there was a loss of potency, a reduction in the protective activity of the pertussis vaccine when benze- thonium chloride rather than Merthiolate was used as the preservative. This loss occurred only when the vaccine was exposed to variations in temperature. While there is no knowledge as to the manner in which benzethonium chloride affects the unidentified protective antigen of the pertussis vaccine, considerable knowledge has been accumulated as to the physical effects of benzethoniurn chloride on pertussis bacteria placed in a solution including benzethonium An adjuvant in immunology is any substance that, when mixed with an antigen, en- hances the antigenicity and gives a superior response. PAGENO="0281" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4571 chloride. It has been demonstrated that benzethonium chloride partially disap- pears from the solution during storage, coming down from twenty-five parts per million to only seven parts per million. Benzethonium chloride is a quate- nary ammonium compound and has a positive charge, whereas the bacterial cell wall has a negative charge. By attraction, the benzethonium chloride is ad- sorbed to the cell. Such adsorption on the bacterial cell wall may cause its denaturation and favors the leaching of the toxin from the bacterial cell, result- ing in the leakage of the contents of the organism. Cei~tainly, it is reasonable to conclude that the effect of the use of benzethoniurn chloride was to release the endotoxin from the bacteria cell into the fluid that was injected. One such endotoxin, the lipopolysaccharide, causes fever, and fever can produce con- vulsions and brain damage. Indeed, fever is one of the recognized etiologies or causes of post-pertussis vaccine encephalopathies. [1, 2] It is reasonable to conclude, as I do, with reasonable medical certainty or probability that the release of the endotoxin into the fluid injected into the infant plaintiff was the cause of the unusually high fever which, in turn, caused the severe and permanent brain daniage. I find defendant's suggestion that the cause of such damage was a viral encephalitis caused by some unspecified virus, a sepsis or meningitis, or an allergic reaction, totally unconvincing. It is not plaintiffs' burden to disprove every possible ground of causation suggested by defendant, nor must the findings of the Court meet the standards of the labora- torian. Plaintiffs' experts have furnished impressive evidence to support the conclusions reached herein, evidence which has clearly withstood the attack of defendant's experts. Having found Quadrigen to have been the causative factor, I turn now to the question of warranty, express and implied, and the further question of negligence. Warranty Generally. [3, 4] Liability for breach of warranty arises where persons or property are damaged because of a product's failure to live up to an express or implied representation by the manufacturer or other supplier. It is distinguished from negligence liability in that it is not based upon fault or upon the failure of such manufacturer or supplier to exercise reasonable care. 2. Frumer & Friedman, Products Liability § 16.01[1] (1967) (hereinafter referred to as "Frumer & Friedman") ; cf. Rheingold, Products Liability-The Ethical Drug Manufac- turer's Liability, 18 Rutgers L.Rev. 947, 977 (1964) (hereinafter referred to as "Rheingold"). [5-8] An express warranty will arise where a manufacturer, supplier or other seller positively represents a fact concerning the goods he sells. 2 Frumer & Friedman § 16.02; cf. Uniform Commercial Code § 2-313. In the instant case, plaintiffs allege that defendant warranted Quadrigen as "safe, effective and free from harmful side effects °." Amended Compit. ¶ 20.8 An implied warranty, on the other hand, is imposed by operation of law. 2 Frumer & Friedman § 116.02. The implied warranties allegedly breached in the ease at bar are the warranties of merchantability and fitness for a particular purpose. Amended Complt. ¶ 28. The warranty of merchantability is that "the thing sold is reasonably fit for the general purpose for which it is manufactured and sold." Henningsen v. Bloomfield Motors, Inc., 32 N.J. 358, 161 A.2d 69, 75 A.L.R.2d 1 (1960) ; 2 Frumer & Friedman § 16.04[2] [d]; see Burr i~. Sherwin Williams Co., 42 CaL2d 682, 268 P.2d 1041 (1954) ; Twombley v. Fuller Brush Co., 221 Md. 476, 158 A.2d 110 (1960) ; Ryan v. Progressive Grocery Stores, 255 N.Y. 388, 175 N.E. 105, 74 A.L.R. 339 (1931) ; Rheingold at 978 (reasonable fitness for ordinary purpose for which sold). The implied warranty of~ fitness for a particular pur- pose is virtually self-explanatory, the major distinction from the merchantability warranty being reliance on the particular seller's skill and judgment. 2 Frumer & Friedman § 16.04[2] [dl; see Henningsen v. Blomfield Motors, Inc., supra. Privity and Related Problems. a. Privity. The last decade has seen a vigorous frontal assault on the previously near- impregnable "citadel of privity" so that in many states the insulation of the man- 8In paragraph 20 of the amended complaint, plaintiffs also claim that defendant ex- pressly warranted that Quadrigen "was fit for the use as an immunizing agent against various ailments and was of good merchantable quality." These are normally considered to be implied warranties and do not appear to be expresly warranted in the Quadrigen package insert or advertisements to the medical profession. Indeed, in paragraph 28 of the complaint, plaintiffs make these same allegations in their cause of action for breach of implied warranty. PAGENO="0282" 4572 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ufacturer of defective goods from direct liability for breach of warranty, express or implied, is a thing of the past. See generally the excellent state~by-state analysis of the privity problem in 2 Frumer & Friedman § 16.04; Kessler, Prod- ucts Liability. 76 Yale L.J. 887 (1967) ; Prosser, The Assault Upon the Citadel (Strict Liability to the Consumer), 69 Yale L.J. 1099 (1960). The decision which provided the impetus for the collapse of privity was Hennington v. Bloomfield Motors, Inc., supra, wherein the New Jersey Court held that public policy demanded the extinction of the privity doctrine because of mass marketing conditions causing the manufacturer to become remote to the ultimate consumer, sales being accomplished through intermediaries, and product demand being created by use of advertising media. It was obvious, in- dicated the Court, that manufacturer contemplated the cultivation of the ulti- mate consumer and that at least with respect to the purchase of a car, the implied warranty of merchantability should extend to the ultimate purchaser of such vehicle and those persons who would reasonably be anticipated to use it, such as members of the purchaser's family and .those occupying or using the vehicle with his consent. [9. 10] Of course, no extended discussion is necessary to show that this Court is bound by the New York law of warranty. And it is clear that if the requirement of privity is not dead in this jurisdiction, it has at least been dealt a deliberating blow by the New York Court of Appeals in Greenberg v. Lorenz, 9 X.Y.2d 195, 213 N.Y.S.2d 39, 173 N.E. 2d 773 (1961) ; Randy Knitwear, Inc. v. American Cyanamid Co., 11 N.Y.2d 5, 226 N.Y.S.2d 363, 181 N.E.2d 399 (1962); and Goldberg v. Kollsman Instrument Corp., 12 N.Y.2d 432, 240 N.Y.S.2d 592, 191 N.E.2d 81 (1963). See generally 2 Frumer & Friedman § 16.04 [2] [b] [xl. In Greenberg v. Lorenz, supra, the Court held that a retailer impliedly warrants the wholesomeness of food and household goods to all members of the buyer's household since a presumption should arise that the purchase was made for all such persons. Randy Knitwear, Inc. v. American Cyanamid Co., supra, dis- ljensed with the requirement of privity in an express warranty case. Frumer & Friedman point out that the real importance of Randy Knitwear was that it paved the way for the New York Courts to abrogate privity as a requirement in implied warranty cases since the Court noted (1) a trend away from privity; (2) privity was an outmoded technical rule; (3) that the separate indemnity actions required by the privity rule were a waste of time spent in litigation (obviously both on the part of the courts and the various parties who would be involved) ; and (4) that warranty was historically a tort action. Id. at § 16.04 [2] [b] [x]. Finally, in Goldberg v. Kollsman Instrument Corp., supra, the New York Court of Appeals went about as far as Hennin.gsen by holding that an airplane assembler could be liable for the death of an airplane passenger under an implied warranty theory. It was held, however, that the manufacturer of a component part was not liable since "adequate protection is provided for the passengers by casting in liability the airplane manufacturer which put into the market the completed aircraft." 12 N.Y.2d at 437, 240 N.Y.S.2d at 595, 191, N.E. 2d at 83.~ It is apparent that the refusal to hold the component part manufacturer was not because of lack of privity. 2 Frummer & Friedman § 16.04[2] [b] [xl. From the foregoing, it should appear obvious in the instant case that privity presents no bar to recovery.'0 b. Necessity of a &iie In Perimutter v. Beth David Hospital, 308 N.Y. 100, 123 N.E.2d 792 (1954), the Court held that a hospital administering a blood transfusion is rendering only a service and is not making a sale. Whether a sale is necessary to impose war- ranty liability today is questionable (see 1 Frumer & Friedman § 19.02; Rhein- gold at 974), but even assuming such a requirement, it is submitted that Perimutter would not bar a recovery in the instant case. Faced with the argu- For an apparent extension of Goldberg v.. Kolisman Instrument Corp., see Rooney v. S. A. Healy Co., 20 N.Y.2d 42, 281 N.Y.S.2d 321, 228 N.E.2d 383 (1967), where the de- fendant supplier sold used protective masks to the City of New York. The Court of Ap- peals held defendant had breached the implied warranty of merchantability since the defect was in design. 15 Gottsdanker v. Cutter Laboratories, 182 Cal. App. 2d 602, 6 Cal. Rptr. 320, 79 A.L.R. 2d 290 (1960), used a novel but valid approach to solve the privity problem. The reason- ing of the Gottsdankcr Court was that both food and drugs are intended for human consumption and that such consumption is one of the basic reasons for the food exception. Therefore, the courts should extend the exception to drugs. Of course, in light of the New York cases cited supra, there is no need to resort to the Gottsdanker reasoning herein. See generally 3 Frumer & Friedman § 33.02 [2] [a] ; Rheingold at 978. PAGENO="0283" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4573 rnent that cases such as Perirnutter would prevent recovery, in Gottsdanker V. Cutter Laboratories, 182 Cal.App.2d 602, 6 Cal. Rptr. 320 (1960), the iive-polio vaccine case, the California Court stated: "Clearly it is the patient, and not the doctor, who is the ultimate consumer of the vaccine. While a sale is essential to impose liability under the implied warranties, the intial sale to distributor or retailer of pharmaceuticals is sufficient to impose upon the manufacturer the responsibility of fulfilling the implied warranties which run to the benefit of the persons whom the manu- facturer intended to be, and who in fact became the `consumers'." Id. at 605, 6 Cal.Rptr. at 324. [11] The Gutter rationale is a sound one. Moreover, the case at bar is dis- tinguishable from Perimutter (as was clutter). Similarity would have been present if the physician who had administered the vaccine to Eric Tinnerholm had been sued for breach of warranty. See 3 Frumer & Friedman § 33.02[b]. Under the law as it existed at that time, plaintiffs would possibly have been denied any recovery. But the later decisions of the New York Court of Appeals in Greenberg v. Lorenz, Randy Knitwear, Inc. v. American Cyanamid Co., and Goldberg v. Kolisman Instrument Co. would allow a direct recovery against the manufacturer, a result not inconsistent with Perlin utter. Accordingly, I find that even if the technical requirement of a sale is necessary, such requirement has been fulfilled under the Gutter Laboratories decision and Perirnutter presents no obstacle to recovery. \~rith these hurdles cleared, I turn to a consideration of the warranty causes of action. Ewpress Warranty The package insert (Plaintiff's Exh. 1) which was apparently sent to the administering physician with his purchase of Quadrigen stated that: When given in accordance with suggested methods, local and systemic reactions following the administration of Quadrigen are usually mild. The incidence is usually no greater than is normally experienced with trivalent vaccine. Local reactions and fever of short duration may occur, however, and parents should be cautioned not to apply local treatment, such as wet dressings or heat. Any child who shows a febrile reaction should be kept quiet, should be offered water repeatedly and may be given one or more doses of aspirin as indicated. Occasionally, a residual induration or cir- cumscribed nodule may persist for a week or more. In instances of more marked reaction, the immunization may be completed with monovalent antigens or other combinations of antigens. Local reactions have been known to be more severe when the child is in the incubative stage of pertussis. Encephalitic symptoms occasionally occur with acute pertussis though rarely with the use of the prophylactic vaccine. Such severe symptoms of the central nervous system include convulsions and lethargy. They may be followed by mental or physical manifestations, sometimes permanent, or even by death; but fortunately such reactions are extremely rare. Whether this statement establishes an express warranty and a breach there- of need not be reached herein, for it is clear, as will be hereinafter developed, that the defendant has breached a warranty implicit in the package insert. How- ever, certain of the problems which need be considered in express warranty causes of action will be briefly discussed. Discussion of the sufficiency of the warning will be reserved for that portion of this opinion wherein the negligence issues are considered. The unique characteristic of drug-product-liability litigation is that while the product is actually meant for the patient, the sales pitch is made to the physician in an attempt to get him to prescribe a particular product or course of treatment to the ultimate consumer. Rheingold at 976. Thus, advertising will take the form, among other things, of promotional literature to the physician, statements of "detail" men who solicit purchases by the physician, package inserts, labels and the like, and/or articles in medical journals. Id. at 965. Can liability of the manufacturer be sustained even though the consumer has not relied on any representation? One New York decision has held that the physician is an agent of the patient for the special purpose of receiving statements from the manufacturer. Wechsler v. Hoffman-La Roche, Inc., 198 Misc. 540, 99 N.Y. S.2d 588 (Sup.Ct. 1050). A number of commentators have expressed the view that the representation need not be made directly to the injured consumer. See, e. g., 2 PAGENO="0284" 4574 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Frumer & Friedman § 16.04[04]; 2 Harper & James, Torts § 28.7 (1956) ; Rhein- gold at 976-77. Nevertheless, if direct communication is dispensed with, it would appear that a plaintiff must still prove reliance by the physiciall. See id. at 977. Dr. Feinberg, the administering physician, testified that he had read the package insert (TR 610, 616). According to him, it presented no more than he had already been taught in his formal medical education and in his practice (TR 460-63, 617). But, as will be discussed infra, the evidence clearly indicates the greater incidence of febrile reactions resulting with the use of Quadrigen, so that the statement as it appears in the package insert is incorrect. Moreover, the statement regarding encephalitic reactions is, at the very least, an ambiguous one (TR61O-18). However, whether these statements can be properly characterized as express warranties which were breached need not be reached in light of my subsequent decision with respect to the implied warranty of merchantability. Implied Warranty In Picker X-Ray Corp. v. General Motors Corp., 185 A.2d 919, 922 (D.C.Mun. Ct.App.1962), it was stated that: Implied w-arranty recovery is based upon two factors: (a) The product or article in question has been transferred from the manufacturer's pos- session while in a "defective" state and (b) as a result of being "defective" the product causes personal injury or property damage. The critical problem, then becomes the meaning of the word "defective". One commentator has attempted to distinguish between pure and impure drugs, the former being "those sold as the manufacturer intended, but with the harm aris- ing as a side effect because of some inherent quality" and the latter being defined as "those sold other than as the manufacturer intended, and containing deleteri- ous impurities." Rheingold at 970. According to this article, additional consiclera- tions flow from a finding that the drug is pure. Id. at 983. The problem with this definition is that in the instant case it is unclear whether a pure or impure drug is involved. It can be argued that Quadrigen was pure because its ingredients were as the manufacturer intended. On the other hand, it can be as persuasively contended that the drug was impure because the endotoxiii that was released from the bacterial cell into the fluid was "a deleterious impurity" and thus the drug was defective. Another commentator suggests a more reasonable test: "[T]he issue as to whether a substance not intended to be present is natural or foreign is com- pletely immaterial on the ground that a product is to be regarded as defective if a reasonable man would not have sold it lied he hnown of the presence of the substance in the product. Keeton. Products Liability-Liability Without Fault and the Requirement of a Defect, 41 Texas L.Rev. 855, 861-62 (1963). (Em- phasis added.) The commentary to the Torts Restatement provides perhaps the best working definition of a defect: "the product is, at the time it leaves the seller's hands, in a condition not contemplated by the ultimate consumer, which will be unrea- sonably dangerous to him." Restatement (Second) of Torts § 402A, commenting at 351 (1965). [12] Whatever definition is used, in my opinion the proof amply sustained the fact that Quadrigen was defective and that time defect was the proximate cause of the injury sustained by Eric Tinnerholm. Compare Stromsodt v. Parke- Davis & Co., 257 F.Supp. 991 (D. N.D.1966). I need not discuss the evidence with respect to the biological and clinical testing of Quadrigen by Parke-Davis and the National Institutes of Health at this time although such matter has been fully considered by me in reaching conclusions on the warranty issues. The matter of testing will be amply discussed in the negligence portion of this opinion. However, certain of the articles that have been written in the field and received in evidence, the deposition of Dr. Margaret Pittman of the Division of Biologics Standards (hereinafter referred to as "DBS") of the National Institutes of Health (hereinafter referred to as "NIH"), and testimony elicited at the trial are all important, have been coilsidered by me in reaching this conclusion and will be discussed at some length herein. [13] The occurrence of encephalopathics following administration of vaccines containing a pertussis component has been long known but the specific element that causes this explosive assault to the brain has not been discovered. See Berg, Neurological Complications of Pertussis Immunization, British Medical Journal 24 (July 5, 1958); Byers & Moll, Encephalopathies Following Prophylactic PAGENO="0285" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4575 Pertussis Vaccine, 1 Pediatrics 437 (1948). However, the fact that an encephalop- athy can be caused by pertussis vaccine would not mean that liability would be incurred for breach of warranty in the instant case. Rather, the finding of an implied warranty breach is predicated on the fact that by manufacturing Quad- rigen in the method chosen by defendant, the changes of contracting an encepha- lopathy were enhanced. Aside from the clinical and laboratory studies of the benzethonium chloride preserved Quadrigen which, in my opinion, indicate a defect in defendant's product, the earliest literature which noted a problem with Quadrigen was pub- lished in 1960. Massachusetts Department of Public Health, Pertussis Immuni- zation, 263 New England Journal of Medicine 410 (Aug. 25, 1960). The investigation indicated by this group "established that the potency of the pertussis-vaccine component in the quadruple antigen products * * was relatively unstable." Pittman, Instability of Pertussis-Vaccine Component in Quadruple Antigen Vaccine, 181 Journal of the Am. Medical Ass'n 113 (11162). It is interest- ing to note this Pittman article points out that with the adoption of a unit of potency in 1953 with an upper limit placed on potency, no cases of fatal encepha- lopathy due to pertussis vaccine were reported to DBS although "occasional nonfatal neurological reactions" continued to occur. Id. at 114~ Dr. Pittman hypothesized that "the preservative and the tissue-cell enzymes present" in the quadruple antigen vaccines "may be factors which contribute to instability." Id. at 148. In 1964, a study was made with bordetella pertussis cells which showed that various substances influenced leakage from the bacterial cell. Niwa, Yamadeya & Kuwajiina, Leakage of Cell Components of Bordetella Pertussis, 88 Journal of Bacteriology 809-10 (1964). Although benzethonium chloride was not used in that study, certain chemical substances similar thereto were employed (TR 1529-30). Finally, in 1965, in an article co-authored by Dr. Pittman, it was stated: "Recent work has' shown that pertnssis vaccine in DTP-P[diphtheria-teta4ius- pertussis-polio vaccine] preserved wit/b benzethoninm chloride is unstable in potency * `~. This surface-acting preservative, no doubt, contributed to the greater toccicity of DTP-P * * by favoring the leaching of the towin from the bacterial cell. It is well known that alkalinity favors lysis and thereby promotes toxicity." Pittman & Cox, Pertussis Vaccine Testing for Freedom-from-Toxicity, 13 Applied Microbiology 447,453 (1965). (Emphasis added.) When testifying at her deposition, Dr. Pittman attempted to water down her statement by contending that she considered this statment to be a mere hypoth- esis (Pittman deposition of Nov. 17, 1967, at 83 (hereinafter referred to as "Pittman I")), but that it was based on scientific experimental data (id. at 83- 84). The statement in her article, written when she was not involved in the instant litigation, seems far more significant than her later attempt to diminish its importance. Dr. Pittrnan, throughout her testimony, appears to consider the instant litigation a personal attack and an indictment of DBS as well (Pittman deposition of Nov. 27, 1967, at 214-15 (hereinafter referred to as "Pittman II")). Dr. Pittman also testified that leakage would be immediately ascertainable in the toxicity tests conducted by the defendant and DBS (Pittman I, at 79-80). However, she later stated she bad absolutely no idea as to the extent of leakage or how long it would take (Pittman II, at 79-81), so it is most difficult to see how she could predict with any certainty that the toxicity tests would reveal the leakage phenomenon. The foregoing documents lend significant credence to the testimony of one of plaintiffs' expert witnesses, Dr. Lapin, who stated that in his opinion Quadrigen was toxic and that the administration of the vaccine to the infant plaintiff caused the injury involved in this litigation. Coupled with this is the complete failure of defendant to offer any reasonable alernative cause of Eric Tinnerholm's injury. The "defect" involved was, in my opinion and as already stated hereinbefore, the leakage of endotoxins from within the bacterial cell and it has been shown by a preponderance of the credible evidence that such defect was the proximate cause of the injury. Nor can defendant argue that this was a marked improvement over Triogen so that it should be shielded from liability even if the above finding is correct. I will state now, and will have occasion to reiterate later that no need justified a risk of marketing Quadrigen at an early date. Other products which performed the same function as the indicated vaccine without the danger involved were on the market and readily available to the medical profession. Although there is PAGENO="0286" 4576 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY testimony that it is beneficial to the patient and the medical profession to reduce the number of infections, when balancing this with the tragic occurrence in the case at bar and perhaps several other cases, the reduction of injections argument pales into insignificance. [4] Accordingly, it is my opinion that the defendant has breached its war- ranty of merchantability to the plaintiff. In view of this discussion, the issues involving liability for breach of the warranty of fitness for a particular purpose need not be considered. Negligence [15-16] The finding of implied warranty liability does not preclude this Court from finding the defendant liable in negligence. ~S~tromsodt v. Parks-Davis c~ Go., supra, 257 F.supp. at 995. However, it is fundamental law that plaintiffs will be limited to one recovery. [17] Defendant herein is chargeable w-ith negligence in failing to adequately test its product, for thereafter releasing the product for commercial distribution in the face of certain danger signs emanating from the test results, and in failing to adequately warn the medical profession of the risks inherent in its use. [18] It is established law that where a drug manufacturer develops a new drug subsequently foimd to produce harmful side effects which the manufacturer failed to discover in the course of testing the product, the manufacturer is liable in negligence where it appears that the drug in fact was inadequately tested or that the manufacturer failed to exercise due care in the development of the product prior to its release on the market for commercial distribution. 3 Frumer & Friedman § 33.O1[2] ; Roginsky v. ftieltardson-Merrell, Inc., 378 F.2d 832 (2d Cir. 1967); Stromsodt v. Parke-Davis c~ Co., supra. The tests which the various lots of vaccine had to undergo prior to their release on the market were generally biological and/or clinical in nature. Not only was it required that each lot fall within the acceptable standards of potency and toxicity established by DBS, but also the reports from the doctors in the field as well as those testing the vaccine under clinical conditions had to indicate that the drug was safe for use and that it produced no untoward adverse reactions in the recipients. Both the potency and toxicity tests were first performed in the laboratories of the manufacturer. Once satisfactory results were achieved, the manufacturer would send the lot to DBS which, in turn, would conduct its own independent study. If the DBS test results confirmed the manufacturer's report or protocol, the lot would be approved for release on the market. If, on the other hand, the DBS results conflicted with the results set forth in the manufacturer's protocol, the lot would be returned to the manufacturer for re-testing. As hereinbefore stated, the potency test was performed by injecting groups of mice with varying dilutions of vaccine, and, after a period of time, challeng- ing the mice with virulent organisms. The protective activity of the vaccine w-as judged by the number of mice which survived the challenge at the various dilution levels. In addition, it w-as required that the pertussis vaccine com- ponent have no greater potency than 12 protective units per total human immu- nizing dose (THD) .~ Because a standard deviation is inherent on a test of this nature, a vaccine would be deemed satisfactory if the result of one test or an average of the combined results of two or more tests indicated that the calcu- lated protective activity of the vaccine fell within the allowable range of 8 to 36 protective units. Any result falling outside this range indicated that the par- ticular lot was not fit for public use and consequently was unacceptable for distribution. The standard toxicity text was preformed by weighing a group of ten mice, injecting them with a test dose of vaccine and weighing them again at the end of periods of 72 hours and 7 days. A vaccine was accepted as being free from toxicity if at the end of 72 hours the group weight of the mice was no less than it had been at the initial weighing, and at the end of 7 days was greater than it had been initially. A lot automatically failed the test if it w-as determined that a mouse had died from the vaccine. Although Parke-Davis found no problem in meeting the potency requirements in the testing of its triple antigen vaccine, Triogen, it is apparent from the 11 "THD" is the total dose of vaccine, administered in a series of three separate inocu- lations, that any one individual is required to be given in order to insure full immunizing protectivity. The "12 protective units" standard represents the number of bacteria within a total human dose which successfully immunizes the recipient from the disease without itself causing harmful side effects. PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4577 correspondence between Parke-Davis and DBS during the year 1959 that begin- ning with the very first experimental lots of Quadrigen submitted to DBS for testing, i.e., Lots X-7513 and X-7514, Parke-Davis was having difficulty obtain- ing satisfactory potency values. On January, 9, 1959, Dr. Workman of DBS wrote to Parke-Davis that: "Our potency assays on the pertussis component of this lot (X-7514) showed values of only 7.9 and 3.8 units per total immunizing dose and thereby suggest the potency of the pertussis component is too low. In view of the extreme differ- ence between your and our results, however, we would be willing to give further consideration to this lot if you are willing to retest. * *" Plaintiffs' Exh. 3. Letters of a similar nature were written concerning Lots 049033, 059294, 049032, 049034, 054044, 055961, 051639, 058836 and others, which lots initially produced test results between 2.7 and 7.25 protective units per PHD. Some of these lots were re-tested and eventually withdrawn from processing. Evidencing Parke-Davis' dilemma, on March 5, 1969, only 4 months prior to the time Quadrigen was commercially marketed, George D. Brigham, Director of the Biological Division of Parke-Davis, wrote a letter to Dr. Workman regarding Lot X-7514: "As you know from recent reports, we have been having difficulties in obtain- ing satisfactory potency values in our preliminary production lots of Quadrigen. In view of these results, we are planning to increase the H. pertussis content to 20 opacity units instead of 15 opacity units as was originally intended." Plaintiffs' Exh. 3. In a follow-up letter dated March 13, 1959, from Dr. Brigham to Dr. Workman, it was further stated: "You indicate in your letter that you are concerned with the low values we have been obtaining in the pertussis component of our multiple antigens. As far as we are aware, our only problem seems to be with the quadruple antigens i.e. eacept for an occasional lower than usual result, our other pertussis-containing products are given satisfactory potency tests. Naturally, we have been concerned with the low pertussis test results in Quadrigen and as indicated in earlier correspon- dence, we plan to increase the concentration of organisms to a minimum of 20 opacity units per cc. as an immediate step to correct the situation." Plaintiffs' Exh. 3D. (Emphasis added.) It seems significant to this Court that Parke-Davis, realizing the inherent poten- tial of the pertusis component for causing fatal reactions, and faced with the unique problem of exceptional deficiencies in the potency values of its premarket lots, simply sought to strengthen the pertussis component without considering the possible existence of a defect in the combination itself. This proposed solution, however, also presented problems. On June 4, 1959, Dr. Brigham wrote Dr. Work- man with reference to Lot 52230, the first commercial lot: "We noted the unusually high value obtained in the pertussis vacc~ine potency test. In view of these high results we conducted a re-test on thi slot. A supple- mental protocol summarizing the test is attached indicating 21.5 units per total human dose. Phis confirms our thought that a re-test would probably show aver- age results within an acceptable range." Plaintiffs: Exh. 3F. (Emphasis added.) It appears clear to this Court that Parke-Davis in its rush to commercialization of its product either overlooked or neglected to consider the possibility that Quadrigen was too unstable a vaccine and therefore too unpredictable to be released on the market at that time. [19, 20] Parke-Davis was equally negligent in failing to test its product under market conditions. Inasmuch as it was well known that variations in tempera- ture could have marked effects on the safety and effectiveness of a vaccine, and it was also known, as testified to by Dr. McLean of Parke-Davis, that many of the lots could not be shipped under refrigerated or storage conditions, it was incumbent upon Parke-Davis to subject their pre-release lots to those foreseeable variations in temperature to which their product would be exposed prior to the point of inoculation so as to insure that this exposure would not produce deleteri- ous effects. This was not done. As it developed, tests taken in 1960 by the Massa- chusetts Department of Health and subsequently by DBS, indicated that although samples of the quadruple antigen vaccine which were held in storage under refrig- erated conditions showed no perceptible loss of potency, those purchased on the market revealed a loss of potency below the minimum requirements for a per- tussis vaccine. Although events subsequent to the injury herein cannot be con- sidered in determining the manufacturer's negligence, it could not have been PAGENO="0288" 4578 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY clear during 1959 that tests under market conditions were necessary and that the defects subsequently discovered in 1960 were foreseeable.12 Similarly, Parke-Davis was experiencing difficulty in its attempt to meet the minimum standards of toxicity. Even as late as August 1959, one month alter Quadrigen had been released to the commercial market, certain lots which had been submitted by Parke-Davis to DBS for toxicity testing were being repected. On August 25, 1959, a letter from Dr. Workman to Dr. Brigham, regarding Lot 054043, indicated: "Our tests of the pertussis component for freedom from toxicity do not con- form with the results reported in your protocol. Three tests were performed and 6 of 30 mice died by the end of 7 days." Plaintiffs' Exh. 3. In a letter dated September 16,1959, Dr. Bringham replied that Parke-Davis' own re-test of Lot 054043 resulted in the deaths of 4 of the 40 mice inoculated. Defendant admitted that although this lot passed a 10-mouse test given earlier, the lot "appears upon more extensive testing to have enough toxicity to fail to pass the Minimum Requirements test in a certain percentage of cases." Plain- tiffs' Exh. 3. Clinical trials of Quadrigen prior to marketing were conducted by Dr. Clarence D. Barrett, Director of the Division of Material and Child Health of the City of Detroit, beginning in 1956 and terminating in 1959.12 Although these trials were primarily designed to determine antibody response in children of various ages and to determine the earliest age in infancy at which immunization with Quad- rigen could be started, Parke-Davis used these trials in its license application as a basis for the proposition that the clinical experience involving Quadrigen yielded no greater local or febrile reactions than was experienced with the triple antigen product. [21] Because of the nature of the vaccine used in the Barrett study and the lack of controls placed on the diagnostic and reporting procedures, it was negli- gent for Parke-Davis to have used this study as its basis for making the above representation. The pertussis component which Dr. Barrett used had been in cold storage for the two-year period immediately preceding the inoculations. If had been discovered that during this period of time the potency of the pertussis component had fallen below the NIH's minimum requirements for an acceptable vaccine. Nevertheless, it was used in the study. Although in the standard commer- cial production lots the benzethonium chloride is combined with the pertussis component at the point of manufacture and allowed to remain in combination throughout the entire storage period, such was not the case with the vaccine used in the Detroit study. There, the preservative was not combined with the pertussis component until the time that the children were to be inoculated. Consequently, the clinical trial could not validly test the extent to which the addition of the benzethoniurn chloride (one of the few important changes being made in the quadruple antigen product) increased the reactivity of the product. Although the vaccine used may have been sufficient to determine the antibody response in the children tested, never having been subjected to market conditions and rep- resenting a quadruple antigen of lesser strength and of a different manufacturing process than the one eventually to be released on the market, it should not have been used as a barometer for judging local and febrile reactions. Even had the vaccine used been an acceptable one for this purpose, the ab- sence of controls over the diagnostic and reporting procedures made any con- clusion with regard to the nature and extent of the reactions an invalid one. Mothers, most of whom came from the lowest socio-economic stratum of urban Detroit, had been asked to report, by telephone, all illnesses or reactions suffered by the children following their inoculations. No doctor or medical assistant at any time took the temperatures of the children either on the day that the vac- cine was administered or subsequent thereto unless a mother, suspecting a re- action, brought her child back to the clinic. Needless to say, it was somewhat 12 It must be noted that in 1059 there were no regulations requiring a drug manufacturer to test its product under market conditions prior to releasing it for use to the general public. It is the opinion of this Court, however, that although it would be negligent for a manufacturer to disregard the regulations established by the National Institutes of Health in the manufacture of its drug products, a manufacturer cannot exempt itself from liability in negligence for failure to exercis due care in an area not covered by a specific regulation. See Stromsodt v. Parke-Davis & Co., supra at 997; Frumer & Friedman § 3301[3]. 12 Barrett, Timm. Molner. Wilner, Fahey & McLean, Multiple Antigen for Immunization Against Poliomyelitis. Diptheria, Pertussis and Tetanus, 49 American Journal of Public Health 644 (1959) ; Barrett, Timm, Molner, Wilner. Anderson, Carnes & McLean, Multiple Antigen for Immunization Against Poliomyelitis, Diphtheria, Pertussis and Tetanus, 167 Journal of the American Medical Association 1103 (1958). PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4579 presumptuous to assume the mothers' ability to recognize a "reaction", to as- sume their possession of thermometers with which to determine whether their children were experiencing febrile reactions, to assume the availability of tele- phones with which to communicate the fact that a reaction had been suffered, and hypothesizing the fact that telephones were available, to assume the depend- ability of the mothers to make the requested reports. To allow any implication to be derived from this study with regard to the incidence of reactions following the inoculation of the children was negligence on the part of the defendant herein.'4 [22] Quadrigen was then made available to selected members of the medical profession who were requested to comment on their experience with the prod- uct. Enough of the "field trials" indicated a marked increase in reactions among the patients given Quadrigen over those being given the triple antigen product with a separate inoculation of the pollomyelitis vaccine to have required Parke, Davis to experiment further with their newly-developed quardruple antigen. There were some reports indicating up to 75 per cent reactions in the children tested whereas `other reports indicated that no reactions whatsoever had been suffered. Some of these contrasting reports involved experiences with the same lot of vaccine. In other reports which indicated reaction rates as low as 2 per cent, the "Remarks" sections indicated that "slight fever" was not reported, "high temperature" was designated "no reaction", and "103-degree tempera- ture" designated as a "slight reaction". In one report, only temperature of 105 degrees qualified as a "reaction". Many of the reports which indicated un- realistically low reaction rates were from doctors who, by the nature of their covering letters, seemed primarily interested In obtaining more of the free vac- cine. In addition, it is most significant that the deposition testimony of Dr. John E. Gajewski, employed during 1959 in Parke-Davis' Department of Clinical Investigation and thereafter as Assistant Director of Medical Correspondence, indicated that during the period between July 1959 and September 1961 the re- ported incidents of febrile reactions with Quadrlgen showed more frequent and higher temperature elevations. Similarly, and in the face of the testimony of Dr. Feinberg and Dr. Lapin that it was a rare instance when the triple antigen vaccine produced a fever of 104 degrees, the results of a study conducted by Dr. Sauer, the inventor of the original pertussis vaccine, su:bmitted for publi- cation on June 10, 1959, and published in the fall of that year, evidenced that of the large groups of infants inoculated with Quadrigen 5 per cent reacted with temperatures of 104 degrees and as much as 2 per cent reacted with temper- atures of 105 degrees. All in all, it appears to this Court that there existed a sufficient number of both unrealistic and conflicting reports from the field to have required Parke-Davis to take a serious second look at its product before placing it on the market. Of particular note was Parke-Davis' cursory attempt to investigate the cause of a reported death attributed by the treating physician to his use of Quadri- gen. Although the autopsy report, received subsequently by Parke, Davis, stated that the immediate cause of death was bronchial pneumonia, the hospital recQrd revealed that the patient had exhibited high fever, convulsions, opisthotonus, vomiting and lethargy several hours after a Quadrigen inoculation. The con- clusion of the autopsy report is not necessarily inconsistent with a finding that the child experienced a pertussis encephalopathy prior to his death in that although bronchial pneumonia may have been the immediate caus& of the in- fant's expiration, such condition can frequently be brought about by some other condition, which, in this case, in light of the small hemorrhages found in the subarachnoid portion of the brain, could ~vell have been the vaccinal encepha- lopathy as was originally diagnosed. Nevertheless, there should have been an immediate and thorough investigation conducted by Parke-Davis into the pos- sible connection between the Quadrigen inoculation and the infant's death two days subsequent thereto, especially in view of the fact that the quadruple anti- gen was soon to be released on the commercial market. This was not done nor did Parke-Davis attempt to notify the NIH of the possible existence of a Quadri- gen-related death." U Although a separate study had been conducted by Dr. Barrett in 1958, using fresh experimental vaccine and employing stricter controls over the diagnostic and reporting procedures, this study showed increased febrile reactions with the use of Quadrigen, and was not the principal study relied upon in support of the license application. To the con~ trary, It was the Detroit study discussed in the accompanying text which Parke-Davis attached to its application and upon which it relied most heavily. ii See note 12, supra. 81-280 0-69--pt. 11-19 PAGENO="0290" 4580 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [23] In considering the above discussion, it should be understood that the entry of Quadrigen on the market in July 1959 was not a response to a situation in which an epidemic or need existed justifying the risk of premature market- ing since products were already available to the medical profession w-hich satis- factorily accomplished that which Quadrigen was designed to do. Stromsodt v. Parke-Davis & Co., supra 257 F.Supp. pp. 996-997. [24] In addition to defendant's negligence in failing to further test its prod- uct in the face of evidence that the quadruple antigen w-as unstable, and in the absence of a public need justifying its premature release on the market, de- fendant was similarly negligent in not adequately warning the medical profes- sion of the dangers inherent in its use. 25[-28] It is the opinion of this Court that a drug manufacturer is under a duty to warn the medical profession of dangers inherent in its biological drugs which, in the exercise of reasonable care, it knew or should have known to exist. Sterling Drug, Inc. v. Cornish, 370 F.2d 82, 84-85 (8th Cir. 1960) ; Stromsodt v. Parke- Davis & Co, supra, 257 F. Supp. at 997; Love v. Wolf 26 Cal.App.2d 378, 38 Cal.Rptr, 183 (1904); Alfieri v. Cabot Corp., 17 A.D.2d 455, 235 N.Y. S.2d 753 (1st Dep't 1962), aff'd, 12 N.Y.2d 1098, 240 N.Y.S.2d 163, 190 N.E.2d 535 (1963) ; Marcus v. Specific Pharmaceuticals, Inc., 82 N.Y.S.2d 194 (Sup.Ct.1948); Frumer & Friedman, supra ~ 33.01 [3]; Restatement (Second) of Torts § 388 (1965) Rheingold at 993, 994. "Watering down" the substance of a warning so as to give false assurance to the medical profession that a drug or biological can be safely administered, thereby minimizing the danger which exists in the use of a product, amounts to an inadequate warning. Love v. Wolf, supra, 38 CalRptr. at 193, 197; Alfieri v. Cabot Corp. supra; Rheingold at 993, 994. In- asmuch as doctors have the right to and in fact do rely on the brochures sent to them by the manufacturers regarding safety in the use of their products, Gielskie v. State, 18 Misc.2d 508, 191 N.Y.S.2d 436, 439 (Ct.Cl.1959), rev'd on other grounds 10 A.D.2d 471, 200 N.Y.S.2d 691 (3rd Dep't 1960), aff'd, 9 N.Y.2d 834, 216 N.Y.S.2c1 85, 175 N.E.2d 455 (1961), a manufacturer is negligent who, after reporting the results of its tests to the FDA and on the strength of those reports markets its products, discovers new- harmful side effects produced by the drug, yet fails to send out warnings of this new- development to the foreseeable users, i.e., doctors and dispensaries, Sterling Drug, Inc. v. Cornish, supra, 370 F.d at 85; De Vito v. United Airlines Inc., 98 F.Supp. 88, 96 (E.D.N.Y. 1951); Gielske v. State, supra; Rheingold at 995. Since the relevant portions of the warning which Parke-Davis issued in the form of a package insert are specifically set forth in the express w-arranty por- tion of this opinion, there is no need to recite them at this time: Knowing that the only advantage in administering Quadrigen rather than the trivalent vaccine was the reduction from two to one of the number of inocula- tions required for each immunization, it is reasonable to assume that had the doctors been informed that greater reactivity could be expected from the quad- ruple antigen, they would not have subjected their patients to needless risk by using this product. Fully realizing this, Parke-Davis, employing the technique of ambiguity and a shrewd use of descriptive adjectives, was able to gloss over those facts which would have dissuaded the doctors and dispensaries from using their product, thereby lulling the medical profession into a false sense of security. [29] The brochure states that "[t]he incidence [of reactions with Quadrigen] is usually no greater than is normally expected with trivalent vaccine." (Em- phasis added.) This statement is misleading in that it reasonably permits one to conclude that the results from the studies conducted by the manufacturer have shown that Quadrigen has produced no greater reactions in the recipients thereof than did Triogen, with the exception of an insignificant number of isolated in- stances. Of course, this was not true. If Parke-Davis thought that in this instance it could legitimately use the word "usually" to mean "in a majority of the lots tested", it was clearly in error, for under that interpretation the manufacturer could conceal from the medical profession a 49 per cent increase in the reaction rate of its products. For example, if Product A and Product B produce reaction rates of 50 per cent and 60 per cent, respectively, in all the lots tested, it is con- ceivable that a manufacturer could represent that there is "usually" no greater reaction found to exist in Product B than in Product A, relying on the fact that only 1 additional person out of every 10 tested reacted to Product B. This method of linguistic distortion is grossly misleading. Clearly, any significant increase found to exist in the reaction rate of a particular drug must be disclosed. [30] As hereinbefore stated, a study conducted by Dr. Sauer, submitted for publication in June 1959, revealed that 7 per cent of the children inoculated PAGENO="0291" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4581 with Quadrigen suffered fevers of 104 degrees and above. Parke-Davis alleges that the reason such study was not mentioned in its brochure was that the Sauer report had not been published until after Parke-Davis had written its package insert. However, it would appear from the evidence that Parke-Davis was fully familiar with the contents of this report in light of Dr. Sauer's contin- uing association with defendant since the early days in the development of the pertussis vaccines. As the cases cited above hold, it was Parke-Davis' duty timely to amend its brochure to inform the medical profession of any significant new developments or information which could reasonably be expected to affect a doctor's decision to use the product. Had Parke-Davis promptly amended its literature to include the results of the study conducted by Dr. Sauer, the medical profession would have been apprised prior to the day that the infant plaintiff was inoculated of the unusual reactivity produced by Quadrigen. [31] Having raised the possibility at trial that plaintiff's injury could have been caused by an allergic reaction and therefore due to plaintiff's own particu- lar hyper-sensitivity (a possibility rejected by me herein), it would appear sufficient to note in passing that defendant was under a duty in 1959 to warn the medical profession of this possibility, especially in view of the fact that such an etiological theory had been recognized since 1947. Berg, Neurological Compli- cations of Pertussis Immunization, British Medical Journal 26 (July 5, 1958). Inasmuch as Parke-Davis did see fit to warn of a possible allergic reaction to penicillin and streptomycin, the two antibiotic residuals from the poliomyelitis vaccine, it similarly should have warned of that possibility with regard to the pertussis component. Finally, the warning that "[l]ocal reactions have been known to be more severe when the child is in the incubative stage of pertussis" was ambiguous in that it reasonably could have misled the members of the medical profession to believe that only in cases where the child was in the incubative stage of pertussis would encephalitic symptoms occasionally occUr. Stromsodt v. Parke-Davis & Co., supra, 257 F.Supp. at 997. This was Dr. FeiUberg's interpretation and, in the opinion of this Court, could reasonably have been followed by others. After due consideration and for the reasons set forth herein, it is the opinion of this Court that the defendant was negligent both in its failure to adequately test its product prior to releasing it on the commercial market and for its failure to adequately warn the medical profession of the dangers inherent in its use. As stated by the late Justice Jackson, dissenting in Dalehite v. United States :16 "This is a day of synthetic living, when to an ever-increasing extent our population is dependent upon mass producers for its food and drink, its cures and complexions, its apparel and gadgets. These no longer are natural or simple products but complex ones whose composition and qualities are often secret. Such a dependent society must exact greater care than in more simple days and must require from manufacturers or producers increased integrity and caution as the only protection of its safety and well-being. Purchasers cannot try out drugs to determine whether they kill or cure. * * Where experiment or research is necessary to determine the presence or the degree of danger, the product must not be tried out on the public, nor must the public be expected to possess the facilities or the technical knowledge to learn for itself of inherent but latent dangers. The claim that a hazard was not foreseen is not available to one who did not use foresight appropriate to his enterprise." [32] Finally, as to the damages claimed, I have been guided by the principle enunciated by the New York courts that damages are compensatory, not punitive. Little purpose would be served by further detailing the catastrophe irrevocably visited on this infant child. [33] The plaintiff father is, of course, entitled to recover for the loss of the child's services and for medical attendance and expenses. Kalina v. General Hospital, 31 Misc.2d 18, 20, 220 N.Y.S.2d 733,735 (Sup.Ct.1961), aff'd, 18 A.D.2d 757, 235 N.Y.S.2d 808 (4th Dep't 1962), aff'd mem., 13 N.Y.2d 1023, 245 N.Y.S.2d a99, 195 N.E.2d 309 (1963). The parties have stipulated that his out-of-pocket payment for hospital and medical expenses for the infant total $3,470.55 and payments made by him to the State hospitals total $2,812.97, for which he is entitled to recover herein. Eric has been confined to State institutions since Jan- uary 30, 1962 and will require institutional care, either of a public or private nature, for the rest of his life. [34-36] Defendant suggests that since the infant plaintiff might be cared for at State expense, the doctrine of Drinkwater v. Dinsmore, 80 N.Y. 390 (1880) 16346 U.S. 15, 51, 73 S.Ct. 956, 97 LEd. 1427 (1953). PAGENO="0292" 4582 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY should be applied. Such `collateral source" doctrine, however, has been severely limited in recent years in its application. Klein v. United States, 339 F.2d 512 (2d Cir. 1964); Feeley v. United States, 337 F.2d 924 (3rd Cir. 1964); Cunning- ham v. Rederiet Vindeggen A/S, 333 F.2d 308 (2d Cir. 1964). Moreover, it is in- applicable in the present case since liability for such expenses may be asserted herein against plaintiff father and plaintiff infant. The present cost of maintain- ing the infant at Suffolk State School is $6,000, wthich the State may recover from the father. New York Mental Hygiene Law-. McKinney's Consol.Laws, c. 27, § 24. Even though it has accepted lesser payments in past years, it may recover the full reimbursement rates less the payments already made, § 24(9) (b), which potential recovery for the past period of institutionalization is fixed at $33,000. Such sum is subject to the lien of the State under § 24(5) (b). Defendant may, for his own protection and if so advised, move to have such lien determined. [37, 38] I have not included any amount to cover the nursing services ren- dered by the infant's mother during the period from December 1, 1959 to Jan- uary 30, 1962, for lack of proof that such survices were other than would norm- ally have been rendered by a mother to her child. I do aw-ard the plaintiff father $2,500 for the loss of the child's services during minority. [39, 40] The damages properly awarded to the infant are to cover future medical expenses, to reimburse him for future loss of w-ages, and to cover past, present and future pain and suffering. With respect to future medical expenses, it seems clear that Eric will require institutionalization for the rest of his life. However, in view of the injury, I believe from the evidence that a present life expectancy of 50 years is a reasonable approximation. Also, recognizing the continuing rise in medical costs and the fact that Eric may well be entitled to private nursing and therapy additional to what may be received under State care, I believe that $160,000 would be a fair amount to ensure him adequate future medical care. Loss of wages may also properly be awarded. Grayson v. Irvmar Realty Corp., 7 A.D.2d 436, 184 N.Y.S.2d 33 (1st Dep't 1959). [41] The defendant contends that since the infant will be permanently con- fined to an institution he will have little need for damages attributed to loss of earnings. The only authority cited for this proposition is Scolavino v. State, 187 Misc. 253, 263, 62 N.Y.S.2d 17 (Ct.Cl.) modified, 271 App. Div. 618, 67 N.Y.S.2d 202 (3rd Dep't 1946), aff'd. 297 N.Y. 460, 74 N.E.2d 174 (1947), and is clearly inapposite since the condition of the infant in that case prior to the accident made his future employment impossible, i.e., loss of future earnings was not attributable to the accident. Accordingly, taking into account a 5-percent dis- count factor and making the valid assumption that Eric would not have com- menced to work until age 21, I award him $50,000 for loss of future earnings. [42] To the out-of-pocket losses suffered by this infant must be added the general damages for pain and suffering. Little purpose would be served in fur- tiler dwelling on the various aspects of his past, present and permanent con- dition. He has undergone two spinal taps and a craniotomy, is partially paralyzed and subject to seizures. He is not comatose, however; he is not a vegetable. Accordingly, after careful consideration of this case and of others in which somewhat similar injuries were involved,1~ I consider an award of $400,000 for pain and suffering reasonable and just. In summary, I find as follows: I. For plaintiff Carl F. Tinnerholm- (a) Reimbursement for medical expenses paid $ 6, 283. 52 (b) For Past medical expenses for which liable 33, 000. 00 (c) Loss of Services 2, 500. 00 II. For the infant plaintiff Eric Tinnerholm- (a) Future medical expenses 160, 000. 00 (b) Loss of future earnings 50, 000. 00 (c) Pain and suffering 400,000. 00 The foregoing represents the Court's findings of fact and conclusions of law-. A judgment shall be entered for plaintiffs in conformity herewith. (Whereupon, at 1 :40 p.m., the subcommittee recessed, to reconvene at 10 a.m., on Tuesday, March 18, 1969.) ~ See, e.g., Christopher v. United States, 237 F. Supp. 787 (ED. Pa. 1965) (29-year old man -paraplegic----$350.000) Schwartz v. United States, 230 F. Supp. 536 (ED. Pa. 1964) (4S-year-old man-facial cancer-~over $600,000) : Wolfe v. General Mills Inc., 35 Misc. 2d 996, 231 N.Y. S.2d 918 (Sup. Ct. 1962) (30-year-old man-brain injury-$240,000). PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TUESDAY, MARCH 18, 1969 U.S. SENATE, MONOPOLY SuBcO~IMIrrEE OF THE SELECT Coi~IMIrrEE ON SMALL BusINEss, Washington, D.C. The subcommittee met, pursuant to reôess, at 10 :05 a.m., in the Cau- cus Room, Old Senate Office Building, Senator Gaylord Nelson (chair- man of the subcommittee) presiding. Present: Senator Nelson. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; Jay Cutler, acting minority coun- sel; and Elaine C. Dye, clerical assistant. Senator NELSON. This morning the Subcommittee on Monopoly re- opens its hearings. We have as our witness today the distinguished Dr. Edward Annis, past president of the American Medical Associa- tion, and now one of the 15 trustees of the association. *Dr. Annis, w-e are very pleased to have you here before the corn- imttee this morning. Perhaps for the reëord, you should introduce your associates. STATEMENT OF DR. EDWARD R. ANNIS, PAST PRESIDENT OF THE AMERICAN MEDICAL ASSOCIATION; ACCOMPANIED BY DR. THOMAS HAYES, DIRECTOR, DEPARTMENT OF DRUGS, AND SEC- RETARY, AMA COUNCIL ON DRUGS; AND BERNARD P. HARRISON, DIRECTOR, LEGISLATIVE DEPARTMENT, AMA Dr. ANNIS. Yes, Senator. Mr. Chairman, members of the committee, I appreciate this oppor- tunity and I would like now to introduce Dr. Thomas Hayes, director of our department of drugs, secretary of the American Medical Asso- ciation's Council on Drugs, and a member of the Department of Medi- cine of the University of Illinois. The Senator in the past has expressed his desire to Dr. Hayes to attend this hearing and we are very pleased that he could be with us. With us also is the director of the Legislative Department of the American Medical Association, Mr. Bernard Harrison. Senator NELSON. Doctor, you may proceed to present your state- ment in any fashion you desire. Certainly at any time you wish to elaborate or extemporize on any part of your statement for the record, we will be happy to have you do so. Your statement will be printed in full in the record, along with the appropriate, material that you have submitted along with your statement. I assume if we have some ques- tions in the course of your presentation, you will have no objection 4583 PAGENO="0294" 4584 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to my asking them, but most of the questions, I will ask when you finish. Dr. ANNIS. Mr. Chairman, if it meets your approval, I will not extemporize during my original presentation. This has been prepared pursuant to your request so that we can have a record. We have con- densed it as much as is possible. If I would be allowed to present our entire statement first-I would like to withhold extemporaneous re- marks and answers to the chairman until after that presentation, if this meets with your approval. Senator NELSON. Fine. Dr. ANNIS. In correspondence between this committee and our as- sociation, it has been requested that I include in my discussion these topics: 1. The AMA itself. 2. The evaluation of advertising appearing in AMA publications. 3. Revenue of the association from advertising in its publications. 4. AMA views on a comprehensive drug compendium. 5. Prescription labeling. All of these subjects are included in this statement, along with exhibits of supporting data which I shall not read, but which will be available for your further information. In addition, I will offer some brief comments which I believe you will find pertinent. I would like to hope that what I say here today is as carefully reviewed in the Nation's press and in other communications media as the testimony of earlier witnesses has been. If it is, I know it will buttress the public's confidence in American medicine, which I feel has been weakened by some statements this committee has heard. This Nation is blessed with many hundreds of medical organiza- tions and medical journals, along with hundreds of thousands of phy- sicians and allied medical and health personnel, devoted to improving the health care of the people. Medicine in this country is already good. That fact can be attested to by millions of men, women, and children who are helped by physicians-and by drugs-every day. The goals of this committee will not be achieved, and the best interests of the Government and of the Nation's people are not served by undermining confidence in the medical profession or any of the other professions and occupations working to maintain or restore good health. Mr. Chairman, let me now turn to the topics I promised to cover. THE AMERICAN MEDICAL ASSOCIATION The AMA was founded 122 years ago in a nation and a world en- tirely different from those we now know. In 1847, there were only 29 States with a combined total population less than the present popula- tion of the New York and Chicago consolidated areas. Three primary desires motivated the conscientious physicians and medical school faculties of t.hat day to found a national professional association in medicine. One was the need to establish and maintain a code of ethics by which physicians' behavior and professional performance could be judged by their peers and the public. PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4585 Second was the need to combat the flourishing trade in quackery and nostrums which was endangering the health and lives of Americans. Third was the need to improve and accredit medical education and to establish high standards which persons must attain before being permitted to practice as physicians. All three of these objectives are implicit in the purposes of the association, first written into the AMA constitution when it was adopt- ed May 5, 1847: "To promote the science and art of medicine and the betterment of public health." In 122 years, the association has grown into the world's largest medical association, with 217,000 members-including members who are in the Armed Forces or other Government service and some who are not "active," such as physicians of other nations and dentists and other scientists outside the M.D. discipline who have been accepted into membership because of their contributions to health. The AMA is a federation of 54 State and territorial medical asso- ciations, each of which is autonomous. Remember, it was the State and regional medical societies that existed in 1847 which created the American Medical Association as their national voice; not the other way around. Each State association-one in each State plus the District of Columbia, Puerto Rico, the Canal Zone, and the Virgin Islands-has its own house of delegates as its policymaking body, made up of representatives elected by the county, city, metropolitan or regional medical societies within its geographical jurisdiction. All together, there are 1,955 of these local medical societies in the United States. The policymaking body of the AMA is its 242-member house of delegates, of whom 215 are elected by the, State and territorial medi- cal associations on the basis of one delegate for each 1,000 members. Five other delegates represent the Army, Navy, Air Force, Veterans' Administration and U.S. Public Health Service. The remaining 22 are from the AMA scientific sections, each representing a medical specialty. The wishes of the house of delegates-as expressed through the adoption of resolutions or reports-are translated ito action by the officers of the association; by the staff of the AMA; by one or more of the committees, councils, or commissions; or by the State and local medical associations and societies, according to their nature. Limitations of time make it impratical-if not impossible-to list all of the activities and projects of the AMA on a national scale. But as just one example, the current inventory, of books and pamphlets shows 676 designed primarily for physicians; and another 321 pri- marily intended for public education. Those latter items most com- monly are distributed to the public by the State and local associations and by individual physicians. Mr. Chairman, what follows is a partial list of these publications, exhibit A, and a recent brochure entitled "The Search" containing the 1968 Annual Report of the American Medical Association. I believe that both exhibits will be of interest to the committee and I ask that they be iiiclu~1ed in the report at this point. Senator NELSON. They will be printed in the record. Dr. ANNI5. Thank you. (The documents referred to follow:) PAGENO="0296" 4586 COMPETITIVE PROBLEMS IN THE DR1JG INDUSTRY Exhibit A A PARTIAL LIST OF AMA PUBLICATIONS AVAILABLE FOR DISTRIBUTION (Other Than Subscription Items) Hard and Soft Cover Books The Best of Law and Medicine (192 pp.) U.S. Adopted Names for Drugs (150 pp.) Manual on Alcholism (100 pp.) The Physician's Career (100 pp.) The Extended Care Facility (152 pp.) Current Medical Terminology (976 pp.) Standard Nomenclature of Athletic Injuries (158 pp.) Emergency Department, A Handbook for the Medical Staff (144 pp. Alcohol and the Impaired Driver, A Manual on the Medicolegal Aspects of Chemical Tests for Intoxication (236 pp.) Utilization Review, A Handbook for the Medical Staff (116 pp.) Health Education (430 pp.) School Health Services (414 pp.) Healthful School Living (324 pp.) Today's Health Guide (640 pp.) Let's Talk About Food (148 pp.) The Look You Like (144 pp.) Chemical Tests for Intoxication (104 pp.) Survey of Medical Groups in the U.S. (148 pp.) Health Appraisal of School Children (56 pp.) Continuing Medical Education (128 pp.) New Drugs (591 pp.) Pamphlets and Brochures Keeping Healthy A Letter To You, Mother, About Measles and Your Child Allergies Allergies from the Air and What to Do About Them Anes thes iology Arthritis Blood Tests Cancer: Facts You Should Know Cons tipa tion Diabetes How to Prevent Heart Disease Immunization Old King Cold Smoking: Facts You Should Know TB Control: Prospects for Eradication Tons us and Adenoids Veneral Disease Is Still a World Problem When Hearing Fades Your Blood Pressure PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4587 (A Partial List.... Pamphlets and Brochures - cont.) Health Education Education of Children for the New Era of Aging Health Promotion for Adults Mental Health and School Health Services Suggested School Health Policies Why Health Education? Health Aspects of the School Lunch Program Health of School Personnel Quackery Chiropractic: The Unscientific Cult Did You Know That...? Chiropractic Facts on Quacks Health Quackery Health Quackery-Arthritis Health Quackery Devices Mechanical Quackery The Merchants of Menace Health Quackery-Chiropractic Health Quackery-Cancer Alcoholism How Teens Set the Stage for AlcOholism The Illness Called Alcoholism Test Your Alcohol Quotient To Your Health (Alcoholism) Diet and Nutrition Can Food Make the Difference The Healthy Way to Weigh Less Vitamin Supplements and Their Correct Use Your Age and Your Diet Sex Education Approaching Adulthood A Story About You Facts Aren't Enough Finding Yourself Infertility Parents' Responsibility Contraceptive Drugs and Devices Skin Care and Groomj~g The Aging Skin Man's Oldest Fallout Problem: Baldness The Case of the Sunburned Mannequins Color Her Hair Beautiful PAGENO="0298" 4588 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (A Partial List. Pamphlets and Brochures - cont.) Skin Care and Grooming - cont. Color Is Only Skin Deep Common Sense About Moles Dandruff A Dermatologist Talks About Warts Excess Hair-A Common Problem for Women Housewife and Her Hands Feminine Shaving Practices Psoriasis: The Scaling Disease Shaving Advice For Men Something Can Be Done About Acne Sunlight and the Skin Time Out For Good Grooming Vascular Birthmarks and Your Child What to Expect from Your Deodorant Cosmetic Surgery Doctors and Patients 8 Ways to Cut Your Doctor Bills How to Be a Good Patient Let's Use Not Abuse Health Insurance Medicines and How to Use Them Surgery What Is Hypnosis? What to Look for in a Nursing Home When A Mental Patient Comes Home When To Call Or See Your Physician Why Wait? Your Family Health Record Your Health Examination The Human Body The Miracle of Life The Wonderful Human Machine Safety and First Aid Are You Fit to Drive? Artificial Respiration Card Danger Lurks Emergency Medical Identification Card Emergency Medical Identification Symbol First Aid Manual Protecting Your Home from Unlabeled Poisons Safety Belts Save Lives Tetanus-the Second Deadliest Poison Child _Care A Child in the Family Prenatal Care When Your Child Needs Glasses PAGENO="0299" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4589 (A Partial List.... Pamphlets and Brochures - cont.) Adolescent Years Why Girls Menstruate Why the Rise in Teenage Gonorrhea? Why the Rise in Teenage Syphilis? Your Teenager And Smoking Fitness and Sports The ABC's of Perfect Posture Exercise and Fitness First Aid Chart for Athletic Injuries A Guide for Medical Evaluation of Candidates for School Sports Height/Weight Folder for Boys Height/Weight Folder for Girls Johnny Makes the Team Physical Fitness Safeguarding the Health of the Athlete Seven Paths to Fitness Tips on Athletic Training What Makes a Good Hobby? What You Should Know About Saunas Senior Citizens Health Aspects of Aging How the Older Person Can Get the Most Out of Living A New Concept of Aging Stay Young, Think Young For Young Children Your Friend The Doctor Your Body and How It Works Drug Dependence The Crutch That Cripples - Drug Dependence Amphetamines Barbitura tes Glue Sniffing LSD Mar ihuana For Physicians Mental Retardation Handbook Patient's History Form Who Helps the Physician Help the Retarded Prenatal Record Nursery Record of a Newborn Infant Newborn Nursery Daily Worksheet Labor Record Summary of Labor and Delivery Physician's Record of Newborn Infant Obstetrical Discharge Summary PAGENO="0300" 4590 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (A Partial List.... Pamphlets and Brochures - cont.) Timely Tip~ Buckle Down and Stay Safe Pull a Switch to Exercise How Are You Fixed for Poisons Battling the Cold Recipe for Family Feeding Tune-Up for Motoring The Better to See and Hear Well Done is For Steak Operation: Diet Right Prognosis: Medical Career Pick Your Shots How to Be a Medical Watchdog Key Facts About Tetanus How's Your Medical ID? Take Stock of Your Assets Smarter Than Ponce de Leon Operation Lift How D0 You Shape Up? Don't Test Your Poison Defense Have You Checked on Health Upstairs, Downstairs, All Through the House Silent Killer Let Breakfast Fight Your Battles Badge of Safety How To Be A Good Patient Aid For Acne Measles Vaccine Handle With Care Stock Up for First Aid Partners for Better Health Beware of Food The Everyday Exercise-Walking The Facts About Hay Fever Night Driving - Double Trouble Treat Your Feet Right The Cigarette - A Dubious Companion Two In Every Hundred Building a Better Mousetrap Also Spanish Language Series PAGENO="0301" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4591 the Search EXHIBIT A-i 1968 ANNUAL REPORT of the AMERICAN MEDICAL ASSOCIATION "The Death of Socrates," by Jacques Loais David (French, 1748-1825(, courtesy of The Metropolitan Museum at Art, Waite Fund, 1931. PAGENO="0302" 4592 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY GENERAL OFFICERS President DWIGHT L WILBUR, MD California President-Elect GERALD D. DORMAN, MD New York Immediate Past President MILFORD 0. ROUSE, MD Texas Vice President CARL A. LINCKE, MD Ohio Secretary-Treasurer ALVIN J. INGRAM, MD Tennessee Speaker, House of Delegates WALTER C. BORNEMEIER, MD Illinois Vice-Speaker, House of Delegates RUSSELL B. ROTH, MD Pennsylvania TRUSTEES EDWARD R. ANNIS, MD Florida JOHN M. CHENAULT, MD Alabama BURT L. DAVIS, MD California WESLEY W. HALL, MD Nevada IRVIN E. HENDRYSON, MD Vice-Chairman New Mexico RAYMOND T. HOLDEN, MD Washington, D.C. ALVIN J. INGRAM, MD Secretary Tennessee JOHN R. KERNODLE, MD North Carolina ROBERT C. LONG, MD Kentucky BURTIS B. MONTGOMERY, MD Chairman Illinois MAX H. PARROTT, MD Oregon L. 0. SIMENSTAD, MD Wisconsin The President, President-Elect and Immediate Past President also are Trustees. PAGENO="0303" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4593 FOREWORD WHAT IS THE AMA? It is the publisher of the world-famous Journal of the American Medical Association (JAMA); ten medical specialty journals; a family health magazine; a news- paper for physicians and others interested in the socio- economic aspects of medicine, and numerous books, proceedings, reports and papers on medical science and medical care. It is the sponsor or co-sponsor of approximately a thousand meetings, large and small, every year on a host of scientific and non-scientific subjects of interest to physicians and others in the health field. It is a primary source of medical and health informa- tion for the public, the government, schools and writers of books, newspaper stories, magazine articles or television scripts. Alone, or jointly with other health and scientific organizations, it is the accrediting body for hospitals, extended care facilities, medical schools, internships, continuing education programs for physicians, and edu- cational courses for persons pursuing allied health professions and occupations. More than anything else, however, the AMA is a state of mind . . . a state of mind that aspires to that of the man honored on the cover of this report. Socrates sought the truth, and in imparting it to his generation, passed it to all succeeding generations. Physicians, too, seek truth and impart it to their col- leagues, to their professional successors and to society so that mankind may live not only a longer life, but a better, richer life. As an organization, the AMA reflects the desire of physicians to join together for the "maintenance of their honor and respectability, for the advancement of their knowledge and the extension of their usefulness-as the Association founders said in 1846. It also manifests the belief stated in the last two years by the House of Delegates that "the health and well-being of the patient has always been-and must continue to be-the first concern of the physician," and that "adequate health care should be available to all who need it." This report of some of the activities of the AMA for the year 1968 is designed to highlight the diverse pro- grams in which the AMA is engaged. I commend it to your attention and I hope you will find it useful as a source of information. Burtis 8. Montgomery, MD Chairman Board of Trustees PAGENO="0304" 4594 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SEEKING MORE MEDICAL MANPOWER PAGENO="0305" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4595 Nobody quarrels with the idea that there is a shortage of health services. But a lot of arguments can be started by asking, "Why?" Is there a shortage in the supply, or an excess of demand? Is the shortage only in patient care services, or can it be traced also to areas of teaching, research and the establishment and control of environmental health conditions? Where people are unable to get immediate medical attention, is it because there is no physician nearby? Or is the problem caused by lack of transportation, lack of knowledge about how to get care, poverty which inhibits some from seeking help, and insurance plans that encourage hospitalization and crowd existing fa- cilities? How efficiently is today's medical and health person- nel being used? How much time does a physician spend doing things that don't require his professional knowl- edge, judgment and skill? How often is the same thing true of other professionals and technicians? Adding 10 per cent to the productivity of today's physicians would, in effect, add 30,000 physicians to the nation's re- sources, a figure approximately equal to the yearly production of 300 additional medical schools. A similar increase for all health workers would add the equiva- lent of 350,000 skilled people. Answers are being sought to two obvious questions: How can more medical and health personnel be de- veloped? How can today's workers best be utilized? As one step in seeking the answers, the AMA and the Association of American Medical Colleges issued two joint statements in 1968 calling for expanded enroll- ment in existing medical schools and establishment of new schools; curricular innovations and other changes in the educational programs which could shorten the time required for a medical education; and innovation in educational programs to encourage diversity in the character and objectives of medical schools, From a first-year enrollment of 9,479 in the nation's 94 medical schools in 1967, the figure has grown to an estimated 9,930 in 99 schools in 1968; and it is expected to reach 10,370 in 101 schools in 1969 and 10,930 in 102 schools in 1970, The five schools which opened for the fall term of 1968 were the University of California School of Medicine at Davis, the University of California San Diego School of Medicine, the University of Con- necticut School of Medicine in Hartford, Mount Sinai School of Medicine of the City University of New York, and the University of Texas Medical School at San Antonio, AMA also is working closely with the National Medi- cal Association to attract more young men and women from minority groups into medicine and to find ways of providing both financial and educational help where necessary. In addition to its interest in the education of physi- cians, the AMA also evaluates and approves educational programs for nine groups allied to medicine-medical technologists; x-ray technicians; medical record li- brarians, and technicians; occupational, physical and inhalation therapists; cytotechnologi~ts, and certified laboratory assistants. Standards are currently being developed for programs for radiation therapy tech- nologists, nuclear medicine technologists and tech- nicians, and medical assistants. FIRST YEAR ENROLLMENT PER MEDICAL SCHOOL 81-280 O-69-pt. 11-20 PAGENO="0306" 4596 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "American" is AMA's first nsme, but its interests end activities are by no means limited to these shores. During the past year, for example, 229 foreign guests from 47 nations visited the headquarters of the Ameri- can Medical Association. AMA is the largest of 29 national medical groups that organized the World Medical Association in 1947, now representing more than 700,000 physicians in 59 na- tional associations. A member of the WMA governing Council, AMA has played an important role in such projects as the International Code of Medical Ethics, the Declaration of Helsinki (ethical principles for clini- cal research), and the Declaration of Sydney (organ transplants). In cooperation with the U. S. Agency for International Development (AID), AMA organized and administers the American Project of Assistance to Medical Education in Vietnam, bringing together departments of the Uni- versity of Saigon's Faculty of Medicine and counter- parts in U. S. medical schools, now including Emory University and the Universities of Louisville, Nebraska, Washington, Missouri, Georgetown and Oklahoma. American professors help Saigon's teaching program and Vietnamese faculty and graduates are selected for advanced training and observation of educational methods here. In three years of the Volunteer Physicians for Viet- nam Program, more than 500 U. S. physicians have contributed more than 80 man-years of voluntary medi- cal service to South Vietnam's civilian population. Also done in cooperation with AID, the program has at- tracted.U. S. physicians from 49 states, the District of Columbia, Canal Zone and seven overseas locations. Through AMA's `Doctor-to-Doctor" program, 1,747 American physicians now are corresponding with 2,424 overseas colleagues, sending them medical journals and exchanging information and knowledge. Readers in 139 foreign countries subscribe for 32,000 copies of the Journal of the AMA, the 10 specialty journals, The AMA News or Today's Health. Another 3,000 copies are sent free to 117 countries. A bimonthly International Health Bulletin goes to 2,000 readers here and abroad. A Spanish edition of AMA's Current Medical Termi- nology (CMT) is being prepared through a Barcelona publisher. CMT is a reference book for selecting pre- ferred medical terms, including certain synonyms and generic terms, to provide maximum convenience in usage and publication. AMA is working to make CMT the international language of medicine. AMA also- has filled more than 300 requests from around the world for free medical textbooks through its Medical Missionary Program; has named 22 AMA representatives to foreign national medical meetings or international congresses during the past year; and maintains liaison with 90 per cent of the 73 volunteer foreign aid agencies recognized by AID. The fourth AMA Conference on International Health is being planned for the latter part of 1969. .~ L :1-- - -- PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4597 EXPANDING MEDICINE'S HORIZONS The Faculty of Medicine, University of Saigon. PAGENO="0308" 4598 COMPETITIVE PROBLEMS IN THE DRuG INDuSTRY In more innocent years past, the natural desire of young people to undergo new experiences-and to horrify their elders-led to such activities as goldfish swallowing and telephone booth stuffing. Today that same desire-appar- ently coupled with greater sophisti- cation, a social climate of conflict and a disciplinary philosophy of per- missiveness-is leading increasing numbers of young people into drug abuse. Parents, physicians, educators, lawmakers and others share grow- ing concern about the problem and ways to combat it. As one step toward meeting the challenge, AMA has launched a nationwide educational program on drug abuse. The production and distribution of a comprehensive educational packet of materials aimed at both physicians and laymen has laid the groundwork for a program that can be carried out at the community level. In the packet, among other things, are the AMA's basic booklet on the subject, The Crutch That Cripples (which ran in the Septem- ber and October issues of Today's Health), and a series of JAMA arti- cles reviewing the latest scientific findings on marihuana, other hallu- cinogens, stimulants, sedatives and narcotics. The strategic position of physi- cians as leaders of the health team and their understanding of drug abuse and its possible conse- quences make state and county medical societies and their mem- bers best suited to implement such a program, which already has been well accepted by educators, civic leaders, the military and allied med- ical and health organizations. Materials developed for the edu- cational program are tailored to community needs. TELLING IT LIKE IT IS-DRUG ABUSE PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4599 A pharmaceutical laboratory develops a flaw drug. It is clinically tested and than approved by the federat govarnmant tor marketing. tt is evailabte to patients on preacription through licensed pharmacists. How does the phyaician find out that this new drug is available? Even more important, where can he get accurate, unbiased information on exactly whet it wilt do; what possible side effects can it cause; what con- ditions within the patient forbid ita use? There are a number of sources of such vital infor- mal ion. An important one is AMA. To provide timely drug information 10 practicing physicians, the Journel of fhe AMA carries periodic reports on new drugs based on an evaluation of the published literature plus unpublished information re- ceived from drug manufacturers-which includes phar- macology and toxicology studies in animals. Before publication, each report is reviewed by AMA and other experts in the field. AMA's annual book. New Drugs, has been en out- standing source of drug information for practicing physicians. II contains information on, and evaluations of, new drugs made available during the previous decade. Novi in preparation is a new' publication, to be called AMA Drug Eva/uafions fADEd, which will include every- thing New Drugs contains plus date on commonly prescribed older drugs, both single entities end com- binations. Expected the letter pert of jggg, ADE initially will nave more then 70 chapters covering as many as 1.500 drugs, with comprehensive indexes of names, pharmacologic actions, therapeutic uses end adverse reactions, Staff soreicee for the United States Adopted Names Council, w'hich names new drugs, are provided by AMA, which also maintains a registry of edverse reac- tions to drugs and is developing methods for surveil- lance of drug usage in hospitals. PAGENO="0310" 4600 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4601 Television can sell products, person- alities and ideas. Can it sell good health practices? AMA believes it can. So does the television industry, which is coop- erating by broadcasting one-minute public service messages on the sub- ject. Produced and distributed monthly by AMA, the health announcements are used regularly by more than 600 television stations from coast to coast. Many stations use them as often as 90 times a month. Purpose of the messages is to stimulate awareness of how to stay has been one titled Faith. It urges well by protecting one's own health viewers to "Let the faith that sus- and safety. These spot announce- tains you grow strong," and reminds ments are designed to relieve fear, them that "Faith, too, is a physician, reinforce good health practices and with whose help you need never discourage abuses. Subjects range fear." Since its production in 1963, from the selection of a proper baby- Faifh has been seen by 50,000,000 sitter to drug abuse or the measles people. vaccine. Certain messages are being ex- The messages are animated to be panded to five minutes for use on more attention-getting for adults children's programs. The first, Your and more easily understandable for Body, has been seen across the children, country on such programs as "Rom- The most successful single an- per Room." A second, Your Friend nouncement, in terms of, exposure, the Doctor, now is being distributed. SERVING THE PUBLIC VIA TV An AMA announcement for childrdns.televlsion programs shows importance of a balanced meal. PAGENO="0312" 4602 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY INTERPRETING LAW AND LEGISLATION Imagine a physician trying to keep up with every recent court decision related to health, medicine or phy- sicians. Or imagine him finding time in his busy practice to analyze every piece of pending national or state legislation to see if it would affect his patients or medical practice. Sound impossible? It is. Yet America's physicians are extremely nell informed on medicolegal mat- ters because of the continuing ef- forts of AMA. Every bill in Congress that affects health or medicine is analyzed, and pertinent information is distributed to medical societies. There were 1,600 such bills in the 89th Congress and 1,435 in the 90th. Hundreds of state bills also are analyzed and indexed, providing a valuable source of help for state society legislative committees con- sidering bills for physician support. Every week a report on Law and Medicine appears in the Journal of the AMA. More than 80 of the arti- cles that appeared between January, 1966, and February, 1968, were com- bined in one publication in 1968. Material on legal problems involv- ing medicine or physicians also is published in The AMA News. The Citation, distributed every other week, summarizes individual court decisions involving physicians or medicine. It is the only publica- 4 tion of its type in the country. 4 In addition, more than 200 printed medicolegal items are available from AMA, including model forms, acts and agreements. AMA compiles in- formation on taxes, corporate prac- tice, professional liability, ethics, blood transfusions and blood group- `ing, hospital records and other sub- jects pertaining to law and medicine. AMA also oversees the mainten- ance of medical ethics. It keeps extensive files on health quacks and helps collect evidence for their `. .., prosecution. PAGENO="0313" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4603 "In a split second, my life flashed before my eyes!" The hero of a paperback novel describing a moment of mortal danger? Not at all. Simply the comment of a physician seeing AMA's computerized physician rec- ords for the first time. The visitor was seated in front of a television screen as his code numbers were pressed by the operator. In one fifth of a second-the time it takes to blink-his complete record appeared on the screen, including date of birth, medical education, type of practice, American Board affiliations, specialty society member- ships and other pertinent information. AMA keeps more complete records on physicians than any other profes- sion has on its members. To answer the approximately 200 requests a day for information, clerks formerly had to go through files, find, remove and read the record cards. Now the computer-an IBM 360-40, known to the key-punch operators, programmers, systems analysts and operators as Mod-40-does the job for them in a BRINGING RECORDS TO LIFE V PAGENO="0314" 4604 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY tiny fraction of the time. Keeping physician records-of AMA members and non-members alike-is the computer's biggest job now. However, Mod-40 is capable of serving every division of AMA in addition to organizations affiliated with or close to AMA, such as the Woman's Auxiliary and AMA- ERF, component and constituent medical societies and medical specialty organizations. Mod-40's components include the console, through which it is controlled; memory banks to store millions of items of information for instantaneous retrieval; and input-output devices that accept information for storage and produce figures, charts or reports on the screen or in printed form. Data fed into the computer is stored on discs and tapes. The full information on the nation's 318,000 physi- cians is contained on six reels of tape. Information also is stored in a "data cell," which can file 400,000,000 characters and symbols. The average physician's rec- ord consists of 1,500 characters of information. In addition to keeping statistics on physicians, Mod- 40 prepares mailing lists, survey and research reports and AMA booklets and directories, It keeps statistical records and makes weekly revisions of the AMA mem- bership report. New assignments are being sought for it. All account- ing and budgeting operations are being computerized, and additional work already is scheduled for other departments or sections of AMA. Computer technology is advancing at such a swift pace that it is necessary for Mod-40's "keepers" to undergo continual re-training. A new generation of computers is developed every five years and each innovation leads to changes, improvements, new uses and new operating procedures. The inner complexities of Mod-40 are somewhat a mystery even to its highly trained programmers and operators. "We know what goes into her," one said, "and we know how to get what we want out of her. But we really don't know how she does it." 0 PAGENO="0315" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4605 Put 25 scientists and MD's in a modern laboratory with the latest equipment. Relieve them of all administrative or teaching duties, allowing them to devote their full time and energies to pure research. Give them the help of some 35 research assistants, technicians, engineers, secretaries and others, and permit them to call on the facilities of AMA and AMA-ERF. And what do you have? You have the Institute for Biomedical Research, which, in its second full year of operation, has become an increasingly visible landmark on the scene of bio- medical research in this country and in the world. It is not possible to hold up any one criterion of productivity for an institute completely devoted to basic research, but much of its impact and its worth can be measured by published works in the most reputable and influential scientific journals. More than 80 scientific papers have appeared over the names of Institute staff members in such journals as the Proceedings of the National Academy of Sciences, Journal of Biological Chemistry, Science, Virology, Journal of Physical Chemistry, Archives of Biochemistry and Biophysics and Experimental Brain Research. Thus, the voice of the Institute is being heard in the forums of the worldwhere basic biomedical research is reported and discussed. All of this is in keeping with the mission of the Institute: to further the development of knowledge in those fundamental aspects of biology which broaden and deepen the foundations of an expanding science of medicine. The Institute now consists of an animal research facility and laboratory departments of experimental medical ecology, virology, molecular biophysics, regu- latory biology and neurobiology. With the approval of the House of Delegates, the Institute will move to a location adjacent to the Uni- versity of Chicago campus. George W. Beadle, PhD, retired president of the University of Chicago and Nobel prize winner in medicine and physiology, assumed direction of the Institute December 1, 1968. No date has been set for the move to the new location. REACHING FOR KNOWLEDGE PAGENO="0316" 4606 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SUMMARY 1967 / ~? ~ / 1~' I.' ~ / ., - B'cnicdicst Reseasch. PROGRAM Schools-S 930396 Loan-350.800 Tobacco & Heaith-2,004.156 Medical Journalism-370 Biomedical Research-931 227 Unrestricted-304,21 0 Grants-3,758 $4,524,919 SOURCE Physicians-S 798.059 Woman's Auxiiia~'-373,442 Companies-2.366.519 Medical Organizat'ons-535,874 Non-Medical Organizal~cna-6 351 ... - - Foundations-131,032 , Laymen-10.642 -.-- $4,524,919 ` I / `p / _s~.c. _._...._e - - --.~-.o8~'o - M~s~ O'9ar"zaions . - - ~y~fl -. -- - - ---: Compantee PUTTING MINDS AND DOLLARS TO WORK No dollar goes further or does more good than one that supports re- search. - - helps operate a medical school - - . teaches physicians and medical students journalistic skills so they can communicate more clearly with their colleagues . - or makes loans available so a medi- cal student, intern or resident can go on with his studies, And that's exactly what dollars do when physicians and others con- tribute them to AMA's Education and Research Foundation, AMA-ERF programs include loan guarantees, the Institute for Biomed- ical Research, contributions to medi- cal schools, tobacco and health studies, training in medical journal- ism, and basic medical investigation by independent researchers. During the year, $959,000 was contributed to medical schools by AMA-ERF, providing a source of unrestricted funds which may be used as each dean sees fit. These funds came principally from physi- cians (68%) and their wives through the Woman's Auxiliary to the AMA (30%). The remainder came from medical and non-medical organiza- tions and laymen. In the past 15 years, physicians of the U. S. have given almost $68,000,000 to medical schools, both directly and through AMA-ERF. The Student Loan Guarantee Fund so far has guaranteed 36,707 loans totaling $41,223,000. The guar- anteed loans are made available by commercial institutions to cover only essential training and living expenses. The borrower does not start repaying until he has com- pleted his training. The Woman's Auxiliary, which carries out many fund-raising pro)- ects, has contributed $3,268,000 in 16 years to AMA-ERF, increasing its gift every year-from $15,700 in 1951-52 to $389,800 in 1967-68. About 80 independent investi- gators in 50 institutions in this coun- try and abroad are studying the effects of tobacco on health, sup- ported by grants allocated through AMA-ERF. PAGENO="0317" IN THE DRUG INDUSTRY 4607 Current Assets Cash . 2,794,108.68 Notes & Accounts Receivable 1350,450.59 Inventories 1350,946.52 Total Current Assets Deferred Charges Deposits 112,233.75 Prepaid Expenses 309,941.27 Total Deferred Charges Fixed Assets Land 1,126,047.14 Building less Accumu- lated Depreciation... .7,234,976.95 Furniture & Equipment less Accumulated Depreciation 899,785.08 Total Fixed Assets Investment-Securities U.S. Government Securities 1,138,935.96 Common Stock 5,895,427.22 Total Investment-Securities Other Assets 1,310,715.99 Total Assets 23,523,569.15 Liabilities and Reserves Current Liabilities Aàcounts Payable 1,618,743.03 Accrued Taxes - 293,311.91 Total Current Liabilities 1,912,054.94 Deferred Income Dues & Subscriptions 2,599,903.96 Total Liabilities 4,511,958.90 422,175.02 Reserves Reserves for Replace- ment of Building and Equipment 15,894,766.81 Reserves to finance anticipated needs in the future 3,116,843.44 Total Reserves 19,011,610.25 Total Liabilities & Reserves 23,523,569.15 BALANCE SHEET-DECEMBER 31, 1967 COMPETITIVE PROBLEMS Assets 5,495,505.79 9,260,809.17 7,034,363.18 PAGENO="0318" 4608 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It is the responsibility of the Ameri- can Medical Association, as the rep- resentative of the American medical profession, to continue to foster the advancement of medical science and the health of the American people. Its continuing purposes are to meet this responsibility through the following means: 1. By encouraging the further de- velopment of medical knowledge, skills, techniques and drugs; and by maintaining the highest stand- ards of practice and health care. 2. By creating incentives to attract increasing numbers of capable peo- ple into medicine and other health- care professions. 3. By advancing and expanding the education of physicians and other groups in the health-care field. 4. By motivating skilled physicians who have the art of teaching to apply themselves to developing new generations of excellent practi- tioners. 5. By fostering programs that will encourage medical and health per- sonnel to serve voluntarily in the areas of need for medical care. 6. By developing techniques and practices that will moderate the costs of good medical and health care. 7. By seeking out and fostering means of making all health-care facilities-physicians' offices, hos- pitals, laboratories, clinics and others-as efficient and economical as good medical practice and atten- tion to human values will permit. 8. By combining the utilization of the latest knowledge for prevention and treatment with the vital healing force of the physician's personal knowledge of and devotion to his patient. g~ By maintaining the impetus of dedicated men and women in pro- viding excellent health care by pre- serving the incentives and effective- ness of unshackled medical practice. 10. By maintaining the highest level of ethics and professional standards among all members of the medical profession. 11. By continuing to provide leader- ship and guidance to the medical profession of the world in meeting the health needs of changing popu- lations. THE PURPOSES AND REPONSIBILITIES OF THE AMERICAN MEDICAL ASSOCIATION I ~ - ` PAGENO="0319" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4609 Dr. ANNIS. And a moment ago, I mentioned the committees, coun- cils and commissions of the AMA. There is one whose responsibilities are most pertinent to this presentation. It is the council on drugs. I would like to take a few moments to describe some of its functions and achievements. THE COUNCIL ON DRUGS In 1847-the year of its founding-the AMA House of Delegates passed a resolution calling for regulation of pharmaceutical matters and patent medicines. In 1905, the `board of trustees of the A-MA established the council of pharmacy and chemistry to consider medicinal preparations offered to physicians for use in the prevention, diagnosis, or treatment of disease. `The `primary purpose of the council has been to encourage the prac- tice of what physicians call "rational therapeutics," which simply means prescribing drugs on the basis of knowledge of the disease and knowledge of the actions of the proposed remedy. Since its beginning, the council has engaged in programs of drug evaluation leading to the publication of authoritative, unbiased infor- mation on drugs and drug therapy. And as the scope of drug therapy has changed, the council has enlarged and revised the scope of its evaluation programs. In 1957, after the use of single-entity drugs had become dominant and individually compounded prescriptions had declined, the council changed its name to the council on drugs. As you can see, the AMA's drug evaluation program is the result of more than 60 years of experience and has taken many forms, of which I shall mention only a few. From 1907 through 1957, the association published an annual `book- this is the one that I received when I was in medical school-"New and Nonofficial Remedies." That was followed from 1958 until 1964 by "New and Nonofficial Drugs," which reflected the need for more clini- cally oriented in'formation. An improved annual book first appeared in 1965, called "New Drugs." It provided, for the daily use of the physician, authoritative information on single-entity drugs introduced during the previous 10 years, plus comparative reviews of oldei~- drugs in a particular thera- peutic group. A roster of the members of the `Council on Drugs is included in this statement as exhibit B. I request that it be made a part of the record at this point. Senator NELSON. It will `be made part of therecord. Dr. ANNIS. Thank you. (The exhibit referred to follows:) PAGENO="0320" 4610 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Exhibit B COUNCIL ON DRUGS AMERICAN MEDICAL ASSOCIATION ROSTER Adriani, John, M.D. New Orleans, Louisiana; Specialties - Chairman Anesthesiology, Surgery, Certified by American Board of Anesthesiology; Profes- sor of Surgery, School of Medicine, Tulane University; Member of Subcommittee for Anesthesia and Surgery Committee; National Research Council. Azarnoff, Daniel L., M.D. Kansas City, Kansas; Specialty - Internal Medicine; Associate Professor of Medicine and Pharmacology and Director of Clinical Pharmacology of the Department of Medicine, University of Kansas, School of Medicine; Research Interests - Clinical Pharmacology; lipid metabolism and atherosclerosis. Bass, Allan D., M.D. Nashville, Tennessee; Specialty - Pharma- cology; Professor and Chairman, Department of Pharmacology, Vanderbilt University School of Medicine; Research Interests - Cancer chemotherapy, Mechanism of steroid action, Autonomic pharmacology. Cluff, Leighton E., M.D. Gainesville, Florida; Specialty - Internal Medicine, Certified by American Board of Internal Medicine; Professor and Chairman, Department of Medicine, University of Florida College of Medicine; Member, Com- mittee on Infections, American Hospital Association; Recipient, Cancer Research Award NIH, 1962. Curry, John J., M.D. Silver Spring, Maryland; Specialties - Cardiology, Internal Medicine, Certified by American Board of Internal Medicine; Associate Clinical Professor of Medicine, Georgetown University School of Medicine; Research Interests - Pulmonary physiology, Hemodynamics in cardiovascular field, Allergy. PAGENO="0321" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4611 David, Norman A., M.D. Portland Oregon; Specialty - Pharmacology; Professor and Head, Department of Pharma- cology, University of Oregon Medical School; Research Interests - Chemotherapy of ame- biasis, Pharmacology of sedative and hypno- tic drugs, Chronic effects of opium drugs and synthetic analgesics, others. Freis, Edward D. M.D. Washington, D.C.; Specialty - Internal Medicine (Cardiovascular Disease), Certi- fied American Board of Internal Medicine; Professor of Internal Medicine, Georgetown University, School of Medicine; Chief, Cardiovascular Research Lab, University Hospital Georgetown University, Washington, D.C., 1949; Senior Medical Investigator, Veterans Administration Hospital, Washing- ton, D.C.,~ 1959; Research Interests - Clini- cal evaluation and hemodynamic analysis of hypotensive drugs, blood and fluid volume changes in disease, cardiovascular physiology in man. Moser, Robert H. M.D. Washington, D.C.; Specialty - Internal Medicine; Chief of Medicine, Walter Reed Hospital; Editoral Staff, Archives of Internal Medicine. Paulsen, Charles A., M.D. Seattle, Washington; Specialties - Internal Medicine, Endocrinology; Associate Profes- sor of Medicine, University of Washington; Member of Endocrinology Society, American Society of Internal l4edicine. Rogers, Daniel, M., M.D. Wenham, Massachusetts; Chairman, Board of Health, Wenham, Massachusetts; Massachu- setts Chapter, American Heart Association; Governor's Task Force on Mental Illness; Member of American Academy of General Practice. Shirkey, Harry C., M.D. Honolulu, Hawaii; Specialty - Pediatrics, Certified by American Board of Pediatrics; Professor and Chairman, Department of Pediatrics, Professor of Pharmacology, University of Hawaii; Research Interests - Pediatric-Pharmacology, Therapy, Toxicolo- gy Drug Standardization. 81-280 0-69-pt. 11-2l PAGENO="0322" 4612 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Smith, Donn Le Roy, M.D. Louisville, Kentucky; Dean and Professor of Physiology, Louisville University, School of Medicine. Woods, Lauren, M.D. Iowa City, Iowa; Specialty - Pharmacology; Professor and Chairman of the Department of Pharmacology, University of Iowa; Re- search Interests - Metabolism of Drugs, CNS compounds. Hayes, Thomas H., M.D. Chicago, Illinois; Specialties - Adminis- Secretary trative Medicine and Internal Medicine; Director, Department of Drugs, American Medical Association; Clinical Associate of Medicine, Department of Medicine, Uni- versity of Illinois, College of Medicine. PAGENO="0323" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4613 ADVERTISING EVALUATION Dr. ANNIS (reading). Earlier in this statement, I mentioned the 997 books and pamphlets produced by the AMA for distribution to physicians and the public. None of those contain advertising. At that time, I did not include the regular publications of the association, saving them for my discussion of the criteria used by the AMA to determine the acceptability of ad- vertising. This is the second of my maj or subjects. The AMA publishes the "Journal of the American Medical Associa- tion"-known as JAMA and recognized to be the outstanding medical journal in the country. In addition, the association regularly publishes 10 specialty jour- nals. They are the "American Journal of Diseases of Children." "Ar- chives of Environmental Health," "Archives of General Psychiatry," "Archives of Internal Medicine," "Archives of Otolaryngology," "Ar- chives of Ophthalmology," "Archives of Dermatology," "Archives of Pathology," "Archives of Surgery," and "Archives of Neurology." Besides the scientific journals, the AMA publishes "Today's Health," a monthly consumer magazine of articles on family health and safety; "The AMA News," a weekly newspaper containing items of general interest to physicians; and a large number of special publications. JAMA, the specialty journals, "Today's Health" and "The AMA News" all contain advertising. The scientific publications restrict their adverti~ing to products that are germane to, effective and useful in the practice of medicine. The advertising of certain products, such as to- bacco and alcoholic beverages, is specifically excluded. The AMA has a department of advertising evaluation which reports directly to Dr. Hugh H. Hussey, director of the AMA Division of Scientific Activities. Dr. Hussey is a former dean of Georgetown University School of Medicine. It is important to note that administratively, the department of advertising evaluation is not answerable to the advertising depart- ment. It is a separate function, responsible only to the member of the AMA staff charged with directing the association's activities in sci- entific areas. The wording and illustrations of advertising, to be acceptable in JAMA or the specialty journals, must meet standards estthlished by the "Principles Governing Advertising in the AMA Scientific Pub- lications." Advertising for "Today's Health" or "The AMA News" must meet written principles and policies governing their acceptance for those publications. The principles I have referred to are attached to this statement as exhibits C, D, and E. I ask that they be inserted in the record at this point. Senator NEL50N.They will be printed in the record. Dr. ANNI5. Thank you. (The exhibits referred to follow:) PAGENO="0324" 4614 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY EXHIBIT C PAGENO="0325" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4615 THE AMERICAN MEDICAL ASSOCIATION seeks to promote the science and art of medicine and the betterment of public health. In serving these aims, the AMA communicates regularly with the mem- bers of the medical profession, with professional persons in allied fields, and with the public. A substantial part of this communication is carried on through the regular production and distribution of its publications. In keeping with its avowed purposes, the Association will do all it reasonably can to insure the accuracy, comprehensiveness, timeli- ness, and relevancy of the advertising content of these publications. The evaluation of advertising copy will be based on the considera- tion of available data concerning the product or service. It will not be based on tests conducted by the AMA. The appearance of advertising in AMA publications should not be construed as a guarantee or endorsement of the product by the Association. The fact that an advertisement for a product, service, or company has appeared in an AMA publication shall not be referred to in collateral advertising without specific, written authori- zation from the American Medical Association. As a matter of policy, the AMA will sell advertising space in its publications when (1) the buyer believes purchase of such space represents a sound expenditure, (2) the inclusion of advertising material does not interfere with or seriously detract from the purpose of the publication, and (3) the advertising copy meets the standards established for that publication. Office of Advertising Evaluation American Medical Association PAGENO="0326" 4616 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY general principles These general principles are applied by the American Medical Associ- ation in determining the eligibility of products and services for adver- tising in AMA scientific publications-The Journal of the American Medical Association and the ten specialty journals. The Association reserves the right to change these principles in the light of develop- ments in medicine or in industry. ELIGIBILITY FOR ADVERTISING 1. Products or services eligible for advertising shall be germane to, effective in, and useful in the practice of medicine and shall be com- mercially available. 2. Pharmaceutical products will not be eligible for advertising until a New Drug Application has been approved by the Food and Drug Administration. 3. "Institutional~type" advertising germane to the practice of medicine and "public service" messages of interest to physicians may be con- sidered eligible for appearance in the scientific publications. 4. Alcoholic beverages and tobacco products are not eligible for ad- vertising. 5. The Association may decide that certain products or services are not eligible for advertising in AMA's scientific journals if advertise- ments for these specific products or services in other media consistently or significantly depart from the standards set forth in the following sections. PAGENO="0327" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4617 Data Requirements 1. DRUGS-For convenience, advertisements for drugs (including vac- cines and biologicals) may be separated into four categories, as follows: (a) J~1ew Drugs or Jfew Claims for Drugs Which Have J'Iot Previously Been Advertised in AMA Publications. A new drug is here defined as any pharmaceutical product which has not been advertised previously in AMA scientific journals. Example of a new claim: use of an established antimalarial drug, such as chloroquiné phosphate, in rheumatoid arthritis. In all such cases, the Office of Advertising Evaluation will require supportive scientific evidence for, review. It is suggested that clinical and laboratory data on new drugs be submitted to the Office of Advertising Evaluation at the time a New Drug Application is filed with the~ Food and Drug Administration. This will make it possible, in many cases, to obtain product and advertising clearance prior to the introduction of the drug. However, the Association will not grant final clearance of advertising until notified that the New Drug Application has been approved by the FDA. (b) Drugs Which Represent an Additional Brand of a Product That is Already Eligible. The advertisement alone may be submitted. Sup- portive data are not required. (c) Drugs Which Represent a Modification of an Eligible Product. Ex- ample: Some modification of a previously eligible drug, such as a new salt or ester. All pertinent clinical and laboratory data should be sub- mitted to the Office of Advertising Evaluation. (d) Mixtures of Drugs. Clinical and laboratory data should be sub- mitted for review by the Office of Advertising Evaluation. Clearance depends primarily on showing justification for the rationality of the combination. 2. APPARATUS, INSTRUMENTS, AND DEVICES-The Office of Ad- vertising Evaluation determines the eligibility of products and the suit- ability of claims for medical equipment intended for preventive, diag- nostic, or therapeutic purposes. Advertisements for products which have not been advertised previously in AMA scientific journals, and new claims for eligible devices should be accompanied by complete scientific and technical data concerning the product's safety, operation, and usefulness. The data should include the results of clinical and PAGENO="0328" 4618 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY laboratory examination. The data may be either published or unpub- lished. Samples of apparatus, devices, equipment, or instruments should not be submitted unless specifically requested by the Office of Adver- tising Evaluation. 3. FOOD PRODUCTS AND VITAMIN PREPARATIONS-Advertisements for food products and vitamin preparations may be separated into four categories as follows: (a) General Purpose Foods. Those foods promoted for use by the popu- lation in general. Examples are bread, processed meats, fruits, and vege- tables. Advertisers of such products should submit descriptive literature, labels, and a statement of composition where pertinent. (b) Special Purpose Foods. These are foods for special dietary uses sub- ject to the labeling conditions imposed by section 403j of the Federal Food, Drug and Cosmetic Act. Examples are foods manufactured and promoted for use by certain specific segments of the population, such as infants, invalids, as well as others requiring foods with certain proper- ties, e.g., foods for carbohydrate-restricted diets, sodium-restricted diets, and other therapeutic diets. Advertisers of such products should submit copies of labels, statements of composition, and analytical data. When pertinent, they should be supported by data demonstrating the effectiveness of the product for its intended use. If new claims are made for a previously advertised product, clinical data substantiating such new claims must be submitted. (c) Supplemental Vitamin Preparations. Rational mixtures of the vita- mins recognized to be essential in human nutrition or metabolism in amounts not differing greatly from the recommended dietary allow- ances are eligible. However, with the exception of iron-containing and calcium-containing preparations that are intended for use during preg- nancy, vitamin mixtures to which minerals are added (as contrasted to trace minerals which are inherent in the manufacturing process) are not eligible for advertising. (d) Therapeutic Vitamin Preparations. Rational mixtures of the vitamins recognized to be essential in amounts not greater than five times the recommended dietary allowances are eligible. However, preparations containing a mixture of all or most of the following antianemic factors- vitamin B,2, folic acid, intrinsic factor, iron, ascorbic acid, and copper- are not eligible for advertising. If claims not generally recognized are made for any of the vitamins, such claims must be substantiated by clinical studies in support of such claims. 4. BOOKS-A book may be requested for review so that its eligibility for advertising can be determined. 5. MISCELLANEOUS PRODUCTS AND SERVICES-Products or services not in the above classifications may be eligible for advertising if they satisfy the general principles governing eligibility for advertising in AMA scientific publications. PAGENO="0329" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4619 advertising copy After a product or service has been declared eligible to be advertised in the scientific publications of the AMA, the Office of Advertising Evaluation must approve each advertisement. The AMA's decisions will be guided in all cases by the following principles: 1. The advertisement should clearly identify the advertiser and the product or service being offered. In the case of drug advertisements, the full generic name (including salt and ester designation) of each active ingredient must appear in eight-point type or larger. 2. Advertisements should not be deceptive or misleading. Layout, art- work, and format should be such as to avoid confusion with the editorial content of the publication. The word ~`advertisement" may be required. 3. Unfair comparisons or unwarranted disparagements of a competi- tor's products or services will not be allowed. 4. Claims for superiority must be supported by evidence acceptable to the Association. Unsubstantiated superlatives or extravagantly worded copy will not be allowed. 5. Quotations or excerpts from a published paper are acceptable only if they do not distort the meaning intended by the author. Claims made within quotations must conform to the same standards as unquoted claims. 6. Advertisements will not be accepted if they conflict with the prin- ciples of medical ethics. PAGENO="0330" 4620 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY procedures of the AMA office of advertising evaluation (SCIENTIFIC JOURNALS) The AMA Office of Advertising Evaluatio~ is responsible for applying the foregoing principles and standards to advertising copy submitted for inclusion in AMA scientific journals. It will do so in accordance with the following procedures: 1. Submission of Data-The Office of Ad- vertising Evaluation requires that scientific data be submitted to substantiate claims made for new products (such as drugs, devices, and foods) or new claims for products which have appeared previously in AMA scientific journals. 2. Type of Data )~eeded.-Data should in- clude pertinent reports-published and un- published, favorable and unfavorable-of clin- ical and laboratory investigations covering the efficacy and relative safety of the product under consideration. These data should be based upon sound studies and should be sufficiently comprehensive to permit a critical evaluation of the subject matter. While the quantity of the scientific data required will depend on the type of product, the nature of the medical problem involved, and the claims made in the advertising copy, the quality of the evidence is regarded as highly important; in this respect, the importance of suitable controls is emphasized. Compilations of sub- jective individual case reports and testimoni- als are not considered acceptable evidence. The unpublished portions of all submitted data will be regarded by the Office of Adver- tising Evaluation as confidential, and con- sultants will be requested to treat them ac- cordingly. ions of consultants and recognizes the state- ments formulated by AMA Councils and Committees in determining the eligibility of products and the suitability of claims. The consultants to the Office of Advertising Evalu- ation are persons who have been selected for their competence in the specialties involved. The names and affiliations of the consultants are not made available. Time Requirements of the Office of Advertising Evaluation Although the Office of Advertising Evalua- tion cannot guarantee adherence, in all cases, to a fixed time schedule, every effort will be made to expedite completion of AMA con- sideration in the following time intervals: Advertisements for Eligible Products with Xo Xew Claims-From the time copy is re- ceived, 5 working days should be allowed for AMA consideration. Advertisements Involving )Vew Claims for, or Modifications of Currently Eligible Products, Or Both-From the time copy and, if neces- sary, supportive data are received, 10 work- ing days should be allowed for AMA con- sideration. Advertisements for )Vew Products-From the time copy and supportive data are received, 15 working days should be allowed for AMA consideration. Unless accompanied by sup- portive data, proposed advertisements for new products cannot be considered by the Office of Advertising Evaluation. In those cases in which AMA consideration cannot be completed prior to the expiration of the foregoing time intervals, the advertiser or agency will be so informed. As a matter of policy, the AMA periodically will review its advertising principles with the view of keeping pace with changes that may occur in the industry and in the profession. It is hoped by this practice of continuous review and reevaluation to insure and im- prove the timeliness, relevancy and appro- priateness of the advertising content of AMA scientific publications. Correspondence, proposed advertisements, supportive data, etc. should be addressed to: I Office of Advertising Evaluation American Medical Association 535 North Dearborn Street Chicago, Illinois 60610 3. Consultation.-The AMA Office of Adver- tising Evaluation frequently seeks the opin- PAGENO="0331" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4621 EXHIBIT D NON-HEALTH ORIENTED PRODUCTS AND SERVICES principles governing advertising in ©àrtllhIILR ©~1I1 PAGENO="0332" 4622 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY advertising in tc -~ health TODAY'S HEALTH, published monthly by the American Medical Association, provides interest- ing and authoritative information to the public concerning the care and well-being of the readers and their families. It is distributed to physicians for their office reception rooms and to persons who wish to subscribe. The acceptance of an advertisement for TODAY'S HEALTH by the American Medical Association does not constitute in any way an endorsement or guarantee by the Association. The evaluators will make every reasonable effort to ensure the accuracy, timeliness, and relevancy of the advertising content of the magazine. No laboratory testing of products is done by the A.M.A. In no case may the appearance of an ad- vertisement for a product, service, or company in TODAY'S HEALTH be mentioned in collateral advertising unless specific written authorization has been obtained from the American Medical Association. The following principles are used to determine the eligibility of products and services and the suitability of advertising copy. The American Medical Association reserves the right to change its principles governing advertising in accord with current developments. The Association also re- serves to itself all final decisions regarding the eligibility of any products and services and the acceptability of proposed advertisements. PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4623 eligibility Products and services that are offered by responsible advertisers and which, when used properly, contribute to the general welfare of the consumer are eligible for advertising in TODAY'S HEALTH. Products or services NOT eligible for adver- tising in TODAY'S HEALTH include: 1) Products (e.g., tobacco and alco- holic beverages) or services which, in the opinion of the Association, may be detrimental to the user, and any products related to the use of such a product or service; 2) Product or service claims which can not be supported by data accept- able to the Association; 3) Products or services that are adver- tised in other media in a manner inconsistent with the following prin- ciples. PAGENO="0334" 4624 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY advertising principles Each presentation of advertising copy of an eligible product or service must be approved in- dividually by the American Medical Association, which shall make the final decisions regarding the suitability of copy, artwork, and format. The following principles will be utilized to eval- uate advertisements: 1) The advertisement must clearly identify the advertiser and the prod- uct or service. 2) The message, text, and artwork must be in good taste and in harmony with the purpose of the magazine. 3) The advertisement should present the positive merits of the product or service and not discredit or dispar- age those of competitors. Fair comparisons based on substantial evidence are acceptable. 4) The advertisement shall be de- signed to avoid deceiving or mis- leading the reader in any way. 5) The format should be such as to avoid confusion with the editorial content of the magazine. 6) Claims made within quotations must conform to the same standards as unquoted claims. PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4625 EXHIBIT D-i TODAY'S HEALTH PAGENO="0336" 4626 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0337" COMPETITIVE PROBLEMS IN THE DRIJG INDuSTRY 4627 ADVERTISING IN TODAY'S HEALTH ADVERTISING io~ ~ ~ I I~ ~1e ~ ~ ~ ~ ~ d ~ e ~ ~ ~ ~ ~ PRESEN TAT ION ~) the ~ihIic conc ~rci~:i~' th~ he~ Ith and \\~1far~ of th.. ~ du~~ ~ ~ , ~ ~ ~ ~ ~ ~ rind socicty It is dis~ributd to ph~cid~n~ o~ }u~ir ~ reep ~ ~ ~, ~ ~ ~ ~ ~ ~ ~ ~ t1C),fl rooii~c ~ to )(1S()flc ~ ~O ~ ~h UbSCnb( ~ ~ ~ ~ ~ ~ ~ ~ ~ The acoptar ce of an ar/c ertrsement for iorltv~ / /ra/tb bc rho Medrral or otren hair sn 1/ n a 1/ic American Medical Association c/ne' not r onstr/utr in ar's as as flnOi des c rd n t~ a tzh4tc c an enaiorrcmen, or guarantee by the \mna ration, although hr 00 5000 and orma eva/uators cdli make every o asonabte snort to ensure tire ass a r "s 55rr h s'' 0 race, tirneirness and rekvanrv ol he adser tr mn contort or tire ~ magazine. No /abntrtorc testing of produc I' r~ done by the tO /~ Irate ads" Ii' morn' a mraisan AMA. In no case mae tire appearans e sA an ado's ti,emerrt ~ he///t / rrms a prodarcl service, or norrrpartc in r slam a //ms sit/s be rrrtsrrtis',mem/ in co/l,rteral ads es ti/inc urriess ngm i/is cc rmtten autlrrrrr!atrcrn has 1 kho adc'er'rs' nrcnt nrust ci, arts rderrtrrs heert ohir/ned front lire American Meclms al Association the ads `rtisrr arrri the p'ocatmr m or rs ir e A corn/ste/c St sIr nest or en'" so rrs Tire fol/ocving p'inr iplec are ascesl to deter nina the e/rgibtlity ot qrsa/'tatmve nd a;uarnlitatis e arf m's sO th trroduc/s and mrs ices frrr cc /rtch It `a/lit claims re made attn hr cm rrntsr rsmea/rc,stkrrrs must hr rrlrr'i, 4 suitability of advertisirsg crrpv. The Amrrericarr \tcdmcrt As'ociatrcrrr to lime (Nc,' ot Ar/s enlrbn" by irrr/mrar reserves tire right to charrge ste tsnirrciln/es goes ruing ads ertr rri~' kuçlt infoisratiors nraer/ ma 1 ise ira/mm/cl in acccrrd roth nlevelolanretrts itt rttedrcine or in industra Tire rn tire test nm tire `dr ens csrsmerrt m's r mt Assocmatmorr a/cr) reserves to itself a/i frrm,l cieosiorrs nettars/rnrt ihr wh5a ho Morn toe rs rrsnside ri sr'5 n'ligib/lil/ rrt any products anti sercrcs', rmmnl tire acr epta/ailitc ri a nary larr aurpc'ses or in nt/ri atin"r proposed ardverticesta'rtls, 2 Mrs tm's ge, test, anti antccor/a errs t lam ELIGIBILITY ~ e°~i,m~°'~" cc na//re Products amrd aerv/s cc tiral are of/ered Isv responsila/e ads entr crc and cvhiclr, cc Iran arced trrrsper I~, esmntr ibutr tcr the lrealt/ r r r/~m'mr 3 5/tO arlsertc nrcnt s/s u/ri lrresm'rmr /5 eral cc a/fare of thsr cnn'rmnrer are s'ligrh/e frmr arts en lions, rrm / clay 5 positive nsermL or rise p c drr / rr ~r rca Hr sit/S. and 5 ~ cliscrerlit or rlm'1'aramgr Iri r' cmf Coder is or 5~ tvrcs's NOT e/r~rhle to ar/vs rimsing irr irs/aye I ic it/s ec/sOl 5 titor' 5 cc cc, parr nn~ a. cc / on * S cath, t,rsh ti r s doris a' sr rr cc Tha/s s' nc/eons 1 trot/nra Is *e ,~, tsrheco ann a/crshis/rs icc crogesi mar `r nrc" N Tire `ccii cc `sent s/r / 1,' c/s c~ / cs/tic/s is tin rrprmron of tiss' Acsnrciztiors, mm's rn' c/sstnr rier'tzt tm a' aol ri's em', mg rr r' err o 0 r `sr rise mssr's amrrs r"~ prmraCr 5' re/steal tm tre `sr r r scrm /n a m's's S i'm arm rca' or ss'rcicn' Ic" `sr ns, Is r a. `,, a c /1/ 1 / sr 0 3 i'r,irirsc s cc `a' mc rim cc/sirs, r/re 5 lz'n,s rmr ,nh C' arc ., no ,` snrmg"sr tsar Os n/sir is' c'ptrnt' ,o ,tne is" ratior' 1'0,, ,,` s 4 4. bed, by cram/cc ` ``Ins' `(`rn' r A `a ~c A s, ` ` i~ ` a, `realm',' a' s `roeS a' "br ms rime , irs's rb `ha s' n I `tn `~ , `r *``r mc'' "moms/mi I riced my m' ` n/a ste 0 sr pesr rim' r , , `, , n o ms' 6 Process 5 a ` "aces ml arm a' mn/so's, a/ cc I i/re mnrert', s , m s", ` tm I tam " mimer i'm smsc'O'r,S ssmt/' ` to'/o,' sn' sir re rçrtn c, 5 sC ` I, i 81-280 0-69-pt. 11-22 PAGENO="0338" 4628 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE AMA NEWS ExhibitE ADVERTISING ACCEPTANCE POLICIES The acceptance of advertising to be carried in The AMA NEWS is governed by the following policies: A. ELIGIBILITY FOR ADVERTISING 1. Products or services eligible for advertising in The AMA NEWS must be of interest to physicians and their families as consumers. 2. Products or services directly involved in the prevention, diagnosis or treatment of disease or which involve copy claims pertaining to health of people are NOT eligible for advertising in The AMA NEWS. 3. In addition to the above limitations, advertising will be accepted only from responsible business firms which guarantee to stand back of claims made in their advertising copy. 4. Advertisements which offer the reader information concerning investment opportunities must comply with the above standards and, in addition, must avoid reference to a specific security issue. 5. Advertisements for alcoholic beverages and products to be smoked are not acceptable. 3. SUITABILITY OF ADVERTISING COPY 1. The advertisement should clearly identify the advertiser and the product or service being offered. 2. Advertisements should not be deceptive or misleading to physicians or their families. 3. Layout and format should be such as to avoid confusion with editorial or news items. 4. Unfair comparisons or the disparagement of a competitor~5 goods will not be allowed. 5. Advertisements will not be accepted if they appear to violate the principles of medical ethics, are indecent or offensive in either text or art work, contain attacks of a personal, racial or religious character. 6. Claims made in advertisements for insurance coverage must conform to the above standards and, in addition, must conform to the following specific criteria: (a) Claims relating to policy benefits, losses covered, or premiums must be complete and truthful. (b) Claims made shall include full disclosure of expectations, reductions and limitations affecting the basic provisions of the policy (c) Claims incorporating quoted testimonials must meet the same standards as unquoted claims. (d) Each advertisement for insurance must include a statement indicating the number of states in which the company is licensed. PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4629 Dr. ANNIS. All proposed advertising is screened through the ifiter of the appropriate written principles. If the product is found ineligi- ble, the advertising is rejected. If claims in the proposed ad are ques- tionable, substantiating data are requested and the material is reviewed again in the light of the new information. Finally, the advertisement is reviewed: for clarity; that it makes no unwarranted comparisons or claims of superiority; and that it does not conflict with the principles of medical ethics. On the whole, we believe that no publication surpasses our own standards for acceptable advertising. However, it should be remem- bered that the AMA does not attempt to substitute its principles for the advertising surveillance authority vested in the FDA by Congress. We evaluate prescription drug advertisements to make sure the Jour- nal of the AMA continues to fulfill its scientific purposes and remain acceptable to the profession. In making these decisions, we are aware of the ever-changing world of medical science. As new knowledge becomes available, our judgment factors, must change accordingly. ADVERTISING REVENUE The third subject I promised to cover logically comes at this point. It is the advertising revenue received by the AMA. Your correspondence indicated that the committee is interested in the income received by the AMA from pharmaceutical manufacturers who advertise in JAMA. We do not have a breakdown purely for pharmaceutical advertising. However, I can give you figures for total advertising revenues for JAMA and the specialty journals. I want to preface these figures by making it clear that they repre- sent gross income-not net. To obtain a net figure, it would be neces- sary to substract the expenses of producing the journals, including salaries and wages for the staffs; buying the paper; printing; mailing; and other items. I can assure you the costs are substantial. For the years 1963 through 1968, gross advertising revenues for JAMA ranged from a low in 1963 of $7,831,000 to a high of $10,605,000 in 1966. The revenue in 1968 was $8,643,000. For the specialty journals combined, the gross figure for those years ranged from $1,413,000 in 1963 to $2,234,000 in 1968. (Gross advertising revenues follow:) GROSS ADVERTISING REVENUES Year JAMA SpecialtY journals 1963 1964 1965 1966 1967 1968 $7,831,000 7,968,961 9,983,795 10,605,625 10,546,000 8,643,000 $1,413,000 1,563,702 1,710,510 1,725,695 1,978,000 2,234,000 Dr. ANNIS. Advertising rates for medical journals are expressed most commonly in cost per page of advertising and the cost per thou- sand copies of the journal according to its total circulation. For JAMA, the rate for one black-and-white page rose from $1,600 in 1963 to $2,120 in 1967 and 1968. The cost per thousand was $8.05 in 1963; fell to $7.89 in 1964; and reached $9.89 in 1968, having dropped 2 cents from 1967. PAGENO="0340" 4630 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Advertising rates for JAMA follow:) Year Rate for 1 page, black and white Cost per thousand 1963 1964 1965 1966 1967 1968 $1,600 1,600 1,840 1,840 2,120 2,120 $8.05 7.89 8.88 8.65 9.91 9.89 Dr. ANNIS. I have already referred to the association's substantial expenses. I think it is of interest that the AMA has more than $12 million budgeted for scientific programs in 1969; and more than $6 million for medical service programs. Most of the medical service programs are directed toward health education of the public and community health planning. Almost another million dollars is budgeted for support of other medical organizations such as the World Medical Association, the Joint Commission on Accreditation of Hospitals, and the National Health Council. Two million dollars is earmarked for international health pro- grams; and mamtenance of complete biographical records on all phy- sicians in the United States takes another million and a half dollars a year. The programs of the AMA Education and Research Fouiidatioii receive $1 million a year from the association. Mr. Chairman, I have attached as exhibit F a copy of the associa- tion's 1969 budget, which lists major program expenditures. I ask that it be inserted in the record at this point. Senator NELSON. It will be printed in the record. Dr. ANNIS. Thank you. (The exhibit referred to follows:) ExmBn~ F American Medical Association, 1~6~ Bvdget 1. Scientific programs $12, 357, 903 2. Medical service programs 6, 058,459 3. Communications programs 1,232, 687 4. Support to other medical organizations 759, 700 5. Support to noiimedlical organizations 23,625 6. International health programs 2,031, 757 7. Legislative programs 299, 228 8. Professional ethics 89, 919 9. Medicine and reiigion program 148,907 10. Archive-Library service 238,431 11. Public affairs 1, 230, 100 12. Legal services 397, 528 13. Physician records 1, 422, 962 14. AMA-ERF programs 1,003, 300 115. Adminirtrative costs 6, (105, 1)41 Total 33, 899, 547 Dr. ANNIS. The American Medical Association's programs and policies have never been, are not now, and will never be shaped by any PAGENO="0341" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4631 dependence on the drug industry. And to insure that there is no "con- thct of interest," the AMA has consistently separated the editorial management, advertising acceptance, and business management of each of its scientific publications. The editorial staff of JAMA is in one division; the advertising acceptance responsibility is in a separate division; and business man- agement and sales are in still another. The editorial content of a journal must be objective if it is to be acceptable to members of our profession. If that content were shaped or influenced by commercial considerations, the profession would quickly reject the publication. COMPENDIUM Turning to my fourth topic, legislative proposals have been made regarding publication of a drug compendium which would, in effect, contain information presently included in package inserts for all available prescription drugs. The purpose of the compendium is to compile in one volume corn- plete information on those drugs. It is intended to be, in fact, the single authoritative source of readily accessible drug information for the physician. Under most proposals, drugs would be identified both by their generic and their brand names. You will recall that during my earlier discussion of the AMA Council on Drugs, I mentioned annual publications in the drug field- specifically, New and Nonofficial Drugs, and New Drugs. Today, an important activity of the council is to create a publication that is expected later this year, to be called AMA Drug Evaluations, or ADE. We agree wholeheartedly that the medical practitioner needs an- other source of reliable, unbiased, and current information on drugs and new developments in drug therapy. It is necessary also that the source be in a form that makes the facts he needs available with a minimum of effort and in a minimum of time. ADE will identify various diseases, disturbances, and conditions for which drugs are prescribed. Drugs used in the treatment of the conditions will then be listed alphabetically by their generic names, along with other necessary information, such as actions, uses, principal adverse reactions, dosage, available dosage forms, and the names of manufacturers. In addition-and this is a most important feature-will be informa- tion providing a comparison of the therapeutic effectiveness of drugs having similar uses. A mere compendium, in the sense that it wOuld be a listing of drugs, would leave significant information gaps. Our drug evaluation publi- cation would not. Evaluations are now being prepared for essentially all marketed therapeutic agents that are new, single entity drugs; official in the IJ.S. Pharmacopeia or National Formulary; frequently used or pre- scribed; or otherwise notable. For example, they. might be otherwise notable either because of their therapeutic nature or their unusual toxicity. PAGENO="0342" 4632 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY The book will be thoroughly cross-indexed, including listings by drug name, by pharmacologic and chemical factors, by therapeutic uses and by adverse reactions. It will be revised and updated regularly. And because it will contain special information on newer products, it will, in effect, absorb the earlier publication, New Drugs, by mak- ing that same information available in a more usable form, along with substantial amounts of other infonnation. We believe sincerely that AMA Drug Evaluations will be the most useful publication in the physician's library regarding drugs. And that is not only our opinion. A sample chapter of the publica- tion, on anticonvulsants, was published in JAMA May 20, 1968. I offer it with this statement and ask that it be included as exhibit G at this point in the record. Senator NELSON. It will be printed in the record. Dr. ANNIS. Thank you. (The exhibit referred to follows:) PAGENO="0343" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4633 Council on Drugs Reprinted From The Journal ci The American Medical Association May 20, 1968, Vol. 204, pp. 702-710B Copyright 1968, by American Medical Association Exhibit G A new publication of the Council on Drugs will provide authoritative, unbiased information on drugs in a new format designed to meet the every- day needs of the practicing physician. The Coun- cil herewith presents a sample chapter of the new book, and invites physicians to comment on the book's usefulness by completing the question- naire following p 710. AMA Drug Evaluations A New Book on Drugs The American Medical Association's Council on Drugs announces a new publication on drugs designed to provide an improved service to the medical profession. From its inception in 1905, the Council on Drugs (originally called the Council on Pharmacy and Chemistry) has encouraged rational therapy by providing authoritative and unbiased information on drugs. Throughout its long history, the Council has modified its drug evaluation pro- grams in accordance with new developments in the drug field, and it has continued to alter the con- cepts and format of its publications to reflect the changing needs of the physician. Its earlier evalua- tion program had been limited to those drugs con- sidered to have well-established clinical usefulness, but in 1955 this program was expanded to con- sider all commercially available, newer single-entity drugs. The older books published by the Council- New and Nonofficial Remedies, New and Non- official Drugs, and, more recently, New Drugs- are now being replaced by AMA Drug Evaluations (ADE), a comprehensive reference book that will include information on- both old and new single- entity drugs and mixtures. The book is being pre- pared through a joint effort of the Council, the staff of the AMA Department of Drugs, drug evaluators outside the Department working part-time, and many voluntary expert consultants; as with New Drugs, the cooperation of much of the pharma- ceutical industry will continue to be sought for the furnishing of data relevant to some parts of ADE. The design calls for continuing the practice of having in each chapter an introductory statement that discusses the overall therapeutic category, fol- lowed by brief descriptions and evaluations of all drugs in the class, old or new, if they fall within a very broad priority list. The more detailed mono- graphs on newer agents will be included as an ap- pendix, which will represent a continuation of New Drugs. The priority list of drugs, including mixtures, that will have individual evaluations includes vir- tually all therapeutic agents in official compendia, U$P and NF; the drugs most commonly pre- scribed or used by physicians in the United States; and, as in New Drugs, all single-entity prepara- tions introduced during the past ten years. In ad- dition, other selected drugs will be evaluated if they are judged to be of particular importance be- cause of such qualities as notable value, unusual toxicity, notoriety, or need for notoriety. Many nonpriority drugs that are not individually evalu- ated will be listed in the book if they are distributed nationally; these will be listed and indexed to give information on their therapeutic category and avail- ability. To make the information readily accessible, ADE will be extensively indexed; comprehensive in- dexes on drug names (nonproprietary and trade- marks), pharmacologic actions, therapeutic uses, and important adverse reactions are planned. The evaluations of the older drugs and mixtures will often contain fewer details than the mono- graphs on newer, single-entity drugs. Nevertheless, an effort will be made whenever possible to give comparative statements on relative effectiveness and relative safety and to inform of notable hazards and necessary precautions in the use of the drugs. The inclusion of a particular drug in the book will not imply endorsement by the Council; an evalua- tion may be favorable toward a drug, unfavorable, or a combination of both, depending on the merits. Whenever, the facts clearly warrant, a drug will be described as an agent of first choice, reserve choice, or last resort. The evaluative or interpretive information in the book, particularly on controversial matters, must necessarily disagree with the opinions of some other sources. Statements will be based on the convergent trend of the best information available from such sources as scientific literature, unpublished data, and advice of consultants. Reportorial information will be selective and condensed to represent what the Council regards as the most useful to the phy- sician in his selection and use of the drugs. Ac- cordingly, such information as rare, relatively minor, or uriconfirmed reactions, precautions that relate to clearly obvious or highly remote situa- tions, and unusual or speculative uses of a drug Reprint requests to Secretary, Council on Drugs, American Medical Association, 535 N Dearborn St, Chicago 60610. JAMA, May 20, 1968 * Vol 204, No 8 PAGENO="0344" 4634 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMA DRUG EVALUATIONS may be omitted. It is hoped that ADE thus will provide a convenient reference from an authorita- tive source to give the practicing physician the most important information to help in his prescribing practices. For other details, for basic data, and even for varying points of view, the physician is encouraged to consult and compare the many sources of information on drugs he uses: journal articles, standard textbooks, official compendia, manufacturers' labeling, prominent bulletins and periodicals on drugs and therapeutics, and sym- posia. The sample chapter that follows is presented both to familiarize the physician with the Council's plans and to invite comments and recommendations. Most of the book is in a stage of preparation that still permits flexibility in content and design, and subsequent editions are intended to follow. There- fore, since the Council's aim is to meet the needs of its physician readers, responses to the attached questionnaire can have an important influence on the further development of the book. The book is expected to be published in approximately one year. The accompanying chapter on "Anticonvulsants" is not completely a self-contained unit. The reader will notice several cross-references that presently are only hypothetical, as the associated material is still to be published; nevertheless, they are included to help illustrate the design of the forthcoming book. After reading the sample chapter, please fill out the questionnaire following page 710 and return it to the AMA. Chapter 29 ANTICONVULSANTS Anticonvulsants are used to terminate certain acute convulsive episodes, but their principal use is prophylactic to reduce the number and severity of seizures in patients with epilepsy. Seizures may be classified in various ways; for therapeutic purposes, the following is convenient: major motor (grand mal or focal), petit mal (absence), minor motor, and psychomotor. Although their specific modes of action are not fully understood, a number of drugs have anticon- vulsant activity and are effective in preventing or reducing the frequency of seizures in most patients with epilepsy. The objective of therapy is to con- trol the seizures and at the same time maintain the patient in as normal a physiologic state as is pos- sible. Drug therapy must be individualized for every patient; within the limits of adverse effects and toxicity, the correct dosage of any drug or combination of drugs is that which is "enough" to accomplish the stated purpose. The choice of drugs depends upon the type of seizure. Further, many patients with epilepsy have more than one type of seizure, and drugs effective for one of these types may not help or may even unmask another. The most common causes of failure of treatment are 703 improper classification of type of seizure, failure to recognize a progressive neurologic disease, failure to use the proper drugs or proper dosages, too fre- quent changes in drug therapy, premature with- drawal of drugs, poor indoctrination of patients, and failure to recognize the social and economic needs of patients. With the exception of patients who do not adhere to their prescribed regimen, the largest group of failures is related to the admin- istration of insufficient dosages of appropriate drugs and failure to use two or more of them concomi- tantly when they are needed. The patient should be started on a small or moderate dosage of the drug that is considered to be suitable. This dosage should be increased grad- ually at intervals until the seizures are controlled or until the appearance of minor toxic symptoms makes further increases inadvisable. If more than minor toxic phenomena develop, the medication should be withdrawn and another substituted. When the drug used initially is well tolerated but only reduces the frequency of the seizures, another compound should be added. The dosage information given with the subsequent discussions of individual drugs falls within the ranges given in official com- pendia, those recommended by one or more man- ufacturers, or those considered reasonable by other authorities. However, the size, age, and condition of the patient, his response to treatment, and the pos- sible synergistic or antagonistic effect of concomi- tant medication must always be considered. Reduc- tions in dosages of anticonvulsants for children in comparison with adult dosages are not always as great as would be expected from the difference in age and size. Phenobarbital is still considered the mainstay of anticonvulsant therapy; it is among the safest of the available drugs and is useful in the management of most types of seizures. The other long-acting barbiturates, mephobarbital [MEBARAL] and meth- arbital [GErooNIL], are alternate drugs, the actions of which, with proper dosage adjustment, closely resemble those of phenobarbital. Primidone [MY- SOLINE], which is chemically related to the barbi- turates and has similar action, is frequently useful in refractory epilepsies, especially of the major motor and psychomotor types. The hydantoins, such as diphenylhydantoin [DILANTIN], mephenytoin [MESANTOIN], and etho- tom [PEGANONE], are used primarily in major motor and psychomotor seizures; they are usually not ef- fective in treating petit mal. They may be effective, as may the barbiturates, in certain nonconvulsive epileptic equivalents, a syndrome of recurrent au- tonomic symptoms associated with an abnormal electroencephalogram. Diphenyihydantoin is con- sidered the drug of first choice among the hydan- toins; it is safer than mephenytoin and more effective than ethotoin. However, each of these alternative hydantoins may be considered for trial in special circumstances (see the individual drug evaluations following this introductory statement). JAMA, May 20, 1968 * Vol 204, No 5 PAGENO="0345" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4635 AMA DRUG EVALUATIONS types may be used alone or in combination. The minor motor seizure syndrome of infancy or child- hood sometimes responds to corticotropin or adreno- cortical steroid therapy or to a ketogenic diet program. Recent experience with various ben- zodiazepine derivatives indicates that some of the compounds in this group have effectiveness in minor motor epilepsy; of the benzodiazepine de- rivatives currently marketed in this country, die- zepam [VALIUM] has given the most favorable re- sults. Sometimes, epileptic seizures that apparently are under good control by drugs will escape from control. When a barbiturate or hydantoin is in- volved, the escape may result from a physiologic adjustment in which the patient's metabolism of the drug is increased. With these particular drugs, an increase in dosage will ordinarily reestablish control, and once this is accomplished, there is no reason to expect a repetition of the escape unless the disease itself happens to worsen. Trauma or emotional stress may cause an increase in the dosage requirement, which should be borne in mind if a patient requires surgery. Spontaneous remissions, particularly of petit ma! seizures, are common if convulsive disorders have begun during childhood but are rare if they have begun during adulthood. Anticonvulsant therapy therefore must be prolonged; as a rule, drugs are continued until the patient has been completely free of seizures for two to four years. When a de- cision is made to discontinue their administration, the dosage of one drug at a time should be reduced gradually, since sudden withdrawal of any of these drugs may precipitate a recurrence of seizures or even status epilepticus. However, when a serious adverse reaction to a drug occurs, the agent should be discontinued immediately and another anticon- vulsant should be given to protect the patient dur- ing this period. Status epilepticus is a serious emergency that requires prompt and vigorous treatment to prevent permanent harmful effects or death. It may be terminated by the intravenous administration of phenobarbital. This drug is preferable to shorter acting barbiturates, since its effect is practically as rapid but lasts longer. The full calculated anticon- vulsant dose should be given initially since the use of fractional doses may result in the paradoxic situ- ation of drug-induced depression but continued status epilepticus. Dipheny!hydantoin [DILANTIN] may be given intravenously or intramuscularly, but its onset of action is delayed for 5 to 15 minutes. It has the advantage of usually not depressing res- piration, but intravenous administration must be slow to avoid serious hypotension. Recently dia- zepam has been shown to be effective when given parenterally. Paraldehyde given parenterally is still used occasionally. When anesthetic agents are nec- essary, they should be given under the supervision of an anesthesiologist, when possible, and resuscita- tive equipment should be available. The hydantoins are cumulative in effect; therefore, the dosage schedule must be adjusted gradually over a long period to obtain control without pro- ducing toxic reactions. Ordinarily, a hydantoin should be added to a regimen after an initial trial with the relatively safer phenobarbital has not pro- vided adequate control. Alternatively, many clinics and some of the Council's consultants prefer diphenylhydantoin as the initial drug. The Coun- cil's moderate preference for phenobarbita! is based on considerations of relative safety, although this drug does introduce the inconvenience of drowsi- ness for many patients. Other drugs can be added if a combination of a hydantoin and phenobarbital do not completely control the seizures. Primidone [MY50LINE] ordinarily should not be added to this regimen, but it may be substituted for the pheno- barbital in refractory epilepsy of the major motor and psychomotor types. Also, psychomotor epilepsy may respond to methsuximide [cEL0NTIN]. Phen- acemide [PHENURONE] may be effective in con- trolling psychomotor or various other seizures, but since it is extremely toxic, it is only of limited usefulness and should be used only if other medi- cations are ineffective. Inorganic bromides(eg, so- dium bromide, potassium bromide) also have anti- convulsant activity against grand ma!, but because of their toxicity, interest in them is chiefly histori- cal. However, they may have a limited place in the treatment of children with grand mal. Methsuximide [CELONTIN], phensuximide [MI- L0NTIN], ethosuximide [zAR0NTIN], trimethadione [TRIDI0NE], and paramethadione [PARADIONE] are useful primarily in the treatment of petit ma!. Ethosuximide is the drug of choice in this group, but phensuximide may be considered for initial treatment in mild cases because it is moderately safer. Acetazolamide [DIAM0x], and perhaps keto- genic diets, control petit ma! in some patients. Re- cently, selected new benzodiazepine derivatives, particularly diazepam [VALIUM], have also shown promise and relative safety. Among the remaining drugs, trimethadione is probably the most likely to be effective, but it is also the most dangerous. Petit ma! rarely responds to phenobarbita! alone; nevertheless this drug, because of its broad anti- convulsant spectrum, should be tried initially un- less there is convincing evidence, including a char- acteristic electroencephalogram, that the patient has classical petit ma! uncomplicated by any other type of seizure. Less satisfactory agents like mepro- bamate [EQUANIL, MILTOwN], quinacrine [ATAII- SINE], or the amphetamines may be tried if other medications do not control petit ma!. For patients who have petit ma! and other seizure types, drugs effective in controlling those other types must be combined with the drugs selected for the treatment of petit ma!. Minor motor seizures are akinetic and myoclonic types that are often refractory to drug therapy. They may occur alone or in. association with petit mal or grand mal. Drugs effective for both seizure JAMA, May 20, 1968 . Vol 204, No 8 PAGENO="0346" 4636 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMA DRUG EVALUATIONS 705 Major motor seizures, usually with severe, pro- tracted, clonic convulsions, are sometimes associ- ated with the withdrawal syndrome in persons with physical dependence on barbiturates, alcohol, or certain other sedative drugs. Barbiturates will often help prevent these dangerous convulsions; the by- dantoins are usually of little value. Adverse Reactions and Precautions Many minor reactions to anticonvulsant drugs may be overcome by reducing the dosage of the re- sponsible agent, which may, however, necessitate the addition of another anticonvulsant agent to the regimen. Most anticonvuisants produce gastrointestinal disturbances in at least some patients, especially during the early stages of treatment. The symptoms may be reduced either by administering the drugs after meals or by decreasing the dosage. Many of the anticonvulsants have sedative ef- fects, and drowsiness is sometimes a significant complaint. Again, this effect is most noticeable dur- ing the early period of treatment; if it persists, a reduction of dosage may be indicated. Sedative drugs may cause alterations in mood, which- oc- casionally are serious (see the chapter on Sedatives and Hypnotics). Other anticonvulsants also can cause mental dis- turbances. Phenacemide [PHENURONE] is particu- larly prone to cause serious personality changes including psychoses and suicidal depressions. Ataxia occurs commonly with the hydantoins and, if persistent, requires reduction in dosage. There is evidence that the hydantoins can cause cerebellar damage if a dosage that produces ataxia is administered for a prolonged time. For practical purposes, however, this danger appears remote since the reaction is so troublesome in itself that it demands correction by dosage adjustment. Very young patients can present an exception, as drug- induced ataxia may be confused with the natural unsteadiness of the toddler. Ataxia also may occur with the use of barbiturates. Many anticonvulsants commonly cause skin eruptions, which are usually morbilliform or acne- like and may disappear when the dosage is reduced or the drug is temporarily discontinued and cauti- ously readministered. However, a skin reaction may herald the development of a severe reaction that may warrant withdrawal of the drug. Lupus erythe- matosus, Stevens-Johnson syndrome, angioneurotic edema, serum sickness, and polyarteritis have been associated with anticonvulsant medication. Anaphy- laxis is extremely rare. Other reactions that occa- sionally have been noted with some anticonvulsants include alopecia and hypertrichosis. Because the barbiturates are particularly prone to aggravate porphyria, their use should be avoided in patients with that disease. Several of the anticonvulsant drugs may cause reversible visual disturbances such as diplopia and nystagmus; one of the most notable, hemeralopia (defective vision in a bright light), occurs with the oxazolidinediones, trimethadione [TRIDI0NE] and paramethadione [PARADIONE]. Certain untoward effects are frequently char- acteristic of a particular anticonvulsant and may not occur with a chemically related drug; for e~- ample, diphenyihydantoin [DII.ANTIN] frequently causes gingival hyperplasia, but this reaction sel- dom occurs with mephenytoin [MESANTOIN], and apparently never with ethotoin [PECANONE] - Lymphadenopathies simulating malignant lym- phomas have occurred with several of the anticon- vulsant drugs. Hydantoins have been implicated most frequently. Although it is questionable whe- ther diphenylhydantoin is as prone to cause these pseudolymphomas as is mephenytoin, it is responsi- ble for a greater number of reactions since it is more widely used. The signs and symptoms may show a temporary progression but usually begin to disappear within one to two weeks after therapy is stopped. A few cases of true lymphoma and of Hodgkin's disease have been reported in which a causal relationship to hydantoin therapy seems possible. Megaloblastic anemias, which respond to folic acid or leucovorin (folinic acid) therapy, also have been reported with several anticonvulsants. Ac- cordingly, periodic blood studies are indicated when such drugs are taken. Usually, the drug may be continued if the anemia responds well to treatment. However, because of the possibility that folic acid may interfere with the anticonvulsant action, rou- tine prophylactic treatment with folic acid in pa. tients without anemia is not suggested. Among the most dangerous reactions that de. velop during therapy with anticonvulsant drugs are those that result from damage to the marrow, liver, and kidneys. Severe blood dyscrasias have sometimes been associated with phenacemide [PHENURONE], mephenytoin [MESANTOIN], para- methadione [PARADIONE], trimethadione [TRIDI- ONE], and less frequently with other drugs. Base- line blood counts should be made before initiating treatment with these drugs. Although periodic blood studies during treatment will detect mild leukopenias of uncertain clinical significance, they cannot be relied upon to predict the more serious reactions that ordinarily occur precipitously (eg, agranulocytosis, thrombocytopenia, aplastic ane- mia). There is some chance that an aplastic anemia might be detected early, before symptoms develop, if one were so fortunate as to have a hemoglobin determination at a time during its beginning de- cline, but even moderate expectation of such de- tection would require an impractical frequency of blood studies in view of the extreme rareness of the reaction with most drugs. Since early recognition of the presence of a dyscrasia and discontinuance of the offending drug are essential, the patient should be advised to report promptly such symp. toms as sore throat, fever, easy bruising, petechiae, epistaxis, or other signs of an infection or bleeding JAMA, May 20, 1968 . Vol 204, No 8 PAGENO="0347" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4637 tendency. Clinical and laboratory evaluation is necessary if such symptoms occur. Although the risk of dyscrasias is diminished after the first year of treatment with these medications, the physician should be constantly alert to their possible occur- rence at any time. The mortality rate from aplastic anemia is particularly high and, if the patient does survive, recovery is slow. Except for mephenytoin and phenacemide, however, this reaction is fortun- ately very rare with the anticonvulsants that cause it at all. Severe liver disease, sometimes fatal, has occur- red with phenacemide [PHENURONE] and more rarely with some of the other anticonvulsants, including hydantoins. Before treatment with these drugs is begun, it is advisable to make baseline liver function studies, and patients should be instructed to report promptly any symptoms of hepatitis such as jaundice, dark urine, anorexia, abdominal dis- comfort, or other gastrointestinal symptoms. Since this drug-induced hepatitis is probably idiosyn- cratic, the monitoring of treatment with periodic laboratory studies in asymptomatic patients is of doubtful reliability in predicting a reaction. Phena- cemide may present an exception, as there is some evidence that hepatitis can develop insidiously with its use; liver function abnormalities, eg, decreased prothrombin activity, may herald serious disease. Nephropathies have developed occasionally dur- ing treatment with anticonvulsants, especially in patients receiving the oxazolidinediones, trimetha- dione and paramethadione. Unlike the blood dys- crasias and hepatitis, these reactions may develop insidiously without producing symptoms in the early stages. Therefore, urinalyses should be made before treatment and periodically during treatment. The development of any significant renal abnor- mality is an indication for discontinuing the drug. From the preceding discussion, the question arises of just what type of laboratory monitoring is advisable for patients taking anticonvulsants who have no symptoms suggesting marrow, hepatic, or renal damage. As noted, baseline studies of the functional state of these organs are needed before initiating treatment with drugs known to cause damage even occasionally. Tests should be repeated and perhaps extended if signs or symptoms of a reaction develop. Periodic urinalyses and evalua- tions for anemia are of value with drugs known to cause nephropathy or megaloblastic anemia, as these conditions may occur well in advance of their symptoms. The problem is whether to subject pa- tients to frequent testing for idiosyncratic blood dyscrasias and hepatitis when nothing suggests the presence of these disorders. The Council's con- sultants have expressed widely divergent views on whether such testing is of any significant medical value with most anticonvulsants. It is known that various minor laboratory abnormalities may appear and cannot be relied upon to herald the develop- ment of a serious reaction. Moreover, when a dan- gerous idiosyncratic reaction does occur, signs or symptoms will probably appear about as soon as a diagnosis can be made reliably by laboratory methods (with the possible exceptions of hepatitis from phenacemide, and aplastic anemia from me- phenytoin and phenacemide). Accordingly, and with due respect to those consultants who disagree, the Council regards routine laboratory monitoring with most drugs as optional, rather than man- datory, if the only issue is whether an asympto- matic patient is taking a drug that rarely produces a blood dyscrasia or hepatitis by some apparently idiosyncratic mechanism. This is in contrast with the situation where a drug has a direct toxic action on the marrow or liver. A frequently cited paradoxic effect of anticon- vulsants is the tendency of agents effective for one type of seizure to aggravate or precipitate seizures of another type. However, epileptic disorders tend to be mixed as to seizure type and, very probably, the apparent aggravation of one type is a mani- festation of the natural course of the disease and merely reflects the therapeutic ineffectiveness of the particular drug for that type of seizure. Caus- ally related precipitation of seizures by anticon- vulsant drugs probably is rare, and some consult- ants doubt that it occurs. There is no question, however, that abrupt withdrawal of anticonvulsants can precipitate seizures. Thus, when a drug is to be discontinued, the dosage should be reduced gradually unless rapid withdrawal and substitution of another drug is mandatory because of a serious adverse reaction. In general, there has been little systematic in- vestigation of the anticonvulsant drugs for terato- genic effects, but a lack of reported teratogenicity after extensive use provides some circumstantial evidence of probable safety. Thus, whenever prac- tical, it would seem prudent to use older and more extensively used anticonvulsants if it is necessary to treat epilepsy in a pregnant woman. As a general rule, the more toxic compounds should not be used if an equally effective and less potentially toxic preparation is available. However, minor adverse effects should be expected and ac- cepted with any drug. The anticonvulsant drugs in frequent current use, and a few that are rarely used, are listed and briefly described in the individual evaluations that follow. Not every known adverse reaction is mentioned, but an effort has been made to include those that are notable because of danger to life, unusual frequency of occurrence, proneness to cause significant discomfort, or peculiarity to a particular drug. Barbiturates Phenobarbital Most broadly useful anticonvulsant. Initial therapy of choice in most epilepsy (see general statement). Principal effectiveness is in major motor and psychomotor seizures. Sedative-hypnotic effect, as well as ataxia, may present problems. Produces hyperactivity in some children instead of 706 AMA DRUG EVALUATIONS JAMA, May 20, 1968 * Vol 204, No 8 PAGENO="0348" 4638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY sedation. Amphetamines, which do not interfere with anticonvulsant action, sometimes useful for relieving drowsiness. Occasional skin eruptions; rare progression to exfoliative dermatitis. Abrupt termination in epilepsy may cause withdrawal convulsions, but true addiction and barbiturate in- ebriation unlikely in usual doses for epilepsy. Con- traindicated in patients with porphyria. Usual Dosage-Oral: Adults: Usually 120 to 200 mg daily in divided doses. Range: 50 or 100 mg at bedtime to 300 mg in divided doses. Children: 1 to 6 mg per kilogram of body weight per day in di- vided doses. Preparations-Various, including: Elixir 20 mgI 5 ml; tablets 16, 32, 50, 64, and 100 mg. Many manufacturers. Phenobarbital Sodium Used parenterally in status epilepticus, but may depress respiration. Parenteral diphenyihydantoin may be given concomitantly. Usual Dosage.- (Status epilepticus) Intramus- cular, Slow Intravenous: Adults: 200 to 320 mg. Children: 3 to 5 mg per kilogram of body weight represents a reasonable guide. Preparations-Various, including: Powder 120, 130, and 320 mg; solution 130 mg/ml in 1 ml con- tainers; 160 mg/mlin 2 and 10 ml containers; tablets (hypodermic) 60 mg. Many manufacturers. Mephobarbital [MEBARAL] Metabolized to phenobarbital and has effects similar to phenobarbital, but larger doses are used. Usual Dosage-Oral: Adults: 200 mg at bedtime to 600 mg daily in divided doses. Children: Under 5 years, 16 to 32 mg three or four times daily; over 5 years, 32 to 64 mg three or four times daily. Preparations.-Mebaral (Winthrop): Tablets 32, 50, 100, and 200 mg. Metharbital [GEM0NIL] Similar to phenobarbital, but less potent on basis of weight. Dosage adjustment can compensate for this difference. Has same relation to barbital as mephobarbital has to phenobarbital. Usual Dosage-Oral: Adults: Initially, 100 mg at bedtime to 300 mg daily in divided doses. In- crease to as much as 600 to 800 mg daily if re- quired. Children: 5 to 15 mg per kilogram of body weight daily in divided doses. Preparations.-Gemonil (Abbott): Tablets 100 mg. Primidone [MYSOLINE] Not really a barbiturate by traditional classifi- cation, but closely related chemically. However, larger doses are needed. Principal usefulness is as substitute for barbiturates in patients not respond- ing adequately to regimen of barbiturate and hy- dantoin. No compelling reason why it may not be used as initial anticonvulsant in major motor and psychomotor epilepsy, but it is more commonly reserved for refractory cases because it often causes marked sedation. Sedation often diminishes with 707 continued administration. Dosage build-up should be gradual to avoid incapacitating drowsiness. Ataxia and various relatively minor reactions re- semble those of barbiturates. Skin eruptions oc- casionally occur. Megaloblastic anemia may occur; responds to folic acid. Usual Dosage-Oral: Adults: 250 mg to 2 gm daily in divided doses. Children under 8 years: One-half adult dosage. Preparation.s.-Mysoline (Ayerst): Suspension 250 mg/S ml; tablets 50 and 250 mg. Hydantoins Diphenyihydantoin Sodium [DILANTIN] Drug of choice among the hydantoins. Often used in conjunction with phenobarbital. Used in major motor and psychomotor epilepsy. Has little or no sedative activity in usual doses. Ataxia oc- curs with larger dosages; if persistent, it indicates overdosage, and the dose must be reduced. Ocular signs and symptoms such as nystagmus and di- plopia may also necessitate reduction of dosage. Skin eruptions rather frequent; only rarely serious. Gingival hyperplasia common, and often is severe in children; scrupulous oral hygiene helps prevent it. Hirsutism and excessive activity are less com- mon but do occur, especially in the young. Rare hut serious idiosyncratic reactions include hepatitis, marrow depression, megaloblastic anemia, lupus erythematosus, Stevens-Johnson syndrome, and lymphadenopathy resembling malignant lymphoma (see general statement). Useful parenterally for control of status epilepti- cus. Unlike barbiturates, seldom depresses respira- tion. However, onset of action is slower than bar- biturates. Also, if intravenous administration is too rapid, dangerous hypotension may occur. Usual Dosage-Oral: Adults: Initially, 100 mg three times daily; most common maintenance dose is 300 to 400 mg daily but may reach 600 mg. Children: 3 to 8 mg per kilogram of body weight daily in divided doses. Intramuscular, Intravenous: (Status epilepticus) Adults: 150 to 250 mg. Inject intravenously no faster than 50 mg per minute. Children: Reduce dosage according to weight or body surface area. Preparations.-Dilantin (Parke, Davis): Oral: Capsules 30 and 100 mg. Injection: Powder 50 mg/ml when properly diluted with special solvent provided in 100 and 250 mg vials. Diphenyihydantoin [DILANTIN] See Diphenylhydantoin Sodium. Preparations.-Dilantin (Parke, Davis): Oral: Capsules (delayed action) 100 mg; capsules (Di- lantin in oil) 100 mg; tablets (pediatric) SO mg; suspension 100 mg/4 ml. Ethotoin [PECANONE] Moderately effective in grand mal and slightly so in psychomotor epilepsy, but usually unsatis- factory if used alone. Toxicity resembles that of diphenylhydantoin but incidence of at least some AMA DRUG EVALUATIONS JAMA, May 20, 1968 . Vol 204, No 8 PAGENO="0349" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4639 and possibly all reactions is lower. In summary, the drug is less toxic but also less effective than di. phenylhydantoin. Usual Dosage-Oral: Adults: Initially, 1 gm daily in divided doses; for maintenance, 2 to 3 gm daily in four to six divided doses. Children: 0.5 to 1 gm daily in divided doses. Preparateons.-Peganone (Abbott): Tablets 250 and 500 mg. Succinimides Ethosuximide [ZARONTIN] Drug of choice for petit mal. Also effective for minor motor seizures in some patients, but gener- ally ineffective for psychomotor or grand mal epi- lepsy, or in patients with considerable organic brain damage. Major untoward effects appear to be less fre. quent than with trimethadione or paramethadione; the most frequent are gastrointestinal disturbances. Drowsiness, ataxia, headache, dizziness, euphoria, hiccup, skin eruptions, and psychologic or psychi- atric aberrations have been reported. Aplastic ane- mia, thrombocytopenia, leukopenia, pancytopenia, and eosinophilia have been reported rarely. See the monograph in the New Drugs section for further details. Usual Dosage-Oral: Adults and Children over 6: 500 mg daily initially; increase daily dose by 250 mg every one to two weeks until seizures are con- trolled or untoward effects develop. Dosages ex- ceeding 1 gm per day are seldom more effective than smaller dosages. Children under 6: Initial daily dosage is 250 mg. Preparations.-Zarontin (Parke, Davis): Cap- sules 250 mg. Methsuximide [CELONTIN] May be helpful in petit mal and minor motor seizures, especially when used with other anticon- vulsants. Also may be used as the second or third drug to reduce the incidence of psychomotor at- tacks. Grand mal, if present, must be controlled with other medication. Untoward effects occur fre- quently and may be of minor or major consequence. These include gastrointestinal disturbances and re- actions affecting the central nervous system (drowsi- ness, headache, dizziness, diplopia, and ataxia). Hypersensitivity reactions, such as skin eruptions, fever, hiccup, and periorbital hypsremia, occur only rarely. Many minor untoward effects may disappear spontaneously or be controlled by reducing dosage, but a rash may herald a more serious reaction. Severe mental depression may occur, and patients who have psychomotor seizures particularly should be watched closely for behavioral changes, for these may progress to an acute psychosis unless the drug is discontinued. Renal and hepatic damage may occur. Hematologic reactions, including aplastic anemia, although rare, have also been reported. Usual Dosage-Oral: Adults and Children: Ini. tially, 300 mg daily; this may be increased at weekly intervals until a daily dose of 1.2 gm, given in divided amounts, is attained. The optimal dose is the minimal amount that will control seizures without causing serious untoward effects. Preparattons.-Celontin (Parke, Davis): Cap- sules 150 and 300 mg. Phensuximide [MILONTIN] Used in control of petit mal seizures. Less ef- fective and less potent than ethosuximide and trimethadione. However, it is the safest of the succinimides. Its relative lack of serious toxicity justifies its inclusion among drugs that may be considered for initial trial in petit mal (see general statement), although substitution of a more effec- tive agent usually will be necessary. Adverse effects may inolude nausea, weakness, drowsiness, and skin eruptions. The confirmed reaction of greatest concern reported to date is nephropathy, particu- larly in children, which apparently is reversible on withdrawal of the drug. Agranulocytosis, if indeed it is caused by this drug, has been very rare. Usual Dosage-Oral: Adults and Children: 500 mg to 1 gm two or three times daily. Preparations.-Milontin (Parke, Davis): Cap- sules 250 and 500 mg; suspension 250 mg/4 ml. Oxazolidinedjones Trimethadione [TRIDI0NE] Principally effective in control of petit mal sei- zures. Although among the more effective agents for this purpose, should be reserved for refractory cases because of toxicity. Serious reactions, some of them fatal, include skin eruptions that may progress to exfoliative dermatitis or erythema mul- tiforme, nephropathy, hepatitis, and marrow de- pression with aplastic anemia, neutropenia, or JAMA, May 20, 1968 . Vol 204, No 8 708 AMA DRUG EVALUATIONS Mephenytoin [MESANTOIN] Effective in major motor and psychomotor epi- lepsy, but more dangerous than diphenylhydantoin and thus should be reserved for cases refractory to the drugs of choice. Has a sedative effect usually ab- sent with diphenylhydantoin; otherwise lacks or has lower incidence of some of the more minor adverse effects of diphenylbyclantoin (eg, ataxia, gingival hyperplasia, hirsutism, gastric distress). However, life-threatening and other serious reactions are con- siderably more common: severe skin eruptions, blood dyscrasis (eg, aplastic anemia, leukopenia, agranulocytosis, thrombocytopenia, megaloblastic anemia), liver damage, lupus erythematosus, and pseudolymphoma. Usual Dosage-Oral: Adults: Initially, 50 to 100 mg daily, with weekly increases of the same amount until maintenance dose, usually 200 to 600 mg, is established. Further increases to 800 mg or more occasionally required. Children: Initially as for adults; maintenance dose usually 100 to 400 mg, depending on age of patient and severity of seizures. Preparattons.-Mesantoin (Sandoz): Tablets 100 mg. PAGENO="0350" 4640 COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY agranulocytosis. Pseudolymphomas, lupus erythe- matosus syndrome, and myasthenia gravis-like syn- drome also have been reported. Drowsiness may occur. Reversible visual disturbances, particularly hemeralopia, are quite common. Hiccup sometimes occurs during early treatment. Hair loss may occur. Usual Dosage-Oral: Adults: 0.9 to 2.1 gm daily in three or four divided doses. Children: Reduce initial dosage in proportion to age and weight. Preparotions.-Tridione (Abbott): Capsules 300 mg; solution 150 mg/4 ml; tablets 150 mg. Paramethadione [PARADIONE] Similar to trimethadione and has similar indica- tion, ie, petit mal that is refractory to safer drugs. Somewhat less toxic than trimethadione but also less effective. Reactions that occur tend to be the same as with trimethadione, but some occur less frequently. A few (eg, pseudolymphoma, lupus erythematosus) have not yet been reported with paramethadione. Usual Dosage-Oral: Adults: 0.9 to 2.1 gm daily in three or four divided doses. Children: Reduce initial dosage in proportion to age and weight. Preparations.-Paradione (Abbott): Capsules 150 and 300 mg; solution 300 mg/mI. Miscellaneous Bromides Usually as sodium bromide or potassium bromide. Historically of interest as the first antiepileptic. Moderate anticonvulsant activity against grand mal. Routinely cause sedation. Skin eruptions are fre. quent. Of greatest importance is cumulative poison- ing that causes severe toxic psychoses. Bromides are regarded as obsolete for routine use, although they may still have a role in grand mal in children in whom other drugs, for various reasons, prove un- suitable. Usual Dosage-Oral: Recommendations have varied. The following are reasonably consistent with several suggestions: 20 to 60 mg per kilogram of body weight per day in divided doses up to 1 gm three times daily total. Preparations-Common preparations are tablets or elixirs of various strengths. Many manufacturers. Phenacemide [PHENuR0NE] An effective anticonvulsant that ma~' be useful in refractory psychomotor, grand mal, petit mal, and mixed seizures. However, it is a very dangerous drug and should be used only when adequate con- trol of seizures cannot be achieved with other drugs. Potentially fatal reactions include hepatitis. blood dyscrasias (aplastic anemia, agranulocytosis), and toxic psychoses, often with suicidal tendencies. Nephropathy occasionally occurs. Rashes and gas- trointestinal symptoms are rather common. Usual Dosage-Oral: Adults: Starting dose, 250 to 500 mg three times daily. If necessary, an addi- tional 500 mg daily may be added at weekly inter- vals. Usual maintenance dose is 2 to 3 gm daily in divided doses. Children: Age 5 to 10, approximate- 709 ly one-half adult. dosage. Preparotions.-Phenurone (Abbott): Tablets 500 mg. Acetazolamide [DIArtlox] Has been reported useful in children with petit mal, but effectiveness declines with continued ad- ministration. See chapter on Drugs Used in Glau- coma for properties and other uses. Usual Dosage-Oral: Adults and Children: 8 to 30 mg per kilogram of body weight daily in divided doses. Preparations.-Diamox (Lederle): Capsules (sus- tained release) 500 mg; tablets 125 and 250 mg. Meprobamate [EQUANIL, MILTOWN] May be helpful in some cases of petit mal. When used alone, seldom controls any but the mildest cases. See chapter on Antianxiety Agents for prop- erties and other uses. Usual Dosage-Oral: Adults: 400 to 800 mg three times daily. Children: Age 3 and older, 100 to 200 mg two or three times daily increased as needed to as much as 2.4 gm daily in older children. Preparations.-Equanil (Wyeth): Suspension 200 mg/S ml, tablets (uncoated) 200 and 400 mg, tab- lets (coated) 400 mg, capsules (sustained release) 400 mg; Miltown (Wallace): Tablets 200 and 400 mg; Meprospan (Wallace): Capsules (sustained re- lease) 200 and 400 mg; Meprotabs (Wallace): Tab- lets (coated) 400 mg. Other manufacturers. Paraldehyde Effective in status epilepticus, but should be re- served for cases in which phenobarbital has failed. Beware of decomposed drug. Intravenously, should be given slowly in a drip; otherwise, it induces severe coughing that, at best, makes administration difficult, and at worst, can cause pulmonary hemor- rhages. Some fatalities have occurred. Compatibil- ity with blood has been questioned. Intramuscular injection, though often very irritating, is reason~ ably safe if adequate care is taken to avoid periph- eral nerves. The Council's consultants have divided sharply on whether this agent should be used par- enterally, and if so. by which route. Bronchopul- monarv disease is a relative contraindication. The sedative effect mas' he intensified and prolonged in the presence of liver damage. Usual Dosage.- (Status epilepticus) Intro tnu~rii- tar. Intrarenous: Suggestions have varied, a~d available recommendations of manufacturers are vague. However, dosage for status -epilepticus fe- quently exceeds that given for more benign :-o:'dr- tions. About 0.15 ml per kilogram of body v-ei-'ht is reasonable; sometimes a moderate additional dose will he needed, especially for smaller children. Intravenous injection must be slow, preferably by drip, with the drug diluted by physiologic saline, and with caution to avoid extravasation. Preparations.-Paral (Fellows-Testagar), Paral- dehyde (Tilden.Yates): 2, 5, and 10 ml containers. Quinacrine Hydrochloride [ATABRINE] May he effective in petit mal, but should be used AMA DRUG EVALUATIONS JAMA, May 20, 1968 . Vol 204, No 8 PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4641 only if other drugs have failed. Its toxicity is se- vere and its effectiveness is not great. See the chap- ters on Antimalarial Agents, Anthelmintics, and Antineoplastic Agents for properties and other uses. Usual Dosage-Oral: Adults: 100 mg daily. Chil- dren: 1 to 2 mg per kilogram of body weight per day. Preparations.-Atabrine Hydrochloride (Win- throp): Tablets 100 mg. Diazepam [VALIUM] This drug was introduced as an antianxiety agent, but like other benzodiazepine derivatives, it has anticonvulsant properties. Eventually, it prob- ably will not prove the best anticonvulsant of this group, but it is the l)referred one of these now mar- keted in this country. Conflicting reports of effec- tiveness in various epildpsies have appeared. The drug has shown much promise in petit ma!, but perhaps of greatest importance is it.s value paren- terally in terminating status epilepticus and its fre- quent effectiveness in minor motor epilepsy, which is so often refractory to the conventional anticon- vulsants. Its greatest drawback in maintenance therapy is the eventual tolerance that develops to the therapeutic effect. However, this problem also occurs with other agents in minor motor epilepsy. The most common adverse effects with oral use are drowsiness, dizziness, fatigue, and ataxia, all dose related. Paradoxic excitement or stimulation some- times occurs. Parenteral administration for status epilepticus requires observation for respiratory de- pression and hypotension, and the slight possibility of cardiac arrest must be borne in mind; however, from the limited information available, the overall safety of the drug appears to compare favorably with other agent.s used for this life-threatening emergency. See the monograph in the New Drugs section for other properties ant! uses. Usual Dosage-Oral: Adults: 4 to 40 mg daily in divided doses, beginning with a low dose and in- creasing it gradually. Consider starting with only 2 mg in elderly or debilitated patients. The effect of the drug is cumulative. Children: Somewhat re- duced dosage, beginning with 2 to 4 mg daily in divided doses. Intravenous: (Status epilepticus) Adults: 5 to 10 mg injected slowly. Children: 2 to 5 mg injected slowly. Intramuscular injection may be substituted if the convulsions make sloic intravenous injection impossible. The drug should not be mixed physical- ly with other agents or diluted with intravenous solutions. Preparations-Valium (Roche): Solution (injec- tion) 5 mg/mI in 2 ml containers; tablets 2, 5, and 10 mg. Corticotropin and Various Adrenal Corticosteroids Of value in minor motor epilepsy. See the chap- ter on Adrenal Corticosteroids for detailed discus- sion of these agents. Dosage varies with the agent used. Mixtures Several fixed combinations of anticonvulsants are marketed. They are listed below only to acknowl- edge their availability and not necessarily to en- courage their use. The usefulness of such fixed combinations is limited since, in the management of epilepsy, the dosage of each drug used concomi- tantly should be established individually. After this has been done, if the doses present in an available mixture happen to correspond to the ratio and quantities required liv the patient, the use of such a combination product would seem justified, for the convenience of the patient, unless a subsequent ad- just.ment of dosage becomes necessary. However, some available ,ombinations are unrealistic, since the usual dose of one ingredient carries with it only a trivial dose of the other. Some others contain irrational ingredients that are not effective thera- peutic agents for epilepsy. Still others contain more than two ingredients and appear to be entirely too cumbersome for practical use in view of the impor- tance of individualizing the dosage of every drug the patient receives. ALEPSAL (Fougera): phenobarbital 97 mg, bella- donna powder 20 mg. caffeine 26 mg/tablet 5ARBA-NIACEN (Cole Pharmacal): phenobarbital 32 mg, niacin 16 mg/tablet BARRA-NIACIN FORTE (Cole Pharmacal): phenobar- hits! 97 mg. niacin 46 mg/tablet DILANTIN with PHENOBARBII'AL (Parke, Davis): di- phenylhydantoin sodium 100 mg, phenobarbital 16 or 32 mg/capsule ELMALOIN with PHENOBAISB1TAL (Elder): diphenyl- hydantoin 50(1mm 10(1 nig. phenobarbital 15 mg/ capsule HYDANTAL (Sandoz): mephenytoin 100 mg, pheno- barbital 20 mg/tablet MEBROIN (Winthrop): mephobarbital 90 mg, di- phenylhydantoin 60 mg/tablet NEO-SEDAPHEN (Smith, Miller & Patch): pentobar- hital sodium 30 mg. phenobarbital sodium 10 mg, sodium bromide 300 mg, potassium bromide 200 mg. calcium bromide 100 mg/S ml PI-1ELANTIN (Parke, Davis): diphenylhydantoin 100 mg, phenobarbital 30 mg, methamphetamine hy- drochloride 2.5 mg/capsule QIJADRA-SED (Smith, Miller & Patch): pentobarbita! sodium 15 mg, phenobarbital sodium 15 mg, hutabarbital sodium 15 mg, secobarbital sodium 15 mg/5 ml SEDAI.IXIR (National): pentobarbital sodium 8 mg, phenobarbital 16 mg/S ml SEDAPHEN (Smith, Miller & Patch): phenobarbital sodium 20 mg, sodium bromide 300 mg, potas- sium bromide 200 mg, calcium bromide 100 mg/ Sm! SEDOBARR ~ 1 (Whittier): phenobarbital 16 mg, pentobarbital sodium 32 mg/tablet SE000ARB !=2 (Whittier): phenobarbital 32 mg, pentoharbital sodium 65 mg/tablet JPMA, May 20, 1968 * Vol 204, No 8 710 AMA DRUG EVALUATIONS PAGENO="0352" 4642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. ANNIS. This advance chapter was run in JAMA for good rea- son. To find out if we were heading in the right direction to meet the physician's need for usable drug information, we asked physicians who received the ADE chapter to give us their reactions. To summarize the results, 96 percent said a drug evaluation book like the one in the sample chapter would supply the type of informa- tion needed in their practice; 96 percent said the information in the sample chapter was presented in a readily accessible. form; and 91 percent said the extent of information presented ii4 the sample chapter was "about right" rather than "inadequate" or "ex~sive." Details of that study are included in this statemei. u and I request that they be included in the record at this point as "exhibit H." Senator Nni~soN. They will be printed in the record. Dr. ANNIS. Thank you. (The exhibit referred to follows:) ExIrn3rr H An,aZys~s of ADE Questionnaire (Total Number, 3,761) The questions and results were: 1. Would a book containing evaluations of all drugs that are commonly pre- scribed, as illustrated in the accompanying sample chapter, supply the type of information you need in your practice? Yes ~ 622 No 110 No comment Percent favorable response 96.3 2. As a reference on drugs, is the information in the sample chapter presented in a readily accessible form? Yes 3, 6G1 No 116 No comment Percent favorable response 95.7 3. An effort has been made to present the most useful information for most circumstances in which a drug may be used. In view of this intention, do you believe the extent of information presented is: inadequate, about right, excessive? Inadequate 165 Excessive 137 About right 3,418 No comment 41 Percent favorable response 90. 6 4. Do you have a copy of New Drugs? Yes 1, 243 No 2,677 No comment Percent having new drugs 31.9 PAGENO="0353" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4643 PRESCRIPTION LABELING Dr. ANNIS (reading). Also in connection with drugs and drug in- formation, my fifth subject is labeling prescription drugs. The AMA Council on Drugs has considered the question of labeling prescription drugs many times. The council's recommendations last appeared in JAMA in 1965. Mr. Chairman, I ask that the article, which is attached to this statement, be included in the record at this point as "exhibit I." Senator NELSON. .t will be printed in the record. Dr. ANNIS. ThaI~; you. (The exhibit referred to follows:) 81-280 O-69----pt. 11-23 PAGENO="0354" 4644 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Repeisted Frov& the Josroot of the Ac -ass Slnbeot ~ Deeee,ber 20, 1965, Va!. 194, page 1311 Cepycight 1965, by Aeoeiess 5! od:col A,vs3st:s:: Exhibit I To-~Labe1 or In a less sophisticated era, when the art of medical practice outweighed scientific knowledge, physicians did not tell their patients the identity of the medications they prescribed. Today, this practice is being gradually abandoned, and increasi,,g numbers of physicians ask pharmacists to indicate or the label the names and strengths of the drugs they prescribe. The Council on Drugs believes that all physicians should adopt this policy, and make an exception only when such disclosure would be detrimental to the welfare of the patient. In a prior discussion of this subject,' the Council made a number of the following points: The patient has the right to be informed about his ill. ness and the medications prescribed. In emergency situations, such as accidental poisoning, overdosage, or attempted suicide, immediate identification of a prescription drug from the label may be lifesaving. The information is invaluable when the patient changes physicians, moves to another locality, or contacts the pre. scribing physician at a time when his records are not readily available. The information on the label is of value in group prac. tices in which the patient may not always have the same attending physician. It is advisable that patients with allergies know what is being prescribed. This specific information on the label helps to prevent mix-ups between two or more drugs being taken concur- rently, or between medications being token by different members of the family. Should it become necessary to issue a warning against the use of a particular drug, the name on the label serves as a danger signal to thsse who have been given prescrip. tions for the product. In its earlier consideration of this subject, the Council on Drugs passed the following resolution': The Council resolves that it favors labeling oi prescriptaons as a general practice, and furthermore, it is recommended that pre- scription pads contain hoses for a "yes" or "no" on whether to label; if these hoses are not filled in by the physician, thr pre- scription will be labeled. That resolution was received favorably by many. How- ever, pharmacy organizations and several state medical societies have opposed the nsethod that the Council aug. gested for implementing its recommendation. The Profes- sional Relations Committee of the American Pharmaceu' tical Association agreed with the position expressed by Apple and Abrams,5 who concluded that unless a pre- scriber specifically requests labeling, ". . - a pharmacist should not by himself, or upon request by a patient, dis- close the ingredients in the prescribed medication by labeling." This reflects the feeling of the pharmacist that he needs a directive to label from the physician, who alone has the authority to make such a decision. Physicians and pharmacists who are opposed to labeling as a routine measure and feel that it may create or ac- centuate various problems have the following objections: The practice may lead to self-medication and to "pa- tient-prescribing" for others. A patient who knows the drug name may compare prices at different pharmacies, and thus tempt pharmacists to bid for business on a price basis rather than on a basis of professional service. The information may only co,,fuse and trouble the patient. Not to Label The practice reduces the stature of the physician and lowers the status of the prescription to practically that of an over-the-counter item. Patients may put other drugs into bottles labeled with the previous co,,tests, which may then lead to charges that a pharmacist dispensed the wrong medication. Labeling could make it easier to channel drugs into illegal markets. The Council believes that the advantages of labeling outweigh these objections in almost every instance; the Council always has recognized that there are occasions when such labeling is inadvisable for psychological or other reasons, and that the physician is the one who must decide. However- only in exveptior:al circumstances is it desir- able not to reveal the identity of prescribed drugs under today's conditiot,s. Moreover, the physician's explanation to his patient regarding thc purpose of a prescribed drug and what may be expected from it, together with the public's growing awareness of the effects of drugs-both beneficial and harmful-will help to minimize problems that may occur occasionally After consultation with officers of the national phar- macy organizations and after further deliberation, the Council on Drugs strongly reaffirms its position that in the best interest of the patient the prescription container should, as a rule, be labeled with the name and strength of the drug. To implement this recommendation, the Council suggests that the physician use two sets of pre- scription blanks, one of which is for routine use and is imprinted with an order to label. This procedure is con- sonant with tl- - ethics of medicine and pharmacy, and with the physician's responsibility to decide whether the prescription label should or should not identify the drug. The Council further urges that the physician always designate the number of refills he wishes the patient to have, and that he prescribe only the number of doses usually required in any specific condition, since adjust- ments in dosage are often necessary to obtain the desired result in individual cases. The Council also recommends that any prescription that does not indicate the number of refills, or that is labeled "p.r.n." or "ad lib," not be refilled. The Drug Abuse Control Amendments that were recently passed by the Congress regulate the refilling of prescrip- tions for stimulant and depressant drugs. No prescription for drugs in these cl.isses can be renewed more than five times, or more than six months after the date of issue un- less the physician gives additional authorization for re- filling. The physician's responsibility for the medication regi- men of his patient is clear, and he should therefore heed the pharmacist's requests for specific instructions on cc- The Council hopes that this statement will clarify its position on the question of labeling and refilling of pre- scription drugs, and earnestly solicits the cooperation of physicians, pharmacists, and other health personnel in implementing these irnpurtaist public health recommenda- References 1. Lnbctisg of Picsenptis" Drags, editorial, JAMA 185:316 Jaty 27) ions. 2. Apple, W.S., and Ah:aoe-. Rn.: Problems in Presenpt:sn Order Conossasimtiont, JAMS 185:291-293 (Jaly 27) 1963. JAMA, Dec 20, 1965 . Vol 194, No 12 Pr:oted is U.S.A. PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4645 Dr. ANNIS. May I summarize the council's views? It recommends that in most instances the physician should request that the prescrip- tion label indicate the name and strength of the drug prescribed. Some of the reasons given are these: The patient has the right to be informed about his illness and the medication prescribed. The information is invaluable when the patient changes physicians. It is advisable that patients with allergies know what is being prescribed. Specific information on the label helps to prevent mixups between two or more drugs being taken at the same time; or between medica- tions being taken by different members of the family. However, the council also offered the fact that there are situations when the physician might determine that such information should not be contained on the label. Those situations usually involve psycholog- ical considerations for specific patients. Mr. Chairman, I would now like to add some further remarks that the AMA considers of importance to these hearings. Almost at the beginning of this statement, I listed the three primary reasons for which the American Medical Association was founded 122 years ago; to established a code of ethics; to combat quackery; and to improve medical education. That last point-education-includes the entire spectrum of training and education necessary to produce and maintain a competent physician: Premedical education. Medical school. Postgraduate education through internship or residency training. Continuing education of practicing physicians. The proper use of drugs is a vital part of all medical education, be- ginning with medical school. A survey of medical schools by the AMA in 1~966 revealed that an average of 173 classroom hours was: devoted to pharmacology during the sophomore year. The range was from a low of 62 hours to a high of 396 hours. In the junior and senior years, instruction in drug therapy is pre- sented as a part of each clinical service and through clinical pathology conferences which all students are required to attend. It is not possible to give the total hours of drug therapy instruction received by the student because there is continuous education in that area throughout medical school arid during the internship and resi- dency years. The same observation can be made about continuing medical educa- tion courses. The AMA publishes a list of such courses each year. The latest list, and I have with me a copy for the committee, shows 1,922 courses offered to physicians by 372 institutions and organizations. I will leave it with the committee. This is, I think, the 11th or 12th-the 14t.h consecutive year which this has been made available, so physicians anyplace in the country will know where they can go for continuing education. Senator NELSON. Thank you. Dr. ANNIS. While there are no courses titled "Drug Therapy," with very few exceptions, each course necessarily includes information and PAGENO="0356" 4646 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY discussion of the therapeutic agents used in the treatment and control of the problems being covered by the course. The medical profession has great respect for the results of drug research. It recognizes that a great number of the specific medical ad- vances of the last three decades have been in the area of chemother- apy-of drugs. These advances have come about becausc of the varied support of research and development-by the private drug industry, through aca- demic contributions supported by private and Federal grants and directly from the Federal Government. If financial support for research and development were confined to only one of those sources, it is possible-even probable, I think-that. the research would be directed into whatever approach was of most interest to the sponsoring body. That could mean fewer innovative dis- coveries and applications. Speaking of the application of drug discoveries, the American Medical Association has always advocated the rational use of thera- peutic agents by physicians in treating patients and has consistently expressed its firm belief that the physician should have for his patient the very best drug available for the patient's condition. At the same time, the AMA has urged that physicians be aware of the economic factors connected with the use of drugs. In this regard, I would like to present the essence of a position adopted by the AMA House of Delegates: Physicians should be free to use either the generic or the brand name in pre- scribing drugs for their patients; and physicians should supplement medical judgments with cost consideration in making this choice. A copy of the report is included as exhibit J and I ask that it be inserted in the record at this point. Senator NELSON. It will be printed in the record. Dr. ANNIS. Thank you. (The exhibit referred to follows:) PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4647 Exhibit J Excerpt From Proceedings of the AMA House of Delegates November 1966 Prescribing and Dispensing of Drugs This report is intended to state the position of the American Medical Association regarding the considerations which are pertinent in determining under what circumstances the physician should prescribe generically or by brand name. The present policy of the American Medical Association is that physi- cians should be free to prescribe drugs generically or by brand name for ~j, of their patients, whether they are paying, medicare, or indigent patients, the primary consideration being the best interests of the patient. Medical considerations must be paramount in the selection of drugs. In addition, the physician also has an obligation to be mindful of the economic conse- quences of the treatment he prescribes. The issue of cost is not simply a matter of prescribing drugs generi- cally as opposed to brand name prescribing. Often there will be~substantial variations in the cost of the same drug marketed under differentbrand names by a number of reputable manufacturers. However, gene~ric prescribing alone will not assure that the least costly brand will be dispensed or that the savings will be passed on to the patient. Nor will generic prescribing alone assure the physician that his patient is receiving the product of a manufacturer in whom he has confidence. If the physician prescribes by;brand name, he designates the source of supply. If the physician prescribes generically without naming a manu- facturer, the pharmacist or some other third party chooses the source of supply. The attending physician should not delegate this choice, that is, he should not prescribe generically, unless he is convinced that he can rely upon the quality and purity of the drug that will be dispensed to his patient. If this is not the case, then the physician himself should desig- nate the source of supply by prescribing by brand name or by adding the name of his choice of supplier to the generic name of the drug. Cost Considerations If medical considerations lead the physician to the conclusion that he should not delegate the choice of supplier to anyone else, then he must make the decision. And in doing so he should supplement medical considera- tions with considerations of cost to his patient. PAGENO="0358" 4648 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It is a fact that, in many cases, drugs prescribed by physicians in the United States are available from more than one dependable supplier. They are also available to patients from a large number of retail phar- macies. Thus, in selecting a dependable supplier of the drug of his choice, the physician has an opportunity to serve his patient at the lowest possible cost. The physician should inform his patient of the medical considera- tions which have led him to the decision to prescribe a particular brand. He should also encourage the patient to be cost conscious in having the prescription filled. If medical considerations lead the physician to the conclusion that he can safely delegate the choice of a supplier to a pharmacist, a hospital formularly committee or some other third party, he does not abrogate his responsibility to protect the economic as well as the medical interests of his patient. Just as it does not follow that generic prescriptions automati- cally ensure therapeutic effectiveness, it is also a fact that generic pre- scriptions do not automatically ensure the lowest possible cost. If the third party filling a generic prescription does not reflect the same concern as the prescribing physician, his patient may be charged a higher price than would have been the case given a brand name prescription. Thus, in choosing to prescribe generically, the physician should be assured that whoever actually makes the choice of supplier can and will take into account not only the medical needs of his patient but will protect the patient's economic interests as well. With this clarification of the medical and the economic consequences which can flow from the physician's decision to prescribe by generic or by brand name, the Board of Trustees recommends that the House of Dele- gates: (1) Reaffirm the present policy of the Association which states that physicians should be free to use either the generic or brand name in prescribing drugs for their patients; and (2) Encourage physicians to supplement medical judgments with cost considerations in making this choice. PAGENO="0359" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4649 Dr. ANNIS. This committee has heard testimony that drugs should be prescribed by their generic names only. That recommendation usually is founded on the assumptions that drugs of the same generic name are therapeutically equivalent; and that a prescription written by generic name will automatically save the patient money. Neither assumption is necessarily true. The AMA believes firmly that no : system of prescribing drugs should be compulsory for a physician. instead, a full range of drugs must be available so he can select for his patient the one he believes will achieve the best response. To cope with differences among some patients in their responses to drug therapy, the physician must be allowed the greatest possible freedom in prescribing from a supply~ of drugs that is as large and as flexible as possible. It takes more than laboratory testing-more than just chemistry- to prove therapeutic equivalence among drugs. it takes proper clinical testing. Even assuming equivalence of chemical composition among drugs, other factors are involved. Among these are crystalline size, nature of incipients, flavors, coloring agents, tableting pressures and the num- ber, thickness, and orientation within the tablet of coating films. The physician who prescribes a drug needs to know what to expect from that drug. A generic prescription, filled by a drug the pharma- cist selects, may be filled with any drug within that generic classifica- tion. If the prescription is refilled, the product of a different manufac- turer may be used. As a result the physician may be unable to evaluate fully the patient's response to that course of drug therapy. Mr. Chairman, and members of the committee, that completes the statement of the American Medical Association before these hearings. I have tried at least to touch on, if not to discuss in elaborate detail, subjects that we believe are important both to this committee and to the medical profession. If there are any questions at this time, I shall be glad to do my best to answer them. I will be glad to `be assisted by both Dr. Hayes and Mr. Harrison. We appreciate this courtesy. Senator NELSON. Thank you very much, Dr. Annis. We appreciate this statement of the American Medical Association. You made some reference in the beginning to statements by some witnesses that may reflect in a fair way on the profession. Let me say that in my judgment based upon some natural `bias, coming from a medical family, I consider the medical profession the finest of the pro- fessions, though I am a lawyer. And though we have highly motivated people in all professions and we have some who are not, I think my own unscientific estimate from experience is that there is a higher percentage of highly motivated people in medicine for a very simple reason, that I think more people go into this profession because they want to do something for people. That has been the history of medicine more than perhaps any other profession. I want to say, too, that the fact that Congress conducts hearings of various kinds involving all aspects of the social structure of the coun- try and the economic structure and the professions does not mean that the hearings which may bring out testimony critical of some indus- tries, some profession, or something else, does not mean that that is a PAGENO="0360" 4650 CO~ETITWE PROBLEMS IN THE DRUG INDUSTRY general indictment of the industry or the profession or that the Con- gress feels that that industry or profession or economic or social group is not making a very fine contribution to society. I have introduced a fair amount of consumer legislation involving pesticides and the chemical industry, the tire industry, tire safety standards, the auto industry, and a number of others. I remember when I introduced the tire and auto safety bills, I was attacked in some quarters as being against the auto industry, which it could be said is the greatest, at least in terms of its size, of any industry in the country. I had to point out repeatedly that the fact that I thought there were some things wrong in that industry in terms of the work they are doing in safety, and in terms of the quality of tires the auto industry was using, this is not a general indictment of the industry. There is not any group in the country that has a relationship with the public that is perfect~ The purpose of this hearing is to raise is- sues in which the public has an interest. The problems and issues raised before this committee have not been raised by the members, by me, or the members of the committee. They have been raised by wit- nesses who come before the committee, and, like anybody else, I could agree with some and disagree with others, based upon what they have to say. But in the last 2 years there have been a large number of very reputable witnesses who have been critical of certain practices in the medical profession, of the medical journals, and of the drug indus- try. They have been very distinguished men who have been willing to come before the committee and express their opinions about these various matters. Of course, there have been others who have come before the commit- tee to respond or to criticize those who have criticized. We have made it a point in this committee, which I think we must, to be fair, when we are discussing anything involving the drug industry, and that has been the main thrust of these hearings, that any company that was criticized would have an opportunity forthwith to respond to that crit- icism and whenever they have asked for the opportunity, we have set up the earliest possible date in order to let them respond to anything that was said before the committee. We also have made it .the policy of this committee to hear from all viewpoints respecting any issues raised. And we have been trying to do that. We cannot hear from everybody at once, of course, because we would have to hold the hearing in a stadium. But anyway, the fact that these questions are raised before the com- mittee, as you well appreciate, puts me in an adversary position, in the view of many, since that is the kind of issue that is being raised here. In other words, it is a. hearing to raise public questions of importance which are critical of certain practices in the drug industry. Many times, it has been said, "Well, you are just hearing the bad things about the drug industry." Well, we know a great deal about the good things. However, that is why we have always been happy to per- mit the drug industry or the Pharmaceutical Manufacturers Associ- ation to appear, or anybody else, and delineate in a great detail as they desire the contributions, the work of the particular organization they represent. While we will be pleased to have your summary of the vast amount of work the American Medical Association does-I realize it is, just PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4651 as you have said, a concise, short presentation of an organization that has a long and distinguished history in this country. Nevertheless, since it is the function of this committee to probe these very questions, I necessarily have to ask the hardest questions I can think of. Some- times they are not very hard. And some of the questions I ask may not be very perceptive. In fact, some may be considered foolish. That is because nobody on this committee, particularly myself, poses as an expert on any aspect of this field or as an expert in the issues before this committee. The committee conducts hearings and hears testimony of experts who have conflicting views so that the whole story will be in the hearing record, so that it may be read and evaluated and so that the Congress sitting in the position, so to speak, of a jury, may make some kind of evaluation as to what the testimony means and whether or not legislation is required in some area respecting the public interest. Now, I try, as I said, to make my questions as tough and probing as possible. Som,e witnesses even think, if you can imagine it, that som.e of my questions are offensive, and some people even think the question- er is offensive. That is not my intent. I want to say also that I try to ask the most probing questions I can, affecting all the issues that have been raised here. I note that very frequently I am quoted as advocating some position because of the questions I ask. Dr. ANNIS. I can `appreciate that, Senator, I have had that directed toward me a. few times, too. Senator NELSON. I ask questions that occur to me, saying why is this not a good idea, and then I am put in the paper as saying I advocate doing such and such, and then there will be an editorial someplace, in one of the medical publications, saying how foolish `the proposal I ad- vocated was when, in fact, I did not advocate anything. I am just ask- ing for information. I may conclude after hearing all the testimony that I agree with the proposition implicit in the question I asked. Or I may not. Now, having said that, I would like to ask some questions. First, on the continuing question of generics versus brand names ~and labeling of drugs and so forth, it seems to me, after 2 years of listening to testimony, and after reading the arguments made by the drug manufacturers, that there is a continuous and very successful attempt by the manufacturers to convince the medical profession that you cannot ever trust generic drugs, and that you have to prescribe brand names, particularly the brand name of a particular company. We have not received any adequate `testimony from either sid&-when I say adequate, I mean we have not had any conclusive testimony that a brand name is better than a generic. The FDA is presently testing a whole series of very commonly used drugs to try to settle this question. The test I refer to, a previous test made by the FDA, is of some 4,600 drugs, of which 2,600 were generic drugs and 2,000 brand name, and they tested them only for potency. On that particular test., `the generics came out slightly better than the brand names. Pharmaceutical manufacturers attacked it on the grounds that it was not accurate and the FDA, after reexamining it., conceded that there were six instances, I think, out of the 4,600, that. were erroneous. In any event, as I recall, about 8.8 percent of the brand names failed the potency test; that is, they: were slightly under or `above the TJSP standards, and 7.7 percent of the generics failed that test. PAGENO="0362" 4652 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY So the prcthlem continues, and the drug companies have been very persuasive in trying to make.sure that generics are not trusted by much of the medical profession. However, we have had a number of dis- tinguished witnesses who simply say that they prescribe by generic name-that if the drug meets TJSP standards, there is no evidence, of any consequence, that they are not therapeutically equivalent. First, let me ask you about the question of labeling which you re- ferred to in the latter part of your statement. You recommend that the doctor use the generic name in prescribing, I believe, is that correct? Dr. ANNIS. My recommendation, Senator, is that `a physician `be given the opportunity to prescribe generically as he will do in some instances. - Senator NELSON. I was referring to labeling; I am sorry. Dr. ANNIS. But if he so prescribes, or by brand name, if he feels that he is a little more certain. The recommendation for labeling is one that has come as a result of long discussion by many of the a:ble members on our council on drugs, supported by many others in the profession. With the growth of new drugs with the expanding names, whether they are generic and hard to decipher, to spell, or to pronounce; or whether a simple brand name, it is increasingly difficult, with the tre- mendous mobility of our population-people moving around-to know what they are taking. So the recommendation for labeling is that in most instances, except for a few where for psychological reasons it is not good for a patient to realize what you are giving him is acetylsali- cylic acid-plain aspirin-when they think they need an exotic one- except in those rare instances-for the most part the physician would be wise and it would be safer, and therefore better for the patient who is moving around, and `better for another doctor, should they be travel- ing or should they move, to know exactly what they are getting. So that if, for example, you write a prescription for a tol'butamide for a diabetic, you might write "Tolbutamide" with the name of a producer. You might write it, as I often do, one or the other producer, whichever the pharmacist may have on hand. But label itso that it will say tol'butamide, whatever company. I do not treat diabetes, but if I did, the patient would know ihe drug. Then if they are visiting on a weekend, or if they have a reaction- because they ate inadequately, or because of an upset stomach and their diabetes the effect of the medicine to control their diabetes is too great and. they have a reaction from `the `drug, any doctor can t'ake a look at it and know what the patient is getting. This is a protection for the patient. It gives more information. They know what they are treating, they know what drug is `being used and it helps immeasurably. I `have many patients from out of town, who come down to Miami. They will come in and bring two or three bottles with them, with `a prescription number. Not infrequently, I have had my secretary call various parts of the country to find out from the druggist what the prescription for Mrs. Jones is. Then I will know. For some people, you can't tell them what they are taking. They will not only think it is good for them, but they will prescri'be it for Aunt Lillie when she is visiting. We think it is good practice, it gives greater information and shares with the patient a little of the responsthility in their own care ~nd it will give tremendous aid for our increasingly mobile population in being immediately able to let the doctor know what they are taking, PAGENO="0363" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4653 and the dosage they are taking. This is so important in many drugs, how frequently they take it, and also, how long they have been taking it. Many drugs are not considered dangerous if taken for a week. The same drug you might give for a week, you would not want anybody to refill, and you sure do not want them taking it for a month or two or three. This basically is the summary of the philosophy behind this recommendation. Senator NELSON. I think we have had a number of distinguished physicians testify on this precise point. No one so far as I know, has testified to the effect that the physician should not have a choice of whether it is a brand name or generic, but in order to accomplish this, is it not necessary to have some legislation that would require that the label carry the generic name, and then, of course, the doctor may de- cide that it should he Lilly or Parke, Davis or Merck or something else. It may very well have t.hat on the label, also. Do you see any other way to secure, without legislation, a require- ment that the label shall bear the generic name excepting in those cases where the doctor notes that he: does not wish a patient to have the drug identified? Dr. ANNI5. Well, Senator, in most instances compulsory labeling would cause no hardship. But, especially in the field of psychiatry, sometimes in other fields, for psychological or emotional reasons-if you were to tell someone who is disturbed-an exception must be provided. This is one of the fields that I have to listen to my colleagues. Let me cite an example. There are meprobamates, Miltown or Equanil. These patients will say, "I read about that Miltown, I tried that years ago, and it is of no value." Yet the prescribing physician, the psychia- trist, the internist, the obstetrician, would be very reluctant to let this patient know she is being given Miltown, so lie might prescribe meprobamate made by someone else or meprobamate TJSP. There are many reasons why physicians will not tell the whole story. Psychiatrists dealing with children are totally reluctant to dis- close all to their patients. This is the reason that our recommendations, following the Council on Drugs, with the concurrence of most of these very distinguished men who have been before your committee in the field of physiology and medicine, recommend st.rongly an increase in the. practice of label- ing, but they still leave to the physician the discretion. If it became a matter of law, it is mandatory, then we overcome the part of treatment., the mysticism, for example, that some physicians in certain areas of medicine-in psychiatry-feel is part and parcel of good treatment. This is where the objection comes. In my practice I cannot conceive of but very few 1nstances where a compulsory labeling would make any difference. Senator NELSON. It has been the testimony of a number of distin- guished witnesses that it ought to be described generically on the label, with the caveat that if a doctor does not think it should be, i.t will not be put on the label. So I am wondering why legislation re- quiring it., except when the physician directs otherwise, is not the only way you are really going to accomplish this. Dr. ANNI5. I would not have too strong au opinioii against that as long as the physician-this is the only thing-as long as the physician taking care of this patient. has the right to discriminatory judgment in the interest of the patient. This is all we ask for. PAGENO="0364" 4654 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I would call upon the AMA to support legislation to that effect, as I say, with the freedom of the physician to decide if he does not wish to have the generic label on it. I have a letter from Dr. John Adriani, who is chairman of the council on drugs, endorsing that himself. He said, referring to an educational television program he was on, "I was the participant who expressed the opinion that all drugs should be sold by the generic name, that the generic name should appear in large print and the trade or brand name be put in smaller type below it, or the generic name in parenthesis." Dr. ANNIS. I am acquainted with Dr. Adriani and also this tele- vision show. Dr. Adriani is an anesthesologist and a very capable one in a umversity in Louisiana. There are many people who concur with this basic approach. The thing that they are fearful of is anything that makes it mandatory that physicians prescribe in only one way or that they always label in one way. This is where you take away from the physician his opportunity to discriminate. Senator NELSON. Thus far, we have not had any one who advocated that you not reserve that right to the doctor. One of `the problems raised continuously to which I referred a bit back, is the brand name versus generic name. A year or so ago two drug chains, People's and Gray's, involving, if my memory is correct, about 300 pharmacies, announced that they were stocking across the board generic drugs supplied by Strong, Cobb & Arner, and that the average price of prescriptions would be about one-half of the brand name. Everybody testifying and appearing before the committee has been familiar with that company and spoken very highly of it. The question I am getting at is it seems we have to have adequate legislation, adequate personnel in the FDA, to guarantee inspection and quality control so that we can forever get rid of this argument about brand name being always better, which has never been proven. Would the American Medical Association support, before the Con- gress, legislation that would furnish adequate inspectors for the FDA so that they could sample, check the producers on a regular basis, so that we can have assurances that adequate quality control exists at each producing plant, so that once and for all we can say that these plants are inspected, they do meet USP or NF standards, so that the doctor can be assured that what he is buying meets these standards? Would the AMA support that? Dr. ANNI5. I am under the impression that the F'DA already has that authority. They need a little more money to implement it and to carry it out. I would like to say, however, that I do not think either I or the American Medical Association can be put in a position that we have ever stated that the brand name is always preferable to the generic term. There are many excellent drugs available generically that come from responsible manufacturers who have built-in quality controls to put out good drugs. There are many generic drugs that actually come from these same manufacturers. Again, our point is that pre- scribing generically does not in itself assure that you are going to get what you expected. It has been about 21,4 or 3 years ago, Senator, that I read an article repeated in many of our medical journals about an instance that took place in the Province of Ontario. I am sure that is where it was, wherein PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4655 tolbutamide, a drug taken by mouth to control diabetes rather than injections of insulin, had been purchased in large quantities ty virtue of its price. It was the low priced generic drug purchased. Subse- quently many physicians who were using this drug in government hos- pitals and in that area began to have patients go into diabetic coma or show other evidences that their diabetes was not controlled. Subse- quent investigation found and traced the trouble to the generically purchased drug, tolbutamide. Chemical examination proved that the tolbutamide was in fact what it was supposed to be; it was tolbuta- mide. However, in putting it together, the manufacturer who supplied it compressed it in such a way that it was not properly absorbed. It was not properly utilized. Senator NELSON. We had testimony- Dr. ANNI5. May I continue? I was waiting to see whom you were going to listen to, because this is an important point. The drug was not absorbed. Many people passed it out of their intestinal tract in the same state they took it in. It was a good drug. They got what they bouo~ht. But itdid not have the quality of absorp- tion so the patient would'get the result desired by the physician. About a year and a half ago I had an opportunity to speak in Toronto before a drug trade meeting. On that occasion I raised this question: I said: It is the first time I have been in Canada and I read this a year or two ago. I would like to know more about what really happened. The president of the association said: Gee whiz, I wish you hadn't asked me. I was the main supplier for the drug. He went on to say that when they purchased it, it was purchased by virtue of its price from a supplier, and the chemical ingredient was exactly what it was supposed to be. It did not have the other built-in changes which would come from a quality product of those who had made longer examinations as to its ability to be absorbed and properly utilized. I think this is why a number of physicians feel in prescribing many drugs that they will prescribe it with the brand name with reference to a particular manufacturer. I know this is true of many of my physician colleagues who treat diabetes. They will not just depend on one, but they will prescribe tolbutamide and then put two-either one or the other of two producers. What they want is to be certain that the pharmacist can supply it. from whichever source is the cheaper of three or four sources. The main thing the physician wants is that whatever the source that produces it generically, it comes from a source that also can assure a product that has the other necessary qualities which will make it absorbable and usable by the patient. Senator NELSON. We had testimony on that exact case, and the record will speak for itself. I am simply going by memory. This case was discussed on pages 1340 and 1341 of part 4 of our hearings- Dr. ANNI5. There were a number involved. Senator NELSON (continuing). That is not valid to prove the par- ticular point, because, as I recall it, it did not meet Canadian stand- ards. Whether they use TJ.S.P. I am not sure. Dr. ANNIS. It was generically equivalent. I would not say whether PAGENO="0366" 4656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY it met any other standards, because I do not know where it was purchased. Senator NELSON. We have a constant instance involving generic and brand names where somebody will testify that it proves that the generic is not as good, because here is a case in which it did not do such and such. Every single case we checked is the case of a drug that did not meet U.S.P. standards. Of course, when that happens, that is front page in all the medical press and the pharmaceutteal manufac- turers naturally say, "Here is another case that you cannot trust it." We have cases in the files from the last hearing in which exactly the same thing happened to the brand names, so you might as well say you cannot trust brand names. In the cases I mentioned of the 4,600 drugs tested, with 8.8 percent of the brand name not being able to meet potency standards, that proves the case that you had bettter stick with generics, because generics meet it more often. Dr. ANNIS. My point was just the opposite-that the mere generic equivalence in itself is not sufficient. If we were talking about build- ing in additional safeguards, as I indicated earlier, many generic drugs prescribed come from satisfactory suppliers. We are not opposed to these. All we want is to be sure that when a physician prescribes a drug, he gets the drug that he prescribes and one that has the other qualities over and above its chemical constituency that are essential to its proper and expected action. Senator NELsoN. The point is made very frequently by lISP, manu- facturers and so on, that if the drug meets NF or lISP standards, they are equivalent. Then the other side argues that they are not and they use chloramphenicol as one of their cases, in which there is no proof that there was any theraputic difference between the Chioromy- cetin and the other two in the marketplace. They just reached differ- ent blood levels in a different period of time, but the, FDA decided that they would make them uniform. They could have made them uniform to the other drug as far as any clinical knowledge of the therapeutic efficacy of either one of them is concerned. But the problem is that every time you find a generic t.hat fails a test-and the brand names appear to fail them just as often-that is publicity to all the doctors, who then say, "Well, you cannot trust the generic." Now, the thing that we have to resolve, it seems to me, is how do we get adequate testing to assure the medical profession, whether it is brand or generic, that it does meet the DSP or NF standards. It seems to me there are two things: One of them is to give enough personnel to FDA so that they can make adequate quality control in- spections. You will not get this unless distinguished groups such as the AMA appear before Congress and say this is critical to America. Not just say this in the journal but appear before the Appropriations Committee and say that it is going to be critical to the health and pocketbook of the consumer, and, therefore, we think you ought to give FDA more inspectors. Would the AMA appear before the Appropriations Committee when the issue arises in support of inspection? Dr. ANNIs. Senator, we would be happy to appear before the Ap- propriations Committee or anybody else to assure increasing quality standards for all these products made for the benefit of the American people. PAGENO="0367" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4657 The Senator may be aware of the fact that the AMA is one of the three financial supporters of the Drug Standards Laboratory here in Washington, D.C. We pay one-third of the budget to supply speci- fic research and standardization of these drugs. Few people realize that. But this is just one other area, that indicates our long desire for quality drugs. We will be very happy to testify. We have long felt that the Food and Drug Administration-and the record will show it came into being many years ago with a strong continued support of the American Medical Association-we have no battle with these men who are trying to assure quality products. The only time that we come into conflict with anyone is when they say that by virtue of a chemical similarity the drugs are the same. These other standards are absolutely essential. We would support such a stand for more dollars to enable the FDA to do an ever-better job. Senator NELSON. Are you saying that you disagree with the testi- mony of a representative of the USP and the NF that if a drug meets TJSP standards, it is therapeutically equivalent? Dr. ANNIS. No; I did not say that, Senator. Senator NELSON. Oh, I see. Dr. ANN'S. I did not read their testimony, and if this is indeed their testimony, I would suspect that it would deserve serious con- sideration. I have not seen it. My point is that the general continuing argument has been against brand as opposed to generic, with the assumption that if a drug is generically the same, it therefore has therapeutic equivalence. If the valuations referred to by USP and: NF include these other standards, the absorbability in certain areas Of the intestinal tract within a cer- tain period of time, so that when I give a drug I know it is going to be absorbed within the person's body, I have no quarrel. But this is shown by clinical testing. This will not show up sometimes in the laboratory. What is true in a guinea pig, or a dog, a cat, or rabbit is not necessarily true in a human. So in many cases the laboratory alone, the chemist, the pharma- cologist cannot give the whole answer. So our position is that we must look at the drug in its whole spectrum-from the standpoint of how it is compounded, its basic purity and the rest, including its reaction within the body-so that we can assure a physician when he prescribes the drug generically~ nothing will be supplied his patient that falls short of these desirable physiological reactions and he will know the end result, then I am sure we would be on common ground. Senator NELSON. But the position of the DSP is, and it has been the position of a number of witnesses, including distinguished pharma- cologists and clinicians, that if a drug meets DSP standards, then it is therapeutically equivalent to any other drug that meets that stand- ard and that in the whole history of this debate there have been-there has been I think one proven case where that was not the situation. That would be a case when all the distinguished people who set the standard happen to have missed the point-the clinicians, the chem- ists, and so forth-in evaluating the drug have established the stand- ard and missed some point. But in the whole history of drug testing, there has been a proof of one or maybe two cases. Therefore, if we are going to use any standard at all, it would seem to me the DSP standard is the one that we should use. If clinical evidence is developed PAGENO="0368" 4658 COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY that the two drugs with the sam~ compound did not have the same clinical result and they discovered that some different excipient was used in one and that caused it and lISP had missed that point, that would be an exception to the rule. But when we have never been able to find more than one or two such cases in history. It would seem to me that this is the standard to rely on. Dr. ANNIS. Senator, here is an area I would like to ask Dr. Hayes about. He is much more knowledgeable in this area. Do they set up TJSP standards after the extensive basis of clinical testing? Dr. }IA1~s. Of course, this is a problem which has engendered a great deal of discussion amongst interested parties. In fact, several learned bodies have spent considerable time studying it. Two come to mind, the Academy of Pharmaceutical Sciences and the Drug Research Board of the Nationai Research Council. They have recently, as a result of their study of the problem, called for some improvement of the standards for assuring physiological availability or biological equivalence, as it were, of all drugs reaching the market. I believe that both the lISP and NF at the present time are reevaluating their testing procedures in order to develop tests which will more properly evaluate the biological equivalence of all drugs reaching the market. So I do not think it is possible to say that the existing standards- although I know the people in the NF and the lISP, that they are sin- cere, dedicated scientists, and the fact that they question their own testing procedures and look to improve them-that the matter can be settled as to whether, under existing standards of the lISP and the NF, that they, in themselves, will assure biological equivalence. I think that more work has to be done. I think that work is being done. Dr. ANNIS. Senator, may I add, too, that in this connection-I thought this was true, but I was not certain enough to testify. Recently the Drug Standards Laboratory had to come back to us; they needed more money. They are suffering from something known as inflation, too. The American Medical Association feels so strongly about this kind of testing that you are referring to that, without hesitation, when the Council recommended to the Board that additional appropriations be made, we did so. This is an area where we are concerned. But we are even more con- cerned that it goes beyond what can be done in that chemical or phar- maceutical laboratory, because ultimately the laboratory of a drug for a person who is ill is in that patient's body. This is why that biological testing that Dr. Hayes refers to and other groups apparently feel must be upgraded, too, is so important. Here again is an area where we would want to be assured before testifying along that line. Senator NELSON. I just want to say on this point that Dr. Miller of the lISP and a representative of the NF have not testified that their standards were perfect. They have testified that they are the best standards existent in the world today and that they can be improved, and, of course, they will be. But the question arises, after accepting the lISP standard or NF standard in some clinical .testing we find out a year later that the standard omitted something, then they would cor- rect it. But as of the date that standard is there, it is the best standard there is. Therefore, if a generic drug meets that standard and a brand name meets that standard, on what basis does an individual practitioner say or the PMA, in particular, say that one is better than another? Dr. ANNIS. I would agree if standards are all the same they could PAGENO="0369" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4659 not say "Ours is better." As the Senator is well aware, about a year and `a half ago I had requested, through Senator Smathers the oppor- tunity to come to these hearings and speak as a private physician. At that time I did not realize that I was going to be elected to the Board of Trustees and have an opportunity to serve the American Medical Association. When I went into the practice of medicine, we did not have all these drugs. When I talk to medical students `today, I remind them that 90 percent of the drugs they learn about were not in existence when I went into medical school. I have two sons in medical school, and what they study, what they learn, was not known when I was there. I grew up knowing `that I lost a young brother who died of an infectious disease because what he had could not be controlled. I lost a father at the age of 22 from a ruptured appendix. So I know as a clinician what these drugs mean. I `have seen what they mean. I have seen people and children die of diseases that now we prevent and control. I am one of those who has grown up with great respect for `the pharmaceutical indus~ry. Over this same period of time, with the constant addition of all these new drugs, naturally others have come in with the idea of pro- ducirig. But, though I prescribe generically on occasion and I prescribe generically with the name of two or three producers following, I lean heavily on the reputable, responsible, long-term members of a great industry because I believe that, in most instances, I can depend upon their reliability. There is a second reason. There are only, out of some 1,700 or 1,800 drug manufacturers-~only about 130 or 140 do any significant `amount of research. It is from this group that have come some 95 or 97 percent of all these `drugs that I have seen produced in my 30 years as a physician. So, naturally, I feel obligated as a physician-as an indi- vidual practitioner, for what it has done for me and the tools that they have given-to support that segment of the pharmaceutical industry that is more than just a business, that segment which also does the research and has come up with one tool after another-first to control infection and diseases and then put into the hands of doctors in the field of anesthesiology, upon whom surgeons are dependent, some of the tools that have made possible modern surgery as we know it. So when I prescribe a drug-I do not care what it is-I generally will support that segment of this great industry that continues research, that continues to seek out other and better ways to solve the problems that we have not solved. In my personal experience, it goes beyond just generic or trade mark drugs. It also goes to support that segment of the industry- I do not know what percentage it is, but I would guess 10 percent or less of the total industry-who are doing this great amount of research which I think is a boon to America and to medicine. Senator NELSON. I have some more on this, but Senator Dole has a question. Senator DOLE. First, I apologize for being late. I have been at an- other committee hearing. I am a new member of this committee and I have not had the benefit of the extended hearings held in the past 2 years. I do not want to spend a lot of time covering old ground, but I have a question or two. I am a great believer in drugs. I do not know whether they are 81-280 0-69-pt. 1i-24 PAGENO="0370" 4660 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY generic or brand name. Several years ago I was the recipient of streptomycin when it was in the guinea-pig stage, as a part of World War II, and also lived on streptomycin and Dicumarol for quite a while and became a great believer in drugs and the wonders they perform. I had a letter last week asking me whether I was a generic or brand- name Senator, and I have not decided, yet, which; so I huve not an- swered the letter. But it poses a problem with us, of course. There is a feeling, as you know, Dr. Annis, from your present and past ca- pacity, among some members of the public that there is a sort of con- spiracy or unholy alliance between the AMA and the pharmaceutical industry. This is a matter of concern to all of us. I do not know if you can answer that generally, but I would appreciate your comment. I know it is ground that has been gone over time and time again, but not in my presence. So if yoti could just comment on that, then I have two or three questions I would like to ask. Dr. ANNIS. I know of no conspiracy. If you will look at the de- liberations of our council on drugs, and their evaluation of drugs, and how they have spoken out against drugs that have had bad side ef- fects, the abuse of drugs, the overuse of dangerous drugs, constantly reminding physicians, you would see no such conspiracy exists. I have been raised in the school of therapeutic nihilism. I do not be- lieve in drugs. The next moment, I say they are tremendous. I lean on them. My point ~s that I refuse, and over the years have refused, to let my patients tell me when they should get a pill or a shot or something else. All drugs have a potential for harm. All drugs are dangerous. The medical profession as a whole has spoken out repeatedly on this. Drugs, whether they are aspirin or any of the other more potent drugs of today, all have a real potential for harm. Aspirin has been a great boon. It is a great drug. But it still kills children every year. Penicillin has changed the whole complexion of medical practice, since my early years of practice. Yet penicillin kills people every year. There is no such thing as a truly safe drug. They all have potential danger. I think this is the message that the medical profession has continued to spread. We have no alliance with the industry. If you think so, I would welcome you to come to some of the meet- ings of our house of delegates to hear physicians discuss these con- tributions to medicine, absolutely milestones in our progress, and yet, like so many great things, that also carries a.long with it built-in hazards that are very serious. Had we such an alliance with the pharmaceutical industry, I am sure we would not have carried the thousands and thousands of pages of critical and analytical discussion on drugs that should be elimi- nated, drugs that are dangerous, drugs with a serious potential, and we would not have constantly advised physicians to carefully evaluate the therapeutic use and the necessity for their use before prescribing any drug. Senator DoLE. Does a generic prescription automatically assure thwt the patient is going to save money? Dr. ANNIS. No; there is no automatic assurance that that is the case. A generic prescription leaves to the pharmacist the decision as PAGENO="0371" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4661 to what drug he will prescribe. Assuming it is a neighborhood pharma- cist with some good generic drugs from a good supplier, as opposed to a brand name, and he supplies it on a generic basis, knowing of the background-here, in this instance, a patient could conceivably save dollars. If, on the other hand, a physician prescribed a certain drug without mentioning the name of the supplier, another kind of pharmacist, not of the neighborly, friendly variety, could supply him with the highest priced drug from a generic source. So it is not essentially so. It could be. Senator Doiai. How much influence, in your opinion, does drug advertising have on a physician's decision to prescribe any particular drug? Do you have time to read the Journal of the American Medical Association-do you have time to read this monthly publication or just how much does advertising, whether it is written or verbal, influence your decision? Dr. ANNIS. The journal I have an opportunity to review every week, the Archives of Surgery every month, and many other publications. I have made it a practice for over a year to ask physicians, wherever I have gone, to what extent does advertising or the detail man deter- mine their choice of a drug? You know what? I have yet to find one physician-and I have asked hundreds in medical schools, medical cen- ters, in small cities and large cities-who makes his judgment on them. What they do is remind physicians of many drugs in the field. I run into this frequently, where I will, having read in an ad about a new drug for a certain condition, or a drug that is supposed to be of value in, say, the field of orthopedics or medicine or in areas that I do not know anything about, I will ask doctors, what about this; I read about it in the last few days. Twice in the last week, I have phoned medical centers to find out, to be: brought up to date on the medical use of Dopra, dihydroxyphenyl, something or other. I can't remember the long term hooked up with it. But it is being used now, experimen- tally, under limited circumstances in the research of Parkinson's disease. Now, as a surgeon, I have read about it. I knew that it was taken off the market for a while :because of its dangerous side effects, but allowed back in for experimental use because it had been proven that despite its danger and toxicity, it also has a great potential for good in conditions where we do not have much in the way of treatment. Now, what I read in the journals merely reminded me that there are drugs that are treating this. So when I had a personal request from a friend of mine because his mother is afflicted with this disease, I got on the telephone and called four of my good friends in different parts of the country in the field of neurology and neurosurgery and spoke to a man in one of our large research centers that is working on it. So the advertising in the journal often will remind me of advances in other fields. But as far as having an ad ever determine for me to initiate and to use a drug without further checking it with-I often will write to, as many physicians do, the AMA. Our mail runs at the moment some- thing like 15,000 or 18,000 letters a day. We get requests for informa- tion all the time. I also would check it with medical men in my area who know men who deal with these things all of the time, as well as the pharmacist PAGENO="0372" 4662 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and the pharmacologist. I know of no physicians with clinical experi- ence and no physicians educated in the Nation's medical schools today who would prescribe a drug on the basis of what they read in an ad. Their attention might be called to it so that they look into it. But, gee whiz, you never think of prescribing it on that basis. We have a number of copies of the journal if for any reason you would like to review some of them or some of their various ads. This is a part of advertising. It is like Coca Cola. We have known about it for years, yet wherever we go in the world, you see a sign, Coca Cola. It is a sign that reminds you something is around if you need the pause that refreshes. Even a 5-year-old will tell you that. It is the way America has commercialized its products around the world. But it would be dangerous if we bought drugs like we buy Coca Cola. They just remind you that they are there. I do not know of any physician, and I have asked hundreds, who will prescribe a drug on the basis of what they have seen in ads of any kind. I have yet to know one. Mr. GORDON. Dr. Annis, may I interrupt here? According to the study which was done for the American Medical Association in the town of Fond du Lac, Wis.-are you acquainted with that particular study? Dr. Ai~is. I am acquainted with the city but not with the study. I went to school with some men from Fond du Lac. Mr. GORDON. That study showed that around 50 percent~-that may not be the exact figure, but it is around 50 percent-of the doctors pre- scribed on the basis of advertising and detail men; as a matter of fact, it is mostly the detail men. With respect to certain indMdual items, like Achromycin, a trade name drug, and others, it went as high as 80 percent. Dr. ANNIS. This is a different matter. Had you asked me to what extent the detail men or advertising has called my attention to drugs, that is a different matter. My first years, in my first 8 years in practice of medicine, I was in general practice in the capital city of Florida, Tallahassee. Those were days when transportation was not very good. We didn't have airplanes in and out. I think after a couple of years, Eastern went once a day north and south and National once a day east and west. Transportation was not good. We had no television in those days; radio certainly was not a medium for education. Only the pub- lications of the American Medical Association, the medical journals, and the detail men kept me informed. This was during the time that sulfanilamide, sulfamerazine, sulfa- suxidine, sulfathiazine, right on down the line of the sulfas, that gave us control over gonorrhea, a previously uncontrollable disease, were developed. The sulfas gave us control of pneumonia and kept lives going. But they had side effects. People would be getting sick. They would be nauseated. Half of them would go down. Now, the important point is the detail man or the ad would call my attention to the fact that he have a new derivative that eliminated the side effects, the nausea and vomiting. Very often it would be the detail man who would call it to my attention. You would not start off on a drug or prescribe on that basis initially. These people, however, kept us informed-in those days of a different kind of communications than we have today-as to what is new and reasons to look into these drugs and what they were doing. So their role was there as an initiator, as PAGENO="0373" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4663 a stimulus to look, but certainly they were not the deciding factors as to whether or not we prescribe the drug.1 Senator NELSON. I did not mean to or intend to open up this whole question at this moment involving the drug chloramphenicol, upon which I have some questions to ask later. But I might pose this ques- tion: We have had Dr. Goddard appear before the committee, and to quote him, he said, "I am at wits end on how to dissuade doctors from misprescribing chloramphenicol"-in this case, Parke, Davis' chloro- mycetin. We had Dr. Dameshek, Dr. Best, Dr. Lepper, and two others, all of these whom you know, estimating that between 90 and 99 per- cent of the patients receiving this drug were receiving it for nonindi- cated cases. This was their estimate. It has not been refuted by anybody. A week or so ago, Dr. Ley appeared before the committee and estimated that still 90 percent of the cases are receiving it for nonindicated cases. The medical journal, the literature have all stated what the indi- cated cases are. If advertising and detail men are not important in determining what the doctor prescribes, how do you account for the fact that contrary to all the expertise and all the literature, including articles in the AMA, doctors continue to prescribe this drug for hang- nails, upper respiratory diseases,~ sore throats, infected toes, infected gums, a whole miscellaneous list of cases for which it is not indicated? Dr. ANNIS. Senator, I share with the distinguished array of scien- tists who have been before this committee their concern for the misuse of any drug. I am concerned about the use of a drug with great poten- tial for harm when other drugs with less potential are available and about the use of a dangerous drug for minor conditions, especially when other drugs are available. We are in accord with this. This is a long record of the American Medical Association. I am sure that the Senator is aware that we have agreed and our council on drugs is happy to serve and work with Dr. Ley, and others to increase our efforts to further educate more physicians. What I keep looking for in the records, and what I have yet to find and am hopeful of finding, i's who is prescribing these drugs, where do they fall, for example, in age groups-not just age chronologi- cally-and how long have they been practicing and where are they practicing? Many physicians in the earlier days, before we knew the side effects of this and other drugs, leaned upon it as a drug that was found to be effiective in many conditions. It has been a number of years since the AMA testified that our clinicians, as well as our researchers and ad- vertisers and teachers were finding some of the very serious side effects from the use of chloramphenicol. I suspect two things, but I canot prove ether of them. One, if we could look and see a spectrum of physicians who prescribe the drug, I think we will find that they fall, I would expect, on the basis of my experience with the profession, into two areas. One, the physician in practice a number of years, as I have been, who has gotten into my habit, I have never been a' great prescriber of new drug's. You learn six, eight, 10 or 12 well that serve your purposes and that is generally where you stay. I suspect that some of these, will be found in physi- 1 See app. XII for excerpts of affidavits submitted to FDA by doctors who prescribed Thaliomide on basis of statements by detail nien, pp. 4857-4862, 1nf~ra. PAGENO="0374" 4664 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cians as old as I am, 30 years in practice, who many years ago began to use this drug and because it did give good results. Even in the records presented to you, the fatality is one in 20,000, something of this kind. Too many. One in a hundred thousand is too many unnecessarily. That is not my point. My point is a physician could have been using it for 15 or 20 years and never himself have had a fatality. So they are not persuaded against it. I would suspect that we find a great number in this category. I doubt seriously if you will find many of the medical students of the past 10 years misusing it. I have already talked to my sons and some of those in school with them. They have all been forewarned. The second group includes physicians who work in areas far removed from a medical center, physicians who are often far removed from a hospital where they could run sensitivity tests, where they do not have the chemist and the pharmacologist and the pathologist, to assist them, and where they are dealing with diseases often associated with poverty, with lack of nutrition and other factors. On high temperature diseases, sometimes of a gastrointestinal nature, where they are not quite sure what is the maatter with the youngster or with the patient, and know- ing its broad spectrum applications and that it is readily absorbed, and again on the basis of experience, they will often lean on this drug. Now, again, I am not citing this to justify it, because we share with your witnesses the very serious concern for the use of a good drug in too many instances. But I would not be at all surprised if this is where we are going to find them. Now, we have to increase our efforts to educate these physicians that even though they have not gotten in trouble themselves, or they are not aware of it, the danger is there, the record is there, the potential is there, and that `the use of this drug, like others of tremendous poten- tial, should be limited to strict areas where it is the only drug of choice or where it is preferable because of other conditions of sensitivity or otherwise on the part of the patient. I have to admit to you frankly, Senator, I have never prescribed Chloromycetin. One reason, perhaps, was that Harry Beekman at Marquette, where I went to school, was one who educated me and my colleagues to be very wary of any kind of drugs. So I cannot speak from personal experience. But I have talked to physicians around the country who use the drug. I talked to them especially this past year or so. In every instance, the physician who continues to insist on it has not been persuaded. So I agree with you. This is why the American Medical Association is anxiously awaiting a meeting that had to be postponed twice in the last couple of weeks. Dr. Ley was tied up with other problems of the Food and Drug Administration. We are most anxious to expand our effort to bring the total message to all of our physicians. We feel that the drug itself has proven in the minds and in the experience of every qualified clinician to have a very worthwhile and a very definite place in the armamentarium of drugs. but it is one that should be limited in its use to definite indications. We go along with this completely. Senator NELSON. The issue that was raised, however, is the extent to which doctors base their prescribing upon advertising, promotion, and detail men vis-a-vis the literature- Dr. ANNIS. I think the success of the advertising was 15 or 20 years ago, Senator. I do not think it has continued success today. PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4665 Senator NELSON. I do not think that is shown by the record. When it was taken off the market back in 1952 or 1953 it dropped way down in its usage. Then-Dr. Hayes can answer more accurately, but I think this is roughly correct-it was off the market. The indications for its use were drafted some 15 years ago, very limited for some dis- ease, for limited use in other cases where no other drug was effective and where this drug was effective against the particular organism causing the problem. That has been the indicated use for~ I think, 15 years and it came right back up again and continued to rise. Now, that was against all the medical literature, against all the authorities. Yet it continued to rise and be widely misprescribed. Now, once it dropped, but then people starting using it again-I do not think you can say that the advertising and promotion is not effective. Here you have a case where, since 1954 or 1955, the indicated uses were very limited, and yet it is being widely misprescribed according to the testimony we have had. The AMA Journal carries ads. It used to have lots of reminder ads which simply said, "Chloromycetin, when it counts." In fact, the JAMA ad carried a picture of a broncho- scope. Now, the Drug Council and the AMA knew very well that it is not indicated for bronchial diseases, but the AMA allowed the ad to be run. Now, I think the fact of the matter is that just from a commonsense viewpoint, contrary to all the education, contrary to all the articles in medical journals, contrary to all the expertise in this country, the drug company successfully promoted it and continued to get doctors to use this. I do not know how you explain it. Dr. ANNI5. Senator, I presented to you two theoreticals from my own experience and guessing, because I do not use it. However, Wisconsin is known for its good physicians. I used to do a little fishing in Michigan, where I was born and reared. And for some time, your fine lures are off the market and you cannot use them because they are off the market. But if you hear they are on the market again, you go back to that fine lure with which you caught good bass and pike years back. What I am saying is that the man who built his confidence earlier for whatever reason may be the area where we are going to have to concentrate our education. I do nbt believe it is being prescribed in these ways to which you referred. I doubt if this is prescribed by today's young generation of educated physicians. I doubt if the advertising is educating new physicians to its use. I would have to give a point and indicate and admit to you that if I were a doctor who was persuaded some years ago that it was a good drug, and then it was taken away by what I might call an arbitrary decision of somebody and it : upset me, the advertising might remind me that it is back again. The advertising accepted by the AMA-and I have to absolve the Council of the bronchoscopic ad because the Council itself would not have seen this ad prior; to its being published-I think it was a reflection back to the older days when it was used on children. I have heard pediatricians who used it extensively- Senator NELSON. I do not think it was ever indicated for any bronchial infection. PAGENO="0376" 4666 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. ANNIS. One of the cases has been hemophilus influenza and there are still physicians today who still feel it is the drug of choice in hemophilus influenza or pneumonia. Senator NELSON. That is contrary to the National Academy of Sciences-National Research Council, who said it is no longer "the" drug of choice for any reason. Dr. }ik~rEs. As far as respiratory infections are concerned, there are some who believe that treatment in specific instances of cystic fibrosis, involving the lungs, that chloramphenicol is effective in reduc- ing the possibility or potentiality for serious respiratory infection. I certainly would agree that in a.ny pneumonitis bacterially caused, there may well be other as effective antibacterial agents as chlorain- phenicol. It would be unlikely that you would prescribe chlorampheni- col unless it became a life-threatening situation and for one reason or another other antibacterial agents could not be used, such as sensitivity of the bacteria, itself or possibly in the matter of some reaction of the patient to other drugs that might be used. It would be a rare instance where it might be used. Senator NELSON. Has it ever been indicated in general for upper respiratory diseases, bronchitis, or any other thing like that? Dr. HAYES. Not that I know of as a general indication. However, you must take into account that irrespective of the hazards of chlora.m- phenicol, and they are very real and I think that every physician is aware of them-I do not condone the misuse of the drug in the face of these hazards at all-it is a very effective broad spectrum anti- biotic. In fact, at the institution where I do some volunteer teaching, they `occasionally post a summary of the sensitivities as determined by their routine testing of `bacterial sensitivities to a number of orga- nisms. It is surprising that chloramphenicol in the vast majority of the organisms that they encounter will turn out to be most effective antibacterial agents in and under those tests. I do not say on the basis of those that you would use the drug, but I merely say that to emphasize that it is an effective antibacterial agent and in the face of a life- threatening situation, a physician might elect to use chloramphenicol if he was not certain of the offending organism or organisms. And that is the situation that he might encounter if he is remote from a medical center where all of the sophisticated facilities might be avail- able to him. Again, I would not condone the use of chioramphenicol or possibly any other antibacterial agent for a `hangnail or some incidental infec- t~on. Senator NELSON. I am sure you know better than I do that the indi- cations have been stated as very, very, very limited. As I stated before, according to the National Academy of Sciences, it is not the drug choice for any disease. Dr. ANNIS. I understand that has `been very recent. I do not know how recent, `but I heard it the first time 2 or 3 days ago. Senator NELSON. It was last October. But for 15 years, correct me if I am wrong, it was indicated for ricketsia.l diseases, it was indicated when the disease was serious-it always had to be serious-when no other drug `was effective against the organism and when c.hloramphen- icol was effective `against it. PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4667 So now on the question of advertising and promotion, if I under- stand the experts correctly here, it has never been generally usu'able as a broad-spectrum antibiotic, at least since the first side effects were found in 1952 or 1953. it is not indicated for general upper respiratory diseases, as I understand it. On the question of which is the most effective, the articles of the journals as to its indicated use or drug advertising promotion and detail men, it seems to me that the ad in the AMA Journal with the bronchoscope picture is not saying: "We are ruiming this broncho- scope to indicate that you might use Chioromycetin if there is cystic fibrosis." What they are doing with the bronchoscope is saying, gentle- men, if there is `anyhing in that area, use Chioromycetin when it counts. So obviously, that is an improper ad, making a claim on its face that I do not think any scientist who has testified here would defend. It obviously must have had effect, because it is vastly and widely prescribed for upper respiratory problems. We have had letters of deaths in the files that it was used for that purpose. So on the question of which is effective, just again using horse sense, I would say vis-a-vis the articles by Dr. Dameshek and others in the journal cautioning against it and vis-a-vis the effectiveness of the ad, I think the ad and the detail man run away with the case. So I raise the question, one, I think it is effective, and, two, why would the AMA run an ad with a bronchoscope in it when they know very well it is not indicated for that use? Dr. ANNI5. Mr. Chairman, I would not plead that we do not have human error in judgment. I suspect that in this particular instance, the evaluation of the bronchoscope and the rest, from the standpoint of its implied suggestion that it would alleviate the need for bronchoscopics and conditions of that kind, this undoubtedly was inappropriate. I would think so as I review the record and what is there. But I still would like one of these days to have someone, if we can find out from the records, find out the age of the doctors prescribing it. Are we, in effect, getting new prescribers in the last 5 or 6 years, or, in essence, are we still getting prescriptions coming primarily from the same sources? Or as indicated by Dr. Hayes, from those in medical centers where, on sensitivity tests, it is indicated? These are some of the other perplexing areas that are involved in this drug `and its advertising and we are seriously concerned `about the effects of this or any other drugs that have `similarly serious effects. This is why I reiterate the welcome participation that we will ~- ceive from Dr. Ley in an effort to expand our efforts to inform those segments `of the profession that still use this very dangerous drug that its limitations are even greater than they used to be `by virtue of newer and more effective drugs to take care of conditions that in the past were treated by chioramphenicol. Senator NELSON. But it seems to me the facts in the case scream rather loudly. They use the advertising device very widely. They `have sophisticated advertising, a powerful group of creative minds involved. Dr. ANNIS. It was cleverly done; no question about it. Senator NELSON. And they have been able to get doctors to pre- scribe it. If I can use the expert testimony, they misprescribe it 90 to PAGENO="0378" 4668 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 95 percent of the time. Now, the best estimates are that this involves 4 million people who were receiving tha.t drug in 1967, but anywhere from 90 to 95 percent were for nonindicated cases. Does it not indicate obviously that the precautions of the profession itself and all the ex- perts have just not prevailed, and is that not an indictment on three counts-the doctors who are prescribing it, continuing to prescribe it, and the company who will continue to promote it, and the journals that accept the ads despite the fact that they know it is being widely misprescribed. Dr. ANNIS. May I remind the Senator that today, under the rule of the law, the content of the ads has to meet the many and rather strin- gent requirements of the Food and Drug Administration. But here is a drug, as you indicated, that was taken off the market and a. drug re- turned to the market. The content of what they say in their ads is re- latively controlled by the Food and Drug Ad.ministration. So what you are suggesting is that we had better take a look at some of the regulations and controls there. But again, I see no evidence-4 will not argue, I can't, one way or the other-that the ads in today's journal are increasing the numbers of new prescri'bers of this drug. Now, we do not take ads, for example, of the most dangerous drug in the United States, the drug that contributes toward more deaths than chioramphenicol and all the rest of them put together. And I cite alcohol. Now, here again, we educate all of our public a.gainst the dangers of alcoholism and driving while under the influence. Yet the records of the National Safety Council indicates that it is involved in 50 or 60 percent or more of the accidents: 52,000 Americans last year were killed in automobile accidents. A million nine hundred thousand were injured sufficiently to require doctors. Now, a drug was involved, the most dangerous drug we have. Edu- cation of the masses of the people has `been inadequate and we have to step up our efforts. Senator NELSON. It is not a prescription drug. Dr. ANNIS. In the field of medicine, we have another drug, ex- tremely dangerous, nowhere near as dangerous in its effect on the numbers of people, nor even in its lethal effect, `but one, nevetheless, that poses a very serious and continuing problem. I would again re- assure you of our desire to use every reasonable means to get the message to more physicians. Admittedly, this is an area where the message has not gotten through to everybody. What I question is an indictment on the basis of an ad or a particular drug company's ad about a certain drug when the content basically is controlled by the Food and Drug Administration. What I question is the effectiveness of this or any other ad to `be the prime reason for a physician practic- ing medicine. This is what's not in accord. They have never persuaded me to prescribe it. But perhaps I have not had the indications of others. My only point is that an ad alone is inadequate. I would like to know if the physicians who are prescribing it today are the same ones who were prescribing it 10 or 15 years ago, or with the rare exceptions Dr. Hayes has indicated by virtue of sensitivity tests. This is merely raising a question, Senator. PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4669 Senator NELSON. Well, I have no doubt about that, but the facts are there that the medical profession-the AMA is the leadmg organization- Dr. ANNIS. What would you suggest that we do, Senator? Senator NELSON. Well, I `would not run an ad, if I were in control, with a bronchoscope in it. I think it was an outright fraud. I think it was intended to be a fraud; it was intended to mislead. We received letters about people who died from it. Therefore, why should the AMA Journal be a part- Dr. ANNIS. I have indicated that human fallibility is a part of our structure, too. We `build in as many filters as we possibly can. In th1s particular ad, I would agree with you. This was a good Madison Ave- nue effort that slipped through the screen. Senator NELSON. It has been slipping through for 15 years. Dr. ANNIS. Oh, no. I do not think this ad has been slipping through. Senator NELSON. I think so. As a matter of fact, if we go back-- Mr. HARRISON. Senator, perhaps I can add just a little bit to place this in somewhat its proper perspective. Senator NELSON. I thought I had. Mr. HARRISON. I just want to add something that I think will be of interest to the committee. Looking through our records, I find that in the past 5 years, AMA journals have carried a total of about 84 pages of chloramphenicol ads. Since we publish 52 issues a year, or a total of 260 issues in 5 years, we have had a total of about 65,000 pages of paper. I would say tha.t the total advertising with respect to this drug is something like less than three-tenths of 1 percent. At least here, it is indicated that we are not speaking of an advertising campaign. We have only some 85 pages over a total of 5 years, out of a total of 260 issues, and perhaps some- where in the neighborhood of 65,000 pages. Senator NELSON. I do not really think that answers much. If it is 85 pages in 5 years, you are talking about what, 18 pages of adver- tising a year-19? Mr. HARRISON. This publication, you know, is weekly. That is 52 issues per year, with approximately 250 pages in each issue. So it is a relatively small number and I have computed it to be about 0.3 percent. Senator NELSON. But do you think the percentage is relevant? It is 19 times a year that the ad for Chloromycetin has been in the maga- zine during the whole period. Experts all over this country have been tearing their hair out about the misuse of this drug and the pro- motion, the company has won the battle against the AMA and the medical profession consistently and continuously until they were prescribing 42 or 43 million grams in 1967. It took these hearings and wide exposure to drop that in 1968 down to I think 18 million grams. As I said before, this committee is not the expert on it. Where was the medical profession? The public is entitled to say, my heavens, the AMA carried ads and promotion of it but very, very little about how bad it was. We cannot. find very much in the last 2 or 3 years. There was very little material on our hearings. We found two or three little notes, but it would seem to me it would call for a front-page editorial, just saying, Doctors, are you off your rocker? It seems to me it would PAGENO="0380" 4670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY call for the AMA to say to all its people, call meetings in your State, right now, people are dying from this, have a public meeting, get to the doctors, get it on the front page, tell them they are mispre- scribing these drugs, and that the AMA would do the same. The great., responsible medical profession, did not. And it took these hearings to expose it. Mr. HARRISON. We take strong objection to the statement on wheth~ er or not the AMA has been doing something in this regard. I think Dr. Hayes can respond with respect to what the Council on Drugs is doing. I have here some adverse drug comments taken from the Journal of AMA, very consistent and in great detail. The AMA News which is distributed free of charge to all physicians, members or not, just over a period of recent weeks, and even more so in prior months, has consistently included comments with respect to the discovery of adverse reaction on chloramphenicol, and the statements made by this committee or by others with respect to the dangers involved. The Association is very much concerned and very much aware. Now, we have also accepted advertisements with respect to the drug-that is correct-recognizing that the Food and Drug Admin- istration has not seen fit to take the drug off the market. The AMA has scrutinized these ads and, as Dr. Annis has suggested, it is pos- sible that this one particular ad did carry some background of a pic- ture which slipped by and, perhaps on reflection, should not have been included. But in the overall picture, Senator, I think it can be seen that the Association has been very much concerned, and I would ask Dr. Hayes, if he would, to add to this comment with respect to the activities of the Council on Drugs. Senator NELSON. May I respond just a moment on that? We had the Library of Congress check every single edition of JAMA and of the AMA News since this issue was raised by the committee. As I look through the material, and we have photostats here, I consider it a pitiful effort in terms of notifying the profession about what was wrong. I raise this point again: the medical profession, the AMA has the health of America in its hands. We want to have confidence in it. One can examine these and see how pitifully small these articles are. Dr. ANNIS. Senator, this is just one publication. We have county and State medical societies across the country. We have medical meet- ings where this is presented to physicians. I outlined to you we have 100 pages of medical programs to physicians where there is repeated by physician teachers. This is consistent with the medical profession. You have a drug which our own Food and Drug Administration of this country took off the market and they put it back on the market and allowed it again to be sold. If this is the case- Senator NELSON. For limited application. Dr. ANNIS. If this is the case, they have given tacit approval to the drug. We have always, in accepting advertising, repeatedly told the profession, this is a drug with ever-increasing evidence of its danger- ous side effects and that it. should be used on a limited scale. If further information is demanded by virtue of the facts, these then should come from the Food and Drug Administration. Senator NELSON. Of course, it is interesting to note that the FDA is attacked time after time by various members of the medical profession- PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4671 Dr. ANNIS. Everybody is attacked. We are attacked, too, Senator, Senator NELSON (continuing). For regulating too much. But 1 think, Doctor, in all fairness-we will look through these ads-the fact is that whatever the AMA did, it did not work. That is a fact. Now, what this committee did- Dr. ANNIS. The facts are, Senator, that Moses brought 10 little messages down from Mount Sinai and that message has not gotten through yet. The fact that the message gets out does not mean that it is received on the other end. It takes two people to absorb a message, those that send it out-and we have put effort after effort to get it. out-and those who are to receive it. I have admitted to you that. there is a segment of the profession that has not gotten the message and does not understand it. This does not mean that we have failed to send it out. It has failed to fall on receptive ears. We are willing to meet with you, or with the Food and Drug Administrator, or anybody else in an effort to increase the recep:tivity of these ears that it has not fallen upon. But do not accuse us of not. trying. You can say what we have done has not been enough. We will do more. But this is in keeping with what we have been doing. Senator NELSON. I look at the ads and we can examine them later. There is not much in them. Dr. ANNI5. May we have Dr. Hayes give you at least a summary of what we know we have done? Senator NELSON. Of course. The point I want to make is whatever you have done it is not effective, and then I suppose if you have done all that you think it is feasible to do, you ought to concede that a con- gressional subcommittee, with no experts on it, has been 100 times more effective in telling the doctOrs the story than the AMA, because we got it reduced in 1 year from 43 million grams to 18 million. Dr. ANNIS. This is great. We: are happy about it. But may I give you an example of what was even more effective than your drug hear- ings? That is the conquest of polio. But why? Here is an area of a serious disease. Senator NELSON. What's the analogy? Dr. ANNIS. The analogy is the mechanisms, the communications media, the overwhelming use of press, radio, television, civic clubs, everyone, to tell the story. We had everyone telling the story on this. And it. was tremendous what we were able to do, not just because we had a drug that could solve the problem, but that the great pharmaceutical industry could manufacture it by the millions of doses. Then the story was told to everybody, come, not just with your doctor and your nurse, but with grandma, grandpa, mother and dad and everybody. Here is an example of an overwhelming approach with every communications media available. And it got to the American people. In some instances where the education was poor, buses were sent out into the areas and the kids were given lollypops and balloons and physicians joined with vohinteers all over the country in a massive effort to tell the story. Now, these are the two extremes, one that is undoubtedly tremen- dously effective, and it. was quickly so, and an effort through us to use every kind of medical communication, from publications, meetings at hospitals, medical centers, county and State societies. And we still PAGENO="0382" 4672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY have not gotten the message through to some members of the profes- sion. I still do not know whether it is the same ones that were using it because they were happy with it 10 or 15 years ago. My point is we have to step up the means of communication. My analogy with the polio effort is merely what can happen when every medium of communication is concentrated and where what they are selling has merit, where the problem we are facing is a serious one, and where those who are the potential victims a*s well as those who are their protectors share a common interest. And this, I am satisfied, is what you are seeking. TI1at is better medi- cal care, better drugs, safer drugs. And in the instance of a drug that may have to be kept available for its very limited use, what you want to do is to see to it that all physicians get this message, that they are motivated by it, having received it, and that in the future, they pre- scribe this drug only when it is needed. We are in total accord. Now, the question is what's the best way to do it? But do not say what we have done wrong 5, 10, 15 years ago. Many of the drugs that are in here were not available 5, 10, 15 years ago. We are not carrying an ad today that has not carried the tacit approval of the Food and Senator NELSON. I might say that in the past 2 years, you have carried 10 for which a remedial "Dear Doctor" letter was written. We will look at those later-the FDA forced the company which misrepresented the drug in your publication, as well as in others, to write a letter to every doctor in the country. Dr. ANNIS. But you just admitted, Senator, that there is a contract by regulation between the FDA and the company. You admitted, to, that the ad that was carried was a violation of that contract on the part of the company. And if we carried it, and I willingly admitted that we have human error occasionally on matters of this kind, too, where things get through occasionally that we would not want to have gotten through had we had all of the facts-but I think you will have to admit that if there is an understanding between the Food and Drug Administration and any producer, this, in effect, esta;blishes through that company and their advertising agency the basic princi- ples that they should not violate. Senator Nr~soN. The question was raised, and as you will recall, it was raised around the question of whether advertising or promotion is effective. Something is effective. Dr. ANNIS. I do not think anybody in America can deny the im- portant role of advertising in any area. Senator NEr~soN. My committee counsel advises me-this does not have a date on it; we will recheck it to see if it is correct-but this is a 1968 ad. Dr. ANNI5. I would not be surprised, and I have already indicated- Senator NELSON. This was carried in 1968. My point again is what you said in your articles did not work. It seemed to me that there should have been a meeting, a public meeting in every State in the Union saying that this company's drug is being misused. Dr. ANNIS. Senator, I just asked Dr. Hayes how long we have car- ried the contraindications on chloramphenicol, and he said since 1952. What you and I agree on is that some doctors either do not read it or having read it, they do not comprehend it, or having comprehended PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4673 it, they do not believe it and do not accept i~. But this is not the fault of a failure on the part of the AMA to attempt `to properly inform its members. Senator NELSON. Well, `I think, DOctor, arid I think you will agree with this, that the medical profession, the AMA, has a peculiar responsibility. Dr. ANNI5. I would agree. Senator NELSON. It is not like all ad for a piece of machinery or something else which may be deceptive. It may fall apart and it may do all kinds of things. The AMA is highly regarded by the medical profession and by the public. it seems to me they have to do much more in terms of their responsibility than just saying- Dr. ANNI5. And we do- Senator NELSON (continuing). Than just saying FDA approves. Dr. ANNIS. I agree with you, and we do. Senator NELSON. Let me ask you a question: The AMA Journal is still running the ad: "W]ien it counts, Chloromycetin."? Dr. ANNIS. That is still true. When it counts, it is the drug. When it is indicated, it is the `drug. Senator NELSON. But you and I know what they mean by that. Dr. ANNIS. What do they mean, Senator? You read into it some- thing that some of our doctors `obviously do not. I agree with you, let's get the `message to those who do not.. Senator NELSON. Let me ask you a question: The medical profes- sion does have a peculiar, very important responsibility to the public. Why should they not insist that in big print, right here, it says "The National Academy of Sciences says this drug is not `the' drug of choice for any disease"? You might say, well, this drug passes the FDA. I do not think you can shift your responsibility to the FDA. If you are willing, I have some laws I would like to pass and have your support on. But it is serious enough and they are not reading fine print any more. If it is correct, as you say-and I have no information one way or another, hut I doubt it-I think there are plenty of young doctors prescribing this. Dr. ANNIS. I do not say there are not. I am asking you. I would love to know, too. I do not know any young ones that are. Senator NELSON. I do not know, either. But if it is true that lots of of them, and I think that is correct, that lots of them are people who have been prescribing it for many, many years, therefore, they do not read the new contraindications- Dr. ANNIS. It could be. Senator NELSON. They see the reminder. That helps remind them. They have been using it. It is being widely misused, `and because of the AMA's, the medical profession's peculiar responsibility, why do they not say, this just is not working and it is being overused and if you are going to run this ad in our~ Journal, I want to be sure that the doctor who reads it sees in big print, "Not indicated as the drug of choice for anything" and some other precautions, plus the editorials that are big and displayed prominently in the Journal. Dr. ANNIS. The editorials and all these approaches `there, our coun- cii on drugs and the ranking members of the elected representatives of the association share your concern. I have repeated this over and PAGENO="0384" 4674 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY over again. This is an area of real concern to us. When it comes to advertising, I have specifically raised this question with some of our people. We also have fair trade problems involved in discriminating against one company as opposed to another. If we are talking about broad spectrum antibiotics and we except three or four companies, when they comply to certain other requirements, then we are in this position, too. I do not attempt. to know whether or not this applies in this instance by virtue of the other side effects of chloromycetin, chloramphenicol, its generic name. However, this is an area where we admit there is a real problem. It is one we have tried to solve. And again, I would like to ask Dr. Hayes if he can give a summary at least of what we have done in this area. - Senator NELSON. Of course. Dr. HA~i~s. Well, the first statement on chioramphenicol that the council on drugs published was in 1951. That original statement in- dicates the peculiar and dangerous hazard of chloramphenicol. Since that time, in all of the statements of the council and its publications, the message has been very clear and consistent that there is a peculiar, dangerous hazard to the use of chloramphenicol as regards bone marrow depression, and that as time has gone on and other effective antibacterial agents have appeared for use by physicians, the indica- tions for chloramphenicol have become fewer. Those statements have clearly indicated that. In addition to those statements in the formal publications, the coun- cil has periodically published in JAMA statements firmly enunciating the proper perspective of chloramphenicol as regards its uses and its hazards. Now, I might just say in addition that in JAMA itself over the past 20 years that chloramphenicol has been available, the Journal itself has published some 285 articles on chioramphenicol, of w-hich,. as I recall, 55 were directly related to its toxicity. In the specialty journals, there were some 30 articles published-that is, the 10 specialty journals- of which 20 or more related to its toxicity. But most important, in 1953, recognizing the seriousness of the hazards of chloramphenicol as a cause of aplastic anemia, the council established a Committee on Blood Dyscrasia to look into the matter. They established a registry of blood dyscrasia which collected case reports on all drugs causing blood dyscrasia, but it was generated by the problem involving chloramphenicol. In 1963, the council expanded that r~gistry on blood dyscrasia to include the reporting of adverse reactions of all types on all drugs. And that activity continues to this day. We recognize that in spite of this consistent effort which, when added up, is quite considerable, in my opinion, we need to get our message across in a more effective way. In 1963, we approached the Joint Commission on Hospital Accredi- tation and asked the commission to include in their standards the reporting of adverse reactions to drugs. The commission at that time was not amenable to do that.. They did agree to publish in their bulletin statements encouraging hospitals, through their hospital and pharmacy therapeutics committees if they did exist, to report. adverse reactions. We have continued those conversations, and I am happy to say that it looks as though we are making a little bit of progress. The joint PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4675 commission is rewriting some of their standards and we are hopeful that they will actually get into it, into the standards, the need for drug usage surveillance programs. Now, we recognize that there is a great limitation to the effectiveness of a registry which involves voluntary reporting of adverse reaction to drugs by physicians. A physician for some reason or another, and I am not prepared nor at `any time would I be prepared to say why, is reluctant to report, but the sad fact is that they do not report read- ily. So now, `and for the past year and a half, what we have been doing is developing a plan to establish dru:g usage surveillance programs in hospitals, so that those programs would develop the data, the firm data, reliable data, so we would have some indication of the overall usage of chloramphenicol and `all other drugs used in a hospital and be able to get firm d'ata on their `adverse actions. We would know who is prescribing them-~that is, the local hospital would know who is prescribing them, for what conditions and what the effects were. Out of that, we would have, instead of estimates, we would have firm reliable data. At the same time, the governing body of the hospital, in situations where there was evidence of misuse or overusage of a drug, would be able to take some remedial action against those who'might be misusing or overusing drugs. So we recognize our deficiencies. We are trying to do something about it. I think that over the course of years, the posture of council has been one of progressive deliberation. We are not sticking our heads in the sand; we are trying to `do something about it. I think that we enjoy a considerable amount of success. Senator NELSON. I have some more questions on this, but it is 12:30. Let me ask you, Doctor, I have not covered but a fraction of the ques- tions and areas I want to cover. How much time will you have this afternoon? Dr. ANNIS. I made the whole day available to you, Senator, because I am just as anxious as you are tO present our position and our will- ingness to cooperate toward the end of better drugs and better therapy. Senator NELSON. If it is not possible to finish, can we set another date in the future to finish? Dr. ANNI5. Yes, we could in the future. It would not be in the im- mediate future, but I imagine your schedule is just `as tight as mine. Senator NELSON. Yes. I ask you that because I do not think we can get to all the material today. Dr. ANNIS. I would be very happy to come back. Senator NELSON. Thank you. Why not come back at quarter to 2? That will be 1 hour. Is that all right? Dr. ANNIS. Very good. (Whereupon, at 12:35 p.m., the committee recessed, to reconvene at 1 :45 p.m., this same day.) AP1~RNOON SESSION Senator NELSON. I had not intended this morning, or at that mo- ment, to get off on the chloramphenicol thing, but since we did it, I did have `a couple of questions to ask just to finish what we had before we left. ` 81-280-69--pt. 11-25 PAGENO="0386" 4676 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY On the continuing dialogue we had on the defectiveness of advertis- ing, did JAMA or the AMA News carry the story, and to what extent, on the National Research Council of the National Academy of Sci- ences' recommending filing with the Federal Register that chioram- phenicol was not the drug of choice for any disease? STATEMENT OP DR. EDWARD R. ANEiS ET AL-Resumed Dr. ANNIs. Do you know, Tom, whether they did or not? Dr. HA~s. No, I do not know whether they did or not. Dr. ANNIS. Was it given general currency? Senator NELSON. On October 19, 1968, the FDA published in the Federal Register the results of the National Academy of Sciences' study on chloramphenicol. Copies of the reports- Dr. ANNIS. I must admit, I did not see it in the medical or the lay press. That is the reason I did not know about it until just recently. Senator NELSON. Well, the drug coimcil of the AMA is advised forthwith of whatever goes in on drugs, is it not? Dr. HA~s. No, we ordinarily do not receive any special notification from the Food and Drug Administration of its publication. We do, of course, review its pronouncements as published in the Federal Register. Senator NELSON. I assume you review them on a regular basis, do you not? Dr. II~ri~s. Not entirely. It depends on the substance of the an- nouncement; also, in relation to what is our immediate concern a.t the time. We have taken this into account, that we are reviewing the background information on chloramphenicol for this book that was mentioned, and we are aware of the announcement and are awaiting further developments on it. Senator NELSON. Here is a drug which has been receiving lots of publicity for better than a year, and the National Research Council of the National Academy of Sciences states its indicated use which is filed in the Federal Register, and the AMA knows the publicity all this has had and all this took place 5 months ago. Dr. ANNIS. This might be a good example, of better publicity from some of these ftndings, Senator. I understood this morning, you said December. Senator NELSON. October 19, 1968. Dr. ANNIS. When was it published, do you know? Senator NELSON. It was published in the Federal Register on Octo- ber 19, 1968, according to the information I have. Dr. ANNIS. My only point is, this is another good example that we had better step up lines of communication, especially on matters that are vital. I was not aware of it. Senator NELSON. I would assume that any filing with the Federal Register by the FDA on a drug would be of great interest to the AMA. Mr. HARRISON. May we see the notice? Mr. GORDON. We do not have the notice here. Senator NELSON. We just have the date on which it was filed. Is there any question about that? Mr. GORDON. No, no question about that. Mr. HARRISON. I thought if we had a copy of the notice, we could see the purpose of the notice itself. As you know, some are just pub- PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4677 lished as official notice to the manufacturer so they can submit com- ments with respect to the action that is proposed to be taken, or what- ever would be involved. That is official: notice. I thought if we had a copy of it, we could look to see what is involved in this particular instance. Dr. ANNIS. Merely as a citizen, I am a little surprised, Senator, that after all the publicity that has redounded from your investigation on this drug, a finding of this kind, if it were a final decision, would not have gained more currency if it were: really put into the distribution channels. In other words, here is an essential finding that is very important to the Food and Drug AdministratiOn. We find when they begin to investigate mixed drugs like Panaiba, and Mysteclin and others-this we found in the medical press as well~ as other press, so someone made it immediately available. I must admit I may be derelict, but I read a great deal and it has only come to my attention in the last few days. Senator NELSON. I think it was in the public press. What I am curious about is when the National Academy of Sciences issues an evaluation of the drugs in some detail, and the FDA an- nounces it in the Federal Register, does not the American Medical Association get these fflings and look at them? Dr. ANNIS. In this particular instance, without seeing it, I would not know. Mr. hARRISON. If you are asking,,, Senator, whether we review the Federal Register as to items that are and should be of interest to medi- cine, the answer is "Yes," we review the Federal Register on a regular basis. I `am inclined to `believe that the notice you are speaking of, and I do not recall it, may have been notice to the manufacturer with respect to some finding and an opportunity for the manufacturer to provide some additional information. I do not know. Senator NELSON. No, this wss an evaluation, a new evaluation of the drug by `the National Academy of Sciences, the National Research Council, Division of Medical Studies. It is a drug efficacy study. It was a formal study done on it. They: reached their conclusion and this is an 11-a lOi/2-'page evaluation of' the drug. It is then made public by a filing in the Federal Register. Mr. HARRIsON. This is with respect to the changes agreement that may be required in labeling? Mr. GORDON. Yes. Senator NELSON. That would be part of it. Mr. hARRISON. Most likely it was intended to provide notice to the manufacturer for the purpose of, giving him an opportunity to comment. Senator NELSON. But it evaluates' the drug for all purposes. Staphy- lococcal infections-it makes a statement about that, evaluates it "p05- sibly effective." It gives documentation; ricketsial diseases, and the evaluation is "effective, but * * ~ Evaluation of typhoid fever, "ef- fective, but * * ~" and so on. The NAS-NRC review of cliloramphenicol is filed in the public rec- ord. AMA reviews it, you tell me. I would assume you would. The Federal Register is a public record, Of public notice. PAGENO="0388" 4678 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. HARRISON. Yes, we review the Federal Register, no question about it. Senator NELSON. Then my question is, since this has been an item of such importance and with so much discussion in the past year, and there is such a failure on the part of somebody to convince the doctors not to overprescribe, why did not the AMA Journal, which carries all the ads, give prominent play to the fact that the National Academy of Sciences says it is not the drug of choice for any disease? Mr. HARRISON. I would have to review exactly what is stated there- what is stated in the Register. You do not happen to have a copy of the Register at the moment? I would only say to you, Senator, that we would need to look again at the Register and see what action was taken by the AMA pursuant to it. It would be through the mill to effect the implementation. I cannot respond at the moment, first, because I do not recall the specific situation, except to say as to what it likely must have been, and second, because we do not have a copy of the Federal Register on hand. If you would like further information on that, we shall be glad to supply it to you. Senator NELSON. I would, but do you not agree that this raises a question. Here is a very important document on a very important is- sue, the leading medical organization of America is directly involved in this. It carries ads in the area, carries articles about the drug, is concerned about the misprescribing of the drug, and apparently, no prominent story is run-we could not find any. Dr. ANNI5. Senator, could you get somebody to get a copy of the Register so that we could have some people review it. It might be a good idea for us to know what we are talking about. Senator NELSON. We will see if we can get it upstairs. But I would have thought it was just routine for everybody- Mr. HARRISON. Routine would not be sufficient, Senator. If it is of that importance, it should not be handled in a routine manner. We receive the Federal Register on a regular basis. We also receive copies of the Congressional Record on a regular basis and your daily calen- dar on a regular basis. There are a thousand bills of health interest that are introduced in every Congress we review on a regular basis. I think in the last Congress there were 1,500 health bills. There are many things important to medicine, and the health of the Nation, that the AMA is interested in. On a routine basis, we take these matters and process them through the various councils and committees of the AMA directly concerned with these subjects, and again on a routine basis, give them an opportunity to comment and provide their expert opinion. This may have been in the nature of a routine matter. If so, a copy of that article or a copy of that notice would have been sent to the Council on Drugs to be considered in its usual course of business-when they next meet again. If it was more than routine, perhaps other action would have been taken. At this moment, it appears that this was a notice to manufacturers with respect to changes in labeling. Until some further comment is made and the picture develops, we would be unable to provide further information. Senator NELSON. Well, I did not mean that it is routine in the sense that it was unimportant. I meant that I would assume that it PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4679 would be routine to the American Medical Association in a matter as important as this, that it would be automatically acted upon. Dr. ANNIS. It would have been, Senator, if it had come to attention of the right people. But we are talking about something that we do not even know what was printed in the Register. Senator NELSON. I understood the witness to say that they did regu- larly review the Register. Dr. ANNIS. They do. Mr. HARRiSON. Yes. I do not know the particular item at the moment. I do not know what it was about in the Register. Senator NELSON. I beg your pardon? Mr. HARRISON. I am saying that,: as a routine matter, we do go through the Federal Register and `a number of other publications that come from Washington and the Federal Government. I would assume then that as a routine matter, we would have seen this particular item. I am not familiar with the contents of the item at this moment. Senator NELSON. I would be concerned about two things: one, if the drug evaluation efficacy study, and there is a big one going on as, of course, you are well aware in the medical profession Dr. ANNI5. Many of them all over the country. We are very proud of it. Senator NELSON. Yes, and it is being reported to the Food and Drug Administration. One, is the communication so bad between the National Academy of Sciences, the FDA, and the distinguished medi- cal societies that 5 months would go by on an important issue like this without the societies knowing it? That would be the first question. The second question is, if that is not the case, if attention were called-I mean, if the AMA reviews the Register, why was not the publicity given by AMA? That would be the second question. Dr. ANNIS. I would be able to answer that question when we know what we are talking about. Mr. GORDON. There is an official from the Food and Drug Adminis- tion present. I just asked him what was in the Federal Register. Mr. Schneider would you step forward for just a moment, please? What was in the labeling? Mr. Scimeider is with the Food and Drug Administration. Senator NELSON. Would you, identify yourself, please, and give your agency and title? STATEMENT' OF MORTON M. SCHNEIDER, CHIEF, CONGRESSIONAL SERVICES, FOOD AND' DRUG ADMINISTRATION Mr. SCHNEIDER. My name is Morton M. Schneider; I am Chief of Congressibnal Services for the ,Food and Drug Administration. Mr. GoI~oN. What was in the Federal Register? Mr. SCHNEIDER. The Federal Register announcement contained a statement to the effect that, based upon the NA'S-NRC report, the following labeling is recommended for the drug. It then set forth the complete labeling for the drug. Senator NELSON. The new labeling? Mr. SCHNEIDER. Yes, sir. Senator NELSON. Did it recite the National Academy of Sciences' efficacy study? PAGENO="0390" 4680 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY Mr. SCHNEIDER. The statement is based upon the report. It did not copy it. Mr. GoI~oN. Did you say copies were available? Mr. SCHNEIDER. Yes, that is true. Copies were available from our office, and the address where it could be obtained was given in the Fed- eral Register announcement. Senator NELSON. This was ified with the Federal Register? Mr. SCHNEIDER. Yes, sir. Senator NELSON. Did it give the reason for the revised labeling? Mr. SCHNEIDER. Yes, based upon the NAS-NRC report. Mr. HARRISON. Did that FDA publication, or the publication in the Federal Register, contain the statement that it is not the drug of choice? Mr. SCHNEIDER. In the labeling you are talking about, are you talk- ing about the disease typhoid? Mr. HARRISON. I am talking about the presentation in the Register of which you are speaking. Mr. SCHNEIDER. It gave the labeling as recommended. Mr. HARRISON. Did it contain the statement that this is not the drug of choice? Mr. SCHNEIDER. For typhoid? Mr. ILuuusON. Does the labeling state it is? Mr. SCHNEIDER. The labeling states that the `article is a drug of choice in typhoid. Mr. HARRISON. It does not state that it is the drug of choice- Mr. SCHNEIDER. It restricted its use for severe salmonellosis and typhoid. Mr. HARRISON. This appears to be substantially different from what was just stated here. Senator NELSON. What is substantially different? Mr. HARRISON. There apparently is no statement-again without having the Federal Register available-that there is a labeling re- quirement for a statement that this is not the drug of choice. Mr. SCHNEIDER. You see, the labeling was oriented not toward specific illnesses as much as it is designed or oriented toward specific organisms. You see, that is the difference. Mr. HARRISON. I understand. Dr. ANms. But am I correct that this basically is the information of the Food and Drug Administration on the basis of which regula- tions will be instituted to insist on change of labeling? Mr. SCHNEIDER. This is the labeling that is required, based upon the NAS-NRC review. Dr. ANNIS. And you give the manufacturer 30 days- Mr. SCHNEIDER. I don't know if we gave 30 days to anyone that was adversely affected by the statement in this case. Dr. ANNIS. This automatically would affect the subsequent adver- tising and labeling for us, because the company, in making up its advertising for our publication or any other publications would have to bring about the changes. Is this not correct? Mr. SCHNEIDER. That is correct. Dr. ANNIS. So it is an automatic thing as it pertains to their ad- vertising to the profession. These are their changes that they would therefore institute and would come into subsequent ads submitted to the AMA or any other source. PAGENO="0391" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4681 Senator NELSON. Let me ask another question. What kind of distribution is given to the studies made by the Na- tional Academy of Sciences? Mr. SCHNEIDER. Once it becomes public, anyone who wants it can ask for it and receive it. We do not distribute it per Se. Our press rela- tions office has it available to anyone who is interested. Senator NELSON. That was stated in the Federal Register? Mr. SCHNEIDER. Yes, sir, that is correct. Senator NELSON. Thank you. What puzzles me about it is, here is a very important matter and apparently, there has been no report in JAMA, and 5 months have gone by. Now, I feel like this, where there is an independent press that is reportincr to consumers on things all the time, the moment the Federal Trade dommission says something about the tire or about this or that, there are big stories about it in a number of magazines. STATEMENT OP DR. EDWARD R. ANNIS ET AL-Resumed Dr. ANNIS. I am surprised they did not pick up this one. Senator NELSON. They might have. What surprises me is that the medical journals did not. This brings up a question that people have raised, as you are well aware, over the years, regarding the tie-in be- tween the drug industry and the medical profession-and the large amount of advertising. Dr. ANNIS. Senator, this might be a good place to raise this ques- tion: Has anybody testified as to the percent of drug advertising that is spent with the American Medical Association and our fine profes- sional journals? I think you will find, and this is prescription adver- tising, that we get approximately 13 percent of the total budget expended in this area. Senator NELSON. Thirteen percent of whose budget? Dr. ANNIS. Thirteen percent of the moneys expended for medical drug advertising is spent in our journal. This is where we get our professional readers. Senator NELSON. You mean 13 percent of the total amount of money spent by the industry- Dr. ANNIS. Right. Senator NELSON (continuing). Is spent by the- Dr. ANNIS. No, spent by the industry in advertising drugs. The rest of itis Spent in other competitive publications. Senator NELSON. I do not have that statistic. Dr. ANNIS. My only point is that we are not alone in exposing the profession to this kind of advertising. And if, in truth, as you indicate, there has been advertising that has slipped through our screens, that in retrospect, at least, might better not have been accepted, we plead guilty of human frailty. My point is that in this particular instance we are only-13 percent is a good percentage, but it is certainly not an overwhelming percent- age of the recipients of drug advertising. So that if changes are to be made by the medical association~alone and no change is instituted in other areas, you will not accomplish the desired objective. Senator NELSON. Let me say, Doctor, that I intend to raise the question with all recipients of prescription drug advertising. PAGENO="0392" 4682 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. ANNIS. We are going to assist ~ ou in your efforts to zero in on those who unwisely use an admittedly double-edged sword as it pertains to particular drugs. We are not in disagreement on this. Senator NELSON. Actually there is a very, very brief reference in the AMA News. Dr. ANNIS. You mean we said something about it. Senator NELSON. Yes, we expose everthing here. On August 26, 1968, there is a very, very brief reference in an article on chloramphenicol with brief reference to this in which it said that, as you may recall, chioramphenicol was decertified and then, after examination and study, put back on the market, and those that did not meet the Chloromycetin blood level-time spectrum were required to meet it. This is about that. It says that the Food and Drug Administration, as expected, an- nounces that it will resume certification of chloramphenicol sodium succinate. The National Research Council reported to the FDA, according to this, that the drug is effective only for the limited applications, and it lists them. So there was that- Dr. ANNIS. When was this published? Senator NELSON. August 26. Dr. ANNIS. This is even before it appeared in the Register? Senator NELSON. Of course, there was publicity to the effect- Mr. HARRISON. Which publication is that? Senator NELSON. This is the AMA News. Mr. HARRISON. Which is a publication that goes to every physician in the country. Dr. ANNIS. Whether he is a member of the AMA or not. Senator NELSON. This demonstrates my point that it did appear. Dr. ANNIS. A few minutes ago you were being counseled that we did not have it. Senator NELSON. Correct. Dr. ANNIS. That was in August. That is when I was on vacation with my kids, up in camp in Michigan, enjoying fishing. Senator NELSON. The National Academy of Sciences/National Re- search Council reported to the FDA that the drug is effective only for the limited indications in the drug's new labeling. It does not say what it is. It does not say what the National Academy of Sciences said about it. If that is all that is in here, the point I am making, I think, is still valid, considering what is going on in the drug misuse around the country, considering all the publicity about it, and considering that the AMA News and ~JAMA take a lot of advertising from the company. It would seem to me that those magazines ought to have a big headline to emphasize the fact that the National Academy says it is not the drug of choice for anything. This is my point. Dr. ANNIS. Senator, when we discussed this particular drug with its limited use, and its side effects which-Dr. Dameshek indicated this-side effects and bad reactions are rare, but it is when they occur that they are so serious. We admit this. In this context, maybe we should have put it in the front page of the journal. But if we talk to the National Safety Council, they think we ought to put the over- use of alcohol and "Don't drive when you are drinking" on the front PAGENO="0393" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4683 page of the journal. It kills more people each year than chloramphen- icol in its whole history. I think your point is that we, in reviewing the Federal Register, have not given this information the circulation it deserves. May I ask Dr. Hayes how we handle such routine things-I do not want to say this is routine-how we handle such matters when they appear in the Federal Register, whether it is chloramphenicol or any other drug. Although I am not aware of it myself, I know that they have a regular way of handling reports of this kind. It may be helpful in clarifying the point that has been raised. Senator NELSON. I shall be glad to have him respond to that, but let me say, you raise the question of alcohol. Alcohol is not advertised in JAMA. The point is that chloramphenicol is. Dr. ANNIS. Correct. Senator NELSON. And it is a- Dr. ANNIS. I am talking about putting on the front page of JAMA the dangers inherent in a drug. Senator NELSON. This is actually what puzzled me about the whole thing. I cannot find in journals, in the medical newspapers, big head- lines emphasizing what has happened here. That is why I think Dr. Goddard had to say, "I am at wits' end on how to handle this." But it raises the question then, one, is the medical association being effective in informing the doctors; and, two, what question does that raise about heavy advertising in these journals when there is a big criticism to be made of a drug which is advertised there? That ques- tion has been raised by distinguished doctors in this country. Dr. Console raised it in his statement to the committee this week. Mr. HARRISON. Senator, the Register statement indicated that this drug had some limited uses and that some labeling changes would be required. That was the extent of it. It did not contain the other infor- mation that you speak of, except that perhaps it contained some infor- mation that other documents were available upon resquest. From that, to draw any implication with respect to influence, or undue influence by advertisers would appear to me, at the very least, to be unwarranted. Nor could the public accept such an assumption. Earlier I stated that the amount of Ohloromycetin ads-and if you are going to be influenced, there has to be a substantial amount-repre- sents something like 0.3 of I percent. That was the figure over a period of 5 years. Now, when we start looking for conflicts of interest, Senator, I think we have to recognize that they have to be of some merit or of some substance. So, first, I do not believe that the implication is warranted at all, because all the Federal Register contained was some changes in label- ing and we would examine the ads to see if they complied with our own requirements for advertising; secondly, we are talking about an ad that appeared in the Journal over 5 years at such infrequent times that perhaps to infer that the public would draw an inference of con- flict, even with all other things not being known, would be totally unwarranted. Senator NELSON. I do not say there is necessarily any intention about it. I just say it is, I think, recognized as implicit in the case, that newspapers are very reluctant to run critical attacks on their biggest advertisers. Everybody knows that. PAGENO="0394" 4684 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY Dr. ANNIS. They do not have any compunctions about the medical profession, because we are not very many. Senator NELSON. Well, the medical profession does not advertise in newspapers, either. Dr. ANNIS. That is right. Senator NELSON. This is only one of a whole spectrum that we in- tend to explore, of the drug companies starting out with gifts to the students in medical school, the promotion of their drugs in various ways, and their advertising. Dr. ANNIS. What would you suggest that we substitute? We have so many different avenues, Senator, whereby physicians are educated. I just indicated that only about 13 percent of the advertising dollars spent for advertising drugs is spent with the AMA for advertising in its journal. Senator NELSON. But is that the question? The question is what percentage of that advertising comes in as a percentage of the total AMA income. That is a better question; 13 percent or 1 percent of somebody's advertising could be my total income. Dr. ANNIS. On the contrary, your commenting on the advertising as carried in our journals as, in effect, carrying with it an implied endorsement whch affects the physicians that you are talking about, who continue to use chloramphenicol where it is not indicated. We have repeatedly indicated, and our publications show this, that we have, time and over again, in many publications attempted to reach physicians to let them know of the potential hazards of using a drug where other drugs, less toxic, equally effective, are certainly prefer- able. We admit we have not been successful in reaching all of our phy- sicians, and we will put forth every effort to continue. Mr. HARRISON. And as Dr. Annis indicated earlier, we have in the works, or we are attempting to work out at the present time, recogniz- ing the problem, Senator, to meet with the Commissioner of the Food and Drug Administration for the purpose of providing further information through our communications media. We anticipate, for example, an interview with Dr. Ley and a release in the AMA News on this subject as soon as it can be arranged. Then we will carry on beyond that. Senator NELSON. An interview on what? Mr. HARRIsoN. On the subject of chioramphenicol and its danger- ous side effects and its proper use. In other words, we recognize the problem. There are more things that can be done and we are seeking means of getting that information out even more than it has been in the past. So we are not trying to say that we are not interested in providing this kind of information or we are not seriously concerned about it. We plan more things. It is just that it appears to be unfair to warrant a conclusion on the part of anybody, and in the public's mind espe- cially, that because some limited ads have appeared with respect to a drug that has been approved by the Food and Drug Administration, in our scientific journals as well as in many others, that because of the appearance of these ads, there is some kind of unholy alliance. Senator NELSON. Well, I did not use the words "unholy alliance." But- Dr. ANNIS. Senator, would you suggest that we deliberately sup- pressed this information? I hope this is not a part of the implication PAGENO="0395" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4685 of your questions. Assuming that the: FDA announcement said more than it did, are you assuming that we deliberately suppressed dissemination of this information? Senator NELSON. No; I have not said that, either. Although I will say that I think that most people would recognize that if somebody is a very good friend, you are unconsciously more considerate- Dr. ANNIS. Why have we been so inconsiderate in our publica- tions-where we have called attentipn to these side effects repeatedly in JAMA and the other publications, as pointed out by Dr. Hayes? There were several hundred occasions. Senator NELSON. Yes; I am glad to get into others, but we are just on one that has been a big story. For example, what kind of stories did JAMA run in the News; what kind of play did they give to the very dramatic statements of Dr. Dameshek, Dr. Lepper, Dr. Best, and the others who testified on this? Dr. ANNIS. As I recall, they were given pretty good currency. This is where it was first brought to the attention of many physicians. Senator NELSOI~. Could you send those to us? 1 We could not find many in the past year. We have xeroxed what we have found in the past year on chloramphenicol, and I went through it yesterday. I thought it was quite minor. We shall put it in the record and it shall speak for itself. But it certainly was not commensurate with the dramatic situation. Now, I do not know how you fairly evaluate that, but I think you can certainly say that on a dramatic, important issue in which the responsible custodian of the public welfare, in terms of health, the medical profession failed dramatiôally in this case. Dr. ANNIS. Senator, the profession deals with drama and death every single day, many times a day. If you deal with some of the more serious areas, some of your decisions, affecting life and death, occur many times in one day. In that context, all things have to fall into their proper perspective as they are presented to the public. This is the reason that I did ask if we may have Dr. Hayes indicate to you what happens, not just for this one drug, but how we handle matters that appear in the Federal Register that are of importance to the profession, and. by virtue of drug connections, important to our council on drugs. It is through these methods that basic changes, as well as continuing education, are presented to the physician. Senator NELSON. I shall be glad to hear from him. I am just raising one part of the iceberg. We shall have at a later date extensive testi- mony; we have had some from some distinguished pharmacologists and clinicians about how the~ drug industry has successfully over- promoted dru.gs so that one of our distinguished witnesses, Dr. Fred- erick Wolff, research director of the Washington Hospital Center and professor of medicine, George Washington University, said that he thought that 60 to 70 percent,~ of the drugs taken by people were not indicated; they did not need them at all. Dr. ANNIS. I have read some of those, Senator. There are other people who do not take the medicine that is prescribed, some of them made fearful of drugs by virtue of some public utterances, as reported. 1Material not received. PAGENO="0396" 4686 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The drug not taken often results in a greater tragedy than the drug that is prescribed could cause. Senator NELsoN. There are statistics available that I do not have here on the number of patients in hospitals who are there for drug reactions- Dr. ANNIs. No question about it. Senator NELSON. (continuing). From drugs that were not mdi- cated. They should not have had the drugs. This is what we are talk- ing about as just one item in the whole picture. The reason I have taken chioramphenicol is that it is a very dramatic case that has persisted for 15 years without the medical profession successfully convincing the physicians, and there must be a lot of them, because estimates are that some 4 million people received the drug in 1967. Dr. ANNIS. Its life history is very short alongside of morphine and other opiates. Neither the medical profession of the world nor the legal and law enforcement agencies of the world have been able to control them very well, either. This does not mean that they do not continue to try and continue their efforts. Senator NELSON. I do not know whether that is overprescribed or not. Dr. ANNIS. Let us say it is overused. Senator NELSON. That is not the issue we are on here. We are on the issue that has lasted for 15 years. Dr. ANNIS. Oh, yes, that is part of the issue. A lot of these drug reaction cases are drugs that are purchased over the counter. Prob- ably 40 or 50 percent of all drugs are purchased over the counter. Reactions come from these just as much as from the prescribed drugs. Senator NELSON. Some day we intend to have hearings on over-the- counter drugs. But we are at this moment on prescription drugs. What I am saying is, reviewing what we have had in testimony for over a year, this a dramatic case of the medical profession failing its responsibility over a 15-year period, and I am wondering how much longer it would have gone on if we had not had the dramatic testi- mony we had a year ago, before this committee. Then that raises the question whether the profession is derelict in its responsibilty here. I would say yes. I do not know what you would say. Dr. ANNIS. I would say that is a matter of opinion. What you are saying is that the educational efforts of the organized profession to use its regular channels of communication have been unsuccessful in dissuading some members of the profession from the use of a drug when other drugs could perhaps have been better and more safely used. This is a question of the failure of education. Again I come back to alcohol and the failure of education. Here is another drug that has many good and profitable uses as a drug. It has uses in other areas in our social structure. Yet here again, although we have all been educated that it, like most other drugs, if abused, can result in troubles, we have failed to get that total story to physicians, to lawyers, to lawmakers, the people at home that vote for them, and to our patients. This does not indicate a failure on the part of someone to try to tell the story, but rather a failure, as I in- dicated this morning, on the part of the message recipient. What is true in one area is equally true in another as long as we continue to be humans and fallible. PAGENO="0397" COMPETITIVE PROBLEMS IN THE DRUc' INDUSTRY 4687 We agree with you totally ~ts far as the dangers of the misuse of any drug, and we are doing everything we can. We have made appoint- ments with Dr~ Ley; he has had to cancel them on a couple of occa- sions because of other, more pressing business. But we will continue our efforts. And he has agreed, as quickly as possible, to meet with our council on drugs and our representatives toward this end of improving the effort of communication that you feel is so essential. We are in agreement. Senator NELSON. Let me say I respectfully suggest that alcohol is not analogous. You say the recipient has to listen. Dr. ANNIS. He has to be sold, too. Senator NELSON. But the recipient in the chloramphenicol case does not know, has no option of his own. Dr. ANNIS. The recipient of the message is the doctor ~who still overprescribes or unwisely prescribes. We are talking about getting a message to the physician who prescribes the drug. In this instance we agree with you, we have to get more messages to more physicians who unwisely prescribe it. Senator NELSON. The issue I am raising, Doctor, concerns promo- tion of drugs by the drug industry.. Dr. ANNI5. This is a part of education. Senator NELSON. I think it appears clearer and clearer to me as I read the past hearings, as I read the testimony that comes here, that in fact, we have a case in which the drug industry, by its advertising promotion directly to the doctor .~ and through the medical journals, is so persuasive and effective that it persuades doctors to use drugs for purposes that are not indicated. It seems to me this clearly demon- strates something wrong with the whole method of bringing drug information to doctors. Chloramphenicol is just one dramatic example of the total picture. I do not claim to know the answer. I would think it ought to be a matter of such concern to the profes- sion that it would reexamine the whole relationship with the drug industry and the whole relationship in terms of advertising, in terms of drug promotion, because it is pretty clear that the drug mdustry is outpacing the drug experts in the profession by a country mile day in and day out. Dr. ANNIS. Senator, I would not agree with the premise. I have seen what drugs have done to change the whole face of medicine. Senator NELSON. I am not arguing about that, Doctor. I am not objecting- Dr. ANNIS. But I would object, I would object strenuously when you give the impression that doctors are dolts; that they do not know what they are doing-that they are persuaded by some advertising and the rest, and that this is the only basis on which doctors are acquainted with the drug and upon which they made a decision for a drug. This is only one part of the overall educational process. Senator NELSON. Nobody is saying that the drug industry has not made a great contribution. All I am saying is that there are distin- guished people in the medical profession who have testified already, there will be more who will testify, who say that the influence of the drug industry on the medical profession is far greater than it ought to be. , PAGENO="0398" 4688 CO~PETITWE PROBLEMS IN THE DRUG INDUSTRY Dr. Ars. Senator, may I ask a question? Senator NELsoN. Surely. Dr. ANNIS. If this influence is so great, and I have not counted all the antibiotics that compete with chioramphenicol or even all of the broad-spectrum antibiotics, they are all advertised, too-why is this one particular product used in a relatively small, circumscribed area, even to the extent that it is used, in proportion- Senator NELSON. Chloramphenicol, you mean? Dr. ANNI5. We have 200 million people in this country, so even in the proportion that they are used, why are not all these other manu- facturers of antibiotics equally persuasive in being able to persuade physicians that their product is better? Senator NELsoN. We have had testimony to that effect here and we shall have more. I think you, as a doctor, are quite aware of the fact that there are plenty of your distinguished colleagues who will tell you that doctors frequently prescribe a broad-spectrum antibiotic for sore throat and other such ills. I have had them prescribed over the phone for my own family, for my kids. The doctor did not look to see if there was an organism involved, of any kind. There are plenty of doctors who say: Well, a sore throat, this and that, takes a broad-spectrum antibiotic. This goes on extensively and the organism has not been identified, but it is very handy, a broad- spectrum antibiotic, and ready to go. Dr. ANNIs. Yes; patients will call you up and say I want a shot of penicillin or thus and so. They read the publications that are non- medical oriented, that are not directed to physicians, but only to the consuming public, the women's magazines, the weekly magazines, the monthly magazines and all the rest, including feature articles by science writers and newspapers. This is not only because of the drug advertising by the drug manu- facturer. Senator NELSON. Many of the articles you talk about are induced by the manufacturers themselves, time after time after time. Some of them are already in the record.' The manufactures get an article written on their drug to popularize it. That is again part of the influence of the drug industry on the medical profession. I do not draw any specific, direct conclusion. Dr. ANNIs. Should we eliminate all advertising, Senator? Senator NELSON. I think there is a serious question, under all the circumstances, whether the medical journals should accept advertising. I think there is a serious question. If they do, I think there is a very serious question about the kind of advertising they accept. Dr. ANNI5. If we eliminate from medical journals advertising of drugs-there has been, for many years, a little joke among physicians that they imve to buy the Reader's Digest in order to keep up on the latest drugs. Sure enough, a patient will walk in and ask him: How about getting me a prescription for thus and so? Are you going to propose that such articles also be eliminated? Senator NELSON. No; I do not think you could eliminate them. The advertising, as I read it and look at it in the journals, time after time, 1 See article on Indocin (indomethacin) from Pageant magazine, pt. 8, pp. 3177-3181. See also app. V, "The MER-29 Case," pt. 10, pp. 4202-4296. PAGENO="0399" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4689 is cleverly slanted to promote it for a purpose for which it is not in- dicated. And it is accepted time after time. Dr. ANNIS. Then you are suggesting that the advertising copy itself should be of a different kind? Senator NELSON. I think that the journals in general-I am not just talking about JAMA-just default to the drug companies. When you consider the impact of advertising-doctors are not any different from lawyers and engineers. Publici relations, promotion, advertis- ing-clever people in promotion clearly have an impact on busy people. I think that these chloromycetin ads are disgraceful, myself. I think it has been clear for a long time that if you run one bronchoscope and "when it counts" and then a whole bunch of fine print that you know is not going to be read, but you are required to print it, it has an impact that the journals do not have. You would not accept that stuff as an article in your magazine. I think there is something wrong with what is accepted in the medical journals. I am just saying this as a layman. I have looked at a few hundred ads now, and I see that in 29 instances, better than once a month for the past 2 years, there has been a drug advertised in one of the medical journals in which the company made a claim which was absolutely not justified, and the company was forced to write let- ters to some 300,000 doctors, corrective "Dear Doctor" letters. Now, as I said, there were 10 of those in your journal. The next time we have another journal, I shall just take that as an example. But take the AMA Journal. In the 10 cases in 2 years, in which ads were carried in the JAMA which the FDA said were misleading, some of them grossly misleading, and in which they were required to send a letter to every doctor in the United States, we cannot find a single occasion where the journal said: This ad was misleading, we regret we ran it; they made claims for it that are not justified; we think that is bad advertising practice: we should not have done that. And emphasize it. After all, the doctor is looking at that ad. Dr. ANNIS. You have indicated, Senator, that the drug company has been called to task by the FDA, and rightly so, because they violated that which has been spelled out by the FDA. We admit that the advertising, especially these past couple of years, basically is that which is in accord with the inserts demanded by rules and regulations of the FDA. We admit this. We admitted this earlier this morning as well. Senator NELSON. The point I am making here is a little different. That is that in 10 cases where they made illegal claims, improper claims, they were required to spend a lot of money to send 300,000 letters to all the doctors in America, this ad was carried in JAMA and we cannot find any case-noW, I shall stand corrected if there is- we cannot find any case where' JAMA made a big point, because the ad is big, a big point of saying: This company was guilty of misleading the doctors in its ad. Dr. ANNIS. `Senator, this morning we indicated `that the reason we stopped the seal of acceptance of the American Medical Association is because, in the minds of too many, it carried implied approval of the safety, efficacy, and reliability of the drugs accepted. One of the reasons we discontinued it was because of the absolute inability to PAGENO="0400" 4690 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY have an organization of sufficient strength-of sufficient scientists, chemists, pharmacologists, and the rest-to examine every drug to be certain as to its efficacy and safety that we could put a stamp of approval on. This was taken over by the Food and Drug Administration. Admittedly, we also agreed that if the Food and Drug Administra- tion, and we have testified to this repeatedly-has inadequate and insufficient funds to do so properly, they should say so. But we cannot be in a position to evaluate every drug that is made available. Now, when we have a department of our Government well financed, or at least it should be, to carry out a certain job, when they make out the rules a.nd the regulations for information to be provided to a physi- cian and when the essence of an ad is in accord with what has been spelled out by the FDA, we feel that as the ad pertains to safety and efficacy, which have been the main role of the FDA in recent years, we feel that they have the means, or should have; have the personnel, or should have; have the finances, or should have, to see that this job is accomplished. There is no such ability on the part of any professional organization. Senator NELSON. Yes, but Doctor, tha.t does not, I think, address itself specifically to the question I raised, which is that 10 times in the last 2 years, ads have been run in JAMA which made false claims, 29 times in all publications. Dr. ANNIS. Some part of which, as you indicated, has been not in accord with the facts; that is correct. The producer violated the regu- lations of the FDA. Senator NELSON. This is the point, though. It made important claims, and if a doctor reads it and it is the official position of the AMA that the ads are educational, so the company makes a false claim, pays for the ad, puts it in JAMA- Mr. HARRISON. Are there instances where we have continued to run these ads. after the "Dear Doctor" has been sent, or after we. have been notified that portion of the ad is unacceptable.? Senator NELSON. I shall give you another example. The point I am trying to get at-I thought I was making myself clear-is that you have a paid ad. A claim was made that was important for the drug. The AMA claims the ads are educational. Dr. ANNIS. Which claim are you talking about? Senator NELSON. The claim of the general counsel of the AMA before the Tax Committee in the House of Representatives. Dr. ANNIS. No, you aren't talking about an ad containing claims that are in error. Senator NELSON. We have a number here. I do not know whether this is the toughest one or not. But it makes my point clear that the claim was made and it is an important claim that is educational to the doctor. He reads it. The FDA says it is false and misleading and forces the company to send a "Dear Doctor" letter. My question is: Whiy does not the AMA feel obligated to run a big story right then, saying, this company misled you? Maybe that doctor would be a little bit more cautious the next time about believing the claims of these brand-name companies that he stands on so firmly. Why does the AMA not do that? PAGENO="0401" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4691 Mr~ HARRISON. Let us take the claim that is made and is subse- quently found to be inaccurate. From my own limited experience, what happens is that the FDA comes back and finds that a particular state- ment, one of many statements that is made, is inaccurate; or that a statement which should have been iiicluded was omitted. In other words, I do not believe that we are speaking about a complete fabrica- tion. FDA may find that one of the contraindications is not noted in the ad. I believe that we would find in most instances, or in all instances, that the fault found by the FDA is the failure to include a contraindi- cation that should have been included, or perhaps a misstatement of one fact which is only one of the many facts that must be included in the advertisement. It is of a limited nature in that respect, and I' wonder whether or not it would warrant the kind of communication you indicate is needed by way of advertising. But going back to my own schooldays, Senator, I recall when `we dis- cussed advertising as such, we found that the best way to communicate, the most effective way, was on a pers'on-to-person basis, and that as you went down the ladder, the next best way to communicate was by direct mail, because that went to everybody, and we assumed that everybody opened up their letters and read the communication. Down the line somewhere was the advertisement in a periodical or newspaper, which might or might not be seen by the individual. Now, apparently, here, the Food and Drug Administration has com- municated with every one of the physicians in the country by way of a "Dear Doctor" letter, or has required the company to communicate by way of a "Dear Doctor" letter. It seems to me, Senator, that a very effective mechanism has been established to provide that physician, even if he never saw the ad `originally-which is probably the case in most instances-with the information that has been required. I do not think anybody can improve upon that situation unless we got on the phone and called all 300,000 doctors in the country. Senator NELSON. I would say to that' `two things: one, I have had several doctors say they never bother to read them. No. 2, that does not relieve the AMA of its responsibility to the profession. It would seem to me that AMA could be quite dramatic and effective in two ways: one; convey to the doctor that you had a brand name company advertising in your' publication `that' lied to you, and they were required to `reform their ad or cut it out; that they were required to write a letter to every doctor in America. That would take a little gloss off of what all the doctors are saying, that you can- not trust anything but the brand-name company. Secondly, I do not know how the doctors are going to keep up with this reading two "Dear Doctor" letters a month, 29 over the past 2 years. Dr. ANNIS. The mail is measured by inches on this, Senator. Mr. HARRISON. The publications are measured by feet. Dr. ANNIS. First-class letters are in that pile. And the publications are measured, as Mr. Harrison said, by the foot. ` ` We have indicated that we are a fallible organization, as `are those who review our advertising, and if there are necessary changes by virtue of the facts, these will be instituted. Senator DOLE. How many persons; other than doctors, receive the journal? What is the total? ` , . ` . ` ` Si-280----69-pt. il-26 PAGENO="0402" 4692 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Mr. HARRISON. The circulation is in the neighborhood of 215,000, I believe. I have the exact figure here. Senator DOLE. How many of those are doctors? Dr. ANNIS. 212,000 are members. Mr. HARRISON. Except for libraries, Senator, and other recipients of that nature, almost all the direct recipients are physicians. Senator DOLE. If they have all gotten the letter, I do not know why you would need to run an ad in the journal, unless you get it twice. Mr. HARRISON. They all receive the letter. Also, the other hundred thousand or so physicians who do not receive the journal also receive the letter. Senator NELSON. I would submit that there is a moral obligation involved. If you run an ad that misleads and it is seriously misleading, as a number of these were, in the place where the ad occurred, you ought to, and are morally obligated to tell the doctor that the com- pany that advertised in here was wrong. If that is not a moral obliga- tion of the AMA, I do not think the AMA has one. My heavens, Doctor, if I ran a publication in which the health of the people- Dr. ANNIs. Senator, we are guided, as I have repeatedly told you, in the basic content by the regulations of the Food and Drug Adminis- tration. Many of these rules have emanated as a result of hearings, such as yours, in an effort to tighten up this situation. If we are going to castigate any organization because they occasionally make an error- because unless you are going to accuse them of deliberate falsification- even those who have testified before your commitee as to the severity of the com~ilications, and Dr. Dameshek is a good example, have recog- nized this. One of his earliest statements was that this drug is rare in its complications. Senator NELSON. Which? Dr. ANNIS. Chloramphenicol. He indicated that it is rare that it event has side effects and that its absorption in youngsters was and is great. So many pediatricians used it. It is the rare thing that does occur that is tragic. There is not any question about this. There is no argument about this. But the point is that even these men have not held that the drug, for example, should be abolished. It still has limited but nevertheless essential uses. For this reason, the manufacturers have a legitimate right for it to be advertised. Do not forget, as I indicated this morning, there is no question in my mind that many of the physicians who have used this drug `are among physicians, such as myself, who have learned to use and depend upon a few basic drugsin the past. If a drug that I used for 4,5,6,8 or more years was consistently successful, was consistently giving me good results, and I never had a bad effect-and that could easily be in a drug that has had a bad effect in one in 20,000, or up to one in 200,000-I would continue to use it. I can easily see if `a drug is pulled off the market, when it comes back, a physician could say, in effect, that the FDA is saying, "look, after we have looked into this, we find this is still a good drug, and once again we will allow it to be sold, and the `advertising to be done." And once again, it comes on the market, and the content of that copy is contained in the inserts, as prescribed by the Food and Drug Ad- ministration. I maintain that we have not been derelict because we have not read fine print or taken occasional exceptions. PAGENO="0403" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4693 When you get to this point, you ran into disagreements between physicians. For example, the one who may have used the drug for years and who has never had a side effect, the other who, by virtue of scientific, laboratory and other facilities available, and greater expo- sure to literature7 is well aware of them. These are basically conflicts. There is no reason on the basis of a difference of opinion to castigate anyone or told them up as though, by virtue of this, they deliberately misled the profession. They are still advertising a product that our Government's FDA admits is acceptable for manufacture, sale, and distribution. So if there are objections to certain of the facts t.hat are contained in ads, the Food and Drug Administration has full authority at the present time to bring about any necessary changes. This is neither the responsibility nor the prerogative of the medical profession. Senator DoLE. In other words, the FDA could require- Dr. ANNI5. They could require, in big red letters on the front page, if they so desire, "This is a dangerous drug except under certain cir- cumstances." Even its danger may be ignored because it is the only, or one of the only treatments available for certain conditions. Anything they could put in there. All they have to do is do it by regulation, and they have the authority right now. Senator DOLE. But instead, they: require a letter, as I understand it. Dr. ANNIS. No, they set up certain standards. Then, if the advertis- ing that we receive and the rest of the drug advertisers receive, they put it in print, assuming it meets the basic requirements of the law. The FDA, after reading it, says to the manufacturer, "look, you have exceeded what we have allowed or, you have failed to comply with the law; you must send out a `Dear Doctor' letter." And the FDA requires it to be in a special envelope. I do not care how busy you are, these envelopes doctors have come to recognize and they read them. Because whether you prescribe these drugs or not, the drug may come to your `attention and you want to know which ones are involved. Senator NELSON. I repeat, Doôtor, at the risk of `being boring, that I am talking about the case where the ad was misleading. I will find an example or two here for you. Dr. ANNIS. I am satisfied you could find these, Senator. You have indicated that. Senator NELsoN. When you carry an ad and it is educational; it is intended to convince the doctor of something. Dr. ANNIS. Senator, here are six or seven publications. You see how thick they are. If you would pick them up, you would see how heavy they are. I do not doubt that we have errors in there. But they are not errors of coimmission; they are not errors deliberately made. They are errors *inherent in human beings, and by virtue of our desire to bring up to date knowledge in an obviously changing area of communication and knowledge. What appears to :be true today experience will prove is not true 6 months from now, even in the use of other drugs. Senator NELSON. I am not saying that it is an error of commission for the Journal not to notifi~ its readers that false claims have been made in an ad in its Journal. It is an error of omission. All I am say- ing is, since doctors to a large extent do prescribe on information they get out of the ads, the Journal has the obligation immediately to cor- PAGENO="0404" 4694 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY rect that misleading ad in the same place, in the same way, something similar to the way in which the claim was made. Do you not think so? Dr. ANNIS. I would suggest that you give the Food and Drug Ad- ministration enough money to do the job for which they are author- ized and which they are qualified to do. Senator NELSON. What is your obligation in JAMA? You are a private, independent, publication in an area that has run a false and misleading ad that was paid for- Dr. ANNIS. Not deliberately. Senator NELSON. I did not say that. Dr. ANNIS. May I ask how long Dr. Goddard said it required the Food and Drug Administration to review one ad for approval? Senator NELSON. I do not recall. Dr. ANNIS. I do not, either, but it was 11, 12, 13 days or more. I am talking about reviewing each ad on this basis. Senator NELSON. No, I am not talking about that. I am talking about the case where you ran the ad, you did not know that they were making false claims. FDA discovers they were making false claims. Dr. ANNIS. Maybe they do not know it. Senator NELSON. We have seen enough of it, so we do not think there is any question of it. It happens all the time. They are leading to- ward getting wider use of the drug than the FDA thinks- Dr. ANNIS. As an attorney you are better at this than I am, but if there is evidence that they are deliberately trying to get around the law, they should be called to task on. Senator NELSON. They rim a bronchoscope in one of your ads. If that is not fact, I do not know what it is. If that does not indicate that that is to be used for general use in that area, I do not know how any other person in the world would interpret that, "When it counts," and a bronchoscope. Dr. ANNIS. No, they said, "When it counts, think of Chloromycetin." Senator NELSON. You and I are sophisticated enough to know what it means. Dr. ANNIS. I have told you I have never used it. But my point is that many physicians still feel, and have testified before your com- mittee, that there are indications for it. Senator NELSON. We know that. But it is being used 90 percent of the time, 90 to 95 percent, in nonindicated cases. Dr. ANNIS. These are guesses, and the men who testified admitted this. I do not know what the figure is. If somebody else says 20 per- cent, I would say, could be. I do not know that, either. But the essential point is to get the message. It would seem to me that this should be the main point of what you are driving at; that is, that more physicians get notice of the potential side effects of this drug so that they are critical in their appraisal of the need and justification for its use. And again, I would agree with you-we are m total agreement. I believe the records will show that since you have started this in- vestigation, many physicians have paid attention. In fact, I believe, according to Dr. Ley, there has been a decrease in the use of chloram- phenicol to a considerable degree. Senator NELSON. From about 41 or 42 million grams in 1967 to 17 or 18 million grams in 1968. PAGENO="0405" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4695 Dr. ANNIS. Then I would say we must be on some proper wave- lengths; let us increase the speed with which we use them to accom- plish an objective that both of us desire. Senator NELSON. But I think a major share of the credit comes from what the committee did with it. Dr. ANNIS. My point is we are not in disagreement with you. Senator NELSON. But I still cannot~ quite get an answer to the point that I-apparently you do not think; is important. You say the FDA can correct any of this. Dr. ANNIS. They have troubles, too. Senator NELSON. I think the FDA had some problems with the in- dustry and with the medical profession. Dr. ANNIS. They do. Senator NELSON. I think that since Dr. Goddard and I hope in the future, the FDA has done a superb job compared with what has been done in the past. I would be sure that Dr. Ley and Dr. Goddard would say that they would do a lot bettei~ and will hope to and try to. But I would have quarrels with them about what they permit in ads. Dr. ANNIS. And they have the same problems we do. Senator NELSON. But you have no problem at all, it seems to me. Dr. ANNIS. Oh, yes, we do. Senator NELSON. In this respect: the company runs an ad and it is found to be -false and misleading. I still have not got an answer to the question, why do you not feel as a custodian, a most important custodian, with a special relationship to the people as custodian of the health of the people of this country, why you do not feel a moral obligation to run a prominent story saying that the claim made in X issue on this drug was false and misleading, according to the FDA, and here is their language; this claim was made and it is not in- dicated for that. Dr. ANNI5. Probably because there are some reaJ sharp lawyers in this country that have arranged the laws in such a way that we had better be careful what we put in print, especially any indication of malicious intent. Senator NELSON. You would just report the news. Dr. ANNIS. Well, that is all right. To say that they have made an error, that is all right. A lot of people make errors. I do not know anybody who does not. Senator NELSON. I did not say malicious intent. Dr. ANNIS. But you said lied to them. Senator NELSON. False and misleading. Dr. ANNIS. That is lying to them. Senator NELSON. I think I could use the language of the FDA, but I would go further than that, Doctor. Since the responsibility of the profession to the American people is special, I think you could make an agreement, if that is what is worrying you, with any company that advertised, that you intend to run a story on any misleading advertising as found by the FDA, you intend to run it prominently. T do not think there is anybody, and if any manufacturer says, we would not advertise with you on that basis, that is about the time they ought to be kicked Out of your pages. I am saying you have a moral obligation. Dr. ANNIS. We will take it under advisement. PAGENO="0406" 4696 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I was asked whether it was intentional. I can oniy repeat what the FDA said. This is a July 8 memorandum of the FDA. Here are three ads that ran in JAMA on June 29, 1964. Dr. A~is. Senator, we do not deny that we have ads that you have indicated. In retrospect, I can think of a lot of things that have been wrong in the past. Senator NELSON. Let me just read here. You raised the question of whether there was ever any intent. I shall just read what was said. These are on Pree MT. This is just one, June 8 and June 29, 1964. This is a July 8 memorandum, 1964. To the Bureau of Regulatory Compliance, Joseph F. Sadusk, Jr., M.D., Medical Director- Through him from Robert S. McCleery, M.D., section on adver- tising and promotional labeling- 1. We believe the faults- What happened here was that they ran two ads, the first two. When they got to contraindications, they printed in the ad, "None known." Then when they got the complaint, they ran one on the 29th and they did not put contraindications in at all. They left it blank. So they had "None known," and there were contraindications, and they knew it. Then on the third ad, they did not put in the contraindications. Dr. A~is. Were they prosecuted by the FDA? Senator NELSON. Counsel advises me that the company was prose- cuted and found guilty. 1. We believe the faults of the ad and the attached mail pieces are significant and that we can help you support any action you deem advisable. We are deeply concerned that the action chosen might also have as a consequence the immediate cessation of this type of promotion which can mislead the reader into using the drug in a manner that could jeopardize the safety of his patients. 2. An interesting and disturbing event has occurred since our interest in the Pree MT ads began on June 9. (See attached copies of June 8 and June 22 issues of Modern Medicine and June 8 and June 29 issues of J.A.M.A.) Note that the heading "Contraindications" has disappeared from the June 22 and the June 29 ads. The June29 ad was in JAMA. This kind of change is very easy to accomplish technically. It could have been handled by a telephone call from the company or the agency to the printer. In a few minutes the printer could knock off the offending type, without the need to produce new plates. The only difference is that the J.A.M.A. printer was not an expert. As a consequence, he also damaged the type for the word "Dosage." a. The fact of the change is an obvious admission by the company that it had been wrong. That is leaving out the contraindications entirely. b. The cynicism of the company is disclosed by its willingness to continue the ad and merely change an error of commission to one of omission. c. Since Section 502(n) of the Act requires a true statement of contraindica- tions, they have not really removed the basis of our complaint. Further, the other errors, pointed to in our June 10 memo, still stand. d. The act of the J.A.M.A., re: the June 29 issue, raises an important point. Its Council on Advertising could be perhaps excused, on the basis of ignorance, in accepting the June 8 ad copy. However, their agreement to delete the line, "Contraindications: None Known," makes it appear that the Council became a knowledgeable participant in an act of omission contrary to law. This is FDA speaking. Now, I suppose somebody in JAMA might have an argument to respond to that. But again, they run an ad that is important. They run one in June- PAGENO="0407" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4697 Dr. ANNIS. Whose letter was that, Senator? Senator NELSON. It was a memorandum from Robert S. MeCleery, M.D., section on advertising and promotion, to Joseph F. Sadusk, Jr., M.D., Medical Director/BM. Mr. HARRISON. Dr. Sadusk, I now believe is with Parke, Davis & Co. Senator NELSON. Yes, he is. Mr. HARRISON. I have some statements here with respect to the promotion, or lack of overpromotion, of Chloromycetin. The point I make is he has made some references here as to whether he believes- Senator NELSON. Whom is he with now? Mr. HARRISON. Parke, Davis. Senator NELSON. And who manufactures Chloromycetin? Mr. HARRISON. Parke, Davis. All I am saying is there are some other statements here. Dr. ANNIS. I hear proper action was taken, Senator. Senator NELSON. Yes, but again; I raise the point that an ad has been run in JAMA in which it tells all about Pree MT, and then it runs nothing on contraindications. Again, a doctor reads that and looks and says, great ad. I think I will use that because there are no contraindications. Now, it seems to me- Dr. ANNIS. Your point is that, we should have the same kind of check that FDA has. Senator NELSON. No, my point is, I don't know what you ought to have m advance. In your brochure that you submitted today, you say that you require evidence of efficacy and various other things. Dr. ANNIS. And satisfaction of the requirements of FDA. Senator NELSON. We have a case or so that I will show you where there was not any evidence at all. But let us stick with this one. This is a case where they were found guilty by the FDA. They left out con- traindications. A doctor relying upon your ad may be prescribing this and no doubt is prescribing it, and he says, it is great, there is no con- traindications, but there are. it seems to me that there is a moral obligation on the part of the AMA when something like this is done to report that ad was incor- rect. And here is what the FDA has done about it. I do not understand how you can shirk that responsibility. Dr. ANNIS. Senator, we are not shirking any responsibility. But I recall one trip up here a few years ago when our mutual friend, Sen- ator Smathers, returned at noon from the White House where, as a representative of the southern Senate group, he had had bheakfast. I recall, too, that he came in and he said, "Ed, you think you guys have problems. I just came from the President's, and you think that a President of the United States has unlimited power." And he said, "But during most of breakfast this morning he was talking that he will give an order and, by the time it goes down through various people, nobody knows who makes the changes along the way, but ultimately, it comes out-if it comes out-totally different from what was intended." I think he used the illustration that it is like somebody standing on the end of the line and passing a handful of salt or sugar, one to an- other. When it gets to the end of the line, nobody knows how much was lost or by whom, but there is not as much there. PAGENO="0408" 4698 COMPET1TTVE PROBLEMS IN THE DRTJ~ INDUSTRY The fact that you can find errors occasionally, omissions occasion- ally, yes, nobody would deny that these things occur in medicine, in the AMA, in all publications, or in Government. What I am saying is that these are contrary to our basic intent, to our aims, to our procedures, to what we try to do in bringing to the American physician, as best we can, constant and continuing exposure to new drugs which are essential to the armamentarium of medicine. By the same token, because the Government has taken over an im- portant role, and in this the FDA has had strong support from the medical profession. They have taken over this role and have assumed responsibility not only for safety and purity, but also for efficacy. We feel that they have helped us immeasurably. Now, within the confines of our organization, the manner in which we operate-I am satisfied that you can pick instances where we have failed to live up to that which we desire. I would plead guilty of failing to reach that goal in many instances. But this is not a failure because of the lack of desire or because of an unwillingness on our part to direct our efforts toward these things. If it requires a change in our policies or our procedures, we will do so. This is my point. Senator NELSON. The issue I am raising here is not that complicated a question as the President and unlimited power. Dr. ANNIS. It makes no difference. I bet you give orders in your office sometimes and they do not quite come out the way you intended them to. Senator NELSON. If it were a policy issue and it happened 10 times in my office, I would have a new employee. Dr. ANNI5. You are impatient. I do not know .that we would last that long. Senator NELSON. Well, there are about 10 ads here; that is the reason I use the figure 10. But I still get to the point of the obligation of the American Medical Association. You do not have a policy at all. It is not a question of giving an order as a President might on something and all of a sudden it goes through a lot of hands and is not executed the way he liked. It is something I know happens. Dr. ANNIs. But we have a policy- Senator NELSON. There is no policy as to this. Mr. HARRISON. What you are saying, Senator, in summation, I guess, is that when it is found that an advertisement carried by the American Medical Association publications- Senator NELSON. Or any other. Mr. HARRISON (continuing). Or any other, but of course ours would only be with our own publications. When it has been found to contain information which the FDA subsequently feels inappropriate and, after negotiations with the company to issue a "Dear Doctor" letter, AMA should again, with full prominence, say, "look, there was one point here that should have been included," or "something was omitted." Perhaps there is some merit in saying that we could be doing some- thing beyond that which ire are doing. But we should recognize that these letters, again, go out to all physicians, that they were a com- plete sta tement as such. Having iust engaged a bit in some community PAGENO="0409" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4699 politics, on a very local level, I have come to know that sometimes you you give more notoriety than it had when it was read the first time. I am not quite sure, Senator, that it would be appropriate, in all in- stances certainly, to place in large prominence full-page ads with respect to some omission or some mistake that was made in the ad, as subsequently determined by the FDA. However, you have a point there and I think we can review our present policy with respect to that point, and see if we should be doing something more. But I wish the committee would keep in mind that we are speaking here of perhaps an omission which may be only one statement among a number of statements that were included. Perhaps it took the FDA a couple of weeks to review that ad. The manufacturer may have been required to come in and discuss the prob- lem, and then reach an agreement as to what should be done with respect to the way the ad was worded, and how it was in conflict with the statement made in the package insert. And after all this is done, finally, it is agreed, perhaps in this one instance, that a "Dear Doctor" letter should go out to the physicians across the country-all of that. Then the question is, should the AMA in a large-page ad also say, "there is one other statement that should have been made there!" We cannot see that, but perhaps something should be done and, again, we shall take this under consideration, perhaps to improve our communication on this point. Senator NELSON. Well, this is part of the whole context in which these hearings have been conducted, part of it, about the t.remendous influence of the drug industry in promoting the sale of drugs. It seems to me that the AMA's journal is not an ordinary publication, and that when a false claim is made that can and will mislead the doctor to improperly prescribe for his patients, there is a moral obligation of JAMA to say right off the bat-and if every medical publication did that every time it happened, you will see some more honest adver- tising. But if every time something like that happens, the publishers who receive the ads say nothing about it, why should they reform? Mr. HARRISON. I think they are seriously hurt by these "Dear Doc- tor" letters, seriously hurt, because here is a communication that, ~n effect, again goes to every single physician and which states that they have done something in error and done something improperly. And I think this seriously affects them. So I think there is a very pertinent and powerful restraining influ- ence here. Senator NELSON. You are saying after all this discussion that you do not think that the American Medical Association has an obligation to correct misleading advertising in its journal. Is that the conclusion? Mr. HARRISON. We are not saying that at all, Senator. I think I have made the point that certainly we will look at this again, but the ques- tion is whether you use a sledgehammer here to kill a flea. We would have to look at the particular: statement that was made, the context in which it was made, the advertising, and I would say ~.o you that on the basis of what has been related here and more recently through the committee, we would have to evaluate again the procedures involved and perhaps effect some change. PAGENO="0410" 4700 COMPETITIVE PROBLEMS L~ THE DRUG INDUSTRY But to just make a comment that the American Medical Association has failed to do something in this respect when these "Dear Doctor" letters go out to all the physicians and when we do not run the ads again when we are aware of their defects-I think this is the point that is unfair. Senator NELSON. I shall be glad to see the FDA do these things, but I quite frankly say if the doctor read that ad and believed it and mis- prescribed to his patient on account of it, and the journal had not run a correction, the journal has defaulted in its moral responsibility. That is my opinion. I would just like to spend a minute to find another example or two here. Senator DOLE. While the chairman is looking, I might ask a few questions. Senator NELSON. Yes, of course. Senator Don~. Does the journal ever make any reference to these "Dear Doctor" letters? Do you ever rerun the letter or anything of that kind? Dr. ANNIS. I was just asking Dr. Hayes. I know I have seen them, either in the journal or the AMA News, but I do not know if they are run as a regular procedure. I have had my attention called to an AMA News article after I had received the letter, so that I know that it has occurred on occasion. I know, for example, and Dr. Hayes feels the same way, that there was a reminder in the AMA News following the "Dear Doctor" letter, on chloramphenicol. 1?\Thether or not it is the regular procedure, this is one of the matters that we will look into and will take up with our Council on Drugs. Senator DOLE. I think the record probably is clear on how many ads have been run in a period of time, total ads, and how many have been in the category suggested by the chairman. Do you have the figures on how many total ads you may run in a year and how many have been "false and misleading"? Is that information available? Mr. HARRISON. How many false and misleading? Senator DOLE. Out of the total? Is it 5 percent, 1 percent? Mr. HARRISON. The Senator has indicated some 10 ads which have been subsequently found to require corrections through a "Dear Doc- tor" letter, appeared in the AMA Journal, I believe he said over a period of a year. Senator NELSON. Twenty-nine over a period of 23 months. Mr. HARRISON. Of which 10 were with AMA publications? Senator NELSON. And others, but 10 of the 29 did appear in the AMA. Journal. Mr. HARRISON. So that would be 10 advertisements, and I can tell you the number of pages that we have. It is such an insignificant num- ber-that we are talking about something like one-thousandth of 1 percent for just the journal itself, and we have 10 specialty journals. The journal is published once a week. That would be 52 issues during the course of the year. In a period of 2 years, we would have more than 100 issues. There are approximately 100 pages of advertising, somewhere m that area, in each issue. I do not know where that takes us, but the percentage is obviously small. PAGENO="0411" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4701 Senator DOLE. As a matter of practice, do you screen ads that come toyou? Mr. ILUmISON. Yes, we have a department which evaluates drug advertising and it does so in accordance with the principles included in our testimony. Senator DOLE. Yes, I read the principles here. Dr. ANNIs. The screening is there, but when it comes to such things as the drug content, the pharmacology, the chemistry, the efficacy, the safety, these are matters that the Food and Drug Administration is responsible for. Essentially, if they meet the FDA requirements and our requirements-advertising critical of others, or pricewise, saying we are better than someone else's, and all of the other things that are there, plus the keeping of medical ethics, they are acceptable. That is what we screen basically for, but the basic contents, since the FDA has been given that authority by the Congress and has assumed the authority and are doing a good job with a difficult chore, we leave this matter to them, because we do not have the mechanism or the means to go into these details. Admittedly, out of either their screen or our screen, occasionally there are errors. Senator DOLE. The FDA has made errors, too, I assume. Dr. ANNIS. Well, yes. Everybody has. A good example is thalido- mide, a safe drug. You could buy it over the counter in Europe. The main reason it was so popular was that one could not commit suicide with it. One could take a barrel of it and it would not kill. But looking back, for a young: woman in her first 6 or 7 weeks of pregnancy, it created problems. Researchers could not find them in test after test on animals. They only found it in a certain species of rabbits. You have a drug that is safe. Old people take it, young people take it, it has minimum toxicity. People take it for sleeping. If they take too many, it will not kill them. Think what a great thing this was. They could even buy it over the counter in Europe. It was never used in this country, not because of the drug effect on the unborn child, but because it had peripheral side effects-numbness in the fingers and toes, a sort of tingling. But the research group, Richardson-Merrill, continued its research on it. Then we began to hear of the trouble they were having in Europe with this drug. Then, as a result of what happened, they saw the dan- ger. From then, you could set a ëlear course. Chloramphenicol has not been the same, but similar. It is a drug that has not been widely used, a drug with an admitted broad spec- trum, a drug that came along with other drugs at a time when we were looking for something extraordinary. So in the minds of many physicians, older physicians, particularly, of 15 or 20 years ago, here was a great tool. Now even its severest critics-and we are among those-admitted that its side effects are rare. But when they occur, they can be tragic. But a man could have used it for 15, 20 years without any trouble. So when he hears that other people have had trouble, he says, "I have had no trouble." Then the FDA took it off the market. Then, for a while, he could not get his favorite broad-spectrum antibiotic. Now, it is back on the market. He can get it again. And in the mind of this fellow, not one PAGENO="0412" 4702 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY who has kept up with things, but one who had been getting good service from a drug over a number of years, he begins to use it again. I suspect that a number of users of this drug will fall into that cate- gory, where they have never had any trouble with it and it is the same old deal. It has long been a human saying, and it is dangerous in drugs, I will admit, but the saying is "When you have something that works well for you, do not be the first to jump to the new." I suspect-I cannot prove it, but I suspect this from physicians with whom I have had discussions in the last year and where I have zeroed in on this drug. But over the years, I have pointed out the many side effects that have occurred in rare instances. Now, what has happened is that our recognition of it and the safe- guards that Senator Nelson is referring to have not yet, at least in his mind, caught up to today's knowledge. It is different today. We are more secure, more certain. Even the references he made this morning about the National Research Council-even these final pronouncements that apparently, for the first time, indicate that there is no indication left for chioram- phenicol-that other drugs do as well or are better and safer-even this is only a result of today. So we have several years where apparently, it was a pretty good drug with minimal side effects. Then we began to see some side effects. Then we began to see an increasing number of serious side effects-not often, but when they occurred, very serious indeed. Now, the record begins to lay out. So as we look back over those years, the Senator is amazed. Why did you not do something sooner? Well, of course, if we had known about thalidomide-they were not researching defects in children, but researchmg something else. That is the way research has been made. Some of these are just as dangerous as flights in space. We are so proud of what we have accomplished, and it has been tremendous, it has been exhilarating as a nation. But we lost three men. These are the hazards that come with progress, as we move forward. In retrospect, we now fix it so that we will not lose them that way again. But we lost three men. The same is true here. Now, we can ask: should we not have recog- nized this earlier? Perhaps. Perhaps the safeguards we build in now will make it possible for use to recognize other and similar potential tragedies in the future, before they occur. These are some of the very real problems that are the practical prob- lems of medicine. You have a disease, you have a condition that is difficult to deal with. Som~body comes along and says, here is an answer. You begin to use it and you say, "gee, this is great," Then all of a sudden, you realize that the side effects that go with it can be very serious indeed. We have a number of drugs which solve many problems, but they produce deafness, total deafness. One of my good friends, one of the outstanding otolaryngologists in this country, has a patient I met one day. This man is totally deaf from a drug, dihydrostreptomycin, given to him for something else. As we look back, we are adding to our knowledge, and as we keep people alive who used to die, we find that the same drug that saved life produced deafness or inability to see. Aralen-a great drug in the control of malaria, was found by acci- PAGENO="0413" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4703 dent to help arthritis. It was prescribed for arthritis only to find that, though it is great for arthritis, if it is taken over a period of time, it begins to affect your ability to see. This is the progress of medicine. If you look backward, you can find many errors that we have made. But they are not errors that have come because of failure on the part of our researchers, our scientists, our drug manufacturers, to whom we owe so much, or the physicians who use the drugs. These are the human failures. Admittedly, criticism highlights our appraisal of these facts. If, from a hearing of this kind, some of the criticisms can redirect our efforts toward a closer scurtiny, toward a more effective scrutiny, I can assure you that this will be one of the side effects, at least, that will make our appearance a justifiable one and a good investment of time. Senator Don~. Thank you, Mr. Chairman. I have to go to another meeting. Senator NELSON. I would just like to say, Doctor, though, on this question of acquiring new knowledge about a drug, the indications for using chloramphenicol, have been quite limited, according to the testimony before the committee. Dr. ANNIS. According to our publications. We agree with you, Senator. Senator NELSON. For 15 years. Dr. ANNIS. Correct. Senator NELSON. And then along has come tetracyclines, and that re- duced again its indications. But they have been quite limited. And the point here is that the profession was not successful in that 15 years. I am not going to go through all that again. But let me refer to something. The committee has a stack of letters. This is the kind of thing that is so dramatic and so important. Dr. ANNIS. Our medical literature will have a bigger pile than that, Senator. Senator NELSON (reading). "Our eight-and-a-half-year-old daugh- ter, Judy Dianne, was given intermittent doses of Chioromycetin frOm August 1964"-that is recent-"through February 1966 for rea- sons varying from minor ear infections, respiratory infections, and an abscessed tooth." Now, we have lots of them like this. Here is one from a doctor say- ing that just recently, "A lady came into my office"-this is a doctor from Florida-no; I be~ your pardon, these are attorneys. I guess there will be a lawsuit. `A lady came into my office stating that this drug had been prescribed for her only child for acne." Here is one for a common cold. When I raised the issue with Dr. Goddard and others who have been here, that since the failure to convince the profession has been so complete, why should we not do as Dr. Dameshek recommended, and several others-I would have to check the record to be sure that was his recommendation. This was a year ago. But I believe he was the one who recommended that the FDA simply require that the drug be prescribed only in a hospital. Dr. ANNIS. I think that was Dr. Dameshek. Senator NELSON. Subsequently we have had others say the same thing. PAGENO="0414" 4704 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Well, Dr. Goddard said he was "at wits' end" about what to do about this problem. I have a high respect for him and I think I know what his problem was. Dr. Goddard said that restricting its use to hospitals would be an interference with the doctors' practice of medicine. Do you think that would be interference in a doctor's practice, if you have a case of this kind, where little kids like this are dying and 4 million people are getting it, and we have been unable to persuade the doctors. This is a way to guarantee that in most instances it would call the doctor's attention to the fact that it should be used only in a hospial. Besides, in any good general hospital, you have some exper- tise on the drug there. Do you agree or disagree that that would be a good proposal? Dr. ANNIs. Again, Senator, you will recall, as I said before, I am not speaking as a user nor a defender of the drug. But I do know that there are many physicians in this country of ours who practice many miles away from a hospital. One of the real problems is to get physicians to practice in rural areas, in sparsely populated areas, in areas far removed from medical centers and often far removed from hospitals. I suppose that some, at least, of the rather consistent users of the drug fall into that category. If it becomes necessary, if the cir- cumstances justify it, if there are no other drugs, if we fail in our education along other lines, then this, too, would have to be, as with anything, have to be considered. I would suggest, however, that even in some of the testimony that has been presented before this committee, there have been indications that one need not have taken chioramphenicol over a long period of time if one is sensitive to it. One dose in itself can set up the mechanism that ultimately results in the depression of bone marrow production, aplastic anemia, and death. I would also suggest-and I recite these not as arguments but as reasons for a continued dialog in this particular area-that one of my good friends in Miami had his wife take their little girl to the hospital and request a shot of penicillin for an infection a couple of years ago. She went into the hospital to the outpatient department and requested it. The physician who was in attendance agreed that it was all right, and Andrea, the little girl, was given her injection of penicillin. She was dead within a few minutes; they were unable to resuscitate her. So the mere fact that a patient is brought to a hospital for treat- ment or as an outpatient does not necessarily protect him. The theory is, of course, that if they are in a hospital, they are under better care, you can watch their blood count, do other things. If, however, we are dealing with hypersensitivity for any one of a number of reasons, be- ing in a hospital would not protect. I think, ultimately, the point arises that it is not a question of the location at which the drug is given, it is a question of trying to edu- cate our doctors wherever they practice as to hazards, as to new knowl- edge, as to the fact that whatever their experience has been in the past, there are other drugs today that can satisfy their needs much more safely. I still say that the answer to this, like most areas in the field of medical practice, where human beings are dealing with human beings, we should improve one's education to as great an extent as possible. But not forget that a physician may be dealing with people where PAGENO="0415" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4705 they are often far removed from medical centers, far removed from the ability to get the tests and everything necessary, and where his practice or experience over the years with various diseases has led him to use drugs which, in his mind, have saved lives. That is the other angle to this that must not be overlooked. If we want to concentrate on the few with dangerous side effects, including those ending in fatalities, we must also, in fair appraisal of any drug, not just this one that we are talking about, take a look at in how many instances is the evidehce there that it saved lives, prolonged lives, terminated illnesses quickly, protecting against fur- ther complications? . I do not know all these answers, but I do think so far, in reviewing the record of many distinguished physicians who have testified before your committee, and I share their concern about this drug, I am not yet convinced, nor are some of your other witnesses of equal promi- nence yet convinced, that confining or restricting the use of the drug to a hospital will solve the problem we all want solved. I am not opposed to it, but neither am I a proponent of it. I would want to hear more from others in circumstances where its use is dictated by conditions beyond those to which I personally have been exposed. Senator NELSON. But here you have a case in which it is really catastrophic, if Dr. Dameshek and the rest are correct, that this drug is being widely misprescribed and that we have deaths like this. Now, I assume that the person who got the penicillin in a hospital got the penicillin for an indicated case. Dr. ANNI5. I would hope so. Senator NELSON. But here is a case where 90 percent, if it is 90 per- cent, are getting it for nonindicated cases, and the fact that you re- quire it to be administered in a hospital immediately reduces that percentage. Presumably there is somebody there who asks if this disease is serious enough for this and is there another drug that will do the job? Also, is the organism susceptible to chioramphenicol? You would save quite a few lives that way. I believe it was Dr. Dameshek and some of the others, too, who advocated this and said, if they are sick enough to have chiorampheni- col, they ought to be in a hospital. But it seems to me that Dr. God- dard's answer that it interferes with the practice of medicine is hardly a justification in a case where the medicine is being practiced incorrectly. Dr. ANNIS. I think Dr. Darneshek's exposure has been in a great medical hospital where we have up-to-date tools and many qualified people around. He works in a totally different envorinment than those to which I have reference, and I suspect to which Dr. Goddard has reference. But I did indicate, indirectly perhaps, that even the use of chloramphenicol in a hospital would not protect that person, where- in one exposure is adequate to set off the very dangerous and ulti- mately destructive mechanism. Again, I am merely quoting some of the testimony before this committee that it does not have to be pro- longed administration in a certain percentage of people for one reason or another. A very small amoñnt of the drug, just like a small amount of tetanus toxin-antitoxon, I should say-can be sufficient to result in a fatality. This is merely an area where I do not believe that we PAGENO="0416" 4706 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY have had sufficient discussion or have had an opportunity to hear from all parts of the profession as to the limitation of any therapeutic a.gent just to a hospital. In my earlier years of practice, I did a little of what they used to call barehanded practice when I was in Wisconsin. I was out in the country many times. I have seen patients where, if it were a necessity to send them to a hospital, they would rather stay home and die. I do not know, maybe people have changed since that time. How- ever, I am not quite sure. I know of instances in the past couple o± years, at least of two people who have died following automobile acci- dents in Miami because the family, the patient who was dying, and the family, refused to allow the physicians to give blood transfusions, where there was massive hemorrhage as a result of the accident. It was impossible to treat the patient without blood, and there was refusal. In one instance, the mother of two children died. There are these tragedies. We can go on through tragedy after tragedy for the want of proper medication. In another case, the giving of a drug under ideal circumstances results in fatality. In a third, ignorance and unwillingness to allow modern trained physicians to use a therapeutic agent that could be life saving, re- sults in a fatality. All of these are merely examples of the constant problems that face physicians. But many of them face physicians who are far removed from a hospital or medical center. And there I would not attempt to come to a conclusion. I would be reluctant and hesitant to tie the hands of any physician with a therapeutic agent that might, under some circumstances, be the difference between his offering his patient an opportunity to survive a serious or perhaps fatal illness, or de- priving him of any such treatment by virtue of there being no other tool available at that time in that situation, and the inability to get into a hospital. I do not know, and I gather from other testimony that others are not yet persuaded, including Dr. Goddard. Senator NELSON. But the National Academy of Sciences has in- dicated these drugs are for very limited cases, that, in fact, it should not be used until no other drug would work, and since we have tetra- cyclines and other drugs-the doctor would then try those first. If you compare what is happening all over this country with the wide- spread misuse of this drug compared with the limited number of rare cases for which it is indicated-well, the doctor would say "I cannot use chloramphenicol in this case for acne or hang-nail or sore throat or a nonspecific high fever." He would say "I shall try out one of the other antibiotics" and I submit you would avoid this kind of tragedy. Then after a year or 2, I believe you would find the drug would be limited to the uses for which it is indicated-which is very small, according to all the experts we have heard. Dr. ANNIS. I think the record is becoming increasingly clear, Sen- ator. I do believe that as a result of the testimony of very distinguished people before your committee, you have enhanced the effort of the American Medical Association to spread this message. I have indicated earlier that we intend to expand it, that our Coun- cil on Drugs has already indicated its willingness to meet with Dr. Ley and to cooperate and work with him in its behalf. PAGENO="0417" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4707 As Mr. Harrison indicated, Dr. Ley has agreed to an interview with AMA News, for the specific purpose of a full disclosure of the most up-to-date information on chloramphenicol and its side effects. All this has already been done in the sense of establishing the rapport, the agreement for cooperation. The only reason that it has not been done as the moment is because of the many responsibilities on the shoulders of Dr. Ley. He has made a couple of appointments to meet which have had to be postponed. I anticipate that much of the desired effects indicated by the Senator today will be accomplished, and the message will be gotten through various channels to more and more physicians. In so doing, perhaps we shall get it down to the rare usage of this or any other drug. Their use will be limited to occasions when all indications are that it and only it is the weapon of choice against the invader of infection. Senator NELSON. Thank you, Doctor. As I said earlier, I had not expected that I would cover as small an amount of the material I wanted to explore, and I made some other commitments. I think probably it would be helpful if I jotted a note on some of the other areas that I would like to have you comment on whenever we can arrange a future date that is agreeable with you. I think 4 hours-more than 4 hours-is enough time for 1 day, any- way. So if it is all right with you, I shall not pursue any of the other questions I have, and we will work out some future date that is con- venient to both of us. Dr. ANNIS. Fine. If you will indicate the areas, Senator, as we have attempted to do in this presentation today. I do hope that you will have an opportunity to review some of the exhibits and the other material that we have. I do want to leave with you one we are very proud of. As I indicated, with a little prompting, I do not know for how many years, but for 14 years, we have had these continuing educational courses for physicians. In all of these, we are dealing with these and similar problems. But these reflect, and I will see that it is given to the Senator, the continuing effort of the medical profession. We want to cooperate in every way possible to inform you and your committee as to what we are doing, what we are trying to do, our willingness to cooperate, as Dr. Ley well knows, with the Food and Drug Administration. If there are particular areas which were not covered in the presenta- tion, we will be very hapyy to :provide answers. Senator NELSON. I have a number and I will jot them down in a letter to you. I want to thank you very much. I read all the exhibits and all your testimony this weekend. I always try to read in advance, so your effort at least was not wasted on me. Thank you very much for coming here today. We appreciate your taking time to do so. I realize it is an imposition on you with your busy practice, but it is a valuable contribution to the record. Thank you. Dr. ANNIS. Thank you, Senator. Senator NELSON. The committee is recessed until next Tuesday, March 25, at 10 a.m. (Whereupon, at 4 p.m. the hearing was recessed, to reconvene on Tuesday, March 25, 1969, at 10 a.m.) Si-280-----69-----pt. 11-27 PAGENO="0418" PAGENO="0419" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TUESDAY, MARCH 25, 1969 U.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant tO recess, at 10: 10 a.m., in the caucus room, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; and Elaine C. Dye, clerical assistant. Senator NELSON. Our witness this morning is Dr. Marvin Pollard, who is president of the American College of Physicians. Dr. Pollard, we are very pleased to have you appear with us this morning. We appreciate your taking time from your busy schedule to come here and testify. Did you sumit some biographical data? Dr. POLLARD. Yes, before. Senator NELSON. The biographical: data will be printed in the record prior to your statement. Your statement will be printed in the record in full. You may proceed to present the statement in any fashion you de- sire. And if you wish to depart from it at any time to elaborate on anything you have said in your statement, feel free to do so. And I assume if we have some questions as we go along you don't object to being interrupted? Dr. POLLARD. Not at all. Senator NELSON. Go ahead. (The biographical sketches follow:) BIOGRAPHICAL SKETCH OF H. MARVIN POLLARD, M.D. ACP PRESIDENT HEADS VAST TASK OF KEEPING INTERNIST INFORMED PHILADELPHIA, PA.-HOw to help the internist remain stimulated and keep fully informed of the continuing changes in medical knowledge and practice is the job facing the American College of Physicians (AOP), its new president maintains. H. Marvin Pollard, M,D., Ann Arbor,, Mich., who has taken the lead in many new continuing education programs in : the specialty field of internal medicine, was installed as President of the College in April and will serve until the Col- lege's 50th Annual Session in Chicago, April 20-25, 1969. As President, Dr. Pollard will be taking an official part' in a major, 35-year-old program for continuing education of internists-the annual ACP regional meet- ings at which leading research investigators, including internists, present scien- tific papers on clinical studies. Dr. Pollard will attend some of these meetings as both scientific participant and ACP official. 4709 PAGENO="0420" 4710 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "The internist must realize his great responsibility in keeping himself thor- oughly informed with medical progress," Dr. Pollard believes. "He must cope with the enormous amount of research information pouring out of the various institutions, as well as with the problems brought about by government-spon- sored programs such as the Regional Medical Programs, Medicare and Medicaid, in addition to his concern over family practice and community health." Dr. Pollard is Professor of Internal Medicine at the University of Michigan Medical School and Head of the Section of Gastroenterology at the University's Medical Center. I)uring the past decade, the 61-year-old internist has served five years as Chairman of the subspecialty Board of Gastroenterology; served as Secretary- General of a World Congress of Gastroenterology, and spent two years as chair- man of the senior staff at the Medical Center's University Hospital. Dr. Pollard helped organize the first postgraduate course sponsored by the ACP in South America a few years ago. In 1963 he was made chairman of the ACP International Medical Activities Committee, which has organized and presented five subsequent courses in various cities of South America. These courses are designed for the young teachers in medical schools as well as for practicing internists. In this country, Dr. Pollard and his Section on Gastroenterology at the Univer- sity of Michigan Medical Center have organized and held three postgraduate courses for the AUP on gastroenterology. These courses have been part of the ACP's on-going program of continuing education for internists, a program which provides 20 concentrated, formal postgraduate courses on different subjects dur- ing each academic year. The courses are held at medical centers throughout the country. Dr. Pollard has been "a Michigan man" since the start of his medical career, having received his medical degree from the University of Michigan Medical School in 1931. A native of Lamar, Cob. (born, Dec. 7, 1906), he attended school there and took his premedical course at the University of Colorado. Dr. Pollard rose through the medical school ranks to become professor of internal medicine, his present academic title, in 1951. He is certified to practice internal medicine by the American Board of Internal Medicine and to practice his subspecialty by the American Board of Gastroenterology. Among organizations in which he holds memberships are the American Gas- troenterological Association, the American Endoscopic Society, the American Federation for Clinical Research, the American Medical Association as well as its local and state medical societies, the American Association for Cancer Research, the American Association for the Study of Liver Diseases, the Central Society for Clinical Research and the Central Clinical Research Club. He has published more than 100 articles on various subjects in internal medi- cine with special emphasis on gastroenterology. Dr. Pollard is a Director-at-large (1966-68) of the American Cancer Society and Treasurer (since 1962) of the World Organization of Gastroenterology. Among offices he has held are President (1951-52) of the Washtenaw County Medical Society and President (1959-60) of the American Gastroenterological Association. He has also served the ACP as Governor for six years and as Regent for six years. _______ BIOGRAPHICAL SKETCH OF EDWARD C. R05EN0w, Ja., M.D. COLLEGE ExECUTIVE DIRECTOR KEEPS IN TOUCH WITH CLINICAL MEDICINE PHILADELPHIA, PA.-The Executive Director of the American College of Physi- cians (ACP) is one of a special breed of administrative physicians-the M.D. executive who likes to keep in touch with clinical medicine. Edward C. Rosenow, Jr., M.D., who practiced internal medicine for 17 years before becoming the ACP's Executive Director in 1960, holds the title of Adjunct Clinical Professor of Medicine at the University of Pennsylvania. Among projects by which he keeps in touch with the practice of medicine are teaching assign- ments on the University of Pennsylvania's services at Philadelphia General Hos- pital and Pennsylvania Hospital. He serves his specialty also as a member of the Joint Commission on Accredita- tion of Hospitals, the AMA Residency Review Committee in Internal Medicine and as secretary of the Council of Medical Specialty Societies, all of which are involved in improving standards of medical practice. Dr. Rosenow is also on PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4711 the advisory committee for CARE-MEDICO, the international organization of medical services. Playing such an active role in the many facets of his specialty has been a habit with the 58-year-old executive director since his graduation from Carleton Col- lege, Northfield, Minn. in 1931. He received his medical degree from Harvard Medical College in 1935 and went on to the Mayo Clinic where, from 1936-40, he fulfilled his residency requirements in internal medicine. His father, the late Edward Carl Rosenow, Sr., M.D., was a distinguished physician-bacteriologist on the original staff of the Clinic. While at Mayo, Dr. Rosenow received a Master of Science in Medicine degree in 1939 from the University of Minnesota (Mayo Foundation). His formal edu- cation completed, Dr. Rosenow moved to Pasadena, Calif. in 1940 to begin his nearly two decades of private practice. During this time, he undertook many ac- tivities that provided excellent background for his position as Executive Director of the College. He taught at the University of Southern California School of Medicine from 1940 to 1959, attaining the position of Clinical Professor of Medicine. He was also appointed to the same post at the University of California at Los Angeles and at the College of Medical Evangelists, both in 1958-59. From 1951 to 1959, Dr. Rosenow was chairman of the Postgraduate Activities Committee of the California Medical Association and became Editor-in-Chief of Audio Digest, non-profit subsidiary of the association, in 1954. In 1957, Dr. Rosenow retired from active practice to become Executive Director of the Los Angeles County Medical Association, a position he held until moving to the American College of Physicians. Thus, Dr. Rosenow came to the ACP equipped with a well-rounded career of private practice, medical school teaching and medical society administration. In addition, he became acquainted with research medicine as President, from 1955 to 1959, of the Charles Cook Hastings Home in Pasadena, Calif., an institution for tuberculosis research. Among other organizational offices he has held are presidencies of the Los Angeles County Medical Association, the Los Angeles Society of Internal Medi- cine, the Los Angeles County Heart Association, the Huntington Memorial Hos- pital Staff, Pasadena, Calif., the Alumni Association of the Mayo Graduate School, the American Medical Writers' Association and the Association of Medi- cal and Allied Publications. Currently, he serves as President of the Carleton College Alumni Association and of the Commission on Professional and Hospital Activities. Dr. Rosenow is a Fellow of both the American College of Physicians and the College of Physicians of Philadelphia; a Diplomate of the American Board of Internal Medicine, and a member of the American Association of Medical Society Executves and the Professional Convention Management Association. He belongs to the Philadelphia County, Pennsylvania State and American Medical Associ- ations. His honorary memberships include the American Society of Internal Medicine, the Los Angeles County Medical Association, the American College of Chest Physicians, the Los Angeles Society of Internal Medicine and the American College of Gastroenterology. Among honors and awards are an honorary degree of Doctor of Science granted in 1967 by Carleton College; the Distinguished Alumnus Award of the University of Minnesota, given in 1965 and the 15th Peter Bohan Lectureship of the Univer- sity of Kansas School of Medicine, delivered to the 1966 graduating class. He has written papers on blood groups in China, published in the National Medical Journal of China; "Extreme Cardiac Hypertropy," published in Mm- nesota Medicine, "Cahicification of Renal Pappillae," published in the Journal of Urology and "Septicemia," published in the Proceedings of the Staff of Mayo Clinic. Dr. Rosenow, who resides in Philadelphia, is married and has two children. He is a member of St. Christopher's Episcopal Church in Gladwyn, Pa., the Merion Golf Club, the Racquet Club and the Faculty Club of the University of Pennsylvania. PAGENO="0422" 4712 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY STATEMENT OP DR. H. MARVIN POLLARD, PRESIDENT, AMERICAN COLLEGE OP PHYSICIANS; ACCOMPANIED BY DR. EDWARD C. ROSENOW, JR., EXECUTIVE DIRECTOR Dr. POLLARD. I think to open with I will read this prepared state- ment word by word, and then we will proceed from there if there are any questions. My name is Dr. H. Marvin Pollard, and I am the president of the American College of Physicians. I am also a professor of medicine at the University of Michigan School of Medicine. With me is Dr. Edward C. Rosenow, Jr., the executive director of the American College of Physicians. He holds a faculty appointment at the Uni- versity of Pennsylvania School of Medicine as a clinical professor of medicine. The comments I wish to make are my own. STATEMENT OF FACTS The American College of Physicians is a corporation organized under the State laws of Delaware in 1915 for educational and scientific purposes and except under section 501 (c) (3) of the Internal Revenue Code. The college has, at the present time, approximately 15,000 mem- bers throughout the United States and Canada, with a few members located in Mexico and the Central American countries. All of the members are specialists in internal medicine and allied specialties. The headquarters office is in Philadelphia. Pa. The object of the college, as stated in its constitution, is to maintain an organization of qualifIed in the field is to maintain an organization of qualified physicians in the field of internal medicine and its allied specialties for the following purposes: 1. Maintaining and advancing the highest possible standards in medical education, medical practice, and research. 2. Preserving the history of perpetuating the best traditions of medicine and medical ethics. 3. Maintaining both the dignity of internal medicine and the efficiency of its function in relation to public welfare. All of the educational activities of the college are open to non- member physicians as well as members and all of the financial aid programs such as scholarships, fellowships, and residency loans are available only to nonmember. The ultimate beneficiary of all of these programs is the general public. In order to carry out these functions, the college conducts numerous seminars and postgraduate courses. These are presented throughout the year and are held at various locations in the United States and Canada. There are numerous regional meetings during the year, con- ducted for the benefit of the college members and nonmember physi- cians. Once each year a large national scientific meeting is held, which lasts for 5 days, with four large scientific sessions going on simultane- ously. The meeting last year, in Boston, in April of 1968, attracted 3,159 college members and 2.073 nonmember physicians. The college publishes a monthly medical journal, called the Annals of Internal Medicine which contains scientific articles and reports of new developments of importance to its readers. This outstanding mecli- cal journal is distributed all over the United States and, in fact, all PAGENO="0423" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4713 over the world. In addition to college members, the journal is mailed to over 32,000 nonmember physicians, students, hospitals, and medical libraries. Included in the journal are advertisements for pharmaceuticals, medical equipment, and medical textbooks. All advertisements are carefully screened by a special committee to insure that they are con- fined to products related to the care of patients by specialists in in- ternal medicine or in allied specialties.: Senator NELSON. May I interrupt a moment. Dr. POLLARD. Yes. Senator NELSON. Do you have some established principle that the ad must conform to? Dr. ROSENOW. Yes; Senator. You~ have there this folder that is in blue. That is the policy statement and the code for advertising that we use for our advertising. The committee consists of four members, physicians, who screen each ad that comes along. We establish gen- eral policies as to how they should be done. And briefly, that is our primary concern at the present time. It is somewhat easier than it used to be because of the requirement of Food and Drug that you have to put in the information that is in the informational leaflet. But our job is to see that the ad does not exceed the claims in this product in- formation brochure. And also that it refers to internal medicine or the allied medical specialties. We don't take anything that does not relate to our specialty. Senator NELSON. Thank you. Dr. POLLARD. In a recently released report by the Government Task Force on Prescription Drugs it was pointed out that physicians rely to a considerable extent upon advertising by the pharmaceutical manufacturers for their knowledge of drugs. The advertising carried in the Annals of Internal Medicine compliments the other educational activities of the college. Attached hereto is a copy of the December 1968 issue of the Annals of Internal Medicine, to be made a part of this report, as exhibit A.' I think you have a copy there before you. Mr. GORDON. May I ask you a question at this point? Dr. POLLARD. Yes. Mr. GORDON. Do you have any idea how many ads you rejected in the last couple of years? Dr. ROSENOW. I could get accurate information as to that. I would say many less than we did 4 or 5 years ago before the new regulations came along, because at the present time the ads are a little bit more stereotyped. But I know now that we have turned down at least several. One that I can remember is one of the penicillin agents in which the statement was made that this should be the doctor's first thought in infection. Our committee felt that it should be about the second thought in an infection. The first thought should be to prove the infection was due to an organism that would be susceptible to this agent, and we wanted them to put it this way. And at that time they decided that they would not do it. So we did not run the ad for a couple of years. As a matter of fact, this company canceled all of its penicillin advertising in the annals for several weeks. And I think they felt that this w~ould make us feel pretty bad. And it did Exhibit A has been retained In committee files. PAGENO="0424" 4714 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY not. And I notice that just recently they have submitted copy which includes our recommendations. This is one that I can remember. Senator NELSON. What company was that? Dr. ROSENOW. I would have to rely on my memory for this, but I can furnish this for you. I really would prefer to go and look it up and submit it to you. Senator NELSON. Would you submit it for the record? Dr. RosExow. Yes. And I would be glad, if you would like, to give you information about any other ads that we have ref used.1 Senator NELSON. Thank you. Dr. POLLARD. There are other activities of the college worthy of note, all intended to make physicians better able to administer to the health requirements of the public. Teaching and research scholar- ships are granted for a period of 3 years. The 1969 budget contains $116,500 for this purpose. A residency loan fund of over $~OO,OOO is used to assist young physicians to pursue graduate training in accredited mstitutions. Annual appropriations are made to the Joint Commission on Accreditation of Hospitals, by the American College of Physicians in cooperation with other national medical associa- tions, to underwrite the administrative costs of this organization which seeks to assure the general public of receiving highest quality medical care when hospital confinement is necessary. The appropria- tion for 1969 is $43,253. An innovation in medical education was started by the college 2 years ago. The medical imowledge self-assessment program is a very comprehensive examination of approximately 700 questions covering the entire field of internal medicine. The physician, on a purely volun- tary basis, answers the questions, then takes the correct answers out of a sealed envelope and marks his own answers. The confidential nature of the assessment encouraged 11,000 physicians, both members and nonmembers, to participate. Senator NELSON. May I ask a question there? Dr. POLLARD. Yes. Senator NELSON. How many members did you say are affiliated with the American college? Dr. RosENow. Just under 15,000. Senator NELSON. And how many of your own members took the self-assessment examination? Dr. ROSENOW. 6,375. Senator, I might qualify this a little bit by stating this, that we have about 4,000 of our members who are in allied medical specialties who might not take this examination. For example, dermatologists, neu- rologists, phychiatrists, radiologists, and pathologists belong to our college and are a part of the total number, so they would not be expected to. I think the 6,375 realistically represents a little more than 60 per- cent of the ones who would benefit by taking this one. Senator NELSON. I notice that a couple of clinics with which I am familiar require their physicians to take the self-assessment exam. Is this a widespread practice? Dr. POLLARD. I will answer that. I think that it will be increasingly widespread. As I go on in this description here you will find that it is being adopted not only in this country but in areas overseas. So I ~ See information beginning at p. 4734, infra. PAGENO="0425" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4715 am sure that it will be utilized. It is utilized in many ways in this country by the young individuals preparing for examinations, and by older individuals who want to reassess their own knowledge. And I would not be at all surprised but what on an individual basis clinics may well require it. Senator NELSON. Thank you. Dr. POLLARD. This idea has since been adopted by several other national medical organizations and the American College of Physi- cians' medical knowledge self-assessment program is now being trans- lated into the German language for the use of the German medical community. We were recently informed that the program is being used in South Africa, in their education program. Dr. RosENow. May I interrupt here, please. On this test translated into German-and this is very appropriate to the hearing that you are having. As you know, many foreign countries depend even more for their educational efforts in medicine on pharmaceutical companies. I am not absolutely sure that we are going to go through with this, because I have not yet gotten from the German colleagues that want to do this conformance to what our agreement with them was. One of the agreements that we made was that they would have to distribute this exactly as we printed it originally. And what they want to do with it is send it out in serial form, cooperating with a drug company that wants to put some ads in it. And we have refused to do this. So we may not do it, because we do not want to get mixed up in a kind of gimmick for selling drugs. Senator NELSON. Thank you. Dr. POLLARD. There are other programs that the college uses to fulfill its purpose. Unlike many educational organizations, it makes no public appeal for gifts, neither does it receive support from the Government. The principal sources of funds are dues, subscriptions and advertising from the Journal, exhibits at the annual scientific session and income from investments. Senator NELSON. May I interrupt? Doesn't the breakdown, I think it is your exhibit B, show the specific sources, that is, how much of the income is from journals, exhibits, investments? Do you have that figure? Dr. RosEwow. Yes, Senator, I can give it to you in more detail later if you like. At the present time-let us take 1968. When you first told us what you wanted, you wanted the breakdown between advertising revenue. And we have given you this. But in addition to the break- down in. the other total revenue, other than the Journal, the largest amount is $370,438 in dues, $33,000 in initiation fees. We have a total of about $160,000 of income from our endowment investment. And we have $187,000 of income from postgraduate tuition fees. This is al- most-they go right out on the other end as expenses, so we do not really make anything on this. The medical knowledge self-assessment program, when we originally handled it we estimated a deficit of $90,- 000 and now we-I hate to use the word profit-but an excess over ex- penses of about $50,000. Exhibit income is $121,000. Guest fees are $22,000. This, however, I must also tell you, is not an even balance, but on our annual session we go in the hole about $48,000 over this income. Senator NELSON. The income from what kind of exhibits? PAGENO="0426" 4716 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY Dr. ROSENOW. This is for what we call our technical exhibits, which is the place where the pharmaceutical companies, the instrument people like electrocardiogram machinemakers, and other diagnostic things that are used in our profession, and book publishers. Dr. POLLARD. Textbooks. Dr. ROSENOW. There are about 200 exhibits at our annual session. Senator NELSON. And these are the only exhibits? Do you have re- gional sessions? Dr. RosENow. We have regional meetings but not regional exhibits. Senator NELSON. And what amount of the exhibits is income from pharamceutical manufacturers exhibits? Dr. RosExow. Versus the others? Senator NELSON. You gave a total on the exhibits. What amount was pharmaceutical? iDr. IROSENOW. I would have to go back and actually count that up. But I would imagine it is about two-thirds. Senator NELSON. Would you submit that for the record, also? Dr. ROSENOW. Yes, sir. Senator NELSON. And on the income from advertising, as I under- stand the testimony of Dr. Pollard, it is advertising from- Dr. ROSENOW. Internal medicine advertising. Senator NELSON. From pharmaceuticals, books, scientific instru- ments. What amount of the subscription revenue is pharmaceutical advertising? Dr. ROSENOW. I would have to look this up. I can submit this to you.' I would suppose it is about the same. Senator NELSON. Two-thirds? Dr. ROSENOW. I would think so. Senator NELSON. You used the figure subscription revenue on ex- hibit B, subscription revenue net of commission. What do you mean by that? Dr. ROSENOW. Excuse me, I did not get it. Senator NELSON. In exhibit B you used the figures subscription revenue net of commission, and then you have advertising revenue. Dr. RoSExow. Right. I would suppose that more than half of our subscriptions for the Journal which come from nonmembers comes through an agency that takes up subscriptions. This is quite common in medical publications, that a man puts all of his medical journal subscriptions through one agency. And I believe the discount there is 15 percent. In the advertising revenue the same thing. Very few of the phar- maceutical companies, for examples, put their ads in with us direct, but go through an agency. And this is what that is called. And the discount is 2 or 3 percent if they pay by the end of a certain period of time. Senator NELSON. So what you are referring to, then, is the adver- tising revenue received by the publication after payment of the fee, 15 percent of whatever it may be to the advertising agency that places the ad? Dr. ROSENOW. That is right. It is money that we can use. Senator NELSON. I have one more question. What kind of invest- ment? Do you have any pharmaceutical investments? I See p. 4734, infra. PAGENO="0427" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4717 Dr. ROSENOW. We do not restrict-we do not ordinarily take phar- maceutical ads, investments, but wo do not say that we cannot. I would say at the moment that we do not have any, but I am not ab- solutely sure. We had Smith Kline & French a few years ago, but we do not have that any more. We do not have a policy against it. This is run by an investment company we work with, Drexel, Harriman & Ripley Investment Counselors. We are a little bit touchy about to- bacco investments; we do not take those. But we have no firm rule against it. So that essentially I would say that we would have to be a little extra persuaded that a pharmaceutical company was a good investment for our college. Senator NELSON. If you have an investment in pharmaceuticals now, would you notify the committee as to what they are? Dr. RosENow. Yes. Dr. POLLARD. I believe it is true that there are none in pharma- ceutical houses at the present time. Senator NELSON. Thank you. Dr. ROSENOW. You asi~ed the total amount of our investment account. Senator NELSON. Yes. Dr. RosENow. I would also have to furnish this. But I think at its mark value it is somewhere around: $3 or $31~ million. Senator NELSON. Please go ahead. Dr. POLLARD. Because of increased activities, additional office space is required. We are in the planning stages of plant expansion which could cost up to $1 million. The funds to pay for this addition must come from the sources mentioned above. A committee on diagnostic and therapeutic agents has been ap- pointed recently under the chairmanship of Dr. Carter Smith, of At- lanta, Ga. They plan a continuing study of all aspects of these agents. Although no specific policy statements have been developed on some of the matters of concern to your committee, such policy statements will be forthcoming from time to time. 1-lowever, the following gen- eral comments I believe fairly represent what would reflect the atti- tudes of a majority of our members: COMPENDIUM Physicians must have accurate, up-to-date information about drugs. A number of methods are helpfulin this regard. Physicians' Desk Ref- erence is a convenient source of information about the drugs included, but is incon'iplete. The objection raised that there is no editorial review of what goes into PDR has been corrected by requiring that the FDA- approved package insert information be included. Senator NELSON. The FDA doesn't require the PDR to print the whole package insert. I think it requires that it conform to it, however. Dr. ROSENOW. That is right. But PDR has adopted, I believe, that they put in the product insert as their writeup. Senator NELSON. In toto? Dr. RosENow. I believe so. Senator NELSON. I did not realize that. Dr. POLLARD. That is essentially what the PDR is. Senator NELSON. From some that I have looked at in the past, it was PAGENO="0428" 4718 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY my impression that they were condensations of the package insert or that the requirement was that they conform and not conflict. Dr. ROSENOW. I am not absolutely sure of that, either. I have been told that the PDR editors themselves are requiring this. Senator NELSON. The committee counsel reminds me that there have been recent corrective "Dear Doctor" letters based on the advertis- ing in the PDR which did not conform to FDA regulations in the last 2 years. Dr. ROSENOW. I believe that is correct. I think my information ~ this is that it is only very recently that they are doing this. Dr. POLLARD. I have the impression it was in the last 2 years. Senator NELSON. We will check it. Please go ahead. Dr. POLLARD. The AMA's Council on Drugs has announced a new publication, "AMA Drug Evaluation." When available, this should be a very useful reference book. We are impressed by the preliminary chapters which have been circulated. Probably the most useful source of information is the advice and counsel of a physician's colleagues. Very few physicians prescribe a new drug for the first time without discussion with colleagues or hav- ing read about it in a first-class journal article, or having heard about it at a medical meeting. Direct-mail advertising, journal advertising, exhibits at medical meetings, and the work of detail men are all important sources of in- formation. It must be recognized, however, that the latter, though giv- ing the doctor accurate information, are primarily directed to selling products. We believe our physicians accept advertising for what it is in our free enterprise system and judge it accordingly. We would have no objection to a compendium, and certainly would approve the inclusion of generic and trade names. Probably the in- clusion of the chemical name should also be included. We are not convinced that inclusion of prices would necessarily reduce the cost of drugs to the consumer. Senator NELSON. Why do you think that? Dr. POLLARD. I think largely because the actual pricing is out of the hands of these people-because the actual pricing is out of the hands of anything that is listed in the book. Senator NELSON. I do not follow that. Dr. POLLARD. It is not the responsibility of the book to dictate the final selling price. Senator NELSON. But might it not make a difference if the price were stated, in other words, if the doctor had a choice between several companies, and the drug of one of them was a fraction of the price of the other, might that not affect the price to the consumer? Dr. POLLARD. I can seen where that should influence it, or it could influence it. GENERAL PRESCRIBING In general, our view would be that each physician should use his own judgment about how lie prescribes a drug. It has never been shown that generic prescribing necessarily insures comparable quality or a lower price. The experience with chioramphenicol and Chioro- mycetin is an example much cited. A sutcly in Chicago by the AMA indicated no relationship existed between prices of drugs ordered generically even in the same drugstore chain. PAGENO="0429" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4719 Senator NELSON. May I interrupt a moment, Doctor? If the brand name is the only drug that the drugstore has stocked, because that is the name the doctor is prescribing most frequently, then when the pharmacist receives a prescription using the generic name, he can sub- stitute any brand name he wishes. Therefore, in the AMA study, the patients probably got the same drugs, whether they were prescribed by the brand or generic name. And many drugs that are cheaper may not be stocked at all simply because~ the doctor is prescribing them by brand name, and under the law in some 40-odd States a pharmacist cannot substitute another brand or another generic name. So the test that was used by the AMA in my judgment was not a fair test of the issue. The fact that the drug was ordered by generic name didn't mean that it was supplied on that basis. Dr. POLLARD. I have not any great comment on that. Senator NELSON. I might add that a year ago the Peoples Drug Stores and the Gray's Drug Chain, one out in Ohio and the other here, announced that they were going to stock a line of generic drugs manufactured by Strong, Cobb & Arner, and that in their public statements the price of the generic would average one-half of the brand name, which I think is a pretty convincing case to demonstrate that you could get a lower price from the generic. And Strong, Cobb & Arner, of course, is a very distinguished generic manufacturer. Dr. POLLARD. Well, I am impressed with that statement. Senator NELSON. Please continue. Dr. POLLARD. We are told by pharmacologists that equivalency is sometimes variable merely by the physical methods of drug prepara- tions. In some hospitals, where it is possible to have a committee of physicians review all drugs, purchasing drugs by generic titles can save considerable sums of money. Physicians sometimes prefer to order certain drugs by trade name merely because they can identify the various pills they have prescribed for a patient who might call by telephone to ask question about his medication. Most physicians really believe they can be more confident their patients will get reliable, con- sistently potent drugs if they prescribe products made by firms in which they have confidence. Senator NELSON. Why do doctors believe that? Dr. POLLARD. I think in most instances they believe it because of past experience. Senator NELSON. What experience could they have had that would indicate otherwise? Most of them prescribe brand names anyway. How would they get the experience? Wouldn't the experience be testimonial? Dr. POLLARD. Sometimes when a drug house comes out with a drug product in the beginning they look upon that as being a dependable drug, as with any new product that comes on the market. And I am afraid that they then get into the habit of prescribing that drug be- cause they have learned how to use it and depend upon it. Senator NELSON. But your statement is that physicians believe that they can be more confident that their patients will get reliable, con- sistently potent drugs if they prescribe products made by firms in which they have confidence. I do not quarrel with your statement. I think that is probably what they do believe. But my question is, What scientific foundation is that belief based on? Dr. POLLARD. It is just based on their past experience. PAGENO="0430" 4720 CO~ETITIVE PROBLEMS ~ THE DRUG INDUSTRY Senator NELSON. The one large test that we have had that I am aware of in the last 2 years was the FDA report on 4,600 drugs re- leased October 15, 1966, from 250 manufacturers in which 2,600 were generic drugs that they had tested and 2,000 were brand names. And the generics had a better potency, consistently met the standard for potency better than the brand names. In fact 7.8 percent of the generic products were not of acceptable potency, they varied from the TJSP standard, the established standard, 7.8 percent of the time. But with the brand names, 8.8 percent varied from the potency standard. I just raise this question because I think the fact is-it is my judgment from looking at this over a period of 2 years of hearings-that what has happened is that the brand name companies have convinced the physi- cians of this, but there is no scientific basis for that. Dr. ROSENOW. Senator, this statement in itself is true. Senator NELSON. I do not doubt it. I said I did not quarrel with that. Dr. RosENow. When we wrote this up we recognized that it is prob- ably possible and susceptible of proof that they should not believe this way. But I think it is a fact that they do believe this way. And it is a little bit like everything that you buy in this country, some people have confidence in one kind of product because it is made by a certain company. Even though your experience might be different from this, you may have a lot of different things that you do this way. I would also say that part of it is-I think what you do is sort of- let me take the drug digitalis, for example. I am a physician who likes to use the whole leaf digitalis. I always used the Davis Rose digitalis, not because I really thought it was a lot better, but because as far as my treatment of this patient was concerned I could do it better by knowing that I always prescribed this same kind of pill. For one thing, it was easily identified, because it was a kind of a round pill instead of an oblong one, and when they called up and wanted to know whether they should take one less pill or one more-digitalis is a pretty toxic drug-I felt more confident if I knew they had this. I recognize that there are many good products of digitalis, including generic ones, that I could have used. We are just trying to make a point that this is one of the reasons why doctors are opposed to not being permitted to prescribe by brand names. Senator NELSON. I could not in any way differ with you in your statement. I think it is absolutely correct. A substantial percentage, maybe a large percentage, of the medical profession are more con- fident of the consistency and potency of the brand name drug than the generic even though the tests do not come out that way, and perhaps the generics are better. The reason I raised the questioii is that it does involve the issue we have been raising over the past few years, that is, the very powerful influence of the propaganda of the manufacturers upon the medical profession. And consistently that statement is made before this committee-the same statement that Dr. Pollard says they believe in, which I think is an accurate statement. Many of these who testified and commented on it simply asserted flatly that it is a fact. And this committee has been raising the issue of the effectiveness Of the promotion by the companies of their products under their brand names versus generic names, and so forth. And that is why I raise the issue here, that so far as testimony before this committee, we have PAGENO="0431" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4721 not been able to find any evidence that demonstrates that the generic or the brand, either one, was any better than the other, consistently or otherwise. Thank you. Dr. POLLARD (reading). DETAIL MEN Many detail men offer the physician useful information about a product lie is selling. Many times he renders a real service in getting a supply of a medicine his company makes in small amounts for rare diseases. If he is the kind of man who is poorly trained or a pressure type of salesman, his chances of getting to see the doctor again are pretty slim. In other words, there are detail men both good and bad and most physicians have no difficulty telling the difference. TESTING DRUGS Drugs should be treated by someone who knows about testing drugs. Many of our members are superb clinical investigators and do in fact carry on a lot of the clinical testing of drugs. With the kind of regula- tions being required by FDA, it would seem logical that the experts in a pharmaceutical company should continue to test drugs. Any good company would be as interested as anyone else in the quality uniform- ity and effectiveness of its products. RELATION OF DRUG INDUSTRY TO THE MEDICAL PROFESSION It would seem obvious that such a relationship would be a close one, because the therapeutic agents developed by the pharmaceutical com- panies can only be used for patient care upon order of a licensed physi- cian. Probably the physicians exert more control over the industry than vice versa. In any case, we will attempt to delineate what rela- tionship exists between the American College of Physicians and the pharmaceutical industry. As we have already stated, the college's only function is to pro- vide its members and other physicians with adequate educational op- portunities in our specialty. One part of this educational activity re- lates to educating the physician about drugs and other therapeutic agents. Although the college's educational program is much broader than offering only information about drugs, we will outline at this time the ways in which we help educate physicians about drugs. The college publishes the Annals of Internal Medicine which is the leading journal in our specialty. Its circulation is 47,000, of which approxmiateiy 15,000 are members of the American College of Physicians. In this journal, as you can see, we display advertisements for a variety of products, including drugs, instruments, books, and educa- tional opportunities. The policy of the college is that advertising pages will occupy no more than 40 percent of the total. Usually the percentage is less than this. Each advertisement is subject to review by a committee of four physicians. The work of this committee has been considerably lessened since the FDA rules on advertising copy have been adopted. However, the committee does look carefully at PAGENO="0432" 4722 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the copy and determines whether claims or emphasis are in keeping not only with the FDA required information but in addition conform to good medical practice. If one member of the committee Votes against an ad, it is reconsidered by the committee and the ad agency is noti- fied and requested to make changes. Usually the required changes are made and the ad is approved. If changes are not made, the ad is de- clined. And we will supply you with the number that we have declined in the past 2 years. The decisions are based upon adherence to the code which is fur- nished to all advertisers-copies are herewith included.' The college has resisted all efforts by the advertisers to incorporate ads within the editorial pages of the journal. As a matter of fact, we separate the editorial pages from the ads even more by having the executive director be in charge of the advertising and publishing of the journal and by restricting the two physician editors' responsibil- ities to the editorial pages. The income we derive from journal advertising is considerable and one of the principal sources of income. However, it can in no way be considered of such importance that the college would change any of its policies in order to maintain this income. Furthermore, the percentage of advertising income related to total journal income (sub- scriptions plus advertising) is probable smaller than comparable fig- ures from newspapers, nonmedical magazines, and medical journals published by commercial publishers. The controlled circulation jour- nals such as Modern Medicine, MD and Medical Economics depend entirely on journal advertising revenue. Our percentage of advertising income related to the total income of the college for the past 5 years is attached, labeled exhibit B.' Inasmuch as this income is used completely in the total continuing education program for physicians, we feel it offers a way in which physicians may participate in our programs at a lower cost. If the physician has to assume the entire cost of his educational activi- ties, the costs would be passed on to the public in higher fees. In any case, the public benefits by this arrangement through the education of physicians. The college sponsors an exhibit at its annual session. The same rules apply to screening the exhibits to be sure they are of high quality and have relevance to our specialty. Last fall, we surveyed physician atti- tude about our annual session. Of interest to you should be the fact that 86.4 percent of the respondents voluntarily visited the exhibits regularly and 86.7 percent of these found them to be informative and useful. The total physician registration at the Boston annual session was 5,232. The net income incidentally from this activity falls far short of paying the entire cost of the annual session. We do have a few other activities sponsored jointly with drug com- panies. You should be interested in the general policy of our college regarding good will support of an activity by a drug company. It is as follows: The college does not solicit drug companies for financial support of any of its activities but will consider accepting any grants offered on an individual basis. See pp. 4730-4733. PAGENO="0433" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4723 The following are important activities supported in part by phar- maceutical companies: 1. Smith Kline & French has for 20 years operated sophisticated color television equipment in order that we can conduct hospital clinics at the time of our annual session and bring these conveniently to the doctors at the site of the session. All parts of the program are planned by the American College of Physicians. Smith Kline & French is re- paid solely by acknowledgement in the program that the technical pro- duction of the TV program is sponsored by them. 2. Mead Johnson & Co. furnishes the college with 14 fellowships which the college grants to young men during their training. Inci- dentally, prior to 1962, this company furnished $3,500 for entertain- ment at our annual banquet. In 1962, we declined further support of this activity and suggested increasing the number of fellowships ac- cordingly. Thus, $4,000 more was granted for this purpose by Mead Johnson. 3. The Wyeth Foundation for Postgraduate Medical Education has over the years helped finance new parts of our annual session pro- grams. A new section devoted to basic science lectures was given fi- nancial support. Recently a part of our program called "Meet the Pro- fessor" was given support. 4. Merck Sharp & Dohme recently offered to support several of our postgraduate courses in South America. Several years ago, they fi- iianced a film which one of our committees planned. The title of this is "Portrait of an Internist." It is an excellent educational film which depicts for the public what a specialist in internal medicine really does. It has had widespread appeal and we are told it has been shown to approximately 10 million people over public television and at public meetings. No products are mentioned and only a line of credit is given to the company. 5. The Eli Lilly Co. has offered some support to our postgraduate courses in South America. Parke, Davis & Co. and the Kellogg Foun- dation have also helped us start these important programs. The Kel- logg Foundation incidentally has also provided financial support to a Latin American fellowship activity which our college supervises. In this program, young medical school teachers from South America are brought to this country for a period of training after which they return to their own countries. : Of interest also is the fact that all of these 200 teachers have remained in their own countries. Each year the college awards two honorary fellowships. These are made to distinguished medical scientists from other countries. They are brought to our annual session where they give lectures and receive their honorary fellowship. Eli Lilly supports the cost involved in bringing one of these and the college finances the other. Both are se- lected independently by the Committee on Awards of the College of Physicians. We think all of these activities are manifestly in the public interest and indicate a wholesome and worthwhile relationship between our college and the drug industry. We remind you again, however, that what we have just described is only one small part of our entire edu- cational program. Senator NELSON. *Thank you very much, Doctor. Do you recall an article or a study that was made by Upjohn last fall? Sometime in November of 1968 Upjohn released a study they had 81-280-69-pt. 11-28 PAGENO="0434" 4724 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY made on tolbutamide. They are the only manufacturers, and they took the standards of DSP which were, in fact, the standards of th~ coin- pany, because it was the only product in the market. And they set up a comparison making some variances in the production of the drug product, yet staying within the DSP standards which, as I say, were the standards of the company, a.nd those were the only standards there were. They came out with a result which showed that the two drug products were not equivalent. And the Journal of the American Medi- cal Association on November 18, 1968, ran an article entitled "The Generic Inequivalence of Drugs." Did your publication treat with that at that time? Dr. RosENow. I don't know without looking. You mean on this same subject? Senator NELSON. In other words, did your journal report this find- ing which was reported in the American Medical Association? Dr. RosENow. It would be unlikely, Senator. If the article was published in another journal, they would not submit it to us as well. It is seldom that an original article is submitted-it may be submitted to several journals, but the editors do not particularly like to publish it. They have a little pride of ownership, as they call it. So I do not think there would be any likelihood that it would be published in two places. The one thing that might happen in our journal is-and I do not know whether it did in this instance-is that someone else might refer to this article in, say, Clinical Notes, or something like that. But it would not be an original article. Senator NELSON. And you do not know whether your publication commented on that editorially or otherwise? Dr. RosExow. No; I do not. Dr. POLLAED. I am not familiar with it if they did. Senator NELSON. That occurred November 18 in JAMA. Would you mind just checking since November to see what coverage your publication gave to it, if any? Dr. ROSENOW. Yes; I would be glad to.' Senator NELSON. I want to thank you very much for your testimony. I just make this point. You have been raising the point here, and others who testified have expressed the view that the relationship between the pharmaceutical manufacturers and the medical profession is not an unhealthy one. I think there is some question to be raised about that. But we notice in the testimony we have had that you have phar- maceutical manufacturers starting out at the medical school level and supplying various things to the students, stethoscopes, medical l)ags, research grants, and so forth; most of the journals receive sub- stantial support in advertising from the pharmaceutical manufac- turers; they provide income from exhibits at conventions; that they, in fact, in some instances-in one instance that we know of, paid part of the cost across the board in sponsoring of conferences, the medical conference itself, that there are free samples directly to doctors; that detail men see the physicians regularly, and $4,000 to $~,000 per year is spent in advertising per physician in the country; that the medical press, as contrasted with the journals, many of them are 100 percent supported by advertising by the pharmaceutical manufacturers; that you almost never see a critical editorial of the pharmaceutical manu- ~acturers themselves. 1See p. 4734, infra. PAGENO="0435" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4725 I have never seen one. I do not say there have never been any, I have never seen one; news stories about the industry, especially when there have been conspiracies as to prices, seem to have played them down in the medical press if covered at all; that the AMA itself gave wide prominence to tolbutamide IJSP which Dr. Miller of the USP, destroyed by his analysis of it; that the task force report of the FDA found a significant difference in generic and brand names does not seem to be covered in the medical press very prominentl,y at all; that the 4,600 drug tests do not seem to be publicized widely if at all; and that the testimony before this committee-I am not referring specif- ically to anything in particular to any of yours, I am just referring generally-by representatives of medical groups and by individual doctors recites consistently exactly the same arguments that the phar- maceutical manufacturers made; that you cannot trust the generics, that they are not equivalent, that brand-name companies do research, and therefore they are entitled to our support, that in general, as I said, the one group of people whO are qualified in the profession to make criticisms of practices in the profession-practices by the man- ufacturers-is, I think, effectively silenced by the close information check. Now, there have been very distinguished individual physicians, pharmacologists, clinicians, and experts of various kinds who have made some very strong criticisms~ of the practices of the pharmaceuti- cal manufacturers in relationship to the subject, but we did not find that, at least I did not, in the journals I look through or in the medical press. So does it not really raise the question that there is a very close relationship here, just in the nature of it, and everybody is so friendly that everybody ends up by not criticizing anybody else; is not that the kind of thing we get? Dr. POLLARD. Well, Senator, if I may express my own reaction to your comments, my information and my knowledge about this prob- lem is really not in keeping with your comments. Senator NELSON. Pardon? Dr. POLLARD. I said my reaction and my knowledge is not in keeping with the comments which you have just made. And let me tell you why I say that. Your one comment was that there were very few if any critical comments about drugs or pharmaceutical products appearing in medical journals. Is that-that has not been my experience. In medical journals-and I brought with me a group of programs of regional meetings throughout the United States just the past 12 months, and I ticked off in here the papers that were presented in all of these relative to drug intolerance, drug sensitivity, damage to the liver, damage to the stomach- Senator NELSON. Were these papers delivered at medical confer- ences? Dr. POLLARD. Oh, yes. These are regional meetings of the American College of Physicians-and by region I mean usually a State or, in some instances, two or three States together. Now, these are just our ways and means of educating our physicians. And all I am doing is pointing out that I think we attempt to keep the doctor educated by meetings. By publications, by articles in the annals, and by our annual scientific sessions, plus our postgraduate courses on all of the complica- tions that go along with it. And then for that reason, while we must PAGENO="0436" 4726 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY maintain close cooperation with the drug conwanies-I would not deny that 1 single minute, because we are dependent upon drug companies in a great way for the development of new products and for the refine- ment of products-yet we are totally independent in our opinion and decision as to how effective those products are. Senator NELSON. I wasn't suggesting that at medical conferences the profession did iiot call upon its most distinguished members to present the best possible papers on all aspects of medicine. I don't suppose you could find experts who would be willing to say anything other than what they believed in at these conferences, and I could not expect that anyone in the profession would think that any other presentation ought to be made in medical conferences. I was raising the question as to what the publications themselves really say about practices in the industry. For example, what kind of prominence did your publication give to the FDA findings on 4,600 drugs in which the generic caine out bet- ter in terms of potency than brand names? Dr. ROSENOW. May I try to clarify a little bit how this operates. If a physician or a clinical investigator interested in that report would send to our journal an article that lie wanted to put in here about that, then our editors would do this. Now, sometimes our editors look for these things themselves, and would write au editorial about this. I am quite sure that in this par- ticular instance this was not done. And we do not have a mechanism where we screen every single release that comes out from the Food and Drug or from any of these other agencies. But our editors would not hesitate to put this in if they felt and their editorial staff felt that this was important information for our members to get. Senator NELSON. The point I am making is that the argument-that you must rely upon brand names, that you cannot trust generics, that generics are not as good as brand names-that that argument is widely spread to all the medical journals in this country, it is advertised and widely spread to physicians in promotion. And here comes a study that is a significant one, it is a very significant study by the FDA of great importance to the medical profession. My point is-I have not looked at your journal, you may have run something, I am not address- ing myself specially to your journal on this question-but this finding was rather massively ignored so far as I was able to determine. And all I am saying is that if you have this kind of relationship, don't you end up, because of the closeness of such a relationship, as a matter of human nature, muting the criticism of the indepeiident industry whose relationship is so close? It seems to me that through years and years and an expenditure of millions of dollars, that doctors have been con- vinced, as Dr. Pollard said in the beginning of his statement, that they can rely upon the consistency and the potency of the brand name more than the generic, that all the journals ought to have a positive moral responsibility to run big editorials saying, it has been found that the claim made by the brand name people does not stand up. Now, if it were a separate, completely separate situation-for ex- ample, when we introduced the legislation involving tire safety, a number of journals hit the issue real hard with editorials, big stories about the tires being put out by the automobile manufacturers. It is a shocking story, they ran it big, but they are not relying upon their support from the independent industry. But here is a case where PAGENO="0437" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4727 there is faith by the profession, as stated by Dr. Pollard, that the con- sistency and the potency of the brand named drug is better, and sud- denly a finding by a massive study is made, and most all the journals who have ads are silent, or play it down. This is the question I am raising. Dr. RosENow. May I make one other comment about the Food and Drug Administration, and what we try to do. This was over 4 or S years ago. And we have repeated it over, that any time the Food and Drug would like to reach the members of the American College of Physicians-I have made this as a personal offer, and also as a let- ter from our colleagues-if they will send us information that they want published to go to our doctors, we will publish it. The first time I made this offer it was very quickly that I got on apparently nine different mailing lists. And I got piles of material, and, I did not really personally have the time tO go through every one of these things to find out what I wanted. And I had made the offer that I did not have time if they did not have time to state exactly what they wanted in, not just give me-everything came with no selection what- ever, volumes this big [gesturing]. And you probably have some problem getting through the mail, too. I finally wrote them, I said, I would really like to get just one copy of everything. The girl said I would have to tell her which mailing list I was on. And of course I did not know. We have made this offer many times, and we will still make it, that if FDA wanted to make an announcement they could reach our 15,000 members within the next publication date. One other time, I might add-you will recall the thalidomide episode several years ago. The first notice to the professional public was made at our annual session, it was at on.e of the meetings-I am not quite sure whether it was-where we rearrange the program to have announcement made at our meeting about this. Dr. POLLARD. It was in San Francisco. Dr. ROSENOW. This was the first notice to this company. So I am not quite sure-the thing that I would like to assure you of, I really do not think it is always kind of a conspiracy of silence so much as it is poor communictions as to how we get this information from that re- port you have, how it gets to our editors. Senator NELSON. I would assume that every medical journal in this country has somebody who is responsible for keeping track of the major pronouncements by the FDA. We do not quarrel with that. Dr. RosENow. I was tyring to explain how we keep track of it. We do not have enough people on our staff so that we can read all the material they send us. Senator NELSON. There was a major drug report by the National Academy of Sciences. Dr. RosrNow. This was done by the Committee on Drug Efficacy. Senator NELSON. This was done by the FDA itself, and the Corn- mittee on Drug Efficacy of the National Academy of Sciences/ National Research Council, made another report in which they observed, paraphrased, that there did not seem to be any significant difference between the generic drugs and the brand name drugs. But I am simply raising the questions that these are major issues-this was a task force report-these are major issues that directly affect the drug PAGENO="0438" 4728 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY industry and the medical profession. And I just wonder how vigorous anybody can be in raising this kind of an issue when the relationship is so close. I do not know of any circumstance in human relations where the relationship is close financially and socially or otherwise in which the parties are inclined to be as vigorous in their criticism of each other as they are if there is no relationship. It is just in the nature of the human animal. And I think it will always be so. This is one of the questions we are raising. When the drug industry makes such a major point of this lack of equivalency between generic and brand names, they have been able apparently for one reason or another- the reason I think is that the relationship is too close-for one reason or another they get by without having the major authoritative inspec- tive body in this country, the American physicians, and their journals and their spokesman, rising up and saying, they have been pushing this phony propaganda for 20 years. And now we find a study which shows that they have been fibbing to us. I would think that this would be a major, important point right off the bat. The whole profession ought to be told that they have been living by a propaganda pitch which the drug industry has promoted for years, and here is an answer to it. Why not? Now, I say that the inclination is to draw the conclusion that the relationship is so close that criticism by the profession of the industry has not occurred in the past and will not occur in the future. Individ- uals, yes, we have had them before the committee. But that is the problem that this relationship raises, I think. Dr. POLLARD. Senator, if I interpret your point, it is whether or not generic versus trade names is the answer to the whole drug prob- lem. And I am not sure that even you believe that. Senator NELSON. I am not saying that is the answer to the whole drug problem, I am just saying that the assertion has been made for years by the drug manufacturers-and now here is a scientific report of major consequence which refutes the claims that have been made for years by the brand-name companies. And the general profession is quite silent about the matter. Dr. POLLARD. Let us interpret that with a little bit of caution. Be- cause this comment that the profession has said nothing about it, I will still go back to the point that I mache, that where we spend our time in the medical Profession is evaluating drugs and reporting upon their complications in our scientific meetings. Now, perhaps we have not touched on generic versus trade name as the key to the whole drug problem. And I still think what we have attempted to do is to keep the doctor educated about his drugs, what they are, and what their applications are in a very fair and open way. And that is where we have been beating our drums, as it were. And maybe we have not made a great issue about the brand name versus the trade name. Frankly, I do not think we have any strong feelings about it one way or the other. There probably are other studies that would take generical named drugs, make studies of them and find disturbances there. Just because one chooses one or the other I do not think necessarily will resolve the whole drug problem. It may help it, but I do not think it will resolve it. And I think what the medical profession is after, what we in the college of physicians prefer, is that the physician be left to make his own choice. PAGENO="0439" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4729 Senator NELSON. In the 2 years that we have had the hearings, we have announced publicly on several occasions that we will hear all viewpoints and that anybody who manufactures drugs is entitled to first preference to appear before this committee. In that period of time we have not had any scientific testimony that proves the claim that the industry consistently makes, that the brand name is better than the generic name. The assertion by the DSP and the National Formulary and the distinguished pharmacologists before the committee is that if two drugs meet the official compendium standards they are equivalent. And there are rare exceptions, which do not even count up to one, and they are not even certain of that. But the profession becomes con- vinced that that is not the case. My point is that the profession believes what you stated in your opening remarks, I agree-I think that is exactly what they believe. But what responsibility do the journals and the medical press have for pointing out that the claim that is being made consistently to the profession is not true, it has not been true? That is my point. Dr. POLLARD. Senator, may I just comment on this recent publication of the AMA drug evaluations. This, I believe, is their first chapter on this, published May 20, 1968. As you go through the listing of all of the drugs they are listed by generic name in bold type, and in very small parenthesis is the trade name. I think that is a little along the line that you are talking about. Senator NELSON. Yes. Dr. ROSENOW. Senator, may I ask a question? If your feeling is that doctors should prescribe by generic name, would you have objection to them including also the brand name or the manufacturer? Senator NELSON. First let me say, doctor, that I would not make any independent judgment of my own about what a physician ought to do. I have not decided what some of the authorities would do because I do not have any independent expertise of my own. The testimony of experts before the committee consistently has been that doctors ought to prescribe by generic name, but the doctor would have complete freedom to designate the brand that he wants. No one has testified before this committee that the doctor must prescribe by generic name and not indicate the manufacturer or brand. All of our testimony has been that he should be able to select the company if he desires to do so. So we have introduced legislation based upon the testimony of a number of highly regarded pharmacologists and physicians that the label should contain the generië name, and if desired by the physician, the brand name or the manufacturer himself. What is your view of that? Dr. RosENow. I personafly~ would have no objection-in fact, I would say over 30 years my attitude is changed about how much you should let the patient know anyhow. I think they ought to know as much as they can. That is as I get older. It is harder and harder to find out how to take care of people anyway. But I think with the American public traveling as much as they do and moving from place to place it is really a good idea to have on the label what the drug is, what drug he is taking, and what the dosage is. And preferably, I think I would like to know not only the generic name of that drug PAGENO="0440" 4730 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY but I would like to know which company makes it to see whether it is the one I am used to or not. I would have no objection to this. Dr. POLLARD. Senator, in our own institution, the University Hos- pital in Ann Arbor, we have required our pharmacy there that fills the prescriptions for any patient that we write prescriptions for to put on the label specifically what the product is and what the dosage is, and how many grains or milligrams, and what each tablet contains. So that is required, unless one ticks off a little area and indicates that this is not to be noted. Otherwise every prescription going out of there for at least, I think, the past 7 years has had written on the prescription exactly what it is. Senator NELSON. By official name or generic? Dr. POLLARD. I would have to check that to be sure. I think they write it merely the way the doctor has written it. And I say, in keeping with your comments, that the Chairman of our Department of Inter- nal Medicine encourages openly and constantly when the residents write their prescriltiOns, when they are ordering drugs, that they use the generic term. He prefers that. Senator NELSON. Thank you very much. We appreciate your taking the time to come here and present your very valuable testimony. Dr. POLLARD. Thank you very much, Senator, for this privilege. Dr. ROSENOW. Thank you very much. Senator NELSON. We are pleased to have you. Dr. ROSENOW. And I will send the information that you have requested. (The supplemental information submitted by Dr. Pollard follows:) THE AMERICAN COLLEGE OF PHYSICIANS ADVERTISING IN THE ANNALS OF INTERNAL MEDICINE-EXHIBITING AT THE ANNUAL SESSIONS The following criteria will be used in screening product advertising to be carried in the Annals of Internal Medicine publication and for exhibition of the Annual Sessions of the American College of Physicians. The Committee on Advertising makes the final decision regarding the acceptability of all products and services to be advertised and exhibited and gives final approval of the advertisement or exhibit. The Commit- tee reserves the right to change these standards in the light of develop- ments in medicine or in industry. A. Eligibility for advertising and ewlii biting I. Products or services.-Only those products or services relevant to the prac- tice of internal medicine or in allied specialties shall be eligible for advertising and exhibiting. 2. New drug applications.-No pharmaceutical products will be eligible for advertising or exhibiting until a New Drug Application from the Food and Drug Administration has become effective. 3. Institutional-type advertising.-Only that copy which is relevant to the practice of internal medicine and "public service" messages of interest to our physicians will be considered eligible for appearance in the ANNALS OF IN- TERNAL MEDICINE. 4. Special-purpose foods-Foods which are used by certain specific segments of the population who have specific diseases or conditions requiring foods with certain properties, are permitted. PAGENO="0441" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4731 B. Products not acceptable for advertising and exhibiting 1. General purpose foods.-Foods promoted for use by the population in gen- eral; Examples-Fruits, meats, eggs, bread, processed fruits and vegetables. 2. Beverages.-Alcoholic Beverages. 3. Miscellaneous products.-Tobaccos, cosmetics, patent drugs, automobiles, etc. C. Detailed information required on modified old and new products 1. New drugs.-A new drug is defined as follows: As a single active ingredient (e.g. reserpine, deserpidine), or an extract from a single source (e.g. alseroxylon, rauwolfia). 2. Modification on drugs of approved products.-A drug previously approved must be re-submitted for review if a modification of the drug has been made subsequently, for example such as a new salt or ester. 3. Combination of one or more drugs.-Combination of one or more drugs a~- ready considered acceptable-clearance will depend on rational grounds for justify- ing such a new combination. 4. Additional brand of product.-An additional brand of a product already considered acceptable (copy of proposed advertisement only need be submitted). In order for a pharmaceutical manufacturer to become eligible to advertise the products in the ANNALS OF INTERNAL MEDICINE, or to exhibit them at the annual meetings, the following data concerning a product must be submitted to the Committee for review before acceptance. This ruling applies to new products and on established drugs or equipment which have been modified. (1) Five copies of the currently approved package insert be forwarded to the American College of Physicians and addressed to the attention of the Advertising Manager. (2) Indicate whether approved by FDA. (b) Indicate whether approved by AMA or other publications. The Advertising Committee frequently seeks the opinions of consultants in determining the eligibility of products and suitability of claims. The Advertising Committee expects that the medical department of the pharmaceutical company has approved not only the product but the advertising copy before its submission. Drugs introduced before 1961 should include if available the package insert and other data supporting the efficacy, instructions of uses and relative safety of the product. Evidence of such medical department approval must be furnished on request. D. Advertisements for specific types and classes of products and services 1. Apparatus, instruments and devices.-The eligibility of medical equipment intended for preventive diagnostic or therapeutic purposes is determined by the Advertising Committee. Advertisement for new products and new claims should be accompanied by FIVE COPIES of information, presenting full and adequate scientific and technical data concerning the products' safety, operation and use- fulness, including the results of laboratory and clinical examination. These data may be either published or unpublished. Samples of apparatus, devices, equip- ment or instruments should not be submitted unless requested by the Committee. 2. Books.-A book may be requested for review so that its eligibility for ad- vertising may be determined. PAGENO="0442" 4732 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (3) Miscellaneous products and services.-Products or services not in the above classifications may be eligible for advertising provided they are closely related to the practice of internal medicine and can meet all requirements. E. Advertising or eahi bit copy After a product or service has been submitted for advertising in the AN- NALS OF INTERNAL MEDICINE, the Advertising Committee makes the final decisions regarding the acceptability of new copy. The Committee's decision in this regard will be guided by the following principles: (1) Advertisements should not be deceptive or misleading. The layout, art work and format of the advertisement should be such as to avoid confusion with the editorial content of the publication and be in good taste. The Com- mittee reserves the right to reject the format of the advertisement as it would appear in the ANNALS. It is understood this would be at a stage be- yond the approval of ordinary advertising copy. (2) The Committee reserves the right to. reject the format of any exhibit. (3) Advertisements should clearly identify the advertiser and the prod- uct being serviced or offered. (4) Unfair comparisons or offensively forward and unwarranted depre- ciation of a competitor's products or services will not be permitted. (5) Advertisements will not be accepted if they appear to, conflict with the principles of medical ethics. (G) Exaggerated or extravagantly worded copy will not be allowed. Any claims for superiority must be supported by evidence acceptable to the Committee. (7) Excerpts or quotations from published papers are acceptable provid- ing they do no,t distort the meaning intended by the author. Claims made within quotations must conform to the standards as unquoted claims. All exhibitors are prohibited from using any of the following tactics for pro- moting their products at our meetings: (1) Exhibitors shall not use any gimmicks, door prizes, lucky number drawings, etc. (2) There shall be no-button-holing doctors in the aisles. (3) High pressure "pitch" of any kind will not be permitted. (4) All exhibitors must conduct their exhibits, at all times, in a clean and dignified manner and at no time display a side-show atmosphere. Those exhibitors not abiding by the above regulations while attending the meeting will be immediately expelled. DEADLINE DATES Receipt of material for committee review Proposed advertising copy on pharmaceuticals or biologicals not previously advertised in the ANNALS, and NEW advertising copy only, on products already approved for advertising or exhibiting, must be submitted for Committee review at least two weeks before the Closing Date for advertising in the scheduled issue. It is imperative that FIVE COPIES each of currently approved package inserts and proposed advertising be submitted. Indicate whether approved by FDA, AMA, or other publications. Closing date The Closing Date for insertion orders is the 20th of the second month preced- ing publication. PAGENO="0443" 0 t~j EXHIBIT B ANNALS OF INTERNAL MEDICINE 1964 1965 1966 1967 1968 Amount Percent - Amount Percent Amount Percent Amount Percent Amount Percent Subscription revenue net of Commission $221 688 16 4 $244 511 17 3 $272 056 16 5 $291 078 15 6 $343 278 15 7 Advertising revenue net of Commission and discount 374, 060 27. 6 432, 597 30. 7 602, 802 36. 5 719, 747 38. 4 796, 947 36. 5 Total revenue from annals 595, 748 44. 0 677, 108 48. 0 874, 858 53. 0 1, 010, 825 54. 0 1, 140, 225 52. 2 Total revenue including annals 1, 353, 489 100. 0 1, 409, 301 100. 0 1, 649, 617 100. 0 1, 872, 455 100. 0 2, 184, 286 100. 0 FF2 PAGENO="0444" 4734 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (The subsequent supplemental information submitted by Dr. Rose- now follows:) THE AMERICAN COLLEGE OF PHYSICIANS, Philadelphia, Pa., April 7, 1969. MONOPOLY SUBCOMMITTEE OF THE SENATE SMALL BusINEss COMMITTEE, U.S. Senate, Washington, D.C. (Attention of Mr. Gordon) This letter is to give you additional information in response to Senator Nel- son's questions asked of Dr. Pollard and me recently. First of all the following is a breakdown of Exhibit B of our report to show what percentage of Advertising Revenue w-as represented by pharmaceutical advertising in the annals. 1967 1968 Amount Percent Amount Percent Pharmaceutical Instruments Books Other (miscellaneous) Breakdown for exhibit revenue: $823, 738 21.296 13,250 4, 160 95. 5 2.5 1.5 . 5 $898, 019 34,470 13,020 5, 670 94. 41 3.62 1.37 . 6 Pharmaceutical Instruments Books Other 58, 011 15, 795 11,391 11,091 60. 0 16.0 13. 0 11. 0 65, 350 27, 950 11,325 19, 100 53 23 10 14 A second question concerned our endowment fund and whether w-e had any stock in a pharmaceutical company. At the present time our total portfolio in invested capital is as follows: Market, as of Cost Feb. 28, 1969 Operatisg fund $307,912 $426,416 Endawment 3,524,830 3,945,303 Building fund 889, 835 1, 051,064 Total - 4,722, 577 5, 422, 783 Holdings in pharmaceutical stock: - Baxter Laboratories convertible 4 percent, Mar. 1, 1987__ 49,688 56,400 Rorer-Amchum 60, 788 54, 000 Total 110,476 110,400 Psrcent 2. 3 2.0 It can be seen that 2% of the total invested capital is in pharmaceutical com- panies. I remind you that we invest our funds upon advice of Drexel, Harriman and Ripley. I have checked with our Editors and we have not commented on the AMA journal article November 18, 1968 on Generic Inequivalence of Drugs by Alan B. Varley, M.D. During the past couple of years we have rejected a number of ads which were so totally unsuited to a journal devoted to Internal Medicine that we did not circulate to the committee. The following represent those we would have re- jected if the agency did not comply with our request to make certain changes. 1. Stuart Company-Ad submitted by Sudler & Hennessey Company for Myli- con (brand of simethicone). We asked that the statement "This liberating action of Mylicon is unlikely to mask organic disease-And side effects and seldom re- ported-even during prolonged use." They dropped this and the ad appeared in the August, 1967 issue of Annals of Internal Medicine. 2. Rowell Laboratories-Agency Barickman & Shelders Advertising, Inc. Product-Cortenema.' Attached is copy of our letter dated October 4, 1967. The company did not submit further ads for this product. PAGENO="0445" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4735 3. A. H. Robins Company-Agency Martin & Woltz, Inc. Product-Robitussin DM, Entozyme, and Exna-attached is copy of o~ir letter of December 28, 1966. None of these have run as ads in our journal. 4. Pharmacia Laboratories Inc.-Agency Paul Klemtner & Company-Product Azulfadine. Attached is copy of our letters of December 14, 1966 and December 20, 1966 indicating their willingness to comply. 5. Organon, Inc.-Agency Erwin Wasey, Inc.-Product Accellerase. Attached note dated December 15, 1966-Did not comply with suggestion so agency can- celled contract. 6. Massengill Laboratories-Agency Ramsdell Buckley & Company-Product Obedrin LA. Attached is letter of November 23, 1966 speaks for itself. 7. Lederle Laboratories-Product Levoprome submitted for exhibit. Rejected by committee because no reprints were submitted to substantiate claims made. 8. Key Pharmaceuticals-Product Nitroglyn. See attached letters dated Jan- uary 13, 1967, to the company and letter of January 24, 1966 making changes requested. 9. Bristol Laboratories-Product Prostaphlin-Agency Sudler & Hennessey. This is the one I mentioned at the hearing. I was in error at the time this oc- curred and also that they cancelled all ads with us. They only cancelled the ads for Prostaphlin but continued advertising other products namely, Kantrex-Jan- nary to June, 1967 and April to November, 1968-Polycillin-all of 1967 and Jan- uary, 1968; May & October to December, 1968. Attached letters explain our im- passe over Prostaphin. Memo to me October 18, 1963 Letter to Mr. Phillips, A.C.P. Advertising Manager from Mr. Wilkins. Letter, October 28, 1963 to Mr. Wilkins from Mr. Phillips. Intermittently we had inquiries about again considering a Prostaphlin ad- My letter of March 18, 1968 is self explanatory. Finally my letter of March 19, 1969 resolves the problem because the company has submitted copy satisfactory to the committee. If there are other questions we can answer please write me. Sincerely, EDWARD C. ROSENOW, Jr., M.D., Eceecutive Director. Memo to: E. C. Rosenow, Jr., M.D. From: Andrew P. Phillips. Date: October 18, 1963. Re Bristol Laboratories, Prostaphlin advertisement scheduled for the November issue. In reviewing the November proofs sent from Lancaster Press I noted that the changes which the committee requested has not been made. The changes are as follows: The heading of the advertisement reads "Whenever You Suspect Staff", the committee suggested that this copy be changed to read "In Staff Infec- tions." Also the word "suspected" appearing on the first line in the first paragraph would be changed to the word "present" and that the asterisk appearing in the close of the first sentence and foot note at the bottom of the page be deleted. I immediately called the agency regarding these changes. After a lengthy con- versation, the agency called Bristol Laboratories and they had informed us that no change would be made in the copy as it is a repeat of the October advertise- ment. Their interpretation of our letter was that they felt this being a repeat would not require a change. However, they are aware that all future advertise- ments must be approved by the committee before they precede in preparing plates. The complete issue is at Lancaster Press and locked-up to run. If we cancelled this spread it would have meant using College ads, which unfortunately we can- not supply. Therefore, I informed the agency and client that we would run this advertisement for this issue. I realized our instructions could be interpreted as future copy as opposed to New Copy, to future advertisement which could be repeats of previous insertions. PAGENO="0446" 4736 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SUDLER & HENNESSEY, INC., iVew York, October 21, 1963. Mr. ANDREW P. PHILLIPS Advertising Manager, The American College of Physicians, Philadelphia, Pa. DEAR Mn. PHILLIPS. Regarding your letter to Mr. Rich of October 18th, we in- tend to rerun the present Prostaphlin ad "Whenever you suspect staph" in the December issue of the Annals of Internal Medicine. We do not intend to change this ad at this time or in the foreseeable future. As I believe I mentioned to you before, the decision to accept or reject the ad is yours. Bristol supports this position. Sincerely, WALTER K. WILKINS. OCTOBER 28, 1963. Mr. WALTER K. WILKINs, Sudler c~ Hennessey, Inc. New York, NY DEAR MR. WILKINS. Thank you for the reply to my letter regarding the copy revisions for your client's Prostaphlin advertisement, scheduled to run in the December, 1963 issue of the Annals of Internal Medicine. Unfortunately, there seems to have been a misunderstanding on the accept- ance of our request for copy changes. We understood from Dr. Kitto's conversa- tion with our Executive Director, Dr. Rosenow, that your client knew the October and November advertisements were accepted on the premise that the revisions would be made in all forthcoming advertisements on this product. The copy changes though slight were important, e.g. quoting one of the Committee members, "I do not like the statement, `whenever you suspect staph-start with Prostaphlin". One should never start treating staph just on suspicion and an A-i physician would consider the best drug. In other words this advertisement constitutes poor teaching". The word "suspect" in the caption of the advertisement was to be deleted and "suspected" in the body of type to be changed to "present". The caption would read "In staph Infections". Also, the asterisk at the end of the first sentence and the footnote to be deleted. I have referred your letter to Dr. Rosenow and he feels inasmuch as the ruling for copy changes requested by authorized members of our Committee, applies to all of our advertisers, the Prostalphin advertisement could not run in our journal without being revised. Sincerely, ANDREW P. PHILLIPS, Advertisement Man~ager. JANUARY 13, 1966. Mr. BERNARD FRIEDLAND, Assistant Medical Director, Key Pharmaceuticals, Inc., Miami, Fla. DEAR MR. FRIEDLAND: While "Nitroglyn" may be a fine product the Committee on Advertising feels the copy is ambiguous and misleading when you state "Gives 24-hour protection against attacks *and possible myocardial damage". This claim is not substantiated in the material forwarded to us, if it was please indicate where or submit additional information which will prove this statement. It will, therefore, be necessary for you to substantiate this claim or revise your ad copy before this ad can appear in the Annals of Internal Medicine. Sincerely yours, EDWARD C. RosENow, Jr., M.D. Ewecutive Director. KEY PHARMACEUTICALS, INC., Miami, Fla., Jan/u ary 24, 1966. ANNALS OF INTERNAL MEDICINE, The American College of Physicians, Philadelphia, Pa. (Attention of Edward C. Rosenow, Jr., M.D.). GENTLEMAN: In reply to your letter of 13 January concerning the advertising copy for our product Nitroglyn®, we have studied your comments, and wish to PAGENO="0447" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4737 submit the following change in the copy which you brought to Our attention. Item 1. has been amended to read "Give 24-hour protection against attacks, taken twice or three times a day ;" We trust that this change now meets with the approval of the Committee on Advertising, and will be satisfactory for the desired insertions. Sincerely yours, BERNARD FRIEDLAND, Assistant Medical Director. NOVEMBER 23, 1906. Mr. FRANK HENSOHEL, Ramsdell, Buckley c~ Go., Inc., Philadelphia~ Pa. DEAR Mn. HENSCHEL: This is to confirm our telephone conservation of yester- day regarding the advertisement your client wishes to run in the January, 1907 issue of the Annals of Internal Medicine. As I mentioned the members of our committee feel "Holy flabbergast-it's Fatman," does not lend itself to our journal. At the present time I understand you will repeat the "Jim Nathans sat here" advertisement which ran in the December : issue. I would like to mention, how- ever, several members of the committee have told me they feel the "Jim Nathans" ad is more in keeping with our journal and an eye-catcher. I will assume that a revised insertion order will follow shortly. Sincerely yours, ANDREW P. PHILLIPS, Advertising Manager. DECEMBER 14, 1960. Mrs. LORRAINE MoonE, Space Bvyer, Paul Klerntncr i Go., Inc., New York, N.Y. DEAR MRS. MOORE: I have submitted the "Azulfidine" advertisement #4700 one drug has distinguished itself by having a place in the treatment of almost any patient with ulcerative colitis-Azülfidine, the mainstay of therapy for colitis. The following, therefore, is an excessive claim. "But, to achieve the ultimate aim of restoring normal intestinal function, one drug has distinguished itself by having a place in the treatment of almost any patient with ulcerative colitis-Azulfidine, the mainstay of therapy for ulcerative colitis." Unless this is revised we will not be able to run this advertisement in our journal. Sincerely yours, (Miss) BARBARA RAIJSCH, Secretary to Mr. Phillips, Advertising Manager. DECEMBER 15, 1906. Dn. RosENow: Organon, `Accelerace' #4706 Rev, has been submitted to appear in the February, 1967 Issue. The following comments were made regarding this product: Dr. Rosenow.-"We have no objection to Accelerase but do object to combin- ing with P-B. Therefore, they should remove that from ad." Dr. Frost.-"This product is no different from numerous others in our adver- tising. If we are not going to accept this product then I think we should review our position entirely and eliminate all products that are not scientifically proven to be effective. Believe Committee should establish a few guidelines and princi- ples that are consistent rather than saying as was the old procedure of "it isn't valuable but won't do harm." Dr. Rouse.-"No clinical material included. It appears to me to be `shot gun' therapy." Dr. Wise.-"See letter from Dr. Franz Goldstein." Please advise. PAGENO="0448" 4738 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DECEMBER 20, 1966. Mrs. LORRAINE MOORE, Space Buyer, Paul Klemtner ~ Co., Inc., New York, N.Y. DEAR MRs. MOORE: This is to confirm our telephone conversation of today re- garding the "Azulfidine" advertisement #4706 which has been revised to read: "Many patients-many measures-from the use of simple antispasmodics to intensive psychotherapy. But one drug has consistently proven its value in the treatment of each and every stage of ulcerative colitis-Azulfidine (salicylasosUlfaPYridifle) the mainstay of therapy of ulcerative colitis." The Committee has approved the above for insertion in the Annals of Internal Medicine. Your insertion order was received in this office yesterday. Sincerely yours, (Miss) BABBARA RAuscM, Secretary to Mr. Phillips, Advertising Manager. REVISED CoPY FOR PHAi~MACIA LABORATORIES "AZTJLFIDINE" Many patients-many measures-from the use of simple antispasmodics to in- tensive psychotherapy. But one drug has consistently proven its value in the treatment of each and every stage of ulcerative colitis-Azulfidine (salicylazo- sulfapyridifle) the mainstay of therapy of ulcerative colitis. DECEMBER 28, 1966. Miss HELEN R. LLoYD, Martin ~ Woltz, Inc., Richrnoiid, Va. DEAR Miss LLOYD: Earlier this month you sent material to us for Committee review on "RObit~55ifl-DM," "Entozyme" and "EXNA" for your client, A. H. Robins Company. These products have been submitted to our Committee, however, they feel that no evidence has been given to show that adding DM to Rohitussin does anything more than Robitussin alone. "EXNA" has been approved but ad copy was not submitted and must be in the future before it appears in the Annals, as I am sure you are aware. Regarding "Entozyme", although there is no advertising copy presented this product is acceptable as a pancreatic substitution therapy but is unrelated to the relief of functional gastrointestinal disorders and any copy should not include such an inference. I would appreciate it if you could send addditional information on the Robitus- sin DM product and ad copy on all of these ads for further consideration by our Committee. I will be looking forward to hearing from you in the near future. Sincerely yours, ANDREW P. PHILLIPs, Advertising Manager. OCTOBER 4, 1967. Miss ELAINE SKJELSTAD, Barickman ~ S/i elders Advertising, Inc., Minneapolis, ]Iinn. DEAR Miss SKJELSTAD This is to inform you that the "Cortenema" advertise- ment for your client, Roweli Laboratories, Inc., has been approved by our College Committee and was scheduled to appear in the October and November, 1967 issues of the Annals of Internal Medicine as per your instructions received in this office. Our Committee feels, however, that the advertisement should state that signifi- cant absorbtion occurs. They also feel it is an exaggeration to say "an absorbable steroid is safe and should be used in most cases of chronic ulcerative colitis". They feel it w-ould be better to say "in cases of chronic ulcerative colitis in which steroids would be indicated". We would appreciate your revising this advertisement before it reappears in the Annals. Thank you so much for your cooperation in this matter. If you should have any questions regarding this revision please feel free to contact me. Sincerely yours, ANDREW P. PHILLIPs, Advertising Manager. PAGENO="0449" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4739 MARCH 18, 1968. Mr. WILLIAM W. GORDON, Product Advertising Manager, Bristol Laboratories, Syracuse, N.Y. DEAR Mit. GORDON: Referring to your letter to Mr. Phillips, you do not inter- pret his letter of March 8th correctly. I can understand why you interpreted it as you do, however, the long standing objection goes back to 1003 and the objec- tion we have is to the statement which you have put in the middle of the second page in bold print which states "Start therapy immediately with Prostaphlin". The members of the Committee feel that this is generally bad advise and is not acceptable unless it is agreed by a clear statement that a staphylococcus or other suitable infection has been diagnosed. Until you are willing to change this statement the Committee will not accept the ad as proposed. In January of 1007 Dr. Robert Wise wrote a long letter to your President, Mr. J. D. McNitt, explaining in detail our feeling about this type of advertising statement. I would be happy to discuss this further with your medical department. Sincerely, EDWARD C. RosaNow, Jr., M.D. Eceecutive Director. MARcH 14, 1069. Mr. JOHN L. ROBINSON, Director of Promotion, Bristol Laboratories, Syracuse, N.Y. DEAR MR. RoBINSoN: I am pleased to inform you that the College Committee on Advertising has approved ad #8433 for your product Prostaphlin. Also ap- proved is "Kantrek" advertisement #8345. These ads will be scheduled to appear in the May, 1969 issue of the Annals of Internal Medicine upon receipt of your further instructions. Sincerely, (Miss) BARBAB4 RAnSOM, Secretary to Mr. Phillips, Advertising Manager. Senator NELSON. Senator Hruska of Nebraska is here, I believe, to introduce our next witness. We are very pleased to have the distin- guished senior Senator from Nebraska appear here this morning. STATEMENT OP HON. ROMAN L. HRUSKA, A U.S. SENATOR PROM THE STATE OP NEBRASKA Senator HRUSKA. Thank you, very much. It is my happy privilege today to introduce your next witness, a constituent and good friend of mine, and a long-time practitioner in the city of Omaha. He is Dr. Robert S. Long. He got his doctor of medicine degree in the University of Nebraska. He served as intern and resident of the Harvard Medical Service City Hospital, and was a fellow in internal medicine at the Lehigh Clinic in Boston. He served as a major in the Medical Corps of the U.S. Army, and has engaged in the practice of internal medicine in Omaha since 1947. He is a fellow of the American College of Physicians, and currently president of the American Society of Internal Medicine. I would ask unanimous consent, Mr. Chairman, that a biographical sketch a little more detailed in character be inserted in toto in the record. Senator NELSON. Senator, Dr. Long has submitted a biographical sketch. And it will be printed in the record immediately prior to Dr. Long's statement. 81-280-69--pt. 11-29 PAGENO="0450" 4740 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator HRUSKA. And now, Dr. Long, I turn you over to this very generous and distinguished chairman of this subcommittee. Dr. LONG. Thank you very much, Senator. Senator RRUSKA. And with your permission I will go back to the Appropriations Committee where I have a hearing. Senator NELSON. On the way out you may get into some argument about the use of that word "generous". Thank you, Senator. We will place Dr. Long's biographical statement in the record at this point. (The biographical sketch follows:) BIOGRAPHICAL SKETCH OF ROBERT S. LO~cG, M.D., OMAHA, NEBR. 1. President, American Society of Internal Medicine. 2. Diplomate, American Board of Internal Medicine. 3. Fellow, American College of Physicians. 4. Associate Professor Internal Medicine (Volunteer Faculty), University of Nebraska College of Medicine. 5. Associate Medical Director and Consultant on Medicare for Mutual of Omaha. 6. Member, Medical Relations Committee Health Insurance Council of America. 7. Member, Public Relations Committee Medical Section American Life Con- vention. 8. Chairman, Insurance Committee Omaha Douglas County Medical Society. 9. Member, Coding and Relative Values Committee, Nebraska State Medical Association. 10. Member, American Therapeutic Society, American Rheumatism Associa- tion, American Heart Association, American Medical Association, and other medical scientific societies. 11. Clinical Investigation of New Drugs prior to release Cortisone, ACTH, Diuril, Orinase, Tapazole, Decadron, Prostaphlin, Valium, and others. 12. Past-President Medical Staff Nebraska Methodist Hospital. 13. Private practice of Internal Medicine in Omaha, Nebraska since 1947. 14. Major, Medical Corps, AUS, World War II with overseas service as As- sistant Chief of Medical Service, 98th General Hospital. 15. Born Cowles, Nebraska, February 25, 1916. B.Sc. and M.D. University of Nebraska, Intern and Resident Harvard Medical Service City Hospital, Fellow in Internal Medicine The Lahey Clinic, Boston, Massachusetts, Married, 2 chil- dren. STATEMENT OP DR. ROBERT S. LONG, PRESIDENT OP THE AMERICAN SOCIETY OP INTERNAL MEDICINE Dr. LONG. Senator, I brought with me some items which I would like for you to see. And I brought some extra copies of the memoran- dum which will illustrate my statement. One of my organizations I represent here today does in general deal with internal medicine. And I have here some specific data that you requested in your letter that I did not have available before. Senator NELSON. Thank you very much, Doctor. Do you have an extra set of these memorandums? Dr. LONG. Yes, I have it here. Senator NELSON. May I ask at the beginning, does this memorandum that you submit have a breakdown of the advertising by source, that is, drug manufacturers and other sources? Dr. LONG. The advertising in the Internist, of which you have a copy in that little bundle right in front of you, is almost entirely drugs. PAGENO="0451" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4741 Occasionally I have an advertisement for an instrument. But I have no breakdown, sir. Senator NFi.soN. It is almost entirely pharmaceutical. Dr. LONG. Pharmaceutical products, yes. Senator NELSON. This memorandum will be printed in the record at this point. (The document referred to follows:) MEMORANDUM AMERICAN SOCIETY OF INTERNAL MEDICINE, $an Francisco, Calif., March 11, 1969. rfo: Robert S. Long, M.D. From: W. R. Ramsey. Subject: ASIM finances-5 year period. The following figures are provided in accordance with your request: Donations Advertising Period Dues income income Cash Services I 1968-69 2 $401,046.50 $4,275.83 1967-68 3 363, 200. 00 10. 113. 84 $5, 000. 00 $476. 09 1966-67 ~261, 505. 00 8, 558. 90 500. 00 619. 54 1965-66 233, 790. 00 5. 830. 80 b. 711. 15 338. 10 1964-63 225, 600. 00 3, 941. 76 6 3, 216. 20 497. 54 7200.00 1963-64 152,105.00 1,606.45 64,3.0.00 7700.00 1 Binders for house of delegates meeting and plastic briefcases for delegates. 2 Dues increased to $50 per year. 3 Dues increased to $40 per year. 4 Exhibits: Our records indicate exhibits were discontinued after the 1966 annual session. 1 Dues increased to $30 per year. 6 Exhibits. 7 Grants. Senator NELSON. Dr. Long, we are very pleased to have you take the time to come here today to present your testimony. You may present it in whatever fashion you desire. If you wish to depart from it and elaborate on any aspect of it, feel free to do so. Dr. LONG. Thank you, Senator Nelson. I think my statement is relatively shOrt and it will take me only a few minutes to read it for the record. I think our best interest would be served timewise and otherwise if I might read this first. This will then perhaps give you a clue as to any questions you might wish to ask subsequently. Senator Nelson and members of the committee, I am grateful for this opportunity to appear before your committee to present my views regarding some of the matters you have~ under consideration~ particu- larly the responsibilities of practicing physicians in the prescribing and administration of drugs, biologicals, and chemical agents in the treat- ment of patients, and the relationships between physicians and organi- zations of physicians and the drug industry. I am the president of the American Society of Internal Medicine, an organization of approximately 10,500 specialists in the field of internal medicine. Senator NELSON. What is the total number of internists in the country? Dr. LONG. This would be a little hard to judge. There are some 40,000 physicians who are self-designated internists in the AMA Directory PAGENO="0452" 4742 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of some 300,000 physicians. A sizable percentage of those are not men whom those of us who took the additional training would categorize entirely as specialists in internal medicine. By that designation I think they mean to indicate that they restrict their practice to the field, in other words, they do not do surgery, let us say, or deliver babies, and so forth, whereas in our organization, as I will indicate in a moment, our 10,500 specialists who must meet certain requirements of training in order to belong. I think a realistic figure, in answer to your question, as close as he could get it, would be somewhere in the neighborhood of 25,000, per- haps, 20,000 to 25,000. Senator NELSON. Who are internists? Dr. Loxc. Who are qualified specialists in the field; yes. On February 4, 1969 I mailed to you. a copy of the bylaws of our organization, several copies of our monthly Newsletter, a pamphlet entitled "Aims and Purposes of ASIM", and a brief biographical sketch of myself, I have brought with me today a few of the pamphlets and other publications of our society as well as a roster of our member- ship and a list of our committees and councils.1 All our active members are doctors of medicine who have completed an internship, three years of special training in internal medicine and 2 years of practice in the specialty. Our basic goal is to assure that high quality medical care is rendered to all. We are especially concerned with the working domain of medical practice, and with the profes- sional, socioeconomic and political conditions under which such prac- tice is carried out, whether in the hospital, the physician's office, the patient's home or elsewhere. Our efforts have to do primarily with the practical aspects of how to translate medical science and knowledge into the day-to-day care of sick patients in the most efficient, effective, and economical way possible without sacrificing any of the quality of such care. Inasmuch as the specialty of internal medicine has to do with the diagnosis and treatment of diseases and disorders by nonsurgical means, you would know that my training, experience, and interest have been in the use of drugs and related materials in the practice of medicine. While I have had some experience in the clinical investiga- tion of drugs both in my private practice and in connection with my teaching of students at the University of Nebraska College of Medi- cine, my principal knowledge and experience have been gained in the study and use of drugs and related materials in the day-to-day prac- tice of medicine with private patients. I served for many years on the pharmacy committee of the Nebraska Methodist Hospital in Omaha, Nebr. on the executive committee for 10 years, and was chief of staff for 2 years. In these positions I gained some knowledge as to the practical problems involved in operating a pharmacy in a large, private, general, metropolitan hospital. My father was a pharmacist, so I know something, too, of the private druggist's problems from his side of the counter. I have been active in several organized medical societies for many years, including the American Therapeutic Society, an organization which has to do with the scientific study and practical application of ~ Material retained In committee files. PAGENO="0453" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4743 the use of drugs in clinical medicine, the American Diabetes Associa- tion, the American Rheumatism Association, the American Heart As- sociation and others. These activities have naturally brought me in contact with many pharmaceutical companies and their representa- tives in scientific matters as well as in business matters having to do with arrangements for meetings, contributions for clinical research and similar joint projects. With respect to the internal organization and operation of medical societies themselves, I have had experience as an officer in many of them at the State and local level. For the past 6 years I have been a member of the board of trustees of the American Society of Internal Medicine and president this past year. In this position I have necessarily become familiar with the financial as well as all other aspects of the operation of these organizations. As the principal liaision officer. I have spent a great deal of time with the officers of other professional organizations in the health care field as well as with governmental agencies having to do with health care matters both at the national and State level. I have been interested and active in the health insurance field for many years. This, of course, involves the insurance considerations related to the use of drugs as well as other matters pertaining to health care insurance. I am associate medical director of Mutual of Omaha and their consultant on medicare. Mutual is one of the fiscal intermediaries for the Department of HEW in this program as well as for the Department of Defense in the CHAMPUS program, formerly known as military medicare. I will be in Baltimore at SSA headquarters the next 2 days for a regional meeting of medical direc- tors and consultants of the fiscal intermediaries for the medicare pro- gram. One of the important subjects wewill discuss is the use of drugs and related materials in the program. I have read many of the press releases and some of the official testimony given to this committee. If I can make any contribution which might be of help to you I believe it would be in the area of the relationships between the drug industry and organized medical societies and in the areas involved in the practical translation of medical scientific knowledge to the care of patients. I will be glad to answer any questions that I can. PHYSICIAN EESPONSIBILITY With respect to the prescribing drugs, I believe it is the physician's responsibility to be fully informed about any of the drugs he prescribes_-the dose, the expected pharmacologic effects, side effects, toxicity and all similar matters. It is equally important for him to know his patient because the identical drug may produce an entirely different pharmacologic effect in one person than another. Dosage requirements and tolerances may vary widely in different patients and even in the same patient at different times. Treatment with drugs, as with all other modalities, should be highly individualized. Physicians have an economic responsibility to their patients too, and some consideration should be given to the cost of drugs prescribed so long as cost is not the sole determining factor. If a cheaper drug will not accomplish the desired result, then obviously it is not cheaper PAGENO="0454" 4744 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY at all but really more expensive and the delay in obtaining the desired result might be harmful to the patient. Naturally, no prescribing physician should have any secondary financial gain in prescribing one drug or one brand as compared with another. He should always be guided by what he believes to be best for his patient. Senator NELSON. In what way does the sole practitioner decide to prescribe one drug at a certain price and not another which may be equivalent? Dr. LoNG. In the final analysis, Senator, it is not the advertising or the claims of the pharmaceutical houses that determine what we prescribe. Myself and all the physicians whom I know, and have known over the years, decide what kind of a drug to prescribe and which drug, based upon our examining our patient, and talking with our patient, and prescribing for the patient, and then reexaminating, reevaluating, and assessing the results obtained. When we start out initially to prescribe a new drug for the very first time, this, of course, happens. Then we depend upon information we have obtained about this drug from reading in the scientific medical literature, from hearing about it at medical meetings as previously described this morning by Dr. Pollard, or by talking with our col- leagues formally and informally as we meet together. Senator NELSON. What I was getting at, if you have a cheaper drug which would not accomplish the desired result, then obviously it is not cheaper at all? Dr. Loxo. Yes. Senator NELSON. To use the example I have used here before be- cause it is based on the medical letter on prednisone, the price to pharmacies is $17.90 for Meticorten and $17.80 for Paracort. It drops down to $2.45 for Merck, and then to $1.80 and 50 cents for Wohns. And then the Letter said that the laboratory testing was done for them and all met lISP standards, and that in their consulting with clinicians they found they were equivalent. On what ground would the doctor, the sole practicing physician, decide that, say, Meticorten, at $17.90 to the pharmacist, was better than Merck's Deltasone at $2.20? How does a. physician practicing on his own make that decision? Dr. LONG. A practitioner practicing alone makes a decision based on his results and his experience with the drug. And if he prescribes a certain drug, and in his hands it works well, and in his hands he can predict with reasonable accuracy how his patients will respond to it to given dosage levels, and can predict with reasonable accuracy, when, a.t what levels, and what periods of time he may be in trouble with side effects or complications or unwanted effects from the drugs, if he becomes, then, thoroughly familiar, I think it is understandable that lie might be hesitant to change on the basis of price alone, unless and until the time comes that someone-and this does come to all of us in some instances-and I think prednisone is a good example- unless and until it can be shown and demonstrated to him on the basis of the experience of people in whom he has confidence, on the basis of reports in medical journals in which he has confidence, if then it can be demonstrated that an equivalent product at a lower price is in fact therapeutically equivalent, not just lISP, which does not really mean much. Senator NELSON. Pardon? PAGENO="0455" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4745 Dr. LONG. I think therapeutic equivalency is an entirely different matter than chemical equivalency. Senator NELSON. Do I understand you to say that the USP standard did not mean very much? Dr. LONG. It does not mean very much with respect to therapeutic results. Let us take the old common aspirin, for example, aspirin grains five, TJSP. You can find on the market lots of different kinds of aspirin, some at 9 cents a hundred, if you will, and some at 49 cents a hundred. And in some instances there is no difference, perhaps, between the 9 cents and 49 cents. But in other instances there is. Be- cause there is a difference in the way the tablet is compounded, the dis- integration rate, the permissible-even under lISP standards the permissible variations in quantities of something other than pure acetylsalicylic acid may be permitted up to certain tolerances of purity. So that, therapeutically, equivalency is a good deal more im- portant to the physician than the term lISP alone. So I think perhaps I should change my statement to say that lISP does not mean any- thing. It means a good deal, of course, because it does tell you about the chemical quantities that are in there, and the tolerance limits that are permitted for impurities, if you will, within a given product. lISP does provide for that. But in addition to that, one needs to know some- thing about biologic or therapeutic equivalency, which may be affected by many many things, as you know. Senator NELSON. It is the position of the lISP as well as many others, including Dr. Modell who testified here, that if a drug meets TJSP standards it is therapeutically equivalent until they find some evi- dence to the contrary. In other words, the best knowledge that the pro- fession has, physicians as well as pharmacologists, is put into the lISP sLandards, they may not have all the knowledge, but when something new is discovered they put it into the standard. So their position is that if it meets the standard it is therapeutically equivalent according to the best available expertise. I notice you are shaking your head. Dr. LONG. I do not agree, Senator. Senator NELSON. Do you have a specific example of a case where two drugs meet the tTSP standards and were proven not to be therapeuti- cally equivalent? Dr. LONG. Oh, yes. FDA has that, for example, in chloramphenicol. Senator NELSON. As an example, the FDA does not say they were not therapeutically equivalent. They just did not reach the same blood level. Dr. Ley will tell you that they did not have any test to find Chlo- romycetin vis-a-vis the two that did not meet the Chloromycetin level. There is no test to say that they are not therapeutically equivalent. So apart from that, FDA simply says there is no proof on therapeuti- cally equivalency. Do you have another example? Dr. LONG. I think there are many examples. I did not research this subject because I did not come prepared to testify on that particular line of testimony, Senator. But I can tell you, on the basis of my own experience, `and on the basis of experience of many of my colleagues with whom I visited, that there are situations in which there is not therapeutical equivalency. Senator NELSON. You say in your own experience. Do you have a case in which you had the drugs assayed, two drugs, and they both met tJSP standards, and they were not equivalent? PAGENO="0456" 4746 COMPETITIVE PROBLEMS ]i~ THE DRUG INDUSTRY Dr. LONG. That is correct. Senator NELSON. Testimonial proof or clinical proof? Dr. LONG. This is clinical proof. In the final analysis, Senator-and this is really the only point I want to make-in the final analysis it is iiot what it says in the drug manufacturers' advertising. It is what does the patient tell you about how he feels after he has taken this drug or that. And it is the clinical examination of the patient by physical means, physical examination, and examination of the patient by labo- ratory means, if you will, in addition, the total evaluation of the pa- tient. This to me is the therapeutic result. This is what happens to the guy who is sick. Senator NELSON. Do I understand you to be saying that if you pre- scribed a particular drug- Dr. LONG. Let us take a common one like aspirin. I treat a lot of people with arthritis. And I have over the years had many patients who on a given kind of aspirin-I cannot even tell you the name of it-let us say a cheap aspirin, if you will, or let us say a low-cost aspirin, if you will-and these patients with rheumatoid arthritis, for example, will take a dozen tablets a day, and do badly, they are just not comfortable, their joints are still stiff and painful and swollen, and then they will change to a different brand of aspirin-both of them plainly labeled IJSP-and they will immediately get relief from their symptoms on the same dose. Senator NELSON. Did they meet TJSP standards, is the question. You recognize- Dr. LONG. Let us say they are plainly labeled USP in both in- stances. Senator NELSON. That is not the question, because we know that brand names and generic name drugs go into the marketplace lacking adequate quality control and supervision and they cannot meet TJSP standards. The testimony before the committee by lISP and other dis- tinguished pharmacologists is that if they meet lISP standards they are therapeutically equivalent. I am asking did they, in fact, meet US? standards? Dr. LONG. I have to assume so, if the manufacturer is following the labeling law. I have the impression that he isviolating the law if he labels it lISP and it is not TJSP. Senator NELSON. Correct, and that is what is happening in both brand and generic names. And many of them are pulled off the mar- ket every year. But the real question we are getting at is-do you have a case? We have been seeking one. The reason I raise this, Doctor, is that we have been seeking one publicly in this forum for 2 years, and I would think that the manufacturers themselves would come up with an example. But they do not. And all I am saying is, do you have an example of two drugs meeting lISP standards and not being therapeutically equivalent? I do not mean testimonials, because I do not think that means much. Do you have a case in which you have done double blind testing with an adequate sample and proved that the 20 drugs that were assayed to meet USP standards are not therapeutically equivalent? That is the case that we have not been able to get. Dr. LONG. Well, as I say, I did not research this scientifically or in the medical literature. I am persuaded on the basis of my nearly 30 years of experience as a. practicing physician, and my contacts with PAGENO="0457" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4747 hundreds and thousands of physicians, I am persuaded that there is something else besides chemical equivalency that has to do with thera- peutic results in the treatment of patients. Senator NELSON. I think the TJSP will say that. Of course chemical equivalency-that includes coating and~ tablet pressing and all that? Dr. LONG. That is what I mean. Senator NELSON. But TJSP insists, they take all the best available knowledge, based upon all of their consultants, and put into the standard, the best knowledge that is known today. They will concede that some better knowledge may come later, and then they will put it into the standard. But as to the standard today, until additional evidence is produced they say that if drugs meet TJSP standards they are therapeutically equivalent. And only in the rarest of cir- cumstances has this not been true. Dr. LONG. I wonder why the statement is always put that way? Why would you not say that they are not therapeutically equivalent until it is proven that they are? Senator NELSON. The experience of the consultants and clinicians, pharmacologists, and authorities when they establish the standard is that if they meet the standard, they are equivalent. Dr. LONG. I think this is not the consensus of the opinion in my experience, or in my contacts with practicing physicians who have been taking care of sick people day after day and week after week and month after month. That consensus of experience is that thera- peutic equivalence and chemical equivalence are not always identical, that with the same dose of a given drtig in the same patient for the same disease, that brand X, let us say, the therapeutic results are not the same as with brand Y, if you will. Now, this may be true in many instances, that X and Y will result in the same. But I think there are many other instances in which this is not true. Senator NELSON. You see, the drug companies will argue, well, the coating will make a difference, the excipient will make a difference, the size of the granule will make a difference, how hard the tablet is pressed will make a difference. Everybody knows that. Dr. LONG. Yes. Senator NELSON. Including the TJSP. So they set a standard for dissolution, and the excipient, and so forth. And the amount of the active ingredient can only vary, depending upon again the consulta- tion with the experts, it has to have X percentage of the active in- gredient, and in aspirin it is 95 to 1O5~percent pure aspirin. And their consultan.ts advise that if you get within that tolerance you get the same result. All I am saying is, we have been asking for proof of in- stances where they meet the standard and were not equivalent, and we have received testimonials, but we have received nothing scientific from the drug industry or from any clinician or anybody ~lse, except what they stat.e what their personal experience has been. Well, in that kind of case it might be very well true that maybe they did not meet [TSP standard. None of the testimonials we have had, in the case where the drug was assayed to see whether it met [TSP standards first-that is our problem, trying to get that kind of a case. Dr. LONG. I think maybe if I read a little further I may answer your question in part, and then perhaps we will come back to it if you wish. PAGENO="0458" 4748 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY RELATIONSHIP OF PROFESSIONAL MEDICAL ORGANIZATIONS TO THE PI-IARMACEUTICAL INDUSTRY It is not only natural and inevitable but highly desirable that there be a c-lose relationship between the pharmaceutical industry and the medical profession. This is essential in the public interest and neces- sary in order for us to provide the best care and treatment that we- can for our patients. That is what we all want in the final analysis with the best care a-nd treatment that we can get for our patients. We are providing professional services for our patients in the course of which we use drugs, biologicals, instruments, and supplies of various kinds. We need to know something about the companies that provide these materials. At the same time, the drug, instrument, appliance, and other pro- ducers of materials used in health care need to know a good deal about the problems we practicing physicians have in usmg these materials in the care of patients. They need to know how and when and under what circumstances we use their products, and what the results are~ both good and had. Th~re is no way for us to find out what we need to know from each other without a continuing dialogue and exchange of information between us, in person as well as in writing. This necessarily takes place at an individual level, such as between the individual physician and the individual manufacturer's personal representative, and at an orga- niZational level. The latter is particularly important because of the complex matter of logistics. There are more than 300,000 physicians and several hundred manufacturers. To provide the necessary exchange of information on an individual basis obviously would be impossible. To try to do it on the basis of a single publication or even a few would be as impractical as to try to do it on the basis of a single meeting. Each of us has to get our message to the other in many different ways. The science of medicine, particularly as related to drugs and instru- mentation as well as techniques, has advanced so far and so rapidly in the pa-st 20 years that no one method of disseminating information, acquiring information, or translating it to the care of sick patients can suffice. It has become necessary for many different techniques and many different organizations to be developed to do the job. Just as we are all dependent on each other in the philosophic and scientific sense in the pursuit of our common goal, it necessarily fol- lows that there is a certain amount of financial interdependence too. It costs money to do research, to produce a drug or an instrument, to publish literature, and to have a meeting. It seems natural and logical that a manufacturer of drugs would provide information about his products in a magazine or journal published and read by physicians. In the same journal, of course, medical scientific information is trans- mitted from one physician to others. So long as the advertising a-nd the medical scientific information in the articles written by the physi- cia-n-authors is ethical, accurate, and honest t-hen the best interests of the public are being served. It is not t.he advertising campaign of the drug manufacturers, nor their contributions to medical organizations for scientific or social affairs that convinces the practitioner of the virtues or safety of a new or old drug, but only his own personal experience gained from listen- PAGENO="0459" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4749 ing to and examining his patients and his knowledge of the experience of his colleagues. I hope that this very sincere and dedicated committee will not be diverted in its efforts to help identify and solve some of the trouble- some socioeconomic problems related to the health care field by those few persons who presume to see some sort of collusion between the drug industry and practicing physicians which they believe exists to take unfair advantage of the public. Believe me, gentlemen, there is no exchange of material goods or servièes or money that I know of which is contrary to moral or statutory law or ethics. NATIONAL DRUG COMPENDIUM The matter of publication of a national drug compendium has been discussed at length and in detail by medical, governmental, and other organizations for several years. The consensus of opinion of practicing physicians generally is, I believe, that such an effort would not be de- sirable, practical, useful, or in the public interest. If such a book were to be all-inclusive, several volumes more than 3 inches thick would be required. It would have to be loose leaf and updated regularly and fre- quently. It would have to be compartmentalized for the best use of the different medical specialties, yet there is sufficient overlap in all that there would have to be some duplication of entires. It would, indeed, be difficult to find any agency or group of physicians, however knowl- edgeable, who could put such a mass of information together in read- ily usable form. By the time it was published and distributed, much of the informa- tion would be outdated. The editors would not dare put in anythin too new, yet much of the new is very, good and useful as time an experience later prove. It would be difficult to leave out some of the old, yet much of it is outdated or so very well known generally that it would be in the way. However much disclaimed, if published by or with the approval of the Government, the material contained in it would be interpreted as having legal Federal sanction. Then if a drug were used in the treat- ment of a condition not listed in "the book," or in a different dosage range, the physician might be presumed guilty of malpractice. Conversely, if a drug were listed as useful for a certain condition and the attending physician did not use it even for very good and acceptable reasons, then he might also be presumed guilty. A further disadvantage would be its use as a lever to impose com- pulsory prescribing by generic name. This simply cannot be, in my opinion, handled by the majority of practicing physicians. All of us prescribe some drugs by generic name, but we cannot possibly remem- ber all of the generic terms for all the drugs we are accustomed to prescribing. To be required to look them up in "the book" would use up too much valuable time and would further aggravate our existing health-manpower shortage. Further, and more importantly, a compendium would further con- fuse the question of generic equivalence. 1~Ve have already found out, as has the FDA, that drugs identified as being the same generically are not always the same clinically. Senator NELSON. I am not familiar with what the FDA found on that point. PAGENO="0460" 4750 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LONG. I do not have the citation with me. All I can tell you is that I have read this. And as I say, I did not come prepared to discuss that in detail. But I have read this in what I consider to be a reliable and authoritative publication. Gentlemen, the last book on therapy has not yet been written. What person, or committee, or agency is to say with finality that this or that vitamin is better than another, that this or that antibiotic should or should not be used, that the dosage range of this or that drug is from here to there but no less and no more, that this or that drug is very good for this condition but must never be used for that? I can think of nothing worse for the health and care of the American people than for individual physicians to be compelled, directly or by implication, to treat their patients according to a majority vote of a committee of other physicians or scientists, however honest, capable, and sincere the members of that committee might be. Treatment must be individualized and scientific areas where precise- ness of measurement is almost nonexistent should not be highly regu- lated. Pharmacology, toxicology, absorption factors, excretion factors, blood levels, bacterial sensitivity studies in the test tube and the like fail to inform us really of what drugs do at the cellular level. Until we have better methods for making such determinations, these studies, while necessary and important, are only gross guides for drug therapy. There are no "standardized" patients and I do not believe there can be any "standardized" drugs to meet their needs. Previous testimony before this committee indicates that more than 90 percent of prescriptions ifiled called for a product by brand name or the product of a particular manufacturer in whom the physician had placed his confidence. It also has been stated here that 86 percent of the dollars spent by the Federal Government went for the purchase of products of brand name manufacturers when all the testing and elabo- rate screening procedures were completed. Physicians, depending on manufacturer integrity to secure the high- est quality medicines for their patients-and Government, refusing to accept anything except scientific proof of quality-both arrived at the same drug counters to secure healing agents for those for whom they were responsible. DRUG LABELING FOR PATIENT The matter of labeling prescription drugs dispensed to a patient is a highly individual matter and often involves medical judgment which only the attending physician who knows his patient should exercise. I hold no brief for the physician who labels a bottle of medicine "take as directed," unless those directions are given in writing to the patient by the. physician. This is necessary in certain situations. It is my own practice to identify the name of the drug, the dosage schedule, and the purpose for which it is prescribed in most instances. Even here, there are exceptions. For example, there are certain patients who develop so much anxiety from seeing the name of a drug on the bottle when the possible harmful side effects of that drug have been discussed in re- cent newspaper and magazine articles, that it is better for them just not to know the name of it. Again, the doctor has to know his patient and act accordingly. A pa- tient should almost never he given the usual "package insert" to read. They already have enough anxiety about their condition without be- PAGENO="0461" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4751 ing frightened by reading information which they cannot possibly interpret properly without a medical background. One other item that I do not have in this written statement. Some- times when medicines are labeled to exactly what they are, ~t IS quite surprisnlg sometimes how often patients prescribe for other patients, or they exchange medicine, when the name of it is on the bottle. And there has been an article by one of the columnists in the newspaper telhiilg how, for example, some friends, neighbors, grandma, a rela- tive, or someone else, say, you have got some of that so-and-so medi- cine, I should take some, and how in that respect sometimes people take drugs that they should not be taking because their friend has it and they saw the name of it and recognized it from some article in the lay press. So that is one disadvantage. I think there are many advantages, but there is occasional disadvantages that I have run into. From the testimony given here previously as I have read it, I believe most witnesses and also this committee recognize the advantages and disadvantages of generic prescribing and everyone is generally agreed that the attending physician has the privilege and the duty to prescribe what lie believes to be best for the particular patient in the particular circumstances which exist at tIme time the decision must be made and that dispeilsing pharmacists should never make substitutions for the specific preparation prescribed. I will be glad to answer any questions I can. Thank you for your kind attention. Senator NELSON. Just so that it will be clear, I think, no witness that has testified here has suggested that the physician should not be able to designate the manufacturer or the brand. Dr. LONG. Yes, I read your staternentin the testimony to that effect. Senator NELSON. Thank you very much, Doctor, for taking time from your busy schedule to come here and testify. It has been very helpful to the committee. Thank you. Dr. LONG. Thank you, sir. Senator Nelson. The committee will meet at 10 o'clock tomorrow morning in room 4221, the Foreign Relations Committee room. (Whereupon, at 12:10 p.m., the subcommittee was recessed, to me- convene at 10 a.m., Wednesday, March 26, 1969.) PAGENO="0462" PAGENO="0463" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WEDNESDAY, MARCH 26, 1969 U.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMErTEE ON SMALL BusINir~ss, Washington, D.C. The subcommittee met, pursuant to recess, at 10: 10 a.m., in room 4221, New Senate Office Building, Senator Gaylord Nelson (chair- man of the subcommittee) presiding. Present: Senators Nelson and Dole. Also present: Chester H. Smith, staff director and general counsel; Benjamin Gordon, staff economist; and Elaine C. Dye, clerical as- sistant. Senator NELSON. Our witness this morning is Dr. Maynard I. Shapiro, president of the American Academy of General Practice. Dr. Shapiro, the committee is very pleased to have you take time from your busy schedule today and appear before the committee. STATEMENT OP PETER CHUMBRIS, CHIEF MINORITY COUNSEL OF THE ANTITRUST AND MONOPOLY SUBCOMMITTEE, COMMITTEE ON THE J~UDICIARY, U. S. SENATE Mr. CHUMBRIS. Good morning. My name is Peter Chumbris, I am chief minority cot~nse1 of the Antitrust and Monopoly Subcommittee of the Senate Judiciary Com- mittee, and I am appearing here this, morning on behalf of Senator Dirksen and Congressman Annunzio to introduce to you the witness, who is from the State of Illinois, Dr. Maynard Shapiro, president of the Academy of General Practice. Dr. Shapiro is a very highly professional gentleman and highly re- spected gentleman in his community. And it gives me great pleasure to introduce him to you this morning. Senator NELSON. Thank you very much; He comes here with very distinguished credentials and we are pleased to have you, Doctor, why don't you introduce your associates for the purposes of the record, and then if either of them wishes to ôomment, see that they identify themselves so that the record will be straight. STATEMENT OF DR. MAYNARD I. SHAPIRO, PRESIDENT OP THE AMERICAN ACADEMY OF GENERAL PRACTICE; ACCOMPANIED BY MAC F. GAHAL, EXECUTIVE DIRECTOR AND t+ENERAL COUNSEL; AND WALTER KEMP, SECRETARY, COMMISSION ON PUBLIC POLICY Dr. SHAPIRO. With me today on my right is Mr. Mac F. Cahal, executive director and general counsel of the academy. And on my left, Mr. Walter Kemp, secretary of its Commission on Public Policy. 4753 PAGENO="0464" 4754 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Your statement will be printed in full in the record. Did you submit a separate statement of biographical data, or did you wish to present anything in that regard? Dr. SHAPIRO. That can be submitted, Mr. Chairman.' Senator NELSON. If you wish, we would be pleased to print it in the record preceding your statement. Dr. SHAPIRO. Thank you. Senator NELSON. You may proceed to present your statement in any way you desire. If you wish to depart at any time to elaborate on any- thing you have said, feel free to do so. I assume you have no objection if we interrupt occasionally with questions, and if your associates wish to comment at any time, they are free to do so. Dr. S~&PIRo. We have abbreviated this statement to the maximum extent, Mr. Chairman, and possibly the flow of our prepared testimony would be best uninterrupted. However, I have no objection if it is necessary for clarity to stop at any time. Senator NELSON. Very well. Dr. SHAPIRO. Mr. Chairman, I am Dr. Maynard I. Shapiro, a family physician with offices at 7531 Stony Island Avenue in Chicago. I am also clinical associate professor of medicine at Chicago Medical School and director of medical education at Jackson Park Hospital. I am a member of the Medical Assistance Advisory Council of the Depart- ment of Health, Education, and Welfare. I am here today as president of the American Academy of General Practice. The academy is the Nation's second largest medical association and presently has more than 31,000 members. I have not read all or even most of the testimony presented since your committee hearings started almost 2 years ago. I will not pose as an expert on all health care matters but I can and do speak as a practicing family physician who is primarily concerned with people-be they healthy, ill, injured or infirm. Your letter asked for information about the academy, its member- ship, its admission requirements, its publications, it advertising accept- ance criteria, its advertising revenues and its other financial relation- ships with the drug industry. The letter closed with a suggestion that I comment on drum compendium proposals. I will attempt to give you the information you have requested and then add a few comments-in my official capacity as president of the academy. To become an active member of the academy, a physician must be engaged in the general practice of medicine, be a graduate of an approved medical school, be duly licensed to practice medicine and be a member of his State medical society. But, to remain a member, he must complete 150 hours of academy-approved postgraduate study every 3 years. The academy is the only national medical association which requires continuing postgraduate study. This should adequately illustrate the academys continuing deter- mination to maintain high health care standards. As another example, most recently, the academy, in conjunction with the section on general practice of the American Medical Association, has been successful in its determined efforts to establish an examining board for family practice. This board will certify to the competence of family physi- ~ See pp. 478~-478S, infra. PAGENO="0465" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 4755 cians who render the major portion of medical services delivered in this country today. We believe this latest development will swell the ranks of family physicians, an increase which is sorely needed in order to assure the availability of continuing comprehensive health care for the people of America. The academy publishes two journals, both primarily scientific. Senator NELSON. Would you name the two, Doctor? Dr. SHAPIRO. GP and the American Family Physician. Senator NELSON. I do not recall that you recite any place in your statement the circulation of each-or do you? Dr. SHAPIRO. GP is circulated to members on a subscription basis. The American Family Physician is circulated to all nonmember gen- eral practitioners in the country. Senator NELSON. Is that by subscription? Dr. SHAPIRO. No, sir. Senator NELSON. Is the GP by subscription? Dr. SHAPIRO. Yes, sir. Senator NELSON. And the one that is circulated to all family physi- cians is the American Family Physician? Dr. SHAPIRO. Yes, sir. Senator NELSON. And that is in the form of a newspaper? Dr. ShAPIRo. No, sir; it is a journal. Senator NELSON. The circulation is a total of how much, just in round figures? Mr. CAHAL. It is about 40,000. And GP is about 32,000. Senator NELSON. Thank you. Dr. SHAPIRO. Mr. Chairman, the American Family Physician con- tains the leading scientific articles from GP. But the difference in the two magazines is that GP contains much Academy information. Senator NELSON. Much Academy information? Dr. SHAPIRO. Yes, sir. Senator NELSON. What do you mean by that? Dr. SHAPIRO. Reports from chapters,reports on postgraduate courses for Academy members, things of that type. Senator NELSON. Are they separately edited and printed? Mr. CAHAL. Mr. Chairman, GP is the official journal of the Ameri- can Academy of General Practice, and as Dr. Shapiro stated, it goes on a subscription basis to all Academymembers 31,000 and about 1,500 nonmember subscribers, including libraries, et cetera. American Family Physicians is actually a reprint of the leading scientific articles which have appeared in GP magazine. American Family Physician goes to all general practitioners in the United States under age 65 who are not members of the Academy, who have not main- tained the 150-hour postgraduate training requirements. The combined circulation, therefore, is around 70,000. GP contains internal business matters pertaining to the organiza- tion. American Family Physician does not. Senator NELSON. On that point, the GP is supported by subscrip- tions. Is the American Family Physician supported by advertising? Mr. CAHAL. It is not self-sustaining. It takes advertising, but it is i~ot fully supported by that revenue. The Academy subsidizes it from its general revenues. Senator NELSON. What percent is the subsidy? 81-280-69-pt. il-30 PAGENO="0466" 4756 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. CAHAL. Well, we have lost about $100,000 a year on it in recent years. Senator NELSON. That is what percent of the total cost of getting it out? Mr. CAJIAL. I am afraid, Senator, I would only hazard a guess, but I would be glad to look that up and communicate with the committee secretary if you wish. I would say roughly its total revenues are prob- ably $300,000, and it costs approximately $400,000 to publish. But this is a hazardous guess on my part. Senator NELSON. Could you submit that for the record? Mr. CAHAL. I shall be glad to, sir.' Senator NELSON. Thank you. You may continue, Dr. Shapiro. Dr. SHAPIRO. One magazine goes to American AOademy of General Practice members, the other goes to nonmember family physicians. Advertising is screened by a group of physicians, all of whom we considered qualified to perform their task. We do not list the names of these physicians in our magazines because we believe they prefer a degree of anonymity. All are medical school faculty members and all, in our opinion, are well qualified to screen pharmaceutical advertising. In your letter, you asked about Academy income from pharmaceu- tical advertising. Exact figures would take substantial digging be- cause our advertisers include equipment companies, book publishers, and so forth. However, it would not be far off to say that our drug in- dustry advertising income has run between $1 million and $1.5 million a year since 1962. Our total advertising revenues-from both publications and includ- ing nondrug advertising-are as follows: 1962, $1,155,000; 1963, $1,236,000; 1964, $1,493,000; 1965, $1,587,000; 1966, $1,725,000; 1967, $1,538,000; for 11 months, because the fiscal year ended on November 30, 1968. Senator NELSON. But your books do not show a breakdown by source? Mr. CAHAL. Yes, Mr. Chairman, our annual financial statements show the revenues from subscription versus advertising. This is only advertising revenue, though, that Dr. Shapiro has given. Senator N~soN. That is what I was inquiring about. What amount is pharmaceutical industry, what amount is books, and what amount is surgical instruments, and so forth? Mr. CAnAL. As a matter of fact, our financial records do not segre- gate those classifications. Senator N~soN. We have a breakdown done by the Library of Congress, but it is only for the American Family Physician. I will submit it for the record. We did not get it from them on the UP. This one shows that in terms of space, we do not know what the dollars are, but in terms of space-drug advertising-as a percent of all adver- tising in 1967, was 91.5 percent.2 Mr. CAHAL. That would be my guess also. Senator NELSON. Do you have a figure on what percent of total income all advertising is, percent of total income for the Academy? Dr. SHAPIRO. Approximately 50 percent. `See pp. 4781-4786, infra. 2 See app. XIII, "A Study of Pharmaceutical Advertising in Selected Medical Journals," pp. 4863-4998, infra. PAGENO="0467" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4757 Senator NELSON. Fifty percent of the total income of the Academy is advertising? Dr. SHAPIRO. Yes, sir. Senator NELSON. And the rest is- Dr. SHAPIRO. Dues. Senator NELSON. Do you have, as a number of the other organiza- tions, have, revenue from displays at conventions, for example, by the drug industry? Dr. SHAPIRO. We do have, but our conventions are always a loss. Senator NELSON. But you do have have an income from that source from the pharmaceutical industry? Dr. SHAPIRO. There is an income for exhibit space which only partly displaces the cost of our meeting. Senator NELSON. Do you have a figure on the amount of that income? Mr. CAHAL. It approximates in recent years $108,000, the gross rev- enue from the sale of exhibit space at our annual convention. As Dr. Shapiro has pointed out, this is about half of the annual convention. Senator NELSON. And what percentage of that $108,000 would be pharmaceutical advertising? Mr. CAI-IAL. I would guess, Mr. Chairman, that ratio would be lower than the one for advertising in the journals. And I would estimate that the revenues for exhibit space for drugs is 70 percent at the annual convention, the balance being other classifications. Senator NELSON. The figure we discussed a moment ago from the Library. of Congress, 91.5 percent for advertising in the American Family Physician, is that roughly an equivalent percentage of the advertising in the GP. Mr. CAnAL. I would imagine, sir. Senator NELSON. Apart from advertising and exhibits, are there any other. funds from the drug industry? Mr. CAI-IAL. No, sir; there are no other revenues from any source except the sale of supplies to members. Senator NELSON. Any other from the drug industry of any kind? Mr. CAHAL. No other sales to the drug industry. Senator NELSON. Or any other grants or scholarships or research, and that sort of thing from the drug industry? Mr. CAHAL. Occasionally, Mr. Chairman, there are grants from pharmaceutical companies to endow a speaker at a meeting. Or, for instance, Mead Johnson & Co. makes a grant to the Academy which is used to subsidize preceptorships, medical students who go out and spend a portion of their time with practicing family physicians. This is a grant from Mead ,Johnson & C., a pharmaceutical company. We have had occasionally grants of that nature. Senator NELSON. Thank you. Go ahead, Dr. Shapiro. Dr. SHAPIRO. Mr. Chairman, in this next paragraph we have `some changes in the arithmetic which are substantial. This was our error in calculating. I will read them correctly. If our drug advertising income averaged out at $11/4 million per year, it is then reasonable to state that the pharmaceutical industry suppOrts our publishing efforts to the extent of approximately $18 per family doctor per year. PAGENO="0468" 4758 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. This is in place of the figure $41? Dr. SHAPIRo. Yes, sir. Senator NELSON. And when you say family doctor, are you talking about all fainil doctors in the country? Dr. SHAPIRO. Yes, sir. Senator NELSON. What is the total of the family doctors by that mathematics? Dr. SHAPIRO. 68~000. Senator NELSON. And your publications go to about 40,000 of those? Dr. S~IRo. No, sir. We cover them all. G-P goes to 32,000 and the American Family Physician goes to the remainder. Senator NELSON. There is no duplication? Dr. SHAPIRO. No, sir. With this $18, what can we do for the individual doctor? We can deliver, to the door of his office or his home, about 84 original scien- tific articles and 240 well-edited abstracts. We can also tell him about the government medical programs and about hundreds of postgradu- ate study programs. In short, we can provide him with more useful information than we could if we sent him a first-class letter every day. We think it is $18 well spent-by both the Academy and the pharmaceutical industry. Allow me to touch on another point which involves liaison between the Academy and the pharmaceutical industry. In January, we started publishing a six-installment course on the "Diagnosis of Diabetes." The course was programed to our specifications by a firm in New York City. However, it was made possible by a no-strings grant from jhe Upjohn Co. What does Upjohn get for its money? A small credit line, a letter of appreciation, hopefully some satisfaction-and that is about all. Please note that the course is concerned only with the diagnosis of diabetes-not the treatment of diabetes. Senator NELSON. May I ask a question at this point? Dr. SHAPIRO. Yes. Senator NELSON. What would your view be of the reason for Upjohn sponsoring such a progra.m if there is not any credit in doing that? Dr. SHAPIRO. As an important cog in the health team, the pharma- ceutical industry feels that this is necessary. They are totally involved in continuing education. Senator NELSON. The only question I would raise-and I do not say that there are no public spirited people in all industries, I am sure there are-but tolbutarnide is Orinase, is it not? Dr. SHAPIRO. Yes, sir. Senator NELSON. And that is the only drug of its kind in the market- place, is it not? There is no other tolbutamide but Orinase? Dr. SHAPIRO. Not to my mind. Senator NELSON. So would it be fair to say that there is a benefit in the promotion of their drug Orinase? Dr. SHAPIRO. There would be an indirect long-range benefit to them as well as to all other manufacturers of oral antidiabetic drugs, or insulin. Basically we are hopefully uncovering unfound diabetics who must be treated, not necessarily by Upjohn's product. Senator NELSON. I know. But Orinase is the only tolbutamide in the market, and it is under patent, and it is only made by Upjohn. PAGENO="0469" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4759 And is it not correct that if they can establish the name Orinase widely in the mind of the physician in the 17-year period of the patent pro- tection then there is an expectation on their part that when the pat- ent runs out the doctor will continue to prescribe under the brand name of Orinase. Dr. SHAPIRO. But Orinase is only one of the antidiabetic agents. Senator NELSON. But it is the only tolbutamide? Dr. SHAPIRO. Yes, sir. Senator NELSON. So if the doctor wants to use tolbutamide and the company has established it under its brand name Orinase, and the doctors have been writing Orinase for 17 years, and the patent runs out, isn't it the hope of the company and the expectations based on experience that the physician will continue to write Orinase even after the patent has run out? That is my point. Dr. SHAPIRO. Possibly, yes. But my point, then, is that this will not alter the percentage of the number of diabetics that are being treated by their medication. There is also Diabinese, or DBI, and other agents available to us. Senator NELSON. I realize that. But isn't there expectation-that is part of the advertising program-that when any doctor desires to use tolbutamide, after 17 years of advertising and prescribing by the name Orinase rather than by the name tolbutamide, that when the patent runs out and competition comes into the marketplace they could maintain a better position than they otherwise could, because the doctor will continue to write the name Orinase, or at least a good percentage would; isn't that the expectation? Dr. SHAPIRO. I believe so, yes. Senator NELSON. I just wanted to point that out, that there certain- ly are additional reasons other than the desire to promote continuing education. There is a very good, sound selfish reason for this kind of program. Dr. SHARPIRO. However, Mr. Chairman, this sales pitch for their product will not be included in this series. Senator NELSON. Upjohn is identified with the product, and every- body there will know it is Orinase, won't they? Dr. SHAPIRO. There is no product. This is on the diagnoses of diabetes. Senator NELSON. But it is Upjohn that sponsors it? Dr. SHAPIRO. Yes, sir. Senator NELSON. All right. Mr. CAIIAL. Mr. Chairman, it is not Upjohn that sponsors it. The articles are prepared by the medical~ editorial staff of GP magazine. A company is employed in New York to structure this in programed learning. This is an innovation in medical teaching of the American Academy of General Practice. The series is not sponsored by Upjohn. Senator NELSON. I meant paid for, rather. Mr. CAHAL. A small portion of the total cost is paid for with the grant, no strings grant from Upjohn. There is no reference to it in the article. Senator NELSON. How much is the grant? Mr. CAHAL. Mr. Kemp? Mr. KEMP. $36,000. Senator NELSON. Did you say this is a four-part program? PAGENO="0470" 4760 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Dr. SHAPIRO. Six installments. Senator NELSON. Over a period of how many months? Dr. SHAPIRO. Six months. Senator NELSON. Please go ahead. iDr. SHAPIRO. There will be no "plugs" for Upjohn products, no waving of banners, no coupons, no sales pitch, nothing commercial at all. Is the cost of this program part of the $3,000 per doctor that the pharmaceutical industry is supposed to spend each year? I do not know. Also, I do not know if it is always possible to draw a line be- tween a (a) the educational and (b) the advertising efforts of the pharmaceutical industry. To my personal knowledge, there is no other industry that spends a larger share of its dollars not only on research but on professional education. Senator NELSON. How much do they spend on research? Mr. CAHAL. Are you referring to the industry? Senator NELSON. Yes. Mr. CAHAL. This figure has been produced in testimony before this committee, I believe, but I do not have it at my fingertips. Dr. SHAPIRO. Not on research alone. Senator NELSON. We have never been able to get from the companies a real breakdown on research. We do not know whether they consider detail men part of the research and promotion and advertising. We really have not been able to get that. And the assertion is made con- tinually by the industry that they spent more on research than any- body else. And then we have distinguished people like you appearing and saying they spend more on research than everybody else, but we cannot get anybody to tell us exactly what it is and what kind of research. That is our problem. I wonder where you got the information that they spend more on research than anybody else? Dr. SH~u?mo. I do not have any figures on this, Mr. Chairman. But having visited many varied industries, including the pharmaceutical industry, I am very much impressed myself on the amount of their plant that is earmarked for research. Senator NELSON. The only witness we have had who would have reason to have knowledge was Mr. George Squibb, who said it was about 6 percent. And that is not a tremendous percentage. Dr. SHAPIRO. You raised the point yourself, Mr. Chairman. If we were to follow their annual financial reports, they show the portion of their income that is earmarked for research. But as you mentioned, we do not know where they draw the line, where research ends. Senator NELSON. That is right. We have had other independent in- dustries claim they are doing great things in research, but when you go to breaking it down we found out that it really does not qualify as research. I would be very pleased to have the industry-I guess we will have to ask them again-come in and just say, here are the dollars, and here is the breakdown, and here is the kind of research, and here is how much we spent. But as many hearings as we have had I do not think either the late distinguished Senator Kefauver or anybody else ever got from the industry anything other than this assertion. I notice that the very authoritative and distinguished Task Force on Prescription Drugs Final Report states on page 8: Since important new chemical entities represent only a fraction-perhaps 10 to 20 per cent-of all new products introduced each year, and the remainder PAGENO="0471" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4761 consists merely of minor modifications or combination products, then the Task Force finds that much of the drug industry's research and development activities would appear to provide only minor contributions to medical progress. We likewise find that to the extent the industry directs a share of its research program to duplicative, noncontributory products, there is a waste of skilled research manpower and research facilities, a waste of clinical facilities needed to test the products, a further confusing~ proliferation of drug products which are promoted to physicians, and a further burden on the patient or taxpayer who, in the long run, must paythe costs. Doesn't that strike you as a rather powerful indictment of the claim for the research by the independent industry? Dr. SHAPIRO. It sounds very condeinning Senator NELSON. That is the Task Force on Prescription Drugs composed of some very distinguished people. And this was issued on March 16, 1969. Dr. SHAPIRO. I have no knowledge of .this report, Mr. Chairman. It comes to my mind that possibly something that you read is a little out of context, and could be qualified. I do not know the report, I am very sorry. Senator NELSON. This is the summary. And we would be entitled to go back, of course, and check the basis of their finding. But this is the finding that they made. The thing that is disturbing to me, just as an observer, is how often it is asserted by representatives of the medical profession that no other industry in the United States invests more in research than the drug industry, which is the drug industry line, yet no one from the medical profession can ever explain how they came to that con- clusion except that they are repeating what the pharmaceutical manu- facturers said. Doesn't that bother you a little bit? Dr. SHAPIRo. In that context, yes, Mr. Chairman. But having been out of school now for a little over 30 years, and watching the great innovations and the changed health care so completely, this came from some place. Senator NELSON. The statement came from the pharmaceutical manufacturers. Dr. SHAPIRO. I mean the progress that we have enjoyed. It did not just grow like Topsy, someone had to do it. We know it has been done. Senator NELSON. No witness before the committee of which we have had a large number, has ever said that~ the industry has not made a val- uable contribution in terms of research, and neither has any member of this committee said that. The committee is concerned about overdrawn claims. And when we have tried to chase this one down we never can get the answer. But the task force, which is a very distingmshed group, makes a rather telling indictment of some of the kind of research and dissipation of money and presumed valuable research that the indus- try makes. That is my point. Dr. SHAPIRO. We have no further information. As a matter of fact, you have more information than we have. Mr. GORDON. Mr. Chairman, may I; interrupt for a moment? Dr. Goddard on April 6, 1966 at Boca Raton, Fla., at the annual meeting of the Pharmaceutical Manufacturers' Association said this: Let me begin with investigational new drugs. I can say that I have been shocked at the quality of many submissions to our IND staff. The hand of the amateur Is evident too often for my comfort. So-called research and so-called studies are PAGENO="0472" 4762 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY submitted by the cartonful, and our medical officers are supposed to take this all very seriously. This confirms what the task force says about the quality of research. Dr. SiIAPnio. That is, I believe, why we have regulations to control the releases. And they are good. Senator NELSON. Please continue. Dr. SHAPIRO. Allow me to comment on drug compendium proposals and make a point that perhaps has been overlooked in previous pro and con discussions. Think for a moment, please, about the use to which physicians put drug compendia. The drug compendium is not a cata- log and thus does not serve the purpose that a catalog serves. When you and I consult a catalog, mail order or otherwise, we ex- pect to find that each item comes m a variety of shapes, sizes and colors-and we choose the one we want. On the other hand, a doctor does not normally use a drug compendium to help choose between prod- ucts A, B, C and D. Instead, he uses it to check out a drug he already expects to prescribe; to review, if necessary, the contraindications, et cetera. This does not mean that he never changes his mind after con- sulting a compendium but this happens only occasionally. In short, the compendium is a reference book-not a catalog. In this connection, let me make one more point quite clear: If a physician knows nothing a.bout a drug, he is most certainly not going to prescribe it simply on the basis of compendium listing-no matter how many compendia are available or who published them. As an aside, I hope that my own health and well-being are never entrusted to a physician who feels he must consult a drug compendium every time he writes a prescription. So a compendium is a reference volume-nothing more. How, then, do we learn about drug products? We read, listen, observe-and discuss. I read many scientific articles-not all of them but as many as possible of the ones that I consider of value to a physician in active family practice. I attend medical symposia and other meetings and I talk to my colleagues and detail men-about whom I will comment in a moment. In other words, gentlemen, drug compendia are not an integral part of my drug therapy education. The scientist has his book of mathematical functions, the physician has his compendium. Both are useful, both are valuable-but neither is a substitute for knowledge. I hope I have made this point clear because perhaps you will then understand why I see no urgent need for still another compendium. Senator NELSON. Do we have an authoritative, objective compendi- um available now? Dr. SHAPIRO. I believe I touch on this further on in the testimony, Mr. Chairman, I make reference to the AMA. May I continue? Senator NELSON. Yes, sir. Dr. SHAPIRo. In the months that have passed since the compendium proposal was first mentioned, I have iiot had a single colleague tell me that he thinks we need another compendium. So if there is no demand, isn't it then a bit unfair to suggest that the drug industry spend $6 million for an item that physicians do not seem to really want or need? Senator NELSON. I might. say on that, Doctor, that the proposal that Dr. Goddard made was that the $6 million that was spent on the package insert, be used for the compendium, and that the package PAGENO="0473" COMPETITIVE PROBLEMS IN THE DRLTG INDIJSTRY 4763 insert not be required, since the physician does not see the package insert very often; it goes to the pharmacist. Dr. SHAPIRO. The package insert has not done a great deal for me, Mr. Chairman. I can read everything I want to except the package insert, and that is why I got these glasses. The printing is so fine and everything is so piled on a thin piece of onionskin that it is difficult to handle. If the Government does decide to publish its own compendium, I am afraid that the printed product will not be of substantial value or use to the practicing physician. It will be little more than a collection of package inserts, neatly bound together but almost unreadable. When you start listing every adverse reaction to every listed drug-such as one minor skin lesion in 10,000 patients-you cannot emerge with anything but a tome. Senator NELSON. Doesn't the doctor when he checks on the drug want to know all adverse reactions? If the doctor is going to prescribe a drug, doesn't he want to know all indications and all adverse reactions? Dr. SHAPIRO. Yes, sir. Senator NELSON. Then what is his objection to having it in the compendium? Dr. SHAPIRO. You are assuming that a doctor will prescribe a drug from a compendium. And my assumption is that he will not, he will have the information that he needs before he will consider using a drug. Senator NELSON. Where does he get the information on all the drugs that he might need? Dr. SHAPIRO. He does not use all the drugs. Senator NELSON. Where does he get the information on all of those that he does need? Dr. SHAPIRO. As I have covered already in this testimony by reading proper scientific articles, attending meetings, symposiums, discussions with colleagues, hospital staff meetings. Senator NELSON. You have been told by a number of physicians that a lot of them rely on PDR, for example? Dr. SHAPIRO. To that extent, I question very much. I use PDR for one specific function. In being cost conscious for my patients, I usually check PDIR to see what the trade size package is, and I usually pre- scribe that amount. This enables the pharmacist to merely add a lable to the trade size package, and not use another bottle. I have found that if a liquid item is supplied in, say, 60 cc. form, and I write for 40 cc., the patient will be charged with the full 60 cc., and I am cost con- scious for all my patients. This is the major use that I put to the PDIR. Senator NELSON. I do not know what the compendium would answer, I am not an expert in that, of course, or anything in this field. But I quote from the final report of the Department of Health, Education, and Welfare's Task Force: We find that few practicing physicians seem inclined to voice any question of their competency in this field of therapeutics. We also find, however, that the ability of an individual physician to make sound judgments under quite confusing conditions is now a matter of serious concern to leading clinicians, scientists and medical educators. A distinguished pharmacologist, for example, has stated that lack of sophistication in proper use of drugs is perhaps the greatest defi- ciency of the average physician today. PAGENO="0474" 4764 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Do you have any comment on that? In other words, they are saying that there is something wrong here. Dr. SHAPIRO. There is a need, Mr. Chairman, for continuing educa- tion in therapeutics and drug use. We in the Academy are attempting to do this through a section in our journal called Practical Thera- peutics. The results that appear in print are not always complimen- tary to the drug or the pharmaceutical house. We attempt to give the doctor basic information that he can use. We have run editorials on drugs-the thing that sticks in my mind right now is that we had run advertising for Merrell and MER-29, and of course when this thing blew up and it was known in the market, we were one of the first journals to run a full editorial on this and bring all the information to the physician, those who had not possibly read the letter that was mailed out. The need for continuing education is great here, this I will not question at. all. . . You are aware that the American Medical Association is publishing a compendium for physicians. I do not know when copies will be avail- able but I would want to examine it in detail before planning still another compendium. Senator NELSON. But there is not now a general compendium. Dr. SHAPIRO. I believe Some portion of this has already been pub- lished, I have not seen it. Senator NELSON. You mean a total compendium? Dr. SHAPIRO. Not yet. Perhaps prices should be included, hut this is not necessary, because when the doctor needs price information, he can obtain this informa- tion from a pharmacist. To satisfy this need and obtain information on actual costs, I keep a copy of the pharmacists' Red Book in my office. In short, there seems to be no real need or demand for another compendium of the kind that has been proposed. Please also remember that most physicians do not prescribe on a strict cost basis-for the same reason you do not shop around for a bargain-basement doctor. It is not my intention to become involved in the generic-equivalency debate because I am not a pharmacologist, but as a practicing family physician I am certainly quality-conscious. Allow me to give you an example. A doctor knows that product X is manufactured by the ABC company, a first-line pharmaceutical firm that each year spends millions of dollars on research. He has read two or three articles by eminent physicians who have used product X and found that it is effective. He has also talked to colleagues who have prescribed product X for patients with similar conditions. On the basis of the results they have obtained, which correlate with his findings, he determines the best product to prescribe. Would you then expect him to prescribe product X-or a so-called generic equivalent that is supposed to be "just as good" or "almost as good"? If the. patient happened to be your wife--or one of your children- would you want your doctor to prescribe a product in which he has less than complete confidence? Medicine does not lend itself to either production lines or bargain-basement economics and I would certainly not want anyone to tell me when to prescribe, how to prescribe, or what to prescribe. I would call your attention to the words of John Ruskin who wisely pointed out that "there is hardly anything in the PAGENO="0475" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4765 world that some man cannot make a little worse and sell a little cheaper, and the people who consider price only are this man's lawful prey." A moment ago I mentioned detail men and I would now like to add a comment or two. Detail men are often referred to as salesmen and in a sense, they are. But I must again urge you to think of the detail man's function and his relationship with the individual physician. He-the detail man-is a source of information. I said earlier that I would not prescribe a drug just because it is listed in a compendium and by the same token, I would also not prescribe a drug just because a detail man has listed its indications, contraindications, et cetera. I have read some of the newspaper stories generated by these hear- ings and it seems to me that one important point has been almost entirely neglected. Medicine, and thank God this is true, is practiced by physicians-not by detail men, not by advertising agency copy- writers, not by the Food and Drug Administration and not, with all clue respect, by the Congress of the United States. To get an M.D. degree, you need 4 years of pre-med, 4 years of medical school and at the very least, a 1-year internship. You do not have to be a mental giant to be a doctor but most of us are not witness ninnies ready to be gulled by a sharp-tongued detail man or a clever copywriter. So instead of pointing one finger at the detail man, another at the copy- writer and a third at the fellow who mans an exhibit, take a look at the composite and remember that most physicians are involved in a series of 1 to 1 relationships with people-people who are sick, ill, injured, or infirm. When I see a sick child or a pregnant woman or an elderly diabetic, I am Dr. Maynard Shapiro and that person is my patient and I am his doctor. Whatever you do, please do not destroy or impinge upon that relationship. Health legislation, or related legislation, has enjoyed fantastic popularity in recent years. Such legislation has a certain emotional and political appeal and I would be the last to claim that the Nation's health care structure is perfect. But as it is not all good, it is not all bad-and I would urge you nOt to destroy the good while seeking to improve the bad. Senator NELSON. May I ask a question here? Dr. SHAPIRO. Surely. * SenatOr NELSON. 1 do not understand these general statements, "Whatever you do please do not destroy or impinge upon that relation- ship," and the sentence, "I would urge," meaning the committee- "not to destroy the good while seeking to improve the bad." What is the basis of those statements, something the committee has done? Dr. SHAPIRO. No, sir. This is referring more to a tendency, not the committee specifically. If you will notice in what I have presented just now, I did not refer to a health care system, I referred to a health care structure, It is my contention that we do not have a system in this country for the delivery of health care; Senator NELSON. So you were not~ referring to issues raised before this committee? Dr. SHAPIRO. No, sir. Senator NELSON. Please go on. PAGENO="0476" 4766 CO~ETITWE PROBLEMS IN THE DRUG INDUSTRY Dr. SH~rnio. I think we could all agree that the pharmaceutical industry has been raked over some pretty warm coals in recent years and let me again emphasize that I am in no way wedded to the indus- try. However, I have many patients-perhaps literally hundreds of patients-who are alive today because pharmaceutical industry research came up with the drug they needed. And where is most of this research being done? Right here in America. The Russian phar- maceutical industry, for example, cannot hold a candle to the American industry. This is why I shudder when someone suggests that we impose rigid controls on drug industry prices or profits. Senator NELSON. May I ask a question? Dr. SHAPIRo. Yes, sir. Senator NELSON. What do you refer to there? Nobody before this committee has suggested that. Dr. SEAPIRo. The excess profits that have been discussed so widely in the newspapers, supposedly from this committee hearing. Senator NELSON. But nobody, if I recall, has suggested imposing rigid proposals on the drug industry prices or profits, have they? They have been criticized for the profits and for the pricing structure, and I have criticized them myself. Dr. Su~pmo. The unions have suggested this in some of their releases to the press. I am not referring to the committee or testimony. We are here trying to give you our Senator NELSON. I just thought that you might be referring to some comments that have been made by the committee suggesting rigid controls. Dr. SHAPIRO. I do not believe that anyone will deny that lower profits will mean less research and although drug industry profits are certainly substantial, I know of no industry more committed to research. Drug industry research will not put men on the moon or speed up an SST but it will save a great many young and not-so- young lives. I firmly believe that the relationship which now exists between the individual physician and the drug industry is essentially healthy and I hope it will not be stifled. Thank you. Senator NELSON. Thank you very much, Doctor. Your last statement raises a question that has been discussed before the committee, as you well know, by a number of witnesses, including representatives of some of the other distinguished medical organiza- tions before this committee, AMA and the American College of Surgeons in the past week. So I will just raise with you some of the same questions that I raised with them. This involves the relation- ship between the drug industry and the medical profession, which, as I say, we have raised with every representative of medical organiza- tions appearing before the committee as well as with the drug industry itself, so that we can explore it and see what the relationship is and see whether or not it is a relationship that is not healthy for either the profession or the country as a whole. And pursuant to that line of ques- tions, I would like to ask some of the same ones that I have asked of other organizations. In 1967 you published a brochure called "News and Views of Interest to the Pharmaceutica.l Industry." As you know, this brochure is made PAGENO="0477" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4767 up of editorial comments that occurred in,~ the GP, or American Family Physician. I am puzzled by the purpose of it. It says, "News and Views of Interest to the Pharmaceutical Industry." Why would you be interested in publishing a brochure that recites a group of editorials, all of which, as I read them one way or another, defend the pharmaceutical industry position? What is the purpose of the brochure? Mr. CAHAL. Dr. Shapiro has asked that I comment on that, Mr. Chairman. This brochure was published for the very reason you stated, sir, that we thought it would be of interest to the, pharmaceutical industry, the things we had to say about this matter. By the same token, the phar- maceutical industry sends to our office many of its publications. The pharmaceutical companies regularly send us their annual reports, be- cause the pharmaceutical industry and the medical profession and the nursing profession and the hospital profession are all engaged on the same team, and I think have a natural and healthy interest in each other. Senator NELSON. Did the PMA distribute this? Mr. CAIJAL. No, they did not distribute the original. Senator NELSON. Did they reprint it and distribute it? Mr. CAnAL. I would not know. I doubt it without our permission. Senator N~soN. What was the circulation of it? It is printed, and it is the views of the pharmaceutical industry-how many did you print? Mr. CAHAL. I cannot answer that at this moment, Mr. Chairman. A few hundred, I presume. Senator NELSON. And it was sent to the pharmaceutical manufac- turers? Mr. CAnAL. Yes, sir. Senator NELSON. You don't know whether the PMA circulated it themselves or reprinted it and circulated it? Mr. CAnAL. Of my own knowledge I do not, sir. Senator NELSON. Does anybody? Mr. Ki~n~ir. I do not believe that they did, sir, I do not know that they did. Senator NELSON. I am still puzzled by the purpose. The editorials appeared in G-P and the American Family Physician. They all defend, directly and frankly, right down the line, the manufacturer's position on every issue that is discussed. And looking at it as an outsider, if I were in business, I would say that it is a direct and blatant appeal to the industry for more advertising. What other purpose does it have? Mr. CAnAL. Mr. Chairman, it has been some time since this was pub- lished, and I do not remember all the editorials that were in it. I would like to repeat what Dr. Shapiro said in his direct testimony, that our journals, GP and American Family Physician, have from time to time published articles and editorials quite critical of the industry and of individuals in the industry. And I would like to report to you, sir, and for the record, that some of these editorials have resulted in a cancellation of heavy advertising schedules. Senator NELSON. Who has canceled because of some editorials? Mr. CAnAL. One that I specifically recall is Wallace Laboratories. Another, I think, was Pfizer-for editorial comments we made, as a PAGENO="0478" 4768 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY result of the editorial comments we made critical of them or the in- dustry, they have canceled out. Senator NELSON. When was this? Mr. CAnAL. Well, they were at different times, different occasions. Senator NELSON. For how long did they cancel them? Mr. CAnAL. I think Wallace is still canceled. Senator NELSON. When did they cancel? Mr. CAnAL. I think about 2 years ago. Senator NELSON. Do you have file copies of the editorial comments that caused them to cancel? Mr. CAHAL. I shall be glad to send them to you, sir.1 I remember one editorial of ours which offended some of our friends in the industry. It was one in which we stated that we were suspect of any pharmaceutical company which manifested an interest in a scientific article we were preparing to publish in our journal, that we were sacrosanct in our scientific and editorial material and we did not want any pharmaceutical company to have any interest in it, and if they manifested one, it would put us on guard that they had an interest. Senator NELSON. Did some company cancel based on that, do you know? Mr. CAnAL. I suspect they did. I do not know that they told us, frankly, that they were canceling because of that editorial attitude of ours, but I know that it resulted in critical and complaining comment in the industry. Senator NELSON. How many times has any drug industry, any manu- facturer canceled, based upon critical material in the publication? Mr. CAHAL. Well, Mr. Chairman, we were not always certain of the reason for the cancellation of advertising, or a failure to buy adver- tising. But from our intimacy in the field we have reason to believe that sometimes our editorial posture has resulted in a loss of advertising sales in our journals. Senator NEI~soN. But do you have any specific case that you know of where the industry did cancel because of a specific adverse editorial comment in either of your publications? Mr. CAnAL. Yes, sir. I refer to Wallace Laboratories, which advised us that they were canceling because of an editorial. Senator NELSON. Pfizer and Wallace? Mr. CAnAL. Yes, sir. Senator NELSON. Are those the only two specific cases? Mr. CAHAL. That I can recall at this moment, sir. Senator NELSON. And they were how recent? Mr. CAHAL. Wallace was 2 years ago, at least 2, maybe 3. Mr. KEMP. Closer to 3, I think, on Wallace. I do not remember when Pfizer did. Mr. CAHAL. The two had no relation to each other, they were two different episodes. Senator NELSON. The point that this whole issue continues to raise, it seems to me, and I am saying this not just as to your publications, but with regard to all journals and all medical news publications, some of which are 100 percent supported by advertising from phar- 1 See pp. 4779-4781, infra. PAGENO="0479" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4769 maceuticals, and some of which are substantially supported, such as yourself and other distinguished medical associations-the point it continues to raise is that, since there is a heavy dependence on adver- tising, do the respective journals of the respective professional medi- cal organizations pursue as vigorously a policy of criticism when it is appropriate as they would if there was no dependence on advertising? It seems to me that that is the issue that is continually raised here. And in looking at a large number of the publications I rarely find anything critical of the industry itself, even though there are critically important issues that are raised. For example-maybe you can tell me about your publication, I do not know about this-but I cannot find any publication that ran big strong stories pointing out the misuse of chloramphenicol. Did your publication? Mr. CAHAL. Mr. Chairman, I cannot speak for all publications, but I have just tried to make it clear to you, sir, that the journals of the American Academy of General Practice are independent editorial spokesmen, and are not the slave of their advertisers any more than the Washington Post is the slave of its advertisers. I shall be glad to furnish for your committee, Mr. Chairman, copies of editorials which have appeared in GP magazine critical of individuals and of the industry. As for the misuse of chloramphenicol, we have from time to time had articles in GP written by distinguished authorities about the dangers of abuse in antibiotic therapy, and I do know that we reported fully the antitrust action. Dr. SHAPIRO. Some of the members of the industry- Senator NELSON. The problem, it seems to me, of the medical publi- cations is that as contrasted with a large daily newspaper, their de- pendence is on two things: One, the dependence of the journal upon a single industry source, that is, pharmaceuticals, is very high. In the case of American Family Physician, 911/2 percent of the advertis- ing is pharmaceuticals. A publication that accepts advertising from a single source is quite a different case from one that accepts advertis- ing from many sources. Secondly, it seems to me that there is a very special relationship and responsibility toward the public on the part of the medical pro- fession as the custodians of the public health, so to speak, a very special ethical responsibility that I think is unique. That is why I think this poses a serious question. In~ reading through this brochure "News and Views of Interest to the Pharmaceutical Industry," and I read it through. twice last night and once this morning, it seems to me it raises some very serious questions. I made some notations on it as I went through. For example, on the next-to-the-last page of the brochure, "News and Views," it says: From time to time and with increasing frequency we get weary of listening to au the flack which relates, however remotely, to pharmaceutical prices. We hear that company A sells a particular tablet for 8 cents apiece, but company B charges only 3 cents for its version of the same product. In the first place, let there be no mistake about this, most of the people who make noises about "generic equivalents" do not know an aspirin tablet from a jelly bean. They will shout that frozen tutti-fruitti pies "are not as good as mother used to make" and then turn right around and claim that generic and trade name prod- ucts are like two peas in a pod. You can buy a cow for $25-or $250. A local jeweler tells us that we can buy a one carat diamond for $300 or $2300. In other words, we are always required to make decisions based on the qualtiy of the merchandise and this axiom applies to anyone who wants to buy anything. PAGENO="0480" 4770 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We are a bit amused by acquaintances who will go out of their way to consult a high-priced specialist-and then complain when he gives them a prescription which costs $3.50. The average retail prescription charge is $3.48-on which the manufacturer nets 18 cents. We have made these same statements, perhaps more diplomatically, in earlier "Publishers' Memos." We may be compelled to repeat them again-perhaps even less diplomatically. Our parting plea is this: When you run across what seems to be an outrageous fact concerning prescription drug prices, consider t.he source, consider that the statement may have been made with ulterior motives-and remember that a bargain basement price almost always bespeaks bargain basement quality. Now, this is a strong direct plea, really, for the brand-named drugs. But let me recite a case which we have used a number of times before and will continue to use. We could give you a dozen, but this one is based upon the conclusion of the Medical Letter, and it would not be subject to the same kind of attack that another example might be. But referring to the prices now, a cow for $25 or $250, the Medical Letter of June 1967 published an analysis on prednisone tablets. And referring to the paragraph in here which says: Our parting plea is this: When you run across what seems to be an outrageous fact concerning prescription drug prices, consider the source, consider that the statement may have been made with ulterior motives-and remember that a bargain-basement price almost always bespeaks bargain-basement quality. The Medical Letter concluded from testing done by an independent lab and in consultation with clinicians around the country that all these drugs, all 22 prednisones by 22 different companies were thera- peutically equivalent. The prices have changed since our hearings on this, but Meticorten, which was the original `and most widely pre- scribed, was $17.90 a hundred to the druggist, and Paracort, $17.88. And it got down to Merck at $2.20, and McKesson at $2.25, down to Upjohn $2.25, and finally to Wolins at 59 cents a hundred. Now, here they are, with a price differential of 30 times. What is your conclusion about that? Dr. SHAPIRo. Mr. Chairman, I think this committee has won its badge on this particular instance. You were successful in having the prices brought within a range of reality. And I would say nothing to support this 30-times price differential. Senator NELSON. But the problem that your editorial, which went to about 60,000 physicians, raises is that it tells them the pharmaceu- tical manufacturers' line. And this is a national refutation of it. This is just one of many examples. I use the Medical Letter repeatedly, since I do not find anybody in the medical profession or pharmacy or phar- macology who does not highly regard the integrity and the quality of the letter. If I used another ekxample they would say "Yes," but Wolins' is no good, or McKesson's product is no good, or they aren't as good as Meticorten. Schering claimed before us, that they respected the Medical Letter, but some were not as good- Dr. SHAPIRO. In this particular instance I believe that the therapeu- tical equivalence was proven, not the generic equivalency, of the cheaper products. And I believe that across the country every doctor who has read anything at all in the journals regarding the corti- costeroids is aware of this. Senator NELSON. But the same thing on prices goes across the board. We have lots of examples. When the editorial takes the position that when you run across what seems to be an outrageous fact concerning PAGENO="0481" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4771 a lower price, consider the source. Well, what I do not understand is then why-for, example, you take Serpasil, reserpine. Ciba sells this to the pharmacies for $39.50 a thousand. Now, American Pharmaceu- tical sells it to New York City for 72 cents a thousand. Now, there is the low price, 72 cents. Thirty-nine dollars is 50 times as high. How does that fit in with the statement here that the price is low, consider the source? You just have dozens of examples which absolutely refute the editorial claim made in your magazine. Dr. SHAPIRO. As a practicing physician and not as a pharmacologist, I would not like to use this particular example of an extract of rauwol- fia Serpentina, because each company has purified a different fraction of the alkaloid. And in my practice I have found that a trade name made by Lilly, Sandril, gives me better results than generic rauwolfia. Senator NELSON. As you know, New York City, the Defense Supply and the Veterans' Administration use their own independent testing to see that the drug meets the appropriate NF or IJSP standards. Well, then let me ask you this one on prices, again referring back to this paragraph. How would you explain why Ciba's Serpasil is sold to the pharmacist at $39.50, but when they wanted to sell to New York City in competitive bidding they bid a $1.10 a thousand? Dr. SHAPIRO. I cannot. defend it. Senator NELSON. As I understand this editorial, it is an across-the- board defense of the prices. Dr. SHAPIRO. I believe the words ai~e "usually," or "most of the time," toward the end. Senator NELSON. It says: Our parting plea is this: When you run across what seems to be an outrageous fact concerning prescription drug prices, consider the source, consider that the statement may have been made with ulterior motives-and remember that a bar- gain-basement price almost always bespeaks bargain-basement quality. Dr. SHAPRIO. The sense of it seems to be-there was something before that, I believe. I may be mistaken. Senator NELSON. The article starts out "Attacking generic equival- ence," and ends with this conclusion. All I am saying is, you can take their own products, you can take Ciba Serpasil, and they are charging this outrageously high price, and then when they bid in New York City in competition, they bid $1.10. Well, that is one-thirtieth as much. Now, that is outrageously low compared with what they are charging the pharmacist. All I am saying is this editorial is really a defense of the drug industry, they are saying you pay for what you get when you see the big price differential, and what they are really trying to say is that generics are not as good. They start out with that. If it is not a brand name, then you had better watch out, you are getting what you pay for, whether it is cows or diamonds. All I am saying is that that same company will come in with $1.10 when they have to bid honestly in competition, but $39.50 when they are running on their brand name to the pharmacist. Now, you say you cannot explain that. I simply say your editorial defends the pricing structure. If it defends the pricing structure right across the board as it does here, what is your comment about this aspect of the pricing structure? Senator Dor~. He does not write the editorial. 8l-280-69-pt. 11-31 PAGENO="0482" 4772 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. SiI.AIIRo. No, this editorial was written by the staff, I had nothing to do with it. Senator NELSON. Dr. Shapiro is the president of the organization. But we are on the whole question here of the close relationship of the drug industry. I give you a dramatic example of an all-out defense of the pricing structure and the attack on generic drugs, and a caution to watch out: When you run across what seems to be an outrageous fact concerning prescrip- tion drug prices, consider the source, consider that the statement may have been made with ulterior motives-and remember that bargain-basement price almost always bespeaks bargain-basement quality. Well, I can give you dextroamphetarnine, I can give Thorazine and Compazine, all the same pattern here. And all I am saying is that it seems to me that each one of the representatives of the medical profession who appear here and defend the pricing structure and the cost of drugs ought to be prepared, then, to discuss the pricing struc- ture, you must be prepared to defend it. If you cannot defend the pricing structure, then it seems to me that it is hardly justifiable to run an editorial like that and then claim that you are not influenced by the drug industry. This is the whole problem. Mr. CAHAL. Mr. Chairman, I think the thrust of that editorial, if I understood it correctly, is directed toward another situation. During the past couple of years, I think doubtlessly as a result of the hearings conducted by your distinguished committee, there has been a rash of articles appearing in lay magazines and newspapers which tended to frighten the consumers of medical care, or to convey the idea that they are being gouged by their pharmacists or drug manufacturers. And I think the thrust of that editorial is directed toward this. I am sure you have seen such square headlines and articles in lesser consumer magazines, "Are you paying too much for drugs?" "Are you being gouged by your druggist?" "Can you afford for your parents to be sick ?"-I recall such editorials. And I think that was the thrust of that point. Senator Nelson. You are correct that articles have appeared saying in one way or another that the public is being gouged. I have said that the pricing structure is inexplicable by any rational competitive stand- ard in a free enterprise system. You talk about being gouged. I think there is a reason for it. Let me point something out which I do not think the medical profession as a general rule is familiar with. For example, if you are going to use the word "gouging," let us take a look. Ciba sells reserpine, its brand name is Serpasil, a thousand 25-milligram tablets for $39.50 to the pharmacist. They bid $1.10 to New York City the same day, across the State in city hall, they bid $1.10 to New York City, and they lost it to American Pharmaceutical for 72 cents. But now they package it overseas and they sell it~ not for $39.50, but in Bonn, Germany, for $10.53 a thousand versus $39.50 here; in Berne, Switzerland, $11.09, and in London, $11.20-in every case less than a third of the price they are charging the American pharmacist. Take prednisone. Schering ships it overseas. They sell it for $170 a thousand for 5-milligram tablets to the pharmacists in this country. They offered to sell to New York City at $12. They sell to the pharmacist at $170, but in competi- PAGENO="0483" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4773 tive bidding they dropped to $12, which is $1.20 a hundred, and they lost it to Lannett, which bid not $170 but $4.58 a thousand. That is 45 cents a hundred. On prednisone they go overseas, and they charge not $170, as they charge the American pharmacist, but $43.70 a thou- sand in Berne, $53 in Rio, and $70 in Australia. One of them is one- fourth the price, and one of them is less than a third the price, and. one of them is less than half the price. Then another distinguished company, Smith Kline & French-for Thorazine they charge the American pharmacist $6.06. This drug is sold in Paris for $1.18; in London for $1.08; and in Bonn for $2.40. This is why the stories appeared in the paper saying that the public is getting gouged. There has been no explanation from the industry as to why they will charge a third and a fourth as much .to a foreign pharmacist after shipping it overseas as they charge the American public. If that is not gouging I cannot think of a better word for it. But the medical profession is appearing here with considerable regularity defending the pricing structure of the industry. The indus- try is the heaviest support of all the professional organizations. The professional organizations defend the structure and claim that they are not influenced by the industry. I think that is a fair question to raise. I raised it with everybody else. What is the answer? Dr. SHAPIRO. To what? Senator NELSON. What is the answer tO the proposition that you are influenced by the industry because you accept and use their line of prop- aganda while at the same time we can give you examples of all these discrepancies in the pricing structure. Mr. CAHAL. Mr. Chairman, if I may, 1 have pointed out that our publication is not a captive of the industry, and we are prepared to submit evidence to your committee to prove that. I have also stated that it seems to me understandable and reason- able that those two members of the health team would be close to- gether, have mutual understanding. They are engaged in the same business, the same as the lumber industry and the nail industry. Senator NELSON. I would be attacked all over this country in all the medical journals if I compared the medical profession and the drug industry with the lumber and nail industry, but it is your comparison. I would have thought that the-~ Mr. CAHAL. I did not say which was the nail. Senator NELSON. Or who was getting nailed. As I said to the AMA, I have raised as tough a question as I can think of, and you are entitled to answer as extensively as you please. But I think, if I sat on a jury, the physical facts would lead me to believe as a juror that the tie be- tween the industry and the profession is close, and very close, too close, and that the profession is too dependent upon the money from the industry, that the industry is too influential with the profession, and that the profession defaults substantially in its re- sponsibility to put the industry under the kind of critical view that the public is entitled to have them do in terms of industry practices in the promotion of the drugs and in prices they charge. If you look through the record, I would think it would be an embarrassment. But it is true that doctors who have appeared here and the representative of every organization that has appeared has in one way or another PAGENO="0484" 4774 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY given every single argument that the industry itself gives in behalf of its research and in behalf of its prices, and in behalf of the generic brand name argument. You could not tell the presention of the medi- cal profession in terms of content from that of the pharmaceutical manufacturers. I would think that that would give one pause-unless you are prepared to say that the industry is right on every single claim they make. Now, let me turn to something else. I will read something here. This is from an article by Morton Mintz. Mr. Mintz is probably the most; distinguished writer in this field in the lay press. In his article "Medical Press Shifts News for Physicians," let me read something: Another case in point is the handling of an October 13 hearing by the gen- eral practitioners, GP, the witness was Richard M. Furlaud~ President of E. R. Squibb & Sons. He came before Nelson's subcommittee with a lengthy pre- pared statement defending the system of dual prices under which a medicine prescribed by brand name can be very expensive, but prescribed under its gen- eric or chemical name can be quite inexpensive. An editorial in the New York Times found Furlaud's case unpersuasive. But GP was so impressed that it turned over four and one-half glossy pages in its February 1968 issue to ex- cerpts from Furlaud's text. GP did not, however, tell its 30,000 doctor readers of a development at he hearing that was not in Squibb's script. This was the sub- committee's introduction of documents which the FDA had prepared in recom- mending criminal prosecution of Squibb. They recited a long history of "mix- ups, recalls and warnings," that Indicated in the agency's view that the firm had "failed to understand its responsibilities as a drug manufacturer." In March 1967 Squibb pleaded no contest to the charges in that case, although it has sweepingly rejected the FDA allegations at the hearing. How do you account for the fact that you select four and a half pages to write a praiseworthy defense of Squibb, but neglect inform- ing your readers about the long history of mixups, recalls and warn- ings? This is a pattern of-I want to emphasize, I am not trying to select your publication, but this is a pattern that runs all through the medical press, the criticism that ought to come, comes but rarely. Dr. SHAPIRO. Mr. Chairman, it is not our duty or thought to defend an industry and say that everything they do is perfect. On the question of influence, I believe there is a reciprocal influence. We would be less than honest not to admit that ads have some impact, and we are carry- ing ads in our journal. At the same time, the industry generally, and specifically certain companies that I could not possibly mention with- out research, are influenced in what they are doing by our needs, by our stated needs. As far as the major question that you are posing, I have no expertise in this purely business matter, and I watch what the committee accomplishes with great interest. I have no defense for these things, nor am I trying to present a defense for the industry. As for prednisone, I believe every doctor to my knowledge is ordering. it without even a manufacturer's name after it. And this is all due to the good efforts of this committee. Senator NELSON. The questions I have been raising, though, with the distinguished spokesman of the various professional medical organiza- tions is this very question, that there is heavy reliance upon advertis- ing. And it does not seem to me there is almost total absence of the kind of critical analysis and comment about industry practices that would be made by purely independent journals. And the pattern runs so clearly, the continuous praise and promotion of the industry. Then when a dramatic case occurs, the medical journals, medical press in general, ignore it. That is what disturbs me. PAGENO="0485" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4775 Dr. SHAPIRO. No, sir; we do not ignore it. I mentioned earlier our section on practical therapeutics which is serving for drug therapy education to our readers, and which is written by medical faculty members. And they may be laudatory or they may be critical. And we do not have editorial privilege on these, we print them. And we have many critical practical therapeutics articles. Second, the advertising we are carrying is not only the business as- pect of what a corporation is selling, but it is a service to our members to bring them more detailed information than they may have on a visit from a detail man, if you will, or present some use of a drug in an article where the actual total insert is not printed. So we are using this as a service to our members. Senator NELSON. But the point raised in this one, Doctor. President Richard Furlaud of Squibb made a presentation to the committee in defense of the system of dual prices under which a medicine prescribed by brand name can be very expensive, but~prescribed under its generic or chemical name can be quite inexpensive. On this economic issue- which is critically important, the point is critically important to the manufacturers-your publication gives them four and one-half glossy pages. Have you ever run four and a half glossy pages on what they charge overseas and what they do at the Defense Supply Agency, and how they offered to sell at one-tenth, one-twentieth the price to Defense Supply in competitive bidding versus what they are charg- ing the pharmacies where the doctor's patient goes? If you can run Fur- laud's stuff, why not the other? Dr. SHAPIRO. I have asked Mr. Kemp4-it seems to me that we did run something on Defense Supply prices, ~ut I cannot be certain. Edi- torially I would state that our editorial staff could easily work up such a presentation. And I would be most happy to bring this up before the board of directors and see if we will direct them to do so. Senator NELSON. I think that would be laudable. But the point I am making is that this pattern of treatment of the drug industry is the same throughout, roughly the same throughout all the publica- tions, the medical journals, and the medical press. And that is a his- torical fact right up to this day. That certainly leaves unresolved the question of the effect of the close relationship I do not think any body has suggested that they are directing, or dictating. It is just the question of-if I have just like you-a good personal friend, and he has some faults, they "ain't" half as bad as the same faults in someone I don't like. And if I am economically dependent upon somebody-that is human nature-I am not as critical of the person I am economically dependent upon as I am of one I am not dependent upon. I think that that is recognized universally among human beings, and that is why you have independent audits in Government and in industry, the board of directors is not permitted by the stockholders to audit their own books, because they are pretty friendly to each other, and the errors and mistakes would not be exposed. And in exposing what is wrong in C overnment, if you left it up to the Congress or the Legislature to tell the country what is wrong with what they are doing, you would never hear about it. Because there is a special interest in not exposing what is wrong. It strikes me that this is the kind of case this presents. When you look at what happens editorially and in the news within the journals themselves, that kind of picture shows up, does it not? PAGENO="0486" 4776 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. Sii~pruo. Yes, sir. We are dealing with the third largest in- dustry in our country. I think the Secretary of HEW says 50 billion, and growing at the rate of 5 billion per year. It is peculiar and different from any other industry that we can consider, in that the frontline men like myself are involved with life and health and the well-being of the people. I am sure that the pharmaceutical industry at the other end feels some of the pressures that must pass over to them because they are the suppliers to us. And I hate to say "lumber and nails," because in a great way they are involved with the health and well-being of the people. Senator NELSON. Let me cite another one here along the same line. I do not know whether you commented off the cuff on that or not. But on page 3 here in your brochure-do you have this there ~ Dr. S~pruo. No, sir. Senator NELSON. This is a question again involving the dispute over generics and bra.nd names, and referring back to the fact that your editorials have taken the side, I think, quite clearly, of the brand name companies on this argument. In June of 1967-first, the FDA did a study of 4,600 drugs that were in a miscellaneous way collected from 245 manufacturers. And 2,000 of these were generic and 2,000 were brand names. That study by FDA was solely for potency-did the drug meet the USP-NF standards of potency. The variance out- side the range established by the official compendium was that 7.7 percent of the generics did not meet the standard for potency, and 8.8 percent of the brand names did not meet it. So here is a case of a substantial size study-which did not claim to be a scientific selec- tion-it was just a selection from 245 companies, I believe, but the generic came out better in that test than the brand name. Now, it says in this June 1967 editorial: Four days prior to the date set for the opening of the Nelson subcommittee hearings, the Pharmaceutical Manufacturers Association issued a stinging and factual rebuttal of an earlier FDA study on the potency of prescription drug prod- ucts. Mr. 0. Joseph Stetler, PMA president, said that the FDA study contained "gross inaccuracies" and demanded that the FDA "repudiate the survey out- right." Stetler said that four PMA member firms have already received letters from the FDA, admitting that the FDA erred when it claimed that their products were below acceptable potency limits. Said Stetler: "Isn't it fair to require that an agency which. demands the truth delivers the truth?" The FDA claimed that 7.8 percent of the products studied "deviated to a material extent from the declared potency," but followup studies, done by the firms and often reconfirmed by inde- pendent laboratories, showed that only 1 percent were out of line with acceptable potency limits. Furthermore, of the 42 firms which reputedly sold subpotency products, only six were so advised by the FDA during the seven months after the survey was completed. The other 36 were not told of the source of the samples checked or given a reasonable opportunity to check on alleged potency violations. Well, this is a pretty strong rejection of the FDA report. I do not have everything that you have written on it, but I raise this question. Did you publish the answer made by Dr. Goddard to Mr. Stetler's charge? Dr. Goddard said: There were 245 manufacturers represented in these 4,575 samples examined. And then he goes on to say: In six samples involving five firms, six samples out of 4,573 involving five firms after the review of the original data, we did concede that we had made an error. Now in three of these six samples involving two firms the NDA potency limits were incorrectly tabulated. In the other three samples the examining laboratory PAGENO="0487" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4777 had not followed the prescribed methodology, and the letter acknowledging the error was sent to five firms. Now, the other original findings I still say are correct. We stand behind them. Did you run this answer in as prominent a way. as you ran Mr. Stetler's attack on the `FDA study? I would think that six samples out of some 4,600 on the tabulation error is avery small computation error on the part of the FDA. Mr. CAI-JAL. Mr. Chairman, subject to~ correction, to the best of my recollection we did make mention of Dr. Goddard's refutation of that statement. I think it can be found. Senator NELSON. Then why would it not be in this publication? Mr. CAHAL. It probably was after that was published. Senator NELSON. Would you-so that the whole record would be clear then-would you send for the record what you published and on what date, and we will print it in the record at this point? Mr. CAETAL. To whom do we direct those, to Mr. Gordon? Senator NELSON. Yes. (Material not received.) Senator NELSON. If there is anything you would like to respond to in what I have raised or said, we would be happy to hear you. Just one more point to make. There is an editorial in September 1967 on prescription policies, and it recites an AMA study which was not scientific, to say the least, the AMA study of price of generics versus brand names in the drug industry. And~ I will not get into an elabora- tion on that, except to say that, of course, if you go to the drugstore and you have a generic-name prescription, and the drugstore only is carrying one brand name, you are going to pay the same price, because you can substitute as you would for the brand name. But it states here: "The AMA study showed that generic-name prescriptions are filled with brand name 63 percent of the time," that obviously would be be- cause that is what is stocked and that is what is prescribed. But I would just like to make one point for the record here, and that is on the question of whether, contrary to the conclusion of AMA on the price of generic versus brand names, Gray's drug chain and Peoples announced a year ago that they would put in stock a line of generic drugs made by Strong, Cobb & Arner, which I guess everybody recog- nizes as a distinguished manufacturer of generics, and that the aver- age prescription price would be one-half the average brand-name price. But again here in the editorial is support of the brand-name com- panies. If there is anything you would like to add to the question I raised, I want to be fair and be glad to have you answer it. But it disturbs me to see how consistently the professional groups support the industry and how rarely they put them under tough criticism. Is there anything you want to add, Doctor? Mr. Ki~ip. I would only say this, Mr. Chairman, not in a full defense of what you are saying, but I do think that sometimes our liaison or our communications with, for example, the Food and Drug Adminis- tration, is not what it might be. I believe you were reading a few moments ago from some remarks made by Dr. Goddard after the earlier study or `after the comment by the PMA. I do not know. I have no reason to know or have no way of knowing at the moment whether we received these. I would call your attention, sir, to the fact that the "Dear Doctor" letters, if you will, whiCh are being mailed periodically to members of the medical profession-we do not receive them. PAGENO="0488" 4778 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Senator NELSON. You do not receive copies of the "Dear Doctor" letters ~ Mr. Ki~n'. No, sir. I have often thought this would be a good idea. Senator NELSON. I agree with you, you ought to receive them, and I think it would be a good idea to print them. Mr. Ki~ip. That is my thought, too, sir. Senator NELSON. Well, thank you very much. I appreciate your tak- ing the time from your busy schedule to come here and testify today. Thank you. (Subsequent information follows:) AMERICAN ACADEMY OF GENERAL PRACTICE, Kansas City, Mo., April 9,1969. BENJAMIN GORDON, Staff Economist, Subcommittee on Monopoly, Senate Select Committee on Small Business, U.S. Senate, Washington, D.C. Dear Mr. GORDON: In obedience to the request made by Senator Nelson at the time Dr. i\Iaynard Shapiro testified on March 26 before Senator Nelson's com- mittee, I am sending by parcel post today the following: (1) A biographical sketch of Dr. Maynard Shapiro, myself and Mr. Walter Kemp, who accompanied us. (2) Annual financial statements of American Family Physician showing the losses incurred on that publication. (3) Copies of representative editorials appearing in GP and APP. (4) Copies of "Practical Therapeutics" series which have appeared in GP magazine.1 It was a pleasure to make your acquaintance. Sincerely, MAC F. CAHAL. ITS. SENATE, SELECT COMMITTEE ON SMALL BusINEss, Washington, D.C., April 22, 1969. MAC F. CAHAL, J.D., Executive Director and General Counsel, American Academy of General Practice, Kansas City, Mo. Dear Mr. CAHAL: During your appearance before our Monopoly Subcommittee on March 26, you stated: ". . . that our journals, GP and AMERICAN FAMILY PHYSICIAN, have from time to time published articles and editorials quite critical of the industry and of individuals in the industry." You also stated that you would supply us with copies of these editorials and articles. Since the editOrials and articles you have sent us are not responsive to the Chairman's request, we would appreciate your sending us the relevant material as soon as possible. Sincerely, BENJAMIN GORDON, Staff Economist. AMERICAN ACADEMY OF GENERAL PRACTICE, Kansas City, Mo., April 25, 1969. Mr. BENJAMIN GORDON, staff Economist, U.S. Senate, Select Committee on Small Business, Washington, D.C. Dn~n Mn. GORDON: The material we sent you may not, by your standards, be considered critical of the pharmaceutical industry but you may rest assured that this view was not fully shared by the industry. May I respectfully point out that we do not normally index material by the degree to which it is favorable or unfavorable to the drug industry and we 1 "Practical Therapeutics" series has been retained in committee files. PAGENO="0489" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4779 have thus not perused every page of every issue. (GP was first published in April, 1950.) However, if members of my staff turn up additional material, I will see that copies are sent to Senator Nelson. Sincerely, MAC F. CAnAL. [From American Academy of General Practice, January 19651 Vivz LA DIFFERENCE Another instance has recently come to our attention in which members of the "weaker sex" have demonstrated a superiority over their masculine counterparts. Exeprimental work both in dogs and in rabbits has indicated that the female of the species is more resistant to digitalis cardiotoxicity than the male. This extra tolerance seems to be due to estrogen and related steroid compounds. A survey of hospitalized patients under age 40 with rheumatic heart disease indicated that approximately 20 percent of the male patients receiving digitalis develop signs of digitalis intoxication at some time during hospitalization. In the group of females, only 10 percent of those receiving digitalis develop digitalis- induced arrythmias (American Heart Journal, September 1964). Because of the limited size of the series, the results are not of high statistical significance and there are other weaknesses which the authors appreciate in a retrospective study. However, digitalis preparations are frequently, if not usually, administered as a "standard" dose. Therefore, the finding of a lesser incidence in the some- what smaller group of patients (the females) presents added weight to the valid- ity of the study. This new piece of information, coupled with the relatively high rate of toxicity noted particularly among male patients in the study, would in- dicate that there is still much for us to learn about the actions and usage of digi- talis preparations. As for the plus on the female scoreboard, we are becoming used to that. [From American Academy of General PractIce, June 1965] PHENACETIN AND THE NEPHROLOGISTS A Food and Drug Administration ruling still requires a printed warning label on over-the-counter preparations containing phenacetin, stating that these prod- ucts may damage the kidneys when used in large amounts. Despite such official warnings, evidence pointing to the nephrotoxicity of phenacetin is still largely cir- cumstantial. (Incidentally, the great strides in the understanding and the management of medical renal disease have brought into great prominence the medical sub- specialty now called "nephrology." To be sure, the functional unit of the kidney is the nephron. However, one might consider~ some of the other terms that would seem equally suitable for labeling this field of study. Why not "renology"? Of course, "urology" does not seem acceptable to the "salt and water" doctor.) Back to phenacetin. Several years ago, Schreiner queried many nephrologists on the relationship of phenacetin to kidney disease. More than half of 74 ne- phrologists reported that they had never seen a case of nephritis related to phenacetin. Now, Strickler suggests that phenacetin may have been singled out unjustly. He cites the conflicting findings in the clinical investigative literature. It is pos- sible that "phenacetin nephrits" is in reality chronic pyelonephritis. The problem still has not been studied in systematic fashion. [From American Academy of General Practice, September 19671 Dnua REMOVAL Suicidal or accidental ingestion of potentially lethal drugs continues to rep- resent an important clinical problem. Two recent trends have been of interest in this regard. The first is the variety of new drugs involved in overdosage situa- PAGENO="0490" 4780 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tions. Tranquilizers and antibiotics of various sorts are a case in point. The clini- cal pharmacology and, indeed, methods for measuring blood levels are not avail- able in every instance. The second trend deals with improved methods of drug re- moval, particularly by hemodialysis. Maher and Schreiner have recently reviewed some of these methods in the Transactions of the American Society for Artificial Internal Organs for 1067. Several drug removal rates are given, using the well-established figures for hemo- dialysis into an aqueous bath as the basis of comparison. For example, in the case of lipid soluble poisons, e.g., glutethimide (Doriden®), it is possible to greatly accelerate removal by hemodialysis against a lipid (soybean oil) bath and this has been sucessfully used clinically. A newer development is hemoperfusion through an activated charcoal column which appears to be superior even to lipid dialysis in removing glutethimide from experimentally poisoned animals. Pen- toneal dialysis with various modifications of the dialyzing fluid is appropriate for certain barbiturate poisonings. Further, there may be a significant increase in the rate of drug removal in the patient's own urine by alkalinization and forced diuresis. Drugs of the same class, e.g., barbiturates, differ from one another in response to these therapeutic measures and the clinician must acquaint himself with their individual characteristics. Calcium can be removed by hemodialysis but if the stimulus to hypercalcemia is strong enough, e.g., hyperparathyroidism, there may be no change in blood level. The phenothiazines and chlordiazepoxide (Librium®) illustrate two types of nondialyzable poisons for which no removal procedure is yet available. Information on drug removal is slowly accumulating and will con- tinue to be important as long as chemical or physiologic methods of treating a poisoned patient remain unavailable. [From American Academy of General Practice, April 1969] Aonoss THE MEDICAL EDITOR'S DESK ANOTHER LOOK AT IMMUNIZATIONS Mass immunization programs have become a way of life in this country within the past few years. When the oral poliovirus vaccine first became widely avail- able, many communities instituted programs for administering the vaccine to any citizen desiring it. In a number of localities, the development of a successful vac- cine against measles was the signal for another mass immunization program for school-age children. The pattern may be expected to continue. New vaccines are appearing on the scene almost yearly-this year, mumps vaccine; next year, rubella vaccine, and so on. Operation Head Start provides a further example of how long-standing im- munization programs (DPT) are coming in for their share of popularity. Par- ticularly in this socioconomic group, parental recollection of past immuniza- tions is often hazy. In any socioeconomic group, many families which frequently change residence do not take records with them. Whether speaking of mass immunizing programs or those directed toward patients seen in private practice, the proved efficacy of most vaccines and the relatively low incidence of adverse reactions often have led private and public medical resources into some rather slipshod practices. Is it too much to inquire whether the child has had measles before administering the vaccine? Should we not have immediate prior evidence of a negative tuberculin test? Recent examples from the medical literature further highlights the problem: Children who have received inactivated measles vaccine, when subsequently exposed to measles, may develop a severe illness characterized by high fever, prostration and a maculovesicular rash beginning on the lower extremities and progressing cephalad. Other children who have received inactivated vaccine, when subsequently given live attenuated vaccine, may develop severe local re- actions at the site of injection (Nader et al., Journal of Pediatrics, January 1968, p. 22). In this country, morbidity from smallpox vaccination now exceeds that from the naturally occurring disease. In one survey of reports from more than 4,000 physicians in four states, generalized vaccinia and eczema vaccination occurred at a frequency of 238 and 80 per million primary vaccinations respectively (Neff et al., Pediatrics, June 1967, p. 016). Complications occurred disproportionately during the first year of life, suggesting that vaccination should be deferred be- yond this period. PAGENO="0491" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4781 Current recommendations call for booster doses of tetanus toxoid at 3, 6 and 12 years of age, despite evidence indicating that 96 percent of children receiving a primary immunizing series have tetanus antitoxin titers well above the pro- tective level after 12 years. In older individuals receiving repeated injections of tetanus toxoid, a 1 to 3 percent morbidity may be expected, consisting of urticaria with or without angioneurotic edema or localized vascular injury (Steigmara, Journal of Pediatrics, May 1068, p. 753). Still unresolved are questions of subtle, long-term hazards of "overimmuniza- tion." In addition to local Arthus-type reactions resulting from tetanus toxoid injections, for example, there is evidence that a delayed hypersensitivity can occur. This involves the toxoid antigen portion of the complex with its homol- ogous antibody. These are early straws in the wind. American medicine increasingly is moving from a curative to a preventative approach. As one consequence, the underlying mechanisms of patient morbidity from immunizing procedures will need con- tinual reassessent. Period ending Nov. 30, Month of November 1968 1968 Circulation: Postage 37,.992. 18 3, 188. 58 Directory service 7, 183. 85 588.07 45,176.03 3,776.65 Production: Authors alterations and plate changes 837 35 30 76 Composition 6, 124.61 511.83 Electrotypes and foundry 6,399.85 417.02 Freight and express 1, 615.76 134.91 Paper 61,142.15 4,113.70 Printing and binding 170, 432.47 12, 403.27 Salaries 12,808.34 1,091.66 Total, production 259, 360. 53 18, 703. 15 General expense:c~pyrightfee 72.00.. 6.00 Total expense 307,476.40 22,788.48 Profit or (loss) - 24,821. 96 8, 277. 27 AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, NOV. 30, 1968 Income: Gross advertising sales Less: Discounts to advertising agencies (15 percent) Discounts to advertising agencies (2 percent) Net advertising sales Other income: Subscription income Single copy sales Total income Expense: Editorial: $407, 623. 00 $37, 121. 50 68, 955. 85 5, 568. 29 6,857.05 525.18 331, 810. 10 31, 028. 03 422.66 27.72 65.60 0 Engraving Total, editorial Total, circulation 332, 298. 36 31, 065. 75 1,761.07 190.91 1,106.77 111.77 2, 867. 84 302. 68 PAGENO="0492" 4782 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, NOV. 30, 1967 Year ending Month of - Nov. 30, 1967 November 1967 Income: Gross advertising soles Less discounts to advertising agencies (15 percent) Net advertising sales Other income: Subscription income Single-copy sales _____________ ____________ Total income Expense: Editorial: Art Engraving ___________ Total editorial Circulation: Postage Directory service Total circulation Production: Authors' alterations and plate changes 3,294. 38 49. 49 Composition 4, 403. 17 539. 70 Electrotypes and foundry 12, 515.21 421. 30 Freight and express 3, 106. 68 494. 84 Paper 77,805.61 7,954.89 Printing and binding 203,624. 10 19, 302. 67 Salaries 5, 000. 00 1, 000. 00 Total production 309,749.15 29,762.89 General expense: Copyright fee 66. 00 6. 00 Total expense 370, 138.92 36, 298. 75 Profit or (loss) (1,368. 00) (1,216. 67) AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1966 Period ending Year ending Dec. 31, 1966 December 1966 Income: Gross advertising sales Less discounts to advertising agencies Net advertising sales Other income: Subscription income Single copy sales _____________ ___________ Total, income - Expense: Editorial: Art Engraving __________ Total, editorial $541, 802. 00 173, 376. 65 368, 425. 35 263.64 81.93 368, 770. 92 $51, 536. 00 16, 491. 52 35,044.48 33.72 3.88 35,082.08 1,516.59 1,133.87 2, 650. 46 167.61 113.42 281. 03 49, 867. 22 4, 622. 41 7, 797. 09 1, 626. 42 57,673.31 6,248.83 $345, 291. 50 110,190.68 235, 100. 82 232. 84 4.09 235,337.75 $40,659.50 12, 922. 64 27,736.86 21.64 27,758. 50 2,012.12 1,344.92 3,357.04 397.53 117.50 515.03 40, 824. 10 7,252.55 48,076.65 Circulation: Postage Directory service Total, circulation - Productinn: - Authors' alterations and plate changes Composition Electrotypes and foundry Freight and express Paper Printing and binding Total, production - General expense: Copyright fee - Total, expense - Excess expense over income 4, 217, 67 0 4,217.67 2,884. 34 203. 55 2,087.55 291.85 15,344.02 1,770.15 914.08 41.27 59, 630. 21 6, 044. 13 197, 837. 89 17, 094. 94 278,698. 09 25,445. 89 72.00 6.00 330, 203. 78 30, 184. 59 94, 866. 03 2,426. 09 PAGENO="0493" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4783 AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1965 Period ending Month of Dec. 31, 1965 December 1965 Income: Gross advertising sales Less discounts to advertising agencies Net advertising sales Other income: Subscription income Single-copy sales Total income Expense: Advertising: Advertising promotion Circulation: Postage Directory service Total circulation $303, 559. 50 $24,313. 00 97,139.04 7,780.16 206, 420.46 16, 532. 84 213.06 67:32 109.00 206,742. 52 16, 600. 16 1,036.76 (246.54) 40,912. 83 3, 087. 05 8, 806. 01 851. 72: 49,718.84 3,938. 77 Income: Gross advertising sales $241, 382. 50 Less discount to advertising agencies 76,983. 15 Net advertising sales 164,399. 35 Other income: Single-copy sale Subscription income Total other income -- Total, income Expense: Advertising: Advertising promotion - Circulation: Directory service Postage Total, circulation Production: Art Engraving Paper Printing and binding Composition Authors' alterations Freight and express Electrotypes and foundry Total, production General expense: Copyright fee Fees and dues Total, general expense - Total, expense Excess expense over income - 18.85 18.85 163.31 64.91 Production: Art Engraving Paper Printing and binding Comnosition Authors' alterations Freight and express Electrotypes and foundry Total production General expense: Copyright fee Total expense - Excess expense over income 1,655.69 162.47 1,637.34 107.210 60, 185. 93 4,696. 98 199,964. 20 15, 538. 66 2,626. 87 467. 810 2, 190. 13 223. 50 878. 91 65.64 10,621.60 714.30 279,763. 67 21, 976. 55 50. 00 6. 00 330, 566. 27 25, 674. 78 123, 823.75 9, 074. 62 AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1964 Period ending Month of Dec. 31, 1964 December 1964 $25,807.50 8,201.45 17,606. 05 182.16 83.76 164, 581. 51 17,689. 81 1,441.00 2,732. 41 2,732. 41 35, 017. 19 3, 651. 57 37,749. 60 6, 383. 98 2,240.43 395.96 1,813.20 1,455.29 53, 257. 01 5, 210. 21 170, 201. 82 16, 161. 19 2, 092. 45 296. 50 2, 332. 33 223. 86 849.11 152.73 8,491.52 751.53 241,277. 87 24, 647. 27 48.00 4.00 100.00 148.00 4.00 280,616.47 31,035.25 116, 034. 96 13,345.44 PAGENO="0494" 4784 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1963 Period ending Month of Dec. 31, 1963 December 1963 Income: Gross advertising sales $205, 668. 40 $12, 563. 50 19~ Less discounts to advertising agencies 66,376. 72 3,972,28 ~1Net advertising sales 139, 291. 68 8, 591. 22 Subscription income 151. 69 12. 56 Single copy sales 8. 36 Total income 139,451. 73 8,603.78 Expense: Advertising Sales promotion 69 69 Advertising promotion 1,356. 88 Market research service 3, 000. 00 Total advertising 4,426. 57 Circulation: Printing and office supplies 39. 78 Postage 77.76 5.25 Mailing 29,912. 77 2, 657. 50 Total circulation 30, 030. 31 2,662. 75 Production: Art 2,369. 10 223.37 Engraving 1,754.68 Paper 51, 528. 53 4,413. 45 Printing and binding 166, 135.84 13, 146. 25 Composition 2,287.90 276.75 Alterations and plate changes 1, 806. 64 173. 80 Freight and express 963. 17 70. 06 Electrotypes and foundry 7,413.21 477. 67 Total production 234,259. 07 18,781. 35 General expense: Printing and office supplies 285. 26 Copyright fee 48. 00 4. 00 Fees 80. 00 Total general expense 413. 26 4. 00 Total expense 269, 129. 21 21,448. 10 Excess expense over income 129,677.48 12, 844. 32 PAGENO="0495" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4785 AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1962 Period ending Month of Dec. 31, 1962 December 1962 Income: Gross advertising sales Less discounts to advertising agencies Net advertising sales Subscription income Single copy sales Total income 75, 252. 73 Expense: Advertising: Sales promotion 167. 41 69. 18 Printing and office supplies 196. 50 Dues and subscriptions 500. 00 Advertising promotion 6, 552. 84 62. 63 Market research service 545. 24 Total advertising 7,961.99 131.81 Circulation: Circulation promotion Printing and office supplies Postage Mailing Total circulation ______________________________ Production: Art Engraving Paper Printing and binding Composition Authors' alterations Freight and express Electrotypes and foundry Total production 203, 844. 68 General expense: Printing and office supplies Copy right fee Total general expense 1, 000. 04 Total expense 241,290.83 22,436.49 Excess, expense over income 166, 038. 10 15, 872. 01 $8, 143. 24 2,493.97 i~ingraving 2,568.19 Paper 18, 137.62 Printing and binding 68,200. 62 Composition 3 428. 75 Authors' alterations 478. 85 Authors' reprints 433. 04 Freight and express 529.27 Electrotypes and foundry 3,910.36 Printing and office supplies 345.72 108,669.63 $109,947. 00 $9, 663. 00 34,777. 90 3, 092. 32 75, 169. 10 6, 570. 68 76. 63 (6. 70) 7.00 .50 6,564.48 161.29 125. 97 72.93 171.46 6.12 28, 025. 40 2,541.96 28,484. 12 2,621. 01 2,936. 81 481.99 1,949.97 217.64 45, 189.81 4,388. 84 141,811.76 14,018.36 2,857.77 295. 35 1,855.28 189.64 1,771.53 51.85 5,471.75 19,643. 67 960.04 40.00 40.00 40. 00 Production: Salaries Art Family physician income and eopense analysis, January through December 1961 Total PAGENO="0496" 4786 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Family physician income and eapense analysis, Ja~wary through December 1961-Continued General: Printing and office supplies 2, 655. 29 Office equipment 617. 10 Total 3,272.39 Total expense 161, 144. 94 Excess expense over income 113, 169. 92 Income: Gross advertising sales-981/2 pages 62, 189. 19 Less: Discounts to advertising agencies 14,217.49 Net advertising sales 47, 971. 70 Subscription income 2. 82 Single copy sales . 50 Total income 47, 975. 02 Expense: Accounting: Salaries 1,359.42 Printing and office supplies 9.38 Total 1, 368. 80 Administration and publishing: Salaries and commissions 1, 000. 00 Advertising: Salaries and commissions 4,225. 73 Printing and office supplies 470.49 Market research 3, 638. 29 Sales promotion 3, 852. 31 Advertising promotion 7,975.28 Total 20, 162. 10 Circulation: Salaries 1, 427. 35 Mailing 11, 856. 90 Postage 28. 12 Promotion 1, 000. 00 Printing and office supplies 2, 395.39 Part time personnel 537. 00 Total 17,244. 88 Editorial: Salaries 9,374. 64 Printing and office supplies 52.50 Total 9,427. 14 BIoGRAPHICAL SKETCH OF MAYNARD I. SHAPIRO, M.D. DR. SHAPIRO TAKES HELM Dr. Maynard Irwin Shapiro of Chicago will be installed tonight as the Aca- demy's 21st president, during his 20th anniversary year as an AAGP member. The 53-year-old Chicago native becomes chief spokesman for the Academy after a steady rise from the ranks which triggered his election to the Board of Direct- ors in 1903. While a director, Dr. Shapiro served as chairman of the Commission on Mem- bership and Credentials and the Commission on Education. Upon completing a three-year term on the Board, he was elected vice president and then became PAGENO="0497" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4787 president-elect last year in Dallas. This past year he has been on the Executive Committee, the Residency Review Committee for General Practice and the Family Health Care Services Committee. Many key honors have come to Dr. Shapiro during the year. He was named a member of the HEW Medical Assistance Advisory Council and a trustee of the Family Health Foundation of America. In Illinois, he became a member of the Task Force on Health Manpower of the Illinois Regional Medical Pro- gram and a consultant in the Family Health Care Project of Illinois Masonic Hospital. In his home state, Dr. Shapiro has held every elective office of the Illinois chapter, culminating in the presidency in 1961-62. He has been on innumerable committees and commissions and continues to serve in the Illinois Congress of Delegates. He has served his regional chapter in many capacities and was president in 1955. He was co-chairman for the inception of the postgraduate school which has continued to be recognized as a model. Dr. Shapiro also has remained active in the Cook County Medical Society, in- cluding his local branch, and the Illinois State Medical Society. Currently, he is chairman of the industrial committee of the South Chicago Branch of the COMS, on the committee on careers in medicine and allied sciences of GUMS and on ISMS advisory committee to the Illinois Medical Assistants Association. He is a consultant to the ISMS advisory committee to the Health Careers Council of Illinois, and continues as a member of the house of delegates of the ISMS. Dr. Shapiro has worked as a member or co-chairman of several committees of the AMA and currently is serving as alternate delegate from the Section on General Practice and as a member of the Council on Health Manpower. He also is a national advisor to the Student American Medical Association. He is on the active surgical staff of Jackson Park Hospital, where he also is director of the Department of Physical Medicine and Rehabilitation, director of medical education and director of the Summer Student Program, as well as a member of the Executve and Credentials committees. Previous hospital affiliations were as clinical assistant in surgery at Mt. Sinai Hospital and as medical-surgical consultant to the Neurological Hospital in Chicago. In addition to teaching both undergraduate and graduate medical students in the community hospital setting, he is a visiting lecturer in the graduate program in hospital administration in the Graduate School of Business of the University of Chicago. He is a fellow of the Industrial Medical Association, Central States Society of Industrial Medical and Surgery, Academy of Psychosomatic Medicine and the American Geriatrics Society. He also holds memberships in the Chicago Society of Industrial Medicine and Surgery (he is a past member of the board of governors), American Congress of Rehabilitation Medicine, Mid-America Society (and Illinois division) of Physical Medicine and Rehabilitation, Association of Hospital Directors of Medical Education and the Association of American Medi- cal Colleges. His civic activities have been equally varied. He served in the city and state venereal disease campaigns, as well as on a medical advisory committee to the city, culminating in the presentation of a citation of service plaque. He currently is president of the Health Careers Council of Illinois (he was elected to an un- precedented third term), on the advisory board of the Health Improvement Foundation of the Illinois Health Improvement Association, a director of the Illinois Social Hygiene League and a member of the professional advisory coun- cil of the National Easter Seal Society for Crippled Children and Adults. Dr. Shapiro is a life member of Phi Delta Epsilon medical fraternity, a mem- ber of Scottish rite and Medinah Temple (Shrine) and a member of Beth Am Synagogue and Men's Club. He was born in Chicago on December 18, 1914. He has remained there, with his residence currently at 8911 South Chappél Ave., and office for full general practice in the Jackson Park Hospital. Dr. Shapiro received his premedical training at Crane Junior College and Central YMCA College, Chicago. He was graduated from the University of Illi- nois College of Medicine in 1939 and served his internship and residency at Mt. Sinai Hospital in Chicago. 81-280-69-pt. 11-32 PAGENO="0498" 4788 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY His military service was with the Army Medical Corps on active duty from 1941-46 in the South Pacific, rising in rank to lieutenant colonel. Dr. Shapiro and his wife, the former Lenore Martha Gold of Providence, RI., have one daughter, Jull Ann, 16. BI0GnAPHICAL S~ToH OF MAC P. CAnAL, J.D. Mac F. Cahal, Executive Director and General Counsel of the American Academy of General Practice, Publisher of the Academy's medical publications, GP and the American Family Physician, and Secretary-Treasurer of the AAGP Foundation, Kansas City, Missouri; born March 28, 1907, Kiowa, Kansas; son of Frank B. and Carrie (Fullerton) Cahal; A.B. University of Kansas School of Journalism, 1931; J. D. (Doctor of Jurisprudence) Be Paul University College of Law, Chicago, 1935; attended Northwestern University 1937-38; married Wilma Marshall, June 1, 1935; one daughter Caroyln, and son William Marshall. Doctor Cahal began his work with organized medicine as Executive Secretary of the Sedgwick County Medical Society (Wichita), Kansas, in 1932. In 1937 he became Executive Secretary and General Counsel of the American College of Radiology. During a leave of absence in 1944 he served as Executive Vice- President of the Southwestern Medical Foundation in Dallas. In 1948 he resigned from the American College of Radiology to become General Counsel and Execu- tive Secretary of the American Academy of General Practice. He is an associate Fellow of the American Medical Association, a member of the American Bar Association and the Chicago Bar Association, an Honorary Member of the Sedwick County Medical Society, and a member of numerous clubs and societies. Doctor Cahal was founder and president in 1948 of the Medical Society Execu- tives Association. He is a past president of the Association of Medical and Allied Publications, and serves on the Board of Directors of the American Society of Association Executives. He is the author of numerous monographs on the social, economic, and legal aspects of medicine, published in both the medical and legal literature. He has been a frequent speaker before medical and lay audiences on the above subjects and has testified on several occasions before government boards and committees in Washington. His home is at 6610 Indian Lane, Mission Hills, Kansas. BIoGI~s.iHIcAL SKETCH OF WALTER H. KEMP Mr. Kemp is managing editor of GP and American Family Physician maga- zines, both published monthly by the American Academy of General Practice. He is also secretary of the Academy's Commission on Legislation and Public Policy and has previously served as advertising sales manager, director of pub- lic relations and director of the Communications Division. He holds B.S. and B.A. degrees in psychology and economics from Northwestern University and is the son of Dr. and Mrs. Howard M. Kemp (both deceased) of Greenfield and Shelburne, Mass. Mr. Kemp was earlier employed by Armour Research Foundation and the American Medical Association in Chicago. He was a police reporter and special features writer on the Greenfleld (Ma~ss.) Recorder-Gazette. He is a member of Beta Theta Pi, DERU (seniormen's honorary society) and Sigma Delta Chi. During World War II, he served in the airborne infantry and was honorably discharged after being wounded during the Normandy and subsequent cam- paigns. Mr. and Mrs. Kemp have three children and reside at 9332 Catalina Drive, Shawnee Mission, Kansas 66207. (Whereupon, at 12 o'clock, the Subcommittee on Monopoly of the Select Committee on Small Business was adjourned, to reconvene sub- ject to the call of the Chair.) PAGENO="0499" APPENDIXES APPENDIX I [From the Virginia Medical Monthly, vol. 94, Feb. 1967, pp. 110-114] THE IMAGE OF THE DRUG INDUSTRY, AS SEEN BY TOWN AND GOWN (By William J. Hagood, Jr., M.D., Clover, Virginia, John A. Owen, Jr., M.D., Charlottesville, Virginia) (Presented before the Public Relations Section of the Pharmaceutical Manufacturers Association, Sixth Annual Meeting, Hot Springs, Virginia, October 4-7, 1964.-From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Vir- ginia School of Medicine, Charlottesville. Aided by Training Grant HE 5544 from the U.S. Public Health Service.) Results of a questionnaire with regard to the pharmaceutical in- dustry and products are presented. During the last several years the pharmaceutical industry has repeatedly made headlines-not always to its advantage. Perhaps for this reason, the Public Relations Section of the Pharmaceutical Manufacturer's Association in- cluded in its 1964 convention program a panel discussion on the industry's image in the eyes of the physician. In preparing our independent presentations for this program we distributed two questionnaires: one to 200 general practitioners in the rural areas and small towns of Virginia and the other to the medical students, interns, and residents of the University of Virginia Medical Center. The contrasting responses from the two grOups have given rise to some discus- sion and conclusions which may be of interest. THE GENERAL PRACTITIONERS' QUESTIONNAIRE There were five general questions on this list, as follows: 1. What is your impression of the pharmaceutical industry? Why do you have the opinion you have expressed? 2. What influences you to use a drug company's product? Why do you think the influences you have expressed `are important? 3. Do you favor the continuing use of the medical service-representatives or "detail men" `by the drug companies? Why? 4. Do you think the cost of drugs is too high, too low, or about right? What would you suggest the pharmaceutical industry do to better inform the patients why drugs cost what they dO? 5. What is your opinion of the `apparently growing practice of physicians gaining a financial interest in pharmacies and drug distribution firms? Why do you have this opinion? Of the 200 physicians queried, 80 (40%) responded; these 80 resided in 55 of Virginia's 99 counties and had practiced medicine from three to 61 years in offices located either in open rural country or in villages ranging in population up to 4200. In the following paragraphs, percentage figures will be based on the 80 responses. In reply to the first question, 64 physicians (80%) affirmed that they have a good impression of the pharmaceutical "industry, based primarily on the in- dustry's extensive research programs and high ethical relations. Another 9% were non-committal. Only nine physicians (11%) actually criticized the industry be- cause of exorbitant prices, pushy and garrulous detail men, or excessive adver- tising. As reasons for using a `specific company's product, 40% claimed to be guided mainly by previous results with the product, 33% by the positive influence of de- 4789 PAGENO="0500" 4790 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tail men, 28% by the over-all integrity of the company, 21% by medical jour- nals, and 14% each cited the research behind the drug and the relative cost of the drug as being crucial to their decision. There were in all 17 reasons given the least popular (1 physician, 1%) being the evaluation of the drug by the Medical Letter. Regarding the utility of the detail man, 85% of general practitioners gave him a strong vote of confidence, because his new drug information was valuable to them and he could order drugs directly for dispensing physicians. The other 15% felt that in view of the abundant available literature his services could be eliminated and the resultant savings be passed on to the patient. Questioned about drug prices, 51% of general practitioners thought that they were "about right," and 45% thought that they were "too high"; none con- sidered them "too low." Furthermore, 24% urged a better public relations at- tempt to help the layman understand why drugs cost what they do. However, one physician urged the opposite course: "reduce the cost instead of spending more money to tell the patient why drugs are expensive." Finally, the general practitioners were definitely opposed (75%) to the prac- tice of physicians gaining a financial interest in pharmacies and drug distribu- tion firms. TIlE MEDICAL CENTER QUESTIONNAIRE Questions 1 and 2 required a listing of material gifts from drug companies and stock ownership in them. Questions 3-5 asked for a graded evaluation of the pharmaceutical industry on its (1) record in the development and testing of new drugs, (2) margin of profit in prescription drugs, and (3) performance in dis- seminating information about new drugs. Questions 6 and 7 tried to assess the impact of the new Food and Drug Administration regulations concerning clinical trials in terms of general awareness and reaction. In question 8, each person was asked to compare and rate the following over-all sources of comprehensive in- formation about new drugs: faculty and house staff, scientific meetings, scien- tific articles, advertisement in medical journals, mail literature from drug com- panies, detall men, the "Physician's Desk Reference," the Medical Letter and drug inserts. Question 9 asked for a correct matching of both the generic names and the therapeutic effects to the trade names of twenty common drugs. Question 10 was multiple choice: "The pharmaceutical industry could bet- ter serve the medical profession by (1) continuing just as it is; (2) cutting prices; (3) developing more new drugs at a faster rate; (4) sponsoring more post-graduate courses; (5) distributing more educational material; (6) chang- ing its advertising policy as follows; (7) changing its drug development policy as follows; (8) changing its detail man program as follows; (9) changing its drug sample policy as follows; or (10) other." Question 11 asked each person to assign a grade rank to the following factors as strongly affecting his opinion (good or bad) of a specific drug company: "(1) advertisements; (2) experience with its products; (3) gifts and services to you; (4) research support; (5) as- sistance in post-graduate and medical educational programs; (6) detail men; and (7) other." Returns from this questionnaire were scattered, ranging from a 7% response from the second-year class to a 30% response from the fourth-year class. There were 73 questionnaires completed and returned from the 384 persons polled, an over-all 19% response. Almost everyone had received some sort of gift from one of the drug com- panies. Eli Lilly and Company had donated 57 pen lights, 46 medical bags, 45 percussion hammers, 35 stethoscopes, 30 pocket notebooks, 28 tuning forks, 19 pen knives, and 18 tape measures, as well as sundry other diagnostic aids, to the 73 persons polled. Burroughs Welcome & Company had given 18 pocket notebooks, Ciba Pharmaceutical Company had distributed 11 subscriptions to the Ciba Symposia, and Wyeth Laboratories had given 10 pen lights. In all, 19 drug companies were listed as donors, some only once, of generally minor and inexpensive gifts. Of the 73 polled, six owned stock in one or more drug companies and 58 of the nonowners considered such stock to be a good financial investment. Most answers rated the pharmaceutical industry's record in development and testing of new drugs as good (41, or 56%), its margin of profit in prescription drugs as wide (35, or 48%), and its performance in disseminating information about new drugs as good (39, or 54%). Most of the other answers were equally divided between the two evaluations nearest the mode ("very good," and "fair"). PAGENO="0501" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4791 Knowledge of the current Food and Drug Administration regulatioins regard- ing clinical drug trials seemed to be greater among residents than medical students: 26 out of 35 students had at most a vague cognizance of them; 17 out of 32 residents had a fairly good or exact knowledge. Most medical students felt they were "necessary and reasonable", but the residents were divided equally between this viewpoint and "necessary and unreasonable". In addition, five residents felt them to be "unnecessary and unreasonable", and three "highly commendable and long over-due". The ratings of best sources of comprehensive information about new drugs are shown in Table I. The influence of faculty and house staff rises to a peak during the intern year and then progressively declines. Articles in medical journals appear to be the most consistently~ respected authority throughout, with the Medical Letter running a close second during the post-graduate period. Advertisements, mailed literature and the detail man are usually at the bottom of the list, although the latter performs better during senior residency years. TABLE I Q. 8. Which do you believe to be the best overall source for comprehensive information about new drugs? M.S.2 M.S.3 M.S.4 I. R.l R.2 R.3 R.4 Insert P.D.R. Journ. FaclIS. Journ. Journ. Journ. Journ. Journ Journ. FacHS. Journ. MedLet MedLet MedLet MedLet FacHS. FacHS. P.D.R. P.D.R. FacHS. FacHS. Insert Meets. Meets. MedLet Insert MedLet Meets. Insert Fad-IS. FacHS P.D.R. Meets. MedLet Meets. P.D.R. P.D.R. Detail Detail Ads Mail Meets. Insert Insert Meets. P.D.R. P.D.R. Insert Mail Ads Ads Mail Meets. Detail Ads Mail Detail Ads Mail Ads Detail Detail Mail Detail Ads Legend: MS-medical student; 1.-intern; R.-resident. Numbers indicate years of training. Abbreviations for sources self-explanatory. In the matching quiz, some generic names were almost as familiar as their corresponding trade names but there were some impressive discrepancies: 60 persons correctly described Elavil (Merck Sharpe and Dohme) as a mood eleva- tor but only 14 of these knew that its generic name was amitriptyline; 60 persons knew the therapeutic action of Dulcolax (Geigy) but only 23 knew its generic name. The last two questions produced the most spontaneous responses. The sugges- tions for the pharmaceutical industry are summarized in Table II. The same general sentiments are reflected in the responses to the last question, illustrated in Table III. The same three sources of dissatisfaction (detail men, advertise- ments, and gifts) are again apparent. TABLE II Q. 10. The drug industry could best serve the medical profession by- Sponsoring more post-graduate courses - Distributing more educational material Cutting prices - Changing its advertising policy - Changing its drug sample policy - Changing its detail man policy Developing more new drugs at a faster rate. - Changing its drug development policy - Continuing just as it is - TABLE III Q. 11. Your opinion (good or bad) of a specific drug company is most strongly affected by: Factor Total response Favorable Unfavorable Either Experience with products Detail men 57 32 9 1 1 12 1 Advertisements Personal gifts, etc Postgraduate education support Research support 23 19 17 14 2 7 3 6 3 8 8 18 18 16 15 15 14 7 7 5 PAGENO="0502" 4792 COMPETITIVE PROBLEMS IN THE DRtIG INDUSTRY COMMENT It would be imprudent to attempt multiple interpretations of the responses to two different questionnaires, distributed to two different and heterogeneous groups, with such a variable percentage of replies. However, the following sim- ilarities deserve emphasis. 1. There is general appreciation for and satisfaction with the over-all per- formance of the pharmaceutical industry. 2. A feeling that drug costs are too high or profits too wide is evident in 45% of the answers from the general practitioners and in 48% of those from the Medical Center. 3. Most doctors judge a drug company by the efficacy of its products, with the activities of the detail man receiving second place in consideration. In addition, one may ask what is the comparative efficacy of the three forms of advertising: direct mailing, medical journal ads, and the detail man? The physician has a built-in bias against them all, knowing that none is likely to give him what he wants: a carefully balanced comparison of the product vs. (a) older, simpler substances, (b) new products of competitors, and (c) no treatment at all. Also, to make best use of his limited reading time he glady dispenses with all save the most authoritative sources of information. So it is unlikely that mail literature and journal advertising have any lasting impact; both could probably be curtailed completely without much effect on the practice of medicine. This is true because in their absence the detail man could serve the same functions. Conversely it is hard to see how impersonal mailings and glossy ad- vertisements could take the place of an ideal detail man: cheerful, helpful, dis- armingly proprietary, willing to listen and happy to debate. Although the physician spends time with him, be spends it as he chooses; he can in effect carry on a conversion with a person, with a drug company, or with the entire phar- maceutical industry. If the ideal detail man exists, he is clearly outnumbered by his imperfect brethren who reportedly interrupt the office routine, parrot stereotyped en- coniums, hawk their wares in a truculent manner, and talk without listening. This confrontation destroys the one thing the physician wants: a chance to learn some valid information. Since the physician is unlikely to change his attitude, the pharmaceutical industry must become more information-oriented. This metamorphosis cannot occur spontaneously but requires active and vocal effort on the part of the physician. The following avenues of information have been worked out at many teaching medical centers: 1. A hospital policy for detail men requires that any "detail visit" (five min- utes) to any physician be scheduled through a central office. 2. A similar policy encourages drug companies to work through a central office in arranging clinical trials of new drugs, thus bringing together the mOst promis- ing drug and the best-qualified investigator. 3. Books, films or other educational material can be useful in both medical and post-graduate education; courses and lectureships, research fellowships and hon- oraria for visiting speakers have been deeply appreciated gifts from the phar- maceutical industry. 4. Occasionally the drug company may support an entire laboratory or clinical research area, where patients are hospitalized for study by all the. newer tech- ñiques of clinical pharmacology. Implicit in all of these programs is the presence of a professional person or persons who maintains a liaison with the drug house representatives and ar- ranges these collaborative efforts. At every opportunity such a person works to- ward one specific goal-to help bring the best information available from the drug houses to the physicians. Whenever the physican works actively in cooperation with the pharmaceutical industry in these areas, he appreciates anew its sceintific contributions and puts aside his built-in resistance to its commercial aspects. Thus these possible ap- proaches to a closer working relations, while sometimes apparently restrictive, cannot fail to increase the physician's appreciation of the industry-a reservoir of good will which is a powerful reality and capable of even greater enhance- ment. The medical profession and the pharmaceutical industry, working together, should bend themselves to that task. PAGENO="0503" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4793 APPENDIX II [From the Virginia Medical Monthly, vol. 93, August 1966, pp. 459-461] TEACHING THE EVALUATION OF DRUG ADVEIITISING TO MEDICAL STUDENTS (By D. R. H. Gourley, Ph. D., professor of pharmacology, University of Virginia School of Medicine, Charlottesville, Va.) Physicians until the present have developed their own methods for evaluating the advertising of pharmaceutical manufacturers. Now a course is being given in medical school to prepare the student for this task. From time to time, spokesmen for the pharmaceutical industry have attempted to justify the expenditure of heavy sums for the advertising of prescription drugs to a limited group as "postgraduate education of the doctor." The charac- ter of drug advertising in the United States today under regulation by the Food and Drug Administration(6) has improved considerably since the abuses de- scribed by May (5) and others. However, there is reason to believe that many physicians in private practice have been introduced to a large proportion of the drugs they are now prescribing by communications from the pharmaceutical manufacturers. Baehr (1) noted that many general practitioners and specialists in his experience were motivated to shift from one drug to another by the per- suasive propaganda of advertising literature and by visiting representatives of manufacturers. It is clearly desirable for the~ physician to have a set of guidelines by which *he can evaluate the claims that will be made for drugs introduced to the thera- peutic scene in the years following graduation from medical school. The course in pharmacology appears to be a logical place to begin to introduce such guide- lines and studies of the evaluation of drug adyertising ha\ e been initiated in the pharmacology courses in some medical schools. (2, 3) Typically, a program of drug advertising evaluation is modified in some details from year to year, but the principles can be illustrated by a description of the program most recently undertaken with second year medical students in the Department of Pharma- cology at the University of Virginia School of Medicine The objectives, of the evaluation of drug advertising (EDA) program were: (i) to develop in the medical student a skeptical attitude towards advertising claims for new. drugs; (2) to provide the medical student with training and ex- perience in the evaluation of these claims and with some knowledge of the relia- bility of various authorities. The practical exercise of the EDA program was limited to direct mail advertising although it is recognized that this is only one of several channels through which drugs are advertised. To obtain the neces- sary material, three cooperating physicians saved all of the drug advertisements and samples received through the mail during the three-month period immedi- ately preceding the project. The program was scheduled during the latter part of the pharmacology course after the students had completed their study of drugs which affect the central nervous system, autonomic nervous system, cardiovas- cular system and kidney. The mass of accumulated mail was gleaned for material advertising drugs in these general categories. Most of the drugs were relatively new but a few older agents were included for balance. Advertised material that included literature references was selected in preference to poorly documented brochures. Although this bias favored the advertising material, it was a neces- sary concession in order to provide the students with certain leads. The class was divided into 18 groups of four students each. Therefore, 18 drugs were chosen. All of the available direct mail advertising for one drug was given to one group for their analysis. At a preliminary session, the students were given their assignment and in- structions for the program. The peculiar features of drug advertising and the relative role of direct mail advertising in overall drug promotion were discussed. The volume of drug samples received through the mail during the collection pe- riod was dramatized by emptying a large galvanized can containing the drug N0VE.-Numbered references at end of article. PAGENO="0504" 4794 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY samples on the lecture table. A considerable portion of the introductory session was devoted to methods for assessing reports of drug trials. The criteria outlined by Mahon and Daniel(4) were emphasized. The method consists of the stepwise application of the following criteria: (1) the presence of adequate controls, in- cluding the effects of a placebo preparation as well as standard therapy; (2) ran- domization of treatments; (3) objective assessment of drug effects, including the principle of the double-blind trial to avoid biased evaluation; and (4) sta- tisical analysis of results. The students were instructed to determine how many of the cited references were actually available in the Medical Library (which has 1250 scientific journals on the subscription list) and what proportion of those available were adequate according to the above minimal criteria. Attention was also directed to other source material such as the Medical Letter, the A.M.A. Council on Drugs reports, New Drugs, etc. it was not an objective of this program to criticize or rate individual drug manufacturers. The important role of the pharmaceutical industry is emphasized in many ways in this course. During the EDA program, for example, a one-day visit to a nearby pharmaceutical firm was arranged. In addition to seeing the excellent pharmacological and medicinal chemical research and the manufac- turing and packaging functions of this firm, the students were addressed by an executive officer of the firm who, by prearrangement, presented much valuable additional material on drug advertising from a viewpoint somewhat different from that of the instructors. Each group of students was assigned a clinical advisor, usually a physician who had had considerable clinical experience with the assigned drug. The students were instructed to discuss their assignments with their advisor follow- ing the introductory session and from time to time during the progress of the program in regard to questions relative to the evaluation of the drug, the other drugs available for comparable therapy, and the state of knowledge in the field for which the particular drug is intended. They were urged to obtain as many opinions on these questions as possible by also consulting other clinical instruc- tors and to consult several pharmacists regarding available preparations and relative costs to the patient of equivalent doses of the assigned drug and of other comparable drugs. Students were offered secretarial assistance if they wished to write to pharmaceutical firms for additional information. The students were allowed eight hours of laboratory time over a three-week period to work on the EDA program. At the end of the program, each group submitted a written report of their study and each member of the group was prepared to present an oral 10-minute report. The oral reports were presented to the class and discussed by the class advisors and departmental staff. The person chosen from each group to present the oral report was not announced in advance. The staff of instructors and the clinical advisors report that the students rapidly developed a skeptical attitude towards the particular advertising claims which they studied. The students were particularly impressed with the number of quoted "references" which were not available even in a good medical library. Many groups found that of the references they could find in the literature only about 5% fulfilled all of the criteria for a satisfactory clinical trial of a new drug, which is in general agreement with results of the large study reported by Mahon and Daniel. (4). At the end of the pharmacology course, student opinion of various aspects of the pharmacology course was polled in an unsigned questionnaire. The class was unanimous in its belief that a study of drug advertising belonged in a medical pharmacology course. Ninety-five per cent of the class thought that the project outlined in this report was a valuable learning experience and 85% thought that the time allotted to the project was "about right". Further polls of the same class will be sought just before graduation and after a period of time in practice to determine whether attitudes towards drug advertising and reports of clinical trials of new drugs developed as a result of this teaching exercise have been maintained. In the meantime the enthusiasm of the students and the members of the faculty who participated is ample justification for continuing the project with modifications designed to improve the attainment of the objec- tives or to better suit further developments in drug advertising and regulations of the Food and Drug Administration. PAGENO="0505" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4795 Acknowledgements: It is a pleasure to acknowledge the contributions to the success of this program of the A. H. Robins Co., Inc., Richmond, and the follow- ing members of the faculty of the University of Virginia School of Medicine: Drs. A. J. Bollet, E. D. Brand, G. Goldstein, C. D. Green, J. I. Kitay, C. M. Kunin, D. N. Mohier, J. A. Owen, Jr., L. E. Rudolf, 0. A. Thorup, Jr., and F. B. Westervelt, Jr. REFERENCES 1. Baehr, G.: Drug Costs and the Consumer in Drugs in Our Society. Ed. by Talalay. The Johns Hopkins Press, Baltimore, 1964, p. 179. 2. Daniel, E. E.: Are Laboratories in the Basic Medical Sciences Necessary? Canad. Fed. News 7: 69, 1965. 3. Garb, S.: Teaching Medical Students to Evaluate Drug Advertising. J. M. Educ. 35: 729, 1960. 4. Mahon, W. A. and Daniel, E. E.: A Method for Assessment of Reports of Drug Trials, Canad. M. Assoc. J. 90: 565, 1964. 5. May, C. D.: Selling Drugs by "Educating" Physicians. J. M. Educ. 36: 1, 1961. 6. Sadusk, J. F.: Planning in the Food and Drug Administration for Regula- tion of Prescription Drug Advertising. Current Therap. Res. 7: 332, 1965. APPENDIX III APRIL 22,1969. Dr. W. J. HAGOOD, Jr., Little Retreat Clinic, Clover, Va. DEAR Dn. HAGOOD: When you appeared before our Subcommittee on February 19th, you stated that you had prescribed the drug combination, Signemycin to one of your patients. I am enclosing copies of two drug efficacy studies by the National Academy of Sciences which may be of interest to you. The NAS/NRC appraisal of this drug applies to every dosage form. I would appreciate any comments you might have. Sincerely, GAYLORD NELSON, Chairman, Monopoly Subcommittee. (No reply was received from Dr. Hagood.) PAGENO="0506" 4796 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL Division of Medical Sciences DRUG EFFICACY STUDY Farm A (To be submitted in duplicate by applicant) Reg. No. 146c.23]. I. NSA N.mb.r_._-_- 2. Dcc. Ocgrclly Appccr.d 4/21/SR * 3. Cc ~ OTC Q 4. t~d Nsm._-__Si em~tcin_Cap.sza1e.s_125._tog.._.and 250 tog.., Signemy~--3-G.op&u~ee------------9--- 3. Applksric Ncr. Chas. Pfizer 8z.Co., Ioi~. erd Add.,, 235 East 42nd Street, New York, New York 10O17 - 6. Quantitative Formula cct.blichcd tN.e.Pr.p,i,~.ryt Noac .1 Acti,. lmgr,dl.ets lit s.c.. .,cmcr tcb.II A.ucc par tablet, p.r act,, Signetoycin Capsules 125 tog. Signenyciro 125 tog. (83 tog. of tetracycline hydrochloride, 42 tog. `of oleandornycin as triacetyloleandotoycin) Signetoycin Capsules 250~~g. Signetoycin 250 tog. (167 tog. of tetracycline hydrochLoride, 83 tog. of oleàndoonycin as triacelyloleandotoycin) ~4gn~pycin 375 Capsules Signeroycin 375 tog. (250 tog. of tetracycline hydrochloride, 125 tog. of oleandotoycin as triacetyloleandotoycin) 7. D..co. F.... licbI.I,, .15.1 Capsules ~ :z:::~:: ~ ~ 9. Th.rcp.u.s Ctcim,-Aitc,P. to -`--i. --4 10 pc,keu, r,.tc lit cc.dt to crigir.t Form A tbtu.) acid 1 copy to duplloot. Focvs A leNtil. to Li., ci I., tar..,,, i.c.r pcrri..c.it to cci ccc luclic,, ci it,. eff.,Ii,.cicsc ci the dmg icr .... purp~scs f.r mht,t. it is .,cad Ii, the fob,F, it.. p.ockcg. ir..,t. ci b,,,hcr.. Appic.imotctm 5 to to t.,9 r.t.r.rc.s ci. r.qu.cl.d, it oroilcbto. (Attoch 10 oopi.s cc eriginot For,. A (big.) c'd t copy to dupliict. Form A tmhii.i.t t. it.. cppl.,c'i ic .`-.t.d. it 5. cc dccin.c. I. ibbacit c.yunpu blich.d .,ctutict hot is p.nilir.nt to ih. .,otuoliocs .1 h. drug by cbs Ai.dam~'-. i,,.or,t. Cccn,iI. Thi, ccppl.m,itory cot.ti~t should b. pockcg.d ellb Form A tsNtcl. A slngl., ocpy *tthlc material ii rcqesotcd, 2. Ii It.. p.,.. pl.e,. ci end d.cor.b. bni.Fy Iha scppl.ni.nlory ,.sl.tict that is scbmill.d mitt, Form fr (chit,), PANEL ON ANTI-INFECTIVE DRUGS (III) INDICATIONS I. Signemycin is indicated in the therapy of acute severe infections caused by susceptible organisms and primarily by bacteria more sensitive to the combina- tion than to either component alone. Evaluation: Ineffective as a fixed combination. Comments: Although either tetracycline or oleandomycin is effective in the treatment of some infections, there are serious objections to the use of the combination as formulated. Oleandomycin is present in insufficient amounts for effective treatment. If sufficient oleandomyci.u is administered for effective treatment, tetracycline overdosage results. The Panel is not aware of infections caused by bacteria more sensitive to this combination than to either of its components. PAGENO="0507" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4797 Establishing efficacy would involve demonstrating that the clinical response to the combination is greater than to either agent used alone. No such evidence is available. In vitro studies of this combination have given variable results. The effects may be antagonistic, additive, or synergistic, and are unpredictable for any particular organism. Thus, there is no evidence that each of the active ingredients contributes to the effect as claimed. Documentation: 1. Jones, W. F., Jr., B. L. Nichols, and: M. Finland. Development of resistance and cross resistance in vitro to erythromycin, carbomycin, spiramycin, oleando- mycin and streptogramin. Proc. Soc. Exper. Biol. & Med. 93:388-393, 1956. 2. Jones, W. F., and M. Finland. Antibiotic combinations. Tetracycline, erythro- mycin, oleandomycin, and apiromycin, and combinations of tetracycline with each of the other three agnts.-Comparisôn of activity in vitro and antibacterial action of blood after oral administration. New Eng. J. Med. 257:482-491, 536-547, 1957. 3. Fofar, J. 0., and A. F. Maccabe. Erythromycin, spiramycin and oleando- mycin. Brit. Med. J. 1 :581, 1957. 4. Editorial. Erythromycin, oleandomycin and spiramycin-and their combina- tions with tetracycline. New Eng. J. Med. 257:525-526,1957. II. Favorable clinical response to Signémycin has been Observed in the follow- ing categories and indications: infections of the respiratory tract and related structures and the genitourinary system, ~: surgical infections, and miscellaneous (amebiasis and lymphogranuloma venereum have been found responsive to Sig- nemycin). Dental infections caused by susceptible organisms are candidates for Signemycin therapy. Evaluation: Ineffective as a fixed combination. Comments: There is no evidence that each of the drugs present in this combi- nation contributes to the effect as claimed. Although case reports can be found indicating favorable response, this response is similar to that expected follow- ing administration of tetracycline alone or, more rarely, oleandomycin. Documentation: Informed judgment of the Panel. III. In streptococcal infections, therapy should be continued for 10 days to minimize the possibility of the development of rheumatic fever or glomerulo- nephritis. Evaluation: Ineffective as a fixed combination. Comments: The Panel is not aware of convincing evidence that treatment with Signemycin will prevent either of these conditions, regardless of the dura~ tion of therapy. More effective drugs are available for therapy of streptococcal infections. Documentation: Informed judgment of the Panel. Approved by WM. KIRBY, Chairman. PAGENO="0508" 4798 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY NATIONAl. ACADEMY OF SC)ENCE~-.NATIONAI. RESEARCI~ COUNCIl. DMsion of Medical Scionce; DRUG EFFICACY STUDY Form A 2r4~fj (To be submitted in~dtSIic~)~eb~pPPIicanl) P4DA fdusb.: JA6c'.23]. ~. Dotc'Od;toIIy Approred October I~, 1956 3:RO ~ .CTC Q 4. Ocard N~.- Sinezycin (Si~carn)Capsu]&a..1Q~.1QO ant 250 m~. 5. Apphoort's Nose Chas. Pfizer & Co. Inc. (EcTEREATIO1iAL) . - 235 East 42nd Street, Ne~' York, New-York 1O~O17 6. Quootit~tivo Formula f,tcbHshad )Pder.Pt.pri.tarp) f4.s. .5 Aot.o. )rvodi.ttt. (!r order shoot lob.!) Asousc (p.r tobI.t, p.r st. etc.) Tetracycline (Hcl) 33.3 ~z~* Oleandoaycin (phosphate) 16.7 ong. 100 rag. Tetracycline (HC1) 66.7 ui5. Oleandomycin (Phosphate) 33.3 mg. 250 mg. Tetracycline (sd) 167 mg. Oleando~rcini (Phosphate) 83 zig. 7. O*sog. Pots (tobl.tc. Capsules S. ,.ut. .5 Ads, 0,.!. etc. WI'... a to. drug oppkoototooc.r. dfet.st cult, ot od ticttotOt sep-.rc!. tots. .hocld be used.) Oral 9. Thetop..c~.c Cloktc-Aysch tO oh.!, s.d tO pookoge tced~ (5 used) to o:k,itot F.t.t A bk,.) cod 5 copy to Juptroot. Peter A (ottO.). (0. List at ta..cr.... ,ctet.soe, sect peditest to on ctclu.tlos of the .t'.at.cete,. .f:th. drug for A.. purpo.m fir which fit .a.r.d to tb. label, 4.. p-echo;. c~err, or br.chom. Approsieo!.ly 5 to 10 boy a.t.r.eo.s ore t.qv..t.d, it oteil,btc, (Attach 10 c.p.a to .r!girot Purrs A )btu.tt ord I copy to dcp!kete huts A )r.kit,t.) tt~ The eppkcest I, itoSod, it he .o dosres, a ,ebeit sty stpublish.dt.r.tetk,t thor is pec'fit.tt to (ho .rotcotk,s of ha drug by the Aood.sy..- O.st~roh Cosecil. Tb!. eoppteeettory *et.t,o) shostd be psok.g.d `alA. form A (oNto). A sir;!, copy of this rstet(ol Is re~o.et,d. 12. to ks .p.c., pt..sc Sct .sd d.scribe br,efy ho soppl..,ttory treterig) th.( is subtr!tt,d with Pot's A (oNto). PANEL ON ANTI-IN~scTIvE DRUGs (III) INDICATIONS I. Sigmamycin -is indicated in the therapy of acute severe infections caused by susceptible organisms and primarily by bacteria more sensitive to the combina- tion than `to either component alone. Evaluation: Ineffective as a fixed combination. Comments: Although either tetracycline or oleandomycin is effective in the treatment of some infections, there are serious objections to the use of the com~ bination as formulated. Oleandomycin is present in insufficient amounts for effec.. tive treatment. If sufficient oleandomycin is administered for effective `treatment, tetracycline overdosage results. PAGENO="0509" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4799 The Panel is not aware of infections caused by bacteria more sensitive to this combination than eo either of its components. Establishing efficacy would involve demonstrating that the clinical response to the combination is greater than to either agent used alone. No such evidence is available. In vitro studies of this combination have given variable results. The effects may be antagonistic, additive, or synergistic, `and are unpredictable for any particular organism. Thus, there is no evidence that each of the active ingredients contributes to the effect as claimed. Documentation: 1. Erythromycin, oleandomycin and spiramycin-and their combinations with tetracycline. New Eng. J. Med. 257: 525-526, 1957. (Editorial) 2. Forfar, J. 0., and A. F. MacCabe. Erythromyein, spiramycin, and oleando- mycin. Britt. Med. J. 1: 581, 1957. (Correspondence) 3. Jones, W. F., Jr., and M. Finland. Antibiotic combinations; tetracycline, erythromycin, oleandomycin, and spiramycin, and combinations of tetracycline with each of the other three agents-comparisons of activity in vitro and anti- bacterial actions of blood after oral administration. New Eng. J. Med. 257: 482- 491; 536-547, 1957. 4. Jones, W. F., Jr., R. L. Nichols, and M. Finland. Development of resistance and cross-resistance in vitro to erythromycin, carbomycin, spiramycin, oleando- mycin and streptogramin. Proc. Soc. Exp. Biol. Med. 93: 388-393, 1956. II. Favorable clinical response to Sigmamycin has been observed in the follow- ing categories and indications: infections of the respiratory tract and related structures and the genitourinary system, surgical infections, `and miscellaneous (amebiasis and lymphogranuloma venereum have been found responsive to Sig- mamycin). Dental infections caused by susceptible `organisms are candidates for Sigmamycin therapy. Evaluation: Ineffective as a fixed combination. Comments: There is no evidence that each of the drugs present in this com- bination contributes to the effect as claimed. Although case reports can be found indicating favorable response, this response is similar to that expected follow- ing administration of tetracycline alone or, more rarely, oleandomycin. Documentation: Informed judgment of the Panel. III. In streptococcal infections, therapy should be continued for 10 days to minimize the possibility of the development of rheumatic fever or glomerulo- n~phritis. Evaluation: Ineffective as a fixed combination. Comments: The Panel is not aware of convincing evidence that treatment with Sigmamcyin will prevent either of these conditions, regardless of the duration of therapy. More effective drugs are available for therapy of streptococcal infections. Documentation: Informed judgment of the Panel. Approved by WM. KIRBY, Chairman. APPENDIX IV [From the New England Journal of Medicine, vol. 261, No. 26, Dec. 24, 1959, pp. 1318-1321) FATAL CIRCLATORY COLLAPSE IN PREMATURE INFANTS REcEIvING CHLORAMPHENICOL * (By Lafayette E. Burns, M.D.,~ Joan E. Hodgman, M.D.4 and Alonzo B. Cass, M.D.,~ Los Angeles, Calif.) A survey was made of premature infants born twenty-four hours or longer after spontaneous rupture of the fetal membranes, because of a higher mortality *From the Premature Center of the Los Angeles County Hospital and the departments of Pediatrics, University of Southern California School of Medicine and College of Medical Evangelists School of Medicine. tAssistant in pediatrics, University of Southern California School of Medicine. tAssistant professor of pediatrics, University of Southern California School of Medicine. ~Associate clinical professor of pediatrics, College of Medical Evangelists School of Medicine. PAGENO="0510" 4800 COMPETITIVE PROBLEMS tN THE DRUG INDUSTRY in this group than in the premature infants whose membranes had ruptured at birth. Routinely, these infants had been placed on antibiotics shortly after birth because of assumed exposure to infection. The role of antibiotics in this higher mortality was questioned. A comparative study of these infants on different treatment schedules was conducted from March, 1958, to February, 1959. This is a report of that study. METHOD All premature infants delivered in the birth suites of the Los Angeles County Hospital after spontaneous rupture on the fetal membranes for twenty-four hours or more were assigned to one of four groups according to the time of admission to the premature center. Group 1 received no antibiotics. Group 2 received chioram- phenicol,~J 100 to 165 mg. per kilogram of body weight per day intramuscularly. Group 3 received procaine penicillin, 150,000 to 600,000 units per day, and strep- tomycin, 50 mg. per kilogram of body weight per day. Group 4 received all three antibiotics in the same dosage previously mentioned. Half of the daily dose of each antibiotic was given intramuscularly every twelve hours. RESULTS Table 1 lists the results of the study. The mortality rates in the nontreated group and the group treated with penicillin and streptomycin are similar. The mortality in both groups given chloramphenicol is strikingly higher than that in the groups not receiving it. The higher mortality is most obvious in the infants weighing 2001 to 2500 gm., that of the babies given chloramphenicol being 45 per cent and that in those not given it 2.5 per cent. TABLE 1.-COMPARISON OF MORTALITY Group 1 (no treatment) Group 2 (chioramphenicol) Group 3 (penicillin and streptomycin) Group 4 (penicillin and streptomycin and chioramphenicol) Percent- Percent- Percent- Percent- Total age Birth weight (grams) infants who died Total age infants who died Total age infants who died Total age infants who died <1,000 1 100.0 0 0 3 100 1 100 1,001-1,500 5 40.0 5 100 2 0 4 100 1,501-2,000 9 22. 0 9 67 4 75 11 90 2,001-2,500 17 5. 9 16 50 24 0 15 40 Total 32 30 33 31 Average 19.0 60 18 68 The general care of the babies in this study followed the established routine for the nursery. All babies came from the socioeconomic group cared for by the county hospital. All babies had ruptured fetal membranes for twenty-four hours or longer before delivery. Analysis for sex and race showed no significant difference among the groups. CLINICAL STUDY The clinical histories of the infants were reviewed. Figure 1 lists the common physical signs and symptoms and presents the percentage in each group who were symptomatic. The two groups given chloramphenicol were similar and were combined to simplify the presentation. All the signs and symptoms but jaundice were present in markedly increased numbers in the babies receiving chloram- phenicol. The higher number of gastrointestinal symptoms in the infants treated with penicillin and streptomycin as compared to the nontreated group should be noted. The clinical courses of the chcloramphenicol-treated babies who died were strikingly similar. The symptoms appeared in a typical order. Figure 1 lists the overage age at onset of each symptom for the chloramphenicol-treated groups. ¶In the form of Chioromycetin Intramuscular, Parke, Davis and Company, Detroit, Mich. PAGENO="0511" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4801 SYMPTOMS AVE.D~O~ON5C GROUPS 2 & 4 JAUNDICE 3.6 VOMITING I2~L~L~ 4 ANOREXIA - ~ RESPIRATORY DISTRESS / ~ ABDOMINAL DISTENTION / ~ -~ - CYANOSIS - GREEN STOOLS ~~~_~____ LtTHARGY - w ~- ~__ 5 ASHEN COLOR DEATH - -~ --~ 5.7 EJ~J~ATMCNT ~ ~E?~C~L~UN& ~ FIGURE 1._Comparison of Symptoms. Treatment was started in all cases within twelve hours of birth. The infant's condition at forty-eight hours of age was generally satisfactory. The first evil- dence of toxicity was vomiting or regurgitation of feedings, which appeared from two to nine days after the start of treatment, with an average onset at four days of age. Refusal to suck followed shortly. Respiratory distress, manifested by irregular, rapid respirations, appeared within a few hours, followed by abdominal distention, periods of cyanosis and passage of loose, green stools. By twenty-four hours after the onset of symptoms these infants were seriously ill. Progression of symptoms continued rapidly, with the appearance of flac- cidity, ashen color and a drop in temperature during the next twelve hours. Death usually occurred late in the fifth day of life. Fifty-eight per cent of the babies who survived ran a similar course, recovering twenty-four to thirty-six hours after the chloramphenicol was stopped. These infants appeared normal at the time of discharge. Of the 126 infants studied, blood cultures were taken on admission to the nursery in 99, and again at death in 27. In no case was there any agreement between the admission and terminal blood cultures. The pathological findings at autopsy correlated with the organism recovered from the blood culture in only 1 case. This infant had a negative blood culture on admission to the nursery. Escherichia coli was recovered from the terminal culture. He received no treat- ment, becoming sick on the fifth day and dying three days later. Autoposy re- vealed subarachnoid hemorrhage and meningitis. Cultures of the gastric contents were taken on admission to the nursery in 89 infants. Thirty-nine of the cultures showed no growth. From the remaining cultures, the following organisms were recovered: Staphylococcus albus, 17; Bacillis subtilis, 12; Esch. coli, 6; coliform organisms, 10; gamma-hemolytic streptococcus, 5; beta-hemolytic streptococcus, 3; Staph. aureus, 1; and diph- theroids, 1. There was no correlation between the organisms recovered and the clinical course of the infants. Random throat, urine and stool cultures were equally nonspecific. Blood chemical studies were done in some of the infants. All the infants studied had an elevated non-protein nitrogen. As their condition deteriorated, the serum carbon dioxide fell, and the serum potassium rose. Spinal-fluid chemical findings in 2 of the infants were normal. White-cell counts ranged from 6000 to 30,000. Autopsies were done on 34 infants, or 68 per cent of the deaths. Gross findings were not remarkable in 25 of them, the cause of death being obscure. Of the remainder 2 had bronchopneumonia, 5 had cerebal hemorrhage, and 2 died after surgical correction of a tracheoesophageal fistula and a duodenal stenosis. Micro- scopical findings will be reported in detail in a later paper. Chloramphenicol blood levels were obtained in 2 of the infants. The levels were determined by testing for aromatic nitro compounds after the method of PAGENO="0512" 4802 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Glazko et al, (1, 2) which includes both the active and the inactive metabolites of chloramphenicol. Figure 2 shows the levels in the babies. Both infants died within four hours of the last blood level indicated. Autopsy showed intraventricu- lar hemorrhage in baby E. No autopsy was done on baby J. WUOLE-TIT.OOD LEVZLS OF TOTAL NITRO COMPOUNDS inicrogrn./ml. I8O~ IBABYC 170r ~ ~ `60r / 14O~ `4 1~~'* I' ~rL0RAMPH~1C01~ 0* ~ *.+-,.~--~4 2 +3 444 AGE days FIGURE 2.-Chloramphenicol Blood Levels. Although the groups were small, there was no increase in mortality in infants who received 140 to 165 mg. of cliloramphenicol per kilogram of body weight as compared to those given 110 to 140 mg. per kilogram per day. DISCUSSION Physiologic studies have shown that liver and kidney functions are poor in the premature infant as compared to the adult. Potter and Thierstein (3) found his- tologically immature kidneys in almost all premature infants weighing 2000 mg. or less. The volume of urine excreted is small, and the ability to concentrate it is poor. Glomerular filtration, as measured by urea and mum clearance, and tubu- lar excretion, as measured by iodopyracet compound and para-amino-hippurate excretion, are markedly reduced. (4-6) Deficiency in the glucuronide conjugation of bilirubin in the premature liver has been well established. (7-9) This deficiency is thought to be due to a lack of conjugating enzyme. (10) In adults, Glazko and his associates (11) demonstrated that chloramphenicol is detoxified in the liver and excreted by the kidney. They found that detoxification is mainly by glucuro- nide conjugation. They were able to recover 90 per cent of a given dose from the urine of adults. (12) The bulk of the excreted drug was in the form of an inactive glucuronide conjugate. Less than 10 per `~ent was excreted unchanged. Renal plasma-clearance studies in adults suggest that the active form is filtered by the glomerulus, and the inactive form is excreted by the tubules. The toxicity of chloramphenicol has been extensively studied in animals. Smith et aL (13) found that the LD50 for chloramphenicol given by mouth to adult mice was 245 mg. per kilogram of body weight. Smaller doses caused tremors and pros- tration followed by recovery. They also found that dogs given chloramphenicol intravenously responded with a fall in blood pressure. With the use of high doses, the bloodpressure fall was followed by respiratory failure and death. Several reports in the European literature describe fatal circulatory collapse in patients with typhoid fever treated with chloramphenicol, the shocklike state appearing three to five days after the start of medication. (14-18) Norz.-Numbered references at end of article. PAGENO="0513" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4803 Sutherland and his co-workers (19, 20) recently reported 5 cases of fatal cir- culatory collapse in newborn and premature infants that they believed to be due to chioramphenicol toxicity. (19, 20) Their findings clinically and at autopsy were similar to our findings. They postulated that the high blood levels demon- strated were due to poor absorption, poor excretion or failure of conjugation. Porn and Smith (21) reported prolonged blood levels in the newborn and the premature infant after a single dose of chioramphenicol. SUMMARY AND CONCLUSIONS Premature babies delivered after rupture of the fetal membranes for twenty- four hours or longer were assigned to one of four treatment groups. Group 1 re- ceived no antibiotic, Group 2 received chloramphenicol alone, Group 3 received penicillin and streptomycin, and Group 4 received all three. The mortality of the group treated with penicillin and streptomycin was the same as that of the un- treated group, but a higher number of the treated babies had gastrointestinal symptoms. The mortality rates of the two groups given chloramphenicol were significantly higher than those of the other two groups. The babies receiving chloramphenicoi followed a typical clinical course. Gastro- intestinal symptoms appeared first, followed by circulatory collapse and death. Blood levels of chloramphenicol showed a continuous rise. Removal of the drug stopped the progession of symptoms. Recovery left no sequelae. Since the administration of chioramphenicol was the only factor common to the two groups having the high mortality, and the absence of chioramphenicol the only factor common to the two groups with the low mortality, chlorampheni- col in the dosage used must have been responsible for the increase in mortality observed. Poor liver function, especially in the glucuronide conjugation system, as well as decreased kidney function, allowed normally safe doses to accumulate to toxic levels. This toxicity manifested itself by a characteristic picture of cir- culatory collapse. If toxicity is partially due to failure of glucuronide conjugation, other drugs using this pathway of metabolism should be evaluated for use in the premature infant. No benefit to the infants from administration of penicillin or streptomycin could be demonstrated. Since there were more symptoms in the group treated with penicillin and streptomycin than in the non-treated group, these drugs may not be harmless. Therefore, the use of prophylactic antibiotics has been discon- tinued in this nursery. We are indebted to the Pediatric Attending and House Staff of the Los Angeles County Hospital for help with this study, to Dr. Frederick Moore, who prepared the statistical analysis, to Drs. Charles F. Weiss and A. J. Glazko, Parke, Davis and Company, who did the assays on blood levels, and to Mary Finley, R.N., and the nursing personnel of the Premature Center. REFERENCES 1. Glazko, A. J., Wolf, L. M., and Dill, W. A. Biochemical studies on chioram- phenicol (Chloromycetin) I Colorimetric methods for determination of chloram- phenicol and related nitro compounds Arch. Biochem. 23 :411-418, 1949. 2. Glazko, A. J. Personal communication. 3 Potter, E. L., and Thierstein, S. Glomerular development in kidney, as index of fetal maturity J. Pediat. 22: 695-706, 1943. 4. McCance, R. A. Renal physiology in infancy. Am. J. Med. 9:229-241, 1950. ~. Barnett, H. L. Kidney function in young infants Pediatrics 5 :171-179, 1950. 6. Barnett, H. L., and Vesterdal, I. Physiologic and clinical significance of im- maturity of kidney function in young infants. J. Pediat. 42:99-119, 1953 7. Lathe, G. H., and Walker, M. Synthesis of bilirubin glucuronide in animal and human liver Biochem. J. 70:705-712, 1958. S. Billing, B. H., Cole, P. C., and Lathe, G. H. Excretion of bilirubin as di- glucuronide giving direct van den Bergh reactions Biochem. J. 65 :774-~784, 1957. 9. Schmid, R. Direct-reacting bilirubin, bilirubin glucuronide, in serum, bile, and urine. $cience 124:76 1956. 10. Driscoll, S. G., and Hsia, D. Y.-Y. Development of enzyme systems during early infancy Pediatrics 22 (4) :785-845, 1958. 11. Glazko, A.. J., Dill, W. A., and Rebstock M. C. Biochemical studies on chlor- amphenicol (Chlormycetin). III. Isolation and identification of metabolic prod- ucts in urine J. Biol. Uhem. 183 :679-691, 1950. 81-280-69-pt. ll-33 PAGENO="0514" 4804 COMPETITIVE PROBLEMS IN THE DRUG ~DUSTRY 12. Glazko. A. J., Wolf. L. M. Dill, W. A. and Brattan A. C. Jr. Biochemical studies on chloramphenicol (Ohloromycctin) : tissue distribution and excretion studies J. Pharmacol. ci E3Jper. Therap. 96 :445-459 1949. 13. Smith, R. M., Joslyn, D. A., and Gruhzit, 0. M. Chioromycetin: biological studies. J. Bact. 55 :425-448 1948. 14. Stephens, P. R. Unsuccessful treatment of typhoid fever with chiorampheni- col Lancet 1 :731, 1950. 15. Patel, J. C., Banker, D. D., and Modi, C. J. Ohioramphenicol in typhoid fever; preliminary report of clinical trial in 6 cases. Brit. Al. J. 2 :908, 1949. 16. Farinaud, M. E., and Portes, L. La chioromycetine a doses progressive dans le traitement des fievres typhoides a forme hypertoxique. Presse med. 59:3, 1951. 17. Izar, G. Collasso acuto di circolo da cloroamfenicolo. Riforma med. 64:1237- 1240, 1950. 18. Chatterjee, P. K., and Roy, B. B. Vasomotor collapse after chioramphenicol. Brit. 211. J. 2:1334, 1950. 19. Sutherland, J. M. Fatal cardiovascular collapse in infants receiving large amounts of chioramphenicol. J. Dis. Child. 97:761-767, 1959. 20. Sutherland, J. M., et al. Toxicity of chloramphenicol for newborn infant. Presented at twenty-ninth annual meeting of Society for Pediatric Research, Buck Hill Falls, Pennsylvania, May 8 and 9, 1959. 21. Dorn, A., and Smith, M. Blood levels of palmitate ester of chioramphenicol in infants and children. Presented at twenty-ninth annual meeting, Society for Pediatric Research, Buck Hill Falls, Pennsylvania, May 8 and 9, 1959. APPENDIX V {From American Journal of Diseases of Children, vol. 101, February 1961, pp. 140-148] SAFE AND EFFECTIVE CHLORAMPHENICOL DOSAGES FOR PEEMATUItE INFANTS (By Joan B. Hodgman, M.D. and Lafayette E. Burns, M.D., Los Angeles) Infections are a significant cause of death in premature infants. Arey and Dent(1) reported, in 1953, a survey of 102 neonatal deaths of which 84 were pre- mature. They listed infection as the major cause of death in 13 (15.4%) of the prematures. Six years later Branton, (2) in a report of 176 consecutive newborn deaths, of which 136 were prematures, attributed death to infection in 20 (14.7%) of the prematures. He reported gram-negative coliform bacilli in 5 of 6 positive blood cultures. Infection also plays a significant role in the mortality at the Premature Center of Los Angeles County Hospital, which cares for over 1,200 premature infants yearly. The main organisms cultured from infections have been gram-negative coliform bacilli,' particularly E. coil and Klebsiella aerogenes group. Studies have indicated that these organisms are most consistently sensi- tive to chloramphenicol. The toxicity of chioramphenicol to premature infants in doses over 100 mg/kg is well documented(3-6). Reported studies have correlated this toxicity with high blood levels of chloramphenicol. Prophylaxis with chioram- phenicol as well as other antibiotics has been discontinued at the Premature Center, since in a controlled study they did not lower the mortality rate (3). Chloramphenicol would still be useful for the treatment of infected prematures if a safe dosage schedule were established. This paper is a report of studies of blood-level responses to intramuscular and intravenous chloramphenicol made to determine whether lower doses would give therapeutic blood levels without toxicity. METHOD Premature infants of varying weights and ages were given microcrystalline or the succinate ester of chloramphenicol intramuscularly and intravenously, ac- cording to planned dosage schedules. Blood levels of total nitro compounds were Accepted for publication Oct. 27, 1960. 1200 N. State St. (33). Supported by a grant from Parke, Davis & Company, Detroit. From the Premature Center of the Los Angeles County Hospital and the Department of Pediatrics, University of Southern California School of Medicine, Assistant Professor of Pediatrics (Dr. Hodgman) and Instructor in Pediatrics (Dr. Burns). N0TE.-Numbered references at end of article. PAGENO="0515" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4805 determined by analyzing capillary blood according to the method of Glazko(7).* This method measures both active and inactive metabolites of chioramphenicol as total nitro compounds. Timed urine specimens were collected by plastic bags from some of the in- fants. These were analyzed for chioramphenicol content by microbiologic assay against Shigella sonnei (8), as well as by chemical determination for total nitro compounds. Microchemical analyses for serum sugar, BUN, and potassium levels were performed at the start of treatment, at 24 hours, and at 96 hours in the group of infants receiving chloramphenicol 25 mg/kg/day. Serum bilirubin determinations were done on any infant who developed jaundice. MICROCRYSTALLINE CHLORAMPHENICOLt Figure 1 shows the average blood level of total nitro compounds obtained in premature infants 1 to 6 days old given microcrystalline chioramphenicol, 10 mg/kg every 12 hours intramuscularly. The average level is low and probably inadequate for 12 to 24 hours after the start of treatment. From then on, it gradually rises as the nitro compounds accumulate. A tendency for the level to plateau may be noted during the fourth~ day of treatment. Of the 13 babies studied, 11 reached therapeutic levels of 10-20~g/cc(9), and showed no toxic symptoms. One infant failed to reach a therapeutic blood level. One infant ac- cumulated nitro compounds to high levels and developed symptoms of chioram- phenicol toxicity. This infant was 3 days old at the start of treatment and weighed 1,980 gm. On the third day of treatment, he was noted to be voiding very little. During the next 24 hours he became limp and lethargic, at which time his blood level of nitro com- pounds had risen to 78~g/cc. Following the omission of one dose, the blood level fell to 52, and his symptoms became less severe. Treatment was continued for 3 more days, during which time he was anorexic and somewhat listless. His symptoms disappeared 3 days after treatment was stopped. Figure 1 also shows the average blood level of nitro compounds in 5 premature infants 12 to 67 days old on the same dosage schedule, 10 mg/kg every 12 hours intramuscularly. Of the 5 infants, 4 had been tested previously in the 1- to 6-day- old group. The absence of accumulation in this group is clearly demonstrated. None of these infants reached adequate blood levels on this dosage. * AGE 16 DAYS / \ ~,, ~.._..RANGE. / \ c~~O WEIGHTS / \ 1001- 1501- 2001- D ~n-* `500 2000 2500 ~i 2 3 8 / / / `. o~ / P-i / Z4g- / ._J I / *~35~-. L/~J'~..T ~V-' :... ~ /..~ 0 / U1CKA~ ~ TICK N ~. E -S--. ~_AVERAGE 5 PREMATURES AGE 2-67 DAYS ~.L. - - RANGE WEIGHTS: 1001-1500 1501-2000 2001-2500 2 3 .~ ~` ,~ *zo~. so io so. ~ io~ so 90.'r ~ *~ ~ ~ .7. ~. TIME INHOURS FIGURE 1.-Blood levels during treatment with microcrystalline chiorampheni- col iO mg/kg every 12 hours i.m. *Analyses were done by the Parke, Davis & Company Laboratories. tCbloromycetin Intramuscular. PAGENO="0516" 4806 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The average blood level for 15 premature infants, 1 to 2 days old, given a single injection of microcrystalline chloramphenicol, 50 mg/kg intramuscularly, is shown in Fgure 2. Adequate blood levels were attained within 7 hours in all but 2 infants. The peak was reached at the 23-hour sample, followed by a grad- ual fall. The half-life of the administered dose was 28 to 44 hours as compared to a half-life in adults of 15 to 24 hours. (10) Two premature infants 8 and 9 days old were given the same dose. The blood levels as shown in Figure 2 were lower than in the younger babies, and the fall in level was more rapid. The birth weights of the infants tested are grouped on the charts. There was no correlation between birth weights and blood levels. Further studies were carried out on week-long dosage schedules. Premature infants, ages 1 to 4 days. were given microcrystalline chloramphenicol, 50 mg/kg intramuscularly, every 48 hours. Of 12 infants tested, 8 had adequate levels but with marked fluctuations. Only 1 of 4 prematures, ages 13 to 27 days, similarly tested, had adequate levels. Using a schedule of 25 mg/kg given once daily, all of 12 infants tested had adequate levels in the 1- to 6-day-old group, but only 2 of 8 in the 14- to 23-day-old group. Given 50 mg/kg once daily to premature in- fants 9 to 36 days old produced adequate levels in all 8 infants tested without toxic symptoms. FIGURE 2.-Blood levels following a single dose of microcrystalline chloram- phenicol 50 mg/kg I.l~J. CHLORAMPHENICOL SODIUM SUCCINATE~ Chloramphenicol sodium succinate is a recently introduced ester of chloram- phenicol which is highly water soluble `and hence more readily absorbed than the micronized form. (11) Figure 3 shows the average blood level of nitro com- .t~ do >~ ~:i 00, 3x. S_i ~ I.J S_i ......../~/ERAGE 15 PREMATURES AGE 1-2 DAYS - ~RANGE wEIGHTS: 001-1500 1501-2000 2001-2500 1~~ - -i 5 / S / */ 4 .3 .3 _8 DAY PREMATURE WEIGHT 560 oms ...~9 DAY PREMATURE WEIGHT 350 ~ms. IN `~s~ .; ~ 7//I//I ////4~/T~~ ~ 7/ .19 ~Q ~Q 3~ 49 TO 4~) 90 0 20 30 ~0 50 40 70 CV 90 TIME IN HOURS AVERAGE.15 PREMATURES.I~4 DAYS Sr~~t RANGE ~5 ";:.wEIGHTS:Ioo-500 1501-2000 200F2500~ °~r1 ~ 2 6 * 7 .45 -siil \~--. * "~ ..~._.AVERAGE 5 PREMATURES 10-19 DAYS ~.. RANGE ~. WEIGHTS 1001-1500 l50I~ 2000 2001-2500 0 4 I i-I \ TIME' IN HOURS FIGURE 3.-Blood levels following a single dose of chloramphenicol sodium sue- cinate 50 mg/kg I.M. ~Ch1oromycetin Succinate. PAGENO="0517" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4807 pounds following a single 50 mg/kg intramuscular injection of the succinate ester in 15 prematures 1 to 4 days old. Peak levels were obtained within 3 hours, clearly showing rapid absorption. Adequate levels were present for over 48 hours, but fell more rapidly, the half-life being 24 hours, as compared with a half-life of 28-44 hours with the microcrystalline form. Levels fall even more rapidly in older children, the half-life being 4 hours in 5-year-olds given the succinate ester. (1,10) Figure 3 shows the average blood level found in 5 prematures, 10 to 19 days old, given the same dose. Absorption was again rapid, and here, too, excre- tion was more rapid than with the younger prematures. The half-life was 14 hours with adequate levels maintained for 12 to 18 hours. Eight premature infants, 2 to 4 days old, given chloramphenicol sodium suc- cinate, 25 mg/kg intramuscularly once daily, after an initial dose of 50 mg/kg, had adequate levels for the week they were treated. One infant accumulated nitro compounds on this schedule, the blood level on the third day reaching 5G~g/cc. At this time the infant's abdomen was distended; he had liquid stools and grunt- ing respirations. The infant recovered, and the blood levels dropped without stopping the drug. Although the symptoms disappeared while treatment was continued, they may represent a toxic reaction. Three prematures, 12 to 22 days old, had inadequate levels when given 25 mg/kg/day intramuscularly. Five prematures, ages 10 to 18 days, had good levels on 50 mg/kg/day without toxic symptoms. Again, no correlation between birth weights and blood levels was found. Chloramphenicol sodium succinate given intravenously to premature infants was also slowly excreted, as shown in Figure 4. Three 1-day-old infants were given 25 mg/kg in 50 cc. 5% glucose in water over a 5-hour period. Blood levels remained in the therapeutic range for 18 to 24 hours following completion of the infusion; the half-life was 15 to 22 hours. Two infants, 13 and 23 days old, were given 50 mg/kg over a 3-hour period. Again, adequate levels persisted for the succeeding 12 and 21 hours, with a half-life of 8 and 15 hours, respectively. One infant developed ashen gray pallor and lethargy within 1 hour after starting the infusion, when his blood level was 72~g/cc., The symptoms disappeared in the next 3 hours coincident with the fall in blood level to 53pg/cc. : ~ ~ ~)5O m9m/k(~ In 50cc of 50~1o ~1L5~ i~ cc ~ AGC I DAY 25 rngm/Icg ~n 50 cc of 57* 913ic03e ~n H~ z -~I.V.RUNNING I ~ .. .1..., ~ ~ ~ i h ~ . 0 a ~ ~ io 11. ~ 20 22 2+ 2~ 28 30 Ia 44 46 48 50 TIME IN HOURS FIGURE 4.-Blood levels following I.V. administration of chioramphenicol sodium succinate. PAGENO="0518" 4808 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY URINE STUDIES Twenty-four-hour excretion studies of microcrystalline chioramphenicol were made. In a study of 19 premature infants under 7 days old, an average of 20% of the daily dose was recovered (range 5%-52%). A higher average, 33%, was recovered from 5 infants over 10 days old (range 1.4%-50%). In similar studies on adults Glazko (12) was able to recover 90% of the daily dose, of which 5%- 10% was excreted as the active form. In our studies on 8 premature infants under 7 (lays old, 7.7% of a dose was excreted in the active form, in older prematures, 0.2%. BLOOD CHEMISTRIES Blood chemistry determinations taken at the start of treatment, 24 hours later, and at 96 hours, w-ere studied in 32 1- to 2-day-old premature infants on chioram- phenicol injections of 25 mg/kg daily. BUN levels ranged from 8 to 30 mg%, ex- cept for 3 infants w-hose levels were 37, 53, and 89 mg%. The 2 infants with levels of 37 and 53 mg% had the low-est levels of nitro compounds in their respective test groups. The remaining infant, whose blood urea nitrogen level at the start of treatment was 89 mg% and at 24 hours was 85 mg%, gradually accumulated nitro compound levels to 56~ig/cc at 72 hours. This infant, who weighed 1,162 gm. at birth, was 4 days old and in apparently good condition at the start of treatment with 25 mg/kg/day of microcrystalline chloramphenicol. Except for mild dehydration, his clinical condition remained good until the fifth day of treatment when he developed lethargy, respiratory distress, and abdominal distention. The chloramphenicol was discontinued, but the baby's symptoms progressed until death 48 hours later. A. white blood cell count on the day before death was 29,500, with 74 segmented forms, 5 band forms, and 21 lymphocytes. A blood culture before death grew E. coli, sensitive only to polymyxin. Autopsy revealed pulmonary hemorrhage. With the exception of the infant mentioned above, there was no consistent correlation between the BUN and nitro compound levels. Of 8 infants who had BUN levels betw-een 25 and 30 mg%, 7 had nitro compound levels similar to others in their test groups. BUN levels below 10 mg% were not accompanied by low nitro compound levels. Serum potassium levels were under 7 mEq/L in all except 3 infants. Two of these had low blood nitro compounds levels. The third w-as the infant mentioned above with elevated BUN levels, who died. Blood sugar levels ranged between 26 and 107 mg%, except for the infant described above w-hose level was 144 mg% initially, and 126 mg% at 24 hours. There was no correlation between serum bilirubin levels and levels of nitro compounds in 30 infants tested. For example, one infant had high blood nitro compound levels and a bilirubin level of 17 mg%. Another had a bilirubin of 16.8 mg% and low nitro compound levels. Infants receiving chlorampbenicol had no increase in incidence of jaundice. MORTALITY Tests were performed on 126 premature infants. Six infants died during or after treatment. In general, infants in good condition were selected for study, making the mortality rate in this group meaningless. The clinical course of one of the infants who died is outlined above. A brief résumé of the histories of the remaining 5 infants follows: Baby, birth w-eight 2,180 gm., demonstrated webbing of the neck and minor skeletal anomalies, but was in good general condition at the start of treatment with 50 mg/kg/48 hours of microcrystalline chioramphenicol. At 10 days of age, following 7 days of treatment, the infant died suddenly. Autopsy revealed infantile coarctation of the aorta. Blood levels of nitro compounds were con- sistently low. Baby, birth weight 1.280 gm., died at 2 days of age after 1 injection of 50 mg/kg. Blood level at 24 hours was 40~mg/cc. Autopsy revealed intraventricular cerebral hemorrhage. Baby, birth weight 1,920 gm. was in good condition at 4 days of age when treatment with mg/kg/48 hours of microcrystalline chloramphenicOl w-as started. The baby developed lethargy, cyanosis, abdominal distention, and apnea at the start of treatment. Blood and spinal fluid cultures grew an organism of the Klebsiella-Aerobacter group, sensitive to chioramphenicol. Treatment was con- tinued `but the infant died at 6 days. Autopsy confirmed the diagnosis of puru- lent meningitis. PAGENO="0519" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4809 Baby, birth weight 1,420 gm., was started on treatment of 50 mg/kg/48 hours of microcrystalline chioramphenicol at 4 days of age. Forty-eight hours later, the infant developed vomoting, followed by loose yellow stools, lethargy, ashen gray pallor, apnea, and death at 8 days of age. Blood levels reached a peak at 5~g/cc 24 hours following the start of the treatment, dropped to 40kg/cc at 48 hours when symptoms appeared, fellow to 25jig/cc at 72 hours, and rose again to 5Qag/cc at 96 hours. Death occurred 14 hours after the last blood level noted. Blood culture drawn at death was sterile. No autopsy was permitted. Baby, birth weight 1,990 gm., was started on treatment of 50 mg/kg/48 hours of microcrystalline chloramphenicol on the first day of life. Respiratory distress was present from birth. Tremors appeared on the third day, followed by dis- tention of the abdomen, lethargy, ashen gray pallor, apnea, and death on the sixth day. Blood levels were 41kg/cc at 24 hours, and 38pg/cc at 48 hours. Blood culture drawn at death was sterile. No autopsy was permitted. COMMENT The normal metabolic pathway for chloramphenicol is absorption, conjuga- tion with glucuronic acid in the liver, and excretion by the kidney tubules. (12) Some active chloramphenicol is removed from the circulation by glomerular filtration. (13) Aecumulation of chloramphenicol in the premature infant must be due to differences in one or more of these factors. Single-dose studies of the microcrystalline form of chloramphenicol clearly demonstrate its slow absorption, the peak level not being attained for 24 hours. Considering the low solubility of this form of the drug, a depot effect could be anticipated. Single-dose studies of chloramphenicol sodium succinate showed rapid absorption with a peak within 4 hours, but also gave prolonged levels with half-lives 2 to 3 times those of adults. Half-lives of the succinate ester given intra- venously were much longer than those reported for adults, eliminating sldw absorption as the explanation for the prolonged levels. Decreased kidney func- tion in the premature is well established. (14-16). The glucuronide conjugated, or inactive, chioramphenicol is excreted by the renal tubules while the active form is filtered by the glomerules. Tubular excretion is quantitatively the most im- portant excretory pathway, as 90% of the chloramphenicol in the urine is in the conjugated form in both the adult and premature. (12). However, the adult ex- cretes 90% of a daily dose, in contrast to 1.4%-52% in the premature. Therefore, a decrease in tubular excretion in the premafture must be one of the factors ac- counting for prolongation of blood levels~ A deficiency in conjugation by the liver must also be present to explain the prolonged levels of active chloramphenicol. If hepatic conjugation were normal with poor kidney function, only the inactive form would accumulate. This is seen clinically in anuric adults, where a renal defect only is present, the conjugated form alone accumulates to high levels and patients exhibit no toxicity. (17) In the premature, however, only 35% of the circulating ehloramphenicol is in the in- active form. (5,10) A deficiency of the glucuronidase in the liver of the newborn has been documented. (18,19). The accumulation of active chloraphenicol in the premature can be explained by this deficiency. The finding that blood levels plateau on the third and fourth day, plus the correlation of levels with chrono- logical age rather than birth weight, lend support to the idea that enzymatic deficiencies, which improve as the infant matures, are responsible for the pro- longed blood levels. As chloramphenicol and bilirubin apparently follow the same metabolic path- w-ay, some correlation between blood levels of bilirubin and chloramphenicol could be expected. No correlation was demonstrated. In a previous study, there was no increase in the incidence of jaundice among premature infants receiv- ing chloramphenicol compared with a similar group not receiving it. (3) In the same study, autopsies on infants who died with chloramphenicol toxicity did not reveal kernicterus. V There was no correlation between the levels V of nitro compounds and a BUN of 53 mg% or less. One infant with a BUN of 89 mg% at the start of treatment accumulated nitro compounds, as did another V infant with a low renal output for 24 hours. Infants with a BUN above 60 mg%, or other signs of defective renal function should be treated cautiously with a reduced dosage. Premature infants were tested in all weight groups over 1,000 grams. No correlation between birth weight and blood levels was found. A definite correla- tion between age and blood levels was demonstrated. Tendency to accumulate nitro compounds in the blood stream was most marked during the first 4 days PAGENO="0520" 4810 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY of life. None of the infants tested after 7 days of age showed accumulation of nitro compounds in the blood. The majority of these older infants failed to maintain levels in the therapeutic range on 25 mg/kg/day, whereas doses of 50 mg/kg/day produced therapeutic levels without toxic symptoms. Premature infants over 1 week of age can be treated with 1 daily dose of 50 mg/kg of chioramphenicol with reasonable safety. The young infants also showed greater variability of levels on a given dosage than did prematures over 7 days of age. This is well demonstrated in Figure 1, representing 1-4-day-old infants given microcrystalline chloramphenicol, 10 mg/kg every 12 hours. On this dose, one infant accumulated nitro compounds to toxic levels, while another failed to reach therapeutic levels. The young infants tested on low doses of microcrystalline chloramphenicol given twice daily accumulated nitro compounds more rapidly than when a larger dose was given once a day; Since adequate levels are maintained for 24 hours after a single injection of both types of chloramphenicol tested, the total dose should be given once daily. The symptoms of chloramphenicol toxicity in the premature infant have been reported by several authors. (3-6) The time necessary for symptoms to appear depends on the dose used. When 125-165 mg/kg/day were given intramuscularly, the earliest symptoms appeared from 48 to 96 hours after the start of treatment and involved the gastrointestinal tract. (3) The infants refused to nurse, began to regurgitate formula, their abdomens became distended, and they developed loose green stools. Within 24 hours after the appearance of toxic symptoms, they became ashen gray, lethargic, and developed rapid, shallow respirations. Death, when it occurred, followed within an additional 24 hours. The infants who recovered had no demonstrable sequelae on discharge from the nursery. Of the 126 infants tested during this study, 6 developed symptoms similar to those described. One infant was receiving intravenous medication, and the correlation between symptoms and blood levels seems clear cut. Lethargy and grayish pallor appeared within an hour of starting the intravenous medication, when the blood level was 72pg/cc. and the symptoms disappeared rapidly coincident with a fall in level to 53~g/cc. The accumulation of nitro compounds in this baby was caused by too rapid an intravenous infusion, and the symptoms could have been prevented by slower administration. This is a precaution that must be carefully observed when giving chloramphenicol intravenously. Two infants, both under 4 days of age, developed symptoms of chlorampheni- col toxicity on intramuscular medication, but recovered. In both of these infants the symptoms appeared on the third day of treatment, when their blood levels were over 50j~g/cc. and the symptoms disappeared as the levels fell. In the 3 surviving infants, toxic symptoms seemed to be correlated directly with elevation in blood levels of nitro compounds. The blood levels varied from 53jig/cc to 73~tg/cc at the time symptoms appeared. Three infants died while receiving chioramphenicol, with symptoms similar to those described above. The symptomatology of septicemia is very similar to that of chloramphenicol toxicity. One case had abnormal blood chemistries at the start of treatment, and a chloramphenicol-resistant organism was grown from blood culture taken before death. Symptoms appeared after 5 days of treatment, when the infant was 9 days old. This death was probably due to infection, but may represent a toxic reaction to chioramphenicol. Autopsies were not performed on the remaining 2 infants, and blood cultures taken at the time of death were sterile. The levels of chloramphenicol in these infants were never over 54kg/cc. A definite cause of death could not be determined on the basis of the clinical findings. Unexplained deaths, particularly without autopsy, are too common on a premature service to definitely assign these deaths to chioramphenicol toxicity; however, it is possible that these 3 infants represent a toxic reaction at relatively low blood levels. It is perhaps important that these babies were under one week of age at the start of treatment. If chioramphenicol is used for young premature infants, it should be given in a dosage of 25 mg/kg once daily. If toxic symptoms appear, the drug should be discontinued immediately and blood levels determined where possible. Blood levels can be determined by following the method of Glazko et al. (11) .~ The determination requires 0.2 cc. of whole blood, which can be obtained from a heel puncture. The method is a relatively simple colorimetric comparison, which could be performed by the average hospital laboratory. §Detailed procedure available from Parke, Davis & Company. PAGENO="0521" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4811 Of the 5 infants exhibiting toxicity on intramuscular medication, 4 were given microcrystalline chioramphenicol. This preparation has the disadvantage of slow absorption, resulting in low initial blood levels and greater tendency to accumula- tion with repeated dosage. In tratment of the premature infant, the more rapidly absorbed chloramphenicol sodium succinate would be preferred. SUMMARY Recent investigations have documented chioramphenicol toxicity in premature infants given doses over 100 mg/kg/day. Toxicity was shown to have a correlation with elevated blood levels of chloramphenicol. In order to establish whether lower doses would result in therapeutic levels without toxicity, we determined blood nitro compounds in premature infants after intramuscular and intravenous administration of 20 to 50mg/kg/day. Initial levels were lower and toxic reactions occurred more commonly with microcrystalline chloramphenicol than with the sodium succinate ester. The latter form should be preferred for treatment of the premature infant. A tendency to accumulate chloramphenicol in the blood was observed only in the young in- fants, regardless of birth weight. Two infants under 4 days of age accumulated blood levels over 5Opg/cc and developed toxic symptoms after daily dOses of 25 mg/kg intramuscularly. Two infants died with blood levels below50~tg/cc without clinical explanation of their death. Two of the infants with toxic symptoms had clinical or laboratory evidence of reduced renal function. Such infants should be treated cautiously with a smaller dose. Premature infants 7 days of age or less maintained blood levels in the thera- peutic range when given 25 mg/kg of chioramphenicol sodium succinate intra- muscularly once daily. Premature infants over 7 days of age failed to maintain thereapeutic levels on this dose, but developed adequate levels without toxic symptoms when given 50 mg/kg intramuscularly once daily of the same drug. The same doses of chloramphenicol sodium succinate in each age group, given intravenously, gave adequate levels for 24 hours. This form of the drug must be infused slowly over a period of 3 to 5 hours to prevent accumulation of chioramphenicol to toxic levels. All premature infants, especially those in the first week of life or with evi- dence of reduced renal function, should be carefully watched for the development of abdominal distention, lethargy, respiratory distress, and gray cyanosis. The drug should be discontinued promptly if these symptoms appear. We wish to thank Alonzo Beecher Oass, M.D., Chairman of the Newlnrn Committee, for his help and encouragement. We are indebted to Miss Maxine Wertman and Miss Leola Westover for tech- nical help. The cooperation of Mary Finley, R.N., Head Nurse, and the Nursing Staff of the Premature Center was essential to the completion of this study. REFERENCES 1. Arey, J. B., and Dent, J.: Causes of Fetal and Neonatal Death with Special Reference to Pulmonary and Inflammatory Lesions, J. Pediat. 42:1-25 (Jan.) 1953. 2. Branton, L.: Neonatal Mortality with Special Reference to Infectious Causes of Death, Am. J.M. Sc. 238 :760-771 (Dec.) 159. 3. Burns, L. E.; Hodgman, J. E, and Cass, A B.: Fatal Circulatory Collapse in Premature Infants Receiving Chloramphenicol, New England J. Med. 261:1318-1321 (Dec.24) 1959. 4. Sutherland, J. M.: Fatal Cardiovascular Collapse of Infants Receiving Large Amounts of Ohlorampehnicol, A.M.A. J. Dis. Child. 97:761-767 (June) 1959. 5. Sutherland, J. M.; Michael, A F; Giesel, R G.; Keller, W. H., and Beber, B. A.: Toxicity of Ohloramphenicol for the Newborn Infant, presented at 2~ith Annual Meeting of Society for Pediatric Research, Buck Hill Falls, Pa., May 8-9, 1959, A.M.A. J. Dis. Child. 98 :648-649 (Nov.) 1959. 6. Kent, S. P. and Widemann, G L.: Prophylactic Antibiotic Therapy in Infants Born After Premature Rupture of Membranes, J.A.M.A. 171 :1199-1203 (Oct. 31) 1959. PAGENO="0522" 4812 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7. Glazko, A. J.; Wolf, L. NI., and Dill. W. A.: Biochemical Studies of Chior- amphenicol. I. Colorimetric Methods for the Determination of Chioramphenicol and Related Nitro Compounds, Arch. Biochem. 23 :411-418 (Oct.) 1949. 8. Joslyn, D. A., and Galbraith, NI.: A Turbimetric Method for the Assay of Antibiotics, J. Bact. 59:711-716 (June) 1950. 9. Bliss, E., and Todd, H. P.: A Comparison of Eight Antibiotic Agents in Vivo and in Vitro, J. Bact. 58:61-72 (July) 1949. 10. Weiss, 0. F.; Glazko, A. J., and Weston J. K.: Physiological Disposition of Chloramphenicol in Newborn Infants, New England J. Med. 262 :787-794 (April 21) 1960. 11. Glazko, A. J.; Carnes, H. E.; Kazenko, A.; Wolf, L. NI., and Reutner, T. F: Succinic Acid Esters of Chloramphenicol, in Antibiotics Annual, edited by H. Welch and F. NIarti-Ibdflez, New York, Medical Encyclopedia, Inc., 1958, Vol. 5, pp. 792-802. 12. Glazko, A. J.; Wolf. L. NI.; Dill, W. A., and Bratton, A. C., Jr.: Biochemical Studies on Chloramphenicol. II. Tissue Distribution and Excretion Studies, J. Pharmacol. & Exper. Therap. 96:445-459 (Aug.) 1949. 13. Glazko, A. J.; Dill, W. A., and Rebstock, NI. C.: Biochemical Studies on Chloramphenicol (Chrioromycetin). III. Isolation and Identification of Metabolic Products in Urine, J. Biol. Chem. 183 :679-691 (April) 1950. 14. Barnett, H. L.: Kidney Function in Young Infants. Pediatrics 5 :171-179 (Feb.) 1950. 15. Barnett, H. L., and Vesterd'al, I.: Physiologic and Clinical Significance of Immaturity of Kidney Function in Young Infants, J. Pediat. 42:99-119 (Jan.) 1953. 16. MeCance, R. A.: Renal Physiology in Infancy, Am. J. Med. 9 :229-241 (Aug.) 1950. 17. Kunin, C. NI.; Glazko, A. J., and Finland, NI.: Persistence of Antibiotics in Blood of Patients with Acute Renal Failure II. Chroramphenicol and Its Metabolic Products in the Blood of Patients with Severe Renal Disease or Hepatic Cirrhosis, J. Olin. Invest. 38:1498-1508 (Sept.) 1959. 18. Driscoll, S. G. and Hsia, D. Y-Y.: The Development of Enzyme Systems During Early Infancy, Pediatrics (Supp.) 22:785-845 (Oct.) 1958. 19. Vest, NI.: Insufficient Glucuronide Formation in the Newborn and Its Re- lationship to the Pathogenesis of Icterus Neonatorum, Arch. Dis. Childhood 33 :473-475 (Oct.) 1958. EDITORIAL COMMENT This report documents the considerable variability of chloramphenicol blood levels achieved in individual prematures even when the intravenous or intra- muscular route of administration is used. Observe that several less than week old infants showed signs and symptoms of toxicity while receiving doses currently recommended. Also note the frequent failure to achieve blood levels claimed to be therapeutic when the "cautious" dose is used after the first week. The sus- pected inability of newborns to absorb adequately the palmitate form of the drug when given by mouth is not dealt with here. APPENDIX VI [From Annals New York- Academy of Sciences, 1967, pp. 488-498] BAc~rEnIAL MENINGITI5* (By Paul F. Wehrle. Allen W. Mathies, John NI. Leedom and Daniel Tyler, Departments of Pediatrics and Medicine, University of Southern California and the Communicable Disease Service, Los Angeles County General Hospital, Los Angeles, Calif.) INTRODUCTION Bacterial infections of the central nervous system still constitute serious medi. cal emergencies, despite the availability of numerous effective antimicrobial agents. Death occurs in at least 10% of these patients, and serious sequellae are frequently seen among those who survive. In spite of the serious nature of these *Supported in part by the Hastings Foundation Fund National Institutes of Health Grant 5 TO1-AI-00275 and Contract ~DA-49-l93-MD2874 from the U~S. Army Research and Development Command, Office of the Surgeon General, Department of the Army. PAGENO="0523" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4813 infections and the significant disability among many of those who survive, the various therapeutic regimens proposed have not been evaluated as thoroughly as is desirable. Some of the problems that complicate analysis of the various therapeutic routines advocated in the past are readily apparent. The incidence of bacterial meningitis infections is not great, and the relative etiologic importance of par- ticular bacterial species varies with the age group considered. Rates of bacterial meningitis approach 1 :1000 live births during the neonatal period. The rates fall rapidly during infancy and childhood. This progressive decline in age specific rates continues until the fifth decade. Itthen rises slightly with the increase in pneumococcal infections among older persons. Because of these low rates, rela- tively few patients are available for study in any single hospital. In addition, the diagnosis of these infections is often made in hospitals other than those pro- viding definitive treatment. Referral for definitive treatment may be made after some form of treatment has been initiated. This referral is usually to other hos- pitals on the basis of age group, economic status, or other selective determinants. These factors make the interpretation of experience within a single hospital, unless carefully controlled, subject to serious errors. It is also obvious that experience in different hospitals with different routines cannot be compared, yet several attempts to do so have been made. As yet, no well controlled cooperative study has been attempted, involving several large institutions, to evaluate the management of this type of infection, although such an effort might yield useful data. If such a study were contemplated, these and still other factors must be properly controlled. The severity of the illness and the progressive nature of the disease often intro- duce additional variables with respect to supportive therapy. This support, de- pendent upon experienced nursing and medical personnel, is necessary if the patient is to survive long enough for an antimicrobial drug to have any benefit. This situation is further complicated by a fixed and mystical belief that if one antimicrobal agent is good, two must be better, and three even more efficacious, despite evidence to the contrary. (1) It is the purpose of this paper to examine some of the characteristics of bac- terial meningitis and the factors important in survival. In addition, the results of treatment with ampicillin alone and ampicillin plus chloramphenicol sup- plemented by two days of streptomycin therapy will be presented. If one examines the case fatality rates for a particular type of bacterial meningitis on our service during successive years, it is interesting to note the substantial variation in mortality. If one contrasts selected years, this varia- tion is greater than expected by chance alone. As yet, we have no explanation for these variations. This pattern is clearly illustrated by meningococcal infections treated on our service during the past six years. as shown in Table 1. During this time, Type B meningococci have been predominant, and approximately one-third of the strains tested have been resistant to sulfadiazine (MIC»=10 mg/100 ml). (2) NATURAL VARIATION IN CASE FATALITY RATES TABLE 1.-MENINGOCOCCAL DISEASE, CASE FATALITY RATIOS BYYEAR, LOS ANGELES COUNTYGENERALHOSPITAL Outcome of patient Case fatality Year of treatment Survived Died Total cases (percent) 1961 34 4 38 10.5 1962 64 6 70 8.6 1963 67 6 73 8.2 1964 85 14 99 `14.1 1965 88 3 91 `3.3 19662 86 6 92 6.5 Total 424 39 463 (8. 4) 1 X2=6.74; p2 months ol age, 15; unusual organisms, 15; error in treatment assignment, 9; en- docarditis, mechanical defect. 6; total exclusions, 45 with 11 deaths. Additional data from our most recent study of the treatment of meningitis in patients older than 2 months of age are shown in Tables IV.2, IV.3, and IV.4. Therapy consisted of ampicillin alone in an initial intravenous push dose of 50 mg. per kg., followed by 150 mg. per kg. per day in six divided push doses at 4- hour intervals, and contrasted ampicillin alone with ampicillin plus two other drugs. Alternate patients received therapy consisting of a combination of the same dose of ampicillin plus chioramphenicol at 100 mg. per kg. per day, to a maximum of 4 gm. each day for the total duration of therapy, and streptomycin at 40 mg. per kg. per day (to a maximum of 2 gin.) for the initial 2 days of treatment. Administration of chloramphenicol was delayed until 30 mm. after ampicillin had been administered in an effort to avoid antibiotic interference. As noted in Table IV.2, the response to ampicillin was excellent, with only five deaths among 129 patients treated or an over-all mortality of 3.9 per cent. Mul- tiple antibiotic treatment yielded 13 deaths among 111 patients, a mortality rate of 11.7 percent. The difference is statistically significant (w2=5.33; p7 days) Subdural effusion Prolonged hospital stay (»=19 days) Complications of therapy (rash, eosinophilia, phlebitis, etc.) Hematological 27 20. 0 23 6 4.5 6 47 35.0 36 38 27. 6 30 0 0 3 21. 6 5.4 32.2 27. 0 2.7 TABLE 3.-TIME OF DEATH AFTER INITIATION OF THERAPY BY TREATMENT GROUPS IN 2 SEPARATE PATI ENTS WITH BACTERIAL MENINGITIS SERIES OF Source of data Single drug Combination of drugs Death Death All Total All »=48 hr. >48 hr. deaths cases »=48 hr. >48 hr. deaths Total cases Lepper and Dowling (11) Percent 9 69 4 31 Present report Percent 4 66. 7 2 33. 3 3 8 11 14 27.2 72.8 100 4 9 13 124 30.8 69.2 100 -- PAGENO="0542" 4832 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DISCUSSION The data presented support the thesis that antibiotic interference or antago- rdsm can be observed in a clinical situation. The interference of one antibiotic with another may be expressed clinically in several ways, as illustrated in Table 4. As previously mentioned, Lepper and Dowling (11) observed an increased case fatality rate in patients with pneumococcal meningitis treated with penicillin plus clilortetracycline. A similar observation was made by Olsson, Kirby, and Romansky (16) in patients with the same diasease. In comparing various treat- meats regimens, excessive mortality was present only in the treatment group which combined penicillin and a tetracycline (16). Increased case fatality rates are not the only manifestations of antibiotic interference. Lepper, Wehrle, and Blatt (12) observed a slower response to therapy in patients with H. i~nfivenzae meningitis who received multiple drug therapy; in that series, penicillin was not used, although chlortetracycline was common to each treatment group. Strom (18, 19) reported apparent interference of chlortetracycline and erythromycin with the action of penicillin in streptococcal disease. Antimicrobial antagonism may occur in the treatment of infections with gram-negative enteric bacilli, as illus- trated by the report of McCabe and Jackson (13). These authors (13) clearly showed a relationship between in vitro antagonism and clinical outcome, as meas- ured by failure to eradicate bacteriuria. Bacteriological correlations are less apparent in patients with meningitis. Excepting neonates, almost all patients who die with meningitis have negative post-mortem cultures. TABLE 4.-CLINICAL STUDI ES DEMONSTRATING ANTI BIOTIC ANTAGONISM Reference Disease Manifestation Combination therapy Lepper and Dowling (li) Pneumococcal meningitis~ Increased mortality Penicillin+chlortetracycline. Olsson et at. (16) do do Penicillin+a tetracycline. Lepper et at. (12) Haemophilus influenzae Slower response Chloietracycline+streptomycin± meningitis. sulfisoxazole. Strom (18) Scarlatira Persistence of organism - - - Penicillin+chlortetracylcine. Strom (19) do Slower response Penicilin+erythromycin. McCabe and Jackson Urinary tract infection Relapse Various. (13). Present study Bacterial meningitis Increased mortality and Ampicillin+chloramphenicol± residua. streptomycin. TABLE 5.-PERSISTENCE OF VIABLE ORGANISMS IN CEREBROSPINAL FLUID AFTER 24 HOURS OF ANTIMICROBIAL THERAPY Patient Age Complications Initial therapy Organism Outcome C. V 26 yr None Chloramphenicol+peni- Haemophilus influenzae._ Successful. cillin G. D.D 3yr do do do Do. M.W l6months do do do Do. D. 0 2 yr do do do Do. T. P 18 months do do do Do. P. H 7 months Subdural Chloramphenicol do Reaidua. J. A 64 yr None Penicillin G Pneumncocci Death. J. M 32 yr do do do Do. What factors are responsible for the apparent antagonism in bacterial menin- gitis and its seeming absence in other severe infections requiring antiliotic therapy? The difference probably is due to the lack of surface phagocytosis and other host defense factors which act together with antibiotics to effect recovery (17). In meningitis, a "test-tube" situation is more nearly approximated. Wallace et al. (21) have clearly shown interference of chioramphenicol with the rapid bactericidal action of penicillin in experimental pneumococcal meningitis in dogs. That this situation may pertain in humans is suggested by the data in Table 5. The eight patients listed were observed in a previous study (15) ; all had viable organisms in the cerebrospinal fluid after 24 hr of antibiotic therapy. One might speculate that the host defenses in patients J.A. and J.M., who died 3 days after admission with pneumococcal meningitis, were totally inadequate because PAGENO="0543" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4833 of age or underlying illness such as alcoholism. Likewise, the persistence of organisms in patent P.R., who had a subdural effusion, might be explained by a drug diffusion problem. In the other five patients, there were no obvious explana- tions for persistence of viable organisms other than antibiotic interference. These five patients received a rapid intravenous infusion of penicillin and chlorampheni- col on admission, followed by a continuous intravenous infusion containing the two antibiotics in our standard dosage (15). In contrast, no ampicillin-treated pa- tients with the usual types of meningitis have had positive cultures after 24 hr of therapy. Similar observations, after 12 to 36 hr of therapy, have also been made by Fleming et al. (7) in a controlled study of the treatment of meningitis. Lepper and Dowling (11), in comparing the two regimens which they em- ployed, noted that the majority of deaths in the penicillin-treated group occurred within 48 hr of admission, whereas only 3 of the 11 patients who died while re- ceiving combination therapy did so during the first 48 hr. An analysis of our patients revealed the same distribution (Table 3). Our observations would tend to substantiate the view that the effective single-drug and multiple-drug regimens both failed to effect recovery in a certain number of patients. In addition, mul- tiple-drug herapy seems to have failed in, potentially salvageable patients, pre- sumably because of antibiotic interference. It is somewhat surprising that in our study the only obvious difference be- tween the single- and multiple-therapy groups was disability or death. One would have expected other differences, which might have been manifested in cerebro~ spinal fluid findings, days of fever, or hospital stay. Although no differences were apparent in the large groups, more detailed analyses of subgroups may be fruitful. CONCLUSIONS Many investigators have demonstrated the phenomenon of antibiotic antagon- ism in vitro and in experimental animals. Clinical examples of this phenomenon are restricted to a few situations in which the rapid bactercidal acton of an anti- biotic is apparently necessary for a good response. Bacterial meningitis, par- ticularly that which is severe on admission, appears to be one of the situations in which a combination of bacteriostatic and bactericidal agents is undesirable. ACKNOwLEDGMENTS These studies were supported by the Hastings Foundation Fund; contract #DA-49-193-MD-2874 from the U.S. Army Research and Development Corn- mand, Office of the Surgeon General, Department of the Army; and Public Health Service grants of 5 T1-AI-275, 5 RO1-AI-06346, and 1 K3-AI--23,479. REFERENCES 1. Ahern, J. J., J. M. Burneil, and W. M. M. Kirby. 1952. Lack of interference of chioramphenicol with penicillin in a hemolytic streptococcal infection in mice. Proc. Soc. Exptl. BioL l\Ied. 79 :568-571. 2. Ahern, J. J., and W. M. M. Kirby, 1953, Lack of interference of aureomycin with penicillin in treatment of pneumococcic pneumonia. Arch. Internal Med. 91 :197-203. 3. Barrett, F. F., W. A. Eardley, M. D. Yow, and H. A. Leverett, 1966. Ampicillin in the treatment of acute suppurative meningitis. J. Pediat. 3 :343-353. 4. Dowling, H. F. 1965. Present status of therapy with combinations of anti- biotics. Am. J. Med. 39 :796-803. 5. Dowling, H. F., M. H. Lepper, and G. G. Jackson, 1953. When should anti- biotics be used in combination. J. Am. Med. Assoë. 151 :813-815. 6. Elek, S. D., G. R. F. Hilson, and P. Jewell. 1953. Laboratory aspects of com- bined antibiotic treatment. Brit. Med. J. 2 :1298-1300. 7. Fleming, P. C., J. D. M. Murray, M. W. Fujiwara, J. S. Prichard, and G. A. McNaughton. 1967. Ampicillin in the treatment of bacterial meningitis. Antimicro- bial Agents and Chemotherapy-1966, p. 47-52. S. Ivler, D., L. D. Thrupp, J. M. Leedom, P. F. Wehrle, and B. Portnoy. 1964. Ampicillin in the treatment of acute bacterial meningitis. Antimicrobial Agents and Chemotherapy-1963, p. 335-345. 9. Jawetz, E., J. B. Gunnison, J. B. Bruff, and U. R. Coleman. 1952. Studies on antibiotic synergism and antagonism. J. Bacteriol. 64:29-39. 10. Jawetz, E., J. F. Gunnison, R. S. Speck, and U. H. Coleman, 1951. Studies on antibiotic synergism and antagonism. The inteference of chloramphenjcol with the action of penicillin. Arch. Internal Med. 87:349-359. PAGENO="0544" 4834 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 11. Lepper. M. H., and H. F. Dowling. 1951. Treatment of pneumococcal meningitis with penicillin compared with penicillin pins aureomycin. Arch. Internal Med. 88:489-494. 12. Lepper, M. H., P. F. Wehrle, and N. Blatt. 1952. Treatment of Hemophilus influenzae meningitis: Comparison of aureomycin alone versus aureomycin, streptomycin and gantrisin. Am. J. Diseases Children 83 :763-768. 13. McCabe, W. R.. and G. G. Jackson. 1965. The treatment of pyelonephritis. Bacterial, drug and host factors in success or failure among 252 patients. New Engl. J. Med. 272 :1037-1044. 14, Manten, A., and M. J. Wisse. 1901. Antagonism between antibacterial drugs. Nature 192 :671-672. 15. Mathies, A. W., Jr., J. M. Leedom, L. D. Thrupp, D. Ivler, B. Portnoy, and P. F. Wehrle. 1966. Experience with *ampicillin in bacterial meningitis. Anti- microbial Agents and Chemotherapy-lOGS, p. 610-617. 16. Olsson, R. A., J. C. Kirby, and M. J. Romansky. 1901. Pneumococcal meningitis in the adult. Clinical, therapeutic and prognostic aspects in forty-three patients. Ann. Internal Med. 55 :54~-549. 17. Smith. M. R., W. D. Perry, J. W. Berry, and W. B. Wood, Jr. 1951. Surface phagocytosis in nyU. J. Immunol. 67 :71-74. 18. Strom, J. 1955. The question of antagonism between penicillin and chiortetracycline, illustrated by therapeutical experiments in scarlatina. Antibiot. Med. 1 :6-12. 19. Strom. J. 1961. Penicillin and erythromycin singly and in combination in scarlatina therapy and the interference between them. Antibiot. Chemotherapy 11 :694-697. 20. Thrupp, L. D., J. M. Leedom, D. Ivler, P. F. Wehrle, J. F. Brown, Jr., A. W. i~Iathies, Jr., and B. Portnoy. 1964. H. influenzcie meningitis: a controlled study of treatment with ampicillin. Postgrad. Med. J. (Suppl.) 40 :119-125. 21. Wallace, J. F., R. H. Smith, M. Garcia, and R. G. Petersdorf. 1967. Studies on the pathogenesis of meningitis. VI. Antogonism between penicillin and chloram- phenicol in experimental pneumococcal meningitis. J. Lab. Clin. Med. 70:408-418. 22. Wehrle, P. F., A. W. Mathies, J. M. Leedom, and D. Ivier. 1967. BacteriaJ meningitis. Ann N.Y. Acad. Sci. 145:488-498. APPENDIX IX [From the Journal of Pediatrics, September 1966, vol. 69, No. 3, pp. 343-353] Al~rPIcILLIN IN THE TREATMENT OF ACUTE SUPPURATIVE MENINGITIs1 (By Fred F. Barrett, M.D., Warren A. Eardley, M.D., Martha D. Yow, M.D., and Howard A. Leverett, Houston, Tex.) During 1903 and 1964 in vitro sensitivity studies indicated that ampidillin was effective against the three common etiologic agents of bacterial memningitis in children. Blood and cerebrospinal fluid studies revealed high blood levels and detectable cerebrospinal fluid levels of ampicillin in patients with and without meningeal disease but the mean cerebrospinal fluid/serum ratio was significantly higher in patients with bacterial meningitius. Twenty-eight chil- dren with acute bacterial meningitis were treated with ampicillin alone. No significant differences in mortality or complications were noted when the results of this therapy were compared with those in two groups of patients treated with conventional "triple therapy." Ampicillin, alpha-aminobenzyl penicillin, became available in England in 1961. This semisynthetic penicillin is of particular interest since it is bactericidal against both gram-positive and grain-negative bacteria. Ampicillin has been found to be highly effective in vitro against Diplocoecvs 2)neumo?~iae, Neiescria meningltidi$. and Hcniopiiilus in flnenzae, to achieve good blood levels when administered by oral and parenteral routes, and to have a low incidence of side 1From the Department of Pediatrics, Baylor University College of Medicine and Ben Taub General Hospital. Address, Department of Pediatrics, Baylor University College of Medi- cine. Houston, Texas 77025. This study was supported in part by the Bristol Laboratories, Syracuse, New York, and by Public Health Service Training Grant iT 1 AI-258-O1. NoTE-Numbered references at end or article. PAGENO="0545" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4835 effects. (1-7) These characteristics suggested that ampicillin might be an ideal single drug for the treatment of acute suppurative meningitius due to D. pneu- moniae, N. nceioingitidis, or H. influenzae. The parenteral form of ampicillin was released for clinical trials in the United States in 1963. During 1963, Tyler and his associates (8) published a preliminary report of in vitro studies and clinical experiences, in the management of 31 patients with purulent meningitis due to various organisms, including D. pneumoniae, N. meningitidis, and, H. intluenzae. A more detailed report of the treatment of H. inflnenzae meningitis with am- picillin was presented at the International Conference on Therapy With the New Penicillins (9) in 1964. These investigators found that 126 strains of H. inlluenzae isolated from the cerebrospinal fluid were sensitive to ampicillin. Ninety-one per cent of the strains were killed by 0.4 meg. per milliliter and only one strain required as much as 1.6 meg. for bactericidal activity. Ampicillin and penicillin G were both bactericidal at 0.4 meg. per milliliter for greater than 90 per cent of 72 strains of N. meningitidis and 37, of D. pneurnoniae. Tyler, Thrupp, and co-workers (8, 9) found that ampicillin was comparable to chloramphenicol and equal to penicillin G in efficacy for the treatment of bacterial meningitis. Ampi- cillin did not appear to have any definite advantages over chloramphenicol other than freedom from hematologic depression. During 1963 and 1964 similar laboratory and clinical investigations were con- ducted at the Texas Medical Center in Houston. This report summarizes the results of these investigations. Since the majority of the laboratory studies were performed as a base home for the clinical stt~dies, the laboratory data are presented as Part I and the clinical studies as Part II. PART I. LABORATORY STUDIES In vitro sensitivity tests. Prior to the initiation of clinical studies, strains of D. pneumoniae, N. meningitidis group C, and H. inftuenzae Type B freshly iso- lated froni patients with meningitis in the Houston area were tested for suscep- tibility to ampicillin,~ tetracycline, chloramphenicol, and penicillin G. The two- fold serial tube dilution technique using tryptose phosphate broth and an mo- culum of approximately iO~ organisms was employed for the determination of the minimal bactericidal concentration (MBC) of pneumococci and ineningococci. Agar diffusion plates were used in determining the minimal inhibitory concen- tration (MIC) of H. influenzae. Oasman's agar base with 10 per cent heated blood was employed as the medium. The plates were inoculated from a 24 hour culture in 5 per cent blood and brain-heart infusion broth with a standard 5 mm. wire loop. All of the strains tested during the preliminary phase of investigation were sensitive in vitro to all four of these antibiotics. Since the results of sen- sitivity tests of organisms isolated from patients enrolled in the later clinical trials were similar to those obtained in the preliminary studies, the cumulative results are presented in Table I. TABLE I-MINIMAL INHIBITORY CONCENTRATIONS OF AMPICILLIN, CHLORAMPHENICOL, PENICILLIN G AND TETRACYCLINE AGAINST HEMPOHILUS INFLUENZAE AND MINIMAL BACTERICIDAL COCENTRATIONS OF THESE SAME DRUGS AGAINST DIPLOCOCCUS PNEUMONIAEANDNEISSERIA MENINGITIDIS STRAIN~ SOLATED FROM PATIENTS WITH MENINGITIS Antibiotic concentration Number of 0. 012 0. 025 0. 05 0. 01 0. 20 0. 39 0. 79 1. 56 3. 12 strains (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ Antibiotic tested ml.) ml.) ml.) ml.) ml.) ml.) ml.) ml.) ml.) Hemophilus influenzae: Amipicillin 41 2 10 26 3 Chioramphenicol 24 4 6 4 10 Penicillin G 15 2 9 1 3 Tetracycline 27 2 7 7 11 Diplococcus pneumoniae: Ampicillin 12 2 6 4 Chloramphenicol 11 3 8 Penicillin G 12 s 7 Tetracycline 11 5 3 2 1 Neisseria meningitidis: Ampicillin 15 1 8 5 1 Chloramphenicol 7 3 4 Penicillin G 13 1 4 7 1 Tetracycline 7 3 4 °Polycillin (Bristol Laboratories). 81-280-69--pt. 11-35 PAGENO="0546" 4836 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY A total of 41 strains of H. injiuenzae, 12 of D. pneumoniae, and 15 of N. menin- gitidis were tested for their sensitivity to ampicillin. Varying numbers of these same strains were tested for their sensitivity to chioramphenicol, penicillin G, and tetracycline. All of the strains of H. influenzae were inhibited by anipicillin in a concentration of 0.78 mc. per milliliter or less, the majority by a concentra- tion of 0.39 mcg. per milliliter. The MBC of ampicillin and penicillin G for pneumococci and meningococci were similar and ranged from 0.012 to 0.05 mcg. per milliliter for pneumococci and from 0.025 to 0.20 for meningococci. Serum and spinal fluid ampicillin levels. Thirty eight simultaneous serum and spinal fluid samples were obtained one hour after a parenteral dose (intra- venously or intramuscularly) of ampicillin. Eight of the paired specimens were from patients with no evidence of meningeal disease, 10 from patients with viral meningitis or encephalitis, and 20 from patients with bacteria meningitis. Am- picillin levels in the serum and spinal fluid were assayed by Bristol Laboratories using the cup-plate method with Sarcina lutea as the test organism. The rela- tionship between the dose of ampicillin and the cerebrospinal fluid and serum levels could not be assessed in this series of patients because of variations in dosage and route of administration. However, data are presented to demon- strate the ratios between simultaneous cerebrospinal fluid and serum levels (Tables II and III). The dose employed varied from 25 mg. per kilogram (150 mg. per kilogram per day divided into 6 doses) to 50 mg. per kilogram (250 mg. per kilogram per clay divided into 6 doses). The paired samples were obtained one hour after administration of the dose and all patients had been on the drug for a period of ito 4 days at the time of sampling. Satisfactory serum levels were obtained in all instances and ampicillin was detectable in each spinal fluid specimen. However, there w-as a striking differen- tial between the simultaneous cerebrospinal fluid and serum levels. The highest mean cerebrospinal fluid-to-serum ratio (expressed as percentage) was obtained in patients with bacterial meningitis (ii per cent) while the ratio in the patients with viral meningitis was 9 per cent and in patients without evidence of menin- gitis was 4 per cent. Although the mean cerebrospinal fluid ampicillin levels in the patients with `bacterial meningitis and the group without evidence of menin- gitis, 1.9 mg. per milliliter and 0.8 mg. per milliliter, are not significantly differ- ent (p=>0.1), the mean ratios in those two groups of patients, 11 and 4 per cent, respectively, are significantly different (p=1O5~ F., symptoms >5 days, or complicating disease. 1+ None of the above. TABLE VI.-SEVERITY OF ILLNESS: STUDY AND MATCHED CONTROL PATIENTS Number of matched control Number of study patients patients Severity of illness 1 4+ 3+ 2+ 1+ 4+ 3+ 2+ 1+ H. influence 8 2 4 2 7 2 2 1 N. meningitidis ~ 1 3 D. pneumoniae 1 1 1 2 Unknown etiology 3 1 1 Total patients 3 1 1 Total patients 12 3 10 3 10 4 4 7 I See text. PAGENO="0549" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4839 As can be seen in Table VI, the severity of the illness was comparable in the study and matched control groups. The duration of fever prior to admission to the hospital was used as a rough index of the stage of illness (Table VII). There were no outstanding differences in the three groups except for a wide variation in the duration of illness in the "unknown" category. Bacteriologic studies. Cerebrospinal fluid and blood cultures were obtained from all the study, matched control, and 5 year review patients on admission to the hospital. Repeat spinal fluid cultures were performed on all patients. In the ampicillin-treated and matched control groups the repeat cultures were obtained within 24 to 48 hours after the original culture. Additional cultures were obtained at suitable intervals and prior to discharge. Repeat cultures were also performed on all patients in the "5 year review group"but the time interval was less uniform than in the former two groups. The antibiotic sensitivity tests are described in the previous section on laboratory studies. TABLE VII.-MEAN DURATION OF FEVER PRIOR TO ADMISSION: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS Study patients (days) Matched control patients (days) 5-year review patients (days) H. influenzae 4 9 3 5 3. s N. meningitidis D. pneumoniae 1. 1 2. 0 1. 6 2. 3 2. 0 4. 2 Unknown etiology 2.3 8.5 5.2 Antibiotic management. The study patients received ampicillin, 150 mg. per kilo- gram per day divided into 0 intravenous doses for at lear 48 hours. The ampicillin was diluted with 5 c.c. of 0.85N saline and given over a period of 60 seconds. Unused portions of ampules were discarded so that each dose was freshly pre- pared. After 48 hours the intramuscular route was employed except in instances where patients exhibited a slow response to treatment. In these cases, intravenous therapy was continued for longer periods of time. The average total duration of ampicillin therapy was 2 weeks. The matched control patients and the 5 year review patients received penicillin, chloramphenicol, and sulfadiazine until an etiologic agent had been identified. Thereafter, the appropriate antibiotic was continued and the unnecessary oneS discontinued. The dose of penicillin was 4 to 12 million units per day depending on the size of the child, chloramphenicol, 100 ing. per kilogram per day, and sulfa- diazine, 150 mg. per kilogram per day. RESULTS A susumary of the results of treatment in the three groups of patients is pre- vented in Table VIII. Seventeen of the 28 ampicillin-treate'd patients recovered completely (01 per cent), 2 died (7 per cent mortality), subdural effusions were demonstrated in 4 (14 per cent), 1 (4 per cent) had severe neurologic sequelae, and 4 (14 per cent) had minor neurologic sequelae which subsequently disappeared. TABLE VIII.-RESULTS OF THERAPY: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS Study patients Matched control patients 5-year review patients Number Percent Number Percent Number Percent Satisfactory course Deaths 17 2 61 7 12 3 48 12 123 18 64 9 Severe sequelae Subdural effusion 1 4 4 14 1 5 4 20 24 25 13 14 Minor sequelae 4 14 4 16 (1) Total 28 100 25 100 190 100 I Unknown. PAGENO="0550" 4840 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Twelve of the 25 matched control patients recovered completely (48 per cent), 3 died (12 per cent mortality), subdural effusions were demonstrated in 5 (20 per cent), 1 (4 per cent) had permanent neurologic sequelae, and 4 (16 per cent) had minor neurologic sequelae which subsequently disappeared. The mortality in the 5 year review group (9.5 per cent) was strikingly similar to that of the other two groups. Twenty-five of the 190 patients (14 per cent) had subdural effusions. The incidence of permanent neurologic sequelae in this group of patients (13 per cent) was not significantly different from that of the other two groups (p - < 0.1). Minor neurologic sequelae could not be adequately evaluated in the 5 year review patients. All of the deaths in the study and matched control groups occurred in patients who were in coma and/or shock on admission to the hospital. Four of the 5 deaths took place during the first 48 hours of hospitalization. The cerebrospinal fluid was sterile at the time of death in all 5 patients. Table IX presents the mortality figures in relationship to the etiologic agent. The incidence of subdural effusion and severe neurologic sequelae according to etiologic agent is shown in Table X. TABLE IX.-MORTALITY RATE: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS H. influenzae N. meningitidis D. pneumoniae Unknown etiology Overall mortality 1/16 1/8 0/1 0/3 2/28 3. 5 3.5 0 0 7 2/12 1/7 0/4 0/2 3/25 8 4 0 0 12 9/88 0/8 7/35 2/59 18/190 4. 7 0 3.7 1. 1 9.5 TABLE X.-INCIDENCE OF SUBDURAL EFFUSION AND SEVERE NEUROLOGIC SEQUELAE ACCORDING TO ETIOLOGY: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS Study patients Matched con trol patients 5-year revi Subdural ew patients Severe neuro- Subdural Severe neuro- Subdural Severe neuro- effusion sequelae effusion sequelae effusion sequelae Num- Per- Num- Per- Num- Per- Num- Per- Num- Per- Num- Per- Etiologic agent ber cent ber cent ber cent ber cent ber cent ber cent H. influenzae N. meningitidis D. pneumoniae Unknown etiology 3/16 0/8 1/1 0/3 19 100 1/16 0/8 0/1 0/3 6 4/12 0/7 1/4 0/2 33 25 1/12 0/7 0/4 0/2 8 14/88 0/8 7/35 4/59 16 20 7 8/88 0/8 7/35 9/59 9 20 15 Total 4/28 14 1/28 4 5/25 20 1/25 4 25/190 13 24/190 13 TABLE XI.-MEAN DURATION OF FEVER AFTER INITIATION OF THERAPY: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS Study patients (days) Matched control patients (days) 5-year review patients (days) H. influenzae 6. 9 8. 5 7. 0 N. meningitidis D. pneumoniae Unknown etiology 6. 3 5.0 3. 0 6. 3 2.5 2. 0 4. 0 5.2 - 9 Study patients Matched control patients 5-year review patients Number Percent Number Percent Number Percent PAGENO="0551" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4841 a STUDY ~ 200f ~ MATCHED CONTROL ~ l8Ot~~ z 160 ~~L1 ~` I 2-6 7-Il 12-16 DAY OF THERAPY FIGURE 1.-Mean cerebrospinal fluid cell counts of study irnd matched control patients. RANGE OF CEREBROSPINAL FLUID PROTEIN VALUES IN MILLIGRAMS PERCENT Day 1 Days 2-6 Days 7-11 Days 12-16 Study group 13-480 30-970 14-76 23-120 Control group 22-684 34-571 21-1, 400 20-140 ~ STUDY 0 MATCHED CONTROL w U) 0 0) -J L~. U) U DAY OF THERAPY FIGURE 2.-Mean cerebrospinal fluid glucose values of study and matched control patients. RANGE OF CEREBROSPINAL FLUID GLUCOSE VALUES~ IN MILLIGRAMS PERCENT Study group 10-92 20-98 50-94 30-80 Control group 10-78 20-95 35-75 28-58 PAGENO="0552" 4842 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY E -J -J w U 1- z 0* U -j -J w U U) U FIGURM 3.-Mean cerebrospinal fluid protein values of study and matched control patients. RANGE OF CEREBROSPINAL FLUID CELL COUNTS PER CUBIC MILLILITER Studygroup Control group 90-19,500 52-11,000 3-6,000 3-4,150 2-237 0-182 0-103 0-115 In addition to mortality figures and neurologic sequelae, other criteria used to assess the efficacy of antibiotic therapy were: duration of fever after initiation of therapy; eradication of bacteria from the spinal fluid, and return of the spinal fluid cell count, sugar. and protein to normal values. The duration of fever in the ampicillin-treated patients, the matched control patients and the 5 year review patients is show-n in Table XI. There does not appear to be any significant differ- ence in the time of defervescence in the three groups. The bacterioligoc response to antibiotic therapy was rapid in the groups of patients studied in 1904 and 1965 (study and matched controls). There were no positive cultures within 48 hours after initiation of therapy in either of these two groups. There were in- sufficient data to evaluate the rapidity of bacteriologic response in the 190 patients receiving conventional therapy during the last 5 years~ The cerebrospinal fluid findings of the study and matched control groups are presented in Figs. 1 to 3. No significant differences in the initial cerebrospinal fluid cell count, protein, and sugar values are apparent in the two groups. These values returned to normal at the same rate in the two groups. The difference in protein values at 7 to 11 days may be a reflection of the small number of lumbar punctures done during that phase of the illness. There were insufficient data to evaluate the cerebrospinal fluid findings in the 5 year review group. The incidence of drug hypersensitivity and toxicity could be evaluated in the study and matched control patients but not in the 5 year review group. No skin manifestations of hypersensitivity developed in the ampidillin-treated patients. Eosinophilia was observed in 8 patients. The serum glutamic oxaloacetic trans- aminase (SGOT) was slightly elevated in 8 patients. Three patients developed mild diarrhea which may have been related to ampicillin therapy. The eosin- ophilia and diarrhea cleared spontaneously in every case, usually without dis- continuation of drug therapy. The 8GOT returned to normal after cessation of therapy in all patients in whom repeat values were obtained. No hematologic abnormalities developed in the study patients. None of the patients in the matched control group developed evidence of penicillin allergy. Four patients with STUDY D MATCHED CONTROL. DAY OF THERAPY PAGENO="0553" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4843 Heniophilus influenzae meningitis developed anemia and/or absolute neutropenia while on chlorarnphenicol therapy. One patient with pneumococcal meningitis developed anemia while on triple antibiotic therapy. In all instances the anemia and neutropenia resolved spontaneously with cessation of chloramphenicol therapy. SUMMARY AND CONCLUSIONS During 1963-1965, strains of H. iaftuen,zae, D. pneunumiae, and N. meningitidis isolated from patients with purulent meningitis were tested for in vitro sensitivity to ampiciflin, chloramphenicol, penicillin G, and tetracycline. These studies indi- cated that, in vitro, ampicillin was as effective or slightly more effective than chloramphenic'ol, penicillin G, and tetracycline against H. influenzae and was equally effective in vitro as penicillin G against D. pneumoniae and N. menin- fTjitidis. Simultaneous serum and cerebrospinal fluid ampicillin levels were determined in 8 patients with no evidence of meningeal disease, 10 patients with viral menin- gitis or encephalitis, and 20 patients with bacterial meningitis. High blood levels were achieved in all three groups. The drug was detectable in the cerebrospinal fluid of patients with normal meninges as well as patients with inflamed men- inges. The mean cerebrospinal fluid/serum ratio, however, was significantly higher in patients with bacterial meningitis than in those with no evidence of meningeal disease. Twenty-eight patients admitted consecutively to Ben Taub General Hospital from July, 1964, to April, 1965, with the diagnosis of acute bacterial meningitis received single drug therapy with ampicillin (study group). Twenty-five patients admitted from April, 1965, to July, 1965, received conventional antibiotic therapy and served as a matched control group. In order to establish a base line of mortality and morbidity of bacterial meningitis in our hospital, the charts of 190 children (2 months to 14 years of age) who received conventional antibiotic therapy for bacterial meningitis from 1959 through 1963 were reviewed (5 year review group). The mortality rate and the incidence of severe neurologic sequelae were not significantly different in the three groups of patients studied. The incidence of subdural effusion was approximately equal in the three groups of patients, and the incidence of minor neurologic sequelae was approximately the same in the study and matched control groups. The rapidity of response to therapy as measured by: (1) the duration of fever after the institution of antibiotic treatment in the three groups studied and (2) the return of the cerebrospinal fluid values to normal in the study and matched control groups indicated no significant difference betwen therapy with ampicillin and conventional drugs. No serious drug reactions occurred in the ampicillin-treated patients. Eosino- philia, diarrhea, or slight elevation of the SGOT were encountered in a few- patients but these often subsided without cessation of therapy. Five patients in the matched control group developed anemia and/or absolute neutropenia while on chioramphenicol therapy. In all instances, the anemia and neutropenia re- solved with cessation of chioramphenicol therapy. Ampicillin appears to be an excellent drug for the- treatment of acute bacterial meningitis due to D. pneumoniae, N. nieningitidis, and H. influenzac in children. It is as safe and as effective as conventional triple therapy and in addition has the following advantages: (1) simplicity of administration, and (2) apparent free- dom from hematologic and renal complications encountered with chloramphenicol and sulfonamides, respectively. REFERENCES 1. Brown, D. M., and Acred, P.: "Penbritin"-a new broad-spectrum antibiotic. Preliminary pharmacology and chemotherapy, Brit. M. J. 2: 197, 1961. 2. Knudsen, B. T., Rolinson, G. N., and Stevens, Shirley: Absorption and excre- tion of "Penbritin," Brit. M. J. 2: 198, 1961. 3. Stewart, G. T., Coles, H. M. T., Nixon, H. H., and Holt, R. J.: "Penbrithi": An oral penicillin with broad-spectrum activity, Brit. M. J. 2: 200, 1961. 4. Rolinson, G. N., and Stevens, Shirley: Microbiological studies on a new- broad-spectrum penicillin, "Penbritin," Brit. M. J. 2: 11, 1961. 5. Klein, J. 0., and Finland, M.: Ampicillin, activity in vitro and absorption and excretion in normal young men, Am. J. Med. Sc. 245: 544, 1003. 6. Quinn, B. L., Cox, F., Jones, D., and Farns, L.: Clinical experience with parenteral ampicillin, Antimicrobial Agents & Chemother. 226, 1964. 81-280 0-69-pt. 11-36 PAGENO="0554" 4844 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7. Turck, M., Anderson, K. N., McKee, W. M., Shulman, J. A., Smith, R. H. and Petersdorf, R. G.: Further studies with ampicillin, Antimicrobial Agents & Chemother., 220, 1964. 8. Ivier, D., Thrupp, L. D., Leedom, J. M., Wehrle, P. F., and Portnoy, B.: Ampicillin in the treatment of acute bacterial meningitis, Antimicrobial Agents and Chemother., 335, 1963. 9. Thrupp, Lauri D., Leedom, John M., Ivier, Daniel, Wehrle, Paul F., Brown, John F., Mathies, Allen W., and Portnoy, Bernard: H. inflvenzac meningitis: a controlled study of treatment with ampicillin, "Therapy with the new penicillins," Proceedings of a Conference held at the Apothecaries' Hall, London, 119. 1964. APPENDIX X [From Post Graduate Medical Journal, December 1964, pp. 119-125] H. INFLIJENZAE MENINGITIS: A CONTROLLED STUDY OF TREATMENT WITH AMPICILLIN (By Lauri D. Thrupp, John M. Leedom, Daniel Ivler, Paul F. Wehr.le, John F. Brown, Allen W. Mathies and Bernard Portnoy) From the Communicable Disease Service, Los Angeles County Gen- eral Hospital, and the Infectious Disease Laboratory, the Depart- ments of Medicine and Pediatrics, University of Southern California School of Medicine THE case fatality rate in Hemophilus inlluenzae meningitis has been reduced to 5-10% by present methods of anti-bacterial and supportive therapy. As this rate is still far from optimal, the incidence of both early and late neurological sequelae is appreciable, and the antibiotics presently employed have definite and occasionally serious toxicity, new approaches to therapy must be evaluated. Preliminary in vitro studies performed in our laboratory (Ivler, Thrupp, Lee- dom, Wehrle `and Portnoy, 1963) indicated that 126 strains (118 type B) of H. influenzae isolated from cerebrospinal fluid (C.S.F.) were sensitive to ampicillin. Bacteriostatic and bactericidal levels did not differ significantly, and 91% were killed by 0.4 ~g./ml. Only one had a bactericidal level as high `as 1.6 yg./ml. In addition, sensitivities of meningococci `and pneumococci to ampicillin were simi- lar to those to penicillin G. These data, in conjunction with the apparent low toxicity of ampicillin suggested the trial of ampicillin as `a single drug treatment for bacterial meningitis, in contrast to control groups treated with conventional therapy. The present report summarizes the experience to date with H. influen.zac meningitis. Eighteen of these 70 patients were included in a preliminary report (Iveret al., 1963). MATERIALS AND METHODS (1) Selection of Patients: All patients more than two months of age with bacterial meningitis admitted to the Communicable Disease Service of the Los Angeles County General Hospital were included in the ampicillin study. Chart numbers assigned at the hospital central admitting office, and not subject to control of the ward physicians, were used to insure proper randomization. Pa- tients with even (2, 4, 6, etc.) numbers were assigned to the ampicillin group while patients with chart numbers ending 1, 3, 5, etc., were given conventional therapy. During the period considered (June, 1963 to March 1964) a total of 72 patients were admitted with H. in/luenzac meningitis. Of these, 44 with odd chart numbers were assigned to the control group, and 28 with even numbers were eligible for ampicillin therapy. The difference in the size of the two groups was unexpected, although within the limits of chance variation. Tw-o of the 28 patients were excluded from the ampicillin group, one by error in assignment and the other because of concomitant severe facial cellulitis following a dog bite where additional therapy was indicated. These two patients w-ere not tabulated with either group. Most of `the patients had received some antibacterial therapy prior to admission, usually subtherapeutic dosages, ineffective drugs, or both. NOTE.-References at end of article. PAGENO="0555" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4845 No attempt was made to evaluate this, since it was assumed to provide an equal, and probably negligible, effect in both treatment groups. (2) Administration of antibacterial therapy: Sodium ampicillin was reconsti- tuted in 0.85 per cent NaCl and administered rapidly (15-20 minutes) at four hour intervals in a total daily dose of 150 mg./kg. of body weight. (The first seven patients treated received 100 mg/kg. per day intravenously at six hour intervals). The intravenous route was used invariably for at least the first 48 hours, w-hile after adequate initial clinical response many patients were given the same daily dose by intramuscular injection at four hour intervals during the remainder of the period of treatment. Ohloramphenicol was given by continuous intravenous infusion in a total daily dose of 100 mg./kg. In some patients in whom the diagnosis of H inflaenzw was not certain on admission, sulfisoxazole and penicillin G (150 mg./kg./day of each drug) were also given until isolation and identification of the organisms were completed. (3) Duration of therapy: Treatment was continued until the patient was afebrile for at least five days, the spinal fluid contained less than 40 cells per cmm. with few or no polymorphonuclear leukocytes, and the C.S.F. sugar was normal. (4) Evaluation of response to therapy: Response to therapy was evaluated by the usual clinical criteria, including duration of fever, improvement in neuro- logical status, decrease in peripheral blood leukocyte count with a return of the dif- ferential count toward normal, and improvement in C.S.F. finding, including pres- sure, cell count, percentage polymorphonuclear leukocytes and glucose and protein content. Subdural taps were performed whenever indicated (Platou, Rinker and Der- rick, 1959). In this report the outcome of therapy was evaluated according to the patient's course in the hospital and status at the time of discharge from the hospital. Untoward findings during the course of treatment in the hospital and any neurological abnormalities were recorded. "Delayed resolution clinically, but no squelae at discharge" is a descriptive category which included patients with one or more findings such as: (a) transients subdural effusions, (b) convulsions persisting beyond the first 24 hours in the hospital, (c) persistence of a positive C.S.F. culture the day following admission to the hospital, (d) persistence or recurrence of O.S.F. pleocytosis, (e) documented persistence of nuchal rigidity or neurological findings such as cranial nerve palsies beyond five days even though resolution has occurred by the time of discharge. An additional "slow response" category incorporated the above plus other patients with no abnormality but fever persisting beyond five days of treatment. (5) Bacteriological methods: Isolation and identification of the organisms were accomplished by conventional methods utilizing blood and chocolate agar, serum and thioglycollate broth and both aerobic and CO2 incubation. Quellung was done in C.S.F. if adequate numbers of organisms were present. Bactericidal levels of ampicillin and chloramphenicol were determined using serial tube dilution techniques in GC medium containing 1% supplement B. (Difco). RESULTS Bacteriologic confirmation of the diagnosis of H. influenzw type B infection was complete in 68 of the 70 patients in the study group. Blood and O.S.F. cul- tures were both positive in 34 patients and organisms were cultured from the C.S.F. alone in the remaining 34. Two patients admitted with partially treated purulent meningitis had no positive cultures; they are included in this series on the basis of organisms seen of Gram's stain of the C.S.F. The cultural recovery of H. influ~uzw from 68/70 patients supported the assumption that antibiotic therapy given prior to admission had little effct on the course of the illness. To date, 164 strains of H. influenzw isolated from C.S.F. have been tested for i~v `i~itro sensitivity to ampicillin. Ninety-one per cent of the strains were killed by 0.4 ~g./ml., and only two had bactericidal end points as high as 1.6 and 3.1 ~ig./ml. respectively. The age and sex distribution of the patients studied is indicated in Table I. Two of the patients were more than 15 years of age. It should be noted that 14 of 26 patients in the ampicillin group were two years of age or older, and 13 of 44 patients in the control group were in this age group. This was believed to be an unimportant difference, since the distribution of severity of illness, accord- ing to the criteria in Table II, was similar within each age group and apparently PAGENO="0556" 4846 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY was not related to age. The expected male predominance was found in both study groups. The duration of illness prior to admission was similar in both groups. In Table II the patients in each group are recorded by severity of illness on ad- mission. There was no difference between the two groups. The duration of fever after therapy was instituted as indicated in Table III. No significant difference is apparent between the two groups. Sixty-four per cent of the chloramphenicol treated patients were afebrile by the fifth hospital day, while 72% of the ampicillin group were in this category. The C.S.F. was re-examined within one or two days following admission in 24 ampicillin and 38 control patients. Cultures of these follow-up C.S.F. samples were positive in three of 31 specimens from the ampicillin patients and three of 46 samples from controls. These six positive specimens were all obtained less than 18 hours after the start of therapy; no positive C.S.F. cultures were ob- tained from either treatment group later than 18 hours after admission. The similarity of response in the two treatment groups is further emphasized in Figs. 1 and 2, in which changes in O.S.F. cell count and glucose are shown dur- ing the period of therapy. In addition to the data shown, the rate of decline in percentage of polymorphonuclear cells in the O.S.F. during the period of treat- ment was similar in the two groups. TABLE I-H. INFLUENZA MENINGITIS, AGE AND SEX DISTRIBUTION OF PATIENTS BY THERAPY GROUP Therapy group and sex Less than 1 year 1 year 2 to 4 years 5 to 29 years Total Control: Male Female Total Ampicillin: Male Female Total 10 9 7\ 5 3 5 3 2 23 21 19 12 8 5 44 7 2 3 0 6 6 0 2 16 10 9 3 12 2 26 TABLE 11.-H. INFLUENZA MENINGITIS, CLINICAL STATUS ON HOSPITAL ADMISSION ACCORDING TO TREATMENT GROUP Severity group * Findings Control Number Percent Ampicilli Number n Percent 4+ 3+ 2+ 1+ Coma,shock,semicoma,hypoteflsiOn1 Convulsions without coma or shock Temperature of 105° R. or more, symptoms 5 days or more, complicating disease, marked lethargy 1~ None of above Total patients 8 10 15 11 18 23 34 25 3 7 9 7 12 27 34 27 44 100 26 100 11 or more of the findings listed. TABLE 111.-H. INFLUENZAE MENINGITIS, DURATION OF FEVER IN HOSPITAL BY TREATMENT GROUP INumber (percent distribution) of patients with maximum temperature > 100° Fl Therapy group Days in hospital 0-I 2-3 4-5 6-7 8-9 10+ Total Control 3 11 11 8 2 4 1 39 (100) Ampicillin (8) 6 24 (28) 3 (12) (28) 9 (36) (21) 1 (4) (5) 2 (8) (10) 4 (16) 2 25 (100) Total 9 14 20 9 4 8 64 1 4 fatalities and 1 case with incomplete temperature record excluded. 2 1 fatal case excluded. PAGENO="0557" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4847 TABLE IV.-H. INFLUENZAE MENINGITIS COMPLICATIONS AND SEQUELAE BY TYPE OF TREATMENT Control Number Percent Ampicillin Number Percen Death 4 9 1 4 Neurological residual ` 5 11 3 12 Severe Mild or questionable Subdural effusions 1 4 4 9 2, 1 4 15 Required surgery Mild neurological residual Nosequelae Seizures persistent 2 Delayed resolution clinically 3 but no sequelae at discharge Temperature of 100° F. or more for 6 days but without any of the above findings Good response (none of above findlngs). 0 1 3 1 2 13 30 5 11 18 41 2 1 1 2 8 8 31 1 4 13 54 1 At hospital discharge. 2 Some seizures persistent 24 hours or more after admission. 3 Tabulation includes patients with slight subdural effusions which cleared without surgery or neurological sequelae. TABLE V.-H. INFLUENZAE MENINGITIS, STATUS ON DISCHARGE FROM THE HOSPITAL Slightorno residual with Serious Age group-Treatment group No residual satisfactory response minor subdurals or slow response neurologic residual or death Total Less than 12 months: Control 9 9 1 19 Ampicillin Total 12-23 months: 0 6 3 9 9 15 4 28 Control 7 3 2 12 Ampicillin Total 2ormoreyears: Control 2 1 0 3 9 4 2 15 6 5 2 13 Ampicillin Total All ages: Control 12 2 0 14 18 7 2 27 22 17 5 44 Ampicillin 14 9 3 26 Total 36 26 8 70 TABLE VI.-H. INFLUENZAE MENINGITIS (POSSIBLE REACTIONS OR COMPLICATIONS OF THERAPY) Type of reaction Control (44 patients) Number Percent Ampicillin (26 patients) Number Percent Anypossible reaction Phlebitis Skinrash Gastrointestinal Miscellaneous Eosinophilia I Hematologicdepression Leukopenia3 Rel. granulocytopenia4 Thrombocytopenia5 Anemia° 20 (45) 9 (20) 4 (9) 3 (7) 6 (14) 3 (7) 10 (23) 5 5 2 3 16 (62) 10 (38) 5 (19) 1 (4) 1 (4) 1 (4) 22 (8) 0 1 1 1 I >10 percent eosinophils in peripheral smear. 2 1 patient failed to respond to Ampicillin, and developed mild anemia and thrombocytopenia 14 days after the substi- tution of chloramphenicol. <4,000 per cmm. (or <5,000 if other hematology abnormal). <15 percent polys and bands. Marked reduction in platelets on smear. Drop in hemoglobin of >2 g./100 ml. PAGENO="0558" 4848 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY Complications seen are recorded in Table IV by type of sequehe and method of therapy. Again, it is apparent that no significant difference is present between the two groups. A strong association was found with coma, shock and/or con- vulsions on admission and fatal outcome or serions neutrological residual. This was the case in both therapeutic groups. None of the 42 patients admitted without the above serious clinical signs had a fatal outcome or neurological sequehe of consequence. Among the 28 patients admitted with coma, shock or convulsions, four of 18 treated with chlorampheMcol died and one had a serious residual. One of 10 in the ampicillin series died, and an additional two patients had severe residual involvement (hydrocephalus). The status of the patients at the time of discharge by age group and type of therapeutic response is recorded in Table V. A Ithough minor differences were noted among the various age groups, the numbers were small and of doubtful significance. In the total group, the proportion with entirely satisfactory re- sponse was 22 of 44 control patients and 14 of 26 ampicillin patients. These pro- portions may be regarded as nearly identical. Possible drug reactions or complications of therapy are listed in Table VI. These findings were not proven to be due to the specific antibiotic therapy in any instance. The high incidence of local phlebitis in both groups accompanied the frequent use of polyethylene, indwelling, venous catheters. Twelve patients with some evidence of hematologic depression are also listed in Table VI, although the findings were minimal in most. Eleven cases accompanied the administra- tion of chloramphenicol. One three-month-old patient treated with ampicillin had a peripheral white blood cell differential count of 15% polymorphonuclears and no bands on the seventh day of therapy. This finding was of doubtful sig- nificance in view of the age of the patient, lack of accompanying anemia or leukopenia, and a reticulocyte count of 1.6%. The other patient with hemato- logic depression included in the ampicillin group was treated initially with am- picillin with prompt sterilization of O.S.F. However, the pleocytosis failed to clear, and subdural effusions and hydrocephalus were noted. The marrow de- pression appeared two weeks after chloramphenicol had been substituted. Pf. .INFI.UENZAE MENINGITIS .0. U ..1~ U ~n. U. FIGuuz 1.-C.S.F. cell counts during the treatment period. H. INFLUENZAE MENINGITIS ~ co~ 6SF. CLUCOS~ ~ ~7OI: *. 60 ~ (0) CM ~ ~ 40 ,p.~?%~1) (2) (19) (~ (24) (23) D~ 30 ~ ,`AIG) U 20 ~ MEDIAN' 0 f~OPJIl1OL * ..(2oMr.% * AMPIGILLIN 10 (2!) C ) M~MuCR OF PATIENTS TESTED 0 I 1 I ...~q - ADM I 2 3 4.5 6.7 U-Il 12.15 16+ GDASE DAYS AFTER HOSPITAL ADMI~SION FIGUBE 2.-C.S.F. glucose levels during the treatment period. NEDIAN CFI.1. i-... AM?ICILLIK COUNT lo....o CONTROL RANGE I'2~3 4.5 DAYS AFTER HOSPITAL ADMISSION PAGENO="0559" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4849 DISCtJSSION The patients with H. infIuenzw meningitis in this study comprised a group similar to series previously reported (Haggerty and Ziai, 1964). 90% of the patients were between two months and four years old. This age distribution followed the characteristic pattern which, as shown by Fothergill and Wright (1933), reflects inversely the age prevalence of bactericidal serum antibody. Three per cent (two cases) were young adults, a proportion similar to the 2.7% of patients more than 20 years of age reëorded in Dolphin and Popham's (1951) review of 915 cases. There was the expected male predominance. Analysis of the results of therapy with ampicillin and chioramphenicol in these two comparable groups of patients failed to elicit any clear-cut differences. General clinical criteria such as mortality, neurological sequeloe, duration of fever, subdural effusions, sterilization of the C.S.F. rafes of reduction in the number of cells, per cent polys and protein content in O.S.F. and rise in C.S.F. sugar, were similar in both groups. The C.S.F. cell counts and sugar levels showed no differences on the first and the third days after admission, or afterwards Among small numbers of observations on the second day, the larger variation in in values for the ampicillin patients resulted in differences in distributions of values about the medians for that single day of bordering significance (Figs. 1 and 2). However, in view of the data for the days prior to, and following, this second day of treatment, it is doubtful that these differences were meaningful. Although all nine ampicillin patients less than one year of age manifested at least some deficiency in response to therapy, nine of 19 controls in this age group had satisfactory responses (Table V). A trend toward fewer unsatisfactory responses with ampicillin than chioramphenicol was observed in patients two or more years of age. As stated previously, neither therapeutic group was weighted with disproportionate numbers of, severely ill or moderately ill patients at any age. Disregarding age, the proportion of satisfactory responses in both therapeutic groups was almost identical. The apparent minor differences in response to ampicillin and chloramphenicol by age group would probably dils- appear if more patients were tested. Consideration of these data emphasizes the difficulty of being certain that every important variable is known in any clinical study. The one patient in the ampicillin group who died and the two who survived with major residua were all severely ill on admission. Nevertheless the clinical findings in these two survivors were of interest in that C.S.F. pleocytosis with polymorphonuclear predominance persisted in one, and both developed subdural effusions and hydrecephalus eventually requiring neurosurgical correction. None of the patients in the control group required neurosurgery, although it should be noted that four deaths occurred in this group. Several studies have demonstrated the in vitro effectiveness of ampicillin against H. influenzae (Rolinson and Stevens, 1961; Klein and Finland, 1963) including type B strains isolated from C.S.F. in our hospital (Ivler et al., 1963). Although ampicillin displayed significantly more activity in vitro than penicillin G against C.S.F. H. Influenzae isolates, the differences were small and of ques- tionable clinical significance (Ivler et al., 1963). Nevertheless, the pverall response of patients with H. influenzae meningitis treated with ampicillin ~vas comparable to the results observed with chloramphenicol. These favourable results with ampicillin stand in contrast to the reported experience with penicillin G even when patients treated with the latter drug had meningitis due to H. influenzae strains sensitive to penicillin G, and C.S.F. penicillin G levels were maintained by intrathecal therapy (Drysdale, McIntosh and Brodie, 1946; Zinnemann, 1946; Thomson, Bruce and Green, 1947). Perhaps qualitative differences in the activity of ampicillin and penicillin G against H. influenzae account for the more effective results with ampicillin. Ampicillin levels in the O.S.F. samples studied to date have been variable, ranging from 0.1 to 1.0 ~ig./ml. with average C.S.F.-to-seruin ratios of 20 to 30%. These C.S.F. levels seem rather low in view of the overall satisfactory clinical response to ampicillin. Indeed, C.S.F. levels of 0.1 to 1.0 pg./ml. barely approxi- mate the in vitro minimum bactericidal concentrations (Ivler et al., 1963) and clinical responses have not correlated well with C.S.F. levels. For example, a C.S.F. sample from an eight month old patient who developed subdural effusion and hydrocephalus contained more than 7.0 ~zg./ml. of ampicillin, one of the highest levels found in any patient. The peripheral blood differential count of 15% neutrophils noted in a three month old in the ampicillin group on the seventh day of therapy could not be PAGENO="0560" 4850 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY considered definitely abnormal. The anemias, leukopenias granulocytopenias and thrombocytopenias observed in the control patients on chloramphenical therapy all subsided after the drug was discontinued. One control patient who developed anemia, thrombocytopenia and leukopenia, concurrently developed staphylococcal pneumonia and extensive phlebitis and cellulitis at the site of an intravenous polyetheylene catheter. However, as the patient's differential count remained normal, and the lowest total white blood cell count recorded was 3,100 per cmm. the superinfection was not necessarily related to the mild leukopenia. SUMMARY Overall results of treatment of H. influenza meningities with ampicillin or chlor- amphenical appeared comparable, but no definite advantages were demonstrated in the use of ampicillin other than the freedom from hematologic depression. While one death occurred among the ampicillin group and two additional patients required neurosurgical procedures for correction of hydrocephalus, four control patients died and one had severe neurological residual. Further study, perhaps with higher dosage, is indicated. This study was supported in part by the Hastings Foundation, and a grant from Bristol Laboratories, Syracuse, New York, TJ.S~A. John M. Leedom is an Epidemic Intelligence Service Officer, Epidemiology Branch, Communicable Disease Center, U.S. Public Health Service. Dr. Bernard Hanes provided statistical advice. We should like to thank Robert A. Murray for technical assistance and Drs. A. Burckin, A. Christiansen, P. R~bbie and V. Spilotro for assistance in reviewing clinical data and *the house staff of the Communicable Disease Service, Los Angeles County General Hospital for their co-operation and excellent care of the patients. The diagnostic bacteriology was directed by Margaret Parrish and Patricia Hagen, in the Communicable Disease Section of the Microbiology Laboratories, Dr. Robert Cleliand, Director, Los Angeles County General Hospital. Ampicillin assays were performed by Bristol Laboratories, Syracuse, New York. REFERENCES DOLPHIN, A., and POPHAM, R. P. (1951) : Lancet, ii, 472. DRYSDALE, 0., MCINTOSH, D., and BRODIE, J. (~1946): Brit. med. J., ii 223. FOTHERGILL, L. P., and WRIGHT, J. (1933): J. Imnwnol., 24, 273. I~AGGERTY, It. J., and ZIAT, M. (1964) : Advanc. Pediat., 13, 129. ~ivi~, P., Tmiupp, L. D., LERDOM, J. M., WEHBLE, P. F., and `PORTNOY, B. (1963): Antirnierbial Agents ansi Chenwtlierapy-1963 p. 335, American Society of Micro- biology. KLEIN, J. 0., and FINLAND, M. (1963) : Amer. J. med. Set., 245, 544. PLATOV, R. V. RncKER, A., and DERRICK, J. (1959) : Pediatricts, 23, 962. ROLINSON, G., and STEVENS, S. (1961): Brit. med. J., ii, 191. THOMSON, J., BRUcE, L., and G~sic, M. (1947): Brit. med. J.. ii, 414. ZINNEMANN, K. (1946) : Brit. medJ., ii, 931. APPENDIX XI [From Antimicrobial Agents and Chemotherapy, 1965, pp. 610-617] EXPERIENCE WITH AMPICILLIN IN BACTERIAL MENINGITIS (By Allen W. Mathies, Jr., John M. Leedom, Lauri D. Phrupp, Daniel Ivier, Bernard Portnoy, and Paul F. Wehrle) Departments of Pediatrics, Medicine, and Microbiology, and the Hastings Foundation Infectious Disease Laboratory, University of Southera California, and the Communicable Disease Service, Los Angeles County General Hospital, Los Angeles, California ABSTRACT The mortality of bacterial meningitis is 10 to 15% in large contemporary series and prompts continuing search for effective, nontoxie therapeutic agents. PAGENO="0561" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4851 Ampicillin was highly effective in vitro against Haenzophilus influenzae, Neis- seria meningitidis, and Diplococens pneurnoiviae, and, being a penicillin, would be expec:ted to have low toxicity. Therefore, ampicillin as a single drug treat- ment for bacterial meningitis was contrasted with "conventional" therapy. From 1 July 1963 to 30 April 1965, 541 bacterial meningitis patients over 2 months of age were assigned to ampicillin therapy or to conventional therapy with peni- cillin, chloramphenicol, or both, according to chart number. Error in drug assign- ment, fulminant meningococcemia, unusual organisms, or concomitant disease requiring other therapy excluded 88 patients. The severity of illness on admission was comparable in both treatment groups. Overall mortality rates in the am- picillin (A) and control (C) groups were 8.3 and 11.8%, respectively. Case fatality rates varied slightly according to etiological agent, i.e., H. influenzac (6.0 with A versus 9.3 with C) ; N. meningitidis (5.3 with A versus 9.1 with C); D. pneumoniae (22.0 with A versus 28.7 with C) ; purulent meningitis, no isolate (0 with A versus 5.7 with C). The overall incidence of neurological residua was 12.5% with A and 10.7% with C. Duration of fever and cerebrospinal fluid abnormalities were comparable. Possible complications of therapy were more frequent in the control group, primarily because of hematological changes with chloramphenicol. The data indicate that ampicillin is effective as a single drug for the three major causes of bacterial meningitis and purulent meningitis of unknown etiology, and also illustrate the difficulties inherent in naming a "regimen of choice" when two effective modes of treatment are compared. Although serum therapy, sulfonamides, and subsequently the use of various antibiotics have substantially reduced the mortality of bacterial meningitis, the total case fatality rate remains between 10 and 15% in many large series. Current therapeutic recommendations for the most frequent types of bacterial meningitis include one or more of several different antimicrobial agents. Of the drugs most frequently recommended, only benzylpenicillin lacks major pharma- cological toxicity. A new 6-amino-penicillanic acid derivative, ampicillin, demon- strated marked bactericidal activity against Haemophilas injluenzae in vitro and resembled benzylpenicillin in potential toxicity and efficacy against organisms customarily penicillin-sensitive (Ivler et al.. 1964). Therefore, it seemed desir- able to evaluate this antibiotic in the therapy of H. inflnenzae and other types of acute bacterial central nervous system (CNS) infections. After treatment of a small nuntber of patients seemed to indicate clinical efficacy and no toxicity, a controlled clinical evaluation of parenteral ampicillin in comparison with groups treated with penicillin or chioramphenicol or both, was started at the Communicable Disease Service of the Los Angeles County General Hospital in 1963. A preliminary report of this study (Ivler et al., 1964) and some of the data concerning patients with H. inf1~ei~zae have been presented previously (Thrupp et al., 1964). MATERIALS AND METHODS $election of patients. The Gemniunicable Disease Service of the Los Angeles County General Hospital is the major referral center for the entire County for patients with ON1S infections of all ages and from all socioeconomic groups. Patients were included in the present study in accordance with the following criteria. All patients 2 months of age and older who were admitted to the Com- municable Disease Service of the Los Angeles County General Hospital with bacterial meningitis were in~luded in this study. Patients were assigned to the ampicillin or control groups on the basis of hospital chart numbers. Ch!art num- bers were obtained by telephoning the central admitting office, which obviated physician bias in assignment of patients to one group or another. Patients with even chart numbers were assigned to the ampicillin group, and those with odd chart numbers, to the control group. Administration of antibiotic therapy. One-third of the 24-hr dose of the re- spective antibiotic was given by' rapid intravenous infusion on admission to the service. Sodium ampicillin was given in a daily dose of 150 mg/kg, intra- venously, in equally divided doses at 4-hr intervals. Each dose of ampicillin was dissolved in 0.85% sodium chloride and was administered as, a rapid infusion. Reconstituted drug was stored in a `refrigerator at 4 C for not more than a 24-hr period. After a minimum of 2 or 3 days of intravenous therapy, the antibiotic was given intramuscularly, at the same dosage, on `a 4-hr schedule. Control therapy consisted of penicillin G in `doses approximating 150 mg/kg for patients with NOTE-References at end of article. PAGENO="0562" 4852 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Neisseria nwningitidis or Diplococous pneurnoniae infections. For those with H. influenzae, chioramphenicol was used as a single drug dosage of 100 mg/kg, for 24 hr. Both of the latter antibiotics were administered by continuous intra- venous infusion. As with ampicillin, after 2 or 3 days of therapy, these drugs were given in the same dosage intramuscularly. Control group patients with meningitis of unknown etiology received both aqueous penicillin G at 150 mg/kg and chloramphenicol at 100 mg/kg. As outlined above, the initial 24-hr dosage of ampicillin or penicillin G was therefore approximately 200 mg/kg and for chioramphenicol was 133 mg/kg. Sulfisoxazole was added to the regimen of a few patients in the control group at the beginning of the study. In control patients in whom no organisms were seen on the initial direct examination of the spinal fluid, but who had subsequent isolation of an organism, either penicillin or chloramphenicol was discontinued, depending upon the organism identified. The response to therapy was evaluated by the usual clinical criteria, including duration of fever, improvement in the mental and neurological status, and im- provement in the cerebrospinal fluid (OSF). Treatment was continued until: the patient was afebrile for at least 5 days; the spinal fluid cell count was less than 30 cells, with less than 10% polyrnor-phonuclear cells; the OSF sugar w-'as normal: and the protein approached normal. Subdural taps were performed when- ever indicated. Bacteriological methods. Gram-stained sediment of spinal fluid was examined both by the admitting physician and by laboratory personnel. The quellung test for specific confirmation of H. inftuenzae infections was used if adequate num- bers of organisms were present. Isolation and identification of the causative organisms were accomplished b~ conventional methods, including both aerobie and 002 incubation techniques. In vitro data concerning ampicillin, chioramphen- icol, and penicillin G sensitivities have been presented previously (Ivler et al., 19~4). TABLE 1-TOTAL MENINGITIS PATIENTS STUDIED, LOS ANGELES COUNTY GENERAL HOSPITAL, JULY 1963 TO APRIL 1965 . Bacterial etiology Treatment regimen Ampicillin Control Patients excluded Total patients Haemophilus influenzae Neisseria meningitidis Diplococcus pneumoniae Unknown Other organisms 66 107 56 77 41 42 29 35 16 23 22 9 18 189 156 105 73 18 Total cases 192 261 88 541 TABLE 2--IDENTIFICATION OF ORGANISMS FROM MENINGITIS PATIENTS BY TREATMENT GROUPS 1 . Etiology and regimen Sourc e of organisms Total Smear2 Total cases included CSF Blood CSF plus blood Haemophilus influenzae: Ampicillin Control therapy Neisseria meningitidis: Ampicillin Control therapy Diplococcus pneumoniae: Ampicillin Control therapy Total 60 94 39 55 34 30 35 51 7 12 21 17 32 42 5 7 20 13 63 103 41 60 35 34 3 4 5 6 6 8 66 107 o 56 77 41 42 312 143 119 336 32 389 1 Total cases studied 453, 81 percent with known etiology (88 exclusions). 2 Direct examination only. Includes 10 clinical diagnoses. Includes 11 clinical diagnoses. PAGENO="0563" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4853 RESULTS Distribution of patients. During the period from 1 July 1963 through 30 April 1965, a total of 541 patients with bacterial meningitis were admitted to the Communicable Disease Service. The distribution of these patients by etiological agent is shown in Table 1. The 88 total exclusions comprise patients who were inadvertently assigned to the inappropriate therapeutic group (43), or were subsequently discovered to have nonpurulent meningitis (7). Those with under- lying disease [brain abscess (4) or bacterial endocarditis (7)] were also ex- cluded, as were those with dual infection (1), unusual organisms (10), and those patients known to be hypersensitive to penicillin (6). Within the meningococcal category, those considered by the admitting physician to have fulminant menin- gococcal disease were also excluded. Five patients who would have received ampicillin and five patients w-ho might have been assigned to the control group were thus excluded. All received penicillin G, and two deaths occurred among these 10 patients, one in each category should they have been included. Source of organisms. Of the 453 patients suitable for analysis, precise bacterial etiologies were determined in 368, or 81%. Although many of the patients had received at least some antibacterial therapy prior to their admission, this was not a reason for exclusion, since, despite previous antibacterial therapy, the organism was recovered on culture from the great majority of patients, as is noted in Table 2. In 32 instances, organisms were identified on direct examina- tion of spinal fluid or petechiae without subsequent growth in culture. Twenty- one patients with purulent meningitis and a petechial-purpuric rash were in- cluded in the meningococcal category on clinical grounds. Severity of illness. To properly categorize patients for comparative purposes, they were divided into four groups according to the severity of illness at the time of admission to the hospital. Included in the 4+ (severe) category, were patients who were comatose or semicomatose, in definite shock, or with signifi- cant hypotension. The 3+ (moderate) category included patients with convul- sions, but who were not hypotensive or comatose. The 2+ (mild) category had patients in whom either the temperature was greater than 105 F rectally on admission, or symptoms had been present for more than 5 days; also included were those with a complication already present on admission or with marked lethargy. The 1+ (mild) category was reserved for those patients with none of the above findings but with definite bacterial, meningitis. Since the 2+ and 1+ categories were associated with low mortality and few complications, these grades have been combined and are presented for allgroups in Table 3. As is apparent, the distribution of severe and lesser grades of illness was essentially the same for the ampicillin and the control groups. The method of randomization was effective, although minor differences in proportions of patients in moderate and severe categories were seen. In the pneumococcal severe category there was an apparent difference in the assignment of excess patients in the severe group to penicillin therapy. This difference is not statistically significant (X2=3.28; P=0.077), and is explained by the difference in age distribution for pneumococcal cases (Table 4). Fewer control patients appear in the 1 to 15-year group, and an excess is apparent in the 30 to 44-year and 60 to 74-year groups. The slightly lower mortality in pneumococcal disease with ampicillin therapy may be explained entirely by the age and severity distributions in this study. TABLE 3.-TYPES OF MENINGITIS BY SEVERITY ON ADMISSION Clini cal estimate on severity Severe Moderate Mild Total Etiology and regimen Number Percent Number Percent Number Percent cases Haemophilus influenzae: Ampicillin Control therapy Neisseria meningitidis: Ampicillin Control therapy Diplococcus pneumoniae: Ampicillin Control therapy Unknown: 13 18 13 23 22 31 20 17 23 30 54 74 10 15 20 18 10 18 4 5 3 7 2 5 43 69 33 50 16 9 65 65 59 65 39 21 66 107 56 77 41 42 Ampicillin Control therapy 3 5 10 14 5 17 0 0 21 30 73 86 29 35 PAGENO="0564" 4854 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 4.-PERCENTAGE DISTRIBUTION OF MEN INGITIS PATIENTS BY AGE AND TREAMENT GROUP Regi- Etiology men 1 Age group in years Less than 1 1-4 75 or 5-14 15-29 30-44 45-59 60-74 more Total cases Haemophilus influenzae A C Neisseria meningitidis A C Diplococcus pneumoniaa A C Unknown A C Total 241 41 12 14 15 16 28 25 50 51 39 29 19 5 28 20 9 5 2 1 14 11 9 11 4 22 18 9 4 3 1 12 5 8 17 19 5 5 5 19 19 26 5 14 14 6 10 20 6 17 6 6 66 107 56 77 41 42 29 35 26 35 12 7 7 6 6 1 453 1 A=ampicillin; C=control therapy. 2 Percentage of total group. Therapeutic response. Over 85% of the patients were afebrile or had a tempera- ture lower than 100 F rectally by the 7th day in both the ampicillin and control groups (Table 5). Five H influenzae patients who received ampicillin had sub- dural effusions, and 3 of these required surgery, whereas 12 of the control group had effusions, and 1 required surgery. The CSF was re-examined 1 or 2 days after admission. No positive cultures were obtained from H. influenzae patients later than 24 hr after admission in the ampicillin group, whereas 6, or 5.6%. of the 107 patients had positive cultures after more than 24 hr of treatment in the group treated with chloramphenicol. It was somewhat surprising that one and three positive cultures after 24 hr were also seen in meningococc'al and pneumococcal categories, respectively, during penicillin G therapy. The data conceiming sequelae and mortality are presented in Table 6. As noted, 4 deaths occurred among 66 patients with H. influenzae infection in the ampicillin group, giving a case fatality rate of 6.0%. There were 10 deaths, or 9.3% among 107 patients in the control group. With respect to neurological residua, the figures are similar, since 6 of the 66 patients had neurological residua in the amipicillin group, `and 11 of the 107 patients had neurological residua in the chioramphenicol group. The slight increase in residual rate and decrease in fatal outcome in the meningocoecal patients treated with ampicillin can be explained by a single pa- tient recovering with sequelae. This difference is not significant. TABLE 5.-PERCENTAGE DISTRIBUTION OF COMPLICATIONS OF DISEASE AND RESPONSE TO THERAPY BY TREATMENT GROUP Problems observed Subdural effusions Regi- Etiology men I CSF posi- Persistent Require tive at 24 fever 2 Total surgery hrs. Total number of patients Haemophilus influenzae A C 19.4 7.6 4.5 12.3 11.3 .9 5.6 66 107 Neisseria meningitidis A C Diplococcus pneumoniae A C 5.3 3.6 1.8 11.4 2.6 1.3 1.3 12.4 7.3 26.2 4.7 7.1 56 77 41 42 Unknown A 10.3 29 C 8.6 2.9 35 Total A 12.5 5.2 2.1 192 C 13.5 6.5 .8 3.8 261 1 A=Ampicillin; C~=control group. 2Temperature >100° F; (R) >7 days. PAGENO="0565" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4855 TABLE 6.-STATUS ON DISCHARGE FROM HOSPITAL BY ETIOLOGY AND TREATMENT GROUP Cat egory of patients studied No apparent defect Recovery with sequelae Fatal outcome Total number of Etiology and regimen Number Percent Number Percent Number Percent patients Haemophilus influenzae: Ampicillin Control groups Neisseria meningitidis: Ampicillin Control groups Diplococcus preumoniae: Ampicillin Control groups Unknown: 56 85.0 86 80.4 ~ 45 80.4 63 82. 0 24 58.5 22 52. 5 6 9.0 11 10.3 8 14.3 7 9. 1 8 19.5 8 9. 0 4 10 3 7 9 12 6.0 9.3 5.3 9. 1 22.0 28.7 66 107 56 77 41 42 Ampicillin Control groups Total: 27 93.1 31 88. 6 2 6.9 2 5.7 0 2 0 5. 7 29 35 Ampicillin Control groups Grandtotal 152 79.2 202 77.5 354 78.1 24 12.5 28 10.7 52 11.5 16 31 47 8.3 11.8 10.4 192 261 453 Both the case fatality rate and the frequency of sequelae upon recovery were extremely high in the pneumoccocal category. This can be expected, since many of the older patients were alcoholics and in poor nutritional state, and, at times, substantial delay was encountered before hospitalization. The slightly decreased fatality rate in those receiving ampicillin is without significance, since, as was noted earlier, a slight excess of patients' in the older, poor-risk category received penicillin G. The neurological sequelae in this category represented major defects, including mental retardation (1), hearing loss (2), definite weakness or paresis involving one or more extremities (2), expressive a'phasia (1), and other similar defects. The types of residual defects noted were similar in both control and ampicillin groups, since three patients in the ampicillin category had definite hearing loss, one a spastic hemiparesis, and others had defects as noted above with penicillin G. No differences in sequelae or fatality rates were seen among patients in the purulent unknown category. This iS particularly interesting in view of the fact that the randomization of the patients in this category yielded almost identical age and severity distribution figures. Patients receiving both chloramphenicol and penicillin G in large doses had similar responses with ampicillin alone. With respect to the overall figures, 47 deaths occurred among the 453 patients treated for purulent meningitis in the various categories. Although this was a 10.4% case fatality rate, it must be remembered that our Service accepts all age groups, and a substantial portion of our patients come to us with delayed diag- noses, are severe alcoholics, or are persons found in their residence by an inter- ested neighbor who has not seen them for sometime. All patients with detectable heart sounds on admission to the hospital have been included in this report, whether or not respiratory aids were required. It is of particular interest to note that there is no significant difference with regard to either fatality or number and type of sequelae between the ampicillin and contol categories. TABLE 7.-POSSIBLE COMPLICATI ONS OF THERAPY Category considered Ampic Number illin Percent Contro Number I Percent Total Number Percent Total treated Phlebitis Rash Local Eosinophilia 10 percent Other hematological 1 Other 192 32 18 4 20 7 8 100 16.7 9.4 2.1 10.4 3. 6 4.2 261 39 20 5 18 23 14 100 15.0 7.7 1.9 6.9 8. 8 5.4 453 71 38 9 38 30 22 100 15.7 8.4 2.0 8.4 6.6 4.9 1 Depression of reticulocytes<0.1 percent, or marked reduction in platelets on smear, or 4,000 white blood cells/cm, or <15 percentpolymorphonucleocytes and bands. PAGENO="0566" 4856 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The neurological residua tabulated were those present at the time of discharge from the hospital, and may or may not have persisted. It is possible that in some instances additional defects will be found on careful follow-up study during sub- sequent years. It is important to note that there do not appear to be significant differences in proportion or severity of residual defects in any category between the study groups. Evaluation of the side effects of therapy reveal no significant differences in the frequency of phlebitis, rash, eosinophilia >10%, or local reactions (Table 7). There was, however, a substantial difference (12=5.26; P= <0.05) in the fre- quency of signs of heinatological toxicity. The most frequent change was a depres- sion of reticulocytes, although granulocytopenia, and thrombocytopenia were also observed. Only I of 66 patients who received ampicillin for H. infiuenzae meningitis had a transient depression in granulocytes, whereas 17 of 107 who received chioramphenicol had hematological abnormalities. All of the hema- tological changes observed have been reversible, although in two patients in the chloramphenicol group granulocytic depression persisted for more than 2 months. DISCUSSION During the early period of the development of effective antimicrobial agents, it was apparent, without equivocation, that several caused substantial decreases in mortality and sequelae in bacterial meningitis. At the persent time, with num- erous effective and relatively safe drugs available, selection of specific antibiotic agents for clinical use becomes more complex. These studies were conducted to determine whether it would be possible to simplify the therapy of acute bacterial meningitis, so that only a single compound could be used with results equivalent in safety and effectiveness to currently accepted therapy. Multiple drug therapy increases the hazards to the patient, as well as the expense of therapy, and, in addition, complicates nursing care. Since H. influen~rae infection is often difficult to identify on direct examination of the spinal fluid, even by experienced person- nel, it has been necessary frequently to administer either tetracycline (with at- tendant phlebitis with initial intravenous therapy or local reactions on subsequent intramuscular administration) or chioramphenicol (with a definite hematolo- gical hazard) to be certain that proper therapy is provided prior to confirmation by culture. It would appear that these studies demonstrating the efficacy of ampicillin offer an escape from this dilemma. As one of the indices used in determining the response to an antibacterial regimen is the ease fatality rate, it should be noted that this was 8.3% for the ampicillin group versus 11.8% in patients treated with conventional antibiotic routines. This difference was not significant, however, and may have been due entirely to the difference in age distribution of the pneumococcal group. As noted above, all patients with detectable heart sounds on admission were included, whether or not aids to respiration were employed in transit, and whether or not cardiac arrest occurred within minutes. If one adjusts the overall mortality rate to exclude deaths occurring within the 12 hr immediately after admission, the corrected case fatality rate in the ampicillin group is 6.3% and among controls is 9.2%. With regard to evidence of neurological residua, the rates were also similar in the two groups. Excluding fatalities, the pro~)ortions with residua at the time of hospital discharge was 13.6% among ampicillin-treated patients and 12.2% for the control group. Ampicillin, although appearing to be somewhat more effective than chlor- amphenicol in vitro (Ivler et al., 1964), did not have a substantially greater clin- ical therapeutic benefit than chloramphenicol in H. inftvcnzac meningitis. It is of interest, however, and consistent with the in vitro data, that six patients with H. inflt~~enzae meningitis had positive spinal fluid cultures 24 hr or more after initiation of chlorainphenicol therapy, whereas none had similar positive cultures in the anipicillin category. The in vitro differences between benzylpenicillin and anipicillin against pneumococci and meningococci, were even less marked, but ainpicillin appeared slightly more active (Ivler et al., 1964). It is interesting to note that three patients with pneumococcal meningitis and one with meningococcal meningitis had positive OSF cultures after 24 `hr of therapy with benzylpenicillin, whereas none had positive cultures after 24 hr of ampicillin therapy. While no significant differences were noted between the treatment groups with regard to phlebitis, skin rashes, local reaction, or eosinophilia, 17 patients (16%) who received chloramphenicol alone had evidence of hematological depression. Bone marrow examinations presented the classic picture of chioramphenicol tox- PAGENO="0567" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4857 icity. Fortunately, none of the reactions was permanent, although two patients had persistent and marked hematological depression for more than 2 months. Although ampicillin is not significantly more effective than penicillin G or chloramphenicol in the treatment of the common types of bacterial meningitis, the advantages of a single drug and the absence of significant toxicity suggest that this agent be considered as the drug of choice for the initiai treatment of bacterial meningitis in patients more than 2 months of `age. It should be emphasized, how- ever, that, with definite confirmation of the infection as either due to pneumococci or meningococci, penicillin G provides a less expensive and equally effective mode of therapy. ACKNOWLEDGMENTS This investigation was supported by the Hastings Foundation Fund, Bristol Laboratories, Inc., Syracuse, N.Y., and by Public Health Service grant 5-PI-AI-275 from the National Institute of Allergy and Infectious Diseases. We thank Pat Hagen for the primary isolation and identification of bacteria. REFERENCES Ivler, D., L. D. Thrupp, J~ M. Leedom, P. F. Wehrle, and B. Portnoy, 1964. Anipicillin in the treatment of `acute bacterial meningitis. Antimicrobial Agents and Ohemotherapy-1963, p. 335-345. Thrupp, L. D., J. M. Leedom, D. Iv'ler, P. F. Wehrle, J. F. Brown, A. W. Mathies, and B. Portnoy. 1964. H. infiuenzae meningities: a controlled study of treatment with ampicillin. Postgrad. Med. J. 40:119-125. APPENDIX XII EXCERPTS OF AFFIDAVITS SUBMITTED TO THE FOOD AND DRUG ADMINISTRATION FROM VARIOUS PHYSICIANS RE PRESCRIBING OF DRUG THALIDOMIDE BASED ON INFORMATION GIVEN BY DETAIL MEN D. Scott Bayer, M.D., 2122 West E~id Avenue, Nashville, Penn., Obstetrician- Gynocologist, signed an affidavit which states in part, "About November 1, 1960 I was approached by a representative of the Wm. S. Merrell Company regarding the use of Kevadon. This representative told me that Dr. Jere C. Robertson had agreed to use the product in St. Thomas Hospital where he was a resident physician in OB-GYN. . . . This representative told me that the firm just wanted a clinical impression based upon our use and testing or laboratory work were not necessary.. . . Because of the safety representation made by the representative at that time and because it was my understanding that no real clinical experimentation or reporting was required, but that only a clinical impression was wanted, I agreed to sign a statement of investigation for the representative in order to allow Dr. Jere C. Robertson to use the product. It was my understanding that Kevadon would very shortly be available as a prescription item Bernard A. Bercu, M.D., Wayne County General Hospital, Eloise, Michigan, Internist, signed an affidavit stating in part, "The detail man on first visit concerning Kevadon asked me if I would like to try some on patients. I decided to use Kevadon as a sedative for sleep for some of my patients on the basis of the representation made to me by the detailman and the preliminary medical brochure that Kevadon had a very low toxic effect as compared with the other sleep inducing agents such as barbiturates.. .. I have submitted no reports of any kind to Wm. S. Merrell Company or to its representatives concerning Kevadon. I do not consider my use of Kevadon as part of an investigational program to determine safety. I did use it for familiarization. I had not planned any clinical trial. I was not prepared to study the drug Jack B. Brants, M.D., 751 E. 63rd Street, Kansas City, Mo. Internist, signed an affidavit quoted in part, "In October or November 1960 I was approached by Frank Johnson, a detailman for Wm. S. Merrell Company, concerning the drug Kevadon. He presented the drug as a non-barbiturate, non-narcotic, safe sleep PAGENO="0568" 4858 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY inducing drug. . . . The claims for safety and non-habit forming characteristics of the drug were largely responsible for my using the drug. . . . I submitted no written reports on the use of this drug, and the drug was given to me with this understanding. I did not pretend to do any research on drugs used in my regular practice. My agreement with Mr. Frank Johnson was that I would submit no written report but would give oral reports to him. I made it clear that I was not a research man and that I would want the safety of the drug deter- mined before I would give it to any of my patients. . . . In my opinion this drug was made available to me to familiarize me with its use." John D. DeIlIott, M.D., 1440 Professional Bldg., Kansas City, Mo., Psychiatrist, signed an affidavit stated in part. "Just prior to November of 1960 I had dis- cussions with Frank Johnson, detailman for Wm. S. Merrell Company, regarding my use of the drug Kevadon. I also talked to Dr. T. L. Jones, of Wm. S. Merrell Company by phone, concerning this same drug and its use. I decided to try the drug largely because of its claims regarding efficacy and safety which are of great importance in my type of practice. When arrange- ments were made for my using the drug, I understood that a clinical report was to be submitted after I had used the drug for a period. I signed no par- ticular agreement but drugs were to be supplied to me in the amount that I requested. The drug was supplied to me to allow me to evaluate its ef- fectiveness . . . I have not submitted any written reports to Win. S. Merrell Company but I have given verbal reports to the firm's detailman, Frank John- son concerning the use of the drug . . . I have received a number of pieces of literature from the home office of Win. S. Merrell Company and Inspector Souder made copy of this literature as follows: "1. Dated August 21, 1962 from Thomas L~ Jones, M.D. giving a current status report on the use of Kevadon .. ." Milton Ende, M.D., 121 S. Market Street, Petersburg, Va. Internist, signed an affidavit stated in part, "The representative contacted me at my office dur- ing the latter part of 1960 at which time he offered to supply me with Kevadon for my use as a sedative. The representations made indicated that the drug was safe for use as a sedative. I do not recall any direct claims for the drug other than its safety as a sedative. Information supplied me concerning the drug was of a casual nature with no specific details concerning the drug ex- cept that I had obtained the impression from the representative that the drug was completely safe. This drug was represented to me in a manner similar to the manner in which detailmen or medical representatives present me with physicians samples of commonly marketed drugs. I was persuaded to accept the drug for use due to its apparent safety and due to the fact that it was a free sample for which I would not have to charge my patients . . . I have not submitted any written reports to Merrell Company but may have filled out any investigator statement. I do not recall if this statement was supplied by Mer- roll Company . . . In my original contact with the medical representative con- cerning this drug I was lead to believe that written reports concerning my use of this drug would not be necessary, however, I do not recall any positive statements indicating the need for or non-necessity of written reports and records . . ." Ray Firestein., M.D., 416 Sherland Bldg., So. Bend, Indiana, Internist, signed an affidavit which is quoted in part "The detailman stated or else there were statements in the literature supplied by Merrell to the effect that Kevadon had been carefully studied in Europe. I was impressed by the claim that no lethal dose was known for Kevadon. This alone would have made the use of Kevadon highly desirable as a hypnotic . . . I did not submit any written reports to Wm. S. Merrell regarding my use of Kevadon. I did not consider my use of Kevadon as part of an investigational program to determine safety. I considered that the manufacturer had supplied me with the drugs so that I could familiarize myself with its use. I w-as not testing safety. . PAGENO="0569" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4859 John V. Hummel, M.D., 273 S. Bellevue, Memphis, Tennessee, Obstetrician and Gynecologist, signed an affidavit which he first wrote out himself and which is quoted in part, "I was first approached about Kevadon in the winter of 1960 when Mr. James M. Walker, representative for the Wm. S. Merrell Company was visiting our office. . . . He was our friend and called on us often. He told us of a new drug called Kevadon that Merrell had and was waiting to get approval before putting this drug on the market. He wanted to know if we would like to have some to try to see if we liked it, how the patients liked it, and so we could be using it by the time it came on the market. He told us the fundamentals of the drug. We said that we would try the drug. He sent us a large folder containing a full account of the drug and stressed how safe it was, that it was of the same strength as the barbiturates and there was no contraindications that I can remember. . . . This was not done as a clinical investigation, but as a friendly personal basis so that we would get an impression of the drug before it was put out on the market as a sleeping pill S. Bruce Kepart, M.D., 303 S. Main Street, Bluifton, Indiana, Obstetrician- Gynecologist, signed an affidavit which is quoted in parts, "I did discuss Kevadon with Mr. Brenner on/or about November 28, 1960. Probably at that time, I was supplied with the Wm. S. Merrefl Company's statement of investigator which I signed. Inspectors Glassner and Maclejewski showed me a copy of this signed statement. The phraseology under the sectiOn `Brief description of proposed inves- tigation indicating facilities namely evaluation of above' . . . facilities is not mind. Under the section animal and human experiments appears the type response `animal.' I had no intention of conducting any animal experiments on Kevadon nor do I have experimental animals available. . . Regarding the safety of Kevadon, I received the aforementioned letter from Mr. Brennan dated November 19, 1960 which indicated that the drug had no fatal dose, that fatal toxicity was not known. Also, the preliminary medical brochure described above stated that Kevadon was not addicting and was not habit forming; that tolerance had not been a problem; that no withdraw-al symptoms had been experienced; that very large dosages had not produced respiratory depressions; that Kevadon had been administered to expectant and nursing mothers and that all of the babies were born or nursed without any abnormality or harmful effects from the medication; that Kevadon resulted in a very low in side effects; that Kevadon produced no measurably impairment of the functions of the vital organs. "As a result of the representa tion made to me as described above, I concluded that I would try Kevadon in my practice, because (1) it would not be a hazard in the medicine cabinet in the patient's home in the event of accident ingestion of over-dosage and because of its non-habit forming property. (2) Its reported effectiveness in producing normal sleep and not a deep sleep from which a nursing mother would not be easily aroused to nurse her baby. (3) Because it was as effective as the most active barbiturate. (4) I was told either by the Merrell detailman in the fall of 1960 or by Mr. Brenner on/or about November 28, 1960 that Kevadon was soon to be made commercially available and that it was already being sold in Canada.. . I was not aware at an~y time of instructions from Wm. S. Merrell Company or its representative that reports from me were unnecessary, similarly I did not have the impression that the reports from me were required. In my use of Kevadon, I was not testing its safety; I was not condu~ting a basis testing program. I was determining its efficacious application so as to be able to report my experience with its use.. Richard W. Miller, M.D., 1265 Union Avenue, Memphis, Tennessee, Surgeon, signed an affidavit which is quoted in part, "When first approached, the Mer- rell representative supplied me with both verbal assurances and literatures at- testing to the safety of Kevadon. The majority of this literature comprised re- prints of clinical studies, information as to dosage, contraindications, etc. . It was my distinct impression that Kevadon w-as not considered an experimental drug since it had been tested and widely used in Europe and since the literature and verbal assurances of the Merrell representative pointed up the safety of the drug. I definitely feel that the manufacturer sought my participation in this program not to supply clinical evidence but to familiarize myself with Kevadon and to test the patient acceptance of the drug. It was these verbal and written 81-280 0-69-pt. 11-37 PAGENO="0570" 4860 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY assurances furnished by the Merrell representative which persuaded me to use Kevadon. . . . When first approached by the Merrell representative with regard to my trying out Kevadon, I made it clear to them that I was not going to keep any records or furnish them with any written reports. I was informed that re- ports would not be necessary. I explained that I was not setup to do research or provide clinical data because I deal with paying patients in a private practice. I urged the representative to seek their data from a clinical which had the personnel, equipment and facili- ties to do justice to a valid research program. It was my impression that reports were not required. . . - To reiterate, I felt that verbal and written assurances on the safety of Kevadon were valid, or else I would never have used the drug. It is my practice to use experimental drugs. The manufacturer never asked that I pay for any Kevadon which I received. With this in mind, I felt that the Wm. S. Merrell Company wanted me to participate in a program which was not to supply data as to the safety and efficacy of Kevadon since such had already been dem- onstrated in Europe, but to familiarize myself with the drug and test patient acceptance. . . ." Donald J. Nenno, M.D., 490 McKinley Parkway, Buffalo, New York, Obstetri- cian-Gynecologist, signed an affidavit quoted in part "Mr. Rose represented Keva- don as being absolutely safe in that according to him it had been proven safe through wide spread use in Europe and was superior to other hypnotic drugs such as barbiturates and that it was impossible to be used for suicidal purposes and was not habit forming. However, Wm. S. Merrell Company advised me not to give the drug before administering anesthesia as the effect of the drug with anesthesia had not been documented even though they were certain it was safe. I accepted the drug on these representations. From our discussion with Mr. Rose, I had no idea that Kevadon was an experimental drug, the safety of which had not been cleared by the U.S. Food and Drug Administration. I thought it was simply for clinical comparison study. I have many drugs offered to me by pharmaceutical companies for my determination if their effects are superior to competitive products on the market. Kevadon was represented to me as just another one in that category. To the best of my knowledge I never signed a clinical investigator statement. Mr. Rose supplied me with the evaluation forms on which the attending nurse could record how the patient felt about the drug. Mr. Rose said that these forms were provided to keep the information on, but it was not necessary to return them ~1?. C. John Pearson, D.O., 3416 S. W. Webster, Seattle, Washington, General Practitioner, signed an affidavit which is quoted in :part "The Merrell detailer stated that he had a new sedative preparation named Kevadon. He strongly indi- cated a human lethal dosage had not yet been determined and even gross amounts consumed in suicidal attempts had not been fatal - . . that this was an important drug since it was a highly effective sedative yet non-toxic. . .. During Mr. Cowles' visit of 11/3/60, I agreed to evaluate Kevadon in my hospital practice to learn if the drug was as effective a sedative as indicated by the detailer and the above brochure. The studies were undertaken on the basis that it was an effective seda- tive and non-toxic. From Mr. Cowles approach, I considered the use of Kevadon as an opportunity to determine its efficacy and not to determine its safety since I had no facilities for this type of study... I gave him my verbal report. . . I do remember receiving a letter dated August 21, 1961 from the Wm. S. Merrell Co. where it states among other things `Nulsen administered Kevadon to expectant mothers with a sleep problem without effects on the newborn infants.' Roy J. Phillip, M.D., 44 W. Main Street, Carbondale, Illinois, Internist, signed an affidavit which is quoted in part, "Mr. Howard informed me his firm had a new- sedative, a drug name Kevadon arid gave me a brochure on the drug. He in- formed me to note in this brochure that the drug had no LD5O. He also stated that he would have his firm send me an investigator's statement to sign. He made no representations as to safety of the drug and other claims except that I should note or read the information under the safety data. . . But after reading the brochure I was impressed with the statement under the caption of safety data that LD5O could not be determined. This specifically persuaded me to under- PAGENO="0571" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4861 take the use of this drug as a sedative. . . . That I consider the use of the Kevadon drug as a means to familiarize myself with it and not as part of an investigational program to determine the safety of the drug." Jere .C. Robertson, M.D., 1110 S. Main Street, Hopkinsville, Ky., signed an affidavit which is quoted in part "I was approached by a Wm. S. Merrell detail- man and asked if I would like a new type of sleeping pill to use in the clinic known as Kevadon. I remember specifically that the detailman stated that he could take as much as two bottles and not commit suicide. . . . I recall that the detailman emphasized the drug's safety. It was my understanding that the drug Kevadon was due to be marketed momentarily. . . . I believe that the detallman showed me charts and brochures to emphasize the safety and use of Kevadon. Because of this I did not believe it was an experimental drug which required clearance from Dr. D. S. Bayer, Head of the OB-GYN Section of the St. Thomas Hospital. I am almost positive that I did not sign an investigator statement before use of the drug. Any experimental drug or drug for investiga- tional purposes require clearance from Dr. Bayer. I was lead to believe that this drug, Kevadon, was not in that category. No records of any kind were kept on the use of this drug and no reports concerning its use were rendered to the firm as it was my understanding that this was not necessary. I would not have been persuaded to use this drug had it not been for the assurances given me by this detailman that it was completely safe and had been thoroughly tested George P. Roseinond, M.D., 3401 North Broad Street, Philadelphia, Pa., Surgeon, signed an affidavit which is quoted in part, "The Merrell representa- tive told me that this product Kevadon was not yet available for general use. He told me that his firm was interested in obtaining my opinion of the product. He told me that Kevadon had been studied quite extensively in Europe and that its safety had been well established. The latter point of established safety was well stressed. As I recall, he called to my attention to certain statements in a product brochure which stressed the safety of Kevadon. He left a copy of this brochure with me but I no longer have it available. As a result of this initial meeting, I decided to undertake the use of Kevadon tablet as a hypnotic convinced by the detailman that the safety of Kevadon had been well estab- lished by oral representations and statements made in the firm's brochure. The detailman had me complete a statement of investigator dated November 2, 1960, . . . a copy of a letter from Wm. S. Merrell Company dated August 21, 1962 addressed to me which states Nulsen administered Kevadon to expectant mothers with a sleeping problem without effects to the newborn infant. I believe I did receive this reference letter although I do not have my original copy. I have not submitted any written or verbal reports covering my use of Kevadon to Wm. S. Merrell Company during the period of my use of the prod- uct. I had been told by the detailman during his initial contact that such reports were not necessary. It was my understanding that Kevadon was given to me to familiarize me with the product and was in no way associated with or considered as part of an investigational program. I am familiar with the procedures to be followed for clinical investigations of new drugs. Had I been told by the Merrell detailman that Kevadon was an investigational new drug I would have maintained more adequate recOrds covering its clinical use. . . ." Herbert F. White, M.D., 4741 Broadway N. E., Knoxville, Tenn., Internist, signed an affidavit which is quoted in part, "Mr. Hurley advised me that Kevadon was an excellent sedative with no side effects which had been used extensively in Europe. I was given to understand that Kevadon would be re- leased in this country for general use very shortly and that Kevadon was the Merrell name for thalidomide. I was lead to understand that the drug had been thoroughly tested and was safe and at this time clinical evaluation was all that was being requested. It was my understanding that Kevadon was not to be considered an experimental drug in the true sense and that controlled experiments with laboratory testing was not required. Mr. Hurley had litera- ture which he showed me during this first presentation which confirmed the above statement on the drug's efficacy. I agreed to use the product because of PAGENO="0572" 4862 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY the above representations and because I had a number of elderly people in the hospital with a sleep problem on whom I expected to use the drug. I did receive a letter from Wm. S. Merrell dated August 21, 19G1 which stated among other things `Nulsen administered Kevadon to expectant mothers with a sleep problem without effect on the newborn infants.' This letter also requested that I fill out a brief summary report of my clinical experience with Kevadon. I did not complete or return these forms because of the extremely limited use I had made of the drug because I had initially not been asked for any reports and understood that such were not necessary. . . ." H. Glenm Williams, M.D., 273 South Bellevue, Memphis, Tenn., Obstetrician- Gynecologist, signed an affidavit which is quoted in part "Mr. Walker told me about Kevadon and stressed both the safety of the drug and the fact that it had about the same potency as barbiturates. Mr. Walker also stated that it was almost impossible to take an overdose of Kevadon. He said that his firm wanted physicians with private practices such as mine to try the drug. He said that this was to be done both to acquaint the doctor with Kevadon and to test patient acceptance of the drug. Mr. Walker said that the drug had already been proven safe in Europe and this program which was promotional in nature was to be accomplished prior to the formal release of Kevadon early in 1~61. . . . I cannot recall whether or not I signed a Statement of Investigator for Merrell. In any event I made it quite clear that I did not plan to do further research on the drug. . . . To reiterate, I did not furnish the Wm. S. Merrell or their repre- sentative with any written reports. I told them from the beginning that I did not have time to keep records. If they still wanted me to try their drug out I would do just that. It was my impression that reports would not be required. I recall at least one instance on an undetermined date where the Merrell rep- resentative possibly Mr. James M. Walker asked me informally how I liked the drug. I told him I liked it fine. There was no detailed questioning, and as far as I remember my answer was confined to how I like Kevadon. I do not know whether this impression of Kevadon was to be considered as clinical data. I did not give it as such as I had not agreed to enter into an investigational program. From the beginning it was my impression that Kevadon was not an experi- mental drug. I was lead to believe from both the clinical reports and by verbal assurances from the Merrell representative that Kevadon was safe. I actually thought the drug had been released by FDA. I even wrote several prescriptions for the drug which bounced, of course. I felt from the very first that the Wm. S. Merrell Company wanted physicians with private practices to become familiar with Kevadon and test patient acceptance. It was my impression that my par- ticipation in this program was promotional in nature and was to precede formal introduction of Kevadon to the American market early in 19f31 Uknsde H. Workman, M.D., 273 S. Bellevue, Memphis, Tenn., Obstetrician- Gynecologist, signed an affidavit which is quoted in part "When Mr. Walker approached me about Kevadon in late 1960, he told me that the drug was safe. Mr. Walker did not seem to know much else about the drug but he said that he would send me some literature which contained all of the necessary details. To the best of my knowledge Mr. Walker wanted me to try Kevadon to see how I liked it. I interpreted the program to be promotional rather than investiga- tionaL To the best of my knowledge I did sign a statement of investigator. I told Mr. Walker that I did not plan to enter into a formal investigation of Kevadori. I was informed that Merrell just wanted me to try the drug. It was my impres- sion that the drug had been proven safe and would be on the market in a few months. . . . During the period in which I was trying Kevadosi, I did not `submit any written reports to either Wm. S. Merrell Company or to any of their repre- sentatives. I do recall giving a verbal report on at least one instance to Mr. James M. Walker, Merrell representative. He asked me informally how I liked the drug, I told him it was the best sedative that I had run across. . . . It is my firm belief that the Wm. S. Merrell asked me to enter into this Kevadou program for promotional investigation reason PAGENO="0573" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4863 Appendix XIII A Study of Pharmaceutical Advertising in Selected Medical Journals (I-~ ~ THE LIBRARY OF CONGRESS WASHINGTON, D.C. 20540 10~~ ~ LEGISLATIVE REFERENCE SERVICE March 6, 1969 TO: Senate Subcommittee on Monopoly, Select Committee on Small Business FROM: Education and Public Welfare Division SUBJECT: Study of Pharmaceutical Advertising in Selected Medical Journals This is in reply to a request from the Chairman of the Sub- committee asking the Legislative Reference Service to undertake a de- tailed study of the patterns of pharmaceutical advertising appearing in selected medical journals over the last several years. The Chair- man also asked that we ascertain to what degree such advertising con- stitutes a source of revenue for these journals and the medical or- ganizations which publish then. We were also asked to proyide the Subcommittee staff with other m;terials showing the relationship be- tween the organizations which publish the journals analyzed in this report and the manufacturers who advertise in the journals studied. 1. The Advertising Survey Design At the direction of the Subcommittee staff, the Legislative Reference Service undertook a survey of the pharmaceutical and other advertising which appears in four medical journals, each of which is published by a different professional association of medical practi- tioners. The journals selected for the survey were: The Journal of the American Medical Association, published by the American Medical Association; The Journal of Abdominal Surgery, published by the Ameri- can Society of Abdominal Surgeons; The Annals of Internal Medicine, published by the American College of Physicians; and the American Family Physician, published by the American Academy of General Practice. The survey period covered a span of five years for each pub- lication, from January 1963 through December 1967. Each issue of each magazine was reviewed by the staff, except for four issues of ~ Journal of Abdominal Surgery during 1967 and the six issues of the PAGENO="0574" 4864 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY LRS-2 American Family Physician for 1963, and one issue of the Journal of the American Medical Association for 1963, which were unavailable for review. The review was made from the collected sets of these journals maintained by the Library of Congress and the National Library of Medicine. The data contained in this report were obtained fron a review of the advertising pages found in each journal and, in part, fron a re- view of the advertising index which each of these journals publishes in each issue. Where the advertising indices were used, careful exanination of the particular index was nade to assure that the information contained therein accurately reflected advertising copy appearing in the publica- tion. Where the indices were deemed unreliable, a page-by-page review was made of the issues under study. For some journals, a page-by-page review was necessary for every issue. The advertising copy found in the four journals was studied in sufficient detail in order to obtain information on the firms which ad- vertise in particular issues, the trade-names of the products advertised by these firms, the frequency with which some products appeared, and the volume of advertising copy devoted to the promotion of each product. Summary data were compiled for each journal, for each year, showing the journal page-to-advertising ratios of the magazine studied, and the distribution of pharmaceutical advertising to other advertising appearing in each magazine throughout the study period. In addition to the summary data, a detailed manufacturer and product survey for each year of each journal is contained in this report to the Subcommittee. In the case of the Journal of the American Medical Association and the Annals of Internal Medicine, the data gathered are so extensive, that additional summary data have been prepared showing the ten leading firms by volume of advertising for each year, the ten most frequently advertised products for each year, and the ten most heavily advertised products for each year, for each of these two journals. 2. The Survey Criteria Certain criteria were employed in carrying out the survey in order to determine which products would be specifically identified in the study. These criteria were adopted to select out that advertising in the four journals which could not properly be termed "pharmaceutical advertising." Advertising copy not satisfying the criteria used in the study are excluded from the detailed data representations appearing here- in, but are accounted for in the aggregate under the term "other journal advertising." Each page of each journal was classified into one of three categories: journal pages, pharmaceutical advertising, and other journal advertising. Journal pages represent the residual number of pages PAGENO="0575" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4865 LRS-3 remaining in any particular issue after pharmaceutical and other journal advertising are accounted for. Pages so counted are those devoted to articles, papers, indices, announcements, tables of contents, classified advertising, and other pages not otherwise counted in either of the other two categories. The term "other journal advertising", is used to account for non-medical trade advertising such as advertising copy promoting soaps, coffee, soft drinks, foods, and other similar products. Also included in this category are advertisements for medical devices and instrumen- tation, books, educational opportunities and courses, employment oppor- tunities except when they involve placement bureaus, and other service promotions. Institutional promotions, even for manufacturers whose prod- ucts may be otherwise included in the detailed survey, are also shown in this category. The term "pharmaceutical advertising" is intended to apply to prescription-legend drug products and to certain non-legend or over-the- counter items, including for example certain antacids, topical prepara- tions, and so on. Vitamin products and certain contraceptive agents are also identified in this category. Persons desiring to limit the detailed data to prescription-legend items only could do so simply by eliminating other products in the detailed analysis and by adding the number of pages for such products to the category of "other journal advertising." For the purpose of this study, any page which contains a com- mercial advertisement is considered a page of advertising, rather than a journal page. And, where two or more commercial advertisements are found on the same page, each is counted as a distinct page of advertising. This apportionment of advertising pages, however, does not alter substantially the conclusions from the survey, since the overwhelming majority of com- mercial advertisements are full-page promotions. To further test the validity of this method, a comparison was made between the results of the Anerican Medical Association's own study of advertising-to-editorial page ratio in their Journal with the results of this survey for the same time period. In a report found in the Journal, the following statement was made: The editorial-to-advertising pages ratio was ~/ Journal of the American Medical Association, Vol. 202, No. 1, October 2, 1967. PAGENO="0576" 4866 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY LRS-4 55:45 based upon the total of 6,864 pages published during this period [first 6 months of 1967]. Findings from the LRS survey, using the assumptions and criteria set forth above, produce a ratio of 56.2:43.8. We believe, therefore, that the data contained in this report fairly represent the volume and dis- tribution of advertising in the medical journals studied. 3. Organization of Report The summary and detailed data given in this report are arrayed by the particular journal surveyed. The Journal of the American Medical Association which is the largest of the four publications, in terms of volume of pages and circulation, is discussed in Part I of the report. Parts II, III, and IV are devoted to the Annals of Internal Medicin~ the American Family Physician, and the Journal of Abdominal Surgei~y, in that order. Each Part in the report begins with summary data covering the entire period of the survey for each journal studied. Among the data sunmiarized are the total pages published for each year, the total jour- nal pages, total advertising pages, total advertising pages classified as pharmaceutical advertising, and the total of other advertising pages. The data are also represented as percentages for each of these cate- gories for each year studied. Following the summary data, a detailed product survey for each year is given, showing the names of the manufacturers, the trade-names of the products advertised, the frequency of the products advertised, and the volume of copy devoted to each product. In the case of the Journal of the American Medical Association and the Annals of Internal Medicine, special annual summaries are given showing the leading firms which advertise in these two journals, the most frequently advertised products, and the most heavily advertised products appearing in the two journals. 4. Income from Advertising Revenue The Chairman asked that we attempt to ascertain to what degree advertising revenue constitutes a source of income for the nedical asso- ciations which publish the four journals surveyed in this study. We have obtained data showing this relationship only for the American Medical Association. Other publications by the remaining three organizations, insofar as they are available for review in the Library of Congress, PAGENO="0577" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4867 LRS-5 produced no usable data in this area. The staff of the Subcommittee has been advised of this finding, but we understand that sone of the data needed by the Subcommittee has been subnitted by the organizations thenselves. We have, therefore, included in this report only the infor.- nation on the American Medical Association. Should it be necessary to obtain comparable information for the other three organizations, direct inquiry to the associations probably will be required. Table 1 on the next page shows the total incone and income from advertising of the American Medical Association for the period 1961-1967. Table 2 shows the total income and income from exhibit space sales for the sane period. Income from exhibit space sales is'in~luded since many of those organizations which purchase such space are pharmaceutical manu- facturers who also advertise extensively in the publications of the Asso- ciation. Table 3 shows the sources of income of the American Medical Association by each source of income, including that obtained from adver- tising revenue. Table 4 gives the A.M.A.'s financial status for the six- year period 1962-1967. If there are any questions in connection with this report, please let us know. Glenn Markus Joe Licata Attachment Table I - Total Income, Income from Advertising, A.M.A., 1961-1967 Table II - Total Inoome, Income from Exhibit Space Sales, A.M.A., 1961-1967 Table III - Sources of AMA Income During 1961-1967 Table IV - American Medical Association Financial Position 1962-1967 Survey of Pharmaceutical Advertising in Selected Journals PAGENO="0578" 4868 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY LRS-6 TABLE 1 TOTAL INCOME, INCOME FROM ADVERTIS ING, A. M. A., 1961-19671/ ADVERTISING AS % ALL INCOME YEAR TOTAL INCOME ADVERTISING INCOME - 1961 $17,589,537 $ 8,906,993 51.0% 1962 19,524,435 9,017,383 47.0% 1963 22,516,013 10,122,065 45.0% 1964 23,110,239 10,356,640 44.8% 1965 27,772,879 12,770,825 46.0% 1966 27,759,623 13,290,714 47.9% 1967 31,677,215 13,565,106 42.8% TABLE 2 TOTAL INCOME, INCOME FROM EXHIBIT SPACE SALES, A.M.A., 1961-19671/ INCOME FROM EXHIBIT EXHIBIT INCOME YEAR TOTAL INCOME SPACE SALES AS % ALL INCOME 1961 $17,589,537 $664,753 2.0% 1962 19,524,435 605,104 3.0% 1963 22,516,013 577,092 2.6% 1964 23,110,239 638,471 2.8% 1965 27,772,879 832,341 3.0% 1966 27,759,623 782,680 2.8% 1967 31,677,215 730,646 2.3% 1/ Fron Reports of Annual or Clinical Conventions of the American Medical Association for each year. PAGENO="0579" SOURCES OF AMA INCOME DURING 1961-19671/ C t~j H 1965 ~t-4 At ____ ____ H 1961 Amount 1962 Amount 1963 Amount 1964 Amount Advertising $ Subscriptions Membership Dues Directory Report Service... Exhibit Space Sales Investments Miscellaneous Publications. Other Gross Income 8,906,993 (51) 6,475,289 (37) .~J 749,839 (6) 664,753 (2) 410,372 ~2) 382,291~ (2) .~ $ 9,105,636 (47) 2,533,995 (13) 5,483,388 (28) 776,615 (4) 605,104 (3) 666,320 (2) 353,377.~I(2) ±1 $10,122,065 (45.0) 2,713,269 (12.0) 7,210,680 (32.0) 822,089 (3.7) 577,092 (2.6) 597,086 (2.6) 473,7322.1(2.1) .~I $10,356,640 2,279,444 7,337,043 1,054,787 638,471 670,760 441,384 331,710 (44.8) (9.9) (31.7) (4.6) (2.8) (2.9) (1.9) (1.4) Total $17,589,537 $19,524,435 $22,516,013 $23,110,239 C H H Advertising $12,770,825(46.O) Subscriptions 2 316 535 (8 4) Membership Dues 7,446,612 (26.8) Directory Report Service... 1,241,980 (4.4) Exhibit Space Sales 832,341 (3.0) Investments 1,001,338 (3.6) Miscellaneous Publications. 1,862,024 (6.7) Other Gross Income 301,224 (1.1) Total $27,772,879 1966 Amount $13,290,714 (47.9) 2,436,550 (8.8) 7,508,058 (27.0) 1,451,451 (5.2) 782,680 (2.8) 824,739 (3.0) 1,144,254 (4.1) 321,177 (1.2) $27, 759, 623 1967 Amount $13,565,106 (42.8) 2,726,217 (8.6) 11,547,120 (36.5) 1,538,139 (4.8) 730,646 (2.3) 589,393 (1.9) 822,386 (2.6) 158,208 (.5) $31,677,215 L/ From Reports of Annual or Clinical Conventions of the American Medical Association for each year. Figures in parentheses are percentages of total income. 2/ Amount of Income from Membership Dues included in Subscriptions. 3/ Shown only as "miscellaneous income" for the years 1961-1963. 4/ No "other income" reported for 1961-1963. PAGENO="0580" AMERICAN MEDICAL ASSOCIATION FINANCIAL POSITION 1962-19671/ 1962 ASSETS Cash $ 600,973 Accounts and notes receivable 876,274 Inventories and prepaid expenses.... 691,316 Building and equipment 4,489,752 Investments and other assets 8,367,660 ___________ ___________ TOTAL $15,025,975 LIABILITIES Accounts Payable $ 967,623 Income Received but not yet earned.. 1 684 823 ___________ ___________ TOTAL $ 2,652,446 NET WORTH $12,373,529 ASSETS Cash $ 271,206 Accounts and notes receivable 856,402 Inventories and prepaid expenses.... 1,704,330 Building and equipment 8,946,458 Investments and other assets 6,424,119 __________ __________ TOTAL $18,202,515 1963 1964 $ 109,794 844,605 741,584 5,237,299 10,636,581 $17,569, 863 $ 1,112,914 1,721,021 $ 2,833,935 $ 117,989 953,021 890,900 7,420,071 8,688, 685 $18,070,666 $ 1,650,682 1,920, 765 $ 3,571,447 ********* ** 1965 $14,735,928 $14,499,219 1966 1967 Co $ 353,652 1,151,498 1,550,382 9,275,467 7,095,887 $19, 426,886 $ 234,524 1,150, 304 1,498,944 9,260,808 11,102,365 $23,246,945 LIABILITIES Accounts Payable $ 1,844,057 Income Received but not yet earned.. 2,051,124 TOTAL 3,895,181 NET WORTH $14,307,334 $ 1,715,381 $ 1,909,609 2,030, 126 2,325,726 $ 3,745,507 $ 4,235,335 $15,681,379 $19,011,610 1/ From Reports of Annual or Clinical Conventions of the American Medical Associa- tion for each year. PAGENO="0581" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4871 SURVEY OF PHARMACEUTICAL ADVERTISING IN SELECTED JOURNALS TABLE OF CONTENTS Part I The Journal of the American Medical Assotiation pages 1. Summary Data: 1963-1967 1 2. Year: 1963 a. 10 Leading Firms, by Advertising Volume 2 b. 10 Most Frequently Advertised Drugs 2 c. 10 Most Heavily Advertised Drugs 2 d. Detailed Product Data 3 3. Year: 1964 a. 10 Leading Firms, by Advertising Volume 15 b. 10 Most Frequently Advertised Drugs 15 c. 10 Most Heavily Advertised Drugs 15 d. Detailed Product Data 16 4. Year: 1965 a. 10 Leading Firms, by Advertising Volume 27 b. 10 Most Frequently Advertised Drugs 27 c. 10 Most Heavily Advertised Drugs 27 d. Detailed Product Data 28 5. Year: 1966 a. 10 Leading Firms, by Advertising Volume 40 b. 10 Most Frequently Advertised Drugs 40 c. 10 Most Heavily Advertised Drugs 40 d. Detailed Product Data 41 PAGENO="0582" 4872 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 6. Year: 1967 pages a. 10 Leading Firms, by Advertising Volume 52 b. 10 Most Frequently Advertised Drugs 52 c. 10 Most Heavily Advertised Drugs 52 d. Detailed Product Data 52 Part II The Annals of Internal Medicine 1. Summary Data: 1963-1967 62 2. Year: 1963 a. 10 Leading Firms, by Advertising Volume 63 b. 10 Most Heavily Advertised Drugs 63 c. Detailed Product Data 64 3. Year; 1964 a. 10 Leading Firms, by Advertising Volume 71 b. 10 Most Heavily Advertised Drugs 71 c. Detailed Product Data 72 4. Year: 1965 a. 10 Leading Firms, by Advertising Volume 79 b. 10 Most Heavily Advertised Drugs 79 c, Detailed Product Data 80 5. Year: 1966 a. 10 Leading Firms, by Advertising Volume 87 b. 10 Most Heavily Advertised Drugs 87 c. Detailed Product Data 88 PAGENO="0583" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4873 6. Year:, 1967 a. 10 Leading Firms, by Advertising Volume 96 b. 10 Most Heavily Advertised Drugs 96 c. Detailed Product Data 9.7 Part III The American Family Physician 1. Summary Data: 1963-1967 104 2. Year: 1963 105 3. Year: 1964 107 4. Year: 1965 110 5. Year: 1966 113 6. Year: 1967 116 Part IV Th.e Journal of Abdominal Surgery 1. Summary Data: 1963-1967 120 2. Year: 1963 121 3. Year:, 1964 122 4. Year: 1965 123 5. Year; 1966 12~ 6. Year: 1967 125 iii PAGENO="0584" *Based on review of 5lof 52 issues published in 1963. JOURNAL OF AMERICAN MEDICAL ASSOCIATION SUMMARY DATA Advertising, 1963 through 1967 4874 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Volume in Pages Total Pages Year Magazine Total Pages Journal Total Pages Advertising Total Pages Drugs Advertising Total Pages Other Advertisi'~ 1963* 12,418 6,548 5,870 4,526 1,344 1964 12,702 6,863 5,839 4,650 1,189 1965 13,438 7,244 6,194 5,149 1,045 1966 14,286 7,664 6,622 5,354 1,268 1967 13,332 Total... 66,176 7,501 35,820 5,831 30,356 4,964 24,643 867 5,713 Percentag~ Year Percent Total Pages Percent Journal Pages Percent Advertising Pages Drug Advertising as Percent All Advertising as Percent All Advertising 1963* 100.0% 52.7% 47.3% 77.1% 22.9% 1964 100.0% 54.0% 46.0% 79.6% 20.4% 1965 100.0% 53.9% 46.1% 83.1% 16.9% 1966 100.0% 53.6% 46.4% 80.8% 19.2% 1967 Total... 100.0% 100.0% 56.2% 54.1% 43.8%_ 45.9% 85.1%, 81.1% 14.9% 18.9% 1 PAGENO="0585" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4875 THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION SUMMARY DATA 1963* 10 Leading Firms, by Volume of Advertising RANK FIRM NO. DRUG ADVERTISING PAGES 1 2 Wallace Laboratories Merck, Sharpe, & Dohme 524 457 3 Warner-Chilcott 239 4 Abbott Laboratories 192 5 Lederle Laboratories 174 6 Upjohn 163 7 Wyeth Laboratories 158 8 Burroughs-wellcome 157 9 Lilly 145 10 Pfizer 144 RANK 1 2 3 4 5 6 7 8 9 10 10 Most Frequently Advertised Drugs ISSUES IN WHICH ADVERTISED DRUG NO. Deprol (Wallace) Miltown Wallace) Meprospan (Wallace) Appertrol (Wallace) Sums (Wallace) Capla (Wallace) Aldomet (Merck) Miltrate (Wallace) Tepanil (National) Orinase (Upjohn) so so 48 40 38 34 33 33 33 31 RANK 1 2 3 4 S 6 7 8 9 10 10 Most Heavily Advertised Dr~~ DRUG NO. Peritrate (Warner-Chilcott) Aldomet (Merck) Miltown (Wallace) Deprol (Wallace) Diuril/Hydrodiuril (Merck) Capla (Wallace) Orinase (Upjohn) Orenzyme/Parenzyme (National) Neprospan (Wallace) Darvon (Lilly) PAGES ON WHICH ADVERTISED 97 96 93 89 67 64 64 54 49 48 *Based on a review of 51 of 52 issues published in 1963. 2 81-280 0-69-pt. ll-38 PAGENO="0586" 4876 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 19 63* COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Laboratories 1. Compocillin-VK 8 16 2. Desbutal 11 21 3. Desoxyn 12 24 4. Enduron 2 8 5. Enduron/Eutonyl 2 10 6. Erythocin 13 28 7. Eutonyl 8 28 8. Nembutal 4 8 9. Norisodrine 10 14 10. Placidyl 3 3 11. Quelidrine 2 2 12. Radio pharmaceuticals 9 9 13. Selsun 3 3 14. Surbex-T 13 13 15. Various 1 1 16. Vi-Daylin 2 4 Total... 192 Arch Laboratories 1. Dicarbosil 10 Total... 10 Armour 1. Acthar 6 6 2. Chymar 10 10 3. Chymoral 12 26 4. Listica 4 5 5. Thyroid 4 6 Total... 53 Ayerst Laboratories 1. Gristactin 6 12 2. Mesulf in 1 2 3. Premarin 6 10 4. Thiosulfil 5 14 Total... 38 Breon Laboratories 1. Bronkometer - 12 12 2. Bronkotabs 11 _J:~;L_~ Total... 23 * Based on review of 51 of 52 issues published in 1963. PAGENO="0587" COMPANY CIBA Pharmaceutical Davies, Rose, Hoyt De~itin Chemical 1. Kantrex 1. Aerosporin 2. Antepar 3. Cardilate 4. Cardilate-P 5. Empirin 6. Lanoxin 7. Leukeran 8. Mantadil 9. Migral 10. Nyleran 11. Narezine 12. Perazil 13. Purinethol 1. Esidrex/Esidrex-K 2. Doriden 3. Ismelin 4. Serpasil 5. Vioform 1. Digitalis 2. Quinidine sulfate 1. Come-dab 2. Cort-Dome 3. Cor-Tar-Quin/others 4. Neo-Domeform 1. Desitin ointment 4 Total... 8 8 20 10 8 15 24 12 6 4 12 23 3 12 Total... 157 30 34 24 23 13 Total... 124 3 3 3 3 Total... 6 4 4 6 6 3 3 2 2 Total... 15 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4877 PRODUCT Bristol Laboratories Burroughs-Wellcome NO. ISSUES NO. PAGES 8 20 7 7 12 12 11 6 4 11 23 3 11 19 23 11 21 12 Dome 11 Total... 12 4 PAGENO="0588" 4878 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Eaton Laboratories 1. Furacin 27 29 2. Furadantin 21 25 3. Tricofurcn 12 12 Total... 66 Endo Laboratories 1. Coumadin 26 43 2. Hycodan 10 10 3. Numorphan 22 22 4. Percodan 10 10 5. Valpin/Valpin-PB 16 24 Total... 109 Flint, Eaton, & Co. 1. Synthroid 9 Total... 9 1. Butazolidin 10 10 2. Persantin 6 18 Total... 28 Glenbrook Laboratories 1. Bayer Aspirin 7 7 2. Philips Milk of Magnesia 6 6 Total... 13 Hynson, Westcott, & Dunning 1. Broniosulphalein 4 4 2. Lactinex 1 1 3. Lutrexin 6 6 Total... 11 Holland-Rantos 1. Nylmerate 6 Total... 6 Ives Laboratories 1. Cyclospasmol 16 19 2. Isordil 12 16 Total... 35 Johnson & Johnson 1. Liquiprin 5 Total... 5 PAGENO="0589" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4879 COMPANY PRODUCT NO. ISSUES NO. PAGES ~y Pharmaceuticals 1. Nitroglyn 7 Total... 7 Lakeside Laboratories 1. Imferon 14 Total... 14 Leeming, Thomas 1. Metamine 8 Total... 8 Lederle Laboratories 1. Achromycin 16 25 2. Aristocort 14 28 3. Bainadex 10 15 4. Declomycin 20 40 5. Ferro-Sequels 10 10 6. Hydromox 14 28 7. Orimune 4 8 8. Pathibamate 11 21 Total... 175 Lilly, Eli 1. Anhydron/w/K, KR 2 8 2. Darvon 26 48 3. Haldrone 12 40 4. Ilosone 16 18 5. Novrad 5 17 6. Quintess 2 2 7. V-Cillin-K 9 12 Total... 145 1. Doxidan 4 Total... 7 Mallinkrodt Chemical 1. Codeine 12 Total... 12 Mead Johnson 1. Beta-Chlor 13 15 2. Mucomyst 1 3 3. Quibron 9 18 4. Vasodilan 16 16 Total... 52 McNeil Laboratories 1. Butisol 14 Total... 27 6 PAGENO="0590" 4880 ~o~jpETITIvE PROBLEMS I~ THE DRTJG INDUSTRY C0MP~ANY PRODUCT NO. ISSUES NO. PAGES Merck, Sharpe, & Dohme 1. Aldomet 33 96 2. Aldomet/Rubeovax 1 2 3. Aldoril 11 21 4. Aramine 7 14 5. Benemid/Colbenemid 5 20 6. Codeine 1 1 7. Cuprimine 4 4 8. Decadron 21 34 9. Decagesic 25 30 10. Diuril/Hydrodiuril 20 67 11. Diupres 13 17 12. Elavil 13 26 13. Hydropres 15 20 14. Mephyton/Aquamephyton 9 11 15. Periactin 7 7 16. Redisol/AipharedisOl 16 16 17. Respihaler some WI Xylocaine 24 47 18. Rubeovax/Gaminagee 11 19 19. Urecholine 5 5 Total... 457 Merrell, Wm. S. 1. Bentyl 4 8 2. Tenuate 13 13 Total... 21 National Drug 1. Orenzyme/Parenzyme 27 54 2. Parenzyme 3 6 3. Tepanil 33 41 4. Vaccines (various) 13 13 Total... 114 1. Hexadrol 6 Total... 6 Ortho 1. Ortho-Novuni 4 Total... 4 7 PAGENO="0591" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4881 Parke-Davis Pfizer, Chas. Purdue-Frederick 1. Benadryl 2. Chioromycetin 3. Dilantin 4. Elase 5. Norlutate 6. Pitocin 7. Povan 1. Diabinese 2. Renese 3. Terramycin~ 4. Vistaril 1. Jefron 2. Novahistine DH 3. Novahistine Elixir 4. NovahistineLp 5. NovahistineMelet 6. Novahistine Singlet 1. Silain/Sibel 2. St. Joseph's Aspirin 1. Mudrane 2. Trocinate 3. Synirin 4. Solfoton 1. Cardioquin 2. Paremycin 3. Senokot 20 44 17 1 9 12 4 Total... 107 22 44 16 32 21 44 12 24 Total... 144 16 11 4 11 4 5 Total... 51 2 12 Total... 14 14 15 4 4 1 1 7 7 Total... 27 4 4 5 5 16 16 Total... 25 COMPANY PRODUCT NO. ISSUES NO. PAGES 10 25 9 1 9 12 4 Pittman-Moore Plough, Inc. Polythress, Wa. P. 9 7 2 7 2 3 2 12 8 PAGENO="0592" 4882 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMRANY PRODUCT NO. ISSUES NO. PAGES Radium Chemical 1. Radium 12 Total... 12 Riker Laboratories 1. Medihaler-Duo 11 22 2. Norflex 8 16 3. Rauwiloid 2 4 4. Ulo 4 7 Total... 49 Robins, A. H. 1. £Ambar 3 3 2. AllBee w/C 6 6 3. Dimetane 10 13 4. Donnatal 12 15 5. Naclex 4 8 6. Robaxin 11 18 7. Robaxisal 3 5 8. Robinul/Robinul-PH 7 11 9. Skelaxin 5 10 Total... 89 Roche Laboratories 1. Alurate 1 1 2. Gantrisin 6 6 3. Gantanol 1 4 4. Librium 17 26 5. Nestinon 2 4 6. Nadribon 2 4 7. Roniacol 1 1 8. Taractin 11 11 9. Tigan 4 4 10. Valium 2 10 Total... 71 Roerig, J. B. & Comp~ 1. Atarax 7 15 2. Antivert 14 14 3. Enarax 7 15 4. Narax 12 12 5. Tao 12 32 Total... 88 9 PAGENO="0593" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4883 COMPANY PRODUCT NO. ISSUES NO. PAGES Rorer, Wa. H. Sandoz Pharmaceutical Schering Corporation Searle, G. D. Schmid, Julius Sherman Laboratories 1. Ananase 13 22 2. Maalox 5 5 Total... 27 1. Cafergot/Cafergot-PB 6 6 2. Fiorinal 4 4 3. Mellaril 19 19 4. Sansert 26 Total... 26 55 1. Celestone 4 8 2. Chlortrimeton 16 16 3. Coricidin 7 7 4. Fulvicin 6 9 5. Meticorten 2 2 6. Naqua 9 9 7. Naquival 9 9 8. Rela 10 10 . Total... 70 1. Aldactazide/Aldactone 6 6 2. Dramamine 6 6 3. Enovid 9 14 4. Flagyl 8 14 5. Lomotil 10 10 6. Nilevar 1 1 7. Pro-Banthine 23 Total... 23 74 1. Imolin 5 5 2. Vagesic 8 Total... 8 13 1. Elixophyllin 9 Total... 13 10 PAGENO="0594" 4884 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CONPANY PRODUCT NO. ISSUES NO. PAGES Smith, Kline, & French 1. Compazine 9 2. Dexedrine 6 6 3. Parnate 18 18 4. Stoxil 4 8 5. Thorazine 12 12 6. Various 2 2 Total... 55 Squibb 1. Delautin 7 12 2. Delestrogen 6 12 3. Deluteval 3 6 4. Feramel 3 3 5. Fungizone 5 5 6. Kenalog 2 2 7. Mycolog 6 6 8. Mysteclin 10 10 9. Naturetin 8 12 10. Noctec 6 6 11. Pentids 6 6 12. Prolixin 15 17 13. Rautrax-N 10 10 14. Raudixin 4 4 15. Theratuss 8 10 16. Theragran 7 19 Total... 140 Strassenburgh Laboratories 1. Biphetamine/lonamin 12 22 2. Biphetamine-T 5 6 3. Metropine 4 8 4. Omnituss 12 16 5. Tussionex 9 9 Total... 61 Stuart 1. Dialose 2 2 2. Mulvidren 3 3 3. Mylanta 14 14 4. Mylicon 3 3 Total... 22 11 PAGENO="0595" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4885 COMPANY PRODUCT NO. ISSUES NO. PAGES Syntex 1. Synalar 12 Total... 25 Trent Pharmaceuticals 1. Tocosamine 12 Total... 12 Upjohn 1. Didrex 1 1 2. Depo-Medrol 5 11 3. Depo-Provera 13 13 4. Medrol Veriderm 16 47 5. Medrol 7 12 6. Orinase 31 64 7. Provera 15 15 Total... 163 U.S. Vitamin & Pharmaceutical 1. Arlidin 8 8 2. Aquasol 4 4 3. Dexemeth 8 13 4. DBI-TD 10 10 5. Emivan 6 6 Total... 41 Towne 1. Various 2 Total... 2 Wallace Laboratories 1. Appertrol 40 40 2. Capla 34 64 3. Caplaril 8 32 4. Deprol 50 89 5. Meprospan 48 49 6. Milpath 28 31 7. Milprem 18 18 8. Miltown 50 93 9. Miltrate 33 33 10. Soma 38 42 11. Soma Compound 17 17 12. Somacort 16 16 Total... 524 12 PAGENO="0596" 4886 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CONPANY PRODUCT NO. ISSUES NO. PAGES Wampole 1. Vo-Sol 11 Total... 11 Warner-Chilcott 1. Amphocortrin 6 18 2. Colymycin 16 36 3. Gelusil 17 22 4. Nandelamine 12 24 5. Papase 15 30 6. Peritrate 26 97 7. Tedral 6 12 Total... 239 White Laboratories 1. Asperguin 22 22 2. A&D 23 23 3. Cod Liver Oil Tabs 14 14 4. Disophrol 1 2 5. Gitaligin 24 24 Total... 85 Winthrqp 1. Creamalin 2 2 2. Isuprel 9 9 3. Neo-Synephrine 6 6 4. Nebaral 5 5 5. Telepaque 1 1 6. Trancogesic 11 11 7. Trancopal 6 6 8. Winstrol 11 11 9. WTZ 1 1 Total... 52 Wyeth Laboratories 1. Bicillin 10 19 2. Cyclamycin 7 14 3. Equagesic 13 23 4. Equanil 12 35 5. Equanitrate 8 8 6. ~1epergan 5 7 7. Pen-Vee-K 8 11 8. Polymagna 3 3 9. Phenergan 3 3 10. Prozine 1 1 11. SMA 10 18 12. Sparine 8 13 13. Zactirin 3 3 Total... 158 13 PAGENO="0597" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4887 1. Aininophylline 2. Histadur 3. Nuina 4. Quinaglute 2 2 6 6 8 8 22 22 Total... 38 CONPANY ~ynn Pharmacal PRODUCT NO. ISSUES NO. PAGES 14 PAGENO="0598" 4888 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Summary Data 1964 10 Leading Firms, by Volume of Advertisip~ No. Drug Advertising ~ Wallace Laboratories 585 Merck, Sharpe, & Dohme 522 Warner-Chilcott 267 Upjohn 214 Roche Laboratories 189 CIBA 154 Schering Corporation 152 Abbott Laboratories 148 Burroughs-WellcOme 145 Lederle 145 Firm Rank 1 2 3 4 5 6 7 8 9 10 Rank 1 10 Most Frequently Advertised Dr~g~ No. Issues in which Advertised Miltown (Wallace) 52 2 Meprospan (Wallace) 51 3 Deprol (Wallace) 50 4 Soma/Soma Compound (Wallace) 49 5 6 Diuril/Hydrodiuril 37 Neggram (Winthrop) 34 7 Valium (Roche) 34 8 Elavil (Merck) 32 9 Vioform (CIBA) 31 10 Miltrate (Wallace) 29 Rank 1 10 Most Heavily Advartised Dr~gR No. Pages on which Advertised Soma/Soma Compound (Wallace) 129 2 Diuril/Hydrodiuril (Merck) 119 3 Miltown (Wallace) 110 4 Deprol (Wallace) 100 5 Peritrate (Warner-Chilcott) 97 6 Neggram (Winthrop) 79 7 Valium (Roche) 68 8 Elavil (Merck) 67 9 Celestone (Schering) 61 10 Thyroid (Armour) 61 15 PAGENO="0599" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4889 THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 1964 PRODUCT 1. Desbutal 2. Descixyn 3. Enduron/Eutonyl 4. Eutonyl 5. Erythocin 6. Nembutal 7. Rad:to pharmaceuticals 8. Selsun 9. Surbex-T 10. Triosorb 1. Dicarbisol 1. Chyinoral 2. Thyroid ___________________________ Inc. IXylocaine ____________________ 1. Mesulfin 2. Penbritin* 3. Premarin 4. Spartocin 5. Thiosulfil Forte _____________________ 1. Polycillin *Distributed by Ayerst for Beecham Laboratories, 16 Inc. 10 21 9 18 3 13 10 30 16 32 11 11 6 6 2 2 12 12 3 3 Total... 148 12 Total... 12 3 6 15 61 Total... 67 3 Total... 6 7 14 4 18 16 17 3 9 3 6 Total... 64 15 Total... 41 CONPANY NO. ISSUES NO. PAGES Abbott Laboratories Arch Laboratories Armour Pharmaceuticals Astra Pharmaceutical Products, 1. Ayerst Laboratories bristol Laboratories PAGENO="0600" 4890 COMPETITIVE PROBLEMS fl~T TEE DRuG INDUSTRY COMPANY PRODUCTS NO. ISSUES NO. PAGES Burroughs Weilcome and Co., Inc. 1. Antepar 12 12 2. Aerosporin 10 10 3. Alkeran 7 7 4. Cardilate 13 13 5. Cardilate-P 9 9 6. Cortisporin 3 3 7. Empirin 5 5 8. Lanoxin 13 22 9. Leukeran 10 10 10. Mantadil 5 5 11. Marezine 20 20 12. Myleran 10 10 13. Nigral 2 2 14. Neosporin 4 4 15. Perazil 3 3 16. Purinethol 10 10 Total... 145 CIBA Pharmaceutical 1. Esidrex/Esidrex-K 17 34 2. Doriden 7 7 3. Pyribenzatnine 13 13 4. Ritalin 19 26 5. Serpasil 26 34 6. Vioform 31 40 Total 154 Davies, Roae-Ro~t and Co. (Division of Kendall) 1. Quinidine/Digitalis 2 2 2. Quinidine sulfate 1 1 Total... 3 Dome Chemicals, Inc. 1. Doinol 1 1 2. Cort-Dome 7 7 3. Cor-Tar-Quin 2 2 4. Domeboro 2 2 Total... 12 17 PAGENO="0601" Endo Laboratories Rynson, Westcott, and Dunning 1. 2. Ives Laboratories 1. Furacin 2. Furadantln 1. Coumadin 2. Hycodan 3. Nutnorphan 4. Percodan 5. Valpin/Valpin-PB BSP Lactinex 1. Cyclospasinol 2. Isordil NO. PAGES 17 30 Total... 47 36 8 16 11 6 Total... 77 12 13 Total... 32 7 7 6 Total... 13 2 2 11 Total... 13 16 16 13 13 Total... 29 4 Total... 4 14 14 12 12 3 6 Total... 32 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4891 Eaton Laboratories COMPANY PRODUCT NO. ISSUES 15 15 18 7 16 11 6 7 6 13 Geigy Chemical Corporation Glenbrook Laboratories 1. Butasolidin 2. Preludin 3. Regroton 1. Rayer Aspirin 2. Philips Milk of Magnesia Key Pharmaceuticals Lakeside Laboratories, 1. Inc. 1. 2. 3. Nitroglyn Cantil Imferon Norpramin 18 81-280 0-69-pt. 11-39 PAGENO="0602" 4892 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Lederle Laboratories 1. Achromycin 1 2 (Division of American 2. Aristocort 12 24 Cyanimid) 3. Amicar 3 16 4. Bamadex 10 18 5. Declomycin 17 24 6. Perro Sequels 9 9 7. Hydroniox 17 24 8. Orimune 2 4 9. Pathibamate 13 14 Total... 145 Lilly, Eli & Compai~y 1. Anhydron 12 16 2. Darvon Compounds 18 21 3. Dymelor 5 5 4. Ilosone 14 16 5. V-Cillin K 14 14 Total... 72 1. Doxidan 4 Total... 6 Mallinkrodt Chemical 1. Codeine 1 Total... 2 McKesson Laboratories 1. Various 1 1 2. Tetracycline 2 2 Total... 3 McNeil Laboratories 1. Butisol 25 25 2. Tylenol 14 14 Total... 39 Nead Johnson 1. Nucomyst 1 2 2. Vasodilan 21 21 Total... 23 Nerrell, William 5. 1. Bentyl 10 10 2. Bendectin 10 10 3. Tenuate 9 9 Total... 29 Miles Products 1. Alkaseltzer 12 Total... 12 (Division of Niles Laboratories) 19 PAGENO="0603" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4893 1. Aldomet 2. Aldoril 3. Aramine 4. Benemid/Colbenemid 5. Codeine~ 6. Cyclex 7. Decadron 8. Decagesic 9. Diuril/Hydrodiuril 10. Diupres 11. Dornavac 12. Elavil 13. Hydrodiuril-KA 14. Hydropres 15. Hydropres-KA 16. Mephyton 17. Periactin 18. Respihaler Decadron 19. Redisol/Alpharedisol 20. Rubeovax 21. lJrecholine 1. Orenzyme 2. Tepanil 1. Durabolin 2. Deca-Durabolin 3. Hexadrol 1. Ortho-Novum 20 NO. ISSUES NO. PAGES 12 27 22 43 12 22 25 38 2 2 6 6 21 39 13 13 37 119 17 17 3 6 32 67 10 10 12 12 5 5 19 20 18 18 12 22 15 15 5 9 12 12 Total... 522 4 12 Total... 16 17 17 3 3 8 Total... 28 5 Total... 8 PRODUCTS COMPANY Merck, Sharpe, & Dohme National Drug Organon Ortho 4 10 PAGENO="0604" 4894 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY CONPANY NO. ISSUES NO. PAGES Parke-Davis 1. Adroyd 3 3 2. Benylin expectorant 1 1 3. Benadryl 23 36 4. Chloromycetin 2 2 5. Dilantin 26 38 6. Norlestrin 18 36 7. Nidicel 3 3 8. Pitocin 5 5 Total... 124 Pfizer, Chas. 1. Daricon 9 18 2. Desitin* 7 10 3. Diabinase 10 26 4. Terra-Cortil 5 10 5. Terramycin 10 22 6. tJroscreen 2 4 7. Vistaril 22 44 Total... 134 Pittman-Hoore Company 1. Jefron 4 8 2. Novahistine DH 14 20 3. NovahIstine LP 1 1 4. Novahistine TMelet 4 5 5. Novahistine Singlet 5 6 Total... 40 Plough Inc. 1. St. Josephts Aspirin 12 Total... 12 Polythress.. Wa. P. 1. Nudrane 6 7 2. Solfo-Serpine 10 10 Total... 17 Purdue/Frederick 1. Otalgine 4 4 2. Parelixir 4 4 3. Senokot 10 10 Total... 18 Radium Chemical 1. Radium 12 Total... 12 21 PAGENO="0605" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4895 1. Medihaler-Duo 2. Norflex 3. Norgesic 4. Titralac 1. Ambar 6 2. AllBee W/C 9 3. Dimetane 9 4. Dimetapp 1 5. Donnatal 12 6. Exna 5 7. Robaxin 7 8. Robinul 4 9. Robinul.Vorte/Forte-PH 4 10. Quinidex 13 11. Skelaxin 2 12. Robaxisal 3 1. Gantanol 2. Librax 3. Librium 4. Roniacol 5. Taractin 6. Valium 1. Atarax 2. Antivert 3. Enarax 4. Narax 5. Tao NO. PAGES 18 6 16 8 Total... 48 6 9 14 1 15 10 11 8 8 13 4 6 Total... 105 30 21 38 18 14 68 Total... 189 13 6 4 12 22 Total... 57 24 4 Total... 28 COMPANY PRODUCTS NO. ISSUES 9 4 7 4 Riker Laboratories Robins, A.H. Roche Laboratories Roerig, J.B. & Company 8 18 15 9 14 34 6 6 4 8 11 11 4 Rorer, Wm. II., Inc. 1. Ananase 2. Naalox 22 PAGENO="0606" 4896 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCTS NO. ISSUES NO. PAGE~ Squibb 1. Feramel 2 2 2. Fungizone 1 1 3. Kenacort 12 16 4. Kenalog 6 10 5. Medotopes 2 4 6. Mycolog . 4 4 7. Mysteclin-F 7 7 8. Naturentin w/K 4 4 9. Noctec 9 9 10. Pentids 400 6 6 11. Prolixin 10 10 12. Raudixin 10 22 13. Rautrax-N 6 9 14. Theragran 6 15 15. Theratuss 6 6 Total... 125 Strassenburgh Laboratories 1. Biphetamine-T 7 9 2. Biphetamine/Tonamin 6 12 3. Omnituss 6 8 4. Tussionex 7 7 Total... 36 Stuart 1. Nylanta 18 24 2. Softab 2 2 Total... 26 Syntex 1. Norinyl 18 Total... 43 Trent Pharmaceuticals 1. Tocosamine 3 Total... 3 U.S. Vitamin & Pharmaceuticals 1. Aquasol-A 1 1 2, Arlidin 12 12 3. DBI/DBI-~TD 13 14 4. Dexameth 4 4 5. Emivan 6 7 Total... 38 23 PAGENO="0607" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4897 CONPANY PRODUCTS NO. ISSUES NO. PAGES Sandoz Pharmaceutical 1. Belladenal 1 1 2. Fiorinal 17 17 3. Mellaril 25 25 4. Sansert 14 14 Total... 57 Schering Corporation 1. Afrin 13 26 2. Celestone 24 61 3. Chlortriiñeton 15 15 4. Coricidin 5 9 5. Demazin 5 5 6. FulvIcin 14 22 7. Rela 7 14 Total... 152 Schmid, Julius, Inc. 1. Candeptin, 1 2 2. tmmolmn 4 4 3. Vagesic 5 Total... 11 Searle,G.D. 1. Anavar 7 14 2. Aldactazide 10 10 3. Dramamine 5 6 4. Enovid 6 6 5. Enovid-E 11 15 6. Enovid/EnovJd-E 6 8 7. Flagyl 7 8 8. Lomotil 9 9 9. Pro-BanthIñe 17 20 Total... 96 Sherman Laboratoriec 1. Exlisophyllin 11 Total... 12 Smith, Kline, & French. 1. Dyrenium 12 23 2. Parnate 3 3 3. Stelazine 17 17 4. Thorazine 18 18 Total... 61 24 PAGENO="0608" 4898 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCTS NO. ISSUES NO. PAGES Upjohn 1. Depro-Nedrol 4 8 2. Didrex 13 26 3. Medaprin 13 26 4. Nedrol 13 26 5. Neo-Nedrol Veridem 10 21 6. Orinase 24 46 7. Provera/Depo-Provera 17 33 8. Provest 5 18 9. Painine 2 4 10. Solu-Nedrol 3 Total... 214 Wallace Laboratories 1. Capla 13 21 2. Caplaril 17 41 3. Deprol 50 100 4. Neprospan 51 51 5. Niltown 52 110 6. Miltrate 29 29 7. Nilpath 23 41 8. Nilprem 16 16 9. PreeMI 20 - 29 10. Soma/Soma Compound 49 129 11. Somacort 13 18 Total... 585 Warren-Teed 1. Meprobamate 3 Total... 3 Warner-Chilcott 1. Amphocortrin 6 6 2. Colymycin 20 40 3. Gelusil 18 27 4. Mandelamine 17 57 5. Papase 2 4 6. Peritrate 26 97 7. Sinutab 13 22 8. Tedral 11 14 Total... 267 Wampole 1. Vosol 9 Total... 9 WTest~-Ward 1. Meprobamata 3 Total... 3 25 PAGENO="0609" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4899 COMPANY PRODUCTS NO. ISSUES NO. PAGES White Laboratories 1. Disophrol 2. Permitil 10 7 13 14 Total... 27 Winthrop Wynn Pharniacal 1. Isuprel 10 10 2. Mebaral 4 4 3. Neggrani 34 79 4. Neo-Synephrmne 5 5 5. Phisohex 2 2 6. Telepaque 3 3 7. Trancogesic 10 10 8. Trancopal 8 16 9. Winstrol 7 Total... 7 136 1. Bicillin 7 14 2. Cyclamycin 2 2 3. Equagesic 11 20 4. Equanil 9 17 5. Nepergan 2 2 6. Oxaine N 5 12 7. Pen-Vee-4C 2 2 8. Phenergan 4 5 9. Polyinagna 3 4 10. Sparine 4 8 11. lJnIpen 9 26 12. Zactirin Coinp. 4 Total... 122 1. Aininophylline 7 7 2. Numa 9 9 3. Quinaglute 23 23 26 PAGENO="0610" 4900 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Summary Data 1965 10 Leading Firms by Volume of Advertising Rank Firm No. Drug Advertising Pages 1 Merck, Sharpe & Dohme 609 2 Warner-Chilcott 590 3 Wallace Laboratories 381 4 Roche Laboratories 295 5 CIBA 208 6 Wyeth Laboratories 189 7 Upjohn 172 8 Lilly 144 9 Lederle 128 10 Robins, Burroughs-Wellcome 121 10 Most Frequently Advertised Drugs No. Issues in which Advertised No. Pages Rank 1 Pre-Sate (Warner-Chilcott) 159 2 Peritrate (Warner-Chilcott) 145 3 Miltown/Meprospan (Wallace) 107 4 Valium (Roche) 95 5 Indocin (Merck) 82 6 Diuril (Merck) 77 7 Soma (Wallace) 73 8 Polycillin (Bristol) 62 9 C-Quens (Lilly) 56 10 Pyribenzamine (CIBA) 56 Rank 1 2 3 4 5 6 7 8 9 10 Miltown (Wallace) Soma (Wallace) Milpath (Wallace) Diuril (Merck) Elavil (Merck) Neggram (Winthrop) Pre-Sate (Warner-Chilcott) Polycillin (Bristol) Pyribenzamine (CIBA) Gelusil (Warner-Chilcott) 10 Most ~ 50 41 39 39 35 33 32 32 31 29 ~ Dru~ on which Advertised 27 PAGENO="0611" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4901 THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 1965 Arch Laboratories Armour Pharmaceuticals 1. Desbutal 2. Desoxyn 3. Enduron 4. Erythocin 5. Eutonyl 6. Eutron 7. Nembutal 8. Radio pharmaceuticals 9. Surbex-T NO. PAGES 24 12 6 15 15 5 24 12 14 104 13 12 Astra Pharmaceutical Products, Inc. Ayerst Laboratories 1. Xylocaine 1. Penbritin* 2. Premarin 3. Thiosulfil 4. Riopan Forte 1. Polycillin (injectables and oral) 2. Tegopen 3. Tetrex *Distributed by Ayerst for Beecham Laboratories, Inc. 28 COMPANY - Abbott Laboratories NO. ISSUES 12 6 6 3 5 2 12 12 14 Total... 13 Total... 3 Total... 1. Dicarbosil 1. Thyroid Bristol Laboratories 5 8 10 6 7 32 22 4 Total... 8 24 10 12 11 Total... 57 62 37 8 Total... 107 PAGENO="0612" 4902 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Burroughs Wellcome and Co., 1. Actidil 2 2 Inc. 2. Aerosporin 9 9 3. Alkeran 5 5 4. Antepar 10 10 5. Cardilate 17 17 6. Cortisporin 11 11 7. Empirin 8 8 8. Emprazil 3 3 9. Lanoxin 17 17 10. Leukeran 6 6 11. Nantadil 4 4 12. Marezine 9 9 13. Myleran 9 9 14. Neosporin 11 U Total... 121 CIBA Pharmaceutical 1. Esidrex 26 54 2. Esidrex-K 2 4 3. Ismelin 14 28 4. Pyribenzanine 31 56 5. Ritalin 26 39 6. Vioform 18 27 Total... 208 Davies, Rose-Hoyt and Con- 1. Digitalis 13 13 pany (division of 2. Quinidine 13 13 Kendall) Total... 26 Dome Chemicals, Inc. I. Cortarquin 4 4 2. Cort-Dome 6 6 3. Neo Cortdome Octic 4 4 Total... 14 Eaton Laboratories, Inc. 1. Puradantin 7 14 2. Furoxone 7 13 3. Tricofuron 6 12 Total... 39 29 PAGENO="0613" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4903 COMPANY PRODUCT NO. ISSUES NO. PAGES Ives Laboratories Lederle Laboratories ` (Division of American Cyanamid) 1. Butazolidii~ 2. Dulcolax 3. Hygroton 4. Persantin 5. Preludin 6. Regroton 1. Bayer Aspirin 2. Philips Milk of Magnesia 1. Cyclospasmol 2. Isordil 1. Akineton 1. Imferon 2. Norpramin 1. Amicar 2. Aristocort 3. Aristocort Tabs 4. Bamadex 5. Declomycin 6. Hydronox 7. Pathibamate 8. Stresscaps 9. Varidase Total... 52 15 12 8 10 16 24 Total... 98 7 7 6 6 Total... 13 8 8 3 3 Total... 11 4 Total... 4 10 10 16 32 Total... 42 7 7 7 14 7 6 18 26 26 38 2 3 12 12 6 6 16 - 16 Total. . .128 1. Coumadin 2. Numorphan 3. Percodan Endo Laboratories, Inc. Geigy Chemical Corpora tion Glenbrook Laboratories 32 10 10 16 10 10 15 12 4 5 8 12 Knoll Pharmaceutical Lakeside Laboratories, Inc. 30 PAGENO="0614" 4904 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Lilly, Eli & Company 1. Anhydron 2 2 2. Aventil 6 24 3. Darvon 17 17 4. Darvon Compound 1 1 5. Darvon Compound-65 1 1 6. Dymelor 11 11 7. C-Quens 14 56 8. Ilosone 2 2 9. Keflin 9 21 10. V-Cillin K 9 9 Total... 144 1. Surfak 7 Total... 7 McNeil Laboratories, Inc. 1. Butiserpine 26 26 2. Butisol 26 26 3. Tylenol 26 26 Total... 78 Nallinkrodt Chemical 1. Codeine 1 Total... 2 Mead Johnson 1. Vitamin series 6 18 2. Dracon 22 55 Total... 73 Merrell, William ~. 1. Bendectin 6 6 2. Bentyl 6 6 3. Cepacol 1 1 4. Tenuate 14 14 Total... 27 Miles Products (Division of Miles Laboratories) 1. Alkaseltzer 12 Total... 12 31 PAGENO="0615" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4905 Merck, Sharpe, & Dohme (Division of Merck & Company) National Drug 1. AVC/AVC Dienestrol 2. Tepanil NO. 3 6 4 4 Total... 10 *Merck Chemical Division ot Merck & Uompany 32 COMPANY PRODUCT NO. ISSUES PAGES 1. Aldomet 10 20 2. Aldoril 19 37 3. Aramine 10 20 4. Benemid .15 18 5~ Codeine* 2 2 6. Cosmogen 2 2 7. Cuemid 2 2 8. Cosmogen/Cuemid 2 2 9. Cremomycin/Cyclex 7 13 10. Cyclex 2 4 11. Decadron 25 52 12. Decagesic 11 18 13. Diuril 39 77 14. Diupres 10 20 15. Diuril/flydrodiuril 1 2 16. Dornavac 4 8 17. Dronactic/Periactin 5 5 18. Elavil 35 75 19. Elavil/Diuril 6 12 20. Hy~1odiuril 1 2 21. Hydropres 6 10 22. Hydrodiuril MA 7 14 23. Hydropres MA 7 7 24. Indocin 9 82 25. M~phyton 11 11 26. Periactin 11 11 27. Rubeovax 6 6 28. Respihaler 12 24 29. Triavil 6 30 30. Urecholine 12 21 . Total.. . 609 PAGENO="0616" 4906 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Organon, Inc. 1. Hexadrol (and injection) 22 23 2. Maxibolin 2 6 Total... 29 Ortho 1. Contraceptive products 3 Total... 8 (Ortho-Novum) Philips Roxane Laboratories 1. Measles vaccine 4 Total... 11 Pittman-Moore Company 1. Lirugen 13 16 2. Novahistine DH 13 19 3. Nova LP 3 3 4. Nova Singlet 5 5 Total... 43 Polythress, Wm P. 1. Solfo-serpine 5 5 2. Trocinate 3 3 Total... 8 Purdue Frederick Company 1. Otalgine 3 3 2. Senokap 1 1 3. Senokot 1 1 4. Sulfabid 4 6 Total... 11 Parke-Davis 1. Benadryl 24 25 2. Dilantin 24 39 3. Measles virus vaccine 1 1 4. Nidicel 3 3 5. Norlestrin 10 22 6. Pitocin 13 13 Total... 103 Pfizer, Chas. 1. Daricon 4 8 2. Desitin Ointment* 10 10 3. Renese 13 36 4. Vistaril 16 46 Total... 100 *Leeming Division of Pfizer. 33 PAGENO="0617" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4907 COMPANY PRODUCT NO. ISSUES NO. PAGES Plough, Inc. 1. St. Joseph's Aspirin 10 Total... 10 Radium Chemical 1. Radium 13 Total... 13 Riker Laboratories 1. Medihaler Duo 4 8 2. Norgesic 12 Total... 32 Robins, A. H. 1. AllBee W/C 9 9 2. Dimetapp 8 8 3. Dimetane 9 18 4. Donnatal 7 14 5. Phenaphen 6 6 6. Quinidex 12 12 7. Robaxin (and Robaxin 750) 12 32 8. Robaxisol 4 8 9. Robinul 11 22 Total... 121 Roche Laboratories 1. Gantanol 8 24 2. Gantanol Suspension 8 23 3. Gantrisin 6 12 4. Librax 9 24 5. Librium 17 42 6. Librax/Librium 10 45 7. Roniacol 13 26 8.Tegan 1 2 9. Valium 35 95 Total... 295 Roerig, J. B. & Company 1. Atarax 6 12 2. Antivert 6 6 3. Enarax 4 4 4. Marax 5 10 5.Tao 5 21 6. Tetracyn 8 16 Total... 69 Rorer, Wm. H., Inc. 1. Ananase 13 Total... 13 34 81-280 0-69--pt. 11-40 PAGENO="0618" 4908 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Sandoz Pharmaceutical 1. Bellergal 19 19 2. Cafergot 27 27 3. Fiorinal 17 17 4. Mellaril 25 30 5. Sansert 3 3 Total... 96 Scherer, R. P. Corporation 1. Hydrospray 1 Total... 1 Schering Corporation 1. Afrin 6 12 2. Celestone 6 12 3. Celestone Soluspan 11 22 4. Celestone Solutab 1 2 5. Chlortrimeton 6 12 6. Coricidin 1 4 7. Denazin 2 2 8. Rela 2 4 Total... 83 Schmid, Julius, Inc. 1. Candeptin 8 9 2. Vagesic 5 5 Total... 14 Sherman Laboratories 1. Elixophyllin 13 Total... 13 Strasenburgh Laboratories 1. Biphetamine 10 21 (Division of Wallace & 2. Biphetamine T 3 3 Tiernam, Inc.) 3. Oinnituss 5 5 4. Tussionex 10 11 Total... 40 Stuart Company (Division 1. Mylanta 18 Total... 38 of Atlas Chemical) Syntex 1. Norinyl 12 17 2. Synalar 3 7 Total... 24 35 PAGENO="0619" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4909 COMPANY PRODUCT NO. ISSUES NO. PAGES Searle, G. D. 1. Aldactazide 5 5 2. Aldactazide A 2 2 3. Dramamine 3 3 4. Enovid 11 19 5. Enovid-E 20 30 6. Enovid/Enovid-E 1 3 7.Flagyl 5 9 8. Lomotil 7 7 9, Pro-Banthine 16 16 10. Pro-Banthine/w Dartal 1 1 Total... 95 Smith, Kline, & French 1. Compazine 15 2. Cytomel/Compazine 4 3. Cytomel/Parnate 1 4. Cytomel/Stelazine 1 5. Dexamyl 5 6. Dyazide 1 7. Dyrenium 12 8. Dyrenium Caps 4 9. Parnate 10 10. Stelazine 11 11. Thorazine 7 15 4 1 1 5 1 13 4 10 11 7 Laboratories Total... 72 Squibb 1. Kenacort 2 2. Kenalog 3 3. Kenalog IM 7 4. Kenalog/Mycolog 1 5. Mysteclin-F 10 6. Naturentin 7 7. Noctec 6 8. Pentids 7 9. Pentids 400 1 10. Prolixin 8 11. Raudixin 6 12. Rautrax-N 13. Theragran 4 6 16 1 10 7 6 7 1 14 12 12 4 Total... 100 36 PAGENO="0620" 4910 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY CONP~NY PRODUCT NO. ISSUES NO. PAGES U. S. Vitamin & Pharmaceu- 1. Arlidin 11 11 ticals 2. Aquasol 3 3 3. Aquasol-A 3 3 4. Dexameth 5 5 5. DBI (DBI-TD) 16 16 Total... 38 Upjohn 1. Depo-Nedrol 1 2 2. Didrex 14 28 3. Lincocin 12 37 4. Medaprin 1 2 5. Medrol 13 26 6. Medrol/Veriderm 9 18 7. Panalba 14 20 8. Provest 22 39 Total... 172 Wallace Laboratories 1. Deprol 25 46 2. Milpath 39 39 3. Milprem 10 16 4. Miltown (Meprospan) 50 (24) 107 5. Solacen 21 46 6. Soma 41 73 7. Soma Compound 16 16 8. Somacort 18 33 Total... 388 Warner-Chilcott 1. Anusol 1 2 2. Colymicin Injectable 19 40 3. Colymicin Octic 13 17 4. Gelusil 29 30 5. Mandelamine 18 64 6. Peritrate 24 145 7. Pre-Sate 32 159 8. Proloid 11 24 9. Papase 17 34 10. Tedral (Tedral SA) 9 45 11. Sinutab 19 30 Total... 590 37 PAGENO="0621" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4911 COMPANY PRODUCT NO. ISSUES NO. PAGES Warren-Teed Products Compapy~ 1. Chymolase 2.Kaon 6 3 6 3 3. Ventussin 1 1 Total... 10 Winthrop Laboratories 1. Isuprel 2. Mebaral 3. Neggram 4. Neo-Synephrine 5. Radiologics 6. Trancogesic 7. Trancopal 8. Trancopal/Trancogesic 9. Winstrol 6 7 33 11 6 14 2 1 1 6 7 38 11 6 14 2 2 1 Total... 87 Westward, Inc. 1. Meprobamate 12 Total... 12 Wampole Laboratories 1. Vosol 9 Total... 9 White Laboratories 1. Permitil 2. Permitil Chronotab 6 2 12 4 Total 16 Wyeth Laboratories (Division 1. Bicillin 2. Equagesic 3. Equagesic/Mepergan 4. Equanil 5. Mepergan 6. Phenergan 7. Pen-Vee K 8. Polymagna 9. Sparine 10. Serax 11. SMA 12. Sulfose 13. Unipen 14. Zactirin Compound 8 10 1 9 3 3 1 6 7 15 10 3 14 4 8 18 2 18 3 6 1 12 14 44 20 3 28 12 of American Home Products) Total... 189 38 PAGENO="0622" 4912 COMPETITIVE PROBLEMS ]~ THE DRUG INDUSTRY 1. Ainnophyllne 2. Nanna 3. Quinaglute 8 8 8 8 20 20 Total... 36 COMPANY wynn Pharnuacal Corp. PRODDCT NO. ISSUES NO. PAGES 39 PAGENO="0623" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4913 THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Summary Data 1966 10 Leading Firms, by Volume of Advertising Rank Firm No. Drug Advertising Pages 1 Wallace Laboratories 623 2 CIBA 559 3 Merck, Sharpe, & Dohme 496 4 Warner-Chilcott 365 5 Lilly 290 6 Upjohn 200 7 Wyeth Laboratories 186 8 Squibb 164 9 Pfizer 152 10 Lederle Laboratories 144 Rank 1 10 Most Frequently Advertised Dr~gs No. Issues in which Advertised Miltown (Wallace) 50 2 Doriden (CIBA) 48 3 Sotna (Wallace) 48 4 Milpath 47 5 Deprol (Wallace) 46 6 Mandelamine (Warner-Chilcott) 39 7 Solacen (Wallace) 39 8 9 Pyribenzamine (CIBA) 35 Gantanol (Roche) 35 10 Neggram (Winthrop) 31 Dialog (CIBA) Rank 1 10 Most Heavily Advertised Drug~ No. Pages on which Advertised Deprol (Wallace 107 . 2 Doriden (CIBA) 106 3 Miltown (Wallace) 105 4 Ser-Ap-Es (CIBA) 91 5 Terramycin (Pfizer) 84 6 Darvon (Lilly) 83 7 Solacen (Wallace) 77 8 Diuril (Merck) 74 9 C-Quens (Lilly) 72 10 Dialog (CIBA) 72 40 PAGENO="0624" 4914 COMPETITIVE PROBLEMS 1N THE DRUG INDUSTRY THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 1966 COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Laboratories 1. Desbutal 1 2 2. Desoxyn 1 2 3. Desbutal/Desoxyn 6 24 4. Erythocin 5 18 5. Eutron 8 26 6. Placidyl 13 13 7. Radio pharmaceuticals 12 12 8. Surbex-T 2 2 9. Vercyte 4 8 Total... 107 Arch Laboratories 1. Dicarbosil 18 Total... 18 ~yerst Laboratories 1. Penbritin* 19 38 2. Premarjn 12 12 3. Riopan 16 17 4. Thiosulfil 5 6 Total... 73 Bristol Laboratories 1. Polycillin (oral & inject.)2O 40 2. Polycillin-N 1 2 3. Prostaphlin 4 8 4. Tegopen 14 24 5. Tetrex 10 20 Total... 9~4 *Distributed by Ayerst for Beecham Laboratories, Inc. 41 PAGENO="0625" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4915 Burroughs-Wellcome and Co., Inc. COMPANY PRODUCT NO. ISSUES NO. PAGES CIBA Pharmaceutical Davies, Rose-Hoyt and Co. 1. Actifed 4 8 2. Aerosporin 7 7 3. Alkeran 2 2 4. Antepar 6 6 5. Cardilate 26 26 6. Cortisporin 8 11 7. Einpirin 7 10 8. Lanoxin 24 24 9. Leukeran Lidosporin 9 9 10. 4 4 11. }~yleran 6 7 12. Neosporin 11 13 13. Zyloprin 2 Total... 6 133 1. Dialog 31 72 2. Doriden 48 106 3. Esidrex 27 65 4. Esiinii 19 64 5. Ismelin 17 34 6. Pyribenzamine 35 51 7. Ritalin 26 59 8. Ser-Ap-Es 20 91 9. Vioform ~ 9 Total... 17 559 1. Ipsatol 1 1 2. Luride 9 9 3. Pil-Digis 20 20 4. Pil-Digis/Davoxin 1 1 5. Quinora 13 Total... 13 44 42 PAGENO="0626" 4916 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Dome Chemicals, Inc. 1. Cor-Tar-Quin 3 6 2. Cort-Dome 6 6 3. Domeboro 3 3 4. Lidaform 4 4 5. Neo Cort-Dome 8 8 6. Uval 1 1 Total... 28 Dorsey Laboratories 1. Triaminic 3 Total... 9 Eaton Laboratories, Inc. 1. Furadantin 13 26 2. Nitrofurans 4 4 3. Tricofuron 4 4 Total... 34 Endo Laboratories, Inc. 1. Coumadin 30 33 2. Nurnorphan 13 13 3. Percodan 4 4 Total... 50 Geigy Chemical Corporation 1. Butazolidin 8 8 2. Dulcolax 7 7 3. Pertofrane 5 10 4. Persantine 16 35 5. Preludin 12 24 6. Regroton 6 6 7. Tanderil 6 12 Total... 102 Glenlirook Laboratories 1. Bayer Aspirin 7 7 2. Measurin 8 21 3. Philip's Milk of Magnesia 6 6 Total... 34 Hoechst Pharmaceutical 1. Doxidan 4 4 2. Lasix 5 44 Total... 48 Hyland Laboratories 1. Hemophilia-A 1 Total... 1 43 PAGENO="0627" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4917 COMPANY PRODUCT NO. ISSUES NO. PAGES 1. Cyclospasmal 2. Isordil 1. Nitroglyn 1. linferon 2. Norpramin 1. Butiserpine 2. Butisol 3. Grifulvin 4. Tylenol 30 48 Total... 78 3 12 Total... 15 18 26 13 15 Total... 72 Ives Laboratories Key Pharmaceutical Lakeside Laboratories. Inc. 16 27 3 Total... 3 Lederle Laboratories Lilly, Eli, & Co. McNeil Laboratories 1. Aristocort 2. Bamadex 3. Declomycin 4. Rydrinix 5. Levoprome 6. Pathibamate 7. Stresscaps 8. Varidare 1. Aventyl 2. C-quens 3. Darvon 4. Keflin 5. Ilosone 6. V-Cillin--K 3 12 5 12 28 5 1 6 12 15 13 10 29 20 9 5 18 26 13 15 10 23 46 22 4 12 12 15 Total... 144 42 72 83 56 27 10 Total... 290 44 PAGENO="0628" 4918 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Mead-Johnson 1. Oracon 10 Total... 40 McKesson 1. Kessodrate 1 1 2. Kessotetra 1 1 3. Various 4 4 Total... 6 Merrell, William S. 1. Tenuate 3 Total... 3 Miles Products 1. Alkaseltzer 13 Total... 13 Merck, Sharpe, & Dobme 1. Aldomet 12 24 2. Aldoril 2 4 3. Arainine 5 10 4. Benemid/Colbenenijd 15 30 5. Codeine* 5 5 6. Cyclex 12 24 7. Decadron 18 34 8. Decagesic 8 16 9. Diuril 27 74 10. Diupres 10 20 11. Dornavac 3 6 12. Elavil 23 44 13. Hydrodiuril 3 6 14. Hydropres 9 18 15. Hydrodiuril-KA 2 3 16. Indocin 24 60 17. Nephyton 11 11 18. Periactin 11 11 19. Respihaler 8 16 20. Triavil 18 42 21. Triavil/Hydropres 3 6 22. Tr~avil/Urecholine 4 8 23. tjrecholine 12 24 Total... 496 *Merck Chemical Division of Merck & Co. 45 PAGENO="0629" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4919 COMPANY PRODUCT NO. ISSUES NO. PAGES National Drug 1. AVC 6 7 2. AVC/Dienestrol 2 2 3. Avcen 7 7 4. Tepanil 11 Total... 36 Organon, Inc. 1. Hexadrol 10 Total... 10 Parke-Davis 1. Benadryl 21 30 2. Cholormycetin 17 17 3. Dilantin 16 28 4. Elase 3 6 5. Norlestrin 27 37 6. Pitocin 10 10 Total... 128 Philips-Roxanne 1. Duphaston 3 Total... 3 Pittinan-Noore 1. Novahistine Singlet 11 13 2. Novahistine DG 6 12 3. Neo-Polycin 4 8 4. Lirugen 13 13 Total... 46 Pfizer, Chas. 1. Daricon 6 6 2. Desitin* 6 6 3. Rondoniycin 12 56 4. Terramycin 28 84 Total. .. 152 Plough, Inc. 1. St. Joseph's Aspirin 10 Total... 10 Polythress, Wa. P. 1. Nudrane 2 2 2. Trocinate 3 Total... 5 46 PAGENO="0630" 4920 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Purdue-Frederick Company 1. Senokot 1 Total... 1 Radium-Chemical 1. Radium 13 Total... 13 1. Gantanol (various) 2. Gantrisin 3. Librax 4. Librium 5. Menrium 6. Valium 70 14 28 12 12 7 Total... 143 1. Atarax 2. Antivert 3. Marax 4. Signemycin 5. Tao 6. Tetracyn 12 24 10 4 15 8 Total... 73 Roerig, J.B. & Company Roche Laboratories Robins, A.H. Rorer, Wa. H. 6 24 5 2 15 4 35 7 6 10 6 7 8 8 1 4 13 1 8 1. AllBee w/C 2. Dimeta~,p 3. Donnatal 4. Exna-R 5. Phenephan 1. Ananase 2. Maalox 8 8 2 10 13 Total... 143 1 12 Total... 13 47 PAGENO="0631" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4921 COMPANY PRODUCT NO. ISSUES NO. PAGES Sandoz Pharmaceutical 1. Bellergal 4 4 2. Caf ergot 12 19 3. Piorinal 17 17 4. Nellaril 18 36 Total... 76 Schmid, Julius, Inc. 1. Candeptin 3 3 2. Vagesic 11 JL Total... 14 Schering Corporation 1. Chlortriineton 5 10 2. Etrafon 14 28 Total... 38 Searle, G.D. 1. Aldactazide 8 9 2. Enovid-E 2 4 3. Flagyl 13 13 4. Lomotil 10 10 5. Mutamucil 2 2 6. Ovulen 13 33 7. ProBanthine 12 12 Total... 83 Sherman Laboratories 1. Exlisophyllin 9 Total.. 9 Smith, Kline, & French 1. Combid 13 17 2. Dyazide 10 23 3. Dyrenium 10 10 4. Teldrin 3 3 5. Thorazine 10 15 6. Stelazine 16 27 Total... 95 48 PAGENO="0632" 4922 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Sguibbs, E.R. 1. Kenacort 10 10 2. Kenalog 14 14 3. Kenalog IN 7 14 4. Nycolog 10 10 5. Mysteclin-F 9 18 6. Noctec 7 8 7. Naturetin 17 20 8. Pentids 13 21 9. Prolixin 12 16 10. Raudixin 14 14 11. Rautrax-N 14 19 Total... 164 Strassenburgh Laboratories 1. Biphetamine 5 5 2. lonamin 6 6 3. Omnituss 4 4 4. Tussionex 8 8 Total... 23 Stuart Company 1. Nylanta 12 Total... 24 Syntex 1. Synalar 4 Total... 10 1. Depo-Nedrol 11 22 2. Depo-Nedrol/Nedrol 1 1 3. Lincocin 20 48 4. TMedrol Dosepak 13 24 5. Orinase 24 39 6. Panalba 20 26 7. Provera 2 4 8. Provest 11 21 9. Tolinase 8 15 Total... 200 49 PAGENO="0633" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4923 COMPANY PRODUCT NO. ISSUES NO. PAGES Aquasol Arlidin DBI-TD Dexameth Vaponefrin 1. Capla/Caplaril 2. Deprol 3. Neprospan 4. Nilpath 5. Niltown 6. Milprem 7. Miltrate 8. Solacen 9. Soma 10. Soma Compound 4 15 3 2 8 4 15 3 2 8 Total... 32 30 107 55 55 105 54 27 77 59 54 Total... 623 Wampole 1. Vosol 6 Total... 1. Choledyl 2. Colyinycin 3. Gelusil 4. Mandelamine 5. Peritrate 6. Pre-Sate 7. Proloid 8. Papase 9. Sinutab 10. Tedral 8 42 35 54 48 70 14 18 36 40 Total... 365 6 Total... 6 U.S. Vitamin & Pharmaceutical 1. 2. 3. 4. 5. Wallace Laboratories 15 46 24 47 50 25 9 39 48 30 Warner-Chilcott Warent-Teed White Laboratories 8 20 29 39 21 14 7 9 18 15 1. Chymolase 1. Disophrol chrobotabs 5O~ 3 Total... 82-280 0-69-pt. ll-41 PAGENO="0634" 4924 COMPETITIVE PROBLEMS ll~ THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Winthrop Laboratories 1. Isuprel 11 11 2. Mebaral 4 4 3. Neggram 31 46 4. Neo-Synephrine 10 10 5. Phisohex 9 9 Total... 80 West-Ward, Inc. 1. Meprobamate 3 Total... 3 Wyeth Laboratories 1. Bicillin 1 2 2. Equanil 12 25 3. Equanil/Equagesic 2 4 4. Equanil/Phenergan-VC 1 2 5. Equagesic 8 15 6. Nepergan 9 12 7. Omnipen 10 20 8. Pee-Vee-K 7 14 9. Phnergan 6 10 10. Polymagna 5 10 11. Serax 10 21 12. SMA/S-26 3 6 13. Sparine 6 12 14. Sulfose 2 4 15. Unipen 9 18 16. Zactirin 6 11 Total... 186 Wynn Pharmacal Corporation 1. Arninophylline 7 7 2. Numa 11 11 3. Quinaglute 23 23 Total... 41 51 PAGENO="0635" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4925 THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Summary Data 1967 10 Leading Firms, by Volume of Advertising Firm No. Drug Advertising Pagç~ Rank 1 Merck, Sharpe, & Dohme 747 2 CIBA 405 3 Warner-Chilcott 359 4 Wallace Laboratories 355 5 Lilly 279 6 Roche Laboratories 262 7 Squibb 210 8 Upjohn 207 9 10 Parke-Davis ~ 150 144 -- 10 Most Frequently Advertised Drug~ No. Issues Rank in which Advertised 1 Indocin (Merck) 50 2 Esidrex (CIBA) 43 3 Doriden (CIBA) 43 4 Ritalin (CIBA) 39 5 Ser-Ap-Es (CIBA) 38 6 Miltown (Wallace) 37 7 Elavil (Merck) 36 8 Triavil (Merck) 36 9 Peritrate (Warner-Chilcott) 35 10 Diupres (Merck) 32 Rank 1 10 Most Heavily Advertised Dru~g~ No. Pages on which Advertised Miltown (Wallace) 90 2 Indocin (Merck) 84 3 Esidrex (CIBA) 82 4 Maolate (Upjohn) 80 5 Peritrate (Warner-Chilcott) 80 6 Triavil (Merck) 78 7 Elavil (Merck) 72 8 Ritalin (CIBA) 69 9 Ser-Ap-Es (CIBA) 69 10 Darvon (Lilly) 69 52 PAGENO="0636" 4926 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 1967 COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Laboratories 1. Desbutal 1 4 2. Desbutal/Desoxyn 8 32 3. Enduron 7 7 4. Placidyl 14 14 Total... 57 Ames 1. Glucola 1 Total... 1 Arch Laboratories 1. Dicarbisol 13 Total... 13 Ayerst Laboratories 1. Atromid-S 5 20 2. Penbritin* 24 48 3. Premarin 11 11 Total... 79 Bristol Laboratories 1. Polycillin 31 68 2. Prostaphlin 14 28 3. Tegopen 4 8 4. Tetrex 14 28 5. Tetrex-F 4 4 6. ~etrex-B 2 4 Total... 140 Bristol-Meyers 1. Bufferin 2 Total... 2 Burroughs-Wellcome and 1. Aerosporin 8 8 Co., Inc. 2. Actifed 8 16 3. Antepar 6 6 4. Cardilate 26 30 5. Cortisporin 6 10 6. Empirin 4 8 7. Leukeran 10 10 8. Lanoxin 22 22 9. Lindosporin 2 2 10. Neosporin 5 5 11. Zyloprim 8 27 Total 144 *Distributed by Ayerst for Beecham Laboratories. 53 PAGENO="0637" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4927 NO. NO. COMPANY PRODUCT ISSUES * PAGES CIBA Pharmaceutical 1. Dialog 1 2 2. Doriden 43 54 3. Esidrex 43 82 4. Esimil 16 48 5. Ismelin 11 32 6. Otrivin 11 11 7. Ritalin 39 69 8. Ser-Ap-Es 38 69 9. Vioform 19 38 Total... 405 Cutter Laboratories 1. Hyper-Tet 5 Total... 9 Dome Chemicals, Inc. 1. Cort-Dome 1 Total... 1 Dupont 1. Symmetrel 8 Total... 30 Eaton Laboratories 1. 2. 3. 4. 5. Chioraseptic Furacin Furadantin Nitrofurans Tricocuron 11 7 14 8 12 Total... 11 7 28 8 24 78 Endo Laboratories 1. 2. 3. Coumadin Numorphan Valpin 20 12 3 Total... 35 12 3 50 Flint Laboratories 1. Choloxin 8 Total... 17 Frost Laboratories 1. Chlorazene 11 Total... 11 Geigy Chemical Corporation 1. 2. 3. 4. Dulcolax Hygroton Preludin Tandearil 6 6 6 6 Total... 6 15 12 13 40 54 PAGENO="0638" 4928 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Glenbrook Laboratories 1. Bayer Aspirin 7 7 2. Haley's NO 8 8 3. Measurin 1 2 4. Philip's Milk of Nag- 6 6 nesia Total... 23 Hoechst~ 1. Doxidan 1 1 2. Lasix 13 74 3. Surfak 4 4 Total... 79 Ives Laboratories 1. Cyclospasmol 12 18 2. Isordil 16 16 Total... 34 Key Pharmaceutical 1. Nitroglyn 9 Total... 9 Knoll Pharmaceutical 1. Akineton 2 2 2. Dilaudid 13 13 3. Metrazol 8 23 4. Quadrinal 19 20 5. Theokin 18 18 Total... 76 Lederle Laboratories 1. Achromycin 2 2 (Division of American 2. Aristocort 5 10 Cyanamid) 3. Bamadex 7 14 4. Declomycin 17 21 5. Diamox 6 6 6. Hydromox 5 11 7. Leverprome 4 8 8. Pathibamate 2 4 9. Stresscaps 10 10 Total... 86 Lakeside Laboratories 1. Imferon 11 11 2. Norpramin 14 Total... 25 55 PAGENO="0639" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4929 COMPANY PRODUCT NO. ISSUES NO. PAGES Lilly, Eli, & Co. 1. Aventyl 20 57 2. C-Quens 21 61 3. Cordran 8 8 4. Dymelor 7 21 5. Darvon 23 69 6. Keflin 17 63 Total... 279 Mallinkrodt Chemical 1. Codeine 1 Total... 2 McKesson 1. Amphicol 1 1 2. Kessorate 1 1 3. Kessotetra 2 2 4. Meprobamate 1 1 5. Various 1 1 Total... 6 Mead-Johnson 1. Oracon 7 14 2. Questran 2 2 Total... 16 Merrell, Wm. 5. 1. Tenuate 3 Total... 9 McNeil Laboratories 1. Butisol 24 24 2. Butiserpine 15 15 3. Grifulvin 15 15 4. Haldol 8 40 Total... 94 Miles Products 1. Alkaseltzer 5 Total... 5 56 PAGENO="0640" 4930 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Merck, Sharpe, & Dohme 1. Aldomet 24 48 2. Aldoril 15 45 3. Aramine 4 8 4. Benemid 18 36 5. Codeine 2 4 6. Cuprimine 7 7 7. Diuril 8 16 8. Duipres 32 64 9. Elavil 36 72 10. Edecrin 17 67 11. Hydropres 27 54 12. Indocin 50 84 13. Mephyton 15 15 14. Periactin 19 19 15. Respihaler 23 46 16. Triavil 36 78 17. Turbinaire 11 33 18. Urecholine 8 16 19. Vivactil 7 35 Total... 747 National D~pg 1. Tepanil 9 Total... 9 Neisler Laboratories 1. Rynatuss 5 Total... 5 (Division of Union Carbide) Organon, Inc. 1. Hexadrol 8 16 2. Monosticon 6 6 Total... 22 Parke-Davis 1. Benadryl 26 32 2. Chloromycetin 18 36 3. Dilantin 12 17 4. Elase 12 24 5. Norlestrin 12 34 6. Pitocin 7 7 Total... 150 Pfizer, Chas. 1. Bondornycin 22 53 2. Terraniycin 23 61 3. Vibramycin 5 22 Total... 136 57 PAGENO="0641" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4931 Roche Laboratories Rorer, Wm. H., Inc. PRODUCT 1. Lirugen 2. Novahistine 3. Tussend 1. St. Joseph's Aspirin 1. Senokot 1. Radium 1. Dimetapp 2. Donnatal 3. Phenaphen 4. Robitussin 5. Tybatran 1. Antivert 2. Atarax 3. Navane 4. Marax 5. Signemycin 6. Tao 1. Azo Gantanol 2. Gantanol 3. Librax 4. Librium 5. Libritabs 6. Menrium 7. Roniacol 8. Tigan 9. Valium NO. PAGES 9 25 6 Total... 40 Total... 7 Total... 9 6 Total... 6 7 7 12 24 11 11 6 12 7 28 Total... 82 9 9 4 8 2 6 2 6 4 8 6 6 Total... 43 4 4 29 45 21 51 11 28 9 18 19 38 13 26 7 8 26 44 Total. . .262 4 Total... 4 NO. ISSUES 9 22 3 COMPANY Pittman-Moore Plough, Inc. Purdue-Frederick Radium Chemical Robins, A. H. Roerig, J. B., & Company 1. Maalox 58 PAGENO="0642" 4932 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Sandoz Pharmaceutiç~,l 1. Cafergot 6 6 2. Fiorinal 16 16 3. Mellaril 18 44 4. Sansert 8 8 Total... 76 Schaid, Julius 1. Candeptin 16 16 2. Vagesic 12 12 Total... 28 Schering Corporation 1. Chlortrimeton 17 17 2. Etrafon 5 16 Total... 33 Searle, G. D. 1. Ovulen 15 25 2. Ovulen-2l 11 14 3. Aldactazide 7 7 4. Enovid-E 1 1 5. Lomotil 8 8 6. Flagyl 11 12 7. Probanthine 10 10 Total... 77 Sherman Laborator~~es~es 1. Elixophyllin 1 Total... 1 Smith, Kline, & French 1. Diazide 3 6 2. Stelazine 3 6 3. Thorazine 4 7 4. Vontrol 3 9 Total... 28 Stuart Co~p~pj 1. Mylanta 2 Total... 2 1. Kenalog 26 51 2. Mycolog 24 24 3. Mycostatin 27 27 4. Mysteclin 1 1 5. Noctec 20 30 6. Pentids 12 24 7. Rauzide 14 42 8. Sumycin 11 11 Total... 210 59 PAGENO="0643" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4933 Syntex Unimed, Inc. U. S. Vitamin & Pharmaceu tica]. Upjohn 1. Otnnituss 2. Tussionex 1. Synalar 1. SERC 1. Arlidin 1. Depo Medrol, 2. Medrol 3. Medrol Dosepak 4. Maolate 5. Orinase 6. Orinase/Tolinase 7. Panalba 1. Deprol 2. Capla/Caplaril 3. Meprospan 4. Miltown 5. Miltrate 6. Milpath 7. Milprem 8. Sotna 9. Soma Compound 1. Colymycin Injectable 2. Colymycin Octic 3. Gelusil 4. Mandelamine 5. Neba ir 6. Papase 7. Peritrate 8. Pre-Sate 9. Proloid 10. Pyridium 11. Tedral NO. PAGES 3 10 13 8 42 3 Total... 3 13 26 3 3 4 8 26 80 15 25 16 46 19 19 Total... 207 26 58 9 18 7 19 37 90 14 31 27 54 7 20 22 44 7 21 Total... 355 7 45 8 8 19 19 16 44 3 14 11 21 35 86 12 67 3 7 16 16 16 32 Total... 359 COMPANY PRODUCT Strassenburgh Laboratories NO. ISSUES 3 10 Total... 1 Total... 30 Total... Wallace Laboratories Warner-Chilcott 60 PAGENO="0644" 4934 COMPETITIVE PROBLEMS LN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Warren-Teed 1. Chyinolase 1 Total... 1 Winthrop Laboratories 1. Isuprel 16 16 2. Neggram 23 31 3. NeoSynephrine 4 4 4. Phioshex 2 2 5. Talwin 8 22 Total... 75 Wyeth Laboratories 1. Bicillin 2 3 2. Equagesic 3 6 3. Equanil 6 12 4. Omnipen 5 10 5. Pen-Vee-K 5 10 6. Phenergan 8 16 7. Polymagna 3 6 8. Serax 6 12 9. Sparine 8 16 10. Unipen 4 8 11. Wyanoids 4 4 Total... 103 61 PAGENO="0645" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4935 ANNALS OF INTERNAL MEDICINE SuMMARY DATA Advertising, 1963 through 1967 Volume in Pages Total Total Total Total Pages Total Pages Pages Pages Pages Drugs Other Year Magazine Journal Advertising Advertising Advertising 1963 4,228 2,392 1,836 1,402 434 1964 4,372 2,565 1,807 1,511 296 1965 4,764 2,637 2,127 1,695 432 1966 4,598 2,830 1,768 1,439 329 1967 4,701 2,940 1,761 1,426 335 Percentages Percent Percent Percent Drug Advertising Other Advertising Total Journal Advertising as Percent as Percent Year Pages Pages Pages All Advertising All Advertis~rc~ 1963 100% 56.5% 43.5% 76.3% 23.7% 1964 100% 58.6% 41.4% 83.6% 16.4% 1965 100% 55.3% 44.7% 79.6% 21.4% 1966 100% 61.5% 38.5% 81.3% 18.7% 1967 100% 62.5% 37.5% 80.9% 19.1% 62 PAGENO="0646" 4936 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ANNALS OF INTERNAL MEDICINE SUMMARY DATA* 1963 10 Leading Firms, by Volume of Advertisip~ Rank Firm No. Drug Advertising Pa~ 1 Wyeth Laboratories 106 2 Wallace Laboratories 101 3 Pfizer 94 4 Merck, Sharpe, & Dobme 89 5 McNeil Laboratories 80 6 Roche Laboratories 79 7 Lederle Laboratories 62 8 Mead-Johnson 52 9 Smith, Kline, & French 48 10 CIBA 46 10 Most Heavily Advertised Drugs Rank Drug~ No. Pages on which Advertised 1 Equanil (Wyeth) 32 2 Aldomet (Merck) 26 3 Benemid (Merck) 26 4 Aristicort (Lederle) 24 5 Daricon (Pfizer) 24 6 Librium (Roche) 24 7 Parafon (McNeil) 24 8 Butisol (McNeil) 23 9 & 10 Diabinase, Miltown, Terramycin 22 * Frequency table not given. 63 PAGENO="0647" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ANNALS OF INTERNAL MEDICINE 1963 4937 PPflT~1T(~T - 1. Desbutal 2. Eutonyl 3. Norisodrine 4. Optilets 5. Placidyl 6. Tridione 1. Alphalac 2. Andercid 1. Chymoral 1. Mesulfin 2. Riopan 1. Kantrex 2. Prostaphlin 3. Salutensin 5 18 10 4 2 1 Total... 40 4 8 3 3 Total... 11 7 Total... 7 2 4 1 1 Total... 5 3 6 2 4 8 16 Total... 26 COMPANY - -- NO. ISSUES NO. PAGES 5 7 7 4 2 1 Abbott Laboratories Anderson Armour ~yerst Laboratories Bristol Laboratories Burroughs-Wellcome 1. Empirin 2 2 2. Lanoxin 1 1 3. Leukeran 3 3 4. Methedrine 3 3 5. Myleran 4 4 6. Purinethol 2 Total. 2 .. 15 64 PAGENO="0648" 4938 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CONPANY PRODUCT NO. ISSUES NO. PAGES Burton & Parsons 1. Neutra-Carb 2 Total... 2 CIBA 1. Doriden 12 19 2. Ismelin 11 18 3. Ritalin 6 9 Total... 46 Cutter Laboratories - 1. Peridial 8 8 2. Polysal 1 1 Total... 9 Chic~g~ 1. Urised 2 Total... 2 Davies, Rose,~y~ 1. Pil-Digis 1 Total... 1 Endo Laboratories 1. Coumadin 10 16 2. Percodan 12 12 Total... 28 Paugera 1. Digitoxin 3 Total... 3 Geigy Pharmaceutical 1. Butazolidin 12 12 2. Tofranil 6 12 Total... 24 Ives 1. Isordil 11 Total... 15 Glenwood 1. Patoba 3 Total... 3 Dome 1. Decholin 3 Total... 3 65 PAGENO="0649" 1. Butibel 2. Butisol 3. Butiserpine 4. Parafon 5. Tylenol 1. Aldomet 2. Aramine 3. Benemid 4. Decadron 5. Dornavac 12 23 12 24 9 Total... 80 11 26 7 14 8 26 9 11 12 12 Total... 89 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4939 COMPANY NO. ISSUES NO. PAGES PRODUCT 1. Dilaudid 6 6 2. Quadrinal 5 Total... 14 1. Aristocort 12 24 2. Declomycin 8 13 3. Hydromox 9 9 4. Pathibamate ~ 8 Total... 16 62 1. Cordran 3 3 2. Cytellin 4 4 3. Darvon 7 19 4. Haldrone 3 3 5. Ilosone 3 3 6. Novrad 2 2 7. V-Cillin-K 2 2 Knoll Pharmaceutical Lederle Laboratories Lilly, Eli & Co. McNeil Mead-Johnson Merck, Sharpe, & Dohme 12 12 12 12 9 9 9 2 8 11 1. Beta-Chlor 2. Colase 3. Mucomyst 4. Quibron 5. Vasodilan 10 9 6 16 11 Total... 52 66 81-28~ 0-69-pt. 11-42 PAGENO="0650" 4940 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY C0NP~ANY PRODUCT NO. ISSUES NO. PAGES Merrell, Win. S. 1. Bentyl 5 10 2. TACE 5 10 3. Tenuate 9 9 Total... 29 Or~anon 1. Cotazym 4 4 2. Deca-Durabolin 2 2 3. Hexadrol 4 4 Total... 10 Parke-Davis 1. Adroyd 4 4 2. Benylin 7 8 3. Chloromycetin 3 3 4. Carbrital 11 11 5. Dilantin 6 11 6. Ther-Combex 2 2 Total... 39 Pfizer, Chas. 1. Booms 12 12 2. Daricon 12 24 3. Diabinese 11 22 4. Niain.id 5 10 5. Terratnycin 11 22 6. Tetracyn 4 4 Total... 94 Pharinacia 1. Azulfidine 12 Total... 12 Purdue-Frederick 1. Senokot 1 Total... 1 Biker Laboratories 1. Estomul 2 4 2. Norflex 7 14 3. Rauwiloid 3 6 Total... 24 67 PAGENO="0651" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4941 CONPANY PRODUCT NO. ISSUES NO. PAGES Robins, A. H. Reed & Carnick Roche Laboratories Rorer, Win. H. Sandoz Pharmaceutical Schering Corporation 1. AllBee w/c 4 4 2. Diinetane 7 7 3. 4. Donnagel Donnatal 4 3 4 6 5. 6. 7. Donnazyme Phenaphen Robaxin 2 * 4 3 2 4 3 8. 9. Robaxisal Robinul 2 3 2 3 10. Robitussin 3 3 11. Skelaxin 4 Total... 4 42 1. Phazyme 5 Total... 5 1. Gantanol 8 16 2. Librax 12 12 3. Librium 12 24 4. Roniacol 6 6 5. 6. Tigacol Tigan . 12 9 Total... 12 9 79 1. Maalox 5 Total... 5 1. Belladenal 3 3 2. 3. 4. Bellergal Cafergot Fiorinal . . 12 4 1 12 4 1 5. Nellaril 12 12 6. Sansert 12 Total... 12 44 1. Meticorten 3 3 2. 3. Naqua Sigmagen 5 12 Total... 5 12 20 68 PAGENO="0652" 4942 COMPETITIVE PROBLEMS ll~ THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Searle, G. D. 1. Enovid 12 18 2. Pro-Banthine 6 6 Total... 24 Smith, Kline, & French 1. Conbid 6 6 2. Cytomel 12 12 3. Compazine 6 6 4. Eskatrol 6 6 5. Parnate 12 12 6. Thorazine 6 6 Total... 48 ~q~ibb 1. Benograf in 1 1 2. Cholorgraf in 2 2 3. Mysteclin 6 6 4. Noctec 5 5 5. Pentids 5 5 6. Oragrafin 2 2 7. Pronestyl 5 5 8. Rautrax-N 4 4 9. Renografin 3 3 10. Retrografin 3 3 11. Raudixin 5 5 Total... 41 Syntex 1. Synalar 7 Total... 7 Upjohn 1. Orinase 10 20 2. Solu-B 7 7 Total... 27 U.S. Vitamin & Pharmaceutical 1. Arlidin 6 12 2. DBI-TD 5 10 Total... 22 69 PAGENO="0653" PROBLEMS IN PRODUCT 1. Capla 2. Deprol 3. Meprospan 4. Milpath 5. Milprem 6. Miltown 7. Miltrate 8. Soma 1. Nicalex 2. Uticon 1. Trancogesic 2. Trancopal 3. Winstrol 1. Bicillin 2. Equanil 3. Equanitrate 4. Mepergan 5. Oxaine 6. Pen-Vee-K 7. Prozine 8. Sparine 9. Thiomerin 1. Quinaglute 70 10 13 12 10 10 22 12 12 Total... 101 4 4 1 Total... 5 12 Total... 12 7 1 9 Total... 17 16 32 8 3 20 5 3 13 6 Total... 106 12 Total... 12 COMPETITIVE THE DRUG INDUSTRY 4943 COMPANY NO. ISSUES NO. PAGES 5 10 12 10 10 12 12 12 Wallace Laboratories Walker Warrent-Teed Winthrop Wyeth Laboratories 1. Kaon 7 1 9 4 12 8 3 10 5 2 8 6 PAGENO="0654" 4944 COMPETITIVE PROBLEMS Th~ THE DRUG INDUSTRY ANNALS OF INTERNAL MEDICINE Summary Data* 1964 10 Leading Firms, by Volume of Advertising Rank Firm No. Drug Advertising Pages 1 Pfizer 115 2 Wyeth Laboratories 106 3 Merck, Sharpe, & Dohme 105 4 Wallace Laboratories 93 5 Warner-Chilcott 77 6 Sandoz Pharmaceutical 72 7 CIBA 69 8 Bristol Laboratories 54 9 Mead-Johnson 51 10 Parke-Davis 43 10 Most Heavily Advertised Drugs No. Pages on which Advertis 1 DBI (U.S. Vitamin) 40 2 Unipen (Wyeth) 26 3 Deprol (Wallace) 24 4 Diabinese (Pfizer) 24 5 Furadantin (Eaton) 24 6 Gelusil (Warner-Chilcott) 24 7 Vistaril (Pfizer) 24 8 Equanil (Wyeth) 22 9 Polycillin (Bristol) 22 10 Aldomet, Colymycin, Aquinitrate 20 * Frequency table not given. 71 PAGENO="0655" 1. Formatrix 10 2. Mesuif in 7 3. Premarin 3 1. Kantrex 2. Polycillin 3. Salutensin 1. Doriden 2. Esidrex 3. Forhistal 4. Ismelin 5. Ritalin 6. Reg~itine 7. Serpasil 10 11 3~ Total... 24 3 4 5 2 Total... 14 14 22 18 Total... 54 18 8 6 10 9 16 2 Total... 69 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4945 COMPANY - ANNALS OF INTERNAL MEDICINE 1964 PRODUCT 1. Opilets 10 2. Placidyl 2 3. Surbex-T 12 1. Dicarbosil 8 NO. ISSUES NO. PAGES * 10 2 * 12 Total... 24 Total... 8 Abbott Arch Ayerst Bourroughs Bristol CIBA 1. Alkeran 2. Empirin 3. Leukeran 4. Migral 3 1 5 2 7 8 9 12 4 6 5 5 8 1 72 PAGENO="0656" 4946 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CONPANY PRODUCT NO. ISSUES NO. PAGES Cutter 1. Polysal-M 12 12 2. Perdial 5 5 Total... 17 Davies 1. D.I. Digitalic 6 Total... 6 Eaton 1. Furadantin 12 24 2. Furoxone 7 7 Total... 31 Endo 1. Percodan 12 12 2. Coumadin 7 14 Total... 26 Glenwood 1. Potaba 9 Total... 9 1. Butazolidin 6 6 2. Persantin 3 6 3. Preludin 7 14 4. Tofranil 12 12 Total... 38 Ives 1. Isordil 7 Total. .. 7 Kenwood 1. Papavatral 6 Total... 6 Knoll 1. Delaudid 6 6 2. Quadrinal 6 6 Total... 12 Lederle 1. Aristocort 4 8 2. Declonycin 7 14 3. Hydromox 9 9 4. Pathibamate 11 11 Total... 42 73 PAGENO="0657" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4947 COMPANY PRODUCT NO. ISSUES NO. PAGES 1. Co-Pyronil 3 3 2. Cytellin 2 2 3. Darvon 6 13 4. Haldrone 2 2 5. Keflin 2 8 6. Novrad 2 2 7. Mi-Cebrin-T 3 3 Total... 33 McNeil 1. Butibel 12 12 2. Butisol 11 17 3. Tylenol 12 12 Total... 41 Mead-Johnson 1. Colace 12 12 2. Mucoinyst 7 14 3. Peri-Colace 9 9 4. Quibron 1 2 5. Tribute 1 2 6. Vasedilan 12 12 Total... 51 Merck, Sharpe, & Dohme 1. Aldomet 9 20 2. Aramine 7 11 3. Diupres 8 8 4. Diuvil 8 18 5. Dornavac 8 12 6. Elauil 9 18 7. Hydropres 8 8 8. Mephyton 10 10 Total... 105 Merrell 1. Bentyl 10 10 2. Tace 1 2 3. Tenuate 12 12 Total... 24 74 PAGENO="0658" 4948 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Organon 1. Durabolin 6 12 2. Hexadrol 6 6 3. Wigraune 4 5 Total... 23 Parke-Davis 1. Benylin 4 4 2. Carbrital 12 12 3. Dilantin 12 12 4. Norlestrin 5 11 5. Thera-Cambex 4 4 Total... 43 Pfizer 1. Bonine 12 12 2. Daricon 10 18 3. Desitin 8 8 4. Diabinese 12 24 5. Renese 5 11 6. Terramycin 9 18 7. Vistaril 12 24 Total... 115 Pharinacia 1. Azulfidine 7 Total... 7 Pitman-Moore 1. Phenoxene 12 Total... 12 Riker 1. Norflex 2 4 2. Norgesic 7 16 3. Titralac 3 6 Total... 26 Rob ins 1. Albee 5 5 2. Dimetane 6 6 3. Donnagel 4 4 4. Donnazyrne 2 2 5. Phenaphen 6 6 6. Quininidex 5 5 7. Robaxisal 2 4 Total... 32 75 PAGENO="0659" THE DRUG INDUSTRY 4949 COMPANY NO. ISSUES NO. PAGES Roche Rorer Sandoz Searle COMPETITIVE PROBLEMS IN PRODUCT~ 1. Gantanol 1. Ascriptin 2. Maalox 1. Belladenal 2. Caforgot 3. Fiorlnal 4. Mellaril 5. Sansert 6. Torecan 1. Aldactazide 2. Anavar 3. Enovid 4. Pro-Banthine 1. Compazine 2. Cytomel 3. Eskatrol 4. Dyrenium 5. Feosol 6. Parnate 7. Thorazine 1. Chlorografin 2. Kenacort 3. Mysteclin 4. Noctec 5. Pentids 6. Raudixin 7. Rautrax 8. Renograf in 9. Retrograf in 10. Oragraf in 76 Smith, Kline, & French 12 12 10 12 12 12 12 12 3 2 12 2 3 4 2 3 4 2 3 1 9 5 7 1 5 1 2 1 1 Total... 12 12 12 Total... 24 10 12 12 14 12 12 Total... 72 3 4 18 2 Total... 27 3 4 2 6 5 2 3 Total... 25 1 9 5 7 1 10 1 3 1 1 Total... 39 Squibb PAGENO="0660" 4950 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Stuart 1. Mylanta 4 Total... 4 U.S. Vitamin 1. D3I 10 Total... 40 Upjohn 1. Pamine 4 4 2. Unicap 1 1 3. Solu-Cortef 12 12 Total... 17 Walker 1. Nicalex 6 Total... 6 Wallace 1. Capla 4 8 2. Deprol 12 24 3. Meprospan 12 12 4. Miltown 12 14 5. Milprem 2 2 6. Miltrate 12 12 7. Preemt 7 9 8. Soma 12 12 Total... 93 Warner-Chilco tt 1. Anugesic 3 4 2. Anusol 12 12 3. Coly-Mycin 10 20 4. Gelusil 12 24 5. Mandelamine 8 17 Total... 77 White 1. A&D 7 14 2. Permitil 5 10 Total... 24 Warren-Teed 1. Ilopan 2 2 2. Kaon 6 6 3. Modane 2 2 4. Ventussin 3 3 Total... 13 77 PAGENO="0661" COMPANY COMPETITIVE PROBLEMS IN THE PRODUCT - 1. Trancopal 2. Trancogesic 3. Winstrol 1. Bicillin 2. Cyclamyciñ 3. Equagesic 4. Equanil 5. Equanitrate 6. Mepergan 7. Pen-Vee-K 8. Phenergan 9. Purodigin 10. Sparine 11. Thiomerin 12. Unipen 13. Zactirin 4 6 3 3 12 12 Total... 21 4 4 2 2 2 2 11 22 12 20 8 8 2 2 2 2 2 2 2 4 2 2 9 26 4 10 Total... 106 1. Quinaglute 78 12 Total... 12 DRUG INDUSTRY 4951 Winthrop NO. ISSUES NO. PAGES PAGENO="0662" 4952 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE ANNALS OF INTERNAL MEDICINE SUMMARY DATA* 1965 10 Leading Firms, by Volume of Advertising Rank Firm No. Drug Advertising Pages 1 Merck, Sharpe, & Dohme 134 2 Wyeth Laboratories 120 3 CIBA 100 4 Pfizer 95 5 Bristol Laboratories 66 6 Lilly 64 7 Wallace Laboratories 63 8 Warner-Chilcott 60 9 Robins 59 10 Geigy 58 10 Most Heavily Advertised Drugs Rank Drug No. Page on which Advertised 1 Darvon (Lilly) 26 2 Diabinese (Pfizer) 26 3 Keflin (Lilly) 25 4 Decadron (Merck) 24 5 Diuril (Merck) 24 6 Dornavac (Merck) 24 7 Quinidex (Robins) 24 8 Tetrex (Bristol) 24 9 Mylanta (Stuart) 23 10 Robinul (Robins) 23 * Frequency table not given. 79 PAGENO="0663" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4953 THE ANNALS OF INTERNAL MEDICINE 1965 COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Arch Laboratories Ayerst Laboratories Bristol Laboratories Burroughs-Wellcome CIBA 1. Fero-Grad 11 11 2. Optilets 6 6 3. Surbex-T 12 Total... 12 29 1. Dicarbosil 5 Total... 5 1. Forinatrix 11 11 2. Mesulf in 4 8 3. Premarin 1 Total... 1 20 1. Kantrex 11 22 2. Polycillin 10 20 3. Tetrex ~ 12 Total... 24 66 1. Alkeran 5 5 2. Leukeran 3 3 3. Migral 3 3 4. Myleran 3 3 5. Purinethol 3 Total... 3 17 1. Doriden 11 11 2. Esidrex 9 18 3. Ismelin 7 14 4. Regitine 11 11 5. Ritalin 9 18 6. Ser-Ap-Es 6 18 7. Serpasil 5 Total... 10 100 80 PAGENO="0664" 4954 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY NO. ISSUES NO. PAGES COMPANY PRODUCT Dorsey Products 1. Trest 2 Total... 4 Davies, Rose, H2y~ 1. Pil-Digis 12 Total... 12 Eaton Laboratories 1. Puradantin 6 Total... 12 Endo Laboratories . 1. 2. 3. Couxnadin Hycodan Percodan 10 4 11 Total... 17 4 11 32 1. 2. 3. 4. 5. Butazolidin Pertofrane Persantin Regroton Tofranil 8 10 3 11 9 Total... 13 22 3 11 9 Ives Laboratories 1. Isordil 9 Total... 18 Kenwood 1. Papavatral 11 Total... . 11 Knoll Products 1. Dilaudid 12 Total... 12 Glenwood 1. Potaba 9 Total... 9 Lakeside 1. 2. Nercuhydrin Norpramin 6 9 6 18 81 PAGENO="0665" 1. Bentyl 2. Kolantyl 3. Tenuate 10 3 12 82 10 6 12 Total... 28 THE DRUG INDUSTRY 4955 COMPANY NO. ISSUES NO. PAGES 8 7 10 6 12 8 10 4 7 1 8 14 10 12 12 Total... 56 8 26 4 25 1 Total... 64 COMPETITIVE PROBLEMS IN 1. Artane 2. Aristocort 3. Diamox 4. Declomycin 5. Pathibamate 1. Anhydron 2. Darvon 3. Dymelor 4. Keflin 5.. V-Cillin-K 1. Obedrin-LA 1. Butibel 2. Butisol 3. Tylenol 1. Sustagen 1. Aramine 2. Aldomet 3. Benemid 4. Decadron 5. Dornavac 6. Elavil 7. Diuril 8. Mephyton 9. Hydropres Lederle Laboratories Lilly, Eli & Co. Massengill Company McNeil Laboratories Mead Johnson Merck, Sharpe, & Dohme Merrell, William S. 10 Total... 10 12 12 12 12 11 11 Total... 35 8 Total... 8 10 20 1 2 5 5 12 24 12 24 8 16 12 24 12 12 4 7 Total... 134 81-280 O-69--pt. 11-43 PAGENO="0666" 4956 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPMW PRODUCT NO. ISSUES NO. PAGES Neisler Laboratories 1. Dainite-KI 8 8 2. Diutensen 11 22 Total... 30 National 1. Nicalex 5 5 2. Quinamm 2 2 Total... 7 Parke-Davis 1. Benylin 7 7 2. Carbrital 11 11 3. Dilantin 8 8 4. Thera-Combex 3 3 Total... 29 Pfizer, Chas. 1. Bonine 11 11 2. Daricon 10 20 3. Diabinese 12 26 4. Desitin 5 5 5. Renese 8 20 6. Vistaril 5 13 Total... 95 Pharinacia Laboratories 1. Azulfidine 7 Total... 7 Purdue-Frederick 1. Senokot 3 Total... 3 Riker Laboratories 1. Nedihaler-Duo 10 20 2. Norgesic 1 Total... 22 Robins, A. H. 1. Diinetane 12 12 2. Quinidex 12 24 3. Robinul 12 23 Total... 59 83 PAGENO="0667" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4957 COMPANY PRODUCT NO. ISSUES NO. PAGES Roche Laboratories 1. Librium 9 18 2. Tigan 6 12 Total... 30 Rorer, Wm. H. 1. Ascriptin 12 13 2. Maalox 12 21 3. Parepectolin 3 3 Total... 37 Sandoi Pharmaceutical 1. Belladenal 12 12 2. Cafergot 11 11 3. Fiorinal 11 11 4. Nellaril 12 14 5. Sansert 1 1 Total... 49 Schering Corporation 1. Signamycin 3 3 2. Soluspan 2 Total... 7 Searle, G. D. 1. Aldactazide 8 8 2. Anavar 3 6 3. Enovid 10 19 4. Flagyl 2 2 5. Pro-Banthine 1 1 Total... 36 Smith, Kline, & French 1. Combid 9 9 2. Cytomel 7 8 3. Ecotrin 6 6 4. Esketrol 1 1 5. Dexedrine 3 3 6. Dyrenium 8 9 7. Spansule 9 9 8. Thorazine 3 3 Total... 48 84 PAGENO="0668" 4958 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Squibb 1. Kenacort 6 6 2. Medotopes 2 2 3. Nysteclin 3 3 4. Noctec 11 11 5. Oragrafin 2 2 Total... 24 Stuart 1. Dialose 3 3 2. Mylicon 9 12 3. Mylanta 10 23 Total... 38 U.S. Vitamin & Pharmaceutical 1. Arlidin 5 20 2. DBI 5 20 Total... 40 Upjohn 1. Solu-Medrol 9 Total... 9 Wallace Laboratories 1. Capla 2 2 2. Deprol 11 21 3. Meprospan 2 2 4. Milprem 8 8 5. Miltrate 5 5 6. Miltown 11 22 7. Soma 3 3 Total... 63 Warner-Chilcott 1. Anusol 12 12 2. Colymycin 9 14 3. Gelusil 12 12 4. Peritrate 11 22 Total. ~. 60 Warren-Teed 1. Ilopan 10 10 2. Kaon 9 19 3. Modane 9 9 Total... 38 85 PAGENO="0669" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4959 COMPANY NO. ISSUES NO. PAGES 1. A&D 11 2. Permitil 3 3. Disophrol 9 1. Isuprel 2. Winstrol 1. Aldurox 2. Equagesic 3. Equanil 4. Equinitrate 5. Mepergan 6. Oxaine 7. Serax 8. Unipen 9. Zactirin 1. Quinaglute 8 10 Total... 18 1 17 20 17 4 17 14 18 12 Total... 120 12 Total... 12 White Winthrop Wyeth Laboratories 22 22 Total... 50 7 7 1 10 10 9 4 6 5 9 4 86 PAGENO="0670" 4960 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ANNALS OF INTERNAL MEDICINE Summary Data 1966 10 Leading Firms, by Volume of Advertising Rank Firm No. Drug Advertising Pages 1 Smith, Kline, & French 78 2 Geigy 73 3 Lilly 73 4 Stuart 70 5 Wyeth 70 6 Robins 68 7 Squibb 62 8 Merck, Sharpe & Dohme 61 9 Bristol Laboratories 55 10 Mead-Johnson 49 10 Most Heavily Advertised Drugs Rank No. Pages on which Advertised 1 Dymelor (Lilly) 36 2 Vasodilan (Mead-Johnson) 32 3 Kantrex (Bristol) 25 4 Darvon (Lilly) 24 5 Librium (Roche) 24 6 Mylanta (Stuart) 24 7 Quinidrex (Robins) 24 8 Pertofrane (Geigy) 23 9&lO Isordil, Ritalin, Roniacol 22 87 PAGENO="0671" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4961 COMPANY Abbott Laboratories Burroughs-Wellcome 1. Actadil 2. Alkeran 3. Empirin 4. Lukeran 5. Various 6. Zyloprim NO. PAGES 12 4 8 24 8 11 2 8 6 Total... 14 25 21 9 Total... 55 4 2 3 2 1 6 Total... 19 Total... 7 ThE ANNALS OF INTERNAL MEDICINE 1966 Amf re-Grant Arch Laboratories Armour Ayerst Laboratories Bristol Laboratories PRODUCT NO. ISSUES 1. Fero-Grad 12 2. Surbex 4 3. Vercyte 4 1. Neo-Corovas 5 1. Dicarbosil 11 1. Pentritol 1 1. Formatrix 8 2. Thiosulfil 3 1. Kantrex 11 2. Polycillin 10 3. Tetrex 6 Total... Total... Total... Total... Chesebrough-Pond, Inc. 4 2 3 2 1 4 1. Measurin 88 PAGENO="0672" 4962 COMPETITIVE PROBLEMS ll~T THE DRUG INDITSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES CIBA Pharmaceutical Company 1. Doriden 9 11 2. Regitine 6 6 3. Ritalin 10 22 Total... 39 Cutter Laboratories 1. Peridial 12 12 2. Polysal-M 12 12 Total... 24 Davies, Rose-Hoyt Pharmaceutical Co. 1. Pil-Digis, Davokin, Myodigin 4 4 2. Pil-Digis 8 8 Total... 12 Dome Laboratories 1. Aniinet 6 Total... 6 Dorsey 1. Trest 1 Total... 2 Eaton Laboratories 1. Furadantin 9 Total... 12 Endo Laboratories 1. Coumadin 4 8 2. Hycodan 3 3 3. Percodan 12 12 Total... 23 1. Anturane 2 4 2. Hygroton 4 8 3. Persantin 4 8 4. Pertofrane 7 23 5. Preludin 7 14 6. Tandearil 4 8 7. Tofranil 4 8 Total... 73 89 PAGENO="0673" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4963 CONP~NY PRODUCT NO. ISSUES NO. PAGES Hoechst 1. Lasix 2 Total... 20 Glenwood 1. Myocholine 1 1 2. Potaba 6 6 Total... 7 Ives Laboratories 1. Isordil 11 Total... 22 Knoll Pharmaceutical Co. 1. Dilaudid 12 Total... 12 Lakes ide 1. Norpramin 4 Total... 5 Lederle 1. Aristocort 6 12 2. Artane 1 1 3. Declomycin 5 10 4. Hydromox 1 2 5. Pathibamate 6 12 Total... 37 Eli Lilly & Company 1. Darvon 12 24 2. Dymelor 12 36 3. Keflin 4 13 Total... 73 S. E. Massengill Company 1. Obedrin-LA 9 Total... 9 McNeil Laboratories 1. Butisol 12 12 2. Tylenol 1 1 Total... 13 90 PAGENO="0674" 4964 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Merck, Sharpe, & Dohme 1. Aramine 3 6 3 2 2. Benemid 10 3. Decadron 6 4. Diuril 14 5. Dornavac 6 6. Elavil 14 7. Hydropres 2 2 8. Mephyton Total... 61 5 5 Mead-Johnson 1. Colace 6 32 12 2. Muconiyst 3. Vasodilan Total... 49 11 11 Merrell 1. Bentyl 10 2. Kolantyl 10 18 3. Tenuate Total... 39 National 1. Tepanil 6 Total... 12 5 5 Neisler 1. Dainite 10 2. Diutensen Total... 15 4 2 Organon 1. Durabolin 10 11 2. Hexadrol 12 12 3. Wigraine Total... 27 3 3 Pfizer 1. Daricon 1 2 2. Terramycin Total... 5 91 PAGENO="0675" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4965 COMPANY PRODUCT NO. ISSUES NO. PAGES Parke-Davis 1. Benylin 8 8 2. Carbrital 12 12 3. Dilantin 9 9 Total... 29 Pharmacia 1. Azulfidine 12 Total... 12 Purdue-Frederick 1. Senokot 5 Total... 5 Riker 1. Duo-Medihaler 1 Total... 2 Robins 1. Dimetane 12 12 2. Dimetepp 11 11 3. Phenaphen 9 9 4. Quinidex 12 24 5. Robaxin 6 12 Total... 68 Roche 1. Librium 12 24 2. Roniacol 11 22 Total... 46 Roerig 1. Tao 1 Total... 1 Rorer 1. Ascriptin 11 11 2. Maalox 12 20 3. Quaalude 1 1 Total... 32 Sandoz 1. Belladenal 10 10 2. Belergal 4 4 3. Cafergot 12 12 4. Mellaril 6 12 Total... 38 92 PAGENO="0676" 4966 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Schering 1. Celestone 5 Total... 15 Searle 1. Aldactazide 5 16 2. Enovid 1 1 3. Lomotil 1 1 4. Ovulen 2 2 5. Probanthine 9 10 Total... 30 Sherman 1. Elixophyllin 5 Total... 9 Smith, Kline, & French 1. Combid 10 12 2. Cytomel 11 11 3. Dexedrine 6 6 4. Dyazide 8 20 5. Dyrenium 10 10 6. Eskatrol 4 4 7. Feosol 1 1 8. Stelazine 10 10 9. Thorazine 4 4 Total... 78 Squibb 1. Kenacort 5 5 2. Kenalog 7 14 3. Medatopes 2 3 4. Naturetin 4 7 5. Noctec 8 8 6. Pentids 1 1 7. Prolixin 2 4 8. Pronestyl 3 6 9. Raudixin 5 5 10. Rautrax 7 9 Total... 62 Stuart 1. Dialose 12 12 2. Mylanta 12 24 3. Mylicon 12 18 4. Stuartinic 11 16 Total... 70 93 PAGENO="0677" 1. Orinase 2. Tolinase 1. Arlidin 2. DBI-TD 3. Vaponefrin 1. Deprol 2. Miltown 3. Soma 1. Quinainm 2. Nicalex 1. Anusol 1. Kaon 2. Modane 1. Isuprel 2. Tranco-Gesic 3. Winstrol 1. A&D 2. Disophrol 7 14 5 10 Total... 24 4 7 4 9 4 4 Total... 20 3 6 3 6 2 3 Total... 15 1 1 1 1 Total... 2 1 10 20 8 14 Total... 34 3 3 7 7 3 3 Total... 13 8 9 2 3 Total... 12 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4967 COMPANY PRODUCT NO. ISSUES NO. PAGES ~pj~hn U.S. Vitamin Wallace Walker Warner-Chilcott Warren-Teed Winthrop White Total... 1 94 PAGENO="0678" 4968 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES 1. Equagesic 6 13 2. Equanil 9 18 3. Equanitrate 1 2 4. Mepergan 5 10 5. Oxaine 3 6 6. Serax 3 9 7. Unipen 1 2 8. Zacterin 5 10 Total... 70 1. Quinaglute 12 Total... 12 95 PAGENO="0679" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4969 ANNALS OF INTERNAL MEDICINE Summary Data 1967 10 Leading Firms, by Volume of Advertising. Rank Firm No. Drug Advertising Pages 1 Merck, Sharpe, & Dohme 96 2 Geigy 94 3 Head-Johnson 93 4 Lilly 91 5 CIBA 87 6 Lederle Laboratories 74 7 Ayerst Laboratories 63 8 Robins 60 9 Squibb 57 10 Abbott Laboratories 47 10 Most Heavily Advertised Drugs Rank No. Pages on which Advertised 1 Vasodilan (Mead-Johnson) 48 2 Dymelor (Lilly) 39 3 Lasix (Hoechst) 36 4 Aventyl (Lilly) 28 5 Atromid-S (Ayerst) 25 6 Darvon (Lilly) 24 7 Roniacol (Roche) 24 8 Ritalin (CIBA) 23 9 Tofranil (Geigy) 23 10 Zyloprim (Burroughs-Wellcome) 23 96 PAGENO="0680" 4970 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ANNALS OF INTERNAL MEDICINE 1967 COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Laboratories 1. Ferro-Grad 2. Nacroscan 3. Pertscan 4. Surbex-T 5. Vercyte l~ 8 12 12 11 1 11 12 12 Total... 47 Arch Armour 1. Dicarbosil 1. Letter 2. Pentritol 3. Thyrar 11 Total... 11 8 8 1 16 16 2 Total... 34 Ayerst Laboratories 1. Atromid-S 2. Penbritin 3. Riopan 4. Thiosulfil 5 6 6 7 25 12 12 14 Total... 63 Breon Laboratories Bristol Laboratories 1. Bronkometer 1. Kantrex 2. Polycillin 6 Total... 6 10 6 18 20 Total... 38 Burroughs-Wellcome 1. Actidil 3 4 2. Alkeran 3 3 3. Empirin 1 1 4. Leukeran 3 3 5. Myleran 3 3 6. Purinethol 3 3 7. Thioguanine 3 3 8. Zyloprim 9 Total. 1L .. 43 97 PAGENO="0681" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4973 COMPANY PRODUCT NO. ISSUES NO. PAGES Merck, Sharpe, & Dohme 1. Aldomet 9 18 2. Diuril 1 1 3. Elavil 3 6 4. Hydrodiuril 8 18 5. Hydropres 8 16 6. Indocin 11 22 7. Mephyton 9 9 8. Triavil 2 6 Total... 96 Merrell, Wa. S. 1. Bentyl 5 10 2. Kolantyl 5 10 3. Tenuate 10 22 Total... 42 National 1. Tepanil 9 Total... 13 Neilser 1. Diutensen 3 Total... 5 Ortho 1. Ortho-Novum 2 Total... 4 Parke-Davis 1. Benylin 4 4 2. Carbrital 10 10 3. Eldec 9 13 4. Thera-Combex 3 3 Total... 30 Pfizer, Chas. 1. Diabinese 2 6 2. Renese 6 12 3. Terramycin 2 4 Total... 22 Pharinacia 1. Azulfidine 9 Total... 9 100 PAGENO="0682" 4974 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Purdue-Frederick 1. Cardioquin 2 Total... 2 12 12 Robins, A. H. 1. Dimetapp 6 12 2. Donnatal 8 8 3. Entozyme 4. Phenaphen 12 19 5. Robaxin 1 2 6. Quinidex Total... 60 Roche Laboratories 1. Roniacol 12 24 18 9 2. Tigacol Total... 42 8 8 Rorer, Win. H. 1. Maalox 6 8 2. Quaalude Total... 16 Rowell Laboratories 1. Cortenema 2 Total... 4 12 Searle, G. D. 1. Aldactazide 2 6 2 2. Metamucil 3. Lomotil 4. Pro-Banthine Total... 24 4 Smith, Kline, & French 1. Combid 2 3 2. Cytomel 3. Dexedrine 11 21 4. Dyazide 1 1 5. Dyrenium 1 1 6. Eskatrol 7. Stelazine 2 2 8. Thorazine Total... 38 101 PAGENO="0683" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY .497 5 COMPANY PRODUCT NO. ISSUES NO. PAGES - Schering Corporation 1. Celestone 3 6 2. Soluspan 3 Total... 12 Sherman 1. Elixophyllin 8 Total... 8 Squibb 1. Kenacort 9 9 2. Kenalog-IM 9 . 17 3. Medotopes 11 11 4. Pronestyl 10 20 Total... 57 Stuart 1. Mylanta 12 21 2. Mylicon 9 12 Total... 33 Unimed 1. SERC 2 Total... 4 U.S. Vitamin & Pharmaceutical 1. Emivan 6 10 2. Vaponef rim 6 10 Total... 20 Wampole 1. Theo-Organidin 1 Total... 1 Warner-Chilcott 1. Anusol 2 4 2. Mandelamine 3 6 3. Peritrate 4 9 Total... 19 Warrent-Teed 1. Kaon 4 11 2. Modane 1 2 Total... 13 102 PAGENO="0684" 4976 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES White Laboratories 1. Disophrol 6 Total... 9 Winthrop 1. Trancogesic 4 4 2. Winstrol 2 4 Total... 8 ~z~a 1. Numa 4 4 2. Quinaglute 10 15 Total... 19 103 PAGENO="0685" ANERICAN FAMILY PHYSICIAN Summary Data 1963-1967 YEAR TOTAL PAGES MAGAZINE TOTAL PAGES JOURNAL ADVERTISING DRUG ADVERTISING OTHER ADVERTISING 1963 (6 mo.)* 470 290 190 137 53 86 1964 1,058 602 456 370 88 1965 1,240 707 533 445 60 1966 1,261 677 584 70 1967 1,738 913 825 755 *Sjx issues unavailable for review 0 0 ~J2 H 0 ~ Percent~~~ OTHER ADVERTISING YEAR PERCENT TOTAL PAGES . PERCENT JOURNAL PAGES PERCENT ADVERTISING PAGES DRUG ADVERTISING AS PERCENT ALL ADVERTISING AS PERCENT ALL ADVERTISING 1963 lOO~ 61.7% 38.3% 72.1% 27.9% 18.9% 1964 1965 1966 1967 100% 100% 100% 100% 56.8% 57.0% 53.7% 52.5% 43.2% 43.0% 46.3% 47.5% 81.1% 81.2% 89.7% 91.5% ~-__________________ 18.8% 10.3%. 8.5% PAGENO="0686" 4978 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMERICAN FAMILY PHYSICIAN 1963 COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Laboratories 1. Calcidrine 3 3 2. Placidyl 1 1 3. Selsun 1 1 4. Vi-Daylin 3 3 Total... 8 Ayerst Laboratories 1. Mysoline 1 1 2. Premarin 6 6 Total... 7 Eaton 1. Furacin 2 Total... 2 Ernko 1. Enko Foam 1 Total... 1 Lilly 1. Haldrane 2 2 2. Ilosone 4 8 Total... 10 Mead Johnson 1. Natalins 3 9 2. Tacaryl 2 2 3. Tempra 2 4 Total... 15 Parke-Davis 1. Benadryl 5 5 2. Carbrital 5 5 Total... 10 Pfizer, Chas. 1. Bonine 6 6 2. Daricon 6 7 3. Renese 6 10 4. Tetracyn 4 4 Total... 27 105 PAGENO="0687" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4979 PRODUCT 1. Albee w/c 2. Dimetepp Extentahs 3. Donnagel 4. Phenaphren 5. Robavisal 6. Robaxin 7. Robihussin 1. Enovid 2. Lomatil 3. Pro-Banthene NO. PAGES 5 2 2 2 3 3 2 Total... 19 2 1 4 7 3 2 1 12 7 6 Total... 25 COMPANY Robins, A. H. Searle, G. D. Smith, Kline, & French Syntex Wallace Laboratories wyeth Laboratories NO. ISSUES 5 2 2 2 3 2 2 2 1 4 Total... 3 Total... 2 Total... 1 Total... 4 6 3 1. Daprisal 1. Synalar 1. Milltown 1. Bicillin 2. Equanitrate 3. Equagesic 106 PAGENO="0688" 4980 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY AMERICAN FAMILY PHYSICIAN 1964 PRODUCT 1. Placidyl 1. Chymer 2. Pentritol 1. Plegine 2. Preinarin 1. Asbran 1. Hycodan 2. Rycotnine 3. Percodan 4. Valpin-PB 1. Geyrite 2. PeritinIc 1. Butibel-Zynne 2. Butisol 1. Teinpra 2. -. ~oIy-vi-F1or 3. Trii-vi-sol NO. ISSUES NO. PAGES 3 Total... 3 1 2 5 __~Q_ Total... 12 2 2 4 Total... 4 6 3 Total... 6 1 1 4 6 9 9 6 11 Total... 27 4 4 7 Total... 11 6 6 6 6 Total... 12 12 12 3 8 3 5 Total... 25 CONPANY Abbott Armour Ayerst Dorsçy Endo Lederle McNeil Nead-Johnson 107 PAGENO="0689" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4981 COMPANY PRODUCT NO. ISSUES NO. PAGES Neisler 1. Di~tensen 6 12 2. Krem 4 6 3. Rynatan 10 13 4. Rynatuss 10 13 5. Synatan 9 14 Total... 58 Ortho 1. Ortho-Novvm 4 Total... 8 Parke-Davis 1. ABDEC 7 7 2. Adroyd 6 10 3. Benadryl 2 2 4. Carbrital 10 10 5. Dilantin 2 2 6. Elase 2 2 7. Thera-Cainbey 9 9 Total... 42 Pfizer 1. Oalmito 4 4 2. Darican 2 4 3. Signemycin 12 34 4. Terramycin 4 11 5. Vistaril 7 17 Total... 70 Robins 1. J~iiae1tepp Extentabs 10 13 2. Donnagel 6 6 3. Exna 2 4 4. Robitussin 6 6 5. Robinul 2 Total... 35 Roche 1. Valium 7 Total... 7 108 PAGENO="0690" 4982 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODU(~ NO. ISSUES NO. PAGES 6 3 Searle 1. ~ 2. Enovid 2 2 3. Flagyl 4. LamotIl 5. Netamucil 6. Pro-Banthene Total... 18 Smith, Kline, and French 1 2 1. Chiorpromazine 6 6 2. Thorazine Total... 8 Syntex 1. Synalar 10 Total... 13 3 3 ~~lace 1. Neprospan 3 6 2. Hiltown Total... 9 109 PAGENO="0691" COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY DRUG 1. Chymar 2. Dentrital 3. Pentritol 1. Butazolidin 2. Persantin 1. Butthel-Zyme. 2. Butiserzapide 3. Buti~ol 4. Parafan-Forte 110 4983 PAGES 20 2 17 Total... 39 Total... 12 Total... 2 6 3 12 Total... 21 4 5 9 1 7 9 2 Total... 11 10 20 9 12 Total... 51 COMPANY AMERICAN FAMILY PHYSICIAN 1965 NO. -- NO. 1. Preniarin 1. Asbron 1. Hyconiine 2. Percodan 3. Valpin Armour Ayerst Dorsey Endo Hankscraft Lederle Lilly 1'1cNeil ISSUES 10 1 9 12 1 3 3 12 4 3 Total... 1 Total... 7 Total... 1. Zyinenol 1. Peritinic 1. Darvon 2. Tetra-Solgun 3 2 10 12 9 12 PAGENO="0692" 4984 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY DRUG NO. ISSUES NO. PAGES Neisler 1. Dainite-KL 8 8 2. Diutensen 12 25 3. Rynatan/Rynatuss 9 32 4. Synatan 8 18 Total... 83 Ortho 1. Diutenstrol 5 5 2. Ortho-Novuin 12 29 3. Sultrin 5 5 Total... 39 Parke-Davis 1. ABDEC 6 6 2. Benadryl 8 8 3. CarbrItal 11 11 4. Nyadec 7 7 5. Thera-Coinbey 10 10 Total... 42 Pfizer 1. Bonine 10 10 2. .Calmetrol 3 3 3. Daricon 5 10 4. Diabinese 12 28 5. Meclezine-HCL 1 1 6. Vistaril 5 14 Total... 66 Robins 1. Albee 2 2 2. Donnatel 2 2 3. Entozyme 4 4 4. Robitussin 3 6 Total... 14 Riker 1. Duo-medihaler 6 Total... 12 111 PAGENO="0693" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4985 COMPANY DRUG NO. ISSUES NO. PAGES Schering 1. Afrin 4 8 2. Metretan 2 2 3. Metriderm 1 1 Total... 11 Seozle 1. Enouid 5 9 2. Flagyl 3 6 3. Lamotil 1 2 4. Pro-Banthene 3 3 Total... 20 Smith, Kline, French 1. Stelazine 3 Total... 3 Winthrop 1. Negram 2 Total... 2 112 PAGENO="0694" 4988 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY CONPM~Y DRUGS NO. ISSUES NO. PAGE~ Robins 1. Albee 3 3 2. Entozyme 11 11 3. Robaxin 6 12 4. Robitussin 4 12 Total... 38 Schering 1. Afrin 7 14 2. Celestine 5 13 3. Coricidin 3 3 4. Chlor-trimeton 2 2 5. Fluvicin 2 4 6. Baramycin 6 21 7. Polaramine 6 12 8. Tinactin 2 4 Total... 73 Searle 1. Aldactazide 3 6 2. Flagyl 3 6 3. Lomotil 2 4 4. Ovulen 4 20 5. Pro-Banthine 3 5 Total... 41 Smith, Kline, and French 1. Dexainyl 6 Total... 6 Warner-Chillcott 1. Peritrate 1 Total... 2 1. Bi-cillin 5 10 2. Omnipen 8 16 Total... 26 115 PAGENO="0695" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4989 AMERICAN FAMILY PHYSICIAN 1967 COMPANY PRODUCT NO. ISSUES NO PAGES Abbott 1. Compocillin 4 6 2. Erythrocin ~ 12 Total... 18 24 Cole 1. 2. Asniinyl Indo-~N1acin 1 3 Total... 2 6 8 Endo 1. 2. 3. Hycomine Percodan Valpin 7 5 8 Total... 14 10 8 32 9~~z 1. 2. 3. Pertofrane Preludin Tofranil - 6 5 6 Total 16 10 10 36 Hankscraft 1. Zymenol 5 Total... 5 1. 2. 3. C-Quens Ilosane V-Cillin-K 2 11 11 Total... 6 28 28 62 McNeil 1. 2. 3. 4. 5. 6. Butiserpazide Butiserpine Butisol Butisone Parafon Tylenol 12 12 7 5 7 12 Total... 21 15 9 8 7 34 94 116 PAGENO="0696" 4990 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Mead Johnson 1. Oracan 2 Total... 16 Merck, Sharp, & Dohme 1. Benemid 10 20 2. Diuril 3 3 3. Indocin 8 16 Total... 39 Merrell 1. Bentyl 5 Total... 9 Organon 1. Accelerase 7 Total... 12 Ortho 1. Delfen 2 2 2. Ortho-Gynol 3 3 3. Ortho-Novum 11 39 Total... 44 Parke-Davis 1. Benylin 9 9 2. Carbrital 12 12 3. Cosanyl 4 4 4. Paladec 3 3 5. Pitocin 8 8 6. Povan 2 4 Total... 40 Pfizer 1. Diabines 2 5 2. Urobiotic 8 16 Total... 21 Pitrnan-Moore 1. Orifer 6 Total... 12 Riker 1. Estomul 7 Total... 8 117 PAGENO="0697" 4991 THE DRUG INDUSTRY COMPANY - NO. ISSUES NO. PAGES Robins Roche Schering Searle Sherman Smith, Kline, & French Squibb COMPETITIVE PROBLEMS IN PRODUCT, 1. Albee 2. Entozyme 3. Robaxin 4. Robitussin 1. Gantanol 2. Gantrison 3. Roniacol 4. Tigan 1. Afrin 2. Celestone 3. Coricidin 4. Etrafon 5. Garamycin 6. Medilets 7. Polaramine 8. Tinactin 1. Flagyl 2. Lomotil 3. Ovulen 4. Pro-Banthene 1. Persisten 1. Stelazine 1. Delestrogen 2. Kenecort 3. Hematinie 4. Principen 5. Raudixin 6. Theragran 118 12 12 6 6 4 5 8 11 Total... 34 4 5 2 2 3 3 3 .3 Total... 13 12 14 8 20 2 2 3 5 12 24 1 1 4 8 1 2 Total... 76 5 8 4 8 1 2 2 4 Total... 22 5 Total... 5 2 Total... 2 4 8 5 5 4 4 2 2 12 12 12 23 Total... 54 PAGENO="0698" 4992 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMPANY PRODUCT NO. ISSUES NO. PAGES Stuart 1. Dialose 4 8 2. Nylanta 9 18 3. Mylicon 9 12 4. Prenatal 11 Total... 49 1. Equanil 3 6 2. Oxaine 4 4 3. Phenergan 3 5 4. SMA-526 5 10 5. Sparine 3 6 6. Thiomerin 4 7 Total... 38 119 PAGENO="0699" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4993 JOURNAL OF ABDOMINAL SURGERY SUMMARY DATA Advertising, 1963 through 1967 Volume in Pages Total Total Total Total Pages Total Pages Pages Pages Pages Drugs Other Year Magazine Journal Advertising Advertising Advertising 1963* 221 155 66 43 23 1964* 221 171 50 20 30 1965* 279 158 121 77 44 1966 626 397 229 162 67 451 298 153 110 43 * Bi-monthly Percentages Percent Percent Percent Drug Advertising Other Advertising Total Journal Advertising as Percent as Percent Year Pages Pages Pages All Advertising All Advertising 1963 100% 70.1% 29.9% 65.1% 34.9% 1964 100% 77.3% 22.7% 40.0% 60.0% 1965 100% 56.6% 43.4% 63.6% 36.4% 1966 100% 63.4% 36.6% 70.7% 29.3% 1/ 1967 100% 66.0% 34.0% 71.8% 28.2% 1/ Data based on review of 8 out of 12 issues for 1967. 120 PAGENO="0700" 4994 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JOURNAL OF ABDOMINAL SURGERY 1963 COMPANY PRODUUI NO. ISSUES NO. PAGES Baxter 1. Cozyme 4 Total... 4 1. Darvon 4 10 2. V-Cillin-K 2 2 3. losone 2 2 Total... 14 Merck, Sharp and Dohme 1. Sulfathilidine 1 1 2. Neothalidine 2 2 3. Sulfasuxidine 2 2 Total... 5 ~~anon 1. Cotazyme 2 Total... 2 Pfizer 1. Terramycin 6 Total... 12 1. Mepergan 4 Total... 5 121 PAGENO="0701" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4995 JOURNAL OF ABDOMINAL SURGERY 1964 COMPANY PRODUCT NO. ISSUES NO. PAGES Merck, Sharp and Dohme 1. Sulfasuxidine 1 1 2. Aramine 1 1 3. Mephyton 1 `1 Total... 3 Robins, A. H. 1. Donnazyme 5 Total... 9 1. Mepergan 2 3 2. Oxaine 2 5 Total... 8 122 PAGENO="0702" 4996 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JOURNAL OF ABDOMINAL SURGERY 1965 1. Surbex 1. Kantrex 2. Polycillin 3. Prostaphlin ISSUES NO. PAGES 1 Total... 2 3 3 3 4 2 2 Total... 9 Knoll Merck Mead-Johnson Roche Upjohn Warren-Teed Warren-ChilcOtt 1. Dilaudid 1. Sulfasox 1. Sustagen 1. Librium 1. Solv-cortef 1. Ilopan 1. Coly-Mycin 1. Aludrot 2. Oxaine 3. Equ'inol 5 Total... 5 5 Total... 10 5 Total... 5 6 Total... 6 Total... Total... Total... Abbot Bristol COMPANY PRODUCT NO. 5 6 2 1 5 3 5 13 2 1 11 7 Total... 19 123 PAGENO="0703" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4997 JOURNAL OF ABDOMINAL SURGERY 1966 Abbott Bris tol Knoll Merck Massengill Robins, A. H. Roche Sandoz Searle Rorer Upjohn 1. Surbex 1. Kantrex 2. Prostaphilia 1. Dilaudid 1. Neothialidine 1. Adrenosen 1. Albee w/c 1. Librium 1. Torecan 1. Metamucil 2. Dramamine 1. Argnase/maalox 1. Solv-Cortet 2. Gelfam 1. Winthrop/carbocaine 1. Coly-mycin 1. Ilopan 1. Oxaine 124 ISSUES NO. PAGES 5 Total... 7 6 6 6 6 Total... 12 11 Total... 11 8 Total... 16 3 Total... 12 12 Total... 12 12 Total... 12 12 Total... 12 6 6 5 5 Total... 11 5 Total... 5 12 12 1 1 13 1 19 12 6 Total... 1 Total... 10 Total... 12 Total... 3 Total... COMPANY PRODUCT NO. Winthrop Warren-Chilcott Warren-Teed PAGENO="0704" 4998 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JOUBNAL OF ABDOMINAL SURGERY 1967 (8 Issues) COMPANY PRODUCT NO. ISSUES NO. PAGES Abbott Surbex 8 8 Ayerst Riopan 4 8 Bristol Kantrex 7 7 16 Darvon Merck Neothalidine 12 Mead-Johnson Partagen 4 7 Robins Ailbee 4 4 Entozytne 4 4 Total... 8 Roche Librium 8 8 Rorer Maalox 4 4 Searle Metamucil 5 5 Dramamine 3 3 Total... 8 Warren-Chilçp~ Coly-Mycin 7 10 0 125