When the additional dog kidney function tests were submitted to the Food and Drug Administration in October 1958, the pharmacologist reviewing the data stated in a one-sentence memorandum of October 28 that "The added submission on kidney function tests indicates this drug is safe."

Without objection I shall insert the entire memorandum in the record at this point.

EXHIBIT 56-INTRA-AGENCY MEMORANDUM RE ADDITIONAL ANIMAL DATA ON

SUBJECT: Added submission on Orabilex (NDA 11584); F. Fougera & Co., Inc.

The added submission on kidney function tests indicates this

drug is safe...

cc: ECHagan

ECHagan: jem....

10-22-58
INIT:BIV.

E. C. Hagan

This form to be used in lieu of yellow Agency Route Slip when requesting comments of recommendations.

Division name only to be gred in "To" column. If individual is to be desi Suated, indicate trimes in body of form to right of livision.

* Mouble line under conclusion of Individual's dated recommendatLon;

Mr. FOUNTAIN. On what basis did he arrive at that conclusion?

Dr. Vos. Unfortunately, in those days we were not requiring him to summarize the data which was the basis for his conclusion. Many of the comments were simply as brief as that. They reviewed the data and gave an opinion without stating the basis for it.

The only conclusion I can reach is that he reached his decision after reviewing the data that was submitted to him.

Mr. FOUNTAIN. When did you change that procedure, or have you changed it yet?

Dr. Vos. Yes.

Mr. FOUNTAIN. You now require a review of all of the information and a summary of the basis on which a decision is made?

Dr. Vos. Yes The precise date which this occurred I can't give you. I would estimate it must have been perhaps late in 1960 or early in 1961. In other words, there was no sharp date on which this happened. We began putting, you might say, pressure on the people who were doing the review, to provide more description of the data that was the basis of their evaluation.

Certainly, in 1961, there was a little mimeographed, shall I say, synopsis, or outline that they were given of the type of information they were expected to include.

Mr. RANKIN. This change in our procedure, Mr. Chairman, was one of the results of a study made by a committee selected by the National Academy of Sciences to look into the new drug and antibiotic drug review and evaluation procedures of the Food and Drug Administration.

This committee reviewed our operations in 1960 as I recall. It submitted a report with numerous recommendations. If you would like to have it, we can submit a copy of that report for the record. Mr. FOUNTAIN. We would be glad to receive that report, Mr. Rankin.

Mr. RANKIN. One of the recommendations was that each new drug application have a summary of the review that was performed by the scientist and the conclusions that he reached. And that recommendation is being followed throughout at this time.

Mr. FOUNTAIN. I would like to say, Mr. Rankin, that it is inconceivable to me that it would take a committee of the National Academy of Sciences to impress upon the Food and Drug Administration the importance of such a procedure, and I am surprised that it was not required a long time ago.

That you would permit this drug, or any drug, to be approved without a summary of the basis upon which the pharmacologist or medical officer made the decision is inconceivable to me.

Mr. Gray?

Mr. GRAY. Aside from the question of whether or not there is a summary, Dr. Vos, I believe Mr. Rankin stated that all of these decisions were institutional decisions.

Did you participate in the evaluation of this additional submission of the dog studies?

Dr. Vos. My initial occurs at the bottom of that memorandum, I believe.

1 The report referred to was submitted to the subcommittee at its hearing on Apr. 29 and appears on p. 637.

Mr. GRAY. Yes, it does.

Dr. Vos. At the present I have no recollection of the extent to which I independently reviewed the data.

Mr. GRAY. Have you reviewed it since that time?

Dr. Vos. Yes.

Mr. GRAY. As a pharmacologist, perhaps you could tell us what new evidence this added submission provided concerning the possible effects of Orabilex on kidney function which would enable this type of decision? In short, what was the significance of this added submission and what did it show that was new?

Dr. Vos. A second test was conducted using a larger number of animals. There were five animals that received a dose of 1 gram per kilogram, dogs, five dogs received 1 gram per kilogram per day. Five received 12 grams per kilogram per day, and there were three control dogs.

Mr. GRAY. This was 3 dogs more than the original study then, which included 10. Is that correct?

Dr. Vos. Yes, but they are concentrated at the higher doses.

And there were more kidney function tests. They were performed on the 7th day, the 10th day, and the final day of the test. So it gave a clearer picture of any possible effect on kidney function.

There is in all groups a tendency of the kidney function test to show a variation with progression toward lower levels. There was one dog on the 1 gram per kilogram dose which had a kidney function which was 43 percent, compared to an initial value of 74 percent. This is a lower kidney function than occurs in any control dogs. But that same dog on the 10th day had a 100 percent excretion of the dye.

Mr. GRAY. Why should there have been a decrease in any of the control dogs? They didn't receive the drug, did they?

Dr. Vos. This would have to be interpreted as spontaneous variation. It isn't like a simple chemical assay, where you get always the same answer. It is what we call biological variation. That is why we need control dogs, to get a measure of what the normal variability

is.

Dr. GOLDBERG. Doesn't that perhaps suggest a defect in the experiment and the need for further tests, when you get that result in the control dogs?

Dr. Vos. It is extremely difficult to appraise this on its face without considering what we know now since then.

Dr. GOLDBERG. Let's say as an abstract problem.

Dr. Vos. Aside from what I do know about Orabilex, my reaction is, if there is any suggestion of decreased kidney function here, it is of such small magnitude in consideration of the excess dose that the animals are getting each day and also the excess duration of the experiment, that it doesn't appear to me to be of significance.

Dr. GOLDBERG. I asked the question in terms of good pharmacological procedures and principles, and not particularly with respect to Orabilex. When you find kidney depression in a control animal, irrespective of what drug you happen to be testing, does this suggest that perhaps the experiment is not reliable and you ought to start again?

Otherwise, what is the function of a control animal?

Dr. Vos. It is a fact of life that you have to live with in doing tests on animals, that the results are not always uniform and clear cut and that is why the controls are included. And if the treated animals don't show a marked effect that is different from the controls, that is the conclusion or the interpretation of the experiment. I don't think that this would be ordinarily taken as evidence that the experiment needed to be done over.

In other words, there is a slight suggestion here. If it had been more marked it should have been done over. But at this level, since it was already a second experiment, and it showed less in the way of kidney injury than the first

Mr. GRAY. To recapitulate and get back to my original question, your statement on the original submission was that there weren't enough animals involved to tell whether there was kidney damage or not. As I understand what you have said so far about the significance of the added submission, you say it contained some indication of depressed kidney function in both the control and the experimental animals, but you weren't able to tell whether it was significantly greater in the experimental animals or not.

Now it seems to me that the added submission instead of showing the drug to be safer than the original data, might raise some further questions. Would you agree with that?

I started out by asking you what there was in this added submission that showed greater safety for the product than had been demonstrated in the original submission. So far the only thing you have quoted to me is something which seems to raise further question concerning its safety. Is that a fair assessment?

Dr. Vos. No, I don't believe so.

Mr. GRAY. Why not?

Dr. Vos. Well, as I started out, I said there were additional animals, concentrated at the higher dose, or more concentrated at the high doses, there were more control to permit evaluation of them, there is a doubtful suggestion, shall we say, of reduced kidney function, which is in my opinion not enough to consider that the drug has caused it. If it is a slight effect, when you take into account the dose which is administered and the number of times that the dose is repeated, it is unlikely to be of clinical significance.

Mr. GRAY. But was it enough to require still further tests maybe? Dr. Vos. Not in my opinion.

Mr. GRAY. Was it enough to show that the drug was safe?

Dr. Vos. Well, to show that a drug is safe in an absolute sense is impossible. You can never absolutely show a drug is safe.

Mr. GRAY. Did it show that the drug was safe under the conditions of its intended use?

Mr. FOUNTAIN. I think we all understand what you meant by the term "safe." I don't believe any of us think any drug is so absolutely safe that something might not happen as a result of its use, if it is not used properly and so on.

Mr. GRAY. I asked if the added submission showed the drug to be safe under the conditions of use which they indicated in their application?

Dr. Vos. To the extent the animal tests can. We recognize limitations, that something may show up in man that doesn't show up in animals.

Mr. GRAY. Even though it showed depressed kidney function in all of the test animals, including the controls?

Dr. Vos. Well at the final reading there is reduction in kidney function tests, yes, in all of the test animals and in two of the controls. But I think you have to take the results of the 10th day into consideration also. There in many instances the readings on the 10th day show increases above the initial values. If there had been a constant downward trend from the 7th to the 10th to the final, then we would attach more significance to it. But as I evaluate it now, there is a slight suggestion of depressed kidney function which is of a small magnitude.

Mr. FOUNTAIN. In connection with what we are talking about, Dr. Vos, our consultant, Dr. Davison, found-and I realize that you gentlemen in this field don't always agree that the data in the added submission, were inadequate to substantiate the safety of the drug in the terms in which we understand safety. In support of his position, he points out that all of the dogs, including the control animals were shown to have depressed kidney function, and that because of the small number of animals employed, and the poor reporting and the incompleteness of the data, it was impossible to evaluate the reasons for this phenomenon.

And as a matter of fact, Dr. Davison's observations on the added submission are supported by those of the consultant retained by the manufacturer of Orabilex in 1963, to review all of the animal data in connection with this product.

Dr. W. B. Deichmann, professor of pharmacology at the University of Miami, concluded on the basis of that added submission that "There is some, even though inconclusive indication, that repeated dosing with 1 and 112 grams per kilogram of Orabilex may lead to progressive kidney damage."

If there is no objection, a copy of Dr. Deichmann's report will be placed in the record.

(Dr. Deichmann's report follows.)

EXHIBIT 57-EVALUATION OF ANIMAL STUDIES WITH BUNAMIODYL SODIUM (BUN) (ORABILEX) BY CONSULTANTS TO E. FOUGERA & Co.

UNIVERSITY OF MIAMI,
SCHOOL OF MEDICINE,
Coral Gables, Fla.

REPORT ON BUNAMIODYL SODIUM (BUN) (ORABILEX)

Prepared for Dr. Arnold Urdang, research director, E. Fougera, Hicksville, N.Y., by Wm. B. Deichmann, Ph. D., professor of pharmacology, W. A. D. Anderson, M.D., professor of pathology, University of Miami, School of Medicine, Coral Gables, Fla.

The individual reports submitted were reviewed. Comments are as follows: Leberco Laboratories Report, No. 70313: The animals were observed for a five-day period for signs of toxicity as evidenced by loss of body weight, vomiting, etc. The oral LD50 was found to be 2.2 g/kg.

Comments. A five-day experimental period for the determination of acute toxicity data is, as a rule, not really sufficient. Animals should be observed for at least one week. We do not discontinue acute toxicity studies before a period of two weeks to make certain that we "catch" the late deaths, and to produce some meaningful pathological changes.

The oral lethal dose was stated at 2.2 g/kg of Orabilex. Chances are that the toxicity would have been higher (and the LDs lower) had the animals been