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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
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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
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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
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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
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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
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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
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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
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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,
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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
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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
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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,
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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
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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
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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
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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
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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
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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.