Mr. FOUNTAIN. Let me say this; my question, gentlemen, was more or less for the purpose of finding out what is being done and what can be done. I have no preconceived notions as to what you ought to do.

Of course, Mr. Gray and Dr. Goldberg may have their own opinions based upon their study. We on the committee are simply trying to get the facts. I have no opinions at all as to how far you ought to go in these areas, and I can easily see what you are doing could be extremely beneficial to the Food and Drug Administration. Whether or not they should be able to call upon you and get certain research done, I do not know. But they are useful questions. We simply are trying to get the benefit of your thinking about what you could or might do.

Dr. BRODIE. I could tell you something interesting that happened in Rome. They had a group corresponding to the NIH, and they have gradually done this by edict. And first, Chain, the Nobel Prize winner left, and then Bovet, the Nobel Prize winner left. So it is going to become just an FDA.

Dr. MIDER. Mr. Chairman, I would like to observe that in the 1920's and 1930's, the Food and Drug Administration was one of the most active and highly respected scientific groups in the Federal establishment.

Mr. GRAY. Is that all of the observation? [Laughter.]

Mr. FOUNTAIN. I have a few questions for Dr. Zubrod before we close this particular hearing.

Doctor, in the background paper which you prepared for the subcommittee, you mentioned the Cancer Chemotherapy National Service Center and its vast clinical apparatus for the study of cancer drugs and nationwide clinical trials of such drugs. I wonder if you would tell us briefly how this nationwide testing program operates?

Dr. ZUBROD. When the service center was formed about 1955, they developed a clinical panel of some of the major scientists and physicians around the country interested in the clinical trial of antitumor drugs. There had been until that time no systematic trials except those that were done at Sloan-Kettering.

Because of the fact that cancer is a kind of wastebasket term containing hundreds of entities and no one hospital really had enough of any of these, it was decided to form cooperative groups. This has been the basis for clinical trial apparatus. Rather than detail the whole structure, let me give an example from the acute leukemia studies. There are five leukemia cooperative groups. Each cooperative group will have about 20 senior investigators representing 20 hospitals or institutions. Generally, most of the best university hospitals in the country are members of these groups.

In these five groups which are widely scattered around the country, perhaps 25 percent of all acute leukemia that is seen in this country is available for study. The center provides the drugs, the screening information, the toxicity information, to these clinical cooperative groups. They, as physicians, decide if they want to undertake this study of a new antileukemic agent.

Then they will design the way the study should be run, not only as physicians, but they will invite in biostatisticians and pharmacologists and pharmacists and fully design the study.

We have recognized for some time that at times there are omissions, gaps, repetition, and so on. Partly for this reason we formed the leukemia task force on which sits the chairmen of these five cooperative

groups. The members of the task force try to decide what is the most reasonable way to study new drugs in acute leukemia; what drugs need to be studied, what information needs to be gotten. At the same time, the task force can turn on CCNSC and say, "We are going to study drugs A, B, and C at such and such times, and we will need the drugs, the information on toxicity, and then pharmacology." Considerable planning is needed so that drugs and information will be coming along at the time that the clinicians will need them.

It does not, of course, always operate as smoothly as I described it, but I am being very superficial. But this is the emerging pattern of clinical research with antitumor drugs. It is perhaps better done in acute leukemia than in others. The same sort of apparatus exists for the study of lymphomas. Also the surgeons have a big group in which they are studying drugs in association with surgery. The radiologists are beginning to develop groups where they study drugs in association with radiation. And there are many similar other cooperative groups who join together to analyze their particular field of interest and who turn to CCNSC in order to carry out these studies.

Most of these are phase 3 studies. There are very few places that are equipped or have the talent to do phase 1 studies. Phase 1 studies are difficult, expensive, and require special resources and physicians who are highly trained in clinical pharmacology.

There are perhaps 100 clinical pharmacologists in the country and not very many of them are working in the cancer field; certainly not a majority of them. So that the block in rapid advancement in our knowledge of chemical control of cancer really is the phase 1 type of study.

When one group completes a phase 1 study and the information as to safety and efficacy begins to emerge, then the apparatus-the national network can quickly take up with the phase 2, 3, and beginning phase 4 type of studies.

Mr. FOUNTAIN. I have several other questions, and members of the committee may have questions, but it is getting on to 1:30. Some of us ate early this morning, and I do not think any of these questions are of such an urgent nature that we could not submit them to you for replies for the record if necessary. Are there any comments or observations which you, Doctor, or any of the other panel members, would like to make in connection with any questions which have been asked, or by way of supplement to any statements you have already made?

Dr. MIDER. Mr. Chairman, I would simply like to thank the subcommittee and the staff for the courteous, considerate, treatment we have had and also to thank my colleagues for helping me prepare that opening statement.

I have not ever pretended to be an expert in therapeutic research, pharmacology, or toxicology. These gentlemen are far better informed than am I and I thank them most graciously for their help.

Mr. FOUNTAIN. As a layman, not fully understanding a good portion of what you said, I could detect that a lot of mental activity had gone into the preparation of that statement, because every sentence and paragraph in it was extremely meaty. And I expect to reread it in the hope that I might become more enlightened about this whole field.

(Whereupon, at 1:30 p.m., the subcommittee recessed, subject to the call of the Chair.)

DRUG SAFETY

(Part 2)

WEDNESDAY, MAY 6, 1964

HOUSE OF REPRESENTATIVES,

INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE

OF THE COMMITTEE ON GOVERNMENT OPERATIONS,

Washington, D.C. The subcommittee met, pursuant to call of the Chair, at 9:40 a.m., in room B-300, Rayburn Office Building, Hon. L. H. Fountain, (chairman of the subcommittee) presiding.

Present: Representatives L. H. Fountain, Florence P. Dwyer, and Bill Stinson.

Professional staff present: Dr. D. C. Goldberg and W. Donald Gray, Intergovernmental Relations Subcommittee; and Raymond T. Collins, minority professional staff, Committee on Government Oper

ations.

Mr. FOUNTAIN. The subcommittee will come to order. Let the record show a quorum is present for the purpose of taking testimony. The subcommittee resumes its hearings on drug safety this morning with the taking of expert testimony on the testing of new drugs. We are interested in examining the question of what constitutes good testing practices, both in the preclinical work in animals and in the clinical studies in man, prior to the approval of a drug for marketing. We are fortunate to have with us today two distinguished scientists affiliated with pharmaceutical companies. However, I think I should point out that they are not appearing as spokesmen for their companies or for the pharmaceutical industry, but, rather, as individual scientists experienced in the testing of new drugs.

Our first witness is Dr. Gerhard Zbinden, vice president, research division, Hoffmann-La Roche, Inc. Dr. Zbinden will discuss preclinical animal testing.

Before we begin, I would just like to note that my distinguished colleague, Congressman Peter Rodino, of New Jersey, who represents the district from which Dr. Zbinden comes, was here earlier to introduce the witness, but unfortunately, had to leave before we could get underway.

Dr. Zbinden you may come up now, and before proceeding with your statement, we would be pleased to have you give us any biographical information you may care to concerning your training and experience in this field.

STATEMENT OF DR. GERHARD ZBINDEN, VICE PRESIDENT, RESEARCH DIVISION, HOFFMANN-LA ROCHE, INC., NUTLEY, N.J.; ACCOMPANIED BY DR. V. D. MATTIA, VICE PRESIDENT FOR MARKETING, HOFFMANN-LA ROCHE, INC.

Dr. ZBINDEN. Thank you, Mr. Fountain.

Mr. Chairman, I am a Swiss physician and I have been trained in the University of Berne, Switzerland. After finishing my studies in medicine and obtaining my M.D. degree in the University of Berne, I spent time in pathology, experimental pathology, and pediatrics_at the University of Berne. After 4 years I joined the Hoffmann-La Roche Research Department in Basle, Switzerland as pathologist, hematologist, and became group chief for the department of toxicology and experimental toxicology in this pharmaceutical company. After 4 years, I was sent over to the United States, this was in 1959, and became director of biological research of the Hoffmann-La Roche Research Department in Nutley, N.J.

Two years later, I was named vice president in charge of research. My professional experience is particularly in the field of experimental pathology and toxicology. I have been interested in the effect of drugs on animals and have tried to carry over the changes which we observe in animals to humans in order to make our animal testing more meaningful for testing of drugs in humans.

I would like to introduce to you, Mr. Chairman, my friend, Dr. V. D. Mattia, who is an M.D. He is vice president for marketing and a director of Hoffmann-La Roche Inc., in Nutley, N.J.

Mr. FOUNTAIN. Doctor, we are also delighted to have you with us. Dr. MATTIA. Thank you, sir.

Dr. ZBINDEN. If I may proceed with my statement, Mr. Chairman. I am very pleased to be here to discuss with you some of our problems which we have, particularly in view of drug toxicity. I have filed a written statement, which contains many technical details, but I propose that I concentrate today on just three points; one point would be to go with you through all the possible forms of drug toxicity, which we have to expect in humans, and the second, would be to explain briefly how we test drugs for safety in animals and early clinical trials, and then, I would like to analyze with you how we can carry over our animal experience to humans and how efficient we are in our prediction of drug toxicity in man from preclinical trials.

Now, as far as the forms of drug toxicity are concerned, I draw your attention to our table, No. 2,1 and would like to go very briefly, through all these different classes of drug toxicity, just to show that there is not only one form of poisoning of patients, but that there are many forms of drug toxicity which may occur.

For example, let's take class A, subclass 1: These are drug reactions which occur because the patient is particularly sensitive to a particular drug. Subclass 2 relates to toxic drug effects which occur in the following way: All drugs act on various organs. Only the action on one organ may be beneficial. However, their action on other organs may be harmful and cause side effects. For example, a drug which cuts appetite, which is beneficial, may also cause palpitation and high blood pressure.

1 The table referred to appears on p. 497.

Then we have to consider drug toxicities which are related to the effect for which the compound is intended, but because of the disease or pathological condition of the patient, these effects are exaggerated. For example, a patient who has a liver disease, and takes an anticoagulant drug, a drug which inhibits blood clotting, may overreact and suffer from severe hemorrhage.

Another form of drug toxicity, which I have classified under C, needs additional contributing factors, for example, another drug; or if a patient has been treated with X-rays, and he then is given a drug, toxicity may occur even though the drug alone would be perfectly well tolerated.

One of the major classes of drug toxicity includes the poisonous effects which are clearly related to the harmful pharmacologic action of the drugs.

Mr. FOUNTAIN. Doctor, may I interrupt you a minute. Some of the members of our subcommittee have not had a chance to read your statement. Are you summarizing your prepared statement?

Dr. ZBINDEN. Yes, sir; I am summarizing.

Mr. FOUNTAIN. It may be better, even though it will take time, for you to start at some appropriate point and read your prepared statement.

Dr. ZBINDEN. Good.

Mr. FOUNTAIN. Some of the members of the subcommittee have not had a chance to study it, due to the lateness of its arrival.

(Dr. Zbinden proceeded to read into the record his prepared statement.)

Mr. Chairman, we are grateful for the opportunity to review for you and the members of the subcommittee some of the many problems of drug toxicity as they appear in the view of a researcher responsible not only for the development and initial clinical trials of new therapeutic agents but also interested in the continued safe use of the compounds by the medical profession at large. In our discussion we will put much emphasis on the great variety of adverse reactions to medicaments and the multiplicity of mechanisms by which toxic drug effects are caused. It will be shown that the chance to recognize or predict harmful side effects of drugs during preclinical evaluation in animals and clinical trials in man depend on the nature and mechanism of drug action.

It is a fact that only by a comprehensive evaluation of all drug effects in animals and man together with a detailed knowledge of the patient's condition and the nature of his disease is the physician capable to weigh the expected therapeutic benefit of a drug against its potential toxic hazards. The accumulation and dissemination of this enormous body of knowledge which is a prerequisite for the most beneficial and safe use of a new drug is to a large extent the responsibility of the pharmaceutical manufacturer. This job, however, could not be done without the guidance by basic researchers of universities, NIH, and other institutions, the close collaboration with clinical investigators in medical schools and research hospitals as well as experienced practitioners and a trustful liaison with the scientists of the FDA.

As the new drug is being introduced on the market and becomes generally available, the pharmaceutical manufacturer loses his tight