In evaluating drugs the council considers scientific clinical and laboratory evidence (published or unpublished) submitted by manufacturers and such other reports as may be available. The council also endeavors to obtain the opinions and advice of other experts who serve in a consultant capacity. The council does not undertake to conduct clinical and laboratory tests or experiments in evaluating drugs.

The council may from time to time reevaluate a drug or evaluate evidence relating to a new use or route of administration for a drug.

The views of the council with respect to the actions, uses, dosage, contraindications, hazards, limitations, and other pertinent characteristics of each evaluated drug are submitted in the form of a monograph to the editor of the Journal of the American Medical Association for publication in the council column. These monographs are subsequently included in the council's annual publication, New and Nonofficial Remedies.

If the council's reevaluation of a drug reveals a significant change in its status, such information is submitted to the editor of the Journal for publication and subsequently incorporated in New and Nonofficial Remedies.

The council encourages the early adoption and use of a nonproprietary name for general use in prescribing, naming, and identifying each drug. The council believes that such names tend to diminish confusion and are in the interest of the patient and physician. Each drug evaluated is described by a nonproprietary

name.

When the council has knowledge that a drug is no longer available commercially or when it has been included in the United States Pharmacopeia, National Formulary, or New and Nonofficial Remedies for 20 years, the monograph may be deleted from New and Nonofficial Remedies.

The council does not accept, endorse, recommend, or guarantee any individual brand or preparation of a drug described in New and Nonofficial Remedies. The council does not undertake to test or analyze samples or to review or investigate manufacturing and control procedures. The council does not purport to ascertain whether or not any firm has complied with Federal, State, or municipal laws and regulations.

SPECIFIC PROCEDURE

1. All pharmacological and clinical evidence or data in the form of published and unpublished reports on a new drug that are made available to the council office will be referred to a number of recognized experts who will be asked to serve in a consultant capacity.

2. The views of the consultants regarding the adequacy of the evidence for the claimed uses of the new drug, as well as comments regarding such information as the limitations, contraindications, hazards, and dosage will then be transmitted to a member of the council who will serve as a referee.

3. The referee will consider all the available evidence, as well as the views and comments of the consultants, and will make an evaluation recommendation. 4. A member of the council staff will prepare a proposed report or monograph on the new drug based upon the referee's evaluation and recommendation. 5. The proposed monograph, the referee's recommendation, the views and comments of the various consultants, and reprints or photostats of all the available evidence will be transmitted to all the members of the council for consideration. 6. The proposed monograph will be revised in accordance with the comments and criticisms of the members until it is satisfactory to the council as a whole and adopted for publication in the Journal.

7. A copy of the proposed monograph will then be sent to the pharmaceutical firm or firms that supplied the evidence and data on which the council's evaluation was based in order that they will have an opportunity for comment or criticism. 8. If there is no criticism of the proposed monograph, it will be sent to the editor of the Journal for publication in the council column. Any criticisms offered by the firm will receive due consideration before the proposed monograph is sent to the editor for publication. When the monograph is published, credit will be given the firm or firms supplying the evidence or data on which the council's evaluation of the drug is based.

9. Provision will be made for frequent publication of supplementary council statements or reports on each new drug as evidence accumulates to justify recognition of additional valid claims for use, dosage changes, hazards, and contraindications. The same procedure for evaluation will be followed in these instances as with the initial consideration of a new drug.

10. Necessary changes or revisions based upon these supplementary statements or reports will be made in New and Nonofficial Remedies at the end of each year.

[Reprinted from the Journal of the American Medical Association, July 30, 1955, vol. 158, p. 1175. Copyright, 1955, by American Medical Association]

PRINCIPLES OF ADVERTISING FOR AMERICAN MEDICAL ASSOCIATION PUBLICATIONS All advertising contracts and advertising copy are subject to the principles of advertising for American Medical Association publications. The association reserves the right to accept or reject advertising copy for any reason.

The following general rules are applicable to all advertising copy:

1. The advertiser may be required to submit data in support of the usefulness of the product and the validity of the proffered claims.

2. Advertisements should not be deceptive or misleading.

3. Sweeping superlatives and unfair comparisons will not be allowed. Extravagantly worded copy is subject to revision or rejection.

4. Disparagement of a competitor's goods will not be allowed. Any claims for superiority must be supported by evidence acceptable to the association.

5. Quotations or excerpts from a published paper are acceptable only if they do not distort the meaning intended by the author. Furthermore, the mere appearance of a paper, or of several papers, may not necessarily supply sufficient evidence to suport the proffered product or claim, and the association in such instances may request more complete data. When excerpts are taken from a published paper for use in an advertisement the association may require the advertiser or his agent to obtain written permission for such use from the author and, if necessary, from the editor or publisher of the publication in which it appears.

6. If testimonials or quotations appear in advertising, the validity of the claims, the expert knowledge of the person offering the testimonial, and the probable effect of the advertisement on the reader will be considered. The association may request evidence of the authenticity of the testimonial.

7. The association will not accept advertisements which in the judgement of the association: (a) appear to violate the principles of medical ethics; (b) are indecent or offensive in either text or illustration; (c) contain attacks of a personal, racial, or religious character or appear to be contrary to the regulations and laws for the prevention of discrimination; (d) contain claims found by any court or Federal or State agency to be invalid or in violation of law.

8. Advertisements proposed for Today's Health can make reference to certain minor symptoms but not to any disease. In other words, such advertisements cannot suggest treatment for disease-only temporary relief from a symptom. 9. The advertiser and the agency agree to protect and indemnify the association against any and all liability, loss, or expense arising from claims for libel, unfair competition, unfair trade practice, infringement of trademarks, trade names, or patents, violations of rights of privacy and infringement of copyrights, proprietary rights, and any other claims resulting from the publication of advertisements by the association.

10. The association reserves the right to change without notice the foregoing principles.

Questions concerning advertising copy should be directed to the advertising department of the American Medical Association, 535 North Dearborn, Chicago 10.

EXHIBIT 9

12

[Reprinted from Bulletin of Academy of Medicine, April 1957, pp. 282-289] REPORT ON TRANQUILIZING DRUGS BY THE COMMITTEE ON PUBLIC HEALTH OF THE NEW YORK ACADEMY OF MEDICINE

The committee on public health was requested by the commissioner of health of New York City to ascertain whether the present widespread use of tranquilizing drugs constitutes a menace to public health. Subsidiary to that was the question whether the literature about the drugs sent by pharmaceutical houses to physicians contributed to improper use.

1 Approved by the committee on public health of the New York Academy of Medicine, December 3, 1956.

2 Report prepared by subcommittee on tranquilizing drugs, comprised of: J. Murray Steele, M. D., chairman; Linn J. Boyd, M. D.; McKeen Cattell, M. D.; Hubert S. Howe, M. D. (deceased, February 4, 1957); Stephen P. Jewett, M. D.; M. Ralph Kaufman, M. D.; Asa L. Lincoln, M. D., ; H. D. Kruse, M. D., secretary.

It is germane to inquire exactly which drugs are to be considered as tranquilizing drugs. However, it is not easy to arrive at a satisfactory definition. One definition which has been offered is that a tranquilizing drug is any drug given for the purpose of making a person feel better when he is tense. But the major difficulty in a clinical definition is the fine line between tranquilization and sedation. The tranquilizing drugs as a group are known commonly by other names. Professionally they are called ataractics. The lay press often refers to them as happiness pills.

The tranquilizing drugs may be conveniently divided into two groups. The first contains drugs of the Rauwolfia alkaloid type. The second group comprises synthetic compounds. Each member of the latter group may bear as many as three different names: Its full chemical name, a short and more convenient name, and finally, its proprietary name. For example, the full chemical name of one is 2-methyl-2-n-propyl-1, 3-propanediol dicarbamate. Its abbreviated name is meprobamate. It is marketed under at least two different proprietary names, Miltown and Equanil.

It should be emphasized that the tranquilizers are exceedingly useful drugs. Wide usage of them attests to their value. Originally they were utilized mainly in mental institutions in order to bring patients under control and make them more accessible to other therapy. It is asserted that they have greatly mitigated the problems of custodial care, reduced admissions, and have brought about earlier discharge of the patients.

Very soon, however, the drugs were prescribed in private practice for the many who were seeking relief from anxiety and tension. Their usage in this area has been on a gigantic scale. The American Psychiatric Association has stated that 35 million prescriptions for these drugs will be written in 1956, and that of 10 compounds most frequently prescribed by physicians in 1955, 3 were tranquilizers. At the present time 5 to 10 percent of all prescriptions in New York City are for tranquilizing drugs and an increased percentage is anticipated.

In some minds this widespread use of tranquilizers in meeting everyday situations raises a question about the rationale underlying it. Anxiety and tension seem to abound in our modern culture and the current trend is to escape the unpleasantness of its impact. But when has life ever been exempt from stress? In the long run is it desirable that a population be ever free from tension? Should there be a pill for every mood or occasion? It has been noted that when the drug is used satisfactorily in an emergency, there is a tendency among some persons to regard more and more of life's situations as emergencies until the pattern results in everyday usage of tranquilizing drugs. Their use is said to be becoming more and more common among persons in certain occupations.

All drugs have a range of safety and recommended dosage. Many of them have side effects or produce reactions in a proportion of persons either at the recommended dosage or especially beyond that level. Hence, all new drugs are subjected to test. By accepted procedure, they are tested in the laboratory prior to their clinical use, next they are tested on patients under controlled conditions by a few clinicians, then they are released to the medical profession on an experimental basis for further clinical testing.

Like many drugs, the tranquilizers are not without their side effects and undesirable consequences. Kramer has reviewed the clinical reports of toxic effects produced by two of the tranquilizing drugs: chlorpromazine and reserpine. For the present purposes it is sufficient to summarize the untoward effects. Chlorpromazine, for example, has led to Parkinsonism-fortunately reversible-allergic dermatitis, constipation, diarrhea, jaundice, agranulocytosis, and torsion syndrome. As for reserpine, prominent among its side effects are the production of Parkinsonism and the occurrence of severe depressive reactions, sometimes when the drug was administered as an antihypertensive agent, not for a psychiatric disorder. Its use may also be accompanied by a variety of other side effects.

In pointing to the need for additional precautionary steps in the marketing of reserpine, the Food and Drug Administration reviewed the recent evidence on the side reactions from the use of this drug. It stated: "Continued use of reserpine in doses of 0.32 milligrams daily has been shown to increase gastric secretion and gastric acidity in a significant number of cases whereas daily doses of 0.25 milligram have not been shown to do so. Doses of 0.5 milligram daily for as short a time as 2 weeks produced this effect in most of the individuals tested and have resulted in massive gastrointestinal hemorrhage or perforation

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 10 months of 1956. In 1955 there were no fatalities associated with the tranquilizing drugs; for the first 101⁄2 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 10% 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."