8:01 a.m.

Thursday, July 18, 2002
















Versailles Ballroom

Holiday Inn - Bethesda

8120 Wisconsin Avenue

Bethesda, Maryland




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


Professor, Department of Medicine

University of Alberta

251 Medical Science Building

Edmonton, Alberta, Canada T6C37


Professor of Pediatrics

Pediatric Cardiology

New York University Medical Center

530 First Avenue, FPO Suite 9-V

New York, New York 10016


Professor of Medicine

Houston Veterans Affairs Medical Center

Medical Service (111)

2002 Holcombe Boulevard

Houston, Texas 77030


Consumer Representative

Professor, Department of Biobehavioral Nursing

School of Nursing, Box 357266

Seattle, Washington 98195-7266

ATTENDEES (Continued)



Professor and Chair

Department of Biostatistics

University of Washington

Box 357232

Seattle, Washington 98195-7232


Professor of Medicine

Division of Cardiology

University of Colorado Health Science Center

4200 East Ninth Avenue, B-130

Denver, Colorado 80262


Professor of Medicine

Cardiovascular Division

Beth Israel Deaconess Medical Center

330 Brookline Avenue

Boston, Massachusetts 02215


Vice Chairman, Department of Cardiology

Professor of Medicine

Ohio State University

The Cleveland Clinic Foundation

9500 Euclid Avenue, F15

Cleveland, Ohio 44195




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)























* * *

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

AstraZeneca LP,

For a Proposed Claim of Comparative Efficacy of

Candesartan Cilexetil and Losartan in Hypertension

* * *



By Ms. Jayne Peterson 8



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


By Ms. Cindy M. Lancaster 73






* * *

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

* * *



By Ms. Jayne Peterson 168



Introductory Remarks

By Dr. Todd Baumgartner 170


Safety and Dosing Considerations

By Dr. Rene Belder 176

Summary Overview

By Dr. Fred Fiedorek 190








(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.


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

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


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


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.


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. BORER: Okay.


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. 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.


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.


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. 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.


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. 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.


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 --


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. 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. 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.


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. 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.


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. 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. 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.


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. 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?


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.


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.


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. BORER: Steve.


DR. BORER: Blase.


DR. BORER: Susanna.


DR. BORER: Beverly.


DR. BORER: Mike.






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. BORER: Blase.


DR. BORER: Susanna.


DR. BORER: Beverly.


DR. BORER: Mike.





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.


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. 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.


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?



DR. BORER: Steve.


DR. BORER: Blase.


DR. BORER: Susanna.


DR. BORER: Beverly.


DR. BORER: Mike.





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.


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.


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?


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.


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.


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?


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. 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.


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.


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.)










(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.


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. 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. 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.


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. 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.


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.


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. 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. 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.


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. 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. 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.


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?


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.


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. 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. 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.


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.


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.


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.)