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
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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
3
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
7
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
8
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,
9
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
10
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
14
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
15
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
16
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
17
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
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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
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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
20
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
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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
22
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
23
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
24
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
25
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
26
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
27
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
28
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
29
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
30
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
31
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
32
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
33
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,
34
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
35
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
36
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,
37
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
38
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
39
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
40
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
41
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
42
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
43
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
44
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
45
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
46
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
47
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
48
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
49
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
50
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,
51
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
52
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
53
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
54
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
55
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
56
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
57
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
58
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
59
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
60
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.
61
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
62
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
63
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
64
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
65
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
66
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
67
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
68
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
69
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
70
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
71
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,
72
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
73
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
74
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
75
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
76
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
77
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
78
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
79
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
80
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
81
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
82
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
83
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,
84
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
85
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
86
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
87
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
88
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
89
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
90
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
91
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
92
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
93
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
94
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
95
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
96
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
97
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.
98
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
99
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
100
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
101
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
102
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
103
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
104
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
105
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
106
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
108
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
110
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
111
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
113
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
114
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
116
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.
118
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
123
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
128
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
129
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
130
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
131
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,
132
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
133
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
134
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
135
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
136
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
143
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,
144
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
slow the progression of Alzheimer's
disease. In
these studies, rofecoxib 25 mg was
compared to
placebo in an elderly population.
An initial review of the
cardiovascular
data, in March, 2000 when the VIGOR
results were
first learned, did not show an
imbalance. In a
subsequent review, undertaken in
September, 2000,
146
in advance of the VIGOR advisory
committee, which I
will show you next, at that time there were
over
2000 patients enrolled, with a median
duration of
therapy of approximately one year.
The analyses at that time were
based on
investigator-reported events since at
that time few
had been adjudicated. Subsequent analyses that I
will show using the adjudicated data were
consistent with these initial
analyses. Clearly,
there was no evidence to suggest an
increased risk
with rofecoxib based on the aggregate
endpoint
shown on this slide, or based on the
analysis of
individual type of events such as
myocardial
infarction or stroke shown in the
background
package.
Consistent with the approach
envisioned in
the adjudication SOP, we also performed a
pooled
analysis of all the available
cardiovascular data
to obtain more precise estimates of the
relative
risk for rofecoxib versus each of the
various
comparators. The pooled analyses include all
randomized, controlled trials from Phase
IIb
147
through our Phase V postmarketing trials
of 4 weeks
or longer duration that had been
completed by
September, 2000 and also included the
Alzheimer's
data that I just showed you.
Studies were included if there
was a
placebo or an NSAID comparator. For the pooled
analysis we prespecified to use the
anti-platelet
trial as collaboration combined endpoint
of
myocardial infarction, stroke and
vascular death.
There were several reasons for this
choice. First,
the rofecoxib pooled analysis included
data from
studies that antedated the adjudication
SOP.
Investigator reports of the APTC
endpoints had the
highest confirmation rates in the studies
that were
adjudicated so restricting the analyses
to these
events ensured consistency among the
data. Second,
the APTC combined endpoint was a standard
and would
allow comparison to other published
reports. The
analysis pooled double-blind patient
level data
stratified by disease. In September, 2000 there
were data from over 28,000 patients and
over 14,000
patient-years of exposure.
In the analysis for the three
data sets,
placebo, non-naproxen NSAIDs and naproxen
controlled data, a difference was only
observed in
148
the naproxen data set. It was, therefore,
considered not appropriate to combine the
three
data sets as this would tend to obscure
the
difference from naproxen.
In our plots the triangle
points to the
estimate of relative risk and the size of
the
triangle is proportionate to the overall
exposure.
The 95 percent confidence interval is
shown as a
horizontal line, and the same information
is
provided numerically along with the numbers
of
events in each data set.
In the placebo and non-naproxen
NSAID data
sets the data do not suggest an increased
risk
standard rofecoxib. The data in the naproxen set
were largely driven by the VIGOR data
and,
consistent with VIGOR, there was an
increased risk
for rofecoxib compared to naproxen. The 95 percent
confidence interval did not cross 1,
consistent
with the statistically significant
difference.
Our conclusions: There was a clear
evidence for GI safety benefit of
rofecoxib
compared to non-selective NSAIDs. Because the data
did not suggest increased risk of
cardiovascular
events with rofecoxib compared to placebo
or
non-naproxen NSAIDs, we believe that the
weight of
149
the evidence was most consistent with
naproxen
having provided a cardioprotective
benefit in
VIGOR.
Data to support that naproxen 1000 mg can
provide sustained anti-platelet effects,
as well as
animal data with naproxen and clinical
data on
agents with similar properties are all
provided in
the background package. Subsequent data with other
selective COX-2 inhibitors would also
show a
cardiovascular difference from naproxen
while
having similar cardiovascular events with
non-naproxen NSAIDs.
The Arthritis Advisory
Committee agreed
that the VIGOR study had shown a GI
safety benefit
for rofecoxib compared to naproxen. With regard to
the cardiovascular data, they determined
that the
results were inconclusive. They recommended that
150
both the GI and cardiovascular data be
described in
the rofecoxib label. Those recommendations were,
indeed, reflected in the approved
labeling. There
is now a modified GI warning
acknowledging that the
risk of GI toxicity with rofecoxib 50 mg
once daily
is significantly less than with naproxen
500 mg
twice daily.
There was a new cardiovascular
precaution
which provided the cardiovascular results
from
VIGOR and from the Alzheimer's disease
studies
which concluded that the clinical
significance of
the cardiovascular findings were
unknown. The
specific precaution stated that caution
should be
exercised when Vioxx is used in patients
with a
medical history of ischemic heart
disease.
Finally, because there were
dose-related
trends and NSAID type adverse experiences
with
rofecoxib 50 mg and no greater efficacy
at 50 mg
compared to 25 mg, the new label further
emphasized
that the chronic use of rofecoxib 50 mg
was not
recommended.
I would like to turn now to the
period
151
starting after we learned the results of
VIGOR up
to the unblinding of APPROVe, and I will
focus on
the unique information that Merck can
provide to
this committee, information on our
approach to the
design of a study of cardiovascular outcomes
that
we implemented in 2002, and the final
data from our
programs in arthritis and Alzheimer's
disease that
were completed in this time frame. I will briefly
touch on data that others will be
presenting or
have presented, such as epidemiology
studies and
the ongoing preclinical work, and will
end this
section of the presentation with our
assessment of
the data available before APPROVe.
In considering outcome study
designs, we
recognized two different approaches we
could take.
Each had different merits and would
answer
different questions. The first would be to perform
an NSAID-controlled study. This could involve
arthritis patients so we could study the
patients
in whom the drug was indicated, knowing,
however,
that a placebo control would not be
appropriate in
a several-year study of patients who
require
152
chronic NSAIDs, and the use of chronic
NSAIDs over
several years was not appropriate in
patients who
did not have that need.
The alternative was to do a
study versus
placebo.
Obviously, this would preclude the
ability to study patients with chronic
arthritis.
So, the applicability of the finding to
arthritis
patients would need to be inferred. Despite this
potential limitation, we decided for
rofecoxib to
answer the question for difference from
placebo.
I think it would be useful to
discuss with
this committee how bit these studies need
to be.
As we all know, it is easier to prove a
difference
than to prove similarity. In order to exclude even
a 30 percent increased risk with 95
percent
confidence and with 90 percent power, you
need data
on over 600 confirmed events. Based on anticipated
event rates and typical dropout rates on
our
studies, this would require enrolling
approximately
25,000 patients for a study design to run
over
about 3 years. To exclude a 20 percent increased
risk you would need approximately 1300
events and
153
over 60,000 patients. To exclude a 10 percent risk
you would need approximately 4800 events
and over
200,000 patients in the studies.
We considered several
placebo-controlled
designs.
One study in acute coronary syndrome was
rejected for a variety of reasons after
extensive
discussions with our consultants. First, these
unstable patients are at particular risk
for bad
outcomes associated with GI or
renovascular effects
known to be present with rofecoxib, and
considering
the unknown benefit this raised concerns.
Second, these patients would
all need to
be taking aspirin and, as you recall, one
of the
hypotheses at the time, and it still
continues to
be a hypothesis, was that aspirin would
abrogate
any increased cardiovascular risk of
selective
COX-2 inhibition and, thus, a negative
finding
would not have answered the question
raised by
VIGOR.
However, the emerging data on
possible
chemopreventative benefits of COX-2
inhibitors and
the extending database that we had of
154
chemoprevention studies with rofecoxib
versus
placebo provided an alternative means to
address
this question. In addition, these patients present
a broad spectrum of cardiovascular risk
similar to
the arthritis patients in whom rofecoxib
was being
used.
Thus, it was decided to develop a study of
cardiovascular outcomes for rofecoxib
based on a
combined analysis of placebo-controlled
chemoprevention studies.
The APPROVe study comparing
rofecoxib 25
mg to placebo had already been initiated
during
2000 and a second study, also comparing
rofecoxib
to placebo, was initiated in 2002,
VICTOR, a study
to assess reduction in colon cancer
mortality. A
third study examining the ability of
rofecoxib to
prevent prostate cancer in men at risk,
the ViP
study, was initiated in 2003. Together, these
three studies would provide information
on
thrombotic cardiovascular events in over
25,000
patients and targeted to enroll 20-30
percent of
patients on aspirin. The combined analysis had its
own protocol analysis plan and an
external safety
155
monitoring board to monitor the cardiovascular
safety in the three combined studies.
The protocol for the combined
outcome
study was finalized in October of 2002
and was
submitted to and discussed with the FDA
and with
the regulatory agency in the United
Kingdom.
Also during the 2000-2004 time
frame final
data became available from our programs
in
arthritis and Alzheimer's disease. As the data
became available, we performed updates to
our
cardiovascular pooled analysis and, in
2003,
performed a final cardiovascular
update. Also, in
2003 we updated our pooled analysis of
upper GI
clinical events so I will show you now
the final GI
and cardiovascular data from these
programs.
Final GI data from the
osteoarthritis and
rheumatoid arthritis programs were
analyzed in
pooled analysis of clinical upper GI
events using
the same approach to the data as in the
initial
analysis I showed before, except now we
had data
that extend up to 30 months of
treatment. The
pooled analysis included all Phase IIb
through
156
Phase V randomized clinical trials 4
weeks or
longer and excluded VIGOR as those data
would
otherwise overwhelm the data in the
pooled
analysis, and that is shown separately on
this
slide.
As you can see, even excluding
VIGOR, the
relative risk of a confirmed clinical
upper GI
event for rofecoxib compared to the
combined NSAIDs
was 0.36, a 64 percent reduction, and a
similar
benefit could also be demonstrated for
confirmed
complicated events.
In this final pooled analysis
there was
sufficient data to assess whether the
findings for
the combined NSAID groups were
consistently
observed for each of the comparator
NSAIDs,
diclofenac, ibuprofen and naproxen and,
as you can
see, this was clearly the case.
I will turn now to the
cardiovascular
data.
This is the Kaplan-Meier plot of the final
data for the osteoarthritis Phase
IIb/Phase III
studies for rofecoxib compared to the
non-naproxen
NSAIDs.
Over 30 months the curves are
157
indistinguishable from each other,
although
starting around 18 months, as you can
see, the
numbers of patients begin to drop off and
the 95
percent confidence intervals begin to
widen
consistent with the data becoming sparse.
This is the time to event plot
for the
final cardiovascular data. For the
Alzheimer's
disease studies, these are the confirmed
events
from these studies. The average relative risk
across the Alzheimer's program was very
close to 1.
However, in this data set there was a
statistically
significant non-constant relative risk,
with an
apparent decreased incidence for rofecoxib
compared
to placebo for the first approximately 24
months of
the study and an apparent increased risk
for
rofecoxib thereafter. however, as the overall
relative risk approximated 1 and as data
in our
pooled analysis did not suggest this
pattern of
changing relative risk in any of the data
sets, the
data from Alzheimer's were interpreted to
represent
variation about a mean and no difference
between
the treatment groups.
I want to point out that there
were 90
patients with confirmed cardiovascular
thrombotic
events in the Alzheimer's disease data
and there
158
have been over 70 in the osteoarthritis
data set.
Thus, each of these data sets was large
enough to
exclude the 2-fold increased
cardiovascular risk
with rofecoxib that we had seen in VIGOR.
This is the final update to the
pooled
analysis.
The pooled analysis included data now
from 28 studies in over 32,000 patients
and over
19,000 patient-years of exposure. Again, relative
risk for rofecoxib compared to placebo
and
rofecoxib compared to non-naproxen NSAIDs
approximated 1. However, the relative risk
compared to naproxen continued to show a
difference
with a 95 percent confidence interval
excluding 1
and, thus, indicating statistical
significance.
So, what was our assessment of
the data in
2004 before we learned the results of
APPROVe? The
data available in 2004 came from three
sources,
observational epidemiology studies,
preclinical
studies and randomized controlled
trials. There
159
were 10 observational epidemiology
studies, either
published or publicly presented, on the
cardiovascular risk with these drugs and
an
increasing literature on preclinical
models. These
are described in detail in the background
package
and I will not go into these data as
others will be
speaking to them.
With regard to these other
studies, I will
just observe that the results were mixed
and they
did not provide clarity on the
cardiovascular risk
with rofecoxib or selective COX-2
inhibition. We
believe that clarity would best come from
the
outcome study that we had initiated.
Also in this same time frame
the TARGET
study results with lumiracoxib were
published.
These were consistent with the pattern of
overall
cardiovascular findings that with had
observed with
rofecoxib, with cardiovascular event
rates similar
to a non-naproxen NSAID, in that case
ibuprofen,
but a cardiovascular event rate higher
with
lumiracoxib than with naproxen. With rofecoxib we
had also observed similarity to placebo
in the
160
Alzheimer studies. Thus, in assessing these
different data we place the greatest
emphasis on
data from randomized clinical studies
and, based on
these, the assessment was that the
risk/benefit
profile remained favorable for
rofecoxib. With
regard to any remaining questions our
ongoing study
of cardiovascular outcomes would provide
the
answers.
APPROVe was the first component
of the
study on cardiovascular outcomes. It was
anticipated to complete in November of
2004.
However, on September 23 we received a
call from
the administrative committee that they
had accepted
a recommendation from the external safety
monitoring board to terminate treatment
in the
study.
APPROVe studied rofecoxib 25 mg
versus
placebo in approximately 2600 patients.
Stratification was by baseline aspirin
use because
aspirin had been shown in previous
studies to
reduce the incidence of colon
polyps. There was a
3-year on drug treatment period and
1-year off-drug
161
period.
Colonoscopies were performed at screening,
year 1, year 3 and there was a year 4
follow-up
after withdrawal of therapy to assess the
possibility of rebound. The primary endpoint was
the cumulative incidence of patients with
adenomatous polyps at year 3. The first patient
was screened in December of '99 and the
first
patient was randomized in February, 2000.
Patients had to be 40 years or
older and
have a histologically confirmed large
bowel adenoma
at screening. Patients with a prior history of
thrombotic cardiac events could be
enrolled if they
were more than a year post event; 2 years
for a
cerebrovascular event. Patients were excluded if
they were medically unstable, for
example, if they
had uncontrolled hypertension or angina
or CHF at
rest.
The data that led the ESMB to
terminate
the study early are the data on this
slide. These
are the preliminary data from the ESMB
September
meeting.
In the final data, which are now
published on-line, there were two
additional
162
events, one myocardial infarction in each
treatment
group so the current curves look very
similar.
Overall, there was an approximately
two-fold
increase in risk with rofecoxib compared
to
placebo.
However, there was a statistically
significant change in relative risk over
time.
Event rates were similar to placebo over
the first
approximately 18 months, consistent with
our
previous data. Starting after 18 months of
treatment the curves began to separate
with the
difference becoming significant.
Looking at the types of events,
you can
see that there were imbalances in
myocardial
infarction, 20 versus 8 here or, in the
final
numbers 21 versus 9, and imbalances in
stroke, 11
versus 6.
In addition to these findings, we also
observed differences from placebo in
NSAID-like
renovascular effects, for example, edema,
congestive heart failure and
hypertension.
After APPROVe our assessment of
the risk
of cardiovascular thrombotic events with
rofecoxib
had changed. APPROVe was the first study to show a
163
statistically significant increased risk
of
cardiovascular thrombotic events with
rofecoxib 25
mg versus placebo. Although the risk had been
similar to placebo for the first
approximately 18
months, the risk in APPROVe began to
diverge from
placebo starting after approximately 18
months.
The mechanism for this finding
at that
time was uncertain. At the time, available
clinical data on other agents did not
support a
class effect so we were left with a
potentially
molecule-specific effect. As I previously
indicated, the administrative committee
indicted
its recommendation to terminate study
treatment to
us on September 23 and, on the basis of
the data
Merck voluntarily withdrew Vioxx from the
market on
September 30th.
APPROVe was the first clinical
trial with
rofecoxib that showed an increased
cardiovascular
risk versus placebo. At the time alternative
therapies were available without evidence
of a
similar cardiovascular risk and, thus,
Merck
believed that voluntary withdrawal best
served the
164
interests of patients.
Since withdrawal of Vioxx we
assiduously
worked to obtain the final data from
APPROVe and
preliminary data from the other
placebo-controlled
chemoprevention studies, VICTOR, the
colon cancer
study, and ViP, the prostate cancer
study. I will
start with the final analyses of the
APPROVe data
and additional exploratory analyses that
we
performed to identify possible
relationships
between various risk factors with
increased
relative risk.
I want to start by pointing
out, however,
that we performed numerous post hot
exploratory
analyses of the data to identify factors
that might
predict patients with increased relative
risk. We
looked at well over 10 different baseline
risk
factors.
We looked in multiple different analyses
and we also examined patients who were
not taking
aspirin.
We also examined over 40 analyses of
blood pressure. We analyzed these by one subgroup
factor at a time with tests for
treatment-by-subgroup interaction.
Given the large number of
subgroups tested
and the post hoc nature, the data that I
am about
to show you need to be regarded as
hypothesis
165
generating and not definitive.
So, let me start
with the analyses of risk factors other
than blood
pressure.
This slide shows the relative
risk for
rofecoxib versus placebo for different
cardiovascular risk factors. To conserve time, I
am only showing the few in which possible
trends
were seen. Patients with what we called increased
risk are patients with two or more
baseline
cardiovascular risk factors, or a history
of
symptomatic atherosclerotic
cardiovascular disease;
aspirin users in the study which we
defined as
patients who used aspirin at least 50
percent of
the time on study and before an event;
patients
with diabetes; and patients with a
history of
atherosclerotic cardiovascular
disease. However,
these four subgroups were not
independent. The
events in the patients with a history of
atherosclerotic cardiovascular disease
were also
166
included in the aspirin user and in the
increased
risk subgroups and, in fact, were driving
the
differences in these subgroups. So, what we have
are potentially two independent risk factors,
patients with a history of
atherosclerotic
cardiovascular disease and patients with
a history
of diabetes. For these two subgroups, the test for
treatment-by-subgroup interaction was
borderline,
with a p value between 0.05 and 0.1. At this time
these observations can only be regarded,
as I said,
as hypothesis generating.
We also looked at blood
pressure in
APPROVe.
Blood pressure was measured in this study
once per visit which occurred at 4-month
intervals.
The blood pressure measurements, however,
were not
standardized across sites for example
with respect
to time of day or measurement
technique. And,
blood pressure changes in APPROVe were typical
of
what had been published for NSAIDs,
between group
differences and the change from baseline
and
systolic blood pressure of about 4 mm Hg
systolic
and for diastolic about mm Hg. Baseline mean
167
systolic and diastolic blood pressure
data from
population studies or from studies on the
cardiovascular effects of lowering blood
pressure,
the change in mean systolic and diastolic
blood
pressure we observed in APPROVe would not
appear to
account for the magnitude of the
cardiovascular
findings that we have observed. Nonetheless, we
performed numerous analyses to assess
whether
associations could be identified between
the blood
pressure and cardiovascular data.
Multiple blood pressure
analyses are
described in your background
package. Neither the
preliminary nor the final analyses
identified
consistent patterns or consistent patient
subgroups
or covariates associated with increased
relative
risk.
Variables assessed included baseline blood
pressure, change from blood pressure, on
treatment
blood pressure and hypertension reported
as an
adverse experience. The one subgroup of the many
we tested in which a trend was identified
was in
patients with systolic blood pressure
greater than
or equal to 160. However, other data sets, in
168
particular VIGOR and our
placebo-controlled data
from the pooled analysis, did not show a
similar
trend when assessed in this manner.
With the final data we also
learned the
results of the efficacy endpoint. The primary
efficacy endpoint was the cumulative
incidence of
patients with recurrent colon polyps over
the
3-year treatment period. The primary approach to
the data was intention-to-treat, and the
primary
population was patients at increased risk
for
colorectal cancer based on baseline risk
factors
such as histology and number of
polyps. Rofecoxib
use was associated with a 24 percent
reduction in
the risk of colon polyp recurrence, and
the p value
was highly significant.
As I indicated earlier, the
study of
cardiovascular outcomes was the pooled
data from
APPROVe, ViP and Victor. We have preliminary data
from ViP and VICTOR and wanted to share
those
preliminary data with you as well.
This slide shows a pooled
analysis for the
primary endpoint that we had prespecified
for the
169
cardiovascular outcome study confirmed
thrombotic
cardiovascular events. Again, I want to emphasize
that VICTOR and ViP data are still
preliminary.
There are still five cases that are
pending
adjudication to which we remain
blinded. For
VICTOR we have very limited information
on overall
exposure and on patient demographics.
The study was conducted by
Oxford and they
are working hard at getting the
information to us.
Given the preliminary nature of the ViP
and VICTOR
data, we are unable to draw at this time
definitive
conclusions from these data.
Also with the data available,
we can
provide a comprehensive perspective on
mortality in
the rofecoxib clinical program. Shown is all-cause
mortality. This is a bit busy so let me orient
you.
Rofecoxib is shown in yellow; NSAID
comparators are shown in blue; and
placebo is shown
in white.
The figure provides mortality rates per
100 patient-years and 95 percent
confidence
intervals.
Compared to the NSAIDs, overall
mortality
170
rates were similar for rofecoxib. In one instance,
the osteoarthritis Phase IIb/III studies,
there
were significantly fewer deaths on
rofecoxib than
the comparator but this was not
reproduced in other
data sets. With respect to placebo, mortality
rates were similar between rofecoxib and
placebo in
all the data sets except the Alzheimer's
disease
where there was a significantly higher
rate on
rofecoxib and the difference was
statistically
significant.
We looked at this carefully. Although
some of the imbalance was due to a
difference in
mortality due to thrombotic
cardiovascular events,
the larger part of the difference was due
to
trauma, poisoning and infections, causes
that one
would not expect to be associated with an
NSAID
type drug effect. So, we don't have an explanation
for this observation in the Alzheimer
studies.
What do we believe the
implications of
these data to be? As I alluded to earlier, we
believe that there are several public
health
questions raised by the new data. The first is the
171
risk/benefit for selective COX-2 inhibitors
relative to standard of care in their
established
indications. Rofecoxib has a GI safety profile
superior to ibuprofen, diclofenac and
naproxen.
The cardiovascular profile is
more
complex.
Although there have been no differences
observed between rofecoxib, ibuprofen or
diclofenac, based on what we learned from
APPROVe,
the type of long-term data needed to
establish
similarity to these agents does not exist
and at
the time we withdrew data for a class
effect of
COX-2 inhibition was limited.
Amongst the non-selective
agents, naproxen
100 mg appears to have the lowest risk of
thrombotic cardiovascular events, but
also the
highest risk of upper GI clinical
events. Can we
identify risk factors associated with
increased
risk for thrombotic cardiovascular events
with
these drugs? I have shown you our data to support
the effect of duration in our exploratory
analyses
on patient demographics. More work needs to be
done to investigate the hypotheses raised
by our
172
data.
With regard to dose, our data cannot
definitively address this.
Finally, is the increased
cardiovascular
risk that we observed with rofecoxib a
class effect
of COX-2 inhibition? We believe that the data that
have been reported on celecoxib from the
APTC study
and on valdecoxib and from the CABG
study, together
with the APPROVe findings, strongly
suggest an
effect of COX-2 inhibition on increasing
cardiovascular risk.
If the committee agrees that
this is a
class effect, the next critical question
will be
determining the size of the class. Traditional
NSAIDs such as ibuprofen and diclofenac
have not
shown a different cardiovascular risk
profile from
the selective COX-2 agents. However, those data
are limited beyond one year. We would argue that
long-term comparative studies of these
agents are
needed to better assess the relative
cardiovascular
risk.
Well, what do we think are next
steps? At
Merck, we are continuing to analyze our
clinical
173
data and we will be analyzing, for
example, frozen
samples from patients to try to identify
markers
that correlate with an increased relative
risk of
cardiovascular events with COX-2
inhibition. In
addition, patients in APPROVe are being
followed
off-drug as had been prespecified in the
protocol,
and we are in the process of meeting with
consultants to further explore scientific
hypotheses for the findings.
We are also aware of efforts
that are
under way to analyze data across the
different
drugs, and we support those efforts.
Finally, comparative outcome studies,
we
believe, are needed to determine the
relative risk
amongst these agents in relevant
populations. Dr.
Curtis will talk to you tomorrow about
one such
study that we are conducting at Merck,
the MEDAL
study.
This is the largest study in arthritis
patients ever conducted and compares the
long-term
safety of etoricoxib with that of
diclofenac, the
most widely used traditional NSAID
worldwide. We
believe MEDAL will provide the kind of
information
174
needed to weigh the risk/benefits of
these drugs
and improve the ability of physicians to
make
recommendations for arthritis pain and
treatment
that is in the best interest of their
patients.
Thank you, Dr. Chairman, members of the
committee,
FDA.
I am available for your and the committee's
questions.
DR. WOOD: Great!
Thanks very much. As I
am sure you would agree, the primary job
of this
committee is to assess all the risks and
benefits
that these drugs can produce, and we have
certainly
been encouraged to do that by everybody
who has
spoken so far.
That being the case, I was very
surprised
not to see the Kaplan-Meier curve for
pulmonary
edema.
can you show us that from the APPROVe
study?
DR. BRAUNSTEIN: Certainly.
That would be
slide 213.
DR. NISSEN: Yes, heart failure and
pulmonary edema would be helpful.
DR. BRAUNSTEIN: We certainly examined
175
that.
You know, the question that has been on the
table--we believe the hypothesis we were
exploring
was the incidence of thrombotic
cardiovascular
events.
Pulmonary edema is a mechanism-based
effect of selective COX-2 inhibition that
has been
well appreciated and, in fact, is already
described
in product labeling.
So, we did see an effect. This is in our
publication. As shown here, we saw an effect.
This is a combined endpoint of congestive
heart
failure, pulmonary edema of cardia
failure, so all
congestive heart failure type of events
that we
observed in the study.
DR. WOOD: And this had a hazard ratio of
4.6 and a p value of less than
0.004. Right?
DR. BRAUNSTEIN: Yes.
DR. WOOD: So, I mean, it is important for
the committee--and this goes to all the
speakers I
think, that if there are other hazards
with a
hazard ratio of 4.6, that we see these as
they are
presented so that we can make some
cumulative
estimates of what the hazards are for
these drugs.
176
Just because they are in the label does
not mean we
shouldn't hear about them here, it seems to
me.
The second question I have,
which has
always worried me, is when you go back to
the
original label change that you made, you
know, when
you changed the label to say caution
should be
exercised when Vioxx is used in patients
with a
medical history of ischemic heart
disease, as a
physician what am I supposed to do with
that? Am I
supposed to say to patients take the drug
slowly,
or swallow it with milk, or only take it
with the
lights on? Tell me what I am supposed to do with
that information. I am not being facetious here
because as we go through this process we
are going
to have to decide how we make whatever
labeling
changes we make, if that is the decision
we make,
and that doesn't seem to me to have been
helpful.
But maybe you knew something that I
didn't. So,
what did you intend me to do with that
information?
DR. BRAUNSTEIN: At the time when we
conducted negotiations with discussions
with FDA on
that labeling, there were no specific
data that
177
showed a statistically significant
increased risk
in one patient group or another. However, given
the uncertainty in the data, it was felt
to be
prudent to recommend that caution be
exercised in
that patient group if you are considering
using the
drug.
What we meant by that was that
you need to
carefully weigh the risks and benefits of
the
different treatment options. We think that when
evaluating the options on patients it
needs to be
done on an individual patient
case-by-case basis.
Patients differ with respect to their
cardiovascular risks, with respect to
their GI
risks, with respect to their history of
allergies
and with respect to how they responded to
these
different medications in the past, and
all of that
information needs to be taken into
consideration
when assessing and determining what type
of therapy
should be used versus another. And, we felt that
one of the things that should be
considered was
cardiovascular history, and that is what
we meant
by that.
DR. WOOD: Okay.
Other questions?
Stephanie?
DR. CRAWFORD: Thank you.
I appreciate
178
the presentation. I heard both the speakers say
that the sponsor, Merck in this case,
made the
decision to voluntarily withdraw
rofecoxib in the
interest of public health although the
drug could
have been continued on the market. When we look at
adverse events we desire to predict
uncontrollable
events and control controllable
events. The bottom
line question which is really important
to me as we
consider these issues when we look in
this case at
the issue of hazard of cardiovascular
events is how
much is too much? In other words, how did the
sponsor come to the conclusion that the
evidence
was so compelling as to take the step of
voluntarily removing the drug product from the
market?
DR. BRAUNSTEIN: Well, at the time when we
saw the increased risk compared to
placebo there
were not data to allow us to conclude
that this
could be a class effect, and we felt that
there
179
were other options available to patients,
including
therapies that adverse event not known to
have this
increased cardiovascular risk. So, given those
options and alternatives, we felt that
the
responsible action at the time was to
withdraw
Vioxx.
DR. CRAWFORD: Excuse me, but I am asking
specifically what was that signal that
was at the
level where, in the interest of caution
or whatever
the mechanism was, you said this level is
unacceptable at this time based on the
given
evidence?
DR. BRAUNSTEIN: Well, we saw overall a
two-fold increased risk and that was seen
versus
placebo so it was something that we knew
was
statistically significant. The magnitude of the
risk was on the order I think of one or
two
percentage points, but still at the time
the other
agents--it was a determination that amongst
the
choices that patients had available to
them there
were other agents that were not known to
have this
risk and, given the ability for patients
to have
180
alternatives that they could discuss with
their
physicians, we felt that we should
withdraw Vioxx
at that time.
DR. WOOD: Dr. Shafer?
DR. SHAFER: Two questions. I will make
them fast. Do any studies show improved analgesia
on Vioxx?
DR. BRAUNSTEIN: No. I
mean, all of our
efficacy studies show very similar
results at
comparable doses to NSAIDs.
DR. SHAFER: Okay.
The other thing is can
you go to slide number 36?
DR. BRAUNSTEIN: Yes?
DR. SHAFER: I just can't help but notice,
but the upper bounds of the confidence
intervals
for the first two groups encompass the
mean of the
naproxen comparison. Does that give you pause in
justifying excluding naproxen as a
separate
comparison group? If you take a look at the upper
bounds, they include the mean of naproxen
which
might suggest that statistically those
groups
really shouldn't be segregated as you
have done.
DR. BRAUNSTEIN: Well, when you look at
this, if you were to combine all the data
one would
not see a statistically significant
difference. It
181
would tend to obscure the naproxen
finding, and we
felt, given what we observed in VIGOR and
what we
had observed all along the program, that
that
wasn't the right way to go, especially
given the
difference pharmacologically. I mean, in terms of
looking at the data we also were taking
into
context what we understood about the
pharmacology
of these agents and the ability for
naproxen to
provide that kind of inhibition of COX-1
that Dr.
FitzGerald talked about. So, we thought that not
only were there differences in the
clinical data
but there were differences in the
pharmacology data
that supported keeping naproxen separate.
DR. WOOD: Dr. Gibofsky?
DR. GIBOFSKY: One of the stratifications
we are
asked to do during the next three days is,
of course, the risk/benefit
relationship. I am
wondering if you have calculated the
risk/benefit
of cardiovascular thrombosis outcome
versus the
182
benefit of cancer prevention in the
population. I
can understand where the relative risk of
1.92 is.
I understand what it means when the
relative risk
goes up above a certain number above 1.0
but, you
know, you can't go much below 1.0. So, have you
calculated to what extent your risk of
cardiovascular events is related to your
protection
against cancer?
DR. BRAUNSTEIN: Well, we didn't actually
study cancer as an outcome. We were looking at
polyps which are precancerous lesions.
DR. GIBOFSKY: The same question
basically.
DR. BRAUNSTEIN: Well, even there, you
know, polyps are easily--there is a
different
mechanism. There is an alternative therapy
available for the treatment of polyps. So, in
order to evaluate risks and benefits one
has to
compare the risks and benefits of one
treatment
option versus the risks and benefits of
another
treatment option. In doing so, I think
that this
wouldn't--
DR. GIBOFSKY: Well, let me ask it
another
way then, if you did not see a
cardiovascular
signal in APPROVe would you have
concluded that the
183
reduction in risk in polyp formation was
efficacious?
DR. BRAUNSTEIN: We concluded that the
reduction in risk in polyp formation was
efficacious regardless of the
cardiovascular
finding.
Are you asking whether the overall
risk/benefit would have been favorable???
DR. GIBOFSKY: Yes.
DR. BRAUNSTEIN: That would be speculative
for me.
We haven't looked at the data with that
specific question in mind. I think we would need
to take a look at all the patients that
we looked
at in all the different subgroups to see
if that
remained the case. You know, you saw some
congestive heart failure. We say NSAID type
typical effects that one would see in one
of these
studies, not just cardiovascular risk but
there was
a small increase in ulcers, not as much
as one
would anticipate to see with a
non-selective NSAID
184
but still present. There was a small increase in
other NSAID type effects like edema and
hypersensitivity. So, we haven't made a formal
risk/benefit assessment.
DR. GIBOFSKY: Just one last point, you
stressed the concept of their being other
modes of
therapy available and so that factored
into your
decision to take this agent off the
market. But
there are other ways of treating polyps
as well,
which leads me to question in that
context the
rationale for the APPROVe study.
DR. BRAUNSTEIN: We thought this was an
interesting and important scientific
question that
had been raised in the literature.
DR. WOOD: That sounds like a
retrospective question so I will let you
off the
hook.
Let's move on. Ralph?
DR. D'AGOSTINO: Two quick questions. In
slide 48 you, I think quite sensibly and
again post
hoc, split out the cardiovascular risk
and redid
the analysis. Now, if this were preplanned and I
got a result like that I would say that
this is
185
great; this shows me that placebo is
better no
matter what I do. I mean, the cardiovascular does
increase a bit but the placebo is still
maintaining
itself even in individuals without
cardiovascular
risk.
DR. BRAUNSTEIN: This slide shows the
relative risks in each of these
groups. It is not
placebo and then rofecoxib.
DR. D'AGOSTINO: Well, it is all against
placebo.
DR. BRAUNSTEIN: It is all compared to
placebo, yes.
DR. D'AGOSTINO: Right, and placebo wins
everywhere. So, no matter if you have
cardiovascular risks or not, still
placebo was
better.
Am I misinterpreting this?
DR. BRAUNSTEIN: You know, in this we only
see trends for some subgroups and in
others we
don't identify particular subgroup
factors where
there is an important difference.
DR. D'AGOSTINO: Well, that is a subgroup
and it sort of indicates consistency to
me. In
186
slide 42 there was consistency regardless
of CV
risk.
In slide 42, if I look at those numbers on
the bottom, I presume those are
individuals
available. You are dropping about 100 individuals
after 12 months or so. Do we know anything about
the loss to follow-up on these
individuals?
DR. BRAUNSTEIN: We did not see
differences, for example, in changes in
cardiovascular risk associated with
patients who
discontinued--
DR. WOOD: Wait a minute, these are not
all patients who dropped out, are they?
DR. BRAUNSTEIN: These are all the
patients who remained in the study.
DR. WOOD: So, some of these patients may
not have advanced to the end of the
study.
DR. D'AGOSTINO: Well, if you start at the
beginning--that is my question, I mean it
is
randomized, right? So, there must have been about
a 50-50 break so you would think at each
point you
would have approximately the same numbers
in the
two groups.
DR. BRAUNSTEIN: Well, there is a
differential dropout due to adverse
experiences for
example that one would normally see in an
NSAID
187
trial against placebo.
DR. D'AGOSTINO: Well, why couldn't they
be followed for CV events? Why wasn't it like an
intent-to-treat analysis or something?
DR. BRAUNSTEIN: Yes, the way we had
prespecified the analysis was that all
events were
determined up to 14 days after
discontinuing
therapy.
The only intention-to-treat analysis was
one done for mortality overall.
DR. WOOD: Dr. Nissen?
DR. NISSEN: Yes, I think Ralph's point is
very, very important. We need to see an
intent-to-treat analysis. You are telling
me that
14 days after they dropped out of the
study these
folks were not followed beyond that?
DR. BRAUNSTEIN: We are following patients
who are off-drug, who terminated
treatment in the
study, and we don't have data yet on
that.
DR. NISSEN: Because there are a lot more
188
people dropping out of the rofecoxib arm
and the
question is why are they dropping out and
what
happened to them. The signal here could be a lot
stronger than we see using this somewhat
selective
analysis.
I am used to an intent-to-treat
analysis, Ralph, for a trial like this
and I am
confused as to why it was done in this
way. You
know, a cardiovascular hazard, if this is
a
pro-atherogenic therapy, is going to
persist quite
a while after you stop the drug. So, I think we
really do need to see--I mean, to clear
the air
here we have to see that intent-to-treat
analysis.
I would track those people down and find
out what
happened to them.
As a cardiologist, I obviously
use a lot
of low dose aspirin so I am very familiar
with the
low dose aspirin literature, and we see
in low dose
aspirin perhaps up to a 20 percent
reduction in
cardiovascular risk in individuals who
are at risk.
So, what I am really confused about is
that you
attributed what you found in VIGOR to the
beneficial effects of naproxen, but you
are talking
189
about a 4- or 5-fold difference in
myocardial
infarction rates and I just want to know
how you
came to the conclusion that that amount of
difference could be explained by
naproxen.
Naproxen would have to be a lot more
effective than
aspirin.
We know aspirin inhibits platelets as
well as anything else out there. So, how did you
guys arrive at that conclusion that it
was naproxen
related?
DR. BRAUNSTEIN: Well, other than in
addition to the data that support that
naproxen can
have this effect, and specifically with
regard to
the magnitude that you are pointing out
in
myocardial infarction, there were only 24
events in
VIGOR.
The cardiovascular outcome studies that you
are referring to oftentimes have
hundreds, if not
thousands, of events that they are
assessing and
that allows one to very carefully and
with
precision identify what the relative risk
reduction
is.
In VIGOR we had fairly wide confidence
intervals and, in addition, VIGOR studied
exclusively patients with rheumatoid
arthritis.
190
These are patients with chronic
inflammatory
disease, elevated C-reactive protein and
in those
patients we know that the effect of aspirin
is also
magnified. So, given those factors, we felt that
it was certainly compatible with an
aspirin-like
effect.
DR. NISSEN: Again, I am not sure I buy
that.
You know, post-MI patients have a very
elevated risk and the most we ever expect
from
aspirin is perhaps a 20 percent reduction
in
recurrent events. Even with dual platelet
antagonism with aspirin and clopidagrel
we don't
get a whole lot more than that. So, this story
about naproxen, as I think Garret
FitzGerald apply
discussed--it doesn't stand the test of
any kind of
scientific rigor.
I guess the other question I
wanted to
challenge you on is this comment that you
made that
the blood pressure effects in APPROVe
were
consistent with what is seen in other
NSAIDs. I
hope many of you have had a chance to
look at the
Archives manuscript that compares a
meta-analysis
191
of blood pressure effects. It sure looks like
rofecoxib is an outlier here, showing a
weighted
mean difference of about 5.5 mm Hg or
almost 6 mm
Hg compared to NSAIDs which are substantially
smaller.
Is it your position that rofecoxib does
not produce greater degrees of
hypertension than
comparable NSAIDs?
DR. BRAUNSTEIN: Most of the studies that
are referenced in that analysis,
unfortunately, are
confounded by dose. We think it is very important
when one looks at a pharmacologically
mediated
effect, especially one that is known to
have a
dose-dependent association, that the
drugs be
assayed at doses that provide
pharmacologically
equivalent degrees of inhibition of
COX-2. For
example, for rofecoxib and celecoxib that
would be
25 mg of rofecoxib and 200 mg twice a day
of
celecoxib.
DR. NISSEN: Okay.
I want to clear the
air on one more thing and, obviously,
this drug has
been the subject of a great deal of
public
attention and I think it would be a great
192
opportunity for you to explain, from your
perspective, why did it take 14 months,
from
February of 2001 to April of 2002, for
the label to
change?
Were you fighting the FDA? Was
there a
big battle over what the wording ought to
be of the
label? I mean, it seems like 14
months is an
awfully long time after an advisory
committee
meeting that recommended a warning to
take for
agreement to be reached about what that
warning
ought to say.
DR. BRAUNSTEIN: The advisory committee--
DR. WOOD: I think that is something
probably we should let him pass
on--unless you want
to; go ahead.
DR. BRAUNSTEIN: No, no, no.
DR. WOOD: Go ahead.
DR. BRAUNSTEIN: After the advisory
committee there were a lot of discussions
with FDA.
There were data requests from them which
we
provided to them. We submitted at that same time
the NDA supplement for rheumatoid
arthritis because
we felt it was important. As you know, VIGOR had
193
been conducted in rheumatoid arthritis
patients at
50 mg and it was important to communicate
to
physicians that the appropriate dose in
those
patients was 25 mg. So, there was a lot of
information for the FDA to review. They also asked
for updated analyses of all our safety
data. So,
they had a lot of work cut out ahead of
them, and
we worked diligently with them to provide
the
information, conduct the analyses that
they
requested, and collaborated in that way
to make
sure they had that information, and then
we worked
assiduously to conclude a label. So, I don't
think, considering the wealth of
information, that
the time frame is unusual.
DR. WOOD: And after 14 months, it was
"take the tablets slowly."
DR. BRAUNSTEIN: Well, after 14 months the
advice was that cardiovascular risk
factors,
cardiovascular history should be taken
into
account--
DR. WOOD: Well, that is not what it said.
It is most important to remember it
didn't say you
194
shouldn't give it to people with
cardiovascular
risk factors. It didn't say it shouldn't be given
to people who had had an MI or any other
expletive
statement like that. It said caution should be
exercised in patients with history of
heart
disease.
That is quite different.
DR. BRAUNSTEIN: What I tried to say or at
least what I was trying to communicate
was that the
risk/benefit assessment we felt needs to
be done on
a patient by patient basis and, in
addition to
taking GI risk into account, one should
also take
cardiovascular risk into account given
the
uncertainty of the data that was
available at that
time and, as the label said, the clinical
significance of these cardiovascular
findings were
unknown and that, therefore, the
cardiovascular
information should be taken into account
when
considering the use of rofecoxib.
DR. WOOD: Dr. Hennekens?
DR. HENNEKENS: I would be interested in
knowing the total number of deaths in the
randomized trials of rofecoxib against
all other
195
comparators and then against placebo,
non-naproxen
NSAIDs and naproxen.
DR. BRAUNSTEIN: You have that on your
slide.
The numbers of deaths are underneath the
rows.
I don't have the numbers at the top of my
head.
We would have to do a quick tally.
Also,
the only problem with looking at the
numbers is
that the numbers themselves don't take
into account
imbalances in exposure, which is why we showed
them
as rates per 100 patient-years because it
certainly
takes into account the differences in
exposures.
Compared to the NSAIDs we did not see
differences
in the rates, and compared to placebo we
did not
see differences except, as I pointed out,
in the
Alzheimer's disease study where there was
a
statistically significant higher rate
with
rofecoxib.
DR. WOOD: Dr. Cannon?
DR. CANNON: You mentioned in the VIGOR
and APPROVe clinical trials that the
major driver
for the increased cardiovascular events
on
rofecoxib was acute myocardial
infarction. My
196
question is were these myocardial
infarctions
apparently random events or was there any
setting
in which they seemed to occur more
frequently? For
example, in relationship to a procedure,
including
a coronary interventional procedure, or
surgery, or
were the myocardial infarctions random
events? I
am thinking in terms of Dr. FitzGerald's
presentation and the recent valdecoxib
experience
with bypass surgery.
DR. BRAUNSTEIN: We haven't identified any
kind of associations such as you are asking. But I
am not sure that we have specifically
looked at the
question the way you are asking. So, I am not 100
percent sure.
DR. WOOD: Dr. Abramson?
DR. ABRAMSON: Yes, I guess one of the
surprises or unexpected findings in
APPROVe was
that it took 18 months for these curves
to separate
with rofecoxib. I was unaware of the heart failure
and pulmonary edema data until this morning. Often
fluid retention occurs early in the
course of
putting people on NSAIDs. So, I am wondering could
197
you tell us more about when those heart
failures
occurred over the course of time. Were they early
events, or was this also something that
took some
time to appear in the population?
DR. BRAUNSTEIN: As one would expect from
an NSAID, fluid retention, heart failure
were early
events.
If you look at discontinuations for
example due to edema-related adverse
experiences,
including heart failure, patients tended
to
discontinue--if they were going to
discontinue,
they discontinued early and then the two
groups
continued in parallel. But, yes, it was an early
finding as you would expect.
DR. WOOD: Tom?
DR. FLEMING: Could you show us the curves
back from the VIGOR trial that looks at
complicated
confirmed upper GI?
DR. BRAUNSTEIN: Complicated confirmed
upper GI?
DR. FLEMING: Correct.
DR. BRAUNSTEIN: We don't have those.
DR. FLEMING: You just quickly referred in
198
your presentation to the results being
positive.
DR. BRAUNSTEIN: The results were that the
two curves showed the same V-like
difference and
they continued to separate over
time. I am just
looking here and apparently we don't have
that
slide.
DR. FLEMING: You showed us the confirmed
upper GI and those cumulated to rates of
4.5
against 2.1. The data we have been provided
separately for the complicated confirmed
upper GI
are 1.4 against 0.6. So, it is the same relative
risk but a much less frequent event.
DR. BRAUNSTEIN: Sure, yes, and those were
mostly GI bleeds.
DR. FLEMING: I was just curious to see a
pattern as to whether that is, in fact,
cumulatively increasing or more apparent
early in
time.
Let me go on to the next
point. That
reflects approximately numerically almost
exactly
the same number of prevented cases of
complicated
confirmed upper GI as there were excess
numbers of
199
thrombotic cardiovascular SAEs. In essence, what
you have said is that the analgesia was
comparable.
So, essentially what we are really
looking at is
relative safety profiles and the goal
here is to
reduce the upper GI. And, we are essentially
preventing an equal number of upper GI
complicated
events for equivalent numbers of excess
events in
the thrombolytic cardiovascular
arena. Yet,
essentially I think you were saying the
latter
didn't seem as established yet
numerically it was
the same.
There were also in the trial
excess
numbers of deaths of 22/15 and when you
presented
the Alzheimer's data you gave us I think
slide 35
that indicated that when you looked at the
Kaplan-Meier curves for confirmed
thrombolytic
cardiovascular events that didn't seem to
reinforce
the excess rates that you were seeing
with VIGOR
and, yet, it did reinforce the excess
mortality as
you have now circled back and reported at
the end.
In 2003 the excess mortality is quite
significant
but it was also significant in 2001. The latter
200
date is in Tab G, page 2 but the former
data is in
Tab F, page 39 where excess mortality was
significant at 33/20 and the
cardiovascular were 8
to 4.
So, you were seeing from these two sources
excess mortality and you were seeing
excess numbers
of thrombolytic events that were
equivalent in
number to the number of prevented
complicated
confirmed upper GI events. Am I correct on this
summary?
DR. BRAUNSTEIN: Well, no.
There are a
couple of points I would disagree
with. First, in
VIGOR the difference in mortality was not
statistically significant and also in
terms of
looking at the causes of death,
cardiovascular
mortality which is the difference we
would see was
not different between the two
groups. There were 7
on rofecoxib and 6 versus naproxen. So, I am not
sure--
DR. FLEMING: Well, I don't think we
disagreed. I am not talking about statistical
significance here. I am talking about what the
data are actually suggesting in what is
available--
DR. BRAUNSTEIN: Well, I must say there is
a lot of data that you pointed out to me
and--
DR. FLEMING: Well, just to summarize the
201
essence, while you have emphasized
appropriately
the upper GI events being decreased, when
you look
at the actual number prevented in
complicated
confirmed upper GI it is numerically
almost
identical to the number of excess
thrombolytic
cardiovascular SAEs that were seen in
VIGOR. You
also saw a numerical increase of a
relative risk of
1.5 on mortality, which was also seen in
the
Alzheimer's study which you were saying
at the time
was contradicting the sense of concern
related to
the overall thrombolytic excesses. And, what you
were seeing at the time, even back in
2001, was a
statistically significant excess in death
rates
with a doubling in cardiovascular-related
deaths.
DR. BRAUNSTEIN: Let me ask Dr. Reicin
because she perhaps has a better handle
on it and I
am sort of getting lost in the mass of
data that is
coming up.
DR. REICIN: I think there are two issues
202
that I think you brought up.
DR. WOOD: Sorry, just for the record, can
you identify yourself?
DR. REICIN: I am Dr. Alise Reicin, Vice
President of Merck Research Labs. In terms of
looking at VIGOR, I think you are
correct. There
was excess in cardiovascular events on
Vioxx and
there was a decrease in the complicated
GI events
on naproxen.
DR. FLEMING: Which numerically were
almost identical.
DR. REICIN: And I think that that is also
fair to say. If you compare our data versus
diclofenac and ibuprofen at the time,
there was no
difference in cardiovascular events. In fact,
numerically it was in favor of Vioxx and,
yet,
there was a significant reduction in GI
events.
So, that takes care of that. So, versus naproxen,
I think you are right, there was excess
in CV,
lower in GI versus ibuprofen and
diclofenac,
however, no evidence of an increase in CV
and a
reduction in GI.
In terms of the mortality data
that we had
at the time, we had a significant
reduction in
mortality on Vioxx versus non-naproxen
and the
203
NSAIDs that we had in our Phase III OA
studies, and
at the time we actually did not make a
lot of
those.
We thought it was potentially by chance.
That was actually driven by CV mortality
in the
non-naproxen group.
In VIGOR there was a numeric
imbalance, 22
to 15 in deaths, but cardiovascular
mortality was
similar.
In terms of Alzheimer's I don't think
there was statistical significance back
at the time
of VIGOR.
There was a numeric imbalance. In
terms
of cardiovascular I think the numbers
were 8 versus
4.
They were put in the label. So,
pretty small
numbers.
The rest of the difference that we saw
was due to things like poisoning,
electrocution and
other things that we thought were no drug
related.
DR. FLEMING:
You are correct, it was 8
versus 4 in cardiovascular related
deaths, but it
was statistically significant in total
mortality at
that time as well. It was 33 against 20, with p
204
values reported, depending on the method,
of 0.007
to 0.26.
Now, the final data are
significant but
even the early data were significant and
reflected
the level of excess mortality that VIGOR
was
establishing but not in a significant
fashion.
DR. REICIN: Again, we didn't see it
though in any of our other data
sets. In fact, in
the early data sets statistically it went
the other
way, non-naproxens had higher one. I think you can
see that in RA also there was no evidence
of an
excess.
In ADVANTAGE there was no evidence of an
excess.
You see now in ViP and--
DR. FLEMING: But there was in ADVANTAGE.
There was an excess.
DR. REICIN: Not in overall mortality.
DR. FLEMING: Yes, in overall
mortality--oh, I am sorry, in
Alzheimer's.
DR. WOOD: Tom, have you finished?
DR. FLEMING: Yes.
DR. WOOD: Dr. Shapiro?
DR. SHAPIRO: I guess I want to follow up
205
on a comment that you, Dr. Chair,
made. I am still
concerned about the label change and how
helpful or
not helpful it was, not only because it
may not
have been as helpful as it might have
been to
clinicians but also to patients in the
informed
consent conversation. What else was made available
or should have been made available or
could have
been made available to clinicians to make
some
sense out of this, caution should be
exercised when
Vioxx is used in patients with a medical
history of
ischemic heart disease?
DR. BRAUNSTEIN: Were you addressing me or
the Chairman? Me?
What we made available were the
data.
I mean, I think that is the answer to the
question in terms of the labeling and in
terms of
what we had published.
DR. SHAFER: So, the VIGOR and Alzheimer's
results were made available. You just weren't
going to analyze them to make any more
definitive
statements at that time about what
clinicians
should take away?
DR. BRAUNSTEIN: Well, by 2002 we were
206
also starting to implement our outcome
study. We
thought the important message to
clinicians was
that there is a GI benefit and there is
also a
cardiovascular finding that we don't
understand
given the differences between the two
data sets.
It says the clinical significance was
unknown and
that this information needs to be taken
into
consideration when assessing the risks
and benefits
of these drugs in individual
patients. Individual
patients differ in terms of their risk
profiles and
that decision on which drug to be used is
best made
on a patient by patient basis.
DR. WOOD: Dr. Ilowite?
DR. ILOWITE: Rofecoxib was pulled from
the market approximately three weeks
after its
approval in children with juvenile
rheumatoid
arthritis. I have two quick questions. Were there
any cardiovascular events in any of the
trials in
children?
DR. BRAUNSTEIN: No.
DR. ILOWITE: Second, did you give any
consideration to the fact that there were
no other
207
COX-2 inhibitors, other than one NSAID
that was
available as a liquid, before you made
the decision
to pull it from the market?
DR. BRAUNSTEIN: The focus I think was on
the list we had seen versus placebo in
the adult
patients.
This kind of disease, cardiovascular
disease, is not very common in children
and we
hadn't seen anything like that in our
population.
DR. WOOD:
Dr. Boulware?
DR. BOULWARE: I want to go back to the
previous question. What I heard was a discussion
about an offset between complicated GI
events and
it sounds like non-fatal MIs. If I understood the
discussion back and forth here, they are
roughly
comparable. Now, in patients requiring an NSAID,
and I am not talking about the APPROVe
data here
but in patients requiring NSAID treatment
if there
is roughly comparability of complicated
gastrointestinal events with non-fatal
MIs, it
sounds like Merck's thinking was that the
risk of a
non-fatal MI far outweighs, in a patient
requiring
NSAID treatment, the risk of complicated
GI events
208
and that that was what drove the
decision.
The reason I am interested in
this is that
obviously this meeting is entirely about
how you
make a risk/benefit calculation. So, your thoughts
in September about this issue are I think
helpful
to us in thinking about these
risk/benefit issues.
DR. BRAUNSTEIN: I wouldn't put it exactly
the way you stated it, and that is
because the
individual patients at risk for these
problems
differ and there were alternative
approaches for
patients with GI risk that were available
at the
time.
Now, we recognize that rofecoxib had met the
highest standard. Well, yes, it had met the
highest standard but there were
alternatives
available and we did not have data on
what one
could do for more studies. The data was unclear as
to the mechanism so we felt that given
those
options, the withdrawal made the most
sense.
DR. BOULWARE: Can I just make a little
follow-up comment? It sounds like you are trying
to have your cake and eat it too. On the one hand,
you would have liked to have said pre-September
209
that rofecoxib was the only COX-2
selective drug
that had demonstrated effect in reducing
GI
toxicity.
Now you are saying, after you pulled it
from the market, there are lots of other
alternatives that are almost just as
good. I don't
really understand.
DR. BRAUNSTEIN: I couldn't say "almost
just." There haven't been head-to-head studies to
answer that latter part of your
question. There
were alternatives. We did not know that there is a
class effect for cardiovascular.
DR. WOOD: Dr. Manzi?
DR. MANZI: This question actually may
better be answered by Dr. FitzGerald, I
am not
sure--is he here?
DR. WOOD: Here he comes, just in time.
DR. MANZI: He eloquently pointed out that
there is clearly variability in
individual dose
response with regard to COX-2
inhibition. Since we
are grappling with this issue of class
effect
versus a specific drug effect, is it
feasible or
helpful to look at the degree of COX-2
inhibition
210
in association with these events?
DR. WOOD: You are up, Garret. Just take
that microphone.
DR. FITZGERALD: I would say yes amongst
all those things.
DR. WOOD: Amongst all those things? I
don't understand.
DR. FITZGERALD: I mean one of the issues
that you would hypothesize is relevant to
outcome
is the degree of selectivity attained in
an
individual.
DR. WOOD: You mean amongst other things
related to the drug?
DR. FITZGERALD: Amongst other things
related to the drug and underlying--
DR. WOOD: Sure.
Dr. Platt?
DR. PLATT: Compared to other NSAIDs, do I
understand properly that 98 out of 100
patients who
take the drug would have about the same
outcome?
That is, the significant difference
between the
regimens is approximately--2-fold means
about a 2
percent absolute difference.
DR. BRAUNSTEIN: Which outcome are you
referring to?
DR. PLATT: To the GI outcomes.
211
DR. BRAUNSTEIN: There is a range. There
is a small range because it does seem
that we have
a larger difference--you know, if you
line them up
it is a little larger with naproxen and a
little
smaller with diclofenac but I would say
on average
it is about two-fold.
DR. PLATT: Right, but that 2-fold
translates into about two patients out of
100
having a different outcome than they
would have if
they had taken the comparator. I am trying to get
at the question of whether we can
identify those
two patients with greater certainty than
just
treating everyone. And, I would ask the same
question about the cardiovascular
complications.
That is, in this complicated business of
risks and
benefits, can we do better than we have
at guiding
both clinicians and their patients in
having at
least semi-quantitative estimates of what
the risks
will be and what the benefits will be so
they can
212
make an informed judgment?
DR. BRAUNSTEIN: We know that from the
VIGOR results because we looked at
patients with
different baseline risk for GI disease,
and this is
something that is well understood, what
the
different risk factors are for GI
disease,
including things like prior history of a
GI event,
and we saw the same 50 percent reduction
across all
the different risk factors. In terms of
cardiovascular, we are still introduction
he
process of trying to see if we can
identify
particular risk factors that would
correlate. So,
that is still an open question based on
our data.
DR. PLATT: But saying 50 percent really
obscures the fact. Some people may have a baseline
risk of a serious GI event of 20 percent
or 30
percent, in which case 2-fold is a very
big
improvement for them--
DR. BRAUNSTEIN: Yes, of course.
DR. PLATT: If we knew enough we would
know that most people have effectively a
zero risk.
So, there is very little benefit for
them. Have
213
you put the data together in a way that
helps us
identify the people who stand most to
benefit and
the people who stand most at risk, and is
it
possible that those are different groups?
DR. BRAUNSTEIN: Dr. Reicin can I think
provide more information on the VIGOR
results
because she was involved extensively in
the VIGOR
study.
DR. REICIN: Dr. Laine may come up to help
me if I don't remember something. We actually
published a paper on looking at specific
subgroups
in the VIGOR study. What we found is very similar
to what Byron talked about during his
discussion.
Patients with typical risk factors, age
more than
65--do you want to add something?
DR. LAINE: I agree absolutely. The
reason I actually took these data and
published
this paper with the VIGOR results is that
I have
had the same idea. Relative risk isn't important
in practice; it is the absolute change,
the number
needed to treat. So, we looked at that with
absolute incidence of number needed to
treat and
214
for clinical events, for instance, if you
had a
prior event you only have to treat ten
people for
one additional event. But if you don't have a
prior event you have to treat, let's say,
60 or 70.
The same with age, if you are over 75 you
only need
to treat ten people for one additional
event. But
if you are under 65 you need to treat 50
or 60.
So, I agree absolutely that at least with
the VIGOR
data, we stratified by these different
clinical
risk factors that Byron showed earlier.
DR. WOOD: We have three more questions,
Dr. Shafer, Dr. Cush and then Dr. Temple.
DR. SHAFER: Two questions. Can you go to
slide 48?
DR. BRAUNSTEIN: That is the subgroups,
yes?
DR. SHAFER: Yes, is the one on various
subgroup analyses. Can we show the slides? Just
to highlight what the question is, in
slide 48,
this is following on the comment by Dr.
Nissen
regarding the aspirin use, what you show
in the
APPROVe trial is that the risk factor for
those
215
with aspirin on board, in fact, is 3.25
with a
confidence interval which is wide, as Dr.
FitzGerald has suggested it might be
because of
small numbers, but it goes from 0.98 to
13.81.
Now, the hypothesis behind
VIGOR and
interpreting VIGOR as an aspirin-like
effect, was
that aspirin was going to confer
safety. Doesn't
the data on slide 48 essentially disprove
the
naproxen hypothesis in VIGOR?
DR. BRAUNSTEIN: No, there is no naproxen
in the study--
DR. SHAFER: Right, but the hypothesis was
that naproxen was acting like aspirin.
DR. BRAUNSTEIN: Yes.
DR. SHAFER: Yet, here in the presence of
aspirin to provide the safety, you are
not seeing
benefit.
DR. BRAUNSTEIN: I would argue that the
mechanism for what we saw in VIGOR, which
was a
very early difference between the two
treatment
groups, is qualitatively very different
than what
we see in APPROVe. So the mechanism for the
216
cardiovascular difference in the two
studies is not
necessarily the same and, therefore,
whatever
difference we are seeing here or not
seeing with
aspirin doesn't really relate to what we
saw in
VIGOR.
I would also point out, as you have already
pointed out, there are wide
subgroups. I think Dr.
Villalba has pointed out that when we
looked at the
APTC endpoint, which was just myocardial
infarction, stroke and vascular death,
the
difference actually seems to go away but,
again,
there are very small numbers and we don't
want to
over-interpret at this point what the
data say.
DR. WOOD: But the major point here, just
to help you here, is that these people
were not
randomized to aspirin. So, people who were on
aspirin were a different subset than the
people who
were not on aspirin in terms of
cardiovascular risk
and so on. So, it is not like naproxen.
DR. BRAUNSTEIN: Yes.
Yes, of course.
Sure.
DR. WOOD: The one thing I would say while
you have that slide on there is that I
think is
217
going to be important for us is that our
job is not
to identify groups that are at particular
risk,
Richard.
Our job I think is to see if we can
identify patients who are at low risk--
DR. PLATT: Yes.
DR. WOOD: I am not arguing with you. I
am just making a generic point and it is
not clear
to me that there is such a group
identified there.
DR. PLATT: Well, it seems to me that
there will always be risk--
DR. WOOD: Right.
DR. PLATT: --the question is can we help
inform decisions that patients have to
make?
DR. WOOD: Dr. Cush?
DR. CUSH: Dr. Braunstein, a few times you
mentioned that you made this decision
based on the
signal that you found in the alternatives
existing,
and not knowing if it is a class
effect. If you
knew that this was a class effect would
you have
made the same decision? And, knowing what your
COX-2 potency is, does that factor into
that?
DR. BRAUNSTEIN: I couldn't go back and
218
speculate what decision we would have
made based on
a different set of data.
DR. WOOD: I think that is a fair answer.
Let's move on to Dr. Cryer.
DR. CRYER: I would like to come back to a
consideration of the potential
gastrointestinal
benefits of COX inhibitors and
specifically Vioxx,
and I am going to use your slide 33 to
help me with
my questions and comments.
You repeatedly made the point
that Vioxx,
rofecoxib, was unique in its labeling
with respect
to its gastrointestinal benefit and that
was a
label revision that was largely derived
from a
discussion of the data in the VIGOR trial
in which
naproxen was the comparator.
I want to underscore that the
conclusions
reached may be as much of a reflection of
the
comparator as they could be a reflection
of
properties intrinsic to the COX-2
specific
inhibitor. As I look at the pooled analyses from
the rofecoxib experience and specifically
look at
diclofenac, it does not appear that the
difference
219
in reduction compared to diclofenac is
statistically significantly different.
So, the question that I have
for you is do
you think that the revisions in the label
would
have been the same with respect to the GI
observations in VIGOR had diclofenac been
the
comparator rather than naproxen?
DR. BRAUNSTEIN: In an adequately powered
study.
I think the failure here in these confirmed
events, in order to have the confidence
interval
narrow enough we would need enough power
to do
that.
In fact, when we looked at investigator
reports of these events, in all,
including the
unconfirmed, we did have statistical
significance.
So, I think that, yes, in an adequately
powered
study we would show a difference from
diclofenac.
DR. WOOD: Bob?
DR. TEMPLE: Actually, I wanted to pursue
something Dr. Shafer raised. The aspirin subgroup
is a baseline subset. People are probably
reasonably well randomized to whether
they get--
DR. WOOD: They didn't get aspirin.
DR. TEMPLE: No, I know.
They were
different populations from people who
were on
aspirin but they are randomized to the
two
220
treatments, and there is about a thousand
of them.
From everything that I would have
understood from
Dr. FitzGerald's talk, when you are on
both aspirin
and rofecoxib you are not on a selective
drug
anymore, or probably not because you have
plenty of
COX-1 inhibition. But the hazard ratio there is
higher than the other people. I wonder whether
that is easily explained, or it could be
explained
by blood pressure effects which, of
course, aspirin
will not reverse. Because I think it needs some
kind of explanation.
DR. WOOD: So, is that addressed to
Garret?
DR. TEMPLE: Either.
DR. BRAUNSTEIN: With regard to aspirin
data, they are not robust enough. We are talking
about a total of 11 events, as I recall,
in that
analysis for the APTC. There are not a lot of
events in that analysis.
DR. TEMPLE: There were 16.
DR. BRAUNSTEIN: Right, 16 events. There
are very wide confidence intervals, as
you know.
So, I think it is difficult to draw
specific
conclusions about aspirin. With regard to blood
pressure, as I indicated, when we looked
at that
221
the blood pressure changes that we
observed would
not appear to explain the magnitude of
the
cardiovascular findings that we observed
in
APPROVe.
DR. TEMPLE:
One of the reasons to worry
is that people with underlying heart
disease or
diabetes are probably more sensitive to
blood
pressure effects. There is some evidence of that.
Anyway, just a thought.
DR. WOOD:
Garret?
DR. FITZGERALD: I would just say one can
over-parse extraordinarily small amounts
of data in
retrospect, and that there is enough
flexibility in
what one would expect to see to account
for that.
For example, we don't actually know if
inhibition
of COX-1 has no impact on the blood
pressure
222
response to a COX-2 inhibitor. In fact, from what
I showed you in mice, one would
anticipate if one
actually designed a study to address that
question
that the answer would be yes. So, I think that,
coupled with the fact that aspirin, even
if one had
loads of data, would be expected to modulate
rather
than abolish the hazard through this
mechanism
really means that it is not an answered
question
rather than an answered one.
DR. WOOD: Great!
Well, let's stop at
this point and break for lunch. We will restart at
exactly one o'clock.
(Lunch recess.)
223
A F T E R N O O N P R O C E E D I N G S
DR. WOOD: Merck has a couple of slides
they wanted to show to address the blood
pressure
issue that came up in the previous
discussions.
So, let's go ahead and do that first
quickly.
DR. REICIN: The first was in relation to
the issue about congestive heart failure,
which is
a known side effect of all NSAIDs and
COX-2
inhibitors and is reflected in their
labeling.
Since the only data we showed was from
APPROVe, we
had an expected difference from placebo
but if you
look at this slide you see that in our OA database
the incidence of congestive heart failure
was low,
and it was generally similar to
ibuprofen. You can
see that it ranged from 0.1 to 0.4
percent on
rofecoxib; 0.4 percent on ibuprofen; and
0.8
percent on diclofenac--so, generally
similar to the
NSAID comparators. I will acknowledge that there
was one epidemiologic study that
suggested that the
rate was higher on rofecoxib.
DR. WOOD: But the data in the APPROVe
study are up to 1.5 in the rofecoxib
group, and
224
this is for serious heart
failure--congestive heart
failure, pulmonary edema. Right?
DR. REICIN: It was versus placebo. The
rate was higher in that study than we
have seen in
other studies.
DR. WOOD: Right.
But it is not a
question of whether it is against placebo
or not.
The underlying rate is much higher.
DR. REICIN: The rate was higher in that
study.
We didn't see it as high in our other
studies.
The other slide, 232--it was a
question
about whether rofecoxib had effects on
blood
pressure that were very different than
the other
NSAIDs.
This was a study done in elderly patients.
It was not an ambulatory blood pressure
study but
blood pressure was measured in these
patients 4
times a day. If you look, rofecoxib 25 mg was
compared to celecoxib 200 mg BID. That is the
highest recommended chronic dose for both
of these
medications. The medications at that dose had
similar inhibition of COX-2. We compared it also
225
with naproxen 500 BID and placebo, and I
think you
can see that the changes in systolic
blood pressure
and diastolic blood pressure are similar
among the
active treatments and greater than placebo.
DR. WOOD: Okay.
Thanks very much. These
are helpful comments. Are there any questions
specifically and only on these two
things? Steve?
DR. NISSEN: Could you show us the use of
antihypertensive agents in the two arms
of APPROVe?
I would be interested in seeing if there
was a
difference in use of antihypertensive
drugs. I am
also interested--you know, these mean
changes are
useful but it is also useful to know the
fraction
of patients that had sustained increases
of, say,
15 mm or more because that is the kind of
level of
increase that would constitute a
substantial risk.
So, I am interested in use of
antihypertensive
drugs and I am interested in the number
of people
who had greater than a 15 mm sustained
increase in
each arm.
DR. NORGAN: Kevin Norgan, Merck. The use
of antihypertensive drugs in the APPROVe
study, at
226
baseline it was approximately 30
percent. It was
30 percent in one treatment group and 29
percent in
the other treatment group. Then, during the course
of the study the numbers increased to
approximately
40 percent in the rofecoxib group and
approximately
35 percent in the placebo group. The actual
numbers are in the publication that is on
the
Internet.
DR. NISSEN: And was that difference
statistically significant?
DR. NORGAN: I don't recall. I think it
was but we would have to check.
DR. WOOD: Then 25 patients dropped out
because of hypertension versus 7 in the
placebo
group.
Right? So, that should be added
to the
number that actually ended up on
antihypertensives
in the APPROVe study.
DR. NISSEN: What about the issue of the
15 mm or greater? Do you have any data on that?
Bob Temple, isn't that something you guys
like to
look at in the FDA, the sort of 15 mm
outlier
group?
DR. TEMPLE: I don't know.
I think we
look at mean just as often.
DR. NISSEN: All right, but I would like
227
to know because I didn't see that.
DR. REICIN: We will get back to you later
with that data, Dr. Nissen.
DR. WOOD: That being the case, let's move
on to the next presentation which is from
the FDA.
FDA Presentation: Vioxx
(Rofecoxib)
DR. VILLALBA: Good afternoon. My name is
Lourdes Villalba and I am a medical
officer in the
Division of Anti-Inflammatory, Analgesic
and
Ophthalmic Drug Products. I have been the primary
reviewer for Vioxx since 1998 when the
NDA was
originally submitted for approval.
DR. WOOD: You need to move closer to the
mike.
DR. VILLALBA: So the important thing, I
have been the primary reviewer for this
since 1998,
since its original submission for
approval for the
treatment of acute pain, dysmenorrhea and
osteoarthritis.
I am going to show you an
overview of my
presentation. First of all, my goal is to show you
that we were not sleeping behind the
wheel, that we
have been actively engaged in reviewing
the
enormous amount of data that came to our
division
throughout the years, and this has been a
very
228
challenging application, a very
complicated process
to
review a lot of information that was not always
that clear to interpret.
The other issue is that I want
to point to
some observations that may help you to
think about
the best study designs. Everybody is talking about
future studies to clarify the question
but the
issue is exactly what kind of studies we
need; what
should be the comparator; how long, etc.
So, first of all, I am going to
show you a
brief background with a chronology of
events to
point out just some specific areas that I
want you
to remember. Then I am going to give you an
overview of the Vioxx data sources we
reviewed and
that will be presented also in a
chronological
order.
Then I am going to spend a few minutes
229
talking a little bit again about the
different
classification of cardiovascular
events. Then I
will go into the different Vioxx
databases showing
cardiovascular safety in the way we saw
it at the
time they were presented to us. Then a summary,
pointing out again to the challenges in
interpreting this data.
This is a busy slide and I
apologize for
it but I want to point out a few areas
here. The
NDA was originally submitted in 1994 and
it was
approved in '99 after the data was
presented at an
advisory committee meeting. Around the time of
approval there were all sorts of
submissions of IND
investigational new drug applications for
other
indications. One of them was submitted to the
Division of Neuropharm. Products for the
evaluation
of the role of Vioxx in the prevention
and
treatment of Alzheimer's disease. Another one was
submitted to the Division of Oncologic
Drug
Products and that was approved, the
adenomatous
polyps prevention trial that now led to
the
withdrawal to the product. It was initially
230
submitted to the oncology division and
then was
switched to GI. That is just a detail. This was
back in '99.
Then we had the results of
VIGOR in the
year 2000. The advisory committee meeting of
February, 2001, and after that we
reviewed a lot of
information and finally got the labeling
changes in
April, 2002. Later on, in October of that year,
there was a submission of another study in
the
Division of Reproductive Products to
evaluation the
role of Vioxx in the prevention of
prostate cancer.
About the same time Merck came to us with
a
proposal for conducting a pooled analysis
of some
of these studies, particularly APPROVe,
the
prostate cancer prevention and another
study that
was being conducted in Europe.
The Alzheimer's data was very
important
data that I will go into detail later,
but I want
to mention that preliminary data from
these studies
that were placebo-controlled studies were
initially
submitted in July, 2001. The final data from this
database was provided to us in March,
2004.
This is an overview of all the
databases
we reviewed and this does not include
APPROVe. As
you can see here in the first column,
although it
231
says "indication" the
indication refers to the
line.
But here we have the treatments.
We have
Vioxx at 3 doses, the 2 approved for
chronic use
and also for acute pain, the 50 mg, as
well as some
comparators, ibuprofen, diclofenac,
nabumetone and
placebo.
The original NDA did not have naproxen.
Then with have VIGOR which had
Vioxx 50
and naproxen. We had other studies. Unfortunately
this slide is not the last one. There are missing
2 important marks, the 25 mg dose in
study 102,
also known as ADVANTAGE study, and that
was 25 mg
versus naproxen; then the rheumatoid
arthritis
efficacy database that compared Vioxx
12.5, 25 and
50 to naproxen and placebo.
Then we had several studies, safety
outcome reports for various indications
with
different comparators and also with
placebo. I
want to point out here with placebo that
in the NDA
database we had up to 18 weeks. Most of the
232
studies were 6-week studies but there
were 18-week
placebo-controlled studies that were
endoscopic
studies.
We have placebo here in the
rheumatoid
arthritis efficacy data base, but the
most
important data we had was here, in the
Alzheimer's
studies that were long-term
placebo-controlled in
an elderly population. We had data for at least 3
years.
So, we put a lot of weight on this
information. We also had access to the adverse
event report system but, unfortunately,
it is known
that it is not very helpful to look in
this way
when we are talking about relatively
prevalent
events such as cardiac events. Then we also have
literature, epidemiologic studies,
re-analyses and
meta-analyses of data that had been
published.
Before I show every database I
want to
spend a few minutes on the cardiovascular
endpoints
because there are many different ways of
looking at
cardiovascular endpoints. At the FDA we routinely
look at all adverse events reported under
that
category--cardiovascular deaths,
discontinuation
233
due to cardiovascular adverse events,
serious
cardiovascular adverse events--this is
routine and
this is what we did in the NDA
application. We did
the same as well with all the other organ
systems.
So it is a very in-depth review.
At the time of VIGOR and all
studies
subsequently, the sponsor used a standard
operating
procedure that used a subset of
cardiovascular
serious adverse events, a category of
cardiovascular and thrombotic adverse
events, and
these were referred for adjudication to a
blinded
adjudication committee. The committee of three
cardiologists would determine if the
events were
confirmed or not confirmed. Another definition
that was used was if they were part of
the APTC
definition or not.
So, these two ways of looking
confirmed
cardiovascular/thrombotic and APTC are
not a subset
of one analysis; they are
complementary. The APTC
endpoint, the composite endpoint that
looks at
cardiovascular and unknown cause of death
is
non-fatal myocardial infarction and
non-fatal
234
stroke.
It includes ischemic and hemorrhagic
events, but does not include unstable
angina,
transient ischemic attack and peripheral
events.
These kind of events are included in this
definition up here. But this does not include
hemorrhagic events.
So, we looked at the data in
all these
different ways. Again, at the NDA stage we looked
in this general way and we became more
sophisticated and looked in all ways, the
original
one and the others.
This is very important. Let me show you
just an example from VIGOR so you can
have a clear
idea of what I mean. You have different ways of
looking at it. If you look at all investigative
cardiovascular and thrombotic events you
are going
to have more events. If you look at confirmed or
adjudicated events you still see the
difference but
the number of events is small. The same with the
APTC. Therefore, this way of looking is more
specific because it looks at the hard
endpoints.
Although it may be less sensitive, the
other way of
235
looking--let's say we have here all
cardiovascular
events submitted under that category, we
would have
for VIGOR 600 events and 400 events.
So, in my presentation I am
going to use
the APTC way of looking at it because it
also makes
very clear if there were cardiovascular
deaths or
not.
This is a different way of presenting the
data that was already presented by the
sponsor.
Here we have the NDA
database. The NDA,
submitted in 1998, was very large and
involved 5400
patients with substantial exposure in
multiple dose
trials of 6 weeks, 6 months and up to a
year
studies.
Some of the 6-week studies had extensions
to 21 months.
I want to point out that this number
is a
substantial number for an NDA. This is greater
than most NDAs. Although most of the COX-2
selective agents have had this kind of
size of NDA,
but before that we used to approve
products based
on much smaller data. These numbers are above
minimum requirements by the International
Conference on Harmonization Guidances.
In this database, looking the
way I told
you, looking at all adverse events that
were
cardiovascular adverse events and were
potentially
236
thrombotic, serious and non-serious, this
is what
we found.
This was kind of a definition that I
made myself to look at these events. This has not
been validated but, in any case, this is
what we
saw.
In the 6-week studies with
Vioxx with all
doses we have 0.7-1.1 rate, and these are
crude
rates here. There was 0.4 with ibuprofen; 0.2 with
placebo.
Therefore, we said, okay, there may be
something here but if you look at the
number of
patients exposed, they were
different. There were
more patients exposed to the Vioxx
doses. And we
didn't really know what to do with these
percentages. What dose it mean with an endpoint
that is not really well defined?
Then, in the 24-week studies
that had
placebo, up to 18 weeks, the crude rates
on Vioxx
at all doses were right between ibuprofen
and
diclofenac. Ibuprofen was 0.5 percent; diclofenac,
237
2.0; and placebo was 0.8 which was also
in between.
So, based on these data, based on the
fact that
they looked similar to the other NSAIDs
and that it
was a pretty large database, of course,
not
designed specifically to address
cardiovascular
issues, what we said was that there
doesn't seem to
be a big problem here, however, we cannot
rule out
that there could be something but this is
not the
right database to address it. On the other hand,
this was 1998. There were theoretical concerns
regarding that inhibition of prostacyclin
could
induce prothrombotic events. But based on these
data, there was not much to say about
it. Also,
Celebrex had recently been approved, in
December,
'98, and Celebrex had not shown anything
either.
So, again, based on adequate
evidence of
efficacy, safety for the intended uses
and the
similarity to the comparators, this drug
was
approved in May, 1999. If you look at the safety
profile, it was pretty similar to other
NSAIDs.
Cardiovascular safety was between
ibuprofen and
diclofenac. Hypertension, there was a very clear
238
dose response with the 50 mg being
greater than the
12.5 and 25. Endoscopic data suggested that Vioxx
was better than ibuprofen and the liver
suggested
that Vioxx was better than
diclofenac. So, it was
an NSAID.
The sponsor wanted to pursue
the claim
that this was a COX-2 selective agent;
this needs
to be different. We really don't want to see the
GI warning template in our label. And, that was
even before the NDA was submitted. It was
discussed a long time before. If you really want
to
have a substantial change in the GI label, then
you have to do large outcome studies or
at least
one large outcome study. That is why we had VIGOR.
VIGOR was not a requirement. It was something that
the sponsor decided to do because they
wanted to
distinguish themselves from the other
NSAIDs.
We know the result of
VIGOR. I am showing
here the APTC results. From now on I will use the
same format for all my slides. So, please
bear with
me for this first slide. We have the APTC total
events in the first row; then
cardiovascular
239
deaths; non-fatal myocardial infarction;
non-fatal
stroke; and non-fatal hemorrhagic
stroke. We have
the comparators here. N is the number of patients
randomized. Here, in the footnote, I have the
number of patients in patient-years of
exposure. N
gives you the number of events. Rate is the rate
based on 100 patient-years of exposure,
and the
relative rate is the overall rate for
Vioxx as
compared to the comparator.
I think I don't need to spend
too much
time describing VIGOR. It was a large study, 400
patients per arm; patients with
rheumatoid
arthritis, 60 percent using
corticosteroids, 40
percent using methotrexate and most were
women, and
patients on low dose aspirin were not
included in
this study.
This is what we found. There was a
difference in rate of
cardiovascular/thrombotic
events or APTC events, and the different
risk was
driven by the non-fatal myocardial
infarction.
This number was statistically significant.
But if you look at
cardiovascular deaths
240
there was no difference. Non-ischemic stroke,
there were no differences. So, this was the first
time when we saw the signal of Vioxx
being
different from naproxen. This is the time to vent
plot that shows the cumulative incidence
of events
over time. This is for the
cardiovascular/thrombotic events but it
looks very
similar for the APTC events.
I did show this slide back in
2001 at the
advisory committee meeting that we had to
discuss
VIGOR.
You see that the curves start to separate
here, at 6 weeks, but this separation is
more
marked after 8 months. So, if you look at the
overall hazard ratio it is 2.4, but after
8 months
that hazard ratio increases and is
4.0. There was
a lot of discussion with the sponsor
about the
interpretation of this part of the curve
and our
position was that there was increased
risk after 8
months.
Finally we got that into the 2002 label in
the form of a table that shows an
analysis of
cumulative rate of events over time that
shows that
the
hazard ratio increases after 8 months.
In any case, that difference
between
naproxen and Vioxx was driven by the
non-fatal
myocardial infarctions. There wee 9 myocardial
241
infarctions during the last 3 or 4 months
of the
study on Vioxx and there were none on
naproxen.
The position of Merck was that this was
the
cardioprotective effect of naproxen. However, we
did state clearly at the advisory
committee back in
2001 that we were very skeptical about
that
interpretation and that actually there
was
biological plausibility for a
prothrombotic effect
of Vioxx as well.
This is another study that was
submitted
to us in June, 2000 along with
VIGOR. That was
also presented to the advisory committee
meeting in
2001, showing study 090 and 085. These were two
identically designed studies,
placebo-controlled, 6
weeks in duration comparing 12.5 mg of
Vioxx with
nabumetone and placebo. Of note, they have a 2:1
randomization. That means that the number of
patients in the active treatment groups
was twice
the number of patients on placebo.
In this study, study 090,
showed 3
non-fatal myocardial infarctions and 1
non-fatal
stroke on Vioxx, 1 on nabumetone and none
on
placebo, and no cardiovascular
deaths. Study 085
showed only 1 non-fatal myocardial
infarction in
the Vioxx 12.5 mg and nothing else in any
of the
242
other arms. Therefore, with this information, the
small number of events, the fact that
study 085 did
not reproduce the findings in 090 which,
to start
with, were very mild, we didn't know what
to do
with this. This was discussed at the advisory
committee and there were not any
meaningful
conclusions from these studies. Again, I want to
mention that there were twice the number
of
patients in the Vioxx group as compared
to placebo.
The conclusions of the advisory
committee
were that Vioxx showed a superior GI
safety profile
as compared to naproxen; that the
cardiovascular
signal was of concern, however, given the
study
design it was unclear how it would apply
to other
populations, other doses, NSAIDs other
than
naproxen in populations that were at high
243
cardiovascular risk because this trial
had excluded
patients using low dose aspirin. And, that
labeling changes should reflect both
benefits and
potential harms and that additional data were
needed to clarify these issues. There was no
recommendation for a specific trial to be
conducted, or specific design. That is why I think
it is important that today you actually
give some
kind of firm recommendations and give us
direction
as to which kind of studies you want to
see.
We asked for more data and we
got more
data.
That came continuously right after the
advisory committee and at the end of
February we
had the application for the rheumatoid
arthritis
efficacy indication. It was relatively large.
There were 1500 patients on Vioxx and the
active
comparator was naproxen. There were not other
comparators.
There was also placebo here.
There were 5 studies. The endoscopic
studies were 12-week studies but the
other studies
had a 12-week base study with
re-randomization of
patients who were on the lower doses of
Vioxx to
244
Vioxx 25 and 50. And placebo here, to 25, 50 or
naproxen.
So, it was a pretty complex NDA to
review.
In any case, here we have the summary.
This follows a different format but this
is the
summary of the results. In the first column you
have the treatment and the number of APTC
events;
patient years at risk; and risk per 100
patient-years. As you can see here, it is clear
that Vioxx 25, 50 and 12.5 showed a
greater risk
than naproxen and than placebo. However, if you
look at the number of patient-years at
risk you
really cannot reach the conclusion that
there is a
clear signal against placebo. What is clear is
that there is a signal against naproxen
because
exposures to naproxen and Vioxx were
closer. I
think that the risk with the 12.5 dose is
6.9 as
compared to 0.3. So, there is something wrong; you
have too small numbers to compare. If you were to
believe this, I mean, here naproxen had
half the
risk of placebo.
So, the conclusion was that
Vioxx 25 and
245
50, both doses, in a rheumatoid arthritis
population had a higher risk of
cardiovascular/thrombotic events as
compared to
naproxen.
Then we had the ADVANTAGE
study. I am
presenting you this data on one slide but
this took
months to review, and we were not looking
only at
cardiovascular safety; we also looked at
GI, renal,
liver, everything, fractures, so anything
that was
of a theoretical concern we were looking
at. So,
this took months. Also, when you get the
information you get questions, get the
responses
within one or two months so it is a long
process
for each one of these studies.
That was for the RA. This was ADVANTAGE.
ADVANTAGE, or study 102, was submitted in
March and
another piece in April, 2001. This was a 3-month
study in patients with osteoarthritis
comparing
Vioxx 25 mg with naproxen. Approximately 2700
patients were randomized to each
arm. Here you
have the patient-years of exposure,
although I
don't like to use this number because
this is a
246
3-month trial but, still, you have it
there in case
you are interested. But if you look at the
numbers, the number of APTC events was
about the
same.
There was a signal for cardiovascular death
and non-fatal MIs. There were 9 events here and 1
here.
However, there were 6 non-ischemic strokes
on naproxen and 1 on Vioxx.
So, again, the conclusion here
is that
there is a signal. There is a signal for Vioxx as
compared to naproxen but we still didn't
know what
the role of naproxen was here because it
may have
some role but it wasn't clear what the
extent of
that was.
Based on epidemiologic data, the data
were conflicting. I think I would like to know if
someone knows exactly what is the role of
naproxen
from all these findings.
Then we had several safety
update reports
that came in July, 2001 that included
studies in
the original NDA and that were follow-up
from
patients who had been included in the
original NDA.
There were also new studies, short-term
studies and
long-term studies. The most important was the
247
study 083, the bone density study with
Vioxx 25
versus ibuprofen. The most relevant data for us
was the Alzheimer's data that compared
Vioxx 25
with placebo. That included 3 long-term studies.
There was also an updated
meta-analysis of
cardiovascular events. The sponsor had presented a
meta-analysis in February, 2001 at the
time of the
advisory committee initially and here
there was an
update.
Basically there was no difference in
confirmed or thrombotic APTC events. Actually, I
am talking about these other studies
because the
meta-analysis was done with APTC events
only.
Here is a description of the
Alzheimer's
studies.
There were 3 studies, 2 of them on
established Alzheimer's disease that had
identical
design, 15 months in duration,
placebo-controlled,
350 patients per arm, with age of at
least 65 years
or older.
One of these studies has been
completed
and showed no efficacy, and the median
exposure in
this trial was 13 months. The second one being
conducted was stopped because the first
one had not
248
shown efficacy. The median exposure was 6 months.
Then there was another study that was
ongoing at
the time of the safety update. That was study 078
that was designed as a 2-year study and
was
eventually extended to a 4-year study and
had 730
patients per treatment arm. At the time of the
safety update report that we received in
July, 2001
the exposure in this study was 18 months.
Regarding the population here, 60 percent
of them
were male with a mean age of 75 years,
and aspirin
was not allowed in this study initially
but it was
then amended to allow low dose aspirin
for those
patients who needed it. Approximately 7 percent of
patients were on low dose aspirin.
Here we have the results of
that study.
Again, here you have the APTC
events. I am sorry,
this is wrong. This should be 0.73 but still it is
below 1.0. If you look at total events you have 17
and 27.
This doesn't look bad for Vioxx.
If you
look at cardiovascular deaths, yes, there
were 8
and 5, of which 3 were thrombotic and 1
was
hemorrhagic and the other was a ruptured
aortic
249
aneurysm.
There was twice the number of non-fatal
myocardial infarctions and 12 non-fatal
ischemic
strokes.
So, based on these data, it was
puzzling
that cardiovascular deaths tended to be
against
Vioxx but, still, the number is relatively
small.
You have 8 versus 5. Looking at the myocardial
infarction and stroke, there were more
events on
placebo than on Vioxx. So, that is why I am saying
the interpretation of this data was very
challenging. How do we put together this
information for 14 months, because there
was a
median of 14 months. Putting the 2 large studies
together, 091 and 078, had a median
duration of 14
months and here we do not see the signal
that we
saw
with VIGOR.
Here is the table with the
summary of the
meta-analysis that was conducted by the
sponsor,
the updated meta-analysis comparing Vioxx
all doses
with placebo events. I think this is the most
valuable part of this slide because the
other one
is comparing non-naproxen NSAIDs and I
would agree
250
that not all non-naproxen NSAIDs are the
same. But
the total number, in any case, doesn't
look bad for
Vioxx.
The relative risks are below 1.0.
Here is what we had so
far. In the NDA
database in '98 where we didn't look
specifically
at APTC but, let me tell you because I
forgot to
mention it before, there were 3
cardiovascular
deaths with the 12.5 mg dose of
Vioxx. There were
no cardiovascular deaths with the 25 and
50 mg
doses, and there were 3 cardiovascular
deaths with
diclofenac, and diclofenac had much lower
exposure,
number of patients and time of exposure,
as
compared to Vioxx. So, there were not signals in
the original NDA.
Then we had VIGOR that showed a
signal in
APTC and non-fatal MIs. Then we had the rheumatoid
arthritis ADVANTAGE study that, as
compared to
naproxen, showed trends. Again, this should be all
yellow and this, here, should be
"no" because there
were no cardiovascular deaths in the
rheumatoid
arthritis database.
Then we have the safety update
reports
251
with the Alzheimer's studies that had
14-month,
placebo-controlled studies without
difference in
MIs and strokes, but with that
cardiovascular
trend.
After 2001, after the
presentation at the
advisory committee meeting of 2001, there
were
several epidemiologic studies and
re-analysis of
the data that had been presented or
published, and
meta-analysis but they showed conflicting
results.
Basically we had to do our labeling
changes. By
this time we were around October,
November probably
of 2001.
After negotiations with the sponsor, we
ended up in April of 2002 including a
label that
for many of you may be very confusing or
not
helpful, but that was the situation in
which we
were at that time. We had conflicting data. So,
what we did, we put the result of VIGOR
there. We
included two tables showing the
cardiovascular
events over time, the list of
cardiovascular events
by category. There was also some language in the
precautions section and the indications
because the
rheumatoid arthritis indication was
approved now,
252
after we reviewed all the data, not 6
months before
when we should have approved--not 6
months, we have
a
10-month clock to review efficacy supplements.
Anyway, they were not approved
until we
had reviewed a substantial amount of
data. There
was something also in the adverse
reaction section
that pointed out to the risk of
hypertension in
patients with rheumatoid arthritis with
the lower
dose.
Before we had something that referred to the
50 mg dose being worse than the 25 and
12.5 but in
rheumatoid arthritis patients the 25 mg
dose also
showed to be worse than naproxen. There was also
some language in the dose and
administration.
I am not going to go through
all this,
don't worry, but I just want to point out
that we
put a lot of information there and we
said that we
didn't know how to interpret this data;
that
prospectively designed studies have not
been
conducted.
Following these label
changes--again, I am
not going to insist on this but we also
had
language regarding the 50 mg dose not being
253
recommended for chronic use.
In October, 2002 we had the
proposal by
the sponsor to conduct a prospective analysis
of
cardiovascular thrombotic events that I
mentioned
earlier in the 3 long-term
placebo-controlled
studies.
One of them was ongoing already since
early 2000. Another one was being conducted or was
going to start soon in Oxford. They submitted the
prostate cancer prevention study at that
time so it
had not even started. But all the 3 studies
together were going to provide
approximately a
25,000 patient database that was placebo
controlled.
the prostate cancer prevention studies
were planned to be up to 6 years in
duration. So,
we had potentially a lot of information
there.
We agreed with the concept of
pooling
these studies and we specifically said it
is
possible that these studies may address
the
question we have, however, we cannot
assure you
that if you don't show anything in this
study you
are out of the woods So, that was a review issue.
Also, there were a lot of discussions
regarding the
254
data analysis plan for these pooled
analyses.
Here we have the result of the
updated
data from the Alzheimer's studies. This was
submitted to us in March, '04. As you can see
here, the rate of APTC events still is
not worse
than placebo. It is about the same. There are
more events on placebo but there was also
longer
exposure if you look at patient-years of
exposure.
There was no difference in cardiovascular
deaths as
adjudicated by the committee. There were 14 and 14
non-fatal myocardial infarctions; 17 and
6
non-fatal strokes. The strokes were all in the
placebo group--sorry, not all. The point is that
here we don't see a signal on stroke; we
don't see
a signal on MI. Death kind of is there, maybe or
maybe not, because if you look at the
subset of
cause of death then you may argue that,
okay, there
were more sudden deaths in Vioxx as
compared to
placebo maybe but all together they
looked about
the same.
So, this is what we had up till
March.
Actually, when the APPROVe study was
presented to
255
us this application was still under
review. It is
still under review because we had
requested
additional information so it takes time
until it
comes to us and we can review that data
again. So,
there are still many questions we have
regarding
this database.
Let me show you the
Kaplan-Meier curve
first.
This is again the percent of patients with
events versus time. As you can see here, placebo
was about here up to almost 24 months and
then they
completely overlap. But the confidence intervals
all along were very wide.
If you look at this table that
I took from
the sponsor looking at relative risk over
time,
again you see that after 18 months the
risk was
higher on placebo as compared to Vioxx
and after 18
months the risk switches and is higher on
Vioxx
compared to placebo.
Again, if you look at adverse events with
an overall risk you have a number, but it
is very
important to look at risk over time
because down
here, after 36 months, it seems that
Vioxx is
256
picking up. But, still, I mean the confidence
intervals are so wide we can't make any
conclusion
out of this.
This is the total-cause
mortality in the
Alzheimer's studies. As I think has been pointed
out before, there was a difference in
total-cause
mortality in Vioxx versus placebo, but if
you look
at the cause of death they were kind of
not
clustered under one specific organ
system. They
were all over. Also, this is the first time that
we had a placebo-controlled database of 3
years of
an NSAID or a COX-2 selective NSAID. So, it is
very hard to make any conclusion based on
a
comparison of Vioxx with placebo when we
do not
have any information on diclofenac or
ibuprofen,
the same kind of data up to 3 years. Still, it is
of concern because, as I said, we are
still
reviewing this application.
Then I want to mention the
epidemiologic
studies because there were many
epidemiologic
studies and re-analyses and
meta-analyses.
Although I will mention that those
meta-analyses
257
did not include substantial information
that we had
access to. Unfortunately, we could not share that
with the world if they were not published
in the
literature. But epidemiologic studies in general,
the ones looking at Vioxx and the ones
looking at
naproxen--some of them were
conflicting. What was
consistent was that there was increased
cardiovascular/thrombotic risk for Vioxx
50 and
that was in the label already. Actually, we have
said that for everyone with ischemic
disease people
should be cautious. There was no clear evidence
with the 12.5 and 25 mg dose. Again, we had seen
the signal but as compared to naproxen,
not to
placebo.
And, there was conflicting evidence
regarding the cardioprotective effect of
naproxen.
Out of 9 studies, 5 would say it is
cardioprotective and another 5 would say
it is not,
or 4 would say it is not and 1 would say
it
actually causes myocardial infarction.
So, I think that up to today I
am not
clear as to what is the role of
naproxen. I think
that it is possible, it is plausible that
there is
258
a prothrombotic effect of Vioxx but that
big effect
that we saw in VIGOR and in the other
databases as
compared to naproxen--I think that
naproxen does
have a role there too but that does not
explain
everything, for sure.
In the meantime, during this time we were
awaiting the results of the long-term
placebo-controlled studies and then we
had APPROVe.
This is data submitted to us in January,
2005. So,
I am not sure if they are exactly the same
numbers
that the sponsor has shown because there
was
another submission from October that is
slightly
different. Anyway, the point is that here it is
very clear if you look at APTC
events--for fatal MI
there was only 1. So, if you look at non-fatal MI,
there were 10 and 8. For ischemic stroke there is
also a signal, but not for hemorrhagic
stroke. But
looking at cardiovascular deaths, there
were 6 and
5.
This is the time to event plot
that you
already saw several times. I want to show you this
later.
What I want to show you now is that up to
259
here what we had was a signal for Vioxx
as compared
to naproxen. That is clear. But compared to
placebo, in the Alzheimer's data the only
thing is
there was a trend for cardiovascular
death. In
APPROVe it is completely opposite. You have a
negative effect on
cardiovascular/thrombotic
events, non-fatal MIs, stroke, but not in
cardiovascular death. If you look throughout, this
is the first time where stroke appears as
being a
problem with Vioxx.
This refers more to the second
goal that I
had.
Well, first of all, it was to show you that
you need to look at risk over time. The other
issue is what is the role of aspirin in
these
studies in how it may affect different
endpoints.
This is how it affects APTC
endpoints. Don't even
look to the left side. There are too many numbers
here.
The point is that the difference in
cardiovascular and thrombotic events or
in APTC
events is driven by the non-aspirin users. In the
aspirin users the relative risk
decreases,
particularly because there is an increase
in the
260
patients in the comparator. I think that this has
to do with the kind of population that
you want to
see in the studies. You would want to see patients
at high risk but not all patients at high
risk
because I think that use of aspirin may
make it
actually difficult to find a difference
between
treatments. Anyway, we should have both high risk
an not high risk. These were not very high risk;
they were just patients that needed
aspirin.
I am going to show you this
slide just
quickly.
I know that Dr. Temple is going to spend
more time talking about blood
pressure. The
sponsor conducted several analyses of
blood
pressure and I chose this one, which is a
very
simplistic one but, still, I think it
makes the
point that when you look at on-treatment
hypertension those who develop no
hypertension
still had increased risk for Vioxx 25
compared to
placebo.
The risk is very obvious here, that it
increases in patients with hypertension. This is
using the definition of patients who
develop a
diastolic blood pressure of 100 or
systolic blood
261
pressure of 160.
The point of this slide is that
if we are
going to look at those patients with very
high
blood pressure we are missing the boat
here because
we need to look at those patients who
have not as
bad hypertension. We need to look at those
patients who are within the range of
140/90 or
maybe even high normal blood pressure.
This is again a busy slide and
I am not
going to walk through it, but just to
make the
point that if you go through different
databases
you
have different numbers, all over, and the rate
of events in the Alzheimer's studies was
higher,
particularly in placebo. Here in the Alzheimer's
study it was 2.07--I am sorry, I am going
too fast.
Let me start again. You have VIGOR, Alzheimer's
database and APPROVe with Vioxx/naproxen;
Vioxx/placebo; Vioxx/placebo. Here with
have APTC
events, myocardial infarction and
total-cause
mortality. N is the number of events and this is
the patient-year rate in 100
patient-years of
exposure.
The point was that placebo
here--the
patient-year rate is 2.07 while here it
is 0.54 in
the APPROVe study. Naproxen here is in between in
262
the VIGOR study. The point is different
populations, different background rates
in the
active treatment and also in the
comparator
treatments. So, again, we need to define what kind
of
population we want to have in these studies.
The other point is that if you
look at
total-cause mortality, the one that
looked bad was
Alzheimer's. There was no difference in
total-cause mortality in APPROVe. There was a mild
imbalance here in VIGOR and in the other
databases
there was no difference in total-cause
mortality.
So, I hope you understand how
challenging
it was for us as we were reviewing this
data.
There was a clear signal compared to
naproxen that
was not consistent when compared to
placebo. And,
we have no comparative data, particularly
cardiovascular safety data, for Vioxx and
non-naproxen NSAIDs or not a lot of data
on
long-term placebo controlled with traditional
263
NSAIDs.
We still need to clarify the
role of blood
pressure and what is the role of aspirin
in
protecting for cardiovascular
events. I think that
is it.
I kind of said this while I was talking.
So, this is the end of my presentation.
Committee Questions to the
Speakers
DR. WOOD: Thank you very much. Could you
go back three slides, and then I am sure
Dr.
Fleming will want to ask you a question?
DR. VILLALBA: Which one?
DR. WOOD: The third last slide in the
handout.
That one.
DR. VILLALBA: This one?
DR. WOOD: Yes.
Am I right?
DR. FLEMING: You read my mind. I wanted
to follow-up on this because it is also a
follow-up
to a question I asked this morning. Just to get a
sense of what the totality of the data is
telling
us about whether there is an all-cause
mortality
risk increase, and the two studies on the
left
definitely strongly suggest that there
is. In the
264
discussion this morning it was pointed
out that
there are other sources of data that
might
complicate the interpretation, the
ADVANTAGE trial
being one of those. But if you look on sponsor
slide 54, which we won't go back to now,
the other
studies are all very small relative to
the numbers
of events. More than a half of the total deaths in
the meta-analysis of all the studies are
from the
VIGOR study and the Alzheimer's studies
and that is
where we are seeing the signal. The ADVANTAGE
study that we were told about that didn't
show
significance still had one more death,
and you said
in your presentation it was 4 versus 0 in
the wrong
direction. There are 2 in the cardiovascular.
I guess my concern here is that
when I
look at this it is on-drug, and I think
it is
getting back to a question Ralph was
asking earlier
today.
All of these analyses, are we correct, are
only giving us that deaths that occurred
within--what?--30 days of being on drug?
DR. VILLALBA: Two weeks actually.
DR. D'AGOSTINO: Yes, I raised that
265
morning.
I mean, why weren't these individuals
followed till the end of the study to
find out
about mortality?
DR. VILLALBA: Well, actually that is a
good question to the sponsor because we
know that
they were followed as much as they could
do it, but
it was not mandatory. They tried to collect all
the data they could but it was
actually--I would
prefer them to answer.
DR. WOOD: Well, let's not involve
motivation right now. Let's just keep going with
the facts. So, Tom, keep going.
DR. FLEMING: Well, that is the essence
that I wanted to get at. It was just to understand
that this is just on-drug and there is
nothing else
you can provide us in terms of a true
ITT? Is that
correct?
DR. VILLALBA: There were more deaths also
after but there was not a balanced
exposure.
DR. WOOD: No, what he is asking is do you
have an intention-to-treat analysis?
DR. FLEMING: Correct.
DR. VILLALBA: No, I don't have it with
me.
That is why I said this is still under review.
There is pending information.
266
DR. WOOD: But before we leave this slide
though, it is important to remember why
we are
here.
I mean, this is a drug whose indication is a
safety indication, and the reason to give
the drug
was to reduce an adverse event which is
always
thrown up as causing this terrible
outcome,
although the outcome has improved
substantially
over the last 10, 15 years.
It is certainly worrisome when a drug that
is supposed to produce a safety benefit,
in fact,
is producing an increase in mortality, it
seems to
me, and that is worthy of some
discussion.
Certainly, an ITT analysis would have been
important.
DR. VILLALBA: Again, I completely agree.
We are concerned, but we don't know how
other
NSAIDs would look here.
DR. WOOD: I understand.
DR. VILLALBA: We need to put it into
267
context.
DR. WOOD: That is what my teenaged kids
say as well. Curt?
DR. FURBERG: I was wondering whether you,
within the agency, considered the risk of
heart
failure.
I mean, when I look at the tables and in
your presentation you are using the term
heart
arrest signal in a narrow sense. There is nothing
in your tables on heart failure. It is an issue.
As the Chairman found out a little bit
earlier, in
the APPROVe study, a 4-fold increase in a
long-term
trial.
Do you have information from the Alzheimer
trials on heart failure? If you look at the
adverse effects of the drug, we shouldn't
just
narrow it to heart attacks and
stroke. Let's
broaden it to heart failure and make that
part of
our evaluation.
DR. VILLALBA: Yes, I don't have slides
with me regarding congestive heart
failure but,
again, we don't have the data for other
NSAIDs.
That is the only thing that I can keep
saying. But
there was more heart failure, for
example, in VIGOR
268
clearly as compared to naproxen.
DR. WOOD: I sense that there is a
response coming from the sponsor. Do you want a
couple of minutes to think about that
before you
get up?
You can take a couple of minutes and we
will take another question, if you
want. Take your
time; we won't forget you. Dr. Bathon?
DR. BATHON: I am a little confused about
the aspirin issue. On your slide 35 you showed a
decreased hazard ratio or relative risk
for the
aspirin users compared to non-aspirin
users. But
in Dr. Braunstein's presentation it was
the
opposite.
I realize that the outcomes were
measured a little bit differently.
DR. VILLALBA: That is a very good point.
These are APTC endpoints and the way that
Dr.
Braunstein showed it was all
cardiovascular/thrombotic events that
included also
peripheral events, unstable angina and
TIA. So,
the point of this slide is precisely that
when we
design a study that is going to address
these
issues in the best possible way we need
to choose
269
the right endpoint. And I don't know what that
endpoint is because if you look at all
cardiovascular events you may see more
than if you
look only at APTC.
DR. WOOD: Dr. Shafer?
DR. SHAFER: I know it is always easier in
retrospect to try to make sense of things
than
prospectively when you are looking at
many possible
adverse outcomes and trying to figure out
where to
focus one's attention. But if you could go back to
slide 23, what we see here, in slide 23,
is a lot
of suggestions of danger signals. Dr. Braunstein
made an interesting point earlier when he
said that
it would take about 30,000 patients to
demonstrate
an increased risk, and yet we see danger
signals in
very small studies of short
duration. So, that has
obviously to be a cause for concern.
Then along comes the VIGOR
trial. As I
understand, basically VIGOR had a 2-5X
increase in
serious adverse cardiovascular events
depending on
the endpoint you chose to look at. Now, there are
two possible interpretations of
that. One
270
interpretation was that rofecoxib
increased risk.
At the time you had this background
worrisome
signal rate which was consistent with the
mechanisms that Dr. FitzGerald spoke
about, and if
that were the true state of things, then
potentially millions of patients were
being placed
at risk.
The converse choice is that
Naprosyn
decreased risk. There were very weak data to
support that. As we heard from Dr. Nissen, the
effect was too large to be really
explained by any
known effect of aspirin. And, the safety data that
were used to support the safety of
rofecoxib was
far less than the 30,000 patients that
would be
required to significantly show the
difference. By
Dr. Braunstein's own statements, you
know, it would
take far more patients to really
statistically
significantly show that up.
What I first thought was the
company and
the FDA chose to give pretty good
credence to the
naproxen hypothesis. It sounds from the comments
today that that is still the position of
Merck.
271
What would it have taken, what kind of
data would
it have taken, given the results of the
VIGOR trial
and the two alternative hypotheses, for
the FDA at
that point in time to either put a black
box
warning or perhaps even remove Vioxx from
the
market?
What kind of data would you have had to
have in addition to what you have?
DR. VILLALBA: I cannot answer that
question.
What I can tell you is that this was as
compared to naproxen. We never bought the naproxen
theory, but we also did not have evidence
that
Vioxx was worse than placebo or other
NSAIDs.
DR. SHAFER: You have great evidence in
VIGOR though.
DR. VILLALBA: I completely agree but it
was naproxen, and I think the
presentation tomorrow
with the epidemiologic data on naproxen
will be
very informative about how confused we
are until
today.
Regarding the signals, yes,
those were
observed but that was after VIGOR, not
before.
Again, we have that long-term, placebo-controlled
272
data in Alzheimer's patient elderly
population that
had shown no difference in myocardial
infarctions
or strokes. There was that signal of
cardiovascular death that, by the way,
was put in
the label. But there were 8 versus 3 events and we
didn't know what to make of that.
DR. KONSTAM: Hi, there.
I am Marv
Konstam.
I am from Tufts University and I am here
with Merck as a consultant. In 2001 I was first
author on the overall pooled analysis for
the
entire rofecoxib database so I just think
I want to
speak to it, and the interpretation of
VIGOR and
where the company I think was, and the
world was,
at that point.
I think it is really difficult
to look at
individual studies with very, very small
numbers
and find signals, and one can draw all
kinds of
conclusions from them; and there may be
signals in
the other direction in some of the other
small
studies.
So, what was done at that time
was, you
know, there was a signal from the VIGOR
study.
273
This finding was unexpected. It showed an adverse
effect on cardiovascular endpoints. Now, one thing
I want to stress about that is that of
all of the
information that could be brought to
bear, I think
the point estimate for the hazard ratio
from that
is probably the least important to
me. You know,
you are looking at very small numbers of
events,
unexpected finding, wide confidence
intervals. So,
I just want to point that out.
What was done at that point was that the
entire rofecoxib database to that point
was
reviewed in a systematic way, and all of
the data
were pooled. They were divided, as you heard,
between Naprosyn comparator, other NSAID
comparator
but, most importantly, the placebo
comparator.
Because VIGOR was an active controlled
study and
none of us to this day know exactly to
what extent
the result was contributed to by an
adverse effect
of rofecoxib, a favorable effect of
Naprosyn or a
combination. So, the most valuable data are the
placebo-controlled data. And, reviewing all of the
placebo-controlled data to that point,
pooling all
274
of those data, there was 3000
patient-years of
follow-up, there was not a hint of an
adverse
signal--not a hint of an adverse signal.
Now, granted, there were
confidence
intervals around that signal so that is
real. We
still didn't know, and I think we know a
lot more
today thanks to the APPROVe study, but at
that
point in time if you look at all of the
placebo-controlled data that existed
there was not
a hint of a problem, which I think led me
at that
time and I think led others at that time
to say
this may be contributed to by a
significant
beneficial effect of Naprosyn.
DR. WOOD: Just let me make sure I
understand. Are you saying that that is still your
position?
DR. KONSTAM: No, no.
That was the
position at that time. One might then ask, okay,
what is different between the APPROVe
data, and I
might say that I was on the data safety
monitoring
board for APPROVe, and why is APPROVe
different
than the pooled placebo-controlled at
that time? I
275
think that is a really cogent question to
ask and I
have asked myself that question.
I believe the difference now,
in
retrospect, is exposure time. From APPROVe we see
no evidence of a hazard in the thrombotic
events
through 18 months and then there is a
separation.
The median follow-up in that pooled
analysis that I
just referred to is relatively
short. I don't know
what it was exactly but it was
months. It
certainly wasn't the 9 months that was
there in the
VIGOR study or the 2.4 years in the
APPROVe study.
So, that is a substantial
difference. There are
other differences, but to me that may be
the
explanation for why the pooled analysis,
back in
2001 and as it went forward, showed no
problem but
APPROVe then came and did show a
problem. I think
it probably was the exposure time.
DR. WOOD: But just to be absolutely
clear, you are not saying that you still
believe
the VIGOR study was due to a totally
protective
effect of naproxen, are you?
DR. KONSTAM: No, no, I am not.
DR. WOOD: Good.
I just wanted to be
clear on that.
DR. SHAFER: While you are there, Dr.
276
Konstam, in terms of the relative risks
of the two
possible choices--either rofecoxib
increases risk
or Naprosyn decreases risk--was that part
of your
thinking as well? What are the possible outcomes
of the two competing hypotheses? The truth is
probably somewhere in between.
DR. KONSTAM: Well, first of all, let me
just add one other point that I should
have
mentioned. The other point about the VIGOR study
was the dose. So, there was a very high dose used
in VIGOR and there were lower doses in
the pooled
analysis.
APPROVe was 25 mg; an intermediate dose.
What was your question
again? I am sorry.
DR. SHAFER: There are somewhat different
potential concerns with the conclusion
that
rofecoxib increases risk as opposed to
the
conclusion that Naprosyn decreases
risk. Was that
part of your decision analysis at the
time?
DR. KONSTAM: Yes, thinking back at that
277
time, there was no adverse signal from
the
placebo-controlled data. I don't think, you know,
most people were completely satisfied
with that.
If you look back at what the company did
at that
point, first of all, there was a warning
put on the
label and we can argue whether that was
good enough
or not.
But then we embarked on a large
placebo-controlled program with a
prespecified
adjudication process for cardiovascular
events, and
that is the process that led to the
definitive
finding of APPROVe, even with a much
smaller N than
they were planning to do so they had a
much larger
program planned and we decided to stop
APPROVe
because we saw it in APPROVe.
DR. WOOD: Let's go on.
Dr. Nissen?
DR. DOMANSKI: We have heard a lot of
discussion about who know what, when, and
we have
seen a tremendous amount of data
presented, and in
the end this committee is going to have
to make
some recommendation about what to do
going forward.
I am very interested, if we could, in
hearing from
each of the pharmaceutical manufacturers,
as well
278
as everybody else of course, before they
sort of go
away into the distance. I am very interested,
given the totality of data that are
currently
available--not what you knew when or who
should
have known what, how or when or who
should have
done something else--I am very interested
in what
you think ought to be done now going
forward,
knowing what we know. What recommendation would
you make?
What would you like to see come out of
this?
Or, maybe what do you think we should see
come out of this?
DR. WOOD: Dr. Nissen?
DR. NISSEN: Yes, a quick comment and a
question.
The comment is--and I think for people
in the audience who may not fully
understand why we
are drilling down on this intent-to-treat
aspect of
the
analysis--that it may be that the individuals
who are dropping out of these trials
because of
adverse events, that received the COX-2
inhibitor,
they may be pharmacogenomically more
susceptible to
the adverse effects of COX-2
inhibitors. So, you
are taking out of the trial the people
that are at
279
greatest risk. If you don't follow those people
you may not find that out.
This idea of censoring events after two
weeks--you know, I think we have to all
learn
something from what happened here, and
this is the
first time I really realized that that
was the way
these studies were conducted. That was a mistake.
Once a patient is exposed to drug you
ought to
follow him as long as you can because
there may be
a persistence of risk and we learn
something from
that.
So, a lesson is learned. I think
it is a
useful lesson to learn.
I guess the second
question--and, you
know, you may or may not want to answer
this but if
you had to do it all over again would you
do it
differently?
DR. WOOD: Let's keep the tense in the
future tense. Let's not keep regurgitating that.
Bob, do you want to say something in the
future
tense?
DR. TEMPLE: Yes. I
just want to remind
people that intent-to-treat analyses are
generally
280
loved by people because they are
conservative
analyses.
They ten to make effects go away.
That
is why we like them. If you are worried about
informative censoring and other stuff
like that--
DR. WOOD: But it tends to make efficacy
effects go away.
DR. TEMPLE: That is correct. They also
make time effects go away.
DR. WOOD: Not if you are dead.
(Laughter)
DR. TEMPLE: No, no, you have to count the
deaths.
It is not that you shouldn't follow people
up but the analysis that includes all
people long
after they are off the drug has a very
high
likelihood, I believe, or not showing the
effect of
the drug.
You have to remember it is a
conservative analysis for looking for
effects.
Before we get too enthusiastic about it,
if I make
the effect look less when it really
doesn't deserve
to look less--
DR. FLEMING: Could I just quickly add to
that?
Historically we look at safety and often we
281
do truncate follow-up after two weeks or
a month.
That is based on the premise that safety
risks are
acute.
If they are, in fact, acute, then you are
going to get a clear sense of what is
going on with
the type of approach you are talking
about.
Mortality effects, I would think, are
much more
difficult to justify as being purely
acute. There
is a basis to what you are saying. If you follow
everybody for a long time after they are
off
therapy there could be some diluting.
Nevertheless, if you want an unbiased
assessment of
the truth you need to do what Steve is
talking
about, an ITT analysis, and then make
your judgment
as you look at the hazard ratio over
time.
DR. D'AGOSTINO: We are sitting here and
we don't know the answer. It may have washed it
away and it may not have.
DR. TEMPLE: I am not saying don't get the
analysis but, for example, our ordinary
position in
an outcome study is that we want to see
the
intent-to-treat analysis.
DR. WOOD: Let's hold this for the
282
discussion. Let's just keep focused on the
questions right now. Any further questions for the
speaker?
I am not forgetting about you.
Hang on
just a moment. Dr. Holmboe?
DR. HOLMBOE: I just had a question to the
speaker.
Again, we are trying to give you some
advice and some guidance as to this. Given, as
Alastair said earlier, that this drug was
really
evolved for a safety indication,
therefore, being
compared to another class of drugs, in
retrospect
learning that those comparisons were based
on drugs
approved prior to new knowledge that has
been
accumulated, such as presented by Dr.
FitzGerald,
it would be helpful for me to hear what
has the FDA
learned about the process or form? What can you
tell us that might help in the future
when you are
faced with these sorts of things? For example, the
diclofenac is a perfect example, well, it
turns out
that maybe it is not, you know, your
run-of-the-mill NSAID. A lot of what you presented
in the original data was, like, well, it
was
between ibuprofen and diclofenac,
therefore, we
283
determined it was probably okay. So, I would be
anxious to hear what you have learned
since you
have been with this project now for seven
years.
DR. VILLALBA: Well, actually we wanted to
have the recommendation from you to know
how to
proceed now because we have close to 20 approved
NSAIDs so what do we do with them?
DR. WOOD: Ever the optimist, right! Dr.
Domanski?
DR. DOMANSKI: I guess before Merck gets
away I would still like to hear their
view of where
we should go from here. I am really quite curious
about that. I understand about intention-to-treat.
We do clinical trials. But I would just like to
hear what their thoughts are.
DR. WOOD: Their thoughts on what?
DR. DOMANSKI: What their thoughts are on
where we should go from here.
DR. WOOD: I thought we were talking about
where we have been. I am happy to hear them on
where they should go. Do you have thoughts on
that, Bob?
DR. DOMANSKI: No, I am asking that of
Merck.
DR. WOOD: Oh, I am sorry.
284
DR. BRAUNSTEIN: I think we showed that on
our last slide. Can I see our last slide, 57? I
mean, for the short term what we are
trying to do
is trying to better understand our data;
trying to
better understand which patients were at
increased
risk for the events that we observed in
APPROVe
based on both the clinical data and also
the
specimens that we have from these
patients. We
also are working with various people to
try and
explore different hypotheses for the
data, and we
are collaborating with others who are
looking at
the data across all the drugs in order to
get a
better feel to see if we can understand
when we
pool all the data because I don't think
any one
data set that we have is powerful enough
to address
these questions. So, hopefully, by pooling the
data we will be able to get a better feel
for this.
The last is that we think we need to do
comparative
outcome studies to better understand the
relative
285
risks of the selective COX-2 agents with
the
traditional NSAIDs. There are not long-term data
on the traditional NSAIDs to really
establish what
their cardiovascular risk profile is, and
we think
that the study that we are doing, for
example the
MEDAL study is one such study in the
right
direction.
DR. WOOD: Merck wanted to present some
other data. Right?
DR. REICIN: I think there was a question
about congestive heart failure in the
Alzheimer
studies.
DR. WOOD: Right.
DR. REICIN: So, just put up slide for us
12-22 and then we will go to 12-28. I showed you
this slide just at the beginning and you
noted that
in our 6-month population--so this is a
shorter
population than either APPROVe or what I
am going
to show you in Alzheimer's--the rates
were quite
low and they were similar to the NSAIDs.
If you go now to 12-28, in the
Alzheimer's
studies, in protocol 078 which was a
4-year study,
286
interestingly, the rate of congestive
heart failure
was similar between the two groups, 2.2
percent on
rofecoxib 25 mg, 2.6 percent on
placebo. In 091,
however, which was a one-year study the
rate was a
little bit higher on rofecoxib, 3.2
percent versus
1.4
percent. I think these rates are more
what you
would expect in an elderly
population. The mean
age of this patient population was 75
years old.
DR. WOOD: Thanks.
DR. REICIN: One other thing, there was a
question about ITT mortality. In APPROVe we are
following patients in an ITT way for
mortality.
That is still ongoing. To date, there were 3
thrombotic events in each treatment group
following
that 14-day period.
DR. WOOD: Dr. Paganini?
DR. PAGANINI: I have a question on the
comparative data with other NSAIDs. Is there not a
post-approval period of time for drug
review, and
from that post-approval Phase IV type
studies can
you not draw anything from that to
compare to?
DR. VILLALBA: Phase IV commitments are
287
made at the time of approval. If there were not
specific agreements between the FDA and the
company
to conduct those studies we have no legal
power to
mandate any kind of studies. So, some studies are
done basically pursuing different--I mean
with
promotional, advertisement or whatever
there are
many studies. But those are really not usually
large outcome studies. They are short studies with
small numbers of patients. I don't know if I
answered your question.
DR. PAGANINI: You did in a way. One of
the issues that I think we are going to
have to
face is how do you compare these things,
both
things that have already been approved
and new, to
the same standards when they were
approved back
then to current standards? Perhaps one of the ways
around that might be an approval
comparison with
longer Phase IV commitments by companies
to
follow-up on what is happening to that
drug over
time.
That way, you would have the ability to
compare a new to a similar in a similar
population
of patients.
DR. VILLALBA: Absolutely.
That is
something that we learned, yes.
DR. WOOD: Ralph?
288
DR. D'AGOSTINO: I am all for torturing
data and during Lent I always read
Dante's
"Inferno."
(Laughter)
But shouldn't we be impressed
with the
APPROVe study? You leave us with a table that
compares a lot of studies and you throw
out some
obviously important questions, but
shouldn't we
sort of look very seriously at the
APPROVe study?
It was well designed--
DR. VILLALBA: Of course.
DR. D'AGOSTINO: --and shouldn't we sort
of diminish in our view some of the
previous
studies?
DR. VILLALBA: The Alzheimer's studies, do
you mean?
Now, yes. What I was saying is
that
these are different populations and I do
not have a
good explanation for why we didn't see
the same in
an elderly population.
DR. D'AGOSTINO: Well, could it be that
the APPROVe study was going after a particular
set
of outcomes and the others weren't, and
it was more
retrospective?
DR. VILLALBA: No, because in the
Alzheimer's studies they also used the
same
289
standard operating procedures to
adjudicate the
event.
DR. D'AGOSTINO: But do they have the same
ascertainment? You know, in designing a
placebo-controlled study where you go
after
something retrospectively, looking at
that and
trying to say the ascertainment might
have been the
same.
DR. VILLALBA: You are completely right.
That is possible but that is a question
to the
sponsor, if the ascertainment could have
been
different in the Alzheimer's studies.
DR. WOOD: Dr. Hennekens? Actually, I
would like to ask Marvin a question. Marvin, the
APPROVe study was scheduled to terminate
at about 6
weeks after the early termination on the
basis of
290
the board's recommendation that you were
on. As I
recall, the numbers of events were 45 and
25 at
that time. So, was the board unanimous in its
decision to terminate, and was the basis
clearly
related to that particular endpoint?
DR. KONSTAM: Yes.
Yes, that is exactly
right.
I would say that the reason, if I might say
why we recommended termination--the
reason we
recommended termination is that we felt
at that
point in time that we had a definitive
piece of
information that wasn't going to
change. The
reason we recommended termination was
that we felt
the patients in the APPROVe study were
not aware of
this and had not been consented to this
adverse
effect.
So, in our judgment, you know, from an
ethical viewpoint if you were going to
continue you
would have to go back and re-consent them
and that
certainly wasn't practical at that point
in time.
So, that is the specific reason we
recommended
termination.
DR. WOOD: But you told them that caution
should be exercised in patients with heart
failure.
291
Right?
DR. VILLALBA: May I say something?
DR. WOOD: Sure.
DR. VILLALBA: I don't want to leave you
with the impression that we think or I
think that
APPROVe is not important. I just want to show you
how puzzled we were with all the
data. So, until
APPROVe we didn't have a firm reason to
really take
a regulatory action that was different
from what we
had done up to that time.
DR. WOOD: Ralph again?
DR. D'AGOSTINO: In terms of the
Alzheimer's study, do you have
information on the
all-cause mortality? I forget what you said. Do
you have anything about CVD,
cardiovascular
mortality when off drugs?
DR. WOOD: Let's take that under
advisement unless you have it right
there. Do you?
No?
All right, we will get back to that.
Any
other questions? Yes?
DR. TEMPLE: Actually, I wanted to respond
to Ralph.
The thing about APPROVe is that it was
292
longer than the rest of the studies and
most of the
effects were seen sort of late. So, it provided
the kind of information that really
didn't exist
before.
DR. D'AGOSTINO: When we come to the
discussion of designing the trial, there
is so much
emphasis on how many events we should have
and I am
always bothered by that because I would
like to
make sure people have taken the drug for
a long
enough time. I think this is a case where you are
seeing where length is where something is
happening.
DR. WOOD: Unless there are any other
questions, let's stop our discussion of
Vioxx at
this point, rofecoxib, and take a
ten-minute break.
We will reconvene and start on celecoxib
when we
get back.
(Brief recess)
DR. WOOD: If you will get to your seats
we can get started, otherwise we will be
here half
the night. Just go ahead.
Sponsor Presentation: Celebrex
(Celecoxib)
DR. FECZKO: Dr. Wood, thank you. I will
keep these introductory remarks brief,
briefer than
I was planning. I will just introduce our
293
presentation today. I am Dr. Joseph Feczko. I am
President of Worldwide Development at
Pfizer. I
would like to thank the Food and Drug
Administration and the advisory committee
for this
opportunity for Pfizer to share their
data that
demonstrates the cardiovascular safety
profiles of
our COX-2 inhibitors, Celebres and
Bextra,
especially in comparison to the
non-selective
NSAIDs.
For Celebrex questions arose
recently from
the preliminary data from a longer-term
study, the
APC trial sponsored by the National
Cancer
Institute. A cancer prevention trial would suggest
an increase in cardiovascular risk
compared to
placebo for patients taking Celebrex at
daily doses
of 400 mg and 800 mg per day. The important
findings must, and will, be put in
context and
evaluated with the large body of prior
data on
Celebrex.
Celebrex has been extensively
studied both
by Pfizer and by independent
investigators in
randomized, controlled clinical trials
and
epidemiologic studies. With all this research, we
continue to investigate GI toleration in
arthritis
patients and the ability to treat rare
form of
294
precancerous polyps, familial adenomatous
polyps,
for which we have an indication.
We also are continuing to study
Celebrex
in cancer prevention, and we have a large
number of
trials in cancer treatment where Celebrex
is added
to conventional chemotherapy for a
variety of
cancers.
In a moment Dr. Kenneth Verburg
will
outline for you several bodies of data. One, he
will review the cumulative safety
tolerability data
for Celebrex. Two, he will review the results of a
new meta-analysis of Pfizer's database,
one of the
largest analyses of its kind conducted to
date.
This includes extensive information
looking at
Celebrex in comparison to other widely
prescribed
non-selective NSAIDs. Third, Dr. Verburg will also
295
present results of multiple published
epidemiological studies which show a
consistent
lack of the cardiovascular signal for
Celebrex when
used in the real-world setting in
arthritis
patients.
Throughout the presentation we
will also
look at this issue of whether or not
there are
differences or similarities in a class of
COX-2
compounds or across the non-selective
NSAIDs. I
think we all know that within a class of
compounds
there are still opportunities for
individual
variation of individual drugs. We see that
frequently, especially when we look at
severity,
incidence or frequency of uncommon or
common side
effects.
So, we hope to bring this out within our
presentation.
With no further ado, I will
turn this over
to Dr. Kenneth Verburg and we will be
happy to
delve into any other questions that you
have at the
end of his presentation.
Cardiovascular Safety
and
the Risk/Benefit Assessment of
Celecoxib
DR. VERBURG: Thank you, Dr. Feczko. Good
afternoon, everyone. Again, my name is Ken
Verburg.
I lead the clinical research and
296
development programs in arthritis and
related
conditions for Pfizer. In this respect, I have
been studying celecoxib, valdecoxib and
parecoxib
for nearly eight years now.
My presentation over the next
40 minutes
or so is focused to the cardiovascular
safety of
celecoxib and a risk/benefit assessment
of this
compound.
I am joined here today by several of my
Pfizer colleagues, as well as external experts
in
the field of cardiology,
gastroenterology,
rheumatology, epidemiology and other
disciplines as
listed on this slide. I will not spend the time to
read each of the individually but they
are here to
contribute to the discussion afterwards.
So, what is Pfizer's position
with respect
to the cardiovascular safety of celecoxib
and the
risk/benefit of this compound? Our position is
perhaps best summed on this slide in
terms of
conclusions.
First, there are few therapeutic
297
alternatives for patients with chronic
arthritis
pain.
Patients who discontinue celecoxib then will
likely turn to NSAIDs for treatment.
In our view, celecoxib is an
effective and
safe therapy for arthritis patients, and
we base
that on the following conclusions: First,
celecoxib provides improved GI safety
compared to
NSAIDs.
Secondly, all lines of evidence show that
the cardiovascular safety of celecoxib is
similar
to NSAIDs for up to one year.
The caveat on this is that
beyond one year
little is known for any of these agents,
and
evidence for coxib versus NSAID class
effect on
cardiovascular safety is not
established. Thirdly,
rofecoxib appears to be distinct
celecoxib and
NSAIDs with respect to cardiovascular
safety.
Finally, only further study of NSAIDs and
coxibs
would define the longer-term
cardiovascular risks
against the known risks of GI ulcer
complications.
I want to begin my discussion
by going
back and framing it in terms of the
patients who
require these therapies. In 2002, it was estimated
298
that 1/3 adults suffer from arthritis or
other
related joint conditions, and that is an
estimated
70 million individuals. Of these, about 7 million
have significant impact on their daily
activities.
Here are shown some data from
the Centers
for Disease Control, indicating that
arthritis and
other related conditions, joint
conditions, results
in significant functional impairment as
compared to
other diseases. About 39 million physician visits
per year occur with arthritis patients
and there
are more than 500,000 hospitalizations
due to
arthritis each year.
NSAIDs are an important
treatment option
for arthritis patients. The American College of
Rheumatology and other professional
societies have
indicated that first-line therapy is
acetaminophen.
That is perhaps an appropriate
choice. But
acetaminophen in many patients with
moderate to
severe forms of the disease does not
provide
adequate control of pain and other
symptoms.
The data on this slide are from
a
double-blind, randomized, cross-over
study in which
299
one group of patients was randomized to
receive
first acetaminophen therapy for 6 weeks,
followed
by a washout period, and then to receive
diclofenac
in combination with a gastroprotective
agent,
misoprostol. In comparison, the second group was
randomized first to receive a
diclofenac-misoprostol combination, then
following
a washout period, was to receive
acetaminophen for
the subsequent 6 weeks.
Very quickly, the point that I
want to
make on this slide is that diclofenac
offers
significant improvements in terms of the
Womack
Target Joint Score, which is a composite
score of
pain, joint stiffness and physical
function, as
compared to acetaminophen at a total
daily dose of
4000 mg, so a full dose of acetaminophen.
We have known for over two
decades now
that the efficacy of NSAIDs comes at a cost,
and
that cost is the risk of upper GI ulcer
complications, that is, ulcers causing GI
bleeding,
perforation or leading to gastric outlet
obstruction.
Largely, this risk was
identified and
characterized by pharmacoepidemiology
studies. One
such study is shown on this slide. Here we are
300
showing the absolute incidence in terms
of events
per 1000 patient-years, the incidence of
hospitalizations for GI bleeding or for
perforations. Current users of NSAIDs are shown in
the yellow line, subdivided by men and
women, and
they are compared to non-users of NSAIDs,
shown in
the white line.
What is readily apparent is
that the
absolute risk of hospitalization for GI
bleeding or
perforations increases substantially as a
function
of age.
However, for each 5-year interval of age
we see that NSAIDs increase the risk over
non-users
by approximately 4- to 6-fold. Of course,
arthritis patients lie over to the far
right-hand
portion of this curve. This is the same population
that is often characterized by
cardiovascular risk
factors or underlying cardiovascular
disease.
Well, the discovery of the
consistent
enzyme and the characterization of the
resulting
301
biology around this enzyme led to the
hypothesis,
in 1992, that inhibition of COX-2
selectively would
offer efficacy in the disease targets of
arthritis
and pain while obviating the side effects
associated with the inhibition of COX-1.
Indeed, the discovery of
celecoxib and the
subsequent clinical development program
supported
that hypothesis. Here we show data from a trial of
over 1000 rheumatoid arthritis patients
in which
efficacy was evidenced at 100 mg, 200 mg
and 400 mg
twice daily of celecoxib. What we see relative to
placebo is that all of these doses
provided
significant efficacy in terms of the
ACR-20
Responder Index. This efficacy was comparable to
that observed with naproxen at a full
therapeutic
dose of 500 mg twice daily. The treatment period
was 12 weeks in duration.
So, if we focus now on the
right-hand
panel of the slide, we are looking at the
incidence
over 12 weeks of endoscopic ulcers. What we see is
that celecoxib at full therapeutic doses
and a
super-therapeutic dose was associated
with similar
302
incidences of endoscopic ulcers as
compared to
placebo treatment. This is in contrast to the
naproxen treatment group which had an
incidence
rate of 25 percent and was significantly
different
than all other treatment groups. Thus, 1/4
patients treated in this trial over 12
weeks with
naproxen was found to have an endoscopic
ulcer.
This is data from a
meta-analysis that
will be published this month. This meta-analysis
was based on 31 arthritis randomized
controlled
trials of Celebrex and included over
39,000
patients with osteoarthritis and
rheumatoid
arthritis, with a mean exposure of 7
months. The
GI safety benefit is split into 3
different looks.
The first is symptomatic ulcers and GI
bleeding.
The second is clinically significant
blood loss,
defined as reductions in hemoglobin of 2
gm/dL or
more.
Then also we focused on withdrawal due to GI
intolerance.
As compared to NSAIDs, which
are comprised
basically here of naproxen, ibuprofen and
diclofenac, we see that the relative risk
for any
303
of these events favors celecoxib,
significantly so.
This occurs at both the therapeutic doses
of
200-400 mg or at any dose of celecoxib.
The data from the randomized,
controlled
trials has been further substantiated by
observational epidemiology studies, and I
will show
data from two of these studies.
the first study that was
published in 2002
evaluated the risk of hospitalization for
upper GI
bleeding with celecoxib, rofecoxib, the
combination
of diclofenac and misoprostol and
NSAIDs. The
point estimate of relative risk for the
NSAID
treatment group as compared to the
non-users was 4.
That relative risk agrees very well with
a large
body of literature evaluating NSAIDs in
the
epidemiology or observational
setting. Celecoxib
was similar to non-users in terms of the
relative
risk of hospitalization for upper GI
bleeding.
The data from the first study
was
basically confirmed in the second study.
In this
case, the risk of hospitalization for GI
bleeding
was evaluated in patients with prior
304
gastrointestinal disease who would be at
high risk
for subsequent GI ulceration.
Again focusing your attention
over here,
to the right, NSAIDs were associated with
a
relative risk of hospitalization for
upper GI
bleeding of a little over 3,
significantly
different from non-users. Celecoxib users had a
similar risk of hospitalization as
compared to
non-users.
To sum then our conclusions
regarding the
safety benefit of celecoxib are stated as
follows:
The medical need for improved GI safety
is
fulfilled standard celecoxib. This is based on
evidence from randomized, controlled
trials in
which celecoxib has a favorable GI safety
profile
versus NSAIDs, and also from emerging
data from
epidemiology studies which indicates that
celecoxib
is associated with a lower risk of
hospitalization
due to GI bleeding than non-selective
NSAIDs.
So, the results that I just
reviewed
basically supported the fundamental
hypothesis put
forward in 1992 regarding selective COX-2
305
inhibitors. What emerged at the same time,
however, was a concern over cardiovascular
safety,
and the first clinical evidence for an
increased
cardiovascular risk with a selective
COX-2
inhibitor was observed with rofecoxib 50
mg once
daily versus naproxen in the VIGOR trial.
At the same time, however, data
emerged
from the CLASS trial with celecoxib at
400 mg twice
daily, 2-4 times the full therapeutic
dose,
demonstrating that the cardiovascular
safety
profile of celecoxib was no different
than the
NSAIDs diclofenac and ibuprofen combined
introduction he CLASS trial.
For the remainder of my
presentation this
afternoon, what I would like to do is
focus on
cardiovascular safety using the following
organization, and then conclude with some
comments
on risk/benefit.
So, let's begin with the
longer-term
studies evaluating celecoxib and its
cardiovascular
safety profile versus placebo
treatment. Although
we have been through this several times
already, it
306
stands to reason that we should spend a
moment to
define some of the fundamentals of the
cardiovascular event definitions as we go
through
them.
So first, as we have heard
already today,
the APTC endpoint is a well-recognized
endpoint
with respect to the evaluation of
cardiovascular
therapeutics. It is comprised of non-fatal
myocardial infarctions, non-fatal strokes
or
vascular deaths, as outlined on the
slide.
The meta-analysis results that
I will
provide or review shortly have a similar
construct
to the APTC but they are based on
investigator
reports of serious adverse events to the
company.
In other words, there was not a process
of
adjudication and, of course, unlike
cardiovascular
endpoint trials, there were no
definitions a priori
about what a cardiovascular event would
or would
not be in order categorized
appropriately.
Finally, we need to recognize
that
epidemiology studies rely on
hospitalization for
acute MI alone as their endpoint or in
combination
307
with coronary death predominantly.
So in collaboration with the
National
Cancer Institute, Pfizer and the NCI
initiated two
three-year placebo-controlled trials, beginning
in
1999 or so, evaluating the effect of
celecoxib on
the prevention of sporadic adenomas. These trials
are known as the APC and the PreSAP
trials. The
hypothesis being tested in these trials
was that
celecoxib would reduce polyp recurrence
by greater
than 35 percent in a high risk cohort,
that is,
patients who had a history of a prior
adenoma.
Importantly, the setting
allowed for the
first longer-term comparison of celecoxib
versus
placebo.
Trials of similar duration would be very
difficult, if not impossible, to do in an
arthritis
population. Also, celecoxib was an obvious agent
of choice here based on the emerging data
demonstrating that it had superior GI
safety to
non-selective NSAIDs.
Dr. Ernie Hawk and Dr. Bernard
Levin will
review the results of these studies
separately and
go through them in some detail later this
308
afternoon. To sum the results though, there was a
significant cardiovascular risk
associated with
celecoxib in the APC trial and no such
risk was
observed with celecoxib in the PreSAP
trial.
As we go through the studies
and the data
sets, it is useful and perhaps
instructive to keep
a score card of some of the study
descriptions, as
well as the patient populations because,
as we have
heard, none of these trials a priori were
conducted
to evaluate cardiovascular safety. That was not
their primary objective. Thus, the types of
patients, the durations entered into
these trials
can vary substantially.
So, beginning with the APC and
PreSAP
trial, you can see that over 1500
patients were
enrolled in each of these trials. At the time
study drug administration was
discontinued there
was about 2.5 years of exposure. And, the number
of cardiovascular events, and these are
APTC
events, was 41 in the APC trial and 31 in
the
PreSAP trial. The mean age was about 60 and these
patients were characterized by a fairly
significant
309
degree of underlying cardiovascular risk
factors or
cardiovascular disease. What is interesting is
that there seems to be a little bit of a
difference
in the use of concomitant aspirin between
the two
trials, nearly twice as great in the APC
trial as
in the PreSAP trial.
Next, turning to a brief
description of
the Alzheimer's disease anti-inflammatory
prevention trial, known as the ADAPT
trial, this
was a randomized, controlled trial. First of all,
this trial was conducted and sponsored by
the NIH.
Pfizer's role in this study was to
provide blinded
study medication in the form of placebo
and
celecoxib only.
This was a randomized, controlled
trial
evaluating celecoxib at 200 mg twice
daily or
naproxen at the over-the-counter dose of
220 mg
twice daily versus placebo
treatment. Elderly
patients were enrolled in the trial, all
greater
than 70 years of age, who were at risk
for
Alzheimer's disease, that is, they had a
first-degree relative with the disease.
Except for uncontrolled
hypertension,
there were not other restrictions for
cardiovascular disease in order for
patients to be
310
eligible for the trial. The hypothesis being
tested was that celecoxib would reduce
the
incidence of Alzheimer's disease by over
30 percent
in a high risk cohort.
So, this represents the first
longer-term
placebo-controlled experience with a
non-selective
NSAID.
Most of the results have not yet been
disclosed into the public domain. What we do know
though from the investigators is that
naproxen was
associated with a significant increase in
all
cardiovascular events, as well as all
cerebrovascular events, versus placebo
and no such
effect was seen with celecoxib.
We also know from this trial,
again in
terms of preliminary information, that
naproxen was
associated with a significantly elevated
increase
of upper GI bleeding as compared to
placebo
treatment and, again, no significant
difference was
seen in celecoxib users.
Returning to our score card, in
the ADAPT
trial near 2500 patients were
enrolled. The mean
exposure at the time the trial was
stopped was
about 1.6 years per patient. The number of events
reported and in the public domain appear
to be
about 70.
Those are probably APTC endpoints-plus
311
some. And, we know nothing about the underlying
patient population at this point.
So, the conclusions that we can
draw from
the information so far, and as the week
unfolds we
will see if these conclusions hold, are
as follows:
In the APC trial celecoxib was associated
with a
cardiovascular risk as compared to
placebo after
approximately one year of continuous
administration.
In the companion PreSAP trial
no
differences were observed with continuous
treatment
of celecoxib for up to 3 years of
exposure.
In the ADAPT trial naproxen
showed a
cardiovascular risk compared to placebo
over an
exposure period of about 1.5 years, and
this was in
contrast to the findings with celecoxib.
When you distill this
information down
even at this point it is obvious that
celecoxib
requires further study to estimate the
longer-term
cardiovascular risk. An NSAID comparator in such a
trial would be critical in our view.
Next let's turn to a comparison
of
celecoxib predominantly versus NSAIDs,
and we will
use a meta-analysis of the randomized
controlled
trials to do so. So, 41 completed randomized
312
controlled trials and a total of over
44,000
treated patients were included in this
meta-analysis. They were predominantly patients
with osteoarthritis or rheumatoid
arthritis. There
was a small minority of patients with
chronic low
back pain, ankylosing spondylitis or
Alzheimer's
disease.
Of these patients, nearly
25,000 received
celecoxib; 4000 receiving placebo; and
over 15,000
patients were treated with an active
comparator.
We evaluated all doses of celecoxib,
ranging from
50 mg to 800 mg daily. The primary NSAIDs in this
comparison were naproxen, ibuprofen and
diclofenac.
313
The study durations ranged from 2 weeks
to 1 year.
In terms of the comparisons to
NSAIDs, the
celecoxib exposure is shown down here, in
the
yellow box. Of the patients in the meta-analysis
treated with celecoxib, 55 percent were
treated for
3 months or longer; 12 percent were
treated for 9
months or longer; and 4 percent, a total
of 803
patients, were treated for 1 year or
longer.
I too will review the results
using the
APTC-like construct, first reporting a
composite
endpoint of any cardiovascular death,
non-fatal MI
or non-fatal stroke, and then I will
report the
results of each of these components
individually.
Back to our score card one more
time, here
now we are comparing and juxtaposing the
study
descriptions and the patient populations
for the
meta-analysis in comparison to the
longer-term
trials.
So, we see that the number of patients is
increased substantially in the
comparisons of
celecoxib to placebo or NSAIDs. We also take note
of the fact that the mean exposure is
much less,
being on the order of only 6 weeks in the
314
comparison of celecoxib to placebo, and
on the
order of about 3.5 months for celecoxib
compared to
the NSAIDs.
The number of events is fairly
similar
from placebo across to the other
settings, about
2-3 time the number of events in the
comparison of
NSAID to celecoxib, meaning that each was
approximately the same as the polyp
prevention
trials.
And, there was a significant degree of
underlying cardiovascular risk in this
population
but perhaps less so than in the polyp
prevention
trials.
So, first the results of the
meta-analysis
comparing celecoxib versus NSAIDs are
shown on this
slide.
Here we are reporting the absolute number
of events that occurred in each treatment
group,
and then the event rate in parentheses as
events
per 100 patient-years. What we have done here is
we have taken all doses of celecoxib, 200
mg or
greater, and combined them. So, we are looking at
full therapeutic doses of celecoxib and
super-therapeutic doses of
celecoxib. In essence,
315
this is 200 mg, 400 mg and 800 mg daily.
What we see here is that in
terms of the
composite event rate of cardiovascular
death,
non-fatal MI or non-fatal stroke there
are no
apparent differences between the two
treatment
groups, and that is generally true for
cardiovascular death. There is an apparent
increase in the event rate in terms of
non-fatal MI
in the celecoxib treatment group and a
reduction in
non-fatal stroke in the celecoxib
treatment group
when compared to the NSAID group.
If we evaluate the data in
terms of the
relative risk and 95 percent confidence
intervals,
the following results are evident: First, the
relative risk for the composite endpoint
is
slightly below 1 favoring celecoxib, as
was
cardiovascular death and as was
stroke. Non-fatal
MI was slightly above 1 favoring
NSAIDs. However,
in all cases the 95 percent confidence
interval for
this comparison did not exclude 1 with
the
exception of non-fatal stroke in which
the relative
risk was nearly 3 times lower than in
NSAID users.
If we now break this down a
little bit
further and evaluate the risk of
celecoxib versus
the NSAIDs that comprise the predominant
exposure
316
in the aggregate NSAID treatment group,
i.e.,
naproxen, diclofenac and ibuprofen, we see no
real
pattern of difference in the comparison
of
celecoxib to these three drugs
individually.
As a point of reference, I am
also putting
on this slide the comparison of celecoxib
to
placebo and you can see that the relative
risk was
1.26 favoring placebo but not
significantly
different.
Next, if we subdivide the
celecoxib 200 mg
or greater treatment group into its
component
doses, again using the composite endpoint of
cardiovascular death, non-fatal MI or
stroke as the
endpoint of interest here, we see no
obvious
dose-response relationship in the
relative risk of
celecoxib as compared to the NSAIDs.
Two of the trials in the
meta-analysis
included patients with substantial
exposure to
celecoxib. Those trials were the CAESAR trial and
317
the CLASS trial. The CAESAR trial was a trial of a
little over 800 patients with
osteoarthritis who
were treated with either celecoxib or
diclofenac
for a period of one year. The CLASS trial was a
trial of nearly 8000 patients, with a median
duration of exposure with respect to
celecoxib of 9
months and 15 percent of patients treated
with
celecoxib were treated for one year or
more.
Here we are showing the time to
event
analysis comparing celecoxib in these two
trials
and at doses ranging from 200 mg to 400
mg per day
versus the NSAIDs used in the two trials,
which
were diclofenac and ibuprofen. We see no
difference in the APTC composite endpoint
between
the two treatment groups through the
exposure
period.
So, our conclusions from the
randomized,
controlled trials are as follows: There is no
association for increased cardiovascular
risk
detected with the use of celecoxib up to
one year
compared to the NSAIDs combined and also
compared
to naproxen, diclofenac or ibuprofen
individually.
318
And, a dose-related increase in cardiovascular
risk
with celecoxib was not apparent.
Next let's turn to a
consideration of risk
factors.
We will stay within the construct of the
meta-analysis. About 33,000 patients or so were
available for this analysis with respect
to
cardiovascular risk factors and, again
here we are
going to be comparing celecoxib to the
NSAIDs. The
risk factors were based on either a
history of
hypertension, diabetes or hyperlipidemia
or
coronary heart disease as evidenced by a
previous
MI, a history of angina or other
significant
ischemia or revascularization procedure.
So, the patients with none of
these risk
factors are shown in the white bar; with
one risk
factor only are shown in the yellow bar;
and with
two or more risk factors are shown in the
orange
bar.
Again, what we are showing is the absolute
event rate in terms of events per 100
patient-years
for celecoxib users over on the left,
NSAID users
over on the right, and here we show a
breakdown by
the composite endpoint and each of the
components
319
of the endpoint. What catches your eye is that as
the patients are characterized with
greater risk
factors, the absolute event rates
increase in both
treatment groups.
Did they increase
proportionally? This is
the relative risk now comparing celecoxib
versus
NSAIDs by cardiovascular risk
factors. So, no risk
factors here; one risk factor; greater
than two
risk factors over to the far right. First a quick
inspection across all three risk strata
suggest
that there were no significant
differences in the
relative risk between celecoxib and the
NSAIDs,
with the exception of non-fatal stroke in
patients
with no cardiovascular risk factors.
The second point I would like
to make on
this slide is that if you scan across to
evaluate
whether there were any patterns that were
occurring
that were altering the relative risk
between the
two treatment groups as a function of
risk factors,
that is not readily apparent when
evaluating either
the composite, cardiovascular death or
MI. There is
a trend for favorable comparison with
stroke to
320
become less favorable with additional
risk factors,
but I want to caution that this
particular point
estimate is based on a total of only 6
non-fatal
strokes.
So, as the confidence interval suggests,
there is wide uncertainty around that
point
estimate.
If we use low dose aspirin as
an indicator
now for underlying cardiovascular
disease, this
slide shows the comparison of the
relative risk for
celecoxib versus NSAIDs again in the
construct that
we have shown before, and showing the
relative risk
in a non-aspirin cohort over here, on the
left and
the aspirin cohort, over here, on the
right.
Again, this is about 10-12 percent to the
total
population. Here we see that there are no
significant differences in any of the
endpoints of
interest, with the exception of non-fatal
stroke
favoring celecoxib this time in the
aspirin cohort.
There is a noticeable change in the
relative risk
of cardiovascular death from the
non-aspirin cohort
to the aspirin cohort. But this again is shaped by
very few events, as evidenced by the wide
321
confidence intervals around the point estimate.
Next, if we return to the CLASS
trial and
evaluate the composite APTC endpoint by
aspirin or
non-aspirin use in terms of a time to
event
analysis, we see nonsignificant
differences in the
two time to event curves by log rank test
in either
the non-aspirin cohort or in the aspirin
cohort.
Approximately 22 percent of the patients
in the
CLASS trial were taking low dose aspirin.
So, our conclusions concerning
risk
factors are as follows: The cardiovascular safety
profile of celecoxib remains comparable
to NSAIDs
regardless of cardiovascular risk factors
as
determined by medical history or use of
low dose
aspirin.
Next turning to epidemiology
studies, 7
epidemiology studies have now been
completed and
reported as full-length publications in
peer-reviewed journals, and have
evaluated
cardiovascular risk of celecoxib.
Returning to the concept of the
score card
but this time just evaluating the
epidemiology
322
studies in isolation, if you aggregate
the studies
together there was a total of over 30,000
myocardial infarctions in the studies for
all
treatment groups and over 1000 MIs in
patients
taking celecoxib. Both in terms of the number of
events and in person-years, you can see
that in
terms of the total as well as for
celecoxib users,
these numbers are substantial in
comparison to
randomized, controlled trials.
I am going to review these
studies
individually very quickly, starting here
with the
study of Ray et al., published in 2002,
in this
study celecoxib at doses less than 300 mg
daily or
300 mg or greater daily had a similar
relative risk
of hospitalization due to myocardial
infarction or
coronary death as compared to
non-users. These
results were very similar to the relative
risk seen
with ibuprofen and naproxen. In contrast, we see
that the relative risk associated with
doses of
rofecoxib greater than 25 mg were
significantly
different than non-users.
The second study, published in
2003,
323
showed that there was basically no
difference
between celecoxib, rofecoxib, naproxen or
any of
the other NSAIDs in terms of the relative
risk of
hospitalization for MI as compared to
non-users.
In a third study, conducted by
Solomon and
co-workers at Harvard, found that
celecoxib at all
doses combined or subdivided into low and
high
doses was associated with a relative risk
for
hospitalization for myocardial infarction
no
different than non-users. In contrast, in this
study as in the first study, rofecoxib at
doses of
25 mg or greater was associated with a
relative
risk of 1,58, significantly different
from
non-users.
Next we turn to the study
published by
Kimmel and co-workers earlier this
year. In this
particular observational study celecoxib
was
associated with a significantly
protective effect
with respect to the relative risk of
myocardial
infarction, as were all NSAIDs
combine. Rofecoxib
was associated with no such effect when
compared to
non-users.
Next we turn to perhaps the
largest study
conducted and published thus far. Here again we
see, as in the previous trials that
celecoxib was
324
associated with a relative risk of
myocardial
infarction or coronary death, this time
to remote
use of NSAIDs, that is no different in
terms of
remote use. In contrast, here again we see that
the relative risk associated with high
doses of
rofecoxib were significantly
elevated. In terms of
the NSAIDs, the point estimates of
relative risk
ranged from 1.06 for ibuprofen to 1.60
for
diclofenac. None of those point estimates were
different from remote users.
Next, turning to the results of
Shaya at
al., these investigators used an
APTC-like endpoint
in their observational trial. They found that
celecoxib alone, rofecoxib alone or the
coxibs
combined were similar in terms of
adjusted odds
ratio to non-naproxen NSAIDs in their
study.
Finally, the publication of
Levesque et
al. reports the following, they show that
celecoxib, subdivided into low and high
doses, was
325
no similar to non-users in terms of the
relative
risk of MI. Here again we find the observation
that rofecoxib at doses of 25 mg or
greater was
associated with a significantly elevated
risk, and
the NSAIDs were generally also similar to
non-users.
These investigators also
subdivided the
evaluations of the compounds into
non-aspirin users
and aspirin users. We see that either in the
non-aspirin cohort or the aspirin cohort
the
relative risk of celecoxib is similar to
non-users.
We find a significantly elevated risk in
patients
taking rofecoxib at doses of 25 mg or
greater.
Trying now to sum all the
previous
observations into one trial, the results
are shown
here.
They are subdivided by low doses and high
doses of celecoxib and rofecoxib. We see that
celecoxib at either low doses or high
doses is
similar to non-use with respect to risk
of MI. In
contrast, rofecoxib at high doses is
systematically
associated with an elevated relative risk
of MI as
compared to non-users.
So, our conclusions from that
rapid review
of
epidemiology studies are that the risk of
myocardial infarction with celecoxib as
used in the
326
real-world population, that is at the
doses that
patients actually take and the duration
for which
they actually take them, is consistently
similar to
non-selective NSAIDs in non- or remote
use of
NSAIDs.
These findings are in contrast to the
increased risk associated with
rofecoxib. The
available data suggests that the risk of MI
is
similar for low and high doses of
celecoxib.
So, turning now to a
consideration of the
topic of mechanism, a unifying hypothesis
that
would attribute cardiovascular risk to
the coxib
class only conceivably could explain the
VIGOR
results, the APPROVe results with
rofecoxib and the
APC results with celecoxib. But it couldn't
explain the consistent comparability
between
celecoxib and the NSAIDs as viewed in the
meta-analysis or versus non-use in the
epidemiology
studies, and could not explain the lack
of effect
of celecoxib in the PreSAP trial or other
results
327
in the ADAPT trial where the
non-selective naproxen
was associated with increased
cardiovascular risk,
unlike celecoxib.
So, if we try to sum up all of
the
clinical observations to date, it would
appear that
the absolute cardiovascular risk
associated with
coxibs may be small in terms of the order
of
magnitude, but the risk may be different
between
compounds within the class, and that
non-selective
NSAIDs may carry the same risk. Therefore, that
draws into question the clinical
significance of
the prostacyclin-thromboxane imbalance
and its
importance in leading to a prothrombotic
state.
In support of the hypothesis,
NSAIDs may
not
provide effective blockade of platelets even
though thromboxane production is reduced
throughout
their entire dosing interval. This would be more
or less a unifying hypothesis across both
classes.
It would unify the coxibs and the NSAIDs
together
if this was the case, to some degree.
Alternatively, what all these
compounds
have in common, which was discussed this
morning,
328
is that they inhibit COX-2. But by doing so, they
not only inhibit the formation of
prostacyclin but
they also inhibit the formation of other
prostaglandins that are formed by COX-2
activity
and subsequent enzymatic activity.
So, the data on this slide go
back to
point one on the previous slide. Here we are
showing the effect of a single dose of
ibuprofen
800 mg on platelet aggregation responses,
over on
the left.
What you can see here is that following
ibuprofen administration in normal health
volunteers there is a significant
reduction in the
platelet aggregation response to
arachidate, but
that this effect is largely eliminated by
8 hours
and the platelet aggregation responses
return to
essential control levels. This occurs despite
significant inhibition of thromboxane-A2.
Over on the right-hand panel is
the time
course of the urinary excretion of the major
prostacyclin metabolite, and here we can
see that
ibuprofen comparably inhibited the
urinary
excretion of this metabolite to a degree
comparable
329
to that seen with celecoxib, and that the
inhibition was significant even at the
6-12 hour
time period.
As was mentioned this morning,
this effect
will vary from NSAID to NSAID, but using
the
example of ibuprofen, it is conceivable
that, as
again was mentioned this morning, mixed
inhibitory,
non-selective COX-1 and COX-2 inhibitors
could act
in terms of platelet function, in terms
of vascular
effects as selective COX-2 inhibitors
during a
portion of their dosing cycle.
Alternatively, COX-2, as I
mentioned
previously, in the vasculature has been
linked to
several cardiovascular disease states,
and the
up-regulation of COX-2 expression not
only results
in the production of prostacyclin, which
would then
lead to downstream beneficial effects on
endothelial function and prevention of
platelet
aggregation, but has also been shown to
increase
the production of prostaglandin E2 which,
again
through a cascade, could result in
reduction in
plaque stability ultimately. Also, COX-2 could
330
lead to the formation of thromboxane-A2
which would
obviously have effects opposite of those
to
prostacyclin.
That particular scheme would
suggest that
the results of COX-2 inhibition might be
more
complicated than just focusing on
prostacyclin, and
also that the clinical outcomes of such
effects
might be more difficult to predict than
we would
envision.
If we move this consideration
of mechanism
a step further and ask the question,
well, if that
may be the case in the coxibs and the
NSAIDs are
all alike, then what may account for the
differences that are seen with rofecoxib
as
compared to the other agents in terms of
cardiovascular risk?
We should not forget in this conversation,
and this was brought up this morning,
that each of
these compounds has unique pharmacology,
pharmacologic activity, unique
pharmacokinetics and
other properties that could mitigate or
worsen a
cardiovascular risk profile that is
embedded in a
331
mechanism-based effect.
What we are showing on this
slide is some
of the recent work and so all these
compounds may
be
characterized by that. Rofecoxib has
been
heavily studied in this respect, as has
celecoxib.
What has emerged from some of these
studies is that
rofecoxib and/or some of its metabolites
may have
pro-oxidant effect which could ultimately
lead to
increase in blood pressure or
thrombosis. Do we
know for sure that this is an overall
effect of
rofecoxib? No, but it is clear from the clinical
literature that rofecoxib has been
associated with
elevations in blood pressure to a degree
that are
not seen with other agents, whether they
be
non-selective NSAIDs or celecoxib.
The most recent example of this
is shown
on this slide. This is the third of three studies
now that basically confirm the same
observations.
So, at equal efficacious doses for
osteoarthritis,
that is, 200 mg of celecoxib once daily,
25 mg of
rofecoxib once daily, or 500 mg twice
daily of
naproxen, we see that over both 6 and 13
weeks of
332
therapy with these agents in patients
with
osteoarthritis and treated for
hypertension, as
determined by 24-hour ambulatory blood
pressure
monitoring, that rofecoxib was associated
with a
significant elevation in systolic blood
pressure at
both the 6- and the 12-week time point,
and was
significantly elevated as compared to the
celecoxib
and naproxen treatment groups.
So, we know from outcome
studies that
reductions in this order of magnitude in
terms of
systolic blood pressure can have a
significant
impact on cardiovascular mortality and
morbidity.
In summary then, it is not
established
that the prostacyclin-thromboxane
imbalance
contributes tot he effects observed for
coxibs or
NSAIDs clinically. Furthermore, the underlying
pharmacology is more complex, involving
other
prostaglandins and pathways and raises the
potential even for benefit for COX-2
blockade.
And, there is emerging evidence for
molecule
specific mechanisms.
Finally some brief concluding
remarks on
333
risk/benefit of celecoxib as it currently
stands,
just by way of recap, celecoxib in
comparison to
the NSAIDs in terms of GI safety within
the
randomized, controlled trial setting has
a lower
incidence of clinically significant GI
outcomes,
and in epidemiology studies has similar
risk of
hospitalization for GI bleeding versus
non-users.
Celecoxib versus NSAIDs in
terms of
cardiovascular safety--the randomized,
controlled
trials indicate that there is a
comparable
cardiovascular safety profile versus the
alternative therapies. The epidemiology studies
indicate that there is a similar
cardiovascular
risk in celecoxib users as compared to
non-users.
In conclusion, the overall
risk/benefit
assessment of celecoxib is as
follows: In the
currently approved arthritis indications
the
risk/benefit of celecoxib remains positive
relative
to NSAIDs. There is comparable efficacy that
demonstrates a GI safety benefit, and it
has
comparable cardiovascular risk based on
the data
that we have currently.
There is shared uncertainty of
the
cardiovascular safety beyond one year of
continuous
treatment for all of these
therapies. Thus,
334
further studies are planned by Pfizer to
evaluate
the longer-term GI and cardiovascular
safety of
celecoxib versus NSAIDs in arthritis
patients.
Thank you.
DR. WOOD: Thanks very much. Questions
from the committee? Yes?
DR. DWORKIN Could you go back to the
blood pressure slide, and do you have any data on
what it would look like if you had 400 mg
daily of
celecoxib? I think you just showed 200 mg. I am
sort of interested in 200 BID.
DR. VERBURG: We do not have a direct
comparison of 200 mg BID celecoxib versus
rofecoxib. We have done a 24-hour ambulatory blood
pressure trial evaluating 200 mg BID of
celecoxib
relative to placebo, and we have found
very minor
differences in the blood pressure profile
of
celecoxib at that dose as compared to
placebo.
That is as close as I can come to that.
DR. WOOD: Curt?
DR. FURBERG: I think the focus of your
presentation troubles me a bit. You really spent
most of the time on comparative trials,
and if you
are really interested in safety comparing
two
active drugs is not the best way to
go. You get
335
much better information by looking at the
placebo-controlled trials.
I think we are here to answer
two
questions, is Celebrex safe? And I think what you
talked about is not going to help us
answer that
question.
We need to look at the
placebo-controlled trials.
You answered the second
question, is the
safety of Celebrex different from the
NSAIDs?
Let's come back to the placebo-controlled
trials.
There is information in the briefing
document from
Pfizer that you did not bring out, and I
would like
to refer people to table 4 which presents
a summary
on the Celebrex experience in
placebo-controlled
trials, and it is showing risk ratios of
1.7, 1.8
versus placebo for thromboembolic
events--trends
336
that are not too dissimilar to what we
see in other
placebo-controlled trials of the other
COX-2s.
I think in addition to that, you did
not
address at all the issue of heart failure
that we
talked about earlier. We were informed that in the
APPROVe study there was a 4-fold increase
in heart
failure in that placebo-controlled
trial. For
Celebrex, if anything, it is worse. If you look at
your table 6, although there are small
numbers,
there is a 6-fold increase in heart
failure,
statistically significant, and that is
not
mentioned.
So, if you are going to talk
about safety,
my plea is that let's look at all aspects
of
safety, including the thromboembolic
events and
heart failure, and let's pay a little bit
more
attention to the placebo-controlled
trials because,
as has been said over and over again, we
really
don't know the safety profile of the
various
non-selective NSAIDs, and to compare to
those drugs
is not very informative. Thanks.
DR. WOOD: Do you want to respond to that?
DR. VERBURG: I think the only way to
respond to that is actually review some
of the
data.
Why don't we take a look at a couple of the
337
slides?
So, why don't we go to slides C-112?
Going back to the
meta-analysis, with the
caveats that it is 11,000 patients and it
is 6
weeks of exposure and it is roughly 31
events. So,
we are shaping conclusions based on a
very small
data set over very small durations. The composite
endpoint for placebo was 1.4 in terms of
events per
100 patient-years as compared to 1.8 for
celecoxib.
In terms of cardiovascular death and MI,
you can
see that the results were lower with
placebo and
there was no difference in non-fatal
stroke.
Indeed, if you plot these out
in terms of
relative risk, you find that the point
estimate of
relative risk for three of these
endpoints favors
placebo but the confidence intervals are
fairly
substantial, indicating very low
precision around
those points.
DR. WOOD: What was the exposure for that?
DR. VERBURG: Six weeks.
DR. WOOD: I think we should emphasize
that.
You missed that out. Just go back
to the
slide.
DR. VERBURG: This is 1.7 months of
exposure.
DR. WOOD: As long as we have that on the
338
record.
DR. FLEMING: But in essence, if you are
doing a non-inferiority, if you want to
show you
are not worse, there is a major issue of
you are
not giving very long exposure here as to
whether
you might be really underestimating
excess risk.
DR. VERBURG: In our view, that is why we
did not focus on these data in the
presentation.
We felt it was really non-informative and
we would
really leave the discussion of placebo
comparisons
over longer term to Dr. Hawk and Dr.
Levin when
they present.
DR. WOOD: Well, why don't we put up the
Kaplan-Meier curve from the trial, the
APC trial?
DR. VERBURG: Again, I don't have those
data.
DR. FURBERG: For any myocardial
thromboembolic events the relative risk
is 1.77.
So, I don't know why you have that
discrepancy.
You have much lower relative risks in
your slide
than in the briefing document that was
sent to the
committee members.
DR. VERBURG: I probably should step back,
it is a little bit different construct in
my
presentation than in the briefing book,
and it was
339
really based on our desire to get to what
was a
more meaningful endpoint and that was the
APTC. I
don't think that the differences between the
analyses in any way change the overall
conclusions.
DR. FURBERG: Well, we may disagree on
that point. How about heart failure then?
DR. VERBURG: Sure.
Let me just check my
notes here. Can you bring up for me C-248? These
are data that were provided in the
briefing book I
believe--
DR FURBERG: Correct.
DR. VERBURG: --comparing
celecoxib to
placebo in terms of reports of adverse
events from
340
investigators, not adjudicate,
hypertension and
peripheral edema and cardiac failure, and
celecoxib
is associated with a significant
increased
incidence of all these events, as are all
non-selective NSAIDs.
Let's go to the next slide.
DR. WOOD: What duration?
DR. VERBURG: Same duration.
DR. WOOD: Six weeks treatment?
DR. VERBURG: A mean of six weeks of
treatment.
DR. FURBERG: So, the patients didn't even
have a chance to develop heart
failure. You raised
their blood pressure and caused fluid
retention and
you followed them for a few weeks. They didn't
have a chance to get into heart failure.
DR. VERBURG: So, let's step back. What
we are doing is we are trying to
determine some
cardiovascular safety parameters from
trials that
were designed to test fundamentally the
efficacy of
arthritis.
DR. FURBERG: Sure.
DR. VERBURG: So, again, we have
recognized all of the faults in what we
are doing.
There is no getting around that. But if we want to
341
see what the data look like in order to
form some
conclusions, this is what it looks
like. We hear
the criticism but, again, these are from
NDA trial
databases of 12-week, placebo-controlled
trials to
evaluate efficacy in arthritis. So, we are limited
by the purpose of those trials.
DR. FURBERG: Yes, but these are trials
that you designed and set up, and you are
not
providing the answers that we need to
evaluate the
efficacy and safety.
DR. WOOD: I don't understand the answer
to the last question. You are telling us you don't
have the data that you published in The
New England
Journal two days ago with you in this
presentation
of a placebo-controlled trial?
DR. VERBURG: I do not.
That trial was
conducted by the National Cancer Institute.
DR. WOOD: You are welcome to download a
slide from The New England Journal. They have a
342
web site that let's you do that.
DR. VERBURG: And we will cover that topic
later.
I just don't have a slide with that in my
presentation.
DR. WOOD: Any other questions? Byron?
DR. CRYER: Yes, throughout your
presentation you suggested that there may
be
cardiovascular risk, specifically
thrombotic risk
associated with non-selective
NSAIDs. You
suggested this mechanistically with
ibuprofen and
with naproxen based upon the ADAPT trials
from
observations.
My sense and my understanding
of the
literature is that there are no good data
with
non-selective NSAIDs to suggest an
increased
cardiovascular risk when one looks at
meta-analyses, specifically a
meta-analysis
published by Garcia Rodriguez as recently
as 2004.
The relative risk of ibuprofen was right
at 1 and
there was a relative risk for an overall
reduction
of events, albeit modest, associated with
naproxen.
My specific question to you is
that in the
343
ADAPT trial you stated that the increase
in events
with naproxen was significant. My question is do
we, in fact, know whether that increase
was
statistically significant because my
assessment of
the math from the ADAPT trial, given the
limited
data that we have, is that it is
mathematically
unlikely that the increase in events with
naproxen
would be statistically significantly
increased.
DR. VERBURG: We have not seen the data so
I think it is speculation. My interpretation of
what was put into the public domain is
that there
were significant differences, but without
having
the data to review I can't answer that.
DR. CRYER: But I think your wording is
very important and somewhat misleading
because you
specifically say "significant"
and many of us, when
we hear the word significant, we are led
to a
conclusion that that is a statistically
significant
increase.
And without having the data, as you just
said, I think it is just a little
misleading. All
we can say for now is that there was a numerical
increase which, if not statistically
significant
344
with naproxen, could have been entirely
due to
chance.
DR. VERBURG: Point taken.
Thank you.
DR. WOOD: Ralph?
DR. D'AGOSTINO: I just want to get
clarification from you. Given the discussion we
had previously with the APPROVe trial and
waiting
18 months before you started seeing a
separation of
serious events, and so forth, how do you
respond?
I mean, your presentation was talking
about six
weeks, a year at most. So, how do I interpret your
presentation? And I was going to ask about the
placebo trials also.
DR. VERBURG: So, the purpose of my
presentation really was to go back and
review what
we know about the cardiovascular safety
of
celecoxib in the approved indications for
this
drug, which are osteoarthritis and
rheumatoid
arthritis. We reviewed all of the data that is
available to review the safety of that
drug versus
placebo or versus alternative therapies.
Subsequent speakers I think will expand
into other
345
indications that are currently being
explored.
DR. D'AGOSTINO: So, your presentation
would leave it that we really don't know
what to
make out of any long-term use?
DR. WOOD: Wait a minute. It is one thing
to say you presented the data for
placebo-controlled trials in the approved
indications, but it is not reasonable to
say you
presented all the data in
placebo-controlled
trials.
The largest placebo-controlled trial
presented in The New England Journal you
haven't
presented and you say you don't have the
data here.
That just doesn't pass the laugh
test. Here it is,
do you want it?
DR. VERBURG: I have seen it.
DR. FECZKO: Just for clarification of
this, the APC trial will be presented I
think later
on this afternoon by Dr. Hawk. It is sponsored by
the National Cancer Institute. We were not part of
that trial. We are not privileged to the data. We
were just given some top-line commentary
about the
data.
The same holds for the ADAPT trial.
We were
346
not part of that data safety monitoring
board or
the results of that trial. I believe that is
planned to be presented on Friday.
DR. D'AGOSTINO: My concern is the
conclusions which we heard. I mean, you know
something is coming down the line and why
were
these conclusions given as opposed to
saying here
is what we have at this point in time and
walking
away from it? It is a very positive presentation.
DR. WOOD: Dr. Manzi?
DR. MANZI: I think probably my questions
can wait until they review the APC trial
because it
really has to do with the long-term
issues.
DR. WOOD: All right, thanks. Dr. Shafer?
DR. SHAFER: One might think I am fixated
on low dose aspirin here, and perhaps I
am. But
once again we have three bits of
information on low
dose aspirin. We have table 4 in the handout that
Pfizer prepared or the document that
Pfizer
prepared which again shows that actually
the risk
factors that existed, in fact, got worse
on low
dose aspirin.
We have in the APC trial, which
will be
coming up, table 4 from those data, again
showing
that the risk factors maybe were
ameliorated a
347
little bit but still with low dose
aspirin the
risks persisted. So, we don't have a protection,
if you will, from low dose aspirin.
Then in your own slide 48, now
in 48 it is
not a placebo-controlled result and it is
not
blinded, but we can use the relative
risks in the
ASA versus non-ASA used for the other
drugs to see
that in the case of the high-dose
rofecoxib group
low dose aspirin conferred no protection.
Do these data, this sort of
persistent
signal that low dose aspirin provides no
protection--are those data that actually
pretty
strongly support your contention that
there are
other mechanisms besides the COX-1 and
COX-2
balance at play here?
DR. VERBURG: I am not sure that I follow
where you are taking the question.
DR. SHAFER: You had suggested that
perhaps there is something else besides
the
348
COX-1-COX-2 balance.
DR. VERBURG: Right.
DR. SHAFER: If it is the COX-1-COX-2
balance low dose aspirin ought to make
these COX-2
drugs look like non-selective drugs.
DR. VERBURG: Correct.
DR. SHAFER: The fact that low dose
aspirin doesn't do that repeatedly would
look to me
to support your contention that there is
something
else going on, and that is what I am
asking. Is
this something that Pfizer has
considered? Have
you had more thoughts on that?
DR. VERBURG: Only to reiterate some of
the thoughts that I think were brought up
this
morning, and that is that this would not
necessarily obviate or alter any changes
in blood
pressure that might occur with these
drugs. It
might but it might not. Also, it sort of lends
itself to is there other molecule-based
pharmacology that could moderate or
modulate the
effects that one sees from one compound
to another?
But that is about the extent of it.
DR. WOOD: Garret, this keeps coming up.
Do you want to address this?
DR. FITZGERALD: It is always difficult to
349
address a straw-man when the construct is
laid out
and the arguments are assembled. I find the
aspirin story really straws in the wind
as opposed
to anything definitive. For example, a comment was
tossed out about blood pressure. We have
absolutely no information as to whether
low dose
aspirin impacts on the blood pressure
elevation by
COX-2 inhibitors by controlled
experience.
I think as far as the
mechanistic issues
that we talked about this morning, we
would only
expect aspirin to have a diminishable
effect as
opposed to an abolitional effect on that
type of
hazard because, as I mentioned this
morning, it
isn't a prostacyclin-thromboxane yin-hang
balance.
Prostacyclin acts as a more general
constraint on
factors that transmit cardiovascular
risk. So, I
find the arguments unpersuasive.
As far as molecule specific
effects are
concerned, it is quite true that almost
every drug
350
has multiple mechanisms of action that
relate to
dose-response relationships. But, in contrast to
the mechanism we discussed this morning,
the in
vivo basis for the molecule specific
effects are
tenuous to non-existent and that includes
the
pro-oxidant effect of rofecoxib which is
based on
one paper in the literature using
quantitative
estimates of oxidative stress that those
of us in
the community view as highly
questionable. Thank
you.
DR. WOOD: I think your job, Garret, is to
take Dr. Shafer for a drink and make sure
that the
two of you have sorted this out
tonight! Dr.
Domanski?
DR. DOMANSKI: I was just waiting for
discussion of APC and I can wait a bit
longer.
DR. WOOD: All right.
Dr. Dworkin?
DR. DWORKIN: Yes, given the results that
you allude to for the APC trial, suggesting
that
you don't really begin to see a
difference until
after a year, do you think it is going to
be
ethically possible, going forward, to do
long-term
351
placebo-controlled trials of
celecoxib? You were
suggesting that we need to do that, but I
am not
sure how given the results that we have
in The New
England Journal.
DR. VERBURG: I don't but I really want to
address the question of ethics. I think I will
step back and answer the question as
follows, the
APC was not the only trial which you will
hear
today.
There is also another trial that shows that
there was no risk associated with celecoxib. What
does that inform us about the true risk
of
celecoxib over the long run? Relative to placebo,
the drug may carry a cardiovascular
risk. That I
don't think is something that is known
entirely.
If the risk is there it seems to be small
because
it is not seen on a consistent
basis. You could
throw in the ADAPT trial. The results there are
shown to be the same.
So, our sense is that you know
something
about the long-term cardiovascular
profile of
celecoxib. You know nothing about the long-term
cardiovascular effects perhaps of
non-steroidals.
352
Yet, many patients would take them
continuously.
So, I don't know that it necessarily
would be
unethical. In fact, you might suggest that it
would be mandatory for us to go and
evaluate that.
Patients have a need and a desire to know
what
risks they will be taking with their
drug, not just
in comparison to alternative therapies
but what is
the true risk if they decided not to
select any
therapy at all.
DR. WOOD: Allan?
DR. GIBOFSKY: Just a comment. I think it
is important when we consider the safety
issue to
bifurcate the safety issue because there
may be a
dichotomy between how we are approaching
it. I
think some are approaching it with is the
drug
safe, while others are approaching it
with is the
drug safe for the intended use as
prescribed in the
label?
I think those are two very different
issues.
The test of whether a drug is
safe or not,
to test it across all indications is one
thing. To
test it across all other indications is
something
353
else.
So, I really think we need to discuss safety
in the context of intended uses. Many drugs, when
tested for unapproved uses, will turn out
not to be
safe, whereas they may very well be for
the
indications for which they are approved,
and that
is why I think we have to be a bit
relative in our
discussion as well as being absolute.
DR. WOOD: Dr. Friedman?
DR. FRIEDMAN: Two points, first, you
touched briefly on the issue of blood
pressure.
Surely, there must be ways of getting
some good
data on what celecoxib really does to
blood
pressure.
The data you have shown are from
relatively small numbers of people,
followed for a
very short time, and we don't know
anything at all
about what other medications or how they
were
otherwise protected. Do you have any plans for
getting better, longer-term information
in a more
consistent way?
DR. VERBURG: Well, I think what I would
like to do is turn the discussion over to
Dr.
Welton who has been studying the blood
pressure
354
effects of celecoxib and NSAIDs for many
years. He
can at least recapsulize for you what we
have and
perhaps also indicate what the future
directions
might be.
DR. WELTON: Thank you so much. Andrew
Welton, from Baltimore. I have, I have to tell you
quite frankly, been itching to get up
here to the
microphone to clarify at least the clinical
aspects
of the evolution of the blood pressure
story
because I do not think it has come across
entirely
clearly either this morning or this
afternoon,
specifically, the human component
thereof.
So if you will bear with me for
a moment,
I will tell you, if I might have slide
C2-42, that
sequence, please? I would point out that this is a
fascinating story that first came to our
attention
with NSAIDs in 1993. These were the observations
of Janet Pope, who was then a first-year
rheumatology fellow, who pointed out in
this
meta-analysis, published in The Archives
of
Internal Medicine, that, indeed, all
NSAIDs, when
compared with placebo, do distort blood
pressure
355
and elevate blood pressure.
If I might have the next slide,
the
following year we learned something else
in an
additional meta-analysis. That was, once again,
that NSAIDs disrupt blood pressure, the
mean
increase being 55 mm, but particularly
learned that
this dominantly emerges during the
treatment of
hypertension, which then set up the issue
that
maybe we are looking at an issue of
drug-drug
interaction.
If I might have the next slide,
this was
about the time frame with respect to the
start of
the first two coxib development programs
and,
therefore, we were very mindful of the
importance
of blood pressure as these drugs went
into a human
evaluation.
I show you here the data for
the
osteoarthritis studies as they were
incorporated
into the new drug application. You can see,
scanning from left to right, that there
really
isn't much in the way of hypertension
adverse
events reported, and here we are at the
mercy of
356
the investigators doing the trials. In the CLASS
trial, as Dr. Verburg already pointed
out,
additionally not much in the way of blood
pressure.
If I might have the next slide,
taking
exactly the same approach, using NDA osteoarthritis
trials for the second of the coxibs, this
then gave
us the emergence of a very obvious
dose-correlated
increase in hypertension events but,
again, at the
mercy of the investigators doing the
trials. This
wasn't correlated with specific
elevations in blood
pressure.
Next one, please. It was at this point
that I and my colleagues thought the only
way to
resolve this correctly is to do
head-to-head,
prospective, double-blind, randomized
trials. And,
the logical subset in which to do these
studies is,
in fact, patients who are being treated
for
hypertension because this was emerging
now more as
a story of disruption of blood pressure
control
rather than the genesis of new onset
hypertension.
In brief, our first trial was
powered to
look for a 3 mm or greater difference in
blood
357
pressure effects between the two coxibs
using that
because it is a guidance rule from our
colleagues
in the Cardiorenal Division of the
FDA. The
essence of it is it showed in treated
hypertensives
early disruption of blood pressure with
rofecoxib,
as seen on your left; continued for 6
weeks of
observation; and not seen with celecoxib.
This was reasonably
curious. Standard
rule of thumb, make sure your
observations are
correct.
So, on the right-hand side of the panel
it shows repeating these studies in over
1000
people.
Next one please. The additional issue
that emerged--
DR. WOOD: Try and get to the point
quickly because you are answering a
single question
and we are running really short of time.
DR. WELTON: I understand.
Mr. Chairman,
I beg your pardon. Bear with me for a moment.
DR. WOOD: One moment.
DR. WELTON: Over 24 hours pressures are
sustained. Next one.
There are differences in the
358
antihypertensive drugs. There are differences seen
in the responses of the drugs also at the
doses
that cause comparable efficacy.
Next one, please. Let me simply wind up.
If I might have the next one,
please. As you will
see at the top right-hand side, what it
shows is
that if you shift in the population blood
pressure
by as little as 2 mm, on the right-hand
side at the
bottom, you can see the reduction and
mortality.
So, these small changes in blood pressure
in large
numbers of patients are very, very
important.
I would end to answer the
question of Dr.
Nissen that he asked earlier on, if I
might have
C-28-3, and that, Mr. Chairman, is my
final point.
DR. WOOD: It really is.
DR. WELTON: Here we are showing
elevations of greater than 20 mm Hg and
it does
show between these two coxibs there are
important
differences in these big swings in blood
pressure.
I regret I cannot show you placebo
results in this
trial because we didn't incorporate them
but that
speaks to your earlier question, Dr.
Nissen.
DR. WOOD: Thanks a lot.
Curt?
DR. FURBERG: I just wanted to say for the
record that we have some missing
information.
359
There is a fairly large number of studies
sponsored
by the NIH that have information on
cardiovascular
outcomes.
An effort was initiated to get that
information together but no real
follow-up. So, it
looks to me like the NIH has dropped the
ball and
not provided the information that we need
from
those other trials.
DR. WOOD: Cardiovascular outcomes in
what?
In celecoxib?
DR. FURBERG: Yes, with Celebres, yes.
DR. WOOD: I see.
DR. FURBERG: So, I think we should
request that information and, if
necessary, even go
to the director.
DR. WOOD: Tom?
DR. FLEMING: I commented earlier about
how one struggles to try to interpret the
data when
there are such short-term interventions,
the 41
trial meta-analysis that if you focus on
the
360
placebo control you only have 6 weeks of
treatment.
It certainly tempts me to focus much more
on the
half a dozen studies that have
longer-term
follow-up.
You mention in slide 36, the
CAESAR trial
and the CLASS trial, although diclofenac
is the
control and, as Dr. FitzGerald said, is
that
Celebrex with hepatic side effects? What does it
mean if there is not a difference? Interestingly
though, when you look at the CLASS trial and the
non-aspirin users there is also an
ibuprofen arm
and the summary that is given here is in
atrial
SAEs, anginal SAEs, MI and
thrombophlebitis. There
are four times as many events on Celebrex
than
ibuprofen in the non-ASA users.
If we go to the
placebo-controlled trials,
we have seen that in the APC trial there
is a
three-fold increase in the rate of CV
death, MI and
stroke.
Another placebo-controlled trial that you
didn't mention is the Alzheimer's trial,
the
9702001 trial, that being
placebo-controlled is of
interest, and it had I think a doubling
in the rate
361
of targeted events.
Then, the last issue related to
this is
the PreSAP and the ADAPT trials will also
be very
informative, and I am very confused in
exactly what
you do know. I think someone has already alluded
to.
On slide 821 it is written as though you know
that these results will be neutral or
favorable.
So, I have a multi-component
question
here, am I interpreting this--can you
tell us more
about the Alzheimer's 9702001 trial? And, what
exactly do you know today about the
PreSAP and
ADAPT trials?
DR. VERBURG: Let me start with the second
one first. So, the PreSAP results will be reviewed
by Dr. Bernard Levin later this afternoon
in full
detail.
So, those results will be disclosed to the
committee. For the ADAPT trial I know no more than
what has been published, what has
appeared in the
newspapers, nothing more.
DR. FLEMING: And what about the 9702001
trial?
DR. VERBURG: Right.
So, let's go to
362
slide C-214. Let's talk about this for a minute.
So, the Alzheimer's trial, study 001, was
a small
randomized trial comparing celecoxib 200
mg twice
daily to placebo over one year of
treatment.
Notice that the randomization was 2:1 and
that the
mean patient exposure was on the order of
about 10
months or so.
This goes back now to the
concept that we
used in the briefing book and we will
update this
in a minute, but for any cardiovascular
event you
can see that there were 3 events versus 11
events.
There were 4 myocardial events in
total. Two of
those I believe were angina and 2 were
MI.
Cerebrovascular events are listed here
and then
further down.
Of course, these are based on
investigator
reports to us. Also, if we go back--
DR. FLEMING: Well, before you leave this
slide, which I guess you have just
done--is there
data that you have on heart failure as
well?
DR. VERBURG: I am sure we do. I just
don't have that right at hand but we can
certainly
363
get that for you. I just don't have that in my
presentation.
I am looking for the background
medical
history in this trial. Do I have the wrong slide
number?
So, what concerned us a little bit about
the results of the trial you can see
here, again
coming back to my comment earlier, when
the
purposes of the trial are not
cardiovascular in
nature, they can be heavily confounded
because you
are not controlling for distribution of
patients by
risk factor. So, what you see here is a trend for
a higher degree of underlying risk in this
patient
population.
Also, I want to add one
comment--
DR. FLEMING: Although somewhat modest I
would say when you are looking a relative
risks of
2 in the outcomes. A valid point, small numbers,
but
it doesn't explain a large part.
DR. VERBURG: So, we didn't entirely
dismiss it there either so we took it one
step
further and, in fact, at about the time
of the
CLASS and the VIGOR results we did employ
a blinded
364
adjudication process of all
cardiovascular events,
serious cardiovascular events that Dr.
William
White, who is with us today, conducted
along with
some of his colleagues. That trial was published
several years ago.
Could I have slide C-217? That article
that Dr. White wrote was targeted to
arthritis
patients.
At the time, he and his co-workers also
adjudicated the events from the
Alzheimer's trial.
Dr. White, if you would care to make a
comment? I
think you are most informed on these
results.
DR. WHITE: Thank you.
William White,
University of Connecticut Cardiology Center. So,
these were done in accordance with the
other
clinical trials that you have heard,
using strict
criteria between two blinded
adjudicators. As you
can see, there was a 2.9 percent incident
rate in
the placebo group and a 3.5 percent rate
in the
celecoxib group, which was not
statistically
different.
To answer the heart failure
question,
there were just too few cases of
adjudicated heart
365
failure, not different between the two
treatment
groups.
DR. WOOD: So, these were adjudicated
events that had already been
reported? Or, where
these prospectively defined?
DR. WHITE: Yes.
DR. WOOD: So, tell us what you did.
DR. WHITE: I am not sure what you are
asking, were the cases prospectively
defined when
the study started?
DR. WOOD: Right.
DR. WHITE: No.
DR. WOOD: So, maybe somebody should
comment on that. Richard, to you want to comment?
Okay, well, we will get to that.
DR. FLEMING: For heart failure you said
there were two adjudicated cases. They broke out
in what manner?
DR. WHITE: i believe it was equal in each
group.
It was a very small number. There
was
either one and one or two and two. I can't recall,
to tell you the truth.
DR. FLEMING: Why don't we check?
DR. WHITE: We will check.
DR. WOOD: Any other questions? Dr.
366
Shafer?
DR. SHAFER: This does not involve
aspirin.
DR. WOOD: Thank goodness!
DR. SHAFER: One of the things we are
looking at is overall safety, and you
brought up
the subject about alternatives, NSAIDs
being the
alternative. What data are there about celecoxib
GI tolerability versus NSAIDs when
combined with a
proton pump inhibitor?
DR. VERBURG: I am not aware of any data
that evaluate GI tolerability issues--
DR. WOOD: There is lots of data on that.
DR. VERBURG: There are data with respect
to complicated ulcers, but with respect
to whether
patients stay on therapy longer with
celecoxib
alone versus the combination of an NSAID
and, say,
a proton pump inhibitor, I am not aware
of any such
data.
DR. WOOD: Do you want to take that,
Steve?
No? Actually, the last sponsor
presented
some of that data in their presentation.
DR. NISSEN: I want to explore with you
for a moment the issue--you have several
times used
the term "equally effective
doses" and this is
367
important.
In several of the trials we see a
relationship between dose and the amount
of
cardiovascular toxicity. It is particularly
important because you have done a lot of
blood
pressure comparisons between rofecoxib
and
celecoxib and one of the arguments I have
certainly
heard is that the equivalent dose of
celecoxib to
25 mg of rofecoxib is 200 mg BID, not
once a day.
So, I would be very interested in
understanding
that, particularly when you consider that
there is
a much shorter half-life and, you know,
particularly if you do an ambulatory
blood pressure
study the effect of the drug may be gone
toward the
end of the dosing interval, which would
tend to
bias the study in favor of celecoxib. So, could
you address any data that you have that
indicates
368
that 200 mg once a day has the same
effectiveness
as 25 mg of rofecoxib? DR. VERBURG:
200 mg of
celecoxib in terms of 25 mg of rofecoxib
in terms
of effectiveness?
DR. NISSEN: Yes, I want to know about
efficacy, and then I would also like to
know about
any blood pressure comparisons of 200 BID
to 25. I
am trying to understand. You have made a case that
the drugs have a very different effect on
blood
pressure and I am testing that a little
bit with
you to make sure that we got that right.
DR. WHITE: Do you want me to answer that?
DR. VERBURG: Yes.
DR. WHITE: Well, I have conducted two
controlled clinical trials in this
regard. The
first one was done about three or four
years ago in
178 patients treated with celecoxib at
200 mg twice
daily versus placebo twice daily,
specifically in
hypertensives treated with an ACE
inhibitor to
bring out the worst-case scenario with
regard to
interference with the drug. The 24-hour systolic
blood pressure difference was 1.3 mm Hg
between
369
celecoxib at 400 daily and placebo, which
was not
statistically different. That was giving it BID.
Now, in the other realm, not
placebo
controlled but published two weeks ago in
The
Archives of Internal Medicine, was a
500-patient
study in which patients with
osteoarthritis of the
hip or knee, plus hypertension, plus type
II
diabetes, also treated with a angiotensin
blocker
were then randomized to celecoxib 200
daily,
rofecoxib 25 daily and naproxen 500
BID. At 6 and
12 weeks into the double-blind period a
very formal
cluster of arthritis efficacy assessments
were made
using the same standards for any
arthritis drug,
and they were, in fact quite equivalent
using
Womack and Visual Analog Pain Score and
so forth.
So, from the patient
perspective at 6 and
12 weeks, they were therapeutically
equivalent. At
those same endpoints as you already saw,
there was
a significant pharmacodynamic interaction
between
rofecoxib and perhaps the underlying
treatment
because there was very little salt and
water
retention, evident based on edema and
weight gain,
370
with about a 4.2 mm increase in 24-hour
systolic
pressure.
That was a sustained increase during the
daytime.
With regards to naproxen and
celecoxib,
there was no such increase seen, yet,
there was
clinical equivalence with the regards to
anti-inflammatory responses. That is pretty much
what there is. There are no other studies like
those.
DR. VERBURG: Dr. Simon, do you have a
comment?
DR. SIMON: Yes, I was one of the authors
of the hypertension study in the Archives. As a
hypertension study and as a
rheumatologist, why
would I be involved in such a study? In fact, I
was involved to ensure that the outcome
measures
for osteoarthritis, as measured by
Patient Global
and Womack, which is a functional outcome
scale,
and the VS scale for pain would then be
the
appropriate way to look at equivalence of
benefit.
The data sets that suggest that
there
isn't equivalence in this kind of
analysis of 200
371
mg versus 25 are really based on
different ways to
look at the evidence, such as night pain
and other
aspects of components of some of these
outcomes.
This was really a very robust way that
is, in fact,
typically used for approval at the FDA in
determining efficacy of a particular
therapeutic.
And, we were able to demonstrate both at
6 weeks
and at 12 weeks that there were equivalent
benefits.
But you are absolutely correct,
differences in half-life, if you ask
different
questions will give you different
responses.
DR. WOOD: Do you really want to say
something because I really want to get to
the
next--all right.
DR. BRAUNSTEIN: Yes, I just want to
show--
DR. WOOD: Be quick.
DR. BRAUNSTEIN: Well, I will show you
actually the pharmacologic responses for
COX-2
inhibition.
DR. WOOD: All right, go ahead.
DR. BRAUNSTEIN: This shows you the
372
average 24-hour inhibition of COX-2 for
different
doses of rofecoxib and celecoxib. This is a
standard ex vivo PGE-2 inhibition
assay. What you
can see is that there is a dose response,
as we
know, for all NSAIDs to inhibit COX-2,
and over 24
hours celecoxib 200 mg twice a day has the
equivalent COX-2 inhibition of
approximately
rofecoxib 25 and celecoxib 200 once a day
is
roughly the same as rofecoxib 12.5.
May I have 233? These are the results of
a clinical study looking at Patient Global
Assessment in response to therapy,
acetaminophen
4000, celecoxib, rofecoxib 12.5 and then
rofecoxib
25.
Without getting into an argument--although
statistically rofecoxib 25 had the
greatest
effective, you can see that rofecoxib
12.5 is the
dose that has the most similar efficacy
to
celecoxib 200 once a day, you know,
similar to what
you would expect based upon the
pharmacologic and
the pharmacodynamics.
DR. WOOD: All right, thanks. Let's move
on to the next presentation, which is
from the FDA
373
and is by Dr. Witter.
FDA Presentation: COX-2 CV
Safety: Celecoxib
DR. WITTER: Good afternoon. I am going
to try and push along here to make up
some time. I
am a practicing rheumatologist. I have been with
the FDA for almost ten years.
One of the first drugs that I
was given at
its
30-day IND stage safety review was celecoxib.
So, although I could say a lot about it I
am going
to limit myself to the topic of interest
to day and
I will try to move along as expeditiously
as I can.
Just to remind everyone, and we
have been
discussing this but it factored into my
historical
perspective in terms of why we did what
we did, or
what kind of discussions went on, to
remind
everybody that there are different
reasons for drug
exposure which have been talking about,
acute and
chronic pain for example. I will be talking later
about some acute pain issues so, to some
extent, I
have two presentations that are tied
together.
But, you know, in this situation you are
a patient;
you have a reason to be taking it because
of the
374
pain.
The issue of placebo control and how we
might define placebo, and we can discuss
that for
quite a while, but in a short-term trial
for
example placebo control might generally
be viewed
as acceptable because there is rescue
available.
On the other hand, in a long-term chronic
pain type
study there are problems to deal
with. It is not
realistic; it is difficult, and that has
impacted
some of the ability for us and the
sponsors to do
the kinds of things we might want to have
done.
On the other hand, if you are
trying to
prevent disease progression, such as the
Alzheimer's and the polyps studies that
we will be
hearing about later today, one can
classify them as
subjects, not really patients, and so in
this
situation, again depending on the
placebo, it may
be more acceptable to conduct such
studies.
So, having said that, let me
just take
this opportunity to thank the sponsors,
past and
present, be they from the industry or
from the
private sector or from government, for
their
efforts in this regard in this complex
area and,
375
more importantly, to thank the patients
and the
subjects for the topics that we have been
discussing and will be discussing in the
next few
days.
This is a very complex area of medicine but
very important. So, we have the privilege of
seeing some data today that we didn't see
back when
I started. And one of the points, if you take
nothing else from my presentation, is
that we have
had a paradigm shift in this area. It has been a
dramatic shift in terms of looking at
safety events
and the kinds of data that we have. So, one of the
themes I am going to try to develop is
exactly
that.
So, this slide is to remind us
all that
there are available OTC, some of the
medications we
have been discussing, be they ibuprofen
or
naproxen, that have been available for a
while and
available for the studies for the most
part that we
have been discussing. Although we try, and I know
the investigators try to limit that
exposure, it is
also a factor that I think has to be
remembered,
particularly here as we think through
these data
376
that we are looking at.
In preparation for the meeting
then I also
looked back--and not meaning to pick on
any drug in
particular but I went back to the
diclofenac
approval back in 1988 to try to give us
all a sense
of what were the databases available back
then and
how decisions were made.
So just very quickly here, we had some
pivotal trials in OA that involved 97
patients for
56 weeks.
We had patients in pivotal RA trials
that went on for anywhere from 6-12
weeks. We had
Phase I/II trials, which are the PK kind
of trials
for example, with 950 patients or
volunteers.
Those were mostly 2 weeks. There were some
supportive trials that had 11 patients
for 12
weeks.
We had some long-term open-label trials
that involved 252 patients for about 38
weeks. So,
I had one of the statisticians do this
calculation
for me and that comes out to be around
224
patient-years. So, keep that number in mind as we
move forward.
I would also like to point out
that as I
377
was reviewing this I noted that there
were two
myocardial infarctions with diclofenac;
none that I
could see in the other comparators which,
by the
way, included aspirin and one of the
adverse events
that used to be looked at a lot was
tinnitus and
people would get evaluations for hearing
loss. In
any event, there were two MIs, one during
double
blind and one in the open-label
trials. So, I just
thought this might be of use as we think
through
where we are.
Part of my challenge here today
is to
present to you then a bit of a historical
perspective and to try and merge some of
the
different approaches in terms how
sponsors
conducted the trials and how we
subsequently
analyzed the information.
So, I just want to step back
just for a
bit.
I am presenting here the World Health
Organization terminology that was used to
define
cardiovascular events in the celecoxib
NDA base.
These kinds of reporting systems have
evolved over
the years, as we all know, but just to
give you a
378
sense of what were some of the terms that
were
looked at in the original approval for
celecoxib,
just a few of them are listed here.
Then just to remind everybody
that we, for
the most part, will be describing and
discussing
today--at least I will--mostly serious
adverse
events.
There is a regulatory definition for that.
Deaths are obviously the hard endpoint
which will
be also discussed. The point I think has already
bee made that in the celecoxib NDA these
were
spontaneous investigator reported
events. They
were not prespecified or not
adjudicated. In my
subsequent presentation what I will do is
give you
some information about the adjudication
process and
how sometimes that is problematic. Also, in
discussing CLASS I would like to point
out that the
GI endpoints, because that is what the
trial was
intended to do, were prespecified and
adjudicated
but, once again, the cardiovascular
events were not
prespecified and not adjudicated. These were
spontaneous investigator reports but we
look at all
this information.
This is a slide that Dr.
Villalba had
shown earlier. I have just added one
column here,
and the only point I want to make from
this is that
379
as we might look at events--and I am not
going to
talk about the various categories--these
are
different ways to look at cardiovascular
events.
We are all familiar with the APTC we are
all
familiar with. But I just wanted to make the point
that as you look at the numbers and you
make just a
rough ratio comparison, they appear to be
similar,
leading one to make an assumption that
the
inferences that would be drawn by looking
at any of
these data sets, at least in a
qualitative way,
would be the same.
Turning specifically to
Celebres, this is
my reminder to you that this information
is
available on the web. It has been an effort that
has evolved over the years. We have tried to put
as much information as we can in our
reviews so
that all of you can have a chance to look
at this
information.
The original NDA was submitted
on June 29
380
or 1998.
It consisted of 51 studies. I
have just
listed them briefly here as to the
types. There
were 29 studies in Phase I. There were 14 studies
that were arthritis patients either with
OA or RA.
There were 7 post-surgical analgesia
studies.
There was one long-term study which went
out 2
years, study 024.
To remind everybody, although
you probably
weren't here, when we talked about the
original
approval of Celebrex at an advisory
committee
meeting, one of the things that I
discussed in
particular was this concept of dose
creep, that
patients tend to increase their dose if
they are
allowed to. I would also like to reemphasize the
point that in any of these kind of
long-term trials
there is no controlling arm and that
really makes
it difficult to try and get a handle on
how to
interpret these events, particularly from
a
perspective of common events like
cardiovascular
events.
So, in my own thinking anyway, you always
want to have some kind of a controlling
arm
whenever you do long-term studies. Then, again,
381
with this particular type of drug how OTC
medications may impact some of these
results.
That is just a summary of what
I will be
talking out and I will just point out
what I will
be talking about, which is the ADAPT
trial and two
other trials which will be discussed a
bit.
The reviewing process for an
NDA and
particularly for this one when it came
in--it was a
very large database and so this was
really a team
effort and that is one of the things I want
to
stress here. This data is looked at by multiple
people with multiple talents for long
periods of
time.
So, there isn't just one person looking at
the data; it is done as a team
effort. In this
case, for example, I was the primary
medical
officer to look overall efficacy and then
to come
to an overall conclusion about
safety. To assist
me was a renal/cardiovascular
consultant. We also
had another medical officer who reviewed
the data
and also paid attention to the
cardiovascular
results.
We had a GI consultant who served as a
secondary medical reviewer also looking
at the
382
safety data. Then we had people specifically
looking at analgesic trials and the
platelet safety
trials.
So, there really is a team of people who
look at these results whenever they come
in.
I am going to stick with just
the OA and
RA exposure because that is the most
robust
exposure that you have in here. What I am doing is
displaying results from some of the
consults that
we had to the Division about these
issues. I will
be describing most of the results either
in terms
of patient-years or crude rates, and I
will try and
tie this together at the end to
Kaplan-Meier
approaches.
But just to give you a sense,
in the
original NDA in the controlled trials there
was not
a lot of information for exposure beyond
180 days,
not surprisingly, but when you looked at
the
open-label trials we had a larger
exposure. To the
extent that these numbers make any sense,
I am just
pointing out a 16,208 patient-year
exposure versus
diclofenac, as I pointed out earlier, at
324.
Turning then to the
cardiovascular
383
mortality in the NDA database for
Celebrex, the
comparisons here in the information that
we had are
against placebo, Celebrex itself and the
NSAID
comparators in two different ways. They don't
differ that much; there was a slightly
different
definition. Then also in the long-term open-label
studies.
You can see that there were not many
events.
When you do the math here and divide it
using the patient-years to get an
estimate of the
crude mortality rate, you can see the
highest
number comes out here for the NSAID
comparators in
both situations. It also is higher than what was
found when looking at the all known
cardiac deaths
in the long-term open-label arthritis
experience.
So, there didn't appear to be any large
signals
when looking at this particular outcome.
Turning then to serious adverse
cardiac
and renal events, i have again here the
columns of
placebo, differing doses of celecoxib and
the NSAID
comparators. When you look at these events overall
there were no important differences. In fact, they
looked worse for the NSAID comparators
and the
384
placebo looked roughly equivalent to
celecoxib.
When you look at some of the
individual
events, and let me see if I can point to
the
particular events that have been
discussed so far
today, heart failure for example, there
didn't
appear to be any major differences
between
celecoxib and placebo; myocardial
infarction, again
there appeared to be no important
differences
between all the groups.
So, looking at this data in
summary, there
didn't appear to be any major clear
signals that
distinguished celecoxib as it appeared in
the NDA
database from NSAID comparators and, at
least in
some of these comparisons, from placebo
as well.
Looking then at the data from
the
extension trial after the NDA in a bit
different
way, we configured the data to display
the events
of cardiovascular mortality based upon
the last
known dose that the patient had at the
time of the
event.
So, that is what is displayed here.
As you
can see, you go from zero at 100 mg and
up to 200
mg, 300 mg and 400 mg. When you do the math again
385
using patient-year of exposure, there
certainly
appears to be a trend here. As you go up in the
dose, the cardiovascular mortality goes
up. These
are small numbers and, again, it was
difficult for
us to place this in context with no
controlling
arm.
For example, if an event had
been
adjudicated away, and we don't do this,
it would
bring the rates down to what I have given
here just
for comparison's sake. So, we are aware of this;
didn't know what to do with it; difficult
to make
comparisons without some kind of a
controlling arm.
I would like to turn then to
the
SUCCESS-1, which stands for Successive
Celecoxib
Efficacy and Safety Study. In terms of what we are
discussing today, this was a short
12-week study in
patients with osteoarthritis. It had two
comparisons with celecoxib, two different
doses,
naproxen and diclofenac. It was a large study
involving 39 countries, lots of centers,
and it was
really intended to evaluate the
homogeneity of
efficacy and safety around the
world. it was not
386
intended as a cardiovascular outcome study. None
of what I am discussing today was
intended as a
cardiovascular outcome study.
I have put up here a bit more
of summary
results to give you a sense--and these
results were
described previously at other meetings--between
celecoxib, diclofenac and naproxen. What I have
tried to do is highlight for you in
yellow who has
the most events. As you can see, for the most part
with the exception of a small increase of
cardiovascular events, there wasn't
anything that
in particular distinguished celecoxib
from the
other groups.
I have noted down here an
update last
month.
There were, in fact, 8 myocardial
infarctions in the 100 mg group; 2 in the
200 mg
group; and 1 in the NSAID
comparators. And, I have
done the calculation for the rates to
make some
comparisons here. But as you can see, and I think
the points are starting to emerge as we
discuss
more and more data, that when you look at
the
comparator NSAIDs they have their own
sets of
387
problems which we were certainly aware of
as well.
Turning to the CLASS trial, in
case you
don't know, it stands for the Celecoxib
Long-Term
Arthritis Safety Study. I have highlighted the
term arthritis here because, again, this
is for the
indication of arthritis and that is where
this was
studied.
This is a unique trial. It was
intended
to mimic a real-world setting. We have been
hearing criticisms that trials were not
extrapolatable and generalizable so what
we were
trying to do, and the sponsor as well, was
to come
up with a trial that was in a more
realistic
setting.
I should point out that the
only trial
that was available, large outcome trial,
was the
MUCOSA trial published in 1995. So, this was a
unique trial at the time. A lot of discussions
went on about how to design this
trial. One of the
things that we had been discussing was
aspirin use
if indicated. Patients had either OA or AR. As we
will be hearing more about, RA, we know,
traditionally increases the risk of
cardiac
388
problems.
In particular, there is something that
just came out in Arthritis and Rheumatism
this
month which points out that RA doubles
the risk of
heart failure. This seems to be, according to the
authors, an independent risk associated
with the
disease itself.
So, just to reiterate, this was
designed
as a GI safety study and it was intended
to try and
change the NSAID template regarding this
particular
outcome.
This was not powered nor designed as a
cardiovascular safety study.
This is a slide that back then,
in 2001
when we discussed these particular CLASS
and VIGOR
trials and what we were bringing to the
forefront
at that point of time was this concept of
2X. So,
let me just tell you a bit about the
history of
that.
The X dose was intended to be the highest
dose for the intended chronic
indication. The idea
of 2X was to give us some assessment of
the
robustness of the safety results. We have
certainly heard, as somebody rolls in the
door as
an NSAID that, you know, we are
safer. So, we
389
wanted to see the data. We were also skeptical of
the surrogacy for endoscopic results and
how that
might translate into rigorous
outcomes. So, it was
that kind of thinking that impacted upon
the design
of these kinds of trials.
Again just to remind you, at
the time--and
this is still the language in the GI
portion of the
FDA warning label, it describes in terms
of looking
at GI ulcers, gross bleeding of
perforation, that
there is one percent of patients if
treated for 3-6
months who experience this event, but
this occurs
in about 2-4 percent of patients if they
are
treated for one year. So, this is data that we had
previously known from other NSAIDs. And, I saw
this on a slide earlier today--the kind
of
information that we had available from
other
databases, suggesting that there were
lots of
hospitalizations and lots of deaths
associated with
this particular adverse event.
Some of the baseline
demographics then in
terms of looking at the CLASS trial, the
mean/median age was about 60 years; 11
percent of
390
the patients were 75 years or older. These were
mostly white females. Approximately 27 percent of
the patients had RA; 10 percent had a history
of GI
bleeding or gastroduodenal ulcers; and
about 21
percent were taking aspirin.
In terms of looking at the
inclusion
criteria and exclusion criteria, they
were fairly
open.
Basically you needed to be able to give
informed consent; that you required
something like
this kind of a medicine and that you were
not
pregnant.
On the other hand, that you didn't have
any active disease of any signals in
terms of
looking for hepatic events.
The aspirin use in CLASS
deserves some
comment.
It was at less than or equal to 325 mg
daily.
Again, this was if patients needed for
cardiovascular events. But the use was not
stratified in the CLASS trial. The dose and the
duration of use also varied. It wasn't a constant.
So, I think this is one of the things
that we had
discussed back in 2001, that it was
probably not a
good idea to try and draw any firm
conclusions from
391
the aspirin use from this trial, and that
only
observations and possible directions for
future
studies might be the most value for this
particular
study.
To give you a sense then of the
exposure
in the CLASS trial, it was again a large
trial. In
terms of making some comparisons here,
this one
trial to the extent that we believe, or
you
believe, patient-years of exposure and
how
adequately that assesses risk, there was
three
times more information in this one trial
on
diclofenac than we had in other trials,
the point
being that, you know, we had been very
comfortable
with much larger databases in this regard
which is
a good thing.
The exposure, in terms of
looking at the
durability and long-term, is listed here
for
celecoxib, diclofenac and ibuprofen. The patients
who were exposed from 12-15 months, there
were not
many patients in the diclofenac group
compared to
the other two arms. This was a confounding
observation and when we were trying to
understand
392
some of the benefits in this trial we got
into
discussions of informative censoring,
which I won't
get into today, but this was a factor in
terms of
trying to understand and put some of
these results
in context.
Turning to deaths, I have
listed here--and
this is the same information I have
talked about at
other advisory committee meetings--there
were 36
deaths overall, 19 in the celecoxib
group, 9 i
diclofenac and 8 in ibuprofen. I have calculated
roughly the patient-years here for
comparison. No
important differences, at least to my
eye. Most of
these patients were 65 years or
older. Most of
these deaths were from cardiovascular
events.
There were 11/19, or 58 percent, in
celecoxib and
roughly the same in diclofenac, a bit
more in the
ibuprofen group.
In terms of looking at this
data, and in
spite of my own caution earlier about
looking at
aspirin versus non-aspirin, it is exactly what I am
going to be doing to give us a sense of
what the
data look like. Again, here are the three
393
treatment groups. This displays all deaths and
this displays the cardiac deaths, broken
down this
time into all patients, those that use
aspirin and
those that were not using aspirin. When you look
at this data in terms of all-cause
mortality,
again, there do not appear to be any
point
differences. When you look at aspirin users there
were more events in the ibuprofen
group. When you
look at non-aspirin users there were more
in the
diclofenac group. This pattern basically held
through when we looked at the entire
study for
cardiovascular deaths. There was the same trend.
Turning then to serious
cardiovascular
events in the CLASS trial, here again is
displayed
a comparison between aspirin users and
non-aspirin
users.
Looking at the groups, you can see then
that there were not as many patients that
did take
aspirin so the numbers are smaller; the
patient-years of exposure are
smaller. But,
nonetheless, here are the results. When you look
in the aspirin users and at the issue of
myocardial
infarction you can see that there were
more of
394
those in the ibuprofen group. When you look at the
combined atrial endpoint, which was a
combination
of atrial fibrillation, bradycardia,
tachycardia--I
am not remembering one of them, anyway,
it was a
composite endpoint that we had come up
with to get
a handle on this. There were more events in the
ibuprofen group. For combined anginal disorders,
which was a combination of unstable
angina and
coronary-artery disorder, there were more
in the
diclofenac group.
Looking at the non-aspirin
users and
looking at the same types of endpoints,
in this
situation it looks different in that
there are more
events in the celecoxib group than in the
other two
comparators--small differences but
differences
nonetheless.
What I have tried to do in this
slide is
to put together some of this information
in terms
of looking at APTC-like events, recalling
again
that these were not adjudicated. I don't want to
diminish the importance of APTC so I am
calling it
"like" events. So, I have just simply added up
395
cardiovascular deaths, MI and strokes to
give us a
sense of what this endpoint might look
like if it
had been done, and you can see in this
comparison
that there are more of these events in
the
ibuprofen group versus the other two.
This is Kaplan-Meier analysis
that I took
from one of the publications that I have
listed up
here, by Dr. FitzGerald, in Nature/Drugs
Discovery,
in 2003.
There also was something by Dr. Strand
and Hochberg in 2002 in Arthritis and
Rheumatism.
I
put this slide up here to try and make some
comparisons for us. This displays the Kaplan-Meier
analysis for serious thromboembolic
cardiovascular
events, arguably in the most important
population
to look at, in the non-aspirin users, and
as you
can see from this particular analysis
celecoxib
appears to be between the comparators
here. It
might not be showing up well in the
back. This is
diclofenac; here is ibuprofen.
What I have displayed over here
then is to
give us some comparisons, if one looks at
true rate
comparisons with these number of events
or
396
patient-years to tie back to earlier
looks of the
data, and again it is probably hard to
see, this is
0.97, 0.7, 7.45 versus 1.78, 1.33 and
0.8. the
point being is that there do not appear
to be any
important differences in the conclusions
or
inferences that are made no matter how
you look at
this data.
I would like to turn then to
the
Alzheimer's study, 001, which has been
discussed a
bit today. This was under an IND in a different
division, Neuropharmacologic Drug
Products. We
were aware of this study. This information had
been discussed previously.
This was a study that was
started in 1997.
It was a double-blind, placebo-controlled
trial
that lasted for a year. It was a comparative study
of celecoxib for the inhibition of
Alzheimer's
disease.
One of the results in terms of efficacy
conclusions was that celecoxib did not
limit
progression in this situation.
There were other studies that
were ongoing
at the time, 004. This was an open-label study
397
looking at long-term safety. This study was
terminated when the results of 001 were
made
available.
There was another study under
this IND,
002, which was a placebo-controlled,
long-term
study.
It had vitamin E co-use in it as well.
This was intended to look at brain size
by MRI and
to look at Alzheimer's disease-associated
proteins
and inflammatory mediators to get a sense
of
mechanisms. This study was also terminated due to
the results of the 001 study. So, the IND was
inactivated in July of 2001.
As we have been preparing for this
meeting
it came to our attention, the following
letter
which I just want to bring to your
attention
regarding this particular study. I am just
highlighting a few things here rather
than showing
the whole letter. But this was basically a letter
from the DSMB that was involved in this
particular
study.
What the letter points out is that the
trial was conducted between 1997 and
1999; that
there were, according to this letter, no
adverse
398
events to support stopping the trial
while it was
ongoing, however, at final review there
was an
excess of cardiovascular-related and
other risks
but it was difficult to interpret,
according to
this letter, because of the small sample
size which
made relative risk and odds ratios
unreliable.
This was conducted in a frail and fragile
population that had substantial
co-morbidities and
concomitant medications, making it
difficult to
know how to generalize these
results. It was
commented that there were indications of
failure in
randomization in baseline cardiovascular
disease
and cardiovascular medications, meaning
in
particular that there were more in the
celecoxib
group than in the placebo group.
The letter went on to state
that the
members were concerned that this data had
not
previously been made available, other than
i an
abstract form, and they were concerned
about this
because this may be the only information
available
in medically ill elderly populations with
placebo
control.
Looking then at cardiovascular events, I
have summarized them briefly here
comparing the
Celebrex 200 mg versus placebo. I just summarized
399
the events. With the one exception of
cerebrovascular disorder, there don't
appear to be
any differences in all the adverse
events--deaths
overall, cardiac deaths, serious adverse
events,
cardiovascular, and no matter how you
look at
it--congestive heart failure, atrial
fibrillation
and then I made another APTC-like
calculation here,
they all wind up on the celecoxib side of
the
ledger here.
This is also information that
we had
available to us in preparing for this
meeting in
terms of addressing the issue or
randomization.
These are results from the sponsor that
you saw
already.
When you look at the Celebrex group there
were imbalances in terms of hypertension,
diabetes,
those that had bypass surgery, those that
had
history of ischemia and those that had
history of
coronary-artery disease. Whether or not this, in a
small trial, is enough to explain the
results is to
400
be determined.
So, that is what I have to say
today.
Thank you.
DR. WOOD: Thanks a lot.
You also have
not covered the APC trial. Right?
That is sort of
surprising. Does the committee want to go on to
the next two presentations and wait for
questions
to Dr. Witter at that point? Let's do that. Let's
go on to the next two presentations.
DR. FLEMING: Could I have jut one?
DR. WOOD: Sorry.
DR. FLEMING: Just on slide 35 as you were
presenting those 001 results, it is
certainly
noteworthy that there is a pretty
consistent excess
across all of these key categories for
Celebrex.
We talked, for example, about heart
failure
adjudication. It is kind of hard to adjudicate
something in a blinded way when all the
events are
in the one arm. I don't know if the adjudication
committee was aware of how the results
broke out
before they did their adjudication. In any event,
we were told those broke out at 1/1 after
401
adjudication. They were 5/0 before. So, that
seems difficult to justify as well. So, I look at
this as one of a small number of
placebo-controlled
trials with a fairly long period or
treatment
exposures. So, this is of some relevance.
DR. NISSEN: Tom, did you attempt to do a
p value there from those numbers?
DR. FLEMING: For which aspect of this?
DR. NISSEN: Well, say, APTC-like or just
the serious AEs? Is that going to be significant?
DR. FLEMING: Probably borderline.
DR. WOOD: You know, the elephant in the
room is the next trial so let's move on
and see if
we can get some of these questions dealt
with
afterwards. Let's go on to Dr. Hawk's
presentation.
DR. WHITE: Do you mind if I make one
comment, jut for cleaning the air? The
adjudication committee was not aware of
the results
when they looked at the data at all.
DR. WOOD: Right.
Let's come back to that
point later because there are lots of
problems with
402
that adjudication. Let's go on to the next two
talks.
NIH and Investigator
Presentation:
Celecoxib in Adenoma Prevention
Trials:
The APC Trial (Prevention of
Sporadic Colorectal
Adenomas with
Celecoxib)
DR. HAWK: My name is Ernie Hawk. I work
at the National Cancer Institute,
currently Office
of Centers, Training and Resources. The study I
will share with you was done while I was
a member
of the Division of Cancer Prevention, and
it is the
APC trial.
The story I would like to share with
you
over the next 20 minutes or so--I will be
followed
by my colleague from M.D. Anderson who
led the
Pfizer-sponsored PreSAP trial--the story
I would
like to share with you really has three
important
components. That is, the data that are available
today; the data that I can't share with
you today
because they are still emerging. These two trials
that I will discuss now are still
ongoing. Drug
administration was halted in mid-December
with the
403
finding of the risk that I will share
with you
today, but the trials remain ongoing,
looking at
efficacy and other issues with regard to
overall
safety.
Then, finally, one of context because
while the discussion this morning and
early
afternoon is centered upon the usefulness
of these
agents in inflammation and pain, they
have another
very important potential indication in
terms of
cancer risk reduction, both in a
preventive as well
as a therapeutic context. And, I hope to bring a
bit of that to your awareness.
Depicted here is the disease in
which we
are attempting to intervene. It is colorectal
cancer. When looked at globally or within
the
United States, despite the availability,
as we
heard earlier, of effective approaches to
this
disease in terms of screening and risk
modulation
through things like polypectomy, we
remain with a
significant problem, with 145,000 new
cases
anticipated in 2005 and about 55,000
deaths, and
obviously a much larger issue ii the
worldwide
scene.
So, the National Cancer Instituted is
404
devoted to not only extending available
techniques
but exploring new areas to combat this
disease.
I am trained as a medical
oncologist and,
therefore, my focus of attention and my
training
was to the right side of this slide, that
is
cancer.
But cancer, as with most diseases, is
actually a process--if only we had the
tools to be
able to identify it. Depicted here is the process
moving from normal mucosa in the
intestine through
a variety of stages, intermediate polyps,
adenomas,
to invasive disease, invasive cancer.
This process is time dependent,
taking
typically years in most settings, and
already this
process is becoming the focus not only of
cancer
itself, but the process of cancer
development has
become the focus of clinical screening
and surgical
intervention when adenomas are
identified, that is,
they are commonly removed on
identification.
Because we are understanding the
molecular
pathogenesis of the disease, it provides
opportunities to not only address at a
pharmacologic level cancer itself but
potentially
405
to address the development of cancer
through
targeting of a variety of the parameters
that drive
the process on a molecular level. COX-2 is one
important target in this process.
Depicted on this slide is the
talk I
usually give over the course of about
half an hour.
So, I will summarize for you the really
profound
amount of data suggesting that
non-steroidal
anti-inflammatories and COX-2 selective
inhibitors
may be useful in terms of preventing
and/or
treating cancer. The data is most compelling in
the intestine, particularly the large
bowel,
however, as you will see it extends to
other organs
as well.
It is one of the reasons why the NCI has
invested so heavily in this area and why
we believe
it still holds great potential to benefit
patients
living with cancer or at risk for cancer.
There are four lines of
evidence here that
I would like to share with you with,
again,
probably hundreds or thousands of studies
underlying these points.
On a mechanistic level,
non-steroidal
406
anti-inflammatories and COX-2 selective
inhibitors
have been shown to induce apoptosis of
neoplastic
clones, to reduce angiogenesis in animal
models, to
inhibit proliferation and to stimulate
immune
surveillance of neoplastic cells--all
things which
should retard carcinogenesis.
In vivo, in the intestine alone
there are
more than a hundred animal studies now
published,
90 percent of which roughly show profound
benefits
in terms of reducing intestinal
carcinogenesis, as
depicted by reductions in cancer
incidence,
multiplicity in these animal models,
delays in time
to progression, reductions in advanced
characteristics of tumors.
In terms of epidemiology, there
are now
more than 35 studies--retrospective,
prospective,
nested case control studies--which pretty
consistently, with the exception of two
studies,
show 30-40 percent reductions across the
spectrum
of intestinal neoplasia, that is,
reductions in
adenoma incidence, cancer incidence and
cancer-associated mortality.
So, we believe, based on the
observational
animal and mechanism data, that changes
in adenomas
will ultimately in the longer term
translate into
407
improvements in later outcomes such as
colon cancer
incidence and mortality, at least with
this class
of drugs, again, because of the really
profound
database.
The epidemiologic studies alone amount
to several million individuals involved
in those
studies.
Finally, there are now three
published
randomized, controlled trials of aspirin
in the
peer reviewed literature that suggest
30-40 percent
reductions in recurrent adenoma. They were
designed very similar to the APC and
PreSAP trials
that I will share with you in greater
detail.
So, based upon this abundance
of
literature with its great consistency, we
believe
that non-steroidal anti-inflammatories
and/or
coxibs may very well reduce the risk of
colon
cancer.
Importantly, what we learn in the colon
may very well extend to other organs as
well.
There are similar sorts of
evidence, not
408
nearly with the volume nor the
consistency
necessarily but suggesting that COX-2 is
a relevant
target to carcinogenesis in a variety of
other
epithelial organs, and that these agents
may very
well reduce risk of cancer development and/or
be
useful in cancer therapy.
I will point out that already
these agents
are used not only with the hope of
preventing or
treating cancer but also in treating many
important
conditions in cancer patients, such as
pain and
inflammation. coxibs are particularly useful
because they tend not to interfere with
platelet
function, an important parameter in
cancer patients
because so many of our other therapies
actually
suppress bone marrow production, and we
are faced
with the situation where, with
thrombocytopenia, we
need to try to identify agents that are
useful in
those populations for other indications.
I won't belabor this
point. You already
know the safety concerns with traditional
NSAIDs
that are established. The question is what others
lie out there still to be discovered
because,
409
indeed, as you have heard several times
this
morning, we don't believe that there are
the same
sort of information databases that we
have now with
celecoxib and, as we heard earlier, with
rofecoxib
with traditional NSAIDs.
We embarked on this effort to explore
non-steroidal anti-inflammatories and
coxibs
specifically back in the late '90s when
the data
based upon the relevance of COX-2 to
cancer
development became apparent with the
growing body
of data I summarized two slides
previously. So, we
joined a collaborative relationship, a
clinical
trial agreement, with Searle, Pharmacia,
Pfizer--a
migration of companies over time--to
evaluate
celecoxib in a cancer prevention setting
based upon
the lines of evidence summarized here.
Our first attempt to do that
was in a very
high risk situation, that is, patients
with
familial adenomatous polyposis. I won't belabor
this point greatly. This is a surgical specimen in
the upper left and an endoscopic view of
the
intestinal burden of precancerous polyps
in
410
individuals born with this germline
condition with
defect in the APC gene. It is a relatively rare
condition but confers essentially 100
percent
lifetime risk of cancer if not mitigated
by surgery
or other maneuvers. So, typically these patients
are subjected to a variety of standard
care
procedures involving genetic screening,
endoscopic
screening, surgical prophylaxis--actually
removal
of all or part of the colorectum, as well
as
standard surveillance for any remaining segments.
Despite that standard of care, these
individuals,
compared to age matched controls in a
landmark
study done at St. Marks, one of the
leading
institutions for care of these patients,
had a
three-fold increased risk of death,
mostly from
cancer.
So, this led us to do a trial
of celecoxib
in which we showed efficacy. At the moment it is
the only approved pharmacologic
adjunctive therapy
for this condition. However, earlier randomized,
controlled trials had documented solidex
efficacy
as well, although that is not an approved
411
condition.
These are the data that led to
that
approval under the Subpart H guideline,
with
further definitive trials required and
those are
ongoing and planned. This is with 6-month
intervention involving 83 patients in a
differential randomization, 1:2:2. This is
endoscopic parameters. This is worsening below the
line.
Here is endoscopic improvement.
What we see
here, focused on the colorectum, is no
mean change
in the placebo group; a slight
improvement at the
100 mg twice a day dose; and a
substantial
improvement at 400 mg twice a day.
Importantly, as someone pointed
out
earlier, individual activities are
probably
important because, clearly, some patients
respond
quite dramatically even to lower doses of
celecoxib, although clearly you have a
more
profound and robust improvement at the
400 mg twice
a day dose. Just as an example of what was seen,
this is a non-selected patient. This is before.
This is after 6 months of exposure, only 6
months
412
of exposure with reductions in the
intestinal tumor
burden.
Importantly, these folks are at
risk for
duodenal cancer as well and we assess that in a
variety of ways and feel that there is a
suggestion
of benefit in the upper GI tract as well,
but it is
certainly something that requires
subsequent
confirmation because that was not
statistically
significant.
That trial then led us to
consider the
possibility that celecoxib, as with
aspirin and
other agents that have been tried for
adenoma
prevention, may be useful in adenoma
prevention in
a cohort at moderate risk due to prior
sporadic
adenomas.
So, the NCI and
Pfizer-sponsored APC trial
was initiated. It involved 2035 patients with
prior sporadic adenomas who were
randomized in a
balanced manner to celecoxib 400 mg twice a
day,
the dose that was effective in FAP
patients,
administered over 36 months versus 200 mg
twice a
day, a dose that had previously not been
413
interrogated in oncologic settings versus
placebo.
It was conducted with a baseline
colonoscopy, a
colonoscopy after 12 months and after 36
months,
evidencing adenoma recurrence, with
collection of
all adenomas while on trial.
The study was a major effort
and really I
should note the dedication of both the
practitioners in the study team but also
the
patients involved, involving 91 sites,
English
speaking, most of those in the United
States but
with participation in Canada, Australia
and the
U.K.
Accrual began in late November and extended
to March of 2002.
Well, the trial moved forward
with careful
monitoring by the standing data safety
monitoring
board, and was largely unchanged until
September of
this year when, following the Vioxx
announcement,
the data safety monitoring board convened
and
recommended the initiation of a dedicated
effort.
Previously safety was a specified
secondary
endpoint but not cardiovascular safety
specifically. So, they recommended to the steering
414
committee that we initiate a process of
cardiovascular adjudication and analysis
focused on
CV serious adverse events. So, that was done by
drawing upon the expertise of a group of
cardiologists and statistical team that
is outlined
here, based at Brigham and Women's, with
the
clinical endpoint committee involving two
individuals who conducted the
adjudication process
in a blinded manner, created a database
specifically focused on cardiovascular
risk, and
handed that off to a cardiovascular
review
committee, again with representation from
Brigham,
University of Glasgow and Dr. Wittes
doing the
statistical analysis.
The process of that
adjudication, which we
think is terribly important in this sort
of trial
that didn't up front specify
cardiovascular
endpoints, involved three steps. First of all
planing.
The team put together standardized
definitions, hierarchical analytic
categorization
scheme and a statistical analysis plan.
Next, the data were compiled,
verified and
415
adjudicated. All SAE forms were reviewed along
with source documents. Sites were queried to
supply supplemental data focused on
cardiovascular
events.
The events were adjudicated in the
prespecified manner and a database was
created for
those events, handed off to the analytic
team who
then obtained randomization codes and
relevant
baseline data and analyzed the data
according to
intent-to-treat principles, and presented
the data
back to the data safety monitoring board
in
December.
Now to move to the data which
has just
been published on-line within the last 24
hours, I
believe, on The New England Journal of
Medicine web
site.
This slide depicts the baseline
characteristics of the patients involved
in the APC
trial split out by treatment arm. What we see is
that randomization worked quite well in
terms of
distributing these factors: Age roughly 60 years
of age was the mean. About 70 percent of the
cohort was male. About half of them had a history
of some form of cardiovascular event
that, of
416
course, mainly being represented by
hypertension in
approximately 40 percent; diabetes in
about 10
percent.
Importantly, aspirin use and
lipid-lowering drug use in this cohort
was on the
order of 30 percent and was balanced
across arms.
When we come to the
hierarchical
characterization of cardiovascular
endpoints--I had
a heart attack when I saw the earlier
presentation
and different numbers were presented, but
I realize
that they were presenting the death from
cardiovascular causes or myocardial
infarction or
stroke.
That is the third line on this slide, not
the fourth line which is the one that the
steering
committee and the safety assessment team
chose to
focus upon, which includes cardiovascular
death,
myocardial infarction, stroke or heart
failure
because we feel these are all clinically
relevant
and important outcomes that could be
considered
together.
Although the events are quite
infrequent
in this 2000 patient, 3-year study we see
a
differential occurrence regardless really
of the
417
categorization you are looking at when
you are
looking across treatment arms, whether
expressed as
number or percentage of patients or the
rate per
1000 patient-years, there is a consistent
increase
in risk moving from placebo to 200 BID to
400 BID.
I will make a point that these
are
expressed as hazard ratios, that is
relative to
placebo, and again with all the various
categorizations, and this really moves
from the
hardest endpoint, cardiac-associated
death at the
top, down through progressively felt to
be more
subjective assessments of cardiovascular
risk to
the bottom where you are dealing with
cardiovascular death, myocardial
infarction,
stroke, heart failure, angina or need for
a
cardiovascular procedure. You will notice that the
risk decreases as you move toward a
broader
categorization of cardiovascular
events. But when
you focus more specifically--again, I
will
highlight the blue line, the one that is
highlighted in the manuscript--we see a
2.3
increased risk at 200 mg twice a day
compared to
418
placebo and a 3.4 increased risk compared
to
placebo at 400 mg twice a day. I will note that
the lower number of 2.3 percent in the
200 mg group
is marginally statistically significant
but clearly
significant at most assessments in the
higher dose
group.
If we focus, instead of that
sort of
assessment, on death, we see that there
was a
difference, not statistically significant
per se
from cardiovascular causes perhaps, but
that death
from non-cardiovascular causes does not
follow the
same trend. Indeed, when we look at death from any
cause, overall mortality, there is really
no
significant difference across these arms,
with the
200 mg group and placebo being equivalent
in this
study.
Similar to the discussions we
have heard
earlier, we considered a variety of
cardiovascular
risk factors based upon baseline
characteristics at
this point, and we evaluated age, gender,
CV risk
factors, diabetes, aspirin use and use of
lipid-lowering drug use at baseline. We saw no
419
statistical evidence, assessed by
interaction
terms, looking at the risk factor and
treatment to
suggest a differential hazard by any of
those
baseline factors. Of course, the analyses are
limited by few events and, therefore, limited
power.
If we look at a time to event
analysis,
with the Y axis including all 2000
patients and 3
years of follow-up, we see relatively
slow event
rates.
However, if we then change the Y axis to
focus specifically on a probability up to
5 percent
we see the diverging curves similar to
what was
seen previously with rofecoxib, but the
divergence
coming somewhere arguably around 12-14
months.
Importantly, these are intent-to-treat
analyses.
I want to conclude with just a
couple of
points.
you have already heard alluded to by Dr.
Furberg the possibility of compiling a
larger set
of data from NIH-sponsored trials. Indeed, we have
been very busy over the last several
months trying
to get this data in shape for
presentation here
from these two dedicated trials. I will point out
420
that although the PreSAP trial is
specifically
sponsored by Pfizer alone, they shared
their data
with us and the adjudication and analysis
process I
described was applied to both the
NCI-sponsored APC
trial as well as the PreSAP trial, and
funded by
the NCI.
So, that was our first effort
at an across
trials analysis. You will hear in a moment from
Dr. Levin that the analyses from PreSAP
are not
completely mature yet so we have a plan
of doing
this across the two that we have done as
well as
four others that we know exist that are
NIH-funded,
and it is simply a matter of trying to do
this in
an expedient manner at this point.
These are the six trials that we feel
have
long enough exposure. That is, these are defined
by at least 2 years of exposure and we
generally
try to shoot for sizeable trials, all
placebo-controlled, because we felt these
would be
informative to the question at hand.
I will point out that the last
study down
there, the NEI study, is very small but a
very high
421
risk cohort and, therefore, they state
they have a
significant number of events, on the
order of 20
events in just 86 patients.
Finally, I have tried to
highlight for you
that these agents may very well have a
unique set
of
contributions to make to patients living with
cancer or at risk for cancer, and we
believe that
strongly holds true and needs further
investigation.
This study, with the caveats
mentioned
earlier this morning--this is an
unpublished study
but has come to our attention recently
because we
have investigators interested in looking
at
traditional NSAIDs given now the
cardiovascular
risk that has been identified with
coxibs. What we
see in a cancer relevant population, that
is,
patients with oral cancer in a closed
population-based nested case control
study in
Scandinavia, is that the risk in this
small study,
unpublished yet, may extend to other NSAIDs. I
think this, combined with some of the
other
observational data and the experimental
data from
422
the National Institute's of Aging study,
may very
well raise questions about other NSAIDs,
and we
think it is terribly important to answer
those
questions given the potential opportunity
thee
agents present for patients with cancer.
I will close with this slide,
just stating
that with most good research you are left
with more
questions than answers. Indeed, I think that is
the case here. We believe that there are many
issues still to be answered about this
cardiovascular risk and what it means for
patients
with or at risk for cancer. I will leave this
really to Dr. Levin to come back to at
the
conclusion of his talk, and turn it over
to him at
this point.
NIH and Investigational
Presentation: The PreSAP
Trial (Prevention of Colorectal
Sporadic
Adenomatous Polyps)
DR. LEVIN: Thank you very much, Dr. Hawk.
Mr. Chairman, committee members, it is my
honor to
present a summary of the data in the
PreSAP trial.
My co-principal investigator, Dr. Nadir
Arba, in
423
Tel Aviv University, and I have been
aligned with
this trial since its birth with Searle,
Pharmacia
and Pfizer.
In this trial, depicted here
are 1561
patients with sporadic adenomas who were
randomized
in a 3:2 manner and stratified by aspirin
use and
clinical center into celecoxib 400 mg
daily for 36
months and placebo for 36 months. Colonoscopy was
performed after 12 and 36 months of
exposure
evaluating recurrence, and collection of
all
pathological endoscopic information.
As you have already heard from
Dr. Hawk,
some of this information is still in a
preliminary
status.
This study involved 106 clinical research
sites in 32 countries. Patients were enrolled from
March, 2001 and completed approximately
one year
later.
The cohort characteristics at
baseline are
shown in this slide, somewhat similar to
the APC
trial in terms of age and gender. What is
different is that the smoking status is
higher, 25
percent, and baseline aspirin use is
lower. Some
424
of this data may still be in a
preliminary format
so I am not going to discuss it
significantly
further.
Depicted here, and somewhat
similar terms
to that which Dr. Hawk showed, is the
incidence and
hazard ratio of the hierarchical
cardiovascular
composite endpoints. Again, the blue column that
is highlighted reflects the death from
cardiovascular causes--myocardial
infarction,
stroke or heart failure. I would draw to your
attention the placebo rate of 6.4,
approximately
double that in the APC trial, and a
hazard ratio of
1.1.
Similar to the APC trial, the
cardiovascular events examined by
baseline
subgroups were somewhat similar in age,
gender and
baseline cardiovascular risk. There was no
statistical evidence of a differential
hazard ratio
by baseline risk groups. Of course, there are few
events and it has limited power.
Depicted here on this
Kaplan-Meier
estimate, one can see that the number of
events is
425
low, and when this is magnified, similar
to what
Dr. Hawk showed, the curves are
essentially
similar.
There are a number of issues
which arise
from these two trials. Perhaps the most important
one which concerns us as the
investigators, apart
from the safety, is the efficacy and we
don't have
that information yet. We have some idea with the
signal from the Vioxx trial about which
you heard
earlier.
It is tantalizing. That will help
us to
make risk/benefit assessments for future.
We have to take into
consideration in any
of those discussions the relative
gastrointestinal
and cardiovascular safety referent to
other
non-steroidal anti-inflammatory
drugs. Overall
toxicity and safety, of course, are prime
concerns
when it comes to asymptomatic individuals
and the
public, and we don't have any information
in these
trials yet on gastrointestinal
ulceration.
The cross trials meta-analysis that Dr.
Hawk alluded to will also provide a great
deal of
information. What, of course, is most tantalizing
426
to everyone involved is why is there a
difference
in this trial compared to the APC
trial? At this
point, all we have to go on is the
frequency or the
schedule of administration of
celecoxib. We don't
have any other information from the
patients
enrolled in this trial on other possible
factors.
In this trial there was no
increased risk
of cardiovascular adverse effects, but
one overall
would want to consider whether one could
mitigate
any increased risk by better clinical
management if
that were necessary.
Some of the differences, but
that doesn't
really apply to this trial, might be in
metabolic
polymorphisms but there is no evidence
for that and
we don't have that information.
So, for future research there
are many
questions that are of great
importance. COX-2
remains a relevant oncology target and,
as Dr. Hawk
already presented, we want to consider
the
possibilities that there are other
pharmacological
targets besides COX-2 in the prevention
and therapy
of cancer. We already have some information on
427
that, the effect of these agents, and
they don't
all do the same, on 15-lipoxygenase-1 and
also on
the modulation of PPOD delta.
But primarily what we are
interested in
now is establishing efficacy or
determining
efficacy in these two trials and that
information
should be forthcoming in the next few
months.
Thank you for your attention.
Committee Questions to
Speakers
DR. WOOD: Thanks very much. Any
questions? Dr. Farrar?
DR. FARRAR: If you could show the
PreSAP
cohort characteristics slide, which I
guess is your
second or third slide, I would ask my
colleagues to
look on page 6 of the presentation of the
study and
if you just compare the baseline
characteristics, I
was struck by the fact that you said that
what was
different in the trial was the rate in
the placebo
group.
There are, in fact, several major
differences in the two groups. The age is the
same.
Male distribution is approximately the same.
Cardiac history is the same. But if you look at
428
diabetes, there is more than twice the
rate in the
PreSAP than there is in the APC. The smoking rate
is substantially higher. The baseline aspirin use
is half.
The lipid-lowering drugs are remarkably
lower.
I don't know what that means, but Dr.
FitzGerald suggested this morning that
this whole
system is very complex and I would simply
posit
that, in fact, there is probably an
interaction
there that may be very informative. We need a lot
more information about your trials. Obviously you
are working hard to do that and I think
there is a
lot of information to be gathered there.
DR. LEVIN: If I might answer that?
DR. WOOD: Go ahead.
DR. LEVIN: Yes, Dr. Farrar, I agree
entirely.
I didn't want to highlight these
differences which suggest that this is
potentially
a higher risk group to begin with,
distributed in
countries where the prevalence of use of
lipid-lowering drugs would be anticipated
to be
lower.
But some of this data is still a little bit
preliminary so I didn't want to hark on
it but I
429
think your point is very well made. Thank you.
DR. WOOD: Dr. Shafer?
DR. SHAFER: Yes, you showed a slide
which, from my perspective, was somewhat
unwelcome
because I was trying to understand these
things.
That was the slide about the risk of the
other
NSAIDs which was based on unpublished
data. I
actually went looking for such data and
had some
trouble pulling it up. Are there published
studies, or are there data that you are
aware of,
because this is relevant to the
discussions that we
are going to be having on Friday,
suggesting
cardiovascular risk from the other
standard NSAIDs?
DR. WOOD: And while you are doing that,
can you comment on the increased risk in
that study
of aspirin?
DR. SHAFER: I tried to avoid mentioning
aspirin in my question.
DR. WOOD: I will do it for you, Steve!
DR. HAWK: The only other data that I am
personally aware of is the study done in
the
Kaiser-Permanente database that we saw
alluded to
430
in an earlier presentation. I am not aware of
other data. I put this up with all the caveats,
and I believe I mentioned that this
preliminary and
so it violates some of the rules that we
heard this
morning.
But it is particularly relevant to the
Cancer Institute because, again, we have
applicants
suggesting that they should move now to
traditional
NSAIDs and that is a very important
question to
answer but we don't think the answer is
there, that
is, the absence of evidence doesn't
necessarily
prove that they are safer and I think
that is an
important context issue, at least for us.
DR. WOOD: But in commenting on that, the
second line, it shows aspirin increases
the risk of
cardiovascular.
DR. HAWK: I wish that John Baron were
here because John Baron did one of the
three
aspirin trials in adenoma prevention that
I alluded
to.
I didn't have time to show the data but if you
go into that study--it is published in
The New
England Journal of Medicine--he studied
placebo
versus aspirin at 81 mg versus 325 mg,
and if you
431
look at the adverse event table you see
that the
aspirin groups actually had more events
in a
dose-dependent manner than did
placebo. I don't
know what that means but it is very
similar to the
sorts of information we have from the APC
trial.
But, again, you know, there are a lot of
long-term
placebo-controlled trials showing that
aspirin
prevents cardiovascular risk in other
settings. So
I don't want to use that to impugn
aspirin. I am
merely stating what is published.
DR. WOOD: Dr. Hennekens?
DR. HENNEKENS: Dr. Hawk, I would make a
comment that leads me to a question. The totality
of evidence for aspirin from 135 trials
for the
treatment of secondary prevention shows a
highly
statistically significant and clinically
important
15 percent reduction in cardiovascular
mortality.
In contrast, in 5 trials of primary
prevention with
55,180 or so patients, with much lower
endpoints,
there is not a statistically significant
benefit of
aspirin but the confidence intervals are
still
compatible with that. We need more data on this.
So, with that as a background,
as a chair
or member of various data safety
monitoring boards,
I try to follow the principle of early
stopping
432
based on proof beyond a reasonable doubt
that is
likely to influence clinical practice,
with some
asymmetry in that you have greater
concern about
safety than efficacy but, nonetheless, included
in
this algorithm is the statistical
stopping
guideline whether you follow the
teachings of
O'Brien and Fleming or Land and de Mets
or Peto and
Haybittle. Intrinsic in this is that during the
course of a trial, if you reach a
statistically
extreme p value then there is a high
likelihood
that by the scheduled end of the trial
that p value
will at least be at 0.05. But if you fail to
achieve that extreme p value, then it is
highly
likely that by the end of the trial you
may find no
significant difference.
So, one of the questions is
what were the
considerations in stopping this trial,
and is the
play of chance a likely explanation for
the
findings?
DR. HAWK: I would say that the trial was
still blinded to efficacy and broader
issues of
safety.
The data safety monitoring board still
exists so I am not privy to all of their
closed
session discussions and
deliberations. What I can
tell you is that this trial was about
three months
433
away from the last patient going off of
it. We
were told that there was a cardiovascular
risk and
it was the considered opinion of the data
safety
monitoring board that it would be the
better part
of valor to halt drug administration in
this trial
and continue to follow patients for
relevant
outcomes.
That is what we did and that is my level
of insight into the issue.
DR. WOOD: Dr. Furberg?
DR. FURBERG: Yes, I would like to make a
plea that we are not making too much out
of the
findings from the PreSAP trial. For the combined
outcome the hazard ratio is 1.1. The 95 percent
confidence interval is very wide. So, the PreSAP
findings are consistent with a 40 percent
benefit
and a 2.34-fold increase in risk. So, the trial
434
doesn't add much to our knowledge.
DR. O'NEILL: You may not have this
information right now but I notice the
APC trial
had 72 sites in the U.S. and the PreSAP
trial
looked like it had 132 sites. What is the relative
U.S. versus non-U.S. distribution in
those two
trials?
DR. HAWK: In the APC trial there were
70-some sites in the U.S.
DR. O'NEILL:
No, I mean denominator-wise,
subjects.
I am trying to see whether the placebo
rate differs inside or outside U.S. in
the two
trials.
DR. HAWK: That is a very good question
and I don't have those data.
DR. O'NEILL: Yes, I think that would be
useful to have.
DR. WOOD: Byron?
DR. CRYER: I understand that in your APC
trial results you haven't yet analyzed
the
potential polyp reduction effects of
celecoxib, but
you pointed out a couple of very real
observations,
435
that aspirin is an effective agent for
the
reduction of polyps, associated with a
20-30
percent reduction of recurrent adenomas,
and we
heard earlier in the APPROVe trial that
rofecoxib
was associated with a 24 percent
reduction of
recurrent adenomatous formation.
So, assuming, let's say, that
celecoxib
achieves a result that is in the same
realm, let's
say 20-30 percent and given that aspirin,
as Dr.
Hennekens pointed out, is such an
effective agent
for prevention of cardiovascular events,
I was
wondering if you could postulate as to
potential
reasons for us to use celecoxib for this
indication
over aspirin, assuming a similar
endpoint.
DR. HAWK: Sure, i would be glad to. I
think the answer will come with the data.
What I
am going to say is conjecture. In animal models
aspirin is one of the least effective of
the
traditional NSAIDs. Celecoxib was one of the most
effective in traditional animal
models. So, we had
reason to believe, both on the basis of
an improved
efficacy profile in animal models as well
as
436
potential for an improved safety
assessment that
existed at the time of the initiation of
the trial,
that in both ways we could improve the
therapeutic
index.
I think we don't know if these
cardiovascular events are occurring in
patients
that have efficacy or in the group that
don't have
efficacy.
We don't know the level of efficacy
here.
So, it is very difficult to answer you
question in a scientifically rigorous
way. I can
tell you the premise but I can't tell you
the data
because I don't yet know whether this
drug is
efficacious at all.
I will say that in FAP settings
there was
a small Japanese trial done with
rofecoxib which
showed I believe something on the order
of a 10
percent reduction in adenoma burden. We saw about
a 30 percent reduction in our randomized,
placebo-controlled trial. That is a suggestion
that in a different patient cohort
celecoxib may be
more efficacious but it is really
speculation and
what we really need are the data from
these two
437
trials in order to be able to answer your
question
accurately.
DR. CRYER: Just to reiterate, you pointed
out data from animals and the human data
with
aspirin is quite good with respect to
prevention of
recurrent adenomatous polyps.
DR. HAWK: We were hoping for better.
DR. LEVIN: I think, Dr. Cryer, I might
answer your question as well. It is valuable to
look at the two studies. In particular, one study
showed that there was, as you quote,
approximately
a 30 percent reduction. But what was particularly
interesting was the effect on advanced
adenomas, a
49 percent reduction. So, I think we don't have
these data but the question will be, in
my opinion,
very relevant to what will be the impact
of this or
any other kind of they on the more
significant
lesions that have an enhanced propensity
to develop
into cancer. That might be an important
differentiation between aspirin and
rofecoxib or
any other agent.
DR. WOOD: Dr. D'Agostino?
DR. D'AGOSTINO: Curt already raised the
issue I was going to. I don't think the two
studies contradict each other.
438
DR. WOOD: Peter?
DR. GROSS: I wonder if one of the factors
to be considered is that when celecoxib
is given
once a day the suppression of
prostacyclin and
whatever else is going on does not last
for 24
hours, whereas when celecoxib is given
twice a day
you get more sustained suppression.
DR. WOOD: All right.
Dr. Nissen?
DR. NISSEN: I was going to echo what Curt
had to say and also Ralph, but then I had
a
question.
Clearly, the confidence intervals for
these two trials, for virtually every
endpoint,
overlap.
But because they are so similar in
design, long before you have all the
trials in this
list you could combine APC and PreSAP and
look at
an analysis of the two combined which
would give us
more stable estimates of the hazard
ratio. I think
it might be useful. I am going to guess somebody
has done that and, if you have, I sure
would like
439
to know about it. Maybe Tom has already done it on
the back of an envelope. I can see him shaking his
head.
But I am trying to get a more stable
estimate, particularly for the
non-super-therapeutic dose, the 400 mg
dose which
was common to both trials--try to get
more stable
estimates for what the hazard ratios
really are.
DR. HAWK: First of all, I want to
highlight that the
"super-therapeutic" dose is
based upon our frame of reference that is
different
than the indication where we are applying
it here,
in cancer prevention. Here the only effective dose
we have is 400 mg twice a day. So, I take your
point but please take mine as well.
In terms of the combined analysis,
that
has been done based upon preliminary data
that were
analyzed back in December. Since that period of
time we have confirmed all the events so
that we
can do the intent-to-treat analysis that
was
discussed here as well. So, I don't think it has
been done yet on the mature data. Janet Wittes is
in the audience. Janet, can you speak to that?
DR. WITTES: It is not done on very mature
data but I am sure that if you calculate,
you can
do it by hand.
440
DR. SEIBERT: Dr. Hawk, perhaps I can
clarify.
Karen Seibert, from Pfizer,
pharmacologist. We have evaluated 400 mg once
daily versus 200 mg twice daily looking
at the
exposures. The total exposure as an AUC is about
equivalent. As you might expect, the C-max for the
400 is about 30 percent higher. The C-min at 12
versus 24 hours for the 200 and 400 is
about 20
percent different. The total exposure is the same.
And we believe that the C-mins which are
achieved
at steady state still exceed that which
is
necessary to inhibit COX-2. We are happy to
provide those data to this committee but
we don't
see a clear differentiator there in the
dosing
regimen.
DR. WOOD: Other questions? Richard?
DR. PLATT: I would like to circle back to
Dr. Shafer's question. Were you asking if there
are data about the other non-selective
NSAIDs?
441
Because in Tab S of our book there are a
couple of
articles that speak to that. They are
observational studies but they seem to be
saying
that there doesn't appear to be excess
risk.
DR. SHAFER: That is what I was wondering
about, finding one that shows excess
risk.
DR. PLATT: There does seem to be some
literature that looked and didn't find
it.
DR. WOOD: Dr. Fleming?
DR. FLEMING: Well, I have been, just out
of curiosity, doing a back of the
envelope
calculation to see what it would look
like on the
primary endpoint, if we take the primary
endpoint
to be CV death, MI and stroke, and the
standard
error is the square root of 4 over the
number of
events, so just using that without doing
a formal
stratification, I would come out with a
relative
risk of about 1.82. So, one study says 10 percent
increase; the other study says a relative
risk over
3, and it is just barely over the
statistical
significance.
So, it is borderline statistical
significance in the meta-analysis with an
estimate
442
of about 80-85 percent relative increase.
DR. WOOD: So, they would be compatible,
in other words. Any other questions? Yes?
DR. DANNENBERG: My name is Andrew
Dannenberg, Weil Medical College, Cornell
University. I am here today as a consultant for
Pfizer, but I am one of the would-be
authors of the
data demonstrating an increased risk of
cardiovascular death in those taking
non-selective
NSAIDs versus acetaminophen. That NIH-funded
research is based on the following
hypothesis: It
is known that COX can activate tobacco
carcinogens
and convert them to mutagens. We, therefore, were
interested in the possibility that NSAIDs
could
protect against tobacco smoke-induced
oral cavity
cancer.
To be enrolled in that trial, which was
led by a group in Norway and M.D.
Andersen, a
retrospective study, one had to smoke 15
pack years
or more.
We observed a significant decrease in the
risk of oral cavity cancer in those
taking NSAIDs
but not acetaminophen. However, when we looked at
443
life span there was no apparent increase
in life
span despite the reduction in risk of
oral cavity
cancer.
That led us to interrogate the
data set to
look at all causes of death. We noted a hazard
ratio of 2.06 in those taking NSAIDs from
the
standpoint of death due to cardiovascular
disease.
By contrast, acetaminophen did not impact
on the
risk of cardiovascular death. So, that is a more
complete description of the rationale for
the study
and how we arrived at interrogating the
data set.
DR. WOOD: Thanks very much. Let's move
on to the next presentation, which is
also by Dr.
Verburg.
Sponsor Presentation:
Cardiovascular Safety and
Risk/Benefit Assessment
of Valdecoxib and
Parecoxib
DR. VERBURG: Thank you very much. I will
be brief.
The next 25 minutes or so are focused on
the cardiovascular safety of valdecoxib
and the
parenteral prodrug of valdecoxib,
parecoxib, and
brief risk/benefit assessment.
Just by way of some quick
background,
valdecoxib was approved in the U.S. for
the
indications of osteoarthritis and
rheumatoid
444
arthritis in November, 2001. The approved dose is
10 mg once daily. In terms of the NDA database,
over 15,000 individuals were studied,
which was
roughly comparable to that which we
supplied for
celecoxib. Since the approval we have been
focusing this drug in terms of its effects
in acute
pain as well as other non-arthritis
chronic pain
conditions.
Our overall assessment or
position of
valdecoxib is stated on this slide. First, it is
our view that valdecoxib remains a viable
treatment
alternative for patients with
osteoarthritis and
rheumatoid arthritis. We have data to suggest that
valdecoxib provides improved GI safety
compared to
NSAIDs.
The valdecoxib cardiovascular safety
database is smaller than celecoxib at
present,
however, the emerging CV safety profile
of
valdecoxib appears similar to alternative
therapies
in arthritis patients, that being
non-steroidals,
445
for up to 6 months. And, the cardiovascular signal
in the CABG surgery setting, therefore,
does not
appear to extrapolate to the arthritis
population
based on the data at hand.
Just as with celecoxib, we have shown that
valdecoxib exhibits the properties
expected of a
selective COX-2 inhibitor. That is, as shown on
the left-hand portion of the slide, it
provides
efficacy--in this casein a trial of
osteoarthritis
patients--that is superior to placebo
treatment and
in every way comparable to patients
treated with
naproxen at a full therapeutic dose. At the same
time, over the same 12-week period we see
that the
rate of endoscopic ulcers, with
valdecoxib doses
ranging from 5 mg to 20 mg once daily,
were similar
to placebo and in contrast, again, to the
results
seen with the non-selective agent
naproxen.
In our prespecified, predefined
way, we
also evaluated 8 of the randomized,
controlled
trials with durations of 12-16 weeks in
the NDA
database, and also evaluated the same in
3
open-label studies up to 1 year. This was done
446
according to prespecified definition,
prespecified
protocol and by a blinded events
committee.
What we see here is that the
incidence of
ulcer complications, that being GI
bleeding,
obstructions and perforations, were
significantly
higher in the combined NSAID group, that
being
comprised of naproxen, ibuprofen and
diclofenac, as
compared to placebo treatment. No such difference
was seen in the valdecoxib treatments as
compare to
placebo at doses ranging from 5 mg up to
80 mg
daily.
We also see that in long-term exposure at
doses of 10 mg to 80 mg daily out to 1
year in
nearly 3000 patients the event rate seen
with
valdecoxib looks similar to that which we
saw in
the more short-term but controlled
settings.
As I have mentioned before,
there are more
limited safety data than with celecoxib
and the
analysis is largely confined to the
randomized,
controlled trials in arthritis at
present, as well
as some short-term acute pain studies
alone or
valdecoxib in combination with
parecoxib. There
are no completed epidemiology studies to
report,
447
although we are aware of three that are
ongoing.
In the meta-analysis of
valdecoxib there
were 19 randomized, controlled trials
included,
with a total of over 12,000
patients. Again, the
majority of the patients were
osteoarthritis and
rheumatoid arthritis patients, with a
smaller
minority of patients with chronic low
back pain or
chronic cancer pain.
The distribution of patients is
shown
here.
The study duration ranged from 2 weeks to 12
months, and 11 of the 19 studies were 3
months or
longer in duration. We evaluated all doses of
valdecoxib in the meta-analysis.
In terms of exposure, 50 percent of the
patients treated with valdecoxib were
exposed to
the drug for periods of 3 months or
longer; 22
percent for 6 months or longer; and 4
percent for 1
year or longer.
Here we show the distribution
of events,
as well as the event rate, comparing
valdecoxib at
doses of 10 mg or higher, in other words,
it is
full therapeutic dose and
super-therapeutic doses
448
that were tested as compared to a
combined NSAID
category.
We find here that for the composite
endpoint of cardiovascular death,
non-fatal MI or
stroke valdecoxib compares with a
somewhat lower
rate than that seen with the NSAIDs. There are
very few events to shape this comparison,
21 in
total.
But as we go down to the various components
of that composite endpoint we see
essentially the
same kind of pattern.
If we translate that into a relative risk
comparing valdecoxib to NSAIDs, we see
that the
point estimates of relative risk all lie
under 1,
or the large confidence intervals do not
allow any
strong conclusions to be drawn at this
point.
On this slide we break down the
comparison
of valdecoxib to the individual NSAIDs,
as well as
compare it to placebo. Again, this is in terms of
a composite of these 3 events. We see for placebo
that the risk estimate is 1.26 but not
significantly different. Then breaking out the
comparison between naproxen and
diclofenac, we see
that again the point estimates are below
1 but not
449
significantly so. No comparison could be done
against ibuprofen. There were no events in either
the valdecoxib or ibuprofen patients in
which to do
so.
Again, we have very limited
information to
establish any type of dose-response
relationship or
relationship of dose to cardiovascular
safety with
valdecoxib. The data that we do have are shown
here.
At 10 mg and 20 mg the point estimate
compared to the NSAIDs is below 1, not
significantly so. We noticed the point estimate
moves to favoring NSAIDs at a 40 mg dose,
however,
when we move up to 80 mg there were no
events in
either treatment group in which to shape
a
conclusion. Again we are moving to very small
numbers of patients as we begin to
subdivide the
meta-analysis for valdecoxib.
In terms of the incidence of
cardiorenal
events, as was the case with celecoxib,
there are
significant differences in the incidence
of adverse
events--these are investigator reports
now--as
compared to placebo. But comparing valdecoxib at
450
doses of 10 mg or greater to NSAIDs, we
see that
there are no significant differences for
either
hypertension, edema or cardiac failure in
over 7000
patients in this particular evaluation.
There is one other safety issue
that we
need to bring up with valdecoxib, that
being the
reports of serious skin reactions. Spontaneous
reports of serious skin reactions, that
being
Stevens-Johnson syndrome, etc., received
approximately 6 months after the launch
of
valdecoxib in the U.S. This rate appears to be
higher than celecoxib or rofecoxib and,
as a
result, a black box warning was added to
the
prescribing information for valdecoxib or
Bextra in
November of last year.
In brief then to summarize the
conclusions, valdecoxib shows efficacy
that is
similar to NSAIDs, and there is emerging
data to
establish that GI safety benefit is
superior to
NSAIDs and the CV safety profile is
comparable to
NSAIDs.
The added warnings allow
physicians to
451
choose appropriately based on the
evidence of rare
although severe skin reactions.
The future plans for valdecoxib are very
similar to those proposed for celecoxib.
Longer-term studies are planned to
evaluate the GI
safety and the cardiovascular safety of
valdecoxib
in the arthritis patient population.
Now briefly a discussion of
parecoxib.
Parecoxib is the water soluble prodrug of
valdecoxib. Its water solubility allows it to be
administered parenterally either by
intravenous or
intramuscular injection. Parecoxib itself does not
have any inhibitory activity at the COX-2
enzyme
but, once administered, it is rapidly
converted to
valdecoxib. In fact, there is nearly total
conversion within 30 minutes following
administration.
So, the choices of parenteral
therapeutics
for the treatment of acute pain, whether
it be
post-surgical or other conditions, are
fairly
limited.
As a result, there is an additional need
to provide agents that improve the
postoperative
452
pain control or other acute pain
situations with
parenteral therapy.
As we have seen from various
reports,
inadequate postoperative pain is one of
the most
important factors in prolonging
hospitalization and
also in progression of acute pain to
chronic pain
following surgery.
Postoperative analgesia at
present is
traditionally provided by opioids but we
all are
aware of the complications of those
therapies, and
also opioids do not provide adequate
analgesia upon
movement and, of course, both of these
issues also
prolong the post-surgery recovery course.
There has been an increasing move
towards
the use of multimodal analgesics, that
is, drugs
from two or more classes, to minimize the
adverse
effects of the drugs alone by reducing
the dose, or
to improve the ultimate efficacy
output. In terms
of the addition of agents to opioid
therapy,
therapy are very limited at present for
parenteral
therapy and basically limited to
ketololac which
has issues of its own in the
post-surgical setting
453
but, nonetheless, when studies are done
this allows
for early oral intake, ambulation and
hospital
discharge. The net comment on this slide
is in the
box here, which is that parecoxib is
intended to
provide significant analgesia, while
sparing
opioids without the GI and bleeding risks
of
parenteral NSAIDs.
This is just some data that
illustrates
the point that I made on the previous
slide. These
are two studies taken from the ambulatory
surgery
setting.
On the left is a study of nearly 4000
patients who were asked to evaluate their
pain one
day after surgery, and we can see here
that over 25
percent still had moderate to severe pain
despite
being treated with standard of care
opioids.
Over on the right-hand portion
of the
slide is a much smaller study, conducted
in
patients undergoing laparoscopic surgery
or hernia
repair, and what we can see is that
patients
struggle to return to their pre-surgical
functional
status after surgery. Although the time course of
recovery is somewhat dependent on the
type of
454
surgery they undergo, there is still
significant
functional disability several days after
ambulatory
surgeries.
So, by way of background,
parecoxib was
approved for the short-term post-surgical
pain in
Europe in March of 2002. At this point in time
over one million patients have been
treated. The
parecoxib NDA is currently under review
in the U.S.
for the management of acute pain.
In total, the clinical registration
program for parecoxib looks as
follows: There are
64 studies completed. Of these, 26 were analgesia
studies.
In total there were about 10,000 patients
randomized to one of the three treatment
groups
shown here; 1670 patients received
treatment for 3
or more days with parecoxib and over 1000
patients
received treatment for 10 or more days
with
parecoxib and then transitioned to oral
valdecoxib
therapy.
One of the earlier studies that
we
performed in the program was in a high
risk
surgical population to gauge the overall
safety of
455
parecoxib. We chose the CABG surgery population to
perform such an analysis. This was a 2-treatment
arm, double-blind, randomized, controlled
trial.
Patients were randomized in a 2:1 fashion
to active
treatment. Following CABG surgery they received
parecoxib at 40 mg IV Q 12 hours for a
period of at
least 3 days, and then once they were
able to
transition to oral treatment they
received
valdecoxib at the same dose.
The other treatment arm received
placebo
treatment throughout the course of the 14
days.
Both treatment groups received as needed
supplemental analgesia in the form of
morphine
during the parenteral treatment period or
oral
acetaminophen codeine during the oral
treatment
period.
It is important to note that
prior to
randomization or receiving study
medication all
patients were to receive 80-325 mg daily
of
aspirin.
Approximately 89 percent of these
patients underwent CABG surgery with
cardiopulmonary bypass, and about 11
percent of the
456
patients were off-pump cases.
Here we show the results that
emerged from
the first CABG surgery trial. We had put in place
an endpoint committee to adjudicate the
events in
this trial according to prespecified
definitions
and, of course, they were blinded to
study
treatment. What we see here is that if you look at
the composite endpoint made up of these
various
components, we see that over the course
of the
entire trial there was an increase in the
incidence
of any thromboembolic cardiovascular
event in the
parecoxib/valdecoxib treatment
group. This result
was driven primarily by this imbalance
that we see
here in stroke or TIAs, although those
incidence
rates and differences between the
treatment groups
did not achieve statistical significance.
In light of those results, we
elected to
evaluate the cardiovascular safety of
parecoxib and
valdecoxib in a larger CABG surgery
study. The
study design is outlined on this
slide. In total,
this was a trial of over 1500 patients. Following
CABG surgery the patients were randomized
to one of
457
three treatment groups. They either received
parecoxib as a 40 mg IV loading dose and
then 20 mg
IV Q 12 thereafter, transitioned to
valdecoxib
after a period of 3 days, and then for an
additional 7 days of oral treatment.
The second treatment group
received
placebo during the parenteral period and
then was
transitioned to valdecoxib during the
oral
treatment period. The final treatment group
received placebo throughout both the
parenteral and
oral treatment periods. Again, patients were able
to receive parenteral supplemental
analgesia as
required.
As in the previous CABG trial, all
patients were to receive aspirin at doses
of 75-325
mg daily per protocol. In this trial all CABG
cases were performed with cardiopulmonary
bypass.
We used a slightly different
adjudication
scheme in this trial as compared to the
first
trial, and we were focused in this trial
on
myocardial events, cerebrovascular
events,
peripheral vascular events and pulmonary
embolism.
Here we show the results of the
CABG
458
surgery trial in terms of the overall
composite
endpoint of all adjudicated thromboembolic
cardiovascular events. This is broken down to the
intravenous, oral and entire study
period. If we
look at the entire study period which, by
the way,
included not only the 10 days of
treatment but also
a 30-day post-surgery follow-up period,
we see that
parecoxib/valdecoxib was associated with
a
significantly higher incidence of
thromboembolic
cardiovascular events as compared to
patients who
received only placebo. Patients who received only
valdecoxib had a numerically higher
incidence of
thromboembolic cardiovascular
events. This
difference did not achieve statistical
significance. Also, as you scan up here you can
see that actually 3 of the events in this
treatment
arm occurred in patients prior to the
point that
they ever received valdecoxib.
Similar to the results seen in
the
evaluation of the crude incidence rates,
here we
show the time to event analysis for the
parecoxib/valdecoxib treatment group,
valdecoxib
459
only and the placebo group, again, out to
30 days
post last dose of study medication, as
stipulated
per protocol. Again, we see that based on log rank
test the parecoxib/valdecoxib treatment
group was
significantly different from the placebo
group. No
significant differences were seen between
the
placebo and the valdecoxib only treatment
groups.
If we now break down the
composite of
cardiovascular events into its components
and
quickly look at the various components,
we see
again, as we saw in 035, that a major
driver for
the difference overall is the CVA or TIA
category,
as well as cardiac arrest and
cardiovascular death
which tended to occur later in the
treatment of
parecoxib/valdecoxib, while the strokes
were
clustered quite closely to the post-surgical
setting.
By the way, I should probably
state that
as a result of those findings we quickly
went to
those countries, those regions of the
world where
parecoxib is currently marketed and have
modified
the
product labeling in those areas to
460
contraindicate parecoxib and valdecoxib
in CABG
surgery or in other revascularization
procedures
since those types of settings have not
been
studied.
We have also taken the step in
the U.S. of
including a contraindication for the use
of Bextra
of valdecoxib in the CABG surgery setting
or
revascularization setting even though
Bextra does
not carry an indication for acute pain.
I just want to go back to the
CABG surgery
setting and make some concluding
remarks. Again we
are faced with limited data to really
evaluate the
effects of parecoxib and valdecoxib as
compared to
NSAIDs in this treatment setting. There is very
little data with respect to NSAIDs.
The mechanism for the increased
cardiovascular risks with parecoxib and
valdecoxib
is not known. We did risk factor analyses but, as
you can appreciate with the small number
of events,
that didn't prove to be too fruitful.
We do know that patients that
undergo CABG
with coronary bypass pump result in
activation
461
platelets, leukocytes and endothelial
cells; that
aortic cross-clamping results in
ischemia,
re-perfusion injury and emboli
formation. There is
a complex time course of changes in
prostacyclin
and thromboxane-A2 that have been
reported
following CABG surgery. And, as Dr. FitzGerald
mentioned this morning, this patient
population is
also characterized by a high degree of
platelet
aspirin resistance. So, the
constellation of all
these factors obviously in some manner
contributed
to the results that were observed with
parecoxib
and valdecoxib, but the importance of all
of these
factors in that respect cannot be sorted
out with
the current study. What we do know though
is that
some of these are isolated exclusive to
the CABG
surgery setting.
At the same time we conducted a
study in
CABG surgery patients, we also undertook
a study in
general surgery patients. This was basically an
all-comers trial. Only patients undergoing
transplant surgery, intracranial surgery,
revascularization procedures or partial
liver
462
resections were excluded from the trial.
The doses tested and the
duration of the
trial are very similar to the CABG
trial. The same
endpoint committee was employed. Events were
adjudicated in the same manner, according
to the
same definitions as the CABG trial. This was a
2-arm trial evaluating parecoxib followed
by
valdecoxib versus placebo and, as in the
previous
trials, patients could receive additional
analgesic
medication as required.
So, if we look at the incidence
of
adjudicated thromboembolic events in the
general
surgery trial, we see that the event
rates--these
were crude event rates--were one percent
in the
placebo group and one percent in the
parecoxib/valdecoxib treatment
group. This study
also had a 10-day treatment window as
well as a
30-day follow-up period. Again, we see that the
distribution of events is scattered
through the
components of the composite with no clear
patterns
established.
The time to event analysis is
shown here.
463
Again, no differences were seen in this
analysis by
log rank test.
We have also expanded our
evaluation of
the cardiovascular safety of parecoxib to
all the
surgical trials that we have performed
with this
drug.
Here we are showing such an analysis,
excluding such minor surgeries as third
molar
extraction, etc. We are really focused here on the
more complicated surgeries, whether they
be
orthopedic, etc. We had about 1900 patients in the
placebo group; over 2600 in the parecoxib
treatment
group.
Again, we saw no differences in the
incidence rates. We tried to collect as much
information as we could over the entire
parecoxib
registration database.
Very quickly, just a brief word
on the
benefit that we see with parecoxib. I want to turn
to the general surgery trial, first
showing you the
analgesic results that were observed with
parecoxib
and valdecoxib in this trial. We saw significant
reductions in pain across the entire
treatment
period with parecoxib/valdecoxib as
compared to
464
standard of care alone. In fact, these reductions
were fairly impressive. They were on the order of
25 percent or more. Those improvements in
analgesic efficacy came in the face of
significant
reductions in overall morphine or opioid
requirements to control pain. There was a 35
percent reduction overall in the use of
requirement
of morphine across the trial in the
parecoxib/valdecoxib treatment group as
compared to
placebo.
You can see that most of that effect
occurred during the parenteral treatment
period.
With that also came an improvement in
opioid-type
side effects but also, perhaps as
importantly, it
also came with improvements in functional
status of
the patients following surgery.
Here we show the Modified Brief Pain
Inventory Functional Questionnaire, and
you can see
that there is a significant improvement
in function
in the parecoxib/valdecoxib treatment
groups as
compared to patients who received
standard of care
opioids only.
Finally to sum the risk/benefit
of
465
parecoxib, parecoxib appears to offer
unique
benefits over existing parenteral
analgesic
medications and has a favorable
risk/benefit ratio
in surgical settings, other than CABG or
revascularization procedures. Because parecoxib is
a parenteral, it is administered in
controlled
settings under physician
observation. This
risk/benefit assessment is also shaped by
the
cardiovascular risk that is found in the
CABG
surgery setting but no in other surgical
settings.
Again, the caveat is that we have no
evaluated the
drug in other revascularization
procedures and have
no assessment of safety in that regard.
At this time I would like to
turn the
podium back over to Dr. Feczko for some
concluding
remarks.
Concluding Comments
DR. FECZKO: Thank you, I will be brief. I
would like to thank the panel and the FDA
for the
opportunity given to Pfizer today to show
the data
that demonstrates the cardiovascular
safety profile
of
our COX-2 inhibitors, both Celebrex, Bextra and
466
parecoxib.
Patients with chronic
inflammatory
arthritis pain have few therapeutic
alternatives.
While there has been a lot of debate
about the
placebo-controlled trials in the
treatment of
arthritis, placebo is really not an
alternative.
So, we did focus today's presentation
predominantly
on relative risk versus traditional
non-selective
non-steroidal anti-inflammatory drugs.
We know about the GI risks of
older
non-selective NSAIDs, but how much do we
really
know about their long-term cardiovascular
safety?
I think it is a question that needs to be
answered.
Part of the problem we had, as noted in
the CLASS
trial, was the high dropout rate
associated with
diclofenac over the dosing period. Given these
unanswered questions, all the data
suggests that
Celebrex and Bextra probably have an important role
to play in treatment of patients with
rheumatoid
arthritis and osteoarthritis.
As you heard, there is an
extensive body
of clinical trial and observational data with
467
Celebrex.
We believe that this data shows that the
cardiovascular safety of Celebrex is at
least on a
par with therapeutic alternatives such as
the
non-selective NSAIDs.
Pfizer is committed to doing
the right
studies with the appropriate study
population and
the appropriate study hypothesis to
confirm what we
believe is the preponderance of data we
have seen
today that Celebrex cardiovascular safety
is
comparable to the non-selective NSAIDs.
The Celebrex protocol is
currently filed
with the agency. We have had one review with a
number of outside cardiology
consultants. We are
awaiting, however, the outcome of this
advisory
committee to determine whether or not the
protocol,
in conjunction with the FDA, is the
appropriate
model to be used for long-term evaluation
of
Celebrex.
We are committed to also continuing the
evaluation of Celebrex in the prevention
and
treatment of cancer, as outlined by Dr.
Hawk and
Dr. Levin. We also agree with Dr. Hawk, and as Dr.
468
Furberg mentioned earlier, that I think
there is a
large body of evidence right now at the
NIH that
has already had a number of patients
treated for
well over two to three years, mainly in
the cancer
setting, mainly in placebo-controlled
trials. I
think it is imperative that we look at
that data as
soon as possible.
While the data for Bextra is
definitely
smaller, it is growing and in the
treatment of
rheumatoid and osteoarthritis we believe
has not
shown any increased risk in
cardiovascular risk.
The extrapolation from the CABG studies
has been
taken as evidence that there is a problem
with
Bextra overall. We actually don't see that right
now, however, I will be the first to say
that the
database is much, much smaller.
We are also committed to
looking at Bextra
in a long-term trial in our arthritis
patients as
appropriate to evaluate the relative risk
associated with Bextra. I think this is important
because I do think rheumatoid and
osteoarthritis
patients do need treatment options and I
will be
469
getting to that in a second.
Parecoxib, as was just
mentioned, is an
injectable drug, approved and marketed in
some 40
countries around the world. It has found a place
in those countries in the perioperative analgesia
setting.
It is found to be highly effective in
relieving postoperative pain and in
morphine
sparing and, therefore, sparing the side
effects
associated with morphine in the
postoperative
setting, such as ileus and respiratory
depression.
It has shown no evidence of the
increase
in severe AEs in the general surgery
setting or the
outpatient surgery setting. These seem to be
confined right now to the post-CABG
setting and, as
Ken mentioned, this is already in the
labels in all
those countries in which it is currently
being used
and is still on the market.
In conclusion, I continue to be
confident
that Celebrex and Bextra have important
treatment
options for arthritis patients. I actually believe
that there is no effective treatment for
arthritis
patients that is safer than
Celebrex. I agree
470
though that we do need to do the long-term
evaluations of both Celebrex and Bextra
to really
see their place in the therapeutic
armamentarium.
For arthritis patients, and
here I include
myself because I also am on chronic
therapy for
osteoarthritis--arthritis patients need
safe and
effective treatment options. Not everything works
for everyone. Patients do try different
therapeutic options and do not tolerate
some and it
is not really clear why. We discussed this fact
earlier on about dyspepsia, people
stopping
therapies, people trying various proton
pump
inhibitors to suppress the dyspepsia or
related GI
effects and these don't often work in
people.
Arthritis patients do need safe and
effective
treatments and they need the to move, to
work and
to make the most out of each day.
So, with this, I want to thank
the
committee and the FDA and we will throw
this open
again to questions for Ken and anybody
else who can
answer them. Thank you.
DR. WOOD: I have a number of questions.
471
In the general surgery study, there are a
lot of
issues about that that you didn't
present. There
is the same number of patients in that
study as in
the CAB study but many of these were
women. They
were much younger patients and the chance
of seeing
events in that study was extraordinarily
small,
don't you think?
DR. VERBURG: True.
The underlying risk
factors and risk factor status in the
general
surgery population was lower.
DR. WOOD: So, the general surgery study
shouldn't give us any confidence to
overrule the
CAB study. Correct?
DR. VERBURG: I would not suggest that it
would overrule the CB study. I would take note of
the fact though that the cardiovascular
events that
occurred in the general surgery trial
occurred at
about an incidence of one percent. That was in the
range of the incidence that we saw in the
CABG
surgery trial which ranged from 0.5 to 2
percent.
So, although it doesn't completely put
the issue to
rest about to what degree the drug has a
472
cardiovascular risk associated with it in
the
general surgery population relative to
standard of
care alone, the trial that we have
conducted, we
believe, moves us down that road
considerably.
DR. WOOD: What percentage of the general
surgery patients were women?
DR. VERBURG: I believe that was 60 or 70
percent female.
DR. WOOD: And they were getting minor
gynecological surgery largely?
DR. VERBURG: Actually, the largest
percentage of surgeries was gastrointestinal,
followed by orthopedic and then
gynecological.
DR. WOOD: And do you recall the age
difference between the two groups?
DR. VERBURG: No. I
can find that.
DR. WOOD: I think it is about 10. I
think it is more than 10 years.
The other issue that we are
here to
address is the total safety of these
drugs. I
wonder if you can show us Table 3 from
your paper
in The New England Journal, or perhaps
you can go
473
through it? It is the one that shows the incidence
and risk ratio of your predefined adverse
events in
the CAB study.
DR. VERBURG: I don't have that on a
slide.
DR. WOOD: You are the author on that
though, right?
DR. VERBURG: That is correct but I don't
have a slide.
DR. WOOD: Well, let me help you. Every
one of the predefined adverse events has
a relative
risk of greater than 1, and not all of
them
significant but every one of them greater
than 1.
So, I was sort of intrigued by the slide
that said
there was obvious benefit of this drug in
surgical
patients.
Tell me how I would recognize the
benefit given these predefined adverse
events.
DR. VERBURG: I would like Dr. Nessmeier
to come up and make some comments. Dr. Nessmeier
was also an author of the CABG surgery
paper, and a
practicing anesthesiologist.
DR. NESSMEIER: I would just like to say
474
that the selective COX-2 inhibitors I
think are
potentially an important tool in the
armamentarium
from the standpoint of an
anesthesiologist for
treatment of postoperative pain, given
that the
alternatives also have side effects. Right now we
have, obviously, the opioids and the
narcotics
cause dose-dependent respiratory
depression and
cause, you know, excessive sedation that
is also
dose-dependent, as well as nausea and
vomiting,
ileus, urinary retention. One has to wonder if
morphine, for instance, would be approved if
it
were subjected to intense scrutiny today.
In addition, we have the
non-selective
non-steroidal anti-inflammatory drugs as
potential
therapy for postoperative pain, but they
also are
not without side effects. The one that is most
commonly used by anesthesiologists in the
perioperative setting would be ketololac
and that
has, as you know, the potential that
surgeons worry
about for post-surgical bleeding
problems, the
potential for gastric ulceration and also
renal
dysfunction.
So, given that the alternatives
also have
side effects, it is I think reasonable to
continue
the study of this drug, and it has been
approved in
475
over 40 countries. I know my colleagues elsewhere
are very favorably impressed with its
analgesic
potential, you know, primarily in relatively
low
risk patients. Certainly we have demonstrated that
it should be avoided in patients
undergoing
coronary re-vascularization. I would certainly
extend that, just based on common sense,
to any
other revascularization procedures. But that does
not apply to the majority of general
surgical
procedures, gynecologic surgical
procedures,
orthopedic surgical procedures. We have no
evidence that any of these concerns apply
right now
to the lower risk patients who are
undergoing the
vast majority of surgical procedures
worldwide.
DR. WOOD: But, Nancy, if you look at your
table, greater than one confirmed adverse
event,
that includes everything you have
predefined and
that is presumably what we are looking
for, and the
relative risk was 1.9, with a p value of
less than
476
0.01.
And, the events were not all
cardiovascular--renal failure, upper GI
events,
every one of them--surgical wound events,
every one
of them, death even, has a relative risk
of more
than 1.
So, I agree there may be an advantage but,
in the absence of demonstrating that
advantage and
in the presence of clear risk, I don't
see where
the advantage is here.
DR. NESSMEIER: Well, the risk is well
demonstrated now in coronary-artery
bypass grafting
population. It just hasn't been seen in any of the
other studies, including the large
general surgical
study that was just completed and that we
are in
the process of writing up. That was over 1000
patients.
But there are these 19 other smaller
studies and it hasn't been seen in any of
them in
the other populations. I certainly agree that
further study is needed because it is a
vast
population we are talking about, and the
power to
demonstrate absolute safety is also vast.
DR. WOOD: Tom?
DR. FLEMING: I have a very parallel set
477
of observations. I thought the final conclusion on
B-36 was very strongly worded, unique
benefits over
existing analgesic medications and a
favorable
benefit to risk when, in essence, the
general
surgery study has ten events and you have
four
times that many events in the two CABG
trials.
And, you were referring to The New
England Journal
article.
We can also go to the background material
at Tab Q, page 18, and we see a very
similar,
striking global safety profile when you
look at the
SAEs in the 035 trial. There is a doubling in SAEs
from 10 percent to 20 percent. When you look
overall at GI SAEs, it is 0 against 7;
cardiovascular renal SAEs, 7 against 33;
cerebrovascular events, 9 against 1;
thrombophlebitis, 3 against 0; atrial fibrillation,
2 to 1; MIs, 5 to 1. Now, the events that we saw,
15 to 2 just had 1 to 1, but I think the
reported
before adjudication events were 2 against
9. Then,
pulmonary postoperative, 5 against
37. So, a very
striking increase across a wide array of
different
SAE categories in the CABG setting for
both of the
478
trials.
DR. WOOD: Curt?
DR. FURBERG: Well, I am troubled by
something else. I am troubled by some
inconsistencies that I have found in the
briefing
document from Pfizer. I would like to just briefly
go over some of them. On page 55 there is a
summary from acute pain studies. It says here are
the safety data from 18 clinical
studies. On page
76 in the summary it says here are the
safety data
from 20 completed studies.
I just wonder what happened to
the other
two trials. They disappeared. Any suppression of
information or is it just an error?
DR. VERBURG: We will check on that.
DR. FURBERG: The other thing relates to
the overall findings from these summary
studies,
the 18 studies. In Table 19, on page 60 for acute
myocardial infarction it says placebo, 0;
valdecoxib, 3. In the following table for
myocardial infarction it says 1 versus
3. So,
there is an internal inconsistency in two
tables
479
after each other.
What is even more striking is
that when
you start looking at the individual
studies that
contributed to the summary statistics for
the 18
studies--I just looked at two of them,
the study we
just talked about, the general surgery
study. In
terms of myocardial infarction, depending
a bit on
how you define it, there were 3 and
2. If you
include cardiac arrest and sudden cardiac
death it
is 6 to 0. The summary statistic was 0 to 3 or 1
to 3 and here I have 6 in one study. I add in the
data from one of the bypass surgery
trials and I
get additional numbers. So, just by combining the
bypass surgery trial 071 and the general
surgery
for MI I have 0 to 8 or 1 to 9; not 1 to
3. And
how about the other 16 studies? That is troubling.
I also find that they included
in the
summary statistic one of the bypass
surgery trials
but not the other one. Why? I
mean, the other
study met the same definition. If you put that in
the numbers get even worse. So, there is clearly
an under-reporting of events the way I
interpret
480
it, and I have to say that we all make
mistakes,
and most of them are honest. Honest means that
sometimes you benefit from your mistakes
and
sometimes you are hurt. But here all the
inconsistencies tend to go in one
direction. So, I
just raise the question whether these are
honest
mistakes.
It has made me wonder how much trust I
can have in the information that we have
received.
DR. WOOD: Dr. Hoffman?
MR. HARRIGAN: Excuse me--
DR. WOOD: All right.
MR. HARRIGAN: This is Ed Harrigan from
regulatory affairs at Pfizer. We would like to
have ten minutes. We are not prepared at this
point to go through table by table to
look at the
questions that you have. We would like ten minutes
tomorrow to do that and I think we will
quite
readily answer all the questions you
raised.
DR. WOOD: Okay, that is helpful. Dr.
Hoffman?
DR. HOFFMAN: I would like to just raise
some questions that are extrapolations
from the
481
CABG study where your explanation for why
there may
have been increased events is both
provocative,
interesting and perhaps, in fact,
true. But what
if this is a phenomenon that does not
have to do
with just perturbation of endothelium and
cross-clamping, etc.? What if the patients going
through a CABG in fact are going to CABG
because
the lesion that they have represents a
generalized
high plaque burden, unstable plaque? We would all
agree then that, if we were to
extrapolate from
that, we would not give perhaps any drugs
in this
class to people at considerable
cardiovascular risk
that we knew of.
But the problem in chronic
therapy for
patients with RA and OA is that many of
them come
to us with perhaps moderate to even
severe
coronary-artery disease that is
clinically silent.
Even with extensive screening we may not
be able to
pick up those patients. We can only postulate that
those patients will be the tip of the
iceberg that
may have events because of the
physiologic effects
of COX-2 inhibitors and perhaps Bextra in
482
particular because of what the data is
that you
have reviewed with us.
So, I am concerned that you
would
advocate, given these unknowns, the use
of Bextra
still in patients who have OA and RA and
might be
taking that drug for years, given that we
don't
have data that goes significantly beyond
six months
to a year long term.
DR. VERBURG: Would you like me to
respond?
Our position is that, again, we are
shaped really by a lack of understanding
about how
other agents would act in the CABG
surgery setting.
I think your point is a good one. You do not know
whether patients are entering CABG and
the result
is because of their history, the
procedure or some
combination of the whole. So, we are left with a
lot of unknowns and we are left with
trying to
shape conclusions based on the data we
have in the
arthritis populations, being mindful of
the concern
that you raised.
DR. HOFFMAN: A follow-up to that but not
directly related to that is, while you
have shown
483
good efficacy for analgesia postoperatively
and
have provided a caution about why you
would not use
Bextra postoperatively for not just
cardiovascular
disease but vascular surgery in general,
do you
have any data from animal models that
tells us
anything about wound healing after
vascular surgery
in animals given Bextra and not given
Bextra?
DR. VERBURG: Not that I have information
specifically about wound healing
following vascular
surgery, we have done wound healing experiments
with Bextra and the other agents. If you would
like a quick synopsis of those, we can do
that.
Dr. Seibert or Dr. Kahn, can you make
some comments
in that respect?
DR. SEIBERT: Dr. Seibert, pharmacologist
for Pfizer. We have looked directly at wound
healing, looking at incisional wound
repair,
tensile strength and seen no effect at
super-therapeutic doses of compounds like
valdecoxib, celecoxib. If wounds are infected
there may be some delay in that wound
healing
process.
We are aware of that. We have no
direct
484
evidence that there is a direct effect on
wound
healing in an incisional setting. We have no
direct experiments looking in a vascular
setting at
this point.
DR. PLATT: It seems to me that in
addition to having to make decisions
without having
all the information we would like, we
have to make
decisions around data that are internally
not
consistent with one another. That is, a lot of
different studies come from a lot of
different
place and say things that can't all be
fit into a
single coherent framework. For instance, I take
your point that the observational studies
of Bextra
seemed to show no real increase compared
to other
non-steroidals. On the other hand, there are
observational studies of other non-steroidals
that
seem to show that they don't have
increased risk
compared to no drug and, yet, there is a
good
placebo-controlled study of valdecoxib
that shows
quite a lot of risk.
So, I don't know a way to them
all
together.
It seems to me--this is a statement to
485
my colleagues on the committee, we have a
tough job
of saying not only is there a lot we
don't know but
we are going to have to decide which
pieces of the
information we do have to put the most
weight on.
Just to sort of herald the discussion
that I know
we will have, the question is what is the
cautious
way to proceed while acquiring the
additional
information that we need to have? How important is
it to think about the way these drugs are
used
while the additional information is being
collected?
DR. WOOD: Agreed.
Dr. Paganini? No?
Was there somebody else down there? Go ahead.
DR. FRIEDMAN: Sometimes vascular surgery,
cardiovascular surgery in particular, has
to be
conducted on an emergency basis. How do you deal
the case of people who may have been on
Bextra, for
example, and then need surgery? Do they have to be
off for a period of time, or what policy
are you
advocating?
DR. VERBURG: Bextra is not approved for
acute pain so if we are talking about
placing a
486
patient perioperatively on Bextra--
DR. FRIEDMAN: No, no, I am talking about
people who may have been on it for
arthritis but
then need emergency surgery.
DR. VERBURG: Well, I don't know that I
have any specific recommendations on
that. I
haven't really envisioned that. I do know that
patients undergo surgical procedures with
selective
COX-2 inhibitors routinely without
discontinuing
medication due to the fact that they do
not result
in excess bleeding. But I don't know that anybody
has really thought through the
implications of the
scenario that you just brought up.
DR. WOOD: Dr. Nissen?
DR. NISSEN: I am going to suggest a
conclusion from this study and I want to
see if you
agree with it, that what we learned from
the CABG
study is that a sufficiently high dose of
a potent
COX-2 inhibitor, given for only ten days
to a group
of people also taking aspirin, is capable
of
producing a highly significant increase
in
cardiovascular thrombotic events.
What is unique about this study
from my
perspective is the rapidity with which
the events
occur with relatively short-term
exposure. So,
487
doesn't it tell us that the potential
exists for
potent COX-2 inhibitors to produce events
quickly
even in patients taking aspirin? I mean, I think
that is something we haven't talked about
with this
study.
Everybody got aspirin, as I understand it.
So, this is a pretty rapid emergence of
the
problem.
We heard about an 18-month delay in
another study and everybody was talking
about,
well, is there an inflection point and so
on? This
is only ten days of therapy. So, isn't that the
proper conclusion from the study?
DR. VERBURG: I would tend to agree. The
onset was obvious by the time to event
curves. All
those rapid events tended to be stroke
events in
both trials, which is also somewhat
puzzling and a
little bit different from the types of
events that
we have been seeing in other settings.
DR. WOOD: Any other questions?
DR. FLEMING: Just one thing to add to
488
what Steve is saying, and that is just
the absolute
increase.
We have seen that in terms of a relative
risk increase this is a multi-fold
increase but
these are frequently occurring events. So, in the
035 trial when we are looking at the
denominator of
311 people we are talking about
cerebrovascular
accidents in 9, an overall event rate
increase from
1.3 to almost 5 percent. So, it is a tripling in
the overall rate but to an absolute
occurrence of
1/30 persons treated.
DR. NISSEN: You are suggesting sort of
the number needed to treat in order to
get an event
is relatively small. DR. WOOD:
Steve?
DR. ABRAMSON: I think it also speaks to
the fact that, because aspirin was
present, perhaps
the importance of COX-2 in this acute
event of
cardiovascular insult but because aspirin
was
present it simply says if you inhibit
COX-2 to a
high degree you may get this result. It doesn't
say that it is a highly selective COX-2
agent that
is necessarily responsible. It may simply be the
process of inhibiting COX-2. So, I think we have
489
to separate whether this is a selective
COX-2
effect.
The presence of aspirin basically says it
is not a selective COX-2 effect; it is
the
importance of COX-2 derived prostaglandins
in this
setting that one is aborting.
DR. SEIBERT: I could just add--I know it
is late in the day but, you know, I think
that is
exactly one of the points we want to
raise, that
the setting that we see these results in,
in CABG,
seems quite different, as Dr. Nissen
pointed out,
from what it takes in very chronic
exposure in the
arthritic patient. In fact, that evokes quite
possibly very different mechanisms or
very, very
different places in the continuum.
What we really don't know is
the effect of
an NSAID in the same CABG setting because
we
haven't seen direct comparator studies
performed,
and we would not be interested in doing
them at
this point. We have conclusive evidence.
But this is quite different
than the
mechanism that we try to unify around the
NSAIDs
and the coxibs like celecoxib in the
chronic
490
setting, where we believe hypertension is
the
driver there. And, if rofecoxib stands outside of
that with unique properties then perhaps
it does.
So, we are really believing that we are
working
with very different hypotheses and
mechanisms here.
DR. WOOD: Well, would you take it if you
were at high risk of a platelet-driven
problem?
DR. SEIBERT: I am sorry, I don't know
where the question came from.
DR. WOOD: Here.
I mean, given that CAB
is a model of platelet-derived problems,
would you
take a drug if you had some other problem
that
looked like that?
DR. SEIBERT: Well, I would get right to
the issue of risk/benefit and what your
alternatives are.
DR. WOOD: And the benefits from Bextra in
clinical trials like VIGOR or what?
DR. SEIBERT: I guess we would have to get
right to the issue of risk/benefit here
and, you
know, perhaps that is best addressed in
terms of
that risk/benefit in that setting by our
clinical
491
consultant.
DR. STRAND: May I answer you--
DR. WOOD: Sure.
DR. STRAND: --as a practicing
rheumatologist, and I teach at
Stanford. Bibica
Strand.
I think all of our patients to not respond
uniformly to one non-steroidal. Similarly, they
don't respond to COX-2 uniformly. Thus, we need
multiple agents, and we have a group of
patients
with chronic OA, rheumatoid arthritis,
even motor
vehicle accidents who need
anti-inflammatories on a
regular basis. Would I recommend that a patient
with high cardiovascular risk be taking
one of
these agents at the present time based on
the data
we just discussed, the answer would be
no. But I
think that there is a risk/benefit
profile here
that is positive in terms of
understanding that
these patients need treatment for their
chronic
pain.
In fact, there is a GI benefit and, in fact,
except in this setting which may be
confounded
somewhat from aspirin in terms of the
CABG studies,
we don't yet see an increased risk with
Bextra. It
492
does not have an increased risk for
hypertension or
edema until you get to 40 or above, and
the doses
are 10 in clinical use.
I think the other point to be
remembered
is that in this CABG study, and of course
it is
confounded and one cannot say that there
is absence
of evidence and presence of safety, but
many of
those cardiovascular events also occurred
either on
placebo or more than five half-lives
after the drug
was stopped in the period of time of
follow-up when
we are not clear with aspirin was continued
or not.
So, I think it is very
difficult to
understand what happened with many of the
delayed
events.
If we look simply at the valdecoxib and
placebo arm versus placebo, we don't see
the same
signal.
So, from that point of view I would argue
that we still need this alternative for
the
patients who need chronic pain relief.
DR. WOOD: Well, we are lurching towards
conclusions here perhaps by Friday. What you are
saying is that the patients you would see it in are
patients who have failed other therapy?
DR. STRAND: I see it in patients who have
high GI risk but, in fact, most of our OA
and RA
patients already have increased risk and
many of
493
them have already had GI bleeds because
they have
tried chronic non-steroidals for a long
period of
time.
I see it in patients who have not already
responded to celecoxib or may have been
forced to
discontinue Vioxx.
DR. WOOD: Let's move on to the next
speaker and, hopefully, that will be our
last for
tonight, you will be sorry to hear.
FDA Presentation: COX-2 CV Safety:
Valdecoxib-Naproxen
DR. WITTER: What I am going to try and do
is bring back some of the discussion I
had earlier
and specifically try and set some of this
into some
kind of a context. I was the primary reviewer for
parecoxib. I was not the primary reviewer for
valdecoxib so I have had to rely on
reviewing
reviews for the information I have here.
In terms of valdecoxib, the NDA
came in on
January 15 of 2001; 60 studies and I have
listed
494
them here again. We like to focus on the arthritis
studies.
There were 10 of those. There was
a
long-term exposure included which I will
talk about
briefly.
I would just note again, as we have been
discussing, that there has not been
conducted a
long-term outcomes type study. So that we are
complete here, the original approval for
valdecoxib
did not contain a sulfonamide
warning. That was
addressed by subsequent label changes and
"Dear
Healthcare Provider" letters.
To give you a sense of
comparison then
from earlier studies, the patient-years
are
described here for OA and RA. You can see that the
numbers are smaller than what we were
describing
earlier for example with celecoxib.
Turning to the deaths in the
NDA database,
there were 22 deaths and 17 of thee
occurred during
the double-blind studies, 4 in the CBG
trial. So I
will discuss that when I talk about
parecoxib. Two
of those were cardiovascular
related. There were 8
deaths in patients receiving valdecoxib. Half of
those were cardiovascular related. There were 3 in
495
patients receiving NSAIDs; 2 were
cardiovascular
related.
There were 2 non-cardiovascular related
deaths that occurred in the cancer pain trial.
During the open-label studies there were
5 deaths,
3 were cardiovascular related.
So, taking that information and
looking at
the number of deaths and patient-years and
trying
to give you some sense of comparison
between my
prior presentation, you can see that the
highest
mortality rate is in the group of
valdecoxib plus
the CABG patients at 4.7 percent. Recall that it
was 3.7 percent; it was the highest from
the prior
discussion. If we exclude the 2 cases in CBG we
come down to a rate of 3.5 percent. In the
open-label studies the rate calculates
out to 1.4
percent.
There were a couple of analyses
that were
conducted, special analyses that are
listed here to
look at the NDA for valdecoxib. This was to
address the rate of serious
thromboembolic
cardiovascular events. They were in two patient
populations, one that was described as
high risk
496
and the other was at risk. So, the high risk
patients were those that had a history of
angina,
myocardial infarction, coronary-artery
disease and
cerebrovascular accident, while the at
risk
patients were described as those patients
who had
hypertension, hyperlipidemia or smoking.
The endpoints as defined by the
NDA at
that point for this special analysis were
MI,
myocardial ischemia, unstable angina,
cardiac
arrest, sudden death, CVA, TIA, pulmonary
embolism,
venous thrombosis, embolism in general,
peripheral
gangrene and peripheral ischemia.
Looking then at the high risk
group and
looking at cardiovascular safety in this
group, you
can see that there are small numbers of
patients
that fit into this category in particular
when
looking at the placebo arm here. When you look at
the incidence rates of the events per 100
patient-years, you can see that there
doesn't
appear to be a consistent dose effect
across the
various doses. Valdecoxib doesn't appear to be any
different than the NSAID
comparators. The result
497
here, looking at placebo, certainly
appears to be a
spurious result based upon the small
number of
patients and the event rates there.
Looking at the at risk patients,
there are
more patients in this category. It gives us more
patient-years to look at. The number of events is
small.
Again, calculating the incidence rates and
the events per 100 patient-years, once
again there
doesn't appear to be any strong
dose-response
correlation here between the increasing
doses of
valdecoxib but they don't appear to be
any
different or any greater than what was
seen in the
comparator group.
As I mentioned, there was a
study that was
conducted at the urging of the agency to
give us a
better idea of the long-term
cardiovascular events.
This was study 047. This was a 6-month study that
was
conducted in patients with OA and RA. It
was
basically naproxen 500 BID against two
doses of
valdecoxib, 20 mg and 40 mg BID. I have listed
here the percentage of patients who
completed the
26-week trial, 43 percent naproxen and
about 50
498
percent in both of the valdecoxib arms.
I would like to draw your
attention to
worsened blood pressure. There was a statistically
significant, at p less than 0.05, increase in
worsened blood pressure in the 40 mg BID
group
compared to naproxen. In general when you look at
this data there was a dose trend against
valdecoxib
for all the events, with the exception
here of
palpitations. It was comparable across all the
groups.
Turning then quickly to
parecoxib, as we
heard it is an intravenous/intramuscular
formulation. One of the questions is why would we
want to develop or anybody want to develop
something like this? So, what I have done here in
trying to help answer that question is
the label
that was in the toradol label--this was
Table 3.
What this table represents is a postmarketing
study
of 10,000 patients non-randomized,
looking at the
issues of incidence of clinically serious
GI
bleeding after 5 days on increasing doses
of
toradol, ranging from, in this case, less
than or
499
equal to 60 mg up to greater than 120
mg. There
are two age categories here, less than 65
and
greater than or equal to 65 years. The patients
are broken out into those either without
or with a
history of perforations, ulcers or
bleeds. As you
can see and I have highlighted here, and
that was
one of the points of having this included
in the
labeling, is that as one increases the
dose you
increase the number of events. A quarter of the
patients in fact had these serious GI
bleeds.
There also is an increase as you go
through the
categories of increasing event rate with
age. So,
I think this is part of the answer to the
question
as to why one we want to develop an
intravenous or
parenteral formulation of a COX-2
inhibitor.
Just to review quickly,
parecoxib has a
half-life of about 15-30 minutes. It breaks down
into valdecoxib. What this does, and this is what
we were concerned about, this allows
exposure to
different patient populations that have
differing
risk factors. The trials, however, were intended
to address the issues in analgesia and we
have some
500
analgesic experts on the panel here. For example,
the concept of multimodal analgesia is
very much in
the popular press these days. It is established
that COX-2 has a role in all forms of pain,
but
there are also studies that looked at
parenteral
analgesia and opioid sparing and certain
of these
studies were conducted in concert with
valdecoxib
which you have heard about, the CABG
trials, and I
will just briefly review those too.
The original NDA for parecoxib
was
submitted on September 11 or 2000, 36
studies.
They had a variety of studies, as I
listed here.
Just drawing your attention to the
post-surgical
analgesia trials, there were 8. There were 4
preoperative or preemptive analgesic
trials, and
there were 2 studies looking at opioid
staring.
The CAB 035 was one of those. The long-term safety
is what I have already described in the
valdecoxib
047.
This was CABG-I. The first CABG 035 as we
know, was 2:1 randomization in terms of
parecoxib
to the placebo. I just want to point out the
501
placebo in this case really refers to
standard of
care so this is patient controlled
analgesia and
opioids.
The study was broken up into two phases,
as we heard. The first 3 days was the IV/IM
formulation and then when patients were
able to
take medicines by mouth they were
transitioned into
the valdecoxib, same dose, 40 mg twice a
day or
every 12 hours up until 14 days. Aspirin was a
requirement for the study at less than or
equal to
325 mg.
Patients were studied to 30 days for
events, which I will point out in a
second.
This was a first of its kind
study. This
was a study to address the concerns that
we had in
the agency about this particular drug
going into a
high risk population. There were a lot of
concerns.
We were certainly aware of the various
hypotheses and issues that are out there
with
COX-2s.
So, we challenged the sponsor to come up
with a study in a high risk
population. This was
the agreed to design of the CABG study
but, as I
alluded to here, it was a complex study
not only
because of the patients but because of
the
502
procedures and the co-medications.
So, to help address this there
were
blinded committees that were established
to verify
that the adverse events met established criteria
to
help figure out dates and attribution,
and this is
what was called then CRAEs, clinically
relevant
adverse events. As has been pointed out just
earlier, there were no active controls in
this CABG
or the other CABG trial, and the
discussion we had,
which is what you are having, is would
that have
been an appropriate control in the first
place
given the risk factors associated with
toradol for
example?
The exposure, just to give you
a sense,
was more than 7 days. The bulk of the patients
achieved that endpoint. To give you a sense of
what the CRAEs were, they were defined as
deaths,
cardiovascular events, pericarditis,
congestive
heart failure, renal failure/dysfunction,
TIA
event, major non-GI bleeding requiring
transfusion
and infection which required institution
of
antibiotics and pulmonary complications.
What I would like to do is just
briefly
talk about some of these and give you a
sense of
the adjudication and what was actually
looked at,
503
pointing out once more that events were
followed up
to 30 days post last dose of study drug.
Looking at myocardial
infarction in terms
of a CRAE, to qualify into that
definition you had
to have two of the following four
criteria as I
have listed on this slide. For example, chest pain
that was typical, not relieved by rest or
nitrates;
you had enzyme elevation as I have listed
here,
CK-MBs, LDHs, troponin levels. You had new wall
motion abnormalities or you had EKG
changes looking
at ST-T and Q waves, as I have indicated
on this
slide.
So, you had to meet two of the four
criteria to be qualified as having an MI.
Turning to the events then and
to some
extent repeating the results you have
seen but just
to
go over it again, there were the two groups,
placebo and the parecoxib 40 mg BID
group. I have
listed here the intravenous for the first
three
days and the entire study. Looking at any event,
504
you have a statistically significant, at
p less
than 0.12 by Fisher's exact test--the
number of
CRAEs in the entire study as compared to
the
placebo arm. When you look essentially at all of
the
adverse events as defined as CRAEs, just going
down the list here, most of these are
against
parecoxib and valdecoxib. I would just draw your
attention to some interesting ones. The MI, for
example, there was only 1 event that fit
the CRAE
definition in both of these. On the other hand,
there were 9 events that fit the CVA
definition in
the parecoxib/valdecoxib group.
Looking at the issue of MI
adjudication, I
just want to make this point, that there
were 13
possible MIs. There were 11 that were in fact sent
to the committee. These were 9 events in parecoxib
and 2 in the placebo. Of these events, only 2 MIs
survived the adjudication process so there
was 1
that was listed for parecoxib and 1
placebo, which
is what I just described in the prior
slide. I
note here that one of the rejected events
was in
the parecoxib group which resulted in
death,
505
probable MI of the patient.
What this brings up is the
difficulty that
we had on both sides trying to, you know,
adjudicate these events relating to the
timing of
the drug.
As I have suggested before, this was a
complex setting. There wasn't a lot of experience
in looking at this. So, that was a factor.
Nonetheless, these results factored into
my
recommendation that this drug not be approved. It
also was not approved because there was
essentially
limited information in terms of
efficacy. It was
essentially single dose information.
So, there was discussion that
ensued with
the sponsor in terms of thinking through
these
events and understanding a way
forward. I am
sorry, let me just describe the deaths
for a second
in parecoxib. There were 4, as I said before.
There was one in a 58 year-old male who
died of a
duodenal ulcer. There was one in a 69 year-old
female who died on day 19 of a probable
MI. There
was one in a 56 year-old male who died of
septicemia, pneumonia. There was also one in a 62
506
year-old male who died of an infarct in
the left
cerebellum.
Given what I just said before,
the issue
was that perhaps the dosing was too high
in that
study.
There was consideration that adjudication
of events on the day of surgery and
giving the drug
on the day of surgery was not a good idea
so that
dosing for parecoxib would be delayed
until the day
after surgery. Then there was an attempt to try to
get
a handle on whether these events were occurring
during the intravenous phase or during
the oral
phase, or both. So, that was part of the
explanation for the repeat study,
CABG-II, 071.
This then also had the CRAE
definition,
again studied for 30 days looking for
events. This
was a larger study. The groups this time are
fairly balanced in terms of the numbers
so you have
placebo/placebo here; placebo for the
first three
days; valdecoxib to finish out the study;
and then
parecoxib/valdecoxib.
When you look at any of the
CRAE events in
either group that contains the COX-2
agents, there
507
is a statistically significant difference
compared
to the placebo arm. When you look at all of the
events of the CRAEs, for the most part
they trend
against the COX-2 selective agent, with
the notable
exception of DVTs. There was one in the placebo
group and none in the other group.
I should just comment because
there was a
comment about it before, in CABG-I as
well as this
there were issues of wound healing and
wound
complication which was, to some extent,
an
unexplained finding. I should also just go back
and remind everyone that there was an
issue of
hypotension that we noted, particularly
in CABG-I
for which still to this day there isn't,
to my
mind, a good explanation for.
The deaths in 071 included in
the placebo
group an intestinal perforation. The
placebo/valdecoxib group included cardiac
arrest,
pneumonia and cardiac failure. The
parecoxib/valdecoxib group included
cardiac arrest,
pulmonary embolism, myocardial infarction
and
ventricular fibrillation.
The question then ensued would
the concern
about what had happened in 035 in the at
risk
population extend to other patients, so
there was
508
study 069 that was designed which was
meant to look
at more general surgery with basically
the same
doses that we had seen in 071, in the
second CABG
trial.
So, there was a 40 mg loading dose followed
by 20 mg BID. These were more general surgical
patients which included a mixture of
orthopedic,
GI, GYN, thoracic and a small amount of
others.
Looking at the CRAEs in this
study, and I
have just then listed here for the entire
study.
Again, the groups are exactly balanced in
terms of
the numbers. When you look this time at the number
of events the results look different in
the sense
that there tends to be more of these
events in the
placebo arm than the parecoxib/valdecoxib
arm.
With the exception of looking at MI,
cardiac arrest
and cardiac death, there are more events
ion the
parecoxib/valdecoxib arm than there are
in the
placebo arm.
This trial was included, as was
indicated,
509
in the current label for valdecoxib, as is
study
071 which I didn't mention.
The deaths in 069 for the
placebo included
a cardiac failure, carcinoma, a
mesenteric vein
thrombosis and a cardiac arrest. In the
parecoxib/valdecoxib group it included GI
hemorrhage, MI and pulmonary embolism.
I will skip these slides and
just make the
following point, that as we think through
safety
for NSAIDs and COX-2s, what we have been
hearing
is, you know, think about the data that
we have but
I think we need to worry about the data
that we
don't have. As others have said and I am just
reinforcing it here, the absence of
evidence is not
evidence of absence. So, there is a lot
there that
we still need to know. Thank you.
DR. WOOD: Great!
Let's move straight on
to the next presentation, and that is our
last
presentation for tonight. Then we will have the
questions after that, if anyone is up to
it still;
hopefully not.
Bayer and Roche Joint Presentation
on Naproxen
DR. BAUM: Good evening.
My name is Len
Baum.
On behalf of Hoffmann La-Roche and Bayer
HealthCare, I would like to thank the
advisory
510
committee and the FDA for allowing us to
come
before you today to talk about naproxen.
Roche and Bayer would like to
share what
we know about the issues and provide
information on
the large body of data that can help the
FDA and
the advisory committee in their
review. We also
would like to help reassure consumers and
healthcare professionals about the safety
of
naproxen.
Today we will provide a summary
of the
information from our briefing book and we
will
quickly go through some of the
information that
both Roche and Bayer jointly
submitted. The
information comes from over 30 years of
clinical
and marketing experience. We will provide a very
brief overview of the history of the
product, and
we will quickly go through some of the
properties
of naproxen since a lot has been covered
today. I
will briefly touch on the ADAPT trial and
then
511
spend most of the time on the safety
evaluation
that has been conducted.
Along with me today is Dr.
Martin Huber
who is the Vice President and Global Head
of Drug
Safety and Risk Management for Hoffmann
La-Roche.
We also have a number of people from each
of our
companies to assist us should we have any
questions
at the end of the presentation. And, a couple of
outside experts also, Dr. Kay Brune
and Dr. Ian
Grainek who could also assist should
there be
questions at the end of the presentation.
Naproxen has been available for
over 28
years now. The prescription was approved in 1976
for a number of indications that you see
up here on
the board. It is available by a number of
manufacturers today for the treatment of
rheumatoid
arthritis, dysmenorrhea, bursitis and the
other
indications that are listed.
In 1994 Aleve was approved as
the
over-the-counter version. That came before an
advisory committee who looked at the data
and then
was ultimately approved by the FDA via an
NDA. The
512
indications are listed up there and it is
currently
marketed by Bayer HealthCare for the
temporary
relief of minor aches and pains, and also
for
reduction of fever.
I wish to note here that
naproxen is safe
and effective for these indications when
used
according to the labeling directions.
Quickly going through this and
just to lay
the groundwork for the rest of the
presentation, we
did talk today extensively about the
class of
NSAIDs, and naproxen has its
anti-inflammatory,
analgesic and anti-pyretic
properties. It is also
known to inhibit platelet aggregation, as
we heard,
with the major differences between the
members of
the class being potency and
pharmacokinetics, and
this includes duration of action.
Just to set the stage and to
remind
everyone, the class of NSAIDs is fairly
large. The
one thing I would like to point out is
that coxibs
as well as the propionic acid class are
listed as
part of the NSAID class. We have heard a lot today
of NSAIDs versus coxibs but this is a
large class.
513
Within the class of the propionic acids
is naproxen
under the form Aleve also for
over-the-counter,
ibuprofen, Advil, motrin. So, there are a large
number of products that we use every day
for both
Rx and OTC.
What is the relevance of what
we are
looking at with naproxen? This compound has been
well documented with a long history. It is
referenced, as you have heard today, for
many
analgesic clinical trials. Naproxen as well as
other selective NSAIDs are important
treatment
options for a broad range of patients and
conditions. As we look at this data, we must also
consider not just the safety data but
also the
efficacy, as has been mentioned a number
of times
today.
The data that has been
submitted in our
briefing document covers a considerable
amount of
patient exposure and experience. I am going to
draw upon our safety discussion today,
information
from clinical trials, observational
studies and
postmarketing information. From the Rx side we
514
will draw from over 110 billion patient use. From
the OTC side, over 550 billion, and this
is courses
of therapy. We have listed this as 2 tablets a day
for 10 days.
When we look at the totality of
the data,
we
have not seen any safety signals related to
myocardial infarction, cerebrovascular
events, and
as we look closely now at ADAPT, what I
am going to
do is just highlight a couple of the
points, and I
do this more to let you know how this
fits into the
spectrum of the data that we have been
presenting
and will discuss today.
One point is that it is an
NIH-sponsored
trial.
Bayer provided product, naproxen, for
investigational use. It was a 3-arm study
comparing naproxen celecoxib and
placebo. The
patient population included 1200
patients. We
don't know the exact breakout of these
but I want
to point out that it was a 2:1 placebo to
the
investigational drug examination. So, it is not
2400 patients on any one drug. Patients were 70
years of age and older, and it was being
looked for
515
as the prevention of Alzheimer's
disease. The
study began in 2001 and was planned for 7
years.
It was suspended after 3 years. One thing about
the patient population I would like to
point out is
that these patients did have a familial
history of
dementia or Alzheimer's.
What is on this slide are
events that have
been publicly reported leading up to the
suspension
of ADAPT.
On December 10 the data safety review
board did not recommend stopping the
ADAPT trial.
In fact, the same safety board reviewed
the data at
least twice over the past three years and
each of
the times did not recommend stopping the
trial.
On December 17 the APC trial
was suspended
due to an indication in
cardiovascular/cerebrovascular risk of
celecoxib
versus placebo. Although there was no significant
risk for celecoxib, the ADAPT trial was
suspended
in part due to the APC findings and this
was
released as part of the NIH
statement. So, on
December 20th the NEI announced the ADAPT
trial
suspension. This information was released to the
516
public by the study group and it was based
on
preliminary findings, not through the
peer reviewed
journals.
Some of these data may be
discussed on
Friday by the NEI. We do not have that information
and will not be covering that in our
presentation.
I put this up to at least bridge into the
data that
we will be covering on the safety
analysis, and to
help put that into its perspective.
In summary, at this point
naproxen is a
non-selective COX-1 and COX-2 inhibitor. It is
widely used, with over 22 million
patients using
the product each year. It has an established
safety profile with over 30 years of both
clinical
and marketing experience. It is used as a
reference standard for many of the trials
we have
heard about, and the unadjudicated
preliminary
findings of ADAPT, and for that matter
the final
findings of ADAPT, will need to be put
into the
context of the wide body of data that is
available
on naproxen to date.
At this point I would like to
introduce
517
Dr. Martin Huber who will review the
totality of
the safety data that supports the lack of
myocardial infarction and cerebrovascular
signals
with naproxen.
Safety Data
DR. HUBER: Thank you, Len. Good
afternoon. I will try to go through this in a
little abbreviated form as I will be
repeating data
that has been summarized by other
speakers.
What we looked at was we did an
evaluation
of the available data to us, looking at
the
question of myocardial infarction and/or
stoke
based on the preliminary findings that were
reported for the ADAPT study. This evaluation
included an overview of the clinical
pharmacology,
the clinical studies from both the NDA
for the OTC
as well as prescription filings. We also looked at
our postmarketing safety data. Furthermore, we
looked at the large randomized
postmarketing
clinical studies that were available in
the
literature, and finally spent some time
on the
observational studies.
With regard to the
pharmacology, I think
we have heard enough about COX-1 and
COX-2 today to
last most of us a lifetime so I am not
going to
518
spend any time, other than t remind you
that it is
a known property of naproxen to inhibit
platelet
aggregation and this has been
substantiated by
studies demonstrating an increase in
bleeding time,
etc.
With regard to the clinical
trials in the
NDA, I would just like to briefly touch
on that.
There have been more than 500 patients
treated in
the original NDA for naproxen, of which
more than
300 were treated more than 6 months.
In addition, a little more than 4000
patients were in the OTC NDA--limited
duration of
treatment for these patients but in each
of these
data sets there was no signal for either
myocardial
infarction or stroke.
Furthermore, we reviewed the
postmarketing
data available in the Roche safety
database which
goes back to the launch of the product in
the early
'70s and in that, with over 100 million
patients
519
exposed globally, we saw no signal for
either MI or
stroke.
A similar review in the OTC postmarketing
surveillance data did not identify a
signal.
I an going to skip over
this. We did some
disproportionality. These are some internal signal
checks we do. It is in your briefing package and
the basic message is we didn't see a
signal even
going back retrospectively. If you have questions
I will be happy to discuss this.
What I would like to focus on
are some of
the large randomized, postmarketing
clinical
trials.
The selection criteria we looked at here
were that they needed to be
published. They had to
have naproxen in them and they also had
to have
prolonged exposure. We weren't looking at short
term.
There are hundreds of trials looking at very
short-term use of these agents.
The first trial is the VIGOR
trial. I
think this has been discussed extensively
and I
will not spend any more time on it. I would like
to spend a little more time on
TARGET. This study
has not really been discussed in detail
today. Our
520
colleagues, I am sure, from Novartis will
be
spending more time on this tomorrow, but
just to
quickly go over a few findings with
relevance to
naproxen.
I am not here to discuss lumiracoxib but
to focus on naproxen.
Of note, this is really two
studies; it is
two sub-studies. One of these studies was
lumiracoxib versus naproxen and another
of
lumiracoxib versus ibuprofen. So, this offers us
somewhat of an interesting opportunity to
potentially look at naproxen in
relationship to
another non-selective non-steroidal in a
large
randomized clinical trial.
In the first sub-study which
was looking
at
naproxen versus lumiracoxib, with regards to
stroke which included ischemic and
hemorrhagic, as
well as for acute MI, naproxen had a
lower
incidence of both of these events
compared to
lumiracoxib.
On the other hand, when we
looked at the
sub-study looking at ibuprofen, ibuprofen
actually
had a higher rate than lumiracoxib. What makes
521
this a little tricky though is that if
you look at
lumiracoxib in the two arms it is not
comparable.
There was actually a higher rate in the
second
study the naproxen study. The authors of the
publication attribute this to a higher
cardiovascular baseline risk in the
second
sub-study. But for our purposes today, what we
would like to emphasize is that we have
to be
careful in these comparisons that if you
use
lumiracoxib as a common reference
arm--the doses,
schedule, et., I understand to be the
same in both
sub-studies, you have ibuprofen higher
than
lumiracoxib here; naproxen lower than
lumiracoxib
here.
The other study, as noted, was
the
Alzheimer's trial. This is not the ADAPT study.
This is a study that was done in patients
with mild
to moderate Alzheimer's disease,
published by
Aisen, in JAMA in 2003. This was a randomized
trial between placebo, naproxen and
rofecoxib.
These data are based on the publication.
Essentially what we see is that in the
placebo arm
522
there are 111 patients and what we have
is death,
MI, stroke and TIA. These data are the serious
adverse event data as reported in the
paper. We
are not aware of any specific
adjudication or any
further analysis.
There has been extensive
discussion of the
trials with celecoxib. The only reason I bring
this up is it is part of White's
meta-analysis.
There were 2000 patients treated with
naproxen.
There are 4 events that were noted in
that
meta-analysis, 1 fatal stroke, 2 fatal
MIs. The
rate of these events for naproxen was
comparable to
the other groups of celecoxib and placebo
as part
of that meta-analysis. We did not see in this
publication evidence of an increased risk
of
myocardial infarction or stroke compared
to either
celecoxib or placebo.
Given the lack of large
long-term
randomized, placebo-controlled studies, I
would now
like to review the observational
studies. We
recognize some of the limitations of
observational
studies but I would like to spend a
little time
523
emphasizing that there are some positive
attributes
of these studies as well.
First of all, these studies can
be done in
a fairly short period of time. I think all of us
have noticed that since this question has
been
raised, there are multiple publications,
2002, 2003
and actually in fact even 2005, because
you can do
an investigation of chronic or prolonged
exposure
but by going retrospectively get the data
in a
relatively short period of time.
They also offer a tremendous
opportunity
to look at relatively rare events. You can say a
one percent adverse event is not that
rare but when
you try to look at a 20-30 percent change
in the
risk of an event that is of one percent
frequency
in a clinical trial, all of you are aware
of the
limitations of sample size. Looking at 10,000
patients is easy to do, or relatively
easy to do in
an observational study.
Maybe more importantly, it is
real-world
use of the drug. These are heterogeneous
populations. There are concomitant medications;
524
there are concurrent illnesses. I think what is
the most important thing when we look at
observational studies, we have already
started to
see isolated reports of limited
observational data.
Every observational study has intrinsic
limitations, the database, how you
identify the
patients.
We can have epidemiologists spend most
of the afternoon or evening if they want
in
debating that, but at the end of the day there
are
limits.
What is the real value of these studies is
what do you see when you do multiple
studies across
multiple databases? Do you find a consistency of
the finding?
These represent the observational
studies
that have been published for naproxen and
myocardial infarction. That is the topic that was
covered here. This was recently summarized in a
meta-analysis by Juni et al. in Lancet in
2004, and
there weren't any other ones out there
besides
these so we kind of borrowed the figure
from Juni.
There has been a huge
discussion in the
literature regarding the validity, the
strengths,
525
the weaknesses of the meta-analysis which
showed
that the overall risk was 0.86, but I am
not going
to spend a lot of time on that. What I would
rather focus on is just to briefly update
the
committee on the weight of these studies.
Each study is represented
here. What you
can see is one is in the center of the
axis here,
and this would show that there was
essentially an
equal risk of MI between naproxen and
whatever the
control group was for the study. This direction
favors naproxen having a lower risk than
the
control.
This direction favors the control.
What we find is most important
about this
data is there are 11 studies and 10 of
them show
the risk either equal to 1 or less than
1, which is
striking consistency. There is one study which had
an increased risk. This is the Graham study which
was recently published in Lancet, which
showed a 14
percent increase in risk. Of note, in the
publication in Lancet the lower limit of
the
confidence interval here did hit 1.0.
What we think is the important
message
526
here is not to spend time going through
each of
these but rather focus on the relative
consistency
of the findings. Based on these data, we do not
see evidence of an increased risk of MI
with
naproxen.
A criticism of this analysis is
that it
includes multiple studies from the same
database.
It seems pretty intuitive that if you do
multiple
studies on the same database you will get
similar
findings.
So, we did a sensitivity analysis where
we took only one study from each
database. The ones
we excluded are here. If you look at the pooled
relative risk it stays at 0.87. Remember, the
original analysis was 0.86. The confidence
interval gets wider, but you would expect
this
because there is a fewer number of
observations.
So, we see no material change in the
conclusions of
Juni et al.
In summary, a review of the
observational
studies shows no increased risk of
myocardial
infarction with naproxen. A review of the
postmarketing data also showed no signal
for MI or
527
cerebrovascular events. The
published clinical
trials do not provide evidence of an
increased risk
of MI or cerebrovascular events. And we would urge
caution that the unadjudicated
preliminary findings
of ADAPT are inconsistent with the known
data and
pharmacologic properties of naproxen and
need to be
carefully considered in your
deliberations.
In conclusion, the vast
majority of data,
collected over 30 years, indicates no
signal for
naproxen and myocardial infarction or
cerebrovascular accident. We believe that
naproxen, both prescription and Aleve
over-the-counter remain safe and
effective and that
they remain important treatment options
for
patients.
Thank you.
Committee Questions to the
Speakers
DR. WOOD: Great, and thanks for going
through that so quickly. Kimberly tells me that
the committee on breast implants went to
eleven
o'clock so we have a bit to go yet before
we beat
them.
Anyway, we will take questions for the last
group of speakers. Curt?
DR. FURBERG: A couple of comments, one
regarding Bextra. I applaud the FDA in the effort
to
standardize myocardial infarction, but to apply
528
the standard criteria of myocardial
infarction to
patients undergoing bypass surgery
doesn't make any
sense because you are opening the chest
so the
whole criterion about pain doesn't make
sense.
The other one is that many of
them have
increases in their enzymes. You cannot apply the
regular criteria to myocardial infarction
to the
population. So, I just think that reclassification
is not valid.
The second point is related to
the ADAPT.
you can add to your list of limitations
of the
study that there is no prespecified
outcome for
cardiovascular events. The investigators looked at
a number of them and it is not clear
which one they
decided to put their money on. And, there is no
adjudication of the cardiovascular
events. They
were all self-reported--very, very soft
data.
DR. WOOD: Nancy?
DR. NESSMEIER: Well, just a comment about
529
the CABG study, the criteria were
different in that
it was diagnosed either by autopsy or by
CK-MB
level of more than 25 ng/mL within the
first 72
hours after CABG, or an excess of 10
ng/mL if more
than 72 hours had gone by, or a peak
troponin of
more than 3.7 mcg. So, those are more rigid
criteria than would be used for a
non-surgical
study.
DR. WOOD: Right, and there was a control
group so it should have shaken out. Right?
DR. NESSMEIER: Correct.
DR. WOOD: Yes, Dr. Hennekens?
DR. HENNEKENS: I have two comments and a
question.
First of all a comment about the CABG
surgery data, in terms of benefit to risk
assessment, I would believe that a priori
any drug,
regardless of its class, that would
increase blood
pressure, fluid retention and risk of
heart
failure, if given during or after CABG,
would pose
very difficult research and clinical
challenges. I
would say to Dr. Shafer, regardless of
the
mechanism that is proposed, this is far
beyond the
530
powers of aspirin.
The second comment to Dr. Huber
as regards
his reassurances from the observational
comparisons, I am concerned that for
small to
moderate effect there are biases
confounding by
indication, and uncontrollable
confounding inherent
in all case control cohort studies, no
matter how
large or how well designed, as well as
their
meta-analysis. They can either produce false
evidence of benefit or harm or false
evidence about
lack of benefit or harm. I just think the
randomized data are far more important,
which leads
me
to my question to Dr. Huber. In VIGOR,
do you
believe the overall randomized findings
are
attributable to a hazard of rofecoxib,
benefit of
naproxen or some combination of the two?
DR. HUBER: I don't know.
DR. WOOD: That is a
surprise! Other
questions? Dr. Shafer?
DR. SHAFER: I just want to re-echo what
Dr. Nessmeier said. The CABG population is very
different, very much a pro-inflammatory
population.
531
In anesthesia we do very poorly at
treating
postoperative pain, particularly in the
first 24,
48.
Multimodal therapy is what we are looking for
and certainly if you say the CABG
population is
very different and you look at the data
in the
acute surgical setting--brief
administration--it is
an area where we do need improved
therapeutic
options and I would just encourage the
committee to
keep that in mind.
DR. WOOD: Other comments? Yes, Tom?
DR. FLEMING: Just looking at the nature
of the data that we have been provided
here, slide
10 where we looked at naproxen exposure
data with
millions of doses and the sponsor
basically said
there is no safety signal for
cardiovascular events
or MIs.
I guess if we were looking at rare events,
Stevens-Johnson's rash or something like
this, this
kind of evidence could be
reassuring. But how is
reassuring when we are looking at MIs and
strokes
where you expect to see a certain rate of
these in
natural history? How do we rule out a doubling?
So, essentially it leads me to really
wanting to
532
focus on the randomized trials as having
a sense.
Looking at slide 17, I am
worried about
how little of this information is longer
term
exposure.
So, if I am understanding correctly, we
really have TARGET and VIGOR and ADAPT as
maybe the
best bases for making an assessment over
a longer
term in a truly controlled fashion for
effects on
cardiovascular-related major events--cardiovascular
death, strokes and MIs. Two of those, VIGOR and
TARGET, we don't have a placebo
control. The
questions that were just raised I think
by Charlie
Hennekens are in VIGOR--basically how do
you make
an assessment there without a placebo
control?
ADAPT is a placebo control.
We heard just now that the data
monitoring
committee specifically didn't stop the
trial on
12/10/04.
By my notes earlier this morning, I
thought we were told that the data
monitoring
committee on that date did stop the trial
due to
naproxen GI bleeds, cardiovascular and
cerebrovascular events. So, I am a little confused
about what actually did happen. Is it true at this
533
point though that we don't have
first-hand access
to what the data actually are in ADAPT?
DR. HUBER: Let me answer your first
comment about the randomized clinical
trials.
Basically what you said was that the
TARGET and the
VIGOR studies are the large randomized,
comparative
trials.
There is also the Alzheimer's study which
is obviously much smaller but it is one-year
follow-up.
With regard to the
postmarketing data, we
recognize the limitations. We were just wanting to
reassure you that there hadn't been
numerous case
reports out there. Also, when we look at
disproportionality there is really no
signal there.
It is something we use in postmarketing
surveillance.
I would be careful on the
observational
studies.
Recognizing the limitations as stated,
that does give us a large number of
patients who
have been exposed to naproxen and gives
us some, we
believe, important data. There are 80,000
exposures in that series of observational
studies.
534
So, we do believe there is some weight to
that
evidence.
It shouldn't be completely put aside.
DR. FLEMING: And the weight you are
placing on that is you are reassured
about what
specific outcomes?
DR. HUBER: That for MI, for myocardial
infarction with 11 observational studies,
we see a
consistency of finding that is at 1 or
lower.
DR. FLEMING: But doesn't the fact that we
have 11 of those give us a more precisely
biased
estimate?
How do you know that all 11 aren't in
fact subject to the same type of
systematic bias
and under-detection?
DR. HUBER: Well, we use multiple
databases. There are different comparisons. There
are past users in several of the
studies. I guess
the question is if we take that approach,
then we
have to question should we even do
observational
studies for any issue?
DR. FLEMING: Not necessarily. It depends
on what you are looking for. My comment was if you
are looking for MIs and strokes, which
are events
535
that would in fact occur in natural history,
unless
you are looking for a ten-fold increase,
isn't it
really difficult for that type of outcome
to truly
be able to rule out a relative risk of
1.5? I
would argue, yes, it is. While there are other
things that were reassuring, if we wanted
to be
reassured about stroke and MI, this is
where it is
intrinsically the most difficult.
DR. HUBER: I agree you.
I don't think we
should rule things out on the basis of
the
observational data, but I think what is
important
is when we looked at this a priori based
on
mechanism of action, etc., the data was
telling us
there was probably not an increased
risk. So, when
we take that as the first line of
evidence and then
we put on the additional lines of
evidence, at this
point in time the only data suggestive of
an
increased risk, to our knowledge, is the
release of
the preliminary findings of ADAPT.
DR. FLEMING: Can you clarify that?
Because I believe we heard something
different this
morning about what actually has been
stated. Can
536
you clarify what actually has been stated?
DR. HUBER: What we are talking about is
the NIH press release. I believe there were
approximately 70 cases, and what was
stated about
it was that there was--I can't remember
the exact
wording of the text, but it was an
increased risk
of stroke or MI.
DR. WOOD: Well, we are going to hear
about that on Friday morning.
DR. FLEMING: So, we will hear about it on
Friday?
DR. WOOD: Yes, unless we keep talking
until then, I guess. It is down for 8:10 on Friday
morning.
Other questions? Yes?
DR. MORRIS: Dr. Huber, while you are
there, did any of the observational
studies
stratify by time on drug? And, was there any
different finding by length of time on
Naprosyn?
DR. HUBER: I am going to have to look to
my epidemiologists? Dr. Thacker is the
epidemiologist for Roche.
DR. THACKER: We did an extensive
537
literature review of all the studies that
were
published up to December, 2004. None of the
studies really gave us any data on
duration of use.
DR. WOOD: Other questions? Yes?
DR. WITTER: I just want to make the point
that in the ADAPT trial naproxen was the
OTC dose.
DR. WOOD: Any other questions or are we
finally getting exhausted? Yes, Ralph?
DR. D'AGOSTINO: Just because we are
exhausted, that doesn't mean that what
was
presented is, in fact, something we can
buy. I
think the comments that Tom is making are
very
important. We have all this meta-analysis. We
don't know anything about those
studies. So, I
think we have to wait until we hear from
the NIH.
DR. WOOD: Right.
Dr. Seligman has
something to say?
DR. SELIGMAN: Just a very brief
announcement to the Drug Safety and Risk
Management
Committee. We would like to meet in the lobby at
eight o'clock and all go out for dinner
if you are
still willing.
DR. WOOD: Before we break, do the FDA
have any final comments or
questions? No? In that
case, we will meet promptly at eight
o'clock and
538
start dead on time. See you tomorrow.
(Whereupon, at 7:30 p.m., the
proceedings
were adjourned, to reconvene at 8:00
a.m.,
Thursday, February 17, 2005.)
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