These compounds must be investigated by biologists to determine their pharmacological activity or their power to destroy bacteria or other disease-causing organisms. Now, with the recent revolutionary discovery that mental disorders may successfully be treated with drugs, testing by psychologists will have to be undertaken as well. This phase of the work is very complicated and to do it thoroughly requires that each chemical compound be tried out in great number of very delicate experiments. After one or a series of active compounds has thus been identified, exhaustive tests must be carried out to determine both their acute and chronic toxicity and indeed what effect they may have on virtually every organ of the body. Pharmacists must study their compatibility with the other chemical products used in putting up pharmaceutical preparations and determine their most effective and convenient pharmaceutical form. If already proven methods do not exist for manufacturing the products on a commercial scale, other chemists and chemical engineers working in laboratories and pilot plants must work out the manufacturing processes. Finally, physicians must conduct extensive and carefully controlled clinical trials with the product in human beings, usually in several thousand as a minimum, before a new product can be put on the market. All of this work requires large and diversified staffs and facilities and years of work.

Thus the size of the research budget will have a great bearing on the scope of the program that can be undertaken by the research force and even the possible fields that can be included. A small budget would automatically exclude from consideration any mass production operation, as for example, the massive screening of hundreds of thousands of soil samples to find new antibiotics, for this work is done on the theory that success is a matter of the probability of occurrence of a few effective products out of the hundreds of thousands tested. "There is, of course, much overlapping of the work in these different fields. Witness, for example, the production of steroids by fermentation processes, the discovery of vitamin B12 as a byproduct of streptomycin fermentation, etc. Moreover drugs developed primarily to treat one disease have not infrequently been found to have totally unexpected uses. Examples are certain antihistamines originally developed to treat allergic conditions which were later found to be good remedies for motion sickness, and reserpine, originally used to reduce blood pressure and now found to have dramatic effect in the treatment of mental disorders."

One member of this committee has indicated her interest in whether industry research is always specifically directed to a particular possibly profitable product. The answer is that any worthwhile research must, as Dr. Kline suggested, deal with basic physiological and pathological inquiries. Many of the major discoveries of the past, and many of those now in the offing, have had and will have their genesis in the basic study of the cells and organs of which our bodies are composed. Insulin was discovered only after the elucidation of a long chain of biologic factors governing the nature and cause of diabetes. Thus also were developed thyroxine, parathormone, ACTH, cortisone, as well as the widely used androgens and estrogens.

Basic studies of the various types of cancer cells and viruses may well lead eventually to the discovery of specific therapy in these areas. For example, enzymic metabolism associated with the construction of nucleic acid, an important constituent of all nucleated cells, appears to be a vulnerable area. Studies of the agents which inhibit the important enzyme, ribonuclease, might eventually lead to the successful arrest or retardation of the growth of cancer cells by slowing down the cellular process through interference with nucleic acid metabolism. To take another general example, we have yet to learn whether rapidly growing cancer cells are stimulated by some active metabolite per se, or by the lack of some vital substance within the cell. It is known, for instance, that the lack of adequate oxygen, as at high altitudes, results in man's compensatory increase of red blood cells-a functional solycythemia. Could rapidly growing cancer cells in blood or tissues likewise result from a deficiency of something or other? It is the solution of this basic type of problem that might eventually lead to successful and probably varied attacks on cancer and possibly on virus infections as well.

To do all of this requires a complicated research organization. In our own company there are now seven divisions in our research department. These are the chemical research division, which is in turn divided into bio-organic and an organic chemistry section.

Next comes the macrobiologic research division which is divided into sections concerned, respectively, with pharmacology, endocrinology, physiology and biochemistry.

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The microbiologic research division contains sections specializing in bacteriology, virology, and parasitology.

The developmental research division is responsible for the development of new processes and the improvment of existing processes for the chemical manufacture of the company's products.

The pharmacy research and development division is responsible for the development of formulas and processes for the compounding of new products and new product forms and the improvement of formulas and processes for the compounding of existing products of the company.

Another very important division to assure quality requirements is that of analytical research and quality control.

Finally comes the clinical or "medical" research division which is composed entirely of doctors of medicine and is responsible for all activities involved in determining the clinical, therapeutic, and diagnostic effects and uses of the products developed in the research laboratories.

Whether this tremendous research effort is worthwhile or the full measure of its contribution to the public welfare must be primarily left to others to judge. May I simply suggest to you that 36 percent of all the prescriptions written in 1955 were for drugs that were unknown 4 years earlier and that some 400 new pharmaceutical products were introduced in 1955 as compared with less than 100 in 1940. In my own view, it is this research in chemistry and medical therapy of the last quarter century that has created the industry today. But since I am a research director, perhaps I should let it go at that. Turning now specifically to the newly developed psychopharmaceuticals in which this committee seems to be principally interested, I believe that the testimony up to this point has established that the few side effects involved are not cumulative, and you almost never would expect to find them all in a particular patient. The particular side effects, moreover, are statistically rare; and they are usually reversible in that upon detection they can be readily dissipated by discontinuance or supplementary medication such as an analeptic drug like methylphenidate, amphetamine, or pipradrol hydrochloride; and that they are reasonably detectable.

Since the development of a side effect of a drug is a functional response of the individual patient, its detection and treatment is a matter of medical judgment for the physician. May I emphasize that this point is true not merely of this group of drugs but of every medication that a doctor prescribes in the light of his intimate knowledge of his patient and the individual case history that he ascertains. As we frequently say in our literature, "the management of each patient is an individual problem."

As for the drug manufacturer, any contraindications to the use of any new drug are noted in the educational materials distributed to the medical profession. This is our practice and that of virtually all ethical drug manufacturers. Our ethical mailings to the medical profession are reviewed by medical men in our company.

In saying this, I think it is only fair to add that there is always an intelligent medical judgment to be exercised. Dr. Kline offered the unfortunate example of a reputable doctor who publicly argued long and vigorously against the use of insulin because of his unfounded fears of long-term pathological effects. Dr. Kline also pointed out, in his vivid fashion, that there are always some individuals who, because they cannot be "the first" to have discovered the use for a new drug, can gratify their ego by being the first to claim that it is "too dangerous for clinical use."

Of course, we are and must be conservative. For the testing of our drugs we select the most competent and experienced and intelligent research doctors. We maintain our own research staffs. As a proper and overriding safeguarding agency, the New Drug Division of the Food and Drug Administration is charged with making its own evaluation as to safety. Merely because someone publishes a paper in which he arrives at a conclusion on obviously inadequate data, developed under conditions which are not scientifically controlled, and makes some extravagantly generalized statements about his apprehensions, may well not be the basis for elaborating contraindications which have never been seen by competent research workers and which cannot be verified. The criteria must be honest and conservative medical judgments.

As the committee is of course aware, materials accompanying an ethical sample sent to physicians are legally part of the labeling that must be submitted to and reviewed by the New Drug Division of the Food and Drug Administration, and remains subject to the control of that Division. The comprehensive regu

lations under the new-drug statute specify that the permit which allows a drug to be sold as a new drug may be suspended at any time if the FDA concludes: "That the application contains any untrue statement of a material fact" (sec. 130.27). Another section of the regulation prescribes that an application will be considered as containing an untrue statement of a material fact wherever there exists

"(b) the unexplained omission in whole or in part of any information obtained from (1) investigations as to safety, or (2) investigations as to identity, strength, quality, or purity of the drug made by the applicant with the drug or submitted to him by any investigator whom he supplied with the drug, when such omission would bias an evaluation of the safety of the drug."

Coming now to the specific difficulties in which the committee has expressed interest: So far as I am aware, I know of no instances in which adverse findings by an investigator as to the hazards of any drug, and I mean any ethical drug and not merely tranquilizing agents, have been suppressed by the manufacturer. I do not know what is meant by the asserted use of a "canned article" but if this is intended to mean the signing of his name to research work for which he had no responsibility, I can say categorically that no reputable research worker would do so and that no research director that I know would accept it. As to charges of quotation out of context, I have heard about, but do not know the details of, one incident in which the affirmative recommendations of a research doctor were used without any reference to the medical disadvantages which he had discovered and reported in the same article. This is the incident referred to by Dr. Ayd.

But if the argument is about condensation and abstracting of materials, I think the committee must understand that it is the function of informative mailings to doctors to keep them up-to-date on important new developments both clinical and pharmacological. The general practitioner welcomes these materials because he wants to be abreast of these new developments. His primary responsibility in time and energy is to his patients. The presentation of materials to him in condensed form-in abstracts, in desk reference cards, in summary reports of clinical work-is a necessary part of the process.

But this is not a "quotation out of context." The use of abstracts is widespread in the scientific world. This type of condensation is not misrepresentation. That practice no reputable drug manufacturer would countenance for the reasons I have already stated and particularly because the reputation and reliability of every product and everything said about it would be endangered. It is my understanding that the Food and Drug Administration has broad powers to correct any misstatements in any promotional materials which accompany any drug product. In my experience, they have been alert and zealous in doing so. Once again, let me emphasize that research workers, like most other people, have differences of opinion. These differences are very often matters of medical judgment. Both we, in our company activities, and, I am confident the Food and Drug Administration, are alert to any medical view backed by sound clinical work and, sometimes, merely the opinion of an experienced medical authority based on his training and experience. As I have said, there is a built-in conservatism in our approach to questions of the medical evaluation of any drug. I know that the Food and Drug Administration has the same approach.

I see no reason for attempting to delegate responsibility to any other Federal agency. Only the Food and Drug Administration is medically staffed. I know that in their drug regulation they could well do with an increased budget, and I agree with Dr. Kline that salary levels should be commensurate both with their responsibilities and with salaries that prevail outside the Government. I might add that this is a common complaint, and not found only in Government agencies. But to diffuse responsibility among several agencies, to invite the intrusion into these areas of fundamental medical judgment by any governmental group which is neither medically staffed nor qualified to pass medical judgments would be extremely hazardous. It would, also, of course, be duplication. But, more importantly, it might have two extremely unfortunate side effects of its own. It might impede the development of new drugs and the dissemination of knowledge about them to the medical profession, where such drugs might be effective in saving lives and alleviating human suffering. And, should serious conflicts of opinion arise between the agencies, it might endanger the confidence of the patient in his doctor, which is the touchstone of effective medical treatment.

EXHIBIT 10B

STATEMENT OF DR. R. H. FELIX CONCERNING PSYCHIATRICALLY SIGNIFICANT DRUGS

I. INTRODUCTION AND ORIENTATION

It has become well known that mental and emotional disorders constitute a serious problem in public health. More than half of the hospital beds in the Nation are occupied by persons suffering from acute or chronic forms of the more severe disorders. Some 363,000 visit mental-health clinics annually. A large number, difficult to estimate with accuracy, visit private psychiatrists. Perhaps as much as 50 percent of the complaints voiced to the general practitioner derive in part from mental and emotional problems. There are, undoubtedly, many more persons with such problems who do not come to the attention of the medical profession.

In the light of these facts, it is not surprising that the advent of drugs presumed to have significant psychological effects would create widespread public interest and deep concern that their effects be evaluated scientifically.

It is with this background in mind that I should like to discuss the several significant new drugs which have been introduced into medical practice during the last few years, drugs which have influences upon several important aspects of personality functioning. Some of these drugs appear to produce a lessening of tension, anxiety, and some of the symptoms of some of the psychiatric illnesses. Others have a quite different effect in that they appear to increase the vigor of psychological functioning and to overcome the depressed feelings experienced by many persons, whether or not their difficulties meet all of the criteria of depression from the psychiatric point of view. It is not surprising that these two kinds of drugs should receive the general and semipopular appellation of tranquilizers in the first instance and of energizers in the second case. More rigorously, the study of the effects of drugs, tranquilizing or energizing, favorable or unfavorable, upon psychological functioning has been termed by the medical and scientific groups as psychopharmacology.

The matter is not quite as simple as the existence of two drug groups which the above-indicated properties would indicate. The effect of both tranquilizing and energizing drugs varies with the individual, his particular condition, and the particular compound involved. What is more, the effects of the drugs are mediated through the various physiological mechanisms of the body, and there are effects, therefore, upon many aspects of bodily function, as well as upon mood and other general aspects of psychological functioning.

As a matter of fact, there is a kind of reverse-English phenomenon involved in the use of these drugs. Physicians have long known that many of the drugsthey use for somatic problems have significant psychological effects. Cortisone is a good example, but not the only one. Medicine has long been aware not only of the physiological but, also, of the psychological side effects of many of its therapeutic agents. The physician has always had to calculate the therapeutic value of each drug for a specified purpose for the patient in question, as balanced out by possible or probable undesirable side effects of either a physiological or psychological nature. The ability to make such decisions properly represents a large part of the successful practice of medicine.

In the case of the new psychologically significant drugs, the focus of the physician is primarily upon the psychological effects, while, at the same time, being alert for the physiological ones. Insofar as these agents have dependable psychological influences, they can be valuable therapeutic devices. In this case,. however, there are also possible side effects of both a psychological and physiological nature. This fact does not really differentiate these drugs from others that the physician uses. It does mean that the proper use of these agents involves knowing their probable therapeutic value for a variety of conditions at all dosage levels, as well as the possible side effects. Again, the physician must make a judgment concerning the overall value or detriment to the patient's welfare of a particular drug at a given level of dosage, a task he has always faced with the use of any drug.

These new compounds are fairly complex chemical compositions, and their action on the body is not simple. The last few years have produced (1) information about their psychological effects on a variety of kinds of psychiatric and other medical conditions; (2) knowledge of their side effects, both psychological and physiological; (3) some data concerning their mode and site of action in the body; and (4) a number of criteria regarding the indications and

contraindications with respect to their use in any particular condition. The record is not yet complete, but it is now possible (1) to describe the general classes of drugs in use and (2) to indicate the present knowledge about the therapeutic values and the associated side effects of these drugs. In fact, although these drugs have been developed only recently, the great public interest they have aroused has led to a tremendous amount of research by the pharmaceutical houses, mental hospitals, university laboratories, and research institutes. The problem will be further clarified, it is hoped, by outlining some of the psychopharmacology activities of the National Institute of Mental Health, including the recently established Psychopharmacology Service Center.

1. Definitions

II. PSYCHOPHARMACOLOGICAL AGENTS

A. THE TRANQUILIZING DRUGS

1

There is no official definition which is commonly accepted by all scientists at the present time. One reason is that the drugs included in this category 1 differ considerably among themselves in their chemical structures, in their generally accepted areas of use, and in their side effects and toxic effects. It is difficult, therefore, to give a precise and inclusive definition of what is, basically, a general descriptive term. However, when scientists state that a chemical compound is a tranquilizing drug, they do have at least two concepts in mind:

(a) The drugs has a calming effect, reducing anxiety, tension, agitated or disturbed behavior, or similar psychiatric symptoms.

(b) The drug produces this relief from symptoms without causing any marked degree of sedation or sleepiness. Barbiturates, bromides, paraldehyde, chloral hydrate, and a variety of other similar sedative drugs have been used in psychiatry for many years to calm or sedate patients. In contrast to the tranquilizers, these sedative drugs, when used in amounts sufficient to calm a disturbed psychiatric patient, also make him sleepy or groggy or "drunk." A tranquilizing drug produces calming with a minimum of such side effects. 2. Classes of tranquilizers

There are three main groups of tranquilizing drugs: The phenothiazine derivatives, the alkaloids of Rauwolfia serpentina, and a chemically heterogeneous group.

(a) The phenothiazines.-The phenothiazine derivatives are chemical compounds of rather complicated structure containing both a nitrogen and a sulfur atom. Chlorpromazine was the first compound in this group to be generally used in psychiatry. As usually happens in pharmacology, when one interesting and active drug is found, a variety of other compounds similar to this drug are synthesized and tested for effectiveness and toxicity in a search for better compounds. A number of such phenothiazine derivatives have been synthesized and six related compounds are now available for prescription use. These include promazine, mepazine, triflupromazine, proclorperazine, thiopropazate, promethazine, and perphenazine.

These compounds differ from each other chemically, but each contains the same basic two-ring central structure, the rings being connected by a sulfur and a nitrogen atom. They may show some differences from one another in clinical action and in the frequency with which certain types of undesirable side effects occur, but it is still too early to make a definitive statements concerning their particular characteristics and their relative assets and liabilities.

(1) Therapeutic uses and value: On the basis of both general clinical observations and well-controlled scientific studies which have been reported in the scientific literaure, it is possible to say with conviction that chlorpromazine is quite effective in the treatment of hyperactive disturbed behavior in hospitalized psychiatric patients. The other phenothiazines have been studied less extensively and it is still too early to make a definite judgment about their action. From the available reports, however, it would seem that they all share this property of reducing hyperactive disturbed behavior.

The various compounds in this group have also been used in the treatment of neurotic illnesses and milder forms of schizophrenia in nonhospitalized patients, and some of the psychiatric disorders associated with old age. Some

1 See appendix for a representative list of psychoactive drugs now available for prescription use by physicians.