FOOD AND DRUG ADMINISTRATION

NINETY-SEVENTH MEETING OF THE

CARDIOVASCULAR AND RENAL DRUG ADVISORY COMMITTEE

8:01 a.m.

Thursday, July 18, 2002

Versailles Ballroom

Holiday Inn - Bethesda

8120 Wisconsin Avenue

Bethesda, Maryland

ATTENDEES

COMMITTEE MEMBERS:

JEFFREY BORER, M.D., Chairman

Director, Division of Pathophysiology

Weill Medical College

Cornell University

525 East 68th Street, Room F467

New York, New York 10021

JAYNE E. PETERSON, R.PH., J.D., Acting Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration

5630 Fishers Lane, Room 1093

Rockville, Maryland 20857

PAUL ARMSTRONG, M.D.

Professor, Department of Medicine

University of Alberta

251 Medical Science Building

Edmonton, Alberta, Canada T6C37

MICHAEL F. ARTMAN, M.D.

Professor of Pediatrics

Pediatric Cardiology

New York University Medical Center

530 First Avenue, FPO Suite 9-V

New York, New York 10016

BLASE A. CARABELLO, M.D.

Professor of Medicine

Houston Veterans Affairs Medical Center

Medical Service (111)

2002 Holcombe Boulevard

Houston, Texas 77030

SUSANNA L. CUNNINGHAM, PH.D.

Consumer Representative

Professor, Department of Biobehavioral Nursing

School of Nursing, Box 357266

Seattle, Washington 98195-7266

ATTENDEES (Continued)

COMMITTEE MEMBERS: (Continued)

THOMAS FLEMING, PH.D.

Professor and Chair

Department of Biostatistics

University of Washington

Box 357232

Seattle, Washington 98195-7232

JOANN LINDENFELD, M.D.

Professor of Medicine

Division of Cardiology

University of Colorado Health Science Center

4200 East Ninth Avenue, B-130

Denver, Colorado 80262

BEVERLY H. LORELL, M.D.

Professor of Medicine

Cardiovascular Division

Beth Israel Deaconess Medical Center

330 Brookline Avenue

Boston, Massachusetts 02215

STEVEN NISSEN, M.D., F.A.C.C.

Vice Chairman, Department of Cardiology

Professor of Medicine

Ohio State University

The Cleveland Clinic Foundation

9500 Euclid Avenue, F15

Cleveland, Ohio 44195

MEETING GUEST (NONVOTING):

THOMAS G. PICKERING, M.D., D.PHIL.

Professor of Medicine

Director, Integrative and Behavioral

Cardiovascular Health Program and

Hypertension Section

Michael and Zena A. Wiener Cardiovascular Institute

Mount Sinai School of Medicine

One Gustave L. Levy Place

New York, New York, 10029-6574

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

ROBERT TEMPLE, M.D.

DOUGLAS THROCKMORTON, M.D.

ASTRAZENECA REPRESENTATIVES:

WILLIAM B. KANNEL, M.D., F.A.C.C.

CINDY M. LANCASTER, M.S., M.B.A., J.D.

ERIC MICHELSON, M.D., F.A.C.C.

VASILIOS PAPADEMETRIOU, M.D., D.SC., F.A.C.C.

BRISTOL-MYERS SQUIBB REPRESENTATIVES:

JEROME L. AVORN, M.D.

TODD BAUMGARTNER, M.D.

RENE BELDER, M.D.

BERNARD R. CHAITMAN, M.D.

LAWRENCE J. DACEY, M.D.

FRED FIEDOREK, M.D.

CHARLES H. HENNEKENS, M.D., DR.PH.

THOMAS A. PEARSON, M.D., PH.D., M.P.H.

ERIC J. TOPOL, M.D.

C O N T E N T S

MORNING SESSION

\* \* \*

NDA 20-838/S015, Atacand (candesartan cilexetil) Tablets,

AstraZeneca LP,

For a Proposed Claim of Comparative Efficacy of

Candesartan Cilexetil and Losartan in Hypertension

\* \* \*

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

By Ms. Jayne Peterson 8

ASTRAZENECA PRESENTATION

Regulatory Introduction

By Ms. Cindy M. Lancaster 10

Comparison of the Antihypertensive

Efficacy of Candesartan Cilexetil

and Losartan

By Dr. Vasilios Papademetriou 18

Epidemiologic and Clinical Significance

of Incremental Changes in Blood Pressure

By Dr. William Kannel 60

Summary

By Ms. Cindy M. Lancaster 73

COMMITTEE DISCUSSION AND REVIEW 79

OPEN PUBLIC HEARING 112

CONTINUATION OF COMMITTEE DISCUSSION AND REVIEW 112

C O N T E N T S

AFTERNOON SESSION

\* \* \*

NDA 21-387, Pravastatin/Aspirin Combination Product,

Bristol-Myers Squibb Company,

Proposed for Long-term Management to Reduce the Risk

of Cardiovascular Events (death, nonfatal myocardial

infarction, myocardial revascularization procedures,

and ischemic stroke) in Patients with Clinically

Evident Coronary Heart Disease

\* \* \*

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

By Ms. Jayne Peterson 168

BRISTOL-MYERS SQUIBB PRESENTATION:

Introductory Remarks

By Dr. Todd Baumgartner 170

Pravastatin/Aspirin:

Safety and Dosing Considerations

By Dr. Rene Belder 176

Summary Overview

By Dr. Fred Fiedorek 190

COMMITTEE DISCUSSION AND REVIEW 196

OPEN PUBLIC HEARING 239

CONTINUATION OF COMMITTEE DISCUSSION AND REVIEW 239

P R O C E E D I N G S

(8:01 a.m.)

DR. BORER: It\'s 8:01 and 57 seconds, so we\'re already a minute and 57
seconds late. I\'d like to call this meeting to order so we can catch
up.

We\'ll begin by introducing the committee members, and we\'ll start over
on the left side with our guest committee member, Tom Pickering, who is
a nonvoting member for this particular meeting. Tom, why don\'t you give
your name, your affiliation, and we\'ll go around the table.

DR. PICKERING: I\'m Dr. Tom Pickering and I\'m Professor of Medicine and
Director of the Integrative and Behavioral Cardiovascular Health Program
and Hypertension Section at Mount Sinai School of Medicine in New York.

DR. CARABELLO: I\'m Blase Carabello from the Houston VA and from the
Baylor College of Medicine.

DR. NISSEN: I\'m Steve Nissen and I\'m Vice Chairman of the Department
of Cardiovascular Medicine at the Cleveland Clinic School of Medicine.

DR. ARMSTRONG: Paul Armstrong, cardiologist, professor of medicine,
University of Alberta.

DR. BORER: I\'m Jeff Borer from Cornell Medical College.

MS. PETERSON: I\'m Jayne Peterson. I\'m the acting Executive Secretary
of the Advisory Committee.

DR. FLEMING: Tom Fleming, University of Washington, Seattle.

DR. LINDENFELD: JoAnn Lindenfeld, University of Colorado.

DR. ARTMAN: Mike Artman. I\'m at New York University School of Medicine.

DR. LORELL: I\'m Beverly Lorell from Harvard Medical School and Beth
Israel Deaconess Medical Center.

DR. THROCKMORTON: Doug Throckmorton. I\'m the Director of the
Cardio-Renal Division at the FDA.

DR. BORER: Alan Hirsch, a regular member of this committee, will not be
here today. I believe that Susanna will be here, but she\'s not here
yet.

This seems a good time to remind everybody that if you want to say
something, please press your button so I can see the light and everybody
can hear you.

We\'ll have the conflict of interest statement from Jayne Peterson, the
acting Executive Secretary of the committee.

MS. PETERSON: Thank you.

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 which have been reported by the participants present no
potential for an appearance of a conflict of interest at this meeting
with the following exceptions.

Dr. Jeffrey Borer has been granted a waiver under 18 U.S.C. 208(b)(3)
for his potential consulting for a competitor to Atacand on unrelated
matters. Potentially he could receive less than \$10,001 a year.

Dr. Susanna Cunningham has been granted waivers under 18 U.S.C.
208(b)(3) and 21 U.S.C. 355(n)(4), amendment of section 505 of the Food
and Drug Administration Modernization Act, for ownership of stock in a
competitor to Atacand. The stock is valued between \$25,000 and
\$50,000.

Dr. JoAnn Lindenfeld has been granted a waiver under 18 U.S.C. 208(b)(3)
for her potential consulting for the sponsor and competitors to Atacand
on unrelated matters. Potentially she could receive less than \$10,001
from each firm per year and for her speaking for the sponsor and
competitor to Atacand on unrelated matters for which she receives
greater than \$10,000 per year.

Dr. Thomas Fleming has been granted a waiver under 18 U.S.C. 208(b)(3)
for his participation on a data safety monitoring board for a competitor
to Atacand on a related matter. He receives less than \$10,000 per 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 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: Thank you.

We\'ll begin then with the presentation by the sponsor of the proposed
amendment to the NDA for candesartan cilexetil tablets. We\'ll begin
with Dr. Lancaster.

MS. LANCASTER: Good morning, Mr. Chairman, members of the committee,
members of FDA, and ladies and gentlemen. My name is Cindy Lancaster
from the Department of Regulatory Affairs at AstraZeneca. On behalf of
AstraZeneca, I would like to thank the division and the committee for
giving us the opportunity to present the results of our clinical program
about the antihypertensive efficacy of candesartan cilexetil compared to
losartan.

I\'m presenting a brief regulatory overview this morning. Following the
regulatory overview, Dr. Papademetriou will present the results of our
clinical program on the antihypertensive efficacy of candesartan
cilexetil compared with losartan. Dr. Kannel will then present the
epidemiologic and the clinical significance of incremental changes in
blood pressure. Following Dr. Kannel\'s presentation, I will provide a
brief summary.

In addition to Drs. Kannel and Papademetriou, Dr. Donald Vidt is also a
consultant for AstraZeneca on the CLAIM program. Dr. Vidt was the
principal investigator for study 230 and the primary author of the
publication describing this study. Other members of the AstraZeneca team
who are identified on this slide are also available to address specific
questions that the committee or FDA may have this morning.

Atacand is a selective AT1 subtype angiotensin II receptor antagonist.
This product belongs to the class known as the angiotensin receptor
blockers and this class is commonly referred to as ARBs.

Atacand was approved in June 1998 by FDA for the treatment of
hypertension. Atacand can be used alone or in combination with other
antihypertensive agents for the treatment of hypertension. The usual
recommended starting dose is 16 milligrams once daily, and this product
can be administered once or twice daily with total daily doses ranging
from 8 to 32 milligrams.

Study 01, the first comparator trial, is one of the 14
placebo-controlled trials included in the original NDA database that
formed the basis of FDA\'s approval of Atacand for the treatment of
hypertension in 1998. Study 01 was a randomized, double-blind,
multicenter, placebo-controlled, parallel group, 8-week comparator study
of 8 and 16 milligrams of candesartan cilexetil, 50 milligrams of
losartan, another product in the ARB class, and a placebo given once
daily. A total of 337 patients with a mean sitting diastolic blood
pressure of 95 to 114 millimeters of mercury were randomized to one of
four parallel treatment groups.

With only a single study of a comparison at the starting dose available
at the time of the FDA\'s review of the NDA database, AstraZeneca did
not propose any comparator text in the labeling based on the positive
results of this trial at that time.

However, a second study was ongoing at the time of FDA\'s review of the
original NDA. Results of the second positive study became available
later in 1998. This was a trial conducted in the U.S. It was a
randomized, double-blind, multicenter titration-to-effect, 8-week study
with parallel treatment groups of candesartan cilexetil initiated at 16
milligrams once daily compared with losartan initiated at 50 milligrams
once daily.

There were 332 patients with a mean sitting diastolic blood pressure of
95 to 114 millimeters of mercury randomized to two parallel treatment
groups.

Since this study was a titration-to-effect design, patients with a mean
sitting diastolic blood pressure of greater than or equal to 90
millimeters of mercury after 4 weeks of initial treatment were titrated
to either 32 milligrams of candesartan cilexetil or 100 milligrams
losartan once daily.

Because the results of study 175 were available in August 1998,
AstraZeneca met with representatives from the Division of Cardio-Renal
Drug Products, the Office of Drug Evaluation I, and DDMAC to discuss the
possibilities of study 01 and 175 supporting a comparator claim of
Atacand versus losartan. Although each study met its primary endpoint,
the agency commented that study 01 did not provide a meaningful
comparison because the starting dose is an arbitrary point in the dosing
regimen and it does not reflect how the drugs being compared would
actually perform over their dose ranges.

In addition, the agency noted that the design of study 175 was not a
forced titration study. Consequently the agency expressed some concern
that in a titration-to-effect study only the poor responders would be
titrated to the highest dose of the drugs.

Following this meeting and in subsequent discussions, the agency asked
AstraZeneca to establish the bioequivalence of the overencapsulated
losartan tablet to the commercial product. The overencapsulation was
done for blinding purposes. In response to this request, AstraZeneca
designed and conducted a bioequivalence study. The study established the
bioequivalence of the test drug, losartan, used for the comparator
studies conducted by AstraZeneca.

AstraZeneca was also asked to focus on the maximum approved of the
comparator drugs, demonstrate the statistical significance with two
adequate and well-controlled trials, and if only once-daily dosing is
studied, then the limitations should be clearly stated in promotional
claims, as well as the study design needed to be either a parallel
dose-response or a forced-titration.

Now, based on these requirements, AstraZeneca designed and conducted the
CLAIM program entirely in the U.S. The results of a specific dosing
regimen of once-daily administration that was used in the CLAIM program
is described in our proposed labeling. AstraZeneca selected the
once-daily dosing regimen for candesartan cilexetil and losartan because
both drugs are prescribed for use once daily, and once-daily
administration is the dosing regimen primarily used in completed and
ongoing studies.

Statistically greater blood pressure reduction was demonstrated with
candesartan cilexetil compared with losartan at the maximum approved
dose when administered once daily.

The proposed labeling is specific to effects on blood pressure
reduction.

Now, based on the results of the CLAIM program, AstraZeneca proposes the
following text be added to the labeling in the clinical pharmacology
section within the clinical trials subsection of labeling after the
first paragraph within our approved labeling.

\"Two identically designed, concurrently conducted, 8-week, multicenter,
double-blind, randomized, forced-titration studies were performed to
compare the antihypertensive efficacy of candesartan cilexetil and
losartan at their once-daily maximum doses. Candesartan cilexetil
initiated at 16 milligrams once daily and forced-titrated at 2 weeks to
32 milligrams once daily was statistically significantly more effective
than losartan 50 milligrams once daily forced-titrated at 2 weeks to 100
milligrams once daily in reducing systolic and diastolic blood pressure
at 8 weeks. In these studies, both agents were well tolerated.\"

This proposed text would be included in the clinical trials section in
the context of our approved indication and usage section of labeling
which states: \"Atacand is indicated for the treatment of hypertension.
It may be used alone or in combination with other antihypertensive
agents.\"

Now, during the course of the review of our supplement, the FDA also
asked us about precedents for comparator and superiority labeling in
other antihypertensive products. We provided several, which are
described in the background information document, and many of these
labels make the claim of similar efficacy. I will review the example of
this comparator information found in labeling for you this morning, at
least one example that we have, which is lisinopril which is marketed
under the trade names of Zestril and Prinivil, and it has a superiority
claim within the clinical pharmacology section of its labeling. It
states that 20 to 80 milligrams of lisinopril was superior to
hydrochlorothiazide in the effect on systolic and diastolic blood
pressure and it was equivalent to atenolol and metoprolol in effects on
diastolic blood pressure.

In summary, AstraZeneca\'s proposed labeling is consistent with the
general requirements of the content and format for human prescription
drugs. This proposal is also consistent with the guidance from FDA on
how these studies should be described in the labeling, and a review of
other approved antihypertensive products confirms that our proposed
labeling is consistent with the content and placement of comparator
information in labeling. More specifically, our proposed labeling is
consistent with the labeling for lisinopril and losartan, as well as
other antihypertensive products such as the ACE inhibitors, Accupril,
and Altace, and the other ARBs, Diovan and Teveten. Consequently,
AstraZeneca proposes that this information be included in the labeling
for Atacand.

At this time, please allow me to introduce Dr. Papademetriou who will
present the results of our clinical program on the antihypertensive
efficacy of candesartan cilexetil compared to losartan.

DR. BORER: Are there any specific substantive questions for Dr.
Lancaster, or can we move right ahead?

(No response.)

DR. BORER: Okay, thank you very much.

DR. PAPADEMETRIOU: Good morning, everyone. It is a pleasure to be here
and I appreciate this opportunity to present to you the comparative data
of two angiotensin receptor blockers, candesartan cilexetil and
losartan.

This morning I would like to present data from the CLAIM program which
consists of two identical, well-controlled clinical trials, studies 230
and 231.

First, let me begin with this slide just to refresh everyone\'s memory
of the cascade of the renin-angiotensin system that lists the production
of angiotensin II. As we all know, angiotensin I is produced by
angiotensinogen through the activity of renin, and angiotensin I is
transformed into angiotensin II through the activity of the
angiotensin-converting enzyme. The same enzyme is responsible for the
breakdown of bradykinin through inactive ingredients. This is the site
where ACE inhibitors exert their activity and decrease the production of
angiotensin II. At the same time, levels of bradykinin increase and this
has been implicated as the cause of some of the side effects of ACE
inhibitors such as cough and angioneurotic edema.

Angiotensin II can also be produced by pathways that do not use the
angiotensin-converting enzyme. This is why sometimes angiotensin II can
return to its baseline after administration of ACE inhibitors. By
stimulating the AT1 receptor, angiotensin II produces all the effects of
the activated renin-angiotensin system such as vasoconstriction, fluid
and sodium retention, sympathetic activation, and in the long-term
self-proliferation and vascular hypertrophy, all of which lead to the
development of hypertension.

Angiotensin receptor blockers accept their activity directly at the
receptor site and prevent activation by angiotensin II.

Because previously published experimental data suggested that the
binding properties of candesartan were different than losartan, studies
were designed to assess whether this observation translates into
clinical differences in blood pressure lowering.

Here we present data from two of these studies, 001 and 175. Both were
randomized, double-blind, multicenter, controlled, parallel group
studies. Both clinical trials were of 8-week durations and were
conducted in patients with diastolic pressures of 95 to 114.

In study 001, 337 patients were randomized to four treatment groups:
candesartan cilexetil 8 milligrams; candesartan 16 milligrams; losartan
50 milligrams; or placebo.

In study 175, 332 patients were randomized to receive candesartan
cilexetil 16 milligrams or losartan 50 milligrams.

If after 4 weeks, the diastolic blood pressure was not below 90
millimeters of mercury, the dose of candesartan cilexetil was increased
to 32 milligrams and that of losartan was increased to 100 milligrams.

Here are the results of studies 001 and 175. As you can see, in study
001, the placebo-corrected reduction in blood pressure was approximately
10.3 millimeters of mercury with candesartan cilexetil 16 milligrams,
and approximately 6.6 millimeters of mercury with losartan 50
milligrams. That resulted in a difference of 3.7 millimeters of mercury
which was statistically significant.

In study 175, there was a reduction of approximately 11 millimeters of
mercury with candesartan and 8.9 millimeters of mercury with losartan, a
mean difference of 2.2 millimeters between the two treatment groups
which was also statistically significant.

The CLAIM program was specifically designed to assess the effect of two
angiotensin receptor blockers, candesartan cilexetil and losartan, in
blood pressure lowering in hypertensive patients. The program included
two identically designed studies, studies 230 and 231. In these trials
the maximum recommended dose of each agent administered once daily, as
described in the respective approved labeling of each drug, was used in
a forced-titration design. This means that the higher dose was
administered to patients even though their diastolic pressure might have
been a target with the lower dose administered.

Eligible patients entered in a placebo run-in period for 4 to 5 weeks
and were then randomized to receive either candesartan 16 milligrams or
losartan 50 for 2 weeks. Subsequently the dose was increased to
candesartan 32 milligrams or losartan 100 milligrams for an additional 6
weeks. The total treatment period, therefore, was 8 weeks, at the end of
which blood pressure measurements were taken 24 hours after the last
dose. To simulate the possibility of a missed dose, measurements were
also taken 48 hours after the last dose was administered.

Eligible patients for these trials were between the ages of 18 and 80.
They were male patients or females without child-bearing potential or
using appropriate birth control measures. They had to have essential
hypertension as patients with secondary causes were excluded, and a mean
diastolic pressure between 95 and 114 on two consecutive visits at the
end of the placebo run-in period. Patients were excluded from the study
if they had one or more of the exclusion criteria listed on this slide.
These are the common exclusion criteria used in most hypertension
trials.

The primary endpoint was the change from baseline to week 8 in trough
sitting diastolic blood pressure. A number of predefined secondary
endpoints were also assessed and these included change from baseline to
week 8 in trough sitting systolic pressure, change in peak diastolic and
systolic pressure, the trough-to-peak ratio, the proportion of patients
considered controlled or responders, and the change in systolic and
diastolic pressure at 48 hours post the last dose.

Now, let me clarify some of the terms used in the CLAIM program. Trough
and peak drug effects, as stated in the approved label of both drugs,
were defined as follows. The trough effect was considered the effect at
24 hours post dose, and the peak drug effect was considered the effect
at 6 hours post dose. Patients with a trough diastolic pressure below 90
were considered controlled, and patients were considered responders if
they either had diastolic pressure below 90 or at least they had
demonstrated a 10 millimeters of mercury reduction from their baseline
diastolic blood pressure.

The primary statistical analysis was performed using an analysis of
covariance, ANCOVA, for the change from baseline to week 8 in trough
sitting diastolic blood pressure. The primary patient population was an
intent-to-treat population where patients had to have a baseline and at
least one post-baseline blood pressure measurement. An analysis using
the last observation of treatment carried forward, or LOCF, was also
performed to account for missing values.

The ANCOVA model included a treatment, center, and center-by-treatment
interaction, and baseline diastolic pressure was a covariate to account
for potential baseline differences.

The differences between treatments are presented as least squares means.

The sample size calculation was based on detecting a difference of 2
millimeters of mercury between treatment groups, a standard deviation of
7.5 millimeters of mercury, a significance level of 0.05 for a
two-tailed test, and a power of 95 percent. This resulted in a sample
size calculation of 735 patients for each study. However, 613 patients
and 655 patients were randomized to study 230 and 231, respectively.

In study 230, a total of 926 patients were screened, of which 613
patients qualified for the study. Of those, 309 patients were randomized
to receive candesartan cilexetil and 304 were randomized to receive
losartan. Of the 309, patients 2 patients were discontinued without
post-baseline contact and 307 patients formed the intention-to-treat
population for candesartan cilexetil. In the losartan group, 304
patients were randomized. All of these patients had post-baseline
contact and formed the intention-to-treat population. Approximately 12
percent of patients were discontinued from each treatment group.

Similarly, in study 231, out of 921 patients screened, 655 were
randomized: 332 to candesartan and 323 to losartan. All patients
randomized to candesartan cilexetil had post-baseline contact and were
considered the intention-to-treat population. In the losartan group, of
the 323 patients, 1 patient had no post-baseline contact and was
discontinued from the study. 322, therefore, formed the
intention-to-treat population. In this study, 4 to 6 percent of patients
were discontinued from each treatment group for various reasons.

The baseline characteristics were similar between the candesartan
cilexetil and the losartan treatment groups in both studies. Patients
were similar in age, weight, duration of hypertension, sex distribution,
and race. Approximately 18 to 20 percent of patients in each study were
African Americans.

Baseline blood pressure was also similar for both treatment groups and
diastolic pressure averaged around 100 millimeters of mercury and
systolic blood pressure ranged between 152 and 153 for all groups
randomized in the two trials.

The primary endpoint, that is, the change in diastolic blood pressure at
week 8, is shown on the left for study 230. In this study, patients
receiving candesartan cilexetil had a mean diastolic blood pressure
reduction of 10.5 millimeters of mercury, whereas patients receiving
losartan had a 9.1 millimeters of mercury reduction in trough diastolic
blood pressure. This resulted in a statistically significant difference
of 1.5 millimeters of mercury between the two treatment groups.

In study 231, shown on the right, candesartan cilexetil therapy resulted
in an average diastolic pressure reduction of 10.9 millimeters of
mercury. Treatment with losartan resulted in an average pressure
reduction of 8.7 millimeters of mercury. The difference between the two
treatment groups was 2.2 millimeters, and this was also statistically
significant.

The primary endpoint is shown here, together with a number of secondary
endpoints, for study 230. As you can see, there is a 3.4 millimeters of
mercury greater reduction in trough systolic blood pressure, a 3.4
millimeters greater reduction in peak diastolic blood pressure, and a
3.5 millimeters greater reduction in peak systolic blood pressure. At 48
hours after the last dose, the difference between the two groups was
maintained and was 2.8 for diastolic and 4.6 millimeters of mercury for
systolic blood pressure. For all primary and secondary endpoints,
differences between candesartan cilexetil and losartan were
statistically significant.

Similarly in study 231, statistically significant differences were
noted: 2.2 millimeters of mercury change in the trough diastolic
pressure, 3.5 millimeters for trough systolic blood pressure, 1.5 and
2.6 for the peak diastolic and systolic blood pressure, respectively.
And at 48 hours, the differences were again statistically significant in
favor of candesartan with a mean change of 4.3 and 5.9 millimeters of
mercury in diastolic and systolic blood pressure, respectively.

This slide shows the trough diastolic blood pressure reduction during
therapy by visit for studies 230 and 231.

In study 230, there was a substantial decrease in diastolic blood
pressure with both agents after 2 weeks of therapy, but the reduction
was greater with candesartan cilexetil. After up-titrating the dose,
further blood pressure reduction was noted with both drugs, but the
difference between candesartan cilexetil and losartan was maintained for
the duration of the study.

Similarly in study 231, there was an initial substantial reduction of
diastolic blood pressure with both agents, but the blood pressure
reduction was greater with candesartan cilexetil at 2 weeks of therapy.
After up-titrating the dose, a further blood pressure reduction was
noted and the difference was again maintained for the duration of the
study.

Similar results were obtained for systolic blood pressure in both
studies, 230 and 231. Differences between candesartan cilexetil and
losartan were observed after 2 weeks of therapy and were maintained
after up-titration for 8 weeks. In study 230, although the mean baseline
systolic pressure was slightly higher in the candesartan group, the
blood pressure reduction was greater and was maintained for the duration
of the study.

The trough-to-peak ratio is an important measure because it indicates
the duration of blood pressure lowering action of the medication used.
The trough-to-peak ratio was a prespecified secondary endpoint in these
studies. As you can see here, in both studies 230 and 231, the
trough-to-peak ratio for candesartan cilexetil and losartan was close to
0.9. This indicates that the blood pressure lowering effect of both
drugs is well maintained over a 24-hour period with once-daily dosing.

This slide shows the percent of patients that were considered either
controlled or responders in the two studies. As you can see, numerically
the numbers of controlled patients or responders for each therapy was
greater with candesartan cilexetil in both studies. The differences
achieved statistical significance in study 231.

This slide shows the blood pressure differences between the two
therapies in the overall population and in prespecified subpopulations
of studies 230 and 231, as well as the pooled data. Although these
studies were not powered to assess the effects in subpopulations, the
results are consistent with the overall effect.

Here are the results for systolic blood pressure reduction in the same
subpopulations and reductions in systolic pressure were also consistent
with the overall outcomes in both studies 230 and 231 and the pooled
data.

The summary of adverse events reported in the CLAIM program is
consistent with adverse events reported in most hypertension trials.
Most events were mild and transient in nature. The number of patients
that reported at least one adverse event was similar between treatment
groups. About 46 percent of the patients in the pooled data reported at
least one adverse event. Serious adverse events and events requiring
discontinuation from the study were infrequent.

Adverse events reported in more than 2 percent of patients are shown
here. In general, these events were similar between the two treatment
groups, were transient and rarely led to discontinuation from the study.

In summary, the efficacy data from the two CLAIM studies indicate that
the reduction in blood pressure was consistently in favor of candesartan
in both studies. Differences in trough diastolic and systolic blood
pressure and peak diastolic and systolic pressures were consistently
greater for candesartan compared to losartan.

If we add to these studies the primary endpoint data for studies 175 and
001, again we can see that reductions in trough diastolic pressure were
consistently in favor of candesartan.

In summary, the CLAIM program, which included two adequate and
well-controlled studies, provides substantial evidence that treatment
with candesartan cilexetil results in greater blood pressure reduction
compared with losartan at the maximum recommended doses administered
once daily.

Furthermore, candesartan cilexetil 32 milligrams once daily consistently
lowered trough, peak, and 48-hour post-dose diastolic blood pressure and
systolic blood pressure more effectively than losartan 100 milligrams
daily.

Both drugs were well tolerated and demonstrated a tolerability and
safety profile consistent with current prescribing information.

In conclusion, the greater blood pressure lowering effect of candesartan
cilexetil compared with losartan in the two CLAIM studies is consistent
with other studies that were conducted previously. This information is
clinically relevant and important for prescribing health care
professionals.

Thank you very much.

DR. BORER: Thank you, Dr. Papademetriou.

I\'m sure there are a number of questions from the committee about
substantive issues. We\'ll get into the interpretation issues later, but
I\'d like to begin with just a few questions about the conduct of the
trials, and these aren\'t meant as criticisms in any way. I just want to
understand how the data were collected.

First of all, do we have any idea within the primary study populations,
or any subpopulation within them, of the distribution of renin sodium
profile data for these patients?

One of the reasons I ask the question is that in 230 the very small
subpopulation of black patients showed no effect of treatment; in 231
they did. I don\'t want to belabor small subset analyses that weren\'t
primarily hypothesized to be done in the first place, but the fact is
that one might expect that black patients would be less likely to
respond to ARBs or ACE inhibitors than white people would. And that
raises the issue of renin sodium profile. So, just for my information,
do we have any data about that?

DR. PAPADEMETRIOU: No, unfortunately, these data were not collected in
these studies.

DR. BORER: Okay.

How about the time at which the blood pressure measurements were made? I
understand they were done at trough and at peak, and that that pretty
well sets a window around the timing of the determination of blood
pressure. But were they predominantly or solely done in the morning for
the trough, or were they done some in the morning, some in the afternoon
for patient convenience?

DR. PAPADEMETRIOU: Almost all patients had their measurements in the
morning time.

DR. BORER: Let\'s see. A couple of other little questions. Oh, yes. The
weight of the patients. These were pretty heavy patients on average. The
women, as I recall, in all the study populations averaged somewhere
around 185 pounds per person. I know there was a wide distribution of
weights, but can you comment, first of all, on the distribution of
weights in the general hypertensive population so that we can know
whether this is really a reasonable microcosm and on what the impact of
weight may have been here?

DR. PAPADEMETRIOU: This is a very good point, and the body mass index
turned out to be over 30 in about half of the patients in these study
populations. But from what I know from epidemiology data, that reflects
pretty much what happens around the country.

DR. BORER: The other issues that I would raise are actually qualitative
or more appropriate for Dr. Kannel. Let\'s go on to Paul as the
committee reviewer. Do you have some specific issues you want to raise?

DR. ARMSTRONG: Thank you. I do. I will come to a specific table in the
briefing document in a moment that I would like your advice on. But I
really have three questions to begin with, actually based on the
chairman\'s question, perhaps a fourth, which I\'ll just put up front.

Given the spectrum of weight, do we have any information about efficacy
when you correct for weight? In other words, was there more of an effect
in patients with a low body weight than those with a high body weight?
Do we know that?

DR. PAPADEMETRIOU: We do have the response in the obese compared to
non-obese, and I can show that to you if you like. As you can see here,
the blood pressure reduction of diastolic blood pressure overall in the
obese and non-obese was pretty similar. The obese patients pretty much
had the same response in diastolic pressure and similarly in the
systolic blood pressure too.

DR. ARMSTRONG: Thank you.

There are really three issues then that I think we\'ll come back to. One
is the evidence to support incremental effect at doses of candesartan
above 16 and losartan above 50. So, I\'d like your comments about the
evidence supporting increased efficacy above those doses.

The second is the time course to stable effect when you begin with
once-a-day dosing as one looks at the time course and when a steady
state is reached and the evidence to support a difference in the time
course with candesartan versus losartan, given the comments about the
difference in the duration in receptor activity of the two drugs.

And the third is the evidence to support b.i.d. dosing versus once-a-day
dosing enhancing effect in one versus the other compound.

Those three issues to me come through repetitively. Can you comment on
those? And then I\'d like to direct your attention to a specific table
in the briefing document.

DR. PAPADEMETRIOU: These data are available. We didn\'t have time to
present them here, but Dr. Michelson probably would be more appropriate
to answer these questions.

DR. MICHELSON: Hi. Good morning. Dr. Eric Michelson, AstraZeneca. Let me
just help with a few of these, if I can.

Dr. Armstrong, if I understood correctly, the first question had to do
with the time course of perhaps stabilization with respect to once-a-day
dosing.

DR. ARMSTRONG: Yes, and if you like, we can work with that and the table
in the briefing document that I think addresses that also, but please go
ahead.

DR. MICHELSON: I think when we designed these studies, we were, to the
best of our ability, trying to be as consistent with the prescribing
information for the label of both drugs, and for each of the drugs,
it\'s stated that these drugs reach their maximum effect within either 2
to 4 weeks or 4 to 6 weeks. In fact, for losartan it\'s 2 to 4 weeks,
and we state in our label 4 to 6 weeks. So, the studies were designed
with the idea in mind that a 6‑week at a stable dose would be
sufficient.

DR. ARMSTRONG: Well, to that point, on page 6 of the briefing document
which addresses the CANDLE study, there is a table which then partitions
the patients who were up-titrated in the lower part of that panel and
not up-titrated in the upper panel. It looks to me as though, as one
looks at the patients who were not up-titrated, that indeed there is a
further effect, as you have implied, between week 2 and week 4; that is
to say it does appear, though, by week 4 that the blood pressure
lowering effect stabilizes.

That being the case, then the patients who were then up-titrated based
on measurements at 2 weeks, it\'s impossible for me to discern the
notion that at 4 weeks that effect relates to an increment in the dose
as opposed to an elapsing of the time. That obviously is a key point. I
wonder if you can shed light on that.

DR. MICHELSON: Yes. Let me try to help clarify. The way it\'s depicted
in the briefing document may not add clarity. The design of the study,
the CANDLE study 175, was actually titration to effect where the
titration was at week 4. The way it\'s presented in the briefing
document, the review by Dr. Fred, suggests that it\'s at week 2, but it
was actually done at week 4. So, there were incidental blood pressure
measurements collected, merely incidental, at weeks 2, 4, 6, just to
watch the traffic as it was going by. But the only decision about
up-titration was made at week 4.

DR. ARMSTRONG: So, the week 4 measures here ‑‑

DR. MICHELSON: Were the sole basis for up-titration.

DR. ARMSTRONG: So, in the patients who were up-titrated, the week 4
measurements were before the up‑titration. Is that correct? I\'m a
little confused.

Can you comment then on the issue of evidence for incremental effect
beyond 16 milligrams and why starting at 16, given that there\'s
substantial evidence that 8 in some of the other material is effective?
Why start at 16?

DR. MICHELSON: Let me just comment first that 175, in part, reflects as
clinicians what we would probably routinely do. The usual recommended
starting dose for each of these drugs is respectively 50 milligrams and
16 milligrams, and in the population being study, nonhepatically
impaired, whatever, this would be the appropriate starting dose. In
fact, that\'s the way the study was designed and then it was titration
to effect.

In this study, the question that was being directly asked for us was to
address the maximum doses. When we discussed this with Dr. Temple, our
understanding was it would have been completely acceptable in this
study, the way this experiment would have been designed, we could have
just started with 32 milligrams and started with 100 milligrams. And
that would have satisfied the question whether or not at the maximum
recommended doses administered once daily was there a difference.

And in designing the study, we suggested that perhaps just to make it a
little bit more comfortable for the clinicians doing the study for them
to have the opportunity to then put in an opportunity to start at a
lower dose. There wasn\'t even a question about how long that could have
been. Dr. Temple even said it could have been 2 days if we wanted, but
we decided to make it, again, just more in tune with clinical practice,
2 weeks.

We would never be recommending on a routine basis that 2 weeks would be
an adequate time necessarily to fully evaluate the effect of any dose,
whether it\'s 8, 16, or 32. In fact, the whole analysis was really
concentrated on what happened at week 8. This was just an instrument to
be able to get the patients up to 32 and 100.

DR. ARMSTRONG: Thank you.

Then the final question I have at this point relates to whether there is
evidence to support b.i.d. dosing is indeed more effective than
once-a-day dosing with candesartan as opposed to the implication for
losartan.

DR. MICHELSON: Yes. Let me see if I can help you here. There is a slide.
I believe it\'s CS-34. Why don\'t you take a look and see if that\'s it.
But it\'s a study by Zuschke, study 116. Let me share this with you.

By the way, the slide we never got to discuss a moment ago in fact
addressed whether or not there was evidence for a dose response above 16
milligrams. So, if you wanted to get back to that, they know where they
slide is. I\'ll be happy to discuss it with you. Okay?

But if you\'re asking whether there\'s any evidence at all, a study was
done, placebo-controlled trial, looking at 8 milligrams twice daily
versus 16 milligrams once daily, and at these doses you can see that the
study had 90 patients per arm. It wasn\'t powered to look for relatively
smaller differences, but as you can see, there are differences of the
order of about 1.7, 1.8 millimeters of mercury for systolic blood
pressure and differences of the order of about 1 millimeter of mercury
for diastolic blood pressure.

DR. ARMSTRONG: But coming back to your request for a label change and
the issue of whether losartan administered twice daily would be as
effective or more effective than candesartan once daily, would you say
that the evidence for losartan b.i.d. is better in terms of efficacy
than the b.i.d. data that you\'re showing us for candesartan?

DR. MICHELSON: If I can, let me address something which is a similar
type of piece of information which we have for losartan. It\'s a study
that actually Dr. Weber did. Let me see if I can help you out here.
Actually Dr. Weber did this for Merck, not for us.

This is a small piece of a more elaborate study that he did. I apologize
to Dr. Weber, without his permission, for taking this out of context,
but just to address your specific question, when losartan was looked at
‑‑ and all this is now, again, this is sitting diastolic blood pressure
at the end of a 4-week period. That was the way Merck designed the study
looking at 100 milligrams once daily versus losartan 50 milligrams
b.i.d., and it\'s the only information I could find on the use of 50
b.i.d. There\'s no other information I could find in the literature. In
this study, you can see again the difference between those two in
diastolic blood pressure is a very, very similar order of magnitude.

DR. THROCKMORTON: Paul, just to remember, that was commented on in the
FDA briefing document too I think on page 14. Dr. Fred had looked at
some other materials as well.

DR. MICHELSON: And about the doses, there\'s one other slide I wouldn\'t
mind showing if we can get it. Would you like to look at the dose
response for either candesartan or losartan? Would that be of interest
or not?

Could we go back to the Rife slide?

DR. BORER: Before you begin speaking about it, Eric, Bob, you had a
comment?

DR. TEMPLE: Just a comment. As a matter of general policy, if the b.i.d.
versus o.d. comparisons that we usually see at least a little data for
even sort of lean towards suggesting that b.i.d. might be better, we say
maybe b.i.d. will be better. One doesn\'t want to treat those
rigorously. Obviously, to validate the kinds of differences we\'re
talking about, you need studies of the same size that were done here,
and that is quite unusual. So, like many dose response things, we look
at the numbers and write down the descriptive data. These are not
rigorously statistically meaningful differences. The impression we had
was that there might be some small advantage to going b.i.d. if you
didn\'t get where you wanted, and you could try it.

DR. BORER: I\'d like to interject one minor point here as well. I think
that Paul\'s question is very important. We\'d like to know the optimal
dosing regimen for any of these drugs. They probably should appear in
the label or what we know about them should.

Even though our decisions aren\'t based on medical economics, I think
it\'s important to recognize that it\'s very useful to have the q.d.
information nonetheless because third party payors are now, in many
cases, refusing to pay for drugs for their clients if a prescription is
written for b.i.d. dosing for a drug, the label of which says it can be
given q.d. And that specifically I know has happened with losartan, so
that although that shouldn\'t prevent any doctor from doing what he
thinks is right and patients taking what they have to take and all,
nonetheless it would be useful to know what the effects of q.d. dosing
are. And we\'ll get to the issue of whether it\'s useful to know what
the relative effects of two drugs in q.d. dosing are, but I think it\'s
important to recognize that this is a practical issue and this is useful
information.

Go ahead, Eric.

DR. MICHELSON: This was a study done ‑‑

DR. BORER: Eric, excuse me just one second.

Tom?

DR. FLEMING: Before we leave this point ‑‑ this is such an important
point ‑‑ I\'d like to understand what Bob Temple\'s comments were just a
moment ago. On page 14 in the FDA briefing document, we have presented
to us data on losartan at 25 q.d. against b.i.d. at week 12, and
differences were a drop of 5.8 versus a drop of 8, which is 2.2
millimeters of mercury. Bob, you had referred to these earlier as
trivial differences. So, basically a 2.2 is a trivial difference?

DR. TEMPLE: I don\'t think they\'re trivial. I think they rarely ‑‑ I
can\'t tell you whether in this case they did. They often don\'t reach
statistical significance, and indeed, when we draw the dose-response
curve for most of these things, the difference between the very highest
dose and the next dose often doesn\'t reach it either. We sort of look
at the whole curve, and you do the best you can because you\'d need
1,000 patients to distinguish between the very highest dose and the
lowest dose, just as you just saw. So, we think it serves people better
to write the description and the general idea of what the dose response
looks like than to not say anything.

But if you ask how rigorous is that, first of all, it\'s usually based
on data pooled across multiple studies which is of different durations,
different populations. You could criticize it if you wanted to treat
this rigorously. We\'re trying to give an impression, and in some ways
that\'s the best you can do with realistic numbers.

Similarly, although this varies from one case to another depending on
how well people look ‑‑ and that is very variable ‑‑ the b.i.d. versus
o.d. comparisons are often treated somewhat qualitatively. It wouldn\'t
surprise you that when the half-life of the drug is relatively short,
we\'re more inclined to think maybe that\'s true that b.i.d. works
better than once a day than when the half-life is 24 hours. So, I\'m
just saying there\'s a certain qualitative aspect to those aspects of
it. That\'s not the fundamental efficacy data which we wouldn\'t treat
qualitatively, but the descriptive aspects of dose response are just
inevitable when you\'re looking at multiple doses with relatively modest
differences as you get to the higher doses or b.i.d. versus o.d.

DR. FLEMING: So, if have data that suggests a 2.2 millimeter difference,
then you consider that irrelevant.

DR. TEMPLE: Absolutely. You\'d say you might try b.i.d. if the patient
doesn\'t give you an adequate trough response to o.d. If the half-life
is 36 hours, we\'re less inclined to put that in because it\'s sort of
implausible.

DR. BORER: Eric.

DR. MICHELSON: Dr. Armstrong, would you like to readdress that question
just quickly?

DR. ARMSTRONG: Yes.

DR. MICHELSON: You saw the dose response for and can I address ‑‑

DR. BORER: Paul, did you have any other issues?

DR. ARMSTRONG: No.

DR. BORER: Let me just ask Tom as our reigning hypertension expert
sitting at the table here, do you have any specific issues you want
answered here?

DR. PICKERING: Thank you, yes. I\'d like to hear more information about
exactly how the peak and trough blood pressures were measured. And
related to that, you\'re inferring that because both showed a
significant difference of a sustained effect over 24 hours, but I
didn\'t hear whether you have any actual data using 24-hour recording to
show the difference is sustained.

DR. PAPADEMETRIOU: Yes. The peak blood pressure was measured at 6 hours
after dosing, and the patients followed all the usual procedures we
follow in these studies. They were seated in a quiet room with a
pressure cuff placed appropriately and the pressure was measured three
times and it was averaged. Then it was again measured the next day prior
to getting their pill of that day. That was the trough 24-hour pressure
measurement.

DR. PICKERING: And any 24-hour readings?

DR. PAPADEMETRIOU: In this study there were no 24-hour readings, but
there are some data from a previous study that compared losartan to
candesartan that did 24-hour readings, and if you like those data, we
can show them to you.

DR. PICKERING: Yes, please.

DR. PAPADEMETRIOU: Here is a study that was done in 106 patients that
received candesartan and 100 patients that received losartan. The
candesartan was 16 milligrams, losartan was 100 milligrams. And all
these patients had 24-hour readings. They had a baseline monitoring and
then they had it at the end of the treatment period. In fact, the
monitoring was for 36 hours. And you can see the average diastolic
pressure for losartan, the change from the baseline here and the change
of diastolic pressure with candesartan of the same time period.

We also have these data for the systolic blood pressure, and again in
the same patient population, you can see the systolic blood pressure
reduction with losartan and the systolic blood pressure reduction with
candesartan. And you can see that pretty much the lowest values were
obtained around this time.

Maybe it\'s important to note that these studies compared 16 milligrams
of candesartan to 100 milligrams of losartan.

DR. LINDENFELD: Could I just ask a question about this slide? On page 10
of the briefing booklet, I was impressed by the blood pressure values at
48 hours and 2 weeks after withdrawal of your drugs. In fact, at least
in the diastolic blood pressure, there was almost no difference. So,
that\'s very different than this. In other words, it says here that
after 2 weeks of withdrawal they were still low. Is that correct? 48
hours?

VOICE: Two days.

DR. LINDENFELD: Okay, two days, but even so at 48 hours after
withdrawal, the diastolics were exactly the same with both drugs.
That\'s very different data than this.

DR. PAPADEMETRIOU: For this study?

DR. LINDENFELD: Right, on page 10. Isn\'t that 48-hour withdrawal data
from the CLAIM trials? Just help me understand this because I was
impressed that at 48 hours a withdrawal of ‑‑

DR. PAPADEMETRIOU: We do have the 48-hour data from the CLAIM program
that showed that difference is maintained.

DR. LINDENFELD: Right. That\'s 48 hours of withdrawal.

DR. PAPADEMETRIOU: Right, after the last dose, yes.

DR. LINDENFELD: That\'s my question because that\'s very different from
this data that looks like at 36 hours the blood pressures come up again.

DR. NISSEN: I think I can help you clarify this. It\'s two different
studies.

DR. LINDENFELD: No, I understand that. But I mean why in one study does
the blood pressure start to climb again and in the other, when you
withdraw the drug, it doesn\'t?

DR. PAPADEMETRIOU: These are the data we have for 48 hours after the
last dose in study 230, and you can see here that the difference is
maintained. It\'s 2.8 and 4.6 at least 48 hours after the last dose.

DR. BORER: Those aren\'t quite as impressive as the trough at 48 hours
before, which is the left-hand side of that slide I guess, but that\'s
okay. What you showed us were data up to 36 hours after withdrawal. And
I\'m not suggesting you should have, but there is no information about
the normal diurnal variation of blood pressure superimposed there. At 48
hours the numbers of both might have been a little bit lower than they
were at 36.

Are you satisfied with what you got?

Blase and then Steve.

DR. CARABELLO: Obviously, the whole study rests upon the ability to
measure blood pressure accurately. What do we know about site-to-site
differences in the way in which blood pressures were measured? Was the
same sort of device used? What was the actual mechanism of measuring the
blood pressure?

DR. PAPADEMETRIOU: Well, the blood pressures were measured in a
standardized way. All the centers were instructed to follow the same
directions, to ask the patients to be seated in a quiet room for at
least 5 minutes and relax without bright lights and any distractions.

Well, these are the instructions that were given to our centers of how
to measure the blood pressure. The patients were seated for 5 minutes, a
sphygmomanometer was used with a column and the appropriate cuff for the
patients was used, and the right arm was used almost in all patients
unless there was a reason not to. And the Korotkoff signs were read,
Korotkoff I for systolic and Korotkoff V for diastolic. Their
determination was based on three sequential readings at 2 minutes apart,
and they had to have less than 5 millimeters of mercury difference.
Qualifying blood pressure was a diastolic between 95 and 114 at week 3
or 4 or occasionally 4 or 5. There was a discrepancy of the placebo
run-in period. So, these instructions were given to all the centers and
they were followed.

DR. CARABELLO: So, these were all manual cuffs?

DR. PAPADEMETRIOU: Right.

DR. CARABELLO: Thank you.

DR. BORER: Steve.

DR. NISSEN: Yes. I had a couple of questions.

In all four of the studies that we heard about, the range of entry blood
pressures was 95 to 114. And I\'d be interested in knowing if in the
development program there is any comparative data for patients outside
of that range. Many of us see patients with relatively mild
hypertension, and of course, there are individuals with very severe
hypertension. So, this speaks a little bit to labeling issues here. I
understand why that range was chosen, but I\'m interested in whether
there\'s any data for people outside of that range.

DR. PAPADEMETRIOU: I haven\'t seen those data, but Eric may know.

DR. MICHELSON: Dr. Nissen, we did studies looking at people with more
severe hypertension, and those studies were included in the original
label. There\'s one study called 117. We have patients with and without
diuretic. We have no studies done that are active comparator studies
directly looking at people with severe hypertension.

DR. NISSEN: And mild hypertension? There is data or not?

DR. MICHELSON: I\'m sorry?

DR. NISSEN: People that are, say, in the 85 to 95 range and that sort of
thing.

DR. MICHELSON: No, we have no direct comparative data in that population
directly. We have done studies in populations that include diabetics,
for example, where the ranges are a little bit lower, but no direct
data.

DR. PAPADEMETRIOU: There is an ongoing study, a trough study, utilizing
patients with high normal pressures.

DR. NISSEN: I\'m interested in that data, but it\'s not available.

DR. PAPADEMETRIOU: There is no data yet.

DR. NISSEN: All right.

And then my second question was related to the diabetes issue. Given the
high body mass index of these patients, I would have guessed that many
of them were diabetic, and I would be very interested. These are tough
patients to treat, and a little bit of improvement in efficacy, as I
think everybody in the room knows, in the diabetic patient is
particularly important at reducing events. So, I\'d love to see that
data.

DR. PAPADEMETRIOU: The percent of diabetics included in the study was
rather small. It was about 9 percent, but here we have 107 patients with
diabetes, and compared to the rest of the group, they did have pretty
much the same response in systolic and diastolic.

DR. NISSEN: And the point estimates are very similar.

DR. PAPADEMETRIOU: Yes, right.

DR. NISSEN: How could you manage to enroll patients with that body mass
index and not have a third of them diabetic?

DR. MICHELSON: These are patients who admitted to being diabetic by
virtue of the medications that they were taking. So, you might think
that in that pool of 50 percent of our patients ‑‑ 45 percent who had
body mass indexes greater or equal to 30, one would suspect there are
many hidden diabetics there.

DR. NISSEN: Or metabolic syndrome patients.

But this actually is helpful because it looks like the point estimates
are about the same. Obviously, the confidence intervals are much bigger
because it\'s a small subgroup.

DR. BORER: Are there any other questions of fact? JoAnn.

DR. LINDENFELD: Just two questions. You said at the beginning the study
was planned to enter 735 patients and yet 230 and 231 both entered about
100 less than that. Can you tell me why that is?

DR. PAPADEMETRIOU: Right. These were comparative studies and
investigators are more likely and more enthusiastic in entering patients
in comparative studies because there\'s no long placebo treatment for
any group of the patients. And the recruitment went very fast, so it was
estimated that with 925 patients or so that were screened, that they
would provide adequate numbers to randomize 735. It turned out, however,
that when the screened patients reached that number, the enrollment was
closed. However, as they were progressing in the assessment for
randomization, a greater number than expected did not qualify primarily
for blood pressure, and it just turned out that the randomized patients
were less. However, the number randomized gave enough power to provide a
statistically significant result.

DR. LINDENFELD: These were concurrently run studies?

DR. PAPADEMETRIOU: Right, they were concurrently run.

DR. LINDENFELD: And another question. Were patients who entered these
trials withdrawn from antihypertensive medications?

DR. PAPADEMETRIOU: Yes, about two-thirds of them were on medication.
They were withdrawn from that.

DR. LINDENFELD: Can you give us some idea if the drugs that they were
taking prior to randomization ended up to be the same in both groups? In
other words, just by classification, ACE inhibitors, ARBs, beta
blockers. Were the two groups equivalent in the drugs that were
withdrawn?

DR. PAPADEMETRIOU: Right. I think we have that data available. Here,
between the two groups, candesartan and losartan, ACE inhibitors, about
the same, 22 to 23; ARBs about 12-14 percent; diuretics, calcium
blockers combination, and beta-blockers. Just about the same
percentages.

DR. BORER: Bob?

DR. TEMPLE: I\'m going to say something. You tell me whether you agree
or not. Because there was no placebo here, the absolute falls from
baseline are really unreliable. You don\'t know how much of those
changes are just a part of the study. It\'s usually 3 to 5 millimeters
of mercury in a typical trial. So, the absolute numbers are not
reliable, but the differences are or could be.

DR. PAPADEMETRIOU: Right. I totally agree with that. We cannot say what
was the absolute effect of either therapy.

DR. LORELL: One question that I wanted to address that\'s raised by your
least squares analysis is the response in comparison of the black subset
population.

DR. PAPADEMETRIOU: I\'m sorry. I can\'t hear you.

DR. LORELL: In your least squares analysis, I\'d like your comments
regarding the comparative data in the black population subset.

DR. PAPADEMETRIOU: Yes. The black population was small, as you saw. The
numbers were small, and the data were not designed to assess statistical
significance in these subgroups. We just showed them for the interest of
everybody, but because of the many subpopulations and the issue of
repeated measures and the small number of patients, statistics were not
done in these patients.

But you can see the reductions in pressures in the subpopulations. We
have them here, and we know that African Americans don\'t respond
usually as well as the caucasian patients to ARBs or to ACE inhibitors,
and this was true for these studies also. But they demonstrated a 6.4,
7.7, 8.2, and 6.6 reduction in diastolic pressure, and that is
consistent with previous data that we have seen.

DR. LORELL: I think my question is a little bit of a different one.
Today you\'re seeking labeling for a comparative analysis, so it\'s not
addressing the overall issue of choice of an antihypertensive in a black
patient. So, I guess my specific question is in the least squares
analysis that you presented, it at least raises the possibility or the
hypothesis that the comparative better efficacy claim might not apply to
the black patient.

DR. PAPADEMETRIOU: Certainly that appears to be true from the data, but
we can\'t say one way or the other because the population was
underpowered to determine that. I think if we want the answer to this,
we should design a prospective study in African Americans, which I would
support.

DR. BORER: Mike.

DR. ARTMAN: If we define control of hypertension as a sitting diastolic
blood pressure of 90 or less ‑‑ I\'m just trying to sort out. It\'s
probably in here somewhere, but it\'s hard for me to figure out what
percentage of patients were controlled. I think that\'s what a lot of
clinicians are going to want to know.

DR. PAPADEMETRIOU: We do have that slide for both studies 230 and 231.
You can see here the controlled patients with diastolic below 90. The
number was a little higher for candesartan compared to losartan. It
didn\'t reach statistical significance in this study, but here with a
little bigger difference in the average pressures, the difference was
statistically significant. So, there were about 9 percent greater
patients controlled with candesartan in the second study.

DR. NISSEN: Michael, can I follow up on that and just ask is there data
on systolic pressure? Many of us are much more interested since that\'s
the metric that has the most relationship to outcome.

DR. PAPADEMETRIOU: The controlled patients by diastolic and systolic
pressure are here. Again, the same trends were noted. The controlled
were 36 versus 31, and this is true for most of the studies we do. We
know systolic pressure is more difficult to bring below 140, and it\'s
easier for diastolic to bring below 90, and that\'s why the percentages
are lower. But again, the trends are consistent.

DR. NISSEN: Actually the relevant one is the third pair of bars over
there, which is the systolic pressure.

DR. PAPADEMETRIOU: Yes.

DR. NISSEN: So, it looks like it\'s 48 percent versus 46 percent.

DR. PAPADEMETRIOU: Right.

DR. BORER: Not to belabor the point ‑‑ and you may not have these data
‑‑ but the importance of systolic pressure seems to be age-related. So,
I wonder if you looked, since you had an age range up to 80, at people
over 55 for whom a systolic pressure really does seem to be the most
predictive measure. You may not have this.

DR. PAPADEMETRIOU: There is a breakdown of the population below 65 and
above 65.

DR. BORER: That would be fine.

DR. PAPADEMETRIOU: Here are the data for the patients over the age of
65, and the point estimates are pretty much the same.

DR. BORER: Okay, that\'s great.

I think Paul will have some questions about drug-drug interactions,
safety here, because we\'re not going to get into it in any other
portion of your presentation.

But just before he does, can you just explain to me ‑‑ I\'m sure this is
some anomaly, but how did 100.5 and 100.3 percent of people in the study
comply with the drug regimen? That was in the CANDLE study, not in 230
and 231. But just for our information.

DR. MICHELSON: We apologize for our implausible compliance numbers.
Those are based on tablet counts, and so what\'s happened is for 2-week
visits enough tablets are dispensed, for example, 20 days, and then
someone comes back and tablet counts are done. So, it\'s conceivable
that the tablet counts could be greater than 100 percent depending on
what day they might come back.

Well, let me just give you something that\'s a little bit more relevant.
If you ask me, for example, what percentage of patients took at least 90
percent of their tablets, as best we can tell by those tablet counts, I
can tell you that in each of the studies for each of the treatments
overall it might be about 93 percent of patients took at least 90
percent of the tablets they were supposed to have taken in any 2-week
interval.

DR. BORER: It sounds pretty good.

Paul.

DR. ARMSTRONG: A few questions on safety. In the label that exists,
there\'s some discussion of drug interactions that do not occur. Is
there now information on, for example, spironolactone, amiodarone, other
drugs that these patients would commonly be on which are not currently
articulated in the label but for which you have new information that
would be relevant to ACE inhibitors?

DR. PAPADEMETRIOU: I don\'t believe any of the patients entered in the
trials were on these medications. I don\'t believe these data are
available.

DR. ARMSTRONG: The second question. In table 12, page 44 of your
briefing document, could you just reassure me? The dizziness appears
twice as common in the candesartan versus the losartan group. Was that
clinically meaningful? What are we to make of this? Was it related to
blood pressure decline or other things?

DR. PAPADEMETRIOU: The dizziness was reported in a good number of
patients, as you said, but it was not temporally related to any
excessive lowering of blood pressure. And when patients complained of
dizziness in the clinic and the pressure was measured, it wasn\'t found
to be low. And it was kind of a sporadic reporting of dizziness. It was
reported in the baseline run-in period. It was reported during the
treatment period and afterwards. And it didn\'t seem to be related to
any excessive blood pressure lowering.

DR. ARMSTRONG: And the final question, on page 58, there\'s an
interesting discussion about the difference in the two agents related to
uric acid. Since many of these patients that presumably these drugs will
be used in, of course, will have gout or a tendency towards gout and
your label will speak to comparative superiority or efficacy relating to
lowering of blood pressure, would you also be wishing to warn physicians
about its use in patients who were susceptible to gout or had gout from
the standpoint of the disadvantage of candesartan versus losartan?

DR. PAPADEMETRIOU: These are the data on uric acid here. Yes, it is true
that losartan has slightly better uric acid than candesartan. In fact,
candesartan had no effect one way or the other. But this is debatable
what kind of clinical importance it has, and I think Dr. Kannel would be
more appropriate to discuss his data from his large cohort in
Framingham. As you know, this issue has been debated one way or the
other, but at the current point, there is no certainty that it plays any
significant role as a risk factor.

DR. ARMSTRONG: So, has no patient had an exacerbation of gout or the
development of de novo gout treated with candesartan?

DR. PAPADEMETRIOU: No patient had exacerbation of gout or a new onset of
gout.

DR. ARMSTRONG: Thank you.

DR. BORER: If there are no other substantive questions from the
committee, maybe we can move on to Dr. Kannel.

Oh, I\'m sorry. Tom.

DR. FLEMING: Just a very quick additional because JoAnn had asked a
question that I was interested in too. I\'m troubled a bit by the
substantial discrepancy between your intention of 735 patients. For
example, in the 230 trial where you had 611, at what point did you
discover that you were well short of your target relative to the
unblinding?

DR. PAPADEMETRIOU: That was certainly after the enrollment was closed
and after the baseline placebo run-in period was completed. And the
sponsor decided that it was too late to go back and reopen the screening
phase.

DR. FLEMING: And at that point, of course, all outcome data were still
blinded.

DR. PAPADEMETRIOU: Yes.

DR. BORER: Okay.

DR. PAPADEMETRIOU: Dr. Kannel.

DR. KANNEL: Good morning. I\'m pleased to have the opportunity to review
with you some of the data that are available to us on the
epidemiological and clinical significance of incremental changes in
blood pressure based on some of our data from Framingham and based on
large data sets from epidemiological studies that are prospective and
also on clinical trial data.

I think we would all agree that hypertension is a major treatable risk
factor for cardiovascular disease. It is a powerful independent risk
factor for coronary disease, for stroke, for peripheral artery disease,
and heart failure. I hope to convince you that the relationship is
continuous and graded, that there are benefits of blood pressure
reduction with pharmacological treatment that are also incremental and
continuous.

Framingham data on coronary disease and also on cardiovascular disease
in general indicate that hypertension is a major risk factor in the
occurrence of these atherosclerotic cardiovascular events, and it
certainly compares with elevated cholesterol and smoking probably in
terms of the absolute risk having a greater impact, and only for
diabetes in women does it seem to not be dominant. This is true also for
the risk ratios comparing those with and without the abnormality. Risk
ratios for hypertension are more impressive than for the other outcomes.

If one looks at the risk for a cardiovascular event by, in this case,
diastolic blood pressure, you note, of course, that for the individual,
as the blood pressure increases, so does the risk of having a
cardiovascular event, and this is incremental throughout most of the
range for diastolic pressure. It\'s also interesting to note that if one
looks at the occurrence of disease in the population, as indicated by
the bars, at specified intervals of diastolic blood pressure, that most
of the events are coming from those with high normal or stage I
hypertension.

Looking at the same relationship for systolic blood pressure, over 38
years of follow-up in the Framingham study for subjects aged 35 to 64,
we see an even greater influence of the systolic blood pressure than the
diastolic, again an incremental increase in risk from the very lowest to
the very highest systolic blood pressures. This indicates that certainly
for the individual the risk increases, the higher the blood pressure.
But once again, we see that for the population most of the events are
coming from people who have high normal or grade I hypertension.

We have an even more impressive data set, which includes the Framingham
study, from MacMahon published in Lancet in which they looked at the
data from seven prospective studies involved with stroke and nine
prospective observational studies with coronary disease from which there
evolved 843 stroke events and almost 5,000 coronary events. In all,
we\'re looking at databases of more than 400,000 people. This gives a
very, I think, compelling indication that there is a graded influence of
blood pressure on the risk of events, going down well into what we might
consider the normal range, for both stroke and for coronary heart
disease. The confidence intervals are very tight, so these estimates
are, I think, very secure from a statistical standpoint.

Now, based on these, MacMahon has estimated what sort of reduction in
risk one could see with specified reductions in diastolic blood pressure
between the range of 5 and 10 millimeters of mercury, and he shows that
the more the blood pressure is reduced, the greater the benefit, that
this is true both for coronary disease and for stroke, and the
reductions are substantial. And there is an incremental benefit the more
the blood pressure is reduced both for stroke and coronary disease, more
impressively for stroke than for coronary heart disease.

Now, these observational studies show rather similar risk reductions
with changes in blood pressure achieved. The estimates from the
observational studies, when applied to the drug treatment trials for
stroke, indicate very, very similar outcomes. We see almost identical
results. For coronary disease, the observational studies seem to
overestimate the benefit a bit, but it\'s important to recognize that
both databases show the more the blood pressure is reduced, the greater
the benefit and that there is a distinct incremental benefit to further
reduction in blood pressure.

Another way to evaluate the importance or advantage of additional blood
pressure reduction is to look at the number needed to treat to prevent
an event, and the event that\'s most feared in hypertensive patients is
stroke. Here we\'ve indicated the Framingham average risk over 10 years
for having a stroke for average-risk and for high-risk individuals. The
high-risk individual is the one who is a smoker, has a blood pressure of
100 millimeters of mercury, already has some indication of
cardiovascular disease, a reduced HDL, high cholesterol. I think several
points are noteworthy.

First is that looking within this category, let\'s say, of a 5 to 6
millimeter of mercury reduction in diastolic blood pressure, one sees
that the number needed to treat to prevent an event is about 28. On the
other hand, if you\'re applying this to high-risk individuals, the
number needed to treat is substantially lower. But if you look and see
if you can reduce the blood pressure by an additional 2 or 2.5
millimeters of mercury, in the average patient you get a substantial
reduction in the number needed to treat, and also in the high-risk
individual, you see a substantial reduction in the number needed to
treat to prevent an event.

Looking at this for systolic blood pressure, I think the SHEP and
Syst-Eur trials are the two that give us a pretty good idea for isolated
systolic hypertension as to the benefit of lowering systolic blood
pressure within these ranges with achievable blood pressure reductions
as indicated here. We see a very impressive reduction in stroke in both
trials, total cardiac events, and total CVD, combining both.

Now, given this demonstration of the benefits of antihypertensive
treatment, it\'s rather disappointing to see that we still have only 68
percent of hypertensive patients aware that they have the thing, that
only 54 percent are treated, and that only 27 percent are controlled.

Also somewhat discouraging are these surveys of general practice and how
physician practices look in the treatment of hypertension, one by
Coppola in the Journal of Human Hypertension, one by Berlowitz, et al.
in the New England Journal of Medicine very recently. And we find that
hypertension, particularly isolated systolic hypertension, is seldom
treated to the recommended goal, that if you look at patients who have
hypertension who come back to see their physician on a return visit,
that they receive no increase in medication 75 percent of the time
despite their having a continued blood pressure elevation. We also see
that the drugs are rarely up-titrated, that there\'s a reluctance to
include additional drugs. Therefore, we would conclude that therefore
more effective monotherapy drugs could facilitate attaining recommended
treatment goals.

So, the conclusion seems to me justified to reflect on the importance of
incremental blood pressure reduction, that hypertension is in fact a
major treatable risk factor for cardiovascular disease, including
coronary disease, stroke, peripheral artery disease, and heart failure;
that incremental blood pressure reduction is meaningful from a public
health standpoint and also in clinical practice; that the benefits of
blood pressure reduction with pharmacological treatment are incremental
and continuous; and that there is a compelling need for clinicians to
use the more effective blood pressure reducing drugs to achieve
recommended goals in individual patients.

Thank you.

DR. BORER: Thank you very much, Dr. Kannel. These are, of course, very
useful data.

Are there any specific substantive questions for Dr. Kannel? Steve.

DR. NISSEN: I\'m going to try to articulate this and I hope I\'m able to
do it. In trials where blood pressure is lowered, there are two issues.
One is the magnitude of blood pressure reduction, and the other is the
class of agent used to lower blood pressure. So, I have two questions,
and maybe we don\'t know the answer to any of this, but I\'d be
interested in your perspective.

One is, if you have a drug in the same class ‑‑ so, intraclass
differences ‑‑ and one drug in that class lowers blood pressure by more
than another, what might we anticipate about lowering events versus two
drugs in two different classes? In other words, if you lower blood
pressure by 12 millimeters with a diuretic and by 10 millimeters with an
ACE inhibitor, you expect that the diuretic will lower events by more
than the ACE inhibitor. Now, that\'s somewhat of a rhetorical question,
but I\'m interested in your perspective on the issue of intraclass
versus interclass differences in event rates when looking at blood
pressure reductions.

DR. KANNEL: The first point is that we have no data which have compared
rigorously individualized therapy for hypertension versus
across-the-board therapy using a single agent. So, we really don\'t
know. I don\'t think that trial is even ever likely to be done.

Now, there is some indication from various studies that there may be
unique effects of some antihypertensive agents aside from their blood
pressure lowering effect. That\'s not to say, however, that given this
unique effect within that class of drugs, the more you lower the blood
pressure, the better off you are. And I think the indications are that
that\'s the case.

Now, if one looks at trials, let\'s say, such as those trying to reverse
left ventricular hypertrophy with different agents, you find that no
matter which agent you use, if you lower the pressure enough and keep it
low, you will reverse LVH. On the other hand, some agents seem to do it
quicker and to a greater degree than others. For example, I think
there\'s some evidence that ACE inhibitors will get you more reversal
faster. So, I think it\'s clear that there\'s an impact of the class of
drugs as well as the amount you change the blood pressure.

DR. BORER: Bob.

DR. TEMPLE: Well, there have been attempts to look at that. There are
these massive meta-analyses, and they compete with each other based on
the bias of the people going in.

(Laughter.)

DR. TEMPLE: But my dominant reaction to them is that the results are
more alike than different. You can argue about whether one does stroke a
little better than the other or one does this a little better, but what
impresses me most is how little difference there is even if there might
be some small difference.

And these are massive numbers of patients. You know, you get over 25,000
in some of these things, and of course, we also have ALLHAT, which is to
some extent attempting to answer the same question. They found one
difference with doxazosin, but the study is still going, as far as we
know.

DR. NISSEN: I guess I was really maybe trying to get the point on the
floor that we may need to view intraclass differences and interclass
differences differently in terms of the potential here.

DR. TEMPLE: Yes. I would say our thinking on that is that across classes
there are many things to think about. I mean, what a diuretic does and
what an ACE inhibitor does is different in a lot of ways, and they\'re
not purely interchangeable although someone might say, oh, well, I think
this one should be used first or that one should be used first for
various reasons. But within a class, you generally think other things
are mostly equal, so it might be that a difference in effectiveness is a
more pure determination.

DR. NISSEN: That was really the point I was trying to drive at. For
example, diuretics increase insulin resistance and that may yield other
results that would be less desirable. So, I have a lot of trouble
interpreting small differences in blood pressure between drugs in two
different classes. I have less trouble in interpreting them within a
class.

DR. BORER: The question I was going to ask you, which you answered
several times, but I\'ll restate just to hear a yes or a no or anything
else you want to say. My inference in reviewing the epidemiological data
before this meeting specifically for the meeting was that the issue of
control that was raised in several questions is based on a consensus
construct about the importance of reducing events at least to where an
inflection point, an event rate, occurs which is somewhere around 90 to
95 diastolic and somewhere around 140 systolic, but that the risk
associated with a blood pressure continues to be lower the lower you go
even below that level of control, which may be important in interpreting
the results of these trials we\'ve seen. I assume that\'s correct.

DR. KANNEL: I think the overwhelming evidence, at least as I see it, is
that there\'s a continuous, graded influence that goes down into what\'s
considered the normal value. If you follow the recommendations for
hypertension over decades, you can see in the old days they said 100
plus your age is normal, and the pressures that were considered worthy
of treatment were really spanking high blood pressures. And some felt
that to lower blood pressure was a foolish thing to do, particularly in
the elderly. We\'re now down at the point where we\'re considering the
fact that perhaps even real modest elevations of blood pressure carry a
substantial risk.

Now, over the years in Framingham, we\'ve been tracking the level of
blood pressure at which events are occurring, and every decade the
average level at which events are occurring goes down and they are now
down to levels which are quite modest. So, I think we\'re going to be
focusing increasingly on treatment of real modest levels of pressure.
That\'s where the incremental benefit of lowering blood pressure becomes
very important because I indicated that most of the events are coming
from these modest blood pressure elevations.

Now, to control really severe hypertension, you need more than
monotherapy. You have to use two or three drugs. But if you get down to
these levels, to push them down to some goal that JNC VI or VII is going
to recommend, you can maybe achieve it with monotherapy if you have a
stronger drug.

DR. BORER: Thank you very much.

If there are no specific questions ‑‑ oh, I\'m sorry. Paul.

DR. ARMSTRONG: Dr. Kannel, there\'s a lot of discussion in the
physiology literature, as you know, about pulse pressure and about the
number of times the blood pressure is elevated with an individual\'s
stroke volume per minute. Do you have data? Are there data? There
obviously are data out there. What are your views about targets apart
from the conventional ones?

DR. KANNEL: Well, I think the field is in evolution, and I think we\'re
going to see more recommendations that focus on systolic pressure and
pulse pressure and arterial compliance. Some of the data your quoting,
which actually come from Framingham and were done by Stan Franklin,
would seem to indicate that in an earlier stage of life in the 30s, one
sees a dominant effect perhaps of diastolic pressure. Then it moves on
to systolic and finally to pulse pressure as you get older and older.
And as one looks at control, you saw that there was only about 50
percent control to the recommended levels. But if you look at that in
some detail, you find that most of the lapses or inability to achieve
control is occurring in failure to control systolic pressure. We found
this in Framingham. Others have found it in NHANES that this applies to
African Americans, to Hispanics, as well as to caucasians and even
diabetics. So, the chief problem seems nowadays to be in failure to pay
enough attention to systolic pressure and to controlling the systolic
component of the blood pressure.

DR. BORER: Thank you very much again.

Dr. Lancaster, do you want to sum up?

DR. KANNEL: Yes, I would like to ask Cindy Lancaster to come up.

MS. LANCASTER: I\'m coming. I\'m coming.

(Laughter.)

MS. LANCASTER: Thank you, Dr. Kannel.

As previously mentioned, AstraZeneca met with representatives from the
Division of Cardio-Renal Drug Products, the Office of Drug Evaluation I,
and DDMAC to obtain guidance about how to develop a program to support
comparator labeling. Based on this guidance and labeling precedents of
other antihypertensive products, AstraZeneca developed this comparator
text to supplement the information already described in the approved
labeling for Atacand within the context of its approved indication,
which is for the treatment of hypertension. This is important
information for health care providers, and therefore AstraZeneca has
proposed its inclusion in the labeling.

In summary, the proposed labeling describes the statistically
significant results from two trials comparing the blood pressure
lowering effects of candesartan cilexetil and losartan in hypertensive
patients. The labeling is specific to effects on blood pressure
reduction.

AstraZeneca will continue to work with the division to finalize
labeling, and we thank you very much for this opportunity this morning
to present the information to you today.

DR. BORER: Thank you very much.

Before you go away or we take a break or anything, I\'d like to ask you
a question to which there really, I think, is no absolute answer and I
think maybe we\'ve gotten the best answer from Dr. Kannel\'s
presentation. But we\'re talking here about amending a label with regard
to lowering blood pressure and the relative efficacy of a drug in
lowering blood pressure compared with another drug.

One might question the strength of data to support the clinical
implications of changing that surrogate. Now, I\'m not suggesting this
is bad, good, or indifferent. I just want to understand what your
thinking is in summary about the clinical implications of changing the
surrogate that we measure in this particular circumstance.

This is an issue that was raised by the FDA medical reviewer in his
review. I don\'t know that I would completely agree with the statements
that were made there, but it doesn\'t matter. I\'d just like to have a
summary statement about what you think about what this blood pressure
lowering means clinically since all we\'re measuring is blood pressure
lowering.

MS. LANCASTER: I\'d like to invite Dr. Papademetriou to come up and
comment on clinical significance.

DR. PAPADEMETRIOU: We believe when we treat patients with hypertension,
that the best blood pressure reduction we get, the better the patient
will be in the long run. The lower the blood pressure, the better it is
for the patient in preventing complications.

The physicians I think will benefit by having all the data available to
them when they are trying to make a decision what will benefit their
patients most and what is more likely to bring them to target and get
their pressure to the level they want. I think this is the implication I
see.

DR. BORER: And I certainly couldn\'t disagree with that. What I was
really sort of driving at here, though, was that this was not an outcome
trial, and you can\'t be held to a standard that isn\'t the standard we
use. But if you look at the events here, there was one myocardial
infarction in a patient who was on candesartan and none in the losartan
group. Does that mean anything at all? Are we using the right surrogate?

DR. PAPADEMETRIOU: Well, this is a fairly large study with 1,100
patients and these are patients that have a lot of other risk factors.
They have hypercholesterolemia, previous history of coronary disease,
vascular disease, and events happen unfortunately, even when we treat
those patients adequately. I think these events are incidental and they
are not drug-related and they\'re not attributed to an excessive
lowering of blood pressure for one thing. We have many, many data sets
from many, many studies indicating that lowering the blood pressure to
lower levels is beneficial.

DR. BORER: Tom.

DR. FLEMING: Well, since you\'ve gotten into this, maybe we\'ll talk
more about this after the break. I\'ve always been troubled by use of
surrogate endpoints, and there is more of an argument in a blood
pressure setting for having more reliance on this as a marker. I view
these as very small studies.

Clearly there\'s a lot that\'s not known about what the actual true
relative efficacy is. The differences in blood pressure are not efficacy
differences. They\'re differences in markers. And the data that we\'ve
seen certainly indicates that there is a correlation between reduction
in blood pressure and reduction in stroke and other clinically important
events.

Many things are uncertain to me. One is we\'re looking at this at 8
weeks. What is the necessary time frame and what\'s the magnitude that
we would have to see in order to know that we have a certain clinical
benefit?

Steve got at a very important issue before and that was different
interventions can have many mechanisms by which they achieve clinical
benefit. Patients should choose those interventions that yield the
overall global optimal benefit-to-risk profile. Blood pressure is one
mechanism by which adverse events occur, and there is certainly evidence
that an agent that has a lower blood pressure, if it\'s adequately lower
for an adequate duration of time, will in fact favorably impact one of
the mechanisms by which adverse events occur, but we don\'t know about
the other mechanisms. This was on a clinical endpoint study.

Safety issues are also relevant here, and I\'m perplexed about knowing
how much safety data we would need to have. The questions that are going
to be posed here indicate up front that we really need to understand
that if we achieve \"superiority\" in benefit that it\'s not coming at
the expense of safety. These studies are not really powered to be able
to look at relative serious safety events. There are more safety issues
in the candesartan group, I think twice as many SAEs and one-and-a-half
to two times as many people withdrew for AEs.

So, I\'m a bit perplexed about what is an adequate amount of information
in understanding benefit to risk because presumably, if one is going to
label an intervention as being superior, that\'s conveying a sense that
it\'s better to use that agent, which ought to mean more than just
through one of the intended mechanisms.

Another issue that we\'ll get into ‑‑ and maybe I shouldn\'t even raise
it because it\'s, in a sense, a separate issue is the issue of what is
the right dose and schedule to assess. I\'m a bit troubled, when we need
two adequate and well-controlled studies, to be doing two studies that
are both very small and essentially identical. It\'s really one study.
Would it have made sense that we would have had two studies and a second
study would have looked at a different schedule, specifically b.i.d.
instead of q.d.? But that\'s really a separate second issue from the
first.

DR. BORER: Okay. If there are no other questions or discussion at this
point, we will have other discussion in the context of the FDA
questions.

It\'s now 9:55. We\'ll take exactly a 14-and-a-half minute break and
come back here at 10:09 and 30 seconds.

(Recess.)

DR. BORER: Okay. Let\'s get together again, if we can, and complete this
morning\'s session.

We have a series of questions from the FDA, and we\'ll orient our
discussion around the questions. Now, Doug Throckmorton, if you\'re here
yet, we need to know which questions you want a specific vote and reason
from each member about.

The Cardio-Renal Advisory Committee is asked to provide an opinion on
the relative antihypertensive efficacy of a regimen containing
candesartan and a regimen containing losartan. Specific guidance is
sought on how to describe any relevant differences in labeling and on
the adequacy of the advice that we\'ve given sponsors to guide future
development programs. There is little published experience or relevant
guidance, but this issue is briefly addressed in ICH guidance E-10. And
for the record, it should be noted that everybody on the committee
received a copy of that quite a while ago to read and review for this
meeting.

In the past the agency has told sponsors that demonstrating superiority
to another antihypertensive medication on blood pressure lowering, when
both were appropriately dosed, was a relevant clinical benefit and that
such a claim required the following data:

First, evaluation of the antihypertensive effects of the respective
drugs at the highest approved doses. If the comparison was not done with
the approved product, bioequivalence of the study formulation and the
approved product must be demonstrated. Our recommendation has been that
this evaluation should include at least two forced-titration trials to
adequately assess the drug\'s relative antihypertensive effects. We have
also said that unless a placebo group is included in the trials, no
information about absolute antihypertensive efficacy can be inferred,
only comparative antihypertensive effect.

Two, data comparing the safety of the two agents, providing evidence
that the superior agent is not inferior with respect to safety.

The present sponsor has provided data from three randomized trials,
including two forced-titration trials. These were conducted comparing
candesartan force-titrated to a dose of 32 milligrams per day and
losartan force-titrated to a dose of 100 milligrams per day. The agency
and the sponsor agree on the numerical results of the efficacy analyses
for the three trials. At the end of 8 weeks, candesartan 32 milligrams
reduced blood pressure by about 3 and 2 millimeters of mercury systolic
and diastolic more at trough than did losartan 100 milligrams, when both
were given once per day.

So, we have our questions.

Which of the following are necessary or sufficient to establish a claim
of relative superiority for an antihypertensive?

We\'ll have our committee reviewer, Paul Armstrong, provide an answer
and then have anybody else comment or disagree if they want to. I\'d
like particularly to have comments on each of the questions from Tom
Pickering, our guest committee member, and of course, from Tom Fleming,
the committee statistician. Paul, go ahead. Number 1.

DR. ARMSTRONG: So, in response to question 1 ‑‑ I guess there are six
subquestions there ‑‑ I would say yes to 1.1, 1.2, 1.3, and 1.4. I would
say no, but desirable to 1.5, and I would raise the issues in 1.6 around
pulse pressure and, of course, issues related to target organ that we
have not discussed. That\'s how I\'d deal with those.

DR. BORER: Tom, do you have any thoughts about this?

DR. PICKERING: I would agree that you need both diastolic and systolic
significant differences not only at trough but throughout the 24-hour
period. I\'m sort of somewhat surprised that the original discussion
didn\'t include a request for 24-hour data on this, but I can\'t fault
the sponsor for that. The mean pressure obviously would be redundant if
both systolic and diastolic are reduced.

In terms of reduction of pulse pressure, my own view is that I think it
would be premature to require that since I think it\'s difficult to show
that individual drugs have significantly different effects on pulse
pressure. And also, we really don\'t know in therapeutic terms what the
implications are. So, I think for the present, it would be appropriate
to stick to systolic and diastolic pressure.

DR. BORER: What about the issue of other measures of effectiveness,
blood pressure being a surrogate? Do we need to have other measures of
effectiveness besides blood pressure alone?

DR. PICKERING: Well, I think if the claim is merely one of superior
reduction of blood pressure, then that\'s sufficient.

DR. BORER: Are there any comments from committee members that would
differ? I\'m sorry. Bob, you had a concern?

DR. TEMPLE: Actually I just wanted to ask Dr. Pickering a question.
There are two possible reasons that one member of a class could perform
better than another. One could be that the absolute effect is different.
The other could be is that one is more truly a once-a-day drug than the
other. In that case, you might see similar effects at peak but different
effects later because one of them is sort of forced into a once-a-day
therapy when it really would be better twice a day. Would that not be
okay? Wouldn\'t it be okay if it came out that way too? Not that that\'s
a problem in this case, but it could be some other time.

DR. PICKERING: I think we really don\'t know. There is some data that
when you\'re looking at regression of target organ damage, the average
24-hour blood pressure is the best predictor of the regression of
increased left ventricular mass. Other than that, I don\'t think really
one can say in terms of interpreting the blood pressure changes in
either outcome or changes in target organ damage.

DR. TEMPLE: So, maybe if it weren\'t different at both peak, and trough,
it would need to be buttressed with some 24-hour data showing an overall
difference.

DR. PICKERING: Right.

DR. BORER: Steve.

DR. NISSEN: I think this is actually a really important question. I want
to say that I think we need to shift our thinking here. We were recently
fooled into believing in a trial like HOPE that there was an
independent-of-blood-pressure effect by the drug ramipril because we
didn\'t really understand what actually happened. I think that we have
to avoid that kind of confusion. It turns out that it was only a 3
millimeter difference in blood pressure reported, but it turns out,
unbeknownst to any of us, it was a trough pressure measured long after
the drug was administered, and when an ambulatory blood pressure study
was done, the average 24-hour difference was 10 millimeters of mercury
which actually more than explained the event reduction.

So, I guess what I\'m trying to emphasize is what Tom said. To
characterize blood pressure, we need to know much more than just trough
pressure. We\'d like to know really kind of what the area under the
curve is. I think that in future development programs ‑‑ not this one,
but in future ones ‑‑ we really probably want to see the peak and trough
numbers but a substudy at least with some ambulatory blood pressure data
to help us understand so we don\'t make the mistake that we made with
the HOPE trial in actually taking a single trough reading and expecting
that that was reflective of what the 24-hour blood pressure effect was.

DR. BORER: I\'d like some comment from Tom and from Doug and Bob. But my
understanding is that to this time there are no data that relate any
parameter measured on a 24-hour ambulatory blood pressure and mortality
and cardiovascular events or cardiovascular events. That doesn\'t mean
it\'s not important to know, but what I\'m suggesting is that this is an
area where a great deal more information is needed so we know what to
measure, but it\'s maybe hard to suggest that we should change the
surrogate now.

Bob.

DR. TEMPLE: Well, the trouble is most of the drugs that have been
studied for outcomes either have very long effects like diuretics, so
peak and trough aren\'t that different, you know, reserpine and things
like that. And almost all of these have effects on both peak and trough,
and if you do that, it\'s hard to imagine that the overall isn\'t also
affected because you wouldn\'t expect square wave changes or something.
So, it\'s very hard to tease those things out. Therefore, no one has
yet.

It may be with ever-huger studies, people could look at something that
has a big early effect and a small late effect and see if there\'s any
difference. But I\'m not aware of anything like that either.

It would also help us to see where that HOPE data are because 10
millimeters of mercury is bigger than the effect of those drugs that
we\'ve ever seen in hypertensives. So, that\'s a surprising result.

DR. NISSEN: It was driven largely by the fact that the nighttime
difference was 17 millimeters of mercury. So, it turned out there was a
very big early effect that tailed off very quickly. And until the
ambulatory blood pressure data were published a few months ago,
everybody was citing the 3 millimeter difference and saying it couldn\'t
have been blood pressure, and now I think we realize that that was
wrong. I think that kind of mistake is going to get made in the future
if we\'re not careful about understanding the full 24-hour effect of an
antihypertensive drug.

DR. TEMPLE: For what it\'s worth, essentially all antihypertensives now
have ABPM data.

DR. BORER: Tom, do you have any other comment about that?

DR. PICKERING: No, but I would agree that while the new drug
applications do, many of the large outcome studies have not included
substudies. I mean, a particular example was the CONVINCE study where
they were interested in different chronotherapy where it would have been
very helpful to have 24-hour data. And HOPE is a classic example.

DR. THROCKMORTON: Steve, I want to press just a little bit. The question
here sort of was layered. One part of it was what advice should we give
sponsors as far as adequate evidence, and to date we\'ve relied on
trough data for the reasons that Bob pointed out. Obviously, we have
those data as far as outcome. So, trough is where we\'ve focused our
energies.

What I\'m hearing, though, is that there might be a couple of reasons
why you might like other data. One, you might imagine that the drugs
have different pharmacologic properties so that there\'s a big peak that
wanes in one of them that maybe doesn\'t wane in the other. I don\'t
know. Hard to imagine. But maybe you\'d want to have that information.

Alternatively, you might imagine that you believe that those other
measurements might, in fact, be a better way to look at benefit.

Can you help me sort of which way actually other people on the committee
too are sort of thinking about that?

DR. NISSEN: What I was thinking I guess is this, that obviously you have
to have a primary efficacy endpoint. I think the trough pressure is, in
fact, the right one to have. But when we review an application like
this, to me the presence of data showing differential effects at peak as
well as trough, on systolic as well diastolic help me define the effect
as a robust one. Again, without necessarily proving to you that that
kind of robustness will make it more likely to have a difference in
events, which I know Tom is concerned about, it sure makes me a lot more
comfortable if I have such data available as secondary efficacy
parameters.

And of those data, the most, I think, robust is to see those 24-hour
curves. I thought the 24-hour curves we saw on ambulatory blood pressure
where the candesartan curve was always beneath the losartan curve makes
me feel a little bit better about whether the effect is real.

Having said that, I think we might want to think about asking that the
primary efficacy parameter shift from diastolic pressure at trough to
systolic pressure at trough as we have new data that now suggests that
it\'s a better predictor. So, that would be one shift I would suggest.

DR. TEMPLE: Yes, I should tell you we\'ve been talking among ourselves
about that. In fact, you should have an effect on both. It\'s not too
much to ask. It\'s not that hard to show. They always do, by the way.

DR. BORER: Paul.

DR. ARMSTRONG: Well, having put the target organ issue out, let me come
back, Mr. Chairman, and ask, just to be the devil\'s advocate, whether
the measurement of blood pressure has anything to do with the disease
called hypertension and the consequences of stroke and myocardial
infarction that Dr. Kannel and others have pointed out. It seems to me
when we look at interclass differences, this issue sharpens.

So, I for one, as a doctor treating a patient, would like to be
reassured that if the blood pressure is lowered, that there might be
surrogates between the blood pressure measurement at one end and the
stroke at the other that might reliably guide me as to the likelihood
ratio of impacting long term on some of those phenomenon that I\'d like
to change.

So, what might be alternatives? Renal function or microalbuminuria as
we\'ve discussed around this table before. Left ventricular hypertrophy,
quantitative retinopathy. There are a variety of measures that are
intermediate that reflect the health of the target organ with this
disease that I think should be debated and discussed.

DR. BORER: Let me try and sum up, if I can, because this is not one of
the questions you wanted a vote on.

DR. TEMPLE: But if we had an extra 4 or 5 days, we ‑‑

(Laughter.)

DR. BORER: I think what the general sense of the comments is is that 1.1
through 1.4 are essential. One might want to get there by using 1.5, but
I suppose there are other ways you could do it. And it would be nice if
there were some information suggesting that the pathophysiology of the
processes that are putatively caused by hypertension are beneficially
affected, but I think we\'re going to have a hard time without a
workshop to come up with a guidance about how you would do that. Of
course, nobody else has yet either.

So, let\'s go on to number 2. The sponsor compared once-daily dosing for
both products, although both products are labeled for once- or
twice-daily dosing. Is a once-daily comparison a legitimate basis for a
superiority claim? Paul?

DR. ARMSTRONG: I would say yes, and I would add but the caveat is that
it, of course, does not extend to b.i.d. dosing if a product has been
marketed and suggested that it might be more efficacious if one moved
from once to twice a day. But on the basis of the data we\'ve seen and
the way it\'s usually prescribed, the answer is yes.

DR. BORER: I think the issue was not so much for this drug, which we\'re
going to get to in a later question, but in general. I assume your
comment is generalizable.

Does anybody on the committee have a different opinion about that? Tom?

DR. FLEMING: Well, I think this gets to this ICH E-10 guideline here
indicating that it may be necessary to look at different doses of the
control either through separate studies or through multi arms in the
same trial.

If one conditions and says that in clinical practice, there\'s a strong
preference for q.d. dosing and conditions this conclusion based on the
assumption that we\'re restricting to q.d. dosing, then this is a
legitimate comparison.

But if in fact there\'s evidence to suggest the control arm could, in
fact, yield better efficacy with b.i.d. dosing than q.d. dosing, then I
think one has to be very careful that one doesn\'t infer from your
statements that, in fact, you have superiority relative to what the
optimal schedule for the comparator regimen would be.

I think there\'s limited data in really understanding the efficacy of
b.i.d. versus q.d. losartan. I had referred earlier to what was in the
briefing document from the FDA on page 14. The magnitude of differences
at 25 for b.i.d. and q.d. were at least as large as what we\'re focusing
on as the difference between candesartan and losartan.

So, my sense is if one were trying to infer from these data a relative
efficacy against an optimal schedule, I think there are a lot of
uncertainties about that. But if one says clinical practice is really
interested in q.d. dosing, so we\'re going to condition on only that as
a restriction, then these data are adequate.

DR. BORER: Steve.

DR. NISSEN: This one is potentially pretty treacherous. Imagine a drug
for a moment that has a relatively short half-life but is very
efficacious that, when given b.i.d., produces substantially better blood
pressure reductions. And now imagine that such a drug is compared to
another drug which is overall, when given once a day, actually less
efficacious. You don\'t want to give a claim to a drug that\'s
long-acting compared to a drug that\'s short-acting without giving the
shorter-acting drug in a more fair way, which is b.i.d.

Now, clinicians may decide that the once-a-day drug, even though it\'s
less effective at lowering blood pressure, is preferable on compliance
basis, and that\'s fine.

But in terms of sticking by the rules, we were helped here by the fact
that the peak-to-trough ratios for these two compounds are both in the
.8 to .9 range. So, it\'s kind of a fair comparison, but I could imagine
another comparison where it wouldn\'t have been fair to use the primary
efficacy parameter of trough pressure and compare once a day to twice a
day. So, we ought to be careful here how we generalize this.

DR. BORER: Beverly.

DR. LORELL: Yes. I agree very strongly with that point. I think for the
specific comparison that we\'re being asked to address today, for the
reasons that Steve mentioned, the once-a-day comparison is very
legitimate. But I too would have concern if this were used as a generic
recommendation for potential present or future comparisons.

DR. BORER: Bob.

DR. TEMPLE: Let me try a distinction and see if this is what you have in
mind. If one drug were labeled for b.i.d. use because that\'s the only
way it works, and then someone said, okay, I\'m going to compare my drug
once a day because I\'m a once-a-day drug with your drug once a day to
show that it really doesn\'t work very well that way, we would probably
have a lot of trouble with that because that\'s really sort of
irrelevant. I think that\'s what you\'re saying.

DR. LORELL: Yes.

DR. NISSEN: I guess I\'m saying a little more than that. Let me see if I
can articulate it.

Some drugs which are labeled for once or twice a day that can be given
either way have peak-to-trough ratios which are bigger, and so yes,
it\'s true the drugs could both be given once a day, but where one drug
perhaps is a bit more optimal when given twice a day, and so you\'re not
clearly comparing a drug given in a way that\'s not in the label and
saying you\'re superior to it. That\'s off the table.

But what about a drug that has a peak-to-trough ratio of .5 and
comparing that to a drug that has a peak-to-trough ratio of .9, both of
which in their label are allowed to be given once a day? I don\'t know
that that\'s a fair comparison.

DR. TEMPLE: The reason we started asking a long time ago for
peak-to-trough ratios ‑‑ I\'ll tell you a little bit of history, which
you probably don\'t really care about. But we got a proposal to use
hydralazine in a once-a-day treatment many, many years ago. And they
measured only peak. Well, it worked very well at peak. But we said, does
it still work when you look at 24 hours, and we found no. That was a
revelation to us. We had never thought about that before, or much of
anything else actually.

(Laughter.)

DR. TEMPLE: So, ever after that, we began asking are you just taking a
short-acting drug and giving a lot, maybe getting extra symptoms at peak
just so you\'ll have a little bit of effect later and trying to get by.
So, we don\'t like that. But as you pointed out, some drugs do lose some
of their effect by 24 hours.

Now, one thought we\'ve had is if that\'s what you\'re doing, if you\'re
sort of stretching a short-acting drug and aren\'t going to the trouble
to make a controlled-release product or something like that, maybe
someone should be able to beat up on you by showing that you don\'t
really work very well once a day. Now, that\'s not what this case is.
These drugs do work once a day. But we hadn\'t necessarily thought that
that was an unfair thing to do if they were both labeled for that. Now,
if they\'re not labeled, as you said, off the table, but if they are,
maybe that\'s not such a bad thing. I don\'t know. A good thing to
discuss.

DR. BORER: This isn\'t one of those questions you require a vote about,
but I\'m going to provide one final comment, if I may. I think the
answer to this is absolutely yes, it is legitimate to use the once-daily
comparison as the basis for a superiority claim when both drugs are
labeled for once-a-day use. That information is useful to the clinician
who\'s going to use the drug that way. It doesn\'t preclude using either
or both drugs b.i.d., if one chooses to do that, because on the basis of
observations made in an individual, one gets greater efficacy with the
product using it in a different way.

But if the drugs are labeled for once-a-day use, which we know means
they can\'t have a peak-to-trough ratio greater than a certain value ‑‑
I think it\'s .5 so that safety doesn\'t become an issue ‑‑ I think
it\'s not only legitimate but useful to know what the relative efficacy
of the drugs are when used in that way. So, I think it\'s legitimate.

Let\'s go on to number 3. Which of the following are necessary or
sufficient to establish a claim of relative superiority for a once-daily
antihypertensive? Paul?

DR. ARMSTRONG: So, 3.1, beating the comparator\'s highest approved
once-daily dose? Yes.

Beating the comparator\'s most effective approved regimen? I would say
no.

Beating the comparator when it is dosed to maximum, perhaps outside the
approved dose range? I would say no.

Beating the comparator when used with other approved agents, such as
diuretics and beta-blockers? A tricky question, but I would have said
no, given the potential drug-drug synergism in one circumstance and not
another. So, I would say establish with monotherapy, and that\'s a
separate, potentially related issue. So, I would say no for those
reasons.

And beating the comparator in special populations? Again, I would say
no; that is, that it would be the broad cross section of populations,
but that clearly for orphan or special populations, a boutique drug,
that might be relevant. So, that\'s the way I\'d answer that.

DR. BORER: Does everybody agree with that? Are there any modifications?
Doug.

DR. THROCKMORTON: Sorry. Paul, I just want to make sure I understand.
Part of this had to do with sort of potential claims. What is it
possible to get? And you can sort of think of some of these as being
more significant. Say I was able to show you convincingly that I could
beat not only a comparator, but a comparator plus another drug. Is that
a more robust claim than just beating the comparator agent at one dose
or however you arranged that?

The other 3.5 had another intent and that had to do with you could
argue, some might argue, that this is a restricted population that was
studied in this trial. That is, these trials were in mild to moderate
hypertension. We\'ve had some discussion this morning that there are
other people out there, obviously, that have to take these drugs
monotherapy as opposed to combination therapy.

Are there other populations that a sponsor might, for whatever reason,
choose to investigate and if done convincingly, the standard that you
guys are talking about today that we\'ve provided to sponsors in the
past and brought that in, that that would be sufficient to get a claim
that we are superior in Norwegians? You know, choose your population. If
done well enough, are there populations you could identify that would be
relevant for that kind of a claim? Norwegians, my apologies.

DR. ARMSTRONG: So, 3.4 and 3.5. Just to clarify then. Entirely
reasonable against a background of a diuretic therapy that one agent
might well be superior to another and that would be enough to establish
a claim, absolutely, and clearly entirely reasonable to select an
elderly population with renal dysfunction and suggest that under those
circumstances, but not in the broad cross section, there would be
evidence for superiority. So, absolutely yes.

DR. BORER: What about 3.3, Paul? I think that everybody probably would
agree that 3.1, 3.2, 3.4, and 3.5 could give a basis for a superiority
claim. But what about 3.3?

DR. ARMSTRONG: Sorry. I thought no.

DR. THROCKMORTON: I heard no.

DR. ARMSTRONG: I said no to that because I don\'t think you want to mess
outside the approved dose range given a safety issue potential and other
issues.

DR. THROCKMORTON: But I also heard, Paul, no for 3.4 and 3.5. Did I
misunderstand?

DR. ARMSTRONG: Now that you\'ve broadened the question and I\'ve
appropriately broadened my thinking, I have tried to reflect the answer.

DR. LORELL: I think that 3.5 is a very important question and not for
consideration for the specific labeling that we\'re required to address
today, but for the FDA in the future. We\'ve already talked about an
extremely important population that wasn\'t addressed in the study at
all, and that\'s isolated systolic hypertension of the older patient, a
very, very large group.

I think the concerns about non-white, non-caucasian populations, whether
they be black or Hispanic Americans, remain a very major concern as a
public health and as a labeling issue.

DR. CARABELLO: But for 3.5, we\'re only talking about studies which were
specifically targeted to those populations, a study that proved that the
drug was better in Sicilians, for instance, not where the subgroup
analysis happened to show that Sicilians did better.

DR. BORER: I think the issue here is that Doug is asking us on what
basis could one come forward and request a superiority claim and not
what is absolutely necessary to have in every package in which a
superiority claim is being made.

Bob.

DR. TEMPLE: This would more relate to cross-class comparisons, but it\'s
completely obvious from data we already know about that it would not be
difficult to show that certain drug classes work better in a black
population than ACE inhibitors or AII blockers. In fact, there already
are published trials saying just exactly that.

I hear you thinking that that might be useful information and would be
legitimate to put into labeling if it was properly done and
appropriately qualified?

DR. BORER: To put into labeling? I think if we had the information, it
would be reasonable.

DR. TEMPLE: What we have now is labeling that says this drug works
equally well in whites and blacks. You have that. You have other
labeling that says this doesn\'t work very well in a black population.
There isn\'t anything that I know about that says I work better than
they do in a particular population. I may just not remember, but I
don\'t think so.

DR. THROCKMORTON: It\'s all pretty general language I think.

DR. TEMPLE: It\'s what I said. It says something about the drug itself.
There have not been comparative claims of that kind. You could argue
about whether that\'s useful, given that the whole class is known to
behave in a certain way, but I sort of hear positive thoughts about such
things because they might be useful. I just want to be sure I\'m
interpreting you correctly.

DR. BORER: If I understood correctly ‑‑ and I\'ll let her speak for
herself ‑‑ what Beverly was suggesting was that it would be very
legitimate if someone wanted to come forward and do those studies and do
them and show that a certain drug is better in a subpopulation, in a
minority population, whatever, than another drug, that that would be a
reasonable thing to do, but not that every package needs to show that.

Steve, you had another comment?

DR. NISSEN: Yes. Here\'s the question I would ask; at least I asked.
What do clinicians need to know in order to optimally care for patients?
Somebody walks in my office with isolated systolic hypertension. If
there is a drug out there that works better in that population than
another drug, would it be useful for me as a clinician to know that? If
it could be proven satisfactorily to everybody involved, the answer is
you bet. Or in African Americans. So, when it\'s clinically relevant,
when there is a population out there, we have to decide which drug to
use. Right now we don\'t have much information about that and I think
that would be potentially very valuable to clinicians.

Similarly, many patients that we see particularly with diabetes are on
poly-drug regimens, complex regimens where it\'s tough to control the
blood pressure. If some combination or permutations of agents had a
particularly synergistic effect such that we could get better blood
pressure control by combining agent X with agent A rather than agent Y
and if that were really robustly shown, then that could have a really
big impact on how we think about this.

For example, if adding a drug to a diuretic, if drug A added to a
diuretic does a better job than adding drug B, even though compared to
each other, they may not be very different, then that\'s useful
information for clinicians, and if it can be proven satisfactorily, I\'d
like to know that and I\'d like that to be in the labeling.

DR. BORER: Paul.

DR. ARMSTRONG: I guess it would be helpful, Bob, ‑‑ and maybe in the
workshop you\'re going to organize, you can deal with this ‑‑ the extent
to which the label should become an advocacy statement for education of
physicians and doctors and used by the drug detailers to impact
favorably on the care of patients.

DR. BORER: Tom.

DR. PICKERING: Yes, just a word of concern about saying that a drug
works better in one ethnic group than another. When ACE inhibitors first
came out, the word was that they didn\'t work as well in blacks as in
whites. I think there was genuine concern that African Americans were
not getting some of the benefits of ACE inhibitors they might have
otherwise have been getting, independent of the blood pressure effect.
In fact, you can get the same effect with just increasing the dose and
combining it with a diuretic.

DR. BORER: Have you gotten all the advice you need about this one, Doug?

I\'m sorry. Tom.

DR. FLEMING: I\'d like to go back then to Paul\'s answers to questions
3.1 and 3.2. Paul, I think you had said yes to 1 and no to 2.

We had talked a bit, when we answered question 2, about a scenario where
the comparator might have substantial evidence indicating that a bi.d.
regimen would be more effective in its delivery than a q.d. One might
imagine that the once-daily antihypertensive experimental regimen,
let\'s say, yields a 6 millimeter drop, and if you compare it to the
comparator\'s once-daily, you would see superiority at 6.4. But it\'s
already known that the comparator is much more effective at b.i.d. And
let\'s say it would be 10. So, it would be inferior. It would be 6
against 10.

In general, my answer, I thought, would have been you want to compare to
the comparator\'s most effective approved regimen if there\'s evidence
strongly indicating that the comparator is more effective at a different
schedule. In the setting in which there isn\'t such evidence, and the
evidence suggests that q.d. and a different schedule would be relatively
comparable in efficacy, then I can understand that it would be, as
you\'ve indicated in 3.1, appropriate to compare it to the highest
approved once-daily dose.

But in those settings where there\'s considerable evidence that the
comparator is more effective in a regimen other than once-daily dosing,
then to claim superiority, I would think we would have to be superior to
that optimal delivery of the comparator regimen.

DR. BORER: For the record, Paul already agreed with you when Doug
clarified his question, that 3.2 would be a reasonable basis for a
superiority claim.

DR. TEMPLE: Tom is saying it\'s necessary. I believe several people said
not necessarily if the drug that doesn\'t work as well once a day has a
once-a-day claim. So, a lot turned on what the nature of the claim is.

DR. BORER: Do you want a more complete clarification of the answer to
that?

DR. TEMPLE: Well, we should be sure that we\'ve heard you correctly.

DR. FLEMING: Let me just emphasize this. What I\'m suggesting is if
there is an approval for the comparator agent at q.d. and, for example
b.i.d., and there\'s considerable evidence that b.i.d. for that agent
delivers greater efficacy, then if I want a superiority claim against
the comparator, I\'m suggesting that it would be necessary to have
evidence of superiority against its known more effective schedule.

DR. BORER: Beverly.

DR. LORELL: I agree with that.

DR. BORER: Mike.

DR. ARTMAN: Yes, I agree with Tom.

DR. BORER: JoAnn.

DR. LINDENFELD: I\'m not sure I agree with that. Let me just be sure
I\'m clear. But I think if the less effective drug is approved for once
a day, then I as a doctor in the office want to know if I can give
another once-a-day drug and it\'s better just once a day. So, I think
even if the drug is more effective at b.i.d., if it\'s approved to be
given once a day, then I think it\'s fair to say that these two drugs
compare and one is better once a day, and then you can make it clear
that the once-a-day drug, the more effective one, is not as effective as
against b.i.d. But giving once-a-day drugs is important, if I understand
your point.

DR. FLEMING: Well, this might be a situation that doesn\'t exist. I.e.,
if the comparator agent is known to be more effective at, let\'s say,
b.i.d. than q.d., would there be a setting where it would be approved in
both schedules?

DR. TEMPLE: It could be if it lowers the blood pressure at trough by 4
millimeters of mercury or so, which is not so different, we might
approve it even though the peak effect was bigger. There are some cases
where that\'s been true, and we\'d try to give as much data as we could
so that people could make a judgment about how they were doing. But
obviously some people, if they were controlled to the physician\'s
satisfaction with the once-a-day regimen might choose that because they
would conclude their patient is more likely to take it. So, there could
be cases like that. Not with this class which seems to have an effect
that outlasts its blood levels to a degree, but with calcium channel
blockers, you could have that certainly where the effect is relatively
evanescent.

DR. THROCKMORTON: But we do first start out saying, yes, it has
potential to be a once-a-day drug or not. Certainly if that\'s not
demonstrated, you\'re right. We\'ll say if you gave tons of it to sort
of symptom levels at peak, you might eke out a trough. That isn\'t
something that we\'re interested in.

The typical label for this class tends to describe the use at once a day
up to maximum dose and then when available what to do after you reach
that top dose. That may mean that you double up the dose, you drop back
and go to b.i.d., what it is, add a diuretic, what the available data
suggested. And that\'s sort of the flavor of these labels.

So, what I\'m hearing is if that\'s the flavor of the label, if the
label has a sort of once-a-day feel to it, then that\'s an adequate
comparator. If the label has a twice-a-day dosing, it doesn\'t even
raise the issues of a once-a-day possibility, then obviously, as you
said before, that wouldn\'t be a fair comparison.

DR. TEMPLE: There are also some in between. I may misremember this, but
for at least one beta-blocker ‑‑ but since I\'m not sure, I won\'t name
it ‑‑ it said usually you should use divided doses, but some people may
be controlled by a once-a-day dose. That\'s sort of in between. That
suggests that usually you need multiple doses, but somebody might get
away with ‑‑

DR. FLEMING: And in that setting in particular, I would think it would
be compelling to argue that you would need to be comparing to the b.i.d.
dose.

DR. BORER: Okay, the unusual setting notwithstanding, my opinion would
be identical with JoAnn\'s. If the drug is approved for once-a-day
dosing and people can expect that it would be effective for once-a-day
dosing, I think it\'s very reasonable to claim superiority for
once-a-day dosing, but you have to be very careful about the way the
label is written so that there\'s no implication that something else is
also true that hasn\'t been studied.

Paul.

DR. ARMSTRONG: Just to clarify and come back to Tom\'s point, my view
would be if we\'re talking about changing a label for comparison of drug
X to compare with drug Y, that first we look at the comparison at once a
day, and secondly we say drug Y, which is already approved for
twice-daily dosing, because it\'s germane to the discussion we\'re going
to have later, you cannot claim superiority to an efficacy dosing
regimen that\'s been approved only on the basis of once a day. So, the
caveat has to be that there may be a more effective way of administering
the drug that you\'re trying to claim superiority over. There I think
the principles of fairness apply in the label and are clear.

DR. BORER: Steve.

DR. NISSEN: Bob, there are some shades of gray here I think. Let me see
if I can help to clarify that. I can imagine a drug which is somewhat
more effective b.i.d. than q.d., where as a clinician, in a patient
that\'s near to their target blood pressure, I might give the drug once
a day because of the convenience effect. But to get maximum efficacy in
a patient that\'s much harder to control, I\'d go to b.i.d. So, that
shade of gray here means that we\'ve got to be careful. So, beating up
on a drug simply because it has q.d. in its label somewhere that you can
give it q.d. I don\'t think is right.

So, I agree with Tom and I don\'t agree with Jeff or JoAnn. I think that
it depends, and it depends a little bit on what the peak-to-trough
ratios really look like. I might use a drug with a .5 peak-to-trough
ratio in certain patients, and that\'s fine, but then I might well
recognize that giving that drug b.i.d. can get a pretty much bigger
effect, and therefore I wouldn\'t want somebody to be able to say that
their drug is superior to such a drug when, in fact, we know that that
drug can work pretty well b.i.d.

DR. TEMPLE: Well, they\'re not saying it\'s superior. They\'re proposing
to say that when you use it once a day, it gives you a difference of X
millimeters of mercury. The proposal didn\'t say how big the difference
was, but we would include what the difference was.

DR. NISSEN: No, but you know, in the nuances of what a detail person is
going to do, once you give them that superiority claim, they\'re going
to ram it down everybody\'s throats. I just think it\'s potentially a
mistake here. We\'re very fortunate here I think that we have drugs that
have very similar peak-to-trough ratios. It makes it very clean. But it
may not be so clean next time, and I think we\'ve got to be careful.

DR. TEMPLE: Let me mention one thing. You have one other thing here too.
The usual reason we worry about peak-to-trough is that we\'re afraid the
pharmacologic effect will emerge and then disappear. What that means is
that if you give the drug that ought to be given twice a day in a single
dose early, it ought to be showing its maximum effect if the usual thing
you\'re worried about is here.

Well, here the differences were observable both at peak and trough. So,
one of the things you might worry about is not present here. That
suggests that it wouldn\'t make much difference even b.i.d. Of course,
we don\'t know that.

DR. BORER: Blase.

DR. CARABELLO: If you have two drugs that are both labeled for
once-a-day dosing and one is superior, I think it\'s perfectly
legitimate to make that claim of superiority. If it turned out that in
that context you had two drugs where one was superior at once-a-day
dosing while the converse was true with twice-a-day dosing, you simply
make the label say that, and then there\'s no question. I don\'t think
these two issues need to be in conflict as long as the label states the
truth.

DR. BORER: Susanna.

DR. CUNNINGHAM: I would agree that I\'d like both pieces of information
and have the label say it. But I also think we have to worry about what
people will really do, and people are most likely to take things once a
day and less likely twice a day. So, that\'s another piece that\'s going
to add in in the real world.

DR. BORER: Tom.

DR. PICKERING: I would say there\'s no simple answer to this question
and you have to judge each case on its individual merits and look at the
time course of the two drugs being compared in each case.

DR. BORER: Now, do you have as much advice as you\'d like?

(Laughter.)

DR. TEMPLE: Oh, yes, we got a lot.

DR. BORER: I neglected inappropriately at the beginning of the session
after the break to ask if there are any speakers who want to say
anything in open public hearing. We had nobody sign up to do this, and
that\'s why I didn\'t ask the question. But is there anyone who needs to
make a public comment?

(No response.)

DR. BORER: If not, we\'ll go on to question number 4. Paul, why don\'t
you just read it and go through it.

DR. ARMSTRONG: Is it possible to claim superiority if the comparator has
other outcome benefits not demonstrated by the test drug? I would say
yes, most certainly.

On clinical endpoints in hypertensive patients, for example, stroke
reduction? Yes, enthusiastically.

And in other populations such as those with heart failure, diabetic
nephropathy, for example? And again, I would say yes.

And then the final question in that section of question 4 is, is it
possible to claim superiority if the comparator has fewer potential
pharmacokinetic interactions such as those related to CYP 2D6 or CYP 3A4
inhibition? And I would say no unless there was clinically relevant
drug-drug interactions or special populations where these kinetic
interactions were shown to have clinical significance.

DR. BORER: Can I ask for a clarification there?

DR. THROCKMORTON: Jeff, I\'m sorry. We left a phrase out of here, and I
think it changes, a bit, the sense of this. I\'ll paint the scenario.

The question I believe should read is it possible to claim superiority
as an antihypertensive, that is, just measuring differences in blood
pressure if the agent you\'re comparing yourself with has some other
effect. So, an example would be you are comparing yourself against
ramipril and measuring only differences in blood pressure. How would you
factor in the description of the HOPE trial that\'s in the approved
labeling for ramipril? Would that mean that showing a difference in
lowering blood pressure isn\'t ever enough to describe in labeling, or
is it something that\'s always useful to describe in labeling, someplace
in the middle presumably?

DR. BORER: Paul, do you want to start on that one?

DR. ARMSTRONG: So, you\'re rephrasing all of question 4. Is that
correct? Or just the last component. I\'m a little confused, Douglas.

DR. THROCKMORTON: Just 4.1 refers to lowering blood pressure compared to
doing other things where clinical outcomes have been measured.

DR. TEMPLE: The question really is suppose blood pressure isn\'t the
whole story for this drug. Is it okay to concentrate on the blood
pressure effect when there\'s outcome data? You could ask the same thing
about cholesterol-lowering drugs. The fact is that some of them have
comparative data on cholesterol lowering when there are existing
considerable differences in how much outcome data they have. But what do
you think about that?

DR. ARMSTRONG: Well, I strongly advocated, in one of the earlier
questions, for intermediate surrogates between blood pressure and
stroke. So, I think my stance on this particular one is pretty clear. I
don\'t know whether it\'s good enough to add a new drug to the ones we
have in our armamentarium that lowers blood pressure and doesn\'t do the
other things that some of the drugs that lower blood pressure do that
are good for patients. Is that helpful?

DR. BORER: Can I just, again, try to get a clarification here? It seems
to me that when we recommend that drugs should be approved for their
capacity to lower blood pressure, we\'re immediately making the
inference to ourselves in that approval that we\'re approving a drug
that\'s going to reduce the rate of myocardial infarction, stroke,
cardiovascular death, renal failure. That\'s a given. That\'s what a
surrogate is.

There are two possible interpretations of the question. One is do we
have to show that the drug is also better than some existing approved
drug for outcomes, and if that\'s the case, I would say no, it
shouldn\'t be necessary to do that. But the other possible question is,
if we believe the new drug is better and we show it somehow ‑‑ and
let\'s not talk about how we show it because that\'s a very different
trial design possibly, but if we could show that a drug were better,
would that be a basis for a superiority claim? Am I somewhere in the
range of what you\'re asking about?

DR. TEMPLE: Let\'s take an example. You, last visit, urged us to approve
two drugs, including the comparator agent here for use in type II
diabetes to prevent the progression of renal disease. Okay. So, when and
if we get around to doing that and agree to it, losartan will contain a
claim that it\'s useful for that. Okay.

The question here is, does that make you want to think in any way
differently about giving a claim that once-a-day therapy with
candesartan lowers blood pressure better than losartan? Should we factor
that in in some way? Should we say something about it? Should we not
allow it?

DR. BORER: That\'s a complicated question.

DR. TEMPLE: That\'s why we pay you the big bucks.

(Laughter.)

DR. BORER: Some relatively quickly stated opinions around the table here
about that. Steve.

DR. NISSEN: Yes. I would say one should be very, very careful here
because what it would mean is let\'s suppose somebody came along with
another ACE inhibitor and showed that it was superior at blood pressure
reduction to ramipril. If we said that HOPE trumps everything else, then
you could never give a blood pressure claim to another drug because HOPE
has got that 10,000-patient, albeit horribly flawed in my opinion, study
that showed a purported clinical benefit. But you\'re giving them that
claim, and so if that trumps everything else, then you\'ve got a really
big problem because then any drug that wants to come along in the class
and say we\'ve got a better blood pressure effect would have to do a
HOPE-sized endpoint trial in order to get a superiority claim.

I think what one could say in such labeling is that drug X had a greater
blood pressure lowering effect than ramipril, although it has not been
proven to have a superior effect on X outcome. And then I think you\'ve
covered yourself. So, you may want to put it in the label, but I think
to say that you can never give a claim for a surrogate once you\'ve
given a claim for a hard endpoint I think is going too far.

DR. BORER: Why don\'t we start at that side of the table and just go
around and get a quicky opinion here. Tom.

DR. PICKERING: Yes, I guess in this context we have the LIFE study, and
I would agree with Steve, that any claim has to be very specifically
focused on blood pressure reduction and there may be subtle nuances
where you say it\'s a better antihypertensive. That doesn\'t distinguish
between whether it\'s better at blood pressure reduction or better at
preventing complications. So, I think it has to be very specific to
blood pressure.

DR. BORER: Susanna, any additional thoughts?

DR. CUNNINGHAM: I think I\'d always like to know it prevented events. If
I was going to be taking something, really my concern is that the event
I\'m going to have, not my blood pressure per se. So, I think we\'ve got
to be very careful. This is very difficult to give a yes/no answer to.
It\'s going to be a maybe answer, and it needs to be as specific as
possible.

DR. BORER: Blase.

DR. CARABELLO: If you had a drug that was superior in lowering blood
pressure but clearly was inferior at other endpoints, I think it would
be very difficult to allow the claim of superiority to stand. Let\'s say
we were comparing hydralazine to propranolol when they first came out.
Well, at their maximum dose, I guarantee you that hydralazine lowers
blood pressure more. Would we have wanted to go on record as saying
hydralazine is a better drug than propranolol? I think not.

DR. BORER: Paul, do you have any additional?

DR. ARMSTRONG: I think this is slippery and I think it\'s time to change
in relationship to blood pressure lowering.

DR. BORER: I think that what Tom said and what Steve said are most
appropriate; that is, if a drug is being judged as an antihypertensive
drug and blood pressure is what\'s been measured and other things
haven\'t been measured, that it\'s fair to give a superiority claim for
blood pressure lowering, if the data support that, and perhaps it\'s
appropriate to say, but we haven\'t studied the other things or
something like that. We\'re not going to wordsmith here.

I think the issue that Blase raises, which is a very important one,
about a drug clearly being inferior on events would be an important
consideration if we had the data to show that. But we don\'t. In fact, I
don\'t think we ever have. So, there would be an important
consideration.

But should a drug company, sponsor, be held to the standard that it is
necessary to do the other study to show superiority or inferiority or
equivalence on the non-blood pressure endpoint, I think that\'s too high
a standard. I think that\'s a separate issue. We all accept that from
Dr. Kannel\'s data that the more you lower blood pressure, the better
off you are, to a certain extent until you faint. Therefore, if one drug
is better than another for that purpose, that\'s something that should
be known and can be legitimately factored into clinical decision making.
So, I think it\'s a reasonable basis for a superiority claim.

Tom, do you have any other comments about that issue?

DR. FLEMING: Well, this is a situation that troubles me greatly in using
surrogates. Ultimately what I want to be superior with respect to are
the clinical endpoints, superiority in reducing risk of stroke and MIs
and death. If I am superior in blood pressure control, then it\'s
certainly acceptable to claim superiority in blood pressure control. And
that\'s one mechanism by which you would be influencing the occurrence
of those other events.

But in a setting, which I think this question is posing, where I know
the comparator has evidence of other effects or other mechanisms of
action other than through blood pressure control whereby it\'s achieving
clinical benefit, then I think it\'s misleading to simply state that the
study has shown better blood pressure control. I think you have to give
a more global presentation of the results. There is evidence of
superiority in blood pressure control, but I think you have to then
indicate where there are these other superior benefits of the comparator
so that someone can make a more informed judgment about global benefit
to risk.

DR. TEMPLE: You don\'t know about superior benefits. All you know is
that they\'ve found something that the other one hasn\'t. You could, in
some sense, say as soon as one member of a class gets an outcome claim,
all the rest of them ought to be labeled that we don\'t have that
outcome claim. Now, that\'s not crazy, but it would be radical.

DR. FLEMING: So, basically there are two ways of reading this question
when you say not demonstrated by the test drug. It could be that the
test drug has been assessed and the benefit wasn\'t demonstrated or that
you haven\'t even looked for it yet. And those are distinct
circumstances. The former circumstance is what I consider to be
especially problematic.

DR. BORER: As a practical matter, what Bob says I think is very
important. Ramipril received a labeling claim on the basis of the HOPE
trial. No other ACE inhibitor has that claim, and in fact if you wanted
to use another one for that purpose, I would suggest that we don\'t know
what dose to use, whereas there was a dose-response curve shown in the
HOPE trial. So, you have a lot of information there.

But, as Blase and I were discussing earlier, if somebody gets his or her
medical care at a Veterans Affairs hospital, you can\'t get ramipril for
the indication that we\'re talking about. So, people wind up perhaps
using other ACE inhibitors without the data. So, the point is well taken
that if we don\'t have these data, it\'s hard to penalize a drug for not
having data that we don\'t have when there are data that may be relevant
for other purposes. Well, enough said.

JoAnn, do you have any other thoughts about this issue?

DR. LINDENFELD: No. I would just agree. I think it\'s fair to say that
the blood pressure control is superior if there are no concerning data
that there might be other events that are bad, and then in the labeling
to take care of the idea that we just don\'t have the same outcome data
as we have with the comparator.

DR. TEMPLE: Well, on the last, though, I just want to emphasize, for
example, we don\'t have all other ACE inhibitors labeled saying I\'m not
ramipril or I\'m not this or that.

DR. LINDENFELD: But they\'re not specifically compared to ramipril, are
they, in the labeling?

DR. TEMPLE: No, but they lack the data that ramipril has. If they were
directly compared, yes, we\'re not burdened by that ‑‑

DR. LINDENFELD: But here you\'re asking to say that one drug is
specifically better than another individual drug, and so I think if you
want that claim, you should say that we don\'t have the same outcome
data with the other specific drug that we\'re claiming to be superior to
in blood pressure. I think that\'s a little bit different situation.

DR. TEMPLE: Well, that is.

DR. NISSEN: A very important point that JoAnn makes. I think what she\'s
saying ‑‑ and I agree with it wholeheartedly ‑‑ is if somebody came
along and said, we lower blood pressure better than ramipril and I want
a claim, then you also force them to add to the label that they don\'t
have the outcomes data.

DR. TEMPLE: Before we leave that, the claim that the comparator agent
might get, based on your recommendation, doesn\'t really clearly have
anything to do with its blood pressure control. Remember, these drugs
were compared with calcium channel blockers that lower the blood
pressure just as much. It seems like it has more to do with something
else. Is that still something that ought to be included in there? Keep
talking.

DR. BORER: At the next meeting.

Mike.

DR. ARTMAN: I agree with what\'s been said. I think that it\'s a little
easier when you have these, as Steve pointed out, within-class
comparisons. When you\'re comparing drugs that have antihypertensive
effects across classes, then that\'s where I think it gets pretty dicey.
I think it\'s very difficult to give a simple yes or no answer to this.
I think I would agree with what\'s been said about explicitly clarifying
those issues in the labeling.

DR. BORER: Beverly.

DR. LORELL: I think this is a very slippery issue. I think a couple of
points that were made are very clear, that if drug A demonstrated a
claim of superiority over drug B on a surrogate endpoint, but that there
were other endpoints that were formally tested that were negative, that
must be said in the labeling.

I think the second instance is that if drug A is seeking a superiority
claim for a surrogate endpoint over drug B and demonstrates it, but drug
B explicitly has gone a step further and demonstrated a major endpoint
that\'s present in its labeling, I think that in fairness to consumers
and those who prescribe drugs, that must also be stated.

However, I agree with your point that I don\'t think it should be
required in labeling to state something that has not clearly been
tested, where there\'s uncertainty as to whether something is explicitly
a poorly understood property of a drug versus a class effect.

DR. BORER: Okay. You now have a great deal of thinking recorded, and
I\'m sure we\'ll revisit this again. But for now, let\'s go on to number
5.

Yes, Tom.

DR. FLEMING: Well, have we covered this adequately, Bob?

DR. THROCKMORTON: We\'re going to give you a chance to revisit this when
you come to tell us how to label any of these products. We\'ll be asking
you the specifics around these particular products. I think that will
give us some additional insight.

DR. TEMPLE: I admit to some difficulty about what I hear at least some
tendency towards suggesting, which is fine, mention that the blood
pressure effect was bigger but add a series of caveats that say, but
they haven\'t shown the outcome data yet for this. We don\'t regularly
do that. Other sartans don\'t say, won\'t say we don\'t know whether we
have the effect that some of them have on type II diabetes. It\'s not
that one couldn\'t do that, but we tend to remain more agnostic perhaps
to help your HMO know what to do because we don\'t know whether it\'s
more sensible to assume that members of a class all behave the same or
to be rigid about saying if you haven\'t shown it yet, you don\'t get it
yet.

And we certainly have not, though, as a matter of practice, which one
could say would be informative, said as soon as we gave a claim to one
of them, relabel all the others saying they don\'t have this claim. The
suggestions I think move a little in that direction. So, that\'s a lot
to think about.

DR. THROCKMORTON: Well, the argument is that because it\'s a strict
comparison against that drug, there\'s a higher burden of labeling. I
think that\'s what I heard.

DR. ARMSTRONG: But isn\'t it also an issue of whether the measurement is
a surrogate as opposed to a direct indicator of the disease process
where we get into this? In other words, the surrogate may go the
opposite way to the very thing that we want to modify and that
conversation can be segmented around that kind of class of agents.

DR. TEMPLE: But in the example we\'re talking about where we see a
difference in a blood pressure effect, we really don\'t know whether
that has anything to do with an effect in type II diabetes. We wouldn\'t
let anybody say anything like that. So, I don\'t know if that\'s the
relevant surrogate for the effect in type II diabetes. Maybe it is.
Maybe it really was the blood pressure, but maybe it\'s really something
vascular that is quite a different matter. So, to add but we don\'t know
whether it has this effect ‑‑ well, it\'s troublesome. We\'ll certainly
think about everything that you\'ve said.

DR. BORER: Beverly.

DR. LORELL: Well, but I think you just made a very important comment,
that when you\'re seeking a claim explicitly for superiority between
drug A and B ‑‑

DR. TEMPLE: On blood pressure.

DR. LORELL: ‑‑ whether it be for hypertension ‑‑

DR. TEMPLE: Only on blood pressure.

DR. LORELL: For blood pressure. But the notion of superiority in a claim
and in marketing and in what consumers are going to be doing carries
some extra burden of labeling in my opinion. So, if drug A is
specifically compared to B for superiority, but B has shown something
otherwise very important in a long-term outcome measure, then it needs
to be stated in the labeling. It can be simple labeling, but I think the
superiority claim carries a higher level of statement.

DR. TEMPLE: Makes it more necessary.

DR. BORER: Tom, hold just one second, if you will. In deference to the
need to complete this review this morning sometime, let me ask if it\'s
okay that we table the remainder of the discussion on this particular
issue that is a more generalized issue than the question we\'re being
asked to focus on because of this NDA, and maybe we can get to some of
the specifics in the later questions or at another time.

DR. THROCKMORTON: That\'s fine. Actually I think, Jeff, question 5 was
generally asking these studies are often hard to do. How enthusiastic is
the committee at encouraging sponsors to continue to do them? I haven\'t
heard any lack of enthusiasm. So, unless someone thinks that we should
say this is useless and we shouldn\'t encourage it, I think we could
probably move to question 6.

DR. BORER: Does anybody think we shouldn\'t encourage more comparative
studies?

(No response.)

DR. BORER: Nobody seems to.

DR. THROCKMORTON: In antihypertensives.

DR. ARMSTRONG: I was just going to say as long as they\'re addressing
relevant questions, it would be safety or compliance or even cost in
terms of making it generally available to a large population.
Presumably, if you\'re in a position of advocacy and advice to sponsors,
you should give them a fair chance and likelihood that they can make a
contribution, and what would be the parameters, and those would be three
that would occur to me.

DR. BORER: Let\'s go on to question 6. This one does require a vote. So,
only voting members can vote.

Overall, candesartan reduced diastolic blood pressure by about 2
millimeters of mercury more at trough than did losartan, an effect size
that would be sufficient for approval if a drug were compared with
placebo.

6.1. Is this difference clinically meaningful for a comparison between
two antihypertensives? Paul, why don\'t you give your answer first. We
don\'t need long reasons, but a sentence might be useful if you want to
give one.

DR. ARMSTRONG: Yes.

DR. BORER: Steve.

DR. NISSEN: Yes.

DR. BORER: Blase.

DR. CARABELLO: Yes.

DR. BORER: Susanna.

DR. CUNNINGHAM: Yes.

DR. BORER: Beverly.

DR. LORELL: Yes.

DR. BORER: Mike.

DR. ARTMAN: Yes.

DR. BORER: JoAnn.

DR. LINDENFELD: Yes.

DR. BORER: Tom.

DR. FLEMING: Yes.

DR. BORER: And I vote yes. It\'s unanimous.

6.2. Are the comparative safety data submitted by the sponsor sufficient
to show that the expected reduction in cardiovascular risk would not be
offset by other risks of candesartan, which was an issue that Paul was
raising earlier. Again, we need a vote on this and perhaps a little bit
of reasoning here, if you want to give some. Paul.

DR. ARMSTRONG: I would say that the data and the references and the body
of information would lead me to answer that question yes.

DR. BORER: Steve.

DR. NISSEN: Yes.

DR. BORER: Blase.

DR. CARABELLO: Yes.

DR. BORER: Susanna.

DR. CUNNINGHAM: Yes.

DR. BORER: Beverly.

DR. LORELL: Yes.

DR. BORER: Mike.

DR. ARTMAN: Yes.

DR. BORER: JoAnn.

DR. LINDENFELD: Yes.

DR. BORER: Tom.

DR. FLEMING: I have some difficulty here because the data are so limited
as it relates to being able to identify relative occurrences of more
serious events. There are twice as many SAEs, but they are fairly
infrequent in their occurrence. If one, though, looks at a broader
experience for agents in this class and is able to, in essence, infer
from that a favorable safety profile, then in that context I could agree
as yes.

DR. BORER: And I would vote yes, but for the record I want to echo what
Tom has said. I think that in voting yes, I\'m voting in part on the
basis of long experience with drugs in this class that make me
reasonably sanguine, although I don\'t think there are enough safety
data in this NDA to make a direct comparison. But with that caveat, I
would vote yes.

6.3. Would your answer regarding the need for comparative safety data be
different if the two drugs were from different classes? For this we
don\'t need a vote, but we do need some opinions.

Paul.

DR. ARMSTRONG: Well, most assuredly yes. I think that we know that
lowering blood pressure may lead in some circumstances to favorable
outcomes and in other situations the target organ and other issues may
behave differently. So, I think we need clearly to look differently
across classes.

DR. BORER: Tom, do you have any thoughts about this particular issue?

DR. PICKERING: I would agree with that.

DR. BORER: Are there any dissenting opinions?

DR. NISSEN: I just want to amplify on this a little bit and say that I
would actually put the standard even differently for both safety and
efficacy because it\'s all interwoven here. While I agree with what you
said earlier, Bob, that in general drugs that lower blood pressure by
more are generally better, but in fact we do know that there are better
rather big differences between classes in the response of lowering that
blood pressure for specific endpoints.

There are some data, which we\'ll learn a lot more from, from ALLHAT,
for example, that may suggest that calcium channel blockers lower stroke
risk more effectively than ACE inhibitors and that heart failure is more
effectively prevented by ACE inhibitors than calcium channel blockers.
These are examples, but the point here being that without very robust
data on those endpoints, small differences in blood pressure can\'t
really be effectively described for the clinician in a way that\'s
really fair. So, I think this really does apply to intraclass not
interclass differences.

DR. TEMPLE: Let me be sure we understand. That in some sense says unless
you\'re prepared to do an ALLHAT-sized study, you really can\'t get
blood pressure claims across classes. I can see that as a general view,
but what about the question of whether some drugs are more effective at
lowering blood pressure in a black population? That might be
informative. Would that mean the difference has to be larger than here,
or is that just not worth even thinking about?

DR. NISSEN: That\'s what I was really saying there is that we said
earlier that 2 millimeters is enough between two drugs in a class, that
we\'re comfortable. I would not necessarily be comfortable in saying
that drug X which was a diuretic and drug Y which was an ACE inhibitor,
that there was a difference in comparative efficacy when there\'s only a
2 millimeter difference because I really wouldn\'t know how much that 2
millimeters translated into differences in clinically relevant endpoints
across two different classes. I think we could mislead clinicians if we
did that. People might say, okay, it\'s more effective. I want to give
this drug. And in fact the opposite effect would be seen on the
clinically relevant endpoint, and we\'d be misleading people about what
the real benefits are.

DR. BORER: I\'d like to offer a slightly different opinion just so that
it\'s on the record for your edification. I think everything Steve says
is very important, and certainly from John Lara and from Tom Pickering,
I\'ve gained a healthy appreciation for the potential importance of
mechanism-specific therapy if you happen to know the mechanism.

But the data that we have thus far suggests ‑‑ and Dr. Kannel showed
them ‑‑ that if you lower blood pressure, you\'re less likely to have
certain problems than if you don\'t do it, particularly in people whose
blood pressure is high. And the approvability of a single drug, before
we get to the comparison of two drugs, is based on demonstration of
effectiveness and acceptable safety for the intended use. So, we start
out with that information about risk and benefit for the individual
drugs.

Now we\'re comparing two drugs. It seems to me that while everything
Steve says may well be true ‑‑ and in fact, my bias is that it probably
is. There are some drugs that do better at some things than others and
alter pathophysiological processes differently ‑‑ we don\'t have those
data yet. And until we do, in terms of outcomes, I think that if one
drug lowers blood pressure more than another drug beyond 2 millimeters,
or whatever the standard is we want to set, then based on the
epidemiological data that we\'ve heard and that have been published for
years, unless there\'s a relative safety concern of one drug versus the
other, that it\'s reasonable to entertain a superiority claim for
lowering blood pressure. That doesn\'t mean that it\'s not important to
look for the outcome events and to modify everything I\'ve said once we
get those data in hand. But we don\'t have them now.

As Tom pointed out earlier, based on putative mechanisms, interaction of
genetics and mechanisms, interactions of gene expression in drugs and
what have you, to make a guess about what we think is going to happen I
think is very treacherous, very dangerous, and we shouldn\'t do it.

So, I would say that it\'s reasonable to give a comparator claim here in
6.3, assuming that the safety database is sufficient so that you can be
reasonably certain that you\'re not adding some other risk by getting
the blood pressure lowering.

Are there any other comments or questions about this?

DR. NISSEN: I just want to take the moment to challenge you a little
bit, Jeff, and say that imagine a drug that produces profound reductions
in blood pressure but a tremendous amount of reflex tachycardia, and now
you\'re comparing it. They come in and they say to the agency, we want a
superiority claim for blood pressure reduction, and there\'s no
comparative data that suggests that that reflex tachycardia is really
bad, but we have a bias that it probably is bad. I think we could really
give the wrong advice to clinicians. Or a ganglionic blocker that
reduces blood pressure very effectively but causes people to get
syncopal.

So, I think we\'ve got to be awfully careful when we compare across
classes because there are unexpected effects, via the physiological
mechanism of blood pressure lowering, that are not factored into the
decision. So, the bar has to get raised a lot higher when you try to do
this across classes.

DR. TEMPLE: And you\'d certainly, I assume, be much more attentive to
differences in the basic side effect profile because they\'re
fundamentally different drugs.

DR. NISSEN: Yes.

DR. TEMPLE: And you\'d need to take that into account at a minimum, if
you did it at all.

DR. NISSEN: You bet.

DR. BORER: Beverly.

DR. LORELL: I think that the example that Dr. Carabello brought up
earlier of comparing hydralazine and beta-blocker is a very important
one. So, I think that as question 6.3 is explicitly worded, would the
need for comparative safety data be different, the answer is definitely
yes. One might require a study of longer duration in a larger number of
patients to be able to tease out differences in safety that might not
have been seen in the size of study we\'re looking at today within a
class.

DR. BORER: Blase.

DR. CARABELLO: Just a comment that we certainly couldn\'t resolve now. I
think the whole issue really is what is the label. What is the purpose
of the label? Is this an educational tool by which we are trying to
teach the people that use the pharmacologic agent about it, or is it a
marketing tool for the sponsor? I think the answer is a little bit of
both.

And how far do we want to go with this? I myself would like to see the
labels be more of an educational tool, but as I say, I think we could
easily be here until next month on this issue.

DR. LINDENFELD: Jeff, just to add to what\'s been said, I think there\'s
a little bit of an even more middle position that that. I think there\'s
a difference between a drug like hydralazine where we have no outcomes
for the treatment of hypertension from a class like diuretics or calcium
blockers where we do know that lowering blood pressure improves outcome.
So, I think we\'d all be very concerned about a drug that raised heart
rate 14 beats where we had no outcome data at all from drug classes
where we know there is a correlation between the reduction in blood
pressure and outcomes data.

DR. BORER: Yes, I think that\'s quite right. Of course, the approval
process requires that experienced regulators look at these data and
raise concerns and that committees like this voice their concerns so
that if potentially important tachycardia were seen, I think that a
number of red flags would be raised. But what I was suggesting was the
principle that if there are no safety data from a reasonable safety
database that Beverly has outlined, if there are no safety data to
suggest a problem that better blood pressure lowering in drugs across
classes is a reasonable basis for a claim.

DR. TEMPLE: Actually one can particularly imagine differential effects
on systolic blood pressure across classes. We haven\'t gotten that yet,
but there are certainly suggestions that there might be.

DR. BORER: Let\'s move on.

DR. FLEMING: Can I just add?

DR. BORER: I\'m sorry. Tom.

DR. FLEMING: Jeff, just a brief addition. I endorse the concerns that
have been stated about caution that would need to be taken, when we\'re
looking at different classes, particularly if there\'s reason to suspect
that there could be a different safety profile.

In fact, I also have that caution from efficacy. My answer, for example,
on question 6.1 as yes is specific only to these two agents being tested
from within the same class.

DR. BORER: Let\'s go on to 6.4 Is the comparison between candesartan and
losartan fair, as defined by ICH E-10? The relevant section is on page 7
of the document.

Paul, why don\'t you go ahead.

DR. ARMSTRONG: The question doesn\'t ask whether it was the best or the
right test, but whether it was a fair test. And fairness isn\'t a
dichotomous variable. But in reflecting on this and on the definition of
fairness, we\'re asked to consider issues around dose, around the
population studied and around the selection in timing of endpoints, all
germane to the current dialogue.

I would grade this about 3 out of 4 on my fairness test in relationship
to the issues. I think it was a sensible and reasonable population.

I have some reservations about the doses. I\'m convinced that 16 of
candesartan is better than 50 of losartan, and 32 is better than 100.
I\'m not sure that 16 is better than 32 or 100 is better than 50,
however. So, in looking at all of the data, I would probably have
redesigned it a little differently in terms of the candesartan piece,
but that\'s en passant.

The other issue is the duration of effect and the timing of the
up-titration that I reflected on in my earlier questions. I think the
timing would have been and could have been different and we could have
been clearer about what dose to use and when to up-titrate, and we\'ll
come back to that discussion in relationship to the actual wording of
the label, assuming that we want to educate practitioners as to how to
use these agents wisely. So, on balance, I think it was a pretty fair
test.

DR. BORER: Is there anyone around the table who does not think it meets
the fairness criteria that are laid out in the document? No.

Tom.

DR. FLEMING: I agree with Paul. This isn\'t simply yes/no. I strongly
endorse the spirit of the ICH E‑10 guideline on page 8, section (a),
pointing out that there really are merits to understanding, when one is
looking at superiority, comparisons at multiple doses. My own sense is
there\'s a fairness here as long as one conditions on what it is that
we\'re claiming here. If we\'re claiming that we\'re comparing q.d. and
q.d., there\'s a fairness here. But if one is trying to go beyond that
and, in a sense, say we have established superiority to another agent
relative to what its optimal efficacy might be, then I think there\'s
uncertainty here. As I\'ve already indicated earlier, it seems to me it
would have been more informative, since we\'re doing two trials, in the
spirit of ICH E-10, that the two trials could have differed in the way
the losartan was delivered.

There seems to be more evidence that candesartan b.i.d. may not be more
effective than candesartan q.d., but the data that\'s presented to us,
though limited, suggests that there may well be a response increase with
b.i.d. over q.d. I think we would have had a more informative answer,
rather than two small, identically designed trials, to have taken the
full benefit of doing two trials here and had the second trial look at a
b.i.d.

DR. BORER: Any other elaborations on this issue?

(No response.)

DR. BORER: If not. Let\'s move on to number 7, and I\'d like to break
this into two parts, if I may, so they don\'t get confounded in
discussion.

First, do you recommend approval of candesartan for superior
antihypertensive efficacy when compared with losartan? And forget about
how the labeling might have to limit that. Let\'s go through that first,
and then if we do agree with that, obviously the label, as everyone has
said, has to be carefully constructed. And we\'ll talk about the
labeling construction as a separate issue. So, forgetting for a moment
that we have to be careful in writing a label, do you recommend approval
of candesartan for superior antihypertensive efficacy when compared with
losartan?

Paul.

DR. ARMSTRONG: Yes.

DR. BORER: Steve.

DR. NISSEN: Yes.

DR. BORER: Blase.

DR. CARABELLO: Yes.

DR. BORER: Susanna.

DR. CUNNINGHAM: Yes.

DR. BORER: Beverly.

DR. LORELL: Yes.

DR. BORER: Mike.

DR. ARTMAN: Yes.

DR. BORER: JoAnn.

DR. LINDENFELD: Yes.

DR. BORER: Tom.

DR. FLEMING: Yes, conditionally given that it\'s clear we\'re talking
antihypertensive efficacy and we\'re talking at q.d. versus q.d.

DR. BORER: I vote yes too and, of course, with Tom\'s caveats, but
we\'re going to get into that in a second. So, you have a unanimous vote
in favor of approvability.

Now we have to talk about what it is we\'ve actually suggested you
should approve. So, if so, how should the findings of these trials be
included in the approved labeling, first of candesartan? And we\'re
going to need a vote about this. So, Paul, why don\'t you give the
statement and we\'ll see if anybody disagrees and we\'ll vote.

DR. THROCKMORTON: Jeff, you\'ve given the one vote that we really needed
for this particular one. I\'d like just discussion in general about the
labels.

DR. BORER: Okay. We won\'t vote.

Paul.

DR. ARMSTRONG: Jeff, I\'d like to make three points in terms of
introducing this. The first is that for me, rather than have a
discussion about a statistically significant difference with no context
of what the blood pressures were or what changes unfolded is unhelpful.
To me we should dialogue or suggest to the regulatory agency that we\'re
serving that, obviously, that be incorporated, a clinical context both
from where the patients were and to what extent the difference was
clinically or biologically significant as opposed to statistically
significant. So, that\'s the first point.

The second point is I have some concerns in relationship to the draft
about the notion or the implication that if a blood pressure change was
not perceived to be satisfactory in the minds of the clinician caring
for the patient, that he or she should up-titrate at 2 weeks. I think
that that\'s a problem based on what we know and indeed what the sponsor
has asserted in response to an earlier question. So, the notion of the
appropriateness of up-titration, on the one hand, and the timing of
up-titrating on the other, vis-a-vis achieving an effect, I think needs
some discussion.

And the third piece is the extent to which, if one were interpreting
this label, seeing a patient on losartan once a day, as to whether one
should be prompted or reminded about the likelihood of increased
efficacy using the same drug twice a day before switching to a new drug
once a day.

So, to me those are the three issues, and I certainly have some
thoughts, but I don\'t want to get into the nuts and bolts of the
wording. But to me those are the three issues.

DR. BORER: May I ask for a clarification here? I\'m looking at the
proposed addition to clinical pharmacology, clinical trials subsection
from the sponsor\'s presentation where it says that candesartan
initiated at 16 milligrams once daily and force-titrated at 2 weeks,
which is the point that Paul was just making, to 32 milligrams. If I\'m
not mistaken, two of the most important trials, 230 and 231, the
forced-titration was made at 4 weeks.

DR. FLEMING: At 2 weeks.

DR. BORER: At 2 weeks, okay. Then what was done at 4 weeks?

DR. MICHELSON: The CANDLE study was titration to effect at 4 weeks.

DR. BORER: At 4 weeks. Okay, I understand. Thank you.

Bob.

DR. TEMPLE: This is a problem. That\'s how the study was done, so you
can\'t really describe it any other way. The dosing and administration
says that you get most of the effect by 2 weeks and really all of it by
4 weeks. So, I think the implication is that the observing physician
looks and sees if you\'re getting close at 2 weeks. If you\'re nowhere,
you maybe increase it. But it\'s a problem as to what to do. The real
recommendation is you can expect you\'re not going to get any more after
4 weeks. That\'s what labeling has said from the beginning based on the
bulk of their data.

I wanted to ask one question. We\'ve already concluded that just saying
statistically significant is not very helpful, but our immediate thought
was that we\'d give the numbers probably with a confidence interval and
a p value. We would not have thought of saying how important and
significant this is, however. Is that what you were suggesting? That\'s
getting dicey since the whole labeling doesn\'t say much about that.

DR. ARMSTRONG: Sorry. Bob, what I was suggesting was that the ‑‑ and
maybe you can clarify then for me. In other words, these numbers ‑‑ that
is, the absolute difference between the two agents ‑‑ I thought should
be reflected in the baseline values from which they occurred. In other
words, the implication of those numbers might be a whole lot different
in a hypertensive population that at entry came in rather different than
this one.

DR. TEMPLE: That\'s a good addition too. It could say who the people
were. Right, that\'s fine.

DR. BORER: Steve.

DR. NISSEN: I wanted two things added to the label that are not in the
current proposal, and they\'re similar to what Paul suggested. The
magnitude of the change. But one of the things that troubles me about it
is that clinicians may look at that and they may say, gee, 2 millimeters
is trivial. A lot of clinicians don\'t really recognize. That in my
opinion is biologically significant. So, it\'s going to tend to
undermine the claim a little bit which I\'m sure is why the sponsor
didn\'t originally propose that. I happen to think that 2 millimeters is
relevant clinically, but it may be misinterpreted. And I don\'t know any
alternative to that. That\'s what I think you were probably getting at
when you were saying that we think that\'s clinically significant, but
we can\'t tell people that.

DR. TEMPLE: So, they could just put something in that says this is a
really big deal?

(Laughter.)

DR. NISSEN: I was thinking about slightly different language than that.

DR. TEMPLE: It\'s a problem.

DR. NISSEN: It\'s a problem. It\'s a problem because clinicians don\'t
necessarily get it. We want to give informative advice to clinicians.
Unfortunately, it may be trivialized by some people which I\'m concerned
about.

Then lastly I think the way to handle the baseline issue is to describe
the baseline range of blood pressures at entry. So, this was shown in
people who came in between 95 and 114. Then say no more than that
because I don\'t think we know what it is for under 95 or over 114.

So, those two additions would be helpful. But I am concerned that we not
trivialize those differences, and anything you could do in the wording
that doesn\'t undermine the clinical importance because I as a
clinician, if I really ‑‑ this will change my practice, and I think that
that is important when that happens. I think when I need more blood
pressure reduction, I\'m going to favor the more effective agent, and to
me 2 millimeters or 3 millimeters is significant.

DR. BORER: Beverly.

DR. LORELL: Thank you.

I actually think the proposed label as worded is an extremely good
starting point. I like it because it states the facts very clearly of
the results explicitly in two trials. So, in a sense it does not have to
get to the point that you were making, Dr. Armstrong, about the issue of
when you up-titrate or don\'t.

I think it is very important in this label that it have an explicit
statement as to who the study population was. This study, unfortunately,
cannot be extrapolated to patients who have isolated systolic
hypertension, and I think it\'s very important not just that there be
sort of a demographic, this is the baseline, but that it be very clear
that an inclusion criteria required having diastolic hypertension.

Secondly, I think going back to the points we\'ve discussed over and
over here, we\'re all extremely sympathetic and hopeful that this
reduction in blood pressure that was seen as the superiority claim will
translate to outcome measures that are very important. But we don\'t
know that. So, I think that probably the most straightforward approach
and also as a precedent for the FDA is to simply state the facts of the
trial, to have a very simple table that lists baseline blood pressure
and the mean and median reduction at the 8-week endpoint. And it can be
left for the clinician to interpret, as he or she sees fit, what that
means.

I think to have a statement in trying either to encourage or to dissuade
interpretation of that right now is very flawed because this study did
not compare endpoints between the between the two drugs. We hope it will
translate to endpoints, but we don\'t know that.

DR. BORER: Before I ask Tom Fleming to comment, because I think some of
his earlier comments are crucial with regard to the response to this
question, let me ask, Beverly, would you modify those parameters you
mentioned, mean, median ‑‑ and I\'m sorry. I didn\'t hear the third one.

DR. LORELL: The baseline demographic absolute blood pressures.

DR. BORER: In addition to the mean and median change, I would suggest
one might want to include either the standard deviation or the range ‑‑

DR. LORELL: Certainly.

DR. BORER: ‑‑ because even if you really didn\'t understand or didn\'t
know all the epidemiological data, you would at least have a sense that
sometimes you can have a fairly marked effect, and that would be
reassuring.

Tom, why don\'t you go ahead and talk about the label.

DR. FLEMING: There were two or three aspects. The first couple have
already been raised by Paul and Beverly for which I would suggest there
be modifications.

First, I think it\'s not sufficient just to provide statistical
significance as the conclusion here. I agree with Paul\'s point that
there really needs to be explicit data indicating the essence of what
the antihypertensive efficacy results are.

By doing that, we address two of my concerns. One is that it be made
very clear that what we\'re talking about here are 8-week results on
blood pressure, and that will become explicit, and what the magnitude of
these effects are, which is critical that that be conveyed beyond just
statistical significance.

The third suggestion that I have or the third issue that I would like to
have addressed is related to what the FDA medical reviewer raised on
page 27, and that is, I think there needs to be a sense, kind of in the
spirit of fairness of E-10, a sentence at the end or at some point that
says that comparisons were not made against losartan b.i.d. that might
be more effective as a regimen than q.d. Then it\'s made explicitly
clear that the superiority in blood pressure effects are q.d./q.d. and
yet it\'s acknowledging that there is not an assessment relative to
b.i.d. losartan that, in fact, might be more efficacious than q.d.
losartan.

DR. BORER: Can I ask for a little bit more discussion about that last
point? My understanding of the data ‑‑ and correct me if I\'m wrong, and
Tom, maybe you can help us with this ‑‑ is that there is the sense from
some of the published data that the b.i.d. dosing schedule may be more
effective than the q.d. dosing schedule of losartan, and that certainly
for some patients it\'s observably better. But are the data sufficient
to make a general statement that it is known that b.i.d. dosing of the
one drug is better? And if not, is it appropriate to include a statement
like that in a new label?

DR. PICKERING: Well, I think from what we\'ve heard so far, the
difference was with the 25 milligram dose but not with the 50 milligram
dose from the data that we saw from the Weber study.

DR. FLEMING: Let me just clarify, Jeff, because I think you said
something substantively different from what I said. I said a sentence
should be added that indicates that comparisons were not made against
the losartan b.i.d. schedule which may be more effective than q.d., as
opposed to what I thought you said which is has established to be.

On page 14 in the FDA briefing document what we have ‑‑ and granted,
it\'s only at the 25 dose, but we have differences of 2.2 millimeters.
It\'s in a study of a size 100 per arm. So, that\'s 1.4 standard errors
larger ‑‑ standard errors are 1.4 times larger than in the two pivotal
studies that had 300 per arm. But those pivotal studies, relative to the
primary endpoint, basically yield, if you look at 8-week results, 1.3
and 1.8 millimeter differences. So, the estimates that we\'re viewing on
primary endpoint as evidence of efficacy, when you\'re comparing
candesartan and losartan, are actually of smaller magnitude than these
differences q.d. versus b.i.d. within losartan. They are statistically a
little bit stronger because they\'re based on three times the sample
size, but they\'re only two-thirds the magnitude of effect. So, the p
values are not all that different.

So, basically I\'m not claiming or I\'m not stating that there needs to
be an acknowledgement that b.i.d. losartan is more effective than q.d.,
but it certainly may be. There\'s certainly some evidence here to
suggest that it is, and that evidence is not a whole lot weaker than the
evidence that we\'re using for the primary endpoint for the conclusion
that candesartan is more effective than losartan.

DR. BORER: Beverly.

DR. LORELL: I would respectfully disagree with that opinion. I think
that it is correct that losartan may be more effective, but I don\'t
think the data is clear enough to state that explicitly in the labeling.
In fact, the current labeling for losartan ‑‑ and perhaps you could
clarify that for us ‑‑ uses very careful terminology of \"could consider
using\" as opposed to making a statement \"may be more effective.\" And
those are really two very different statements.

DR. FLEMING: But let\'s pursue that. Are they different? I intentionally
used the word \"may\" be to be very cautious.

DR. LORELL: Well, I think that the statement in labeling \"could
consider using\" is quite a different statement than \"may be more
effective.\" I think that an alternative approach could be to simply
state that in the labeling as proposed, these studies did not compare
b.i.d. regimens of either drug. And that makes it very clear to the
practitioner who is deciding to use either drug that the comparison
wasn\'t there. We wish it were, but it wasn\'t there.

DR. BORER: Yes. If we mandated a statement about this at all, I would
favor Beverly\'s statement that says we just didn\'t do it, rather than
drawing a conclusion about what it might be.

Steve.

DR. NISSEN: Yes. I really fairly strongly disagree here, and let me see
if I can articulate it.

First of all, if you read the label, it says once daily. I mean, it\'s
very clear that that\'s what\'s being compared when describing the
studies. To me that\'s quite sufficient.

DR. TEMPLE: Which drug are you talking about?

DR. NISSEN: I\'m talking about the candesartan. The proposed label says:
compare the antihypertensive efficacy at their once-daily maximum doses.
It\'s absolutely crystal clear in that proposed label that\'s what\'s
being said.

Look, in designing a clinical trial, you can\'t look at every
combination and permutation of administering a drug. So, you can set the
bar impossibly high here and you can kind of whittle away at it. But the
comparison was fair, by the terms of my interpretation of the guidance,
and I just think we don\'t comment on b.i.d. And frankly, the sponsor
isn\'t suggesting saying anything about b.i.d. administration. The label
says once a day.

My view here is actually colored a little bit by the fact that I wish we
had more comparative trials between agents in the same class like this.
If we kind of whittle away at the claim when there\'s a very clean pair
of trials that show us the answer here, then we undermine our ability to
get data like this in the future.

B.i.d. dosing wasn\'t studied. It would have taken another large study
to actually do it, and maybe some day they will do it. But all they\'re
commenting on in the label is once-daily maximum doses, and I think
that\'s all we should comment on based upon the study.

DR. BORER: Beverly, did you have another comment?

DR. LORELL: I think in a sense we\'re on the same page, Steve. I would
look at adding that labeling simply as a bit of an added clarification
for the naive reader, thinking about labeling not just as marketing, but
an education tool.

DR. LINDENFELD: May I change the topic? Are we done with this one?

DR. BORER: Let me just ask, are there any other opinions different from
what we\'ve heard? You\'ve heard a range.

I\'m sorry. Tom.

DR. FLEMING: Just to follow up on Beverly\'s and Steve\'s comments, if
there were no data or if the data that existed, even better yet, really
provided some considerable reassurance that losartan q.d. and b.i.d.
were the same, I\'d be very comfortable with what you\'re proposing.
There\'s not a lot of data here that were presented. What were presented
on page 14 is suggesting to me magnitudes of effects that aren\'t a lot
different than what we are seeing for candesartan against losartan. But
maybe there\'s a lot more to it than what these data are showing.

So, what is the committee\'s sense about is it your belief that these
data on page 14 that are showing a 2.2 millimeter difference are
entirely misleading and this is irrelevant? And essentially you have the
strong sense that there really isn\'t a difference, in which case then I
understand your recommendation.

DR. LORELL: If I could respond to that. I would say that they raise an
hypothesis that we all wish had been more rigorously tested. I think
that my rationale ‑‑ and I want to be clear about this ‑‑ for adding a
very straightforward comment that b.i.d. dosing was not tested relates
more to the current labeling of the drugs as isolated agents where the
clinician is given the option of using b.i.d. So, I think your concern
is a very fair one. I think we\'d all love to see another trial done to
address that, but we just don\'t know.

DR. ARMSTRONG: Perhaps another way of coming at this, Jeff, would be to
find out from the sponsor, since the label currently for candesartan
lists b.i.d. as an option for the new agent, as to whether we\'re
equally unclear about the efficacy of b.i.d. candesartan as we are
b.i.d. losartan.

DR. BORER: They showed us the data. Well, why don\'t you go ahead and
answer.

DR. MICHELSON: To address that first piece, yes, we have the same
limited data that you saw, very limited and not sufficient to answer
other than there appears to be small differences with each of the
agents.

I would point out just one thing, if I may, just to Dr. Fleming. I could
tell you there\'s been a commitment by both the manufacturers of
losartan and to us in every large outcome study that\'s either ongoing,
completed, or to be done with each of these agents is employing only the
once-daily dosing either, for example, losartan 50 milligrams once daily
or 100 milligrams once daily, and the same for us. All the outcomes
trials we have basically are including either 16 or 32 milligrams once
daily so that all the outcomes data that you\'re going to see and have
seen, in fact, such as RENAAL and others will employ that dosing. So,
that will also make it even more relevant.

DR. BORER: I haven\'t stated my opinion about this, but I will, if I
may. I don\'t think it\'s necessary to include a statement about b.i.d.
dosing in the label. But if the sense was that one needed to, I would do
what Beverly suggested, just state that it wasn\'t studied.

In terms of Tom\'s point, because he asked a question, I\'m not
persuaded by the data on page 14. The number of patients involved was
relatively small so that my confidence in the absolute values, the
absolute changes is not overwhelming. There\'s a wide confidence
interval.

The populations were sufficiently small so that I certainly don\'t infer
immediately that the population involved here was the same as the
population or superimposable upon the populations that were studied in
230 and 231.

In addition, as Tom pointed out, this is 25 b.i.d. It\'s very hard for
me, without a direct comparison, to draw inferences about how those
results would compare with 100 q.d. of losartan or 32 milligrams q.d. of
candesartan, or what have you.

So, I think those are interesting data. They raise questions. As Beverly
says, they\'re hypothesis-generating. But I\'m not influenced in my
conclusion about what to put in this label by those data. Now, that may
be wrong, but that\'s the way I would respond to the question.

Are there any other comments about this issue? I\'m sorry. Tom, if you
would turn on your light, I\'ll see you every time.

DR. FLEMING: Just a very brief added comment. If the FDA, in fact, gains
access to additional data beyond what\'s on page 14 that provides
additional substantive insight and if that in fact suggests that
there\'s less gradient here between b.i.d. and q.d., then I\'m entirely
comfortable with what Steve has proposed as not adding any statements.

On the other hand, if we\'re essentially looking at this evidence, I
would consider Beverly\'s proposal as kind of a compromise middle ground
from what I had proposed as a very acceptable alternative.

DR. TEMPLE: I said this before, but nobody seemed impressed. Let me try
again.

The fact that you see the same differences at peak, it seems to me, has
a lot to do with how worried one should be because the reason you use
b.i.d. for some drugs is that you think their half-life is too short.
But you do expect that the dose, when you first take it, will probably
get into the right range. Even in that circumstance, where the two were
compared at doses that really should have been adequate, there was a
difference at peak, suggesting that it\'s not just a matter of half-life
and timing, but maybe something else.

DR. NISSEN: That was also part of my thinking as well, and also, Bob,
the fact b.i.d. candesartan appears to have a little bit bigger effect
than q.d. candesartan. So, Tom, the reason that I think we\'ve got to be
careful here is that if you did b.i.d. candesartan against b.i.d.
losartan, I think there\'s every reason to expect you\'d see the same
differentials because both drugs show a little bit more efficacy when
given b.i.d. So, to me it\'s just kind of a nonissue.

DR. BORER: Let\'s move on to the issue of the implications for labeling
of losartan. Paul.

DR. ARMSTRONG: I don\'t see any implication for losartan labeling. So,
no.

DR. BORER: Is there anyone around the committee who would suggest any
changes in the losartan label based on these studies? JoAnn.

DR. LINDENFELD: No.

But I just wanted to come back to one point earlier in the labeling. I
don\'t know if this troubles anyone else, but if you do put the numbers
of actual blood pressure, I\'d like to see the numbers for the lower
dose of each drug, 16 and 50, because that\'s where almost all of the
difference is. Now, we could argue about whether or not that\'s fair.
That was not the endpoint of the study, but there was, I think, on page
18 of the briefing booklet a suggestion for a phrase that might indicate
that. I think it would be helpful to the physician using these drugs to
know what the increments of effect are as you go up on the dose. You get
almost all of it early. I think that would be helpful data to have in
there.

DR. BORER: We\'re not suggesting any changes for the losartan label.

Finally, 7.3. Do we suggest any implications of these findings for
combination products containing either of these two drugs, candesartan
or losartan?

Paul.

DR. ARMSTRONG: I\'d have to take them one at a time. I would say that
there may well be implications and each would need to be addressed on
its own merit.

DR. BORER: Specifically with regard to candesartan, how would you
suggest these results should be used?

DR. ARMSTRONG: Sorry. Are we talking about candesartan combined with
something else?

DR. BORER: Yes, a combination with a diuretic or something.

DR. THROCKMORTON: Candesartan with a thiazide or CCB or something.

DR. ARMSTRONG: I would say it hasn\'t been studied.

DR. BORER: Blase.

DR. CARABELLO: Yes. You couldn\'t possibly make a statement about
superiority of this drug when mixed with something else. It could
entirely disappear. We couldn\'t possibly be justified in adding that to
the label of essentially another drug.

DR. BORER: Does anybody around the table disagree with that? Beverly.

DR. LORELL: I strongly agree.

DR. BORER: We have a strong agreement and other degrees of agreement.

DR. THROCKMORTON: Sense of committee so noted.

DR. BORER: I think that that concludes our business, but I would like to
ask one final question just for the edification of the committee, if
nobody else. A precedent was noted here with regard to an
angiotensin-converting enzyme inhibitor that\'s marketed by two
different companies. I am not aware that studies similar to this one
were performed with that drug and its comparators, and I\'d like to know
the basis of the labeling that was quoted here. Can you tell us a little
bit about that?

DR. THROCKMORTON: Can you give me a page number?

DR. BORER: Yes.

DR. NISSEN: It\'s CR-12 in the AstraZeneca presentation.

DR. MICHELSON: Would you like to see the study design?

DR. BORER: Sure. Well, I\'d be interested to see the study design, sure.
It may be obvious why the labels were written.

DR. TEMPLE: I\'ll tell you what. It was probably a brain spasm.

(Laughter.)

DR. TEMPLE: We were trying to think more about giving people some idea
what the ball park was. So, for a number of drugs, we said this is in
the general range of most ACE inhibitors or this is in the range.
That\'s really what that reflects. Is it a non-inferiority study with a
margin calculated? Absolutely not. It\'s well short of that. What it
says is this looks like one of those, and that\'s all it is. We\'ve sort
of stopped doing it because it\'s really hard to justify. But there was
some desire to say, well, you know, don\'t be confused. This is another
one of those. That\'s what it is. We\'re not necessarily proud of it.

(Laughter.)

DR. BORER: So clarified. I would like to suggest, for whatever it\'s
worth ‑‑ and I don\'t think anybody on the committee will disagree ‑‑
that the principles in ICH E-10 here ought to be more rigorously applied
before the label is written again.

Are there any other comments from the committee?

DR. FLEMING: Jeff, we had deferred just a few additional comments on
question 4. Is this timely to return to that?

DR. BORER: Sure, why don\'t we take a few minutes and get some comments
about that.

DR. FLEMING: Let me try to be really brief in clarifying at least what I
was trying to suggest we would need to state in response in particular
to question 4.1. Let me give three scenarios.

The first scenario is you have a comparator agent that has shown a blood
pressure effect and ultimately has a clinical endpoint study that\'s
directly shown effects on stroke reduction. Now, your experimental agent
in comparison to the comparator has been shown to be superior in blood
pressure effects, and that\'s all that you know. But there\'s no reason
to expect that it doesn\'t contain all of the other mechanisms in this
particular scenario. Then I would think that the comparator agent would
be labeled for not only blood pressure control, but actually having
documented that it prevents stroke, whereas the experimental agent in
this case could be called superior in its antihypertensive efficacy. I
don\'t think you\'d have to explain what isn\'t known because there\'s
no specific evidence that it doesn\'t provide the benefits, but you\'re
not making a claim for it having established effect on stroke.

Scenario B is a scenario where the comparator agent has had clinical
endpoint studies and there\'s considerable evidence to show that its
effects on clinical endpoints exceed that that you would expect to be
mediated through blood pressure reduction. In this setting then, if you
have done a comparative study of the experimental agent and showed a
superior antihypertensive effect, you can claim a superior
antihypertensive effect. But what I was saying is I would think there
has to be an acknowledgement, though, that the comparator agent has
achieved clinical benefits in ways that would exceed what you expect to
be mediated through blood pressure lowering.

The third scenario would be one where you actually have the experimental
agent showing a superior antihypertensive effect, but you actually have
clinical endpoints on both and the comparator is superior in clinical
endpoints. In that setting, I would think without question the focus has
to be on the clinical endpoints and you wouldn\'t be even talking about
a label that would talk about superiority in antihypertensive effects.

Those are sort of the cascading three separate scenarios that kind of
cover the possible options. This was what I was trying to argue before
we would need to report.

DR. BORER: Paul, did you have a comment?

DR. ARMSTRONG: Just on point three, there will be circumstances, Tom, it
seems to me, when benefits of an agent are largely a function of the
participation in the clinical trial and the rigor, discipline, and
monitoring associated with it as opposed to clinical practice, and the
issues of efficiency and efficacy come to mind, of course. So, I think
in approving a new drug, one needs to take into account not only the
evidence for efficacy in a clinical trial, the safety, the compliance
issues, and the cost, but the general applicability. So, I would have
some sympathy as a clinician to keeping an open mind, notwithstanding
the fact that the points you raise are good discussion points as we take
each new customer who comes to the table.

DR. BORER: I think the principles that Tom has stated are important for
the FDA to consider. Obviously, they\'re going to have to be considered
in the context of specific data sets and specific trial designs, and you
can take that advice.

With that having been said, why don\'t we adjourn for the moment. We
have 46 minutes and 48 seconds before we will reconvene.

(Whereupon, at 12:13 p.m., the committee was recessed, to reconvene at
1:00 p.m., this same day.)

AFTERNOON SESSION

(1:03 p.m.)

DR. BORER: We\'ll begin very slowly so that our stragglers can come
back.

The committee is composed of the same people that were introduced this
morning. In the interest of complete disclosure, we\'ll introduce
ourselves again. Tom.

DR. PICKERING: I\'m Tom Pickering from Mount Sinai Medical Center in New
York.

DR. CUNNINGHAM: Susanna Cunningham from the University of Washington in
Seattle.

DR. CARABELLO: Blase Carabello from the Baylor College of Medicine.

DR. NISSEN: Steve Nissen with the Department of Cardiovascular Medicine
at the Cleveland Clinic School of Medicine.

DR. ARMSTRONG: Paul Armstrong from the University of Alberta.

DR. BORER: I\'m Jeff Borer. I\'m from the Weill Medical College of
Cornell University. This morning I slipped and said Cornell Medical
College. That should be corrected.

MS. PETERSON: I\'m Jayne Peterson. I\'m the acting Executive Secretary
of the committee.

DR. FLEMING: Tom Fleming, University of Washington, Seattle.

DR. LINDENFELD: JoAnn Lindenfeld, University of Colorado.

DR. LORELL: I\'m Beverly Lorell, Harvard Medical School and Beth Israel
Deaconess Medical Center, Boston.

DR. THROCKMORTON: Doug Throckmorton, Director of the Cardio-Renal
Division, FDA.

DR. TEMPLE: Bob Temple, Director, ODE I.

DR. BORER: Jayne Peterson will read the conflict of interest statement.

MS. PETERSON: Thank you.

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 which have been reported by the participants present no
potential for an appearance of a conflict of interest at this meeting
with the following exceptions.

Dr. JoAnn Lindenfeld has been granted a waiver under 18 U.S.C. 208(b)(3)
for her potential consulting for the sponsor of Pravagard on unrelated
matters. Potentially she could receive less than \$10,001 from this firm
per year.

Also, Dr. Jeffrey Borer has been granted a waiver under 18 U.S.C.
208(b)(3) for his potential consulting for the sponsor of Pravagard on
unrelated matters. Potentially he could receive less than \$10,001 per
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 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: Thank you, and for completeness, our final committee member
will introduce himself.

DR. ARTMAN: I\'m late.

(Laughter.)

DR. ARTMAN: I apologize. I\'m Mike Artman. I\'m at New York University
School of Medicine.

DR. BORER: This afternoon we\'re going to consider the NDA for the
pravastatin-aspirin combination product that was considered initially at
an earlier meeting. Some additional information is going to be presented
by the sponsor and we\'ll start with Dr. Baumgartner.

DR. BAUMGARTNER: Thank you, Mr. Chairman. Good afternoon. My name is Tom
Baumgartner. I\'m Vice President of Regulatory Sciences for
Bristol-Myers Squibb. We market pravastatin and buffered aspirin.

We\'re here before you today as you reconsider our NDA for a combination
product consisting of our lipid-lowering agent pravastatin, along with
aspirin, for use in the setting of secondary prevention in patients with
established coronary artery disease.

As you know, both these agents are approved by the FDA to reduce the
incidence of clinical cardiovascular events in the secondary prevention
population and also are recommended as cornerstone of therapy in
secondary prevention by the American College of Cardiology and the
American Heart Association in their treatment guidelines.

I\'d like to recap for the committee the chronology of events which have
led us to come before you again today. As part of this, I will also
frame what are the issues we\'ve been asked specifically to focus on
today.

Bristol-Myers Squibb originally submitted an NDA for this combination
product in June of 2001. The basis for this application was a
meta-analysis of five pravastatin cardiovascular event trials in
patients with established coronary artery disease. The application was
reviewed by this committee at its January 2002 meeting where numerous
issues were discussed.

Since that time we\'ve worked closely with the FDA to try to clearly
define what were the remaining issues to be resolved to allow for the
approval of this product. Based on these interactions, we revised our
application to address these outstanding issues, and the application was
refiled in May, which has led us to come before you today.

The core of the original application consisted of the meta-analysis of
five pravastatin cardiovascular event reduction trials which
demonstrated that the combination of pravastatin plus aspirin was safe
and effective and that the combination provided added benefit over both
pravastatin and aspirin when given alone in the prevention of subsequent
cardiovascular events in patients with existing coronary heart disease.
Following my presentation, Dr. Rene Belder of our Metabolics Clinical
Research Group will briefly review these analyses for you.

In addition to the meta-analysis, the original NDA also included a
pharmacokinetic study which demonstrated that there were no
pharmacokinetic interactions when the two drugs were given together.

When this application was reviewed by this committee in January, many
issues were discussed. As noted by FDA in the prologue for today\'s
questions for the meeting, at the time of the January meeting, there
appeared to be several areas of the application where general agreement
had been reached.

First, it appeared that there was general agreement that there was
indeed a population which could be identified for which this combination
product would be indicated.

In addition, it was generally agreed that the meta-analysis demonstrated
the safety and efficacy of the combination, as well as the independent
contribution of the components, to the beneficial cardiovascular
outcomes in the secondary prevention population.

Finally, the choice of aspirin doses to be offered appeared to be
acceptable to the committee.

While there appeared to be general agreement on some aspects of the
application, other issues remained outstanding. We feel we have
addressed these issues in the refiled NDA, including the briefing book
which was distributed for today\'s meeting. For today\'s presentation,
we will be focusing on four of these issues as were outlined by the FDA
in their prologue to the questions for today.

In his presentation, Dr. Rene Belder will address issues raised by the
committee in January regarding the range of pravastatin doses to be
available for this combination product.

In addition, he will address aspects related to the safe use of aspirin,
considering that it now will be a component of a prescription
combination product. This will include a discussion of the features of
this product which we feel may, in fact, reduce the risk for the
inadvertent use of aspirin in settings where it might not be desirable,
such as in surgery. In addition, he will address the implications and
risks for bleeding should aspirin not be discontinued prior to surgery.

Dr. Belder also will discuss the potential for inappropriate
discontinuation of pravastatin during times when it might be desired to
temporarily interrupt this product owing to its aspirin component.

In the next few minutes, I\'d like to address the final bullet on this
slide, which is the concern over the potential for inappropriate use of
this product in a non-indicated population such as in primary
prevention.

In addressing this concern, first I\'d like to reemphasize that the
indication we are seeking and the only indication which we plan to
promote is for the reduction of the risk of clinical cardiovascular
events in the secondary prevention population. This is a use in a
population for which both aspirin and pravastatin already are approved
by FDA.

As shown on this slide, we have proposed an intersection label for this
combination product. By that I mean a label which we feel reflects a
population where the secondary prevention claims in both the aspirin and
pravastatin labels intersect. The proposed indication provides for a
medication that allows for and enhances long-term management to reduce
the risk of cardiovascular events in patients with clinically evident
coronary heart disease.

Regarding the potential for off-label use of this product in primary
prevention, the reality is that in the current practice environment with
aspirin available over the counter, aspirin is currently being used in
primary prevention. However, we do not feel that the availability of
this combination product will increase the likelihood of off-label use
of aspirin over what currently exists with aspirin being available over
the counter. Rather, the fact that the pravastatin-aspirin combination
will be a prescription product should actually allow prescribers to have
greater control over ensuring that these drugs are used in the
appropriate population.

In support of our refiled application and our presentation, we have
brought some of the world\'s experts on the topics to be discussed today
who are available to us, as well as to the committee, for the
discussion. These consultants include: Dr. Jerry Avorn, a
pharmacoepidemiologist from Harvard, who authored the literature review
on the risk of aspirin use during surgery which was provided as part of
the briefing book for the meeting today; Dr. Don Berry from M.D.
Anderson who worked with us on the meta-analysis for the original
submission; Dr. Bernard Chaitman from St. Louis University who is an
author on the ACC/AHA guidelines on perioperative noncardiac surgery;
Dr. Lawrence Dacey who is a cardiothoracic surgeon from Dartmouth who
has published on the perioperative use of aspirin in cardiac surgery.
Dr. Charlie Hennekens from Miami has extensive experience on the use of
aspirin in secondary prevention and submitted a citizens\' petition for
aspirin to be approved in secondary prevention which was approved by the
FDA in 1998. Dr. Tom Pearson from Rochester is a preventive
cardiologist. Dr. Marc Pfeffer from Brigham and Women\'s Hospital who
was an investigator on the pravastatin CARE study, and Dr. Eric Topol,
Chair of Cardiovascular Medicine at the Cleveland Clinic, who is an
expert on antiplatelet therapy in cardiovascular disease.

The agenda for our presentations for this afternoon is as follows.
Following my remarks, Dr. Rene Belder from our Metabolics Clinical
Research Group will review the contents of our refiled NDA and address
the issues I noted previously regarding the pravastatin doses which are
now to be offered in the combination, safety aspects related to the
aspirin component of the product, and temporary discontinuation of
statin therapy. Dr. Fred Fiedorek, also of our Metabolics Clinical
Research Group, will conclude by summarizing our application and by
providing the regulatory context and rationale for this product.

I\'d like to introduce Dr. Rene Belder, Executive Director of Clinical
Design and Evaluation for Metabolics from Bristol-Myers Squibb. Thank
you.

DR. BORER: Are there any questions for Dr. Baumgartner at this point, or
are we all set to move on?

(No response.)

DR. BORER: Okay, let\'s move ahead then.

DR. BELDER: Good afternoon, ladies and gentlemen. I\'m very happy to be
back here today to present to you the features of our refiled
pravastatin-aspirin application.

To give a top line overview, cardiovascular disease remains the leading
cause of death in the United States. However, we also know that both
pravastatin and aspirin are approved medications for use in the
secondary prevention population. The pravastatin-aspirin combination
will, therefore, provide a useful tool for both health care providers,
as well as patients, to prevent coronary artery disease.

As Tom already indicated, I will give you a brief summary of the data
that we presented last January for those of you who were not here at
that time.

The efficacy and safety of the pravastatin-aspirin combination was based
on a meta-analysis of five pravastatin prevention trials. These trials
are listed here on this slide. All trials randomized pravastatin 40
milligrams and placebo. All trials had as a prespecified endpoint
cardiovascular events, and in total there were about 15,000 patients
randomized to either pravastatin or placebo. The largest contribution
came from the CARE and the LIPID study that provided about 98 percent of
the total patient-years of exposure, which was almost 80,000
patient-years. In addition, you can see that about 80 percent of these
patients were also taking aspirin.

The results of the meta-analysis are presented here on this slide for
three endpoints considered of most importance for this combination
product, namely fatal or nonfatal MI, ischemic stroke, and the
combination of coronary heart disease death, nonfatal MI, ischemic
stroke, or revascularization procedures. For both comparisons, namely
the combination of pravastatin and aspirin versus aspirin alone,
indicated here in yellow, as well as the comparison between pravastatin
and aspirin versus pravastatin alone, for all these comparisons there
was a significant benefit of the combination over the individual
components.

In addition, we examined the safety of pravastatin and aspirin when used
together in these trials, and we did not find any sign of an increased
incidence of CK or liver function test abnormalities or gastrointestinal
bleeds or hemorrhagic stroke, obviously all events of interest for these
products.

Let me now move on to the topics I\'ve been asked to discuss with you
today.

First of all, the choice of pravastatin doses to be provided in this
combination product. Last January we presented to you the rationale of a
combination product of 40 milligrams of pravastatin with either an 81
milligram dose of aspirin or a 325 milligram dose of aspirin. The 40
milligram dose of pravastatin was chosen because that\'s currently the
approved starting dose of pravastatin. In addition, the 40 milligram
dose was used as a starting dose and maintenance dose in all prevention
studies with pravastatin.

The committee, however, felt that a greater flexibility in the dosing
with regard to pravastatin was desirable, and we\'re therefore now also
offering the 80 milligram dose of pravastatin for those physicians who
like to see greater cholesterol reductions in their patients, as well as
the 20 milligram dose of pravastatin, which is provided for physicians
who are taking care of patients with renal or hepatic impairment or
patients who are also using immunosuppressive therapy.

I\'ll now move on to the potential of excessive bleeding should the
pravastatin combination not be discontinued prior to surgery, and this
aspect is divided into two topics. The first one is the potential of
inadvertent continuation of aspirin with this prescription combination
product, and the other aspect is if aspirin is continued during surgery,
what is the risk associated with its use. Let\'s start with the first
part.

In order to understand the risk of inadvertent use of aspirin, we first
have to understand what is the current situation with respect to
over-the-counter use of aspirin for secondary prevention. The current
situation is characterized by ambiguity for both health care providers
as well as patients primarily because there are many OTC aspirin-only
products available from which the consumer has to make a selection for
secondary prevention. You see some of these products here on this slide.
In addition to these products, there are also numerous generic aspirin
products available. Also, you can see that the doses available of these
products of up to 650 milligrams would not be desirable for secondary
prevention.

Secondly, there are many over-the-counter products available that
contain, in addition to aspirin, other active ingredients, some of which
may not be appropriate for patients with coronary heart disease. And
these are the products that are available for the consumer to choose
from of products that contain aspirin. I would also like to mention that
these products may actually contribute to inadvertent use of aspirin
prior to surgery because many patients or even physicians may not
realize that one of the active ingredients of these products indeed is
aspirin.

Lastly there are also OTC products available that can be confused by a
consumer as aspirin substitutes, and it was indeed shown here by a study
from Cook from Dr. Hennekens\' group that showed that of those patients
who were thinking that they were taking aspirin for secondary prevention
correctly, actually 15 percent came home with aspirin substitutes, such
as acetaminophen. In addition, of note is that in this study in a
general population, only 51 percent of those patients who should have
been taking aspirin for secondary prevention were actually taking it.

These are the products that can easily be confused by a consumer as
aspirin equivalents and products that do actually not provide the
benefit in secondary prevention.

It may, therefore, be clear that the prescription use of aspirin in this
combination product may actually offer some advantages. Physicians will
be better able to ensure that aspirin is used rather than a substitute
and will also be able to select a dose that is most appropriate for
secondary prevention. In addition, we believe that other physicians will
be better able to recognize that aspirin was used as part of a
prescription product and recommend discontinuation or continuation as
appropriate.

Of course, it is important that both physicians and patients are aware
of the aspirin component of this product, and we have, therefore,
developed labeling that clearly indicates the aspirin component of this
product. This is the example of the proposed package showing the aspirin
component indicated four times. In addition, we have developed a patient
information leaflet also clearly indicating that this product does
contain, indeed, aspirin.

I\'ll now move on with what is the risk if aspirin is, indeed, continued
during surgery. What is the risk of excessive bleeding?

Aspirin has been studied in noncardiac patients in several surgical
settings, and the results of these studies are summarized on this slide.

First of all, aspirin has been studied in vascular surgery to prevent
graft occlusion, and the results here are of a meta-analysis performed
by the Oxford Group.

In addition, aspirin has been studied in patients at high risk for
venous thrombosis and pulmonary embolism, and that\'s the middle study
presented here on this slide.

And finally, there was a large prospective study of aspirin in patients
undergoing hip surgery also to prevent pulmonary embolism. In this
study, aspirin was started 7 days prior to surgery.

When we look at the safety of aspirin used during surgery in these
studies, we see that there was no large excess of bleeding and there was
no increase of fatal bleeds associated with its use. Indeed, aspirin
prevented graft occlusions and prevented pulmonary embolism. So, there
was an overall benefit of aspirin in this setting.

Aspirin has also been studied in several studies in patients undergoing
coronary bypass procedures. Of note is that the earlier studies indeed
show that there was an increased need for transfusions and an increased
need for reoperation for bleeding. However, the more recent studies do
not observe this same finding, and there\'s actually a hint of a
possible benefit when aspirin is used during surgery in these patients
undergoing coronary bypass procedures. And I will discuss these data a
little bit more.

We, therefore, believe that the concern about the inadvertent use of
aspirin in surgery in patients with coronary heart disease has actually
decreased over the last number of years for several reasons, and I will
discuss these with you.

First of all, improved surgical procedures reduce the risk of bleeding
complications. This is data from a study from Dr. Dacey\'s group, and as
indicated, Dr. Dacey is here today. If you look at the last
observational period on this slide, indicated here ‑‑ and this is data
from over 12,000 coronary bypass procedures performed in northern New
England ‑‑ you see that the rate of re-exploration due to bleeding is
actually decreased, while during this same period of time, the use of
aspirin in these procedures has actually dramatically increased from 22
to 78 percent. This effect is mainly attributed to improved surgical
techniques and procedures, as well as improvements in hemostatic
measures.

As I indicated before, there may even be some indication of a potential
benefit with respect to the use of aspirin in this particular setting,
patients undergoing bypass procedures. Again, this is data from Dr.
Dacey\'s group who showed in an observational study in over 8,000
coronary bypass procedures that there was no increased rate of
re-exploration for bleeding. There was no difference in the need for
blood products. However, there was a significant reduction in
in-hospital mortality associated with aspirin use.

However, there\'s no good, well-controlled, prospective clinical data of
the use of aspirin in the surgical setting in patients with coronary
heart disease. Therefore, there remains a lack of consensus about what
to do with aspirin in these patients, continuation or discontinuation.
And that is evidenced by the ACC/AHA guidelines on the perioperative
medical treatment of patients with coronary heart disease in noncardiac
surgeries. These guidelines do not provide specific recommendations
about discontinuation or continuation of aspirin. One of the authors of
these guidelines was Dr. Chaitman. Dr. Chaitman is here today to comment
on these recommendations.

However, most importantly, we believe that with the availability of this
combination product as a prescription product, the likelihood of
inadvertent continuation of aspirin is actually reduced compared to the
current situation where aspirin is essentially used over the counter for
a variety of reasons.

The last topic to be discussed today is the potential for inappropriate
continuation of pravastatin, again in a setting where, for instance,
this combination product would be discontinued, if needed, before
surgery.

First of all, it\'s important to note that unlike aspirin, whose onset
of action is very acute, with statins in general in the secondary
prevention population, it takes a while before the effects from
cardiovascular events become apparent. One would, therefore, not expect
a brief interruption of statin therapy, for instance, for a couple of
days before a surgery, would have any immediate adverse consequences.
And indeed, there\'s no data pointing in that direction. However, more
importantly, the individual components will remain available for the
physicians to manage interruption or discontinuation of one component
and continuation of the other.

In summary, we believe that with the actions discussed today, we have
addressed the main concerns. First of all, we have now made three
pravastatin doses available: in addition to the 40 milligrams, also the
20 and 80 milligram doses of pravastatin. In addition, we have developed
packaging and labeling that clearly identifies the aspirin component,
increasing awareness by both patient and physician of the aspirin
component of this product.

I would now like to hand over to Dr. Fred Fiedorek for summary comments
unless there are questions.

DR. BORER: Are there any questions for Dr. Belder? Paul.

DR. ARMSTRONG: I may have missed it, but in the approximately 1 out of 5
patients not on aspirin in LIPID and CARE, were the baseline
characteristics of those patients as compared to the others in those
studies factored into the meta-analysis?

DR. BELDER: Yes. That was extensively discussed last January.

DR. ARMSTRONG: Okay.

DR. BORER: Any other questions? Okay, why don\'t we go on to Dr.
Fiedorek. Oh, sorry. Steve.

DR. NISSEN: In the original application, we were asked to consider this
as if the two drugs would be together in one tablet. Has there been a
withdrawal of the request for approval for a single tablet containing
both compounds?

DR. BELDER: No. The prologue to the initial meeting advised you to
consider this as a single tablet. And we still have a single tablet on
stability. So, a single tablet will be offered as soon as we have enough
stability data to launch it. At this point in time, it\'s a co-packaged
product.

DR. NISSEN: Right. But what you said earlier was that if we wanted to
discontinue the aspirin component for any reason or the statin
component, we would be able to do so. But that\'s true only in the
co-packaged product. The intent is not only to market the co-packaged
product, but also the combination eventually.

DR. BELDER: Correct, yes. But what I meant is that if a physician
continues the single combination tablet, but wants to continue one of
the components, then he would go back to the single component use. So,
it\'s basically back to the old situation.

DR. NISSEN: So, it really isn\'t a change then in what you\'re
requesting.

DR. BELDER: Correct.

DR. BORER: Dr. Fiedorek.

DR. FLEMING: One other question.

DR. BORER: Oh, I\'m sorry. Tom, go ahead.

DR. FLEMING: In the materials that the medical reviewer presented to us
from FDA, there was a lot of consideration to the Nelipovitz article
that set up basically models to try to address the tradeoffs between
bleeding risks against reductions, for example, in MIs. Will you be
giving us more information on that?

DR. BELDER: We were not intending to. We\'re also not making a strong
argument that we think aspirin is beneficial during surgery in patients
with coronary heart disease. Our primary contention is that since this
is a combination prescription product, physicians should be able to
continue or discontinue its use. We believe that there may be some
evidence that aspirin would be beneficial during surgery, but as
indicated before, the guidelines clearly say there\'s not enough data.
We cannot make any firm recommendation.

And the articles that were included in the medical review from FDA was
our initial literature review in March that we discussed with the
agency. Subsequently we have done a lot more work, including work by Dr.
Avorn, and of course, have looked at more literature and other studies.
The Nelipovitz article was just one example of where you could see that
perhaps there would be a beneficial effect of aspirin.

Does that answer your question?

DR. FLEMING: Only partially. Basically what you\'re saying is now that
you\'ve gone further, there are a lot of other sources of information,
if I\'m interpreting you correctly, that you believe to be more
informative and relevant than that article?

DR. BELDER: We believe that with respect to the use of aspirin in
surgery there is no firm evidence about continuing or not continuing.
There\'s no well-controlled data.

Dr. Chaitman, would you want to comment on that?

DR. FLEMING: While he\'s preparing to comment, maybe he can also comment
on this aspect as well. Is it fair to say any evidence that we do have
comes from observational experience as opposed to any specific
intentional randomization?

DR. CHAITMAN: Yes, you\'re correct. There are no randomized clinical
trials looking at aspirin usage in this situation, so it is mainly
observational data. That\'s the reason that there wasn\'t a discussion
of this in the guidelines because the guidelines are evidence-based, and
the evidence wasn\'t strong enough to include them in the guidelines.

DR. BORER: Beverly, you\'re the committee reviewer. Do you have any
issues that you want to raise at this point, or do you want to wait?

DR. LORELL: I\'ll wait.

DR. BORER: Dr. Fiedorek.

DR. FIEDOREK: Thank you, Rene.

Good afternoon, committee members, ladies and gentlemen. If you\'ll
recall, I was here in an introductory role in January, and I\'m now
concluding to provide a final framing of the issues and book-ending, we
hope, of what we\'ve discussed today and back in January. My purpose,
besides giving a brief recap on the issues, is also to provide a final
concluding rationale that is based in part on existing FDA regulations
that provide the context for what we\'re considering today.

This list includes the six key components that we described in January
and we\'ve discussed to a certain extent today. The first four
components, as indicated in the preamble today to the questions that
you\'re considering, were generally reviewed in more detail in January
and there was general agreement by the committee at that time and we
have not dwelt on these in any additional detail today.

The final two points, highlighted in green, are what we\'ve discussed
today, as well as in January. Clearly in the refiled application, we
will now be offering three doses of pravastatin, in addition to the 40
milligrams, the 80 milligram and 20 milligram dose, to go along with the
approved doses of aspirin in secondary prevention, 81 milligram and 325
milligram.

The last point has been one that had particular concerns in January, and
what we\'ve done today is to review the relevant data. As we\'ve just
heard, it\'s relatively sparse data, but we\'ve reviewed it and I think
provided to you the context of using aspirin, or pravastatin for that
regard, inappropriately and possibly either continuing or discontinuing
either component of this combination in such settings. We\'ve put
particular emphasis on the setting of surgery where we\'ve gone into the
best data on this particular topic, and we have experts here today to
answer those questions as well, should you have further questions.

Overall, with the prescription use of aspirin we are offering in this
combination product, we think that the lower doses of aspirin relative
to available doses in the OTC setting, as well as clear labeling that
this product contains aspirin, and sort of the inherent specificity of
prescription use so that the physician is able to implement the use
appropriately for secondary prevention in CHD patients, will be
meaningful in your considerations.

Overall, we feel that this particular prescription combination product
will not impact in any adverse way, in any deleterious way the potential
for bleeding during surgery that exists with the OTC availability of
aspirin currently.

Besides these six points, I want to now provide a context based on the
current FDA regulation for fixed-dose combination products. This
particular regulation was actually established quite some time ago in
1971. I think it\'s worthwhile to read it.

\"Two or more drugs may be combined in a single dosage form when each
component makes a contribution to the claimed effect and the dosage of
each component (amount, frequency, duration) is such that the
combination is safe and effective for a significant patient population
requiring such concurrent therapy as defined in the labeling for the
drug.\"

But I think the emphasis that we provided here in the underlining serves
to stress what we\'ve been bringing forward to committee in January and
again today, the key components of the pravastatin-aspirin combination.
In this context, this regulation from 1971 still provides a valid
framework for considering pravastatin and aspirin. The four key
components listed here have been met in our view based on discussions in
January and again today.

Number one, efficacy through differing mechanisms of action has been met
in the setting of secondary prevention of clinical events.

Number two, safety in CHD patients for secondary prevention, including
in situations surrounding surgery, is assured in terms of the
benefit-risk assessment that we feel exists for aspirin in these
settings.

Number three, the key component of contribution which was discussed in
most detail in January and that the combination with A plus B being
greater than either pravastatin alone or aspirin alone is also a key
feature which was determined by the meta-analysis discussed primarily in
January.

Finally, we\'ve established that there is a clear medical need in the
setting of secondary prevention in a demonstrated population at risk.

Besides these four key features, I think there are some reassuring
aspects to the pravastatin-aspirin product as well. As indicated
earlier, it\'s comprised of component drugs at selected doses previously
approved by the FDA. In addition, it will be labeled for secondary
prevention, an indication previously approved for these component
medicines. And finally, practice patterns and medical guidelines support
the concurrent use of pravastatin and aspirin as a secondary
preventative in the CHD population.

I think it\'s quite instructive to consider this last point very briefly
here. Generally medical guidelines rely on sort of assessment of benefit
and risk as determined by a consensus committee. Recently some of these
guidelines have actually outlined risk based on a possible recurrent
event over the subsequent 10 years.

In this slide here, the risk of a CHD event in some of the populations
represented by the secondary prevention population we intend to treat
with the combination are described. These are based on landmark statin
trials as well as other sources of information. Shown in the column with
the percentages are the placebo event rates in these trials over time.
You can see in patients with a history of an acute MI, the risk of a
subsequent CHD event, either MI or a CHD death, ranges from 26 percent
up to 51 percent over the subsequent 10 years. For patients who\'ve
undergone a revascularization procedure, this risk is between 26 and 30
percent, and for patients with stable angina pectoris, this risk is
about 20 percent.

I think given these event rates and risks in the secondary prevention
CHD population, it\'s also interesting to consider that recent
recommendations and guidelines ‑‑ one of them actually mentioned this
week from the American Heart Association recommends the use of aspirin,
the one component that we\'ve been most concerned about, in patients who
have a relative risk of a subsequent CHD event of 10 percent. Earlier
this year, the U.S. Preventative Task Force also recommended the use of
aspirin in the preventative setting in patients who had a risk of a
subsequent event of 6 percent or greater.

So, to conclude our presentation today, we feel that pravastatin-aspirin
is a rational combination that\'s supported through evidence-based
medicine. We are offering three doses of pravastatin to go along with
the prior doses of aspirin, 81 and 325 milligrams. The safety of aspirin
has been discussed in some detail this afternoon, and we think that the
benefit-risk profile in this patient population, the coronary heart
disease population seeking secondary prevention, is certainly warranted.

We also have described some possible advantages of using the combination
product, pravastatin and aspirin, as a prescription medicine where clear
use as a secondary prevention medicine can be designated by the
physician and that both physician and patient will know with our
labeling that the product, in fact, does contain aspirin.

Thank you for your attention. If there are any other questions, you can
call on me and we can also call on the experts assembled today.

DR. BORER: Thank you very much, Fred.

Beverly, why don\'t you start and then we\'ll move around the committee
if there are any other questions.

DR. LORELL: I think your presentation has been very cogent in addressing
the concerns that were raised by the committee at the last meeting.

I\'d like to open the discussion with one of several points that I think
the committee is going to want to address and that is the issue of
recognition of what a combination product includes. I appreciate the
query by Steve and your clarification that what we\'re really discussing
here is not the temporary co-packaging of two pills, but the ultimate
presentation of both drugs in a single tablet or single capsule. Is that
correct?

DR. FIEDOREK: Yes, that\'s correct. In January, the preface provided to
the questions specified that it was a combination co-tablet. As part of
our development work for this combination, we will have available both a
co-package with each component available to punch out separately, and
that will be available initially. Subsequently we will have a true
combination tablet, but as Dr. Belder mentioned, it\'s undergoing
stability testing currently.

DR. LORELL: I think one of the themes that many of the questions derive
from is the issue of recognition, not short term but long term, by both
patient and clinician provider that a single tablet does contain
aspirin, a potent antiplatelet agent. One of the concerns that I would
raise, based on my own clinical practice from one of the precedents that
we have ‑‑ and that is co-packaging in a single tablet or capsule of
antihypertensive agents ‑‑ is that even though those are often clearly
identified on the pill bottle and on the packaging and the labeling, it
is extremely common to have confusion not only on the part of the
patient as to what a pill actually really contains ‑‑ patients know that
it is vaguely for their blood pressure or for their heart ‑‑ but even on
the part of providers.

I guess that one of the pieces of evidence that we don\'t have, because
this is such an important issue, is actually any prospective data
regarding recognition of the components. I would welcome comments from
others around the table.

DR. BORER: Fred.

DR. FIEDOREK: Yes. We actually took those concerns seriously, and I
think the description of how we would describe in the patient leaflet,
as well as the clear labeling, as effectively as we can that the product
contains aspirin and that both prescribers, physicians, as well as
patients, should recognize that.

We have not done anything other than that at this time, and I\'m not
aware of any label comprehension studies or other label interpretation
studies by patients that would address that point from other products.

But I think our main contention is that the prescription use here in
this product, as well as the clear labeling that we intend to provide,
would not be deleterious at all compared to the current situation that
Dr. Belder reviewed with the availability of many OTC aspirin products
that may not be recognized by the patient or physician as well. That\'s
a general issue that perhaps the agency would want to address regarding
aspirin use in general, and what we\'re trying to do with
pravastatin-aspirin is to be clear that this product contains aspirin
and to make it a prescription product for secondary prevention.

I don\'t know if that helps.

DR. BORER: Steve.

DR. NISSEN: I just want to understand this better. I really like the
label that you show here in the slide set. But isn\'t what happens in
reality that a pharmacist has a stock bottle of a product and then they
take and they put X number of pills in a container and pass it on to the
patient? I mean, these labels aren\'t likely to appear, are they, on the
final product that the patient is going to actually see.

DR. FIEDOREK: Well, the patient package insert would be part of that
product.

DR. NISSEN: Yes. But I mean, this label, which is really terrific, says
aspirin three times on it. The patient doesn\'t see that label.

DR. FIEDOREK: It\'s currently a proposed label, and perhaps Dr. Temple
would want to ‑‑

DR. TEMPLE: Well, a point we\'ve made often in the past goes to the very
question Dr. Nissen raised. If it\'s not a unit-of-use package, there\'s
very little reason to believe that the patient will actually get the
patient package insert. Now, for the combination, obviously with all the
punching out, they will. Sorry. For the co-packaging, then I guess they
will because that\'s how it\'s going to be given out.

But what about for the combination tablet? Are you thinking of
unit-of-use packaging which would assure that the patient labeling goes
to the patient?

DR. FIEDOREK: Yes, it would have the same type of intended labeling.

DR. TEMPLE: Well, I know but unit of use or something that the
pharmacist has to take an active role in handing out? That\'s a crucial
distinction.

DR. FIEDOREK: Yes, that\'s our intent.

DR. BELDER: We have not developed the packaging of the single
combination tablet yet, but of course, we are listening to you and will
definitely take your comments in consideration when we develop that to
assure that the patients, indeed, will get a similar type of package as
indicated here for the initial co-package with a single tablet.

DR. THROCKMORTON: Steve, you and Beverly are saying that the notion
would be that that would increase the awareness of aspirin use. Is that
the particular issue you\'re raising?

DR. NISSEN: Yes. Well, I guess Bev and others of us the last time around
wanted to make certain. Obviously, when a combination product is
administered, there\'s a tendency for physicians and patients to lose
track of the fact that there\'s more than one component. So, part of the
safety issues related here are to maintain that awareness.

I understand how having a blister pack with that on it, nobody in their
right mind could miss it. You put it on there three times. It\'s very
prominent and I think quite desirable.

The problem is a little pill bottle ‑‑ I\'m not so sure that this label
is going to appear. It\'s very challenging. None of the medicines that I
take have anything like that on them. They just have some little
typewritten thing and that\'s that. So, there is a tendency to lose
track of that when you throw it together in a single pill. So, I just
didn\'t want any of us to have the wrong idea about expectations here
about what the patient is actually going to see.

DR. BORER: Two issues relevant to that. As a point of information, is it
possible to mandate that typed labels in a pharmacy must contain certain
information about a certain product?

DR. TEMPLE: Well, we think so. But whether the established mechanism for
insisting is available here is not clear. There\'s something called a
med guide that we can require when certain serious hazards would occur
if the patient didn\'t understand certain things. Given the uncertainty
about whether discontinuing is critical or not, it would be hard to make
the case that you need a med guide.

On the other hand, it\'s clear that you want patients to understand that
they are, in fact, on aspirin and be able to tell their doctor. And
companies can agree to have a package insert that is part of their
labeling, whether it\'s a med guide or not.

The next question is how you can provide any assurance that patients
will get it. Under the med guide rule, pharmacists are required to hand
it out. Now, what that means if they don\'t is not completely clear, but
they are required legally to attach the med guide which is a patient
package insert.

My own view is that if you really care the best way to assure it is to
make it part of the distributed package. That doesn\'t mean a pharmacist
couldn\'t pour it out and put it into another bottle, but they wouldn\'t
have any reason to. So, you create unit-of-use packaging which is how
drugs are distributed in most of the world, just not here.

DR. FIEDOREK: We certainly would agree to abide by that and try to work
to get appropriate labeling for the combination tablet.

DR. BORER: Another issue here. No single mechanism, except maybe
unit-of-use packaging, is going to overcome the possibility totally that
somebody is not going to know what he\'s taking. People have a lot of
ways to not know what they\'re doing.

But another safeguard perhaps could be in the trade name. In this case,
it\'s fortunate that most people understand what the word aspirin means.
I suppose, although I have no idea how you make up trademarks, a name
that emphasized the component that\'s of some concern might be helpful
in identifying it for patients. So, it\'s just something to consider. I
don\'t know if you\'ve thought about your trade name yet.

Are there any other comments? We\'ve raised this as an important issue
about recognition. Any other comments, Tom?

DR. PICKERING: Just one naive question. Isn\'t it likely that when the
pharmacist prints out the patient\'s label with the instructions,
they\'ll paste it right over your very nice label saying aspirin three
times?

DR. BORER: If it\'s unit-of-use packaging then the directions presumably
are on the ‑‑

DR. TEMPLE: The patient insert can be attached as a pull-out. It depends
on how big it is, but it can be attached in a way that it\'s relatively
large print and relatively easy to see.

DR. BELDER: I would also like to mention that this package will actually
contain a blister pack and every time the patient punches through a
tablet, it will say pravastatin or aspirin. So, even then as you punch
through the tablets, as you get the blister pack in your hands, both
components are indicated.

DR. TEMPLE: And you see the same thing for the fixed combination in a
single tablet?

DR. BELDER: As I said, we haven\'t developed the packaging yet. We can
discuss that, of course.

DR. TEMPLE: But I think that\'s what people are concerned about.

DR. BELDER: We\'ll be more than willing to work with the agency to
develop clear identification.

DR. TEMPLE: Can I ask the committee one question, Jeffrey? Part of the
argument here is that we think it won\'t be any worse than it is already
because aspirin is ubiquitous. The second part is that, yes, probably
some people won\'t realize they\'re on aspirin, but given the state of
what people\'s views are, that\'s probably not that bad. We don\'t even
know that\'s bad for you.

DR. LORELL: I\'ll take objection to that.

DR. TEMPLE: Well, I\'m not endorsing it. I\'m just saying I thought that
was part of the argument and that they would do their best to make sure
people understand it, but that it wouldn\'t be an unmitigated disaster
if somebody slipped through. That\'s part of the argument I hear. I just
want to know what people thought of it. So, I guess I\'m about to hear.

DR. LORELL: Yes. Let me respond to that. I think that there is no
disagreement with anyone in this room in the cardio-renal field of the
extraordinary importance of the use of aspirin and statin lipid-lowering
agents for secondary prevention. None of us has to be convinced of that.

I think the data that were presented as supplements clearly raise the
issue that there is still a lot of controversy, disagreement about the
risk of continued antiplatelet agent use, whether it is aspirin or a
newer agent, in the context of minor surgery, major surgery, and
biopsies. So, the answers to that are not yet known.

There clearly can be risk in an individual patient of having very
adverse outcomes, and I think for many patients the risk of even an
increase in ‑‑ or any transfusion requirement might be looked at as a
major adverse event.

I think one of the things that I\'d like to hear your comments on is the
safety data that was presented in detail and alluded to here in the
earlier presentation this winter that comes from the Pravachol secondary
prevention trials. One of the dilemmas there that I\'m wrestling with,
regarding the use of aspirin, was that aspirin was individually
manipulated by the physicians. It was not part of trial design as being
a mandated Pravachol alone, Pravachol plus aspirin, or aspirin alone.

So, I think a concern that might be discussed by the committee is that
we really don\'t have data, either retrospectively or prospectively,
about the sort of forced co-use of both drugs without individual
manipulation. So, I think although we\'re all encouraged by the data
that at least for vascular operations, continuation of aspirin in the
net may be beneficial. There are many other kinds of procedures where
that risk-benefit is very unclear.

DR. FIEDOREK: Yes. In the trials you\'re referring to, the pravastatin
trials, the aspirin use may have been done by the patients themselves.

I\'d like to ask if Dr. Dacey would care to comment on this from the
point of view of cardiovascular surgery, and we can then get to some of
the other aspects.

DR. DACEY: Sure. At least in the cardiovascular field, specifically
coronary bypass, we found in northern New England ‑‑ we talk about
continuing aspirin was beneficial with about a 27 percent reduction in
operative mortality just being on aspirin as opposed to patients that
had the aspirin stopped and had no increase in transfusion, no increase
in chest tube drainage, no increase in re-exploration. Indeed, over
time, as the slide alluded to, the incidence of re-exploration has
continued to go down despite increased aspirin use.

It\'s not a finding unique to us. The Society of Thoracic Surgeons keeps
a database. When they looked at this last in over 78,000 patients, they
also found about a 30 percent risk reduction for mortality in patients
that take aspirin.

We looked at our own data in northern New England over the last ‑‑ I
believe it\'s 5 years, over 13,350 patients or so. Again, about a 28
percent risk reduction in mortality in patients who are on aspirin prior
to surgery. Again, we\'ve noted no harmful effects to this.

I know the company is not touting aspirin is a good thing, but certainly
in our literature, preoperative aspirin definitely decreases mortality
with no discernible adverse effect that we can surmise. So, indeed, we
actually encourage our patients, if they\'re not taking aspirin, to take
it right up to and through surgery.

DR. FIEDOREK: Dr. Avorn, would you care to make any comments on this?

DR. AVORN: I think the most relevant piece of this is not whether it is
necessarily for nonvascular surgery a good thing or a bad thing to
continue aspirin because, as was mentioned, the data simply don\'t
exist, but rather whether the co-packaging or combination of these two
products together, as proposed, would increase, decrease, or leave
unchanged the likelihood of inadvertent misadventures.

One of the compelling pieces for me is that right now we\'re dealing
with a situation where patients often don\'t know what they\'re taking,
as the Cook paper demonstrated. Physicians often don\'t know what the
patient is taking. If it\'s a surgeon who gets a med list and aspirin is
not on it, they may not know what the patient is taking.

So, without taking a stand on whether aspirin should always or never or
sometimes be continued through an operation, I think the point here is
that this packaging will make it more likely that the doctors involved
in the patient\'s care will be able to make a proactive decision on
their own part, whatever their own lights tell them they ought to be
doing, and it\'s giving them more information and that\'s probably the
key distinction.

DR. FIEDOREK: Dr. Chaitman, would you care to comment at all?

DR. NISSEN: Rather than having ‑‑

DR. BORER: Just a second, Steve. We have several people. Why don\'t you
finish your response and then we have Mike and Steve and Beverly.

DR. FIEDOREK: I was just wondering, Dr. Chaitman, if you had any
answers. No, okay.

DR. BORER: Mike.

DR. ARTMAN: My point was raised already.

DR. BORER: Okay. Steve.

DR. NISSEN: I wanted to explore this a little bit further with you. Dr.
Dacey, your data is not prospective, randomized data. Is that correct?
It\'s observational?

DR. DACEY: That\'s correct. Both in New England and STS, it was all
observational.

DR. NISSEN: So, how do we know that the patients in whom aspirin was
continued weren\'t different from the patients in whom aspirin was
stopped?

DR. DACEY: The one paper that we looked at in detail looking at
perioperative characteristics, there\'s no significant difference
between those two patients. So, again, there\'s always a chance of bias,
but as far as we can tell as confounding, we didn\'t find any
confounding.

DR. NISSEN: Wouldn\'t you think that a surgeon that thought a patient
that was at particularly high risk for bleeding might stop aspirin and a
patient that was at particularly low risk for bleeding might continue
it? Obviously, observational data like that has some significant
limitations.

I guess I wanted to follow on with that. Would you have different
recommendations if a patient were going for, let\'s say, reoperation?

DR. DACEY: No.

DR. NISSEN: Would you be more likely to stop aspirin in patients
undergoing reoperation?

DR. DACEY: Absolutely not. The only possible scenario I could think of
would be a Jehovah\'s Witness, and then I think you\'re still dealing
with a mortality tradeoff versus bleeding. But reops, anybody else, we
always keep it going.

DR. NISSEN: The other issue was I heard said several times that there
was no prospective randomized data, and I guess, as I read through the
manuscripts ‑‑ and I also did my own literature search ‑‑ there is some.
The VA cooperative study was prospective and randomized. I think it\'s
important at least we put the issue on the table.

As I read the study, in that study, in patients who were randomized to
aspirin, there was a 6.6 percent risk of having to go for reoperation,
and those that were not aspirin had a 1.7 percent risk of reoperation.
So, the risk ratio was about 4 to 1 for having to go back to the
operating room and have their chest reopened if they were on aspirin.
Now, that\'s prospective randomized data.

I think it\'s important that we not trivialize the issues involved here.
If you look at the manuscript ‑‑ and I\'d like to just call your
attention to page 237 of the handout ‑‑ the differences were highly
significant, p values of .0001 for red blood cell transfusions, for
platelet transfusions, cryoprecipitate administration, fresh frozen
plasma, but not necessarily for whole blood. So, something like
cryoprecipitate obviously means that when you see significant increases
in the use of cryoprecipitate, you\'re talking about a pretty important
clinical effect.

So, regardless of what decision we make ‑‑ and I think the arguments are
understood about whether or not this product represents an increased
risk or not. There are reasons why people on this committee have been
concerned about this, and they relate to some of the data that\'s
available out there.

DR. DACEY: I guess my only rebuttal is sort of in the current era, we
just looked at other, again, observational data. And I admit that we
looked at over 10,000 patients and have a 2.6 bleeding percent for
patients who were not on aspirin, 2.7 percent for patients who were on
aspirin, and no statistical difference. At least in the current era, it
doesn\'t seem to be a problem.

DR. BORER: Blase and then Beverly.

DR. CARABELLO: I think it\'s fair to point out, though, that that VA
study is an old study. Surgery has changed. At least the field of
surgery that I\'m interested in, which is valve surgery, has changed so
dramatically since those data were reported, that it\'s likely that
other fields of surgery have also changed.

DR. BORER: Beverly.

DR. LORELL: I think one way that might be helpful of thinking about this
as a safety issue is there really are at least a couple of components
here. One is the ambiguity and uncertainty about the risk of
inadvertent, which is a little different from what you\'re talking
about, continuation of aspirin for surgery, biopsies, major invasive
procedures. Perhaps your comments I think are very important for how we
practice but may not be quite to point for this issue because I think in
the current era, most cardiologists, cardiac surgeons, vascular surgeons
actually make quite a deliberate, focused decision about inclusion or
exclusion of aspirin or other platelet agents. So, I think the broader
issue for a combination drug that\'s not intended for use short term but
for a very long term is the much broader issue of risk of inadvertent
use of aspirin, perhaps for nonvascular procedures.

I think the second safety issue that is still not really fully addressed
is the issue ‑‑ it\'s been postulated that there would be less confusion
in a prescription drug as to whether aspirin was present or not compared
to current over-the-counter use of aspirin for secondary prevention.

But I\'m concerned that we really don\'t have data to support that one
way or another. One could make the argument that in a 70-year-old woman
who\'s showing up for a colonoscopy or a major breast biopsy, that she
might report that she\'s taking an anticholesterol drug. She might not
even know the name of that drug or bring the drug with her to the
doctor. It\'s a common scenario.

So, I think the second, very separate safety issue is the issue of
whether there is a safety problem regarding ambiguity of combining a
very potent antiplatelet agent in a pill with something else. I guess it
would have been nice or might be nice to actually have some data to
address that. We have only hypothesis right now.

DR. BORER: One of the issues that you may want to talk about, if you
have some specific information to bring to bear ‑‑ and I think you hit
upon this in some of your discussions thus far ‑‑ is what is the
likelihood of this happening, given that multiple layers of
communication that you\'re suggesting will be brought to bear here, in
comparison with the likelihood that somebody who might well benefit from
the combination therapy will not be getting one component if the
convenience of a combination product isn\'t made available. You did
discuss this to some extent in your first presentation several months
ago.

And I think to put this in context ‑‑ just as Beverly says, it\'s a very
important issue. I don\'t have a sense of the magnitude of the
likelihood that with the prescribing doctor knowing what he or she gave
and the patient having been told and the package saying something ‑‑
with all those levels, I don\'t know what the magnitude is of the
likelihood that somebody will slip sure although, sure enough, somebody
will and probably several.

There is, as against that, the benefit to that patient for having been
taking the combination therapy that maybe wouldn\'t have been taken,
which we also can\'t determine the magnitude of. And I\'d like to hear a
little bit of discussion about that. Perhaps, Charlie, you may want to
comment on that.

DR. FIEDOREK: Dr. Topol or Dr. Hennekens, does anybody care to comment?

DR. HENNEKENS: I think, Jeff, as you\'re pointing out, the overriding
benefit of improving compliance overall has to be put in context with
the concerns about safety. But I do think, going back to Bev\'s comments
about titration, that in fact the ability to have a low-dose aspirin new
data from the CURE study helps in that regard with respect to enhancing
safety. And I\'d like to just review that, if I could get the slides
just to point out.

As you know ‑‑ and I think Dr. Lorell mentioned, of course, the
acceptance of aspirin in antiplatelet therapy. One important point from
the recent meta-analysis from the antiplatelet group ‑‑ and as you know,
this is a very large collation of data, over 212,000 patients in 287
trials.

What you can see in these data, of course, the first thing of note is
that the lower-dose aspirin in all of these trials actually fared
somewhat better. This is not a direct comparison, but the dose of one or
two baby aspirin, less than 160, had the highest evidence of reduction
of vascular death, MI, or stroke, as compared to the dose of greater
than that level.

But importantly, as I mentioned, the next slide shows recent data
that\'s been available from this trial. The first point, of course, is
that this is not a randomized dose of aspirin, but it\'s the best we
have today as of July 2002. It\'s a large population of 12,500 patients.
Of course, in this particular study, it was at the physician\'s
discretion as to what dose of aspirin to use. So, that\'s important.
While not randomized, there were no differences in the three different
arms here with respect to the patient characteristics, demographics, or
risk.

But as you can see, the efficacy of either 80 or 160 milligrams ‑‑ this
was an international trial. There are some doses outside the U.S. of 100
milligrams, for example, or 150. The efficacy was at least as good at
the low dose.

And then most importantly, again to address the concern regarding
bleeding ‑‑ and this goes back to Steve Nissen\'s point on the VA trial
and Blase Carabello\'s ‑‑ that that study at the VA was a very high dose
of aspirin. Now, as it turns out, the dose of aspirin of 325, greater
than 200, is associated with the highest risk of life-threatening and
major bleeding. And as one goes down to a dose of 81 milligrams, the
bleeding risk is considerably reduced. So, you can see for
life-threatening bleeding, it\'s half as much as the 325 milligram dose
or in that dose group and also for major bleeding. This would be
associated with biopsies or any other procedures that Dr. Lorell is
concerned about. The bleeding is considerably less.

So, while the questions have been focusing on the bleeding risk, my
concern of course is enhancing compliance. As you know, in the Heart
Protection study just published, only 68 percent of patients who were on
statins or study drug were taking aspirin. So, the compliance still
today remains low. All the recent studies suggest 70 percent for statins
of the 100 percent who should use them and at best 85 to 90 percent of
aspirin use in, again, 100 percent of patients who should be in that
group. So, the idea of improving compliance and particularly stressing
low-dose aspirin, which I think all the data suggests converges on a
lower risk of bleeding, is particularly attractive.

And I think this is one thing that the dose, although many have been put
into the idea of six different doses of 20, 40, 80 of pravastatin and 81
and 325 of aspirin, but actually most attractive is the 40 milligram
pravastatin anchor which has been tested in all the trials and 81
milligrams of aspirin which shows to be the best efficacy and safety
tradeoff. So, it seems there\'s a lot of data to support that as a very
viable and helpful combination not only to improve compliance, but to
markedly be associated with improved safety.

DR. BORER: Yes. I think you\'ve hit the data that would cover the
specific issue I wanted to raise and that is the benefit to the
individual patient. Someone who slips through the safety net may be at
risk of excessive bleeding if a procedure occurs, but up until that
point, that patient presumably has benefitted from the combination. And
it\'s that benefit-risk relation which may be worth our considering as
well.

Also, I want to share with everyone an experience that I had recently
that changed a little bit the way I think about this. I have a patient,
a very prominent movie actor, whose name you would know, who is on a
statin to lower his very high cholesterol and I wrote a prescription for
that. I also prescribed aspirin, 81 milligrams a day. When I last saw
him, we went through, as we always do, his medications, and he had
bought an over-the-counter product. I don\'t write a prescription for
aspirin. The way he described it was different from my understanding of
the way an 81 milligram tablet looks. So, I asked him to go back home
and call up with the dose.

Well, he was taking 325 milligrams of aspirin a day, not what I had told
him to take, not what I suggested. Had I written a prescription, I\'m
reasonably confident that he would have been taking the combination that
I wanted him to take.

That\'s an anecdote, but I think we do have to consider the possibility,
as you\'ve mentioned in several other contexts today, that with aspirin
being available in many forms, many doses over the counter, even if we
tell people what it is we want them to take to co-administer with the
prescribed statin, they may not do that. So, that makes the
decision-making tree just a little bit more complicated I think.

Tom.

DR. FLEMING: Jeff, I\'m glad you\'re bringing these issues up because I
wanted to revisit them as well today. What we\'re balancing, as I
understand, is what I think we referred to a lot on January 18th as
accuracy and adherence, and you\'ve really alluded to the fact that
it\'s not just adherence. There is, in fact, a potential for accuracy
against these safety risks that we\'ve been spending a lot of time
talking about for inappropriate use in given settings.

So, I wanted to revisit what you\'ve already largely touched on and that
is what is our best sense in the intended target population here in
secondary prevention that statins and aspirin would be used. I\'m
hearing 70 percent statins, 85 percent aspirin.

My understanding ‑‑ correct me if I\'m wrong ‑‑ is that a combination
might enhance adherence to both people that would be using aspirin but
wouldn\'t have been using statins now would adhere to statins; people
that would be using statins but not aspirin now would be adhering to
aspirin. Is that the logic here behind this argument?

In particular, if we\'re trying to enhance the aspirin use such that in
settings in which it should be used, as Eric Topol is arguing, we\'re
going to achieve an added benefit there and one has to look at whether
that benefit exceeds the hypothetical or real risk when it\'s being used
inappropriately ‑‑ and I\'m trying to get a better sense of how much
benefit there really is. If in fact we would enhance proper aspirin use,
that\'s a real plus. But are these 15 percent who aren\'t using aspirin
within the 30 percent who aren\'t using statins? Hence, you\'re not
going to increase aspirin use at all. What do we know about who these
people are and the relationship between the group not using aspirin and
the group not using statins?

DR. BORER: Do you want to try that?

DR. FIEDOREK: I think we\'ll call on Dr. Hennekens to answer that.

DR. HENNEKENS: The utilization patterns in secondary prevention range
for aspirin from a high of about 77 percent, but these are in the
registry data from academic centers that are participating in randomized
trials, to perhaps 51 percent in general population surveys. That\'s the
range of aspirin utilization in secondary prevention today.

Secondly, with regard to the patients achieving their ‑‑ on statin
therapy, I think Tom Pearson has published some data that suggests that
it maybe as low as 37 percent. So, if you did nothing more than to
increase the utilization of aspirin and statins in the population
that\'s already receiving aspirin, with whatever benefits and risks are
attendant there, you\'d avoid over 10,000 premature deaths in the United
States each year. Now, that has to be weighed against the hazards, but
the benefits I think are large.

In the Antiplatelet Trialists Collaboration, as Eric pointed out, two to
three years of aspirin therapy were associated with 31 percent
reductions in MI, 25 percent reductions in stroke, 15 percent reductions
in vascular deaths, and less than 1 percent are serious bleeds. Indeed,
that included patients who went on to have surgery and either did or did
not stop their aspirin.

So, I agree with Jerry Avorn that when one considers that minority of
patients who are going to undergo surgery and may be inadvertently using
aspirin when you wished they weren\'t, that has to be viewed in light of
whether having this drug in the hands of a physician as a prescription
product would make it better, worse, or the same than right now, when in
our data so many people who are told by their doctor to take aspirin are
actually on other agents and they don\'t know that some of the things
that they\'re taking contain products that range from a low of 81
milligrams up to maybe 650 milligrams.

As Eric pointed out, while the benefits of aspirin are similar across a
wide range of doses, the risks are related to the dose, and there are
people who are not only taking enough of it but people who are taking
too much of it. I think to put this in the real of the health care
provider would, on balance, be a net benefit.

But I don\'t mean to sweep under the rug the concern about those
surgical patients. I think that\'s a real concern, but I think as Dr.
Fleming pointed out, that has to be viewed in light of the overall
picture of how much benefit there would be to getting better utilization
of these lifesaving drugs.

DR. FLEMING: Charlie, I\'d like to just follow up on this. Maybe two
questions.

The first is the figures you\'ve just given of the prevalence of use of
aspirin seem lower than what we had heard a few minutes ago. If I
understood, you were saying it\'s in the 51 to 77 percent range?

DR. HENNEKENS: What I\'m saying is that if you look the surveys of
registries of patients who were being considered for randomized trials,
not necessarily of antiplatelet therapy, just randomized trials in
academic centers, you might see numbers as high as 77 percent in that
subset of the general population. But in our survey that was done in the
general population of secondary prevention patients, 51 percent of them
had been told to be on aspirin.

DR. TOPOL: The numbers that I mentioned were best case scenarios, the 75
percent statins and up to 90 percent use of aspirin. Those are the
highest that have been published to date in recent studies.

DR. FLEMING: What I actually want are real world scenarios. So, let me
come back to this because others may have insight on this.

I would think a really critical point would be among statin users what
fraction are using aspirin. It\'s entirely possible that we would only
have 70 percent of people using aspirin but the nonusers tend to be the
non-statin users as well. So, are the statin users also achieving only
50 percent or 75 percent? If the statin users have 95 percent aspirin
adherence, then if I understand the logic here, then there wouldn\'t be
so much of an up side. Do you have specific data on the relationship of
where these nonusers of aspirin fall relative to users and nonusers of
statins?

DR. HENNEKENS: Well, in secondary prevention in my view, the nonusers of
statins are much greater than the nonusers of aspirin to begin with. So,
it can\'t be that 95 percent of the users of aspirin are taking statins.
It\'s just not possible.

DR. FLEMING: But what is still possible is amongst the smaller group
that you\'re saying are using statins, a substantial fraction, a high
fraction of them may be on aspirin, and the non-aspirin users are
falling into this large non-statin-using group. So, we still don\'t know
from anything that\'s been said whether or not that\'s not true. If my
concern were true, then the logic that, when you put the two together,
you\'re going to enhance adherence to aspirin doesn\'t seem to be as
compelling to me.

DR. HENNEKENS: What we do know from the randomized trials of pravastatin
are that on balance 80 percent of the patients who were randomized to a
statin were on aspirin, but again, these are academic medical centers
that are enrolling patients in randomized trials where the utilization
pattern is higher. That, as Eric pointed out, may also be a best case
scenario as well, that of the people on statins, 80 percent of them are
on aspirin.

DR. FIEDOREK: Dr. Avorn, do you have a comment to add?

DR. AVORN: Yes. In the materials that were in the appendix to the
briefing book, we were able to get some data which are, unfortunately,
not yet published ‑‑ but we\'re in the process ‑‑ that were drawn from a
set of questionnaires sent out to about 26,000 people as they enrolled
in various insurance programs that asked them what medications are you
on both over the counter and prescription. I think the data that point
to the question that you\'re asking is on the top of page 3. When we
crossed aspirin use with statin use ‑‑ this is the percent of people who
were not taking aspirin among statin users ‑‑ 46 percent of men and 61
percent of women who were on statins were not on aspirin. Granted, they
may have had a reason not to be on aspirin, but those are awfully big
proportions, and we can assume that a huge number of those were
secondary prevention patients.

There\'s other data presented there about people who have a history of
MI, diabetics, and so forth. But the sense that we get from those data
is that people who are on statins are not, by self-report, taking
aspirin, and probably if there is a bias, given that it is an
observational study, if anything, the bias would be in the direction of
these being the boy scouts and girl scouts because they sent in the
questionnaire, they were responsive, they filled in all the blanks, and
they were the ones who said that they were not taking aspirin in these
proportions.

So, I think the data need to be drawn from recent data, and this is
about 2000 and 2001 and was mentioned by Dr. Topol and Dr. Hennekens
from typical settings. One of the problems in the literature is that
those of us who live in university settings do studies of university
patients, but most people in the country are not university patients.

I guess the last thing I wanted to mention was in response to Bev\'s
concern, which I share, about inadvertent use around operations. I think
what we need to think about is really the incremental risk versus the
incremental benefit of the combination because the concerns that Bev
raised were really about the prophylactic use of aspirin, period. That
somebody may not tell their colonoscopist that they are taking baby
aspirin or some other version because in my experience as a primary care
doc, patients don\'t tell you about their over-the-counter drugs. So,
the issues you raised really are worries about the use of prophylactic
aspirin, period, because patients go off and do things and don\'t tell
doctors.

I think the question to really focus on is will the incremental risk ‑‑
that is, how much more of that will go on ‑‑ be worse or better than the
current situation, and as was mentioned by the chair, how will that
relate to the incremental benefit of will more people be getting this
product and will that benefit offset the incremental risk.

DR. FLEMING: So, if I could just close this follow-up discussion of this
then. If I\'m following the logic here, what we\'re saying is with this
combination, if someone would have been inclined to be using aspirin,
then the combination might provide a greater level of adherence to the
statin, and if somebody would have been inclined to have been using the
statin, if we take at face value what you said, only half of them would
be using aspirin, then in this cohort of people that would be inclined
to use statins, we have in half of these people an enhanced likelihood
that they would be achieving a strikingly improved adherence to aspirin.
And that benefit would have to be viewed in the context of the alleged
potential risks associated with inadvertent continued use of that
aspirin in those patients in the setting of surgery. Is that a fair
summary?

DR. BORER: Exactly. Before we go on to Susanna, with regard to Dr.
Avorn\'s last statement, while I think it\'s very important for us to
think in public health terms how many people are going to be benefitted
versus how many people are going to be put at risk, again I think we
have to focus on the individual patient too and the individual patient
who\'s on what we may accept as appropriate prophylactic therapy for
coronary events is benefiting. At some point there is a risk if an
operation occurs and the patient doesn\'t tell anybody about the drug,
or the doctor doesn\'t know about the drug, there\'s a risk. But that
risk has to be weighed against the benefit in that individual, not just
the benefit for society at large, and I think that\'s an important thing
for us to consider.

Susanna and then Tom.

DR. CUNNINGHAM: Yes, I have two points.

One is I\'m ongoingly concerned about the lack of randomized controlled
data here because that\'s just a real problem. We don\'t really know
what we\'re talking about for sure.

The second thing. We\'ve been talking about people not taking aspirin.
I\'m wondering about the problem of people on the other side who are
prescribed this medication who have seen the package, it floated by, and
long since they\'re not looking at, and now they may make a decision to
take aspirin on top of it. How big is that problem going to be? Because
people are not going to necessarily remember, even though the packaging
is stellar, that it\'s in there. And then they\'re going to be trying to
be good and take it. You know, it\'s a pretty common product out there.

DR. BELDER: I would like to comment on that because we believe that
these situations are currently already ongoing. The patients may take
Goody powder for their headache, but they take Nuprin for their
backache, and they will take a variety of products for various reasons,
some of which will contain aspirin, and they may not know that it\'s
aspirin because in some of these products, the aspirin is indicated as
acetyl salicylic acid, and the patient will not know that it is actually
aspirin.

I think as Dr. Topol already indicated, the prescription use of a low
dose of aspirin will probably diminish the likelihood that patients are
taking multiple products at the same time because now there\'s only 81
milligrams of aspirin for their heart instead of currently a lot of 325
in addition to 650 milligrams of aspirin for the headache and perhaps
some other use of aspirin for backache. So, we believe that there should
not be an additional risk by providing this prescription product.

Yet, we do agree and, as we have indicated before, we are committed to
make sure that patients will realize that it is aspirin that they\'re
taking by developing packaging, patient information leaflets, and again
working with the agency, once we have the fixed combination tablet, the
clear indications will continue.

DR. CUNNINGHAM: But there\'s not much likelihood that we\'re going to
change their using headache and backache powders I wouldn\'t expect.

DR. BELDER: Correct.

DR. BORER: Tom.

DR. PICKERING: I wanted to address this issue of the number of patients
who should be taking aspirin and statins together but who aren\'t. There
seems there are two issues here. One, as we\'ve heard, the physicians
are not prescribing either of these drugs enough, and the other is the
adherence or compliance which is sort of a related but separate issue.

I haven\'t heard anything to convince me that having the physician being
able to write one prescription as opposed to writing two prescriptions
or writing a prescription for the statin and then saying take aspirin is
actually going to make the physician more likely to do this.

DR. BORER: Do we have any survey or other information relevant to this
issue? Is it likely that doctors will begin ‑‑ there\'s no way to answer
the question I suppose ‑‑ prescribing a combination product, if it
becomes available, rather than doing whatever they\'re doing now?

DR. TEMPLE: Someone will certainly tell them to.

DR. BELDER: There is one way to find out I guess. Obviously, we\'re
going to investigate what happens should this product indeed be
approved. We hope that it will stimulate more physicians to do the right
thing.

DR. BORER: It seems to me that we have no idea whether doctors will
prescribe more, but again, there is a difference, I think, in the
compliance part of the equation that you mentioned, Tom, if doctors
prescribe both rather than prescribing one on a piece of paper and
telling the patient about what to take without writing it on the piece
of paper for the second component. Doctors who would give both are going
to be sure that the patient is getting both, which is perhaps a
different situation than we have now.

Beverly.

DR. FIEDOREK: Can I call on Dr. Pearson? He\'d like to make a comment
about that.

DR. PEARSON: We\'d like to show a slide that was, I think, presented in
the initial presentation of these data. I think the questions here are
very important.

I think you could argue that the noncompliance and the stoppage of
essential therapies is a much bigger issue than many of these side
effects we\'ve been talking about in terms of the potential of lives
lost. In that context, it\'s interesting there\'s a minimal amount of
data on the effect of combination therapies on compliance. It\'s really
quite an interesting deficit, I think, in our knowledge.

There are three diseases here, two of which are getting close, diabetes
and hypertension. The other is HIV which, of course, nowadays is the
penultimate in combination therapies. I think you can see from these
four studies that there was an improvement in compliance and
consumption. Certainly in our writings of how to boost compliance with
preventive cardiologic therapies, the number of different preparations
and the number of individual pills that a patient is requiring to take
is a major determinant of noncompliance. I think the clinical
epidemiology of noncompliance has shown that. These suggest from a more
randomized trial kind of period that you can do something about it, and
that is reduce the number of pills by putting combination pills
together. The data are slim. I think this is what we have.

DR. LORELL: Well, I think we\'ve moved really into sort of a little
different arena, talking about issues of compliance. I think it\'s
interesting that if one steps back and looks at this, as Susanna pointed
out, we don\'t have data regarding prospective effects on efficacy of
major endpoints regarding co-packaging versus individual manipulation
and prescription of aspirin and a statin-lowering agent. We can
speculate but we don\'t have prospective data regarding safety from
either bleeding side effects or much more rare statin side effects of
individual prescribing or explicit prescribing and manipulation of the
two agents separately versus in combination. So, we\'re now on an
argument that is somewhat compelling that as for individual patients and
for a broader public health issue, that we would enhance compliance with
the use of two agents that clearly reduced cardiovascular risk.

But I think if the issue of compliance is on the table, whether we\'re
talking about broad populations or the individual patient like your
patient that you brought up, we have to bring to the table that there
are several components of patients complying with what a physician
prescribes.

One of them is the benefit that\'s been mentioned of potentially having
fewer drugs to take and less pills piled up on the counter. And that\'s
very compelling.

But the other issue that all of us around the table face with individual
patients and compliance is in fact an economic one, that if a patient is
given a prescription for something that is costly, that prescription may
not even be filled or may be filled once and not renewed. So, I think
that it had not been my intention to bring this up, but I think if
we\'re arguing that a strong rationale is compliance and enhancing that
piece of nonusers to be users, I think one concern is the risk, a real
risk, that a patient might not fill or use a prescription drug compared
to the ability to utilize two drugs separately, one of which costs
pennies.

DR. FIEDOREK: I\'d like to address that. We didn\'t bring that up as
well, and we understand the issue of medical economics is very real.
Since we\'ve been asked, I would like to mention that we intend to offer
the pravastatin-aspirin combination. The aspirin component will be
offered at no additional cost to pravastatin as it currently is
available. So, that\'s one of the things that I know would be a concern
and that\'s our intention.

DR. NISSEN: Well, I had a debate with myself about 3:00 a.m. last night
about whether I was going to bring this up or not, but since the cat is
out of the bag, I think it\'s time to talk about it. Let me see if I can
articulate a question. Again, I recognize this is not a regulatory
issue.

Let me also compliment the sponsor on doing a nice job of resubmitting
this and answering many of our questions from the first time around. I
think the availability of multiple doses and so on is a very useful
thing.

But as I understand the situation, pravastatin, which has been a very
effectively used agent for quite a number of years now, is due to go off
patent within the next several years. When that happens, typically a
drug falls in price by about 80 percent.

I would personally think it\'s important to provide the medical
community with some reassurance here, and the reassurance would be that
if patients in the next, say, two years are switched from brand
Pravachol to brand combination and then subsequently the drug becomes
genericly available, then the pharmacist will be precluded from
substituting generic pravastatin. It\'s essentially an evergreening of
the patent on the drug.

Since we are talking about compliance and Bev raised the issue, if the
combination product is, say, four or five times more expensive than the
generic pravastatin plus generic aspirin, won\'t compliance potentially
go way down? Patients are really worried about the cost of medications.

I know, Bob and Doug, that this is not a regulatory and approval issue,
but I guess I feel in the interest of public discourse on this topic ‑‑
and we represent the public interest not just advising a regulatory
agency ‑‑ I need some reassurance here that what we\'re doing is not to
dramatically increase health care costs by approving a combination
product.

DR. FIEDOREK: Dr. Belder.

DR. BELDER: I can give an answer to that. The approval of this product
would perhaps lead to some additional exclusivity that entirely falls
within the current patent life of pravastatin, and generic companies
would be able to come up with a combination product as well after the
patent life of pravastatin is over.

DR. NISSEN: That\'s very reassuring. Thank you. I\'m glad I asked. I
wasn\'t going to ask, but I\'m glad I did ask.

DR. TEMPLE: I was just going to express some slight discomfort because
the setting could be considered somewhat coercive as to the response.
After all, they\'re seeking approval and we really don\'t get to
regulate that. You did point out it could affect compliance which is a
sort of wedge, if you like, but I just want to express some nervousness
about this direction.

DR. NISSEN: Yes. And knowing that nervousness, I literally had a little
debate in the middle of the night about whether it was even appropriate
to bring it up.

The major case for this is compliance. And since this is a factor in
compliance, I felt it was a nice time to maybe get those issues out on
the table.

DR. TEMPLE: It is true, though, whatever exclusivity becomes associated
with this product ‑‑ and I would not be prepared to say what it would be
because I don\'t know ‑‑ it ends after an absolute maximum of three
years, barring some patent thing that I don\'t understand. And then
other people could make the same combination.

DR. NISSEN: So, in fact, my fear here has been ‑‑ you reassured me that
fears of a large increase in the overall cost of these agents is
unlikely to occur as a consequence of any approval of this combination.

DR. TEMPLE: Or perhaps not for too long.

DR. NISSEN: Yes, I understand, but I want to make sure that that\'s on
the table.

DR. BORER: In the interest of Steve\'s sleep tonight and Bob\'s, I want
to reassure the sponsor that nobody is trying to coerce anybody into
anything.

I\'d like to ask a slightly different question. You dealt with this, as
I recall, in January, but I just want to hear it restated. I think that
at that time Dr. Belder presented data about the timing of
administration of pravastatin during the day since, for a long time, the
short-acting statins had been recommended for administration in the
evening, and I believe you showed data that it really didn\'t make much
difference. But it may make a difference in terms of safety when the
aspirin is taken. One would not want to take it on an empty stomach at
night. So, can you tell us what you\'re going to be recommending about
the timing of administration of the combination product?

DR. BELDER: The recommendation with respect to the timing of the
combination product will be identical to that currently existing for
aspirin. I\'m afraid that I do not know that by heart.

DR. BORER: That\'s fine. That\'s good enough.

Are there any other questions?

DR. CUNNINGHAM: I have a question. I would like the sponsor to review
for me ‑‑ you probably did this in January; I don\'t recollect ‑‑ what
the data for women is on secondary prevention using aspirin. A lot of
the data that you include is for men, so I\'d like for you to remind me
what all we have for women.

DR. BELDER: In the pravastatin trials?

DR. CUNNINGHAM: No. Aspirin.

DR. BELDER: Aspirin trials.

DR. CUNNINGHAM: I\'m just interested in the randomized, controlled trial
data.

DR. HENNEKENS: In the randomized trials of secondary prevention, a
significant proportion were women and the FDA has prescription-labeled
aspirin for the secondary prevention of MI, stroke, and vascular death
in women as well as men.

DR. TEMPLE: Correcting a longstanding error.

DR. HENNEKENS: Well, that\'s an excellent point. In 1980, there was
approval of aspirin for the treatment of TIAs in men but not in women
based largely on a Canadian study that was woefully underpowered to
address the issue in women, but after the two cycles of the Antiplatelet
Trialists Collaborations increasing the sample size of women, it showed
benefits that were quite similar to those in men. So, the indications in
secondary prevention for men and women are identical.

DR. BORER: Any other issues that we need to raise?

(No response.)

DR. BORER: If not, is that the conclusion of your formal presentation?

DR. FIEDOREK: That\'s it. That\'s the conclusion, yes.

DR. BORER: Then let\'s go on. It says that there\'s a break at 3
o\'clock, and remembering what happened the last time when I tried not
to have a break, I think we will. It\'s now 2:52. At 3:02 ‑‑ no. Let\'s
make it 3:07 we\'ll be back here.

(Recess.)

DR. BORER: We\'ll structure our final discussion around the questions.

Oh, sorry. I can\'t forget this one. Are there any comments from the
public about the topic under discussion? There were no requests for
presentation, but I\'m asking now if there are any impromptu requests.

(No response.)

DR. BORER: If not, we\'ll move on to the committee discussion, and
we\'ll use the questions as the format. We\'ll have Beverly, as the
committee reviewer, go through them. I\'ll read the preamble here.

The Cardio-Renal Advisory Committee is asked to reconsider the
co-packaged product of pravastatin and aspirin, based on the additional
materials and references provided by the sponsor.

This product was previously presented to the advisory committee on
January 18. At that meeting, there was general agreement that a
population could be defined for which the co-packaged would be
indicated. There was also general agreement that the sponsor\'s
meta-analysis of the five lipid-lowering studies in a secondary
prevention population ‑‑ and they\'re listed ‑‑ demonstrated that both
pravastatin and aspirin individually contributed to the beneficial
cardiovascular outcomes seen in the separate trials. The advisory
committee also endorsed the choice of the two doses of aspirin.

The advisory committee, however, felt that the risk-benefit ratio of
marketing the co-packaged product was adverse based on the following
considerations:

First, the potential for excessive bleeding should the product be
discontinued prior to a surgical procedure.

Second, the potential for inappropriate discontinuation of the
pravastatin should the patient need to temporarily discontinue aspirin.

Third, the use of the single fixed dose of the 40 milligram pravastatin
dose, where a higher or lower dose of pravastatin would be more
appropriate for the individual.

And fourth, the potential for use of this co-packaged product in an
inappropriate population such as for primary prevention of
cardiovascular events.

Not all members of the advisory committee applied equivalent weight to
each of the above concerns.

The sponsor amended their application by a response addressing aspects
of these concerns, including the following: a proposal to include in the
pravastatin-aspirin co-packaged product two new doses of pravastatin,
that is, 20 and 80 milligrams, in addition to the originally proposed 40
milligram dose, to be co-packaged with 81 and 325 milligram doses of
aspirin; and submission of numerous publications.

So, we are asked to respond to two questions. First, to what extent has
the sponsor\'s submission addressed your concerns regarding the
following. And, Beverly, why don\'t you go through them one at a time
and we\'ll see if we have any comment.

Just before I do, Doug, which, if any, of these do you need formal votes
on?

DR. THROCKMORTON: Certainly the second question.

DR. BORER: Okay. Beverly.

DR. LORELL: Do you wish me to go through each of these?

DR. BORER: One at a time so that we can get other comment if there is
any.

DR. LORELL: The first question is to what extent has the sponsor\'s
submission addressed concern regarding the potential for excessive
bleeding should the pravastatin-aspirin not be discontinued prior to
surgery?

My comment is based on the assumption that we\'re discussing a single
pill or capsule and not a co-packaging of two distinct, different
tablets. To my mind, this concern has not yet been adequately addressed.
I think one could speculate in either direction regarding issues of
patient and provider recognition of the use of aspirin and the separate
issue regarding the magnitude of risk if aspirin is inadvertently
continued. In total, I don\'t feel that this concern has been adequately
addressed for inclusion of a potent antiplatelet agent in the same pill
with a drug that acts very differently.

DR. BORER: Can I ask is it possible, if the committee recommended such a
thing and you agreed, for the dispensers of this medication to be
mandated to provide with each box, each package, however it\'s
distributed, in large, bold type an insert or a piece of paper that
says, if you\'re going to have an operation, you must talk with your
doctor about stopping this drug at the appropriate time? That kind of
warning. I\'m thinking about the mandate that was approved with
cilostazol, for example, where it was absolutely necessary that
something go in that warned people about heart failure issues.

DR. THROCKMORTON: Well, certainly the PPIs, the patient education
materials, answer questions like that aimed to sort of address issues
that are identified as concerns for a patient to understand.

I think probably less than the format necessarily, for today the most
useful thing would be to have committee members identify those aspects
of education that you see as most critical and then exactly how those
things might be addressed. Again, Bob had pointed out some things might
be best addressed with unit-of-use packaging. Other things might be
addressed in patient education or something like that. That would be
something we\'d work with the sponsor on, but to hear the concerns I
think is going to be the most relevant thing for sure.

DR. TEMPLE: Jeffrey, the direct answer is we can require material
accompanying the dosage form. That\'s not that common but we can.

DR. BORER: Number one, would the inclusion of such material,
appropriately designed with appropriately big letters, help alleviate
some of your concerns? And if it would, can you begin to list the
specific kinds of issues you\'d like to see in such a patient education
material piece?

DR. LORELL: I think that\'s a tough question. There\'s no question that
a very vivid and clear labeling with the word \"aspirin\" in several
places, as well as a patient alert, as described would be helpful.

I think I am still concerned for two reasons. One is that in my
experience as a clinician for many years, with chronic use of
combination agents, regardless of what they are, there is confusion on
the part of patients as to what they are taking. So, I am not confident
that even the most vivid packaging, such as the potential example that
we were shown today, would mitigate against this.

I think the second concern is ‑‑

DR. TEMPLE: Bev, can I just ask something?

DR. LORELL: Yes.

DR. TEMPLE: If there were unit-of-use packaging, this would come with
each new refill.

DR. LORELL: Well, I think the second issue is that in some context in
pharmacies, unit-of-use vivid packaging is actually repackaged, as
we\'ve heard earlier, into labeled bottles.

DR. BORER: Not unit-of-use, no. It\'s when it\'s not unit-of-use that
it\'s repackaged in general, I think.

DR. LORELL: I\'m sorry. I\'m talking more about one way of potentially
managing this would be to have it in very distinctive kind of packaging
with sort of blister units so that the packaging itself contained vivid
reminders. But even that I think is a bit of a concern because of the
potential that the drug could be repackaged in a standard bottle with
labeling in small letters. So, it would help, but it wouldn\'t
completely erase my concern.

DR. BORER: Can we just clarify that for everybody? Because I think this
is a key point in terms of assuaging some concerns about safety. If
unit-of-use packaging is mandated and agreed upon by the sponsor, that
would make it very difficult, nigh impossible for a pharmacist to
repackage it. Am I incorrect about that?

DR. TEMPLE: I don\'t think we totally know, or at least I don\'t totally
know. I have heard that sometimes, for example, if there\'s an odd
number of pills, not what\'s in the unit of use, that they will
sometimes put it into their own plain bottle. I can\'t swear to you that
that never happens. No, a blister pack would be more difficult. I can\'t
imagine anybody doing that. But they didn\'t describe a blister pack for
the single pill. Is that what you said?

DR. BELDER: We haven\'t developed the packaging for the single pill. The
current co-packaged product is a blister pack, and every time a patient
punches out a tablet, they will see aspirin or pravastatin.

DR. TEMPLE: That would be a relatively unusual packaging for just plain,
old, single pills, not that it couldn\'t be done. And that would make it
more difficult. It also makes it bulky.

DR. BORER: But I thought that what you had said was that you would work
with the agency to deal with this, if that\'s what was mandated.

DR. BELDER: Absolutely.

DR. LORELL: Jeff, I think the second issue ‑‑ and I want to try to be
articulate about this. I think that issue number 1 is, would very clear
packaging that was quite vivid help? Yes, it would.

The second issue, though, is that we\'re not talking about short-term,
2-week or 30-day use of a drug. We\'re talking about this drug being
used for months to years. This is a setting where a patient may well be
dealing with several different physicians, be dealing with a
colonoscopist, a surgeon, someone doing a biopsy, other than the primary
prescribing physician or cardiologist to whom the patient is going to be
reporting what drug they are taking. I am concerned that even with the
most very meticulous and careful packaging that in long-term patient
reporting of what drug they\'re taking, that there is potential for
confusion or mistake that they are taking an antiplatelet agent. So,
that\'s the second level of my concern.

DR. BORER: JoAnn.

DR. LINDENFELD: Well, I share Bev\'s concerns somewhat, but I think this
problem might be helped if the labeling said to notify your physician if
surgery is planned. I think there\'s a jump from the patient knowing
they\'re on aspirin to being worried about surgery. But at least for
myself, I find patients pick up those kind of signals quite clearly and
often will tell me that if surgery were planned rather than, wait a
minute, I\'m on aspirin. So, that would be one labeling thing I might
think would be very clear to the patients that would help somewhat with
this concern.

DR. BORER: Are there other issues of that level of concern that ought to
be flagged that way? I mean, I could conceive of a warning like the one
you just stated being printed right on the outside of a box if unit
dosing is used. What other issues, if any, do you think need to rise to
that level of patient education?

DR. LINDENFELD: I think that\'s the major one. The major one we\'ve
discussed is bleeding. So, that would be the major one.

DR. BORER: Beverly are there any other specific issues besides the
\"talk to your doctor if you\'re going to have an operation\"?

DR. LORELL: Well, I think we haven\'t talked too much about this today.
I guess there\'s the formal potential for confusion of a patient who
thinks they\'re taking prescription fancy aspirin and not recognizing or
forgetting that they\'re taking a statin regarding the concerns that we
all instruct our patients very explicitly about warnings to report with
use of statins. So, one might consider ‑‑ I certainly haven\'t fully
thought this out ‑‑ but whether such unusual packaging might also
include a very clear warning, alert your physician if you have myalgias,
you know, the similar warnings that we talk about with statins to a
patient.

DR. BORER: Steve.

DR. NISSEN: I wanted to bring this up earlier, but low-dose aspirin is
associated with some increase in gastrointestinal bleeding and so on,
and I think it would be nice to put in there that you should inform your
physician if you have abdominal pain, black, tarry stools, that sort of
thing because some of these patients will, in fact, have that
complication and you want to make sure that it\'s brought to somebody\'s
attention.

DR. TEMPLE: As part of the patient information.

DR. NISSEN: Yes, I think so.

DR. TEMPLE: Yes. That would be consistent with the eventual aspirin
labeling. It doesn\'t really have that yet, but it will.

DR. NISSEN: I think it\'s the right thing to do because if people don\'t
know about that, they may not bring it to their physician\'s attention.
All the studies I\'m aware of do show that that\'s a well-defined, not
an enormous risk and usually not life-threatening, but it can be.

DR. BORER: Are there any other major concerns that have to be flagged in
patient education materials, forgetting about the specific format for
the moment, but by some appropriate format should be flagged at a very
high level so they\'re not likely to be missed? We\'ve hit three.

(No response.)

DR. BORER: Okay. Then let\'s go on to 1.2.

DR. LORELL: The second question is the concern regarding the potential
for inappropriate discontinuation of pravastatin during times when
aspirin is temporarily discontinued.

To my mind, this is much less of an issue. I think there\'s very little
information in the literature regarding risk, if any, of temporary
discontinuation of a statin. We actually didn\'t discuss it during the
discussion, but there is a paper that appeared in Circulation that was
part of our data to review that raised the question as to whether
temporary discontinuation of a statin conferred an increased
cardiovascular risk in a population of patients with unstable syndromes.
That paper I would view as being a very provocative and a very important
hypothesis to be tested, but I don\'t think it\'s to point in this
discussion about co-packaging.

DR. BORER: Also, the concern is raised in the context of purposeful
temporary discontinuation, which might be less likely to happen if
somebody was having crescendo angina when his or her doctor told them to
stop the drug. Okay, so that\'s less of a concern.

Does anyone else have any other comments about that particular concern
or are we all satisfied that that\'s a lesser issue? Tom.

DR. FLEMING: Is it fair to say that there\'s a key distinction between
question 1 and 2? Question 1 relates to an important safety concern that
can arise with inappropriate continuation of aspirin, whereas question 2
relates to ‑‑ is it correct to interpret this as a potential loss of
more full efficacy if there is inappropriate temporary discontinuation
of the statin?

DR. LORELL: I interpreted it slightly differently. Really the question
as to whether statins are providing a very important short-term,
stabilizing factor on unstable plaque as opposed to issues of lowering
measured lipids. So, this is a concern that I think many have as to
whether or not there is both short-term risk of stopping a statin for a
period of several days in patients who are undergoing vascular surgery
or other high-risk surgery.

The converse of that, not relevant today, is whether there\'s short-term
benefit of aggressively starting a statin very early in a high-risk
population.

So, I interpreted this maybe a little differently, Tom, not as whether
you were going to impede the long-term kind of benefit that\'s been
observed in clinical outcome trials, but whether there was a special
kind of niche safety risk in stopping a statin in unstable patients.

DR. FLEMING: Well, that\'s the clarification that I was hoping to get.
Essentially what you\'re saying is the issue here is not so simple as if
there\'s inappropriate discontinuation, you are getting a level of
nonadherence to an intervention, hence you\'re getting less than fully
optimal efficacy. You\'re saying there could actually be a safety risk
associated with these temporary discontinuations.

DR. LORELL: Yes. That\'s the issue ‑‑ I\'m sorry we didn\'t have a
little more discussion about this earlier ‑‑ that was raised in the
Circulation paper that\'s gotten a great deal of attention. This was a
retrospective analysis not a prospective study.

DR. FLEMING: That\'s paper number 1, wasn\'t it?

DR. LORELL: Exactly. But it suggested some very worrisome trends in
terms of major adverse coronary outcomes in patients who had
discontinuation of statins. So, it\'s a very different issue I think.

DR. FLEMING: Although unfortunately, as is the case with the aspirin
data, this is nonrandomized and it\'s entirely possible that this is a
very biased assessment.

So, just to close my thoughts on this, the way I had been thinking about
this issue was that you\'re presumably intending to get meaningfully
enhanced adherence to the statins with the combination. One then has to
look at whether that benefit achieved by higher adherence to statins
overall exceeds the risks associated with potential discontinuation in
some patients.

DR. BORER: We don\'t actually know the risks. The risks are largely
theoretical and were heightened by this article. But I think in all
fairness, if they should prove to be important, there is an obvious
remedy. Since the patients would be stopping their drug in most cases,
not all, because they had been told to do so, they can be told to take
the single component pravastatin by itself in the interim.

DR. LORELL: There\'s another theoretic risk that I\'m sure all have
thought about. Let me see if I can articulate this.

In the use of a combination antihypertensive medication or a combination
antidiabetic medicine, I think the way most clinicians use those
medicines is to start the two not only independently but often at
different points in time. In fact, in the use of aspirin and
lipid-lowering agents, that is also not an uncommon scenario. Some
physicians will start both at the same time, but it is not uncommon and
I would argue, in fact, often quite common to start one first and then
to secondarily add on the second.

The advantage of that strategy clearly seen in the antihypertension
combinations is that one has a track record with a patient regarding
both tolerance and knowing that there are not major side effects that
would require one or the other drug to be stopped.

I suppose there is a formal possibility with this drug that for
secondary prevention, it might be started right off the bat as the first
drug being prescribed for the patient, and we could think of some very
common scenarios for that. A patient presents with new onset angina and
then is begun on this combination agent as part of other therapies.

So, there is some formal risk ‑‑ I don\'t know what it is ‑‑ that when a
combination drug is started without first starting the drugs
independently and getting a clinical track record, that if there\'s an
adverse event ‑‑ let\'s say the patient develops severe GI indigestion
or develops a rash, even non-life-threatening ‑‑ that both drugs might
be permanently stopped because of reluctance to rechallenge with the
individual agents. So, that\'s an unusual possibility with this drug
that I think might not have been seen by the agency in other combination
products that are prescription drugs.

DR. BORER: So, we\'ve listed several concerns that might be at least
mentioned in packaging at some level so that physicians would be aware
of the possibilities and perhaps could take some remedial action.

Let\'s go on to 1.3.

DR. LORELL: 1.3 asks about the concern about the inappropriate use of a
lower or higher dose of pravastatin than is necessary or safe for a
given patient.

This is a tough issue and I think it is one that a lot of time was spent
on in the winter meeting and none today. It goes to the issue of what is
the goal in secondary prevention, how do you use a statin, and do you
aim simply for reduction to a goal measurement of either total
cholesterol, LDL, or elevation of HDL. We now have a more recent study
presented this fall that actually suggests that use of absolute
measurements may be challenged.

So, I think that one of the concerns that was raised by the committee
last time is the scenario that if a patient were started on this
combination agent ‑‑ let\'s take the scenario that one was using the
highest dose of pravastatin and had not yet achieved current guidelines
for secondary prevention. Would there be some risk that the convenience
factor would mitigate against the hassle factor of getting the patient
to transition to a different agent and aspirin use separately?

I think that is some risk. However, I think that\'s actually probably no
more or less a risk than in prescribing of any statin when you don\'t
get to goal and being willing to make a change and convince the patient
to change. So, I look at this, yes, it is an issue, but I look at it as
a lesser one.

DR. NISSEN: I think the sponsor has been actually as responsive as they
could here. One of the objections I had to the first application was it
was that one dose. We\'ve really been trying to educate our colleagues
to treat to a target with statins. So, I really didn\'t like the
original application in large part because of that. Now we have the
three commonly used doses of pravastatin available and actually we have
a total of six combinations.

Now, there still may be patients in whom the LDL is particularly high,
in whom the highest dose of pravastatin is not adequate to get to goal,
and those people have to be transitioned, hopefully, to something else.
But what the sponsor has done is they\'ve been very responsive to those
concerns by offering us choices, and I think that\'s all we can ask of
them.

The concern doesn\'t totally go away here. If you give this combination
product to somebody with an LDL of, say, 240, the odds are pretty good
you\'re not going to get to an LDL of 100. But hopefully physicians are
savvy enough not to do that.

DR. BORER: Does anybody have any lingering concerns about this issue?
Doug.

DR. THROCKMORTON: Jeff, I guess I\'d like just a little more
conversation around sort of a related issue. I heard two visions of how
you would write a description of how to use this drug. One model is the
combination antihypertensive model where the notion is usually you push
one drug to maximal dose and then you add a second agent, and if that
combination is available as a combination, that\'s when we recommend you
use the combination as a possible convenience.

An alternative model would be to say ‑‑ and it might be more appropriate
here ‑‑ a lot of people are going to come in on one or the other of
these therapies at a dose that\'s not driven by any measure, that is, no
change in blood pressure like you would have from hypertension. It may
be a change in LDL, but some of the dosing may not be driven by that
necessarily. It might be driven more by safety concerns or driven by
your following the outcome data. How would you write a label for how
you\'d choose which of these doses to use?

DR. BORER: Maybe I can take a quick crack at that, and then we can have
some other comments.

I don\'t see this as being a major concern. I think that as Steve just
pointed out, there is now the entire range of labeled pravastatin doses,
and if you score the tablets, even below the lowest labeled dose is
available. For the lipid-lowering drug, which presumably one might
choose to titrate to a total cholesterol or LDL goal, and the aspirin
usage associated with that is now up to the doctor because all the
options are available. So, I don\'t think that\'s a problem.

Yes, it\'s true that 80 milligrams a day of pravastatin may not get
every individual to the goal that his or her physician has set for
treatment for hyperlipidemia. Then one would perhaps go off to the use
of a different statin and have to use a separate aspirin tablet. But
that\'s what medical practice might demand. That\'s not an argument
against making the convenience product available.

I\'m not particularly concerned, although I think Beverly\'s example is
absolutely on target. There might be a rare toxic reaction that
couldn\'t be clearly ascribed to either component. Both components might
be stopped and the patient might be denied the benefits that might
accrue from one or the other. That\'s possible. And I\'m sure that
appropriate wording can be added in the label to suggest that doctors
might then want to rechallenge with one or the other. They might do it;
they might not. That\'s true.

But as you say, in the case of other more commonly used combination
products that we\'re more accustomed to hearing about in cardiovascular
medicine, specifically antihypertensive drugs, there is a measure. There
is a goal. It\'s blood pressure. For aspirin there is no measure. We\'re
basing the use of aspirin and the dosing of aspirin on well-controlled
trials showing a benefit, and we really don\'t have dose-response data.
So, there is no goal. It\'s merely the fact that we believe that aspirin
is more likely to be beneficial than detrimental for everyone for whom
secondary prevention is indicated.

Again, for cholesterol we do have a target, perhaps, that some people
might use, and one can titrate the drug as necessary to achieve that
target if it\'s achievable with this product and not alter the aspirin
usage.

So, I\'m not concerned about the co-administration of the two, starting
the two at the same time. I think Beverly\'s point is very well taken
and that information should be given to physicians to encourage them to
rechallenge if one of these rare problems occurs, but I don\'t see it as
a show stopper.

Beverly.

DR. LORELL: I think it\'s an interesting question. I guess I would be
interested in knowing what the rest of the panel thinks as to whether or
not the optimum use for efficacy, as well as safety, would be to
formally treat this drug the way we do antihypertensive combinations and
to advise in patient and physician education and marketing that the two
should be started separately, and if the desired level of lipid
reduction is achieved, then to move to the combination using the
precedent from antihypertensives.

DR. TEMPLE: That\'s not quite the precedent. That\'s one way, but it
also acknowledges that you can titrate, for example, the diuretic by
giving combinations with increasing doses of diuretic. So, in this case,
you could accomplish the same thing, since there\'s nothing to measure
with the aspirin, by moving up the lipid combinations, and it would more
or less be equivalent to what you do with the antihypertensives, mostly
because there isn\'t anything to follow for the aspirin part.

DR. BORER: Paul.

DR. ARMSTRONG: Doug\'s question raises, in my mind, another issue which
we haven\'t talked about and that is the patient who arrives with an
acute coronary syndrome on prior aspirin therapy, which we know is a
risk factor for an unfavorable event. In large part, although the data I
don\'t know is all that well known, many of these patients would be on
325 or more of aspirin and not on 81. So, in the event that a patient
then arrives on this new combination of 40 and 81, under those
circumstances ‑‑ and there\'s a literature, of course, around aspirin
resistance ‑‑ the issue would be would a physician under those
circumstances be wise to prescribe a larger dose of aspirin with the
notion that there might be a better balance between efficacy and safety
in the context of a presenting acute coronary syndrome. So, that\'s one
situation where I can conceive that this issue might come to quite a
sharp focus.

DR. BORER: Blase.

DR. CARABELLO: Obviously, the combination here is being initiated for
secondary prevention. So, it\'s hard to think of a secondary prevention
patient where aspirin wouldn\'t be indicated. So, that\'s pretty much
part of the deal. I think most of the time you would start at 81
milligrams. You\'re not really titering to anything. You leave that in
place and then titrate the pravastatin portion of the drug, which now
the sponsor has given us the ability to do, to the usual targets. Since
the indication here is secondary prevention, almost 100 percent of those
people need to be on aspirin. Unlike the hypertension situation where
you might start with hydrochlorothiazide and then add enalapril and then
finally have the combination drug.

DR. LORELL: I think the issue that was raised in the wintertime about
the concern about inappropriate use of the drug with not getting to goal
was more the elusive issue, is would there be a very powerful incentive
because of the perceived convenience factor by maybe physician and
patient, that if you were started on, let\'s say, the highest dose ‑‑ I
mean, I think that will happen commonly ‑‑ and whatever dose of aspirin
you choose, to then not up-titrate further. So, I think that\'s the only
reason why one could make an argument to start with the individual agent
and, if you get to goal, then to move to the combination.

DR. BORER: Steve.

DR. NISSEN: There\'s at least one other concern about using it as
initial therapy, and that is that every drug has a certain number of
people who will not tolerate it. Both statins and aspirin actually are
both known to produce GI intolerance, and so neither the patient nor the
physician will know, when you start a drug at the same time and together
in a fixed combination, what the source of that side effect is. In
general medical practice, it\'s always desirable to start agents
individually, and then if you find that the right statin dose for this
patient is 80 milligrams of pravastatin and then if you want to give
them 81 milligrams of aspirin, you then give them the combination for
compliance enhancement.

But I don\'t think you want to mandate it because, in fact, by offering
the full dose range, the sponsor has provided us with what I wanted last
time around, which is the ability to titrate. We didn\'t have that
before, and we have it now with this new application. I think that
enhances the attractiveness of the application significantly.

DR. BORER: Have we given you sufficient guidance with regard to number
1?

Then let\'s go to the meat of the issue for which we have to vote. Do
you recommend the approval of the co-packaged pravastatin-aspirin as
therapy for patients for whom both products are indicated? Beverly, why
don\'t we start with you and we\'ll get a sentence or two from anyone
who wants to about why they vote the way they do.

DR. LORELL: Well, I\'m going to actually divide that question into two
answers. As the question stands there, my answer would be no. I have ‑‑
and I\'ve voiced them ‑‑ very serious concerns about both long-term
patient recognition that they\'re using aspirin in a combination drug
and some of the unanswered speculations and issues about safety. So, as
stated, my answer would be no.

As a subquestion, if the common tablet or capsule were packaged somewhat
uniquely, to both enhance recognition that aspirin was in the pill and
that there were safety issues regarding surgery, as well as recognition
of major side effects of statin ‑‑ I\'m not talking about it being
hidden on a small-print package insert that many patients never read ‑‑
then my answer for approval would differ and be yes.

DR. BORER: So, would it be reasonable to say that assuming that the
outcome of the entire vote was negative and the FDA went away with that
recommendation, that if the sponsor showed you packaging that could
answer some of the concerns, that then you would find that acceptable?

DR. LORELL: That\'s correct.

DR. BORER: Mike.

DR. ARTMAN: Jeff, did we really address 1.4?

DR. BORER: I\'m sorry. You know, we did not address 1.4. I\'m sorry. We
didn\'t even mention it. My fault.

Do you want to make a comment about that?

DR. ARTMAN: That to me sort of gets at this point number 4 up above that
we were concerned about in the January meeting, and I raised the issue
at the time about individuals for whom this is going to be prescribed
for really primary prevention. I think we need to have a little bit of
discussion about that, someone who\'s going to be given aspirin who
simply has elevated cholesterol and who has not had any sort of event.
Is that a problem? Are we putting another segment of the population at
some risk for the adverse effects of aspirin?

DR. BORER: Is the company planning to remove unmodified pravastatin from
the market?

DR. FIEDOREK: No.

DR. BORER: So, anyone who wanted to use pravastatin for some purpose
other than secondary prevention could still do it.

DR. ARTMAN: Sure, I understand that. But I think that again the whole
issue is targeting the convenience, et cetera, et cetera. If I\'m the
only one concerned about that, fine, we\'ll let that go.

DR. BORER: Does anyone have any comments about that?

DR. TEMPLE: It\'s only convenient if you were planning to give it off
label, which I have absolutely no doubt many people are doing.

DR. BORER: That people will do and perhaps it\'s the right thing to do.

DR. TEMPLE: It might even be. I\'m sure Charlie could give a long
lecture on all that.

DR. BORER: But I don\'t really think that\'s our concern. That requires
an active will by a physician to do something that he or she believes is
the right thing to do and for the physician and the patient to accept
the potential consequences. That\'s true with any drug. I don\'t think
there\'s anything unique about the combination here.

DR. ARMSTRONG: Could I just clarify then, Jeff?

DR. BORER: Yes.

DR. ARMSTRONG: In the event that the indications for statins change and
cholesterol becomes an irrelevant target and the sponsor then positions
the statin for a different population than is conventional, are we
saying that we do not need to be concerned about the linkage to aspirin
and that that\'s not our purview? I just want to understand that.

DR. BORER: I\'m not suggesting that the linkage, if the two drugs were
prescribed together, might not be a concern in that situation, but
rather that if the unmodified drug is available for prescription and if
physicians are prescribing drugs for a specific purpose, presumably they
must know why they\'re prescribing the drug and for what. And if they
have the capacity to prescribe the unmodified drug, I don\'t think that
the fact that they may inappropriately prescribe a combination precludes
the appropriateness of approving the combination. It\'s just bad
medicine.

DR. TEMPLE: What they said is that their labeling will track the current
labeling for the single entities. If aspirin changes, their labeling
will change. If prava changes, then the combination labeling will change
too.

DR. ARMSTRONG: I\'m not sure that\'s wise. That is to say, if we open up
the use of statins for all comers, irrespective of their cholesterol,
should aspirin necessarily follow. That\'s the essence of the question.

DR. TEMPLE: Only if aspirin is indicated in those people, not if it\'s
not. I think Jeff was addressing that. That would represent a decision
by the physician to use it in that particular setting, and he should be
paying attention to the labeling or deciding to ignore it, whichever he
chooses.

DR. LORELL: I think Dr. Artman\'s comment is very important because to
my mind the ante goes up a lot for safety regarding confusion or
inappropriate use of aspirin in a primary care population. So, if I\'m
concerned about that issue in secondary prevention, I\'m very concerned
about it in a primary care prevention where the potential risk-benefit
ratio I think is quite different in a primary population if they\'re
using a statin and forget they\'re using aspirin. But to my mind, that
concern is partially mitigated again by very, very clear and distinctive
labeling and warnings.

DR. BORER: Not to disagree with the importance of the concern because it
is an important concern, but I don\'t think it\'s totally relevant to
the approval issue that we\'re facing here today. To paraphrase some of
Dr. Avorn\'s presentation, how are we going to change the situation that
now exists? Aspirin is available over the counter. If people want to use
it for primary prevention because of information they get off the
Internet or for any other reason or if doctors want to suggest that it
should be used for primary prevention, even though the drug isn\'t
labeled that way, that\'s going to happen. That isn\'t the issue I think
we\'re facing. We\'re facing a different issue.

If two drugs that are appropriate, as we now believe, and labeled for
use for a specific indication, are appropriate to be used together and
we put them together so that it\'s easier to take them, is that a
reasonable thing to do? The answer that we\'re going to come to is
either yes or no, but I think that\'s our question, not what if people
use it some other way even though the label doesn\'t say you\'re
supposed to and even though the guidelines for medical practice don\'t
say you\'re supposed to. I don\'t think we can deal with that.

DR. ARTMAN: Jeff, the point is you\'re packaging a drug that\'s
indicated for secondary prevention with a drug that\'s indicated for
either primary or secondary prevention. That\'s the difference.

DR. BORER: All right. Well, that\'s reasonable enough. It may be that
doctors will choose to prescribe the combination, and maybe they
shouldn\'t be doing that. But that\'s a matter of physician education I
think not of regulation of drug approval.

DR. ARTMAN: Well, if all this boils down to is physician education, then
we really don\'t need this combination. People know they ought to be
giving people aspirin and people know they ought to be using statins.

DR. BORER: No. The issue here is to make the use of drugs that the
doctor wants the patient to use and the patient agrees to use more
convenient for the patient to use by combining the two pills into one
because the pill burden may cause people not to use what seems to be
appropriate to use.

Now, the doctor doesn\'t have to prescribe the combination drug because
it\'s available. The doctor can still say, well, here\'s your
prescription for pravastatin and I want you to go to the drugstore and
buy some aspirin. That\'s still an option. We don\'t preclude that
option by approving the combination. We just make something that\'s
convenient available for people who want to use it. So, I don\'t think
it\'s quite the same.

Steve.

DR. NISSEN: Michael\'s concern is not trivial. I\'m not saying it\'s
necessarily compelling, but the fact is when you mix together a drug
that\'s designed for primary prevention with a drug that can be used
either in primary or secondary, the potential of bleed-over is real. You
know, physicians are creatures of habit. Some physicians ‑‑ who knows
why ‑‑ tend to prescribe one statin versus another statin. Well, now
they have two products. They have the pravastatin-aspirin combination;
they have pravastatin alone. There may be some tendency, when you have a
product of convenience, to use that product in situations where it may
not be the right thing to do. I\'m not persuaded that that\'s a huge
approvability issue, but there is an issue, and I think that there
probably is some risk here that some people will get aspirin that we
probably wouldn\'t want to have get aspirin. When you mix the two
together, somebody is going to get it that shouldn\'t, and maybe it\'s
going to be more people than would get it if you had to separately talk
about each of the drugs.

DR. ARTMAN: But your sense is that\'s not a big issue.

DR. NISSEN: I don\'t think it\'s a huge issue, but to say it\'s no issue
I think is wrong.

DR. ARTMAN: Your use of the term bleed-over was intentional?

(Laughter.)

DR. NISSEN: It was not intentional.

DR. CARABELLO: But obviously then that same concern has to be weighed
against the number of patients who should be on the two drugs who
wouldn\'t get the two drugs if you didn\'t have the convenience of
formulating it that way. Goodness knows what that is. Presumably there
is a risk in both directions. How you would weigh it, I don\'t know.

DR. BORER: Mike, have we discussed that 1.4 sufficiently?

If so, let\'s go on to the vote. Beverly already gave her vote and her
reasoning. Mike.

DR. ARTMAN: Beverly voted yes and no. Is that correct?

DR. LORELL: I voted no and yes.

DR. ARTMAN: No and yes, okay.

DR. FLEMING: Just before we go on, Beverly, to clarify, it was yes under
what specific packaging restriction?

DR. LORELL: I voted no to the question explicitly, and I voted yes in
the context of very distinctive packaging that both clearly alerted the
patient that the aspirin was in the pill or the capsule and that
secondly had built onto the packaging the warnings that we\'ve
discussed. So, to put it another way, I\'d be very concerned if this
drug ever ended up in a standard CVS or Walgreen\'s little bottle with
the tiny little type label.

DR. BORER: No trademark names, please.

(Laughter.)

DR. BORER: JoAnn. I\'m sorry. Mike.

DR. ARTMAN: I\'m not sure that putting these two drugs together will
increase the utilization. I think we just don\'t know. A lot of this is
just speculation and conjecture.

I am somewhat reassured by the multiple dosing combinations. I think
that is, as Steve mentioned, a big advance.

I\'m not quite as concerned as I was before about some of the potential
risks. So, on balance, I think I would say yes.

DR. BORER: JoAnn.

DR. LINDENFELD: I would say yes. There are so many things we don\'t know
that have been discussed, but the most common question I get is, can I
take fewer pills? Not can I take fewer medications, but can I take fewer
pills. So, I think having more people take these two drugs will be
beneficial. We don\'t know how many more that will be, but I think I
know that in some patients, who are already getting these two, they will
take it more reproducibly if they have a combination available. And none
of the safety concerns that we\'ve heard has risen to the surface enough
for me to be concerned that there\'s a safety issue that overcomes that
potential benefit.

DR. BORER: Tom.

DR. FLEMING: I vote yes with proper packaging.

Just to quickly summarize and kind of bring in a little bit of the
extensive discussion we had back on January 18th as well, I believe we
do have a clear indication, secondary prevention with preexisting
cardiac conditions, where I think the LIPID and CARE studies do provide
considerable evidence of substantial benefit on MI, stroke, and CHD
death, 25 to 30 percent with the addition of pravastatin, 15 to 30
percent with the addition of aspirin.

And as best I can understand from now two meetings of discussion, there
really does appear to be a substantial medical need as evidenced by
substantial fractions of these people who are non-adherent or who are
not taking antiplatelet agents, maybe 15 to 50 percent of this targeted
population, and lipid-lowering agents, maybe 30 percent.

It\'s very unclear to what extent this will enhance adherence, but I\'m
willing to believe that with the magnitude of efficacy that would be
achieved, that it\'s very likely there would be meaningful improvement
in adherence. And so, that\'s the up side.

The down side against that, as we\'ve had a lot of discussions, I think
first of all the sponsor\'s providing now ability to titrate the statin
is an important enhancement to address one of the key issues or concerns
in January, and these concerns about excessive bleeding or inappropriate
use of aspirin ‑‑ it troubles me because of what little we understand
about this. It strikes me that it\'s an issue that is important but one
that would be probably intrinsically very difficult to obtain the type
of data we really would like to have to understand the magnitude.

But I\'ve been persuaded that with appropriate packaging that clearly
would identify the aspirin content and the warnings that Beverly is
talking about that the overall evidence at hand then, to my way of
thinking, is adequately favorable in benefit to risk to support a vote
of approval.

DR. BORER: I vote yes. I think the body of evidence favoring the
effectiveness of both components combined is overwhelming even though
the studies weren\'t designed specifically in the way we might have
liked them to have been to specifically demonstrate that fact. I think
the total body of evidence is overwhelming.

I think that the sponsor is now presenting the product in a way that it
is truly a convenience product. That is, it\'s possible to provide
virtually any conceivable combination of doses, the absence of which was
my primary concern in January and, therefore, that the drugs can be used
together in whatever way the individual physician and patient believe
they should be.

I would share Beverly\'s concern ‑‑ and it\'s been echoed by others ‑‑
about the packaging. I think the caveat to this yes vote is that the
sponsor and the FDA come to an agreement about packaging and warnings
and labeling and whatever that would deal with the concerns that Beverly
listed when she gave them to you, Doug. So, I think that\'s important.

But there is one other point here, and that is if we do recommend
approval to the FDA, this could be seen as precedent-setting in some
ways, and I would like to say a word about that.

The fact that we may recommend the approval of this combination product
is specific to this combination product by which I mean there are two
components all conceivable, currently employed and justifiable
combinations of the components are being made available in combination
so that the drug doesn\'t dictate medical practice. I think that\'s very
important.

The fact that we may recommend to you to approve this combination
doesn\'t mean that every time two different components that do two
different things but are aimed at the same disease process are put
together in the same pill somehow, that we would necessarily suggest
approval of that combination. I think each one has to be reviewed on the
basis of its merits and on the basis of the various factors, including
the doses involved that we\'ve talked about here. So, I think that
should be on the record. The precedent is very limited here.

With that, again my vote is yes.

Paul.

DR. ARMSTRONG: Yes. I\'m persuaded by the sponsor\'s preparation and
work that the balance of benefit and risk is supportive of a yes vote.
My ancillary comment would be that they have provided information and
hypothesis-generating information that such a combination will enhance
the way doctors prescribe drugs and the way patients will take drugs. I
think they would do a real service to patients and physicians and other
sponsors and regulators if they were to test the hypothesis
appropriately, starting now. If this is precedent-setting, then why not
do the research that\'s necessary to establish that this idea is
verified? You\'ve got a unique opportunity and you would do people a
real service to do that.

DR. BORER: My guess is that Charlie already has the protocol written.

Steve.

DR. NISSEN: My original objections in January were most focused on the
fact that I was worried that this combination would undermine all the
work that many of us have done over the last decade in trying to
convince physicians that they should treat to goal for cholesterol. And
we have national guidelines and a national cholesterol education program
that said treat to goal. What we had in January was one statin dose to
choose from, and I was concerned that the convenience of the product
would undermine all the efforts that we had made to try to get people to
treat to goal. Part of this was exacerbated, if I may speak very
candidly, by some of the work that the sponsor has done over the years
around the issue of whether it is in fact appropriate to treat to goal.
And I just saw that whole issue being revisited.

So, when you reformulated to allow us the ability to give at least three
different doses of statin, that went a long way toward reassuring me
that this would not undermine current medical practice. And so, that\'s
a big help.

I think you\'ve done a nice job of partially alleviating the safety
concerns, but not completely. And I share with Bev some of the concerns
about safety. Perhaps there are even some that we didn\'t talk about,
but the notion that some patients are going to get GI intolerance and
they\'re going to stop this product and they\'re going to end up
stopping both the aspirin and the pravastatin. There are a lot of things
to think about here.

On balance, I have been convinced by the presentation today and by the
reformulation that more patients will benefit by having this available
than will be harmed by it, and I therefore can vote yes.

DR. BORER: Blase.

DR. CARABELLO: I vote yes.

I\'m not particularly concerned about the issue of bleeding. I\'m sure
that aspirin creates some, but I think especially in the modern surgical
era, it really doesn\'t contribute an awful lot to postoperative or
intraoperative bleeding.

I think the issue of labeling is an important one, but after the sponsor
goes to whatever lengths they go to to label the product, in the end
it\'s up to us to figure out what the patient is taking. Just like
Jeff\'s sophisticated, up-scale patient who was taking the wrong stuff,
the only way you would know that is to actually have them drag the pills
into your office and see what they are. And I think that\'s the bottom
line. It\'s the only way to really know what our patients are taking
anyway.

I think Paul\'s comment is very cogent. If we could demonstrate as a
medical community that this idea works, that you can take two agents
with entirely different pharmacologic targets that are umbrellaed under
the canopy of here\'s a pill that makes you live longer and that could
be extrapolated to other formulations of different drugs, we might be on
to something here. It would be nice to see somewhere down the road if in
fact this has increased utilization of those types of therapies.

DR. BORER: Susanna.

DR. CUNNINGHAM: Well, I\'m just going to be different. I\'m going to
vote no for the very reason that we don\'t have any science. It actually
says we\'re hypothesizing this will improve compliance. I hope it does.
I think everybody has voted yes. My vote is not going to change
anything, but I really am not comfortable with voting for something for
which there is no science for the combined. I mean, I know there\'s all
the individual, and I appreciate that and I understand that it may
actually have great benefit. But this particular combination has never
been studied.

DR. BORER: I think it\'s been studied. It just hasn\'t been studied in
the format that we might have liked.

Bob.

DR. TEMPLE: It\'s worth mentioning that the combination policy has never
said that there needs to be a demonstration of advantage. Now, I think
if you talked about this more, there would be some desire to have a
reason for having a combination because you can immediately think of
some potential disadvantages, which certainly have been discussed at
great length. So, as a practical matter, maybe you do need to have some
sense that it\'s worth it, but strictly speaking, many combinations
couldn\'t possibly have a medical advantage. They\'re just the same drug
taken in one pill. So, what can they do? And we have never said that
they have to. What we have tried to do is make sure that some of the
disadvantages are mitigated by having all doses available and perhaps by
additional labeling and things like that.

DR. CUNNINGHAM: But aren\'t those usually just for one thing like
hypertension? I mean, here we\'re treating two different things.
Cardiovascular disease, yes, but not just blood pressure and not just
cholesterol.

DR. TEMPLE: You\'re right. Over-the-counter-land drugs for different
things are very common, but for prescriptions it\'s certainly the
exception. Almost all of them have been combinations directed at the
same thing. So, this has some precedent with respect to that too. You
can easily think of a very large number of possible combinations of
drugs for treating various people\'s ills of the elderly.

DR. BORER: I think that Susanna\'s point is a very important one, but
one might argue that this really isn\'t different from the combination
antihypertensive drug product fundamentally because you\'re not really
treating people for their high blood pressure. You\'re treating people
to reduce strokes, myocardial infarctions, and cardiovascular death,
heart failure, and renal disease, five different things here. And this
combination is intended to prevent myocardial infarctions, stroke, and
cardiovascular death. It\'s just that in the one case the putative
pathophysiology is one set of processes that both drugs seem to hit, and
here there are two different processes aimed at the blood vessel in
different ways. So, I don\'t think the differences between the
combination products are as great as they might at first seem, but I
think the point is still an important one.

DR. TEMPLE: An interesting question could arise. There are other
lipid-lowering drugs that don\'t have as much data on prevention, that
have a couple of studies on this and that, or no studies at all. You
might see a proposal sometime for a drug that lowers lipids and has
aspirin attached to it because aspirin is good for people. That\'s a
different set of considerations. We\'re actually internally thinking
about all this stuff. I ran the numbers. You can think of many thousands
of combinations along these general lines.

DR. BORER: Well, that concern is the reason that I said what I did about
precedent. You have to see and we then perhaps have to see the data that
would support such a combination.

Are there any other comments from the committee?

(No response.)

DR. BORER: If not, I want to congratulate all of you for finishing 45
minutes and 50 seconds early.

(Whereupon, at 4:14 p.m., the committee was recessed, to reconvene at
8:00 a.m., Friday, July 19, 2002.)