physician does not always specify-in fact, as far as I can tell, rarely specifies-why the drug is being prescribed.

It is possible for lawyers in their fertile imaginations to construct some sort of a misbranding theory. I suppose that were one inclined to push it that far, it could be applied in a specific situation if you had enough facts, which you would probably never have. And that might be seen as some sort of an enforcement mechanism, but as a practical matter it is not something that the Agency is going to try to do because it does not seem to be very productive and it is not something that would work very often.

Now, there may be State restrictions that I am not particularly expert on. Your general point is, I think, that this particular exclusivity is not worth as much as other types of exclusivity and as much as patent rights. I think that is generally conceded to be the

case.

Mr. MORRISON. What you are really telling me is assuming that it is not mislabeled in a specific and direct way by the manufacturer that any protection that may arise from this is very much on an individualized case-by-case objection by a particular patient to receiving a particular drug; and beyond that, it is very hard to see an enforcement mechanism that is general in nature?

Mr. SCARLETT. I think that is an accurate statement.
Mr. MORRISON. Thank you.

Mr. KASTENMEIER. The gentleman from California, Mr. Lungren.
Mr. LUNGREN. Thank you, Mr. Chairman.

I think Mr. Morrison is absolutely correct. My father is a cardiologist, an internist, and if you look at the practical world of a doctor writing out a prescription lots of times it is tough to just decipher their handwriting in the first place. They do not usually add a whole lot.

The fact of the matter is that there is going to be virtually no protection, as I can see it, in the real world. If you have a law, as many states do, requiring a generic to be offered, it is going to be offered. The protection to the patent holder for this second use is going to be a protection writing, but it is not going to be a protection in reality. I think we have to make a judgment as to whether or not we think they should be granted additional protection in terms of a real protection that protects their investment. That may be a difficult thing to do politically because people do not understand that by protecting patents you also protect the creative environment so that we will have further drugs down the line.

Let me just ask Dr. Young one thing, and maybe it is just something I am missing. Maybe you can explain it to me. Mr. Williams, in his statement that has been handed in for Warner-Lambert, states on page 5 that this is the only Phase IV study ever required by FDA to investigate an unapproved claim. At least on initial reading, that seems contrary to your statement that it was FDA policy to require all sponsors who sought cholesterol-lowering claims to conduct post-approval studies. Or am I misinterpreting that?

Dr. YOUNG. It is a very difficult issue. It is true that this was required in general when these lipid-lowering agents were brought forward. In this particular case, it was in the approvable letter, and an agreement was made by the company to proceed with this

Phase IV study, so that there was a much tighter coupling than in other lipid-lowering agents that we have seen. That is why both of the answers are correct but for different situations.

We do not have the ability to go back and check every one of our Phase IV studies, and, therefore, I could not be as absolute in going drug-by-drug-by-drug on Phase IV studies in relation to approval.

Mr. LUNGREN. How would you characterize this Phase IV study in terms of its extent, the number of patients that came under the review, the cost and the time compared to other Phase IV studies? Dr. YOUNG. This is one of the larger Phase IV studies, to the best of my knowledge, both in scope of patients and in dollars involved. Mr. LUNGREN. How about in time?

Dr. YOUNG. By the very nature of the fact that this was looking at a chronic effect, it would have been a longer study as well. But that really is dependent on the drug, and it is harder to quantify. Mr. LUNGREN. But, since patent life is a question of time, at least one element in my calculation is the Phase IV study that was required here, which, as you suggest, was an investigation of the chronic nature of the condition. It obviously takes more time in order to complete such a study to come up with valid information. Dr. YOUNG. There is no question on that, and I believe that these types of Phase IV studies are more difficult to evaluate. The question is what degree of fairness should be applied. And as the Chairman said, how does this relate to all other Phase IV studies in approvable and approved drugs.

Mr. LUNGREN. Thank you, Mr. Chairman.

Mr. KASTENMEIER. The gentleman from Virginia.

Mr. BOUCHER. Thank you very much, Mr. Chairman.

I think it might be useful if we get on the record exactly what the source of the requirement for this Phase IV study was. It is my understanding that FDA has a long-standing policy of requiring a Phase IV study for any lipoprotein of which this is one. Is that correct?

Dr. YOUNG. That is correct.

Mr. BOUCHER. And it was, in fact, FDA that required the Phase IV study in this case, was it not?

Dr. YOUNG. That is correct. And in the operative paragraphs that I mention on Page 5 of the approvable letter dated September 25, 1981, "Approval of this application is also contingent upon your commitment to conduct an appropriate Phase IV study of certain aspects of effectiveness and long-term safety of gemfibrozil. Satisfactory completion of the ongoing Finnish study would be expected to meet this condition." And then in the letter back, as I mentioned, of December 21st, the operative second paragraph said that, "In your October 8, 1981, letter, you stated that the Phase IV studies that we requested as a condition for approval had been undertaken.'

Mr. BOUCHER. Thank you, Dr. Young. That answers that question completely. Your letter to this Subcommittee, dated September 21, 1987, raises a question concerning the degree of assurance that if this legislation is approved that this will be the only drug which, in fact, is covered. I think we all agree that if this legislation is approved that we would want to address this particular patent and this particular patent only.

Would it satisfy your concern if we amended the legislation to specify that the drug covered is the drug stated in the date of your approval letter? Do you think that would be one way to address that problem?

Dr. YOUNG. That certainly would address the uncertainty that was raised in my letter. We have no way that we can actually give you precise figures at this time, and that would be the cleanest way of removing that uncertainty. But, again, that judgment is one that you have to exercise, and I will be delighted to administer whatever your outcomes are.

Mr. BOUCHER. Well, thank you very much. I am glad to hear you say that would be the cleanest way to do it. We will certainly take that under due advisement.

It seems to me that a case is made here for providing relief. In the testimony of Warner-Lambert, it is indicated that 140 million, or a figure in that vicinity, was invested in the research on this product, and that ultimately they may receive an exclusive marketing period of one year or less within which to justify making that enormous investment. It just seems to me that given the circumstances they have made their case rather well.

I appreciate very much your being with us this morning, and thank you for those responses to these questions.

Dr. YOUNG. Thank you.

Mr. KASTENMEIER. The gentleman from Ohio, Mr. DeWine.

Mr. DEWINE. I have no questions, Mr. Chairman.

Mr. KASTENMEIER. The gentleman from California, Mr. Berman. Mr. BERMAN. No questions.

Mr. KASTENMEIER. The gentleman from North Carolina, Mr. Coble.

Mr. COBLE. Thank you, Mr. Chairman.

Dr. Young, I want to extend Mr. Lungren's question just a minute to be sure I have it firmly in my hand and in my mind. Alluding to Mr. Williams' comment, when he says that the FDA, had never before required a Phase IV study to investigate—well, actually he qualified it. I think he said that as best they could determine no such requirement had been imposed. Then you explained in response to Mr. Lungren's question your position when you said that the policy generally is to require a study.

Is there some sort of a double standard being imposed here?
Dr. YOUNG. That is a good question.

Mr. COBLE. And I do not suggest that there is, but this is nagging at me.

Dr. YOUNG. That is a good question, a very good question. The issue in this particular drug is the use of a drug over one's lifetime. Once one is on the drug, you are looking, therefore, at chronic studies to determine the safety of this drug. You are taking an analysis of effectiveness based on a biochemical change, a change of lowering triglycerides, a change of lowering cholesterol. There was a nagging question in the Agency: Does that change in and of itself indicate a decrease in morbidity and mortality? That was the reason for the Agency focusing in general on this particular issue. In the case of Lopid, there seemed to be, as I have looked at the record, a very tight coordination between the request of Phase IV studies and the implementation of Phase IV studies. That is where

we were playing back and forth on that answer. I hope that clarifies it for you.

Mr. COBLE. I think so. So you are confident that there is no double standard being played with here.

Dr. YOUNG. Correct, because just recently, as I mentioned, when we were looking at the drug that deals with lysing of blood clots, either streptokinase or TPA, we see that same question raised. Can you deal with a correlation between the lysis of a clot on one hand and the extension of morbidity and mortality on the other? So that when you do not have that one-to-one correlation, additional studies are asked so that physicians can be confident about it.

In bringing AZT on the market as rapidly as we did, Retrovir for AIDS, there were Phase IV studies that are required there, and we are looking at that drug very extensively, because in that case, a Phase III study was not done. We had the desperate condition in the United States; there were no drugs available. The Phase II study was completed, which had very great promise. We approved it with confidence. We required Phase IV studies and are very pleased to see that the Phase IV studies have fully documented the confidence that we had in our Phase II analysis.

So it is not unusual to ask for Phase IV studies, and in this category we were, as an Agency action, asking for them routinely. Mr. COBLE. Thank you, Dr. Young, for that. I appreciate your re

sponse.

Mr. Chairman, I have no further questions.

Mr. KASTENMEIER. Are there any further questions?

Mr. MORRISON. Mr. Chairman, I just have one follow-up.
Mr. KASTENMEIER. Briefly.

Mr. MORRISON. Yes, I will be very brief, Mr. Chairman.

Did the need for conducting the phase IV study arise out of the initial approved application, the pancreatitis application of this drug? Or was it required because of the lifetime use that you just described of the second indication for which Warner-Lambert sought approval?

Dr. YOUNG. To the best of my knowledge, it is the latter case. Mr. MORRISON. So the need to do the study, following up on Mr. Boucher's question, was not related to the initial application approval but the second application. Is that a fair statement?

Dr. YOUNG. I think it is both. It is a very difficult issue because we never crossed the decision line of was it going to be required for the first one, because the company decided that it was an important way to go. And the reasons, I think, were involved in both. But because of the rapid agreement on the Phase IV study, I do not think we can answer that question.

Mr. MORRISON. But you did say that the reason, in answer to the double standard question-

Dr. YOUNG. That is correct.

Mr. MORRISON. -that the need was chronic, because it is a chronic condition and lifetime use, and that is not true of the initial approved application.

Dr. YOUNG. The initial approved application would have some long-term use as well, and we could not absolutely distinguish the long-term use on both cases. But we were satisfied that as we went into this we had the safety and effectiveness data for that first

claim, but there were some concerns always on lipid-lowering agents that you wanted to have more data.

I know that is not a very clear answer, but it is the way in which we were trying to struggle through these new classes of lipid-lowering agents to try to get a long-term understanding of the use of these drugs, yet be satisfied as much as we can on the safety and effectiveness for the narrow claim.

Mr. MORRISON. Thank you. Thank you, Mr. Chairman.

Mr. KASTENMEIER. Does our colleague from Oklahoma have any questions? If not, we want to thank you both, Dr. Young and Mr. Tegtmeyer, for your testimony, your contribution to this morning. Doubtless there are probably some loose ends we will need to discuss further with you at some point. In any event, we do appreciate your contribution to this morning.

Dr. YOUNG. Thank you, Mr. Chairman. I shall be delighted on behalf of the Agency to provide any information that we can for the record and also any information on the difficult process of drug evaluation that we could be of help for you.

Mr. KASTENMEIER. We appreciate that. Thank you.

Now, I would like to introduce our third witness. He is Mr. Joseph D. Williams. He is Chairman of the Board and Chief Executive Officer of Warner-Lambert Company. Mr. Williams has devoted the past 37 years of his life to the pharmaceutical industry. He was really very active in legislation to extend patent terms. I think those who are familiar believe he took a very compromising and conciliatory approach to that legislation, which did result in its enactment.

In any event, he is here in a different capacity today, and, Mr. Williams, I will ask you to introduce your colleagues, if you will. TESTIMONY OF JOSEPH D. WILLIAMS, CHAIRMAN OF THE BOARD AND CHIEF EXECUTIVE OFFICER, WARNER-LAMBERT CO.; ACCOMPANIED BY ROBERT I. LEVY, M.D., PROFESSOR OF MEDICINE, COLUMBIA UNIVERSITY, AND PETER B. HUTT, ESQ., COVINGTON & BURLING

Mr. WILLIAMS. Thank you very much. Like the preceding witnesses, my oral statement is much shorter than the written testimony that was submitted.

On my left is Dr. Robert Levy, a very distinguished professor of medicine at Columbia University's College of Physicians and Surgeons. Dr. Levy is the former director of the National Heart, Lung and Blood Institute and was responsible for its coronary primary prevention study that was done several years ago, also a landmark study.

On my right, Mr. Chairman, is Peter Hutt. I think he is known to a lot of you. He is former chief counsel of the Food and Drug Administration and is one of the leading experts in food and drug

law.

Mr. KASTENMEIER. Thank you for that introduction. As you know, my colleagues and those otherwise present, both Dr. Levy and Mr. Hutt, have extensive statements for the record which have been submitted and will appear in the record. I hope you will take