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Mr. FOUNTAIN. And I assume, in addition to what Mr. Larrick has said concerning his expectation, you would also say the company was legally obligated to delete "jaundice" from its list of adverse effects in the proposed labeling which they said had not been reported in any patient receiving Flexin, in view of the reported case of hepatitis, with jaundice.

Mr. GOODRICH. Either to delete it or have the case investigated in enough depth, to where it was not drug related, have an examination for it, one of the two.

Mr. FOUNTAIN. Thank you very much.

Mr. Larrick, I would like to ask how you explain that when this deletion was made in the proposed labeling for the supplemental application submitted on August 14, 1956, that FDA, in your words, "did not detect the changes and, therefore, did not call upon the firm to explain the significance of the change."

Mr. LARRICK. I could only conjecture what procedures Dr. Moulton went through, when she reviewed these five copies of the revised brochure, some of which had the corrections in and some of which did not. If she didn't happen to pick up the one that had the changes in it, why, it wouldn't be any flag to her.

Mr. FOUNTAIN. Inasmuch as these five copies all go to different people for their examination, would it not be necessary, so that all would have the same information for evaluation and study, that all of the copies be alike?

Mr. LARRICK. Yes; the copies should all have been alike.

Mr. FOUNTAIN. So then before they were distributed, there was a responsibility to see that all of the copies were alike?

Mr. LARRICK. Mr. Fountain, when I get a document from somebody and it has the original and five copies, I don't take the time to read all five of them and see if they are identical. I don't believe that is reasonable.

Mr. FOUNTAIN. I am frank to admit I do the same thing. But in this particular area, I am not so sure what I would have done or what should have been done.

Mr. Gray?

Mr. GRAY. That may be true; if you had five that were apparently identical, you might not read them. But in this case, if you recall your testimony, two were Xeroxed copies and three were printed copies with certain typewritten changes taped on them. So it was quite obvious, just from looking at them, that they were not identical.

Mr. LARRICK. Mr. Gray, I have stated the absolute, unvarnished facts about what happened and I am quite content to let you make your own conclusions. If you think it was a mistake, that is your judgment. Mr. FOUNTAIN. Before you ask the question, Mr. Gray, do you feel that you have adequately described the copies?

Mr. GRAY. I believe they were described at the time Mr. Larrick made his statement and they were included in the record as exhibits. One exhibit was a Xeroxed copy, on which no changes were made: the other was a printed copy on which certain changes had been typed and taped over the original print. They were quite obviously of a different size and shape, and so on, and this might well have raised a question.

Mr. LARRICK. I won't argue with you about that. Maybe that should have. But I wouldn't condemn a person too seriously if they had what purported to be five identical copies and they were as busy as these people and they reviewed only one of them.

Dr. Moulton is here in town, she is readily available, and I am sure if you cared to have her, she would be glad to tell you what she did.

Mr. GRAY. The question I was leading up to is whether it was standard operating procedure to have someone review all five copies of labeling submitted and, if not, why do you require five copies?

Mr. LARRICK. No; because in some instances you need to have a multiplicity of reviews. This is particularly true in the initial application. But in a supplemental application, you may or may not need to have it again reviewed by the chemist, by the pharmacologist, by other people, the bacteriologist, or what-have-you and, in this case, I think the change was simply a change in dosage form.

Mr. GRAY. But this was an individual rather than an institutional decision?

Mr. LARRICK. That is right. I am sorry to report it was an individual rather than an institutional decision.

Mr. FOUNTAIN. I would like to ask you whether or not it was standard operating procedure to compare the proposed labeling submitted in a supplemental application with the labeling currently in effect for that product?

Mr. LARRICK. I think I will ask Dr. Smith to answer that.

Mr. FOUNTAIN. Dr. Smith?

Dr. SMITH. Yes, sir; that would be standard procedure.

Mr. FOUNTAIN. Was that done in this case?

Dr. SMITH. I really don't know; I can't answer that question; I don't know exactly what was done.

Mr. FOUNTAIN. Well, it evidently

Dr. SMITH. I presume it was done.
Mr. GRAY. You presume it was?

Dr. SMITH. That it was.

Mr. FOUNTAIN. Evidentally the change was not detected.

Dr. SMITH. That is true.

Mr. FOUNTAIN. Well, I guess we could have a hundred different opinions about this.

Mr. LARRICK. I should point out on some of these copies there was no change. If they compared it with the original application-if they picked up the one where there had been no change there would have been nothing to detect.

Mr. FOUNTAIN. Dr. Goldberg.

Dr. GOLDBERG. Commissioner Larrick, was it accepted practice to permit a company to submit changes in labeling in that fashion; that is, with the five copies in different forms? Did you require some uniformity in these submissions, or did you accept anything that a company chose to send in?

Mr. LARRICK. In our whole operation, we consider many, many labelings, and whether it is a food or drug or cosmetic, or what-haveyou, the initial submission is, in many cases, accepted by us in quite informal form.

We don't require printed labels, for instance, because in our conversations and discussions with people who ask for our advice on

proposed labels almost invariably changes are made as a result and we have not thought it desirable to force them to make printed submissions and to require great formality until we got to the point where the labeling submitted was the labeling actually intended for use. Then, before our official opinion is expressed, we want the label or labeling to be precisely as it is going to be on the label or in the package.

But we do not require, nor have we required, that they all be typed or they all be printed or all be mimeographed. The substance of what they had to say was what we were concerned with.

Dr. GOLDBERG. Would you, today, still accept submissions of that sort?

Mr. LARRICK. We wouldn't make any application effective. The provisions are very definite that no application is effective until the final printed version is in our hands and has been reviewed.

We still would permit anyone to walk in with a typewritten statement and sit down and talk to our people about it and find out what our views are in relation to their views.

Dr. GOLDBERG. However, in terms of the convenience of your staff, would you still allow a firm, even a large corporation, to send you five pieces of paper, all different, or three different from the other two? Mr. LARRICK. If that were done with any degree of regularity, I think we would stop it. Maybe we should, anyway.

Dr. GOLDBERG. It doesn't sound terribly efficient to me.

Mr. LARRICK. No, it doesn't to me, either. But, ordinarily, when proposed labels and brochures are submitted to us, the first drafts are typed, and they are typed so that they are identical.

This Flexin submission was a very unusual situation, in my experience, although I don't see the new drug applications, ordinarily. Mr. FOUNTAIN. Dr. Goldberg.

Dr. GOLDBERG. May I go back for one moment and direct a question to Dr. Vos with respect to the earlier discussion on animal testing? If I understood your statement correctly, some advances have been made in animal testing since 1955. Is that correct? There are higher standards now?

Dr. Vos. Yes, that is correct.

Dr. GOLDBERG. In your opinion, under today's standards, do you think adequate animal testing would predict the possibility of Flexin causing liver damage in human beings?

Dr. Vos. I don't believe you can give a positive answer to that. You have asked my opinion. The incidence in human beings is extremely low, so you would certainly have to have a large number of animals.

In the human beings, I believe the incidence is 1 in 100,000, perhaps, or 1 in 60,000, in that area.

So if the incidence in animals is the same, you obviously won't pick it up with a few dozen rats or dogs. But by giving larger doses, you could hopefully find a higher proportion. In the case of Flexin, however, I believe there would be some difficulty. Because of its muscle relaxant effect, you might be limited in the amount you could give. In other words, there might be no organ damage if the highest dose was tolerated. If the animal was completely paralyzed and can't eat,

there is a limit to how high you can go. So the only way I know is to do the experiment and see.

It is, I think, possible that even higher doses and more animals might not have shown liver damage. There are more extensive tests we are recommending now in addition to simply examining the liver histologically, that is, examining the sections under a microscope. We do liver function tests which measure the soundness of the liver while the animal is still alive, and perhaps in those we would pick up a clue.

Dr. GOLDBERG. Do you know of any experiments that have been carried out along these lines with Flexin, to see whether or not the drug might cause liver damage or any other adverse effects in human beings?

Dr. Vos. I am not familiar with the tests on human beings.

Dr. GOLDBERG. I am referring to tests in animals.

Dr. Vos. No, I am not familiar with such tests.

Dr. GOLDBERG. With respect to drugs that are withdrawn from the market due to their association with adverse unexpected side effects, do you think there might be value in going back into animal tests and designing new experimentation to see if one can find new associations with these drugs which would indicate their toxic mode of action? Would this be a worthwhile type of experimentation?

Dr. Vos. Yes, indeed, this is a very valuable approach, a way to improve our animal techniques and maybe by trying possibly the other species, sometimes we find that the rat and dog aren't the best measure for one type of toxicity, so it would be useful, and it is a common thing. As far as I know, however, no such work has been done yet on Flexin.

Dr. GOLDBERG. I am wondering in this context whether, once a drug is condemned for use in man, it might still have great value for finding out why it went wrong in man, and whether we ought to direct more attention to its negative aspects for the purpose of designing such experimentation.

Dr. Vos. Yes, that is very frequently done. In the case of Flexin, I am not aware of such tests, but it would be a profitable drug for study in animals, in retrospect, you might say.

Dr. GOLDBERG. Thank you very much.

Mr. FOUNTAIN. In your statement, Mr. Larrick, I don't believe you made any mention of two supplemental applications filed by the company on May 10, 1957, for combinations of Flexin with other drugs, one for a product known as Flexilon, a combination of Flexin with an analgesic called Tylenol, and the other for Flexilon-HC, a combination of Flexin, Tylenol, and Hydrocortisone. Both applications under the heading "Full reports of all investigations that have been made to show whether or not the drug is safe for use," included the following statement concerning Flexin:

The reports of the clinical use of Flexin since its introduction on the market are in essential agreement with the experience of the investigators reported in the new drug applications.

At this point, I would like to ask that appropriate sections of these applications be inserted in the record.

(The documents follow :)

EXHIBIT 21A-EXCERPT FROM NEW DRUG APPLICATION FOR TABLETS FLEXILON MCNEIL LABORATORIES, INC.,

May 10, 1957.

(1) Full reports of all investigations that have been made to show whether or not the drug is safe for use.

The drug, Tablets Flexilon,' is a combination of two well-established therapeutic agents, Flexin' zoxazolamine and Tylenol' acetaminophen.

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(a) Flexin.-Pharmacologic, toxicologic, and clinical data demonstrating the safety for use of Flexin were filed as a part of NDA 10250 covering Tablets Flexin, 250 milligrams, which became effective January 13, 1956. A supplemental application covering a new dosage form, Tablets Flexin, 250 milligrams, engestic coated, became effective October 8, 1956. The reports of the clinical use of Flexin since its introduction on the market are in essential agreement with the experience of the investigators reported in the new drug applications. (b) Tylenol.-It is our understanding that this drug, N-acetyl-p-aminophenol, is no longer considered a "new drug" within the meaning of the Federal Food, Drug, and Cosmetic Act.

The amounts of the two active ingredients, Flexin and Tylenol, provided by the recommended dosage of Tablets Flexilon does not exceed that which is commonly employed and considered safe for use for these drugs. In order to be certain that the combination does not produce any unpredictable effects, a clinical investigation of Tablets Flexilon was undertaken. The following report presents the results of these clinical studies and substantiates the safety for use of this product.

EXHIBIT 21B-EXCERPT FROM NEW DRUG APPLICATION FOR TABLETS FLEXILON-HC (Flexilon with hydrocortisone)

MONEIL LABORATORIES, INC.,
May 10, 1957.

(1) Full reports of all investigations that have been made to show whether or not the drug is safe for use.

The drug, tablets, Flexilon-HC1 (Flexilon with hydrocortisone) is a combination of three well-established therapeutic agents, FlexinR zoxazolamine, Tylenol® acetaminophen, and hydrocortisone.

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(a) Flexin.-Pharmacologic, toxicologic, and clinical data demonstrating the safety for use of Flexin were filed as a part of NDA 10250 covering tablets Flexin, 250 milligrams, which became effective January 13, 1956. A supplemental application covering a new dosage form, tablets Flexin, 250 milligrams, engestic coated, became effective October 8, 1956. The reports of the clinical use of Flexin since its introduction on the market are in essential agreement with the experience of the investigators reported in the new drug applications.

(b) Tylenol.—It is our understanding that this drug is no longer considered a "new drug" within the meaning of the Federal Food, Drug, and Cosmetic Act. (c) Hydrocortisone.-Hydrocortisone is included in the U.S. Pharmacopeia IV. The amounts of the three active ingredients, Flexin, Tylenol, and hydrocortisone, provided by the recommended dosage of tablets Flexilon-HC (Flexilon 1 Trademark.

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