of an ulcer. More important, reserpine in daily doses of 0.5 or 1.0 milligram produces severe depression in a significant number of individuals, and has precipitated a very considerable number of suicidal attempts, some of them successful. Many of these depressions have been severe enough to necessitate longterm hospitalization in psychiatric institutions."

Friedman and Marmelzat reported that adverse reactions following the administration of meprobamate included cutaneous, paradoxical cerebral, muscular and gastrointestinal effects. The cutaneous effects were chiefly purpuric with intense itching. Next in frequency was the production of excitement rather than the desired tranquilization. Severe diarrhea and temporary paralysis of the extraocular muscles producing diplopia also occurred.

Lemere has reported that withdrawal symptoms are sometimes experienced by patients taking meprobamate over a period of time. Originally he had believed that no tolerance to the tranquilizing drugs ever developed. But as an addendum to his report, he cited the observation of the tolerance phenomenon in nine patients. Such clinical reports on new drugs are valuable in pointing to levels of proper dosage. Furthrmore, they reveal the nature and severity of side effects which may be encountered. At the same time they bring out contraindications. They may even point to the need for special cautionary statements on the label.

In a letter to pharmaceutical firms, the Food and Drug Administration has stated: "As the drug [reserpine] has been used more extensively it has become inncreasingly apparent that reserpine is not the innocuous substance it was first thought to be, that there are contraindications, and that the safe level for longterm outpatient maintenance is lower than the originally recommended dosage schedule. *** In the treatment of hypertensions, or of anxiety states on an outpatient basis, it is the present consensus that the usual recommended maintenance dose should be 0.25 milligram daily. While doses up to 1.0 milligram daily may safely be recommended for the initiation of therapy, they usually should not be continued for longer than a week *** it is believed that reserpine in daily doses above 0.25 milligram is contraindicated and in lower doses should be used with caution in patients with a history of mental depression, peptic ulcer or ulcerative colitis. Furthermore, physicians should be specifically cautioned with respect to the danger of depression * * *." Also, reserpine in neuropsychiatric use in higher strength "*** should be discontinued approximately 1 week before instituting shock therapy, since it may result in increased severity of convulsions, respiratory difficulty, and other complications; *** the possible dangers of hypotension and fluid retention should be borne in mind when large doses are used in debilitated patients or those with cardiac disease." It is to be noted that chlorpromazine likewise should not be used in patients showing symptoms of depression.

In view of the clinical reports on side effects and contraindications, it is important to determine whether there is any foundation to the concern that misuse of these drugs with undesirable effects creates a problem in public health. The answer to this question lies in whether there is evidence on several points: that both short-term and continuous use of the tranquilizing drugs without medical supervision is dangerous; that persons are using these drugs without medical supervision in an unwarranted or unrecommended manner; that such indiscriminate, unregulated and reckless use results in morbidity or mortality; and that the latter occurrences are on such a large scale as to justify concern over public health.

These are new drugs and clinical experience at this time is revealing but incomplete. It is limited to short-term use. Yet even from the limited observations it may be inferred that these valuable drugs are potentially harmful. As for the effects of prolonged, continuous use, nothing can be said at this time. But on the basis of the available clinical evidence, the committee can conclude that there is a possibility that use of the drugs without medical supervision may be attended with danger.

It should be clearly stated that the magnitude of prescriptions for tranquilizing drugs does not prove that they are a menace to public health. Rather, the danger would lie in the use of them for both short and long periods without medical supervision, whether with or without prescription. Overdosage under these circumstances would be especially a hazard. This is the significant question: Is there access to these drugs and use of them without medical supervision? Presently the amount of these drugs being sold without prescription is not known. It is the considered opinion of the Department of Health that there has not been any great amount of over-the-counter sale of them. Never

theless, it is possible that persons now taking these drugs on prescription and benefiting from them distribute them rather widely among their friends and relatives.

However, the major source of misuse may be in excessive refilling of prescriptions without the physician's knowledge. Under the Sanitary Code of New York City there is no prohibition against refilling of prescriptions for these drugs. The patient may find such relief of his symptoms that he continues to take the medication long after the period originally intended by the physician. Thus it is the Health Department's impression that persons are getting prescriptions refilled without a physician's order, an entirely legal procedure in New York City. Certainly by this means the public does have access to the drug without medical supervision. Whether it has availed itself of this opportunity has not been definitely established.

The potential danger from misuse of these drugs and the opportunity for using them without medical supervision can be accepted. But additional evidence of another character is desirable before pronouncing the situation a menace to public health. What is needed is evidence of morbidity and mortality associated with their use. At present there are definite impressions but few facts; for, the data are difficult to obtain. Despite all the precautions in the preliminary testing of new drugs and the safeguards thrown around their issuance, it is the usual experience that the full effects of new drugs, both beneficial and detrimental are seldom revealed until they have been used extensively over a period of time. This is particularly true of a drug that comes into wide and popular use shortly after its appearance. Hence the difficulty in amassing data on the morbidity and mortality associated with tranquilizing drugs arises from the very short time that they have been widely used. Widespread usage over a short period of time does not reveal the full effects of the drug. It is necessary to obtain more than a sample of short-term experience that is sufficiently large and varied. It is essential also to observe the effects of prolonged and continuous use. There is no substitute for time.

The New York City Health Department has some data which may allow provisional and presumptive inferences. In 1955, according to the records of the Poison Control Center, there were 12 cases of poisoning associated with the tranquilizing drugs as against 76 for the first 101⁄2 months of 1956. In 1955 there were no fatalities associated with the tranquilizing drugs; for the first 102 months of 1956 there have been 2. In neither of these fatalities is there positive finding that the tranquilizing drug was the cause of death, although large amounts had been taken. No known suicide attempts associated with tranquilizing drugs were reported for 1955 as against 16 for the first 101⁄2 months of 1956. It is usually not easy to ascertain suicidal attempts under any circumstances. It is particularly difficult to attach the precise responsibility of tranquilizing drugs. On the one hand, for the person bent upon self-destruction, that may be the method of choice. On the other hand, some of the tranquilizers may plunge the susceptible individual into a depression which leads him to select some other means of suicide. Admittedly this evidence on mortality and morbidity associated with tranquilizing drugs is far from conclusive in determining whether they constitute a public-health problem. But at least they point to a caution and constitute a warning.

Manifesting a concern over the dangers inherent in the casual use by the public of tranquilizing drugs for the relief of everyday tensions, the American Psychiatric Association through its committees on research, therapy, and public information issued a statement condemning the practice. The association expressed its enthusiastic recognition of the benefits derived from the development of the tranquilizing and other drugs for the treatment of psychiatric disorders over the past 4 years and listed the beneficial effects. But, they said: "Psychiatrists are at the same time concerned about the apparently widespread use of the drugs by the public for the relief of common anxiety, emotional upsets, nervousness, and the routine tensions of everyday living. *** Casual use of the drugs in this manner is medically unsound and constitutes a public danger. The tranquilizing drugs have not been in use long enough to determine the full range, duration, and medical significance of their side effects. Use of these drugs is no more to be encouraged than use of any other drug except where proper medical diagnosis determines that a drug is indicated to maintain the life and functioning of a person. The prescribing of drugs for emotional illnesses carries with it an obligation for continuing appraisal and supervision by physicians fully aware of the psychiatric symptoms involved and the potentials of their course of development, alteration, or remission."

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.

It

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. 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.