the potential harm. Under the provisions of the 1962 law, we have proposed a regulation that would require a new-drug manufacturer to report "information concerning the quantity of a new drug distributed and used, in a manner and form that facilitates estimates of the incidence of any adverse effects reported to be associated with the use of the drug." (Proposed change in sec. 130.13(a) of the new drug regulations, published in the Federal Register of Feb. 28, 1964, which was submitted for the record earlier in connection with my discussion of recent regulations proposing a review of all new drugs.)

This brings us, Mr. Chairman, to the third step in the decisionmaking process:

BENEFIT AS CONTRASTED WITH RISK

The decision to approve a drug for marketing, or to withdraw an earlier approval requires a weighing of the benefit to be expected from use of the product against the risk inherent in its use. While this is the same type of decision a physician makes each time he prescribes a drug for a patient, the Government must consider a number of factors not pertinent to the individual physician's decision. The Government must consider:

Not just a patient with a disease process;

Not just the skills of a physician, including his ability to arrive at a correct diagnosis, his awareness of recent scientific discoveries relating to the drug, and his willingness to read the labeling of the new drug, to perform the tests prerequisite to its safe use, and to take the time to make other observations required for proper use of the medication.

The Government must make a judgment as to the hazards likely to be encountered when the drug is employed: by physicians of varying skills and abilities, in patients with a multitude of disease processes, many occurring concurrently, and in patients incorrectly diagnosed or inadequately tested with accepted laboratory procedures.

The average practicing physician, skilled as he is in making daily decisions with regard to individual drugs to be administered to individual patients, is not necessarily qualified to make the broader decisions about permitting nationwide marketing of a drug.

Neither the doctor who has had the misfortune to encounter one of the serious reactions from a drug, nor his colleague who has saved 100 lives with that same drug without untoward incident is in the best position to make a completely impartial judgment.

The Food and Drug Administration takes physicians, pharmacologists, and other scientists skilled in making the individual decisions and gives them the background and training needed to make recommendations involving the broader picture of the relative merits of a drug for all of society. These recommendations are based on evaluation of an accumulated body of data. They are subjected to administrative review which takes into account the applicability of existing law, and the Food and Drug Administration arrives at an institutional decision.

We seek to make decisions about drugs solely on the basis of scientific consideration. But over a period of time, the direction of Government's decisions will inevitably be influenced by public reaction.

The public has developed a growing interest in drug matters. The public is making judgments.

The judgments of society are not necessarily consistent with scientific facts. Neither are they always logical. They can be and sometimes are aribitrary. Even so, neither the executive nor the legislative branches of government can long ignore them. If it should become the overwhelming public view that society should drastically limit the risk no matter how much good a drug can do, then we would be forced to remove from the market many drugs whose good far outweights their harm. Carried too far, such developments would seriously impede the progress of medicine.

In my opinion, the public concern about drugs and drug reactions has not yet resulted in arbitrary decisions which damage medicine. The public needs to realize that the use of any drug carries some risk; that as science advances, it will discover that some drugs quite properly allowed on the market in the light of earlier scientific knowledge now properly must be discarded because of greater scientific knowledge about the effects of those drugs and because of the development of other products which can accomplish the same good with less risk. Throughout medical history, old drugs have been discarded by physicians as newer, better ones appeared, and practices considered quite proper in one era have come to be recognized as poor medicine in another. Bloodletting, once considered a valuable therapeutic tool is no longer employed in treating infections.

The new requirements which have been incorporated in Federal law within the past generation-requirements that drugs be proved safe and now that they be proved effective; requirements for reporting experience with drugs; requirements that drugs be manufactured in accord with good manufacturing practice; stronger controls over clinical trials of drugs; a requirement for truthful and more informative advertising of prescription drugs; and others-were sorely needed and will contribute to more rapid and safer advances in drug therapy.

Today we do not have to wait for a generation to learn that a widely used therapeutic agent is destroying the blood-forming mechanism of the body and harming more people than it saves. Just as science today discovers newer, more valuable agents each year instead of each generation, so new law and improved administration are helping us determine the undesirable effects of drugs rapidly rather than at the more leisurely pace of earlier generations. This is proper. It permits the marvelous medical advances of our day to be made with less risk than society incurred a few years ago.

But the enactment of laws and regulations will not solve all problems. Laws are not better than their administration, and good administration requires adequate personnel, adequate facilities, and adequate support.

As you know, Mr. Chairman, there have been long periods which we hope are in the past when we did not have the wherewithal to do the type of job the American public deserves.

In 1940, we had one medical officer working on new drugs; in 1950, we had two. I was interested recently when I saw a picture of our New Drug Branch staff taken in 1953. It consisted of two medical officers, two clerks, and two chemists.

In 1960, we still had only six full-time and four part-time medical officers. I am pleased to report that today we have 41 full-time and

3 part-time medical officers in our Division of New Drugs. Over half of them have been recruited within the past 12 months. We are beginning to establish a staff which will be equal to the heavy responsibilities imposed upon us.

The workload that falls upon these medical officers and our other scientists is enormous. Manufacturers and producers are spending several hundred million dollars annually on research and they are developing hundreds of new, and often complex, products each year.

In fiscal year 1963, FDA received on the average, every working day, four applications to permit new drugs (human and veterinary) to go on the market for commercial use, and about 10 times this number of contacts about drugs previously approved by the Food and Drug Administration.

From the 1st of June 1963 to the end of the calendar year we received about eight proposals per working day for clinical tests of new drugs; this last figure reflects the initial influx of numerous reports on clinical studies already underway when this new law became effective.

A proposal for marketing a new drug can involve numerous volumes of scientific data to be reviewed by medical officers, pharmacologists, chemists, and other scientists. For example, I recently reviewed the chronology of a particular new drug application that contained over 9 volumes and about 4,000 pages of data as is illustrated on chart 13 accompanying the background statement I have submitted for the record

In all, it took FDA 195 days to review and evaluate this application. During this time, 29 of our professional staff representing 11 different organizational units participated, as did 6 outside expert consultants. This is shown on chart 14. Two special inspections of the drugmaker's facilities were necessary and analytical tests had to be made by two of our district laboratories.

Our Bureau of Medicine held three special staff conferences plus another conference with the manufacturer. During that same time, we had to handle 19 contacts made by the sponsor. Mr. Chairman, this particular case is not unusual.

FDA, in fiscal year 1963 alone, received over 1,100 new drug applications. Some, of course, were much shorter and required less time to process but, on the other hand, many were even more complicated and required an even greater amount of time and effort.

As a result of recent regulations, much of the new drug application process just described is also followed in processing approximately 1,600 submissions on investigational drugs received since about the 1st of June 1963.

Chart 24 illustrates the various types of review that may be required for a new drug application or a submission on an investigational drug. Most of them are required for each submission. These show the various types of inside and outside contacts that have to be made by our scientific people before the facts are fully assembled.

For example, the submission contains basic data from industry, clinicians and hospitals, from medical and other scientific literature, and frequently from experts in universities and elsewhere.

In FDA the document is evaluated by

Medical officers (New Drug Division).

Pharmaceutical chemists and manufacturing specialists (New Drug Division).

87-272-64-pt. 1—11

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DRUG SAFETY

Pharmacologists (Bureau of Scientific Standards and Evalua

tion).

Field chemists (Bureau of Regulatory Compliance) who check the adequacy of analytical control methods submitted with new drug applications.

When the necessity arises, these reviews are supplemented by additional reviews or investigations by other specialists within FDA, such

Bacteriologists (Division of Microbiology or Division of Antibiotics).

Drug inspectors (Bureau of Regulatory Compliance) who investigate the applicants manufacturing facilities.

Additionally our personnel frequently consult outside experts such as clinicians and research scientists in Government institutions and outside clinics, hospitals, or universities. The drug manufacturers' experts are often asked for further information.

upon

The views and findings of all these experts are studied by the FDA medical officers handling the application and they arrive at an institutional scientific decision on the medical facts in the case. Based all of the medical and other scientific skills that we have brought to bear upon the case, the application is approved or disapproved. We have taken a number of concrete steps to improve our operating procedures. In October 1962, for example, we established a group headed by the Assistant Commissioner for Science Resources to develop recommendations for better utilization and dissemination of scientific information within FDA and between FDA and outside groups.

The group's first recommendation called for an outside organization experienced in the design of information-handling systems to study FDA's basic work processes and to design appropriate data processing and communication systems. Arthur D. Little, Inc., of Cambridge, Mass., is now conducting the first phase of this study.

Meanwhile the FDA adverse drug reaction reporting program has been strengthened. We have employed an experienced biostatistician who is in charge of the program; we have increased the medical staff assigned to the program, and we have proposed an enlargement in the budget to expand the program.

Veterans' Administration hospitals, Public Health Service hospitals, and selected Armed Forces hospitals are reporting adverse drug reactions to us, in addition to more than 70 private hospitals.

We have completed written agreements with a number of governmental scientific agencies to provide for an exchange of scientific information in the drug and other fields. I submit for the record copies of several agreements in this field with the National Institutes of Health, U.S. Public Health Service, and with others that have information and facilities that have been helpful to our program. Mr. FOUNTAIN. Without objection, those agreements will become a part of the record.

(The agreements follow:)

MEMORANDUM OF UNDERSTANDING, FDA-NIH

A substantial amount of the information available to the National Institutes of Health and to the Food and Drug Administration, acquired by each in the pursuit of their statutory missions, is of common interest to these agencies.

In the past, both have been keenly aware of this community of interest and have had extensive informal and effective interchanges of views and of information on a wide variety of problems. Such informal interchanges should and will continue and both agencies encourage the members of their staff to provide the utmost assistance and cooperation in all appropriate areas. Both also agree to the essentiality of creating formal relationships which will guarantee the timely flow of potentially relevant information between them. The following mechanisms will be created to achieve this objective:

COMMITMENT OF THE NATIONAL INSTITUTES OF HEALTH

1. The National Institutes of Health designates Dr. Thomas J. Kennedy, Jr., presently Special Assistant to Director, NIH, for Scientific and Technical Information as a point of access for the Food and Drug Administration to the information resources of the NIH, except as otherwise indicated herein.

2. The National Institutes of Health will transmit to the Food and Drug Administration periodic reports on adverse reactions to drugs in clinical investigational projects conducted by members of the staff of the National Institutes of Health. The adverse side reactions reported will be screened at the NIH to eliminate the unnecessary reporting of well-known toxicity of old drugs but will emphasize new or infrequently described reaction to such drugs and all reactions to drugs in the early stages of general use. With respect to recently released drugs, serious adverse reactions will also be reported immediately to the FDA.

3. The National Institutes of Health will transmit to the Food and Drug Administration pertinent_information generated by the activities of the Cancer Chemotherapy National Service Center. This will include, as in the past, the transmittal, upon publication, of Cancer Chemotherapy Reports and Cancer Chemotherapy Abstracts. The former is an instrument designed for the rapid dissemination of results of the clinical trials of antineoplastic agents tested under the auspices of the National Cancer Institute. The CCNSC invites the FDA to utilize its total information file at any time and designates the Chief, Clinical Branch, CCNSC, Dr. Philip T. Waalkes, to serve as a contact point for such activities. Dr. Waalkes will meet with Dr. O. L. Kline or his designee of the FDA immediately to familiarize that individual in detail of the character and scope of the information collected by the CCNSC.

A more detailed set of specifications governing the interrelationships between the CCNSC and the FDA is included in the memorandum dated February 15, 1963, from the Director, NCI, to the Commissioner, FDA, on the subject of NCI compliance with FDA regulations on new drugs.

4. The National Institutes of Health will transmit to the Food and Drug Administration pertinent information generated by the activities of the Psychopharmacology Service Center of the NIMH. The Psychopharmacology Bulletin and Psychopharmacology Abstracts will, as in the past, be forwarded to the FDA upon publication. The Psychopharmacology Bulletin represents an evaluated distillate of up-to-date information available to the Psychopharmacology Service Center on drug research supported by NIMH and by other agencies in the field of psychopharmacology. The Psychopharmacology Service Center invites the FDA to utilize its total information file at any time that the latter agency deems this appropriate and designates the Chief, PSC, Dr. Jonathan O. Cole, to serve as a point of contact. Dr. Cole will meet with Dr. O. L. Kline or his designee of FDA immediately to familiarize that agency in detail with the character and scope of the information collected by the Psychopharmacology Service Center. The Psychopharmacology Service Center will also transmit weekly to the Food and Drug Administration a list of references on the toxicity of drugs derived from the Center's continuous screening of published literature and other materials in the area of psychopharmacology.

5. The National Institutes of Health, through its Division of Research Grants, will provide to the Food and Drug Administration at periodic intervals pertinent information generated by the extramural awards program of the former agency. The detailed specifications of these reports will be worked out through negotiations between the Chief, Division of Research Grants, NIH, and the Assistant Commissioner for Science, Food and Drug Administration. The intent of the National Institutes of Health in this matter is to convey promptly to the Food and Drug Administration information within the purview of interest of that agency, such as the titles, the principal investigators, and the project summaries of NIH supported research, as well as relevant information, especially con