IGDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE**
>
> **98th MEETING**
>
> Tuesday, January 7, 2003
>
> 8:00 a.m.
>
> Kennedy Ballroom, Holiday Inn
>
> 8777 Georgia Avenue
>
> Silver Spring, Maryland
>
> PARTICIPANTS
>
> Jeffrey Borer, M.D., Chairman
>
> Jayne E. Peterson, R.Ph., J.D., Acting Executive Secretary
>
> [Members]{.underline}:
>
> Michael F. Artman, M.D.
>
> Thomas Fleming, Ph.D.
>
> JoAnn Lindenfeld, M.D.
>
> Paul Armstrong, M.D.
>
> Alan T. Hirsch, M.D.
>
> Steven D. Nissen, F.A.C.C.
>
> Beverly H. Lorell, M.D.
>
> Susanna L. Cunningham, Ph.D, Consumer Representative
>
> [Consultants (Voting)]{.underline}:
>
> Thomas G. Pickering, M.D., DPhil
>
> Marc Pfeffer, M.D., Ph.D.
>
> [Acting Industry Representative (Non-voting)]{.underline}:
>
> John F. Neylan, M.D.
>
> [FDA]{.underline}:
>
> Douglas Throckmorton, M.D.
>
> Robert Temple, M.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Opening Remarks 4
>
> Introduction of Committee 4
>
> Conflict of Interest Statement 5
>
> **sNDA 20-297/S-009, Coreg (carvedilol),**
>
> **GlaxoSmithKline**
>
> Sponsor Presentation
>
> Introduction
>
> Clare Kahn, Ph.D. 8
>
> Background to the CAPRICORN Trial
>
> Mary Ann Lukas, M.D. 12
>
> CAPRICORN Trial
>
> Primary Endpoints
>
> Henry Dargie, M.D. 27
>
> Why Are We Here?
>
> Milton Packer, M.D. 67
>
> CAPRICORN Trial
>
> Effect on Non-Fatal Events
>
> Henry Dargie, M.D. 88
>
> Safety and Concluding Remarks
>
> Milton Packer, M.D. 126
>
> Committee Discussion and Review 161
>
> (Committee Reviewer: Marc Pfeffer, M.D., Ph.D.)
>
> Open Public Hearing 195
>
> Committee Discussion and Review (Continued) 195
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Opening Remarks**
>
> DR. BORER: Okay. Everybody has had his or her three minutes grace
> period. We are going to try and get this show on the road.
>
> Today, we are going to be reviewing NDA 20-297 from GlaxoSmithKline,
> which is based on a supplement that was submitted requesting an
> indication for the use of carvedilol in patients with left ventricular
> dysfunction after myocardial infarction.
>
> We will introduce the committee again. As I noted yesterday, we have
> for the first time an Acting Industry Representative who is
> non-voting, that is John Neylan, and today, two SGE consultants who
> are voting, Tom Pickering and Marc Pfeffer, and they will all
> introduce themselves as we go around.
>
> Why don\'t we start from your side today, John.
>
> **Introduction of Committee**
>
> DR. NEYLAN: John Neylan, Wyeth Research.
>
> DR. PFEFFER: Marc Pfeffer, Brigham & Women\'s Hospital.
>
> DR. PICKERING: Tom Pickering, Mount Sinai, New York.
>
> DR. NISSEN: Steve Nissen, Cleveland Clinic Lerner School of Medicine.
>
> DR. HIRSCH: Alan Hirsch, University of Minnesota Medical School.
>
> DR. FLEMING: Thomas Fleming, University of Washington.
>
> DR. LORELL: Beverly Lorell, Beth Israel Deaconess Medical Center,
> Boston.
>
> DR. BORER: Jeff Borer, Weill Medical College of Cornell University.
>
> MS. PETERSON: I am Jayne Peterson, the Acting Exec. Sec. of the
> committee.
>
> DR. LINDENFELD: JoAnn Lindenfeld, University of Colorado.
>
> DR. ARMSTRONG: Paul Armstrong, University of Alberta.
>
> DR. CUNNINGHAM: Susanna Cunningham, University of Washington.
>
> DR. ARTMAN: Mike Artman, New York University.
>
> DR. THROCKMORTON: Doug Throckmorton. I am the Director of the
> Cardio-Renal Division.
>
> DR. BORER: Jayne, can we have the conflict of interest statement,
> please.
>
> **Conflict of Interest Statement**
>
> MS. PETERSON: The following announcement addresses 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 for the meeting and all financial
> interests reported by the committee participants, it has been
> determined that all interests in firms regulated by the Center for
> Drug Evaluation and Research present no potential for an appearance of
> a conflict of interest at this meeting with the following exceptions.
>
> Dr. Michael Artman has been granted a waiver under 18 U.S.C.,
> 208(b)(3) for his employer\'s contract with the sponsor on an
> unrelated matter. Funding received is less than \$100,000 a year.
>
> Dr. Jeffrey Borer has been granted a waiver under 18 U.S.C., 208(b)(3)
> for consulting for the sponsor on an unrelated matter. He receives
> between \$10,001 to \$50,000 a year.
>
> Dr. Tom Fleming has been granted a waiver under 18 U.S.C., 208(b)(3)
> for his consulting for the sponsor on unrelated matters. He receives
> between \$10,001 to \$50,000 a year.
>
> A copy of these waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> In addition, we would like to disclose for the record that Dr. John
> Neylan, a full-time employee of Wyeth Research Labs, is participating
> in this meeting as an Acting Industry Representative, acting on behalf
> of regulated industry.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participants are aware of the need 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 may wish to comment
> upon.
>
> Thank you.
>
> Dr. Borer.
>
> DR. BORER: Thank you, Jayne.
>
> Again, the supplemental NDA from GlaxoSmithKline for carvedilol
> proposes an indication to reduce mortality and the risk of infarction
> in clinically stable patients who have survived the acute phase of
> myocardial infarction\--I am sorry\--the supplemental NDA was based on
> a proposal to reduce mortality and the risk of infarction in
> clinically stable patients who have survived the acute phase of a
> myocardial infarction and have a left ventricular ejection fraction
> less than or equal to 40 percent.
>
> The sponsor\'s presentation will be introduced by Dr. Kahn.
>
> **sNDA 20-297/S-009, Coreg (carvedilol),**
>
> **GlaxoSmithKline Sponsor Presentation**
>
> **Introduction**
>
> **Clare Kahn, Ph.D.**
>
> DR. KAHN: Good morning, ladies and gentlemen, Dr. Borer, members of
> the Advisory Committee and FDA. My name is Clare Kahn and I am the
> Vice President for U.S. Regulatory Affairs responsible for
> cardiovascular, urogenital, and metabolic products at GlaxoSmithKline.
>
> The meeting today is focused on carvedilol. It is a beta-blocker which
> nonselectively inhibits both beta-1 and beta-2 receptors and, in
> addition, blocks alpha-1 receptors. The drug\'s action on beta
> receptors is far more potent than on the alpha receptor and it has no
> intrinsic sympathomimetic activity at any of these receptors.
>
> Carvedilol was first approved for the treatment of hypertension in
> 1995 and in 1997, the drug was approved in patients with mild to
> moderate chronic heart failure. In 2001, the indications for
> carvedilol were expanded towards the end of the heart failure
> continuum to include the treatment of patients with severe chronic
> heart failure and to include prolongation of survival.
>
> Today, we are proposing that the current labeling for carvedilol be
> modified to include experience towards the beginning of the heart
> failure continuum, specifically the treatment of patients who have
> recently survived a myocardial infarction and who have left
> ventricular dysfunction.
>
> GSK met with the FDA, Cardio-Renal Division, and Dr. Temple in May of
> 2002 to review the data that the panel will see today. FDA advised GSK
> to submit the file and was subsequently granted priority review.
>
> Just to give you an overview, the scope of today\'s presentation, we
> will review the use of beta-blockers in patients who have recently
> experienced an acute myocardial infarction and the favorable effect on
> reducing subsequent risk of death and recurrent MI.
>
> Then, there will be two trials discussed - CHAPS, which was actually
> conducted by Boehringer Mannheim, and CAPRICORN, conducted by Roche,
> but the data submitted by GSK for the supplement.
>
> CHAPS is a pilot trial of about 150 patients which supported our
> decision to proceed with the large pivotal trial CAPRICORN, which is
> the focus of today\'s presentation.
>
> Now, at the outset, the primary endpoint for CAPRICORN was all-cause
> mortality. However, following a recommendation of the DSMB, the
> primary endpoint was changed to include a co-primary of death or
> cardiovascular hospitalization in addition to the all-cause mortality.
> You will hear about that later, the reason for that.
>
> Now, although this co-primary was not met, there was a 23 percent
> reduction in mortality, and we are here today to discuss the merits of
> these findings and their inclusion into labeling.
>
> The proposed indication statement that Dr. Borer already alluded to is
> as follows. Coreg is indicated to reduce mortality and the risk of
> infarction in clinically stable patients who have survived the acute
> phase of a myocardial infarction and have a left ventricular ejection
> fraction of less than or equal to 40 percent.
>
> Now, the language includes the indication of a reduction in mortality
> since this was a primary endpoint of the trial, however, we believe
> there is also support for an indication of reduction in the combined
> risk of death and reinfarction, and you will see data to support this
> during the course of the presentation.
>
> To adhere to the agenda, we will begin with a background presentation
> by Dr. Mary Ann Lukas of GlaxoSmithKline, and this is followed by a
> tandem presentation. Dr. Henry Dargie will present the primary
> endpoints of CAPRICORN and Dr. Milton Packer will describe the
> implications of these results.
>
> Now, this will be followed by a presentation of the effects on
> non-fatal events by Dr. Dargie, then concluding with safety data and
> concluding remarks from Dr. Packer.
>
> We are being assisted today by four consultants, all of whom played an
> important role in the CAPRICORN trial. Two are from the University of
> Glasgow. These are Dr. Henry Dargie, the principal investigator for
> CAPRICORN, Dr. Ian Ford, the principal biostatistician, and two other
> consultants from Columbia University, Dr. Milton Packer, who was an
> original member of the CAPRICORN Steering Committee before leaving to
> become the primary investigator for the sister study, COPERNICUS. Dr.
> Jonathan Sackner-Bernstein was on the Endpoint Committee for the
> CAPRICORN trial.
>
> Now, I would like to introduce Dr. Mary Ann Lukas to provide some
> background presentation to today\'s topic.
>
> **Background to the CAPRICORN Trial**
>
> **Mary Ann Lukas, M.D.**
>
> DR. LUKAS: Good morning, Dr. Borer, members of the Advisory Panel and
> FDA, ladies and gentlemen. My name is Mary Ann Lukas and I am Senior
> Clinical Director for carvedilol for GlaxoSmithKline.
>
> Currently, there are three other beta-blockers approved for the
> long-term use in the post-infarction patient: timolol, propranolol,
> and the immediate release formulation of metoprolol. While atenolol
> also carries an indication for use in post-MI patients, that
> indication is primarily based on the seven-day follow-up data from
> ISIS-II.
>
> The major large-scale, long-term trials that were conducted with these
> drugs are listed on this slide. All were landmark studies when they
> were carried out 20 years ago, and despite some limitations as to
> their conduct and analysis, the totality of the data from these
> studies clearly established the efficacy of beta-blockers in reducing
> mortality in survivors of an acute myocardial infarction.
>
> However, specific cohorts of patients were not well represented in
> these early studies and, in particular, high-risk patients were
> generally not enrolled. Patients with heart failure were either
> excluded or were enrolled in small numbers and only if they had no or
> minimal evidence of pulmonary congestion.
>
> Many currently available treatments for the immediate management of
> the post-infarction patient were either not available or not used
> including ACE inhibitors, I.V. nitroglycerin, heparin, and
> thrombolytics.
>
> In addition, many currently available treatments for the long-term
> management of the post-infarction patient were not allowed because of
> the effect that they might have had on showing a benefit of beta
> blockade.
>
> For these reasons, physicians now are uncertain about the role of
> beta-blockers in the management of the post-infarction patient in the
> modern era. Many wonder whether beta-blockers are still needed if a
> patient is already receiving drugs that reduce infarct size, reduce
> the process of cardiac remodeling, decrease the risk of infarction,
> and minimize the adverse effects of neurohormonal activation.
>
> Others are concerned about the safety of beta-blockers in high-risk
> patients, particularly the risk of worsening heart failure in patients
> with a low ejection fraction and the risk of hypotension in patients
> who would be receiving ACE inhibitors or vasodilators.
>
> Complicating matters further is the fact that beta-blockers that are
> approved for use in post-infarction patients are not approved for
> patients who have overt heart failure and, in fact, they currently
> carry a contraindication for use in these patients.
>
> Conversely, the beta-blockers that are approved for use in chronic
> heart failure are not approved for use following a recent myocardial
> infarction.
>
> Specifically, timolol, propranolol, and the immediate release
> formulation of metoprolol are indicated for use in the post-infarction
> patient, but their use is currently primarily focused on patients at
> low risk, whereas carvedilol and the sustained release formulation of
> metoprolol are indicated for use in patients with chronic heart
> failure. However, no beta-blocker is currently indicated for the
> patients in the middle, specifically, those with left ventricular
> dysfunction that is recognized early in the post-infarction period.
>
> Therefore, these patients are least likely to receive such treatment
> even though, given their high risk, they are most likely among
> post-infarction patients to benefit from such treatment. They are also
> the most likely to develop an approved indication for beta blockade in
> the following months and years when symptoms of heart failure develop.
>
> Now, carvedilol has been formally evaluated in controlled clinical
> trials across the entire continuum of patients from those within 24
> hours of an acute infarction to those with post-infarction left
> ventricular dysfunction to those with mild, moderate, or severe
> chronic heart failure.
>
> The U.S. Carvedilol program and the COPERNICUS trial focused on
> patients with advanced left ventricular dysfunction, all of whom had
> heart failure, but only about half of whom had a history of a
> myocardial infarction, and that generally occurred years before
> enrollment in the trial.
>
> In these two studies, carvedilol significantly reduced the risk of
> death, as well as the combined risk of death and cardiovascular
> hospitalization, and the direction and the magnitude of these benefits
> were similar and remained significant if the analyses focused only on
> the patients in those trials with a history of myocardial infarction,
> which as I said represented about half of the patients in these
> trials.
>
> Now, the Australia-New Zealand or ANZ study was a moderately sized
> study of patients with mild chronic heart failure who had moderate
> left ventricular systolic dysfunction. All of these patients had an
> ischemic cardiomyopathy and nearly all had a history of a prior
> myocardial infarction.
>
> Carvedilol significantly reduced the combined risk of death and
> cardiovascular hospitalization in the ANZ study during a follow-up of
> 18 to 24 months both when all patients were analyzed, as well as when
> the analysis was confined to those patients who had a previous MI.
>
> It should be noted that the ANZ trial was not a survival study and
> that only about 50 mortality events were recorded in the trial.
>
> So, the two trials that are the focus of today\'s discussion were
> conducted with the intention of evaluating the effects of carvedilol
> in post-infarction patients even earlier in the disease process.
>
> The CAPRICORN trial evaluated patients who had survived an acute MI an
> average of 10 days earlier, all of whom had left ventricular
> dysfunction, but about half of whom had heart failure. The mean
> ejection fraction in this trial was higher than those in the trials
> that were conducted in patients with chronic heart failure.
>
> The CHAPS study evaluated patients who were within 24 hours of their
> acute myocardial infarction, most of whom had preserved left
> ventricular function and no heart failure. Therefore, the CHAPS and
> the CAPRICORN trials were carried out with the intention of
> determining if carvedilol would be beneficial if initiated far closer
> to the time of myocardial injury than had earlier trials evaluating
> post-infarction patients.
>
> The main focus of today\'s discussion will be on the CAPRICORN trial,
> but before turning our focus to that study, I will briefly review for
> you the results of the CHAPS trial.
>
> Now, CHAPS, which stands for the Carvedilol Heart Attack Pilot Study,
> was a single-center trial which was designed to evaluate in a
> preliminary manner the effects of carvedilol in the immediate
> peri-infarction setting.
>
> The purpose of the study was to gain comfort about the use of
> carvedilol in this setting since the drug had not been used early
> post-MI before. Patients were enrolled if they had an acute myocardial
> infarction within the preceding 24 hours, but they were excluded if
> they had an indication for, or a contraindication to, treatment with a
> beta-blocker.
>
> Patients who fulfilled these entry criteria were randomly assigned in
> a 1-to-1 ratio to placebo or carvedilol. Treatment with the study drug
> was initiated with an intravenous bolus of 2.5 mg of carvedilol or
> placebo, after which patients received 6.25 mg/twice daily of the
> study drug orally beginning four hours later.
>
> This was increased to 12.5 mg/twice daily after 2 days. The dose of
> the study drug was not further increased in most patients although if
> after 12 days, patients taking 12.5 mg/twice daily met the blood
> pressure criteria and heart rate criteria that you see on the bottom
> of this slide, their study drug could be increased to 25 mg/twice
> daily.
>
> Treatment with either carvedilol or placebo was maintained for a total
> of 24 weeks following randomization.
>
> Now, the primary endpoint of CHAPS, as defined in the original
> protocol, was timed to a prespecified cardiovascular event, which
> included death, heart failure, recurrent MI or unstable angina,
> stroke, ventricular arrhythmia requiring medical therapy, emergency
> revascularization, or the use of a new cardiovascular drug with the
> exception of nitrates or diuretics administered within 72 hours of the
> onset of their chest pain.
>
> A total of 151 patients were randomized, 74 to placebo and 77 to
> carvedilol. Of these, a total of 5 patients, 3 in the placebo group
> and 2 in the carvedilol group, were found to have violated one of the
> exclusion criteria. These patients either never received study drug or
> had their study drug withdrawn within 4 days.
>
> So, the remaining 146 patients entered long-term treatment and most
> received 12.5 mg/twice daily. Only 87 of these patients continued to
> receive study drug for 24 weeks and by far the most common reason for
> withdrawal from study drug was the occurrence of the primary endpoint.
>
> The baseline characteristics of CHAPS are shown on this slide for the
> 146 patients who were randomized, had a confirmed myocardial
> infarction, and received at least 1 dose of study medication.
>
> As you can see, this is largely a study of patients who were
> experiencing their first myocardial infarction, who had received
> appropriate therapy for their infarction including thrombolytics,
> aspirin, and intravenous heparin, and who had a normal left
> ventricular ejection fraction.
>
> Overall, the two groups were similar with respect to the majority of
> the baseline characteristics.
>
> This slide tabulates the events that contributed to the occurrence of
> a primary endpoint in the two groups. A primary endpoint event was
> achieved in 31 patients in the placebo group and 18 patients in the
> carvedilol group.
>
> All categories of the events were less common in the carvedilol group
> especially those related to the occurrence of myocardial ischemia.
>
> This slide shows the Kaplan-Meier plots for the primary endpoint. The
> difference between the two groups was apparently early and was
> maintained for the duration of follow-up. The difference between the
> curves was statistically significant at a p value of 0.01.
>
> On this slide, we show you that if the 5 patients who were randomized
> into the trial, but who did not receive long-term treatment with the
> study drug because of their failure to meet the key entry criteria, if
> those patients are included in the analysis according to the
> intention-to-treat principle, the effect of carvedilol remains
> significant.
>
> The mortality results from CHAPS are shown on this slide. Mortality
> was a secondary endpoint, and there were a total of 6 deaths that
> occurred during the 24-week planned duration of the trial. Four deaths
> occurred in the placebo group, 2 deaths occurred in the carvedilol
> group, and this slide shows the reason for deaths and the time that
> the deaths occurred following randomization.
>
> Overall, the drug was well tolerated in the study, as described in the
> briefing document that was distributed to the committee.
>
> I would like to say in summary that the data from this pilot study
> support the ability of carvedilol to reduce the risk of death,
> reinfarction, and arrhythmias in the post-infarction patient, and, in
> addition, demonstrate the tolerability of carvedilol in the immediate
> post-infarction period.
>
> However, CHAPS was a small trial which observed few cardiovascular
> events and in which a large proportion of the patients did not
> continue double-blind treatment for 24 weeks due to the protocol
> requirement that patients achieving a primary endpoint stop study
> drug.
>
> For this reason, at this point, we would like to turn our attention
> away from the CHAPS trial to a much larger and more definitive trial
> known as CAPRICORN. I would call Dr. Henry Dargie to the podium to
> describe the primary results of CAPRICORN to you, but would be happy
> to take any questions that you might have.
>
> DR. BORER: Does anyone have any questions about study design at this
> point?
>
> I have one. It is just a question for information only, there is no
> suggestion that there is anything wrong with having done it. The
> starting dose and up-titration schedule in CAPRICORN and also in CHAPS
> where the ejection fraction was a little bit higher, of course, starts
> at a higher dose and moves up faster than what is labeled for the use
> of carvedilol chronically.
>
> I have no problem with doing that, I just want to understand how you
> came to the rapid up-titration and the higher starting dose for this
> trial of patients with heart failure.
>
> DR. LUKAS: I can answer that specifically for CAPRICORN primarily,
> because GSK was not involved in the design of the CHAPS study back in
> 1992, but the feeling at the time was that it was important to achieve
> beta-blocking levels in these patients as rapidly as could be within
> the bounds of safety, which was why the up-titration period itself was
> shorter than what was used in the heart failure trials.
>
> For the same reason, the initial starting dose was higher, and the
> safety of that was assessed as will be described later by the Data
> Safety Monitoring Board looking at the data from the first 100
> patients or so to make certain that was not\--
>
> DR. BORER: Was there some retrospective review of data from the prior
> trials that suggested you could do this safely? You know, it wasn\'t
> just picked out the air. I assume that there was some experience that
> suggested it was okay to do this, and it turned out to be okay.
>
> DR. LUKAS: Yes. I don\'t want to say that I can remember exactly a
> retrospective analysis to support this point, but I do remember that
> the U.S. carvedilol trial data were looked at and that particularly
> the dose-related information from MOCHA and from the overall program
> to make certain that we\--all of those trials, by the way, started at
> 6.25 in the U.S. carvedilol program, so we got a lot of our sense that
> the starting dose would be safe from those trials.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: Could you clarify two points for me? In Table 3,
> reporting on CHAPS, the death is 3 placebo, 2 carvedilol, and you said
> 4 placebo in your presentation. Did I misunderstand?
>
> DR. LUKAS: No, there were 5 deaths that were counted as a primary
> endpoint, and there were 6 deaths that occurred during the follow-up
> period, so 1 patient who died had a primary endpoint event prior to
> their death, so that by the time to first event analysis, 5 deaths are
> included in the primary analysis, but the 6 deaths are reported for
> occurring in the entire follow-up period.
>
> DR. ARMSTRONG: The issue of the concurrent use or lack of use of ACE
> inhibitors in this population and the instructions, there were at
> least 10 episodes of heart failure, but very low usage of ACE
> inhibitors here by design.
>
> Could you help me understand that issue?
>
> DR. LUKAS: Again, with apologies for not knowing all of the details of
> the design when it was first put together back in 1992, the use of ACE
> inhibitors, as you said, was excluded from the beginning although
> there were 5 patients I believe in total who actually entered the
> trial and were receiving an ACE inhibitor, but the feeling was that,
> in fact, the establishment of the use of beta-blockers in the protocol
> and in the report was still felt to be deserving of further
> confirmation by the investigator. That is how they put it in the
> rationale, and they did not address the desirability or need to use an
> ACE inhibitor.
>
> DR. ARMSTRONG: So, we should interpret the safety and efficacy of this
> study in the absence of ACE inhibitors which would now be, of course,
> background therapy.
>
> DR. LUKAS: Absolutely true, and, of course, the CAPRICORN trial, as
> you will see, the majority of patients did receive an ACE. The only
> other thing I would remind you is, although I can bring up an
> exclusion criteria slide for you, but the exclusion criteria for CHAPS
> were Killip IV heart failure, and Killip II and III heart failure were
> allowed, but as you said, those patients were not receiving anything.
>
> DR. BORER: Okay. Why don\'t we move ahead.
>
> DR. LUKAS: Thank you.
>
> **CAPRICORN Trial - Primary Endpoints**
>
> **Henry Dargie, M.D.**
>
> DR. DARGIE: Good morning, Dr. Borer, members of the advisory committee
> and the FDA, ladies and gentlemen.
>
> My name is Henry Dargie. I am from the University of Glasgow. I was
> the principal investigator for the CAPRICORN study.
>
> The primary objective of the CAPRICORN trial was to evaluate the
> effects of carvedilol on all-cause mortality in patients with left
> ventricular dysfunction who had recently suffered an acute myocardial
> infarction.
>
> CAPRICORN was a multi-center, randomized, placebo-controlled parallel
> group study in patients with left ventricular ejection fraction equal
> to or less than 40 percent, with or without heart failure, and the
> trial was conducted worldwide in 163 centers in 17 countries.
>
> The trial was conducted under the auspices of the Steering Committee,
> of which I was the chairman, an Endpoint Committee chaired by John
> McMurray, and a Data and Safety Monitoring Board chaired by Desmond
> Julian.
>
> Now, all patients in the CAPRICORN trial had had an acute myocardial
> infarction during the previous 3 to 21 days. The use of all modern
> evidence-based treatments for myocardial infarction are including
> thrombolytics, aspirin, heparin, lipid-lowering drugs, et cetera, was
> encouraged.
>
> Patients were required to have an ejection fraction of equal to or
> less than 20 percent, and importantly, to be receiving an ACE
> inhibitor for at least 48 hours and to have been stable for 24 hours.
> In all, about 80 percent of patients were hospitalized at the time of
> study entry.
>
> Patients were excluded if they had unstable angina or various other
> unstable features, but it is important to emphasize that patients may
> have had primary edema or even cardiogenic shock during their index
> MI, but they were required to be clinically stable at the time of
> entry into the study.
>
> Patients were not enrolled, however, if they had an indication for, or
> a contraindication to, treatment with a beta-blocker.
>
> Now, patients who fulfilled all the entry criteria were randomly
> assigned in a double-blind manner to carvedilol or placebo, carvedilol
> beginning at a dose of 6.25 mg/twice a day, increasing every 3 to 10
> days to a target dose of 25 mg/bid.
>
> Should the initial dose of 6.25 not be tolerated, the patients could
> then be challenged with a dose of 3.125 mg/bid. Patients were then
> maintained on their maximum dose of treatment study drug until 630
> patients had died.
>
> If the patient\'s condition deteriorated during the study, the
> investigator could, of course, utilize any interventions that were
> clinically indicated, however, investigators were instructed not to
> institute open-label treatment with a beta-blocker unless there was a
> compelling and unequivocal reason for doing so.
>
> The original primary endpoint of the study was all-cause mortality.
> The protocol originally also specified three secondary endpoints: (1)
> the combined risk of all-cause mortality or cardiovascular
> hospitalization; (2) sudden death; (3) progression of heart failure.
>
> The original protocol anticipated that the study would enroll 2,600
> patients based on the assumption that the 21-month mortality in the
> placebo group would be 29 percent, the risk of death would be altered
> by 20 percent as a result of treatment with carvedilol, and the study
> would have 90 percent power to detect a significant difference between
> the treatment groups with an alpha of 0.05.
>
> The protocol specified the trial would continue until 630 deaths had
> occurred with a minimum follow-up of 12 months to allow the effects of
> carvedilol to become apparent.
>
> This number of events did not allow for any dilutional effect created
> by patients who discontinued the study medication or who were treated
> with open-label beta-blocker, however, fatal or non-fatal events were
> recorded and included in all analyses whether or not they occurred
> while the patient was on study medication.
>
> Enrollment in the CAPRICORN trial began in June of 1997. Nearly two
> years later, in March of 1999, the DSMB notified the Steering
> Committee that it was recommending a change in the protocol.
>
> As you recall, the original protocol for the CAPRICORN trial had
> strongly discouraged the use of open-label treatment with a
> beta-blocker, however, public announcements in late 1998 and early
> 1999 that beta-blockers had been found to prolong life in trials of
> chronic heart failure, namely, CIBIS II and MERIT-Heart Failure had
> raised ethical concerns within the DSMB about our policy of
> withholding treatment with a beta-blocker until the completion of the
> study.
>
> The DSMB believed that patients who developed heart failure during the
> course of the CAPRICORN trial should now be actively considered for
> treatment with a beta-blocker even though it fully recognized that a
> high frequency of open-label beta-blocker use would impair the ability
> of the study to detect a difference between the two groups.
>
> As a result, and in view of the fact that the mortality rate in the
> trial at that time was lower than anticipated, the DSMB felt that the
> best approach would be to expedite completion of the trial by changing
> the primary endpoint to one that would allow a critical number of
> events to be achieved as soon as possible.
>
> I must stress that this recommendation was made prior to having
> conducted any analysis of unblinded data by treatment group.
>
> This slide summarizes the changes made in the protocol by the Steering
> Committee in response to the DSMB\'s recommendation. All-cause
> mortality or hospitalization for a cardiovascular reason was added as
> a new co-primary endpoint. Of the studywise alpha of 0.05, 0.045 was
> allocated to this new endpoint and 0.005 to the original and retained
> primary endpoint of all-cause mortality.
>
> All-cause mortality or cardiovascular hospital was added as a
> co-primary endpoint because it had been the first prespecified, the
> first listed prespecified secondary endpoint in the original protocol,
> and because the critical number of 630 events would be reached rapidly
> if either death or any cardiovascular hospitalization were to count as
> events.
>
> Now, a total of 1,959 patients were randomized into the CAPRICORN
> trial, 984 to the placebo group and 975 to the carvedilol group.
>
> As you can see, the two groups were rather similar with respect to
> their baseline characteristics. It is interesting, however, to note
> that even though about 30 percent of the patients had a history of a
> previous myocardial infarction, most of these patients were receiving
> neither a beta-blocker or an ACE inhibitor prior to their index MI,
> and the index MI was complicated by the development of primary edema
> in nearly 20 percent of patients.
>
> The next slide tabulates other baseline characteristics, many of which
> distinguish these patients and those enrolled in the previous
> beta-blocker trials, beta-blocker post-infarction trials.
>
> About half the patients received thrombolytics or a primary coronary
> intervention during their index MI. A large majority received aspirin,
> heparin, intravenous nitrates, and about a quarter received a
> lipid-lowering drug.
>
> Furthermore, about half of the patients had heart failure, many of
> whom had recently received an I.V. diuretic and, of course, all of the
> patients or virtually all of the patients were receiving an ACE
> inhibitor or, in a very small number of cases, an angiotensin receptor
> blocker.
>
> The mean ejection fraction, as you can see, was 33 percent in both
> groups. The mean systolic blood pressure was about 120 millimeters of
> mercury, but in nearly 25 percent of cases, the systolic blood
> pressure was, in fact, less than 110 millimeters of mercury.
>
> Now, it should also be noted that patients generally were initiated on
> treatment with placebo or carvedilol more than 1 week after the
> qualifying event, so that this trial was not an evaluation of
> carvedilol for the immediate treatment of an evolving myocardial
> infarction, rather, it was an evaluation of carvedilol in the early
> management of post-infarction survivors who had heart failure or were
> at high risk of developing it.
>
> Now, of the 1,959 patients randomized into the CAPRICORN study, 10
> were randomized, but didn\'t receive any study medication. They were,
> of course, included in all analyses.
>
> The target doses were achieved in 84 percent of placebo and 17 percent
> of the carvedilol patients within 12 weeks. Generally, this level of
> medication was maintained for the duration of the study, and the
> duration of follow-up ranged from 3 to 33 months with a mean of 15
> months.
>
> This slide illustrates compliance with study medication. During the
> course of follow-up, 24 percent of the patients permanently
> discontinued study medication, very similar in both the placebo arm
> and carvedilol groups, but importantly to notice in this study is that
> 12 percent of the patients received open-label therapy with
> beta-blocker. This occurred more often, earlier, and for a longer time
> in the patients in the placebo group than in the carvedilol group.
>
> I would like now to review the results of the CAPRICORN trial on the
> two co-primary endpoints.
>
> DR. BORER: Henry, before you get to that, let me ask if anyone has
> questions about design issues at this point.
>
> I have one. The beta-blocker used before randomization, how was
> withdrawal from beta-blockers handled in the patients who were already
> receiving beta-blocker post-MI?
>
> DR. DARGIE: The patients admitted to coronary care units who were
> already on beta-blockers, these are sometimes withdrawn by the
> discretion of the physician, but it is the case that some patients who
> were on beta-blockers and appeared to be stable, on being counseled or
> discussed, the trial being discussed with them, could have had that
> beta-blocker withdrawn then to be subsequently randomized.
>
> This occurred in a relatively small percentage of patients because as
> you can see, not that many patients were receiving beta-blocker prior
> to admission.
>
> DR. BORER: It said 35 percent.
>
> DR. DARGIE: Yes.
>
> DR. BORER: So, there would have been some formal withdrawal period and
> then you would have randomized.
>
> DR. DARGIE: Yes.
>
> DR. BORER: Okay. Tom?
>
> DR. PICKERING: It was basically the same question. You said 3 percent
> had beta-blockers before their MI, and then it went up to 35 percent,
> so there were some who were put on it just temporarily, is that
> correct?
>
> DR. DARGIE: That is absolutely right.
>
> DR. TEMPLE: Tom can tell me if this is a silly question, but did you
> consider different allocations of the alpha\--
>
> DR. DARGIE: Sorry?
>
> DR. TEMPLE: What was done, would be appropriate if the two endpoints
> had no relationship, weren\'t correlated at all? Sort of equivalent to
> a Bonferroni, but oddly distributed, but, in fact, one of the
> endpoints is included in the other, so those numbers seem a little
> more conservative than necessary, right? I just wondered if you had
> thought about other ways of arranging that.
>
> DR. DARGIE: Other ways of expressing the alpha?
>
> DR. TEMPLE: Yes.
>
> DR. DARGIE: Well, we did certainly consider that. We could have split
> the alpha evenly.
>
> DR. TEMPLE: My point is that, for example, if there were two endpoints
> and you did a Bonferroni, you test each at 0.025, but what I have
> learned is that that is over-conservative if the two endpoints are
> correlated.
>
> You didn\'t divide it equally, so the numbers aren\'t that way, but
> maybe they didn\'t have to be as conservative as you chose. It is a
> little late to fix that, but I was just curious.
>
> DR. DARGIE: I wonder if, with your permission, since I am not a
> statistician, I could perhaps get some statistical advice from my
> advisor, Dr. Ford, Professor Ford.
>
> DR. FORD: Hello. My name is Ian Ford from the University of Glasgow. I
> think that is an interesting statistical point, as you said, but
> whatever the answer to that question would have been, we would still
> be having the same discussion today.
>
> We did consider it, but we thought it would be better to take a
> conservative approach to the problem.
>
> DR. TEMPLE: We plan for future meetings and events at the same time,
> so I was just curious.
>
> DR. BORER: JoAnn?
>
> DR. LINDENFELD: An amendment was made I noticed to decrease the
> follow-up from 12 months to 3 months to complete the study more
> rapidly. Can you tell me how many patients had a follow-up of less
> than 6 months?
>
> DR. DARGIE: Not off the top of my head.
>
> DR. LINDENFELD: Or just approximately?
>
> DR. DARGIE: Would it be possible to answer that question a little
> later on in the presentation when we have established that figure?
>
> DR. LINDENFELD: Yes.
>
> DR. BORER: Steve.
>
> DR. NISSEN: I have a couple of questions. The ejection fraction had to
> be less than 40 percent.
>
> DR. DARGIE: Equal to or less than.
>
> DR. NISSEN: Yes. How was that measured and when was it measured in the
> time course of the infarction?
>
> DR. DARGIE: Ejection fraction could be measured by any of the
> established techniques for ejection fraction, so it could conceivably
> be measured also by invasive technique, so that was very uncommon.
>
> The most common method of measuring ejection fraction was
> echocardiography. This was generally measured at a time when the
> patient was stable following their admission for their index MI. So,
> it was very close obviously to randomization.
>
> DR. NISSEN: Right, not necessarily in the very acute phase of their
> infarction.
>
> DR. DARGIE: That\'s right. The ejection fraction was measured
> generally at the time when people were stable, not in the hyperacute
> phase.
>
> DR. NISSEN: And they had to have ST elevation MI, is that correct?
>
> DR. DARGIE: No, they didn\'t. They had to have a definite diagnosis of
> myocardial infarction. They could have non-ST segment elevation
> myocardial infarction.
>
> DR. NISSEN: Do you have any sense of what the distribution was between
> ST elevation and non-ST elevation MI?
>
> DR. DARGIE: Yes, about 25 percent were non-ST segmental elevation, the
> majority were ST elevation.
>
> DR. NISSEN: Does it surprise you that there was such a\--I mean
> usually, non-ST elevation MI\'s don\'t result in ejection fractions of
> less than 40 percent. I presume most of those were people with a
> second infarction, is that right?
>
> DR. DARGIE: Well, it is very interesting question. Of course, patients
> could have had a previous MI and therefore have a depressed ejection
> fraction prior to coming in, but that is probably the most common
> reason.
>
> DR. BORER: John.
>
> DR. NEYLAN: I was curious about some of the deliberations that went
> into the calculation of the sample size since this is relevant to an
> important element of the submission, I believe, with regard to the
> strength of the signal.
>
> You describe a roughly 25 percent dropout rate, roughly equally
> distributed between the two treatment groups and I was wondering if
> you could share with us some of the thoughts in the original design as
> to why a dropout rate was not taken into account when considering the
> original sample size.
>
> DR. DARGIE: What wasn\'t taken into account was the dilutional effect
> of open-label beta-blocker. That was the thing that wasn\'t taken into
> account. I think that we probably anticipated the dropouts would occur
> probably early in either group, but the sample size was simply an
> arithmetic calculation from the power and the reduction in mortality
> and the alpha and power that we wanted for the study.
>
> DR. BORER: Ian, did you want to comment about that?
>
> DR. FORD: Yes, I think it would be useful to say something. There are
> two ways you can do power calculations. You can either start with a
> theoretical benefit assuming everyone will continue on study
> medication and then adjust that down on the basis of an assumed
> withdrawal rate, or you can start with an effective treatment effect
> after taking into account the patients will inevitably withdraw from
> medication.
>
> We took the latter approach assuming there had been no untrivial
> withdrawal rate in the study and we adjusted the effect size down to
> 20 percent to adjust for that.
>
> DR. BORER: Marc.
>
> DR. PFEFFER: While we are on this topic, so there must be some table
> of your projections at the time you made the change, and we are
> talking about drop-ins, so that would influence the process. Somehow
> you must have had some estimate of what the events would be and what
> your drop-ins would be.
>
> Is there a table that one could look at to say this is what we thought
> in 1997?
>
> DR. DARGIE: I don\'t think we have one.
>
> DR. BORER: Henry, I would like to ask one question, and I will ask it
> again later because you may not have the information now.
>
> A number of people were censored at the point where they received
> beta-blockers, and that is perfectly understandable and that is fine.
> I saw nowhere in the briefing document\--all right, then, they
> weren\'t censored, that is just as well, even better, even better.
>
> The point is that people received beta-blockers and they received
> beta-blockers for some reason, and I didn\'t see in the briefing
> document or the FDA review any discussion of specifically why the
> beta-blockers were given.
>
> Now, you may not know, you may not have collected documentation
> sufficient to answer this question, which I think would be unfortunate
> in a way because there is such a clear skewed distribution of
> administration of beta-blockers.
>
> If, for example, people received beta-blockers because they were
> developing heart failure, and that was happening more in one group
> than another, that might well strengthen the case for the efficacy of
> the drug.
>
> So, I am wondering, number one, do we know why they got the
> beta-blocker and was an analysis done, even though it wasn\'t given to
> us to account for that, and, if not, why there was no effort to do
> that.
>
> DR. DARGIE: Dr. Lukas perhaps might be the best person to answer that.
>
> DR. LUKAS: Yes, thank you, Dr. Borer. The answer I am going to give
> you may not be satisfying on all levels. The information on the
> patients who received an open-label beta-blocker was taken from the
> concomitant medication records and did include an indication for why
> the drug was given.
>
> However, when the amendment was made in August 1999, suggesting that
> people should consider putting patients on a beta-blocker if they had
> developed heart failure, the investigators did not really receive
> specific instructions as to indicate that that was the reason why they
> were being put on a beta-blocker.
>
> So, when we looked in detail at the records for these 400 and some-odd
> patients who received a beta-blocker across the two groups, we really
> have a mixture that is difficult to interpret in a very clear way.
>
> Most of the people who received long-term open-label beta-blocker, the
> indications that the investigator gave were post-myocardial infarction
> or ischemia, but there was no effort made\--because this was not
> given, I will just tell you, it was not given a lot of importance at
> the time the analysis was being done. In retrospect, likely it should
> have been.
>
> But we cannot give you based upon the information that we have in hand
> an answer that says 30 percent of the people were for heart failure,
> 40 percent were for other reason, and so on. I can only tell you from
> looking at the data in general that most of the information from the
> investigators said post-MI use.
>
> DR. BORER: Thank you.
>
> Tom.
>
> DR. FLEMING: A few questions. The study\'s enrollment began in June of
> \'97 and by our notes here, was completed, the follow-up was completed
> on February 3rd of 2000, is that correct?
>
> DR. LUKAS: On March the 1st, 2000, the investigators received a fax
> saying that the 633 endpoints had been accrued and that they should
> contact their patients, bring them in, begin down-titration, do the
> end of study assessments, and so on.
>
> The actual last dose of study medication including the down-titration
> was given on May 30th, 2000, so that was the actual end of the
> medication being administered. The last follow-up of patients actually
> went out to about July, August of 2000 to get the vital status on all
> of the patients for whom the vital status was not known at the time of
> the end.
>
> DR. FLEMING: So, the last survival data that exists is through June of
> 2000?
>
> DR. LUKAS: Actually, the last death recorded was July 18th, 2000.
>
> DR. FLEMING: So, there haven\'t been any survival updates beyond that.
>
> DR. LUKAS: No.
>
> DR. FLEMING: A design question. Just as you look at this
> philosophically, you have given us the history of development of
> evaluations of carvedilol. Among those trials were the Australia-New
> Zealand, the U.S. Carvedilol trial, and COPERNICUS, where you referred
> to the time frame there being two to five years post-MI.
>
> From a scientific perspective, the question that CAPRICORN would be
> addressing would be whether it would be useful to use carvedilol
> earlier in the process, initiating it earlier. So, the logical
> question then is really not one of carvedilol, yes versus no, but
> immediate versus delay.
>
> In essence, you are randomizing people that are now within 21 days of
> MI to immediate use of carvedilol versus a strategy that would delay
> initiation of beta-blockers to a time period where clinical conditions
> would indicate proper initiation.
>
> That, I assume is, in fact, your perspective here, you are looking at,
> by design, an immediate versus delay design here, intending to find
> out whether or not there is a 20, 23 percent reduction in death rate
> over time from such a design. Is that correct?
>
> DR. DARGIE: Relatively immediate in the sense that it wasn\'t given
> within the first 24 hours as the first medication.
>
> DR. FLEMING: Right.
>
> DR. DARGIE: And given in the context of the use of beta-blockers in
> other LVD and heart failure circumstances when its limit has already
> been on-board, so it was within that time frame.
>
> DR. FLEMING: And that makes sense to me. Why then is it not possible
> in that framework to have a mortality endpoint? Why was the Steering
> Committee and the sponsor of the perspective that the endpoint needed
> to be changed from something other than mortality?
>
> DR. DARGIE: I could go through the history of that, if you like. I
> mean basically, it was considered that because of the use of
> beta-blockers further out in the trial, after three months or so, and
> that that would have a drop-in effect, and obviously lead to
> difficulty in detecting a difference between the two groups. That was
> the reason for that.
>
> DR. FLEMING: Because it was thought that it would be implausible that
> you could have a mortality difference that would be meaningful if you
> had an immediate versus delay?
>
> DR. FLEMING: You know, the power calculations, of course, are on the
> 630 deaths originally, and that obviously wouldn\'t have occurred
> within that time frame.
>
> DR. FLEMING: Since you haven\'t had a chance to present the data, et
> cetera, I would like to return to that theme a little bit later. Let
> me move to another question.
>
> You referred to the Data Monitoring Committee, and there are a number
> of issues that are perplexing to me in this. First, the membership of
> the committee, if I understand one of the earlier slides, Dr. Ford was
> a member of the committee.
>
> Normally, we would anticipate that the Data Monitoring Committee would
> be an independent committee that would have no representation from the
> sponsor or investigators.
>
> Dr. Ford, were you independent of this process?
>
> DR. FORD: My group was the independent statistical center for the
> study, was responsible for constructing the report for the Data Safety
> Monitoring Committee. I was the person who delivered the report to the
> committee, and I was a non-voting representative on the committee.
>
> DR. FLEMING: So, you are what I would call the liaison statistician
> between the database and the Monitoring Committee, but not a member of
> the committee.
>
> DR. FORD: That\'s correct.
>
> DR. FLEMING: Was there a statistician on the committee?
>
> DR. FORD: Yes, Simon Thompson, who is the Director of the MRC
> Biostatistics Unit in Cambridge University, was the statistician.
>
> DR. FLEMING: The second question. In the materials we had received,
> there was indication the committee was blinded. Can you tell us more
> about that?
>
> DR. FORD: The reports that the committee received were on an A/B basis
> or a treatment 1/treatment 2 basis. They received the report on the
> subjects who were in what we call the \"warm-up\" phase of the first
> 200 subjects where we got very detailed information. They got that
> data on an A/B basis. The more detailed information for the rest of
> the study, they got in a treatment 1/treatment 2 basis.
>
> For all-cause mortality, where the data came directly from the sponsor
> because there was a significant delay in the adverse event data
> passing through the CRO, which was processing the data and then coming
> to my group for analysis, the data was all treatment 1 and treatment
> 2. For the data from the sponsor on all-cause mortality, the committee
> decided that with the exception of interim analysis, they only wanted
> to see completely blinded data as they saw the data as a single group
> for all-cause mortality with the exception of the single meeting where
> they carried out an interim analysis.
>
> DR. FLEMING: As an aside, since the primary responsibility of the Data
> Monitoring Committee is to safeguard interests of study participants,
> and have serious ethical concerns about a monitoring committee that is
> not fully unblinded to information evolving in the trial.
>
> Moving ahead, though the recommendation now came down from the
> Monitoring Committee based on having seen results of CIBIS II and
> MERIT, and this seems very appropriate that looking at emerging
> external information, the Monitoring Committee, in their judgment,
> believed that it would be important for patients who, in fact,
> progressed to heart failure, to be provided beta-blockers.
>
> That was the recommendation. I have no concerns with that, that seems
> reasonable, but the sponsor has indicated that it was then the Data
> Monitoring Committee\'s recommendation to change the endpoint, which
> is a separate issue.
>
> One issue is, is there a need to alter the way patients are managed,
> and I understand the role of the Monitoring Committee in that process.
> I don\'t understand the role of the Monitoring Committee in the
> process of changing the endpoint. That is the Steering Committee and
> sponsor\'s responsibility.
>
> But seemingly from what you are telling us, you viewed it as the Data
> Monitoring Committee\'s responsibility to change the endpoint in the
> trial?
>
> DR. DARGIE: No. As you say, the responsibility of the DSMB is to
> oversee the safety in the trial. I received a letter from the DSMB in
> which they advised that we should consider, I think was the word used,
> a change in the primary endpoint, but the decision to implement that,
> of course, was entirely the Steering Committee.
>
> DR. FLEMING: In the document, it was worded, and I can find the
> wording in a bit, something to the effect that it would have been
> extremely difficult for the\--yes, the study failed to achieve its
> primary endpoint at the prespecified alpha because of a strong
> recommendation by the Data Safety Monitoring Committee to change the
> primary endpoint, a recommendation that would have been difficult for
> the Steering Committee and the sponsor to ignore.
>
> This really is perplexing to me because the Data Monitoring Committee,
> first of all, should be unblinded, in which case they are the last
> group that I want to be intervening in changing my endpoint, but in
> this case, you are saying they were blinded.
>
> But even with that being the case, it is not the Data Monitoring
> Committee\'s responsibility to alter endpoints in trials, so it is
> perplexing to me that you have indicated that it would have been
> difficult for the Steering Committee and sponsor to ignore a
> recommendation from the Monitoring Committee to change an endpoint.
>
> That is entirely your purview to decide what the endpoint is, and it
> is still not clear to me why, if you believed that immediate versus
> delay could influence survival, why you felt it compelling to change
> the endpoint whether or not you believed it was the Data Monitoring
> Committee\'s recommendation.
>
> DR. DARGIE: It is, of course, interesting for me as the chairman of
> the Steering Committee to look back on those events and consider what
> we thought at the time.
>
> We had appointed what I considered to be an extremely knowledgeable
> and very experienced DSMB. Desmond Julian had experience of previous
> MI trials, being on many more DSMBs than probably anyone in the room.
> We had experience on the DSMB in the areas of heart failure and also
> myocardial infarction.
>
> So, it would be fair to say that, as the Steering Committee chairman,
> I was taking very, very seriously any information that would come from
> the DSMB. They didn\'t tell us that we should do anything. They
> didn\'t tell us that we should change the primary endpoint. They
> didn\'t insist it be any given change, any given endpoint that would
> be the new co-primary.
>
> They simply advised us to consider the possibility of a change in
> endpoint in order to expedite the completion of the study. At the
> time, I considered that was within the role of the DSMB in their role
> for the safety of the patients in the study.
>
> I agree with you that it is not their role to actually decide on those
> things, but I would say that it would certainly be within their role
> to ask the Steering Committee to consider that in the interest of the
> safety of the patients in the trial.
>
> It was in that spirit that I received the message and we discussed it
> among the group. It wouldn\'t be any surprise to you to know that this
> was greeted with a mixture of warmth and otherwise by the members,
> many wanting to maintain all-cause mortality.
>
> It was only after quite a lot of discussion, and not just at one
> meeting, that we decided that we would adopt the strategy of
> accelerating the completion of the study, maintaining its viability,
> of course, that was our primary concern, and also to maintain the
> identity of the study as a mortality trial.
>
> So, within that framework, I felt not uncomfortable, if not
> comfortable, with what the DSMB had advised, and I didn\'t think, and
> still don\'t think, that they had overstepped the mark.
>
> But insofar as the workings of DSMB are not the subject of
> written-down textbooks and instructions as yet, I think there will
> definitely be a spectrum of opinion on that.
>
> DR. BORER: Steve.
>
> DR. NISSEN: I guess what we were trying to get at here is there
> appears to have been, at least as I read the documents, two things
> going on. One was the recognition that in the interests of safety,
> that allowing patients to drop in was appropriate, and I personally
> find that highly commendable and the correct decision, and I just
> can\'t find any fault at all with that decision, period.
>
> Obviously, it was a terrible challenge for you, but I think what some
> of us have been trying to understand better as we move forward toward
> this decision was there was also the problem of a trial that was
> enrolling very slowly, so, you know, changing the primary endpoint,
> was the primary endpoint changed because enrollment was slow and this
> was a way to get the trial done more quickly, or were these issues of
> the drop-in the predominant issues.
>
> It is confusing to us as we read these documents to understand the
> thinking. I would have loved to have seen the actual letter that was
> communicated to the Steering Committee. It would be very helpful to
> see exactly how this was communicated.
>
> I don\'t know if that would ever be appropriate for us to actually see
> that, but it is one thing to change a trial for safety, it is another
> to change the endpoint because things are not going well or you are
> going slowly and you want to try to move things along, so you use a
> looser endpoint.
>
> I don\'t know if I am speaking for anybody else, but I would like to
> get a sense of that as we move forward.
>
> DR. DARGIE: I have a series of backup slides that describes the way in
> which this process took place. Would you be interested in seeing
> those? In a nutshell, one can say that this process was the result of
> three things.
>
> One was the slow recruitment. One was the fact that the overall
> mortality rate was considerably lower than I expected, but I think, if
> you like, the straw that broke the camel\'s back or the thing that
> activated the process at the time was the announcement of the results
> of CIBIS II, which by the way, I was the chairman, and also
> MERIT-Heart Failure, and that set the process going.
>
> But there was, of course, concern about the slow recruitment even at
> the beginning, but I think it was that plus the low mortality rate
> plus the drop-in of the beta-blockers.
>
> DR. NISSEN: What Tom I think was hinting at or maybe he was really
> saying it is that you could have said we will allow the drop-in, but
> we are not going to change anything else about the trial, and that was
> the alternative decision that might have been made, so to understand
> the process about why the endpoint was changed is really an
> independent decision of the decision to allow drop-in.
>
> We are all trying to understand how those things weighed upon the
> group that was responsible for conduct of the trial, because it does
> have an impact on how much leeway we give on this whole discovery
> process.
>
> DR. DARGIE: I think it is very difficult to answer that particular
> issue about letting the trial continue with drop-in beta-blockers
> because we really didn\'t know exactly how common that would be. I
> mean it could have been very common.
>
> It could have been along the lines we had, we really didn\'t know, but
> casting your mind back to 1998 and 1999 and the publication and
> presentation of these data, I think did engender a sense of urgency at
> least within the DSMB, which I suppose it communicates to the Steering
> Committee.
>
> Since many of us have been associated with those trials and their
> clear results, we felt and I think you agreed that that was the
> appropriate thing to do.
>
> DR. FORD: Maybe it is appropriate for me, since I was party to the
> discussions at the DSMB, to comment on what actually happened. I
> should say, first of all, that the DSMB had a charter and it was very
> clear to all members of the DSMB that they were an advisory committee
> to the Steering Committee, and I think they were acting in good faith
> in giving advice when they wrote to the Steering Committee.
>
> The issues that they considered were, as has been indicated, that at
> that time it appeared that the mortality rate was about 50 percent of
> what had been predicted. The study was experiencing difficulties in
> recruiting in addition to that, but we had the early stopping of the
> CIBIS II trial and then the MERIT trial.
>
> At the beginning of this critical meeting that took place, there was
> an open discussion with the chairman of the Steering Committee on the
> impact of CIBIS II and MERIT. After that open discussion, the
> committee then decided that this was a very significant finding and
> that the investigators and essentially the patients would have to be
> informed of the results of those studies.
>
> Because of the poor recruitment rate, the very low mortality rate,
> which was particularly important, it was considered that the impact of
> a significant number of patients going on to open-label beta-blocker
> treatment would make it, particularly after subsequent non-fatal
> events would have occurred during the trial, would make it extremely
> difficult to hit the mortality outcome.
>
> It was for that reason that they felt obliged to comment to the
> Steering Committee that they thought there was a difficulty that they
> should consider, but the decision always was actually in the hands of
> the Steering Committee to make a decision.
>
> DR. BORER: JoAnn.
>
> DR. LINDENFELD: I have a slightly different question, so I just want
> to be sure that nobody has any more on this one.
>
> DR. FLEMING: Maybe if you are going to change, just to summarize and
> maybe reinforce a bit, too, what Steve just said, the role of the
> Monitoring Committee here is in looking at emerging evidence, external
> evidence, and making a recommendation about what they viewed to be
> important for ethical management of patients, is entirely appropriate.
>
> Ultimately, the recommendation to the Steering Committee to make such
> a change is advisory, and the Steering Committee would act on that
> recommendation.
>
> A change in the endpoint is entirely in the hands of the Steering
> Committee and the sponsor. If the DSMB has no access to emerging data,
> then they, in fact, can be in a position to provide advice on that.
> Once they have access, it is very inappropriate for them to be in that
> position.
>
> Ultimately, one of my objections or concerns is a statement in the
> Executive Summary that seems to suggest that the Data Monitoring
> Committee was ultimately limiting the options the sponsor and Steering
> Committee had on the endpoint.
>
> I don\'t see that whatsoever, and I am perplexed in a sense because we
> are saying here there are conditions that can emerge
> post-randomization that would lead the patient to be in a position to
> need beta-blockers, and as a result\--if we call that drop-ins, I
> don\'t call that drop-ins, I call that delayed administration\--as a
> result, it is not plausible that you could see a 20 percent reduction
> for immediate versus delay when we are now being asked today to look
> at these data to determine whether or not immediate is better than
> delay.
>
> So, if you believed that it wasn\'t plausible to see a difference, and
> yet you are coming before us today with data to ask us to judge
> whether or not there is evidence that immediate is better than delay,
> so it seems rather odd that the Steering Committee, whether it was a
> recommendation from the DSMB or not, reached the conclusion that
> mortality wasn\'t a viable endpoint if we are being asked today to
> determine whether immediate would improve survival.
>
> DR. BORER: Marc.
>
> DR. PFEFFER: The same topic. I think the internal knowledge and
> external knowledge, so that the external information available is not
> only the two studies you mentioned. You had the U.S. carvedilol
> trials, which was done even before that, known to the leaders of the
> trial.
>
> The recruitment rate was known to the leaders of the trial. Often, the
> leaders of the trial know global overall without dividing by treatment
> assignment the mortality rate, so did the Steering Committee know
> those three ingredients without the DSMB?
>
> In essence, you knew recruitment, you knew the U.S. carvedilol, you
> knew CIBIS as the leader of CIBIS. You didn\'t need the DSMB to tell
> you that. What did you need from them that you didn\'t have?
>
> DR. DARGIE: We didn\'t need that from them. Basically, the DSMB
> exercised their role as far as the safety of the patients to draw that
> to our attention, not insofar as we weren\'t aware of it. We discussed
> it at the open session of the meeting in March of 1999.
>
> Insofar as the U.S. carvedilol trials are concerned, I mean the CIBIS
> II, of course, was the first single randomized, controlled trial to
> demonstrate an impact on mortality of beta blockade, and so the
> question was still in discussion, but you are quite right.
>
> When CIBIS II and MERIT-Heart Failure came along, there was no longer
> any doubt, but you are right, we were in possession of those facts. It
> is just that the DSMB I guess were exercising their role in drawing
> that to our attention, and invited me\--we have an open session, that
> was the plan before each meeting to discuss matters of concern and of
> interest, and it was at that meeting that we jointly discussed it.
>
> DR. LINDENFELD: Could you clarify for me how the beta-blocker drop-ins
> were handled? Just administratively, if an investigator decided to add
> a beta-blocker, the study was unblinded, or exactly how was that
> handled?
>
> DR. DARGIE: No, the study was not unblinded, but the patients then had
> to be down-titrated and then up-titrated on the beta-blocker.
>
> DR. PACKER: There are minutes of the DSMB meeting. I just want to
> share with the committee an excerpt of that, just so that there is
> clarity as to what the DSMB recommended and what it did not recommend,
> just one paragraph.
>
> DR. BORER: For the record, that is Dr. Packer who is speaking. When
> you are speaking, you have got to introduce yourself.
>
> DR. PACKER: I am sorry. D36?
>
> DR. DARGIE: Right.
>
> DR. PACKER: This comes from the minutes. This is a verbatim quote from
> the minutes of the Data Safety Monitoring Board that was held on March
> 10, 1999. This comes from the closed\--it was called \"closed
> section\"\--this is the section where the principal investigator was
> not present.
>
> You can read this for yourself. \"The best option was thought to be a
> change in the primary endpoint to death or cardiovascular
> hospitalization, keeping the target number of events for the primary
> endpoint unchanged.\"
>
> I will let you read the rest of it. Professor Julian was going to
> write to the Steering Committee with this proposal, and I do not want
> to say this was the right thing or the wrong thing. I just want to be
> able to say that that, in fact, did take place in precisely the
> manner, and I wanted to show you the documentation from the minutes
> that, in fact, the process by which this took place.
>
> It could be that the Steering Committee could have figured this out
> all on their own, and didn\'t need the DSMB, but the DSMB did make the
> deliberation. They did, in fact, go as far as they did, and did, in
> fact, make this particular recommendation to the Steering Committee.
>
> So, I just wanted to make clear exactly what took place.
>
> DR. BORER: Okay.
>
> DR. PACKER: For right or wrong.
>
> DR. BORER: Why don\'t you go ahead with the results.
>
> DR. DARGIE: Oh, yes. You stopped me in the middle. Here we are.
> Results on the primary endpoints.
>
> This slide shows the effects on the co-primary endpoints of all-cause
> mortality or cardiovascular hospitalization. You can see there were
> 367 such events in placebo arm and 340 on carvedilol. This reflected
> an 8 percent reduction, which was not lower than the amendment
> prespecified alpha of 0.045.
>
> The next slide is the Kaplan-Meier curve for that combined endpoint.
> You can see the curves are virtually superimposable here, but do
> separate towards the later phase of the trial, but this was not
> statistically significant.
>
> This shows all-cause mortality. There were 151 deaths for all causes
> in placebo and 116 in the carvedilol group. This was a 23 percent
> reduction in the risk of death and at a p value of 0.031, which also
> was higher than the amendment prespecified alpha of 0.004.
>
> This is the Kaplan-Meier curve which shows that the curves do separate
> early, continue to diverge throughout the course of the study.
>
> Now, the annual placebo mortality rate was 12.1 percent in the placebo
> group and 9.8 percent in the carvedilol group. For information, that
> placebo mortality was nearly twice that observed in the earlier
> post-infarction beta-blocker trials.
>
> At this point, Dr. Borer, I was going to pause and ask Dr. Packer,
> because he is going to elaborate on those primary endpoint data.
>
> **Why Are We Here?**
>
> **Milton Packer, M.D.**
>
> DR. PACKER: Dr. Borer, members of the Advisory Committee, and FDA,
> ladies and gentlemen. Today, the Advisory Committee is being asked two
> important and interesting questions that have been discussed I think
> at various regulatory meetings for many years, but never have been I
> think specifically answered.
>
> First, can the findings from a trial that did not meet its primary
> endpoint be used as the primary basis for labeling, and, if so, what
> criteria should the data supporting such a finding fulfill to justify
> incorporation to labeling?
>
> I think it would be fair to say that these questions are what today\'s
> meeting is all about.
>
> Let\'s look at the first question. Can the findings from a trial that
> did not meet its primary endpoint be used as the primary basis for
> labeling? I guess if the answer to that is no, I guess we could simply
> stop here and end the meeting early and go home, but I think that, in
> fact, there would be no reason for me.
>
> But the questions from the FDA indicate that there is a reason for
> meeting, and that is because in the past, the FDA has granted an
> indication based on trials that did not meet its primary endpoint
> because it found the data from such trials to be credible and
> persuasive.
>
> I want to cite two specific examples. The first example is digoxin.
> Digoxin is currently indicated for the treatment of mild to moderate
> heart failure to reduce heart failure related hospitalizations. This
> is true even though the trial that observed this benefit, the DIG
> trial, did not achieve its primary endpoint of all-cause mortality.
>
> Current labeling for digoxin contains a detailed description of the
> trial including mention of the fact that the drug did not have an
> effect on the primary endpoint.
>
> The second example is enalapril. Enalapril is currently indicated for
> the treatment of clinically stable, asymptomatic patients with left
> ventricular systolic dysfunction to decrease the rate of development
> of overt heart failure and decrease the incidence of hospitalization
> for heart failure.
>
> This is true even though the trial that observed this benefit, the
> SOLVD prevention trial, did not achieve its primary endpoint of
> all-cause mortality. Current labeling for enalapril contains a
> detailed description of the trial including mention of the fact the
> drug did not have an effect on the primary endpoint.
>
> I should mention that the decision to approve enalapril for
> asymptomatic left ventricular dysfunction was almost certainly
> favorably influenced by the FDA\'s knowledge that enalapril reduced
> all-cause mortality in the SOLVD treatment trial which enrolled
> patients later in the disease process. I want to get back to that in
> just a few minutes.
>
> Therefore, in the past, the FDA has concluded that data supporting the
> existence of a drug effect can form the basis for labeling even when
> the measure of benefit that had been identified a priori to be of
> primary importance in the trial, was not significantly influenced by
> therapy.
>
> Given these examples, I think that the real question today is not
> whether one can base labeling on trials that did not meet their
> primary endpoint, instead I think the real question before the
> committee is what criteria should the data supporting such a finding
> fulfill to justify incorporation into labeling, or as the FDA has
> phrased it in its questions to the committee, what rules should guide
> the decision to allow inclusion of a discovery into labeling.
>
> To my knowledge, there are no formal rules, in fact, I don\'t think
> that this issue has ever been fully discussed before at an advisory
> committee meeting, but it is a terribly interesting and important
> question.
>
> Let me propose one answer to the question. Specifically, I would
> propose to the committee that the criteria that will allow inclusion
> of a discovery into labeling should have the strength of evidence
> comparable to that which would allow labeling based on a trial or
> trials that achieve their primary endpoint.
>
> In fact, I would say on a personal level that the committee needs to
> set an extremely high standard here, a standard that would be met only
> by the most persuasive of circumstances. So, first, we need to define
> these criteria and then we need to determine if these criteria are
> fulfilled by the current circumstances with carvedilol.
>
> The first step is to define the criteria and I would begin by
> proposing that any benefit being considered for inclusion into
> labeling should be an outcome measure of major importance. Ideally, it
> should be a reduction in mortality. I say this because I think
> everyone would recognize that death is a very special and unique
> endpoint. The finding of a treatment-related reduction in the risk of
> death is always compelling since death is an unbiased endpoint of
> paramount clinical importance.
>
> Indeed, the FDA reviewer has written that the FDA has acted as if all
> clinical trials implicitly have an alpha of 0.05 assigned to the
> analysis of mortality independent of the primary endpoint.
>
> Well, I think we can begin there, but I think we need to go further
> because there are several important examples of how the wrong decision
> would have been made if our only criteria were that all trials
> implicitly have an alpha of 0.05 assigned to mortality.
>
> Here are two examples. In an initial study of vesnarinone in heart
> failure, which enrolled about 450 patients, observed a 62 percent
> reduction in mortality, which was highly significant, but was based
> only on 46 deaths, observed in a trial designed primarily to evaluate
> exercise tolerance.
>
> Subsequently, a larger study, which was specifically designed to
> evaluate the effects of vesnarinone on mortality and which recorded 10
> times as many events, concluded that the drug significantly increased
> the risk of death.
>
> Similarly, an initial study comparing losarten and captopril, which
> enrolled about 700 patients, observed a 46 percent reduction in the
> risk of death, which was significant, but it was only based on 49
> events, and a trial primarily designed to evaluate renal function.
>
> Subsequently, a larger study, which was designed specifically to
> evaluate the effects and compare the effects of losarten and captopril
> mortality, recorded 10 times as many events, demonstrated that
> losarten appeared to be somewhat inferior to captopril.
>
> So, I think we need to be very careful before reaching conclusions
> about mortality effects of drugs based on data from trials that were
> not designed to find them. Such trials generally observe very few
> events, and thus, any mortality risk reduction can only reach
> statistical significance if it is probably large and has very wide
> confidence intervals.
>
> That is why the current example with carvedilol is so interesting.
> Mortality was not an incidental observation or discovery in the
> CAPRICORN trial. The CAPRICORN study was designed and carried out as a
> survival trial, and it observed a substantial number of deaths.
>
> Furthermore, given an annual mortality rate that was nearly twice that
> in earlier post-infarction trials, the trial could provide a
> reasonably precise estimate of the effects of carvedilol on mortality
> with relatively narrow confidence intervals.
>
> In fact, the final results of the study demonstrating the effect on
> the original primary endpoint of all-cause mortality, had a p value
> less than that specified in the original protocol with a magnitude of
> effects similar to that anticipated in the original protocol.
>
> Now, I don\'t want to ignore the fact that there was a protocol
> amendment, but I think it would be unfair to use the existence of the
> amendment to claim that mortality reduction noted at the end of the
> CAPRICORN study was an accidental discovery.
>
> There is no doubt that CAPRICORN was first and foremost a survival
> study, and it continued as a survival study even after the protocol
> amendment.
>
> So, there are many characteristics of the CAPRICORN trial that
> distinguish its mortality findings from the experiences with
> vesnarinone and losarten, however, the most important distinction
> between the results of CAPRICORN and earlier experiences with
> vesnarinone and losarten is reproducibility where the mortality
> observations with vesnarinone and losarten were not reproduced, the
> mortality effects in the CAPRICORN trial have been replicated in other
> post-infarction trials with other beta-blockers.
>
> Now, this last point is really important because even if one were to
> agree that all trials implicitly have an alpha assigned to mortality,
> some may argue it isn\'t 0.05, it is far smaller than that. That is
> because if we are to believe in the existence of a therapeutic effect,
> it must not only be credible, it must be persuasive.
>
> Some may argue that a p of 0.031 for the mortality finding in
> CAPRICORN isn\'t persuasive, the p value needs to be far smaller than
> that, say, 0.00125.
>
> Now, I want to make note of the fact that the FDA perhaps has
> generally not required mortality effects to have extremely small p
> values in order to be persuasive, but I think we need to set a higher
> standard here because the alpha assigned to the mortality analysis in
> the CAPRICORN trial was not 0.05, it was 0.005.
>
> That means for better or for worse, the CAPRICORN investigator set an
> extremely high standard for reproducibility, one which can be met by
> one trial with a very small p value or by two or more trials with the
> same finding, each with a p less than 0.05.
>
> Prior to CAPRICORN, there were five trials with five different
> beta-blockers that reported a mortality reduction during long-term
> treatment with these drugs in post-infarction patients.
>
> These studies were considered sufficiently persuasive individually and
> collectively to lead to the approval by the FDA of three of these
> beta-blockers - timolol, metoprolol, propranolol, specifically for the
> management of post-infarction patients.
>
> Now, this slide summarizes the key features of the four large-scale
> randomized trials that had been carried out with these three
> beta-blockers in patients with a recent MI.
>
> The first two trials carried out with the nonselective beta-blockers
> timolol and propranolol were large-scale studies that observed about
> 2- to 300 deaths, and each reported highly significant effects on
> mortality. The results of the next two trials carried out with
> metoprolol are also favorable although less impressive.
>
> Now, if one combines the data from all placebo-controlled trials
> carried out with beta-blockers in the long-term management of
> post-infarction patients\--and this analysis is the most recent
> analysis that has been done, it is based on more than 2,400 deaths
> observed in nearly 25,000 patients enrolled in 31 trials\--the
> evidence supporting the existence of mortality effect with
> beta-blockers in this setting is extremely persuasive.
>
> The magnitude of the effect is a 23 percent reduction in risk of death
> with fairly narrow confidence intervals.
>
> Now, the results of the CAPRICORN trial are extremely concordant with
> those of earlier trials with beta-blockers approved for the management
> of post-infarction patients. The trial observed a large number of
> deaths and the magnitude of the mortality effect with carvedilol
> observed in the CAPRICORN trial was identical to that seen in the
> meta-analysis of all placebo-controlled, post-MI beta-blocker trials
> with relatively similar confidence intervals.
>
> Now, this was true even when the meta-analysis was restricted to
> patients who had clinical evidence of left ventricular dysfunction or
> heart failure following their acute myocardial infarction.
>
> So, I think if we look at the concordance between the mortality data
> with CAPRICORN and the results of other post-infarction beta-blocker
> trials, it would be fair to say that the strength of evidence is quite
> substantial, equivalent to a very, very small p value.
>
> Now, this argument holds only if it is appropriate to consider the
> results of other post-infarction beta-blocker trials in gaining
> reassurance about the reproducibility of the results with carvedilol
> in the CAPRICORN trial.
>
> Now, the committee has recently dealt with this specific issue in
> another therapeutic area. Earlier this year, the advisory committee
> looked favorably at the results of a controlled trial with losarten in
> diabetic nephropathy, but it expressed skepticism about recommending
> approval based on the findings in a single trial, whose primary
> endpoint, which included a component of questionable clinical
> importance, was achieved at a significant, but unimpressive p value.
>
> However, the committee recommended approval of losarten when the
> findings in the losarten trial were considered together with the
> highly concordant findings of a similar trial with irbesarten in the
> same disease, a trial which when considered alone, did not lead the
> committee to recommend the approval of irbesarten.
>
> So, I think the committee felt comfortable with this recommendation
> because they believed that neither irbesarten nor losarten had effects
> that might detract from their ability as angiotensin antagonists to
> prevent the progression of renal disease, so we should apply the same
> criteria to the current situation with carvedilol.
>
> Specifically, does carvedilol have effects that might detract from its
> ability as a beta-blocker to reduce mortality in the post-infarction
> setting. Well, not all drugs that block beta-1 receptors have similar
> effects in reducing mortality in post-infarction patients.
>
> This trial summarizes the findings of a recent meta-analysis by
> Freemantle and colleagues that explored possible relations between the
> pharmacological properties of specific beta-blockers and their effects
> on mortality in long term, post-infarction trials.
>
> Overall, long-term treatment with a beta-blocker reduced the risk of
> death by about 23 percent, however, the magnitude of the effect
> appeared to be attenuated in trials with beta-blockers that had
> intrinsic sympathomimetic activity, and therefore it is possible for
> beta-blockers to have ancillary effects that detract from their
> mortality benefits, and it is possible using this kind of analysis to
> detect such effects.
>
> It is therefore noteworthy that carvedilol is a nonselective
> beta-blocker that has no intrinsic sympathomimetic activity. In fact,
> if one adds the data from CHAPS and CAPRICORN to the data with other
> beta-blockers, the magnitude of the effect of carvedilol are precisely
> what might be anticipated from its known pharmacological similarity to
> timolol and propranolol.
>
> However, one could look at this and argue that it is still possible
> for carvedilol to exert an unknown pharmacological effect that might
> detract from its survival benefit in a manner that might not be picked
> up by this kind of analysis.
>
> To address this possibility, we need to examine the effects of
> beta-blockers in a disorder closely related to left ventricular
> dysfunction following a recent myocardial infarction, and that is left
> ventricular dysfunction following a remote myocardial infarction.
>
> Now, the two disorders are part of a single disease continuum with
> patients moving from one phase of the disease to the next over a
> period of weeks, months, or years. In fact, similar neurohormonal
> factors are believed to be important both early and late in the
> disease process, explaining why both ACE inhibitors and beta-blockers
> are effective in improving outcomes at both time points in the disease
> continuum.
>
> Please remember it is exactly the same thinking process that was used
> by the FDA when it relied on the mortality reduction seen in the SOLVD
> treatment trial to gain reassurance about their decision to approve
> enalapril for patients in the SOLVD prevention trial.
>
> Now, three different beta-blockers - bisoprolol, carvedilol, and
> metoprolol, have been shown to reduce mortality in patients with left
> ventricular dysfunction and chronic heart failure, and the magnitude
> of this benefit for each drug is similar in patients with or without a
> remote history of a myocardial infarction.
>
> Carvedilol has been shown to reduce mortality in patients with left
> ventricular dysfunction and chronic heart failure, and the magnitude
> of this benefit is extremely similar to that produced by other
> beta-blockers in this disorder both in patients with and without a
> remote history of an MI.
>
> If carvedilol had a pharmacological property that detracted from its
> ability to reduce mortality, for example, alpha blockade or an
> antioxidant effect, such an action should have been apparent in trials
> with the drug in chronic heart failure and should have negated or
> diminished its effect relative to other beta-blockers, and this was
> not the case.
>
> In fact, just as in the post-infarction setting, intrinsic
> sympathomimetic activity has also been associated with reduced
> survival efficacy in chronic heart failure.
>
> So, I think we can conclude that long-term blockade of beta receptors
> can be expected to reduce mortality in the post-infarction setting,
> that drugs classified as beta-blockers can exert effects that may
> detract from their ability as beta-blockers to reduce mortality, and
> current approaches are able to detect such effects; that the
> pharmacological properties of beta-blockers that may diminish their
> survival effects appear to be similar in the post-infarction setting
> and in chronic heart failure, and that the observed effects, the
> observed effects of carvedilol in both post-MI patients and in chronic
> heart failure indicate the drug does not exert effects that might
> detract from its action as a beta-blocker to prolong life.
>
> Thus, the current situation with carvedilol, I think fulfills all the
> requirements that might reasonably be proposed to allow the committee
> to consider the results of other post-infarction beta-blocker trials
> in making judgments about the credibility and persuasiveness of the
> mortality findings in the CAPRICORN study.
>
> So, let\'s return to the original question - is the totality of
> available data sufficiently credible and persuasive to conclude the
> carvedilol reduces mortality in the post-infarction patient with left
> ventricular dysfunction even though the CAPRICORN trial did not
> achieve its primary endpoints at prespecified levels of significance?
>
> I think it would be fair to say that the circumstances surrounding the
> current application are fairly unique. First, the benefit of treatment
> with carvedilol we are talking about today is not a surrogate endpoint
> or a minor clinical effect, but a meaningful reduction in the risk of
> death.
>
> The mortality benefit of carvedilol seen in the CAPRICORN trials was
> not an incidental or unexpected finding, but seen in a trial that was
> specifically designed and carried out to evaluate the effects of the
> drug on survival and was of a magnitude anticipated in the original
> study protocol.
>
> Second, the nature and magnitude of the mortality effects of
> carvedilol in this trial are almost identical to those seen in other
> post-infarction trials. This provides external confirmation within the
> same class of drugs, an example very analogous to the situation with
> losarten and irbesarten in diabetic nephropathy.
>
> Third, experience with carvedilol in trials of chronic heart failure
> shows that the same drug prolongs life when added to an ACE inhibitor
> in post-MI patients who are later in their disease process.
>
> This provides yet another type of external confirmation with exactly
> the same drug, but in patients who are treated several years later.
> This example is very analogous to the situation with enalapril, which
> was evaluated in the SOLVD prevention and SOLVD treatment trials.
>
> So, I think we really do have a fairly unique situation. We have an
> endpoint of unquestioned clinical importance observed in a trial
> designed to find it, and in addition, we have two types of external
> confirmation, confirmation in the same disease, within the same class
> of drugs, confirmation with the same drug later in the same disease
> state.
>
> This means we not only have persuasive evidence of a class effect, but
> we also have persuasive evidence that this class effect applies to
> carvedilol.
>
> So, when the committee considers the questions posed to it this
> afternoon and discusses the criteria that need to be fulfilled to
> allow the inclusion of a discovery into labeling, let me suggest one
> possible set of criteria, in fact, let me suggest the most stringent
> criteria that I can think of.
>
> Here they are. The findings should be a reduction in mortality. The
> trial should have been designed to detect the finding, and the
> magnitude should have been anticipated in the original study protocol.
>
> The observed magnitude of the benefit should be both clinically
> relevant and realistic, and conclusions about benefit should be based
> on a meaningful number of events.
>
> There should be substantial evidence of a similar benefit both in
> nature and magnitude in the same disease state with other members of
> the same class of drug. There should be substantial evidence the drug
> produces the same benefit later in the disease process, and the
> magnitude of such benefit should be comparable to that with other
> members of the same class.
>
> Finally, the findings should be supported within the trial by
> additional evidence of clinical benefits without overriding safety
> concerns, something which you will hear about in the final two
> presentations.
>
> Now, I realize that these criteria fit precisely the current situation
> with carvedilol, but can anyone think of more stringent criteria than
> these?
>
> In my own view, the only way someone could reject these criteria would
> be to insist that a trial must meet its primary endpoint to be
> incorporated into labeling. That would mean the concept of discovery
> as defined in the FDA questions would be impossible.
>
> Now, later today the committee will be asked how much it is willing to
> inflate the false positive rate by accepting data in a clinical trial
> that failed to meet its primary endpoint. I do not know how the
> committee will answer this question, but my own personal response
> would be zero.
>
> I do not think the committee should accept any inflation in the false
> positive rate in making clinical or regulatory decisions. So, in my
> view, today\'s discussion should not be about how much the committee
> should be willing to inflate the false positive rate.
>
> The real question is, in making regulatory decisions based on trials
> that missed their primary endpoint can one reduce the false positive
> rate to acceptable levels given the opportunity considering, not just
> the results of one trial, but the totality of available data.
>
> If one rejects the concept of discovery entirely, it would mean one
> would be giving great weight to concerns about an increase in the
> false positive rate in the single trial while at the same time giving
> little weight to the totality of available data which in the case of
> carvedilol should lead to a marked decrease in the false positive
> rate.
>
> It is up to the committee to determine whether the balance of concern
> and reassurance that I think are unique to today\'s discussion is in
> favor of approval.
>
> I would be happy to take any questions the committee might have.
>
> DR. BORER: Not at this point. What we will do since this actually is a
> philosophical regulatory discussion that is handled in the questions,
> is to table that discussion until we get to that point and maybe we
> can hear the remainder of the results now and proceed with the
> sponsor\'s presentation.
>
> **CAPRICORN Trial**
>
> **Effect on Non-Fatal Events**
>
> **Henry Dargie, M.D.**
>
> DR. DARGIE: Thank you.
>
> I am now going to talk on the effect of carvedilol on non-fatal events
> in the CAPRICORN trial. We have focused so far on concordance of the
> mortality results in the CAPRICORN trial with the mortality results of
> other studies.
>
> But looking for concordance, it is important to look not only at
> mortality, but at non-fatal endpoints across the studies. For example,
> there were two co-primary endpoints in the CAPRICORN trial, the effect
> on all-cause mortality and the effect on all-cause mortality or
> cardiovascular hospitalizations.
>
> The effect on mortality was very similar to that seen in the earlier
> post-myocardial infarction trials, as Dr. Packer has said, but was the
> observed effect of carvedilol on the combined risk of death or
> cardiovascular hospitalizations similar to the earlier post-infarction
> beta-blocker trials.
>
> Well, of course, this question is difficult to answer because this
> endpoint was never assessed in early beta-blocker trials, which did
> not record the recurrence of hospitalizations as endpoints.
>
> We can attempt to answer this question, however, by looking at the
> specific events that were responsible for a cardiovascular
> hospitalization. Now, in the CAPRICORN trial, a cardiovascular
> hospitalization was defined as an admission for any cardiovascular
> reason except for an elective procedure.
>
> As you can see from this slide, which is the time to first event
> analysis of the combined endpoint, you can see many of these
> admissions were for the occurrence of a major cardiovascular event,
> such as death, myocardial infarction, worsening heart failure, cardiac
> arrhythmia, or stroke.
>
> The frequency of these admissions was generally lower in the patients
> randomized to carvedilol, however, about 30 percent of the admissions
> were not related to a major cardiovascular event, and the frequency of
> these admissions did not seem to be affected by carvedilol.
>
> I think this is important because in comparing the CAPRICORN trial and
> interpreting the results, we have to realize that previous large-scale
> trials have focused only on admissions for major cardiovascular
> events.
>
> For example, the primary and secondary endpoints prespecified in
> earlier post-infarction beta-blocker trials were the occurrence of a
> non-fatal infarction or arrhythmia, and no analysis was ever carried
> out of the effect of treatment on all cardiovascular admissions.
>
> In fact, if such an analysis had been performed, it is unlikely that
> effect of beta-blocker would have been found because in the
> beta-blocker group, there were consistent reports of increased
> frequency of heart failure, hypotension, bradycardia, et cetera, in
> most of the trials as you can see. Such events were included in the
> cardiovascular hospitalization endpoint in CAPRICORN, but not in these
> previous trials.
>
> Probably the most detailed information we have about the occurrence of
> non-fatal cardiovascular events comes from the beta-blocker heart
> attack trial. In that study, the proportion of patients reporting
> cardiovascular events other than reinfarction were similar in the
> placebo and propranolol groups with respect to heart failure, angina,
> and so on.
>
> Now, in all recent large-scale post-infarction trials of patients with
> left ventricular dysfunction, which were carried out with ACE
> inhibitors and more recently with aldesterone antagonist eplerenone,
> the prespecified endpoints that reflected the effect of treatment on
> fatal and non-fatal cardiovascular events always focused on major
> cardiovascular events, specifically, the occurrence of myocardial
> infarction, heart failure, arrhythmia, stroke, or varying combinations
> of these events.
>
> So, it is important to note, and this slide is important in that
> respect, that if the effects of carvedilol in the CAPRICORN trial were
> to be reanalyzed using any of the definitions of a cardiovascular
> endpoint used in any of these earlier trials, treatment with
> carvedilol would have been associated with a clinically and
> statistically significant result.
>
> This slide lists the various definitions of a cardiovascular event
> used in earlier trials from the most selective at the top with diffuse
> events to the most comprehensive with the largest number of events at
> the bottom.
>
> Regardless of which definition is used, carvedilol would have reduced
> the risk of a cardiovascular event by 17 to 30 percent, all with
> nominally significant p values.
>
> There is an important point to make here, is that we are not showing
> you these data to conclude that carvedilol does reduce the risk of
> these non-fatal cardiovascular events.
>
> We are showing you these data to provide a credible explanation as to
> why the expected effect on the combined risk of death or
> cardiovascular hospitalization was not met, so the committee need not
> necessarily give great weight to such failure in its deliberation of
> the persuasiveness of the mortality finding in CAPRICORN, which is the
> preeminent event.
>
> I would like now to show some additional data showing the concordance
> of the results of the CAPRICORN trial with the results of other
> post-infarction beta-blocker trials specifically with respect to
> subgroup analyses, mode of death, recurrent myocardial infarction, and
> cardiac arrhythmias.
>
> First of all the mode of death. This slide shows the prespecified
> subgroup analyses for the effect of carvedilol on all-cause mortality.
> The magnitude of the treatment effect across all subgroups was similar
> to that seen in the analysis of all randomized patients.
>
> Any trend towards a different response in a specific subgroup for
> all-cause mortality was not, in fact, confirmed when that same
> subgroup was analyzed for the combined endpoint of all-cause mortality
> or cardiovascular hospitalization.
>
> Now, of the prespecified subgroup analyses of which this is a list,
> only one of them suggested the possibility of heterogeneous effect.
> Specifically, for both of the primary endpoints, carvedilol appeared
> to have an adverse effect in patients who were in Killip class III at
> baseline.
>
> These were the patients, I stress, who had pulmonary rales more than
> halfway up on physical examination, however, there were only 65
> patients and 21 deaths in this subgroup, so one needs to interpret
> this fairly cautiously.
>
> Nevertheless, even the possibility of a finding here raised our
> interest since these patients had been systematically excluded from
> earlier post-infarction beta-blocker trials. So, we went back and
> carried out two post-hoc analyses looking for patients who were
> similarly under-represented or were shown to respond less well to
> beta-blockers in earlier post-infarction trials.
>
> This slide, in green, shows two post-hoc analyses based on the
> presence or absence of elevated cardiac enzymes and based on the
> pretreatment systolic blood pressure.
>
> For both primary endpoints, carvedilol exerted its most marked effects
> in patients who had enzymatic confirmation of their index myocardial
> infarction, and for both endpoints, the higher the baseline blood
> pressure, the better the response to carvedilol or vice versa.
>
> Again, this is interesting because patients without enzymatic
> confirmation of their index infarction and patients with lower
> systolic blood pressures were either excluded from or were shown to
> respond less well to beta-blockers in earlier post-infarction
> beta-blocker trials.
>
> So, we submit that these analyses provide additional evidence that the
> results of CAPRICORN are, in fact, similar to the results of these
> earlier beta-blocker trials.
>
> Now, let\'s move on to analysis of the mode of death. In all earlier
> post-infarction beta-blocker trials that showed a reduction in
> mortality, there was also reduction in cardiovascular death and in
> sudden death.
>
> This was also true in the COPERNICUS study, a trial of carvedilol in
> patients with left ventricular dysfunction and chronic heart failure.
>
> This slide shows the hazard ratios and corresponding 95 percent
> confidence intervals for the risk of cardiovascular death, sudden
> death, and death due to worsening heart failure in the CAPRICORN
> trial.
>
> Patients in the carvedilol group had a 25 percent lower risk of a
> cardiovascular death, a lower risk of sudden death, 26 percent lower
> risk of sudden death, and a 40 percent lower risk of a pump failure
> death. Now, each of these effects was normally significant or nearly
> so.
>
> This slide shows Kaplan-Meier curves for the analysis of time to
> sudden death. Although this was prespecified as a secondary endpoint,
> the CAPRICORN study, however, I must note, was not powered to detect a
> significant effect on any particular mode of death.
>
> Nevertheless, this effect on sudden death is also concordant with that
> seen in earlier post-infarction beta-blocker trials.
>
> The earlier post-infarction trials of beta-blockers not only showed a
> reduction in cardiovascular death and in sudden death, but they also
> showed a reduction in the risk of a non-fatal reinfarction.
>
> Indeed, in several meta-analysis of these early studies, low-term beta
> blockade reduced the risk of a non-fatal myocardial infarction by 26
> percent.
>
> This slide shows the effect of carvedilol on the risk of non-fatal
> recurrent myocardial infarction and combined with fatal events in
> order to address the issue of competing risks.
>
> Carvedilol reduced the risk of a non-fatal myocardial infarction by 41
> percent, the combined risk of a fatal or a non-fatal myocardial
> infarction by 40 percent, the combined risk of a cardiovascular death
> or a non-fatal myocardial infarction by 30 percent, and the combined
> risk of all-cause mortality or non-fatal myocardial infarction by 29
> percent.
>
> All of these effects, as you can see, were nominally significant and
> concordant with those seen in earlier post-infarction beta-blocker
> trials.
>
> I should note here that there is a question to the committee
> concerning the effect of carvedilol on the risk of recurrent non-fatal
> infarction. The question suggested there were only 45 recurrent MI\'s
> in the placebo group and 27 in the carvedilol group.
>
> This appears to be the result of some confusion because these are the
> correct numbers of recurrent infarctions only if one were to look at
> the fraction of first cardiovascular hospitalizations that were due to
> recurrent infarction, but there are many patients who had recurrent
> infarction after first being hospitalized for some other reason.
>
> So, all together there were 60 recurrent infarctions in the placebo
> group and 37 in the carvedilol group. However, none of these analyses
> account for the fact that patients who die cannot experience a
> recurrent infarction, and so the most appropriate analysis is one that
> combines mortality and recurrent infarction.
>
> This slide shows a Kaplan-Meier plot for the combined risk of death or
> recurrent myocardial infarction in the CAPRICORN trial, which I should
> note is the least biased. We are looking at the risk of recurrent
> infarction.
>
> There are 331 events represented in this analysis. The curves
> separated almost immediately following randomization and continued to
> separate for the duration of follow-up.
>
> Finally, in all earlier post-infarction beta-blocker trials, long-term
> beta blockade reduced the frequency of cardiac arrhythmias.
>
> This slide shows the effect of carvedilol in the CAPRICORN trial on
> the risk of supraventricular arrhythmias or ventricular arrhythmias
> reported as an adverse event. Carvedilol reduced the risk of any
> supraventricular arrhythmia, atrial flutter, or atrial fibrillation,
> any ventricular arrhythmia, and ventricular tachycardia or ventricular
> fibrillation, all with very small p values.
>
> This slide shows a Kaplan-Meier plot for the analysis of time to the
> first occurrence of atrial flutter or atrial fibrillation on the left,
> and the time to first occurrence of ventricular tachycardia or
> ventricular fibrillation on the right, and in both cases you can see
> the difference between placebo and carvedilol. Again, these effects
> are concordant with those seen in earlier post-infarction beta-blocker
> trials.
>
> Therefore, the effects of carvedilol in the CAPRICORN trial are not
> only very similar to the effects of other beta-blockers in other
> post-infarction trials with respect to all-cause mortality, but also
> with respect to all other reported benefits of beta-blockers in the
> clinical setting.
>
> Specifically, like other beta-blockers, carvedilol reduced the risk of
> cardiovascular death and sudden death, reduced the risk of fatal and
> non-fatal reinfarction, and reduced the risk of a clinically
> significant atrial or ventricular arrhythmias.
>
> In summary, it is also important to observe that all of these benefits
> were observed in patients already taking an ACE inhibitor and
> receiving all the other appropriate treatments for the immediate and
> long-term management of post-infarction patients.
>
> I would like now to pause there and ask if the committee has any
> questions on anything that I have presented in this section.
>
> DR. BORER: Beverly.
>
> DR. LORELL: Thank you very much. That was a very thorough summary. I
> do have one question relating to the Killip class III patients and the
> original all-cause mortality curve, slide 58, that was presented.
>
> One of the things that is very interesting to me about the survival
> curve admitting the risk of teasing apart time points in survival
> curves, which I recognize, is that to my knowledge, previous trials in
> chronic heart failure with both carvedilol and Toprol XL have not
> shown this early dip, if you will, in mortality that was seen here,
> which raises the question that there might be a little problem.
>
> Was early mortality confined to the patients who were Killip class
> III?
>
> DR. DARGIE: No.
>
> DR. LORELL: No, okay.
>
> DR. DARGIE: That wasn\'t the reason. This slide certainly has been the
> subject of some debate. We know that the curves do separate early.
> There appears to be a little blip here, as you have said, and then
> they continue to separate, but the number of deaths during this
> period, during the first 30 days, was significantly less on carvedilol
> than on placebo just at that particular point that the curves do
> appear to come together.
>
> DR. LORELL: My second question related to your Killip class III data.
> Admittedly, that was a fairly small fraction of the overall
> experience.
>
> Has that led you to think about any specific recommendations or
> thoughts as to whether, at this point in time, early post-infarction
> carvedilol should be started in patients who are Killip class III at
> least using this protocol of dosing?
>
> I would like your thoughts and maybe Dr. Packer has some thoughts on
> that.
>
> DR. DARGIE: I think it is a very important point. As you have observed
> and as I stated, the numbers in this classification were very small,
> but reminding ourselves that these are patients who have rales more or
> less all over their chest.
>
> The question is how does that reconcile with the requirement in the
> protocol that the patients were to be clinically stable. I suppose
> that one could also address that issue to anyone other than in Killip
> class I, because in Killip class II, there were 600 patients or so
> who, in fact, experienced the benefit.
>
> I think one would have to regard that event, that adverse trend as a
> safety signal and that in the management of the patient with heart
> failure either post-infarction or chronic heart failure, one would
> want those patients to be clinically stable, would include absence of
> evidence of fluid retention, so I interpret that as a signal for a
> greater emphasis on that approach, but I don\'t think it negates the
> use of carvedilol in the post-infarction period provided the patients
> correspond to those requirements.
>
> DR. PACKER: Bev, I just wanted to clarify a point that you made about
> the similarity or no similarity between this curve and COPERNICUS. We
> truly looked at these curves, as you might imagine, very carefully,
> and to non-statisticians, I am not certain what the curves separating
> and coming together and separating mean.
>
> We have been told by statisticians that there is a certain amount of
> wobble that occurs in curves and that we shouldn\'t make too much out
> of these things. Having said that, in the first month in CAPRICORN,
> there were 33 deaths in the placebo group and 19 deaths in the
> carvedilol group. That is the first month after randomization.
>
> The other thing that is worthwhile looking at, I do this only for
> entertainment purposes. If you look at this curve in CAPRICORN, and
> can we have the corresponding survival curve for COPERNICUS. It\'s the
> survival curve for COPERNICUS.
>
> Look at the early separation. It comes together at about, oh, three
> four months, and then it separates again. C3. We haven\'t blown up
> COPERNICUS in a similar way, but I think you will get the impression.
>
> DR. BORER: While we are waiting for the slide, Bob, did you have a
> comment to make about this particular issue?
>
> DR. TEMPLE: Yes. I am sorry I missed the first few minutes of this,
> but these patients were randomized on an average of 10 days after
> their infarct. That is quite different from most of the other
> post-infarction trials, which were later, BHAT and timolol, I think
> you had to be 25 days or something like that.
>
> It reminds me that in acute studies like ISIS I, there was some early
> damage in patients especially those who got low blood pressure, so I
> wonder if you want to comment on whether the earlier nature of it
> might have been disadvantageous to some of the patients.
>
> DR. DARGIE: That really\--
>
> DR. LORELL: Before you answer Dr. Temple\'s question, I actually
> think, Dr. Packer, your comment about the very early mortality is
> quite helpful, at least to me, because I think one of the really
> different important points of this trial is can you give a
> beta-blocker early post-infarction in people with very depressed
> ejection fraction, many of whom have clinical heart failure.
>
> So, I think knowing what that signal is in the first month, the first
> 30 days after starting it, mortality is very important.
>
> DR. PACKER: I only put up this slide because the committee has asked
> the question to try to compare mentally the curves with COPERNICUS and
> the curves with CAPRICORN, so I just want to show you that although
> the scale here is different, and I need to emphasize that, there is an
> early separation in COPERNICUS that comes together at three months and
> then separates again.
>
> We have done extensive analyses in the first month and two months of
> therapy in COPERNICUS, and the difference in mortality seen in
> CAPRICORN is exactly superimposable in what is seen in COPERNICUS in
> the first month, and I don\'t know why the curves come together at
> three months and separate. I just wanted to show you the parallelism.
>
> DR. TEMPLE: If I could just add to my question. With ISIS I, we
> analyzed the response in relation to initial blood pressure, and
> although there was considerable debate about noodling with subsets,
> people whose blood pressure was initially low clearly did fairly badly
> in that trial.
>
> It makes you wonder whether there are some people who are more
> vulnerable to early beta blockade than others, and perhaps that is
> what you are picking up in this relatively sick population.
>
> DR. DARGIE: I am sure that must be correct. We did show in the
> subsequent analysis that the lower the blood pressure, the effect of
> carvedilol was less, but just to stress that since we consider the
> most important outcome here to be mortality, the mortality during that
> early period was not in any way increased on carvedilol, indeed, quite
> the opposite.
>
> In fact, if we combine that with important other events arguably,
> recurrent myocardial infarction in that period, there is still also
> that very clear, even clearer separation of the curves at an early
> stage.
>
> So, I don\'t think insofar as these major events are concerned, that
> this early administration addressed the outcome, quite the opposite.
>
> DR. BORER: Steve.
>
> DR. NISSEN: Could you put up slide 105, please.
>
> This is probably more of a rhetorical question than a question, but
> these data here were available to the Steering Committee when they
> redesigned the trial. They knew what the precedents were for choice of
> endpoints, and yet they didn\'t choose those endpoints.
>
> I think it is important that we understand that, that they chose a
> different set of endpoints, yet, these data were in the public domain,
> all but I think EPHESUS were in the public domain, and so just so we
> have the record straight, you guys could have chosen this group of
> endpoints or any constellation of them when you redesigned the trial,
> but you didn\'t do so.
>
> You need not respond unless you want to, to that maybe rhetorical
> question.
>
> If I may continue and then I will yield, unless you want to say
> something.
>
> DR. FLEMING: Before you do, I had a similar thought. It is easy after
> the fact to say, well, these other endpoints are the ones that
> obviously matter the most and look at how significant we would expect,
> but why did you not consider these?
>
> DR. DARGIE: Well, it is certainly very salutary. I mean had we chosen
> death and MI, then perhaps we wouldn\'t be having this discussion,
> however, I think I should just go through the process of why we chose
> that particular endpoint for cardiovascular hospitalizations.
>
> If I could have backup slide D42. This is our way of summarizing
> exactly why we chose that endpoint for cardiovascular hospitalization.
> Now, the original protocol didn\'t pay a huge amount of attention to
> the definition of a cardiovascular hospitalization because it was
> originally a secondary endpoint.
>
> The Steering Committee, and I as the chairman of it, assigned the
> responsibility for defining the cardiovascular hospitalization, what a
> cardiovascular hospitalization was to an Endpoint Committee. Dr.
> Jonathan Sackner-Bernstein here, who is a member, is here if there are
> any supplementary questions.
>
> Now, our Endpoint Committee defined cardiovascular hospitalization, I
> am sure you will agree, in a very broad and strict way, which was a
> hospitalization for which there was no definite known cardiovascular
> cause, and it didn\'t target or specify components of that, that
> previously weren\'t or thought might be influenced by beta blockade.
> You may consider that to be a tactical problem.
>
> That is how the Endpoint Committee defined cardiovascular
> hospitalizations, which is not an unreasonable definition for
> something which is a cardiovascular hospitalization.
>
> The further issue was at the time of changing the primary endpoint, I
> suppose there was another opportunity at that point to make a further
> change in the endpoint in order to perhaps better characterize what
> the effect of carvedilol was doing in this population.
>
> But I have to tell you quite honestly and openly, at the time the
> Steering Committee and I were reluctant to make too many changes. We
> had already made a significant change in the primary endpoint, which
> Dr. Fleming and others have alluded to, is a relatively unusual thing
> to do and one that is only done for the most compelling of reasons,
> which we have discussed.
>
> So, when we changed the primary endpoint, and we simply elevated the
> secondary endpoint, we were reluctant to change the definition of that
> endpoint. We stuck with it. That is the history of the endpoint.
>
> DR. NISSEN: If I may continue, I wonder if you could put up slide 109.
> I just had a question. I am surprised that 300-plus of these patients
> had no increase in cardiac enzymes. I would have thought that would
> have been part of the definition of an acute myocardial infarction for
> purposes of the trial.
>
> So, now I am really confused. What I am saying is, Jeff, even if you
> have got thrombolytics, whatever you get, how do you diagnose an acute
> MI if you don\'t have elevated enzymes, I mean does that mean it was
> only diagnosed by electrocardiographic criteria? Is that what
> happened?
>
> DR. DARGIE: You and other members are fully aware that the new
> definition of myocardial infarction depends, first of all, on there
> being an elevation in enzymes, but we use the WHO definition of acute
> myocardial infarction, which was at the time the standard way of
> defining myocardial infarction, which was two out of three count.
>
> One was a typical clinical presentation, one was a typical change in
> electrocardiogram, and the third was cardiac enzymes, which of course
> by definition means that you can diagnose a myocardial infarction by
> that definition without cardiac enzymes.
>
> Of course, in the early phase of myocardial infarction, ST segment
> elevation, and so on, one obviously proceeds to treatment before
> knowledge of the cardiac enzymes, but that is an aside.
>
> But that was the definition we used, and as a result, for those
> patients entered into the trial, this number of patients were
> diagnosed without enzyme change.
>
> DR. NISSEN: I accept that, but I guess that would mean then that those
> no cardiac enzymes patients, did they all have to have ST elevation or
> could they also just have ST depression?
>
> DR. DARGIE: Good point. I am not sure. But, nevertheless, that
> wouldn\'t be necessarily the reason why it wasn\'t done. You simply
> adhere to the definition, which was the WHO one.
>
> DR. NISSEN: A final question was slide 114. Again, this is maybe more
> of a rhetorical question than a question, but to me, this is not
> discovery, this is data mining. I mean you have taken two endpoints,
> put them together, that were never prespecified, and show us a bunch
> of p values for them. I can\'t let that go unchallenged.
>
> When you are talking here about discovery today, this is not what
> discovery means. The term for this, the nomenclature is not discovery.
> It is called data mining. It just doesn\'t contribute here, to me, in
> my view, to our thinking process.
>
> DR. DARGIE: Essentially, the reason for doing this was to explain why
> the definition we used of non-fatal cardiovascular events didn\'t
> succeed, and also it demonstrates, I believe, excellent concordance
> with previous trials.
>
> We are not suggesting that this was not in any way a post-hoc trial,
> but also describes what I say happened in the trial.
>
> DR. NISSEN: But you see the label that is being asked for is for death
> and recurrent infarction, and this is the data to support that, but to
> buy this, we have to allow you to take two endpoints from a bunch of
> endpoints, put them together, and say, well, these are the two that
> worked, so that is the label we are going to give you.
>
> We will get to the discussion later, but just so we all understand how
> these things came to be.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: I have got three lines of questioning, Mr. Chairman. It
> will take a little time, but before starting them, Steve, the
> definition of infarction in the trial design on page 40 actually
> indicates that ST elevation or evolving Q would be the ECG criteria if
> enzymes weren\'t present, just on a point of clarity.
>
> My first set of questions relates to definitions and, in particular,
> the definitions of reinfarction, unstable angina, and heart failure,
> the extent to which there was concordance between the investigator
> ascertainment and the Endpoint Committee with particular emphasis on
> reinfarction because you, of course, are emphasizing it and we will be
> discussing it later, so could you clarify those definitions and the
> extent to which there was concordance with the investigator and the
> committees?
>
> DR. DARGIE: Yes, I can do that. I don\'t know whether Dr. Bernstein
> might feel that he could be in a better position to do that as a
> member of the Endpoint Committee.
>
> DR. SACKNER-BERNSTEIN: Hi. Jonathan Sackner-Bernstein from Columbia.
>
> In terms of the definitions, it is reported in the briefing document
> how we defined myocardial infarction. Unstable angina was similarly
> defined in the\--
>
> DR. ARMSTRONG: Would you just remind us what your definition of
> reinfarction was, please?
>
> DR. SACKNER-BERNSTEIN: Reinfarction was the two out of three criteria
> as has been previously cited, and in terms of the clinical
> presentation, enzymes with elevation at least two times the upper
> limit of normal, and the third criteria was the EKG changes.
>
> The EKG changes could have either been ST segment elevation or EKG
> changes with evolution including Q waves, could also have been a new
> left bundle branch block if the patient went to Angiography and an
> intervention on an acute lesion was performed.
>
> So, you needed two out of three.
>
> DR. ARMSTRONG: Sorry, the definition that I have in front of me is the
> definition of acute myocardial infarction, which was the index event.
>
> My question is what was the definition of reinfarction?
>
> DR. SACKNER-BERNSTEIN: I am sorry I wasn\'t clear. That is what I was
> just defining. Reinfarction was when a patient was hospitalized for
> more than 24 hours and met two of three of the criteria consistent
> with the WHO criteria.
>
> So, it was the clinical presentation was one of the three components,
> the increase in cardiac enzymes, a CPK greater than two times the
> upper limit of normal was the second component. The third component
> was ECG changes, which I described, either with the ST segment
> elevations or other EKG changes that included development of new Q
> waves, or also, part of that could have been a bundle branch block, a
> new bundle branch block that was associated with an acute intervention
> at that time.
>
> So, that is the definition of reinfarction. The definition of unstable
> angina was the typical ST Q wave changes along with parenteral therapy
> in a hospitalization that lasted 24 hours.
>
> DR. ARMSTRONG: And the definition of heart failure, worsening heart
> failure?
>
> DR. SACKNER-BERNSTEIN: Typical symptoms or signs of volume overload
> associated with parenteral therapy for an admission that lasted more
> than 24 hours.
>
> DR. ARMSTRONG: And the concordance between the information you
> received and your ultimate decision?
>
> DR. SACKNER-BERNSTEIN: I actually don\'t think we have that analysis
> here looking at those endpoints. So, that is something that we would
> have to perform, that analysis.
>
> DR. ARMSTRONG: Then, honing in on reinfarction, since about 75 percent
> of reinfarction that is hospitalized is within the first 72 hours,
> help us understand what the frequency of reinfarction in this
> population was after their index infarction, before they commenced
> therapy, and whether it was balanced.
>
> DR. SACKNER-BERNSTEIN: Well, the way that non-fatal events were
> adjudicated was as follows. The patient had their index MI, they were
> stabilized, they were randomized.
>
> While they were still in the hospital between randomization and before
> they went home, any non-fatal events weren\'t counted as part of this
> reinfarction and other endpoint event analysis, so that mortality was
> counted as soon as people were randomized, but these non-fatal
> cardiovascular events, particularly reinfarction, were counted, were
> adjudicated, were analyzed from the point in time when the patient
> left the hospital, because part of the definition was a
> hospitalization for an event.
>
> DR. ARMSTRONG: So, do we know or do we not know the frequency of
> reinfarction prior to commencement of study drug after the index
> infarction in this population? That is the question.
>
> DR. SACKNER-BERNSTEIN: I do not know the number or nature of
> infarctions that occurred while the patients were still in the
> hospital after being randomized, but there is a relatively small
> period of time between randomization and commencement of therapy, if
> that is the period you are trying to hone in on.
>
> DR. ARMSTRONG: Well, the day 10 was the average time to commencement
> of therapy, which is after the majority of reinfarction, which is the
> point I am honing in on.
>
> DR. DARGIE: Could Dr. Lukas comment?
>
> DR. LUKAS: I certainly understand the concerns about the time frame. I
> just wanted to point out\--which I believe it states in the briefing
> document\--that even given the time frame, 80 percent of patients were
> randomized while they were still hospitalized, so that to Jonathan\'s
> point, we cannot tell you today how many of those 80 percent of the
> patients may have had an extension of their index MI, I guess would
> really be the best way to characterize it, after they were randomized,
> before they went home.
>
> DR. ARMSTRONG: Without wanting to perseverate on this point, Mr.
> Chairman, we are going to be asked about an indication for
> reinfarction in a population whose major risk of reinfarction will
> have passed before the study drug was commenced, and I just want to be
> clear about my understanding of the population that we are looking at
> and our knowledge of the intercurrent likelihood of the event of
> interest from the time of the index infarction to the time of
> commencement of study therapy. That, for me, remains a black box.
>
> DR. LUKAS: I apologize if I misinterpreted your question, but we would
> have to go back and see if the information was available to answer
> that specifically.
>
> DR. ARMSTRONG: My second line of questioning relates to slide 107, if
> we could see that, please.
>
> I think, Dr. Dargie, when you presented this slide, you suggested that
> the only subgroup of interest to drill into, that looked like it was
> heterogenous, was the Killip III, but I was attracted to the patients
> with the inferior myocardial infarction, a rather larger sample than
> the patients in Killip class III, which impressed me as being somewhat
> to the opposite of the others.
>
> You obviously had a reason for prespecifying this subgroup. I wondered
> to what extent your examination of that subgroup led to better
> understanding of why they might have had a different response.
>
> DR. DARGIE: I think we prespecified it in order to define the
> population as clearly as possible into inferior, anterior, and others.
> As you say, there appears to be less a response in the inferior group
> than in the others.
>
> DR. PACKER: Mr. Chairman, if I could just clarify the answer on this?
>
> DR. BORER: Do you want further clarification?
>
> DR. ARMSTRONG: I would be delighted.
>
> DR. PACKER: Paul, I actually had exactly the same question that you
> did and asked further about how this, you know, what could explain
> this.
>
> The other category includes a substantial number of people with
> inferior other, inferior lateral, inferior, posterior, you know, this
> is pure inferior, the other is a hybrid category which includes many
> inferiors, so that one could, in fact, if one wanted to go back and
> look at the inferiors by pulling out the inferior combined with
> something out from the other, and if you look at the point estimate,
> my sense is that the point estimate will shift back to the left. I
> don\'t know if that helps.
>
> DR. ARMSTRONG: We have heard some discussion about hypotension as a
> potential marker in an inferior MI, issues around bradycardia, block,
> hypotension, that we are all familiar with, whether the time course
> and the events in these patients would shed any light on it, but it
> does strike me as being somewhat heterogenous with the other
> population although I recognize the confidence limits are wide.
>
> My third line of questioning. All of us who have shared your
> opportunity to enroll patients in large trials\--if you could leave
> that slide up because it\'s germane\--from Russia recognized that
> these patients are different, and you obviously were concerned about
> that because you prespecified a look at these patients.
>
> I presume, but I don\'t know, that you capped them at 600 or 30
> percent of your population, that is why there is an exact number of
> 600 from that part of the world.
>
> Could you tell us a little bit about the frequency of their events and
> their behavior as it relates to some of these issues that relate to
> surveillance, concomitant medications, and outcomes, and how
> homogeneous versus heterogenous they were?
>
> DR. DARGIE: I could just begin with a description of what went on in
> Russia and the fact that as the chairman of the Steering Committee, I
> visited a number of the countries to hold investigator meetings.
>
> I would say that the investigator meeting experience in Russia, that
> was held in Moscow, was an extremely valuable one because I was
> extremely impressed by the interest and knowledge of the investigators
> from Russia who were at that meeting.
>
> Perhaps that was one of the most interesting experiences in the trial,
> going to Russia. We, because of this issue, because again it is your
> right to prespecify, do we have concerns about it and how would it
> would be extrapolated to the rest of the world, indeed, to the U.S.
>
> We did carry out an audit in the Russian patients, and it appears that
> good clinical practice in the Russian centers was excellent. Really,
> here in this slide, one doesn\'t really see any sense of a difference.
> The confidence interval is perhaps a little bit wider, but looking at
> the same analysis for hospitalizations, we have the same effect, i.e.,
> no obvious difference between the Russian centers and elsewhere.
>
> So, I am not saying I was necessarily very surprised, but the visit to
> Russia was extremely valuable and one had the impression and
> confidence that the trial was going to be carried out okay there. That
> was backed up by our audit.
>
> DR. ARMSTRONG: Could you just\--last point\--clarify what was the
> mortality rate and the reinfarction rate amongst the Russian patients
> as opposed to the others?
>
> DR. DARGIE: I think I would have to get that number for you.
>
> DR. BORER: Henry, there is one issue that was highlighted by the FDA
> reviewer, and I would appreciate your comment about it.
>
> That is, that the time to hospitalization, to cardiovascular
> hospitalization, in the carvedilol group was shorter than the time to
> hospitalization in the comparator group, which might be
> counterintuitive.
>
> Can you discuss this possible inconsistency?
>
> DR. DARGIE: I don\'t think I can. The time to hospitalization in the
> carvedilol group was shorter than in the placebo group.
>
> DR. FORD: Can I comment?
>
> DR. BORER: Sure.
>
> DR. THROCKMORTON: I think that we are referring to something that we
> had actually sent a correction around to the committee about, Jeff. If
> you didn\'t get a chance to look at it, that was an analysis that the
> FDA conducted.
>
> We had a discussion with the sponsor about it, and I think in the
> fairness of time, I think in brief we concluded that our analysis was,
> in fact, not appropriate, we were misunderstanding a bit of it, so I
> don\'t think that is a thing that we need to really go any further on.
>
> DR. BORER: I will withdraw that question then.
>
> Marc.
>
> DR. PFEFFER: I have one point I just want to make sure I understood
> the answer to Dr. Armstrong. So, all the non-fatal events that
> occurred\--now, I am talking about after randomization\--and were not
> part of the non-fatal events, so when Dr. Lorell is concerned about
> worsening the heart failure, we are not seeing that when we are
> looking at the non-fatal events, if they occurred during the initial
> hospitalization, just a clarification.
>
> DR. SACKNER-BERNSTEIN: You have that correct. Non-fatal events that
> are included in the analyses that you are seeing and that are in the
> documents are events that occurred after discharge from the index
> hospitalization.
>
> DR. PFEFFER: And a follow-up on Dr. Armstrong, one of the differences
> across countries is the lengths of stay. In some of the countries
> where you are doing this, there is a rather protracted length of stay,
> which is just their standard of practice. They monitor patients
> longer. So, we are not seeing events during a period that I don\'t
> know.
>
> Now, there are two safety issues that came up that I didn\'t see in
> either the FDA\'s report or the sponsor\'s. One is the 30 percent of
> the people that were on a beta-blocker. So, do we have that subgroup
> the beta-blocker yes, beta-blocker no? That is one subgroup.
>
> The other subgroup I would like to see came up in the discussion today
> is a function of time of randomization. There was a wide window to
> randomize. Some people could have been randomized in the early period,
> some people in the late, so whether it be the median or tertiles of
> time to enrollment, I would like to see those as safety issues.
>
> DR. DARGIE: We do have the first of those analyses, which is just
> coming.
>
> DR. BORER: While we are waiting for that, I am going to peremptorily
> cancel the break that is listed here and we will stop a little earlier
> than is scheduled for a lunch break in the interest of keeping the
> committee together as long as we can, so that we can complete the
> deliberation as a committee because we have one non-U.S. member who
> needs to leave at a certain time.
>
> DR. PACKER: This is the analysis that was requested. This is a
> subgroup analysis based on whether patients had received an oral or an
> I.V. beta-blocker during the index MI or whether they hadn\'t. You see
> the number of patients in each group. You see the hazard ratios. They
> are almost superimposable for both co-primary endpoints, and you see
> the number of events that are analyzed in each of those subgroups in
> brackets.
>
> DR. BORER: Are there any other questions for Dr. Dargie?
>
> DR. PFEFFER: Will we get the time to randomization after lunch?
>
> DR. BORER: I am sorry, the time to randomization.
>
> DR. DARGIE: We will get that after lunch.
>
> DR. BORER: We can go on to the discussion of safety issues then. Thank
> you very much, Henry.
>
> DR. DARGIE: Thank you.
>
> **Safety and Concluding Remarks**
>
> **Milton Packer, M.D.**
>
> DR. PACKER: I would like to conclude with some brief remarks about
> safety and end with some brief concluding comments.
>
> The committee has already seen the strong concordance of the effects
> of carvedilol in the CAPRICORN trial with the effects of other
> beta-blockers in other post-infarction trials.
>
> You have seen this with respect to all-cause mortality including the
> pattern of subgroups effects, which is very parallel to that seen in
> earlier studies, the mode of death, the risk of recurrent infarction
> in cardiac arrhythmias.
>
> It therefore is appropriate to ask whether such concordance also
> exists with respect to the safety of carvedilol in the CAPRICORN
> trial.
>
> This slide lists the safety issues that were identified in earlier
> post-infarction beta-blocker trials. In these earlier studies,
> patients randomized to timolol, propranolol, or metoprolol had an
> increased risk of heart failure and pulmonary edema, hypotension and
> dizziness, bradycardia and heart block, and peripheral vascular
> symptoms.
>
> Exactly the same pattern was seen with carvedilol in the CAPRICORN
> trial. In fact, neither the sponsor nor the FDA identified any new
> safety issues with the use of carvedilol in post-infarction patients
> that had not been previously identified in earlier post-infarction
> beta-blocker trials or in earlier trials with carvedilol and heart
> failure.
>
> In addition, in the CAPRICORN trial, there were many adverse
> cardiovascular events specifically those related to worsening of the
> underlying disease, which occurred less frequently, less frequently
> with carvedilol than with placebo.
>
> In fact, if one focuses only on adverse events deemed to be serious by
> the investigator, nearly all such events were less common in patients
> randomized to carvedilol.
>
> These safety data, together with the data on non-fatal events that you
> have just heard about, strongly reinforce the concordance of the
> results of CAPRICORN with the results of earlier trials.
>
> First and foremost, we have a mortality finding of unquestioned
> clinical importance observed in the trial designed to find it, and in
> addition, we have many different dimensions of both internal
> consistency and external confirmation.
>
> The mortality finding is supported within the CAPRICORN trial by the
> effect of the drug on non-fatal events. The pattern of benefits is
> identical to that seen with other beta-blockers in the same disease
> state and specifically with carvedilol later in the same disease.
>
> I think it would be fair to say the totality of available data make it
> extremely likely that the benefits of carvedilol would be reproduced
> if it were evaluated in a confirmatory trial.
>
> But even if the committee were to agree that the mortality finding in
> the CAPRICORN trial were credible and persuasive, it might still be
> wondering why it should recommend incorporation of the results of
> CAPRICORN into current labeling for carvedilol. After all, carvedilol
> is already approved for the treatment of post-infarction patients
> albeit those with a remote history of a myocardial infarction and
> after they have developed symptoms of heart failure.
>
> Other beta-blockers are already approved for use in survivors of acute
> myocardial infarction, and these other beta-blockers could be used in
> the immediate post-infarction period, and patients could be switched
> to carvedilol if deemed appropriate when the acute phase has passed
> and heart failure has become apparent.
>
> This may all be true, but I think it would be important to remember
> that there are insufficient data to recommend the addition of any
> beta-blocker currently approved for infarct survivors to an ACE
> inhibitor or to other treatments, such as thrombolytics, aspirin, or
> lipid-lowering drugs, in patients who have left ventricular systolic
> dysfunction following an acute myocardial infarction.
>
> All beta-blockers currently approved for use in infarct survivors
> carry a contraindication for use in patients with heart failure, and
> as a result, the frequency of use of any beta-blocker in patients with
> left ventricular dysfunction following acute myocardial infarction is
> low especially outside of academic medical centers.
>
> My sense is that such use will remain low unless physicians are
> educated about the earlier administration of beta-blockers in patients
> likely to require treatment with a beta-blocker in the future.
>
> I think there is a real need to start treatment with these patients as
> early as possible, and perhaps the best opportunity that we have is
> when patients are in the hospital after they have been stabilized
> following their acute infarction, and of all the beta-blockers
> currently approved for use, I think it would be fair to say the most
> persuasive data in post-infarction patients with left ventricular
> systolic dysfunction receiving an ACE inhibitor exists for carvedilol.
>
> So, I believe based on the totality of available evidence that there
> are very good reasons, both from the point of view of strength of
> evidence and from the point of view of public health, to allow
> description of the results of the CAPRICORN trial to be incorporated
> into current labeling for carvedilol.
>
> I would be pleased to take any questions the committee might have.
>
> DR. BORER: At this point, we will limit the questions specifically to
> issues of fact about the safety. We can get into the more general
> philosophical issues a little bit later.
>
> Are there any specific questions about safety concerns for Dr. Packer?
> Beverly.
>
> DR. LORELL: Going back to the issue that Dr. Armstrong raised, I just
> want to make sure I am very clear and others on the committee may have
> this query, too.
>
> Adverse events were reported completely from the time of
> randomization?
>
> DR. PACKER: Yes.
>
> DR. LORELL: So, that the sort of black box period that Dr. Armstrong
> was referring to in terms of adjudication of endpoints, that period
> between randomization and leaving the hospital would include adverse
> events.
>
> DR. PACKER: Yes. The data that you have seen is complete from the
> point of randomization with respect to mortality and with respect to
> adverse events. The blackout period that you are referring to, maybe
> that\'s not the right term, applies only to the adjudication of
> hospitalizations that could have contributed to the combined endpoint.
>
> DR. LORELL: So, that does afford us an understanding in totality.
>
> DR. PACKER: Yes.
>
> DR. LORELL: Including very early start time.
>
> DR. PACKER: Absolutely.
>
> DR. LORELL: About risks including bradycardia, hypotension, and acute
> pulmonary edema.
>
> DR. PACKER: And we have complete data sets from the point of
> randomization for all of those.
>
> DR. LORELL: Thank you.
>
> DR. BORER: Alan.
>
> DR. HIRSCH: I have two questions for you, Dr. Packer. One, I just want
> to bore into two of the adverse effects a little more deeply because I
> do believe that beta-blockers are helpful in this class of patients in
> general from the totality of the data.
>
> The first one is bradycardia. Obviously, there is increased incidence
> when the drug is administered early in about 6 1/2 percent of the
> population. Nadir heart rates, need for pacing, major bradycardic
> episodes, can you make a comment beyond what we have seen in the
> packet?
>
> DR. PACKER: Actually, I have a little bit more information, but
> probably if you need it, we could get more information. The
> bradycardia generally resulted in a reduction in dose without the need
> to stop treatment, so the AE\'s that you see are AE\'s that were
> reported, that then led to a dose reduction, didn\'t lead to
> discontinuation of therapy if you look at the withdrawals.
>
> The withdrawals, bradycardia was not a feature that led to withdrawal
> with any imbalance between the two groups, and literally, the issue of
> bradycardia was almost absent if one looked only at serious AE\'s.
>
> DR. HIRSCH: The second question relates to a small subgroup, which may
> not surprise you from my perspective, which was the peripheral
> vascular symptoms group with beta-blockers. I keep looking at this
> small group.
>
> I presume that the peripheral vascular symptoms, usually ignored in
> these hearings, were\--well, seriously, were potentially one of three
> things. They are either a complaint of claudication, development of
> critical ischemia or potentially even amputation, not usually measured
> in a heart failure trial.
>
> The reason it comes up is because there is a signal again of an
> increase that is twofold in this group. In a global database of
> beta-blockers, which is not adverse when these drugs are administered
> in chronic disease states, patients with arterial disease are going to
> be increasingly part of these heart failure and ischemic event arenas
> in the future.
>
> So, my question is, do we know anything more about what these
> peripheral vascular events really were, my concern being that without
> defining that, there may be a small population that really is at some
> risk.
>
> DR. PACKER: We obviously could try to explore that better. I don\'t
> have any more detail other than what you have seen. We could go back
> and look at the actual descriptions. What you see here are code terms
> that get translated from what the patient says.
>
> Again, there is no evidence that these led to serious problems like
> amputation or anything like that, but what you see is really pretty
> much what I can provide information about in terms of this. We can go
> back and get the actual descriptors.
>
> DR. HIRSCH: I realize descriptors are often quite vague in these
> trials, I have participated, as well.
>
> Do we know, as well, the population with pre-existing lower extremity
> arterial disease entered into CAPRICORN?
>
> DR. LUKAS: We do have that information, but I just wanted to comment
> on your first question.
>
> In agreement with what Milton had said, among the hospitalization
> endpoints that were recorded, there were a group called Other. There
> were about 34 to 40 in each group. We went back and looked
> specifically\--it\'s backup E5, I believe it is, just to provide a
> little bit more information\--that among the others, Dr.
> Sackner-Bernstein was able to provide us more information on the
> classification.
>
> Five in the placebo group and 2 in the carvedilol group of the actual
> endpoint were related to peripheral vascular disease, and they were
> exactly what you said, claudication, one or two amputations, one of
> two fempot bypasses, et cetera. So, that is the totality of
> information that we have.
>
> Then, in terms of were these patients included, peripheral vascular
> disease was not an exclusion criteria unless they had disabling
> symptoms.
>
> DR. HIRSCH: I know it was not an exclusion criteria, but it did
> represent 2 percent of the inclusion population at 30 percent if were
> to amplify this in a more real-world setting.
>
> DR. LUKAS: Right. We will go back and look into that.
>
> DR. HIRSCH: At the end of the day, these symptoms dividing them into
> claudication or loss of leg are just as important as
> infarction/worsening angina, it is too vague.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: In the interests of clarity, as the sponsor tries to
> get some of these timing issues back to us early this afternoon, in
> their document on page 48, I have just come across a paragraph which
> states, \"It should be noted that although some patients were
> randomized and received their study medication one day following their
> qualifying infarction, patients generally were initiated on treatment
> with placebo or carvedilol more than one week following their
> qualifying event.\"
>
> So, as we try to get clarity, if you could give us the information on
> when patients were randomized relative to their index MI, and what the
> window of time was between randomization and the commencement of study
> medicine, was that, in fact, symmetrical or asymmetrical, and how did
> it play out across these issues, because I think it really is quite
> germane to some of the questions that are being addressed, so I have
> just appreciated that there is some ambivalence here in this paragraph
> that we need clarity on.
>
> DR. PACKER: Just to provide one point of clarification now, and we
> will try to get some more information, we will try to get as much
> information as we can on the precise distribution in the patient
> populations in both treatment groups from the point of index MI to the
> point of randomization.
>
> With respect to the point from the time of randomization to the
> commencement of therapy, in almost all patients, it was the same day,
> and we have some data on it, it was fractions of a day essentially,
> and it was the same in the two groups.
>
> DR. BORER: Mike.
>
> DR. ARTMAN: I am still a little confused about the issue of recurrent
> MI. As I understand it, and correct me if I am wrong, to count as a
> recurrent MI, that had to happen after hospital discharge, after your
> index MI, yet myocardial infarction was also recorded as an adverse
> event.
>
> So, what I am trying to get at I guess is back to what Paul was
> alluding to. I am trying to understand how much of this MI as an
> adverse event occurred early in that initial hospitalization.
>
> Do you have that information or can you get that for us?
>
> DR. PACKER: Yes, actually, we do have that information. We need to
> just find the slide. Do we have the early AE\'s in the first 30 days?
>
> While we are trying to find this, it is not unusual to have a
> discrepancy between an event reported as an endpoint and an event
> reported as an AE. One of them is a directed event, the other is a
> spontaneous event.
>
> It is very common in clinical trials to see discrepancies between
> those two ways of recording events at the end of the study, but it is
> a particularly relevant question in this study because of the
> \"blackout\" period, for better or for worse.
>
> Can we have slide S7.
>
> This is all adverse cardiovascular events with a frequency more than
> 1.5 percent, greater or equal to 1.5 percent during the up-titration
> phase. Let me emphasize this is from the point of randomization, there
> is no blackout period here.
>
> You can see what is happening early. Let me just direct you to MI, 28
> in the placebo group, 13 in the carvedilol group, and part of the
> up-titration phase is in hospital, part of the up-titration phase is
> post-hospital. If you would like, we can go back and see how many of
> these were actually in the hospital, but you can see the early events
> are going in the right direction, and this is from the point of
> randomization.
>
> DR. BORER: JoAnn.
>
> DR. LINDENFELD: Just a quick question about the hospitalizations. You
> can help me a little bit with this.
>
> The hospitalizations for MI clearly were more in the placebo group,
> but hospitalizations for unstable angina, chest pain or angina, and
> other cardiovascular reasons were pretty much exactly the same.
>
> Do you find that at all unusual? I know it is back and forth, but
> there is such a big difference in MI, I would sort of think that
> unstable angina and angina and chest pain would follow the MI.
>
> DR. PACKER: I personally wondered about that myself. It is interesting
> if we could have\--
>
> DR. LINDENFELD: It is table 21 in the briefing book on page 68.
>
> DR. PACKER: Let me just hold on, if I might. Could we have\--well, let
> me just summarize it instead of looking for it. JoAnn, you may
> remember a finding, a slide in Henry\'s presentation that looked at
> the frequency of angina, claudication in other trials, other
> beta-blocker trials, including angina, including, by the way, although
> it is not broken up in the slide, unstable angina.
>
> For whatever reason, in all other post-MI beta-blocker trials for
> which there are data, the frequency of angina and unstable angina is
> the same in the placebo group and in the beta-blocker group. Let me
> clarify my own thinking process here.
>
> When you look at these tables, the only thing that you are looking at
> is the proportion of patients who report an event. One is not looking
> at when these events occurred and one is not looking for how often
> they happened in an individual patient, so it is perfectly conceivable
> that a beta-blocker could be anti-anginal, and not be picked up by
> that kind of analysis.
>
> DR. BORER: In that regard, the FDA reviewer did an interesting
> analysis on page 11, because I was caught by that same observation,
> JoAnn, and it turned out it seems that the initial cardiovascular
> hospitalization, the non-fatal MI\'s tilted in favor of carvedilol by
> a margin of 18 events, and the unstable angina or angina was the other
> way by 18 events, so the two types of problems actually showed no net
> gain, but if you looked at causes for all hospitalizations rather than
> the initial hospitalization, the apparent skew was less apparent.
>
> Angina still, for whatever that is worth, was less frequent as a cause
> for hospitalization in the placebo group, but unstable angina, the
> margin narrowed a little, an MI was very much more frequent in the
> placebo group, so the net, the total cardiovascular events, if they
> are considered just as angina, unstable angina, and MI, were less
> frequent in the carvedilol group.
>
> I don\'t know if that helps very much because it is the same issue
> that Steve raised earlier, looking at smaller and smaller subgroups to
> find something, but it is interesting that if you look at all
> hospitalizations rather than the initial hospitalization, the
> intuitively inappropriate result seems less than appropriate.
>
> DR. PACKER: Can we have a backup slide just to illustrate that, I
> think it is E39. It is total number of hospitalizations E39.
>
> Jeff, this is what you are referring to?
>
> DR. BORER: Something, that shows those data, yes.
>
> DR. PACKER: Again, this is not considering which are first events, and
> Ian was just going to come to the microphone and make the point that
> sometimes in a time to event analysis, time to first event analysis, a
> minor event will trigger the Kaplan-Meier tick and suppress the
> occurrence of the event that occurs after the minor event.
>
> So, one way of trying to get information about all events is to look
> at the total number of hospitalizations for various reasons, and these
> are the total number of hospitalizations. This is, by the way, where
> the 60 and 37 came in, what we showed you earlier, and you can see all
> the others on your own.
>
> In order to make this kind of table, one has to make some arbitrary
> decisions as to what the hierarchy is. If someone comes in with an MI
> and heart failure, like which one counts more. You can see the
> arbitrary decisions that were made here. MI counted above heart
> failure, unstable angina.
>
> This is not supposed to be a clinical judgment. This is just a
> classification scheme.
>
> DR. BORER: Were there any other issues, JoAnn? Okay. Tom.
>
> DR. PICKERING: Yes, I have a question related to that actually, if you
> could leave that slide up, please.
>
> It seems that what screwed up the revised primary endpoint was the
> hospitalizations. If you compare CAPRICORN and COPERNICUS, the number
> of patients was approximately similar and the follow-up length of time
> was a little bit longer in CAPRICORN.
>
> The COPERNICUS patients were sicker, they had lower ejection fraction,
> they all had heart failure, so I would have guessed that the
> hospitalization rate would be higher. Yet, for COPERNICUS in the
> paper, you have, in the placebo group, 395 cardiovascular deaths and
> 432 hospitalizations for any reason. In CAPRICORN, you have I think
> 139 cardiovascular deaths and here you have 693 hospitalizations.
>
> There seems to be a disproportionately higher number of
> hospitalizations in CAPRICORN from what you would expect. Again, I
> wonder if this has anything to do with Russia, was Russia part of
> COPERNICUS. When I went there 20 years ago, I had the impression that
> patients actually rather liked being in the hospital because it was
> nicer than being outside.
>
> So, was the hospitalization rate higher in Russia than elsewhere?
>
> DR. PACKER: Russia, Poland, and several other countries in Eastern
> Europe participated actively in COPERNICUS. There was no heterogeneity
> of the response in those countries in a manner similar to what you saw
> in CAPRICORN. I am talking about the COPERNICUS study.
>
> Ian Ford and I were talking about this last evening. The only
> explanation that I think is credible as to why the frequency of
> hospitalizations is higher in a patient population that is earlier in
> their disease state. Again, one has to be careful because the duration
> of follow-up is different and the way these are calculated are
> somewhat different, is that when patients are further on in their
> disease state, they tend to be hospitalized for more and more
> disease-specific related reasons.
>
> Whereas, patient following an acute myocardial infarction, the
> sensitivity to bring them back in the hospital for relatively minor
> reasons, atypical chest pain, can be very, very high. One is almost
> never hospitalized for atypical chest pain when one has severe heart
> failure.
>
> I think that accounts for a big difference in what you are observing.
>
> DR. HIRSCH: Can I follow up on that? Another thing that happens is
> that we give people medications earlier in the disease state, which
> also cause hospitalization, so it is both a disease and what we do to
> patients, both things that are part of the protocol, things that
> aren\'t part of the protocol.
>
> Are early hospitalizations again different? Have you broken this up by
> the first, one week, two weeks between the two groups? I haven\'t seen
> that data.
>
> DR. PACKER: We do have that. One moment, please.
>
> DR. HIRSCH: While you are pulling that up, you know, one of the things
> that Tom said earlier which struck me was, you know, we are really
> looking at the use of beta-blockers early in this disease state, which
> I think we believe is probably a good thing, but the question is when
> is early appropriate.
>
> The drug effects obviously, the beneficial ones, accrue over months to
> years. I think as we reach towards the discussion, the question here
> is are there signals that are beneficial from the very beginning of
> randomization or is there again this blip in dichotomy, does it really
> matter whether we start at day 1 or day 10, parallel to the
> discussions we had years ago about ACE inhibitor initiation.
>
> DR. PACKER: I am very sorry. We do have that slide. I need to go and
> find it for you, and I am afraid I didn\'t hear the second part of
> your question.
>
> DR. HIRSCH: The second part is simply to look at that data vis-a-vis
> the time course of rehospitalization, looking at that as a
> risk-benefit analysis for time of initiation of study drug.
>
> DR. PACKER: The only thing I would say is that\--and I need to perhaps
> pull up that slide\--but for issues related to, for example, recurrent
> MI, et cetera, what is seen in the first 30 days is what is seen later
> on.
>
> If you want, I can try to find that slide, but I just don\'t have my
> index right now that would allow me to do it immediately.
>
> DR. BORER: We can see it after lunch.
>
> JoAnn.
>
> DR. LINDENFELD: Milton, the thing that we are a little bit worried
> about are the events that weren\'t counted in the index
> hospitalization.
>
> Can you reassure me that the time of the index hospitalization was the
> same in the placebo and carvedilol groups?
>
> DR. PACKER: Yes, it was identical in the placebo and carvedilol
> groups. The slide that shows that, which I think I can pull up in a
> second, is D33.
>
> This is a breakdown in two ways. One is the duration of the index
> hospitalization, and the second is the number of patients who had an
> event that prolonged their index hospitalization. This was
> specifically asked for. You can see there is no signal that causes
> concern with respect to carvedilol.
>
> DR. BORER: Milton, I want to perhaps close this session on safety with
> one\--I am sorry, did you have something to add, JoAnn?
>
> DR. LINDENFELD: I would just add 17, almost 18 days, that\'s a long
> time.
>
> DR. PACKER: This was not a trial that was carried out in HMO-guided
> therapy in the United States.
>
> DR. NISSEN: It is absolutely astonishing to me, I mean almost
> unbelievable. I can\'t for the life for me understand this\--third,
> fourth day typically.
>
> DR. THROCKMORTON: Do you have the distribution?
>
> DR. PACKER: It is pretty impressive, isn\'t it.
>
> DR. NISSEN: Do you know the median?
>
> DR. PACKER: I think that\'s a mean.
>
> DR. NISSEN: If anybody has the median, we would be interested.
>
> DR. LORELL: I think it would be interesting to have, if you have it,
> you might not, the U.S. data because there clearly are profoundly
> different practices.
>
> I think many people in Eastern Europe would consider our discharges\--
>
> DR. PACKER: I know we don\'t have it broken down, but I would be very
> surprised if the U.S. data looked like this.
>
> DR. PFEFFER: To follow up on that, I just wanted to hear the reason
> that there were 83 U.S. patients, and usually, Canada outdoes the U.S.
> by a factor of 2 and 5 in Canada. Is that because it wasn\'t an
> emphasis in the trial here? I would just like to know the reason for
> that.
>
> DR. PACKER: I think it would be fair to say that the biggest emphasis
> in this trial was on Europe. The Steering Committee was primarily a
> European Steering Committee. This was really a European trial, and
> that includes Eastern Europe. The number of sites in the United States
> was very, very low.
>
> DR. BORER: Milton, if this drug were going to be made generally
> available for patients post-MI, I want to come back to the issue of
> the Killip class III patients and the titration schedule.
>
> Can we have some sense of what your thought might be about directions
> for use of the drug or limitation of use of the drug given the
> apparent problem in patients with Killip class III - obviously, a
> small number of events, not significant, but a concern that is
> biologically or clinically plausible, and a relatively rapid
> up-titration schedule of this drug compared with how it is has been
> used clinically in the past?
>
> DR. PACKER: I want to echo what Henry said because I think he said it
> very well. I think it would not be appropriate for a patient who had
> rales more than halfway up to be initiated on therapy with this drug
> even if there were no subgroup with Killip class III that went in the
> wrong direction.
>
> This is a clinical judgment, it is not a data-dependent judgment. In
> COPERNICUS, we didn\'t allow patients who had rales related to heart
> failure in the trial even though that was a very sick patient
> population. We required patients to be euvolemic.
>
> The present label for carvedilol, the present package insert which is
> approved for carvedilol clearly instructs physicians that patients
> should be euvolemic prior to initiation of therapy. I think that
> applies very strongly in this sense.
>
> I do not think that patients who have pulmonary Killip class III
> pulmonary rales, I think they should be diuresed or treated in
> whatever way is needed to stabilize them and then considered for
> long-term therapy.
>
> DR. BORER: If there are no other questions about safety, we will break
> now for lunch and come back exactly at 12 o\'clock, which is 45
> minutes from now.
>
> \[Whereupon, at 11:16 a.m., the proceedings were recessed, to be
> resumed at 12:00 Noon.\]
>
> AFTERNOON PROCEEDINGS
>
> \[12:06 p.m.\]
>
> DR. BORER: We are six minutes over our limit here. We are never going
> to stay on schedule if we lose six minutes.
>
> DR. LUKAS: Dr. Borer, I have three answers for you.
>
> DR. BORER: Dr. Lukas, why don\'t you go ahead and present those pieces
> of data, and then we will move on.
>
> DR. LUKAS: Thank you. There may be a few things that were asked for
> that we were not able to provide in the time since we broke up the
> meeting.
>
> The first thing I would just like to tell you is that in terms of the
> duration of the index MI, what you did see were the mean values of 18
> and 17. The median values were 14 in the placebo group, 15 days in the
> carvedilol group. The standard deviations were comparable. They were
> 14 in the placebo group and 11 in the carvedilol group.
>
> So, there were clearly some outliers which contributed to this. What I
> don\'t have is a histogram showing how many people had a normal length
> of stay and how many had an extended length of stay, but we can
> certainly provide that to the Division.
>
> The second thing that I have an answer for is Dr. Lindenfeld\'s
> earlier question about how many people had the relatively short
> exposure to the trial medication after the amendment.
>
> In the placebo group, it was less than 12 percent of patients who had
> a follow-up that was 42 days or less, so that is as exact as I can get
> right now. So, on the order of 10 percent of patients were limited to
> 1-month follow-up.
>
> For the 6-month follow-up, we have 9 percent in the placebo group and
> 9 percent in the carvedilol group. So, in the middle there is the
> 3-month data that you were asking for, so about 10 percent of patients
> were limited to a follow-up of about 3 months.
>
> The only last piece of information regarding the time from index MI to
> the date of randomization, 35 percent of the placebo patients, 39
> percent of the carvedilol patients were randomized between day 1 and
> day 7 after their MI, with 46 percent of placebo, 42 percent of
> carvedilol randomized in the second week, day 8 to day 14, and the
> remainder randomized between day 15 and day 21 in the groups.
>
> The only other thing we want to ask Dr. Borer is Dr. Dargie has one
> thing he would like to share with the committee related to the DSMB
> before you reconvene, if that is all right.
>
> DR. BORER: Sure.
>
> DR. DARGIE: Thank you, Dr. Borer. The question of the letter from the
> DSMB was raised and I wasn\'t certain whether I had it with me, but I
> did. Although I can\'t distribute it because it hasn\'t been made
> public, I would like to read the essential paragraph, which I think
> will help.
>
> There was considerable concern with the implications of the
> beta-blocking trials, such as CIBIS II and MERIT-Heart Failure, both
> because of the ethical issue of giving placebo rather than a
> beta-blocker to patients with heart failure, but also because of the
> possibility that investigators would be less likely to recruit
> patients and more likely to discontinue trial therapy.
>
> The committee noted the relatively slow rate of recruitment, the low
> event rate, and the somewhat higher than anticipated discontinuation
> rate. It seemed most unlikely that the target number of events, 630
> all-cause deaths, would be reached within a reasonable period of time.
> It therefore suggested that the Steering Committee should consider
> making the first secondary endpoint all-cause death and cardiac
> hospitalization a co-primary endpoint.
>
> Thank you.
>
> DR. BORER: Thank you very much.
>
> DR. PACKER: Essentially, I think Tom\'s point on this issue was that
> the Steering Committee could have, in fact, allowed the trial to
> continue, and not only allow it, but perhaps even encourage or even
> mandated the use of open-label beta-blockers when people developed
> heart failure, essentially, therefore, in some ways converting the
> trial from what it was designed to be, which was a placebo-controlled
> trial of carvedilol post-MI, to an early versus late intervention
> trial.
>
> I think that was the point that Tom was trying to make, and I think it
> is clear that the investigators didn\'t do that because that wasn\'t
> the trial that they had, in fact, envisioned doing, that the trial
> they envisioned doing was a post-MI, placebo versus carvedilol, not an
> immediate versus late intervention.
>
> DR. NISSEN: I would have phrased it a little differently. I would say
> that it would become a committed early beta-blocker versus usual care,
> because what happened was when those other trials became available, it
> became usual care to give a beta-blocker for heart failure, so the
> test would have been to giving beta-blockers before heart failure had
> occurred, to waiting until it occurred and then starting
> beta-blockers.
>
> DR. PACKER: I totally agree. I just wanted to make the point that that
> is a different trial than the one that was envisioned, and it was a
> trial given the fact that the treatment effect would be smaller, would
> be a much larger study in the trial that was already having
> considerable difficulties.
>
> DR. FLEMING: It has been stated, but it might be worthy of being
> reiterated one more time. A clinical trial should be designed to
> evaluate an experimental intervention against a standard of care where
> the control regimen is delivered in a way that is within a range of
> what would be an ethical acceptable standard of care.
>
> If the Data Monitoring Committee or an IRB or anybody else that has
> oversight responsibility for a trial at its initiation or during its
> conduct has serious ethical concerns, then, it is, in fact, their
> responsibility, and it would be the Data Monitoring Committee\'s
> responsibility, to note such and make recommendations.
>
> On my part at least, there is no concern about how this process was
> carried out in that regard. The issue is does that require a change in
> the primary endpoint and was it the Data Monitoring Committee\'s
> responsibility to initiate such a change.
>
> It may be the sponsor\'s or the Steering Committee\'s perspective that
> if standard of care does, in fact, require sufficiently early access
> to beta-blockers, that it is not plausible to achieve the targeted
> reduction in mortality, it is then within their purview to determine
> whether or not mortality could remain as the primary endpoint.
>
> The study was designed, by my calculation, for a 23 percent reduction
> in mortality by the sponsor\'s indication of 20 percent reduction, and
> what I am perplexed about is it seems to me, at this point, the
> sponsor is still of the perspective that it is not only plausible to
> achieve a 23 percent reduction, I think they are claiming they have
> established such a reduction, hence, it seems difficult for me to
> understand why, at mid-course in the study, they backed away from that
> as being something they thought they could achieve. That is the
> concern.
>
> DR. HIRSCH: Let me speak to that with a contrary view, Tom, and this
> idea that you get one trial result, whether it is CIBIS or MERIT, and
> you have to immediately adjust because the standard of care instantly
> changed I think is problematic, whereas, we are always obliged to make
> sure we change our trial design in response to clear, unambiguous
> data, there is this moral obligation.
>
> When you have a multi-center trial in many countries, there are
> problems that arise when you immediately change trial design because
> you assume the standard of care is instantly changed in every country.
> Sometimes it is best to stick to one\'s guns with a trial design that
> is ideal and to prove the point more unambiguously as one originally
> had designed the trial.
>
> I have one more question, though, if I can, before we move on.
>
> You presented the data for time from the index event to randomization
> and I appreciate that. I was one of the members that asked for that.
>
> Do we have efficacy and safety broken down again in tertiles by those
> times, one week, two weeks, three weeks, to know whether there is
> equal benefit and risk?
>
> DR. PACKER: No, but obviously, that could be done.
>
> One last comment. I think this trial, this post-MI beta-blocker trial
> is a lot closer to present standard of care than any previous post-MI
> beta-blocker trial, and that is a very important point because if one
> is talking about bringing this up to current standard of care, this is
> a lot closer than anything that exists in the past.
>
> Second, although the mortality effect of 23 percent was an observation
> in this trial, Tom, it is not clear that would have, in fact, been the
> result if this trial had continued all the way and there had been
> large-scale use of open-label therapy.
>
> DR. FLEMING: And, in fact, because you are right about that, there is
> a lot of uncertainty as to whether this agent should be approved
> because we don\'t know if this had been carried out to its proper
> numbers of events, would we still see what we are seeing now. You are
> right, Milt.
>
> DR. BORER: JoAnn.
>
> DR. LINDENFELD: Maybe my numbers are wrong, I did this quickly, but I
> am still bothered by the endpoints in this, what has been called
> blinded phase, this hospitalization phase, because as Paul said, we
> would expect three-quarters of MI\'s to occur early.
>
> So, there were 60 MI\'s that were counted after the hospitalization.
> That would mean that we ought to have seen a total of 240, and yet in
> that early in-hospital period, there were only 2 percent or about 18,
> so clearly, there was a huge discrepancy in the MI\'s that were picked
> up in the hospitalization, I mean as adverse events.
>
> DR. PACKER: Let me just emphasize, if I remember what Paul said, I
> think the point that Paul made was that a substantial number of
> reinfarctions occurred within the first 72 hours of the initial MI at
> periods of time that was not even part of this trial.
>
> This is not a blackout issue. This is the fact that the patients were
> randomized on the average of 10 days later, so that the largest period
> of reinfarction, the first 72 hours was never even studied. It was
> pre-randomization, it wasn\'t even part of the trial, so the trial
> missed its greatest opportunity to have an impact on reinfarction
> because it didn\'t start therapy in the first 24 hours.
>
> DR. LINDENFELD: Right. I overestimated, but 35 percent were randomized
> day 1 to 7, so that is still a fair number of patients in that 72-hour
> time period.
>
> **Committee Discussion and Review**
>
> DR. BORER: I am going to set a couple of ground rules here as we enter
> the committee discussion. First, is that at 1 o\'clock we are going to
> take a pause of public comment if there is any.
>
> Second, is that there is a great temptation when an issue as important
> as the one raised by this supplemental NDA comes up, there is great
> temptation to try to define rules for dealing with this kind of
> situation.
>
> That is not what we are here for today. Today, we are here to
> determine whether this supplemental NDA in the opinion of this
> committee is approvable, to give advice to the FDA.
>
> The questions are written such that one might draw more far-reaching
> conclusions and that may be reasonable, but we are not going to spend
> a great deal of time discussing those philosophical issues today and I
> would strongly suggest, because they are so important, if the FDA
> wants the opinion of this committee about those issues in a really
> comprehensive fashion, that we schedule a workshop meeting as we have
> on some other issues in the past.
>
> DR. THROCKMORTON: Jeff, before we leave that\--
>
> DR. BORER: We haven\'t left it yet, but go ahead.
>
> DR. THROCKMORTON: We do need some of that discussion today.
>
> DR. BORER: We will, we will get it. I will get to that. I am concerned
> about that in part because one of the comments that was made earlier
> today as a precedent for the current deliberation was the approval of
> losarten in a setting of prevention of renal dysfunction for an
> indication of prevention of renal dysfunction.
>
> In fact, that approval was not based on the data from the irbesarten
> trials. There were a number of data that were considered, and the
> approval was highly circumscribed and a strong statement was made by
> the committee that this should not be considered a precedent for
> approval of future drugs, that we had to consider each on its own
> merits.
>
> In any event, with that in mind, because I understand what Doug is
> saying, and I think of course he is absolutely right, these questions
> were written for a reason, and there does need to be some
> understanding of how each of the committee members thinks about these
> issues in order to understand the advice that we give when we come to
> voting for the record on Question 6.
>
> We will have some comments, but I am going to request at least at the
> outset on Questions 1, 2, 3, and 4, that we limit our comments to
> relatively succinct statements from each of the committee members and
> that we move on to the voting issues and then we can come back and
> speak more broadly if we want to or we can wait and have a really
> broad discussion at some later date.
>
> With that having been said, we will begin with discussion of the
> questions. Our committee reviewer is Marc Pfeffer, and he will take
> the lead in discussing the responses to these questions and
> particularly for some of them, I think it would be very important to
> have Tom Fleming\'s opinion because there is an important issue of
> replicability that underlies some of these issues.
>
> The Cardio-Renal Advisory Committee is asked whether an observed
> mortality difference can be a compelling finding far out of proportion
> to its place in a study\'s formal hypothesis testing.
>
> Carvedilol is indicated for the reduction of mortality and the
> reduction of hospitalization in patients with mild to moderate heart
> failure. With the results of the CAPRICORN study, the sponsor seeks to
> extend the indication for carvedilol to patients with left ventricular
> dysfunction subsequent to myocardial infarction.
>
> In CAPRICORN, 1,959 subjects with left ventricular ejection fraction
> less than or equal to I think it is 40 percent and no heart failure,
> within 21 days of myocardial infarction, were randomized to placebo or
> to carvedilol 6.25 mg/bid, titrated as tolerated to 25 mg/bid over
> several weeks, and then followed for a mean of 15 months.
>
> I would like a clarification there to start with. It was not my
> impression that the people had no heart failure, but rather that their
> heart failure had been reasonably stabilized within the
> hospitalization, so this study did include people with heart failure.
> In fact, 47 percent in one group and 49 percent in the other had heart
> failure at the time they were randomized, which I think is important
> in considering the primary question here.
>
> The primary endpoint was overall mortality, but as a result of a
> protocol amendment late in the study, there were two primary
> endpoints, time to cardiovascular hospitalization or death from any
> cause, assigned alpha of 0.045, and time to death alone, assigned
> alpha of 0.005.
>
> After a single interim analysis conducted after the change in
> endpoint, the final results were as follows, and we have the chart
> and, of course, we have seen these results several times today in the
> briefing book.
>
> Basically, the finding, as we know, was that death or cardiovascular
> hospitalization sort of tended to favor carvedilol with a hazard ratio
> of 0.92 and a p value of 0.297, whereas, death alone favored
> carvedilol with a hazard ratio of 0.77 and a p value of 0.031, neither
> coming close to the alpha that had originally been allocated.
>
> So, our first question. Studies are designed to test a formal
> hypothesis. We usually, but arbitrarily, say a study is successful if
> the null hypothesis is rejected at p less than 0.05, meaning that on
> average and without considering other internal data from this study or
> data from other studies, no more than once in 20 times, or once in 40
> times for a favorable result\--I am not sure what that is meant to
> mean\--will we be misled into believing a result that is not
> reproducible.
>
> Can you tell us what you meant by \"once in 40 times for a favorable
> result?\"
>
> DR. FLEMING: I would like to add to that.
>
> DR. TEMPLE: Going the wrong way doesn\'t count.
>
> DR. FLEMING: Right. What has traditionally evolved as the standard for
> strength of evidence for a single trial to be considered positive is a
> two-sided 0.05, but we know that the false positive error rate with a
> two-sided 0.05 is 2.5 percent. You are not going to approve an agent
> that hits two-sided 0.05 in the wrong direction.
>
> So, what we are really doing in most settings is a one-sided 0.025.
> So, what we recognize as the standard for strength of evidence of a
> positive study is something that would occur by chance alone only once
> in 40 times. That is essentially the standard.
>
> DR. BORER: So, no more than once in 20 times or once in 40 times for a
> favorable result will we be misled into believing a result that is not
> reproducible.
>
> Furthermore, to consider a finding to be compelling, we usually expect
> evidence equivalent to more than one study successful at p equals
> 0.05.
>
> Let\'s define discovery, that is our definition here, as any
> opportunity to declare a finding to be compelling outside of formal
> hypothesis testing. Discovery comes at the cost of increasing the
> false positive rate, therefore, how much are you willing to inflate
> the false positive rate in order to enable discovery?
>
> For every potential discovery one can make in a study, the risk of a
> false positive result increases. How many opportunities should a study
> have for discovery?
>
> When should a discovery be confirmed in a separate formal hypothesis
> test?
>
> Do you believe it is always possible to discover something about
> mortality, i.e., is mortality always a primary endpoint? If so, of
> what value is making it a formally tested hypothesis?
>
> Interesting questions. Marc, do you want to begin?
>
> DR. NEYLAN: Mr. Chairman, could I ask for a point of clarification?
>
> DR. BORER: Yes.
>
> DR. NEYLAN: In the early portion of this, it states that the endpoint
> was changed from overall mortality to two primary endpoints, time to
> cardiovascular hospitalization or death from any cause, and time to
> death alone.
>
> I just want a clarification. Is that indeed time to the event or are
> these the summations of those events? My understanding was that it was
> the latter, it was overall mortality and cardiovascular
> hospitalizations rather than time to.
>
> DR. BORER: We would have to look back. Tom?
>
> DR. FLEMING: It was the log-rank test, I believe, Cox regression. It
> is time to.
>
> DR. NEYLAN: It is time to, thank you.
>
> DR. TEMPLE: But that is a point that is frequently obscured. I mean
> one describes the endpoint as if it is the total number of events, but
> what is usually looked at is time to. That is probably something for
> another discussion sometime.
>
> DR. FLEMING: Yes, and there are settings where a fraction of people
> with events may be preferable to time to events. We often say if it is
> an acute setting, what I really care about is the fraction of people
> that have the event. Severe sepsis, I don\'t care if you delay time to
> death over 28 days if you are going to be dead anyway by 28 days, but
> in a longer chronic setting, time to carries a lot more relevant
> information than just percent with.
>
> While we often represent in deaths the number that died, the summary
> statistic is the relative risk and the confidence intervals and the p
> values, and those are all from time to analyses.
>
> DR. TEMPLE: I mean I must say this is for a different discussion. I am
> not sure that is necessarily optimal, and I think the disparity in
> presentation comes because it is easier for clinicians to deal with
> the total number of deaths than to look at those curves and try to
> figure out what they mean.
>
> So, we measure one thing and we translate it in something that is
> easier to understand, which is sort of funny, but another day.
>
> DR. PFEFFER: These comments have nothing to do with this study. These
> questions have nothing to do with this study.
>
> I think, in general, the sanctity of a clinical trial is just that,
> that you define things before you start and you define how you are
> going to make your test and what you are going to make these tests on,
> so, in general, I think to continue clinical trials as we know and
> love them, and to make them better and better, we need to keep the
> standards.
>
> To allow discovery would erode some of that confidence you have in a
> clinical trial. Now, the mortality issue is a very big one because a
> data safety monitoring committee and now that we have more and more
> trials comparing active therapies, looking at combined endpoints, data
> safety monitoring committees in general are saying we will monitor
> mortality even if your endpoint is the combination of four different
> things.
>
> So, I think we have to be cognizant of monitoring plans before studies
> start, asking what the Data Safety Committee said they would monitor,
> and if they said they are monitoring mortality, then, we do have to
> use that because they have the authority to call a halt to a trial if
> they reach some prespecified limits, some of which Tom has very
> importantly defined.
>
> So, I think it is very important to keep trials within the confines. I
> also believe trials have to have some breathing room. A chronic study
> that will go over the course of five years is going to run up against
> changes in the outside world, and that is what you have leadership
> for.
>
> Leadership has to be able to work with that and make an adjustment as
> needed, but make an adjustment as needed that doesn\'t hurt the
> integrity of the trial.
>
> DR. BORER: Let me go to Tom Fleming next and then we will go back
> around the table, and maybe you can make specific comments about the
> specific questions here in the context of your remarks, Tom.
>
> DR. FLEMING: Yes, I think maybe there are two or three main issues
> within this first question that I wanted to address. Milt Packer said
> something that I would like to reinforce. I think he said, in
> principle, what we would like to do is work in a way that we don\'t
> inflate the false positive error rate, and I would endorse that, that
> in principle, we should be doing the best we can in design,
> conducting, analyzing, and interpreting data in a way to try to
> maintain the integrity of the study, both false positive and false
> negative error rates should be controlled.
>
> So, the standard for strength of evidence of a single positive study
> is a 2.5 percent false positive error rate, and typically, we allocate
> alpha to the primary endpoint and say if we achieve that, the study is
> positive.
>
> Does that leave some room for judgment? Absolutely. Statistical
> measures should be guidelines and obviously, they don\'t make
> decisions about whether a study is positive or negative solely on
> whether you achieve that statistical strength of evidence.
>
> There has to be judgment, but that judgment has to be very carefully
> implemented in a way to maintain these error rates. What that means, I
> believe, is that we should have prespecified in the trial, not just
> the primary endpoint and the primary analysis of that endpoint, but
> what would be the key, most important supportive results, so that the
> study is largely confirmatory even though there is an exploratory
> element, any trial, it is important to distinguish the confirmatory
> element from the exploratory element, but that cannot be perfectly
> done in any setting, even in the best planned trial.
>
> So, we have to use judgment. Secondary endpoints clearly have to be
> taken into account and especially those that are profoundly important.
> Survival clearly comes to mind as the classic example. Debilitating
> stroke might be another good example of a profoundly important
> endpoint.
>
> Generally, I would like to see those as the primary, but there are
> reasons that are legitimate in cases not to make them the primary. If
> you don\'t make them the primary, clearly, they should influence your
> judgment.
>
> Now, my belief is there are settings when you can achieve a conclusion
> of positivity on a secondary endpoint such as mortality, but it has to
> be done extremely cautiously. Now, doesn\'t that inflate your error
> rate? I would say no, not necessarily if you are doing this in a very
> careful manner in the following sense.
>
> If I have a non-mortality primary endpoint, and mortality looks
> unfavorable, I am not going to call that study positive even if I hit
> significance in my primary endpoint. So, I am not spending all of my
> alpha on the primary in that sense. I am using judgment that could go
> in either way.
>
> As I look at the totality of data, there are settings where I may hit
> my primary, but judgment says totality of evidence on benefit to risk
> does not provide conclusive evidence that I have established benefit.
>
> In the same sense, if you have not achieved significance on the
> primary endpoint, I believe that there are settings where you could,
> in looking at the totality of the data, judge that favorable benefit
> to risk has been conclusively established. At the same time, I think
> this has to be done extremely cautiously.
>
> Now, the last part of this question relates to the specifics of
> mortality itself. I have already mentioned, I think, even if mortality
> isn\'t a primary endpoint, I think it is an endpoint that does merit
> very special consideration.
>
> I would agree\--I think again Milt had said this\--that saying
> mortality automatically gets a two-sided .05, hence, 2.5 percent false
> positive error rate allocated to it, is a gross oversimplification of
> what should be the case.
>
> Generally, my own personal sense is if mortality hasn\'t been
> allocated to the primary endpoint, it is going to have to be much
> stronger evidence if it were a secondary endpoint than if it had been
> the primary endpoint.
>
> My own personal sense about this is\--again, this is just a general
> guideline\--is if it took a two-sided .05 for mortality at the primary
> for the strength of evidence of a single positive study, I am
> generally looking at a two-sided 001 to 005, i.e., at least 10-fold
> more in terms of strength of evidence if this is a secondary endpoint.
>
> Now, if I am going to be using this as the basis of judging
> positivity, that is just a gestalt that, in fact, is not always the
> case, but a general sense of what it would be in order to address the
> first issue that I mentioned, which is if we are going to go beyond
> the primary, we have to do it in a way that addresses, as Milt said,
> the goal of still maintaining the overall 2.5 percent false positive
> error rate.
>
> So, in summary, my sense is we should be maintaining the error rates.
> It does require, however, judgment in looking at benefit to risk.
> Secondary measures are important particularly those that are
> profoundly important, and it is entirely possible that mortality could
> be of such a nature that it could be a basis for concluding positivity
> of a trial, but it requires much stronger evidence than if it had been
> the identified primary endpoint.
>
> DR. THROCKMORTON: Tom, if I could, I want to ask a couple things.
>
> First, I would like you to comment just a little more and then I will
> ask sort of for other people to comment. This question was framed
> around mortality and what I heard you say was there are other things,
> and you gave a single other example of a thing that was so hard or
> debilitating I think is the word you used, that they could also
> potentially be discoveries, if you will, something so fixed that you
> might allow a finding from a single trial to form the basis of
> adequate evidence.
>
> The second part of it, the second question I had for you is regarding
> that aspect, that is, that this first question revolves around a
> single trial providing the sole basis for a decision of efficacy on a
> particularly hard endpoint.
>
> You will be asked later about other things, but were the comments that
> you made, were they directed at the trial and its sufficiency to form
> the sole basis for a decision, or were they mixed in some way or
> another?
>
> DR. FLEMING: Doug, I am delighted you asked for that clarification. I
> should have made that. I was referring to the strength of evidence
> from a study that would give this, what I call the strength of
> evidence of a single positive trial.
>
> There is a whole additional set of issues here that have to be
> considered in general - is the strength of evidence of a single
> positive study adequate for approval. Generally, we strive toward
> achieving strength of evidence of two adequate and well-controlled
> trials, and that leads to some of us saying what is 025-squared as a
> two-sided p value 001.
>
> If, and this is an if, if we said for mortality we require the
> strength of evidence of two positive trials, then, as a primary
> endpoint from a single trial, you would be talking the 005 to 001 just
> for the strength of evidence of two studies as the primary endpoint.
>
> What I was referring to in my comments, Doug, was what if mortality
> wasn\'t the primary endpoint in a trial, what would be the result you
> would need to see to judge this as a positive study, the strength of
> evidence of a single positive study, and I am saying basically, you
> are going to need, in my own heuristic judgment, an additional zero in
> front of that p value because you didn\'t designate it as the primary
> endpoint.
>
> Now, if you are saying do I need the strength of evidence of two
> studies, then, obviously, a much stronger criterion would be required.
> This is another entire discussion, and that is, for mortality for
> debilitating stroke, for profound endpoints, could something less than
> 025-squared be adequate.
>
> In my judgment, the way we proceed is frequently we would consider
> that, we would require stronger evidence for something like
> hospitalization, two positive studies, but in my experience there has
> frequently been accommodations made for mortality, so that it didn\'t
> have to have that strength of evidence. But I am glad you asked for
> this clarification because all of my initial comments related purely
> to what it would take to judge this study as meeting the standard for
> strength of evidence of a single positive study.
>
> DR. BORER: John, do you have some opinion about this?
>
> DR. NEYLAN: Sure. I would be happy to chime in on the questions if you
> so desire. Taking this from a clinical background rather than a
> statistical, I would look on the issue of discovery in a perhaps more
> narrow and slightly less regulatory definition to encompass the
> opportunity to advance understanding in science.
>
> With that definition, I would consider that discovery should not be
> constrained, but, in fact, be unbridled, but taking that a step
> further and using that as the basis for forming new regulatory
> opinion.
>
> I would agree with both of the preceding speakers, as well as Dr.
> Packer, that one would not do so at the risk of increasing the false
> positive rate, so my answer to No. 1 would be none.
>
> Then, following on what I said about the importance of discovery in
> advancing clinical understanding, certainly I would see that there
> should be as many opportunities as is practical and feasible for
> studies to make explorations, and so again I am speaking a bit more
> narrowly in my definition of discovery.
>
> For that answer, then, I don\'t set a limit, but then going to No. 3,
> when should discovery be confirmed, if you will, as a pilot
> observation, I think in most cases it should always be confirmed in
> some sort of separate analysis that is typically done as a prospective
> trial.
>
> Finally, do you believe that it is possible to discover something
> about mortality and the value of making that a formally tested
> hypothesis, and I defer to I think the very cogent arguments that Tom
> has made, that one can\'t underestimate the importance, but I draw the
> line at making this a de facto component of each trial.
>
> DR. BORER: Tom, do you have any additional thoughts about Question 1?
>
> DR. PICKERING: No, really, I would just say that if discovery is an
> unanticipated mortality finding that is going to lead to approval that
> otherwise wouldn\'t be there, I would say it should be very much the
> exception rather than the rule, and it should be judged in the light
> of the numbers involved and the plausibility as in this case.
>
> DR. BORER: Steve.
>
> DR. NISSEN: Just a couple of additions. I think Tom was implying this,
> as well, that obviously, the answer I am about to give is out of the
> context of any specific application because, you know, one of the
> things I have learned from this committee is there often is ancillary
> information available that allows us to modify up or down how much
> strength of evidence we require, and that is always changing, that is
> always different for everything that comes before the committee.
>
> There is some other precedent or something we know, and so out of
> context, I would argue that 05 is not stringent enough, and the reason
> I would argue that it is not stringent enough is that at the very
> least, I would propose that, at a minimum, if you look at another
> endpoint, at the very minimum you have got to split the alpha between
> the originally designated primary endpoint and some new endpoint.
>
> I mean I don\'t think you can go below 025 very safely because the
> minute you add a second endpoint, you have got to make a correction,
> it seems to me, statistically. But I also don\'t want to tie one on
> behind our backs and say that we are going to be a slave to
> statistics.
>
> The reason I say that is that ultimately, our job as physicians and
> regulators and everybody else is to save lives and reduce suffering,
> and sometimes that means that the rules have to be shaded a bit.
>
> So, you know, I think if we say implicit in every trial that an 05 p
> value for mortality is approvable, that is just too low a standard,
> but how much lower we are willing to go will depend a lot on the
> context, and I would argue that going below 025 is very risky just
> because it really does increase those error rates substantially.
>
> DR. BORER: Alan.
>
> DR. HIRSCH: I think most of the important points have been made, but
> just to re-caution the balance of what Dr. Pfeffer stated, that
> respecting the benefits of a pre-hoc, well-defined hypothesis is worth
> keeping in mind because it avoids, as you said earlier, Steve, the
> difficulty of discovery being data mining.
>
> So, the same thing, I don\'t know how to balance exactly which alpha
> to confer to more than one multiple hypothesis, but that caution is
> obviously always kept in play.
>
> DR. BORER: Beverly.
>
> DR. LORELL: I agree with what has been said and I also would like to
> emphasize that interpreting mortality, I think one should be very
> influenced as to whether it was a predefined hypothesis or derived
> very late after the fact.
>
> Secondly, as Steve emphasized, the context in which that observation
> is made, and that includes not only the context of whether there are
> other well done studies that are consistent and supportive, but also
> the data from within the trial as to whether other endpoints, which
> are also of great clinical importance and merit, go in the same
> direction.
>
> DR. BORER: Mike.
>
> DR. ARTMAN: I really don\'t have anything else to add other than the
> fact that as I am listening and thinking about this, I think we do
> this discovery thing a lot when we look at safety data, and when we
> are looking at safety data, sometimes there are signals, they are not
> part of formal hypothesis testing, but there is something there that
> worries us and concerns us.
>
> I would sort of think about this\--and perhaps this is all
> upside-down\--but kind of in the same say, so that yes, maybe there is
> a signal here, but I think we have to then verify that, we have to
> confirm it, and I think we have to be very rigorous in these
> standards.
>
> So, I would agree with the other members who have answered these
> questions.
>
> DR. BORER: Susanna.
>
> DR. CUNNINGHAM: I really do believe it all has been eloquently stated,
> so I will just agree.
>
> DR. THROCKMORTON: Jeff, I am going to just break off with this.
> Everybody has been talking about mortality, that is, that the only
> thing available is mortality, and that is fine. I mean obviously, you
> could make an argument that other things, or an argument has been made
> in the past that other things are less final, let\'s say, so that, in
> fact, you are in more equipoise and that you can potentially want to
> have to repeat it to minimize your risk of a false positive or drawing
> a false conclusion.
>
> Other things, stroke, something like that, are there other examples of
> things that are so fixed or irrevocable that anyone on the committee
> wanted to sort of put those forward, it is just a request for some
> help.
>
> The other thing is, I guess we are going to get to this in Question 2,
> but it seems to me that the difference between looking at safety, at
> data in safety assessments and what we are calling discovery here is
> that when we are looking in the safety, we are sort of bringing our
> own priors, if you will.
>
> In some sense, we bring to our priors the things that we see there and
> we apply that to whether or not a signal that may or may not show up
> is a relevant thing, a thing to be sort of paid attention to. I am not
> sure about that.
>
> DR. HIRSCH: Doug, just to quickly answer your question. You keep
> asking us what is like mortality. Any irreversible end organ function
> is like mortality, so stroke, which Tom mentioned, amputation, I tried
> to bring up earlier. When you have lost part of your body, that is
> irreversible, is equivalent. There are probably others.
>
> DR. BORER: Two things before you comment, Bob.
>
> With regard to the safety issue, I am not sure I could fully agree
> with what you have said, Doug. I mean I see the safety concern as
> being the potential for doing harm where we actually have
> statistically a less stringent standard because we certainly don\'t
> want to do harm as opposed to the standard for showing benefit of an
> intervention compared with not intervening where the standard might be
> different.
>
> I don\'t want to state what the standard should be in the benefit
> category yet, but I think there is a difference.
>
> DR. TEMPLE: I think you are absolutely right. We have sent drugs back
> for more work on the basis of evidence that if it were presented as
> effectiveness, would never pass muster because we feel we have no
> choice, you don\'t want to hurt people.
>
> I just have one question for everyone about all of this. It may be
> that the way of dealing with mortality findings usually involves data
> like we are going to discuss in 2 and 3, so it doesn\'t turn out to be
> a problem, but I still have a question for Tom and others.
>
> Imagine a finding that was not particularly expected and is not
> supported by other trials and things like that, and it is a 0.02. I
> take it you all feel that you could actually invite people to be in
> another placebo-controlled trial in that setting and that everybody
> would feel comfortable, the patients fully informed about the results
> would be willing to enter.
>
> I just wonder if you think that is really true.
>
> DR. BORER: Let\'s continue around the table and then we can come back
> to everyone else.
>
> DR. TEMPLE: I just want to make one point. Milton showed vesnarinone,
> and I don\'t believe he represented it entirely. There was great
> suspicion about the results of that trial, not because the numbers
> were small, the difference between treatments was almost as large as
> we are talking about here, but because there were other data that went
> the other way and there was a lot of concern about whether it was
> true.
>
> That is different, that is not the same. What would one feel if one
> really thought it was true and there were no reservations, could you
> really get people to enter this thing? It seems like a fix problem.
>
> I would just be interested in comments.
>
> DR. BORER: Paul, in your response, maybe you can incorporate an answer
> to that question.
>
> DR. ARMSTRONG: Maybe a slightly different perspective. On 1.1, my
> openness to discovery depends very much on the natural history of the
> disorder that one is evaluating, what available therapy exists.
>
> We have heard about orphan diseases and other circumstances, the risk
> of the new therapy that is under investigation, and the weighting of
> the endpoints vis-a-vis this issue of splitting alpha and how to
> handle the statistical issues that Tom so eloquently has discussed.
>
> So, my threshold under 0.12 would depend on those issues and might be
> quite liberal under selected circumstances. As it relates to No. 3,
> again, the risk of therapy, the existence of external validity, and
> the potential for disconnect as opposed to connect regarding
> surrogates and more defined endpoints would modify my thinking.
>
> Under 0.14, the answer is most certainly yes. I am involved in trying
> to understand the disconnect between a reliable surrogate and
> mortality at the moment that will probably end up here, so I would put
> those other things on the table.
>
> DR. BORER: JoAnn.
>
> DR. LINDENFELD: Again, I agree with most of what has been said. I
> would add to this p value that Tom talked about in mortality, that it
> is not just the p value, it is numbers, and Dr. Packer showed us data,
> so it is critical that it can\'t just be a p value. There have to be a
> reasonable number of events.
>
> In terms of hard endpoints, I think mortality is the one that I am
> most confident with. A p value that we might acquire in discovery
> seems to me to be larger, that is more significant, the harder it is
> to document the event.
>
> So, mortality is very easy, but as events become more difficult to
> very clearly document, that that p value has to get smaller. For
> instance, I know Alan mentioned amputation, but we had a discussion
> several years ago. Amputation is not nearly as hard an endpoint as we
> might believe.
>
> So, I am not sure I would be willing to give amputation as an
> endpoint. I think disabling stroke, though, would be an important one.
>
> DR. BORER: To cover that last point first, because you have
> specifically asked about it, Doug, I would agree that mortality is an
> overwhelmingly important endpoint and it is very difficult to argue
> about its definition, but I would be hard put in the context of an
> off-the-cuff discussion like this to give you a strong statement, a
> firm conclusion about other endpoints that might be equally important
> because as JoAnn just said, every single one of them that I can think
> of as I am sitting here is open to some interpretation.
>
> Disability depends upon the perception of the disabled person, so I
> don\'t think any other endpoint can have the weight for me that
> mortality has as an irrevocable problem, but in certain situations,
> others might depending upon how the definition was constructed.
>
> With regard to the other aspects of this specific question, just like
> everyone else, I don\'t think that it is appropriate to inflate the
> false positive rate and therefore, for endpoints in general, I don\'t
> think that the opportunities for discovery should be very wide if the
> result of discovery is to recommend approval of a drug for remediation
> of what you have discovered the problem to be.
>
> So, virtually, in every situation, what you have defined as the
> discovery should be confirmed in a separate formal hypothesis test,
> virtually every one except perhaps for mortality, and there I
> completely agree with Steve and with Tom and with everybody else
> around the table, that the standard, if the mortality benefit is to be
> discovered, that is, it comes out of a single trial and hasn\'t been
> declared the primary endpoint, then, there has to be a stronger group
> of evidences to support a belief that this finding is correct than
> merely a p value of 0.05.
>
> Having said that, I think that Beverly\'s point is very important. If
> the mortality endpoint was prespecified, well, if you expected it,
> that would be important. How important I don\'t know, I don\'t want to
> put numbers on this.
>
> If the mortality benefit was unexpected, if it wasn\'t prespecified,
> then, I would give very little weight to a p value of .05. So, with
> those things having been said, Steve, you have the last word and then
> we will move on to the next.
>
> DR. NISSEN: I wanted to directly answer Bob\'s question, which as I
> think a very tough one. I mean suppose an unexpected finding of
> reduced mortality without a lot of other supporting evidence, and an
> 0.01 level of significance were found, could you get physicians and
> patients to enroll in a trial that would be the definitive trial with
> that as a prespecified, and I think it has to be looked at on a
> case-by-case basis.
>
> There will be cases where we might agree that the statistics are not
> strong enough to support giving that label to a drug, and yet the
> definitive trial is just impossible to conduct. I hope we don\'t get
> caught in that, we probably will some day, and if we do, I think we
> are going to have to really think it through very carefully because
> the fact is it is one thing to prove something, it is another thing to
> actually be able to then conduct such a trial, and some trials are not
> conductible.
>
> DR. TEMPLE: Just one last observation. This question, quite
> appropriately, is artificially narrow. It really says you have got no
> hint from anywhere else, you have got no priors, you didn\'t mention
> it in your protocol. It is not that you thought you couldn\'t quite do
> it, you really didn\'t think it was going to happen.
>
> So, for that case, it all sounds pretty sensible, but most cases
> aren\'t like that, which is why the next two questions come up.
>
> DR. BORER: I was going to say all my answers and I think everyone\'s
> answers with regard to 1.4, would depend in part on how much
> additional information we might have from other sources about this
> drug, about other effects of this drug, et cetera, et cetera.
>
> Tom.
>
> DR. FLEMING: Yes, just briefly to add that I agree that Bob\'s
> question is a very important one that regulatory authorities,
> sponsors, and the scientific community would have to carefully
> discuss, which also I think brings us back to gee, it would be great
> to avoid getting into this situation.
>
> So, as we plan trials, thinking ahead to what it would be that we
> would like to have, because if we get in a position of having
> equivocal results, it can be very difficult to know how to proceed.
>
> It definitely would require consideration of the strength of evidence
> as to whether or not this is something that we could replicate. We can
> give examples.
>
> What comes to mind immediately to me is in my own experience, the
> 5-FU/levamisole and levamisole colon adjuvant trials that were done in
> the early 1980\'s showed survival differences for both levamisole and
> 5-FU/levamisole, and yet we started over with a completely
> confirmatory trial that took another six, seven years. Nice that we
> did, because 5-FU/levamisole was proven to be effective in a
> confirmatory way, and levamisole was proven to do nothing in that
> confirmatory trial.
>
> So, it is certainly possible to do so, but the likelihood that we can
> do so depends on how strong the results are in that first trial and
> what the global sense of uncertainty is in the clinical population
> about this intervention\'s effects.
>
> DR. BORER: Marc.
>
> DR. PFEFFER: Well, Tom is using cancer examples. It is a little
> different because those drugs were not generally available, they were
> used in protocols only. Now, we are talking about agents that are on
> the market, so it is much harder to do trials when the every-day
> physician has access to these drugs. It makes it much different.
>
> DR. TEMPLE: There is another difference. Most cancer drugs delay death
> by a month or two on a good day. Here, you are talking about death
> yes/no.
>
> DR. FLEMING: But the example I gave, granted it was cancer, but it was
> reducing death rate by a third from 50 percent down to 33 percent in a
> curative fashion, so that is pretty profound.
>
> DR. TEMPLE: Okay, I will buy that.
>
> **Open Public Hearing**
>
> DR. BORER: Let\'s go on to No. 2, but before we do that, it is 1
> o\'clock, so I want to ask if there is any comment that any member of
> the public wants to make at this meeting.
>
> \[No response.\]
>
> DR. BORER: If not, then, we will go on.
>
> **Continuation of Committee Discussion and Review**
>
> DR. BORER: I think No. 1 has generated probably the longest discussion
> we will have before we get to the vote, so let\'s go on to No. 2.
>
> Without formally specifying how we do so, and that is important,
> without formally specifying how we do so, we may be comforted or
> discomforted about a finding by other information derived from the
> study.
>
> In considering the mortality effect discovery in CAPRICORN, how do the
> following affect your confidence?
>
> The effect on cardiovascular hospitalization.
>
> Consistency of the mortality effect across prespecified groups.
>
> Consistency of the mortality effect across non-prespecified subgroups.
>
> Other secondary endpoints suggestive of a mechanism for the mortality
> effect.
>
> Marc, why don\'t you give us an answer and then we will see if there
> are any additional opinions.
>
> DR. PFEFFER: So, now the blinders are just for within the study
> information, this question, so you can\'t know about anything outside.
>
> Okay. I would say let\'s not talk about this study for a second, but
> if you were overwhelmed by the consistency of non-fatal events, that
> would help you in terms of looking at a discovery of fatal events.
>
> I would have to say in this particular study, although the trends were
> all there, it wasn\'t an overwhelming, the non-fatal endpoint, so I am
> neither comforted nor not comforted. I feel kind of neutral about the
> support from that.
>
> The consistency across the subgroups, I felt best with the additional
> one of the beta-blockers because I was very worried about a withdrawal
> of beta-blockers, and that was helpful to me to see that that was
> there. It did make me feel better.
>
> The mechanistic studies, we had more mechanistic studies presented in
> our brochure than presented here. In general, I think these are
> important, discovery, new studies, but without having the protocol,
> you have to look at a mechanistic study the same way you did the
> overall one, and all too often, clinical trials, and I don\'t know if
> that is the case here, have 16 mechanistic studies with outcomes that
> have multiple outcomes and you don\'t know what you are seeing.
>
> So, I don\'t know how to evaluate some of the echo studies that
> weren\'t presented here, but were in our booklet. It would have been
> helpful to me if there was a rigorous echo study and I knew how many
> people were randomized, they intended to be randomized, what the one
> primary endpoint was, how many people actually had the measurements.
>
> That would have been helpful to me, but what I had in the packet was
> not.
>
> DR. BORER: Let\'s go to our statistician again next and then we will
> go around the table.
>
> Tom.
>
> DR. FLEMING: Looking at supportive evidence, I try to follow the
> directions that the study team and the protocol laid out by their
> intentions, and we had co-primary endpoints and we had two secondary
> endpoints.
>
> We obviously have talked a lot about survival. Survival certainly
> shows a favorable trend, not hitting the specified strength of
> evidence, cardiovascular hospitalization, death shows a very modest
> trend, but a p value of 0.297, and the two secondary endpoints were
> 0.1 and 0.276, so the negative view of all of this is we failed on the
> two primaries, so we failed on the two secondaries.
>
> However, there certainly are some favorable sides. The secondary
> endpoints and the mortality endpoint were favorable trends and
> suffered from sample sizes or overall amount of evidence that was in
> inadequate to discern whether these trends were chance trends or
> whether they were, in fact, a true signal that we were simply unable
> to conclusively establish because of inadequate sample size.
>
> Other supportive measures, which I would have given a lot more
> credence to, in the spirit of Steve\'s earlier questions, endpoints
> such as death, MI, arrhythmias, et cetera, those actually showed more
> signal. They are certainly clinically relevant.
>
> I run into a lot more trouble, though, in understanding how to weigh
> those when they hadn\'t been specified as either primary or secondary,
> so essentially, what were some of the more interesting positive
> signals were tertiary endpoints.
>
> DR. BORER: Let\'s start from this end this time. Mike.
>
> DR. ARTMAN: I really don\'t have anything to add to that. I think that
> Marc summarized my feelings, so I have nothing to add.
>
> DR. BORER: Susanna.
>
> DR. CUNNINGHAM: The only thing I have to say is that the effect on
> hospitalization is hard to evaluate when the systems are so different,
> so that we are looking across many different countries and obviously
> very different from ours, so I don\'t really know how to read that.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: I would agree on the hospitalization and I would also
> have had greater comfort if the Killip III and the inferior MI\'s had
> been on the other side of unity.
>
> DR. LINDENFELD: I don\'t think I have anything to add to those points.
>
> DR. BORER: John.
>
> DR. NEYLAN: The mixture of internal consistency was not sufficient to
> provide comfort. I would also add the length of stay for the index
> hospitalization raises questions in my mind about applicability to
> U.S. practice.
>
> DR. BORER: Tom.
>
> DR. PICKERING: I agree. Obviously, the incorporation of
> hospitalization was a very unfortunate choice in retrospect. I was
> somewhat reassured that when the COPERNICUS criteria were used, there
> would have been, had they used the COPERNICUS criteria, there would
> have been a significant primary endpoint, I believe.
>
> DR. BORER: Steve.
>
> DR. NISSEN: For 2.1, I don\'t find the effect on cardiovascular
> hospitalization at all persuasive. As I said earlier, I just don\'t
> accept that you can post hoc pick those endpoints that went in the
> right direction and lump them all together and say that worked.
>
> So, to me, it has no effect on my thinking at all. It is almost really
> a neutral one. I do think, however, for 2.2, there appears to be
> pretty solid consistency of the mortality effect across subgroups, so
> 2.2 is reinforcing and 2.3 is reinforcing.
>
> I actually think the secondary endpoints are also actually really
> tertiary, if you can use Tom\'s language here, you know, the issue on
> sudden death and arrhythmias, and the things that one might expect
> that carvedilol would have an impact on, all seem to kind of
> consistently go in the right direction.
>
> So, I do think they are tertiary, but I do think they are reinforcing.
>
> DR. BORER: Alan.
>
> DR. HIRSCH: It is hard to add much more than what has been said, but I
> think for the cardiovascular hospitalization, it is intriguing how
> popular that has become as an added-on outcome variable, so here is
> the study where it actually hurt the study outcome.
>
> It is worth reflecting on that. It is important. We have added it to
> many, many cardiovascular trials because of both the real quality of
> life impact, as well as cost impact, but I think future steering
> committees will take heed of this.
>
> Just regarding the other things, like Paul, I always like internal
> consistency across the other prespecified, nonspecified subgroups, but
> the IMI, low blood pressure, and Killip class III groups, I found
> somewhat discomforting in the whole framework. I have nothing else to
> add for 4.
>
> DR. BORER: Beverly.
>
> DR. LORELL: Yes, I agree with what has been said about cardiovascular
> hospitalization. I think it was extremely unfortunate that it was such
> a gamisch of components.
>
> I found some mild comfort in the breakdown data about hospitalization
> for worsening heart failure in non-fatal myocardial infarction. I was
> comforted by the consistency of the mortality effect across
> prespecified subgroups and actually I differ a little in my
> interpretation of the Killip class data.
>
> To me, that data is actually supportive of consistency. It makes sense
> in what we know about giving beta-blockers in heart failure and in
> patients who have acute and still decompensated heart failure. So, I
> actually found that data reassuring.
>
> As with I think Dr. Pfeffer, I was reassured by the data breakdown
> that we saw that wasn\'t in our original pamphlet of information
> regarding the previous beta-blocker use.
>
> I thought that not so much in secondary endpoints, but actually in the
> adjudicated breakdown of causes of sudden death, and here I am going
> to bring in what I know about other heart failure trials, that it was
> reassuring that the data consistently went in the right direction for
> sudden death and death due to worsening heart failure since I think a
> huge concern raised by previous beta-blocker trials, early post-MI,
> was that there might be a risk of worsening heart failure including
> death from worsening heart failure.
>
> So, that is what I have to add.
>
> DR. BORER: I don\'t have anything major to add to what has been said.
> Just to summarize, I have some slight differences. I didn\'t find the
> effect on cardiovascular hospitalization to be particularly comforting
> because I am concerned, as Steve articulated earlier, about the
> potential for data dredging with the subanalyses that were done.
>
> On the other hand, all the subanalyses were consistent with what I
> would have expected and even the overall effect sort of tended in the
> right way, so while I wasn\'t particularly comforted, I wasn\'t
> discomforted at all and at least there was a little bit of support
> there.
>
> The consistency of mortality effect across prespecified groups was
> certainly an important point to me and I agree completely with Beverly
> about the Killip class.
>
> I would have been a little surprised to see a benefit in the Killip
> class III patients, and I think an important safety issue has been
> raised, but I am not concerned with regard to the effect of the drug
> because the Killip class III\'s dissimilarity and the inferior MI
> doesn\'t bother me quite so much either because I can\'t possibly
> understand it, and there were many, many comparisons done in that
> subgroup chart, so that one of them might go the wrong way
> unexpectedly doesn\'t bother me as much as perhaps it might.
>
> I, too, believe that the secondary or tertiary endpoints are
> supportive and I would add to that I was happy to see that the
> beta-blocker distribution, the non-protocol beta-blocker
> administration, skewed in the direction of more being given to people
> on placebo.
>
> I am sorry there is no explanation of it. It certainly can\'t be used
> as strong evidence of anything, but I would have been very unhappy if
> more beta-blocker were given to the carvedilol group than the
> non-carvedilol group.
>
> So, in general, there are some comforting findings here and some
> neutral findings, nothing particularly negative.
>
> Without formally specifying how we do so, we may be comforted or
> discomforted about a finding by information derived from other
> studies. In considering the mortality effect discovery in CAPRICORN,
> how did the following affect your confidence?
>
> We have a list here - COPERNICUS.
>
> How relevant and supportive are the COPERNICUS data for establishing a
> mortality effect on the post-MI population given the relationship
> between the two populations? The types of deaths apparently affected
> by treatment in two settings? The time course over which the effects
> on mortality were manifest? How concordant are the findings on
> cardiovascular hospitalization?
>
> Also similar questions for CHAPS.
>
> Again, Marc, maybe you can summarize a response to that.
>
> DR. PFEFFER: Now, we are broadening it and allowing prior carvedilol
> experience, not just COPERNICUS, I guess, so that reminds me of being
> on this committee when the U.S. carvedilol program was first here, the
> first time, and it is very much like the first question, because they
> found a mortality difference combining, so we are almost ignoring
> history here with this particular agent.
>
> I was not particular comforted with that until COPERNICUS, and
> COPERNICUS was a very well done trial which indicated in the syndrome
> of heart failure with LV dysfunction that the drug had benefit and
> rather profound benefit, so that is very helpful to me to now talk
> about the carvedilol experience and then as we move into the infarct
> population, I have to step back and say this had to be a very
> difficult study to do.
>
> There was a little window of opportunity of who could be studied. If
> you actually read the ACC AHA guidelines from \'99 and for the
> beta-blockers it was probably the same in the \'92 edition, there is a
> little schizophrenia there where people should be on beta-blockers,
> but not the really low risk people and not the really high risk
> people.
>
> That is what this trial was trying to do. Tom, as opposed to the
> cancer trials, and beta-blockers are out there, so physicians could
> use them, so it was really a tough niche shoehorn to put a trial in,
> and I guess maybe that is why it was difficult to do in the United
> States. I don\'t know that.
>
> Having said that, you then have the information and I think it is very
> consistent with\--I won\'t use the other beta-blocker trials until the
> next question\--I think it is very consistent with what you had with
> COPERNICUS and the carvedilol experience, that in people with an
> impaired heart, this did lead to improved outcomes.
>
> Then, if you look at the relationship of the two populations, it is
> somewhat arbitrary. Most heart failure trials have these people, after
> they raise their hand and convince their doctor that they have heart
> failure, you know, the patient two days before, they convinced their
> doctor that they had heart failure, this is the same human being.
>
> So, I think we have that distinction we make and trials have to live
> within that. The modes of death reductions appeared quite similar and
> I think the time course didn\'t particularly help me. The
> cardiovascular hospitalizations we talked about. The beta-blocker
> trials in general have difficulty, sometimes this, sometimes that, but
> mortality is clearly reduced.
>
> So, overall, I was very comforted by the prior experience. CHAPS,
> single-center, interesting observation is again a safety experience
> with even earlier use with the intravenous, so I would use that as a
> safety experience, so overall we are getting more safety information
> and we are getting efficacy information which is consistent in people
> with impaired LV function.
>
> DR. BORER: Tom.
>
> DR. FLEMING: Let me just briefly add to CHAPS. I think what we are
> getting here obviously as it relates to mortality is clearly very
> limited. We have what I think a six-month control time frame and when
> we look at CAPRICORN, the survival differences don\'t emerge until
> roughly after that time point.
>
> The relevant information here to me as I look at it is deaths, cardiac
> deaths, 4 versus 2, heart failure 7-6, MI\'s 8-5, strokes 1-1, so it
> is obviously very limited additional evidence, so the essence of what
> would be relevant external information is what Marc was referring to
> coming from COPERNICUS.
>
> DR. BORER: Let\'s start with Beverly and go back around the other way.
>
> DR. LORELL: I agree with what has been said about COPERNICUS. I would
> add that in contrast to Dr. Nissen\'s point about data dredging, as if
> one were looking for an indication for cardiovascular hospitalization,
> the separate issue of concordance of findings on cardiovascular
> hospitalization, looking at the COPERNICUS indications in comparison
> with the CAPRICORN data experience, I did find reassuring.
>
> I think it is worth mentioning that one important difference between
> the experience in COPERNICUS and CAPRICORN that takes Marc\'s comment
> one stage further is that to my knowledge, this is the first large
> prospective trial that has actually looked at patients who haven\'t
> raised their hand, without clinical symptoms or signs of the syndrome
> of heart failure and low ejection fraction that has been tested and
> shown a benefit, so in that sense I would say this is an important
> difference and may be an adjunctive piece of information.
>
> I would also say I actually found CHAPS helpful only as a safety
> experience. I thought the efficacy data is really not comparable
> because if I understood CHAPS correctly, and correct me if I am wrong,
> ACE inhibitor use was not permitted in that study, so that that study
> is really not relevant to current best practice in the United States.
>
> DR. BORER: Alan.
>
> DR. HIRSCH: Well, I found COPERNICUS and CAPRICORN to be two chapters
> in the same book and I think that how the sponsor laid these out was
> clear in that we are trying the same disease with the same
> intervention that alters the natural history in a comparable way, so I
> will just jump and say that to Item 3.1.1.3, looking at the time
> course data, I think there are implications of that, which is that
> treatment with a beta-blocker obviously must be sustained over a long
> enough period of time to accrue benefit, so assuming that we look
> favorably at these two trials as showing evidence of beta-blocker
> benefit, I think my caution, when this is translated to practice, is
> that we find ways of maintaining adherence, so that those benefits
> really are accrued in real life as they are in clinical trials. Very
> helpful, they are concordant.
>
> DR. NISSEN: Yes, this is where we really get down to the crux of it. I
> mean was this finding a bolt out of the blue, you know, something one
> just wouldn\'t have expected. I mean that is what discovery is a
> little bit all about.
>
> I would be the first one to say that the development program for
> carvedilol has been exemplary. I mean it has been really an
> outstanding one and I think that the whole advance of using
> beta-blockers in heart failure, I mean 10 years ago, none of us were
> doing it and now we are all doing it, and I think all of these trials
> that contributed to this have played a huge role in improvement in the
> standard of care for patients with cardiovascular disease, but they
> have also contributed to a comfort level with this particular drug
> carvedilol that you can give it to pretty sick people and they
> actually get better.
>
> So, I think COPERNICUS is relevant, it has the impact of what Tom and
> I were talking about earlier of beginning now to shade the
> requirements in terms of how much strength of evidence we want for a
> discovery in another trial.
>
> It begins to have a real impact on my thinking, so I consider it
> highly relevant, CHAPS perhaps a bit less relevant, but it is a second
> trial. I mean no matter how you cut it, whether it is in fact
> contemporary standard of care or not, it nominally sort of looks like
> a second trial which has some impact also on kind of lowering the
> threshold, so I think the two together have pretty significant impact
> on my thinking about how high one sets the threshold for the discovery
> of this finding in CAPRICORN.
>
> DR. BORER: Tom.
>
> DR. PICKERING: I would say this is sort of filling in the missing
> pieces of a jigsaw puzzle, that if you take all the data on
> beta-blockers post-MI in heart failure and carvedilol, that this is
> consistent with the other data, and I found COPERNICUS very reassuring
> and I guess with CHAPS, they got lucky.
>
> DR. BORER: John.
>
> DR. NEYLAN: I do find comfort, the external consistency here is very
> strong. I think the sponsor should be commended for doing a landmark
> study with COPERNICUS and CAPRICORN is certainly a logical extension
> of the development program.
>
> CHAPS is a supportive study that, by and large, is useful for its
> safety data.
>
> DR. BORER: JoAnn.
>
> DR. LINDENFELD: I agree. I think that COPERNICUS is very comforting
> here and really lowers my requirement for a p value for CAPRICORN.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: COPERNICUS is helpful to me, as well, and
> notwithstanding the erudition of my two distinguished colleagues, the
> Killip class III issue, these were sick patients in COPERNICUS and
> although I still don\'t know when beta-blocker therapy was started in
> CAPRICORN in sick patients, I am still troubled about what has
> happened and what would be reasonable expectation there.
>
> I was, in fact, looking for benefit and stretching it from COPERNICUS
> and wondering when the therapy was started.
>
> CHAPS actually reassures me on two points, since the therapy was
> started early, that both re-MI and unstable angina go in the right way
> in therapy that started within 24 hours of the index event, so I felt
> that was helpful from a timing issue.
>
> DR. BORER: Susanna.
>
> DR. CUNNINGHAM: I have really nothing extra to add except I am about
> maxed out on acute acronyms, although I guess it does make discussion
> more straightforward.
>
> DR. BORER: Mike.
>
> DR. ARTMAN: Well, I agree that COPERNICUS was supportive and
> reassuring, and the issue from COPERNICUS to me was really the time
> course, and sort of supported my interpretation of the CAPRICORN data,
> as well.
>
> It is at about three months that I think things begin to happen and
> the curves begin to diverge. It gets to this issue of timing, you
> know, do you need to start it early or not, and I think the studies
> are concordant in that the effect begins at about three months, where
> you begin to really see differences.
>
> The CHAPS study I pretty much discounted. I really saw that just as a
> pilot study that showed you it probably wouldn\'t hurt a lot of people
> if you gave them carvedilol.
>
> DR. BORER: Bob.
>
> DR. TEMPLE: The study is interesting because it is a study of two
> things that have been separated to a degree in the past. The previous
> beta-blocker post-infarction studies for the most part didn\'t study
> people with heart failure although some were included. They studied
> people who were characterized as having had a heart attack two or
> three weeks ago.
>
> COPERNICUS, of course, didn\'t study people who had a recent heart
> attack although they had a distant one. That studied people with heart
> failure. It is not so easy, I guess, to say what this is a study of.
> It is a study of people with sort of incipient heart failure who have
> also recently had a heart attack.
>
> What I am hearing people say\--I just want to confirm this because we
> have got to grapple with all of this\--is that you find COPERNICUS
> helpful at least on the aspect of the trial related to poor
> ventricular function and heart failure, but presumably not
> particularly informative with respect to people who have had a recent
> infarction because they didn\'t, although the next question may get at
> that.
>
> So, maybe I am being arbitrary and trying to break things into pieces
> that really are a continuum, but I would be interested in comments
> about that. But I take it COPERNICUS seemed supportive in a population
> of people with poor ventricular function and therefore it makes some
> sense. Is that right?
>
> DR. BORER: Since I am the one left here, I was going to agree with
> everybody about COPERNICUS, but now you have focused the question. I
> was happy to see that the benefit of carvedilol for people with heart
> failure wasn\'t lost in the CAPRICORN study.
>
> I would have expected a benefit of some sort in people with heart
> failure. Because of COPERNICUS, people who enter with severe heart
> failure were benefited, I was happy to see that there was some
> consistency about that, but COPERNICUS, by itself, wouldn\'t be
> sufficient support to cause me to say that CAPRICORN was, by itself,
> sufficient for approvability.
>
> I must say I agree with what I think that Steve and Paul were both
> saying about CHAPS. I find that more comforting than perhaps some of
> the other people on the committee found it.
>
> I think it certainly does suggest, as has been said, it does provide
> some additional safety comfort with regard to the early administration
> of the drug, but I was happy to see that for all its inadequacies as a
> definitive trial, it was small, it was a pilot study, it didn\'t give
> this, didn\'t give that, that the results of benefit in a global sense
> looked the same as the global benefits that one sees from COPERNICUS.
>
> So, forgetting for a moment about the specific issue of mortality, in
> a setting of acute myocardial infarction, I was happy to see that
> there was a second experience that suggested benefit from giving this
> drug early in the course of acute myocardial infarction.
>
> Steve.
>
> DR. NISSEN: Yes. There is also implicit in what you just asked, a
> question that I was a little surprised that you didn\'t ask in here,
> and that is the question of how much weight do we put on the prior
> knowledge from trials albeit 15 years ago and older on the use of
> beta-blockers in the post-MI setting. Oh, I see, it is coming up, I
> haven\'t seen that yet.
>
> DR. TEMPLE: It\'s all in a perfect order, you will see.
>
> DR. NISSEN: I did not read that No. 4 in that way. That is why I
> missed that. But just to answer your question, what we have coming to
> the table is we have COPERNICUS, which tells us something about the
> population who developed overt heart failure, and we also know
> something about the patients that have had a recent infarct from those
> older trials, so there is prior knowledge for those two populations
> albeit from very different sources that allow us to think about this.
>
> DR. BORER: Okay. Without formally specifying how we do so, we may be
> comforted or discomforted about a finding by information described
> from studies of related drugs.
>
> If one were to do that with post-MI use of carvedilol, would one
> include any drug with any of its pharmacological properties -
> beta-blocker, alpha-blocker, free radical scavenger, antihypertensive,
> or only drugs with all of these properties?
>
> Would one be interested in survival trials only, any trials with
> survival data, or other endpoints, as well?
>
> Are there relevant results with other drugs?
>
> Marc.
>
> DR. PFEFFER: Following the line of questioning now, we are allowed to
> go even broader, and I think this is very important especially in the
> context of discovery and the context of what could be done.
>
> So, I want to just step back for a minute. The past beta-blocker
> trials are now almost, well, they are over 20 years old, from the time
> they started, a quarter of a century. The rules have changed. The
> concomitant medications have changed, but the lessons have stood up,
> that these are good therapies in the patients that were studied, which
> in general were the lower risk patients.
>
> Discovery was made in those trials by looking within those at the risk
> groups, and it was found that even though the highest risk patients
> were excluded, the discovery was that the most benefit was seen in the
> fringe of patients at the higher risk.
>
> Now, that was not approvable, that is discovery, and medical practice
> actually was driven by that without coming through this agency,
> without a new trial, but that was always speculation, and that was
> before the ACE inhibitors, so we really didn\'t know if these findings
> would be redundant on top of an ACE inhibitor.
>
> Then, you get, during this 25-year period, the development of ACE
> inhibitors, which were used first in hypertension, but then in severe
> heart failure, and then post-MI.
>
> In the post-MI studies, there were about 30 percent of people on a
> beta-blocker, add all the studies together, those people did better
> than the others, highly selected for who got a beta-blocker, but the
> effects of the ACE inhibitor that was randomized was about the same in
> the beta-blocker or not.
>
> So, there was the beginning of some comfort in saying they are both
> producing benefits. Then, enter the beta-blockers in heart failure on
> top of an ACE inhibitor showing benefit, so we have got that type of
> picture emerging that these are two therapies that work independently
> and give additive benefits to the best that we can show within the
> realm of clinical trials.
>
> Then, that little area that was understudied is studied in this
> particular trial. Now, we can talk about how well it was studied, we
> can talk about what did they do with their endpoints, but this is the
> study, there won\'t be another, and it did show what we have been
> talking about all day. Within the alpha level, we will have to argue
> about.
>
> But I do think it is a very important piece to a very difficult puzzle
> that says the question we have with the therapy for human beings is
> not is this a good therapy or not, but can it improve upon what we are
> already doing, and that is the most difficult thing in a clinical
> trial.
>
> I found some comfort in that, and I think it falls into place.
> Somebody used the analogy of a puzzle. This piece does fit in the
> puzzle of 25 years worth of work. So, that was helpful.
>
> Would you be interested in survival trials only? Basically, if we
> agree, I think it would be very difficult to do a beta-blocker trial
> post-MI in this population. Is this one of the properties? Well, you
> know, this is where I think\--
>
> DR. BORER: Can I just add? I think the importance of that particular
> clause, 4.2, is if you are looking at other studies, would we be
> interested in survival trials only or can we look more broadly.
>
> DR. PFEFFER: Maybe you can help me. What other studies would we
> be\--in this field of beta-blockers post-MI? Give me an example.
>
> DR. BORER: Of anything post-MI.
>
> DR. PFEFFER: Of anything post-MI.
>
> DR. BORER: Studies of related drugs. There are maybe alpha-blocker
> studies, free radical scavenger studies, antihypertensive studies, any
> studies you might refer to.
>
> DR. PFEFFER: I think any other studies I might refer to out of the
> context of what is approved therapy for people as of now, I think
> would have to start from scratch and show that it is of value over and
> above what we should be doing including revascularization procedures
> and things like that, aspirin, lipid-lowering. Maybe I missed your
> question.
>
> DR. BORER: It may be the way the question is worded. I think what the
> FDA is asking here is if we have a trial, a single trial with the
> limitations that we have talked about all day, can we derive any
> comfort by looking at trials that have already been done using some
> other drug that somehow we perceive as being in some way relevant to,
> or similar to, carvedilol.
>
> Carvedilol has beta-blocking properties, alpha-blocking properties,
> free radical scavenger properties, antihypertensive effects. To gain
> comfort, can we look at studies of beta-blockers, can we look at
> studies of alpha-blockers in acute MI, free radical scavengers,
> antihypertensives in people with acute MI or any other related
> disease?
>
> DR. PFEFFER: I now understand your question, Jeff. I was answering
> this as a beta-blocker without intrinsic sympathomimetic activity.
> That was the answer I was giving.
>
> DR. THROCKMORTON: Jeff is exactly right. We are now giving you full
> flight. You have an opportunity to bring in whatever pieces you feel
> like. It is just a matter of defining of what pieces you think you can
> bring in. What I am hearing you say is that this puzzle is
> beta-blockers.
>
> DR. PFEFFER: I was only using the beta-blocker/ACE inhibitor
> experience and both experiences.
>
> DR. THROCKMORTON: So, beta-blockers and ACE inhibitors.
>
> DR. PFEFFER: Yes, ACE inhibitors and beta-blockers adding value in
> heart failure. Now, beta-blockers adding value on ACE inhibitors.
>
> DR. THROCKMORTON: How about ARB\'s?
>
> DR. PFEFFER: I was not using that at all. I think that would have to
> be proven.
>
> DR. TEMPLE: I still didn\'t understand that. Were you looking at the
> effects on beta-blockers, but noting that some of the studies, people
> were already on ACE inhibitors, as well, or were you actually looking
> at post-infarction ACE inhibitor data?
>
> DR. PFEFFER: I was using both, and I went historically that in one
> field, one started with the ACE inhibitor and added the beta-blocker,
> and the way trials were done in the other field, post-MI, you started
> with the beta-blocker, and ACE inhibitor trials were done with a
> background of beta-blocker therapy, and the results have been
> consistent.
>
> Now, this is one that tests specifically beta-blocker, I am calling it
> a beta-blocker on top of an ACE inhibitor, and gives consistent
> findings.
>
> Now, it is discomforting to me, but the sponsor didn\'t start with
> that this is a unique antioxidant. You know, if they did that, I would
> have had trouble, but that isn\'t what they were presenting today.
>
> DR. TEMPLE: I mean how many documented benefits of antioxidants do we
> actually know about?
>
> DR. BORER: We will get to that.
>
> JoAnn, why don\'t we start with you and we will go around in a totally
> different direction.
>
> DR. LINDENFELD: I, as Marc, are comforted by a number of other
> studies, ACE inhibitors with beta-blockers, in this sense. The other
> thing I think that I find comforting is that we all want to know if
> beta-blockers in the current era with all this new therapy that we do
> are important, but there isn\'t any reason to believe that they
> wouldn\'t be.
>
> There is nothing to make me think no, gosh, I don\'t think
> beta-blockers will work today, so I find all of that data and even the
> older data with beta-blockers comforting in this sense.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: I think there is some comfort in knowing some of the
> information from other trials, indeed, I failed to point out that in
> CHAPS, there was uniform reperfusion, and one of the central issues of
> the day is whether all infarcts are the same, and they are not, and
> the notion that this apparently applies to both those who did and
> didn\'t get lysis.
>
> Only about 50 percent of the population that we have been asked to
> look at received some form of reperfusion, and as Steve brought out,
> we know that over 3- or 400 of them didn\'t have an enzyme elevation,
> so the issue of heterogeny within the trial is to some extent handled
> by reassurance from some of the other trials. So, that would be my
> additional comment.
>
> DR. CUNNINGHAM: I think there is comfort from the other studies. I
> think, though, one thing I would say is there is a continuum of
> similarity, and the more similar the drugs were that were used in the
> other studies, the more comfortable I am, and the more you get out in
> the dissimilar, if they only have one property in common, then, I am
> much less comforted.
>
> So, I think if we get out to the free radical scavengers, I would be
> very uncomfortable, so there is no absolute answer.
>
> DR. BORER: Mike.
>
> DR. ARTMAN: I really don\'t have anything to add.
>
> DR. BORER: John.
>
> DR. NEYLAN: Yes.
>
> DR. BORER: Tom.
>
> DR. PICKERING: One point. We have generalized a lot from results of
> other beta-blockers that have beta-1 blockade, but not intrinsic
> sympathomimetic activity. I think if it is approved for this
> particular population, we should be cautious that the findings are not
> generalized to other beta-blockers that don\'t have the additional
> properties like the vasodilation that carvedilol appears to have.
>
> DR. BORER: Steve.
>
> DR. NISSEN: Let me just slightly disagree with JoAnn and say that in
> this contemporary era where everybody is getting reperfused, and so
> on, I mean something that I actually hear is people say, well, in the
> reperfusion era, we are not so sure beta-blockers have much to offer.
>
> So, one of the reasons why I viewed this trial as so terribly
> important is to understand whether, in the ACE inhibitor era with
> thrombolysis, statins, aspirin, and all the therapies that weren\'t
> even thought about back in the early 1980\'s, whether or not, in fact,
> there was an additional benefit.
>
> So, while the prior information is very useful, this trial obviously
> adds to our understanding, and that is why it is incremental
> information.
>
> DR. LINDENFELD: I agree with that, and you can correct me if I have
> the data wrong, but even prior to lytic therapy, half of people
> reperfused at two weeks. With lytic therapy, we agreed that there is
> not 100 percent reperfusion, so I think that difference in who really
> reperfuses is actually quite small.
>
> DR. NISSEN: Actually, at the Cleveland Clinic, everybody gets
> reperfused.
>
> DR. LINDENFELD: But that is not this trial, I mean it is not
> angioplasty.
>
> DR. NISSEN: Sorry, just had to say that.
>
> DR. LINDENFELD: This trial was thrombolytic based. But I think that
> the difference is at two weeks, in the absence of thrombolytic
> therapy, 50 percent of people are open again.
>
> DR. NISSEN: But I am talking about the myocardial salvage era.
>
> DR. LINDENFELD: Right.
>
> DR. NISSEN: In the myocardial salvage era, there is still something to
> be gained\--we are trying to ask that question\--is there still
> something to be gained by giving, you know, beta-adrenergic blocking
> agents, and it is a very important question.
>
> DR. BORER: That reminds me of 20 years ago when I was stupid enough to
> answer a question posed to me by Mason Sones on a big public panel,
> which was, \"How much does it cost to do a catheterization at New York
> Hospital,\" and when I gave a number, he said, \"Everybody should come
> to Cleveland, we do it cheaper.\"
>
> Paul, did you want to make another comment about this?
>
> DR. ARMSTRONG: I just wanted to pick up, and you may want to wait on
> this, but Tom Pickering really signaled for me an issue which I don\'t
> think we can let pass, those of us who are lumpers or splitters on
> this beta-blocker issue.
>
> I think we have accepted that ISA is off the board here, but at one
> point we talked about the special properties of carvedilol. Today, we
> have lumped it with metoprolol and with propranolol, and, in fact, the
> sponsors made a key point that it is very like propranolol.
>
> Tom has suggested that he is not prepared to extend the observations
> today to metoprolol, and I would have a different view, so I guess at
> some point we are going to have to return to that discussion.
>
> DR. BORER: Alan.
>
> DR. HIRSCH: I concur with what has been said before. I will make it
> simple.
>
> DR. BORER: Bob.
>
> DR. TEMPLE: We would certainly not lump in the sense of giving this
> claim to a drug that hadn\'t been studied, but I do want to ask about
> some of the things people have just said.
>
> Carvedilol has alpha-blocking activity in addition to beta-blocking
> activity. Why would anybody imagine that that is a good thing? There
> have been formal studies in heart failure of alpha blockers. They
> don\'t help at all.
>
> The results of drugs post-infarction, as was just shown totally, seem
> very similar perhaps if you don\'t have ISA for drugs that don\'t have
> these extra properties and drugs that do. It looks like it is the beta
> blockade that seems to be doing most of the job.
>
> So, I am not sure why everybody is so worried about it.
>
> DR. BORER: We will get to that. Hold your response to that, Steve, and
> let\'s finish up with Tom.
>
> DR. FLEMING: Just to reinforce some of the general principles here.
> Philosophically, in answering Question No. 4, I would say I would
> certainly give attention to results on studies evaluating members of
> the same class in the targeted setting that we are interested in.
>
> Under 4.2, I would find relevant, not just studies that are primarily
> focusing on survival, but any study that would provide substantial
> survival information would be relevant.
>
> Having said that, what I worry about, and I know all of us have
> thought about this, is the relevance of such information depends
> heavily on how confident we are that the other agents that are being
> studied would not have any favorable mechanisms of action that our
> specific agent in this case, carvedilol, wouldn\'t have.
>
> You would want to avoid overestimating survival benefits because other
> agents have mechanisms that carvedilol doesn\'t, and similarly, you
> would want to make sure they wouldn\'t have any unfavorable mechanisms
> that carvedilol would have that could influence survival.
>
> In my own view, this is what leads me to be thinking at least in
> focusing on members of the same class, but even within that, you are
> not fully reassured that those criteria are met.
>
> In the targeted settings, I go back to the sponsor\'s penultimate
> slide where they said there are no data on any beta-blocker currently
> in infarct survivors being provided ACE inhibitors where these people
> have had LV dysfunction following acute infection.
>
> So, we don\'t have any perfect situation here even with members of the
> same class studied in exactly this manner, so we are left with need
> for some extrapolation and yet that extrapolation in this setting
> obviously, as Milt has summarized, there is considerable experience,
> more so than we would typically have.
>
> My own sense, though, is that each of these cases have to be
> individually considered, and I am reluctant to have certain actions by
> this committee viewed as precedent-setting, and I would like to just
> thank Jeff for pointing out that the losarten example in the renal
> trial in type II diabetic renal disease that this committee had
> considered over the last year certainly shouldn\'t be viewed as a
> precedent.
>
> I certainly didn\'t look at the irbesarten data and view that to be
> particularly substantive in that decision, and I worry a little bit
> about what views will come forward in the future as this committee
> considers this specific application and I would just urge that the
> principle is indeed other experiences with sufficiently closely
> related agents studied in sufficiently closely related settings should
> be considered, but that is very much on an application-by-application
> basis in terms of how much weight that would be given.
>
> DR. BORER: Beverly.
>
> DR. LORELL: I have nothing to add to the previous comments that
> experience with this drug seems to be very congruent and to fit into a
> continuum of experience of the use of beta-blockers in heart failure,
> as well as the use of beta-blockers in the context of ACE inhibitors
> from ACE inhibitor trials where one looked retrospectively at
> beta-blocker use.
>
> I think Question 4.1 is a very important one and I think this trial in
> the context of other studies provides no data about the helpful
> negative or neutral effect of alpha blockade. I mean to my knowledge,
> there are no other large trials that have tested the addition of alpha
> blockade on top of either beta-1 selective or nonselective use in
> myocardial infarction.
>
> Similarly, I think this experience does not speak in any way, nor can
> any prior trials be used to raise conclusions about free radical
> scavenging or antihypertensive effects.
>
> So, I wanted to answer that a little more directly than others have.
>
> DR. TEMPLE: There is a big study of alpha-blocker alone.
>
> DR. LORELL: About what?
>
> DR. TEMPLE: Of an alpha-blocker alone.
>
> DR. LORELL: Yes.
>
> DR. TEMPLE: But not on a beta-blocker.
>
> DR. LORELL: To my knowledge, there is no experience whatsoever of
> adding alpha blockade to beta blockade in this setting.
>
> DR. TEMPLE: Can I mention one other thing? The timolol study actually
> had about a third of its population with acute heart failure at the
> time of the infarction although by the time they were randomized, they
> no longer were.
>
> I don\'t think anybody had ejection fractions on those people or
> anything like that, but there is some experience in a group that at
> least was at somewhat higher risk, and the effects were the same in
> that group or better perhaps in the rest.
>
> DR. BORER: I gain some comfort from other trials using drugs that have
> beta-blocking properties, but not a heck of a lot. It helps me a
> little bit and as Tom said, in the parallel of irbesarten and
> losarten, it may have helped a little bit there, but that wasn\'t the
> basis for a decision, nor would it be the basis of a decision for me
> here.
>
> I have said this many times before and I may be a bit of an iconoclast
> in saying it, but I have heard both Toms and Paul say something very
> similar just now. This is a unique molecule, carvedilol.
>
> When we were hearing about this drug for its approvability for
> treatment of patients with heart failure, the sponsor presented a
> great deal of information suggesting that the uniqueness of the
> molecule, because of its alpha blockade and because of its free
> radical scavenger properties, that these properties were very
> important in mediating the benefits that we saw.
>
> Now, I didn\'t think much of that then, and I don\'t think much of the
> argument that it\'s a beta-blocker and other beta-blockers do this,
> therefore, this one works. I don\'t think all that much of that now.
>
> I think that provides me with some comfort, but this is a unique
> molecule. I doubt very much that we know all of its pharmacological
> effects, in fact, I am sure we don\'t, and I am sure that nobody in
> this room can tell me the mechanism by which other drugs with
> beta-blocking properties have improved mortality after myocardial
> infarction. That is not known.
>
> There aren\'t even a whole heck of a lot of good hypotheses. So, this
> provides me with some comfort, but the reason for my going through
> that discussion a moment ago is to support exactly what Tom said and
> exactly what Beverly said and exactly what Tom Pickering said, that
> is, that I think that we have to look at the body count here and
> decide whether we believe it or not.
>
> We will get some comfort, more or less, from all of these other
> sources of data, and then we are going to make a decision about this
> drug, and it shouldn\'t be widely extrapolated to other drugs.
>
> Now, Steve, you wanted to make one other comment?
>
> DR. NISSEN: No, I just wanted to respond to Bob. Bob asked a
> theoretical question, why might it be beneficial.
>
> I mean at least hypothetically, when one gives a beta-blocker in a
> setting with a depressed LV function, the problem, of course, is the
> negative inotropic effects may, in fact, make patients worse before
> they make them better. At least theoretically, a drug that has some
> inherent vasodilator properties might reduce wall stress, unload the
> ventricle, you know, mitigate against the adverse effects.
>
> Now, whether that happens here or not, I have no idea, but you asked
> theoretically, could the alpha blockade have any therapeutic
> implications, and the answer is it might.
>
> DR. TEMPLE: But I am just pointing out that in a heart failure study
> done by the VA, prazosin did not have any benefit.
>
> DR. NISSEN: Say that again.
>
> DR. TEMPLE: There is a major heart failure study with prazosin, and it
> didn\'t show any benefit. It\'s an alpha-blocker.
>
> DR. NISSEN: No, but I mean I think there are other things that happen
> when you give more of a pure vasodilator.
>
> DR. ARTMAN: And that is a different question.
>
> DR. NISSEN: Yes, and also I think there is all kinds of issues about
> reflux increases and sympathetic tone when you give vasodilators. I
> mean it is very different to give a mixed beta-blocker or
> alpha-blocker than it is to give a pure alpha-blocker.
>
> DR. TEMPLE: No one has documented that one is actually better than
> another at anything. It is all speculation.
>
> DR. NISSEN: I agree, but you asked is there any theoretical reason.
> You asked for a theoretical reason, and I can tell you there is a
> theoretical reason why one might expect that.
>
> DR. BORER: Let\'s move on. May I, Doug and Bob, combine 5 and 6? It
> doesn\'t appear that there is an important difference between 5 and 6.
>
> We are going to get to the point where we actually have to vote for
> the record.
>
> No. 5 is: All things considered, how likely is it that the mortality
> effect in CAPRICORN represents an effect attributable to carvedilol,
> which is another way of saying should carvedilol be indicated to
> reduce mortality in patients with left ventricular dysfunction after
> myocardial infarction.
>
> May I request that we refine that just a little bit. It is not left
> ventricular dysfunction, it\'s left ventricular dysfunction the way it
> was defined here, which is an ejection fraction of less than or equal
> to 40 percent. That is moderately severe or however you want to
> qualitatively define that term. It was with or without heart failure.
>
> But given all those caveats, should carvedilol be indicated to reduce
> mortality in patients with left ventricular dysfunction. We don\'t
> have to go into all the reasoning, we have done that already.
>
> Marc, you are the committee reviewer.
>
> DR. FLEMING: I don\'t know whether Doug or Bob will wish to provide
> any clarification, but in the event that you would, I would be
> interested in hearing FDA\'s perspective on strength of evidence that
> we would generally like to have on a mortality endpoint.
>
> I had mentioned earlier on we talk about two adequate and
> well-controlled trials, and we talk about 025-squared, and we realized
> that for an endpoint such as mortality, that is something that might
> not be required.
>
> I realize, of course, lots of issues will have to be taken into
> account as we think through is this the strength of evidence of two
> studies, one study, it doesn\'t just have to be the evidence from this
> trial as we have discussed in Questions 3 and 4, it could be evidence
> from other studies.
>
> As FDA looks at this, when we look at the totality of evidence that is
> relevant to a given consideration, are we talking about the strength
> of evidence of 1.5, two studies, anything in general you want to say
> about this?
>
> DR. TEMPLE: These questions are all bound up together, that is the
> difficulty, however, just a couple of observations. You saw data on
> what it took to get metoprolol a claim for post-infarction beta
> blockade.
>
> The p value wasn\'t as long as your arm, it was a one-study value, so
> the strength of evidence that was needed there probably, although I
> have to say not explicitly in light of previous experience, was that
> one study would confirm what you sort of thought about the class.
>
> We presented to you what we have done with ACE inhibitor heart failure
> claims. It is very clear we are using one study at a reasonable p
> value standard even though I would say we were not explicit in
> thinking that through, but the weight of evidence from SOLVD on made
> us think that one confirmatory study that was reasonably persuasive
> was good enough.
>
> It depends on how you think of that here. As I was trying to point
> out, you have got a little bit of heart failure and you have got a
> little bit of post-infarction here.
>
> So, my view would be that you need a total amount of evidence that is
> as persuasive as usual, but that you can get it from more than one
> place, one piece of which comes from the study at hand, the other
> comes from the other studies of the same drug, the other comes from
> the studies of the other drug, all of which should add up to
> approximately the usual standard.
>
> But as I have pointed out for metoprolol, we thought it met the usual
> standard, but it did it with one study at a p of 0.02 or whatever it
> was, because we thought we had other relevant information. You know,
> we are all being bayesian here, but we are not admitting it.
>
> You saw similar behavior with the irbesarten/losarten. Each study was
> a reasonable study, nobody had any doubts about that, but it was the
> combined data that made the persuasive case, and I think that is the
> situation you are in here.
>
> Is that too squiggly or is that good enough?
>
> DR. THROCKMORTON: I guess I will just add one thing. I think we are in
> a place we are not going to find ourselves a lot when we think about
> the sort of strength of evidence that we have for this class of drugs,
> for these classes of drugs versus other sorts of therapeutic areas. I
> mean you can think of other places like, I don\'t know, GP2B3a
> antagonists where we have had surprises when we tried to extend what
> we thought we understood from single trials.
>
> Here, we have a relatively robust effect seen across a lot of
> different drugs and a lot of different therapeutic areas, the patient
> populations that makes it an uncommon place, I think, with regard to
> most of the therapeutic areas we think about in cardiovascular
> medicine.
>
> DR. BORER: Marc.
>
> DR. PFEFFER: Well, I found the leading from the agency helpful in this
> case. Sometimes it is not, this time I think it was. Really, it boils
> down to there were some other issues that came up, do you think you
> could do another study in this, or do you think we have enough
> information now to apply to people.
>
> I don\'t think I could personally be involved in a beta-blocker
> post-MI trial unless it were a very small group that we still have yet
> to define, and that is what I think we also need to say of the few
> places that more information is needed, I think we need an answer to
> Dr. Armstrong\'s question about these Killip class III patients, what
> were they like at the time they were randomized, were they cleared and
> then randomized.
>
> The onset, we have now heard that there was a long period and even
> within two weeks could be divided. I would like to see some
> information about the safety, so I am now talking about harm,
> potential for harm of giving this very early. I just don\'t know
> enough about that, and that is what is happening in post-MI especially
> beta-blockers.
>
> So, I would hope we can have the agency dissect out the information on
> day 1, day 2, randomization and events in those people.
>
> But overall I think we have a benefit here that will help patients,
> and I think getting this out, regulations will talk about this drug,
> but guidelines will then talk about beta-blockers, and I think that
> will help people.
>
> DR. BORER: So, that\'s a yes.
>
> DR. PFEFFER: That\'s a yes.
>
> DR. NISSEN: I have to make a few comments before I answer. First of
> all, notwithstanding the nearly heroic efforts of the sponsor to shoot
> themselves in the foot, which continued right up through today, and
> there are some things I have to say.
>
> First of all, Tom and I are, I think, and he will speak for himself as
> I know he will, you know, I don\'t think the Data Safety Monitoring
> Board acted entirely properly here and I think it ought to be said for
> the record, that, you know, there are roles for each of the
> constituencies involved in the trial, and those roles should be
> carefully defined and observed.
>
> There is a penalty to be paid for not following those rules. Now, it
> turns out the rules weren\'t broken as much as it seemed, and this is
> where some more shooting in the foot occurred. I mean when I read this
> statement in the executive summary that said the Data Safety
> Monitoring Board strongly recommended that they change the primary
> endpoint, I was extremely uncomfortable, and then you read the letter,
> and that wasn\'t what the letter said.
>
> The letter didn\'t say that. It said consider. It didn\'t say do this,
> it said you ought to think about this, and that is a little bit, you
> know, it made me more comfortable, but I think we ought to say from
> the beginning what the roles are of these various committees, the
> charters ought to say them, and they ought to follow those rules, and
> the extent that those rules are not followed undermines the
> credibility of the trial process, and it is something we ought to be
> careful about in the future.
>
> Similarly, I think the Steering Committee acted somewhat unwisely in
> the whole way that the study was redesigned and not sort of thinking
> more carefully about what endpoints they wanted to choose, so we got
> into this data dredging problem later on where now we are talking
> about which cause for hospitalization, how you define that, and those
> are avoidable problems potentially.
>
> So, I think that it is important that we say that. Having said that, I
> think that this is an important observation, that, you know,
> beta-blockers are largely forgotten, they get forgotten periodically.
> You know, every time we get a new therapy, everybody is focused now on
> the angioplasty era on how fast the door to balloon time is now the
> thing that counts the most about how you treat a myocardial
> infarction, and they forget about the fact that the patients have this
> period of time afterwards where they are very vulnerable.
>
> The use of beta-blockers post-infarct in America, and I don\'t know
> what it is like in the rest of the world, it is just abysmal, and we
> didn\'t really know before CAPRICORN, we didn\'t have really
> compelling evidence of what happens in the reperfused patient that has
> done very well and gets ACE inhibitors and gets statins and gets
> aspirin, and all the contemporary therapies, and I would bet you there
> are a lot of people out there that think that in this era,
> beta-blockers are passe, and what CAPRICORN teaches us is that they
> are not passe.
>
> So, the reason I am voting yes is not because the conduct of the trial
> was exemplary. I think there were some terrible dilemmas that you had
> to deal with. I am not sure you dealt with them in the best possible
> way, but the fact is that I think that, by and large, lives will be
> saved if this label is granted and if the message is aggressively
> pursued that even in the contemporary era, there is still a lot to be
> gained by giving beta-blockers post-MI.
>
> So, I vote yes because I think the public health considerations here
> and everything else make this a mandatory yes.
>
> DR. BORER: Alan.
>
> DR. HIRSCH: You know, it is very hard to follow Steve, but I will make
> an effort here. I will start with humor, but try to make a clear
> point.
>
> For humor, obviously, the sponsors shot themselves in the foot. The
> FDA, according to Marc, occasionally leads one way or the other. I
> think our committee can sometimes opine in more than one direction,
> and it gets all very confusing.
>
> When I came into this meeting, we talked about discovery, are we
> finding something new that was unique, that wasn\'t part of a pre-hoc
> hypothesis, and I really don\'t think that that encompasses where I am
> going to lead you with my vote.
>
> I don\'t think that this was about discovery. What happened here is
> that we have demonstrated, I think, that carvedilol has a positive
> effect in this somewhat mixed post-MI heart failure state.
>
> We found a gem in a mine discovery here that has come up with many,
> many precious stones as part of a tradition of like-minded
> beta-blocker related positive outcomes in a consistent pattern. So,
> this isn\'t discovery to me.
>
> It gets back to how Tom looks at spending alpha, I think there is
> little doubt that we have carvedilol causing a positive beneficial
> health effect in a very specified population. I think it is also true
> it is unlikely that if we had any doubt about that, we could perform a
> second trial in the real world to better confirm that.
>
> So, the evidence base we have overall, this isn\'t discovery, this is
> I think good data confirming a reality. My vote is yes.
>
> DR. BORER: Tom.
>
> DR. FLEMING: In leading up to an answer, let me begin by thinking
> about CAPRICORN and strength of evidence from this key pivotal study.
>
> The sponsor presented this and said this is a mortality trial and very
> appropriately it should have been. It was initially a mortality trial,
> but a very thought-out decision was made in mid-course to back away
> from that mortality endpoint based on what I as best can understand a
> judgment that the plausibility of achieving a mortality effect of
> sufficient magnitude in this setting was not sufficiently high in the
> context of the size of the trial that was being conducted, and as a
> result, there was a shift to an alternative endpoint.
>
> Hence, prospectively, mortality wasn\'t the primary endpoint, and that
> matters. It matters a lot when we are looking at whether this is a
> confirmatory trial or an exploratory trial, and, of course, life is a
> continuum, it is not simply that dichotomous, but clearly, there was a
> backing away from the thought that yes, this is an endpoint that we
> believe is obviously profoundly important, highly clinically relevant,
> and one that we believe is going to be of sufficient magnitude that in
> the context of this size of a trial, we can establish benefit.
>
> So, it does leave me in the position of interpreting strength of
> evidence from this study in the context of this being an endpoint that
> wasn\'t the primary endpoint. Nearly all of the alpha was assigned to
> an alternative measure.
>
> The target for what was viewed as sufficient evidence to conclude that
> mortality has been proven with the strength of evidence of a single
> positive study here was the 0.005, and as the FDA review indicated, we
> are about a factor of 6 or 8 away from that.
>
> So, I am going to become very quantitative here for a moment. As a
> statistician on a log scale, that is the strength of evidence of
> two-thirds of a trial. Okay. I have to be quantitative in a moment
> because I do think external data is relevant here, and I have to try
> to think of how that is to be considered.
>
> My own view, what does it take for mortality? In my own view, if we
> are talking endpoints such as hospitalization, I strongly endorse the
> concept that we should have two adequate and well-controlled trials
> for the concept of replication, as well as strength of evidence.
>
> For a profoundly important endpoint like mortality, I have long
> believed that somewhat less strength of evidence is acceptable in view
> of the profound importance of that endpoint, and have subjectively in
> my own mind over time thought of it in terms of roughly 1 1/2 trials
> if it is a mortality endpoint.
>
> So, two studies, one of which achieves an 0.03 and a second study that
> doesn\'t achieve significance, but it is close, that is an example, or
> one trial where mortality is the primary prespecified endpoint that
> achieves an 0.005, that is also of that strength of evidence.
>
> So, we are left here with, in my own view, we are halfway there
> roughly in terms of what strength of evidence I would have wanted to
> have seen.
>
> The external data here are very relevant and as Milt Packer had
> described in his presentation, I believe this is, I think he called it
> a unique situation in terms of the magnitude of evidence that you have
> from, first, the agent at hand, carvedilol, in related settings where
> the COPERNICUS trial is particularly important, as well as the
> magnitude of evidence for other members of the class.
>
> This part is unavoidably very subjective - does this get us the rest
> of the way. In my own view, I think it is very rare to have that much
> strength of evidence from supportive studies, but I think in this case
> we are in that rare circumstance.
>
> So, with that overall summary, I think this is a situation where
> overall evidence is sufficient to conclude that mortality benefit has
> been shown, but I would really emphasize that this is, in my own mind,
> a fairly uncommon or I call it rare circumstance, and not one that I
> would consider as precedent setting that would lead to the expectation
> that in the future, if studies that are designed to address the right
> issue, mortality, are, in fact, redesigned, and don\'t achieve
> unfortunately the real evidence that we would need to see, that they
> can be salvaged by looking at other supportive evidence.
>
> I would say, and I know the FDA does this extremely well, I would just
> reemphasize the important role the FDA does play in working with
> sponsors creatively prospectively in designing trials and ensuring
> that the right designs are in place, and this also is relevant when
> the studies are redesigned, that if ultimately, we expect mortality as
> an issue that we want to address, that when the study is initially
> designed or redesigned, we do whatever we can to avoid this type of
> circumstance where we end up getting data that is much less than what
> we would really want to see to answer the questions.
>
> DR. BORER: That is a yes?
>
> DR. FLEMING: That was a yes.
>
> DR. BORER: Beverly.
>
> DR. LORELL: Thank you. I have nothing to add regarding the issues of
> trial redesign. I think they have been addressed very well.
>
> I do vote yes. My vote is based on really three things. One is that
> mortality was predefined as a major and initially, the primary
> endpoint.
>
> Secondly, I think this experience, as was said by others, as well as
> Tom, fits into and in congruent with other data regarding the use of
> this drug, as well as other beta-blockers, in moderate and severe
> heart failure.
>
> Third, I think these data are supported by other studies looking at
> the use of beta-blockers after myocardial infarction.
>
> DR. BORER: I vote yes. I have nothing to add to everything that has
> been said about why, but I would just reemphasize what Tom said a
> moment ago about the extrapolability of my vote, like his, to any
> other situation where it just happens that mortality is considered and
> there has been one trial. I think we have to look at the specific
> circumstances.
>
> That having been said, I vote yes.
>
> JoAnn.
>
> DR. LINDENFELD: Yes, I also vote yes. I think that mortality was a
> prespecified endpoint and although it wasn\'t the only endpoint, that
> was changed. I don\'t see any malintent here. I think just a goof was
> made.
>
> So, I tend to shade this more toward a single good trial, not the
> two-thirds of a trial that Tom discussed. I think it moves more toward
> that way because I think it was just a little bit of a goof.
>
> This was designed to show a mortality benefit. It showed exactly the
> mortality benefit that was prespecified. So, I would shade this more
> toward one trial and vote yes.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: I will vote with the caveats that I thought Marc
> Pfeffer brought out very well, and I would like to reemphasize. I
> think there is a lot of work yet to be done with the sponsor and the
> agency in terms of what the label will say if, indeed, they decide to
> approve this, so that caveat.
>
> The second thing I would like to say, Mr. Chairman, as someone who has
> been both the chair of a DSMB and a member of a DSMB, is a somewhat
> contrary view to what has been expressed. I am satisfied based on the
> presentation of the chair of the Steering Committee and the excerpts
> from the letter, that the DSMB here acted appropriately.
>
> Like many of you, I get a lot of advice in life and I take some of it,
> and I think that the DSMB has a responsibility after assuring patient
> safety to provide an informed opinion and suggestions to a steering
> committee, which they may or may not take.
>
> The issue of blinding, I think has been much discussed. Tom and I have
> a different view about that. I think there is healthy reasons to think
> differently about this, but I don\'t have a problem with the way the
> DSMB acted or the Steering Committee responded in this particular
> instance.
>
> DR. BORER: Susanna.
>
> DR. CUNNINGHAM: I am going to vote yes and I am going to second Bev\'s
> very well-stated reasons.
>
> DR. BORER: Mike.
>
> DR. ARTMAN: Yes.
>
> DR. BORER: Did you want to make a comment?
>
> DR. TEMPLE: I just wanted to support what Paul said. We have recently
> written guidance on what a data monitoring committee is supposed to
> do, and one of the things, difficult as it is that they are supposed
> to do, is keep a watchful eye on the world and on the rate of events,
> and things like that, and give advice that might in some cases salvage
> the study.
>
> They plainly tried to do that, but the outcome was contrary, which we
> now know, but it is not illegitimate for them to consider those things
> or at least we didn\'t think so when we wrote the guidance.
>
> DR. FLEMING: Just to follow up, my only concern with the action of a
> monitoring committee is given that I believe they should be unblinded
> because that is I think critical to being able to fully carry out
> their role of safeguarding patient interests, if they were, if they
> were then to make any recommendation about changing an endpoint
> clearly is inappropriate.
>
> Given they weren\'t\--
>
> DR. TEMPLE: Absolutely.
>
> DR. FLEMING: Given they weren\'t, I see no problem with what they did.
> My concern is not with the Data Monitoring Committee, it was with the
> Steering Committee and in particular today with the presentation that
> indicated it was the Data Monitoring Committee that said we had to do
> this.
>
> The other thing, something for further discussions is how
> conservatively they apportion their alpha. We have had a lot of
> discussions of these things. I believe they could have gotten away
> with saying 0.03 for both of them and might have been much better off
> to have done that, because they are not entirely separate endpoints,
> but that is a discussion for a different time. This was a very
> conservative choice for a very important endpoint.
>
> DR. TEMPLE: Because of the correlation, if we are talking two-sided p
> value, of course, they wouldn\'t have needed 0.025, 0.025. It probably
> would have been close to 0.03, 0.03, as you said, or because they
> weren\'t given it equally, where they were saying 0.045, 0.005, it
> could have been probably 0.047, 0.009.
>
> DR. NISSEN: Bob, what I was reacting to was the implication here in
> the original document that it was somehow coercive, that basically,
> how could we possibly, in the face of this very strong recommendation
> not do this, and that was the way in this document it was stated.
>
> Now, it turns out that is not what they did, and that is why I backed
> off on that, but if you read what was said in here, it doesn\'t look
> like it was done the proper way, and the letter actually, it turns
> out, is to say we think you ought to consider this, and I don\'t have
> any problem with that at all.
>
> But if they had been unblinded, that would have been inappropriate,
> and I don\'t think anybody should leave the room without understanding
> why Tom and I feel so strongly about that, you know, that is off the
> table.
>
> DR. BORER: Okay. We have one final question and then we can discuss
> DSMBs if the FDA wants us to.
>
> The final question is: Regarding the fact that the sponsor also seeks
> a claim for reduction in recurrent MI, based on the observation of 45
> adjudicated events on placebo and 27 on carvedilol, of which 16 and 12
> were fatal, do these data support a claim?
>
> Marc, let\'s have your answer first and then we will go to the other
> side of the table.
>
> DR. PFEFFER: My answer would be no, and I was a little disappointed
> that it was not quite clear in the document that there was this
> relatively long period of silence in terms of non-fatal events, the
> patients couldn\'t express themselves, and also in terms of the
> prespecified criteria for the event itself. I think those things
> weren\'t as robust as I would have liked to have seen.
>
> DR. BORER: Mike.
>
> DR. ARTMAN: I would agree with that. I was really disappointed with
> the data on recurrent MI. I thought it was murky and not very clear,
> and I don\'t think that what we have seen supports this claim in any
> way.
>
> DR. BORER: Susanna.
>
> DR. CUNNINGHAM: No.
>
> DR. BORER: Paul.
>
> DR. ARMSTRONG: A clear no for the reasons that have been stated.
>
> DR. BORER: JoAnn.
>
> DR. LINDENFELD: No, for the same reasons.
>
> DR. BORER: I vote no.
>
> Bev.
>
> DR. LORELL: I vote no for the reasons that have already been said.
>
> DR. FLEMING: No.
>
> DR. HIRSCH: No.
>
> DR. NISSEN: No.
>
> DR. PICKERING: No.
>
> DR. BORER: Unanimous no.
>
> I think the reasons behind that decision should be clear from what has
> been said about why the yes vote was given for the mortality claim.
>
> Do you need further clarification from any of us? Do you want us to
> discuss anything else? Do you want us to discuss DSMBs?
>
> DR. THROCKMORTON: Please do not discuss DSMBs.
>
> DR. TEMPLE: We are all done with that. We wrote a guideline and Tom
> wrote a book.
>
> DR. BORER: I continue again to suggest to the FDA that for a more
> complete discussion of this committee\'s opinion about how to deal
> with data about primary endpoints that are seen in only one trial, we
> might have a workshop.
>
> That having been said, if there are no other comments, we will
> adjourn.
>
> DR. THROCKMORTON: Thank you very much.
>
> \[Whereupon, at 2:23 p.m. the meeting was adjourned.\]

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