and that significance of safety in the new drug provisions of the 1938 act came to be the law of the land.

Mr. GRAY. So this situation really came about through administrative interpretation rather than by legislation?

Mr. LARRICK. Exactly.

Mr. Rankin just handed me this note. He says the treatment for cancer is not safe unless it will do what it is supposed to do. But a drug for athelete's foot may be safe even though it will not cure the athlete's foot.

That was the philosophy we adopted, administratively as you point out, as the rule we would go by.

Mr. FOUNTAIN. This was a peculiar situation under the old law with respect to the burden of proof. The manufacturer had the burden of establishing that the drug was safe and good for the purpose for which it was intended. But you had to determine it was unsafe before you could take it off the market.

Mr. LARRICK. If he applied to us for a new drug application under the old law the safety data went to Doctor Smith and his associates. If they reached the conclusion it did not establish that the drug was safe, they then acquainted the administrative group and Mr. Goodrich and his staff with this fact. The manufacturer would then be notified that in our judgment he had not sustained his burden of proof.

Now up to that point it is a criminal offense per se to ship the drug in interstate commerce for commercial purposes. After the notification the manufacturer could accept our judgment or he could tell us that he wanted a hearing. If he wanted a hearing, Mr. Goodrich and I would appoint a hearing officer and they would hold a hearing as provided by the statute. Both sides would present the evidence and a record would be made. Then the record would come to the Commissioner and he would make a decision on it, which was appealable to the Secretary if the manufacturer didn't agree with the Commissioner. In the event the Secretary ruled against him, he could go on the record to the district court.

As a matter of practice, I think in the whole 20-odd years there were only two or three cases that went to hearing.

Mr. GRAY. This was on approval of drugs?

Mr. LARRICK. That is right.

Mr. GRAY. Did you not have the same situation on the withdrawal of a drug? Would you not also ask for a hearing, under the old law, on withdrawal of a drug and go through the hearing process and actually remove the drug, if you could prove it was unsafe?

Mr. LARRICK. Yes.

Mr. GOODRICH. But you see in approving it in the first instance, you could refuse it to market on the ground the evidence did not show positively it was safe. There the burden was on industry. Once it got onto the market, then the burden shifted and we had to prove in the hearing that clinical experience had shown it to be unsafe, it was not enough for us to say clinical experience in the light of what we know now raises a doubt about it. This was one of the provisions of the Kefauver-Harris amendment saying we can withdraw a drug now on the ground it is not reliably shown to be either safe or effective.

Mr. GRAY. But there was a mechanism available for withdrawing the drug if you could prove it unsafe?

Mr. GOODRICH. Yes.

Mr. GRAY. How often did you go through that hearing procedure during that period of time?

Mr. GOODRICH. Very few times. We took several drugs off the market as you know by saying "Unless this drug is withdrawn or unless this warning is put out, we will proceed to the next step, which is the formal hearing procedure."

Mr. GRAY. And this was often sufficient to remove the drug from the market without a formal hearing process?

Mr. LARRICK. The suggestion of the formal hearing was itself a powerful aid in that direction.

Mr. GOODRICH. You can summarize it up in a sense that the hearings have always been available, either to get a drug on the market or to take it off, but nobody has tried to put a drug on the market against scientific judgment through the formal procedures and we haven't had to take but one or two of them off that way.

Mr. GRAY. So again it gets back to this question of the burden of proof being with the manufacturer in one instance and with FDA in the other instance.

Mr. LARRICK. That is right.

Mr. FOUNTAIN. In your prepared statement, under the heading "Risks," you listed five types of information needed to evaluate the risks of a new drug. For emphasis, I will list them again. These were (1) The interaction of the drug with body processes, including hormonal, enzymic, metabolic, and reproductive processes; (2) the manner in which the drug is absorbed, distributed in body tissues, and inactivated or excreted; (3) whether active compounds arise from the metabolism of the drug by the body; (4) the influence of other chemicals, such as other drugs or even articles of food or drink upon the activity of the drug in question; (5) how the activity of the drug in animals compares with its activity in man.

Does the Food and Drug Administration require that such information be included as a part of the new drug application for a product? Mr. LARRICK. Mr. Chairman, you seemed to notice every time I deviated from my prepared statement. I am sure you must have noticed I did there. When we were coming to the hearing room this morning, Dr. Smith, who had just returned from England, advised me that the statement on page 9 of the mimeographed document was too broad. He said it implied that there was available today a breadth of scientific information which science hasn't yet mastered. So rather hastily I tried to correct the scope of the statement in the mimeographed material by putting in certain qualifications which are essentially these to the extent that science has progressed to the point where these types of information and these types of scientific means of measurement are available, they are required. But there are many instances, Dr. Smith calls to my attention, where science just has not yet reached that point. It won't reach the point where all of these things are solved until we learn the mystery of what creates life.

Mr. FOUNTAIN. That is going to be a long time, isn't it?

Mr. Gray?

Mr. GRAY. If I may, Mr. Larrick, I would like to read a short section from a paper presented by your director of pharmacology, Dr. Arnold

J. Lehman, before the American Society of Experimental Biologists in 1960 which I believe is relevant to this discussion. It says in part:

The most serious problem facing those who are concerned with the toxicology of drugs is that of methodology. We have become so occupied in testing the multitude of new drugs that are being developed that we have not taken time out to make sure that the methods we are using are the best that can be devised.

In the past quarter of a century there has been virtually no change in the way by which the toxicity of drugs is studied. True, we use larger numbers of animals now, we treat them with the drug for a longer period of time, and we use two species where formerly we were frequently content with only one, but basically the procedures have remained the same. If the results had always been satisfactory, there would perhaps be no reason to consider a change, but too often our animal tests have failed to warn us of such side effects as agranulocytosis or jaundice, or have warned us of trouble that failed to materialize.

Now, this was in 1960 and I wonder if the state of science has advanced much since 1960, when Dr. Lehman made this statement, and more specifically, I wonder if you have formulated at this point any standards to be followed with regard to the animal or clinical testing data that are part of new drug applications or investigational drug applications?

Mr. LARRICK. Let me say, Mr. Gray, that I think you have touched on the very foundation of a basic problem in the approval of new drugs, chemical additives including our whole pesticide field, and as a matter of fact the basic problems in approving all of the new environmental factors to which man has subjected himself, in this age.

I have before me a publication entitled "The Appraisal of New Drugs," which is a report of the Council on Pharmacy and Chemistry, that was authored by Dr. Walton Van Winkle, Jr., who at that time was in our new drug setup, Dr. Robert P. Herwick, who at that time was Medical Director of FDA, Dr. Herbert O. Calvery, who at that time was Chief of our Division of Pharmacology, Dr. Austin Smith, who then was secretary of the Council on Pharmacy and Chemistry of the American Medical Association, and as a footnote the authors express appreciation to Drs. Sollmann, Hanzlik, and Tatum. Those three latter men were perhaps among the world's greatest authorities in the subject area to which you have just referred. These men that I have mentioned attempted to deal with laboratory and clinical appraisal of new drugs as it was understood at the time of the publication of this article, December 9, 1944. It goes specifically to your question. There have been evolutionary advances in new drug appraisal and we have with us today, if you care to go into it, by title or by subject matter, a whole series of articles dealing with this, including Dr. Lehman's article, and later articles by Dr. Smith. But Dr. Lehman's comments and Dr. Lehman's hopeful statements were to the entire community, the entire scientific world which concerns itself with why babies are formed without arms or legs, why all of the ills of mankind are as they are. We are advancing. But Food and Drug by itself can do only a tiny bit in this particular field. Our big job is to try to keep abreast of what the whole scientific community does so that our testing procedures and our routine operations will take advantage of the most advanced scientific knowledge.

I wish Dr. Smith could briefly indicate to you some of the articles. that I think are quite responsive to your question.

Mr. FOUNTAIN. Dr. Smith, we will be happy to hear from you.

Dr. SMITH. Mr. Chairman, Mr. Gray, there are a number of articles here which have been published by members of the Food and Drug Administration on this subject or on topics closely allied to it, which may be of interest and I would like to place those in the record if that is agreeable with you.

Mr. FOUNTAIN. If there is no objection, they will be inserted subject to an examination of the staff to be sure they are pertinent.

(The following publications were received but are not reproduced here due to their length and the fact that they are available in the published literature.)

Lehman, Arnold J., M.D., Ph. D., "Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics" (Association of Food and Drug Officials of the United States, 1959).

Lehman, Arnold J., M.D., Ph. D., "Control of Toxicity in Foods, Drugs, and Cosmetics," Proceedings of the Federation of American Societies for Experimental Biology, vol. 19, No. 3, September 1960, pp. 13–16.

Lehman, Arnold J., M.D., Ph. D., "Determining the Safety of an Injectable Drug," Bulletin of The Parenteral Drug Association, vol. 10, January-February 1956, pp. 9-14.

Lehman, Arnold J., M.D., Ph. D., "Newer Trends in the Laboratory Evaluation of the Safety of Drugs," The Bulletin of the Parenteral Drug Association, vol. 13, May-June 1959, pp. 1-5.

Lehman, Arnold J., M.D., Ph. D., et al., "Procedures for the Appraisal of the Toxicity of Chemicals in Foods, Drugs and Cosmetics," Food Drug Cosmetic Law Journal, October 1955, pp. 679–748.

Lehman, Arnold J., M.D., Ph. D., "Proof of Safety: Some Interpretations," Journal of the American Pharmaceutical Association (Scientific Edition), vol. XL, No. 7, July 1951, pp. 305–308.

Lehman, Arnold J., M.D., Ph. D., "Safeguarding the Use of New Drugs," The Modern Hospital, vol. 67, 1946, pp. 94, 96, 98.

Smith, Ralph G., M.D., Ph. D., "Assuring the Safety of New Drugs," Public Health Reports, vol. 71, No. 6, June 1956, pp. 590-593.

Smith, Ralph G., M.D., Ph. D., "Evaluation of Safety of New Drugs by the Food and Drug Administration," The Journal of New Drugs, vol. 1, No. 2, MarchApril 1961, pp. 59–64.

Smith, Ralph G., M.D., Ph. D., "FDA New Drug Requirements," Drug and Cosmetic Industry, 84, 736, June 1959.

Smith, Ralph G., M.D., Ph. D., "Problems Raised by New Drugs," Association of Food and Drug Officials of the United States, vol. XIX, No. 4, October 1955, pp. 144-150.

Smith, Ralph G., M.D., Ph. D., "The Introduction of New Drugs from the Point of View of the Food and Drug Administration." Paper presented at a symposium on "The Evaluation of Therapeutic Agents and Cosmetics," University of California, Los Angeles, August 16-18, 1962. pp. 1-11.

Van Winkle, Walton, Jr., M.D., "The Safety of New Drugs," Stanford Medical Bulletin, vol. 2, No. 3, August 1944, pp. 103-107.

Mr. LARRICK. Mr. Rankin has located one or two other passages from this article to which you referred that I think are pertinent. Mr. FOUNTAIN. All right.

Mr. RANKIN. In the paper you mentioned by Dr. Lehman, a little further on in the passage that was read into the record, Dr. Lehman does indicate that we anticipate some progress and if I may, Mr. Chairman, I will read a brief passage from that:

If one

There is no clear record of how the present system was arrived at. were called upon to justify it, he could mention such points as these: a mammal should be a more promising candidate than one of the lower forms; of the mammals, the dog and the rat with their long close association with man, even to the extent of sharing in his food, might be expected to resemble best his reaction to drugs; and finally two species ought to be better than one. However, it is asking too much of the dog and rat to expect them to forecast down to the last detail the toxic side effects each new drug will have in man. It is un

likely that they will detect such complications as, say, Parkinsonism and depression of spermatogensis with the same competency. The toxicity tests of the future may rely not on one or two such "general utility" types of animals, but rather on a dozen or more "specialist" types, each one chosen, and if necessary created through selective breeding, for its peculiar capability in detecting the one or two types of toxicity for which it is responsible. Rather than requiring more animals, the new system should require less because the "end point" between effect and no effect will be so much sharper.

Then he goes on into a discussion of that. Later on he says:

In such cases, however, the new procedure should prove at least the equal of the current one since some of the many species represented could be expected to be susceptible to the peculiar toxicity involved.

If anyone doubts that such a revolution is on the way, let him look around. He will see that the earliest phases are already here. Ducklings are used to detect cataract-producing drugs, guinea pigs for sensitizers, and special strains of mice for cancer-producing drugs.

I offer the paper for the record.

Mr. GRAY. I have the full text here. I said I hoped I was not quoting him out of context because I was aware of his hopes for the future. However, my question is, to what extent have these hopes been realized? Have you, thus far, made any progress in the types of data that you get in passing on the safety of a drug? Do you require a test on a duckling to see if a product might cause cataracts, and if so, did you require it on some products that have been found to cause cataracts? To what extent have you taken into account these advances in science and established appropriate standards? I don't think we could deny that the requirements of FDA do in effect establish standards for testing.

Mr. LARRICK. These articles to a great extent deal with that.

Mr. RANKIN. I believe it is fair to say the answer to your question, Mr. Gray, is we are making progress. It seems to be slow progress, upon occasion, because the development of science in this field is slow. But as science makes it possible to refine the testing to which a drug should be subjected in order to determine its safety, we do ask the drug industry to utilize the results of that science and to report to us in the new drug applications the results of these refined tests.

For example, for some time now, even before the thalidomide episode brought the matter to public attention, we were asking manufacturers to run reproduction studies on new drugs and certain other chemicals, where there was any reason to believe that these studies might yield results of value in determining the safety of the product. And breeding studies since thalidomide are a standard part of the test procedure that is required. There are other examples of the adoption of the refinements of science as they become available.

Mr. GRAY. I am sure that this will be helpful with respect to the purely toxicological tests which we have been discussing.

However, in Mr. Larrick's statement he mentions another series of pharmacological tests, including interaction of the drug with body processes, metabolic nature of the drug and so on, which he says constitute information needed in evaluating the risks involved in a drug.

I think you modified your statement to say that you do not require all of this information.

Mr. LARRICK. We don't require it where it is not possible to produce it, where science hasn't progressed to the point where it is available. But where it is available, we would ask them to produce it.