Mrs. DWYER. This is an embarrassing question, but I am going to ask it. Has your staff got the high competency which there is in industry? I mean would you say they were as competent as the scientists who did the research in the drug industry.

Mr. LARRICK. In my opinion, yes. I am a little prejudiced.
Mrs. DWYER. That is all at this point, Mr. Chairman.

Mr. FOUNTAIN. Mr. Larrick, was there any indication at all in the animal or clinical data submitted with this application of liver damage which might be attributable to the administration of Flexin.

Mr. LARRICK. Dr. Vos, who is, as I said, a pharmacologist and a physician, is competent to answer that question.

Mr. FOUNTAIN. Doctor Vos.

Dr. Vos. There were reports of several tests on animals. In a test in rats, which extended over a 6-month period at three dose levels, 50, 100, and 200 milligrams, one male rat at the top dose level was reported to have mild focal hepatitis. The pathology report was not submitted in enough detail to evaluate this properly. At the present time I am sure we would ask for more information on a point such as this, but in retrospect, the mild focal hepatitis was in all probability a spontaneous condition.

We did not believe it was drug related. There was also a dog experiment, in which there were two dose levels at the start, 25 milligrams per kilogram of body weight and 35 milligrams per kilogram of body weight. One of the dogs on the second dose, 35 milligrams per kilogram of body weight, died after I believe approximately 20 days on the drug and on examination was found to have severe hepatitis with rather diffuse hemorrhages. The tissues of this dog were examined both by the pathologist who was presumably hired by McNeil Laboratories to examine their tissues, Dr. Donnelly, and he also, we have to presume on his own initiative, sent the sections of the liver to a second pathologist, Dr. McGrath at the University of Pennsylvania. And Dr. McGrath's opinion corresponded with Dr. Donnelly's, that the liver injury was not drug related. They both agreed it was not the typical infectious viral hepatitis to which dogs are susceptible. In other words, that was not the explanation of it, but they felt it was not drug related.

At the time that these new drug applications were being reviewed back in 1955 we in the Division of Pharmacology were not making summaries which reflected the basis of our decision. In other words, we usually made a note for the file of perhaps a few sentences saying, "This is satisfactory" or "not satisfactory." The note did not summarize the evidence on which the decision was made, as we do now.

This particular new drug application was evaluated by Dr. Woodard, and his comment is very brief. It is dated December 30, 1955, and it says:

We would have no objection to this application with respect to the pharmacological evidence of safety. I do believe that some maximum limit on dosage should be put in the labeling at about a total daily dose of 2,000 milligrams for adults and a corresponding dose for children.

So as I say, at the present time it is difficult to reconstruct just exactly what Dr. Woodard evaluated, that is, what things he saw, and what weight he gave to them. In retrospect, at the present time, I would say that although the data which is in this new drug applica

tion, on animals, has scattered through it evidence of diseased livers in the animals, if evaluation of this were made by us today, fresh, without any knowledge of the history which we now have, I don't believe it would give significance to these liver findings. We believe they were probably chance occurrences in the animals. We certainly would now ask for more data than we were supplied then. We would ask for more animals, tested over a longer period of time and specifically we would ask for tests to be made at higher doses.

In the case of the dogs, they did increase the dose later. These experiments started at 25 and 35 milligrams per kilogram of body weight and they were continued on that dose for approximately 3 months, and then at the end of 3 months, they were increased to 85 milligrams per kilogram of body weight and 100 milligrams per kilogram of body weight and then continued for an additional 3 months. So actually some of the dogs got three times as much of the drug as the one dog which died of hepatitis.

I think that adds conviction or is additional evidence that in the case of the dog which died of hepatitis, the injury was probably not due to the drug, since other dogs took approximately three times that dose, without significant liver injury.

Mr. FOUNTAIN. Is that all of the information on animal experimentation?

Dr. Vos. There were some earlier experiments, which preceded these, in which there was much more scattering of liver injury. These were extremely difficult to evaluate, since quite often there were no control animals, and there was a great deal of pneumonia in the animals. It was a poorly conceived experiment, and its animals were in bad shape.

Mr. FOUNTAIN. Was that prior to giving the drug?

Dr. Vos. Well, we don't know. The pneumonia is unlikely to have been caused by the drug. Whether they had pneumonia at the time of the experiment was started or whether they developed it in the course, I don't recall exactly. A careful study of the protocol would

show that.

Mr. FOUNTAIN. Were they long- or short-term experiments?

Dr. Vos. These were by and large short experiments, lasting only a few weeks. I believe there were some that may have extended a little

more.

Mr. FOUNTAIN. So I take it from what you have said that today, if you had the same information which came to you concerning liver damage to the animals, you would make some further inquiries and ask for some further studies and tests?

Dr. Vos. It is difficult to look at this, knowing what you do know, and try to forget what has happened since then, but I do not believe that the liver damage would stand out with a new review by someone unaware of the background. In other words, we would now ask for more information simply because the experiment is not as extensive as we would now require for a drug of this sort. In other words, if there were more animals, we would be better able to evaluate a case of liver injury in one dog and similarly, we would insist that they give the drug at doses high enough so that the top dose does produce definite organ damage, so we can know what organ is affected. That is a very important point. Not just to show that nothing happens when

you give the drug, but to give doses high enough that something does happen to some organ, and if the liver were then injured at the top dose, then we would be concerned about it, we would make sure this possibility was investigated in the human patient.

Mr. FOUNTAIN. Mr. Gray?

Mr. GRAY. You say you would do this now, but you did not do it then. Why?

Dr. Vos. Well

Mr. GRAY. What has happened in the meantime to change your operation?

Dr. Vos. I think you would have to say there has been an evolution, over the years, of what is recognized as appropriate to evaluate the safety of the drug.

Mr. GRAY. Have you established certain standards for the evaluation of toxicity in animals that you did not have at that time?

Dr. Vos. I was starting to say originally, back in 1939, quite often there was little or no animal data submitted. In other words, as I say, there has been an evolution.

Mr. GRAY. But I am comparing 1955 with the present. Now have you put out any guidelines or any standards since 1955, when this application came in, that would specify the further types of studies that you say you would now require and do you now require these as a matter of course?

Dr. Vos. In October of 1955 there appeared an article entitled "Procedures for the Appraisal of the Toxicity of Chemicals in Foods, Drugs, and Cosmetics," which was written by a series of what appears to be about 12 authors, and describes the techniques which we felt were suitable or desirable. These weren't requirements, but these were recommendations.

Mr. GRAY. These recommendations, as I recall were published by the Association of Food & Drug Officials of the United States, and not by the Food and Drug Administration.

Dr. Vos. Well, it was written by the staff of the Food and Drug Administration.

Mr. GRAY. But is this an official publication of FDA or is this something the Association of Food & Drug Officials puts out that drug manufacturers may or may not accept in doing their animal studies for new drug applications?

Dr. Vos. The journal in which it appeared is a publication of the Association of Food & Drug Officials of the United States and the article had no legal standing, in other words, it wasn't a requirement. It had no official standing. But it served as a guide and was widely used by the industry.

Mr. GRAY. You mentioned

Dr. Vos. Excuse me. There has been since then, you were asking what we do now, there has been a revision of this article whichexcuse me. I made a mistake. The first one appeared in the Food, Drug, and Cosmetic Law Journal. That was where the original article appeared. The revision of it, which came out in 1959, was published by the Association of Food & Drug Officials.

Mr. GRAY. When did the original appear?

Dr. Vos. In October 1955.

Mr. GRAY. Which was exactly the time this application was submitted, was it not? In November 1955. One month later?

Dr. Vos. Yes.

Mr. GRAY. So apparently these guidelines that you say make such a great difference now, were in existence in 1955.

Dr. Vos. The October 1955 article is more a description of methods. It doesn't give any recommendations as to what you should do for an appraisal of the toxicity of a drug specifically. In other words, it was not as detailed as the 1959 article which has a special section dealing with drugs.

Mr. GRAY. Would you say the differences between the revised version in 1959 and the original in 1955, indicate the progress that you feel you have made in this area since that time?

Dr. Vos. It represents it up to 1959.

Mr. LARRICK. May I add the progress that is made is not the progress that the Food and Drug Administration alone has made, it is the progress that the entire scientific community has made and has contributed to the scientific literature, and in my opinion we should not publish standards by means of which toxicological and pharmacological and scientific evaluations should be made.

I think the entire scientific community wants the scientific freedom to pursue whatever types of investigation they think are necessary to prove a given point, and that is the way progress is made in this country. I think it is our obligation to let them know what, in the aggregate, we think is necessary.

Congress has given us authority to make standards in certain fields and I think that is very wise. But the Congress also has given the entire scientific community of this country latitude and has not bound them down to Government rules about how they shall do research and investigational work, which will result in the submission of applications to make progress in medicine in this country.

Mr. GRAY. That may be true and we certainly would not want to interfere with the freedom of scientists to pursue their research as they see fit. But do you not think the manufacturers and their scientists would appreciate some guidance from the agency which is going to make the decision on the data they submit, in setting up their experimental design?

Mr. LARRICK. Oh, I should think we should hear from them, and I think they would, I think they have received it, and I think they receive it day in and day out.

Mr. GRAY. So they have a very good idea of what you expect from

them?

Mr. LARRICK. They will probably be here and they can speak for themselves. I think they have a very good idea.

Mr. GRAY. I would like to address another question to Dr. Vos. You mentioned that in the decision made on this application, the pharmacologist, I believe Dr. Woodward, recommended that the maximum dosage be established at 2,000 milligrams. Is that correct? Dr. Vos. Yes.

Mr. GRAY. But the final maximum dosage was actually established at 3 grams, which would be 3,000 milligrams. Is that correct? Dr. Vos. That is correct.

Mr. GRAY. Then can you explain why the maximum dosage was approved at 3,000 rather than at 2,000 milligrams if this was an institutional decision?

What took place to change the situation, and why was the recommendation of the pharmacologist not followed with respect to the maximum dosage?

Dr. Vos. I have no explanation for that. As far as I know-as I say, I have no recollection of it. I don't remember anything that happened and as far as I know

Mr. GRAY. In the light of subsequent developments, do you think this had any possible significance? Was the hepatitis that was later discovered, possibly dose-related?

Dr. Vos. I have not reviewed the data on that. I believe someone else could better tell you whether it was dose-related. Conceivably it would have reduced the chances of injury if the dose was smaller. But whether the difference between 2 or 3 grams would have been sufficient, I don't know. But obviously if you cut it down enough, there would be little or no liver damage.

Mr. GRAY. You mentioned the conclusions drawn by the company's consultants, Dr. Donnelly, and Dr. McGrath, with respect to the significance of the liver lesions found in experimental animals, particularly the dog that died of hepatitis, and the rat which exhibited a mild focal hepatitis. Had one of these consultants not earlier had some other ideas about the significance of these findings? I know their final conclusion was that they probably were not drug-related. But did one of the consultants at an earlier stage not indicate that there might be some causal relationship?

Dr. Vos. Dr. Donnelly, I believe, in an earlier report, said this problem of-I don't have the exact quotation here, but he ended up his letter by saying the possibility of liver injury should be further explored.

Mr. GRAY. I believe I have a copy of that letter, Mr. Chairman, and I ask that it be made a part of the record.

Mr. FOUNTAIN. If there is no objection. Please identify it for the record.

Mr. GRAY. This is a letter of August 1, 1954, from Dr. A. J. Donnelly to Dr. Charles F. Kade, Jr., of McNeil Laboratories, in which he describes some autopsy reports he had done on animals used in experimentation with Flexin. His conclusion in the letter is that:

The drug under test may be an etiological factor in producing the pulmonary lesions seen frequently in the animal tissues studied. Pulmonary and hepatic lesions encountered in the test animals warrant further study.

(The complete document referred to is as follows:)

EXHIBIT 20-LETTER FROM A. J. DONNELLY, INSTITUTE FOR CANCER RESEARCH, PHILADELPHIA, PA., TO CHARLES F. KADE, JR., M.D., MCNEIL LABORATORIES, AUGUST 1, 1954

THE INSTITUTE FOR CANCER RESEARCH AND
THE LANKENAU HOSPITAL RESEARCH INSTITUTE,
Philadelphia, Pa., August 1, 1954.

CHARLES F. KADE, JR., M.D.,
McNeil Laboratory, Philadelphia, Pa.

DEAR DR. KADE: Enclosed are the 23 summary sheets representing autopsy reports sent to me for completion. The histologic studies have been carried out on the tissues referred to us and the individual reports are recorded on the summary sheets.