1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

JOINT MEETING OF

THE ARTHRITIS ADVISORY COMMITTEE AND

THE DRUG SAFETY AND RISK MANAGEMENT

ADVISORY COMMITTEE

VOLUME I

Wednesday, February 16, 2005

8:00 a.m.

Hilton Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland

P A R T I C I P A N T S

Alastair J.J. Wood, M.D., Chair

Arthritis Advisory Committee:

Allan Gibofsky, M.D., J.D.

Joan M. Bathon, M.D.

Dennis W. Boulware, M.D.

John J. Cush, M.D.

Gary Stuart Hoffman, M.D.

Norman T. Ilowite, M.D.

Susan M. Manzi, M.D., M.P.H.

Drug Safety and Risk Management Advisory Committee:

Peter A. Gross, M.D.

Stephanie Y. Crawford, Ph.D., M.P.H.

Ruth S. Day, Ph.D.

Curt D. Furberg, M.D., Ph.D.

Jacqueline S. Gardner, Ph.D., M.P.H.

Eric S. Holmboe, M.D.

Arthur A. Levin, M.P.H., Consumer Representative

Louis A. Morris, Ph.D.

Richard Platt, M.D., M.Sc.

Robyn S. Shapiro, J.D.

Annette Stemhagen, Dr.PH. Industry Representative

FDA Consultants (Voting):

Steven Abramson, M.D.

Ralph B. D'Agostino, Ph.D.

Robert H. Dworkin, Ph.D.

Janet Elashoff, Ph.D.

John T. Farrar, M.D.

Leona M. Malone, L.C.S.W., Patient Representative

Thomas Fleming, Ph.D.

Charles H. Hennekens, M.D.

Steven Nissen, M.D.

Emil Paganini, M.D., FACP, FRCP

Steven L. Shafer, M.D.

Alastair J.J. Wood, M.D., Chair

P A R T I C I P A N T S (Continued)

National Institutes of Health Participants

(Voting):

Richard O. Cannon, III, M.D.

Michael J. Domanski, M.D.

Lawrence Friedman, M.D.

FDA Consultants (Non-Voting):

Byron Cryer, M.D. (Speaker and Discussant)

Milton Packer, M.D. (Speaker only)

Guest Speakers (Non-Voting):

Garret A. FitzGerald, M.D.

Ernest Hawk, M.D., M.P.H.

Bernard Levin, M.D.

Constantine Lyketsos, M.D., M.H.S.

FDA Participants:

Jonca Bull, M.D.

David Graham, M.D., M.P.H.

Brian Harvey, M.D.

Sharon Hertz, M.D.

John Jenkins, M.D., F.C.C.P.

Sandy Kweder, M.D.

Robert O'Neill, Ph.D.

Joel Schiffenbauer, M.D.

Paul Seligman, M.D.

Robert Temple, M.D.

Anne Trontell, M.D., M.P.H.

Lourdes Villalba, M.D.

James Witter, M.D., Ph.D.

Steven Galson, M.D.

Kimberly Littleton Topper, M.S., Executive

Secretary

C O N T E N T S

Call to Order:

Alastair J. Wood, M.D., Chair 6

Conflict of Interest Statement:

Kimberly Littleton Topper, M.S., 13

Welcome:

Steven Galson, M.D., MPH 16

Regulatory History

Jonca Bull, M.D. 24

Gastrointestinal Effects of NSAIDs and COX-2

Specific Inhibitors

Byron Cryer, M.D., 30

Mechanism Based Adverse Cardiovascular Events and

Specific Inhibitors of COX-2

Garret FitzGerald, 80

Committe Questions to Speakers 112

Sponsor Presentation: Vioxx (Rofecoxib),

Peter S. Kim, M.D. 130

Ned S. Braunstein, M.D. 131

FDA Presentation: Vioxx (Rofecoxib),

Lourdes Villalba, M.D., 227

Committee Questions to the Speakers 263

Sponsor Presentation: Celebrex (Celecoxib),

Joseph M. Feczko, M.D. 293

Cardiac Safety and Risk/Benefit Assessment of

Celecoxib

Kenneth M. Verburg, Ph.D. 295

FDA Presentation: COX-2 CV Safety: Celecoxib,

James Witter, M.D., Ph.D., 373

NIH and Investigator Presentation: Celecoxib in

Adenoma Prevention Trials: The APC Trial

(Prevention of Sporadic Colorectal Adenomas with

Celecoxib)

Ernest Hawk, M.D. 402

C O N T E N T S (Continued)

NIH Investigator Presentation: The PreSAP Trial

(Prevention of Colorectal Sporadic Adenomatous

Polyps)

Bernard Levin, M.D. 422

Committee Questions to Speakers 427

Sponsor Presentation: Cardiovascular Safety and

Risk/Benefit Assessment of Valdecoxib and

Parecoxib

Kenneth M. Verburg, Ph.D. 443

Concluding Comments

Joseph M. Feczko, M.D. 465

FDA Presentation: COX-2 CV Safety:

Valdecoxib-Parecoxib,

James Witter, M.D., Ph.D. 493

Bayer and Roche Joint Presentation on Naproxen,

Leonard M. Baum, R.Ph. 509

Safety Data

Martin H. Huber, M.D. 517

Committee Questions to Speakers 527

P R O C E E D I N G S

Call to Order

DR. WOOD: Let's get started. For those

of you who missed the memo, this is the committee

to discuss the safety and efficacy of COX-2

inhibitors. It is worth perhaps just giving some

thought to why we are here. We are here to

evaluate the relative efficacy and risk of these

drugs, and to decide whether the benefits from

these drugs outweigh the risk, in contrast to

whether the risks outweigh the benefits.

It is probably also worth just saying what

we are not here for. We are not here to delegate

blame or revisit the past. We are here to look

into the future and determine what we should do in

the future. It is important I think for everybody

to remember that as we move through the

discussions.

I guess the first thing to do is let

people at this enormous table introduce themselves.

Let's start down in this corner with John.

DR. JENKINS: Good morning. I am John

Jenkins. I am Director of the Office of New Drugs

in the Center for Drug Evaluation at FDA.

DR. O'NEILL: I am Bob O'Neill. I am the

Director of the Office of Biostatistics in CDER.

DR. BULL: Good morning. I am Jonca Bull,

the Director of the Office of Drug Evaluation V, in

the Office of New Drugs.

DR. GALSON: I am Steven Galson, the

Acting Director of CDER.

DR. TRONTELL: Anne Trontell, Deputy

Director of the Office of Drug Safety.

DR. SHAFER: Steve Shafer. I am not the

director of anything. I am a Professor of

Anesthesia at Stanford and Biopharmaceutical

Science at UCSF.

DR. HENNEKENS: Charlie Hennekens at the

University of Miami School of Medicine and Florida

Atlantic University.

DR. FRIEDMAN: Larry Friedman, from the

National Heart, Lung and Blood Institute.

DR. PAGANINI: Emil Paganini, a

nephrologist out of the Cleveland Clinic.

MS. SHAPIRO: Robyn Shapiro, I direct the

Center for of Bioethics of the Medical College of

Wisconsin. I am a Professor of Bioethics there and

I chair the Health Law Practice Group at Michael,

Best and Friedreich.

DR. CANNON: I am Richard Cannon. I am

Clinical Director of the Division of Intramural

Research, NHBLI, National Institutes of Health.

DR. MORRIS: Lou Morris, President, Lou

Morris and Associates.

DR. D'AGOSTINO: Ralph D'Agostino,

biostatistician from Boston University and the

Framingham Study.

DR. ILOWITE: Norm Ilowite, Schneider

Children's Hospital and Rheumatology at Albert

Einstein College of Medicine.

MR. LEVIN: Arthur Levin, Director of the

Center for Clinical Consumers and consumer

representative on the Drug Safety Committee.

MS. MALONE: I am Leona Malone. I am a

licensed clinical social worker and I am here as a

patient representative for the Arthritis Committee,

and I have struggled with rheumatoid arthritis and

osteoarthritis for 35 years.

DR. BATHON: Joan Bathon, Johns Hopkins

University, Department of Medicine, Division of

Rheumatology.

DR. CUSH: I am Jack Cush. I am a

rheumatologist from Presbyterian Hospital, Dallas.

DR. GIBOFSKY: Allan Gibofsky, Professor

of Medicine and Public Health, Cornell University;

Adjunct Professor of Law at Fordham University; and

I am Chair of the Arthritis Advisory Committee.

MS. TOPPER: Kimberly Topper, with the

FDA. I am the Executive Secretary for the

Committee.

DR. GROSS: I am Peter Gross. I am

Professor of Medicine and Community Health in New

Jersey Medical School; Chair of Medicine,

Hackensack University Medical Center; and I chair

the Drug Safety and Risk Management Advisory

Committee.

DR. HOLMBOE: I am Eric Holmboe, Vice

President for Evaluation Research at the American

Board of Internal Medicine.

DR. FARRAR: I am John Farrar. I am a

neurologist and epidemiologist at the Center for

Clinical Epidemiology and Biostatistics at the

University of Pennsylvania.

DR. MANZI: I am Susan Manzi. I am a

rheumatologist from the University of Pittsburgh

Medical Center, and with an appointment in

epidemiology at the Graduate School of Public

Health.

DR. HOFFMAN: I am Gary Hoffman. I am

Professor and Chairman of Rheumatic and Immunologic

Diseases at the Cleveland Clinic.

DR. DWORKIN: Hi. I am Bob Dworkin. I am

Professor of Anesthesiology and Neurology at the

University of Rochester School of Medicine.

DR. BOULWARE: I am Dennis Boulware,

Professor of Medicine, and rheumatologist at the

University of Alabama at Birmingham, and member of

the Arthritis Advisory Committee.

DR. DOMANSKI: I am Mike Domanski. I am a

cardiologist. I head the Clinical Trials Group at

the National Heart, Lung and Blood Institute.

DR. FLEMING: Thomas Fleming, Chair of

Biostatistics, University of Washington.

DR. FURBERG: Curt Furberg, Professor of

Public Health Sciences, Wake Forest University. I

am a member of the Drug Safety and Risk Management

Advisory Committee.

DR. DAY: Ruth Day, Duke University,

Director of the Medical Cognition Lab, and a member

of the Drug Safety Committee.

DR. PLATT: I am Richard Platt. I am

Professor and Chair of the Harvard Medical School,

Harvard Pilgrim Healthcare Department, Ambulatory

Care and Prevention. I am principal investigator

of one of the HHRQ centers for education and

research in therapeutics. I am a member of the

Drug Safety Committee.

DR. GARDNER: I am Jacqueline Gardner,

University of Washington School of Pharmacy and

Pharmaceutical Outcomes Research Program. I am on

the Drug Safety and Risk Management Committee.

DR. ELASHOFF: Janet Elashoff,

Biostatistics, Cedars-Sinai and UCLA.

DR. NISSEN: I am Steve Nissen. I am the

Medical Director of Cleveland Clinic Cardiovascular

Coordinating Center. I am a cardiologist, and I am

the Chair of the Cardiorenal Advisory Panel for the

FDA.

DR. ABRAMSON: Steve Abramson, I am

Chairman of Rheumatology at NYU and the Hospital

for Joint Diseases.

DR. CRYER: I am Byron Cryer. I am a

gastroenterologist from the University of Texas

Southwestern Medical School in Dallas, and the

Dallas VA Medical Center. My role here today is as

an FDA consultant to this group and as a member of

the Gastrointestinal Drugs Advisory Committee.

DR. STEMHAGEN: I am Annette Stemhagen. I

am an epidemiologist with Covance and I am the

industry representative to the Drug Safety and Risk

Management Committee.

DR. WOOD: I am Alastair Wood. I am the

Associate Dean at Vanderbilt and Professor of

Medicine and Professor of Pharmacology.

Now we will have the "reading of the

lesson" from Kimberly Topper.

Conflict of Interest Statement

MS. TOPPER: The following announcement

addresses the issue of conflict of interest with

respect to this meeting, and is made part of the

record to preclude even the appearance of such.

Based on the agenda, it has been determined that

the topics of today's meeting are issues of broad

applicability and there are no products being

approved. Unlike issues before a committee in

which a particular product is discussed, issues of

broader applicability include many industrial

sponsors and academic institutions.

All special government employees have been

screened for their financial interests as they may

apply to the general topics at hand. To determine

if any conflict of interests existed, the agency

has reviewed the agenda and all relevant financial

interests reported by the meeting participants.

The Food and Drug Administration has granted

general matters waivers to the special government

employees participating in the meeting who require

a waiver under Title 18 United States Code, Section

208. A copy of the 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.

Because general topics impact so many

entities, it is not practical to recite all

potential conflicts of interest as they apply to

each member, consultant and guest speaker. FDA

acknowledges that there may be potential conflicts

of interest but, because of the general nature of

the discussions before the committee, these

potential conflicts are mitigated.

Further, during today's session Dr.

Bernard Levin will be presenting data on the

prevention of colorectal sporadic adenomatous

polyps trial, the PreSAP trial, a Pfizer-sponsored

clinical trial. We would like to note for the

record that Dr. Levin is attending this meeting as

a consultant to Pfizer.

With respect to FDA's invited industry

representative, we would also like to disclose that

Dr. Annette Stemhagen is participating in this

meeting as a non-voting industry representative,

acting on behalf of regulated industry. Dr.

Stemhagen's role on this committee is to represent

industry interests in general and not one

particular company. Dr. Stemhagen is the Vice

President of Strategic Development Services for

Covance Periapproval Services, Inc.

In the event that the discussions involve

any other products or firms not already on the

agenda for which FDA participants have a financial

interest, the participant's 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 product they may wish to comment

upon. Thank you.

DR. WOOD: For those of you still

standing, there are apparently seats in the

overflow room. Let's go right on to the first

speaker, who is Steve Galson. Steve?

Welcome

DR. GALSON: Thank you. I want to welcome

everyone and thanks in particular to our Chair, Dr.

Alastair Wood, committee members, special guests,

members of the public and FDA staff who have really

done a tremendous job in putting together a

particularly and unusually complex meeting.

We have some special guests today that I

want to point out. We have representatives from

the drug regulatory authorities of the member

countries of the European Union and six separate

countries--Canada, Japan, Singapore, Australia,

Switzerland and Mexico, and I really want to

welcome them. Thank you for being with us. We

also have several guests from congressional staff

offices and we are very pleased that they are with

us as well to learn about this important issue.

There is really an unprecedented level of

international attention to one of our advisory

committees today, and we are very proud that this

is taking place and we think it represents a new

level of collaboration and discussion around the

world about an emerging public health issue.

Many millions of people all over the world

are taking the products that we are discussing.

Indeed, they depend on them for a range of

conditions from the mild to the severe and

life-threatening. We must keep the interests and

health of these patients front and center in these

deliberations.

I wouldn't be complete in this

introduction if I didn't acknowledge the

controversy surrounding these products,

particularly over the last year. I want to

emphasize that we are anxious to hear all points of

views from the advisory committee and, of course,

from agency staff. It goes without saying that all

FDA staff are free to make any presentation without

fear of any retaliation. I don't want anyone

sitting around this table to be shy.

Also, we look forward to hearing a wide

range of views from the more than 50 members of the

public who are going to be making brief statements

later in the meeting. I want to remind the public

that all members of this committee have been

carefully screened for conflicts of interest and we

have used the same standards in this process that

we have used for other committees and similar

meetings.

A few comments about the challenging

risk/benefit balance that the agency must achieve

in making its regulatory decisions: Although you

have all heard strong opinions in the media and

medical literature about safety issues related to

the drugs we are discussing, our job and, indeed,

your job is to assess any safety concerns when

balanced by the benefit of these products. We

cannot lose sight of the reduced morbidity, pain

and suffering achieved by the products that are

under discussion and the real impact on people that

changes in the regulatory status may entail.

You will be assessing the risk/benefit

balance of these products this week in the midst of

a changing information environment and this

represents a particular challenge. We are aware of

at least a half dozen ongoing meta-analyses and

huge population-based studies, in addition to

several of the studies you will hear about this

week for which data analysis continues as we speak.

Although we have a full three days, the time really

isn't long enough to hear details about every

single ongoing, or incomplete, or unreviewed study

of which we are aware. Leaving them out of the

agenda has absolutely nothing to do with wanting to

keep information from you and everything to do with

allowing you to focus so that you have time to get

to our critical advisory questions.

We must be very cautious about

interpreting data for regulatory decision-making

that has not been thoroughly vetted and peer

reviewed, and even more cautious about interpreting

data of preliminary studies that are not even

complete. You will be hearing about some data in

these categories and I would remind you to exercise

caution in their interpretation.

As scientists, we have all seen examples

of ongoing studies whose findings have changed as

analysis is in the final stages, or examples where

inadvertent errors have led to misclassification in

epidemiologic studies, or when data that comes in

at the end of the data gathering stage influences

results. In today's 24-hour news environment, it

is difficult to not react to these incomplete

reports but we must go back to the basics of

relying on sound science and use the peer review

system to strengthen findings before utilizing them

to make regulatory decisions.

Lastly on the risk/benefit balance, as you

members know but it is sometimes difficult for us

to convey to the public, our job at FDA and your

job in the advisory group is to balance risks and

benefits on a population basis for the nation as a

whole. This is very different from the

risk/benefit assessment physicians do with

individual patients where specific risks of the

medications, family history, a patient's risk

tolerance and other factors must be taken into

consideration. A drug may, based on the weight of

evidence, have a positive benefit/risk balance for

the population leading to approval, yet, cause

grievous harm in a specific subset of individuals.

We say over and over again that all drugs have

risks, but when a person you know suffers an

adverse event the faulty assumption is sometimes

made that we must have made a mistake in the

approval.

I would also like to mention an unusual

feature of many of the data from the trials you

will be hearing over the next few days. The data

on safety of these drugs is, as I have mentioned,

unusually complex and represents the fact that

clinical trial methodology to look at

cardiovascular effects as adverse events has

changed dramatically. When discussions began about

cardiovascular safety of NSAIDs there was no

standard methodology by which cardiovascular

adverse events were confirmed or categorized.

Analyses vary by trial. Confirmatory processes

vary by trial. Only after the VIGOR trial did the

methods of establishing confirmatory processes and

standardization become better established. Of

course, in population-based cohorts and case

control studies case reporting and confirmation is

both rudimentary and completely inconsistent

between studies.

In addition, as you know already, unlike

drugs designed to treat cardiovascular disease,

these trials have not been designed to do a full

cardiovascular assessment. So, major pieces of

information that you might like to have are simply

not available. So, in many ways we are forced to

compare apples to oranges in these trials and

studies, and when you are not doing that you are

trying to draw conclusions based on insufficient

information, making your task even harder.

In spite of all the ambiguity, work in

progress, changing standards and questions, we ask

you for the miraculous job of crystal clarity in

your responses to our questions. We know this is

tough on such challenging scientific and

controversial issues, and we are enormously

grateful to you because we know that you all are up

to this challenge. The agency will act rapidly

within the next few weeks to act on the

recommendations you communicate to us over the next

few days.

I would like to quickly go to the agenda.

Today through midday tomorrow you will hear from

sponsor companies, FDA staff and NIH researchers

about data on both approved and unapproved COX-2

selective and non-selective products. Tomorrow

afternoon we have 54 members of the public

registered to speak. On Friday you will hear about

important methodological issues in interpretation

of these studies, and then we will move on to the

questions.

Again, thank you and on behalf of the FDA

I wish you the very best of luck on this important

endeavor. Thanks, Dr. Wood.

DR. WOOD: Thanks a lot. Two additional

people have joined the cast of thousands that we

have at the table, and perhaps it would be worth

having them introduce themselves. Bob, you go

first.

DR. TEMPLE: I am Bob Temple. I am

Director of the Office of Medical Policy.

DR. WOOD: Stephanie?

DR. CRAWFORD: Thank you, Mr. Chair.

Stephanie Crawford--good morning--University of

Illinois at Chicago, College of Pharmacy; member of

the Drug Safety and Risk Management Advisory

Committee.

DR. SELIGMAN: Good morning. This is Paul

Seligman. I am the Director of the Office of

Pharmacoepidemiology and Statistical Science.

DR. WOOD: Is there anyone else I didn't

notice arrive? No? Then, let's move on to the

next speaker. Jonca?

Regulatory History

DR. BULL: Good morning. Again, I would

like to extend a warm welcome to the members of the

committee and to extend and acknowledge a

particular thanks to our staff at FDA, specifically

Dr. Villalba, Dr. Witter, Dr. Schiffenbauer from

our team, our statistical staff, and colleagues in

the Office of Drug Safety who have put in countless

hours in preparation for this meeting.

The NSAID class is one that probably

everybody in this room has a product in their

medicine cabinet that is a member. It is a large

class of marketed products for both OTC and

prescription indication use. It is a wide range of

products with varying risk/benefit profiles. Their

approved indications are for short-term use such as

dysmenorrhea and acute pain; chronic use for

osteoarthritis, rheumatoid arthritis, familial

adenomatous polyposis in the example of Celebrex.

So, clearly, we have drugs that for everyone, from

the young female with cramps to the senior citizen

with arthritic pain, have importance and clearly

there is a need for them in the marketplace. There

are other proposed uses that are known to be under

investigation, and you will hear about studies in

the setting of Alzheimer's disease, as well as

sporadic polyp prevention.

I would like to briefly review some of the

regulatory history for these products, going back

to December of 1986 when there was a public

advisory committee meeting that discussed the GI

paragraph and databases were discussed at that

time.

This was followed in 1995 where revisions

for the NSAID class label were discussed, as well

as a subsequent advisory committee in 1998 when the

new science of the COX-2s were discussed and their

potential enhanced safety for GI benefit.

In December of 1998 an advisory committee

was held to discuss the data for Celebrex, followed

in December of 1998 when that drug was approved

first in this new class of products. In April of

1999 an advisory committee was held for Vioxx,

followed by its approval in May of 1999. We held

another advisory committee meeting in 2001 which

discussed the large outcome studies which sponsors

had undertaken to further evaluate how clinically

meaningful the data from endoscopic studies was in

order to further evaluate the enhanced GI safety

claim.

This time line has several points I would

like to bring to your attention. The first IND for

these products came in 1994 so we are dealing with

a relatively short time line, given that this is

year 2005, in drug development, marketing and an

evolving picture for safety.

The products below the time line are the

ones that have been approved, and I would like to

bring your attention to those above the line,

Arcoxia, Prexige, the IV formulation of Bextra

which have not been approved in the United States

due to insufficient safety data.

The COX-2 agents--are they different? In

what way? When we look at risk to benefit, how do

these agents differ from the traditional NSAIDs?

Can a clinically meaningful benefit for GI safety

and less risk, that is for CV risk, renal risk,

hepatic risk, allergy--can that be characterized?

What additional study is needed to better

understand the science of COX-2 inhibition?

When we think in terms of labeling risk

management, what risk management options are

appropriate in this settings, ranging from

potential withdrawal of the product to labeling

changes?

Certainly there are lessons learned for

drug development. I cite a quote at the end of an

article by Dr. Temple and Marty Himmel, in JAMA in

May, 2002, and I think the statement is quite a

relevant one to our deliberation, that no

improvements in drug development can completely

eliminate the risk of unexpected events.

Looking at large NDA databases is helpful

but continued monitoring is essential to assess

evolving risk profiles for new products.

Certainly, the impact of aggressive marketing must

be taken into account for these unknowns of drug

safety.

Dr. Galson has already gone through the

schedule for the meeting. I will just briefly

allude to our framework for this deliberation.

Following me, Dr. Byron Cryer will be discussing

the gastrointestinal effects of the NSAIDs and

COX-2 specific inhibitors; followed by Dr. Garret

FitzGerald on mechanisms for cardiovascular risk

from inhibition of COX-2s. This will be followed

by a presentation by Merck and the FDA presentation

by Dr. Lourdes Villalba.

This afternoon you will hear from Pfizer

and their review of cardiovascular safety and

risk/benefit assessment of celecoxib, followed by

the FDA presentation by Dr. James Witter. There

will be a presentation then on the NIH-sponsored

colon polyp prevention trials, with subsequent

presentations by Pfizer on valdecoxib and

parecoxib, and an FDA presentation on valdecoxib.

This will be followed by Bayer and Roche discussing

naproxen.

Tomorrow you will hear about the

epidemiologic studies, followed in the afternoon by

the open public hearing and committee discussion.

Day three in the morning will focus on the

Alzheimer's prevention trials. The ADAPT trial

will be discussed that morning by Dr. Constantine

Lyketsos; followed by a presentation by Dr. Milton

Packer on interpretation of cardiovascular events;

a presentation by Dr. Robert Temple on clinical

trial design and patient safety, future directions

for COX-2 selective agents; and a presentation by

Dr. Robert O'Neill on issues in projecting

increased risk of cardiovascular events to the

exposed population. Dr. Sharon Hertz will then

present a summary of the meeting presentations

prior to the afternoon discussion of our questions.

Again, our thanks to the committee members

for taking time from their extraordinarily busy

schedules for this important meeting as we reach

another milestone in the regulatory history of

these products.

DR. WOOD: Thanks very much. Let's just

go straight on to the next speaker, who is Dr.

Byron Cryer who is going to talk on the GI effects.

Dr. Cryer?

Gastrointestinal Effects of NSAIDs

and COX-2 Specific Inhibitors

DR. CRYER: Thank you. For the purposes

of full disclosure, I would first like it to be

noted that I have been invited to give this

presentation by the Analgesic and Anti-Inflammatory

Division of the FDA. I do have relationships with

sponsors of products being mentioned in today's

presentation, however, I am not being paid for my

participation in this meeting nor for my

presentation today.

For those of you not familiar with me, I

am a gastroenterologist and I am thrilled that the

FDA has been begun this meeting with the focus on

this subject because many of us have forgotten that

the initial reason for the development of the class

of the COX-2 specific inhibitors was entirely

because of the gastrointestinal effects of the

non-steroidal anti-inflammatory drugs and, for that

reason, I think it is very appropriate that we have

this review of the gastrointestinal effects of

NSAIDs and what the data say from the GI

perspective about the gastrointestinal effects of

COX-2 specific inhibitors.

From the perspective of the NSAIDs risk,

listed here are several of the known risks

associated with the non-steroidal anti-inflammatory

drugs, the gastrointestinal risks, the cardiorenal

risks and the anti-platelet concerns. Among these,

as the group knows, the adverse concerns of

greatest risk historically were the

gastrointestinal effects that present with features

such as ulcers, perforations, bleeding, obstruction

strictures and many other interesting

manifestations. Over the last several years, added

to this list and a focus of this meeting are

cardiovascular concerns of the non-steroidal

anti-inflammatory drugs but my perspective are the

issues listed at the top, the gastrointestinal

effects.

When looking more extensively at what the

specific gastrointestinal effects of NSAIDs are, we

have learned that NSAIDs have effects throughout

the GI tract. The upper gastrointestinal effects

are the most pronounced but there are some very

interesting effects that we see throughout the GI

tract, such as in the small intestine and colon.

In recent years we have had an increasing focus on

lower gastrointestinal effects of NSAIDs, a very

interesting phenomenon. Several have been assessed

by endoscopic means but there has been a lot of

discussion as to what are the clinically relevant

untoward major events that might happen in the

lower gastrointestinal tract. While this is

debated with respect to the prevalence of lower GI

effects, these effects are likely somewhere in the

range of 10-20 percent of total gastrointestinal

effects that happen within the GI tract

attributable to NSAIDs. Clearly, the major effects

of NSAIDs in the GI tract are in the upper

gastrointestinal tract, such as ulcers more

commonly in the stomach and the duodenum, and

concerns such as gastrointestinal bleeding,

perforations and obstructions. So, that is really

the focus upon which the strategies were developed

to increase NSAID safety within the

gastrointestinal tract.

With respect to the epidemiology of ulcer

disease in general, some very interesting phenomena

have been observed which have persisted into recent

years. But the overall summary of the phenomenon

that I would like to focus your attention to is

that while in recent years the overall incidence of

uncomplicated ulcers, both gastric and duodenal,

has been markedly declining in the U.S. and

worldwide, very interestingly, the incidence of

complications, specifically gastrointestinal

bleeding, has not declined in similar proportions

and, in fact, has persisted or increased. This

phenomenon, in particular the bleeding, has been

felt to be a manifestation of the effects of the

non-steroidal anti-inflammatory drugs within the GI

tract.

This problem presents itself clearly with

respect to morbidity and, unfortunately, mortality

and several hundreds of thousands of

hospitalizations. The costs have been debated.

The actual quantified amount of mortality in the

U.S. is also a number that is debated. The 16,500

estimate is probably an overestimate. But the

bottom line is that NSAIDs are clearly associated

with morbidity, mortality and costs in this country

as well as worldwide, and this is has been the

issue that has led to the discussions of the need

for increasing gastrointestinal safety for NSAIDs.

So, the various ways in which these

assessments have been done has ranged from studies

which we have seen over the years that have been

short-term evaluations of physiologic or

pharmacologic effects on healthy volunteers to the

more relevant studies of the gastrointestinal

effects of these drugs in arthritis patients.

These studies have ranged from long-term endoscopy

studies to a fewer number but very important

studies that have assessed clinical events such as

symptomatic ulcers, GI bleeding, perforation and

obstruction.

Over the years there has been extensive

discussion as to the relevance of the endoscopy

studies and how the endoscopic observations with

NSAIDs might relate to the outcome studies. One of

the criticisms of the endoscopic studies is that

the endoscopic lesions are numerous. They are

mostly only known from endoscopies that are done as

a part of a scheduled study and they are

asymptomatic. However, what we have learned from

comparing the numerous endoscopic studies to

observations that have been seen in the outcome

studies is that the relative proportions in terms

of outcomes seen in endoscopic studies tend to be

predictive of what one would expect to see in an

outcome study. So, we have come full circle then

in our understanding of the role of endoscopic

studies and, at least in the gastroenterology

community, we now feel that there is some

substantial value in endoscopic studies and that

they are predictive of what one might expect to see

in outcome trials.

Now, with respect to what we see in these

types of trials, when one looks endoscopically

there is a range of findings in people who are

taking high doses of NSAIDs. In greater than 90

percent, if one were to look, we would see this

phenomenon of NSAID gastropathy, which is this

constellation of erosions and hemorrhages but it is

mostly asymptomatic, mostly not clinically

relevant.

With respect to incidences of asymptomatic

endoscopic ulcers, gastric ulcers happen two to

three times more commonly than the duodenal ulcers,

with the ranges that are shown on the slide.

Again, these lesions are mostly asymptomatic and

don't progress in the majority of individuals to

clinically untoward gastrointestinal events.

What these things look like--this is an

endoscopic photograph of gastropathy demonstrating

the constellation of hemorrhages and erosions that,

again, are going to be mostly asymptomatic, ranging

to a picture, shown here, of an endoscopic ulcer

seen in the antrum of the stomach of an NSAID user.

The more clinically concerning endpoint,

that being clinically significant ulcers, occurs

with the non-selective NSAIDs on average about 2

percent, with a range of about 1-4 percent. This

range and this mean are important numbers as

benchmarks to remember because they will become

relevant as we discuss some of the outcome studies

that have been conducted with the COX-2 specific

inhibitors.

Having reviewed what the risks are, I

would now like to move the discussion to what our

strategies have been to reduce the risk of the

gastrointestinal complications with NSAIDs. It is

a simple strategy and most experts will recommend

identifying the patient population who might be at

risk and this is based upon identification of risk

factors. Then, once having identified susceptible

populations for risk, one employs strategies that

would reduce risk, such as either the use of

gastroprotective drugs or the use of safer NSAIDs,

and the category of safer NSAIDs clearly involves

the subclass of the COX-2 specific inhibitors.

With regard to identification of risk

factors, a risk factor not commonly mentioned is

the NSAIDs themselves. NSAIDs clearly provide risk

for gastrointestinal effects. Shown here are

various NSAIDs available by class and by

prescription in the United States. As you can see,

they have been divided into traditional NSAIDs,

non-salicylates; aspirin related, salicylate-based

compounds; and then COX-2 inhibitors which are

currently available, in development or previously

available in the U.S.

With regard to identifying patient

characteristics which may suggest risk, these have

been extensively studied and they are listed here,

things such as increasing age and the threshold age

is widely debated but one category that has been

suggested would be those greater than 65, let's

say. Clearly history of GI ulceration; having had

a complication; concomitant drugs such as

corticosteroids or anticoagulants; cardiovascular

disease, interestingly, such as CHF; and this issue

of multiple NSAIDs all increase the risk.

Of this list that the group is very

familiar with, the one that has probably not been

as widely appreciated and one which has been

highlighted from some of the outcome trials of the

COX-2 specific inhibitors is this issue of multiple

NSAIDs, and it is a risk factor that presents

itself in the context of a patient profile, a

patient who takes prescribed NSAIDs along with

either low doses of aspirin of over-the-counter

NSAIDs. Since we know that the risk for

NSAID-related gastrointestinal events is related to

dose, what one accomplishes in this group of

multiple NSAIDs is essentially to increase the

overall dose of NSAIDs delivered.

With regard to the strategies after having

identified the susceptible population, the first

category essentially is that of co-therapeutic

gastroprotection. As alluded to a minute ago, it

would be desirable to use the lowest effective dose

of an NSAID. Then really the two prevailing

gastroprotective or co-therapy strategies that we

have are the use of either misoprostol or proton

pump inhibitors.

Several studies have been done in either

of these categories. I will just highlight for

purposes of discussion two outcome trials that I

think nicely demonstrate the effectiveness of these

strategies. With regard to misoprostol, the most

widely quoted study was the outcome trial, the

MUCOSA trial in which misoprostol was given to

patients who were chronically taking NSAIDs over 6

months and were demonstrated to be associated with

a 40 percent or less reduction in gastrointestinal

complications.

From the perspective of the PPI outcome

trials, there have been fewer evaluations but there

have been, in fact, some evaluations for clinically

relevant outcomes for PPIs, this being one example

of a trial which was actually not intended in its

design to evaluate outcomes of a proton pump

inhibitor in patients taking NSAIDs but,

nevertheless, provided us with some insight into

the potential effects from the perspective of

gastrointestinal outcomes.

This was a trial that was designed with

the question in mind of whether or not H. pylori

eradication prior to starting an NSAID would be an

effective therapy or not for the reduction

potentially of NSAID-related bleeds. So, in this

group of H. pylori infected NSAID users, half of

them were treated for their H. pylori infections

prior to being started on an NSAID and acted as a

control. The other half were given a proton pump

inhibitor. In this specific instance omeprazole.

What was observed, very interestingly, at

the end of 6 months is that in this instance there

was a 76 percent reduction in the subsequent

incidence of upper gastrointestinal bleeding in the

group that had received the proton pump inhibitor

approach.

From the perspective of the safer NSAIDs,

this is a story that is also well known. Its focus

today is really to look at specifically the COX-2

specific inhibitors shown on the far right. The

concept has been widely discussed and is arguably

somewhat simplistic, but for the sake of today's

discussion, as the group knows, it is highlighted

by the observation that there are 2 COX isoforms

available, COX-2 and COX-1, and that COX-1 is the

isoform which is primarily responsible for the

protective prostaglandins in the stomach which

typically protect against injury. Once inhibited

by non-selective NSAIDs, the prostaglandin products

produced by COX-1 lead to an increased

susceptibility for injury. The concept at least

for COX-2 specific NSAIDs in that they have limited

inhibitory effects on COX-1 is that they would

likely not inhibit prostaglandins, likely not be

associated with ulcers, and likely be associated

with a reduction in clinically significant

gastrointestinal untoward events with NSAIDs.

Having said that, there have been a few

gastrointestinal outcome trials that have been

designed to evaluation whether or not the COX-2

inhibitors would meet this objective or not. Shown

here are two of the outcome trials with rofecoxib

and celecoxib.

As the group knows, there has also

recently been another completed outcome trial with

lumiracoxib. In general, the outcome trials have

compared COX-2 specific inhibitors at higher than

usual therapeutic doses for osteoarthritis to

non-selective NSAIDs and evaluated the clinically

significant events on average over a year. The

major difference of importance between the outcome

trials with celecoxib and rofecoxib was the

inclusion or exclusion of low doses of aspirin. We

know that low doses of aspirin are ulcerogenic. In

the CLASS trial 21 percent of patients took low

doses of aspirin, 325 mg/day or less, and none of

the patients in the rofecoxib experience were

taking low doses of aspirin.

The principal gastrointestinal

observations from the CLASS trial are, as shown

here in this figure, taken from the publication in

the JAMA, which represents the 6-month data point

from this year-long trial. In the top panel are

all the patients who were evaluated in the trial

who were taking either celecoxib or one of the

non-selective NSAIDs, ibuprofen or diclofenac. As

you note, there was a numeric but not statistically

significant reduction in ulcer complications in the

overall group, remembering that 21 percent of the

patients in the CLASS trial were taking low doses

of aspirin and that some of the ulcer effects were

related to the effects of aspirin.

So, to get a better concept of the effects

of a COX inhibitor compared to non-selective

NSAIDs, the middle panel looks exclusively at the

patients in this 6-month evaluation of the CLASS

trial who were not taking aspirin, just celecoxib,

ibuprofen or diclofenac. As you observe in this

middle panel, there were statistically significant

reductions associated for GI outcomes with

celecoxib when compared to traditional NSAIDs in

the absence of aspirin at 6 months.

However, for those of you who were here

four years ago this month at the long-term safety

evaluations of the FDA, the entire CLASS trial data

set was evaluated with respect to gastrointestinal

complications. When compared to either ibuprofen

or diclofenac alone or combined, with respect to

complications there were not statistically

significant gastrointestinal reductions in events

associated, as you can see, with celecoxib.

With regard to the VIGOR trial, just to

refresh the group's memory, this was clearly

exclusively an evaluation of rofecoxib versus

naproxen. There was no low dose aspirin. Their

observations were straightforward in with respect

to either primary or secondary event being

confirmed upper GI events or complicated events.

There was a statistically significant reduction

associated with rofecoxib compared to naproxen.

As I have mentioned, there has also been a

similar in design outcome study with lumiracoxib.

The variable observations between these outcomes

trials have led to extensive debate in the medical

and scientific communities as to why one might have

observed differences with respect to

gastrointestinal endpoints between the outcome

trials of COX-2 specific inhibitors.

While I don't have time to get into the

nuances and specifics of that debate, one point

that I would like to bring to the group's attention

that I do think is worthwhile reviewing is that, to

the extent that there were differences between the

observations in the outcome trials, these

differences may have had more to do with

differences in ulcerogenic effects with the

traditional NSAID comparators such as naproxen,

ibuprofen and diclofenac than they may have had to

do with differences with respect to ulcerogenic

effects between rofecoxib and celecoxib.

The point to be highlighted is that the

non-selective NSAIDs differ with regard to their

ulcerogenic effects and that the delta, the

difference observed between a COX-2 inhibitor and a

non-selective NSAID will matter, and it will be

based upon the choice of comparator being used. I

am not here to speak about cardiovascular effects.

Dr. Garret FitzGerald will talk about

cardiovascular issues in the talk to follow. But I

would like to point out that this concept of

differences in COX-1 effects of non-selective

NSAIDs is also applicable when we turn to a

discussion of considerations of potential

differences in cardiovascular observations between

the trials of COX-2 inhibitors.

Having pointed out the data with the COX-2

specific inhibitors, I would like to mention that

there are other potential approaches, and I would

like to turn the discussion to a consideration, as

shown on the bottom, of potentially older, safer

NSAIDs that may be associated with gastrointestinal

safety, agents such as the non-acetylated

salicylates, nabumetone, diclofenac and etodolac.

I mention this because--these are not

gastrointestinal events, this is a reflection of in

vitro evaluations of COX-1 versus COX-2 selectivity

of various NSAIDs. On the left, in the green, are

NSAIDs which have increasing in vitro COX-1

selectivity and are going in the negative

direction; on the right, is increasing COX-2

selectivity. When one evaluates COX-2 selectivity

in vitro, there is a group of NSAIDs which fall

within this mid-range category of what I would call

moderately COX-2 selective, and this COX-2

selectivity of agents such as meloxicam or etodolac

may be predictive of what one might see in outcome

trials.

Taking etodolac as an example, when it was

evaluated with respect to gastrointestinal outcomes

compared to a non-selective NSAID such as naproxen,

shown in the upper panel, there was a statistically

significant, greater than 50 percent, reduction in

gastrointestinal outcomes associated with an agent

such as etodolac. So, this leads me to conclude,

over here in this group of category for COX-2

specific inhibitors, that there are agents which

have COX-2 selective activity which had not been

widely appreciated historically.

Since aspirin was such and important

phenomenon in outcome trials, I think it is

relevant to review the gastrointestinal effects of

low doses of aspirin. This has been looked at

mostly from an epidemiologic perspective, and

trials such as this have tended to show a

dose-response relationship. Although not

statistically significant in this case, clearly

lower doses, at least numerically, of aspirin such

as 75 mg were associated with a lower rate of

clinically relevant gastrointestinal bleeding than

higher doses such as 300 mg. In this instance, at

least numerically from 75 to 300 mg, the odds ratio

of clinically relevant upper gastrointestinal bleed

doubled.

Because of the risk associated with very

low doses of aspirin such as 75 mg, doses of

aspirin that have been quite low, such as 10 mg,

have been evaluated in human studies to assess the

question of whether or not there would be any daily

orally administered dose of aspirin which would be

without gastrointestinal effects.

When measured by use of an intermediate

marker that would be of COX inhibition or

measurement of gastrointestinal prostaglandins,

daily doses of aspirin given out to 3 months, as

low as 10 mg, were associated with as great of a

reduction of gastrointestinal COX as seen with 320,

and gastric ulcerations were observed with a dose

of aspirin that was as low as 10 mg, suggesting

that there is likely not a dose of aspirin that

would be effective that would be daily administered

that would be without gastrointestinal risk.

Another commonly asked question would be

the potential benefit of an enteric coating or

buffered preparation of aspirin. When assessed in

this cohort from the Framingham trial of patients

who were taking various formulations of low dose

aspirin, as one sees that there was no appreciable

reduction in gastrointestinal bleeding associated

with either enteric coating of aspirin or buffered

aspirin when compared to plain, non-enteric,

non-buffered aspirin preparations.

Coming back to the risk factor which I

mentioned had been not widely appreciated, the risk

factor of multiple NSAID use, that is, combining

low dose aspirin with a non-selective NSAID or

COX-2 specific inhibitor, I think it is valuable to

appreciate for a moment the actual risk, numerical

risk, contributed by the addition of aspirin to

another prescribed NSAID.

From this population study in Denmark, it

was apparent that when one combines the use of low

dose aspirin and a non-selective NSAID the risk of

having a clinically significant bleed, upper

gastrointestinal bleed, more than doubled, such

that several people would feel that the risk of a

6-fold increase in the combination of a

non-selective NSAID plus aspirin is sufficiently

high that this population of users would need to be

further risk reduced.

These are data with non-selective NSAIDs.

The data with respect to COX-2 specific inhibitors

have come primarily from a few sources. In this

previous figure in which we saw earlier the 6-month

data from the CLASS trial we stopped with the

middle panel and had events in individuals taking

celecoxib or non-selective NSAIDs in the absence of

aspirin.

But when one looks at the bottom panel,

rates of events, complications or symptomatic

ulcers and ulcer complications in individuals who

were taking one of these agents in the face of low

doses of aspirin, it is clear that the use of low

dose aspirin in the face of a COX-2 specific

inhibitor markedly increased the rates of

gastrointestinal events.

But a point that I would like you to focus

your attention on is the actual incidence of events

in the patients who were taking either aspirin in

combination with a COX inhibitor or non-selective

NSAID. You will remember that the problem that led

to really the focus and development of classes of

safer NSAIDs is an incidence of ulcer complications

of 1-4 percent in the population that takes

non-selective NSAIDs. When one looks at the

incidence of events that occurs annualized in

patients who take aspirin, at least derived from

the data in the CLASS trial, it is clear that the

incidence that was observed of 2-6 percent is

higher than the original problem.

So, I would like to summarize with respect

to the effects of low dose aspirin that low dose

aspirin clearly increases the risk and mitigates

the potential gastrointestinal beneficial effects

of a COX-2 specific inhibitor. These observations

have been seen in other experiences with regard to

the total lack of outcome data which I previously

showed you, where we stopped on the top panel.

When looking at the observations in patients taking

low doses of aspirin, the beneficial effects of

total lack disappear.

In endoscopic trials recently we have also

seen this effect of aspirin in this trial over 12

weeks in which either aspirin was given alone or in

combination with rofecoxib and compared to

ibuprofen. Focusing on the rofecoxib plus aspirin

comparison, rofecoxib plus aspirin users have a

similar, equivalent incidence of endoscopic

ulcerations to non-selective NSAIDs such as

ibuprofen. So, the short conceptual way of

summarizing this is a COX-2 specific inhibitor plus

aspirin equals the effects of a non-selective

traditional NSAID.

The gastrointestinal discussion that we

have had so far has pointed out some of the

potential gastrointestinal effect benefits of a

safer class of agents such as a COX-2 specific

inhibitor. Clearly, the gastrointestinal benefit

does not exist in the face of aspirin and what we

have recently learned is that the gastrointestinal

benefit derived from a class of safer agents in the

GI tract might be mitigated by adverse events in

other areas, and other areas for consideration for

this week's meeting are potential cardiovascular

effects.

Given the limitations of COX-2 specific

inhibitors and low dose aspirin users or when there

may be potential cardiovascular concerns, one

question that we have been asked to address would

be in a potential world of no COX-2 specific

inhibitors would we return to the problem of

several gastrointestinal bleeds, hospitalizations

or mortality?

Well, this brings us back to the question

of what might be the other approaches to accomplish

the objective of reductions in GI events. We have

discussed some of the older, safer NSAIDs. There

are NSAIDs in development such as nitric oxide

NSAIDs or phosphatidylcholine NSAIDs, the effects

of which we are unsure of now and they are

currently being evaluated. But the other

prevailing strategy to accomplish this objective

would be the consideration of a non-selective NSAID

plus co-therapy with either a proton pump inhibitor

or misoprostol.

Data in support of the proton inhibitor

approach have been looked at in several trials, one

example of which is shown here, endoscopic

ulceration in NSAID users receiving co-therapy with

either placebo, a proton pump inhibitor or

misoprostol. What the data pretty consistently say

is that proton pump inhibitors have similar ability

to misoprostol to prevent recurrent ulceration in

NSAID users.

Given that there are two prevailing

approaches to accomplishing GI safety, either COX-2

specific inhibitor alone or a non-selective NSAID

plus a PPI, an important question which has

presented itself for evaluation has been how might

these two approaches compare directly and this is

an important question to consider when considering

the alternatives to having a world potentially in

which there might not be COX-2 specific inhibitors

available. Could GI safety be accomplished?

Well, this question has been asked at

least in two trials or similar design in which high

risk NSAID users--high risk being defined as people

who previously had a history of bleeding ulcers.

Once the ulcers were healed, they were then placed

on either of the combination of non-selective NSAID

plus a proton pump inhibitor or a COX-2 specific

inhibitor, and then were followed for 6 months for

rates of recurrent gastrointestinal bleeding. The

results of one of these trials has been fully

published in a peer reviewed journals, shown here.

The two endpoints being looked at--on the

right are outcomes such as upper gastrointestinal

bleeding; on the left are the results of endoscopic

ulceration. Either of these endpoints tells us

that the approach of a non-selective NSAID plus a

PPI appears comparable to the COX-2 specific

inhibitor approach for achieving the objective of

reductions in GI safety. However, two important

points that I would like to point out to the group

are, one, we have endoscopy on the left and

outcomes, GI bleeding, on the right. Again, the

endoscopic ulcerations that are seen in the trials

generally predict what one would see in an outcomes

study but, more importantly, if one looks at the

actual rates of events which occurred, on the

right, 5 percent and 6 percent with either approach

in a group of individuals at high risk, meaning

they previously had a history of gastrointestinal

bleed, it is clear that either approach, either

NSAID plus PPI or COX-2 specific inhibitor, is

sufficiently adequate to reduce the rates of events

back to a comfortable range. The rates of events

seen here in a high risk population are similar to

the initial problem for which these approaches were

developed.

In conclusion I have several observations.

The untoward gastrointestinal effects of NSAIDs, as

we know, cause considerable morbidity, mortality

and cost. Secondly, COX-2 specific inhibitors were

developed principally to achieve a reduction in

NSAID gastrointestinal toxicity. That was a very

desirable objective to be reached. But very

interestingly, as we just reviewed, this objective

has been partially reached. It seems that the risk

reduction may not be achieved to the extent that we

would have liked in patients who are at high risk

for gastrointestinal bleeding, and the reason this

is important is that that is clinically the target

group of interest for risk reduction.

Paradoxically, I did not mention that if

one looks at subgroup analyses of outcome studies

it appears that people who are at lower baseline

gastrointestinal risk do have a benefit from

receiving a COX-2 specific inhibitor. However, the

low risk group has a low prevalence of this problem

of NSAID-related gastrointestinal events in the

population.

So COX-2 inhibitors, it appears, have been

widely used by patients who are not at high risk

for GI effects, and we have reviewed over the last

several minutes that there are some limitations

with COX inhibitors. In my opinion, there is no

great clinical need for COX-2 specific inhibitors

in patients who are at baseline at low GI risk. It

is also clear that there is no GI benefit in

patients who are concurrently taking aspirin. We

are here to discuss the possibility that

cardiovascular concerns may exist for some groups

of patients.

So, the strategies to reduce the

gastrointestinal effects of NSAIDs should focus on

patients at greatest risk. Just to reiterate, the

patients at greatest risk may not be sufficiently

risk reduced by either of the prevailing strategies

which we currently have available clinically. For

such patients, COX-2 specific inhibitors may be an

attractive option but it looks like the target

group of interest may not have the anticipated

benefit.

For patients who are taking low dose

aspirin or, if cardiovascular concerns were to

exist, we have been asked to consider that if there

were a world without COX-2 specific inhibitors how

might we accomplish this objective, and it is clear

that there are other strategies available that may

lead to a reduction in NSAID GI effects. Thank you

very much.

DR. WOOD: Thank you very much. Byron,

could you just stay there in case there are

specific questions for you while the slides are up?

I have one. Could you put up slide 4 again? That

shows data through 1990.

DR. CRYER: Yes.

DR. WOOD: What surprised me is Jim Freis

has updated that data through 2000, and that

dramatically changes what that slide looks like.

In fact, he found a 67 percent decline since 1990

in complicated ulcers, the vast majority of which

occurred actually before COX-2 specific inhibitors

went on the market. So, I am interested, first of

all, in why you chose to present 15-year old data

when there is new data out there that contradicts

that, and whether you would like to comment on his

publications from which this data came as well.

DR. CRYER: Sure. It is correct that

there are newer data available that have

demonstrated a reduction in gastrointestinal bleeds

on a population basis. On the other hand, it is

also very true that this problem of

gastrointestinal bleeding with NSAIDs continues to

be a significant problem despite its more recent

decline. But, more importantly, he also

highlighted a very important observation which is

that the declines in gastrointestinal bleeding that

have been seen in populations preceded the

introduction of COX-2 specific inhibitors, and

there are some data sets to suggest, at least in

the U.S., that hospitalizations for

gastrointestinal bleeding since the introduction of

COX-2 specific inhibitors have not markedly

declined compared to hospitalizations prior to

their introduction.

DR. WOOD: Right. So, most of the 67

percent decline occurred before these drugs went to

the market, and that 67 percent occurs from the

points on your slide here.

DR. CRYER: Point well taken.

DR. WOOD: And one other point of

clarification I guess, the data you showed from

CLASS, was that data from the predefined endpoint

of the study at 18 months or the 6-month analysis

that was published?

DR. CRYER: Just for sake of review, I

have pointed out both time-dependent endpoints.

The endpoint that was published and shown here, in

the JAMA, was the predefined 6-month data and the

endpoints that are shown here represent an

evaluation of the entire data set. There are

clearly differences in the conclusions about the

effects of celecoxib which varied by time and

varied by whether one evaluates the data at 6

months or evaluates the entire data set.

DR. WOOD: Just remind us, at 18 months

what did the data set show?

DR. CRYER: At 13 months the data, with

respect to complications, indicate that there was

no statistically significant reduction in upper

gastrointestinal complications associated with

celecoxib, at a dose of 400 twice daily, when

compared to either diclofenac or ibuprofen

individually or when compared to both of them

together. I will point out for the sake of fair

balance that this data does include the 21 percent

of individuals who were taking low doses of

aspirin.

DR. WOOD: Other questions from the

committee? Dr. Nissen?

DR. NISSEN: Yes, this 1-4 percent rate, I

am interested in understanding the time-dependent

hazard. If a patient is put on a non-selective

NSAID and, let's say, for the first year has no GI

events, is the risk in the second and third and

fourth years the same as it is in the first year?

In other words, once you know that a patient is

tolerating an NSAID are they no longer at high

risk?

DR. CRYER: There are a few answers,

sub-answers to that question. It is a complicated

discussion. What is clear that risk persists, that

even in the individual who did not develop a

complication in year one, that individual continues

to have risk in subsequent years--two, three, four,

etc. There are data sets that suggest that the

period of highest susceptibility, highest risk is

within the first three months of administration.

Having said that, there are other data sets to the

contrary. This incidence of gastrointestinal

events that are time-dependent in individuals has

been difficult to assess primarily based upon a

concept of selection of susceptible individuals.

People drop out because of other reasons such as

dyspepsia. So, it is difficult to get a firm

estimate on that. But it is clear, in summary,

that the risk after one year or after any period of

time is always persistent as long as the NSAID

exposure is present.

DR. NISSEN: Two more quick questions. I

didn't see any analysis of COX-2 plus low dose

aspirin versus a non-selective NSAID plus low dose

aspirin. The reason I am asking that is that, as a

cardiologist, in my patients who are taking

conventional NSAIDs, if they need aspirin for

cardiovascular prophylaxis I give them aspirin.

So, the question is are there any studies looking

at NSAID plus aspirin versus COX-2 specific

inhibitor plus aspirin?

DR. CRYER: Well, the CLASS trial

addressed that question in a subpopulation of

individuals which was under-powered statistically

to give a definitive answer to that question. That

is an ongoing debate within the medical

communities. I will say, however, that while the

debate continues what is clear is that with either

approach COX-2 specific inhibitor plus aspirin or

non-selective inhibitor plus aspirin the ensuing

rates of gastrointestinal events are too high for

us to feel comfortable that we have risk-reduced

those patients sufficiently.

DR. NISSEN: And a final question,

symptoms of dyspepsia are obviously one of the

issues as well, and I want to make sure I

understand what fraction of the population, let's

say an osteoarthritis population, simply cannot

tolerate NSAIDs because of GI discomfort. Do we

have data on that?

DR. CRYER: Sure. A couple of comments

about dyspepsia which I didn't mention, NSAID

dyspepsia is common. Its prevalence varies

depending on how dyspepsia has been defined in

trials, and because there have been variable

definitions of dyspepsia, its reported rates have

varied anywhere from 10-30 percent of NSAID users,

but it is clearly more common than complications.

In the patient who has dyspepsia, the

presence of dyspepsia is not predictive of the

patient who might have risk. In most of these

studies dyspepsia, in my way of thinking, is

considered more of a nuisance issue that can be

controlled symptomatically with acid reduction

rather than something that presents significant

gastrointestinal concern.

DR. WOOD: Dr. Gibofsky?

DR. GIBOFSKY: You commented extensively

on the upper GI risk but in your second slide you

correctly pointed out that there are problems with

traditional medications affecting the structures of

the GI tract below the ligament of triads. Could

you comment somewhat on the data comparing the

effect of COX-2 specific inhibitors versus

traditional non-steroidals with or without proton

pump inhibitor protection on the lower GI tract?

DR. CRYER: There have been fewer data

sets which have assessed the lower gastrointestinal

events with NSAIDs. A few comments on the types of

studies that have been done, there have been

studies using pill endoscopy which have indicated

that lesions, endoscopic ulcers and erosions occur

in the lower gastrointestinal tract contributed to

by non-selective NSAIDs, an effect which can be

reduced by a COX-2 specific inhibitor, an effect

which is not reduced by the co-therapy approach of

adding a PPI to a non-selective NSAID. I am

speaking of the lower gastrointestinal effects.

Having said that, again similar to the

endoscopic ulcer story, these endoscopically

detected lesions in the lower gastrointestinal

tract probably have very limited clinical

relevance. When lower gastrointestinal clinically

significant events have been assessed from the

prospective trials, the one noted most commonly in

the literature is an assessment of the VIGOR trial

looking at the effects of rofecoxib compared to

naproxen, in which case a 40-50 percent reduction

was seen in lower gastrointestinal events with

rofecoxib compared to naproxen, again to reiterate,

a reduction which would not be expected to be

observed with the proton pump inhibitor approach.

Having said that, in that assessment of

the rofecoxib experience there was an inclusion in

the definition of lower GI events of individuals

who had had reductions in hemoglobin and hematocrit

and who did not otherwise have clinically apparent

gastrointestinal bleeding.

Probably the best assessment in terms of

the risk of lower gastrointestinal events on NSAIDs

comes from population-based observational studies.

While there is variance in that estimate, it looks

like the lower gastrointestinal events probably

contribute 10-20 percent of clinically relevant

events when compared to all GI events that might

happen on NSAIDs.

DR. GIBOFSKY: One last quick point, would

your recognize that there might well be a

population of patients whom you would stratify as

low GI risk who, nevertheless because of either

intolerance, as the last speaker asked, or lack of

efficacy to traditional non-steroidals, would be

candidates for another class of agents?

DR. CRYER: Sure. Their NSAID dyspepsia

is a common phenomenon. I will say that when

dyspepsia has been carefully evaluated in the

prospective trials of COX-2 specific inhibitors in

general there tends to be a reduction in the rates

of dyspepsia associated with the COX-2 specific

inhibitors. However, when one evaluates the

absolute reduction in rates of dyspepsia in the

trials it generally tends to be a few percentage

points. Finally, some of the other strategies that

were mentioned to accomplish risk reduction, for

reduction in GI events in patients on NSAIDs, also

accomplished reductions in dyspepsia in patients

who might experience NSAID-related dyspepsia.

DR. WOOD: Dr. Cush?

DR. CUSH: Byron, two time questions.

One, is there a time point at which peptic

ulcerations and bleeds plateau over time in NSAID

users or COX-2 users? Second, what is the longest

data set that we have as far as the use of a COX-2

agent in a clinical trial where observation is

carried out? Do we have two-year data; five-year

data?

DR. CRYER: Right. There does appear to

be some plateau-ing of the effect. The data sets

do suggest that after long-term exposure the rates

of events with longer-term exposure are not as

great as rates of events with initial exposure to

NSAIDs but, again, that may be attributable to the

phenomenon of dropping out of susceptibles. The

second portion of your question, Jack, was?

DR. CUSH: What is the longest data set we

have on COX-2 agents?

DR. CRYER: Well, when one looks at the

trials, the prospectively defined outcome

trials--we have CLASS, TARGET, VIGOR--there are

periods of observation out to 13 months. Having

said that, we certainly have longer periods of

observations of COX-2 specific inhibitors for

trials in which the specific outcome of interest

was defined for an endpoint that was other than

upper GI bleeding, so specific polyp reduction,

Alzheimer's disease, other trials that we certainly

will hear about over the course of the next few

days, many of which have gone out to periods as

much as 3 years.

DR. WOOD: Is there anyone else who has a

question that specifically addresses something on a

slide that the speaker could show again? If not,

we will come back to these questions and ask you,

Byron, if you would, to be available this

afternoon.

DR. CRYER: Yes.

DR. WOOD: Are there any questions that

somebody has specifically? Tom?

DR. FLEMING: Yes, could we go back to the

slide that showed the CLASS trial with the time to

complicated ulcer?

DR. CRYER: There were two. You can tell

me which one you are referring to, this or the

next?

DR. FLEMING: Both, this and the next.

Basically, here what you are showing us is that in

the presence of aspirin there doesn't seem to be a

reduction in the complicated ulcers although in

those that are not taking aspirin there is this

reduction of about two-thirds. If you go to the

next slide, that is at 6 months. Hence, we see at

6 months this reduction in the rate in the

celecoxib group that is driven by those patients

who are not on aspirin. But that effect, as you

noted, has disappeared out at a year.

I know that is making a lot of a single

data set but is this suggestive of the possibility

that, in response to Steve Nissen's question, there

could be a group that is more susceptible and what

you are doing, in the presence of aspirin, is

achieving not effect; in the absence of aspirin you

are achieving a delayed effect but, in essence, you

are going to have the same overall incidence by a

year even with the COX-2 specific inhibitor?

DR. CRYER: Sure, your point is that there

are likely subgroups of susceptibility for GI risk

on NSAIDs or on COX-2 specific inhibitors. But I

would say also that underlying that argument, which

I think is accurate, is the observation which

confounds the whole discussion, which I have

mentioned previously, which is that early on in any

of these trials you are going to remove the most

susceptible of the individuals and those who

actually persist in the trial tend to be the least

susceptible subpopulation.

DR. FLEMING: Indeed, but that is the

essence of what I am saying, and this would be

consistent then with the theory that if there is a

particular susceptible group, that group is going

to have a higher risk and it is, in fact, going to

have complicated ulcers. They just occur somewhat

sooner with the non-specific NSAIDs. The COX-2s

are not preventing that, they are just delaying the

time to the occurrence.

DR. CRYER: I think we are in agreement

there.

DR. WOOD: Richard?

DR. PLATT: To extend that, on slide 13

you list some risk factors for NSAID-associated GI

toxicity. Can you tell us how well those

discriminate low risk individuals from high risk

individuals? And, if they do, what fraction of the

population falls into low risk, medium risk, high

risk? And, quantitatively what are those risks?

DR. CRYER: That is a complicated question

but it is an important one. When people like

myself have shown these risks we commonly lead to

the assumption that these risk are numerically

equivalent, which they are not. There are certain

risk factors which clearly place one individual at

higher risk than others. The highest risk most

consistently seen in trials would be that of having

had a previous history of a gastrointestinal

bleeding ulcer. But not far behind that would be

the risk of taking an anticoagulant, such as

Coumadin, in association with a non-selective

NSAID. Age as a risk factor is a variable one.

Although we suggest in our discussions of this that

there may be a threshold of age below which one may

be not at risk and above which at risk for having

it. In fact, it is a continuum. In fact, the risk

contributed by age is about a 2 percent increase in

risk per decade of life, such that people who are

in their 80s are at very high risk, much higher

risk than people who are in their 40s.

With respect to your question of

quantifying the risk in a population, that is a

difficult issue because all of these risk factors

do not individually present themselves in any one

patient. The more risk factors one has--two risk

factors present greater risk than one; three

greater than two. I would say, having said that

and trying to give you a reasonable estimate, in my

opinion the percentage of NSAID users who would

likely be candidates for this is probably somewhere

on the order of 20-25 percent, depending on how one

assesses that. If one looks at an OA or RA

population and concludes that age in and of itself

is a risk factor, then you are close to 80 or 90

percent of the population that might be at risk

based upon that risk factor of age. So, it really

depends on which risk factor, and it really depends

on the quantitative contribution of the risk factor

being described. But, certainly, I would say the

one that most clearly and consistently has

presented itself as highest risk in the various

trials has been the risk factor of having had a

previous bleeding ulcer, and it is the one that I

would like to underscore which does not appear to

be sufficiently risk-reduced by either of the

strategies which we have available.

DR. WOOD: Any other questions that are so

burning that they have to be asked now and not in

the discussion? Ralph? Burning? And let's try

and make the answers as brief as we can.

DR. D'AGOSTINO: What are the consequences

of complicated ulcers in, say, the CLASS trial

where you do see this differential and this

catching up? Do they follow to see the

consequences of these ulcers? Were they different

over the time period?

DR. CRYER: I am sorry, I don't

understand.

DR. D'AGOSTINO: What are the

consequences? What happened to these subjects

after? Were they reversible, the ulcer? Does it

lead to mortality?

DR. CRYER: Right, what I assume is

driving your question is whether there are

differences in mortality--

DR. D'AGOSTINO: Well, morbidity,

mortality, what happens.

DR. CRYER: Well, clearly, morbid effects

are hospitalization and the complications of them

having a massive gastrointestinal bleed, which can

be several. The ultimate complication or

consequence of these morbid effects is mortality

and in these outcome trials there were no

differences in the level of mortality. With regard

to the various other consequences, most of them are

clearly going to be reversible after having

suffered a significant hospitalization.

DR. WOOD: Any other smoking questions?

Peter?

DR. GROSS: A question on the third to

last slide, on recurrent ulcer bleeding in high

risk patients, the so-called non-selective NSAIDs

selected diclofenac to compare with celecoxib.

DR. CRYER: Yes.

DR. GROSS: Diclofenac is roughly

comparable in COX-2 selectivity. Is that the right

drug to test with PPI to show that the PPI plus a

non-selective NSAID is comparable to a COX-2

inhibitor like celecoxib? Should they have picked

a non-selective NSAID that was less selective for

COX-2?

DR. CRYER: Sure. Your point is very well

taken and it is one which I tried to underscore

throughout the talk, which is that there are

clearly differences in the COX-1, i.e.,

ulcerogenic, effects of non-selective NSAIDs.

Diclofenac clearly is an agent which is associated

with a lower rate of gastrointestinal ulceration

and complications than non-selective NSAIDs. So,

in this evaluation of the comparison of diclofenac

plus omeprazole compared to celecoxib there is a

valid discussion that the results may have been

biased in favor of the diclofenac plus omeprazole

approach.

The reason I showed that is that that was

a fully published paper. There are, however, other

trials not yet fully peer reviewed, which have been

presented in the gastrointestinal community,

looking at other NSAIDs, such as naproxen plus a

proton pump inhibitor compared to the COX-2

specific inhibitor approach, and the results of

those observations again are comparable endpoints

between the two strategies.

DR. WOOD: I am going to move us on now

and we will come back after the next talk. Dr.

Cryer, we would like you to come back up if there

are questions at that time as well. The next

speaker is Dr. Garret FitzGerald. Garret?

Mechanism Based Adverse Cardiovascular Events

and Specific Inhibitors of COX-2

DR. FITZGERALD: Thank you, Dr. Wood. You

are, please, going to have to forgive me, I feel

quite nauseated; I have a touch of the flu and I

took a medicine to reduce my temperature, but I am

not prepared to tell you what it is!

(Laughter)

I would like to thank Dr. Wood and the FDA

and the committee for the opportunity to visit

Gaithersburg at this time of the year.

(Laughter)

When I boarded the Metro last night at

Union Station and began the apparently interminable

trip to the sylvan embrace of Shady Grove I thought

to myself it might be useful to try and summarize

for you a message that will derive from my talk.

The message is that, just as low dose aspirin

affords cardioprotection and a small but absolute

risk of serious GI bleeds, as you heard from Byron

just now, through inhibition of COX-1, so specific

inhibitors of cyclooxygenase-2 afford

gastroprotection and a small but absolute risk of

cardiovascular events. So, I have titled my talk

mechanism-based adverse cardiovascular events and

specific inhibitors of COX-2.

Well, as every lawyer and broker and

journalist knows, this is the cyclooxygenase

catalyzed pathway of arachidonic acid metabolism.

Arachidonic acid is mobilized for release from cell

membranes by activation of phospholipases and it is

subject to metabolism by two enzymes which we call

prostaglandin JH synthases 1 and 2 but which are

known more commonly as cyclooxygenases 1 and 2.

They give rise to a series of lipid products called

prostaglandins which activate receptors and have

very diverse biological effects.

One of the reasons we are here is that

this, although depicted in a very simplistic way,

is actually a quite complex system. To illustrate

that, I will just mention two of these lipid

products, prostaglandin E-2 and prostacyclin or

prostaglandin I-2. When formed by

cyclooxygenase-1, these two lipid products afford

gastroprotection, and our thinking is that the

common GI adverse events of typical non-steroidal

anti-inflammatory drugs reflect the inhibition of

COX-1-derived PGI-2 and PGE-2, thereby, exposing

people to gastroduodenal liability.

But it turns out that when the very same

lipids, prostacyclin and prostaglandin E-2, are

formed by cyclooxygenase-2 as opposed to

cyclooxygenase-1 they mediate pain and

inflammation. Indeed, it is the suppression of the

formation of these two prostaglandins by COX-2

inhibitors that retains the anti-inflammatory and

analgesic efficacy of traditional non-steroidal

anti-inflammatory drugs which inhibit the two

enzymes together.

But it turns out that these two

prostaglandins, prostaglandin I-2 and prostaglandin

E-2, formed by cyclooxygenase-2 also afford

cardioprotection which can manifest itself in

various ways, and suppression of that capability is

the cogent mechanism which explains the

cardiovascular hazard which has emerged.

Well, I am sure this audience well knows

that cyclooxygenase-2 inhibitors do not inhibit

platelet aggregation, a way that we look at

platelet activation in people that have been

administered drugs. This just illustrates the

absence of an effect at several doses of celecoxib

in healthy volunteers compared to the inhibition of

this signal by a mixed inhibitor at the time of

peak drug action. Of course, that reflects the

absence of cyclooxygenase-2. There should be a big

shade here on this Western Blot if it was present

but, unlike cyclooxygenase-1, which is there in

abundance, cyclooxygenase-2 is not present in

mature human platelets.

The wrinkle in all of this is that if you

look at two structurally distinct members of the

class of COX-2 inhibitors, the depression of the

formation of that protective lipid, prostacyclin,

as reflected by urinary excretion of its major

metabolite which, believe it or not, is the gold

standard of how you look at prostaglandin formation

in people--this depression is comparable on

specific inhibitors of COX-2 with the depression we

see with structurally distinct mixed inhibitors

like ibuprofen and indomethacin.

So, one might logically deduce from this

that even under physiological conditions, never

mind under conditions of pathology, a COX-2 might

be induced by cytokines for example. It is a

dominant source of prostacyclin. We hypothesized

at the time that that reflected a mechanism which

had been described in vitro by Topper and Jim

Broney and which is illustrated here, which is when

you subject endothelial cells to laminar shear

force, which mimics the effect of the blood stream

on the lining of blood vessels, you up-regulate the

COX-2.

Well, that raised a question rather than

answered a question even though it anteceded the

approval of the first of these drugs. The first

proof of principle that prostacyclin did actually

modulate cardiovascular function in vivo stems from

this study where we used mice lacking the

prostacyclin receptor, known as the IP, or the

thromboxane receptor, known as the TP, or both

together. Thromboxane is the lipid which is formed

by COX-1 in platelets and has harmful effects on

the heart and cardiovascular system, and

suppression of thromboxane reflects the

cardioprotection of low dose aspirin.

In these studies we looked at the response

to vascular injury in mice and we found that there

was a signal of increased proliferation in response

to vascular injury in the mice lacking the

prostacyclin receptor which accorded with its in

vitro properties.

Furthermore, when you injure the lining of

a blood vessels in a mouse, just as if you do it in

humans by performing an angioplasty, you get an

attendant increase in platelet activation which is

reflected by a time-dependent increase in excretion

of a major thromboxane metabolite. We were

interested to see that this signal was grossly

augmented in the absence of the prostacyclin

receptor, and that all of these reflections of the

phenotype could be rescued by co-incidental

deletion of the thromboxane receptor along with the

prostacyclin receptor.

Now, these studies were criticized as to

their relevance to the COX-2 inhibitor story mainly

because people said, well, you have taken away the

prostacyclin receptor but when we give the drugs,

although we suppress prostacyclin, we do it to a

substantial but incomplete degree, maybe 60-80

percent on average.

So, we performed these studies in another

model of induced thrombogenesis in mice where we

injured the vasculature in a free radical catalyzed

fashion. In these studies we looked at the effect

of a biochemically selective regimen of a COX-2

inhibitor, and we found that the response time to

the thrombogenic stimulus was significantly

accelerated. Furthermore, as opposed to looking at

the absence of both copies of the prostacyclin

receptor, we looked at the effect of deletion of

just one copy and we found a significant and

intermediate phenotype.

More recently we have devised a technique

which permits us to remove cyclooxygenase-2 from

particular cells. What I am showing here is the

removal of only one copy of cyclooxygenase-2 from

endothelial cells. As you can see, that also

accelerates the response to a thrombogenic

stimulus. So, these new studies are proof of

concept of precisely the mechanism that we

originally proposed.

Well, I think this is a point that we will

come back to. We have some scientific evidence

that there is a very non-linear relationship

between inhibition of the capacity of platelets to

make COX-1 derived thromboxane and inhibition of

thromboxane-dependent function, that is,

aggregation.

To get into the red zone for inhibition of

platelet function you certainly have to be in

excess of 95 percent inhibition of capacity, more

like up in the 98 percent range. Where we have

actually almost no experimental evidence is whether

there is a discordance between that and the

relationship between inhibition of prostacyclin and

inhibition of its protective cardiovascular

function. Perhaps the intermediate phenotype of

the prostacyclin receptor deleted mice losing one

copy of the gene may suggest that that is so.

So, we are back in the mouse model of

induced thrombosis. The reason I am showing you

this slide is that a theme that will recur and is

relevant to the clinical consideration is whether

inhibition of COX-1, along with inhibition of

COX-2, modulates the implications of inhibiting

COX-2.

So, in these studies we have looked at the

rescue from thrombosis induced by intravenously

administering arachidonic acid to mice at two

different doses in mice that either lack completely

COX-1 or in mice that lack 98 percent of the

capacity to make COX-1 derived thromboxane by

platelets. As you can see, these two genetically

modified mice behaved very similarly in terms of

the rescue from arachidonic acid induced thrombosis

or, indeed, the time to complete occlusion induced

by the thrombogenic stimulus I showed you in the

earlier slide. This accords with that

non-linearity of the relationship for COX-1 that I

showed you. You would expect that to be suppressed

in the 98 percent inhibited mice.

Now, that is all very well because it is

in mice. So, you would way, well, how would we

address this in terms of seeking a proof of concept

in people? Well, if you delete the prostacyclin

receptor mice don't fall over dead with thrombosis.

They are more responsive to thrombogenic stimuli.

So, if you wish to seek proof of concept in people,

you would move to a population that had hemostatic

activation and you would postulate that in such a

population you would detect a signal faster and in

a smaller study than might otherwise be the case.

Indeed, given the widespread recognition

that patients undergoing coronary-artery bypass

grafting exhibit hemostatic activation, and some

suggestion also that they may be a model of aspirin

resistance, it is perhaps unsurprising that we are

able to detect a clear signal of cardiovascular

hazard in two placebo-controlled trials in this

condition.

Now, when I think of people at risk of

thrombosis when one is considering where one goes

with these drugs, I tend to think of middle-aged or

elderly people who have suffered a myocardial

infarction or stroke. But I think it is important

to remember that risk of thrombosis can manifest

itself in susceptibility to this cardiovascular

hazard of these drugs in other populations.

This is a ventilation perfusion scan of a

23 year-old athlete who had been on the pill for 3

years, who went on a 6-hour car journey, having

been put on valdecoxib for the antecedent 8 days

and, at the end of the trip, developed left-sided

chest pain; was misdiagnosed and continued on

valdecoxib for another 10 days; had right-sided

pleuritic chest pain that led to this VQ scan.

This is purely an anecdote but it brings

to mind that individuals who have environmental

predisposition to thrombosis, with a relatively

small absolute risk such as being on the pill or

prolonged stasis or genetic predispositions like

Factor V Leiden, might be susceptible to a

geometric interaction of relatively low risk from

this class of drugs.

So, as far as thrombosis is concerned,

where does this take us? Well, first of all, we

have evidence that at least in vitro COX-2 can be

induced in endothelial cells and produce

prostacyclin. We have evidence that it constrains

platelet activation and thrombogenesis in vivo.

Suppression of prostacyclin does not cause

spontaneous thrombosis but augments the response to

thrombogenic stimuli in vivo. So, the hazard from

coxibs would be expected to be particularly evident

in those otherwise predisposed to thrombosis, and

we have evidence that this hazard is modulated by

inhibition of COX-1 in the appropriate zone.

Well, there has been a lot of talk, as we

all know, about mechanisms and one of the things I

have found really curious is the notion that

hypertension is a distinct mechanism. People get

hypertension on traditional non-steroidal

anti-inflammatory drugs as well as COX-2 inhibitors

for a reason. The reason is the same mechanism.

Illustrated here from studies in mice by Matt

Breyer and his colleagues is how inhibition of

COX-2, shown in red, will augment the pressor

response to an infused pressor like angiotensin-II.

Again, as in the setting of thrombosis, COX-1 is

not neutral. As you can see, if he uses a

selective inhibitor of COX-1 he attenuates the

response to angiotensin-II.

Now, these studies have been complemented

by congruent data with gene-deleted mice. They

raise the prospect that the incidence of

hypertension would reflect not only the degree of

inhibition of COX-2 but the selectivity with which

it is attained. Indeed, in this week's Archives we

have the first epidemiological evidence consistent

with that concept.

Now, the products of COX-2 that buffer the

response to pressor agents include prostacyclin and

PGE-2. Here we are looking at the effect on blood

pressure, of deletion of the prostacyclin receptor

and, as you can see, blood pressure is elevated and

the response to salt loading is increased. One

sees exactly the same phenotype deleting one of the

receptors for PGE-2.

So, as far as blood pressure is concerned,

suppression of COX-2 derived PGI-2 and PGE-2

increases blood pressure and augments the response

to hypertensive stimuli in mice. Deletion or

inhibition of COX-1 depresses the response to

vasoconstrictors in vivo so again we see COX-1

modulating the hazard from COX-2 inhibition.

Hypertension on NSAIDs would be expected to relate

to the inhibition of COX-2 and the selectivity with

which it is attained.

Let's think of a more chronically

unfolding cardiovascular hazard. These data

arbitration taken from Narumiya. They are looking

at the development of atherosclerosis in a

genetically prone mouse, and you can see that

deletion of the prostacyclin receptor accelerates

atherogenesis in male ApoeE-deficient mice. In

fact, the impact was most particularly marked at

initiation and early development of

atherosclerosis.

By contrast, deletion of the thromboxane

receptor does the complete reverse, and other

studies conducted by us and others have shown that

inhibition of COX-1 selectively or antagonism of

the thromboxane receptor will have the same effect

as deleting the thromboxane receptor, as shown

here.

So, as far as atherosclerosis is

concerned, we see this buffering capacity between

COX-1 and COX-2. Furthermore, we have shown

recently that in a different genetically proned

mouse model deletion of the prostacyclin receptor

and inhibition of COX-2 dependent formation of

prostacyclin is important in affording the

atheroprotection conferred by estrogen in female

mice.

So, here we see the atheroprotection in

terms of reduction of lesion development with

estrogen treatment in vasectomized mice being

dramatically reduced by deletion of the

prostacyclin receptor, which raises a whole new set

of questions about the use of these drugs in

premenopausal women.

So, as far as this other manifestation of

a cardiovascular hazard is concerned, initiation

and acceleration of early atherogenesis occurs in

response to deletion of the prostacyclin receptor.

I haven't gotten into mechanism but it fosters

platelet and neutrophil activation and vascular

interactions of these cells, and removes the

constraint on attendant oxidant stress.

Now, we know that hypertension, which is

also a consequence of inhibition of this pathway,

itself accelerates atherogenesis. So, one could

imagine that the direct and indirect effect could

converge to transform cardiovascular risk.

Finally, again COX-1 is playing a modulatory role.

There is a lot of speculation, which will

no doubt be addressed in this meeting, as to

whether in the APPROVe study we actually saw a

delayed appearance of augmented cardiovascular

risk. I think, for me, the answer is we are not so

sure but, if we did, this mechanism would explain

not only early events but also the delayed

emergence of cardiovascular phenotype.

The other thing that is often trotted out

is, well, but people on aspirin have had some of

these events. Well, of course, people on aspirin

also have myocardial infarctions. But I think it

is worthwhile remembering as we consider that

prostacyclin will buffer effects of thromboxane on

blood pressure, atherogenesis, hemostasis and,

indeed, cardiac damage, which I haven't gotten into

today. It acts as a general constraint on any

agonist that acts harmfully on these systems. So,

one would expect aspirin, in a perfect world, to

damp rather than abolish the signal.

So, I think, if you will pardon me just

for a moment to muse, one could relate the ability

to detect a signal, expressed here as maybe numbers

needed to treat or trial duration, as a function of

the underlying cardiovascular risk of the patients

involved. The higher the risk, the more you would

be able to detect it easily. The lower the risk,

it may require that you either perform a very large

study or go on for a very long time because we are

all mindful of the fact that clinical trials, even

randomized clinical trials, are very crude detector

systems for uncommon risk.

Additionally, other elements will impact

on this, including elements related to drug

exposure and the degree of selectivity that is

actually attained in vivo. So, I think in some of

the efforts to dismiss this idea of a class-based

effect some have lost sight of the fact that one

would expect not only the underlying substrate to

be relevant, but elements of drug exposure like

dose, duration of dosing, duration of drug action

and, indeed, concomitant therapy to be relevant to

the ability to detect a risk. So, one is looking

for a needle in the haystack and, to some extent,

when one finds the needle it doesn't really matter

how long it has been in the haystack.

So, let's consider the extreme phenotypes

of cardiovascular benefit and hazard in this

pathway. First of all, let's consider aspirin.

Here we have a sustained mechanism of action that

leads to complete and sustained inhibition of

COX-1. Even low dose aspirin inhibits prostacyclin

to a minor degree. But one would expect, and one

sees, a cardiovascular benefit from aspirin, at

least in the secondary prevention of stroke and

myocardial infarction.

In the case of COX-2 inhibitors one sees a

reversible inhibition of COX-2. One also sees

variable degrees of inhibition of COX-1 but,

because of that non-linearity that I mentioned to

you in the relationship, effectively this makes

these drugs selective for COX-2 because you have no

inhibition of COX-1 dependent platelet function.

That brings me to the last topic that I

would like to address, and that is what about the

traditional NSAIDs? Well, here is one way of

comparing aspirin to a prototypic NSAID, ibuprofen.

You take healthy volunteers, you administer them

low dose aspirin to stead-state efficacy, or

ibuprofen 3 times a day to a steady-state effect,

and you look at the offset of effect on enzyme

inhibition and inhibition of function.

With aspirin you see sustained inhibition

over the 24 hours after stopping the drug. As you

would expect, with stopping ibuprofen you see

offset of this reversible inhibitor on the enzyme.

From whatever I have told you about that

non-linearity in the relationship, you are not

surprised to see a steeper offset of inhibition of

function.

Well, of course, we have no randomized,

placebo-controlled trials of traditional NSAIDs.

We have various overviews of the epidemiological

experience, with all the limitations of that

approach and we can see that ibuprofen looks like

it is not really altering cardiovascular hazard.

There seems to be a sort of 10 percent or so

reduction with naproxen, particularly 500 mg twice

a day which was the most commonly used dosage in

these studies.

Now, this would be like a dilute aspirin

effect and, obviously, has relevance to the

interpretation of studies like VIGOR and some of

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the experience with the etoricoxib that you will

hear about as to whether naproxen is actually

behaving like aspirin.

Well, I think actually the epidemiology is

entirely consistent with the clinical pharmacology

of naproxen. This elegant study was performed by

Patrignani. Again we are looking at the offset

action of aspirin and naproxen 500 mg per day

administered to steady state. We are looking at

inhibition of enzyme function, and we see with

aspirin exactly what we would have expected,

sustained inhibition. However, at the end of a

typical dosing interval for naproxen we see

heterogeneity of response. In fact, everybody is

at 95 percent or lower, suggesting that within the

dosing interval there is a variable degree of

cardioprotection afforded through this mechanism,

which would be consistent with the dilute aspirin

effect from the epidemiology.

This is a plot of the IC-50 for inhibition

of COX-2. This is inhibition of COX-1 in whole

human blood. As we move in this direction we are

getting more selective for COX-2. It brings us

back to a point that arose in Byron's study, and

that is that although there is a difference in

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potency, celecoxib and diclofenac look remarkably

similar.

I would also remind you that naproxen,

bearing in mind the Aleve study fiasco, is on the

other side of the line, just like ibuprofen is, and

exhibits preference for inhibition of COX-1.

Well, you have had a nice job giving you a

full data set, demonstrating that actually in whole

human blood diclofenac and celecoxib are

superimposable. So, I would contend that through

various lines of evidence diclofenac is probably a

selective COX-2 inhibitor like Celebrex.

Consistent with that is a pharmacodynamic

interaction where we showed that prior occupancy of

the COX-1 site by a typical mixed inhibitor like

ibuprofen would block access of aspirin to its

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target acetylation site. If we give aspirin and

ibuprofen chronically we actually see a pattern

that looks just like giving ibuprofen alone, an

onset of action and a steep offset of function.

However, if we substitute diclofenac for aspirin it

looks like giving aspirin alone, which is

consistent with the type of information you get

with a selective COX-2 inhibitor like rofecoxib or

celecoxib in this assay.

So, I think we can start thinking of

diclofenac as Celebrex with hepatic side effects.

It has the same selectivity in whole blood in

vitro. It has no pharmacodynamic interaction with

aspirin. It has no clinical interaction with

aspirin in the one epidemiological study which has

addressed this interaction with the two drugs.

Also, it is consistent with the superimposition of

the GI and cardiovascular events in the

retrospective look at CLASS in non-aspirin users.

So, I would suggest the two trials that

you will hear about, EDGE and the ongoing MEDAL,

are actually the first trials that are a comparison

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within the class.

Well, let's come back to this

relationship. I would remind you that while we

have very strong evidence for this being true, we

have almost no evidence that this is true. The

conjecture of this discordance underlies the

argument for the fact that we have a problem with

selective COX-2 inhibitors but, you know something,

we have a problem with all of these drugs which

clearly obscures the message. We have no evidence

for that and you will hear people parsing in

meta-analyses naproxen versus non-naproxen NSAIDs.

Well, I don't think that is a legitimate

lumping of non-naproxen NSAIDs, which is really

diclofenac plus ibuprofen in most instances. I

think it is as legitimate to consider them all

individually as it is to consider naproxen

individually.

So, could there be a hazard from a

non-naproxen NSAID like ibuprofen where there is

coincident inhibition of COX-1 and COX-2 over

typical multiple dosing interval? If there is a

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discordance in the relationship between inhibition

of enzyme function and inhibition of enzyme

product, then there might be a narrow part of the

dosing interval where there could be a potential

exposure to risk. But the likelihood of detecting

this notional risk would be much less than the

likelihood of detecting the clear evidence-based

risk of selective inhibitors of COX-2.

So, there is some suggestion that naproxen

achieves sustained platelet inhibition in some

individuals. I like to think of it as a dilute

aspirin. There is evidence that diclofenac is

Celebrex. There is evidence that ibuprofen may

undermine the benefit from aspirin, although that

is not yet answered one way or the other with a

controlled trial. And, I would say quite

forcefully there is no rationale for lumping

diclofenac and ibuprofen as non-naproxen NSAIDs in

meta-analyses and the like.

I am not sure when a canard becomes a dead

duck--

(Laughter)

--so I decided to dismiss some of the

things that I think are worth dismissing and call

them dead dragons. First of all, naproxen clearly

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is not the full explanation of VIGOR.

Here is another one that needs to be

chopped down, hypertension is not a different

mechanism.

There are a lot of off-target fantasies

being touted around at the moment, strange chemical

interactions that haven't actually been shown to

occur in vivo yet but are postulated as the

explanation for a drug-related rather than a

class-based effect.

Oddly, we never heard any of this

conjecture when we were considering how all the

drugs in this class afforded relief from pain and

inflammation.

Here is another nice notion that makes

clinical pharmacologists squirm in their seat, it

is just a matter of reducing the dose. Well, there

is a lot of interindividual variability in response

to COX-2 inhibitors and we all have our own

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dose-response curves. It has been an approach in

the past when a hazard emerges to suggest that in a

population sense one just cuts the dose--perhaps in

a population sense but it certainly does not

obviate the possibility of individual hazard.

Finally, if there ever was one, I think we

have certainly moved beyond the need for a trial of

a COX-2 inhibitor in patients with acute coronary

syndrome. Indeed, I feel that the evidence that

supports a trial in patients at high cardiovascular

risk to detect protection is scientific quite weak,

and in the face of an emergent hazard is ethically

questionable.

Indeed, in the case of mice if one

combines a thromboxane antagonist as a surrogate

for the suppression of thromboxane by low dose

aspirin with a COX-2 inhibitor, one doesn't see any

benefit in terms of atheroprotection, but what one

does see is the loss of the fibrous cap in the

combination and necrosis of the atherosclerotic

core, consistent with destabilization of the

plaque.

Finally, and you will be glad to know it

is finally, I would just like to mention a couple

of things relating to where we might go from here.

107

Well, I think clearly an easy thing to write down

and perhaps a more tricky thing to do is to exclude

patients at high intrinsic risk of thrombosis, and

you have heard my views on that. Dose reduction

alone is a simple message. It has a political and

legal appeal but in pharmacological terms it is

misleading.

I think we are likely to subject new drugs

that might be approved from this class to

significant hurdles before they are approved. It

seems logical to me that existing drugs in this

class should be subject to the same hurdles to

retain approval, particularly for extended dosing.

And, I think that frankly one should logically

restrict the duration of dosing until the

parameters of safety for extended dosing have been

established.

I mentioned interindividual variability,

and these are log scales but they illustrate

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looking at inhibition of COX-2 either in the

typical ex vivo assay or by excretion of

prostacyclin metabolite or inhibition of COX-1,

that with this sort of display of the data to

highlight it, there is considerable interindividual

variability of response. This is no surprise. It

is true of all drugs.

But perhaps we can exploit the biochemical

variability, the physiological response variability

and, indeed, perhaps some genetic markers such as

these polymorphisms associated with metabolism of

drug or these polymorphisms in cyclooxygenase-1 to

try and identify those patients at emerging

cardiovascular risk before they culminate in

events. So, you might say that the future of these

drugs or the challenge to the future of these drugs

is that if their value--and I believe they have

value as a class--is to be harvested, then to

manage the risk we have to actually move to an

example of personalized medicine.

One would want to obviously restrict these

drugs in some way to people who really needed them,

109

for GI reasons. We need to determine whether risk

transformation actually occurs during chronic

dosing and, if so, whether we can detect it. And,

it is likely, because we have so few events in any

one trial, we can only do this by a combined

analysis across the class in relevant trials.

Then, obviously, we would have to validate

prospectively such an index of emergent risk in a

prospective trial.

So, I really thank you for your patience

and I would like to conclude. Selective inhibitors

of COX-2 depress prostacyclin without a concomitant

inhibition of

thromboxane-A2. This can result in an augmented

response to thrombotic and hypertensive stimuli and

acceleration of atherogenesis in mice. Indeed, the

terrible beauty of this unfolding drama is how

faithfully the emerging clinical information has

fitted the predictable science, and that should

reassure us in terms of the likelihood that the

science can predict a way to conserve the value of

these drugs while managing the risk.

An increase in MI and/or stroke has been

seen at last count, as of yesterday, in 5

placebo-controlled trials with 3 structurally

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distinct COX-2 inhibitors. Given the bulk of

evidence, the mechanism-based evidence from mice

and people, the pharmacopeidemiology and this, it

seems to be that most rational people would accept

a class-based mechanism as they did for efficacy.

Finally, hazard would be expected to

relate at the individual level to the drug

selectivity attained in vivo, dose and duration of

exposure and to interindividual differences in drug

response. Thank you.

DR. WOOD: Thank you. Just before you sit

down, one thing you seemed to be saying is that we

should exclude patients at high risk. The point

estimate in the APPROVe trial for people with no

symptomatic history of heart disease is 1.6 so that

would be one way you would exclude people, I guess,

but the point estimate remains 1.6. Does that

bother you?

DR. FITZGERALD: No, as I alluded to, I

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think the nature of the information we have in the

APPROVe trial so far remains to be played out.

Clearly, there was an attempt to exclude people at

high cardiovascular risk but we all know that

people who are at risk slip through any exclusion

criteria. So, one question is, is all that we are

seeing people who, for one reason or another, are

predisposed to thrombosis and they are the people

that are having events? Or, are we seeing people

who through atherogenesis transform their risk?

Or, are we seeing some combination of the two? I

don't think we know the answer to that.

DR. WOOD: We are running behind time so

we will call a break right now and give everybody a

moment or two to get out. Before we do that, Dr.

Galson wants to say some things and then, whenever

he is finished, we will take a break and we will

reconvene at 10:15. So, those of you who don't

want to hear what Dr. Galson has to say can get out

now and the rest--

DR. GALSON: No, no, just a very brief

announcement, and that is we have a space problem

112

in this facility. There are more people than we

have seats for. So, we have established a live

video feed in our advisors and consultants

conference room on the FDA campus at 5630 Fishers

Lane, designed for FDA employees only. So, FDA

employees who may be sitting in the public section,

I strongly urge you to please move to that area to

make more room for the public and, of course, you

will need your FDA ID badge to get into that space.

But it is ready now and if you could move at the

break, it would be great. Thanks.

DR. WOOD: Okay, we start promptly at

10:15.

(Brief recess)

Committee Questions to Speakers

DR. WOOD: Let's get started and get the

two previous speakers up for questions, Dr. Cryer

and Dr. FitzGerald. Yes, Susan?

DR. MANZI: I have a question for Dr.

FitzGerald. This is really in reference to your

suggestion that we exclude people with high

thrombotic potential. I think there is clearly

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evidence that the natural aging process is

associated with less effective fibrinolytic system,

really increased thrombogenic potential with high

levels of fibrinogen, PI-1 platelet aggregation,

and considering that the elderly population is a

huge target for non-steroidals, would you consider

age as a risk?

DR. FITZGERALD: Well, I think, as you

indicate, lots of things happen as we get older

including the complexity of administering drugs and

it ultimately culminates in death. But I think the

issue of determining cardiovascular risk is

actually a very challenging one because it includes

continuous and discontinuous variables. It is easy

to say if you have had a heart attack or a stroke

you are statistically at greater risk of having

another one. It is harder to say that at an

individual level, somebody who hasn't had a heart

attack or a stroke has a cluster of variables that,

in the eyes of their physician, determines their

cardiovascular risk.

With some of the discontinuous variables

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like some of the genetic mutations we can have an

attributable risk that we can measure but, again,

that can play geometrically into other small but

absolute risks. So, unfortunately, I think it is

where the art and science of medicine intersect.

DR. WOOD: Richard Cannon?

DR. CANNON: You asked my question.

DR. WOOD: Joan Bathon?

DR. BATHON: We know that patients with

rheumatoid arthritis and other inflammatory

conditions are at higher risk for developing acute

MIs and strokes, and these are the very patients

who are taking NSAIDs chronically. This is a big,

confounding problem in interpreting some of the

data and I am wondering if you have any thoughts.

The reigning theory is that there is more

atherosclerosis and RA due to vascular inflammation

but I am wondering if you have any thoughts about

whether the NSAIDs might be the sole contributor to

increased events in these folks.

DR. FITZGERALD: Right. As I indicated,

through a COX-2 inhibitory mechanism one would

115

anticipate that the clinical substrate of

underlying cardiovascular risk would be one of the

modulators of either individual hazard or the ease

of detecting hazard with this crude detector system

we call clinical trials.

As you know, the relative risk of heart

attack or stroke and RA is increased by about 50

percent on average compared to RA or no arthritis.

As a population that would be one of the

ingredients predisposing towards emergence of a

hazard. Of course, within that population there is

a very substantial interindividual variability

conditioned by many other factors that impinge on

cardiovascular risk. So, at the time when we were

naval gazing, looking at the contrast between CLASS

and VIGOR, amongst the many things that were

discussed was whether the preponderance of RA

patients in VIGOR versus the preponderance of OA

patients in CLASS may have been a factor. I think

it is reasonable to say it may have been a factor

but I don't think we can really take it beyond

conjecture in light of any current evidence that I

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am aware of.

DR. WOOD: Garret, let's cut to the chase.

Is what you are saying--that was such a long

answer, I am not sure what it meant!

(Laughter)

Is what you are saying that you think that

COX-2 inhibitors have an effect here that the most

selective, so-called non-selective like diclofenac

and naproxen may also have an effect, and the

non-selective, non-steroidals do not have an

effect, or at least have not been shown to have an

effect? Is that your position? If it is not,

correct that.

DR. FITZGERALD: No, I think that is

pretty true.

DR. WOOD: So, that is what you wanted us

to take away from all the mice and stuff, is it?

(Laughter)

DR. FITZGERALD: You have such a way with

words!

DR. WOOD: Because I am a Scot.

(Laughter)

DR. FITZGERALD: You are very economical

with them.

DR. WOOD: Exactly.

117

DR. FITZGERALD: Unfortunately, reality is

conditioned by a lot of different factors. I think

one of the things, both in terms of benefit and

hazard, we have paid insufficient attention to is

variability in drug response between individuals,

and I think actually one of the things that has got

us to today is not paying enough attention to that.

But I think one of the ways out of the challenge

that faces us today if we are to conserve the value

is to exploit that variability in imaginative ways.

So, I think that that is a tractable issue.

DR. WOOD: Okay. Dr. Abramson?

DR. ABRAMSON: Yes, Garret, even though

you are under the weather I wanted to follow-up

with Dr. Wood's question and put you on the spot a

little bit. It is partly definitions because we

use the word NSAIDs which we elect by inhibiting

COX-2s. Based on your presentation, it is clearly

a continuum and there are highly selective drugs.

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There is a cluster of five or six drugs, like

diclofenac, that are in vitro at least comparably

COX-2 selected. Then you have these very complex

stories of what one might call functional COX-2

selectivity, which is based on the fact that the

COX-1 inhibition may be more transient effectively

than a more prolonged COX-2, which would give you

imbalance. So, I guess the "put on the spot"

question is what do you define as the class? How

do you propose we should think about this continuum

and personalize medicine?

DR. FITZGERALD: I think you are right. I

would remind all of us that COX-2 inhibitors are

NSAIDs; they were never anything else. They are

NSAIDs that are selective for COX-2 and, as you are

rightly pointing out, this is a continuous variable

and within each drug, as I tried to point out,

there is the same continuous variable between

individuals. So, my 800 mg of Celebrex may be your

200 mg of Celebrex for example.

So, I think all I am trying to raise is

that there is clearly a mechanism which reflects

119

the selective inhibition of COX-2. That selective

inhibition of COX-2, in terms of hazard, is

modulated by COX-1 inhibition that occurs at the

same time if it is sufficient to inhibit platelet

activation for example. So, I can't simplify that

because I believe there is that complexity, but

within the class--and I am referring to the class

as the mechanism by which selective inhibition of

COX-2 is attained--I think there is clearly a

mechanism that explains everything that we have

seen.

At the individual level this issue of a

continuum comes into play because not only is there

a continuum in terms of drug action and the degree

of selectivity attained in an individual, but also

many other factors impinging on cardiovascular risk

that condition the emergence of that hazard at the

individual level.

DR. WOOD: Steve?

DR. NISSEN: Yes, I have two quick

questions. You know, I want to talk with you a

little bit more about this issue of dose

120

dependency. I want to make sure we didn't

misunderstand you. What you are saying I believe

is that there is sufficient overlap in the

biological effects that a low dose in one patient

may be equivalent to a high dose in another. But

you didn't mean to suggest that we don't see

evidence, as I think we do see from the trials,

that the higher the dose of the drug on a

population basis, the more we see--

DR. FITZGERALD: No, no, clearly there is

evidence of a dose-related effect in populations.

I am talking more at the individual level, that the

assurance to a population based on population type

evidence that all you need to do is reduce the dose

and you, as an individual, will be protected from

hazard is a false one.

DR. NISSEN: Yes, but it is quite relevant

obviously to our discussions on Friday because one

of the strategies to limit risk with this class of

drugs is to limit dose--

DR. FITZGERALD: Sure.

DR. NISSEN: --and it may not make the

121

hazard go away but it may make it smaller, and we

are going to have to explore that in some detail

before we finish.

DR. FITZGERALD: Well, I think that

distinction between reducing it as opposed to

making it go away and the distinction between

population hazard and individual hazard is an

important one. It is the reason that I raised that

particular point because I think that had not

received sufficient attention.

DR. NISSEN: The second question I have

is, you know, we have very few direct head-to-head

trials amongst the so-called COX-2 inhibitors, but

we do have for hypertension and there seemed to be

really pretty striking differences in the

hypertensive response between rofecoxib and

celecoxib. Would your point of view be that those

differences are strictly a matter of COX-2

selectivity of the two drugs, or do you think that

it is possible that there is some dissociation in

the hypertension response?

DR. FITZGERALD: I would make two points.

122

I would say, first of all, that in that particular

comparison, again on average, we would anticipate

that selectivity and duration of action would be

confounded and it would be impossible to really

segregate the two.

The second is that, in a sense you pressed

my button, I believe we have not performed the

studies in hypertension that let us address the key

questions that are on the table, and that is

standardizing for the degree of selectivity

attained or the degree of COX-2 inhibition attained

do drugs come apart? That question has been on the

table since the mouse studies of Breyer and

Kaufman, and perhaps the first signal of that is

the epidemiological overview analysis from

Australia. But, in fact, we have never performed a

study to address the hypothesis and I think it is

timely that we do.

DR. WOOD: I see Dr. Cryer. Did you want

to say something?

DR. CRYER: Dr. Cryer has a question.

DR. WOOD: Go ahead.

DR. CRYER: Garret, you clearly made the

point that diclofenac appears to have some COX-2

selectivity. In fact, I think you called it

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celecoxib with hepatic side effects. You also made

the point that we should subject drugs already

approved to the same requirements. So, the

specific question I have for you is are you

suggesting that we should evaluate diclofenac as

well for its potential cardiac effects?

DR. FITZGERALD: Yes, I think there are

quite a few unanswered questions on the table. I

think clearly the diclofenac question is one of

them. I think there are other drugs that fall into

potentially the same situation, like meloxicam and

nimesulide which, again, based on the IC-50

comparisons look awfully similar to diclofenac and

Celebrex but we just don't have the information

even at a more fundamental level than outcome

studies. So, I think those questions are on the

table.

The reason I made the comparison between

retention of approval and gaining approval is that,

124

to me, if we do actually have to address some

questions to determine the parameters within which

drugs in this class can be administered safely and

that would be a hurdle that any new drug would be

required to overcome, in logic to me, it would be

sensible to apply the sam standard to the extended

dosing of drugs that already are on the market as a

condition of their retention of approval.

DR. WOOD: Dr. Shafer?

DR. SHAFER: Yes, this is the question we

just talked about briefly at the break, but as you

pointed out, low dose aspirin gives you 100 percent

inhibition of COX-1. One might think then that low

dose aspirin plus a COX-2 selective antagonist

might give you the same risks as a non-selective

NSAID. Yet, in all the studies where they had

aspirin present and they showed a CV risk, when

they stratified by aspirin, among aspirin users the

hazard didn't go away. Now, what did happen is

that some statistically significant hazards became

non-statistically significant hazards but the

actual magnitude of the hazard, at least as far as

125

I can tell in all the studies that I looked at,

didn't change. I am having trouble understanding

how that is consistent with the whole thing being

the COX-2 imbalance.

DR. FITZGERALD: Right. So, one important

missing dimension in your question is time. One of

the key ingredients of aspirin's ability to afford

cardioprotection is that while it inhibits COX-1

like a ibuprofen does, it does it molecularly in a

quite distinct fashion. This results in sustained

maximal inhibition throughout the dosing interval.

By contrast, in the typical non-steroidal you are

in the red zone for platelet inhibition transiently

in the dosing interval. Therefore, one would not

expect the combination of, say, ibuprofen with a

COX-2 inhibitor to be similar to aspirin with a

COX-2 inhibitor in terms of cardiac protection.

DR. SHAFER: Doesn't that head in the

opposite direction?

DR. FITZGERALD: In terms of which?

DR. SHAFER: The fact that the aspirin's

effect is sustained because, you know, it is

126

covalently bonded there--the fact that you are

having a sustained aspirin effect means that you

should absolutely--I mean, it would seem to me that

that would really try to make the COX-2s look--

DR. FITZGERALD: Well, I will come back to

what I said during my talk, and that is that I

think a real mistake is to think of this as a yin

and yang type of seesaw arrangement between

thromboxane and prostacyclin. We know that

prostacyclin acts as a general biological

constraint on anything that will activate

platelets, elevate blood pressure, accelerate

atherogenesis, and so on. So, a priori we would

expect that aspirin would damp rather than abolish

the signal.

Now, I would contend that, first of all,

we have never formally addressed this and, in terms

of the trials that have events, although we have

attempted to look at the relationship to aspirin

the numbers are so vanishingly small that it is

really conjecture. But one would expect a signal

to be damped. Indeed, from some of the

127

epidemiology that is sort of what we are seeing,

you know, a signal goes away at 25 mg of rofecoxib

if they are on aspirin but not at 50, that sort of

stuff. But I would be the first to agree that this

is really a crude stab at the issue that you are

trying to get at.

DR. WOOD: Yes, and these studies did not

stratify by aspirin use. They were post hoc

analyses in the majority of cases. Dr. D'Agostino?

DR. D'AGOSTINO: I would like to go back

to the question that was asked right after the

break about the age. If you tried to say, well,

the perfect way of doing this is to make sure that

people at high cardiovascular risk aren't going to

take the drug, then males over 60, for example, are

almost certain to be excluded. How realistic--

DR. FITZGERALD: Certainly I am not trying

to be dictatorial--

DR. D'AGOSTINO: No, no, your suggestion

is fine, it is just how do you implement it?

DR. FITZGERALD: Yes, so I think all one

can really hope to do is set the bar at some low

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level and then signal it in a way that is explicit

and leave it to the patient-doctor relationship to

divine the individual behavior. I would love to

say there is a different way of doing it but, yes,

as we get older our cardiovascular risk goes up and

multiple other things. But that is where the

balance against value comes into play. As we get

older with get arthritis; as we get older we get

more GI bleeds on non-steroidals.

DR. WOOD: Okay, we got it. Let's not go

too far there. One more question from Dr.

Gibofsky.

DR. GIBOFSKY: Dr. FitzGerald, in response

to Dr. Nissen, I believe, you raised the notion and

asked us to think about population variation as a

factor in addition to individual variation. One of

the things that I am struggling with is exactly

that, and one of the concerns I have is to what

extent then can one extrapolate observations in

populations of patients who may have Alzheimer's

disease or who may have taken a drug for polyp

prevention to the population of patients who are

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taking the drug for their arthritis?

DR. FITZGERALD: Well, I think in a way

this whole cathartic experience is a cardinal point

in the way that we look at drug development. You

know, we have talked about individualized medicine

for a long time and never really had to care, and

here is a situation where we actually do have to

care and it is at the forefront of how we may or

may not be able to find a way out of this. You are

absolutely right, there may be factors associated

with an incident disease which is under study which

modulates the importance or non-importance of the

signal; modulates the way that drugs are

metabolized; may be associated with genetic

variance that influence outcome as well.

DR. WOOD: Any other questions for the

last two speakers?

(No response)

In that case, let's move on to the

sponsor's presentation. I understand Dr. Kim is

going to present first.

Sponsor Presentation: Vioxx (Rofecoxib)

DR. KIM: Mr. Chairman, members of the

advisory committee and FDA and ladies and

gentlemen, my name is Peter Kim and I am President

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of Merck Research Laboratories. My colleagues and

I welcome the opportunity to present information at

this advisory committee meeting, and I would like

to begin with just a few introductory comments.

As you will hear, to determine both its

risks and its benefits, Merck extensively studied

Vioxx before seeking regulatory approval to market

it, and we continued to conduct clinical trials

after the FDA approved Vioxx.

As Merck continued to monitor the

cardiovascular safety of Vioxx, we recognized the

value and interest in obtaining additional

cardiovascular safety data on this medicine. After

deliberations with numerous outside advisors, Merck

developed and discussed with FDA a plan to

prospectively analyze cardiovascular event rates

from 3 large placebo-controlled trials.

It was preliminary information from one of

these long-term trials, the APPROVe trial, that led

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to Merck's decision to voluntarily withdraw Vioxx.

When Merck made the decision to voluntarily

withdraw Vioxx from the market, we stated that we

believed that it would have been possible to

continue to market Vioxx with labeling that would

incorporate the data from the APPROVe trial. We

concluded, however, based on the science available

at that time, that a voluntary withdrawal of the

medicine was the responsible course to take given

the availability of alternative therapies and the

questions raised by the data.

Since that time new cardiovascular safety

data for other COX-2 inhibitors have become

available and were reported on just this week in

the New England Journal of Medicine. We look

forward to hearing and seeing presentations of

these data and to hearing discussions and

interpretation of them during this advisory

committee meeting. Thank you, and now I would like

to turn the podium over to Dr. Ned Braunstein.

DR. BRAUNSTEIN: Good morning, Dr.

Chairman, members of the availability committee,

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FDA, I am Dr. Ned Braunstein, Senior Director of

Merck Research Labs.

Millions of patients suffer with painful

arthritis and need effective therapies. The recent

data that have come to light on NSAIDs and

selective COX-2 inhibitors raise many questions.

Patients and physicians need information and

guidance on the use of these effective medicines

that we know are not without risk. We recognize

that the cardiovascular safety of the NSAID and

coxib classes is an important public health issue

and we welcome the opportunity to present this

advisory committee information that we believe will

help the FDA and the committee in their work in

developing recommendations in the best interest of

patients. To assist us today, we have

brought along as consultants Dr. Marc Hochberg from

the University of Maryland School of Medicine, Dr.

Marvin Konstam from Tufts University School of

Medicine, and Dr. Loren Laine from the University

of Southern California School of Medicine. They

are here to help answer your questions and

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otherwise assist the committee.

Merck's objective today is to provide you

with data on rofecoxib and review how those data

affected our assessment of risk/benefit over time.

The presentation will focus on GI and

cardiovascular data or rofecoxib, starting with the

data in the original NDA and proceeding through the

voluntary withdrawal of Vioxx and the APPROVe data.

In talking about the data, I will try to

highlight some of the methodology we used to

obtain, adjudicate and analyze cardiovascular data,

and I will spend some time discussing the

considerations that went into designing a study of

cardiovascular outcomes with rofecoxib as the

information may be useful in considering similar

studies.

The presentation of data will end with a

presentation of new exploratory analyses that we

have performed and I will follow with a

risk/benefit assessment, the review the major

outstanding questions of the day, and the next

steps we are taking and/or propose.

I will start with an overview of the

issues we face today. Starting with the GI tract,

as you have already heard, NSAID gastropathy has

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been the most common cause of drug-related

morbidity and mortality in industrialized nations.

The development of rofecoxib was based on the

desire to limit and reduce this problem.

You have also heard already about the

COX-2 hypothesis. I just want to emphasize two

points. First, all NSAIDs inhibit COX-2 in a

dose-dependent manner and selective COX-2

inhibitors do not inhibit COX-1 at clinical doses.

The rofecoxib develop program confirmed

the COX-2 hypothesis and demonstrated a reduction

in clinical upper GI events, that is, actual GI

outcomes with rofecoxib versus non-selective

NSAIDs. This was shown for rofecoxib in the VIGOR

study and, based on that, rofecoxib was the only

selective COX-2 inhibitor with a modified GI

warning. Since that time we have accrued

additional information that extend the GI benefit

of rofecoxib and have shown that the reduction in

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clinical upper GI events is consistently seen with

rofecoxib versus diclofenac, ibuprofen and

naproxen.

Although rofecoxib is associated with a

reduced rate of upper GI events compared to these

NSAIDs, rofecoxib is not placebo. In addition to

the upper GI findings, we have also observed a

reduced incidence of lower GI events compared to

naproxen in VIGOR, So, although there remain some

unanswered questions, for example for aspirin

users, the GI benefit for rofecoxib is clear.

As we have also learned, there are

important cardiovascular findings with these drugs

and perhaps with the larger class of NSAIDs. In

1998 Merck had implemented an adjudication standard

operating procedure to methodically study the

cardiovascular effects of its COX-2 selective

inhibitor drugs in clinical trials. Clinical data

on thrombotic cardiovascular events with rofecoxib

show an increased risk of events relative to

placebo. This was seen in APPROVe with

long-standing use.

In contrast to the difference seen from

placebo, we have not observed a difference in

cardiovascular event rates between rofecoxib and

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NSAIDs other than naproxen. Long-term data,

however, are limited. In contrast to what had been

observed versus the placebo, the increased risk

compared to naproxen appears after short-term use.

I think it is worth noting that similar

observations have now been made with other

selective COX-2 inhibitors. We believe that these

new data on rofecoxib and COX-2 inhibitors raise

several questions about these drugs important to

the public health.

First, based on the data available, how do

we currently assess the relative risks or benefits

of selective COX-2 agents? I cannot speak to the

data on all of these drugs but I can talk about

rofecoxib. Clearly, there are risks versus

placebo, and not just cardiovascular risks.

however, placebo is not a choice for patients with

chronic arthritis and pain who require chronic

NSAID therapy. For these patients the question is

137

the risk and benefit of selective COX-2 agents

versus non-selective NSAIDs. I will present data

on this question related to the GI and

cardiovascular safety of these drugs.

Second, can we identify factors associated

with the observed increased risk for thrombotic

cardiovascular events with these drugs? Although

we do not have definitive answers, I will present

the data that we have.

Finally, is the increased thrombotic

cardiovascular risk that we have observed with

rofecoxib indicative of a larger class effect of

COX-2 inhibitor? If so, how big is the class?

That is perhaps the central question of this

meeting. At present we do not know the long-term

cardiovascular effects of traditional NSAIDs.

Other than aspirin, these agents have not been

studied long term versus placebo. We believe that

long-term studies are needed and, in particular,

comparator studies between selective COX-2 agents

and non-selective agents to better understand the

relative risk/benefit profiles.

I will now turn to a presentation of the

data, and will do so chronologically as it

highlights the magnitude of data that were

138

ultimately needed to dine the long-term

cardiovascular risks of selective inhibitors. This

information may be useful regarding the development

of future COX-2 inhibitors and in informing this

committee on its decisions.

I would like to start by reviewing the

initial GI and cardiovascular data that were in the

new drug application. There were two main clinical

components of the GI safety program in the original

rofecoxib NDA, the GI endoscopy studies, which are

described in your background package, and a pooled

analysis of clinical upper GI events, shown here.

Investigator reports of suspected upper GI

perforations, ulcers or bleeds or PUBs were

adjudicated by an external committee of blinded

adjudicators, and the confirmed events formed the

basis of this prespecified analysis.

The Kaplan-Meier plot of the data is shown

on this slide. Throughout my presentation I will

139

be showing several of these so I would like to take

some time to walk through this first one. Time is

shown on the X axis, and below that the number of

patients remaining in the studies at the different

time points. Cumulative incidence is shown on the

Y axis and also shown are summary statistics,

relative risk confidence interval and a p value.

At the time of the original NDA a

significant difference was demonstrated between

rofecoxib and the combined NSAID comparators,

mostly data on ibuprofen and diclofenac. The

relative risk of 0.45 corresponded to a 55 percent

risk reduction with rofecoxib and, thus, we believe

that we had established a GI safety advantage over

these older NSAIDs.

These are the cardiovascular safety data

from the OA development program. Rates per 100

patient years of investigator reports or cardiac,

cerebrovascular and peripheral arterial and venous

serious thrombotic events were examined both in

aggregate, as shown on this slide, and also in

individually, as shown in your background package.

140

As you can see, then rates were similar for

rofecoxib compared to the NSAIDs diclofenac,

ibuprofen and nabumetone and for rofecoxib compared

to placebo.

These cardiovascular and GI data, along

with our other data, were submitted to FDA in 1998

as part of the new drug application for rofecoxib.

They were discussed at the April, 1999 Arthritis

Advisory Committee and the FDA concluded that there

was a favorable risk/benefit profile for rofecoxib,

and rofecoxib was approved in May of 1999.

Around that time we were completing our

Phase III osteoarthritis studies. The results of

studies that we were doing in collaboration with

Dr. Garret FitzGerald became available, and he has

already told you about those and the hypothesis

that selective COX-2 inhibitors could be

prothrombotic by inhibiting systemic prostacyclin

production without inhibiting thromboxane

production.

In addition to that hypothesis, there were

other hypotheses being discussed in the clinical

141

literature and in the basic science literature at

that time, including the possibility that NSAIDs,

through their effects on COX-1, might decrease the

risk of cardiovascular events. Another was that

perhaps by inhibiting COX-2 there may be a

beneficial effect by inhibiting the enzyme in

atherosclerotic plaques.

Merck recognized that it would be

important to continue to acquire cardiovascular

data with its selective COX-2 inhibitors. To

address these hypotheses, in 1998 Merck initiated a

vascular event adjudication standard operating

procedure to standardize the evaluation of

cardiovascular events in all of its COX-2 inhibitor

studies. Adjudication of events was based on

predefined criteria. Under the standard operating

procedure all source documentation on events was

collected and the data were then reviewed by

blinded, external adjudication committees. With

this procedure, over 92 percent of cases had

sufficient data for definitive determination and

adjudication. Thus, we can be confident in the

142

quality of the data. By eliminating questionable

events, we would amplify and improve the clarity of

any signal if present. The standard operating

procedure called for a pooled analysis of events

across all studies to improve the precision of what

would be obtained from individual studies.

In order to obtain more data on the effect

of rofecoxib on GI outcomes Merck initiated the

Vioxx GI Outcomes Research, or VIGOR, study in

January, 1999. GI events would be adjudicated

using the same approach as had been done for the

osteoarthritis studies. The cardiovascular events

in VIGOR fell under the new standard operating

procedure.

VIGOR was designed to definitely assess

the GI components of the COX-2 hypothesis. It was

conducted exclusively in rheumatoid arthritis

patients because Merck believed that a GI benefit

had already been established in osteoarthritis

patients. Rofecoxib of 50 mg, 2-4 times the

recommended chronic dose, was chosen to provide a

rigorous assessment of safety. We chose as a

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comparator naproxen 500 mg twice a day to extend

the GI findings to an additional NSAID and because

that was the most commonly prescribed NSAID regimen

in rheumatoid arthritis. Patients using aspirin

were excluded to avoid COX-1 inhibition as this

could confound the ability to rigorously assess the

COX-2 hypothesis.

The primary endpoint was reduction

confirmed clinical upper GI events. There were 56

events on rofecoxib and 121 on naproxen. The time

to event curve separated early and they continued

to separate, and the relative risk of 0.46

corresponds to a 54 percent risk reduction with

rofecoxib. The p value, as you can see, was highly

significant. A similar GI benefit was seen with

confirmed complicated events, and in a post hoc

analysis for lower GI events.

A second finding in VIGOR was the

difference in the rates of thrombotic

cardiovascular events between the two treatment

groups. There was a relative risk of 2.4 for the

confirmed events, as shown here. The p value,

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again, was highly significant.

Examination of the individual types of

events broken down by vascular bed, cardia,

cerebrovascular and peripheral shows that the

difference between treatment groups was largely

driven by the difference in myocardial infarction,

20 on rofecoxib and 4 on naproxen. Of note, there

were similar numbers of patients with strokes in

the two groups.

Additional exploratory analyses were

undertaken to better understand these

cardiovascular findings. I will focus on the types

of analyses that I will show later for APPROVe. In

VIGOR the use of 50 mg, a dose 2-4 times the

recommended approved chronic doses, was associated

with a higher incidence of hypertension adverse

experiences than with naproxen. In analyses

described in the background package the relative

risk of events was similar in patients with or

without increases in blood pressure during the

study. The relative risk of events was also

similar in patients with or without baseline risk

145

factors for cardiovascular risk.

Finally, multiple analyses were performed

to examine the patterns of risk and relative risk

over time, both by Merck and the FDA. Merck's

interpretation was that there was no significant

increase in relative risk over time for rofecoxib

versus naproxen. However, the FDA felt that a

change in relative risk over time could not be

excluded.

Because VIGOR did not have a placebo

control, we turned to other data from other studies

to better understand these results. Merck had

initiated a program to assess the ability of

rofecoxib to delay the onset of Alzheimer's disease

in patients with minimal cognitive impairment or to