By reason of the evidence on the side reactions from the use of of reserpine, the Food and Drug Administration has suggested an upper limit for the recommended maintenance dose in the treatment of hypertension and a usual maintenance dose in the treatment of institutionalized psychotic patients. Since the two levels of dosage were different, it recommended distinctive statements on the label and the printing of declaration of the strength of the tablets in a different color from the rest of the label.

At the stage when there is widespread use of a drug, presumably much of it without medical supervision, when its full effects have not been determined, and when the evidence of associated morbidity, and mortality points to the possibility of an increase but is so insufficient as to be indefinite and indecisive, it is difficult to predict whether a situation detrimental to public health will develop. Hence it is not easy to reach a decision during this early period as to whether further legal safeguards should be established. When there are only indications but insufficient evidence of potential dangerous effects on a large scale, it becomes a matter of choice between two courses. According to one viewpoint, it is better to act early before the data becomes overwhelmingly decisive. Even if anticipations of the worst are not realized, any hardships incident to the imposition of controls are counted as small cost when balanced against the high dividends of safety ensuing from precautionary measures. The opposing school is of the opinion that it is important to be certain that controls are essential for the management of a public-health problem before action is taken. This view would counsel to defer controls until sufficient evidence of harmful effects on a large scale had been established. Perhaps this position is best epitomized in the phrase "watchful waiting."

The diametrically opposite histories of usage and control of two other groups of drugs, the antihistaminics and the barbiturates, are illustrative. It may be recalled that indiscriminate widespread usage of the antihistaminics with their undesirable side effects occasioned a considerable problem for a time, but eventually the practice subsided. In the early days of the use of barbiturates there were only slight indications that these drugs might be misused and thus it was decided that additional control of them should await evidence of morbidity and mortality. That evidence was not long in coming and within a few years the problem had reached such a magnitude that the committee on public health deemed it desirable to recommend the imposition of further controls over usage of these drugs.

Of course, the important variable in the issue is the nature and degree of any increase in control. The committee is of the opinion that the evidence that tranquilizing drugs are now a menace to public health is inconclusive. It believes therefore that there are now no substantial grounds for establishing controls over tranquilizing drugs to such a degree as those over barbiturates. It is concerned about the possibility of misuse of tranquilizing drugs becoming a danger to public health. Indeed, it is equally or more concerned about the possible misuse of other drugs. As a general principle it believes that all drugs which belong in the category of potentially harmful or new drugs obtainable only upon prescription should be used only under medical supervision. This principle is a sound and self-evident criterion by which to test existing and formulate any new needed regulations and restrictions.

An amendment to the Federal Food, Drug, and Cosmetic Act provides that a drug intended for use by man which is a habit-forming drug or a potentially harmful drug or new drug shall be dispensed only upon a written prescription of a licensed practitioner, and refilling is authorized only upon written or oral order of the prescriber of the original prescription. All of the tranquilizing drugs come under these Federal provisions; hence they can be obtained only on prescription which cannot be refilled without the order of the original prescriber. But this law does not apply within States unless there is interstate commerce in the drugs. The Sanitary Code of New York City lists a number of harmful drugs for which a prescription is required. No prohibition against refilling of the prescription is specified except for three categories: sulfonamides, barbiturates and narcotics. Special rigid restrictions apply to the dispensing of barbiturates, particularly in the maner of refilling prescriptions. In the prescribing and dispensing of narcotic drugs, the code defers to the laws of the State of New York. It is apparent that on the point of refilling of prescriptions for potentially harmful or new drugs, the code is, with the exceptions noted, in many respects much more lax than the Federal Food, Drug, and Cosmetic Act. Consequently it falls short of insuring medical supervision over the use of these drugs.

The committee recommends that the sanitary code be revised to make it accord more fully with the provisions of the Durham-Humphrey amendment to the Food, Drug, and Cosmetic Act in respect to drugs which shall be available only upon prescription. Under this recommendation such drugs would include: new drugs, potentially harmful drugs and habit-forming drugs. This categorization should supersede the present list of individual drugs specified in the sanitary code. It would be more inclusive and at the same time more adaptive to future as well as present contingencies. It should be provided, as at present, that such drugs should be dispensed only upon prescription. The committee further recommends that the sanitary code be revised to provide that prescriptions for potentially harmful drugs and new drugs should not be refillable except upon written or oral order of the original prescriber. As exceptions, it would specifically assert that all existing tighter restrictions on the prescribing and dispensing of barbiturates and narcotic drugs would still prevail and would not be altered by such a proposed revision. This second recommendation would further bring the sanitary code much more in accord with the Federal, Drug, and Cosmetic Act.

It should be noted that prescribing and dispensing of tranquilizing drugs would be covered by these recommendations. Most of all, they would bring the use of potentially harmful and new drugs under full medical supervision.

An additional aspect of the situation is the extravagant and distorted literature which some of the drug houses are distributing to the medical profession. Such literature may be misleading in two respects. First, it may recommend a product in such a way as to lead to, if not encourage, its indiscriminate use. For example, a leaflet accompanying one tranquilizing drug lists under indications an almost endless number of situations and conditions of emotional stress at every stage of life: hyperactivity, irregular sleeping habits, nightmares and homesickness in children; the various circumstances in adolescence which give rise to severe anxiety and tension; in adulthood, apprehension and anxiety over finances, effects of excitement or misfortune in the family such as sickness, accidents, weddings, funerals, separations, and differing opinions. The drug is also said to be indicated in times of occupational stress: such as, anxiety over interviews, competitive examinations, or public appearances. Thus it is recommended for actors and actresses, radio and television performers, business executives, toastmasters, ministers, teachers, professors, and politicians. It is reported to be useful in the journalistic and advertising field with its tension, excitement, and noisy environment. The indications also include competitive sports.

Secondly, some manufacturers' literature which is distributed to physicians and pharmacists contain too frequently little or no mention of side effects and contraindications to the use of the tranquilizers. In one instance it is stated that the drugs are recommended for relatively short-term therapy and temporary conditions where emotional stress is a complicating or a causative factor. Most revealing is the assertion that investigations are underway to determine the safety and efficacy of the drugs during prolonged use. The failure to mention possible side reactions, contraindications, and potential dangers, or to devote a disproportionately small space to them, is likely to be highly misleading to the physician.

Manufacturers' literature on new drugs is presumed to guide the physician, not mislead him. Undoubtedly it will color the physician's attitude toward the drug, his use of it and his recommendations concerning it. Ultimately it affects in part the patient's attitude toward and use of the drug. When it is remembered that the physician may obtain his first information about new drugs from this literature, its validity and cautiousness become a matter of high importance.

The lay press has contributed its share to disseminating premature and incomplete accounts of the miraculous effects of the drugs. This practice has had its effect upon the public and ultimately both directly and indirectly upon the medical profession. From such journalism persons may obtain false impressions and exert pressure on their physicians to prescribe the tranquilizing drugs.

Through its committees on research, therapy, and public information the American Psychiatric Association has urged avoidance of premature and unreliable reports because they violate the standards for testing new therapies. It advised:

"The full cooperation of the profession in accumulating a body of tested scientific data about the drugs is of prime importance. * * * At the same time it is important to be aware of subtle pressures that combine to foster public misunderstanding and misuse of the drugs. There is the eagerness of the public, and of physicians themselves, for good news about a new treatment

for psychiatric disorders. This tends to foster popular stories based on optimistic reports of early and limited research findings with the drugs, before such findings can be reproduced and validated by other colleagues. * * * Persons engaged in any form of research or evaluation of therapy should be most dispassionate and objective in their pronouncements. It is suggested that members of the association be particularly alert to personal pressures (both internal and external) and circumspect in their announcements of early experimental results with the drugs."

The board of health is charged with the responsibility of enacting legislation to prevent not only over-the-counter sales and misuse of prescription drugs but also fraudulent or misrepresentative claims or statements about them. Because of the uncritical nature of some of the medical literature sent to physicians by pharmaceutical houses, particularly the expansive, extravagant, and indiscriminate listing of indications with inadequate citation of side reactions, contraindications, and precautionary measures, the committee on public health recommends that the board of health survey this literature as the first step toward bringing about improvement in it so that it may be a more reliable guide to physicians.

BIBLIOGRAPHY

American Psychiatric Association, committees on research, therapy, and public information. A statement on the contribution of the tranquilizing drugs to the treatment of psychiatric illnesses and the dangers inherent in the casual use of these drugs by the public for the relief of everyday tensions. June 16, 1956.

Friedman, H. T., and Marmelzat, W. L. Adverse reactions to meprobamate (J. Amer. Med. Assoc. 162: 628-630, 1956).

Kramer, M. Facts needed to assess the public health and social problems arising from the widespread use of the tranquilizing drugs. Working paper for: Conference on Pharmacotherapy in Psychiatry held at National Research Council, Washington, D. C., January 27 and 28, 1956.

Lemere, F. Habit-forming properties of meprobamate (Miltown or Equanil) (A. M. A. Arch. Neurol. Psychiat. 76: 205–206, 1956).

Letter from the Chief of the New Drug Branch of the Bureau of Medicine of the Food and Drug Administration of the United States Department of Health, Education, and Welfare, March 1956.

My name is

EXHIBIT 10A

STATEMENT OF DR. FREDERICK F. YONKMAN

Frederick F. Yonkman. I am the vice president in charge of research of CIBA Pharmaceutical Products, Inc., and have my office at Summit, N. J.

In accordance with the committee practice, I will summarize my professional

career.

After obtaining my A. B. in 1925 at Hope College, Holland, Mich., I did a year's graduate work at Yale University in 1925-26.

In 1928 I earned the Ph. D. degree from the University of Iowa, and in 1939 was awarded an M. D. at Boston University School of Medicine.

In 1932 I was awarded the first scholarship in pharmacology to the International Congress of Experimental Medicine in Rome, Italy.

From 1929 to 1939 I was engaged in teaching in Boston, Mass., as assistant, and later as associate professor in pharmacology and experimental therapeutics at Boston University School of Medicine; as professor of biology and physiology at Gordon College, Boston; as professor of anatomy at the Bouve School, and as pharmacologist at the Evans Memorial Hospital in Boston.

I have also served as professor of pharmacology and head of department at Wayne University School of Medicine, Detroit, Mich., and in 1942 was dean of students and chairman of the committee of interns and internships at that institution. I have also served on the postgraduate teaching staff of the University of Michigan and as toxicologist at Mount Carmel Mercy Hospital, Detroit, Mich.

In 1944 I became chief pharmacologist for CIBA, and director of research in 1945.

Between 1944 and 1952 I lectured in pharmacology and therapeutics at the Columbia University College of Physicians and Surgeons in New York City.

I am a member of the advisory council of the department of biology of Princeton University; and a trustee of the Columbia University College of Pharmacy. I am a member of the American and Michigan State Medical Associations, the American Society for Pharmacology and Experimental Therapeutics, the Society of Experimental Biology and Medicine, the Association of University Professors, and of the medicinal section of the American Chemical Society.

There is little that anyone can add to the splendid statements by Dr. Nathan S. Kline and Dr. Frank J. Ayd as to the background of the problem of mental illness, in the resolution of which the tranquilizing pharmaceuticals have come to play so important a role. I have been privileged to read Dr. Kline's statement. His vivid and accurate portrayal of the cost in human suffering, the unwarranted social stigma, and the economic drain when mental illness strikes, particularly in adolescence or young adult life, gave the committee a penetrating insight.

Nor need I attempt to add to his account of the dramatic impact of psychopharmaceuticals in this area in reversing the trend in public and private hospitalization of the mentally ill and in contributing to their private treatment. Seldom has this story been as accurately and as clearly presented as it was by Dr. Kline and in the testimony of Dr. Ayd.

In appearing here this morning in response to Mr. Johnson's request, I should like to make a few preliminary observations.

In the first place, I strongly agree with Dr. Kline that it would be ethically improper for any medical witness, as well as a hazardous disservice to the public, to discuss any specific psychopharmaceutical now being prescribed by physicians for their patients. The dangers of doing so have been fully expounded by Dr. Kline. Nor can I, with propriety, be asked to comment on the products or the practices of any company other than my own.

Secondly, I am in complete agreement with the chairman in what he said in his opening remarks when these hearings began in pointing out that the medical profession by virtue of its extensive scientific and medical training and professional experience is a highly sophisticated audience not easily misled. I would go further and suggest that no one can or should invade or impugn the professional confidence or the intelligence or integrity of any physician. Doctors, especially research workers, like most people in other professions, frequently disagree; but they do so on a professional plane. Only those with comparable professional training may make value judgments about the efficacy or the possible disadvantage of employing medical or any other type of therapy.

The general public is so intensely and understandably interested in medicine and any new medical development that the real danger is probably not that members of the medical profession would be misled but that flamboyant notions about supposed universal panaceas, or unwarranted apprehensions about the course of treatment being given them, might derive from misunderstanding of what has been developed in a hearing of this sort.

Most of all I hope that great care will be exercised not to thrust, even inadvertently, a wedge of doubt between physician and patient by any suggestion that a trained and licensed medical practitioner is perhaps not aware of what he is prescribing for his patients or is not qualified to evaluate what he reads about newly developed drugs. In that respect, I believe the chairman per

formed a valuable service in his opening remarks.

Thirdly, while I cannot, of course, discuss and do not know the operational details of all manufacturers of ethical drugs, I can tell you from my own experience that the ethical pharmaceutical manufacturing industry cherishes greatly its reputation with the medical profession. The integrity of its products and the validity of the claims it makes for them is the most valuable asset that any company has developed. To put this another way, most of the established pharmaceutical companies have been in business for a very long time and hope to continue to be. The interest of this committee in inquiring into the possibility of potential misrepresentation in promotional material sent to members of the medical profession is, of course, proper, but as has been pointed out in these hearings, the interest of the drug industry in these matters is far deeper, continuous and, as Dr. Kline has suggested, even of basic economic importance. By the same token in research-in the screening of newly developed pharmaceutical preparations, in their toxicological testing, and in the sound clinical evaluation of their therapeutic effect and potency-an ethical drug manufacturer

wants facts first and promotional materials secondly provided they are honest statements. It has, I believe, been made abundantly clear that most research grants are made "without strings." And the economic logic and necessity of getting the complete facts has been clinically demonstrated in the splendid achievements of the drug industry as a whole.

Fourthly, this point of potential side effects must never be misunderstood. Possible side reactions are not unknown with any drug, even those in widespread use, and I might add, many that are permitted by the Food and Drug Administration to be sold over the counter freely to any purchaser rather than restricted to prescription use. Dr. Kline has given you the example of aspirin. Many others might have been offered. In fact, in order to be effective any drug, without exception, must produce side reactions of some type in most patients; our task is to develop the most effective drug with the least number and severity of side reactions or undesirable effects.

In a population of almost 172 million there are always occasional individuals who may be allergic to a particular drug, indeed even to certain foods. We also know that some substances often have the faculty of potentiating the effect of others in the human body. But these are rare idiosyncrasies, not what any experienced pharmacologist or research worker would denominate as a common dangerous side effect.

Finally, I think the committee might be interested in a brief description of the functioning and objectives of a research department of a pharmaceutical manufacturing company and how it is organized. In this instance, I can escapebeing immodest by referring to an address recently given by Mr. T. F. Davies Haines, the president of CIBA, at Columbia University. He summarizes five important aspects of the drug industry research.

In the first place, it must be a continuing activity. The development of the necessarily highly skilled and diversified stages, and the providing of laboratory, pilot plant, and other essential facilities, takes many years. A worthwhile exploration of even a strictly limited avenue of inquiry in a narrow field. of investigation is a long drawn out process.

Members of the committee may recall the story of Ehrlich's discovery of salvarsan which is known to most people. As Mr. Haines pointed out, Dr. Ehrlich originally found "that certain parasitic micro-organisms were selectively stained by dyes containing the azochromophore and provided with appropriate auxochromic groups, Ehrlich synthesized and tested 605 compounds before hitting upon the 606th syphilis-destroying salvarsan. Investigators in other fields must test even larger series of compounds before they can expect success. Out of many hundreds of tested and classified antispasmodic drugs, only four are now widely used. More than 5,000 analgesics have been discovered, but only some 8 are commonly used. Of the over 14,000 chemical compounds tested for antimalarial activity, only 3 or 4 have been found satisfactory. To develop one of the broad spectrum antibiotics, a team of some 55 scientists spent 21⁄2 years, screening over 100,000 soil samples at a cost of around $4 million. (Only 76, of the 100,000 soil samples contained organisms showing any antibiotic activity at all.) So planning the research program must be a continuous, not an annual, process."

Next, the committee probably understands that any worthwhile research program must be vast in scope and costly. Mr. Haines reported that today 35. percent of our fixed assets are devoted to research. Laboratory buildings and equipment come high. Approximately $75,000 must be invested for each scientist of the doctor of philosophy level engaged in research. It is likely that the average industry figures would show that about 30 percent of the total capital expenditures made by a company go for research facilities. We have found that our own laboratory costs for doctor of philosophy research scientists (for depreciation, maintenance, lab assistants, supplies, but excluding administration, library, and outside grants) average $45,000 per year.

It must also be emphasized that drug research must be both basic research and, in terms of the types of scientific disciplines demanded, fairly diverse. Once again, to draw upon Mr. Haines: "The reason for this is apparent when oneconsiders how many different types of scientists must collaborate in the discovery and development of a new pharmaceutical product."

First chemists must synthesize, extract, isolate, or otherwise produce a chemical compound or, more likely, a series of related chemical compounds, and because of the high degree of empiricism that exists in medicinal chemistry the series of related compounds to be investigated in any given project is usually a long one.