It is a refinement of our procedures and an attempt to make more meaningful the question of risk versus benefits.

Mr. FOUNTAIN. That regulation is not yet in effect?

Mr. LARRICK. That regulation is not yet in effect, but it will be, shortly.

Mr. FOUNTAIN. It hasn't been published in the Federal Register! Mr. LARRICK. It was published only last February 28,

Mr. FOUNTAIN. Are you getting many responses to the proposal! Mr. GOODRICH. Not yet. Like all lawyers, they come in at the last day. We expect quite a little comment.

Mr. FOUNTAIN. You could be a little more moderate by saying like a lot of lawyers.

Mr. GOODRICH. My experience indicates most lawyers, and I am one of them.

Mr. FOUNTAIN. Mr. Gray.

Mr. GRAY. I'm wondering if this type of information would normally be construed to be covered as a trade secret by section 301(j) of the Food, Drug, and Cosmetic Act!

Mr. GOODRICH. We thought of that, and put it in there in terms of giving us information that would not really get down to the exact you wouldn't have to give us the exact distribution, but close enough to where we would know whether we are dealing with a hundred thousand doses or several million doses. This can be given to us without violating any trade secrets at all, we are confident.

Mr. GRAY. I would guess that is probably going to be part of your problem.

Mr. GOODRICH. Probably.

Mr. FOUNTAIN. I sometimes wonder if there are any trade secrets. Mrs. Dwyer?

Mrs. DWYER. No questions.

Mr. FOUNTAIN. In describing the processes by which FDA weighs the benefits of the new drug against its risk you stated that the agency takes physicians, pharmacologists and other scientists, gives them special training which is needed to make recommendations involving the relative merits of a drug for all of society, and then comes to an institutional decision.

I wonder if you would elaborate on the method by which such decisions are reached. Mr. Larrick or Mr. Rankin.

Mr. RANKIN. The method by which an evaluation is carried through, Mr. Chairman, is that the incoming material is reviewed by several different types of scientists. We have chemists and pharmacists who have made a study of manufacturing processes and also a study of what goes wrong in manufacturing processes. And they review the manufacturer's description of the method of manufacture that will be employed for the drug, the lab controls that will be applied to it to insure compliance with proper standards.

These scientists arrive at their conclusion as to whether the safeguards proposed in the application for manufacture and control are adequate to protect the public.

Then we have pharmacologists who are skilled in studying the results of animal testing. They review the material submitted by the manufacturer which reports the results of animal tests, and the results of microscopic examinations of tissues from the treated animals

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as compared with control animals. These pharmacologists arrive at a scientific decision as to the weight that should be given to the animal safety test.

Our medical experts, representing now most of the principal disciplines of medicine, such as obstetrics and gynocology, general internal medicine and so on, review the clinical reports, the studies that have been carried out on man and the effects that have been observed on man. They compare these results with the labeling that is proposed for the drug to see whether the administration of this drug as proposed in its labeling may be expected to first, give the benefits claimed for the product and, second, give those benefits without adverse effect to the patient.

There are other scientists that may or may not be brought into the picture. If this is a drug that requires manufacture under sterile conditior,ur bacteriologists may be consulted.

When all of the scientific groups have made their evaluations, then there is a decision within the Bureau of Medicine that the safety and effectiveness of this product under the recommended labeling has been established, or that it has not been established.

In many cases, our scientists consult with outside groups about the testing that has been performed. I recall recently we had before us a new drug that was recommended for the oral treatment of diabetes. You wouldn't have to give an injection in treating certain types of diabetes with this product. When the review by all of the Food and Drug Administration scientists had been completed we then got in touch with the president of the American Diabetes Society who had in his society many outstanding physicians who had been testing this drug clinically.

We asked him if he would be willing to give us the advice of his experts. He did convene in New York City a group of individuals about half of whom had actually tested this product in question, and all of whom had studied extensively, after our request was made to him, the file of clinical results submitted to us by the manufacturer. We got by that process in my view the consensus of informed medical opinion in the United States on this drug before it was approved. There were two relatively minor items of information that the diabetes experts thought should be supplied by the manufacturer before the drug was approved. We secured that and made the application effective.

That in general, Mr. Chairman, is the type of review process that goes on within the Food and Drug Administration and outside of the Administration when we feel the need for some outside assistance. On a number of occasions our scientists have gone to the National Institutes of Health by telephone or by personal visit to seek advice in areas where we know that the Institutes are conducting research.

Mr. FOUNTAIN. Dr. Goldberg!

Dr. GOLDBERG. Do you assign an individual medical officer to each new drug application?

Mr. RANKIN. We have, Dr. Goldberg, a medical officer who is principally responsible for review of the application, but for some years now we have very carefully avoided creating a situation in which one scientist approves or disapproves the application. I would say for some years past there have been at least two medical officers that have

reviewed every application and as our staff increases, and as we get the ability to do so, we are moving more and more to the team review approach, an approach in which you will have three or four, even five subgroups of the medical sciences involved. You may have a blood specialist, a nerve specialist, a specialist in other types of body processes, all considering the basic questions put up by the application.

I do not mean that each of these five or more physicians will make his own detailed review of the new drug application. We can depend upon one responsible scientist to review the mass of data and come out with a summary that serves as a convenient point of reference for discussion by the other physicians involved.

The brief answer to your question is: While we have assigned one medical officer the job of reviewing the clinical results and coming up with a summary, we do not assign to that medical officer the sole responsibility for making the medical decision.

Dr. GOLDBERG. Was it the accepted practice several years ago that the medical officer whom FDA assigned made the determination if the drug was to be approved, but if it was to be disapproved the decision was made at a higher level in the Bureau of Medicine?

Mr. RANKIN. I do not believe there was such a system in effect, Dr. Goldberg.

Dr. GOLDBERG. I am thinking about 3 or 4 years ago. It is my understanding that was the way in which the approval process operated in the Bureau of Medicine.

Mr. LARRICK. I believe Dr. Smith can answer that.

Dr. SMITH. Mr. Chairman, Dr. Goldberg: From the practical standpoint, applications were turned down by single medical officers much oftener than they were approved by single medical officers.

It is true that if you went through a whole administrative procedure in turning down an application-that is, giving notice of hearing and conducting a hearing and so forth, then you would have to go through the Commissioner's office and the General Counsel. But under the practical workings of the new drug procedure, when an application was turned down, probably in 90 cases out of a hundred it. was handled by calling it incomplete and not filing it.

So that that part of it was really handled by one medical officer. Dr. GOLDBERG. How long do you estimate it has been now that you have had in effect an institutional decision rather than a decision made by the medical officer to whom the NDA was assigned, with of course administrative review from his superiors to the extent that they might wish to review? How long has that procedure been in operation!

Dr. SMITH. We have required endorsement of any positive action since I really can't remember exactly, but since around 1960 or 1961. Dr. GOLDBERG. Prior to that time, was the situation that I described pretty much the operating procedure, where the individual had a great deal more responsibility for determining whether the application would be approved or disapproved than is true today! Dr. SMITH. I believe that is true.

Mr. LARRICK. There was always consultation, but the formalization of it and the tightening up of the process has increased very greatly since Congress has shown such an active interest in our work. [Laughter.]

That is a very honest answer.

Dr. GOLDBERG. That is a part of the democratic framework.
Mr. LARRICK. That's right.

Dr. GOLDBERG. The Division of Pharmacology is outside the Bureau of Medicine, yet I understand it has an integral part in evaluating the test data that are being acted upon by the Bureau of Medicine. Do you find the arrangement satisfactory? Do you find that the Bureau of Medicine gets as much service and the kind of service that it would like from the Division of Pharmacology as if it had pharmacologists in its own shop?

Mr. LARRICK. I think we are going through some growing pains, Dr. Goldberg. I think the exchange between the Bureau of Medicine and the Division of Pharmacology has been very excellent. Mr. Rankin, who is my immediate assistant, has been spending half or more of his time trying to help with the growth of these groups during this period, which is both a formative as well as a trying period. I am convinced that the evolution of this process is going along rather well. Dr. GOLDBERG. Do you feel it is a satisfactory working relationship? Mr. LARRICK. I think there is a satisfactory working relationship. I think that there are many things that we can and will improve. Considering the tremendous extra burden we have had because of our bigger job, I think very splendid progress has been made, particularly with so many new people.

Mr. GRAY. Relevant to the last point made by Dr. Goldberg, I am interested in getting back to this decisionmaking process. I would like to know the extent to which the pharmacologist participates in the actual decision that is made with regard to the approval of an application.

I know that as a matter of course the pharmacologist is consulted by the medical officer in charge, and an opinion is rendered. But is the Bureau of Medicine then in position to ignore the opinion of the pharmacologist if they so choose, or are they more or less bound to abide by his opinion!

Mr. LARRICK. This answer is one at which I have arrived after extensive consultation and discussion with people in science in whom I have great confidence. The Bureau of Medicine gives full weight, credence, and consideration to all of the views of the Division of Pharmacology. But the Bureau of Medicine as an institutional group, not any one man, but as an institutional group, has reviewed all of this scientific data. In the final analysis the decision of whether or not the drug is suitable for administration to man is a medical decision. And the Medical Bureau, just as the physician in a hospital, is the one which makes that scientific decision.

The only recourse, where there is serious difference of opinion, would be to bring the question to the office of the Commissioner. Then perhaps we would go to outside experts for some more advice.

But basically the question of whether or not the drug should be administered to people is a decision to be made by persons who are licensed to treat people.

Mr. GRAY. Certainly the opinion of the pharmacologist based upon the animal data submitted is relevant to that decision.

Mr. LARRICK. Should have great weight and contributes very heavily to that decision. I am sure that it does.

Mr. GRAY. It perhaps would be helpful, Mr. Larrick, again from the standpoint of an understanding of this institutional decisionmaking process you have referred to, if you would explain exactly how the Bureau of Medicine is organized. I understand there was a reorganization about a year or a year and a half ago, which was, I suppose, in anticipation of perhaps the drug amendments of 1962. I think this might throw some light on this decisionmaking process. Mr. LARRICK. There is the Office of the Commissioner. Under this are the bureaus. One of the bureaus of the Food and Drug Administration is the Bureau of Medicine. And that Bureau of Medicine was subdivided at the time to which you refer into a Division of Medical Review, a Division of New Drugs, a Division of Research and Reference, and a Division of Veterinary Medicine.

Mr. GRAY. Could you explain what each of these divisions is supposed to do in arriving at these decisions!

Mr. LARRICK. The Division of Medical Review basically and originally was set up to deal with the problems that arise from old drugs. They review, for example, the great mass of factory inspections, samples that come in from the field, proprietary remedies, old prescription drugs, and the whole gamut of medicines that come into headquarters with the question or recommendation from the field that some criminal prosecution, injunction, or seizure be undertaken. Originally the latter work was their primary function.

I think the title "Division of New Drugs" is in itself pretty explanatory. They deal, in this reorganization, with new antibiotic drugs, they deal with the status of new drugs. And because the Kefauver-Harris bill broke new drugs down into the investigative stage and the clinical use stage, we have a group that deals with the drug in its investigational drug stage.

We have another group

Mr. GRAY. Was that not a separate division!

Mr. LARRICK. No. Those are units of the New Drug Division; not a separate divison.

You asked me to break down the Division of New Drugs, and that is what I was doing. Let me start again.

There is a Division of Medical Review. I explained what it does. The Division of New Drugs handles new drugs and investigational drugs.

There is a Division of Research and Reference. That is the group that deals with the reports we get in from all the veterans hospitals, Public Health Service hospitals, and private hospitals. They perform the library function for the whole Bureau of Medicine, but they do much more than that because they comb the literature of the world to hunt for these adverse drug reactions that we have talked so much about.

There is, finally, a Division of Veterinary Medicine, and the title of that division is self-explanatory.

Mr. GRAY. Let's go back to the Division of New Drugs and go into the reorganization of the Division of New Drugs and the various branches that have been established and their functions.

Mr. LARRICK. There is the Director and the Assistant Director, who superintend the entire operation in the new drug area. Under