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OCTOBER 23, 1998

The Advisory Committee met in the Masur Auditorium in Building 10, National Institutes of Health, Bethesda, Maryland, at 9:00 a.m., Dr. Milton Packer, Chairperson, presiding.


MILTON PACKER, M.D., Chairperson

JOHN DiMARCO, M.D., Member



LEMUEL MOYE, M.D., Ph.D., Member


DAN RODEN, M.D.C.M., Member


JOAN C. STANDAERT, Executive Secretary


Sponsor's Presentation

Clive Meanwell, M.D., Ph.D., The Medicines

Group, Introduction and Overview .......... 6

John Bittl, M.D., Ocala Heart Institute,

Pivotal Trials ........................... 13

Eric J. Topol, M.D., Cleveland Clinic

Foundation, Integrated Summary ........... 75

Clive Meanwell, M.D., Ph.D., Discussion ........ 79

Committee Discussion and Recommendations ...... 151

Adjourn ....................................... 298



CHAIRMAN PACKER: I'd like to open this meeting this morning. The administrative structure for this morning is slightly different than perhaps what we generally have had in the Cardiac and Renal Drugs Advisory Committee. Today, the Advisory Committee is actually not advising the Division of Cardiac and Renal Drugs. It is advising the GI division.

And the procedure that govern today are similar to the procedures that govern any other day and we are being asked to advise the GI Division In a course of assessments of Hirulog or bivalirudin. Is that correct, bivalirudin? And I would say to the Committee that if they choose they can use either name if they find bivalirudin hard to say. And we will have Joan read the conflict of interest statement this morning.

MS. STANDAERT: The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.

Based on the submitted agenda and information provided by the participants, the Agency has determined that all reported interests in firms

regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.

In accordance with 18 USC section 208(b)3 and section 344(n)4 full waivers have been granted to Dr. Ileana Pina, Dr. Lemuel Moye, Dr. Dan Roden, Dr. Udho Thadani, Dr. Marvin Konstam, and Dr. Milton Packer.

A copy of these waiver statements may be obtained by submitting a written request to FDA's Freedom of Information Office, Room 12A30 of the Parklawn Building.

We would like to note that one of the Committee participant's employer had a previous involvement related to Hirulog, that we believe should be disclosed. FDA believes that it is important to acknowledge this involvement so that his participation can be objectively evaluated.

In the past, Dr. Konstam's employer studied Hirulog. Dr. Konstam has no involvement whatsoever in the study.

In the event that the discussion any other products or firms not already on the agenda in which an FDA participant has had a financial interest, the participants are aware to exclude themselves from

such involvement and their exclusion will be noted for the record. With respect to all other participants we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.

It should be further noted that Dr. Robert Califf has been excluded from the proceedings on Hirulog.

CHAIRMAN PACKER: Thank you, Joan. We generally reserve time for public comment. Is there any public comment?

(No response.)

CHAIRMAN PACKER: There being no public comment, the NDA being evaluated this morning is for Hirulog, bivalirudin. The proposed indication is as an anticoagulant for patients undergoing PTCA for the treatment of unstable angina.

The sponsor is The Medicines Group. In the last 24 hours the questions to the Committee has undergone significant amount of revision so that the questions which have been distributed up front do, in fact, highlight many of the key issues that we will be discussing today, but we will not be going through the questions in the sequence in which the questions distributed outside, in fact, outline.

We will discussing the essence of all of the questions. We will be changing some of the emphasis of the sequence and this has been already discussed with the sponsor and Dr. Talarico. I think everyone feels comfortable with the changes that have been made.

We'll ask The Medicines Group to proceed with their presentation. Dr. Meanwell, I think, will begin the sponsor's presentation of the NDA.

DR. MEANWELL: Mr. Chairman, members of the Advisory Group, members of the FDA, ladies and gentlemen, we are here today to give you information on bivalirudin, an intravenous direct thrombin inhibitor which we believe can be used as an anticoagulant in patients undergoing unstable angina instead of heparin.

My name is Clive Meanwell. I'm the President and Director of the program for bivalirudin. The Medicines Company is a young company with the mission of bringing drugs to patients which might not otherwise get there, particularly drugs which are not considered sufficiently large to warrant the attention of larger pharmaceutical companies.

We acquired the drug bivalirudin from Biogen in March of 1997 after Biogen decided to discontinued their investment in this program for business reasons

I'm joined today by Dr. John Bittl who was the principal investigator in the phase III trial program who will run through the pivotal trial data, the data in PTCA. And then Professor Eric Topol from the Cleveland clinic foundation who was involved in the phase II program and continues to be involved in this product.

Percutaneous transluminal coronary angioplasty, PTCA is a common important intervention. This year it is estimated that 700,000 PCIs

will be performed in the United States and in all cases anticoagulation is considered essential in practically all cases. The intravenous anticoagulant of choice, because there is no alternative, is heparin to be used during the procedure.

Now when heparin is used, the likelihood of thrombosis or thrombo-occlusive events is reduced.

However, there is a trade-off between thrombosis and hemorrhage in this setting.

Heparin use in PTCA is essentially a balancing act. It is illustrated in the schematic on the left of the slide showing the inverse relationship between the risk of thrombosis along the bottom from high, moving left, to low and risk of hemorrhage going up as the risk of thrombosis comes down.

These combined risks usually present as

10 percent death of myocardial infarction or the need for urgent revascularization during the first 7 days after PTCA. Approximately seven to ten percent clinically significant bleeding, including five percent of patients requiring a transfusion of more than two units of blood.

Now these limitations are essentially a result pharmacological deficiencies of heparin

which have been studied extensively since 1996 when it was first introduced.

Bivalirudin is a rationally-designed inhibitor of thrombin, which was actually designed that way to overcome some of the limitations of heparin. It does so in the following ways. The mode of action controls with heparin quite markedly. Bivalirudin does not require cofactors, most notably Antithrombin III, to exert its effect.

Bivalirudin is not inhibited by platelet factor 4 or by other circulating plasmoproteins which are often elevated in acute cardio syndromes. And thirdly, at the molecular level, bivalirudin shows reversible binding to thrombin.

These three features of the molecule tend to provide more predictable linear relationships between both plasma concentration and effect, a feature which is not often seen with heparin.

Importantly, on the limited risk side, bivalirudin is also able to inhibit both thrombin which is bound to fibrin in a clot, as well as thrombin which is circulated in fluid phase. And this we believe underscores the ability to target anti-thrombotic effect where it's needed with a lower systemic or circulating anticoagulant burden.

Now this opens up the clinical thesis for bivalirudin. But it is possible to achieve at least similar or reduced thrombosis, at the same time reduce the risk of hemorrhage. And we think this is an important benefit. This clinical thesis has been tested in a rather broad program of trials, and a complete clinical data set has been submitted to the FDA.

The data set includes approximately 6,000 patients, of whom 3,600 patients received bivalirudin in trials of angiography, unstable angina, medically managed and managed with intervention, PTCA, and myocardial infarction. The others in this slide refers to deep end thrombosis trials which were done but which were not randomized and are not germane to today's discussion we believe. The FDA do have the data.

Now in every situation where bivalirudin was studied, it showed consistent, reversible, dose-dependent anticoagulant effect. In our view, the question whether this drug anticoagulates is not the issue. It seemed quite clear.

In every situation where bivalirudin was tested against heparin in that clinical program, there was evidence of similar or improved effect with clinically striking reductions in hemorrhagic risk of the patients.

And notwithstanding this broad experience, our focus today is quite simply on the proposed indication, which is that bivalirudin should be considered for use as an anticoagulant in patients during the procedure undergoing unstable    undergoing PTCA for unstable angina.

Now before we get on to the main presentation, members of the panel, I'd like to make it very clear, as we stated in all of the documents we sent the FDA, that we understand fully that neither of these two pivotal trials met the prime endpoint for efficacy that was specified in the protocol.

Nevertheless, in view of the important reduction, indeed striking reduction, in hemorrhagic risk and the evidence which we believe supports that bivalirudin is at least as good a heparin in all patients. And we present these data in support of the view that bivalirudin substantially improves the risk-benefit ratio of patients undergoing PTCA for unstable angina.

With that brief introduction, I would propose to hand straight on to Dr. Bittl.

CHAIRMAN PACKER: If I could, I think that you are not proposing to discuss any aspects of the pharmacology, pharmacodynamics, or pharmacokinetics. Is that correct? I know that information is summarized in the briefing documents. I just want to make sure    and you need not present that. I just want to make sure that the Committee does not have any questions about that before we proceed further.

DR. MEANWELL: Absolutely.


DR. RODEN: I don't have any questions at this time.

CHAIRMAN PACKER: Then, let's proceed.

DR. MEANWELL: Thank you.

DR. BITTL: May I have the first slide, please?

Mr. Chairman, panel members, ladies and gentlemen, the goal of systemic anticoagulation during coronary angioplasty is to inhibit thrombus formation within a localized segment of the coronary artery undergoing dilatation.

Heparin is the only anticoagulant used for this purpose, but it has several limitations. Ischemic complications and clinically significant bleeding occur in five to ten percent of patients undergoing coronary angioplasty.

Furthermore, there are no established, no Phase III controlled trials establishing the effect of heparin in this setting, although several retrospective case control studies suggest that patients who have a high anticoagulant response to heparin have lower event rates than those who had low anticoagulant responses. It is possible that a direct thrombin inhibitor such as bivalirudin will be safer and more effective than heparin in patients undergoing angioplasty for high-risk indications.

I will review the structure, the execution, and results of two pivotal trials of bivalirudin versus heparin in patients undergoing angioplasty for unstable angina.

These two trials are unique for several reasons. They have several unique characteristics. Number one, both trials were carried out and governed under a single protocol. And secondly, in contrast to several other recently reported angioplasty trials that studied an add-on to conventional therapy during angioplasty    that is, typically a platelet inhibitor in addition to heparin and aspirin    this trial looks at a substitute or a possible alternative to heparin in the form of a direct thrombin inhibitor, bivalirudin.

Recall, again, that heparin is the only anticoagulant we have at this time for patients undergoing coronary angioplasty.

I think it's important at the outset to discuss the rationale for these trials. The rationale is based on the results of a large Phase II trial of bivalirudin in patients undergoing angioplasty that was chaired by Eric Topol and published in circulation in 1993.

The rationale for the trial was also based on a heparin registry study that we carried out simultaneously when the Phase II trial was carried out to identify the doses of heparin used, event rates, and risk factors for ischemic events.

In the Phase II trial, which was a dose escalation, open label study, six different doses of bivalirudin were studied in patients undergoing angioplasty. And from this trial we identified that the highest dose should be used in the Phase III study.

The heparin registry study actually was a snapshot of angioplasty practice, as carried out in 1992, involving 591 consecutive patients at nine large interventional programs in North America. And in this study we identified, at that time, that the average heparin dose given to these patients was 178 units per kilogram. The mean 24-hour total dose was 41,000 units of heparin given. The target ACT was 350 seconds.

With this protocol of anticoagulation, ischemic event rates occurred in 15 percent of patients, including death, myocardial infarction, emergency revascularization, or abrupt vessel closure. I should also point out that five percent of these patients required transfusion.

One of the most important findings in this paper was that we identified risk factors for increased ischemic complications; that is, patients undergoing angioplasty for the presenting syndrome of unstable angina or post-infarction angina or an increased risk for ischemic complications.

This confirmed the report of Serruys & DeFeyter, a pooled analysis identifying, in particular, the post-infarction patients as a high-risk subgroup for poor outcome after angioplasty. And it also allowed us to test the hypothesis that a direct thrombin inhibitor such as bivalirudin may be superior to heparin in angioplasty for these patients.
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