Does the simple fact that a company's product is not mentioned by name mean that there is no conflict?

Dr. KENNEDY. No, I would think not. Here, of course, we are dealing with the problem of exclusion for an association with prescription drugs and the question whether he should be excluded from discussion of ingredients contained in over-the-counter products manufactured by the same firm.

I think that is something that we might very well want to look into and change our instruction to panel chairmen and executive secretaries about that sort of issue.

Mr. MAGUIRE. In other words, you are saying that the past definition the FDA has used for what is a particular matter or one that ought to be covered is inadequate.

Dr. KENNEDY. I think there may be particular cases in which we show that our definition of that not very precise statutory language needs some modification; yes. I am not saying that I am ready to conclude that this is such a case. I think I would want to have a chance. to look at it a little harder.

I think I should emphasize that our executive secretaries and panel chairmen are learning as we go along with these rather new procedures how to do better.

Mr. MAGUIRE. If I, for example, were serving on an advisory committee and we were talking about limiting the size of automobiles, would it not create a conflict of interest if I happened to work for or be on contract with the Ford Motor Company whether or not we discussed the Ford Motor Company's products by name?

That seems to me rather obvious that there is a problem here. Dr. KENNEDY. I would think that in that specific case I might agree with you that there is a conflict of interest involved. I think that the size of universe, the kind of manufacture in which the firms are engaged, the nature of the interest, all might be variables, however, that one would want to take into account before elucidating a general policy.

Mr. MAGUIRE. Why would it be any different for toothpaste?

Dr. KENNEDY. I think in the case of a firm marketing both overthe-counter and prescription drugs where a disqualification has been made for a research grant given in the area of a prescription drug and that generic classification exercise in the area of over-the-counter drugs is involved, not involving named products, I think that is a tough call.

Mr. MAGUIRE. How many of these advisory committees would be dealing with generic items as opposed to specific items?

Dr. KENNEDY. I may have to get some help on that, Mr. Maguire. Certainly, all of our device panels deal with what amount to classification problems in which we take a whole group of devices and put them either into class 1, class 2, or class 3. Many of our over-thecounter drug panels are involved in the same kind of activity.

So, I would say that generic classification is an important attribute of the work of, perhaps, 20 or 25 of our advisory panels.

Mr. MAGUIRE. Well, the information we have is that it is 40 out of 67.

Dr. KENNEDY. Yes, the number is shrinking, but

Mr. MAGUIRE. This really means that, if you are going to be sloppy about what people can get away with with respect to considerations of generic classifications, that that opens a loophole which affects significantly more than a majority of the advisory committees.

Therefore, I would urge that you give that your attention as you try to work on this because it is not a marginal issue.

Dr. KENNEDY. I agree; it is not a marginal issue. I certainly plan to give it attention.

Mr. MAGUIRE. In case C, we also have a question of working on generic categories. In this case, the chairman had received substantial funds from A. H. Robins. Wyeth Laboratories, and BristolMyers. His reappointment as chairman of the panel on review of internal analgesic including antirheumatic drugs in noted. This went to the Over-the-Counter Drug Review Steering Committee, which decided it was in the public interest for him to continue as chairman to complete existing work provided he filed the proper disclosure forms. But he never excluded himself from deliberations, including those which affected Robins, Bristol-Myers, or Wyeth.

He participated in making technical changes in over-the-counter drug categories in which Robins and Bristol-Myers made submissions. He participated in these discussions.

How can this kind of involvement, which blatantly contradicts the restricts placed in the public record-in this case he was supposed to disqualify himself, as I understand it.

Dr. KENNEDY. I am less familiar with this than I am with the other case, Mr. Maguire.

I think, again, the problem is whether participation in a classificatory exercise involves a particular matter or a class of products.

I should possibly add that there is a considerable problem where we do ingredient reviews where a common ingredient of many drugs like, for example, aspirin would be involved in the product of many, many different manufacturers. If we disqualified on the basis of involvement with one firm using a particular common ingredient, I think it might give rise to some very general difficulties.

Let me add that

Mr. MAGUIRE. My understanding is that those specific firms-some of them at least-had specific products which were, during the course of the discussion, brought into the discussion on that particular panel. Dr. KENNEDY. That is something I would really have to check, Mr. Maguire. I you would like for me to confer with my colleagues now, I can do that. Otherwise, we can supply you with a further account for the record.

[Conference among Messrs. Kennedy, Meyer, and Merrill.]

Dr. KENNEDY. I think to supply a for-certain answer, we are going to have to look at the transcript.

Our understanding, however, is that this is typical of the number of instances of ingredient review in which we are looking at all products containing some common ingredient like aspirin. Although the products of individual firms may be mentioned by name, the purpose of the exercise is to classify a host of products that carry a certain ingredient.

We are just simply going to have to look back at the transcript to get a more specific view of what happened in that record. To the

extent that there is a general problem represented by these cases, we will, of coures, go after a solution to it.

Mr. Moss. Without objection, we will hold the record open to receive it and instruct the staff to review the transcript with the FDA. [The following material was received for the record:]

EXCERPTS FROM TRANSCRIPT OF PROCEEDINGS, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, OTC INTERNAL ANALGESIC PANEL, ROCKVILLE, MD., TUESDAY, Nov. 23, 1976

Dr. C. We have to wait on that, don't we, until we hear back about that. Let's go on. Let's skip Saloxium.

Dr. REDMOND. Then Arthritis Strength Bufferin. (Bristol-Myers products) It has 485 milligrams of aspirin. So again, two tablets to begin with, followed by one to two tablets. And instead of every 4 hours, it would be 5 to 6 hours, like Arthritic Pain Formula. And if they take the whole thing, it would be about 3,800.

Dr. REDMOND. Now, the hairy one is Excedrin. (Bristol-Myers product)
Dr. C. Have we finished Measurin?

Dr. REDMOND. That's a good one. Measurin stays as it is. Identical to Bayer Timed-Release, same dosage regimen, and it's okay.

Now, let's go back to Excedrin. I think we can handle Excedrin now. And I am like George was yesterday. I am a bit confused-and I think Naomi was, too; she expressed some confusion and concern. I the sky the limit while they stay in category III, and only after they go to category I we are going to stick to no more than two? And is the sky the limit again?

Dr. GILBERTSON. It is what is on the market now.

Dr. REDMOND. What is our regulation now until the 3 years?

Dr. C. They have to stay with this for 3 years.

Dr. REDMOND. Even if they have nine ingredients?

Dr. GILBERTSON. The policy reads that any more than two is category III. You have to put an upper limit.

Dr. REDMOND. Moving from III to I, they have to reduce to two?

Dr. C. We have to write that. We haven't told them how to get from III to I yet on combos.

Dr. REDMOND. Maybe we should discuss that at length. This thing has two recognized analgesics, proper threshold doses, but a lot of salicylamide, which only God knows what it does, plus caffeine, so it's a four-ingredient preparation. Here you have aspirin, 194; acetaminophin, 97; salicylamide, 130. And here this has been again empirical because we cannot do anything else better. It adds up to 421. Numerically, as far as efficacy, it is probably less than that. But at the same time, you have a rather large quantity of salicylamide per tablet. So if you take two tablets of this, you already have 260 milligrams, which is enough to interfere, as was mentioned yesterday, with the metabolism of this and this.

So maybe Excedrin is right; it is probably better in the fact it is probably longer lasting. Whether it is longer lasting enough to treat this in a different time interval is what I don't know. This is what I just have no recommedations on. I really would like an input.

Dr. C. Let's go ahead and treat it differently and have a longer time interval and give them time to test and come in and show us, with different dose regimes they want to use, that they don't exceed 20 milligrams percent of salicylamide.

Dr. REDMOND. And maybe when we are talking about combination policies in how to get from III to I, I would like this particular manufacturer to come out with some data of what is the metabolism of aspirin in Excedrin as opposed to aspirin alone. What is the metabolism of acetaminophen as opposed to aspirin?

Dr. C. I think what we will do is write it in a general fashion and say under salicylamide, "If salicyamide is used in combination it must be shown that," and go on with your recommendation. So to apply to all salicylamide-containing products because salicylamide is in any combination if it is in III, and we can put two guidelines in today, then, as to what we want.

Dr. REDMOND. It is in III for multiple reasons. The only reason was at the low dose it is ineffective and the high dose is toxic. The fact it is such a magnificent inhibitor of metabolism of both this and this, and quite dramatic, the company and us could enter it two-fold. If they come with a very good study that it inhibits metabolism, it can be interpreted by them and us to be a good feature, because it is something that will keep the aspirin and acetaminophen in our body and we don't need to take it as frequently.

On the other hand, it can also be interpreted as something bad if it is going to keep it so long that we are going to take the tablet before the next half-life is over. I am terribly concerned, and I don't have any recommendation for Excedrin. I would like somebody else to make it.

Dr. C. Bill, do you have any recommendation on this combination?

Dr. BARR. Yes. I think really what we need to do is set the target level, the appropriate target level we think is right.

Dr. C. Yes. But we don't have a caution about peptic ulcer.

Dr. ROTHFIELD. It should be on it.

Dr. C. Let's see what the sodium salicylate label says.

Dr. ROTHFIELD. All of them should have the ulcer warning.

Dr. C. "Do not take this product if you have stomach distress, ulcers, or bleeding problems."

Okay. So that would be easily disposed of, then, under the same heading, if that is the way we decide to go.

Dr. PISANI. Point of clarification on previous discussion. Did you amend the aspirin labeling, "Do not take this product if you have recurring stomach distress"?

Dr. C. No, we did not.

Dr. ROTHFIELD. Can I cross this out, or do we have to wait for Bill to come back? He is on the phone to Miles.

Dr. C. Does anyone have any suggestions on how we can effectively use the next 15 minutes? Ninfa, do you want to raise the Excedrin issue? Let's take that. I think we can discuss that. No. 18.

Dr. REDMOND. I think we kicked it around sufficiently this morning.

Dr. C. That paragraph we added you will expand on, on moving salicylamide combinations from III to I, will satisfy your concern with Excedrin?

Dr. REDMOND. Yes.

Dr. C. Actually, to get Excedrin into I, they are going to have to do at least three or four studies. So we cross out that.

Let's go over the references. Has anyone had a chance to look at the new references I handed out to see if any of them are worth putting in the monograph?

George.

Dr. SHARPE. Maybe we ought to have Bill here. But in reading on acetaminophen, because it's all later dates, there seems to be more and more evidence when you really go at 1,000 milligrams as a dose, 500 milligrams as a standard dose, it seems that you are really getting a better response.

Dr. C. That's true with the 1,000 milligram aspirin, too.

Dr. SHARPE. But this is safe.

Dr. C. But don't forget, some people get in trouble at 10 grams in terms if irreversible liver damage.

Dr. SHARPE. That's 10 times.

Dr. C. That's not 10 times. That's allowing 4 grams a day. That's two-andone-half times.

Dr. SHARPE. Then there is no need to put that in, I don't think.

Mr. MAGUIRE. Thank you, Mr. Chairman.

With respect to Case A, we had a situation in which the principal investigator on a $140,000 grant to Purdue from the New Dimensions in Medicine Co. was reappointed to a panel on review of cardiovascular devices.

In this case his disclosure statement specifically excluded him from participating in any FDA matters relating to New Dimensions or their electrosurgical electrode. Yet, Mr. A did participate in the

classification of the device. Moreover, the subcommittee staff observed him participating. The executive secretary, who is supposed to control the meeting, did not ask him not to participate; nor did he disqualify himself.

Do you regard this as acceptable?

Dr. KENNEDY. I think, again, this will depend on our resolution of the term "particular matter." The exercise in which Dr. A

Mr. MAGUIRE. I do not think it depends on that at all. His disclosure statement specifically excluded him from participating in any FDA matters relating to New Dimensions. He went ahead and participated in matters relating to New Dimensions.

That seems to be very clearcut. I do not think it would be variable, depending even upon your definition of "particular matter"; do you? Dr. KENNEDY. Well, Mr. Maguire, the exercise in which Dr. A was participating involved a classification of all electrosurgical electrodes, as in Class 2 or Class 3. Again, I guess, we would have to examine the transcript.

I do not believe that, in such exercises, particular products of particular firms are mentioned.

Mr. Moss. Will the gentleman yield?

Mr. MAGUIRE. Yes, sir.

Mr. Moss. This is one that I find rather disturbing. The response is disturbing.

The information that I have is that the disclosure memorandum was agreed to. It was to be a nonparticipation statement, public disclosure memorandum. A member of the panel-Member A-then attended a meeting of the panel and participated, notwithstanding the fact of a nonparticipating disclosure agreement.

He participated in classification proceedings involving the electrode of the very company which had made the grant. The executive secretary knew in advance that the matter would arise at the meeting. He was also aware of the fact that we had a subcommittee staff person present.

He was fully aware, again, of the statement filed. Yet, he permitted the participation by the panel member in the deliberations and the recommendations.

I think that is about as clear a case as you can have of an admitted conflict where the action then taken subsequent to the filing of the statement, based on the statement itself, is clearly in conflict. Is that to be tolerated?

Dr. KENNEDY. Well, I do not think so, Mr. Chairman.

Mr. Moss. Let me say that it must not be. It must not be tolerated, or we will have to take much more vigorous action.

Dr. KENNEDY. Yes, Mr. Chairman. The difficulty I am having is that I do not know whether the classification proceeding was a classification proceeding that was general for all products of that type or specifically for that company's products.

That is the problem I am having. I am simply going to have to go look it up.

Mr. SANTINI. Would the gentleman yield?

Mr. Moss. The Chair is happy to yield back to the gentleman from New Jersey.

Mr. MAGUIRE. I yield.