THE HARRIS-KEFAUVER DRUG AMENDMENTS OF 1962

The American Medical Association has believed, through the years, that it is in the interest of the American people to have effective drug laws and an effective Food and Drug Administration. We have pointed out how the AMA has worked toward this objective since before the turn of the century.

However, as we have stated to the Congress and to the FDA, there is, in our opinion, a limit to the benefits to be gained for the public health from Government regulation. That limit is reached when Government regulation passes that point of supplying needed consumer protection and becomes unnecessarily burdensome and restrictive on private activities which are the basic contributors to the public health.

Following the enactment of the Kefauver-Harris amendments of 1962 and the subsequent promulgation of regulations relating to new drugs for investigational use, much debate has ensued as to the type and extent of premarketing clinical trials which should be required of new drugs. With respect to safety determinations, such tests are essential as a means of identifying adverse effects not detectable by animal testing. However, even the most extensive premarketing clinical tests cannot always be relied upon as completely predictive of human toxicity.

For example, it is now known that the antibiotic, chloramphenicol (Chloromycetin), can produce aplastic anemia, a serious and sometimes fatal disorder which destroys the blood-forming tissue of the bod. The incidence of this adverse reaction has been estimated from as much as 1 in 60,000 to as little as 1 in 225,000. Using the high incidence figure, it can be seen that, statistically, it would be possible to treat 60,000 patients with the drug before a single case of aplastic anemia occurred.

It is impractical and unreasonable to conduct clinical tests of this magnitude. It may be medically unsound as well; that is, it is entirely possible that more lives could be lost by keeping a valuable drug off the market during extensive clinical trials than would be saved by gaining a precise knowledge of the exact type and incidence of all side effects.

Like animal tests, then, premarketing clinical trials are subject to certain limitations and can never supplant widespread clinical use as a means of assessing the ultimate hazards of a drug.

Physicians realize that no drug can be considered completely safe. There is always an element of risk, no matter how small, whenever a chemical agent is administered to a patient. That risk can be minimized by adequate animal testing and premarketing clinical trials; it can never be eliminated.

The American Medical Association has always supported legislation and regulations designed to strengthen the premarketing assessment of drug safety. The association believes, however, that no laws or regulations can ever be devised which can forestall entirely the possibility of drug toxicity. We contend that this vital knowledge can be obtained only by utilizing the combined experience of the ultimate evaluators of drug safety-the well-informed practicing physicians of the United States.

DRUG SAFETY

AMA DRUG INFORMATION PROGRAM

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The American Medical Association provides the medical profes sion with information regarding drug therapy through its council on drugs. From its inception in 1905, the council on drugs (originally named the council on pharmacy and chemistry) has had as its primary purpose the provision of authoritative information on drug therapy. This task has been accomplished by various means and programs which have been instituted and modified over the years.

The most recent updating of AMA's drug information activity began in 1955 when we instituted a new program for evaluation of drugs, based upon principles designed to offer a better service to the medical profession. The program in effect today provides for the evaluation of available evidence and for the publication of statements concerning the actions, uses, and dosages of all commercially available new drugs, whether or not their usefulness in medicine is established. These evaluations include proposed new indications or routes of administration for old drugs. The program also provides for a wider sampling of the opinions of outside consultants to aid the AMA's Council on Drugs in its evaluation of available evidence.

The American Medical Association is in the unique position of being able to call upon its membership to discuss any problem in medicine where a meeting of the best medical minds is required. Its council on drugs takes advantage of this position for its drug evaluation procedure by obtaining the opinions of experts on the available evidence on new drugs. For this purpose, the council on drugs maintains a file of over 1,000 consultants, representing the various medical specialties, who may be called upon to advise the council and to supply expert opinion regarding new drugs and drug therapy.

REGISTRY ON ADVERSE REACTIONS TO DRUGS

An important aspect of the American Medical Association's expanded drug information program is the development of a registry on adverse reactions to drugs. The experience gained in recent years with the registry of blood dyscrasias (disorders of the blood or bloodforming tissue) is being utilized to advantage in developing an overall program on adverse reactions. This new program is designed to make the AMA the clearinghouse for such information.

The registry on adverse reactions to drugs is a natural outgrowth of the registry on blood dyscrasias, which was established by a subcommittee of the council on drugs after several hematologists observed in late 1952 that damage to the blood and blood-forming organs was associated, in some cases, with the administration of the antibiotic, chloramphenicol. The purpose of the subcommittee on blood dyscrasias was the collection of information about blood dyscrasias associated with the administration of a new drug, and the informing of physicians of the potential toxicity of drugs.

Reports of effects are submitted voluntarily by interested physicians. Although at first it was quite difficult to get information about blood dyscrasias from physicians, and even from the hematologists who had a direct interest, the situation has improved with time. The registry has had a steady growth and now contains over 2,000 reports

on about 500 drugs and other chemicals which have been reported to be associated with the development of blood dyscrasias.

It should be noted that the registry accepts reports based on circumstantial evidence, and that such reports do not prove that the drug in question and the associated blood changes are causally related Therefore, the fact that the name of a drug appears in the tabulation does not necessarily mean that the drug is harmful or that it was responsible for the dyscrasias reported. Furthermore, the reports received by the registry may represent only a small part of the potential total number of drug-related blood dyscrasias which might occur; and the fact that the name of a drug does not appear in the tabulation does not necessarily mean that the drug is devoid of the potential for hemotoxicity.

It should be pointed out, however, that all reports received are transmitted to members of the subcommittee, which consists of expert hematologists, who review and evaluate the possible causal relationship between the dyscrasia and the use of the drug. In those cases where additional information is required in order to make a judgment, a followup is made with the reporting physician.

Cumulative tabulations of all reports have been made semiannually and are distributed to over 5,000 interested individuals and institutions in the United States and 40 other countries. Along with each release of the tabulation, the committee issues a résumé of the reports that serves as a guide to understanding the significance of the tabulation. In addition, the committee decides whether there is need for publication of a cautionary statement with respect to a particular drug. It has from time to time published reviews of the reports received by the registry.

The success of this program suggested to the Council on Drugs that this system should not be limited to reports on blood dyscrasias, but that it should be expanded to include all serious adverse reactions to drugs, pesticides, and other hazardous chemicals. Accordingly, a meeting of interested persons was held in late 1962 to explore the problems involved in organizing and operating a central registry on adverse reactions. Encouraged by the interest of the medical profession and the rest of the scientific community, a Registry of Adverse Reactions was established under the aegis of the Adverse Reaction Section of the Council on Drugs. With the Committee on Blood Dyscrasias serving as a prototype, panels were organized in the following disciplines: allergy, dermatology, gastroenterology, hematology, nephrology, neurology and psychiatry, and pediatrics. There is also a panel on hazardous chemicals and a general advisory panel to cover other areas.

During the past few months, these panels have held meetings to work out procedures of operation and have developed a report form. This form has been designed to provide the maximum amount of information with the expenditure of a minimum of time and effort by the reporting physician. The report form is a self-mailer and provides an original report for the registry and a duplicate copy which may be retained with the physicians' records. On the reverse side of the duplicate copy is a suggested list of some of the more common drug-associated reactions, which is provided simply as a guide and is not intended to serve as a comprehensive reference.

The registry is interested in receiving reports of all reactions which are not ordinarily associated with a specific therapy or which may be considered unusual or serious. It does not ask for reports where the reactions may be considered an extension of the effect for which the drug was given. However, the registry does not discourage reporting of any type of reaction. It is interested in receiving reports of all adverse reactions, regardless of their severity, particularly in the case of newer therapeutic agents.

VOLUNTARY REPORTING TO THE REGISTRY

One of the problems which has received considerable attention by the council and the various panels is that of inducing physicians to submit reports of reactions to the registry. The council is convinced that voluntary reporting can be made to work, and different means of encouraging physicians to report are being explored. Several hundred hospitals known to have staff committees responsible for reporting drug reactions have been contacted to enlist their cooperation.

In the near future, a general informative article describing the registry and accompanied by a report form, will be published in the Journal of the American Medical Association in order to publicize it to the general medical profession. This will be followed by periodic reminders in the journal.

In addition to reports received by the registry, other reports of adverse reactions are obtained from the published literature. The Literature Documentation Section of the Department of Drugs reviews approximately 500 journals and indexes all references to adverse reac tions of drugs. This information is added to the data contained in the registry.

In the consideration of adverse reactions, the American Medical Association and its Council on Drugs recognizes the need to maintain contact with other agencies or organizations which share its interest in this matter. Several meetings have been held with representatives of the Food and Drug Administration, and they have cooperated in the development of the report form. Other discussions with this agency have been concerned with the exchange of reports. Other Government agencies have also indicated a desire to share information with the Council on Drugs.

Discussions with representatives of the Pharmaceutical Manufacturers Association, as well as with some individual companies, have indicated that they are willing to exchange information relative to adverse reactions.

Through cooperative arrangements with other agencies and organizations, attempts will be made to coordinate the reporting by physicians of adverse reactions in order that the AMA may serve as the clearinghouse for such information.

The procedures for handling reports are similar to those developed by the Committee on Blood Dyscrasias. As reports are received, they are sent to the appropriate panel for review and evaluation. When additional information is.ed, the reporting physician will be contacted and requested to supply more complete data on a supplemental form. Codes have been developed for the purpose of recording the information received in IBM computers. This procedure will permit the retrieval of data on specific drugs and reactions.

The accumulated information will be compiled into a tabulationtype publication for periodic dissemination. Special articles on certain reactions or certain drugs will be published in the Journal of the American Medical Association or other AMA publications. Publication of this information will (1) serve to alert physicians to the potential toxicity of new drugs; (2) serve as a reminder of the potential toxicity of drugs which have been, or are being, commonly employed; and (3) serve as a reference for physicians who are investigating patients suspected of demonstrating drug-induced reactions.

RISK VERSUS BENEFITS

As has been stated previously, "There is no such thing as an absolutely safe drug." Safety is relative. It is relative to the specific drug, relative to the disease being treated, relative to the individual patient, and relative to the time in the course of treatment that the drug is given. All of these factors must be considered in the evaluation of the safety of a drug, and they should be considered by the physician when he selects a certain drug for his patient. With the information on these factors available to the physician, he is in the best position to decide on the safety of a drug as it relates to risks versus benefits for his patient.

The Registry of Adverse Reactions is one means of obtaining information on possible risks involved in the use of drugs. However, in the dissemination of this information through the publication of articles to the medical profession, the safety of a drug in relation to its use is considered. This relationship is also considered in the evaluation of new drugs by the Council on Drugs. Statements regarding the safety of a drug in relation to its use are found in the monographs published in New and Nonofficial Drugs.

A few examples from the publications of the council, including those of the Subcommittee on Blood Dyscrasias, are cited below: 1. Triparanol (Mer/29):

* since there is a lack of adequate evidence that the administration of this drug to patients with coronary insufficiency or generalized atherosclerosis has produced a beneficial effect, the use of triparanol must be regarded as experimental. * much longer and more careful studies must be performed before the drug can be considered safe for general or long-term use (N.N.D. 1962, p. 617).

The lack of adequate evidence of beneficial effects, when considered in relation to its potential toxic effects, indicated that this drug was not safe for general use. (NOTE.-This drug was subsequently withdrawn from the market because of toxic effects.)

2. Enovid (Norethynodrel with Mestranol):

there does not

On the basis of all available information and statistics appear to be any evidence that the use of Enovid caused the reported cases of thrombophlebitis (Enovid cleared by AMA Council on Drugs, J.A.M.A., 181:23, Aug. 25, 1962).

A subsequent report of an FDA ad hoc advisory committee stated:

The committee concluded, on the basis of the available data, that there was no significant increase in the risk of thromboembolic death from the use of Enovid (J.A.M.A., 185:776, Sept. 7, 1903).