2. Rauwolfia alkaloids: (psychomotor agitation): Reserpine Rescinnamine Deserpidine 3. Chemically heterogeneous tranquilizers (anxiety-tension states): (a) Diphenylmethane derivatives: 1. Examples of failure to emphasize adequate harmful side effects of drugs Drug A: Marketed across the country after only two clinical studies had been published, containing negligible mention of side effects. Harmful side effects of this drug subsequently published in: Journal, American Medical Asociation, 162: 628. 1956. Drug B: Advertising represents the drug as having negligible side effects and complications, yet a report by a reliable investigator in the New York State Journal of Medicine, 57: 1742, 1957 (see also American Journal of Psychiatry 114: 656, 1958), describes important and potentially dangerous side effects. Subsequent advertising of both these drugs had continued to neglect or minimize side effects. 2. Use in advertising of uncontrolled investigations with neglect of negative studies and controlled experiments Drug A. Marketed after only two published clinical reports of its effectiveness. Advertising has continued to quote from uncontrolled and impressionistic observations and to neglect mention of two controlled studies of this drug which show that it is not more effective than a blank placebo or a much cheaper barbiturate. (Editorial: British Medical Journal, Nov. 24, 1956, 1227) "TOXIC EFFECTS OF MEPROBAMATE "The sedative drug meprobamate (Miltown, Equanil) is beginning to be widely prescribed in Britain. It is a drug which has been accepted everywhere in the United States both by doctors and by the public, to whom surprisingly enough it is advertised. Last March a drugstore in Los Angeles displayed a large advertisement, 'Yes, we have miltown.' It has been praised almost daily in the press, on the wireless, and on television, the particular claim being that it is specially suited for the relief of tension, anxiety, and insomnia, since it is almost free from side effects. What is happening now is that the side effects and undesirable actions are being discovered and recorded. Meprobamate has caused severe and widespread skin reactions. H. T. Friedman and W. L. Marmelzat1 describe five cases in which mainly purpurtic rashes were seen. These were accompanied by severe itching, and appeared first in the area of the pelvic girdle, the genitalia, and groin. They say that one 400-milligram tablet of 1 Friedman, H. T., and Marmelzat, W. L., J. Amer. Med. Assoc., 1956, 162, 628. meprobamate may produce the skin lesions in less than 4 hours. In addition they report 3 cases in which the drug produced not sedation but excitement, 1 case of excessive peristalsis and diarrhea, and 1 case of palsy of the extraocular muscles with diplopia. W. J. Carmel and T. Dannenberg 2 also describe 3 cases of purpura, oedema, and erythema observed within 3 months. A patient after taking two tablets suffered from generalized pruritus with petechial dermatitis over the thighs and inguinal region, later affecting arms, hands, and feet. The thighs and buttocks were diffusely swollen and erythematous. This record is characteristic of the others. F. I. Gottlieb has also described a case of a woman of 42 who, after a third tablet, developed a widespread hemorrhagic rash on the axillae, breast, abdomen, thighs, and legs. She had a rise of temperature together with chills and some oedema. After 4 days she had widespread purpura. These results strongly suggest that meprobamate belongs to the class of compounds which can release histamine in the body. F. Lemere * considers that meprobamate is habit forming, since patients become dependent on it and cannot continue without it. Six patients who had been formerly addicts to alcohol and barbiturates refused to continue taking meprobamate because they did not want to become addicted to it also. 4 "In the journal this week Drs. E. D. West and A. F. da Fonseca report some controlled trials with meprobamate. In one of them they compared it with sodium amylobarbitone in the treatment of 51 patients with psychoneurosis and found the results were almost the same. But the authors add that some few patients did benefit from meprobamate only and others from sodium amylobarbitone only. Transient urticarial rashes occurred in five of their patients. Meprobamate has the disadvantage of costing the hospital dispensary 24 times considerations suggest that claims made for meprobamate that it is the ideal as much as an equivalent therapeutic dose of a short-acting barbiturate. These drug for the treatment of insomnia, tension, and anxiety should be accepted with great reserve." Disagree with Dr. Kline as to (a) Capacity of physicians to evaluate drugs. Many examples show their failure to do this: Bleeding, purging, blistering; diet for ulcer, recently studied; many surgical operations. (b) That the market place is the best place for the test of a drug. Alcohol, tobacco, different brands of aspirin, at least one well-known tranquilizer, spa treatments. Advertising will not be continued unless it is valuable, but medical treatments may be. 3. Examples of use of dramatic, pictorial, and symbolic techniques of advertising. (1) Symbolic techniques. Snow in the woods, alpine mountains and lakes to suggest serenity and link this with the tranquilizer named. Many such advertisements contain almost no expository verbal content. (2) Pictures of patients disturbed, depressed, anxious, and subsequently radiantly cheerful with implication that they have been transformed by the drug advertised. Word pictures similarly drawn; brief cases histories. (3) Phrases of dramatic impact, torn out of context and run as leads to and advertisement. Now "care of the man rather than merely his stomach" in ad for a tranquilizer combined with anticholinergic drug quoted from a book, the authors of which have spent years studying the influence of suggestion and who have protested the uncritical widespread use of many drugs having no value. Drug B: Marketed with wide advertising as having "normalizing" effects. A recent article in American Journal of Psychiatry, 111: 656, 1958, reported a study in which this drug was found relatively ineffective compared to other preparations in its group. 3. Use of dramatic, pictorial, and symbolic techniques of advertising Examples provided of drugs C, D, E. 4. Use of quasi-scientific manner of presenting advertising material Example of drug F. 2 Carmel, W. J., and Dannenberg, T., New England J. Med., 1956, 255, 770. 3 Gottlieb, F. I., J. Amer. Med. Assoc., 1956, 161, 96. 4 Lemere, F., ibid., 1956, 100, 1431. 5. Oversimplification of psychiatric treatments in advertising with implications that tranquilizing drugs are sufficient by themselves Examples taken from advertising material for drug B. Additional reference: West, E. D., and da Fonseca, A. F., controlled trial of meprobamate, British Medical Journal, November 24, 1956, 1207. USE OF QUASI-SCIENTIFIC MANNER OF ADVERTISING Drug F: Advertisement in free medical journal given to physicians, but containing scientific articles. Advertising generally considered to be conforming to lower standards than in other medical journals. However, the major drug firms use these journals for their advertising. Why should they pursue two standards of advertising when these are permitted? This advertisement contained seven references: 1. In press. 2. Published, but article contained no controls and longest period of observation was 6 months although ad said drug could be used over long periods of time. 3. In press 4. Published and competent with controls but misrepresented in the advertisement. The author emphasized the point that the drug studied did not offer greater freedom from complications or recurrences than placeboes (blank pills), yet the advertisement implies that it does. 5. Personal communication to the drug manufacturer. 7. Personal communication to the drug manufacturer. In other words of the 7 references listed, 5 were inaccessible for practical purposes. Of the 2 which were accessible, 1 was an entirely inadequate study. The one careful study quoted and accessible was seriously misrepresented as saying something the author never said and in fact he had said the opposite. EXHIBIT 12 [Reprinted from JAMA October 12, 1957, pp. 657-661] "TWIXT THE CUP AND THE LIP Harry F. Dowling, M. D., Chicago The development of a drug is an intricate process, involving researchers, manufacturers, clinical investigators, and many others. All of the information obtained about the drug must be brought to the practicing physician, who is the one to prescribe or administer the drug, and it is important that this information be timely and accurate. In the evaluation of new drugs, the practicing physician should do three things. First, he should learn the mechanism by which the drug works, rather than the results somebody says it will produce. By learning the generic name, the physician can understand much about the drug. Second, when asked by a patient to prescribe a drug that is not indicated, the good physician explains rather than prescribes. Last, doctors should read pharmaceutical advertisements critically, and not be hesitant to write to editors of journals as well as drug manufacturers when they question the truth. Only in these ways can the medical profession advise and assist such a dedicated organization as the Food and Drug Administration to properly judge the merits of a drug. Drugs are discovered, manufactured, and tested by scientific methods. On the other hand they are produced and marketed through a blend of personal and social motives; they are prescribed by doctors with varying knowledges and skills, and they are taken by patients who have different degrees of information, interest, and precision. Drugs are brewed in the cup of science, they are drunk through a patient's lips, and "there's many a slip twixt the cup and the lip." Scientific attention is usually turned toward the discovery of drugs; in the present paper I shall consider the path from their development to their use. As an example, let us take chlortetracycline, one of the first antibiotics to be produced by a pharmaceutical company. After screening hundreds of specimens of soil, Duggar isolated Streptomyces aureofaciens, in the fall of 1945. Its in vitro antibacterial activity was demonstrated later in the same year. Preparation of crude concentrates that protected animals against bacterial infections required an entire year, and further purification and initiation of large-scale production required nearly 2 years more. It was not until September 1948 that clinical tests were considered adequate for submission of the data to the Food and Drug Administration. Approval by this agency was granted in October 1948, and chlortetracycline was finally marketed on December 1, 1948.1 The path of a drug from cup to lip, which took over 3 years in the case of chlortetracycline, is shown in figure 1. Basic research by medical schools, pharmaceutical companies, and others leads to the discovery of a new drug. It is produced in a form suitable for administration by the pharmaceutical manufacturer. Its efficacy must then be tested in vitro, and its efficacy and toxicity, in lower animals. If these tests are satisfactory, the drug is tried in patients by investigators outside of the pharmaceutical industry. The accumulated information is then submitted to the Food and Drug Administration for approval or to the National Institutes of Health in the case of biological products. When approval is forthcoming the drug can be packaged, advertised to the profession, and sold. At the same time, investigators who have tried the drug in patients are informing the medical profession when and how this drug should be used. All of these paths lead a single goal: administration to patients. This benefits the patient through the prevention, amelioration, or cure of disease and brings profits to the pharmaceutical industry and related groups. These twin benefits act as sources of energy to start the process over again. FIGURE 1.-Diagonal lines refer to the pharmaceutical industry; horizontal lines, to the investigators in medical schools and hospitals, and stippled areas to other groups (Government agencies, the practicing physician, and the patient). This system is an outstanding example of man's genius for organization. It has been developed by idealistic motivation, aleng with down-to-earth planning; it balances the interests of scientist, investor, producer, physician, and patient. And it has filled the cup to overflowing. The number of effective drugs is beyond the highest hopes of a century ago and is increasing all the time. In the 30-year period from 1905 to 1935 new drugs were introduced into the United 1 Hardy, S. M., Lederle Laboratories division, American Cyanamide Co.: Personal communication to the author. NOTE. From the Research and Educational Hospitals and the Department of Medicine, University of Illinois. Chairman's address, read before the section on experimental medicine and therapeutics at the 106th annual meeting of the American Medical Association, New York, June 4, 1957. 25489 0-58--15 States Pharmacopeia at a rate that averaged 6 per year, while in the succeeding 20 years the average yearly rate was 37.2 Yet the system, like all systems, can be perverted. The process of fundamental research, followed by the development of worthwhile new products and the successive stages necessary to bring them to the patient, is a long one. The desire to help the patient and the desire for profits provide sufficient energy to power the process; but some have discovered that if this energy is applied at a later stage, the path from profit back to profit again can be speeded up. This is shown in figure 2. Energy, instead of being directed toward research and the discovery of new drugs, is frittered away on dozens of unimportant modifications designed to compete with drugs that are already available. One example of this is the marketing of mixtures of antibiotics. As of November 1956, there were on the market 29 preparations containing 2 antibiotics, 20 containing 3, 8 containing 4, and 4 preparations that contained 5 antibiotics apiece. I have shown elsewhere that there is no good reason for the use of any of these 61 mixtures. 4 If this trend continues, we shall soon reach the chaos that exists in Germany. According to a recent article in The Lancet, there are about 6,000 proprietary preparations marketed in Western Germany, made by 565 different firms. Most of these preparations contain several or many substances; 5 or 6 is the rule, and more than 10 is not at all rare. One firm has put 22 different substances into 1 tablet. It has become unfashionable to use one drug by itself. When the author of the article asked for ephedrine tables in a big hospital, he was told that these were no longer stocked. This sidetracking of energy within the system has further effects. When the drugs that are produced so prodigally are tested in the laboratory, only those are eliminated that are obviously toxic. Drugs that are superfluous because they duplicate the action of others that are already available and drugs that are of dubious effectiveness are continued in the process and eventually reach the market (fig. 2). For instance, 33 different antihistiminic drugs are being sold at present, all having practically identical actions but different names and dosages. Similar excesses can be found among other groups of drugs, especially the vitamins, the antispasmodics, and the tranquilizing drugs. 6 At the next step in the process pressure is applied upon investigators to report that all the drugs recently produced are beneficial to patients, that they are better than existing drugs, and that they have fewer side effects. Since this tremendous multiplication of new drugs exhausts the existing facilities for clinical investigation, inexperienced investigators are cajoled into assessing drugs in patients. Some learn the proper methods and acquire a critical sense during the experience; most do not but unwittingly call a spade a diamord—to the confusion of the Food and Drug Administration, the exasperation of the experienced and honest investigators, the quick profit of that particular manufacturer, and the loss of prestige of the medical profession and of the pharmaceutical industry as a whole. Increased pressure is applied in turn upon the Food and Drug Administration. No words can speak too highly of the services rendered to physicians and patient alike by this dedicated body of public servants. Quietly and unobtrusively, patiently and honestly, they attempt to judge the merits of a drug solely on the evidence presented to them. Their problems, however, are similar to those of every regulatory agency of the Government: they hear one side of the story loudly and incessantly; they hear the other side only sporadically and feebly. It is the drug manufacturer's business to present his viewpoint; it is to his interest to present it attractively and forcibly. The consumers, on the other hand, have no paid advances. Their viewpoint is presented by persons who 2 Beal, G. D.. director of research, Mellon Institute for Industrial Research, and Griffiths, M. C., editorial assistant, Pharmacopeia of the United States of America: Personal communication to the author. 3 Welch, H., Director. Division of Antibiotics, Food and Drug Administration, U. S. Health, Education, and Welfare Department: Personal communication to the author. Dowling, H. F. Mixtures of Antibiotics, Journal of the American Medical Association 164:44-48 (May 4) 1957. Medicine and the Drug Industry in Germany, from a correspondent, special articles, Lancet 2: 1304-1305 (December 22) 1956. Holland, A. H., Jr., Medical Director, Food and Drug Administration, U. S. Health, Education, and Welfare Department: Personal communication to the author. |