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 III
Hilton
2
P A R T I C I P A N T S
Alastair 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:
Steven Abramson, M.D.
Ralph B. D'Agostino, Ph.D.
Robert H. Dworkin, 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.
National Institutes of Health
Participants
(Voting):
Richard O. Cannon, III, M.D.
Michael J. Domanski, M.D.
3
P A R T I C I P A N T S (Continued)
Guest Speakers
(Non-Voting):
Garret A. FitzGerald, M.D.
Ernest Hawk, M.D., M.P.H.
Bernard Levin, M.D.
FDA Participants:
Jonca Bull, M.D.
David Graham, M.D., M.P.H.
Brian Harvey, 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.
Steve Galson, M.D.
Kimberly Littleton Topper, M.S.,
Executive
Secretary
4
C O N T E N T S
Call to Order:
Alastair J. Wood, M.D. 5
Conflict of Interest Statement:
Kimberly Littleton Topper,
M.S. 5
Naproxen
Investigator Presentation
Alzheimer Prevention Study: ADAPT
(Alzheimer's Disease
Anti-Inflammatory
Prevention Trial):
Constantine Lyketsos, M.D. 14
Additional Background Presentations
Interpretation of Observed
Differences
in the Frequency of Events When the
Number of Events is Small:
Milton Packer, M.D. 42
Clinical Trial Design and Patient Safety:
Future Directions for COX-2 Selective
NSAIDS
Robert Temple, M.D. 95
Issues in Projecting Increased Risk of
Cardiovascular Events to the Exposed Population
Robert O'Neill, Ph.D. 109
Summary of Meeting Presentations:
Sharon Hertz, M.D. 132
Sponsor Responses 140
Advisory Committee Discussion of
Questions 147
Question
1: 165
Question 2: 284
Question 3: 320
Question 4: 356
Question 5: 367
Question
6: 391
Question 8: 418
Question 7: 432
Meeting Wrap-up 438
5
P R O C E E D I N G S
Call to Order
DR. WOOD: Let's get started. This is our
third day and thanks to everybody for
coming back.
We have obviously entertained you
sufficiently.
Kimberly has a statement to
read.
Conflict of Interest
Statement
MS. TOPPER: The following announcement
addresses the issue of conflict of
interest with
respect to this meeting and is made a
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 involve many
industry
sponsors in 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 an conflict of
interest
existed, the agency has reviewed the
agenda and all
relevant financial interests reported by
the
6
meeting participants. The Food and Drug
Administration has granted general-matter
waivers
to the special government employees
participating
in this meeting who require a waiver
under Title
18,
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 some
potential
conflicts of interest but, because of the
general
nature of the discussions before the
committee,
these potential conflicts are mitigated.
With respect to the FDA's
invited industry
representatives, we would like to
disclose that Dr.
7
Annette Stemhagen is participating in
this meeting
as a non-voting industry representative
on behalf
of regulated industry. Dr. Stemhagen's role on
this committee is to represent industry
interests
in general and not any one particular
company. Dr.
Stemhagen is Vice President of Strategic
Develop
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 an FDA participant has a
financial
interest, the participants' 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.
There is one administrative
announcement.
Would you please make sure that you take
your phone
calls outside. It is messing up with our audio and
we would really appreciate it. Thank you.
DR. WOOD: The other administrative thing
8
that the sound person has asked me to say
is, to
the committee, try and remember to switch
off your
microphones when you are not using them.
Apparently, it messes it up.
MR. LEVIN: Mr. Chairman?
DR. WOOD: Yes, Arthur?
MR. LEVIN: I wanted to express a concern
I have in terms of the agenda for today's
meeting.
For those of us who have been at advisory
committee
meetings before, we know that there is
often a
tendency to sort of squeeze the most
important part
of these advisory committee meetings
which is the
discussion and answers to the questions
and giving
directions to FDA.
My concern is that, given the
lengthy
discussions we have had over the past two
days and,
given the fact that this is last day,
that we will
not have enough time to fully explore all
of the
questions that have been raised over the
last two
days and to give some definite direction
to the FDA
as to how to pursue these issues.
So I would like to suggest to
the group
9
that we might shorten the presentations,
or
eliminate them entirely, in order to have
adequate
time to fully discuss all of our concerns
and
different points of view around the
table. I think
it would be really unacceptable to leave
here today
unable, because of a time constraint, to
give
direction to the FDA on this issue.
DR. WOOD: Did you have any particular
people you wanted to eliminate? Or do you want to
pass me a note, privately?
MR. LEVIN: It may be something the
committee as a whole should decide.
DR. WOOD: Let me make a suggestion. I
think that is a reasonable approach. I am sure the
committee will want to hear the data from
the ADAPT
study and we should hear that in its
totality.
Milt Packer has come a long way so we
should hear
from him, I think. Milt is always entertaining,
anyway.
Do we really need to hear from
the two
Bobs?
DR. TEMPLE: I don't have any ego involved
10
in this.
A fair amount of--some of what I am
talking about is about the adverse
consequences of
blood-pressure elevation which I think I
could
skip.
So I could shorten it considerably.
But you
guys decide. It is there for you to read if you
want.
DR. WOOD: Why don't you do this. Why
don't you distribute your talk to us.
DR. TEMPLE: I think it has been.
DR. WOOD: Right; I understand that. I
will take that as a given. And both of you make
whatever remarks you would like to make
from your
seats there at the times that you are
allotted, but
brief and pointed. And let's not revisit all the
things we have visited before.
DR. TEMPLE: That's fine.
DR. WOOD: Does that sound fair? Dr.
O'Neill?
DR. O'NEILL: Yes; that is fine.
DR. WOOD: That will save us some time.
So that is a good thought. In addition, we have
got Sharon Hertz's talk which, I notice,
has
11
40-something slides here--45
slides--which is a lot
to get through in a few minutes. So I think, while
we are sort of working up to that, she
may want to
look at that and decide what she really
needs to
say.
I mean, after all, it is very unusual for the
FDA to summarize the meeting for the
committee,
which is partly what the committee is
here to do, I
guess.
So let's make sure that she can
finish
that taking the time she has been allotted for it
which is 30 minutes. She would be better to remove
some slides rather than rush through it,
I think.
Having said all that, let's get
to the
first presentation. Does anyone else have any
thoughts on that? Yes, Annette?
DR. STEMHAGEN: I would like to ask
whether the manufacturers could have just
one or
two minutes to make some summary comments
before we
start our deliberations after lunch.
DR. WOOD: Do they want to do that now?
Is that what you are asking?
DR. STEMHAGEN: No; I think after these
12
presentations.
DR. WOOD: Okay.
DR. STEMHAGEN: Thank you.
I appreciate
it.
DR. WOOD: Let's have some discussion
amongst the committee.
DR.
their having--they have had lots of time
already to
present their data and had lots of mike
time in the
back already.
DR. STEMHAGEN: Just in terms of the
deliberations that have gone on, there
might be
some clarifying comments.
DR.
we can ask for clarifying comments. I think that
is
what we--I would suggest--and I agree with
Arthur Levin in that we should get on to
discussion
as quickly as possible.
DR. STEMHAGEN: I realize this is sort of
in contrast to try to shorten it. But I would like
to ask that that time be awarded.
DR. WOOD: Any other thoughts on that?
13
Let me get a sense of the committee. What is the
committee's pleasure about that? Yes?
DR. BOULWARE: I actually support that
recommendation, too, and would suggest
you give
them a limited time, like you did with
the public
comment where you will cut them off at
two minutes,
so we know it will be limited. I would be
interested in the direction they plan to
take. We
heard some startling news yesterday about
the
possible remarketing of a product that
they have
withdrawn.
DR. WOOD: Does anyone object to them
getting two minutes apart from Dr.
think, the answer on that is that that is
fine.
Remind them that, in contrast to most of
their
experiences in the past for senior
managers, the
microphone will be cut off.
DR. STEMHAGEN: Thank you very much. I
think we saw evidence of that yesterday.
DR. WOOD: Right.
So they got the
message; right? Okay.
Let's move along to the
first speaker, Dr. Lyketsos.
Investigator
Presentation
Alzheimer's Prevention Study:
ADAPT
DR. LYKETSOS: Good morning, everyone. I
14
do not have slides. My name is
Lyketsos.
I am a professor at
presenting here today on behalf of the
ADAPT study,
Alzheimer's Disease Anti-inflammatory
Prevention
Trial.
I would like to thank the committee for
inviting us to present. I am here today with my
colleague, Steve Piantadosi, who is also
on the
steering committee and will be available
to answer
any questions that might come up later on
as well.
I have a prepared statement
that will be
distributed to the committee later on
today. I
delivered it to the staff this morning as
I was
arriving.
Before I get into the
statement, I just
wanted to take a few moments to remind us
of the
public-health importance of Alzheimer's
disease to
somewhat set the context about how the
ADAPT trial
has started specifically. Alzheimer's, as we all
know, is a major public-health
problem. It is a
15
devastating disease, typically runs a
ten-year
course of neurodegeneration affecting
probably
close to 4 or 4-and-a-half million of our
citizens
at present and the number is expected to
rise given
the aging of the population of the next
several
decades to approach, perhaps, 12 to 15
million,
based on current projections.
Because of the these
public-health
numbers, there has been a very
significant effort
in our field for the last several years
to develop
preventive strategies for Alzheimer's
disease
because, once neuronal degeneration has
started,
the evidence that treatments work, so
far, is very
weak.
These preventive strategies
have centered
on several possible treatments but the
most
supported by the observational literature
have been
nonsteroidals with over 24 studies right
now
including four prospective population
studies
suggesting substantial reductions of risk
of
Alzheimer's disease perhaps with risk
ratios, in
some cases, as much as 0.4 or 0.5. So it is within
16
that context that ADAPT was started with
the
support of the National Institute of
Aging.
I will move now to reading the
prepared
statement.
The steering committee of the
ADAPT study
welcomes the opportunity to present the
rationale
for its decision, on
the NSAID treatments in ADAPT. This presentation
is important because there is much public
misunderstanding about our decisions and
their
rationale.
The ADAPT Steering Committee is
deeply
committed to the safety of human
subjects, even
more so in the context of prevention
trials where
risks are typically not balanced by any
promise of
tangible near-term benefit. In this notable way,
prevention trials differ from treatment
trials
whose participants may hope for relief of
symptoms
or improved outcomes in a condition
already
diagnosed.
The risk:benefit balance in prevention
trials is even further removed from a
comparison of
17
the benefits of a proven treatment with
its
acknowledged risks. Because ADAPT has not quite
completed the process of auditing and
tabulating
the trial's cardiovascular safety on the
date of
suspension, we cannot, today, present the
trial
safety results at the time of the
decision to
suspend.
We defer that presentation to a
peer-reviewed publication planned for the
near
future.
For today, we note that, even with the
risk:benefit calculus of a prevention
trial, these
data would not, in themselves, have led
to our
decision to suspend either
treatment. In reality,
those decisions were made in very unusual
circumstances. They reflected events external to
ADAPT that raised strong concerns about
the
practicalities of continuing the
treatments.
As the advisory committee
probably knows,
ADAPT is a randomized, double-masked,
multicenter
trial of celecoxib, 200 milligrams twice
daily, or
naproxen sodium 220 milligrams twice
daily versus
placebo for the primary prevention of
Alzheimer's
18
dementia and for the prevention of
age-related
cognitive decline which is, in many
instances, a
prodrome of Alzheimer's disease.
ADAPT also provides an
opportunity to
study the long-term safety of its
treatments in a
healthy elderly population. Eligibility criteria
include an age of 70 years or older at
enrollment
and a health history that excludes many
of the
known risk factor for adverse events with
NSAID
treatments; for example, we exclude those
with
preexisting uncontrolled hypertension,
anemia or a
history of gastrointestinal bleeding,
perforation
or obstruction.
To provide independent
recommendations
regarding continuation of the trial, the
ADAPT
Treatment Effects Monitoring Committee,
or TEMC,
which, I suppose, is our term for a DSMB,
meets
twice a year. In response to emerging concerns
about cardiovascular risks with NSAIDs,
membership
of the TEMC was recently expanded to
include Dr.
Bruce Psaty, a physician with expertise
in
evaluation of cardiovascular risks in
clinical
19
trials.
As an additional safeguard for
participant
safety, the ADAPT study officers and
consultants
also conduct reviews of safety data at
intervals
between TEMC meetings. Amid the emerging
controversy about the cardiovascular
safety of
selective COX-2 inhibitors, the ADAPT
study officer
had been relatively reassured by their
periodic
reviews of the celecoxib safety data. The
study
chair communicated this information in a
telephone
conversation on
Hertz at FDA.
As of
suspension of treatments and enrollment
in ADAPT,
we had enrolled 2,528 participants. Of these,
2,463 had been randomized before October
1 of '04
with some 20 months average duration of
observation. These participants contributed a
total of 3,888 person years of follow up
to
analyses that were presented to the TEMC
on
Those analyses suggested a weak
signal
20
suggesting increased risks of
cardiovascular and
cerebrovascular events with
naproxen. Reviewing
the data, however, we understood well the
TEMC's
evident conclusion that this signal was
not
sufficiently compelling or definitive to
warrant a
recommendation to suspend the treatment
or to
otherwise alter the protocol. This was on December
10, 2004.
Thus, the study officers were
surprised on
December 17 by announcements that two
trials of
celecoxib for the prevention of recurrent
adenomatous colon polyps had been
suspended citing
increased cardiovascular risks with
treatment in
one of these studies, the Adenoma
Prevention with
Celecoxib trial, or APC. This news led to
extensive discussion among the steering
committee
on that day centering on the following
considerations.
Number one; one arm of the APC
trial had
used the same celecoxib dosing as ADAPT,
200
milligrams twice daily, but over a longer
period of
time.
News reports cited a relative risk of 2.5
21
for cardiac events in this arm of
APC. Although
this risk was reported as only
"marginally
significant," a greater cardiac-risk
signal was
reported with the higher APC dosage of
400
milligrams twice daily.
Thus, we took seriously the
possibility of
harm over time to ADAPT participants
receiving
celecoxib. Especially in a prevention trial with
no strong prospects of immediate benefit,
we had
strong misgivings about continuing
celecoxib
treatments.
Knowing almost nothing at the
time about
the
particulars of the APC trial and, in light of
the apparent lack of risk with celecoxib
in the
other prevention trial, we might have
discounted
the APC data and continued
celecoxib. To do so,
however, we would clearly have needed the
concurrence of the seven IRBs that
oversee ADAPT.
These IRBs began almost immediately to
question us
about implications of the APC results and
seemed
likely to question a decision to
continue.
Even if we had persuaded them
to permit
22
continuation of celecoxib using a revised
consent
process, we would surely be involved in
lengthy
discussions with these IRBs. In the meantime, we
would be unable to offer much explanation
to our
participants, thereby endangering the
relationship
of trust that is vital to the success of
long-term
trials.
Number three; as is common in
long-term
trials, ADAPT was experiencing some
difficulty with
adherence to treatments. This difficulty grew
following the withdrawal of rofecoxib and
we
expected the announcement of the APC
results to
exaggerate the problem further with
scores of
participants stopping treatment, in
effect, "voting
with their feet." This would erode statistical
power and increase the potential for bias
in ADAPT.
Thus, even though the ADAPT
safety data
did not, themselves, warrant suspension
of
celecoxib treatments. There seemed little
practical choice but to do so.
We next confronted the dilemma
of what to
do about naproxen and its placebo. As suggested
23
above, we regarded the accumulated
naproxen safety
data as being somewhat more concerning
than the
celecoxib safety data. Yet, they, also, were not
compelling. Although some post hoc data composites
barely reached statistical
significance--these are
post hoc data composites barely reached
statistical
significance for naproxen versus placebo,
no
singular vascular event was clearly more frequent
with naproxen versus placebo.
Furthermore, vascular risks
were not
expected with naproxen treatment. In fact, a
substantial body of prior data at the
time had
suggested that naproxen offers some
cardiovascular
protection. This lack of prior expectation cast
further doubt on the meaning of the
naproxen data
in ADAPT which were vulnerable, in any
case, to the
problem of multiple comparisons.
We could, therefore, have
attempted to
have revised ADAPT to a two-armed trial
of naproxen
versus placebo, instructing our
participant to stop
taking their "white pills," as they are known in
the study, which are celecoxib and its
placebo, but
24
continue to take their "blue
pills," which contain
naproxen and its placebo.
However the dangers were
several.
Participants might end up getting confused
and
taking the wrong pills and many would
stop taking
their treatments altogether. We faced an ethical
dilemma.
The suspension of celecoxib and
continuation of naproxen would have
created the
impression among participants and among
the general
public that celecoxib was risky but
naproxen was
"safe." At least based on the signals from the
ADAPT data, this impression would have
been
misleading.
What would we then tell participants
about
the risks with naproxen as we led through
the
inevitable process of revised consent
necessitated
by the protocol revision. Would the multiplicity
of IRBs even allow us to follow this
course?
Finally, there was another risk
to
consider.
We began ADAPT expecting to see some
increase with naproxen in
gastrointestinal bleeding
and other events. Even though we attempted to
25
reduce these excess G.I. risks by
excluding
participants with prominent risk factors
other than
age, the ADAPT data showed a notable
increase in
G.I. bleeding with naproxen versus
placebo.
Especially amid concerns that
ADAPT was
exposing its participants to potential
risks that
were immediate, while the trial's
hoped-for
benefits lay in the future, the totality
of the
above arguments lead the steering
committee to
suspend both treatments and to also
suspend
enrollment into ADAPT.
As noted above, we expect,
within a few
weeks, to submit a scientific paper for
peer review
and publication. The paper's focus will be on the
process and rationale underlying the
decision to
suspend treatments and enrollment in
ADAPT.
Because these decisions did rely, in some
measure,
on the ADAPT safety data as of 10
December, the
paper will, also, disclose some of these
data.
We are also cooperating with
ongoing
efforts at the NIH to investigate the
cardiovascular and cerebrovascular risks
of NSAIDs.
26
In addition, the NIA and the ADAPT
Steering
Committee are committed to a further two
years of
additional safety monitoring of our
participants.
In preparation for a later,
more
definitive discussion of the ADAPT safety
data, we
plan to revisit a number of the adverse events to
collect additional information and then
to submit
all information available now or later to
a process
of expert adjudication. Depending on particulars,
the latter process will take months. In the nearer
term, we concur with the expert opinion
that,
having taken these widely publicized
decisions, the
steering committee must fulfill its
obligation to
disclose its reasons for doing so based
upon the
data available.
At the same time, we are intent
that our
public presentation even of the current
"working"
data must be at the highest attainable
standards of
accuracy.
Thank you.
DR. WOOD:
Thank you very much. Are there
questions directed to the speaker? Dr. Nissen?
DR. NISSEN: I fully understand your
rationale and I understand that the trial
was
fundamentally stopped because of an issue
of
27
futility.
You didn't think that you could keep
people in the celecoxib arm. That is all well and
good.
The problem that occurred here is that a
warning was issued on naproxen which had
the effect
of being the medical equivalent of
screaming "fire"
in a crowded auditorium.
All over the country, many of
us got calls
from patients saying, "I want to
stop my naproxen
because it causes a cardiovascular risk." I think,
just a comment here, that it would have
been far
better to have announced that the trial
was
suspended for futility rather than for
hazard when
there was a non-statistically significant
hazard.
So, one man's comment.
DR. WOOD: I agree with that. Any other
comments?
Yes?
DR. FARRAR: I wonder if you could comment
on the G.I. bleed component since,
obviously, one
of
the deliberations we have to undertake is the
28
relative problems with G.I. bleed versus
cardiovascular risk. Certainly, that was known a
priori before starting the study.
As you commented very
carefully, that
wasn't the only consideration. But, in a drug
trial where the outcome is unknown and
the risk is
really fairly well known, I wondered how
you
thought about that in terms of putting
patients at
risk of something on the order of a few
percentage
over the course of a five-year trial who
might have
serious complications from the G.I.
bleeding.
DR. LYKETSOS: I guess you are asking me a
human-subjects question.
DR. FARRAR: I am asking how, in the
design of the study, obviously the choice
was made
to accept that risk for the unknown
potential
benefit of reduction in Alzheimer's
disease over
the course of the same trial. I am wondering if
you have any insights into how that
decision was
made because, clearly, there are issues
there about
the use of these drugs and their risks.
DR. LYKETSOS: Well, I am glad you are
29
asking the question. It certainly is an issue that
we have spent a lot of time discussing
and which we
discussed with study sections, IRBs, at quite
some
length and continue to discuss.
I think the fundamental point
that I would
start with is where I started my
presentation which
is the devastation that Alzheimer's
disease brings
and the fact that all the study
participants were
individuals who had a first-degree
relative with
the disease and had, therefore, personal
experience.
In that context, we were very
careful and
very clear with them about what we thought
at the
time the known G.I. risks were so that,
in the
process of consent, and that was revealed
through
careful discussions in the consent
process as well
as the consent form, the risk of G.I.
bleed was
stated very clearly and that that, in
some cases,
might lead to death.
So I think we felt that this
was a
decision that our participants could
make, given
that the risks were relatively small, and
the risk
30
that they would develop Alzheimer's
disease was
higher and that we felt they could make
the
decision for themselves if they were
willing to
take the risk:benefit calculus as we saw
it.
DR. WOOD: Dr. Gibofsky?
DR. GIBOFSKY: I share Dr. Nissen's
concern about this effect of crying fire
in a
crowded theater. Many of our patients called and
suggested that they were going to stop
their
celecoxib because of the concerns that
were raised
from ADAPT as well. But you raised a very
interesting concern that I confess I
hadn't given
enough thought to and that is the
difference
between a prevention trial and an outcome
trial.
Much of our discussion here
later today, I
suspect, is going to focus on what action
should be
taken, if any, to restrict drugs based on
treatment
from data on prevention trials. I would be very
curious to hear you expound on that a bit
more.
DR. LYKETSOS: That is an interesting
question.
Let me just, if I could, because there
have been three comments now--I just
would like to
31
refer you to the early part of my
statement where I
said the presentation is important
because there is
much public misunderstanding about our
decisions
and their rationale.
Several of you pointed out that
there was
a cry of fire. I don't believe that that came from
the study.
DR. WOOD: We won't ask you to speculate
where it came from. There is certainly a view on
that.
DR. LYKETSOS: I am not sure where it came
from.
But, to address the other issue, I must say
I have not given it much thought as to
whether
prevention-trial safety data would
generalize in
the way that you are thinking about
it. So I will
defer on that because I think it would
need a fair
bit more thought by people who are more
expert in
that.
DR. WOOD: Dr. Fleming.
DR. FLEMING: It is my understanding, from
what you are saying, that the steering
committee
was particularly influenced by the APC
prior data
32
not by the internal data from ADAPT;
i.e., there
were, from you were describing, some
emerging
trends that, in my words, were in the
unfavorable
direction but in the context of
monitoring trials,
we know that one has to be extremely
cautious, when
you are looking at data continually over
time, not
to overinterpret emerging trends that can
easily
ebb and flow.
So my understanding, from what
you are
saying, is it wasn't that there were, at
this
point, some emerging trends that happen
to be in
the unfavorable direction on
naproxen. Rather, it
was the external data on the APC trial
for Celebrex
that was the driving issue behind the
recommendation.
DR. WOOD: Just to develop that question,
what I understood you to say was you
hadn't passed
some stopping boundary; is that correct?
DR. LYKETSOS: I'm sorry?
I didn't hear
the first--
DR. WOOD: You hadn't violated your
stopping rule, or whatever stopping
rules, you had
33
for safety.
DR. LYKETSOS: I think that our TEMC, our
DSMB, had opined the week before with the
same data
from within the trial that they felt that
we should
continue.
So it was interesting how the two events
were back-to-back.
DR. FLEMING: I would like to come to that
second.
I am leading to that. But first I
wanted
to make sure that I understood what was
the nature
of the concern. Is my interpretation correct?
DR. LYKETSOS: I think so.
Back to how I
put it, the issue really was one of
practicalities
more than our internal data, is that we
felt we
would have to talk to IRBs and
participants and
tell them something about--
DR. FLEMING: Could I first understand
what your sense of the evidence was. I want to
discuss that first, versus the
practicality.
DR. LYKETSOS: The sense of the study
evidence.
DR. FLEMING: The sense of the evidence
that was the basis for the decision in
terms of
34
adverse effects. I have heard two things. One is
the naproxen, but that was not compelling
evidence.
That was within the framework of emerging
results
that could be by chance alone when you
are
monitoring data frequently. But external APC data
was very influential to you. That is what I am
hearing.
Is that correct?
DR. LYKETSOS: Well, in fact, we didn't
know all the details of the APC data, as
I pointed
out.
I think it was that plus the climate that had
been created by rofecoxib coming off the
market,
the influence that that had to some
extent on our
participants, then the widely publicized
APC
results and the sense that, even though
the data we
were seeing and that our TEMC the week before had
seen, did not compel us to stop treatment
based on
our own data, that there was now a
climate created
where, practically speaking, we had to
stop and
take stock and get more information, et
cetera.
So it was that sort of the
decision. I
was a complicated decision and that is
why it takes
a three-page statement to try and explain
what went
35
through our minds.
DR. FLEMING: There may not have been, to
the steering committee at this time,
access to data
on PRECEPT for celecoxib or to the
etoricoxib, the
lumiracoxib, data on naproxen that were
very
favorable, but you did have access to the
VIGOR
data which was very reassuring for
naproxen and you
had evidence from the CLASS trial and
some other
data from Celebrex.
I am perplexed that you would look
at the
totality of these data and say that the
results
were conclusive in terms of at least not
being able
to provide information to the IRBs and to
the
patients and caregivers in the trial
representing
the totality of the data when your
data-monitoring
committee had looked at the totality of
the
evidence for benefit to risk.
On a data-monitoring committee,
I have
always argued, don't just show me the
safety data,
even if we are just looking at early
assessments
for safety. It always has to be benefit to risk.
Even though, as you are pointing out,
this wasn't a
36
therapeutic setting, prevention trials
also provide
major opportunity for benefit. Preventing major
diseases is also a very significant
benefit.
My understanding is your
data-monitoring
committee, in looking at the data,
looking at the
benefit as well as the risk, indicated the
study
should continue. How did the steering committee
judge, without access to ongoing data,
that benefit
to risk couldn't be sufficiently
favorable and that
a notification to the investigators, to
the
patients and to the IRBs, that the
monitoring
committee has carefully looked at benefit
and risk
and that the totality of the data is
beyond the APC
trial when you are looking at Celebrex
and
naproxen?
Why wasn't that strategy pursued?
DR. LYKETSOS: First, as I pointed out in
my statement, some members of the
steering
committee did have access to the data
that the DSMB
had seen.
That is the first point. The second
point is, as you point out and as I think
this
whole discussion points out, is these are
very
difficult judgment calls. They have to take into
37
account evidence but also practical
aspects of
continuing to conduct this sort of a
prevention
trial in this sort of a population.
I think it was the judgment
call, and I
can tell you, there was substantial
discussion
around this when we had the steering
committee
meeting, about these very issues. It was the
collective judgement at the time that
this was the
right thing to do, given the various
issues that I
have articulated in my statement.
DR. FLEMING: I will just pursue
one more.
I am dismayed to hear the steering
committee, some
steering committee members, had access to
the data.
That is also a violation of the
principles of
monitoring trials. It should have been in the sole
possession of the data-monitoring
committee.
I am also distressed because I
am not
hearing that monitoring committee was
front and
center in terms of having these issues
brought back
to
it for reassessment. So, to me, what I
am
hearing raises very significant concerns
about
putting at risk the integrity of studies
with
38
prejudgments using only access to partial
external
information.
DR. WOOD: There was one other thing,
though, at least the word on the street
was, and
you sort of mentioned that as well, I
understood
there was a very large number of dropouts
from the
trial after the Vioxx withdrawal and
others and
that one of the perceptions was it was no
longer
possible to continue the trial. Is that true?
DR. LYKETSOS: Let me clarify that. The
adherence had been declining on an annual
basis
even before rofecoxib was withdrawn from
the
market.
So adherence was perceived as an issue in
that we felt that now there were data
about one of
the study drugs and that that would
further erode
adherence. We did not see a huge erosion in
adherence with rofecoxib, specifically,
but there
had already been an erosion that was
concerning and
we anticipated a further erosion.
DR. WOOD: Right.
But the question for
this committee that Dr. Fleming is
pursuing
vigorously, and I agree with him, is that
the
39
announcement that you all made--the
announcement,
as it was picked up--maybe I should put
it like
that--was that this trial was being
stopped for a
safety signal.
What I heard in your statement
and what I
hear from you now is that the trial was
being
stopped for operational problems in the
trial and
the safety signal was a convenient moment
at which
to do that. But you had operational difficulties.
That is a very different interpretation
and a very
different interpretation for the public
and
patients.
Is that what you are hearing,
Tom?
DR. FLEMING: It certainly appears to be.
It is part of what is concerning to me.
DR. LYKETSOS: I think my statement should
speak for itself. In terms of what the data were,
as I have pointed out, they will be
submitted very
soon so that you can judge for
yourselves.
DR. WOOD: Okay.
Any other questions?
Sorry; Dr. Farrar. I beg your pardon. Dr. Farrar,
go ahead.
DR. FARRAR: I think, actually, that this
study provide some vitally important
information
with regards to our consideration of the
entire
40
class of drugs; namely, the NSAIDs. I would like
to just read on sentence from the
statement.
It said, "Although some
post hoc data
composites barely reached statistical
significance
for naproxen versus placebo." Now, clearly, this
discussion would be much clearer after
the
presentation of the data, a careful
review of the
data.
But Dr. Fleming noted that, in the VIGOR
study, there was some reassurance about
naproxen.
I would like to just question that.
What is very clear in the VIGOR
study is
that naproxen was safer than
rofecoxib. But it
does not comment at all with regards to
the
potential risk compared to placebo. In fact, I was
surprised when I heard the statement by
Dr. Fleming
because, in fact, I have assumed, based
on all the
data that we have, that every NSAID will
not fare
well against a placebo.
I think that this data, and
probably will
41
be supported by the publication although
I don't
want to try and foresee the future, but
my guess is
that naproxen will not fare particularly
well
against placebo in terms of its
cardiovascular
safety.
I think we need to be able to accept the
fact that all of them have some risk with
regards
to cerebrovascular disease and this study
is likely
to provide the data to support that.
DR. WOOD: Dr. Nissen?
DR. NISSEN: I don't want to belabor this
because we have got a lot more to discuss
today,
but I think it is extremely important
that, as a
medical community, we learn from this
episode. In
the kind of media frenzy that was going
on during
that period of time, this announcement,
this
warning that was issued on a national
basis about
naproxen, was inappropriate, led to some
panic
amongst the public and we simply can't do
business
this way.
We can't operate in this kind
of a
fashion.
I would urge any of the individuals who
were involved in the decision to issue a
warning to
42
go back and look at what happened and try
to ensure
that we don't do this sort of thing
again, because
once this gets picked up by the media, it
passes
through generations of people and becomes
the topic
of extensive discussion and may lead
patients who
don't have the ability that we have
around this
table to filter data--they don't
understand
data-safety and monitoring boards. They don't
understand stopping rules. And it caused a panic
that was unnecessary and it shouldn't
have
happened, and I hope it doesn't happen
again.
DR. WOOD: Thanks very much. Let's move
on to next speaker, Dr. Packer.
Additional Background Presentations
Interpretation of Observed
Differences in the
Frequency of Events When the
Number
of Events is Small
DR. PACKER: Thank you, Alastair, members
of the advisory committee, FDA, ladies
and
gentlemen. Today I have been invited by FDA to
address a specific question which is how
should be
interpret differences in the observed
frequency of
43
events in a clinical trial when the
number of
events is small.
Let me just say arbitrarily
that I will
define, for purposes of today, what I
mean by a
small number of events and that would
have provided
less than 70 percent power to have
detected a true
treatment difference assuming an effect
size
similar to that generally encountered in
clinical
research.
This is just a thought. Just suppose you
do a trial for a noncardiovascular
indication and
you note that there are 13 major adverse
cardiovascular events in the placebo
group and 33
such events in the drug-treatment
group. How
should this difference be interpreted?
Many would simply perform a
statistical
test, derive the p-value, and get excited
if the
p-value were less than some arbitrary
value such as
0.05.
In this example, the p-value of 0.002 would
suggest, to some, that this difference
between 13
and 33 in a trial of about 3,000
patients, would
have been observed only two times out of
1,000, an
44
effect unlikely to have been due to the
play of
chance.
However, before getting
excited, we should
remember that p-values must be
interpreted in some
context.
P-values are most easily interpreted when
they refer to predefined primary
endpoints in
trials adequately powered, more than 80,
90 percent
power, to detect differences between
treatments.
However, even under such circumstances,
p-values
are not necessarily reproducible.
Bob O'Neill and others have made the point
that, if a p-value in the trial is 0.05,
the
likelihood of seeing 0.05 in a second
identical
trial is only about 50 percent. It is only when
the p-value in the first study is 0.001 that
the
likelihood of seeing 0.05 or less in the
second
identical trial is at least 90 percent.
These calculations are the
basis of the
frequent FDA guidance that, to
demonstrate
persuasive evidence for efficacy, a
sponsor needs
to provide two trials with 0.05 or less
or one
trial with a very, very small p-value.
But what if the event was not
the primary
endpoint in the study? What, in fact, if the event
was not even precisely defined before the
start of
45
the trial? What if the trial was not adequately
powered to detect a treatment difference
for the
endpoint?
What does a p-value mean under these
circumstances?
Unfortunately, this happens
quite
frequently in clinical trials under a
variety of
circumstances. But it is particularly true in the
analysis of adverse events. So lets make a list of
things to worry about when using p-values
to
compare the frequency of adverse events
in a
clinical trial.
First, there are literally
hundreds of
adverse events in a clinical trial and,
therefore,
there are hundreds of possible comparisons
that can
be made.
Now, this is classically referred to as
the multiple comparisons problem. For example, if
a typical large-scale clinical trial
yields as many
of 500 individual terms describing
adverse events
and if a p-value were calculated for each
pairwise
46
comparison, one would, of course, by
chance alone,
expect about 5 percent of the terms, or
about 25
events, at a p-value of 0.05 or less and
1 percent
of the terms are about 5 events to have a
p-value
of 0.01 or less.
The second issue in
interpreting
comparison of frequency of adverse events
is the
fact that adverse events are spontaneous
nonadjudicated reports. Now, adverse events are
reported at the discretion of the
investigator and
then translated into standardized
terms. There is
little uniformity on how an event is
identified,
defined or reported and this uncertainty
increases
when the event is in a field remote from
the
investigator's focus.
Now, some of you may believe
that you can
fix this problem by carrying out blinded
adjudication of events after the fact.
Unfortunately, the rules guiding post hoc
adjudication are inevitably influenced by
the
knowledge that a treatment difference has
been
seen.
In fact, any bar set by a post hoc process,
47
is capable of magnifying or diluting an
effect.
For example, if you set very
strict
criteria, a committee could reduce the
number of
events and, therefore, reduce statistical
power.
By setting very loose criteria, the
committee can
include many questionable events and
reduce the
magnitude of a treatment difference.
To make things more
complicated,
adjudication committees do not generally
examine
individuals who did not report an event
to make
sure they didn't have an event.
The third issue in interpreting
comparisons of frequencies is that some
signals are
apparently only if adverse events are
grouped
together.
Now, that is not much of a problem if
the difference is fairly straightforward
and
focuses on one single event. But things can become
a little bit more complicated if the
analysis
requires a combining event and combining
trends
across two or more events in order to
reach some
magical level of statistical
significance.
Now, the problem is that these
groupings
48
are frequently constructed after the
fact, making
it possible to include only events that
showed the
trend the investigator is interested
in. For
example, if an investigator believed the
drug
increased the risk of a major
cardiovascular event,
he or she might first look at myocardial
infarction
and stroke, but, finding little
difference here, he
or she might be tempted to look at other
related
events; for example, not seeing a difference
in
myocardial infarction, an investigator
might be
tempted to broaden the definition of a
myocardial
ischemic event to include sudden death or
unstable
angina if the differences between the
groups
supported some predetermined judgment.
Similarly, not seeing a
difference in
stroke, an investigator might be tempted
to broaden
the definition to include a TIA. But the
possibilities of grouping is very, very
large and
the possibilities of finding something,
if you want
to be creative, are also quite large,
even though
these differences may be related to the
play of
chance.
As a result, the definition of
grouping
may vary from study to study. Now, some
investigators try to fix this problem by
setting up
49
a uniform definition to be used across
all studies.
But when the definition is developed
after a
concern has been raised, those creating
the
definition have frequently already looked
at the
data or have communicated with those who
have
looked at the data, and know either
consciously or
subconsciously what kind of definition is
required
to capture the events of interest.
The fourth, and what I want to
focus on
the most in my presentation, is the issue
of
interpreting comparisons of frequency of
adverse
events because the number of adverse
events is
small and, because they are small, they
result in
extremely imprecise estimates.
Now, you may think that
investigators
generally understand the difficulties of
analyzing
small numbers of events. For example, most
investigators know that, when the number
of events
is small, the lack of an observed
difference does
50
not rule out the existence of a true
difference.
We have been taught that this should be
apparent by
looking at the confidence interval and,
as you can
see here, the confidence interval is very
wide and
includes the possibility of benefit and
harm.
So investigators, basically,
consider
these kind of data to be
inconclusive. But what is
generally not appreciated is that, when
the number
of events is small, the confidence
interval is
necessarily so wide that it may not truly
represent
the range of values that would include
the true
effect of the drug. As a result, even the finding
of an observed difference does not
necessarily
prove the existence of a true difference.
To illustrate this point, this
slide shows
the effect size and confidence intervals
required
to reach statistical significance in a
hypothetical
trial of 3,000 patients assuming a range
from a
very small to a very large number of events.
Now, assuming the trial shows a
statistically significant effect--that
means that
we are only going to look at this if a
p-value,
51
let's say, is less than 0.05--the smaller
the
number of events, the larger must be the
treatment
effect in order for this effect to be
statistically
significant and the wider the confidence
intervals
have to be.
Put it another way, if the
number of
events is small, the trial will show a
significant
difference only if the treatment effect
is very
large and the estimate of the effect is
very
imprecise.
Unfortunately, when you look at
adverse
events in a trial, the number of events
will always
be small.
This is because the trial, as you know,
was designed to provide enough data to
examine the
primary endpoint, the trial produces a
very precise
estimate of, but it is not powered to
look at any
other analyses and, therefore, at the end
of the
trial, you get generally a less precise
estimate of
the secondary endpoint and an extremely
imprecise
estimate of any specific adverse event.
Now, you may ask, what is wrong
with an
imprecise estimate? Well, imprecise estimates are
52
fine if the intent is to withhold
judgement until
more data are collected to make the
estimates more
precise.
But imprecise estimates are problematic
if the intent is to stop and reach a
conclusion.
That is because, when
calculated in the
usual manner, p-values and 95 percent
confidence
intervals are most easily interpreted in
the
context of a completed experiment. Unfortunately,
the adverse-event data generated in a
typical trial
is not the result of a completed
experiment. In
fact, viewed from the amount of data
needed for a
precise estimate, the adverse-event data
in a
single study only represents a snapshot
of an
ongoing experiment to characterize the
safety of
the
drug.
As a result, performing an
analysis of
adverse-event data is akin to performing
an interim
analysis of primary endpoint data in an
ongoing
clinical trial. Now, this is important because we
know a fair amount of how to interpret
interim
analyses in a clinical trial and here I
really must
apologize to Tom Fleming because what I
am going to
53
review here very quickly is borrowed
heavily from
his extensive work in this area.
But it is really important to
think about
small numbers of adverse events as an
interim look
on a global effort to characterize the
safety of a
drug.
Now, as you know, when you look at interim
analyses in a clinical trial, one plots
the
treatment difference represented by a
z-score
against the amount of information that we
have, and
that is generally represented by the
fraction of
expected events.
We start the trial at zero
effect and zero
information. At the end of each interim analysis,
we add a point until we get to get to the
end of
the study. Now, if we have assigned an alpha of
0.05 to the endpoint, we want to make
sure that we
evaluate the treatment difference seen at
the end
of the trial against an alpha of about
0.05 which
generally corresponds to a z-score of
about 2.0.
Now, some might think, naively, that,
during the course of a study, the
observed
54
difference between treatments will be so
predictable that we would observe a
linear march
between the start of the study and the
end of the
trial.
But know that when the amount of data is
small, things tend to bounce around a
lot, so much
so that early results can be very
misleading.
It is sort of like the
situation of trying
to predict the results of an election
when only 1
percent of the precincts have been
reported and
they are not even representative. So, as a result,
if we got excited about any difference in
z-score
more 2.0 early in the trial, we would be
getting
excited about effects that were not
likely to be
seen or sustained if we had more data
even though a
z-score of 2.0 would normally correspond
to a
p-value of less than 0.05.
In fact, the smaller the amount
of data,
the more things can bounce around a lot,
the more
it is likely that what we will be seeing
will be
due to the play of chance. Therefore, to prevent
investigators from reaching a conclusion
when the
estimates are imprecise, statisticians,
55
particularly Tom, have recommended that
investigators refrain from getting excited
about
nominally significant z-scores when the
amount of
data is scarce.
Specifically, they have
proposed that
boundaries must be crossed before we can
feel
comfortable that an effect seen early is
likely to
be present at the end of an experiment.
Now, Tom, in particular, has
proposed a
curvilinear boundary like this. There are many
other boundaries that have been performed
by
others.
But this is very, very commonly used in
the
an alpha of 0.05 for a primary
endpoint. It sort
of looks like this. Because it is curvilinear, to
be significant at the 0.05 level, the
treatment
difference must be extreme when the
amount of
information is small as would be the case
early in
the study.
However, as the trial proceeds,
treatment
differences required to conclude that
there is an
effect at the 0.05 level decreases and
become
56
closer and closer to a z-score of about
2.0 at the
end of the study.
Now, this is a very different
thought
process and a very different approach
than getting
excited about a p-value less than 0.05 no
matter
when you observed it during the
study. For
example, a z-score of 2.5--that is right
here--would be meaningful if seen at the
end of the
study but it wouldn't be considered
significant if
seen early in the study even though the
nominal
p-value at this time is less than 0.05.
Now, if the number of events is
small, the
difference would need to be far more
extreme--say,
a z-score up here--to be meaningful at
the 0.05
level.
Here is a specific
example. This is an
old cardiovascular trial. This is the Coronary
Drug Project. It was carried out more than 30
years ago.
It included a comparison of clofibrate,
a lipid-lowering drug, and placebo on
coronary
events.
At four separate times during the study,
the difference in favor of clofibrate was
57
statistically significant at a nominal p
of 0.05 or
less.
But, at the end of the trial, there was no
difference between placebo and
clofibrate. The
difference seen early in the trial was
related to
the imprecision inherent when analyzing
small
numbers of events.
In fact, if a boundary had been
used in
this study, at no time during the trial
would the
treatment effect have crossed the
boundary and led
to
the conclusion that clofibrate was better than
placebo.
Now, let me say this kind of
fluctuation
early in a study is very, very
common. There are
even examples that at treatment has been
associated
with a nominally significant adverse
effect which
later was reversed during the course of
the trial
and became statistically significant at
the end of
the study.
Now, I should mention that the
boundary
that I have shown you is a boundary with
an alpha
of 0.05.
This means, when the boundary is crossed,
the p-value for the treatment effect is
less than
58
0.05 not less than the nominal p-value
that
corresponds to the disease score that
allowed the
boundary to be crossed.
Now, for each p-value or each
alpha, there
is a separate boundary. The requirement for
strength of evidence as it becomes more
stringent,
the boundary is shifted upward and to the
right.
You might ask why am I going
through all
this.
Because analyzing data derived in an
underpowered trial raises the same
concerns as
analyzing data derived from an
underpowered interim
analysis in an adequately powered study.
The cardiovascular field is
replete with
examples of how misleading small numbers
of events
can be.
Let me give you a few examples.
For
example, in an early pilot trial, the
ACE/NEP
inhibitor, Omapatrilat, reduced the risk
of a major
cardiovascular event by 47 percent when
compared
with an ACE inhibitor. As you can see, the
confidence intervals are extremely wide
because the
analysis here was based on only 39
events.
Later, a definitive trial was
carried out
59
that recorded nearly 1900 events. There was no
difference between Omapatrilat and the
comparator
ACE inhibitor on the same endpoint in the
same
population.
Here is another example. In an early
pilot trial, amlodipine reduced the risk
of a major
cardiovascular event by 45 percent, small
p-value
but wide confidence intervals. Later, in a
definitive trial which recorded four
times as many
events, there was no effect of amlodipine
on the
same endpoint in the same population using
the same
investigators.
There are even examples when
the effect
seen in a pilot trial was reversed when
the
definitive study was carried out. Two examples.
In two pilot trials, both in heart
failure, one
with the drug Vesnarinone, one with the
drug
Losartan, both drugs significantly
reduced the risk
of death--not a minor endpoint; death--by
50 to 60
percent.
But these benefits were seen in trials
that were each recorded fewer than 50
events and
thus produced treatment estimates with
extremely
60
wide confidence intervals.
When both drugs were
reevaluated in
definitive trials that recorded ten times
as many
events, both drugs were associated with
increased
risks of death, in one case, significant
at the
less than 0.05 level.
Now, notice that the confidence
intervals
of the treatment effect in the definitive
trials do
not overlap with the confidence intervals
of the
treatment effect in the early pilot
studies. So
here we have an effect, two examples, of
an
underpowered trial that showed a significant
benefit whereas the definitively powered
study
showed significant harm.
Here is another example. This is a
meta-analysis of a small number of trials
looking
at the effect of magnesium in acute
myocardial
infarction. A meta-analysis of a number of studies
showed intravenous magnesium associated
with the
striking reduction in mortality, a 55
percent
reduction in risk of death, but wide
confidence
intervals, a very small p-value, in a
fairly large
61
study.
This effect appeared to be
reinforced
smaller treatment effect but wide
confidence
intervals and then, subsequently, in a definitive
trial that recorded 4,000 deaths, there
was a
nearly significant adverse event of
magnesium on
the same endpoint in the same population.
Now, again, please note that
the
confidence intervals of the treatment
estimate in
this definitive study do not overlap at
all, with
the confidence intervals of the estimates
in the
earlier moderately sized study, and not
at all in
the meta-analysis. Again, this is really a
reflection of the imprecision inherent in
looking
at small numbers of events.
Let me give you one final
example because
it actually deals with an adverse
effect. In an
early pilot trial with extended-release
metoprolol--this is a study that looked
at a very
small number of events, about 20 events,
showed a
three-fold increase in the risk of
hospitalization
of heart failure in the metoprolol group
compared
62
with the placebo group. Look at the confidence
intervals here. They go from about Washington to
California, very, however, nominally
significant
treatment effect.
When this trial was replicated
in a
similar population with exactly the same
drug,
exactly the same formulation, exactly the
same
dose, there was now a reduction in the
frequency of
hospitalization for heart failure. Let me just
emphasize, this was recorded as an
adverse event in
this earlier trial.
So what have we learned from
all this?
Well, a couple of thoughts. To achieve statistical
significance in an underpowered analysis,
the
effect size must be extreme and the
estimate must
be imprecise. Yet the more extreme the effect, the
more imprecise the estimate, the less
likely it
will be reproduced in a definitive
trial. That is
why I think, of all the things that we can
worry
about in looking at adverse events, the
most
worrisome is the imprecision inherent in
the
analysis of small numbers of events.
Let me just close with a few
final
thoughts.
You might ask, based on all of this,
what should we do. Well, I think the first step,
63
perhaps the most important first step, is
to
develop an approach to analyzing data in
trials
with small numbers of events which
actually
accurately reflects the true imprecision
of the
treatment effect estimate and its
statistical
significance.
Let me just emphasize one
thing, and I
just want to put this as a proposal. In no way,
would I propose this as a definitive
solution but,
to get the discussion going, this might
be an
interesting first way of thinking about
this.
The conventional way of
comparing small
numbers of events is to calculate 95
percent
confidence intervals followed by the
derivation of
the p-value. However, the conventional calculation
of the confidence intervals incorporates
into it a
z-score that the investigator designates
as the
target value for statistical
significance. For
example, most statisticians, in
calculating a
64
confidence interval, would simply use a
z-score of
about 2.0.
And they would do that because
that is the
critical value for the z-score at the end
of an
adequately powered trial with an alpha of
0.05. So
what they would do is they would take
this z-score
and they will use it to calculate the
confidence
interval.
What a lot of people, I think, fail to
realize is that this z-score is not the
critical
value for decision making if one looks
early in the
same experiment.
Early in that experiment, the
critical
value for a z-score should be determined
by the
interim monitoring boundary appropriate
for the
information content, not the z-score at
end of the
study.
Now, if one uses the boundary
z-score in
the calculation of the 95 percent
confidence
intervals, the confidence intervals here
will be
much, much wider resulting in a p-value
that will
no longer be statistically
significant. Now this
is important because everyone talks about
p-values
65
at these meetings. I showed you these data before.
Conventionally calculated, the p-value
would be
0.002 meaning the likelihood of chance
alone being
2 in 1000.
Well, if, in fact, if one
recognized that
the data here really result in a very
imprecise
estimate and one incorporates the
thinking process
of an O'Brien-Fleming boundary into this,
as a
reflection of this imprecision, then the
confidence
intervals now truly reflect the
imprecision in the
estimate and now the p-value is a lot
interesting
than it was before.
Now, the use of boundary-adjusted
confidence intervals would, I think,
appropriately
describe the great uncertainty inherent
in the
analysis of small-numbers events,
hopefully
markedly reducing the false-positive
error rate.
In spite of using a
boundary-adjusted
confidence interval, adverse effects that
are known
to be characteristic of specific drugs
would
generally remain statistically
significant.
However, this approach, and it is just a
thought
66
experiment, would not provide a way to
interpret
trends observed in imprecise data.
So, lastly, let me just
conclude with some
thoughts about what we should do with
worrisome
trends in imprecise data. The first thing we could
do is believe in those that are
biologically
plausible. However, we need to be very careful
here.
Everyone knows physicians can always be
relied on to propose a biological
mechanism to
explain the validity of an unexpected and
potentially preposterous finding simply
because it
happens to have an interested
p-value. Anyone who
doesn't believe this, you know, I would
be happy to
show you overwhelming evidence that this
is the
case.
Second, is we could look for
confirmatory
evidence in other studies reminding that
we
shouldn't be selective. But, even if every study
showed the same trend, how would you know
that you
had enough evidence to reach a
conclusion? Some
have proposed doing a cumulative
meta-analysis in
which each trial is considered to
represent an
67
interim analysis on the way to a final
judgement.
Indeed, Salim Yusef has
proposed that, as
each trial is added to the meta-analysis,
that one
use interim monitoring boundaries to
interpret this
cumulative meta-analysis. This has, certainly, a
considerable amount of appeal.
Let me just emphasize. Salim has, in
fact, underscored the fact that the
conditions here
are not identical those that exist for a
true
interim analysis. In the case of a true interim
analysis, we generally know that the
types of
patients in studies are similar at all
observation
points.
Here it is different.
In the case of a cumulative
meta-analysis,
the types of patients in studies differ
across the
various trials. So, as a result, Salim has
proposed that, when reaching a conclusion
based on
data that has been combined across
trials, that a
boundary more strict than 0.05 be used.
Now, he has specifically
outlined the
importance of this using the example of
intravenous
magnesium. I showed you the data on intravenous
68
magnesium in myocardial infarction. When the early
trials with magnesium were carried out,
the z-score
of greater than 2.0 was crossed
early. As the
cumulative evidence occurred, the initial
boundary
of 0.05 was crossed.
But then a large study, when
added to the
other cumulative analyses, brought this
treatment
effect down to a 0 level. So Salim, and others, in
fact, have emphasized that, when you are
using a
meta-analysis approach and using
intra-monitoring
boundaries, that maybe one should require
a p-value
of less than 0.05 or even, perhaps, a
small
p-value.
Let me say that most of the
effects the
committee has seen over the past two days
would not
come even close to meeting these
criteria.
Now, some of you may say, why
not avoid
all of this uncertainty and simply carry
out an
adequately powered definitive trial with
the
adverse event as the primary endpoint. Is this
crazy?
No; it is not crazy at all.
Sponsors
pursue encouraging trends. Most are disappointed,
69
but they will pursue them. Sponsors, therefore,
should have an obligation to pursue
discouraging
trends realizing that most of them
probably won't
be confirmed either.
On a definitive trial can
address
ascertainment and classification biases
as well as
concerns about multiplicity of
comparisons and
imprecision of the data. However, can we really
expect sponsors to pursue every adverse
trend?
There are some obvious limitations to
doing this.
Furthermore, if you could decide which
adverse
trend you wanted to pursue, how easy
would it be to
carry out the trial intended to
definitively
evaluate an increased risk of an adverse
effect?
Can you imagine the consent
forms for the
IRBs for such a study? Some may say that we are
being too stringent here, the that
criteria of
raising a safety concern need not be as
stringent
as the criteria for establishing
efficacy. But I
am not so sure that the criteria for
establishing
efficacy and safety should be that
different.
As a rule, we are very strict
in reaching
70
conclusions about efficacy because saying
that
there is a benefit when there is none
means that
millions will be treated unnecessarily
and subject
to side effects and cost. Now, although some might
advocate being less strict in reaching
conclusions
about safety, please remember; saying that
there is
an adverse effect when there is none
means that
millions will be deprived of an effective
treatment.
In conclusion, the findings of
controlled
trials are most easily interpreted when
they
represent the principal intent of the
study. A
non-principle finding is subject to many
interpretive difficulties many of which
we have
reviewed; ascertainment biases, inflated
false-positive rates due to multiplicity
of
comparisons and, the one I have
emphasized the
most, the imprecision of estimates
inherent in the
analysis of small numbers.
I think FDA, industry and
academia remain
in a quandary as to how to respond in a
responsible
fashion to observe differences in the
reported
71
frequency of adverse events. Let me just
emphasize, my presentation shouldn't be
construed
as favoring one particular side in all
the
discussions that have occurred. In my view,
regardless of one's position, it is
critical to
understand the limitations of what we
know and to
resist the temptation to reach
conclusions before
we are justified to do so.
I think only by recognizing our
ignorance
will we be able to take the first step
towards
developing a rational approach that is in
the
interest of all patients.
Thank you. I will be happy to answer any
questions.
DR. WOOD: Dr. D'Agostino?
DR. D'AGOSTINO: Thank you very much,
Milt.
I have a couple of questions that I think, I
hope, are relevant to our
deliberations. In terms
of your sense of large and the idea of
chasing
after a safety event and making more out
of it than
one should, we have a study approved
where there
was a serious up-front prestated deliberation
to
72
make sure they had good ascertainment and
adjudication of cardiovascular events,
and they
come up with 45 versus 25 events,
carefully
collected.
I am struck by that's being
small, but I
am also struck by the carefulness in
which it was
done, say, as opposed to the APD where
they did an
interim analysis that has those
problems. Could
you comment on, say, the approved study?
DR. PACKER: I think that, when you have
incomplete data, as you would if you have
small-numbers events, you need to be a
lot more
careful about the thinking process. That doesn't
mean you can't make judgments. It doesn't mean you
can't incorporate a set of principles
that would
guide decision making by looking at the
totality of
the evidence and bringing to the process
what you
inherently believe. I think that is what the
committee needs to do today.
What I really wanted to
address, however,
is how hard this is and that the normal
reliance--as you know, clinical
investigators,
73
because they don't understand p-values,
rely on
them.
What I am trying to do is to explain that,
in fact, we are less certain about what
we know
here than we, perhaps, should be.
DR. D'AGOSTINO: But that is on the
approved, studies, it was reasonable,
too.
DR. PACKER: I think you need to take that
in the totality of the carefulness in
which it was
done, the prospective nature of it. But, remember,
in
all the examples that I showed you, the trend
seemed sometimes very striking trends in
early
pilot trials that were prespecified,
adjudicated
endpoints but, because they were
small-number
events with very imprecise estimates, the
definitive trial was non-confirmatory.
So just because it is up-front
and
predefined--
DR. D'AGOSTINO: That is my question, yes.
That is my question. You still end up with small
numbers.
Let me have just a couple of other
questions. The second question is really bothering
me very much in terms of how we would
recommend
74
trials.
If you decide--if the group decides and
suggests to the FDA that there should be
more
trials, more randomized clinical trials,
the
sponsors are, then, going to have to go
back and
say, well, they are going to set up a
trial saying
the null hypothesis that the relative
risk is 1.0
versus the relative risk is not 1.0.
Now, the best thing a sponsor
can do is to
run a very sloppy study and they will
accept that
null hypothesis because the confidence
intervals
will so wide and they will contain
1.0. The
alternative is to sort of do a
noninferiority type
idea that you end up the study, you end
up with the
confidence interval, and that confidence
interval
has to be below something like 1.3.
Do you have advice for us if
you did this
sort of second approach? We are dealing with rates
like 1 percent. Could we live with a 1.3 relative
risk that you rule out, a 1.3 relative
risk?
People may be dying if you do that. So how do you
respond to that?
DR. PACKER: I wish I knew the answer to
75
that.
I think that it depends on the type of
adverse reaction. It depends on the particular
drug.
It depends on the vulnerability of the
patient population. All of these need to be
factored together with the actual
feasibility of
doing the study.
The one thing I would say is
that one
learns very little by doing a lousy
trial. So,
doing a good trial is the only way to get
a
reasonable answer or reasonable estimate
of the
answer.
DR. D'AGOSTINO: Just one more. I will
make it quick. In these trials, in many of these
trials, people just won't stay in the
trial. Can
you give us some advice on how to deal
with the
drop-out--now, there are rules that you
could say,
the individual wants to leave, has
decided to leave
because the blood pressure is building up
or
because of G.I. problems building up.
To say, we are only going to
look at that
individual for 14 more days after they
leave, to
me, is a problem because if the blood
pressure is
76
building up, they may be on their way and
it may
take two or three months before they get
an M.I.
and so forth. So you have got the sort of
dropouts, terminations, that are part of
the
protocol but you also have the
individuals who just
stop coming. And they could be substantial. So,
any advice to us?
DR. PACKER: Gee, as you know, when we do
trials for superiority, the effort that
we put into
adherence is extreme. We really want people to
stay on treatment and we organize the
trials to do
everything we can to ethically and
reasonably
maintain adherence.
I take your point that, if the
trial were
a noninferiority trial, it is possible
that the
investigators and sponsor might be less
motivated
recognizing that poor adherence works in
their
favor.
I think that there needs to be a reasonable
effort--I mean, you can maintain
adherence in most
trials if you really, really want to.
DR. D'AGOSTINO: Thank you.
DR. WOOD: I suspect we are not going to
77
solve that problem today. Dr. Shapiro?
MS. SHAPIRO: Just a comment on your
comment.
We all know, of course, that the Federal
Regulations require that participants be
allowed to
withdraw and not be badgered into
staying. But
what I really wanted to talk about was
your
observations about how it is wrong to
suggest that
we should not chase safety quite as
rigorously
because we will, then, deprive ourselves and
others
of information and access to effective
treatment.
I don't think it is as
simplistic as that,
in that, when we are looking at potential
harm or
safety problems, we have to look not only
at
likelihood that it exists but prevalence
and
severity.
So I think that your response
to that
approach has to take account of those
factors as
well.
DR. PACKER: Let me try to reframe my
response.
You can't isolate benefit from risk.
The judgment as to whether a drug should
be used on
an individual basis or on a population
basis has to
78
be the relative value of benefit to
risk. You may
decide that you don't even want to pursue
a safety
trend in a non-fatal event when you know
the drug
prolongs life. That would be a very reasonable
judgment.
On the other hand, you might want to
vigorously pursue a very serious safety
is in a
drug for a symptomatic or cosmetic
condition. So
the risk-to-benefit relationship is the
one that
has to be vigorously defined.
MS. SHAPIRO: Right.
I am sure you will
agree with this; you also have to factor
in
prevalence of the condition and likely
use of that
drug in the population.
DR. PACKER: That's right.
But it is
always--it is risk to benefit. The goal here is
not to say that the risk-to-benefit
relationship
can be altered, simply because you want
to
emphasize one part or another, has to be
in the
context of the clinical problem and looked
at from
the patient point of view.
DR. WOOD: Dr. Cush?
DR. CUSH: I have two questions. One, I
need some education. You were frequently referring
to very wide confidence intervals where
it didn't
79
seem so wide. It was only, like, 0.3 and 0.4
where, obviously, when it ranged from 1.0
to 8.0,
that is very wide. But you used those terms in
both situations. Could you explain the differences
there?
DR. PACKER: Actually, I have used "wide"
to refer to extremely wide, moderately
wide and
wide.
DR. CUSH: And narrow would be--
DR. PACKER: Narrow is less than wide.
DR. CUSH: Okay.
DR. PACKER: Let me try.
All the examples
that I showed you that I characterized as
wide
truly reflected estimates that had a high
degree of
uncertainty associated with it. On the benefit
side, benefits that range from an 80
percent
reduction in risk on the high side to a
20 percent
reduction in risk--remember, and I guess
I should
emphasize this and I guess Tom would
reinforce this
80
dramatically, the concept of how these
curves
looked like in terms of the width is not
symmetrical on both sides of 1.0. The lowest you
can go below 1.0 is 0. So wide confidence
intervals below 1.0 can be 0.2 to
0.8. Those would
be wide confidence intervals. There is no limit
for estimates greater than 1.0, so you
can have 1.0
to 24 on the adverse side of this. So you have to
sort of think about what is wide
differently when
you are looking at estimates below 1.0
than when
you are looking at estimates above
1.0. Maybe that
would be helpful.
DR. CUSH: That does help. Secondly, you
have told us that when we are dealing
with
low-numbers adverse events and that being
very
imprecise and hard to make conclusions
from, is it
even less valid or even greater error to,
then,
take that data derived in one situation,
like in an
Alzheimer's trial, and then try to
generalize that
to the general population?
DR. PACKER: But we do that all the time.
There is a general sense that efficacy is
not
81
extrapolatable across diseases but safety
that is
not disease-specific is extrapolatable.
Let me put it this way. If we didn't do
that, the problem that I put forward
would be
really impossible, really
impossible. So I
actually feel comfortable extrapolating
safety data
across indications as long as the safety
item is
not disease-specific.
DR. WOOD: Dr. Shafer?
DR. SHAFER: Thanks.
That was actually a
very informative presentation and I can
confirm the
distance from Washington to California.
There are really two questions
here that I
think we need to bifurcate. One of them involves
the scientific question of getting at the
truth,
whatever that is. I appreciate everything you say
and, prior to a drug being approved, at
least
ideally, there would be adequate time and
resources
to do exactly what you are proposing.
But there is a second question
which is
how to inform clinical and regulatory
decision
making based on imprecise information
following
82
approval because, in that setting, a
daily decision
is being made by patients and their
physicians as
to whether or not they need to take the
drug.
One question about how to
approach these
sorts of imprecise data when, in fact, a
daily
decision is occurring, is can you take
the
confidence bounds for both the risk and
the benefit
and integrate those over the
public-health hazard
and the public-health benefit to try to
incorporate
the
entire--both the point estimates but also the
uncertainty about them into the
regulatory
decision-making process?
DR. PACKER: Oh, wow.
Just a couple of
comments.
One, the precision of the estimates on
efficacy is almost always more precise,
much more
precise, than the estimates on
safety. So you have
this very precise estimate on
efficacy. You have
this very imprecise estimate, in general,
on
safety.
And you try to sort of integrate them and
you have to now weigh them because it
could be that
the efficacy thing you are looking at is
really
important and the safety is sort of not
very
83
important. Or it could be other way around, the
efficacy is sort of very small--the
efficacy is
small, but the safety is a big risk.
DR. SHAFER: That is exactly the question.
DR. PACKER: You might think that someone
in the world might be clever to create a
statistical model that would allow that
to take
place.
I am actually much more comfortable with
people doing that than statistical models
doing
that.
Somehow, people have the ability to
integrate all of this, especially a group
of people
have an ability to integrate this, much
better than
any mathematical model.
I would be very uncomfortable
if someone
were actually to propose a mathematical
model that
replaced the human, very important human,
element
here.
DR. WOOD: Dr. Farrar.
DR. FARRAR: Every example that I have
seen to date in looking at the risks in
overinterpreting data seem to go from
being a
positive study to a negative study. I wonder about
84
the other way around and whether there
are any
inherent differences in thinking about it
the other
way around, the bottom line being that if
you have
ten studies that show no safety issue
with a
well-measured process, whether you can
then say,
well, maybe the 11th study is going to
show it
somehow.
DR. PACKER: I think you need to find out
how much information there is in each
study, how
easily or how appropriate it is to
combine the data
across the studies to determine how
precise the
estimates, after you have collected and
integrated
all of the data, and put that into a
judgement as
to how much data you actually need to be
confident
about the precision of the estimate.
So there isn't a uniform way of
thinking
about.
It is not like you will know it when you
see it.
There is some guidance, some
mathematical
guidance, that needs to be incorporated
into the
thinking process.
DR. WOOD: Dr. Domanski.
DR. DOMANSKI:
You know, I am not nearly
85
as sophisticated, really, Milton, as you
are about
this sort of thing nor about some of the
people in
the room, but I am a little bit concerned
about
some of the examples. I will give you one. I
don't think ISIS 4 was a definitive trial
of
magnesium, because I know something about
that. We
did the MAGIC study which was a very
large study.
Like ISIS 4, it was negative, but
ISIS 4
was substantially different
methodologically in
terms of when that was given. I think that example
actually, to be honest, is fairly
misleading as a
result.
I think it is an example of a stopped
clock is right twice a day. But, yeah; it came out
right.
But I a worried if that is the
basis for
this--that kind of thing is the basis for
this
discussion across more of the landscape.
DR. PACKER: Let me emphasize,
Mike, that
I knew that if I picked one study and
gave you an
example of one st that I would be at
great risk
because everyone knows something about
these
studies more than what I know about these
studies
86
although some of the studies I actually
mentioned
were studies I was personally involved
with and
think that I know a little more about
them.
So I just wanted to--I would
not
overemphasize--and, in fact, one might
appropriately underemphasize--the
magnesium
example.
But the other examples, time and time and
time and time again. It is just like reaching
conclusions during a very early part of a
study
based on interim monitoring. When you have small
numbers of events, the estimates are very
imprecise
and may not reflect what happens at the
end of a
complete experiment. That is just a general
principle.
I take your point about ISIS 4
but the
number of examples here is just
overwhelming.
DR. WOOD: It is important, Milton, to
remember, we have replication for two of
these
drugs and these safety signals here. So it is not
just single studies.
Dr. Furberg.
DR. FURBERG: Milton, I think that was a
87
great presentation. I think, for balance, it would
be nice if you can have examples showing
the other
side, how trends in smaller studies were
confirmed
in definitive trials. And I know plenty of those.
DR. PACKER: Oh, yes.
DR. FURBERG: That was never discussed.
You are painting a dark picture saying
you can't
trust smaller studies. You are right. You never
know where you are going to end up and
you need to
be careful. But don't say that you can't rely on
those.
DR. WOOD: I was actually on the advisory
committee that turned down Vesnarinone,
that looked
at that study. There were lots of issues that came
up at that time that led us to do
that. So it
wasn't just that there was a study that
was
compelling and that people went with
that.
Dr. Nissen?
DR. PACKER: Curt, let me just say that--I
think your point is very, very
important. What I
have not done is shown many, many
examples of
interim monitoring in trials where the
early
88
results were reflective of the
endpoint. I have
not
shown a whole host, probably more than I could
think of, of all of the pilot trials
where the
initial trends encouraged someone to
pursue it and
that the second study was, in fact, very
confirmatory.
Let me just make my point
clear. It is
just not as reliable as we think it
is. It is not
that it is worthless. I do not want to say that.
If I have implied that, then I do not
want to imply
that.
I just want to say that the risk of error
early when you have small-number events
is much,
much greater than when you have a much
more precise
estimate at the end of the trial.
My plea here is that when you
don't know,
the best thing you can do is say, "I
don't know."
And that is my only plea.
DR. WOOD: Milt, when you have two trials
that replicate one another, with a
p-value of less
than 0.05, if that was an efficacy
endpoint, we
would approve on the basis of that;
correct?
DR. PACKER: That's right.
DR. WOOD: But you are telling us that,
when it is a safety endpoint, we should
not act on
that.
I think it is counterintuitive.
89
DR. PACKER: No, no, no.
DR. WOOD: Hang on.
That seems to me
counterintuitive. We have, for two of these drugs,
two randomized trials that replicate the
outcome.
In three of the four trials, the outcome
was
predefined, adjudicated and so on. That is about
as good as any drug that has been
approved on the
U.S. market that I can think of.
DR. PACKER: Let me just add one
dimension, Alastair, to the thinking
process and
that is that when you have a p less than
0.05 on
two trials, on the primary endpoint
because it is
efficacy, you have two trials that were
designed
for the endpoint and have fairly narrow
confidence
intervals and precise estimates.
That is not the same concept as
having a p
less than 0.05 on two imprecise estimates
which are
combined together.
DR. WOOD: No; I understand that very
90
well.
I think we all do. The issue here
is both
of the second trials--both of the second
trials--were designed to test the safety
issue that
was in the first trial even though they
were
efficacy studies. So it is not like they were just
two trials that fell on the ground from
Mars that
arrived with something. These were designed, at
least according to the sponsors, to check
for that
outcome.
So I think you are overselling
the point a
bit.
Let's move on. Dr. Jenkins?
DR. JENKINS: I found the presentation
very interesting and I wanted to probe a
little bit
further on the APPROVe study because that
is the
one that I think we were feeling very
comfortable
with the finding in APPROVe. Yet, I went back to
Merck's presentation, and their
prospective plan
was actually to combine three studies
that were
going to be placebo versus rofecoxib in
three
different populations.
Their plan was to have 25,000
patients to
91
evaluate the cardiovascular signal. Now, in
APPROVe, presumably, they had stopping
rules that
the Data Safety Monitoring Committee saw
an extreme
effect that met those criteria so they
stopped the
study.
But I am just interested in hearing your
thoughts about how should we interpret
APPROVe
where the stopping rule is met for an
individual
study when the prespecified plan was to
have three
studies combined for 25,000 patients.
DR. PACKER: Gee, I must say that I am
delighted to have everyone ask me the
hard
questions for this afternoon. I sort of think that
this is what this committee has to
do. I only
wanted to add a dimension to the thinking
process
here. I
don't come with any answers on how to put
all of the data together. All of the points on how
to synthesize these data, I am very
comfortable
with the human process of doing so as
long as the
human process incorporates an
understanding of how
difficult and imprecise this is and the
fact that,
in the past, although it has led to
predictions
that came true, it also led to
predictions that did
92
not come true.
DR. JENKINS: I think, more specifically,
the point I was trying to get you to
comment on is
not the overall interpretation of the
rofecoxib
data but the fact that there was a plan
for 25,000
patients in three studies. What I am trying to
understand is how should we, then,
interpret a
finding from one of those three studies
where an
interim analysis crossed the stopping
boundary and
met the criteria for stopping the
study. What
weight should we give to that finding in
that
single study?
DR. PACKER: I don't think there is a
precise answer to that. Any time you deviate from
your preplanned attack on the conduct of
analysis
of a trial, you weaken, to varying
degrees, the
precision of the estimate and the
confidence you
have in the data that you are looking at.
DR. WOOD: Dr. Nissen?
DR. NISSEN: Milt, there is an additional
subtlety here. Let me see if I can drill down with
you on it. What we have here is a class of drugs
93
where we have multiple trials within the
class. So
what we are asked to do is not
necessarily, in some
respects, for each individual drug, say,
well, do
we have replication or not.
But if we take the position
that this is a
class effect, then we have got four, or
perhaps,
five trials. This came up once before. It was
kind of controversial. I think you may have been
on the committee at the time when we had
the
angiotensin-receptor blockers for renal
protection.
What the two companies did with two
different drugs
is they stipulated that the other could
use the
data from the other company's trials as
supportive.
So the reason that this is
really much
harder is that we have a lot of trials
here. We
may not have reached all the evidence in
an
individual drug, but we have trials
across the
class of drugs. I wonder if you have any thoughts
about this because it is obviously a
difference
between studying a single agent and
studying a
class of agents.
DR. PACKER: I think that, Steve--I mean,
94
that is why the process works best when
there are
human beings involved in the thinking
process.
There is no predetermined sense that one
should
bring to the process--that you confine
the analysis
only to one drug. What you should allow yourself
to do is look at the data with one drug,
look at
the data with drugs that you think are
related.
If there are data that you
think are in a
drug that really isn't related, you might
want to
analyze that separately or do it both
ways to see
if it is consistent. There is no statistical
formula that can guide the very important
human
process here.
My major point is that the
precision that
most clinical investigators think exists
here isn't
as precise as we think it is. But that doesn't
mean that you--and Curt would emphasize
this--that
doesn't mean that you can't put together
your own
picture of the totality of the data and
bring to it
a sense of whether it reaches some
critical level
of concern.
In the absence of precision,
you have got
95
to do that. But don't forget inherently that the
data are imprecise.
DR. WOOD: Curt, do you want to say
something else? No.
Then let's move on. The next
speaker is Bob Temple who we are going to
confine
to his seat.
DR. TEMPLE: Alastair, I have a question.
What am I supposed to do about my
slides? Can
someone show them for me? I will delete many of
them.
DR. WOOD: Okay.
You can come up here if
you do it quickly.
DR. TEMPLE: I don't care where I'm from.
I really don't.
DR. WOOD: Then Kimberly will work the
slides for you.
DR. TEMPLE: Okay; if Kimberly will do
that.
Issues in Projecting Increased
Risk of
Cardiovascular Events to the Exposed
Population
DR. TEMPLE: I was not in any way trying
to address the main issues the committee
is
96
grappling which is about what to do about
these
drugs.
But it seems to me you can't help noticing
that there is some data we would all like
to have
that we don't have and that is what I was
trying to
address.
Obviously, the main thing we
are worried
about is the effect of the
COX-2-selective NSAIDs
on cardiovascular outcomes, notably
death, stroke
and heart attack. But are particularly interested
in the single drug effects, whether they
are all
the same.
We are interested in whether we are
looking at true class effects of
differences.
We also can't help noticing
there is not a
lot of long-term data on the nonselective
NSAIDs
and, of course, has been pointed
repeatedly, some
of them are sort of selective anyway.
There is major interest in
possible
differences in the subpopulations that
might be a
different risks. I think there are mechanistic
considerations, how much of this is
really likely
to be platelets and could there be a
blood-pressure
effect.
The importance of that, to me, is that it
97
is not quite clear what to do about
platelet
effects, but, conceivably, you could
manage a
blood-pressure effect if that was a
problem.
There is a lot of importance
and interest
in the dose and dose interval. And it is important
to think about how long studies have to
be to
detect these things. Obviously, some of trials
seem to have shown things in a matter of
seven or
eight months. There is some suggestion that some
of the effects need much longer to
detect.
Skip the next one.
With respect to cardiovascular
effects,
the main question is whether everything
is really
answered.
You know, there are lots of studies, as
Alastair was pointing out. They are not perfectly
consistent, maybe, but there are a number
of
studies with a number of drugs that seem
to be
showing the same thing.
I guess, to me, they don't seem
entirely
consistent. There are a number of possible reasons
for that.
One is that there really are differences
between drugs, or at least between
doses. Another
98
is that even the best controlled studies
sometimes
give different answers. Another is that small
effects are difficult to evaluate in
epidemiologic
and even controlled studies. Then the last is that
the effects may be
population-dependent. That has
been discussed.
So it does seem to me there is
more to
learn.
Skip the next. We all know
that. Platelet
effects.
One of the things that seems
important to
pin down and I don't think it has been
pinned down
yet is the possibility that blood
pressure is a
significant part of all this, that there is some
impression that Vioxx has bigger
blood-pressure
effects than the other drugs, but I don't
think
there is what we would call adequate data
on the
effects of all these.
By adequate data, I mean data that
gives
you information about the effect of drug
over the
entire dosing interval, that has pinned
down dose
response and that has pinned down the
effect of
different dosing intervals. There is an
99
impression, though, that these drugs can
reverse
the effect of other anti-hypertensives,
perhaps,
especially, ones that work through the
renal and
angiotensin system. They seem to have, at least
some of them, an effect on blood pressure
generally
and then there are isolated reports of
hypertension
in trials reported as adverse reactions,
clearly
more common in the treated groups.
I have a bunch of slides
showing that
elevated blood pressure is bad for
you. You can
deduce that from epidemiologic effects,
from a
mountain of clinical studies. The most recent
study that of interest, which I will not
describe--keep going--in detail is a
study that
Steve Nissen knows about called CAMELOT
which you
can read as saying that a change in blood
pressure
of even 5 millimeters of mercury systolic
and 3
diastolic might have a reduction of about
33 percent in the kinds of events we are
talking
about in people whose diastolic pressure
is only
about 100.
That is not definitive. This is a subset
100
of the data and you can look at my slide
to see
what I did.
As I said, we don't know as
much about the
blood pressure as we should.
So a crucial question is in the
larger
assessment of cardiovascular effects;
what can we
really study more. My own view is that, given
VIGOR and fairly consistent epidemiologic
findings,
it would be difficult to study 50
milligrams of
rofecoxib. I doubt you could write a proper
informed consent.
I take Milton's concern to
heart but I
guess my own view is there is probably
enough
information about that. But what you could with
respect to other things depends on what
you
believe.
Suppose you believe that the
cardiovascular risk of 200, 400, of
celecoxib is
not entirely clear. One polyp study says yes and
other studies are not so clear. And you believe,
also, that a class effect is uncertain or,
more
particularly, that the effect might not
apply to
101
certain doses and certain dose intervals
even if
you are inclined to believe that the
class does
have a problem.
If you also believe that more
needs to be
known about the long-term use of all
NSAIDs,
including those that are nominally
COX-2-selective
and those that are not, if you believe
that new
COX-2-selective agents conceivably could
be
developed with appropriate information,
and if you
believe the pharmacology gives hypotheses
that need
to be tested, not necessarily just
believed--sorry
Garret--then here is what you might be
able to do.
Again, I am not, in any way,
saying who
should do this. This will be a massive
undertaking. But it does seem to me that there is
information we all collectively need as a
community. So I am calling it an ALLHAT study for
anti-inflammatory drugs.
This is just one of what people
could
dream up as what might be compared. The drugs, it
seems to me, one might think about
putting in it
include ibuprofen, which we think
probably ought to
102
be neutral, not bad. It may not have the platelet
effects you want. Naproxen--I am embarrassed to
say
this but I am letting myself be affected by the
epidemiology studies. Naproxen sort of looks good.
You might even say it is at least a
placebo, but I
am not quite ready to say that.
Diclofenac seems a good model of
a regular
NSAID that is really COX-2-selective, at
least to a
degree.
Celecoxib possibly at more than one dose,
although, maybe for caution, one would
want to
think about the lower dose first. Then I have two
other groups that I will be interested in
people's
comments on, and I am not totally sure
you could
bring these off.
But could one include an
aspirin full-dose
study.
We know it is an effective agent in
arthritis accompanied by a proton pump
inhibitor.
Now, you would have to first show that
proton pump
inhibitors really do block the
ulcerogenic effects
of aspirin. That is a short-term study and maybe
one could do that. So I will be interested in
whether people think you can bring that
off.
The reason for doing it is we
know the
effects of aspirin are not unfavorable
and we think
they are probably favorable in at least
many
103
populations, in populations at high risk
and
probably not unfavorable in people at low
risk.
The last one that seems worth
considering,
and my understanding is that, in many
parts of the
world, at least osteoarthritis is treated
this way,
to use acetaminophen plus codeine added
as needed
and try to do something about the
constipation.
That would be as close to a
true placebo
group as I think you can get in a setting
like
this.
So it seems quite interesting.
It is worth saying if one had a
new single
agent, my suggestion, and one still
thought that
drugs like this should be developed, that
the
single agent might be compared to naproxen and
I
would still hope for one of the other
last two
comparisons as a true placebo.
Obviously, these are all people
who need
chronic pain medications. You would want O.A. and
R.A. stratified. I don't believe you could use the
104
APAP group for rheumatoid arthritis but
others may
not agree with that. You probably want to study a
range of cardiovascular risks but you
probably
would want to study the lower-risk people
first.
The reason I say that is anyone
with known
coronary-artery disease really has to be
given
aspirin just because that is part of
treatment and
it isn't clear yet, to me, how aspirin
interacts
with the COX-2-selective drugs. You would think it
would make them unselective but the data
don't seem
to necessarily say that.
A good question is how big the
sample
would have to be and that depends on what
you want
to find out. If you are really trying to compare
the drugs with a true placebo, they
wouldn't have
to be that large to rule out, say, a
two-fold risk
or
something like that. We have seen
studies with
about 1,000 per group that have
distinguished
between drugs. So that is not so huge.
But if you really wanted to get
at whether
one drug is a little bit different from
another,
you are talking about studies of massive
kind. I
105
have asked various numerically qualified
people and
the general impression is that if you
wanted to
rule out a 20 or 30 percent difference,
you are
talking about 50,000 per group. That is beyond my
hopes even for ALLHAT 2.
Obviously, the outcomes of
major interest
are cardiovascular death, stroke, AMI and
bleeding.
I have heard some thoughts that maybe
heart failure
should be looked at in addition but I
wouldn't make
that the primary endpoint. I think you can look at
that separately.
A big problem is what to do
about blood
pressure.
My first thought was that you would
monitor it and treat anything over 120
over 80, but
that really isn't standard practice. So a question
I would raise is whether one could leave
people to
go to 130 over 90, would that be
acceptable.
A question one could raise is
why do this
at all?
Do you really need these drugs?
We have
heard fairly strong feelings that G.I.
intolerance
is not trivial. But my answer is more that we
really don't know enough about the whole
range of
106
these drugs. There is no question that people are
going to get something for their
arthritis. I am
not entirely comfortable with looking at
the data
and saying we know what we need to.
You could sort of deduce that
naproxen
usually looks pretty good. It usually beats what
is there except we just heard about a
study where
it was a little worse. But it is not clear where
ibuprofen comes. It doesn't show the same thing.
It seems to me there is a serious
population need
to find out about these things and to
understand
more whether all selectivity is the same.
We have been through diclofenac
at length
and it is not clear what one needs. So I think the
idea of doing a large study has weight.
If you believe that it is
really all
settled, that cardiovascular risk is
clearly
increased with all of the COX-2-selective
agents,
ignoring for now which ones are actually
selective,
there still are things one might want to
know.
It might be of interest to do a
study that
still would have the ibuprofen and
naproxen groups
107
and might still have my aspirin or APAP
groups.
One might consider trying a celecoxib
with the
addition of aspirin. I know the results of that
have not shown that any adverse effect
seems to be
mitigated, but that still doesn't make
much sense
and it might be something one could still
want to
test.
It would seem that if you added aspirin to a
selective agent, you ought to have a de
facto
unselective agent. Of course, that presumes
mechanism and you shouldn't presume
mechanism. You
should test it.
Anyway, those are my thoughts. I think my
main point is that there is really a very
important
need for better information on the whole
array of
these drugs and the kind of study needed
to do that
is mind-boggling large. However, people are
already undertaking studies with 25,000
and 30,000
patients already. So it is not as outlandish as I
would have said it was before we started
this
process.
Thank you.
DR. WOOD: Okay.
I am just interested,
108
why didn't you suggest a PPI with
naproxen? For
your ALLHAT study, why didn't you suggest
a PPI
with naproxen?
DR. TEMPLE: That is a fair question. I
think the answer on--what did I suggest
it with?
DR. WOOD: With aspirin.
It doesn't
matter.
DR. TEMPLE: I will tell you the reason.
Full-dose aspirin is just plainly
impossible to use
because of massive G.I. intolerance. I believe,
historically based, it is worse than we
expect with
naproxen.
So I thought you had to do it there
urgently.
You could do it with naproxen, too.
That would be okay.
I have to point out that we do not have
definitive labeling or evidence that
those drugs
really do prevent this but we have heard
about some
studies that suggest it. I do think that is an
early thing to discover.
DR. WOOD: Okay.
Understood. Let's move
straight on to Bob O'Neill's presentation
who also
is going to do it from his seat.
Issues in Projecting
Increased Risk
of Cardiovascular Events to the
Exposed Population
DR. O'NEILL: I won't go through the
109
slides.
I might point your attention to a few of
them.
I will try and do this in five or ten
minutes.
DR. WOOD: Do you want us to have the
slides up, Bob?
DR. O'NEILL: What I was asked to do is
essentially provide a framework. This is a very
difficult problem of projecting risk to
the
population. Very little has been published about
how to do this appropriate so I was
intending to go
through sort of the logic and the
framework of how
you might think about this.
It requires the integration of
exposure
data at the national population level and
it needs
information relative to how long people
are on
drugs and it uses information from the
clinical
trials as well as from the epidemiology
studies to
the extent that they are relevant to the
question
that is being asked.
This is a very difficult
problem. It was
not intended to give any estimate, any
single
number.
It was intended to show how hard it is to
get there and, at the end of the day, how
variable
and sensitive the estimate might be to
all the
assumptions you have to make.
110
So I used the Vioxx VIGOR and
APPROVe
studies as an example of the process that
one might
go through. I made the point that event
definitions and many things matter. But I guess if
there is anything that I would like
people to take
home is that time matters. The hazard rate
matters.
And the hazard ratio matters as a
function of time when you do any of these
projections.
I would just recall two
slides. One would
be the VIGOR study which is Slide 12 so
that
everybody could remind themselves and
Slide 16.
The VIGOR study shows a separation of
curves.
Behind that is what is called a hazard
rate. I
believe the data supports that the
escalation of
the risk increases with duration of
exposure.
111
Merck and we have talked about this in
the past and
sort of have different views of this, but
we seem
to feel that that risk does escalate.
That does not mean that there
is no risk
in that picture early on. I think David Graham has
made this point that it may be a power
issue but,
nonetheless, it is what it is and I am
not
convinced that the epidemiological
studies at this
stage add anything to our knowledge about early
risk for the points I made yesterday
because I
think time zero matters in terms of
looking at the
risk, in terms of how long you are on.
The next slide is Slide 16 which
is the
APPROVe study. Similar pattern, only delayed a
year.
So instead of the curve separating at
approximately six months, four months,
they
separate a little later on. The idea here is that
the relative risks that are summary
relative risks
for both of these trials, for VIGOR, for
thrombotic
event, it is approximately 2.28 and, for
APPROVe,
it is approximately 1.92 for confirmed
thrombic
events is an average relative risk
averaged over
112
all the time points so that the relative
risk at
different times is a function of time.
That is an important concept
when, then,
you go and you look at the national
projection of
how many people are exposed for how long
a period
of time.
I won't go through that because they are
in the slides. But we have no data in the United
States to do this. So we did a projection based
upon the IMS National Prescription data,
another
separate database that allowed us to look
at how
long exposure, success of exposures,
might be to
get an idea of how long individuals may
stay on the
drug.
Surprisingly enough, a very small
percentage of the millions of people that
are
prescribed the drug are on the drug for
more than a
year.
That is in one of the slides on the
Caremark.
So what this meant is you multiply all
these estimates which, essentially, are
time. We
calculated a time-specific difference in
absolute
incidence rates for the different trials,
made a
projection and essentially used in that
projection
113
a number of assumptions many of which are
not
verifiable, and then came up with some
crude
estimate of what might even be an upper
bound on a
confidence interval for any estimate.
We probably don't believe it
because there
is no real methodology to support that
estimate but
nonetheless to say that an estimate is
very
variable.
So the bottom line, and the
conclusions
here, given the time frame, is that
purpose of the
projection effort was essentially just to
provide--this is the last slide; it is
Slide 47--it
is essentially to provide a framework for
considering how you would think about
developing an
estimate and to provide a range of
estimates and,
also, essentially, to point out that
there are many
limitations to any estimate that you
would provide.
We are not supporting any, or
putting
forward any, one estimate but I do believe that we
need to understand this problem by moving
away from
summarizing nonproportional hazards in
person
years.
It is not a good idea. It begs
the
114
question as to whether the risk is
constant or
whether the risk is dependent on time.
If there is one problem with
the
epidemiological literature, it constantly
reports
person-year risk as opposed to every one
of the
clinical trials we have seen presents a
Kaplan-Meier curve that looks at the
time-dependent
risk.
Unless you understand that, you can't come
to grips with comparing one drug to
another.
You can't come to grips with
comparing a
drug to itself. If you look at the VIGOR study
relative to the approved study, they are
in
different populations. One is in a population of
R.A.
The other is in a polyp prevention trial.
One
is at 50 milligrams. The other is at 25
milligrams.
There are many things that need
to be
sorted out. So the point here is that this is a
very difficult exercise to project. This was just
a framework to say, here is how you might
think
about it.
Most of the estimates are fraught with a
lot of danger and have to have many
caveats placed
115
on them were you to bank on any one
estimate alone.
That is pretty much my bottom
line.
DR. WOOD: Bob, just to make sure
everybody in the audience understands
what you are
talking about with estimates, what you
are talking
about are absolute numbers of people--
DR. O'NEILL: An estimate of the absolute
numbers of individuals that might have
been at risk
and had these events if they were
exposed--if they
were exposed. This is a model projection.
DR. WOOD: Right.
I just wanted to
clarify that. So it is not the relative risk. It
is not the same as what Milt was talking
about.
DR. O'NEILL: Right.
Exactly. This is a
long discussion to get into the concept
of
attributable risk in its own right. Given the
time, I wouldn't be able to do that.
DR. WOOD: So you are talking about the
number of people, these sort of numbers
that are
out there.
DR. O'NEILL: Right; to go through
that
exercise.
It is hard enough to interpret a single
116
study or a collection of studies. To go to an
estimate of what the increased number of
events
might be at the exposed level is what
this effort
was about, all the different, five
different
separate interlinked but disparate
databases that
you would need to get there to make this
kind of an
estimate.
DR. WOOD: Okay.
Good. Thanks.
DR. WOOD: We will take a few minutes, a
very few minutes, for questions to the
last two
speakers and then we will take a break
and be back.
So the panel needs to remember that they
are eating
into their break.
Dr. Nissen?
DR. NISSEN: Quickly, Bob, Bob Temple.
The difficulty, of course, in the ALLHAT
study is
that it is very--it seems unlikely that
it will get
done.
So the question is, putting some constraints
on this, and I thought about this last
night in
some detail into the wee hours of the
morning, it
seems to me that what we really need for
this class
of drugs is a reference standard. That reference
117
standard, unlike many studies, can't be
placebo
because you can't treat arthritis
patients with
placebo.
So I would submit to you that, if you are
going to do comparisons, that the
reference
standard, the best reference standard we
have, is
naproxen because we know as much about it
as
anything else. We think it is, at worst, neutral
and maybe a little better than neutral.
So I would argue that, if you
want to do
ALLHAT light, then what you do is you
test every
agent both that stay on the market and
that are
proposed to bring onto the market against
naproxen
with an adequately sized trial and you
set an upper
bound, which we have to talk about, about
what the
upper bound of hazard you are willing to
accept is,
and the test that you run is on efficacy
and on
cardiovascular hazard.
If your drug is beaten by
naproxen, you
don't make it. If you can show equivalence within
a reasonable upper bound of naproxen,
then we would
be pretty comfortable--I think I would be
pretty
118
comfortable that the drug is not going to
create a
hazard.
What do you think about that
strategy?
DR. TEMPLE: That is actually--I went
through it very fast, but that is
actually what I
said at the bottom of one slide. I still would
like to know better whether the naproxen
is less
bad or is really good. Therefore, as I said on the
slide, in my heart, I would like to see
somebody
try to give full-dose aspirin for a while
because
we are really pretty sure that won't be
bad.
I think the community, in the
long run,
needs that. Who is going to do it? That is a
perfectly good question. I do want to point out,
though, that the way some of the trials
were done,
like TARGET, they could have given
answers on some
of this, or at least closer. But, because they did
separate trials, instead of randomizing
to each of
the treatments, that was obscured.
You could have had a very
substantial
naproxen-ibuprofen comparison, but you
didn't get
it because of the structure of the
trials. So I
119
think it is very important to randomize
to each of
the treatments, obviously, whatever it
is. But
that would be my best guess at the
moment. But, in
line with what Alastair asked before,
when you do
naproxen and you are looking at G.I.
effects, do
you add a proton pump inhibitor? I think you need
a little more information before you do
that, but
you might say that, which then raises the
fundamental question of how much help you
get from
being COX-2-selective.
DR. WOOD: Dr. Cryer?
DR. CRYER: I wanted to comment on several
of the questions, Dr. Temple, that you
raised as
well to ask a question. I guess I will just ask
the question first. When you say "full-dose
aspirin," are you referring to full
anti-inflammatory doses of aspirin, 3.9
grams a day
or--okay.
DR. TEMPLE: Which I assume most people
will not tolerate and there will be huge
bleeding.
So you have got to do something.
DR. CRYER: Right.
See, I think that is a
120
non-practical experiment design and I
think we have
come a long way from 3.9 grams of aspirin
per day,
particularly because of the concerns of
the adverse
events, the silicysm, the G.I.
events. Clearly,
100 percent of those people are going to have
gastric ulcerations assessed
endoscopically.
So I also would prefer one of
the newer
NSAIDs, traditional NSAIDs, in that
comparison.
With regard to--
DR. TEMPLE: Actually, before you leave
that, do you know what would happen if
you added a
proton pump inhibitor to aspirin?
DR. CRYER: Not at 3.9 grams a day. I
don't think anybody thought that would be
a
feasible design.
DR. TEMPLE: Short term, then, just to
look at endoscopic ulcers.
DR. CRYER: I don't know and I don't think
that it will ever be known.
DR. TEMPLE: Then I won't get the answer.
DR. CRYER: What I do know is that, if you
give 3.9 grams of aspirin per day in the
121
short-term, greater than 90 percent of
your
patients who take aspirin will have
endoscopic
ulceration. I don't know what the effect of the
PPI would be.
I wanted to address your last
kind of
question that you threw out there of
whether or not
a short-term study would show that
celecoxib plus
80 milligrams of aspirin would have a
favorable
effect, a G.I. effect, compared to a
non-selective
NSAID.
Those experiments have been done.
With respect to endoscopic
ulcer, COX-2
plus aspirin equals traditional
NSAID. With regard
to hospitalizations, having said that,
there is a
recent study not yet published,
epidemiologic study
from Canada, indicating that COX-2 plus
aspirin,
hospitalizations for that are less than
hospitalizations for non-selective NSAIDs
plus
aspirin.
Then we have outcome studies not yet
fully published in the abstract form
which indicate
that events on COX-2 plus aspirin are
similar to
events on non-selective NSAID plus
aspirin--G.I.
events.
DR. TEMPLE: It is possible that if you
add aspirin--I mean, it is sort what I
would
expect--is that you would get something
that is a
122
lot closer to being--in a cardiovascular
sense, a
lot closer to being just a regular NSAID
and maybe
you would still have some residual
advantage in a
G.I. sense.
But, I must say, the data so
far don't
show that. But they didn't seem definitive to me.
It raises the question of--you
know, the
idea of COX-2 selectivity is, at least,
in part, a
conceptual and promotional idea. As Garret pointed
out the first day, five or six of those
old drugs
that aren't coxibs are
COX-2-selective. So there
is a whole range. My feeling is we need to
understand the consequences of what all
that means
and there is a somewhat artificial
separation
between the coxibs and the others because
those old
drug at least are partially selective and
may have
some of the same properties.
So one of my hopes that we
could look at a
range of these.
DR. CRYER: With respect to your last
comment, I am entirely in agreement with
that.
DR. WOOD: Let's move on. Dr. Cush?
DR. CUSH: ALLHAT, I like the intention of
it.
I would suggest, though, that if you are going
to have a study long enough to pick up
some of
123
these events, a year or two, it is going
to be
very, very hard to keep O.A. patients on
one of
those drugs.
So maybe actually stratifying
according to
pure COX-2-specific drugs to
COX-2-selective drugs
to the non-selective drugs that are more
predominantly COX-1 and then having a
totally
nonsteroidal, non-nonsteroidal group,
which would
be the Tylenol group you talked to or
other
analgesic agents might work over the long
term.
DR. TEMPLE: That would answer a lot of
the questions. My real hope--you have a better
idea whether it is possible than I do--is
that you
could actually find a population that
could be
given what we are pretty sure is a
cardiovascular-neutral treatment. That is really
124
the only way to pin this down and it does
seem
worth pinning down.
DR. WOOD: Dr. Hennekens?
DR. HENNEKENS: I think I gleaned from Dr.
O'Neill that if we determine there is a
class
effect that it varies not just by drug
and dose but
by duration of therapy. From Dr. Temple, the
comment that--I am very attracted to the
concept of
what I would call a large simple trial
rather than
an ALLHAT trial. I think there is merit in seeing
aspirin studied in therapeutic doses and I think
there is evidence that anti-inflammatory
effects
are seen a doses far lower than the 3.9
grams.
But the question I have for Bob
is there
are three currently marketed FDA-approved
coxibs.
So would you include valdecoxib and 25
milligrams
of rofecoxib in your design?
DR. TEMPLE: Part of the reason I didn't
address that is I figured that is what
the
committee is going to talk about. I was willing to
say that the celecoxib data look funny
enough so
that you might consider it.
DR. WOOD: That is part of what we are
going to discuss.
DR. TEMPLE: That is what you are going to
125
discuss so I didn't address it.
DR. WOOD: Let's move that to later. Dr.
Domanski?
DR. DOMANSKI: I will pass.
DR. WOOD: Dr. Abramson?
DR. ABRAMSON: Thank you.
I want to
probably say something rather naive in
support of
the study, Bob, and that is that we are
at a moment
where we can do a paradigm shift, meaning
that
study that you propose is an important
one but it
is very large and it is going to be very
hard to
get any resources to do that.
I think we are at a moment
where for the
companies and the FDA and the government
to think
about a collaborative study where, if you
have a
drug that has some--this information is
important,
that we put together a collaboration
among industry
to do a multi-arm study of multiple
drugs. It is
something, you know, in the
osteoarthritis field,
126
the companies have supported largely this
osteoarthritis initiative through the NIH
to look
at outcomes in large numbers of patients.
I think what we need is a similar
COX-2
initiative where either with the FDA or
the NIH
participating, with collaboration among
industry,
we are doing a multi-armed large study
with
biomarkers, with pharmacogenomics
studies, with
genetics and other blood pressure, but
try and do
it in a utopian way.
I think everyone here wants to
get the
right answer, whether it is in industry
or here at
the table. This could be a good opportunity to do
something very differently than we have
done before
in a large trial.
DR. TEMPLE: I don't disagree at all. I
mean, some of the drugs are generic. They don't
have any company that is massively interested
in
them.
So it is going to be a mixture of
government, generosity and a wide variety
of other
things that are scarce. So I don't know how
to--you noticed I didn't have a slide on
how to do
127
this.
DR. WOOD: Dr. Ilowite?
DR. ILOWITE: Just a minor point. I
understand the need for a
cardiovascular-neutral
anti-inflammatory drug in an ALLHAT study. But I
was a little confused because I am aware
of some
literature directed at people who are
interested in
Kawasaki disease suggesting that
high-dose
anti-inflammatory aspirin is actually
prothrombotic
because of differential effects on
prostacycline
and thrombotics.
DR. TEMPLE: There are aspirin studies
going back to at least moderate doses
that show
beneficial effects. It is not just 80 milligrams.
It is certainly at least a gram a
day. Some of the
early ones were more than that. That is worth
thinking about. I am encouraged by the thought
that you might be able to get away with
doses less
than 3 grams. So I didn't know that it was
considered prothrombotic. I thought aspirin always
looked good. But that is not up to grams. I don't
think any of the studies have done
anything like
128
that.
DR. WOOD: We will give Dr. Fleming the
last word.
DR. FLEMING: I am just debating whether
to do it now or after the break.
DR. WOOD: Let me help you. Go ahead.
DR. FLEMING: Now?
DR. WOOD: After the break will be great.
DR. FLEMING: All right.
I will wait.
DR. WOOD: We will take a break and then
we will be back here in ten minutes.
(Break.)
DR. WOOD:
Okay, folks. Let's get
started.
The next presentation will be given by
Sharon Hertz who is Deputy Director of
the
Division.
DR. HERTZ: Thank you.
I am just going to
spend a very few minutes summarizing some
of our--
DR. WOOD: Let me, in fact, just before
Sharon begins--Sharon Hertz has passed
out a
handout that includes a lot of her
slides. In the
interest of time, she has graciously
agreed to
129
delete some of these slides and just
focus on a
smaller subset of what is in the handout.
However, the committee does
have the
handout and the committee may find that
handout
useful for referring to some of the data.
DR. HENNEKENS: Alastair, a quick comment.
I want to make a quick clarification on
the earlier
comment about pro-inflammatory effects of
high
doses of aspirin.
DR. WOOD: Sorry; I missed that. About
what?
DR. HENNEKENS: In the randomized trials,
135 randomized trials with over 212,000
randomized
subjects, whether the doses of aspirin
are 75
milligrams or up to 2 grams a day, there
are
significant cardiovascular benefits to
aspirin even
at high doses. The issue, as Bob pointed out, at
the high doses, is not that there is a
reversal of
the benefit but that the side effects are
increased.
So I think that is an important
point to
make.
DR. ILOWITE: I just wanted to say that in
pediatrics, we think of anti-inflammatory
doses as
100 milligrams per kilogram. So those are the
130
doses I was speaking of.
DR. GIBOFSKY: Finally, the high-dose
aspirin that would be necessary to treat
patients
with rheumatoid arthritis of 3.9 grams or
greater
would have significant problems on the
stomach, as
Dr. Cryer said, significant problems on
the hearing
of the patient and significant problems,
perhaps,
on other organ systems as well. It is not a study
that could be easily undertaken.
DR. HENNEKENS: I won't debate the value
of the study of 3.9 grams of aspirin but,
from the
perspective of anti-inflammatory effects,
they have
been observed at doses of 2 grams of
aspirin a day
and, in fact, there are randomized
studies going on
directly comparing that somewhat higher
doses of
maybe 1 to 1-and-a-half grams a day might
have
significant anti-inflammatory as well as
anti-atherogenic effects as measured by
endothelial
function, nitric oxide formation and
other
131
parameters.
So I don't think that the
traditionally
high doses are the ones that necessarily
would need
to be done. But I don't want to debate whether we
should be studying doses of 4 grams of
aspirin.
DR. WOOD: What you are telling us,
Charlie, is that you are comfortable that
there is
an antithrombotic effect at the high
doses of
aspirin.
Is that right? Okay. Good.
Dr. Cush wants to say
something.
DR. CUSH: Again, you need not
anti-inflammatory doses but analgesic doses
which
can be substantially lower. I do want to make a
statement with regard to a study that
wasn't
presented here that I think is germane
and we
should know about it, and this is
quick. There is
a very large trial that is NIH supported
that is
called the GATE study, glucosamine in
osteoarthritis of the knee.
This is a 1588 study that is
completed and
is currently being analyzed. That Data Safety
Monitoring Board of the study has
analyzed it for
132
cardiovascular risk because there is a
Celebrex
arm.
There are five arms in this 1500-patient
study; placebo, Celebrex 200 milligrams
once a day,
glucosamine only, chondroitin sulfate
only, and
glucosamine and chondroitin sulfate.
The outcome here, in a
six-month trial, is
pain reduction in osteoarthritis in the
knee.
Because of all this press and what not,
they have
looked at the safety outcomes and they
have not
shown any increase in cardiovascular
events
including M.I., any difference between
the Celebrex
group and the other four control groups.
DR. WOOD: Let's move on to the program.
Dr. Hertz?
Summary of Meeting
Presentations
DR. HERTZ: There are now several versions
of my slides around and you are free to
look at
whichever interests you. There is one correction
on the lumeracoxib slides from the
original set
where I substituted the word diclofenac
for
ibuprofen. So those of you looking at those slides
just be aware of that, please.
What I am really just going to
do now is
just focus down again some of the reasons
why we
are here.
This would not be the current slide set.
133
Any help here?
Looking at the most recent set
that were
handed out, and we will just work from
there
because there is not a lot of data
anymore to
present, but, basically, I want to just
point out
that we are here because we do recognize
that pain
drugs are critically important, that the
COX-2-selective NSAIDs have been
extensively
studied and there are, over time, studies
that
revealed new potential uses as well as
new risks.
We need to determine how we feel
about
these risks. Are they limited to individual
products?
Are they applicable across the group of
COX-2 selectives and how far does this
extend to
the nonselective anti-inflammatories.
There is a slide that
describes--
DR. WOOD: Sharon, apparently everybody
has hard copies of your slides.
DR. HERTZ: Right.
DR. WOOD: So if you want to just go
through them and refer to the slide
number, that
would probably be helpful to people.
DR. HERTZ: Okay.
If we go to the third
slide, you can get a sense of the sizes
of the
databases that were presented in the
individual
134
reviewer descriptions of FDA reviews.
A couple of points. The numbers there
reflect predominantly patients on the
drug of
interest as opposed to the entire
database. The
outcome studies are more reflective of
the entire
populations including comparators. These drugs
were assessed and have been assessed over
time in
fairly large numbers of patients.
I think it is useful to note
that we have
not
approved, in this country, all of the
COX-2-selective NSAIDs that have come to
us in
applications for a variety of
reasons. Some of
these may be related to
cardiovascular-risk
assessment. Some may be related to
non-cardiovascular-risk assessment which
we really
haven't gotten into in this setting.
In addition, you may also note
that
parecoxib has not yet been approved in
this country
although it has been approved
elsewhere. So I
think that we have a lot of issues to
consider with
these products.
When we reviewed the studies
that have
been presented, we see that there is some
increased
risk for cardiovascular events but one of
the key
issues here is that the results are not
consistent
135
across studies and across
situations. We also have
seen that there is risk that is being
associated
with some of the nonselective products.
So we have a story of
conflicting data. I
am up the Slide 5. We have data that has been
present across short- and long-term
studies, the
epidemiologic studies. The challenge is to compare
across populations, across
comparators. It is
striking that sometimes very similar
study designs
have very different results.
It is possible there is more
than one
mechanism. Again, the data has been inconsistent
with the NSAIDs. We also have conflicting
136
information coming back on what occurs in
the
context of concurrent aspirin use. It is really
unclear if aspirin use has a truly
meaningful
effect on whether there is any G.I.
benefit of the
COX-2-selective products. That has not been clear
either.
I have been asked to point out
that, in
addition, time to onset of risk is
something that
we need to consider very importantly,
too, which,
again, is something that is evident when
we look at
the study data and important in our
deliberations
for this.
So, in spite of this conflicting
data and
the many questions, we have to move
forward. We
have to determine what the role of
approved
products are on the market today, what
additional
studies are necessary, what studies would
be most
helpful.
I am going to summarize and
combine some
of the questions that we have posed. These are
questions we dearly would like input from
the
committee. To start, if we think about the first
137
three questions, does the available data
support a
conclusion that celecoxib, rofecoxib and
valdecoxib
significantly increase the risk of
cardiovascular
events.
Does the overall risk-versus-benefit
profile for each of these support
marketing in the
U.S.
If yes, in whom? And which of the
potential
benefits of celecoxib or the others
outweigh the
potential risks and what actions would
you
recommend that we consider implementing
to ensure
safe use?
I think it is also important to
understand
that some of these answers are going to
depend on
if we think that this is a fairly uniform
class
effect and, if not, we are going to have
weigh the
amount of information available for each
of the
products.
It is not the same. We don't have
the
longer outcome studies, for instance,
with
valdecoxib at this point.
Question 4 asks if the
available data
support a conclusion that one or more of
the
COX-2-selective agents increase the risk
of
cardiovascular events and what is the
role of
138
concomitant aspirin in attempting to
mitigate that
risk.
What additional clinical trials or
observational studies, if any, would you
recommend
as essential for us to further evaluate
celecoxib,
rofecoxib and valdecoxib?
What about to further evaluate the
potential G.I. benefits for these same
products?
Would you recommend that the labeling for
these
products include information regarding
the absence
of long-term controlled clinical-trial data
assessing potential cardiovascular
effects and if
you have a recommendation for how that
should be
conveyed in terms of warnings, boxes and
such.
What additional trials would be
essential
to evaluate the nonselective nonsteroidal
anti-inflammatory drugs particularly with
respect
to cardiovascular risk? Similarly, what will now
become essential for products under
development
prior to approval to help gain approval?
We have to determine what
studies would be
necessary to evaluate the cardiovascular
risk of
these products and how much information
do we need
139
to know about the gastrointestinal
risk? If
preapproval studies recommended as
essential do not
demonstrate an increased risk for a
cardiovascular
event, how would you propose the FDA
handle that
information in the labeling? Would the absence of
a
cardiovascular-risk signal preclude the need for
any warnings or precautions in the
labeling of a
new product or should we rely more on a
class
warning or precaution in the absence of a
signal of
increased risk in the preapproval
databases?
If you think a class warning is
appropriate, please advise with
particular
attention to whether you recommend it
apply to all
NSAIDs or only COX-2-selective NSAIDs.
So I want to thank everybody
here for
their time and their commitment to
helping us
through this extremely challenging
program and we
really look forward to hearing your
deliberations
and your recommendations.
Thank you.
DR. WOOD: Thank you very much.
The companies have also asked
for two
140
minutes to respond. We all heard the rules
yesterday so it is two minutes. Microphone gets
turned off two minutes later and just
keep moving.
Sponsor Responses
DR. HARRIGAN: Could I have Slide No. 1.
This is Harrigan from Pfizer. What I would like to
do is first to summarize what we know
about
celecoxib and what we think that tells us
about the
benefit:risk equation for that drug.
I make the point in this slide
about
Celebrex being extensively studies and to
remind
the committee of the contrast of the very
widely
used nonspecific NSAIDs. On the next point, we see
that efficacy has been demonstrated in
arthritis
pain and familial adenomatous
polyposis. Our
prescription data and observational study
data tell
us that approximately three-quarters of
patients
who are taking celecoxib are receiving
daily doses
of 200 milligrams or less.
Celebrex does have a favorable
G.I. safety
profile, a point emphasized by the very
relevant
G.I. safety findings that we heard about
this
141
morning from ADAPT compared to
over-the-counter
doses of naproxen.
Cardiovascular risk was not
detected in
the setting of treating arthritis
patients
understanding all the caveats about that
data that
we have heard over the past two
days. In APC, an
increase in cardiovascular risk was
reported
apparently in a dose-related
pattern. In contrast,
two additional long-term
placebo-controlled trials
did not find evidence of increased
cardiovascular
risk at daily doses of 400 milligrams.
The comment about the ADAPT
findings is
supported by the initial announcements
from
National Institute of Aging. We await that data
with great interest, particularly given
the size,
the duration in the elderly population
study which
would lead us to believe, expect, that
the number
of events in that trial will exceed the
number of
events in either or both of the other two
trials
combined.
The final ADAPT data and the
polyp
efficacy data will make significant
contributions
142
to our understanding of the
benefit:risk. In
addition, as (microphone turned off.)
DR. WOOD: Next speaker?
It might be
worthwhile introducing yourself just so
we know
which company you are representing.
DR. ERB: Dennis Erb, Regulatory Affairs
at Merck.
On behalf of Merck, I want to again
thank the committee and the FDA for
providing us
the
opportunity to present our data and the
benefits and risks of etoricoxib and
rofecoxib.
We recognize that the safety of
this class
of medicines is an important
public-health issue
and, as we have heard over the past two
days, there
are many patients in need of effective
therapies
for their pain. We hope that the data that we
included in our background package and
the
presentations have helped the committee
in its
deliberations.
When Merck made the decision to
voluntarily withdraw Vioxx from the
market, we
stated that we believe that it would have
been
possible to continue to market Vioxx with
labeling
143
that would have incorporated the data
from the
APPROVe.
We concluded, however, that, based on the
science available at that time, a
voluntary
withdrawal of the medicine was the
responsible
course to take given that there were
alternative
therapies and the questions raised by the
data.
Since that time, the science
has continued
to evolve and new data on some of those
alternate
therapies have become available including
the data
that we have seen in this past week. Given this
new information, it appears that the
cardiovascular
risk observed and approved is not unique
to Vioxx.
We believe that the data
suggest a class
effect but the size of the class is uncertain. We
believe that MEDAL is an important study
to address
the important question on the relative
risk of
COX-2 inhibitors versus traditional
NSAIDs. As Dr.
Packer said, studies with a sufficient
number of
endpoints are needed. The planned C.V. analysis
will provide data on greater than 600
events, 200
of which will be in the 18- to 36-month
time
interval.
The importance of the study is
shared by
the steering committee for MEDAL study
who, in a
letter sent to Merck this week, support
the
144
continuation of this trial.
We look forward to the
deliberations of
the committee on the questions before
then and, as
Dr. Kim stated last night, if the
committee and the
FDA conclude that the benefits of this
class of
medicines outweigh the risks (microphone
turned
off.)
DR. WOOD: Next?
DR. ORLOFF: Thank you for the opportunity
to comment. My name is Dr. John Orloff and I
represent Novartis Pharmaceuticals. We would like
to make some general comments on how we
might move
forward.
While it is reasonable to
consider these
drugs as a class, we believe there are
substantial
differences in their profiles that
deviate from an
attempt to ascribe all follow-on their
benefits and
risks to a single unifying mechanism.
For example, the apparent
cardiovascular
145
risks, as noted by Dr. Fleming and others
in the
discussion yesterday, do not seem to
correlate well
with COX-2 selectivity in the
clinic. More
specifically, some of the agents at the
highest
cardiovascular risk may not be the most
COX-2-selective.
In addition, there are
significant
differences in blood-pressure profiles
and in
cardiorenal profiles including edema and
congestive
heart failure as we have shown in TARGET,
a trial
that enrolled over 18,000 patients. In TARGET,
significantly smaller changes in blood
pressure
were observed for lumiracoxib relative to
either
naproxen or ibuprofen.
Furthermore, the strength of
the G.I.
outcomes data varies considerably across
agents, a
benefit that is central to the assessment
of
benefit:risk profiles of COX-2
inhibitors. For
lumiracoxib, an unequivocal reduction in
G.I. ulcer
complications of 79 percent was shown in
TARGET
and, in response to comments made
yesterday, it
should be noted that subgroup analyses of
patients
146
at higher G.I. risk demonstrated that the
magnitude
of this effect, about 70 percent, was
similar to
that observed in the overall population.
Thus, the benefit:risk profiles
vary by
drug, by dose and by exposure. Accordingly, each
agent should be judged individually on
its own
merits.
So how do we go forward? We
believe it is
reasonable to consider, for any
particular
indication, restricting the duration of
use to a
time frame that is supported by the data
and that
this should be accompanied by a robust
risk-management plan including firm
postmarketing
commitments.
Thank you.
DR. WOOD: Thank you.
Oh; there is more.
DR. PEITLER: Erica Peitler, Senior Vice
President, Bayer Healthcare, Global Head
of R&D.
Bayer was pleased to have had the
opportunity to
share safety information on
naproxen. Important
points have been made regarding naproxen
in both
large observational datasets as well as
large
randomized clinical controlled trials.
We welcome the scientific debate and
dialogue on our products. We believe that it helps
to build trust and confidence in both the
products,
147
the industry and well as our
company. We
appreciate the presentations today
specifically on
the ADAPT trial as well as the clarifying
questions
and comments put forth by this committee
regarding
how this study may have caused
significant
physician and consumer confusion.
Lastly, and most importantly,
Bayer is
committed to its consumers and its Aleve
brand
which contains naproxen and believes
that, when
used according to label directions, Aleve
is a safe
and effective pain reliever that offers
millions of
consumers an important treatment option
for
over-the-counter pain relief.
Thank you.
DR. WOOD: Thanks very much.
Committee Discussion
DR. WOOD: Thanks very much. I thought it
would be helpful if I just made a few
comments
about what I think we have seen over the
last three
148
days and why this has difficult.
I think what I have seen, at
least, is we
have seen four, maybe five, randomized
controlled
trials that show a significant
cardiovascular
hazard which was replicated for two of
the drugs,
Vioxx showing VIGOR and APPROVe and
Bextra the
early CAB study and the later CAB study,
and, for
Celebrex, the APC study.
It is important to recognize,
this is a
far larger randomized safety signal than
we have
seen for any of the drugs that have been
withdrawn
for safety reasons. In all of these studies, as
Tom Fleming pointed out a number of
times, the
other adverse events seem certainly to
trend at
least the coxibs in many of them.
So you might say, well, why are
we
discussing this and you might also say,
why has it
taken us three days. I think the reason for that
is that this is probably one of the first
times
that we or the FDA have had to deal with
a drug
that caused a substantial increase in the
frequency
of a common problem, common disease like
MI or
149
heart disease or whatever, in contrast to
an
increase in the frequency of a rare
disease like
acute liver failure, even things like
torsade de
pointes in which there were other issues
that made
it difficult.
So the difficulty of struggling
with that,
I think, is real and has been talked
about by many
people.
The other question that has come up and
has been raised by many people is what do
we see in
the observational studies. Well, from a personal
level, I guess, what I saw was, which is
kind of
backwards, I suppose, is in some of them,
at least,
it seemed to show the same as the
randomized trials
and that is somewhat reassuring, I
suppose.
With all the caveats that we
heard, the
observational studies, may allow us to
rank drugs
by toxicity, and toxicity by dose, with
all the
caveats that we just saw with, I guess,
Vioxx
currently being the most toxic.
In terms of G.I. safety,
although it is
frequently thrown up there, we saw no
data that
showed better G.I. safety at the PUBs and
a hard
150
endpoint for Celebrex or Bextra except
the
discredited JAMA Celebrex paper that failed to
disclose the full dataset and that was
now the
subject of critical and apologetic
comments from
the Editor of JAMA, herself.
We heard testimonials from
patients which
I thought were both moving and important
although,
in fairness, it is fair to say that no
one has been
able to demonstrate specifically better
response
amongst any of these drugs in individual
patients
in any randomized way and, as Bob said
earlier,
such studies--Bob Temple said
earlier--such studies
would be useful.
So that brings us to the $64
million,
probably, question, what should we
do? Well,
first, this is a much bigger--I mean, as
was said
earlier, however one passes these
numbers, this is
a much bigger safety problem than we have
seen with
the 16 drugs that the FDA has
withdrawn. The only
reason that we have not acted, I think,
or the only
reason we have agonized so much is that
this is a
relatively common problem and it is,
therefore,
151
much harder for us to be sure that we
have seen a
signal.
Clearly, though, the Committee needs to
act in a way that limits this hazard to
patients
and the public has the right to expect
us, I think,
to do that and I think we need to focus
on that as
we go through this. Although, it is interesting to
discuss these issues, we really need to
make sure
that, before we leave here, we have
provided some
sort of reassurance.
If there are patients who
uniquely benefit
from these drugs, then we need to
consider any
revised marketing strategy which could
range from
withdrawal to great limitations on the
use of the
drugs.
We need to identify patients who can
uniquely benefit from these drugs and
work out what
they need to be told and what risk they
would be
willing to accept for that small number
of unique
patients who would benefit from the
drugs.
We also, I think, learned a
very important
thing this morning which was that, in
contrast to
some of the information that had been put
out in
152
the press, the ADAPT study seems to have
been
stopped largely for operational reasons
and many of
the "safety signals" that we
heard about in that
were not backed by the usual approach
that we would
take.
That, I think, is an important lesson that
we did get today.
So I wanted to frame our
discussion to
these issues and also to make clear to
everybody
that, when we leave here tonight, we need
to have
made really clear recommendations to the
FDA that
will help them move forward. It is wonderful to
sit and discuss the issues and
pontificate here,
but we really need to come down to some
conclusions
here that they will be able to take away
and act
on.
Now, a number of people have
indicated
they wanted to say something. Garret FitzGerald
wanted to say something in relation to
some of the
comments that came up in the last
session. Garret?
DR. FITZGERALD: Thanks, Alastair. I
thought it might be worthwhile to
reemphasize one
of the points that you have made,
actually, and
153
that is that the focus of our
deliberations would
most appropriately be on the randomized
controlled
trials particularly the placebo-controlled
trials
for two reasons.
One, I believe that the quality
of the
evidence is much greater than in the
observational
studies and I think everybody has said
that and,
two, that the biological plausibility for
the
issues addressed in the
placebo-controlled trials
of the coxibs is much greater than the
biological
plausibility of risk relating to the
traditional
nonsteriodals that were the subject of
the
observational studies.
As far as biological
plausibility is
concerned, there have been several
comments
yesterday and today that seem to cast out
the
symmetry of the evidence with the
plausibility of
the mechanism advanced. I am only going to make
comments about two of those issues. One, the most
recent one, which was the TARGET study.
In the TARGET study, we had a
highly
selective drug which did not reveal a
154
cardiovascular risk significantly. However, as we
heard yesterday, the TARGET study was set
up in a
way by choosing patients at low G.I. risk
to
amplify the detection of a G.I. benefit
and, by
choosing patients at low C.V. risk to
minimize the
likelihood of detecting a C.V. risk.
Indeed, that study was grossly
underpowered to detect a signal albeit
that, in the
non-aspirin users, the hazard ratio for
cardiovascular events was 1.47.
As far as the blood-pressure
aspects of
TARGET are concerned, which are, indeed,
asymmetric
with the mechanism, I draw your attention
to the
fact that blood pressure was assessed
retrospectively in TARGET and the
reliability of a
1- to 2-millimeter change, on average,
under those
conditions, to me, is extremely
questionable
especially as we assume that traditional
nonsteroidal comparators in TARGET were
raising
blood pressure through inhibition of
COX-2 that it
would, indeed, be amazing, if an even
more
selective drug was less effective on
blood
155
pressure.
It certainly doesn't relate to
the
duration of action of lumiracoxib which
is given at
roughly 30-fold greater than the
concentration
necessary to completely inhibit COX-2 so
that,
although it has a short half-life, its
pharmacodynamic half-life is extended and
we were
shown that it is an impact on
prostacycline by a
synthesis. It is sustained throughout the 24 hours
and corresponds to the other drugs in the
class,
yesterday by Paola Patrigniani.
So I think I would not view the
TARGET
experience as inconsistent with the
plausibility of
the mechanism. Finally, the other point I would
make is that Bob alluded to the platelet
activation
issue as being the manifestation of the
mechanism.
As I described, this mechanism has acute
and
unfolding chronic manifestations and,
indeed, the
data that we have seen in the controlled
trials are
entirely consistent with an acute and
chronic
time-dependent evolution of risk.
Thank you..
DR. WOOD: Thanks.
Tom, I put you off
from before the break, so feel free.
DR. FLEMING: It's fine.
Basically, I
156
wanted to quickly comment on the essence
of what I
see from the Packer, Temple and O'Neill
presentations. Clearly, when judging strength of
evidence, it is important to take into
account
multiplicity, as Milt Packer was
indicating. When
you are looking within the context of a
single
trial, that multiplicity can arise as
multiple
testing over time as well as multiple
endpoints.
Clearly, as he notes, with safety
issues,
there is a wide array of different
measures and we
have to take that into account when
considering
strength of evidence; monitoring
boundaries, give
us a guideline. Yet many of us have struggled with
trying to formulate monitoring boundaries
when you
are looking at safety because of the
multiplicity
of safety issues and the fact that you
have to take
into account severity of those safety
issues and
you have to take into account benefit to
risk.
Ultimately, while those
statistical
157
procedures that Milt was talking about
can provide
some guidance, there has got to be
informed
judgment.
Data monitoring committees are critical
and I think we see, from the ADAPT trial,
just
another example of why it is also
critical for the
data monitoring committee to have sole
access to
emerging data on safety and efficacy
during the
course of the trial.
What does this tell us, though,
about
where we are today now that we are
looking at a
wide array of studies. The VIGOR trial was the
first study out. That study, as Milt would say,
needs to be viewed in the context of
confirmatory
and exploratory. There is much less confidence
that you have in the reliability of a
result that
was suggested by the data as opposed to a
prespecified hypothesis.
There is also regression to the
mean. So,
when you are seeing an estimate of the
two-and-a-half-fold increase, there is a
reason to
expect that that single trial might be
overestimating that overall strength of evidence.
But we now have considerable
insight
beyond that first trial. We have got, by my count,
at least a dozen trials and at least half
of those
158
trials show an indication of excess risk
and the
majority of those are placebo-controlled
trials.
So, in my own sense, the issues
that Milt
is raising are very relevant but we are
now in a
context of having an extensive amount of
information. In my own view, it is clearly
sufficient for a measured response and
yet, at the
same time, I would agree with Bob Temple,
that we
need greater insight. What he has put forward is
one strategy for that insight, to get at
a better
sense of the extent to which this excess
is
specific to indication, to the dose, to
the
duration, to whether or not there is
ancillary
care.
Just to kind of get it drilled down on the
numbers here, if you were trying to rule
out a
doubling, it would take about 2,500
people per arm,
or 88 events in a pairwise comparison.
I would be more, in this case,
because my
own sense is I think VIGOR is
overestimating the
159
true risk. I don't think it is a
two-and-a-half-fold increase. My best sense is, in
a general aggregate sense, it is more on
the order
of a 1.4 to 1.5 relative risk.
To rule out a 1.5 relative risk
would take
10,000 people per arm or, in Bob's study,
about
50,000 people, a big trial. But METAL has 23,000
people so this does seem conceivably
doable. Bob
O'Neill makes the key point that
duration--that the
events, the risks, can be different over
time. So
this trial, if it were to be done, should
be done
in a way to get at longer-term effects as
well,
which does, also, allow us to somewhat
reduce the
size of the study.
So, bottom line, is we know a
lot, enough
to certainly take measured responses, but
it is
also going to be important for us to get
additional
insights that are necessary.
DR. WOOD: Dr. Gibofsky?
DR. GIBOFSKY: Mr. Chairman, we very much
enjoy the interactions with our
colleagues in Drug
Safety speaking for my colleagues on the
Arthritis
160
Advisory Committee. But I think I speak for most
of them in suggesting that, while safety
for
patients in the absolute is important,
the
important language for us is the standard
language
of the introduction to the questions;
namely, the
notion that the original approvals and
subsequent
supplemental approvals were based on a
determination by FDA that the potential
benefits of
each product outweigh the potential risks
when used
for the approved indications according to
the
directions included in the product
labeling.
I think that is important
because,
depending upon whether that clause is
inserted into
Questions 1 through 3, quite possibly,
there could
be different answers for both the
absolute and the
relative answers depending upon whether
or not we
consider that clause.
My colleague and friend Dr.
Abramson has
suggested that we may be at the dawn of a
new
paradigm here. If so, I agree with our Chairman
that, when we leave here tonight, we
provide some
clarity.
But I would earnestly implore my
161
colleagues to remember that the last
temptation and
the greatest treason is, perhaps, to do
the right
thing for the wrong reason.
Where drugs have been withdrawn,
whether
it has been because of their numbers or
because of
the increased incidence of risk, it is my
understanding that it has usually been in
the
context of adverse events in the group
for which
the drug was approved and not based on
adverse
events in a prevention or proposed group.
So I think these comments need
to be
considered somewhat carefully and that we
need to
look at our questions both in terms of
absolute
safety, which is critical, as well as
relative
safety as we define the populations which
are going
to get these drugs, namely the patients
with
arthritis and pain.
Thank you.
DR. WOOD: Well, let me just provide some
correction to that. I am not sure that last
comment is correct, the one about drugs
being
withdrawn because of adverse events in
the
162
indication for which they were approved.
DR. GIBOFSKY: Not all of them; that's
correct.
DR. WOOD: Hang on.
Rezulin produced
acute liver failure in two studies in
which it was
being used to prevent onset of diabetes.
DR. GIBOFSKY: I think that is absolutely
correct and it is not a uniform finding.
DR. WOOD: Now, these were not--
DR. GIBOFSKY: My concern is the
extrapolation from trials of prevention
to trials
of treatment and I merely indicate that
we cannot
be universal about that.
DR. WOOD: All right.
I think we are
ready, probably, to start--sorry; go
ahead.
DR. GROSS: I would like to make a comment
for the Drug Safety and Risk Management
Advisory
Committee and it is a perspective for the
future.
The question is, is there something we
can do to
avoid the confusion that comes up every
time
adverse events arise after marketing the
new drug,
particularly when the signal for the
adverse event
163
was not totally clear before the drug was
approved.
I suggest we consider an
approach that our
committee had discussed in the past and
that
approach is the review the drugs that
have been
pulled from the market and look for
commonalities
and differences that could guide policy
decisions
in the future, questions such as what
were the
adverse events, when were they
recognized, what
were the signals before marketing and
what
decisions were made when other drugs that
were
available in the same class, such as the
statins,
were done and what were the decisions
made when
there were no other drugs in the class
such as
occurred with alosetron or Lotronex.
If this were done, lessons
could be drawn.
Advisory committees would be better
informed to
make benefit/risk decisions and the
public would be
better informed because they would be
able to
acquire a better perspective and the
press, along
with the public, would have a better
sense of
relativity of all of these activities.
DR. WOOD: Okay.
You will be glad to hear
164
I am not going to make a statement on
behalf of the
NDAC Committee.
Let me read the first part. Three COX-2
selective nonsteroidals are currently
available for
marketing in the United States, Celebrex,
Vioxx and
Bextra.
The original approvals and subsequent
supplemental approvals were based on a
determination by the FDA that the
potential
benefits of each product outweighed the
potential
risks when used for the approved
indications
according to the directions included in
the product
labeling.
Since approval, additional data regarding
the safety and effectiveness of these
products has
accumulated, in particular, new
information
regarding the potential cardiovascular
risks of
these products. FDA must consider the impact of
these new data on the benefit-versus-risk
profile
of each product in making decisions about
appropriate regulatory actions.
Although--and this is
important--although
Merck voluntarily withdrew Vioxx from marketing
165
worldwide on September 30, 2004,
questions relating
to Vioxx are included below since it will
be
necessary for FDA to determine the
appropriate
regulatory action regarding the approval
status of
this product.
Based on the data presented in
the
background package during the committee
meeting,
please address the following questions.
Question 1: Celecoxib
So let's address the first
question 1.a.
Do the available data support a
conclusion that
celecoxib significantly increases the
risk of
cardiovascular events? Anyone want to
comment on
that?
No comments? Dr. Abramson; yes.
DR. ABRAMSON: I will just start. I
wanted to start by questioning the
premise of the
first sentence which is that there are
three COX-2
selective drugs on the market and just
remember to
point out that the drugs like Celebrex,
there are
four or five of them, diclofenac, et
cetera, that
have comparable pharmacodynamic profiles
in terms
of their COX-2 preferential effects and
that in
166
randomized controlled trials of these
drugs,
whether it is CLASS or the development
program or
TARGET have comparable cardiovascular
adverse
events in those comparator trials.
So I think, just as a premise, as we go
forward for each of these drugs, I think
we need to
circle back at the end to what we mean by
COX-2
selective agents.
That said--
DR. WOOD: I agree with that and let me
just add to that. I think it would be helpful if
we go through each drug individually and
not get
into a big discussion about what we mean
about
COX-2 selectivity right now.
DR. ABRAMSON: Right; exactly.
DR. WOOD: Then we can come back to that
later when we talk about nonsteroidals in
general.
So we are just confining our discussion
to
celecoxib.
DR. ABRAMSON: I agree and I just wanted
to
frame my comments. My own view on
celecoxib,
just to lead off on my opinion, is that,
if there
167
is a cardiovascular event, this, among
the coxibs,
is probably the weakest signal that we
have seen,
that it is in the approved study but not
in several
other placebo-controlled, randomized
trials--although there may be some trends
in the
precept.
We don't see it--and that there is a
large database in the randomized
clinical-trial
development program that does not show a
signal
that is excessive comparators.
So, while I am tending to think
that that
is a cardiovascular signal that is
COX-2-dependent,
celecoxib does not--has the weakest
amount of
evidence that it, in itself, is
significantly worse
than the others.
DR. WOOD: Dr. Nissen?
DR. NISSEN: I will support that. Let me
say that I think it depends on the
dose. The
evidence from the APC trial at the
800-milligram
dose is strong. There is no question about it.
There is a marginally statistically
significant
evidence at the 400-milligram dose and
there is no
evidence in any trial at the
200-milligram dose.
We have a number of pieces of
data that I
consider supportive of that concept. In the
epidemiological studies, while we
recognize that
168
they are flawed, there is no signal. There is
really no signal at all for celecoxib and
yet it
has probably been the most widely
prescribed agent
in the class.
Now, why would there not be a
signal?
Well, as we heard, the vast majority of
use is at
the 200-milligram dose. What happened here was in
the colon polyp trial, in an effort to
get
efficacy, doses of 400 and 800 milligrams
were the
doses that were tested and we see a signal
there.
Interestingly, we don't see
evidence in
CLASS at an 800-milligram dose. We don't see
evidence in PRECEPT. So using, I think, Milton
Packer's logic here, now you have to ask
the
question, does the evidence around
rofecoxib and
valdecoxib--to what extent does it
support a
conclusion around celecoxib.
My view is that I can say that
the
800-milligram dose is very likely to produce
excess
169
cardiovascular risk, that it is probable
at the
400-milligram dose but I can't find any
evidence at
the 200-milligram dose. So I think the answer to
this question has to be based upon dose
and, if
somebody can give me some evidence that
the
200-milligram dose increases
cardiovascular risk.
You can change my mind but I just don't
see it,
weighing the evidence very carefully.
DR. WOOD: Dr. Furberg?
DR. FURBERG: I think the previous
speakers are changing the question. You posed one
question that had nothing to do with the
strength
of the evidence, nothing to do with dose. So the
way the question is posed, the answer is
clear. We
have evidence of significant increase in
risk of
cardiovascular events. I admit, it is in a select
population, in a select dose, but that is
not what
the question is about.
So I think that should be
reflected
eventually in the labeling.
DR. WOOD: That is a fair comment,
actually.
The question right now is just about the
170
drug.
So we are talking right now about the
chemical entity, itself, and then we will
get to
issues of dose and patient subsets,
perhaps,
later--in fact, for sure, later, just to
reassure
everybody.
Dr. Shafer?
DR. SHAFER: Alastair, actually I have a
question for you. I am not sure how we are
actually going to proceed at this point
in time.
Is this the point in time where we
actually start
casting votes on the individual questions
as they
are put forward or is that scheduled for
a later
point during the day because at the time
when we
actually get to individual questions
about
individual drugs, it seems to me--I would
actually
like to hear, in order, from each person
on the
panel rather than us all trying to flag
you for
attention.
So clarification; what are we
doing at
this point?
DR. WOOD: We are discussing the question.
So if you have got discussion on the
question, by
171
all means, say it. Eventually, we will reach a
point where we vote on many of these
questions.
But the issue that we are trying to do is
discuss
the question right now to provide
information to
your colleagues that will help them
inform their
decision.
DR. SHAFER: When it comes to discussion,
will we then go around individually or
are you just
going to look for hands up, hands down,
and we need
to speak now.
DR. WOOD: I am looking for hands up now.
No, no; wait a minute. Are you talking about the
vote?
DR. SHAFER: Yes.
DR. WOOD: The vote, we go around the
table.
DR. SHAFER: Fine.
DR. WOOD: Other comments? Tom?
DR. FLEMING: Looking at the data, I am
basing my sense predominantly on the
CLASS trial,
the Alzheimer's OO1 trial, the APC and
the PRECEPT
studies.
The CLASS study is the largest and
172
generally gives a favorable result of a
lack of
excess although one has to remember that
is against
diclofenac and ibuprofen.
When one does look in the
non-aspirin
users and you are looking at atrial SAEs,
anginal
SAEs, MI and thrombophlebitis, we have
got 30
events on celecoxib and 14 on the
control. So I am
willing to take this as a relatively
neutral study
but there are elements of this that are
consistent
with some concern and we are also looking
at a
comparator group that is diclofenac and
ibuprofen.
The other three studies are
placebo-controlled. The APC trial is probably an
overestimate. In fact, I would--my sense in the
totality of the data is that it is giving
us an
excess and it is giving a fairly
persuasive sense
that there is an excess and yet, when you
look at
this in the aggregate with the PRECEPT
trial, one
gets a more tempered measure, although
the
aggregation of those two is in excess of a
relative
risk of 1.8.
The Alzheimer's 001 trial is
also
173
suggesting an excess, 11 against 3
events, in a 2:1
randomization. So, if we use the three
placebo-controlled trials, the
aggregation of the
evidence is in excess of about 1.6. My sense is,
for all of these together, the excess is
on the
order of 1.4 to 1.5.
If we fold the CLASS trial in and it is
relevant to do so, but remembering that
is not a
placebo-controlled trial, one gets a
sense of about
1.3.
In that regard, I agree with some other
comments, that this seems to be less than
the other
two approved agents. Yet, there certainly is a
suggestion, more than a suggestion, I
would say.
There is definite evidence that there is
an
increase, although potentially more
modest than the
other two agents.
One, though, does need to
factor in what
you know about the totality of the data
from the
other agents in the class. In that sense, you live
by the sword and die by the sword. If those other
agents look favorable, it gives you less
concern.
If they look unfavorable, it is more
concern. So,
174
looking at the totality of the data, I
don't like
using the word "significantly"
here, but I would
say the available data do support a
conclusion that
there is some level of increase in
cardiovascular
events using the totality of the data,
particularly
influenced by the placebo-controlled
trials.
DR. WOOD: Okay.
Dr. Domanski?
DR. DOMANSKI: I will pass again.
DR. WOOD: Dr. Hoffman?
DR. HOFFMAN: Perhaps Dr. Fleming could
elaborate on his response, his comments
in regards
to when one looks at the statistical
analysis of
each of the studies and there being
possibly the
risk of exaggerating the relative risk,
we also
spoke earlier of how, in most studies, we
exclude
people who have more serious illnesses
that would,
perhaps, subvert a clean trial, people
who have
serious cardiovascular disease that is
obvious,
serious congestive heart failure who,
nonetheless,
are people who wind up using these drugs
once they
are on the market.
I don't recall, for each of
these trials,
175
the degree to which there was exclusion
of those
patients but we have agreed that, at
least in some
of those trials, those patients were
excluded. If
we acknowledge that, then the risk, in
fact, for
the general population, may be
underestimated.
DR. WOOD: So, for many of these trials,
people with heart disease were excluded,
so you are
right.
The risk will probably be higher in
patients with heart disease. Certainly, in the
Bextra trial, that would suggest--that
was
certainly true.
Did you want to address that question
to
Dr. Fleming? Did you want--okay. He addressed the
question to you, Tom.
DR. FLEMING: I don't have anything to add
to what you have just said.
DR. WOOD: Okay.
Dr. Farrar?
DR. FARRAR:
One point and then a point of
clarification in terms of our discussion
so I know
how to approach my second point. The first point
is a plea for changing the word
"significantly."
Are we talking about statistical significance? I
176
don't think so. But I think we need to be
absolutely clear that we are talking
about
substantial benefit or substantial risk
or
important.
Significantly continually gets
confused
and so I think that if we all agree what
we are
talking about is important, or
substantial, risk,
not significant risk in terms of a
p-value.
The second question is, in
terms of
discussion of these topics, are we
talking--I think
it would be useful, in fact, to talk
about all
three of the subquestions here as part of
the
discussion as opposed to trying to
discuss each of
the subquestions individually because, at
the end,
we have to take all of them into
consideration in
terms of our recommendations.
So my question is whether, as a
procedure,
can we talk about benefit at this point
or would
you
prefer to restrict it currently to--
DR. WOOD: I think it will be easier to
manage with the size of the committee if
we
actually stick to each subquestion and
then we can
177
vote on that. Obviously, if people think
there are
other issues--as you look at each
subquestion, you
should bring the totality of whatever
issues relate
to that to bear on it. If there are discussion
points you want to bring to bear on that then, by
all means, raise them.
DR. FARRAR: So I will hold my comment to
the next one.
DR. WOOD: Any other comments? Charlie?
DR. HENNEKENS: As I view the totality of
the randomized placebo-controlled
evidence using
vascular events as the outcome, it
appears to me
that there is about a 41 percent higher
risk of
vascular events among those assigned at
random to
the
coxibs, that it doesn't differ significantly by
the drug being studied but, as has been
pointed out
by other people here, because the numbers
are tiny,
strictly speaking, the individual drug
comparisons
do not, on their own, achieve statistical
significance.
DR. WOOD: I passed myself by. I agree
with what Tom said. I think there is clear
178
evidence of risk from celecoxib and we
will come
back to the subgroups later. I am not persuaded in
the absence of data that we can't
extrapolate that
to other disease states. It seems highly
improbable to me that the risk of
cardiovascular
events would be less in situations where
we know
that that population have a higher risk
of
cardiovascular events such as rheumatoid
arthritis.
So just focussing on the risk
right now,
it seems improbable to me that we can't
extend this
information to these other settings. Bear in mind
why we have only placebo-controlled
trials from
non-arthritis patients. The reason we only have
placebo-controlled trials from
non-arthritis
patients is you can't give placebo to
patients for
18 months who have got pain.
So, stepping back from that and
sort of
seeing a safety benefit in patients who
have not
been studied in placebo-controlled trials
seems to
me a very hazardous thing to do,
particularly when
we have non-placebo-controlled trials
that seem to
show the same thing.
Other comments on the
question? Yes?
DR. FRIEDMAN: Do you include hypertension
or edema as major cardiovascular
events? If so, I
179
think it is clearly there as well.
DR. WOOD: I interpreted that to mean
events, meaning hard endpoints such as
Charlie's
events or whatever. Is that, Bob, you meant by
that?
Bob Temple?
DR. TEMPLE: That is what we have been
focusing on. I mean heart failure is of interest,
certainly, but it is a different kind of
thing. It
is potentially manageable whereas a heart
attack
and a stroke are not manageable.
DR. WOOD: Right.
In fairness, in the
published VIGOR trial, there were other
events that
were not in that published trial that
appeared in
other analysis.
Yes, Steve? Dr. Nissen?
DR. NISSEN: I just wanted to comment for
the statisticians here. It is important to
understand how much of the evidence comes
from the
800-milligram dose which is not a dose
that is
180
approved.
So, what we have to understand and we
have to filter into our thinking here is
the fact
that the best signals come from a dose
that is two
times the upper limit of the approved
dose and four
times the most commonly used dose.
Now, that may or may not
reassure
individuals but it is, I believe,
relevant to our
considerations and I would like you all to
think
about that.
DR. WOOD: I think that comes under 1.c.
That is where we should deal with
that. Right now,
we are just addressing whether the drug,
itself,
can cause events.
Any other comments? Dr. D'Agostino?
DR. D'AGOSTINO: Just a comment that is
going to be picked up later on, but I
think that
the data--you can look at it as a full
package of
all the data we have seen but just focusing on the
Celebrex, alone, and the
placebo-controlled trials,
I think, is more than a signal that there
is
something going on there. So I feel very
comfortable saying yes to this.
Dr. Cush?
DR. CUSH: I would concur with the
original statements of Dr. Nissen and
Steve
181
Abramson in that there is a marginal
signal at
best.
But, again, when one considers the use of
celecoxib at prescribed doses and for the
approved
indications, there really is no signal.
DR. WOOD: In the absence of seeing
further discussion, are we ready to vote
on this
question?
DR. TEMPLE: No. I
just want to correct
something I said before that is wrong and
might
make a difference. I was unaware that some
proton-pump inhibitors had actually been
shown to
improve the G.I. tolerance of some drugs
and are
actually approved for that purpose. Lansoprazole
is approved for healing and risk
reduction of
NSAID-induced ulcers and there is a
combination
pill with lansoprazole and naproxen. S-omeprazole
has
a similar claim.
So I don't know if that is
going to affect
anything but I wanted to correct what I
had said
182
before.
DR. WOOD: I think that is relevant,
actually, and that is why I think I was
surprised
about it missed out with the naproxen.
DR. GROSS: I think we might want to
consider altering the question. That is certainly
acceptable for an advisory committee to
do and we
might want to comment on whether there is
a
significant increase in C.V. events at
the approved
dose versus the unapproved higher doses
because,
remember, whatever we approve, it is
going to have
a big impact on the public's perception
and how
they read this may not be how we intend
them to
read it.
DR. WOOD: We could come back to that and
see where we make recommendations about
what doses,
if
we decide--well, it depends how we vote on
this--and deal with that there. I would suggest we
deal with it at that stage and keep the
current
question the same. Sorry.
Tom?
DR. FLEMING: Just for clarification, as
we look at dose and we look at the three
randomized
183
trials, certainly in the APC trial, the
signal was
greater at 400 compared to the 200. The signal was
a
relative risk of 3.4 at the 400 although it was
still a relative risk of 2.5 at the
200. The
second piece of information was the
Alzheimer's 001
trial which also was the 200 BID dose
that showed
basically almost a doubling.
So I am a little
uncertain. Are we
challenging that the 200 BID dose isn't a
dose
level at which there is some evidence for
excess?
DR. WOOD: I'm not.
I mean, are others?
I guess the other thing, which we have
not talked
about at all, has been dose creep in the
use of
these drugs.
DR. D'AGOSTINO: But we are definitely not
saying that we think there is no dose
response and
so forth.
I think it is the dose response that is
going on here.
DR. FLEMING: That's right.
I would
certainly stop short of saying dose isn't
important. That is not my issue. My issue is I
thought I heard some comments that, if I
184
interpreted it right, the 200 BID dose is
one for
which there isn't evidence of an excess
and, it
seems to me, there is.
DR. WOOD: Yes; I agree.
DR. CUSH: Not in approved indications in
the Alzheimer's and the in the APC study.
DR. WOOD: Let's go back to that. The
reason we don't have evidence in the
approved
indications is because the studies couldn't
be done
in the approved indications. So that shouldn't
wrap us in warm, fuzzy feelings, I don't
think.
That is a reflection of the nature of art
rather
than the science.
Any other discussion? Great.
Let's go,
now--now, I have got strict instructions
as to how
to do this. So we have to go around the room and
everybody has to say their name and then
vote yes
or no.
So you precede your vote with your name.
And we are dealing with Question 1.a.
Let's start with Dr.
Abramson. For the
record, Dr. Cryer doesn't get to vote,
apparently,
and neither does Dr. FitzGerald. Neither does Dr.
185
Stemhagen.
DR. ABRAMSON: So I would answer yes,
consistent with the COX-2 inhibition.
DR. NISSEN: Steve Nissen.
Yes.
DR. ELASHOFF: Janet Elashoff. Yes with
respect to placebo. No with respect to the NSAID
comparator.
DR. GARDNER: Jacqueline Gardner. Yes.
DR. PLATT: Richard Platt. Yes.
DR. DAY: Ruth Day.
Yes, and I look
forward to the discussion of dose effects.
DR. FURBERG: Curt Furberg.
Yes.
DR. FLEMING: Fleming.
Yes.
DR. DOMANSKI: Domanski.
Yes.
DR. BOULWARE: Dennis Boulware. Yes.
DR. DWORKIN: Robert Dworkin. Yes.
DR. HOFFMAN: Gary Hoffman.
Yes.
DR. MANZI: Susan Manzi.
Yes.
DR. FARRAR: John Farrar.
Yes.
DR. HOLMBOE: Eric Holmboe.
Yes.
DR. GROSS: Peter Gross.
Yes.
DR. WOOD: Alastair Wood. Yes.
DR. GIBOFSKY: Allan Gibofsky. Yes,
"but."
DR. CRAWFORD: Stephanie Crawford. Yes.
186
DR. CUSH:
Jack Cush. Yes.
DR. BATHON: Joan Bathon.
MS. MALONE: Leona Malone.
Yes.
MR. LEVIN: Arthur Levin.
Yes.
DR. ILOWITE: Norm Ilowite.
Yes.
DR. D'AGOSTINO: Ralph D'Agostino. Yes.
DR. MORRIS: Lou Morris.
Yes.
DR. CANNON: Richard Cannon. Yes.
MS. SHAPIRO: Robyn Shapiro. Yes.
DR. PAGANINI: Emil Paganini. Yes.
DR. FRIEDMAN: Larry Friedman. Yes
DR. HENNEKENS: Charles Hennekens. Yes.
DR. SHAFER: Steve Shafer.
Yes.
DR. WOOD: So the total vote is
unanimously yes.
Let's move on to Question 1.b.;
does the
overall risk versus benefit profile for
celecoxib
support marketing in the U.S.? So this is the
question for which everybody is waiting,
I guess.
187
Discussion?
Dr. Elashoff?
DR. ELASHOFF: I would just like to
comment that, in some trials, like those
of the
statins, it is a potential benefit
weighed against
a potential risk. Here we are talking about
immediate benefit in terms of pain versus
potential
risk.
I just wanted to make that distinction.
DR. WOOD: Right, although it is worth
remembering the rationale for these drugs
is a
safety benefit. There is no evidence that we have
been shown that these drugs have a
greater
analgesic effect than the other drugs.
Other discussion? Dr. Shafer?
DR. SHAFER: I would submit for Question
1.b. that we really don't have the
efficacy data.
There are no data on G.I. risk with
concurrent
steroid use which is a common
co-administered drug
in patients with arthritis, particularly
rheumatoid
arthritis.
I asked the Pfizer
representative if there
were data about celecoxib versus NSAID
plus PPI.
He said he didn't know of any. In fact, there are
188
two such studies both published by Dr.
Chen, one in
New
England Journal 2002, one in Gastroenterology,
2004, with an editorial by Dr.
Cryer. Neither was
sponsored by a drug company and both
showed no net
benefit.
So I don't know what, if
anything, we can
conclude about the efficacy of celecoxib
given
that--versus what is likely the
alternative therapy
which is PPIs plus NSAIDs.
DR. WOOD: The CLASS study also showed no
benefit in the full analysis.
Dr. Domanski?
DR. DOMANSKI: I think that what I am
about to say is true not only for
Celebrex but for
all of them, but certainly for
Celebrex. I think
that the data presented support the view
that the
COX-2 inhibitors are effective for their
intended
use, probably not uniquely so in any
group that we
can define right now but almost certainly
in some
individuals.
Secondly, these drugs, Celebrex
and all of
them, in fact, do place patients at
increased risk
189
for a heart attack or death but the
absolute
increase in risk is not such that these
drugs
should be taken out of the hands of wise
physicians
and their well-informed patients in whom
these
drugs were a last resort for achieving an
acceptable quality of life.
So I think that, with this drug
as with
the others, we need a black-box warning
that is
carefully crafted. But taking them out of the
hands, as though they were a smoking gun,
is
probably too extreme.
DR. WOOD: But you are talking about more
than just a black-box warning. You are talking
about using them as a last resort; right?
DR. DOMANSKI: That is how I would suggest
they be used.
DR. WOOD: That may come in c., I think.
Any discussion on 1.b.? Yes?
Dr. Shapiro?
MS. SHAPIRO: I'm confused by that last
comment.
I have not walked away from this
conversation with the view that they are
a
last-resort option for most of the people
who are
190
taking them. Could you explain.
DR. DOMANSKI: Are you asking me for an
explanation? I think that is how they should be
used.
I think there is clearly a significantly
increased risk. I think many people will derive
benefit from other drugs that probably
are
less--place them at less risk. But I think there
also exists a group of people who don't
derive
benefit.
There clearly are differences among
people in which drug they respond
to. Somebody who
is leading a very poor quality of life,
who
understands the risk they are taking and
is willing
to take it, I think is a reasonable
candidate for
that drug and I don't think it ought to
be pulled
out of the hands of the physicians to
prescribe it.
MS. SHAPIRO: I just want to be clear
that, in thinking about the answer to
this
question, we are considering taking into
account,
for most people, as opposed to the
smaller subset,
the availability of less risky
alternatives in
giving our guidance to the FDA. Am I right?
DR. WOOD: Right.
DR. DOMANSKI: And I would certainly
second that.
MS. SHAPIRO:
Okay. Dr. Farrar?
191
DR. FARRAR: I need to bring up a couple
of points here that I think are vital to
our
discussion. First of all, again, for clarity
perspective, the lack of G.I. side
effects is not
the benefit we are talking about. I agree with Dr.
Shafer that some of the benefit that they
may
provide to our patients is in a reduction
of the
side effects that are seen in the G.I.
tract.
But the benefit that we are
talking about
here is the benefit to patients who are
not
responsive to other drugs perhaps because
of G.I.,
known G.I., toxicity but, perhaps, also
for another
reason which is that these agents work in
a
different manner.
Dr. FitzGerald laid out very
carefully for
us the complexity of the COX-1/COX-2
story and it
is not clear to me, as a pain specialist,
that we
yet understand all of the complexities of
that.
What we have heard from and seen from
patients that
192
we have all treated and heard some
comments
yesterday is that these drugs work very
effectively
in certainly some of those patients where
other
drugs did not work. I would take serious issue
with the comment that we don't know that
they work
better.
For sure, if you look at trials
and you
look at the mean value of the benefit,
these drugs
cannot be shown to be of superior benefit
in an
overall population. However, certainly from the
clinical experience, we know that there
are
patients who will respond to one and not
to
another.
I would argue, in fact, that there is a
very strong reason for allowing drugs, as
long as
the risk is not abhorrently high, that
these drugs
be allowed to be available so that patients
and
clinicians can make decisions
understanding all the
risks in moving forward.
The last thing is, with regards
to it
being a last resort, I think if you
looked at the
comparison of lumiracoxib with ibuprofen,
what we
see there is that there is a reduction in
the
193
cardiovascular--or a lower cardiovascular
risk in
one group compared to what we would
normally
consider and is even over-the-counter as
a therapy,
so one that we would sort of consider
more safe.
I don't think that we have data
yet that
tells us that these are a last-resort
medication.
DR. WOOD: Do we have data, just for
clarification for me, that show that
there are
patients--data-driven studies that show
there are
patients who respond to these drugs who
did not
respond to traditional
nonsteroidals? Can we point
to published studies where that has been
done?
DR. FARRAR: There are no published
studies that I know of.
DR. WOOD: Okay.
That's good. Let's move
on to Dr. Ilowite.
DR. ILOWITE: I just wanted to comment
about the words "last resort"
also. I think it may
convey that you have to go through all 20
NSAIDs or
wait until you have a serious
gastropathic event
before using them. I don't think that is what you
meant to say.
DR. WOOD: All right.
Dr. Hennekens?
DR. HENNEKENS: I find answering b.
difficult without at least thinking about
c.
194
because those patients who are allergic
to
naproxen, those with GERD or other G.I.
toxicities
for whom NSAIDs and PPIs are deemed
contraindicated
by their doctors, those who wish to take
it despite
knowing that there is a 40 percent higher
risk of
CVD, these are things which drastically
alter the
risk:benefit equation, in my view.
DR. WOOD: Okay.
Dr. Domanski?
DR. DOMANSKI: Let me flesh out the term
"last resort." I want to be careful that it
doesn't imply some mechanical necessity
to go
through every drug known to man. I think it is a
matter of judgment. I think that they would be my
last choice in a given patient but not
necessarily
the last of 20.
DR. WOOD: Dr. Holmboe?
DR. HOLMBOE: I agree that I think with
some restrictions that this should be
made
available. I am also troubled that the other
195
available agents, I am not convinced
after this
meeting, that they are necessarily any
safer. I
think the only thing we have seen, some
reasonable
data, has been around Naprosyn but almost
everything else we have seen with the
other
alternatives don't exactly give me great
comfort
that making patients take those over
COX-2s would
be necessarily better.
DR. WOOD: Dr. Nissen?
DR. NISSEN: That is exactly the same
problem that I am having. It would be very easy if
we knew that ibuprofen and diclofenac
were placebo.
See; I answered yes to the question, does
celecoxib
increase risk over placebo. I am convinced by all
the statistical arguments that it does.
What I don't know is if it
increases risk
over ibuprofen or diclofenac. So, you know, it is
a moving target, everybody, and I think
your point
is an extremely important point here. So how you
answer that question depends on whether
you accept
the premise that all the other NSAIDs are
at 1.0
for hazard, and I am not convinced that
they are.
196
I am worried that some of them may be at
1.3, 1.4,
1.5 where we think celecoxib is, in which
case our
decision could be irrational.
So it is a really big problem.
DR. WOOD: Dr. Temple?
DR. TEMPLE:
I don't want to participate
in this discussion but I did want to
point out to
people, however, that where you are very
worried
about a side effect of a drug, it is
possible, in a
very easy way, to show that it works when
other
drugs don't work. You take failures on whatever
the standard therapy is, randomize people
back to
that therapy or to the new drug. That is how
clozapine got into the marketplace. That is how
bepridil got into the marketplace. So, if that was
really an important question, that is not
that hard
a study to do.
DR. WOOD: Right.
But it is not a study
that has ever been done.
DR. TEMPLE: Not to my knowledge.
DR. WOOD: If the data is as compelling as
people would have us believe, it should
have been
197
very easy to do.
Any other discussion? Yes?
DR. BATHON: I am very strongly in
agreement with the last few comments
about safety.
I wanted to throw out one other comment
for
consideration. If a pharmaceutical company brings
a conventional NSAID to the market, they
don't have
to prove that it is better than the
existing
agents.
When the COX-2 drugs were brought to
study, their initial studies were 6
weeks, 12
weeks, long. They were shown to be effective in
reducing pain and so they were approved
on that
basis.
It was later, in the following
studies,
that they used the biology to then work
towards an
indication of safety from the G.I.
perspective.
But, as we are deliberating, I don't
think it is
entirely fair to hold them to higher
efficacy
standards because we don't hold
conventional NSAIDs
to that basis.
Now, if we then add in the
safety
perspective--if they are not more efficacious,
then
198
we have to prove that they are less
safe. The last
few comments are relevant because of the
safety
signals that we might be seeing with
conventional
NSAIDs.
We are in a quandary, I think, saying that
they are more safe at the point.
So I would just like to put
that
perspective.
DR. WOOD: Tom, could I ask you to go back
over for us what you saw as the safety
signals with
conventional NSAIDs. You went through that with us
once.
DR. FLEMING: You mean specifically what
we know from these trials?
DR. WOOD: Right.
Just the conventional
NSAIDs.
It didn't sound very convincing to me, but
maybe I missed it.
DR. FLEMING: I think what I was saying
was just referring to the evidence that
we had from
these 12 to 14 trials and we had evidence
on
naproxen and we had evidence on
diclofenac.
DR. WOOD: But they were not evidence of
harm; right?
DR. FLEMING: My sense was that the
evidence for naproxen, in relative
comparisons
here, was, overall, quite favorable and
that was
199
based on the positive result in the VIGOR
trial and
the positive results in the etoricoxib
setting and
the lumiracoxib setting. The ADVANTAGE trial was
fairly neutral.
So it seemed from those data
that the
naproxen experience looked more favorable
than the
coxibs it was compared to. The diclofenac was
compared in the CLASS trial and in the
etoricoxib
setting.
In the etoricoxib setting, it was neutral
to slightly worse. In the CLASS trial it was what
I might call comparable to the Celebrex.
DR. WOOD: So we are not hearing from you
a lot of evidence-based concern about the
other
nonsteroidals. That doesn't mean they are not
there, obviously.
DR. FLEMING: Certainly the data are much
more limited. My own sense about this is that the
diclofenac seems to be in the range
of--its
experience seems to be in the range of
what we were
200
seeing with the coxibs that it was
compared to
while my own sense, in looking at the
tally of the
data, is that the naproxen does look more
favorable, in the aggregation of
evidence, compared
to the coxib comparators.
DR. WOOD: And the diclofenac would fit, I
guess, with the biology, perhaps.
DR. CRYER: Mr. Chairman, if I may, I feel
compelled to respond to that specific
question
about the safety concerns of traditional
NSAIDs
because the response only addressed
potential
cardiovascular concerns. From a gastroenterology
perspective, I feel compelled to remind
the group
that this was the original problem that
led to this
entire discussion.
DR. WOOD: I don't think anyone doesn't
doesn't recognize that.
DR. CRYER: Okay.
DR. WOOD: Dr. Hennekens?
DR. HENNEKENS: On Tuesday of this week,
Dr. Colin Baigent of Oxford presented to
the
European Medical Evaluation Agency his
preliminary
201
analyses of 113 trials with 135,000
patients.
Looking at the placebo-controlled trials,
the
relative risk was 1.41. In the naproxen
comparator, it was 1.56. In the non-naproxen
NSAIDs, it was 0.86. So we were fortunate to have
Tom here with what he has done because,
in effect,
Tom has given us the same perspectives
that were
reported to the European authorities.
DR. WOOD: Any further discussion on 1.b.?
Dr. Abramson.
DR. ABRAMSON: Just, Alastair, I wanted to
address your point that there is no
evidence in
randomized trials to be suspicious of the
nonspecific nonsteroidals. The nature of the
evidence, I think, is that they were no
different
in many of these trials from the drugs
that we were
imputing some cardiovascular risk. I guess Dr.
Fleming, yesterday, one of the members of
the
panel, was talking about if a coxib is
worse than
placebo.
We have multiple randomized
controlled
trials from TARGET to CLASS and EDGE,
that the
202
comparator nonselective NSAID looked like
the coxib
than b. looks like c., and b. is
different from a.
I think that is the nature of the
evidence in the
randomized clinical trials that gives a
lot of us
some concern about giving those drugs a
pass.
DR. WOOD: Arthur?
MR. LEVIN: Not to be wordsmithing but I
am somewhat uncomfortable with the
wording of b.
and c. and how it may be interpreted, and
I would
say not only for 1., but 2. and 3. as
well. I
guess I would interpret b. as a question
asking
does it support the marketing as "at
present" in
the U.S.
I mean, that is how I would interpret
that.
When we start nuancing that and
modifying
and saying, yes, but with a black-box
warning or
yes, but with this risk management
strategy, that
is for later discussion.
DR. WOOD: I interpret it as--and the FDA
can correct me here--I interpreted that
under any
circumstances. Is that fair?
DR. JENKINS: I can address that. The
203
intent of these questions were that the
questions
would be the same for the three approved products.
So the first question, we wanted to hear
your view
on is are there data to suggest that
there is an
increased cardiovascular risk for the
individual
product.
That is why we put that first.
If you were to answer no to
that question,
it might make the second question less
important.
We also wanted you to answer the question
which is
b., which is essentially, should the
product be
withdrawn from the market It is not stated that
way because, in a desire to keep the
answers all
the same for the three questions, it made
it odd
for the Vioxx, which has already been
voluntarily
withdrawn.
So that is why we asked, do the
data
support marketing. The third part of the question
really gives you the opportunity to say,
yeah; I
think it should be on the market but we
think you
should make the following changes to
manage the
risks that we saw in a.
DR. WOOD:
I mean, given what we heard
204
yesterday about Vioxx not being on the
market but
maybe being back, do you want to change
it? Should
they be withdrawn?
DR. JENKINS: No. I
think it is fine to
leave the questions the way they are
because, you
know, Merck has stated their perspectives
on this
but, presumably, if you find that these
products
have a cardiovascular risk and should
stay on the
market, you are going to give us advice
about what
we should do to change the labeling, the
marketing,
et cetera, et cetera, for these
products. So Vioxx
could not just reappear back on the
market on
Tuesday like a question we got last night
in the
press briefing. There would need to be substantial
agreements to move forward on how to
revise the
labeling which we would have to approve.
DR. WOOD: Right.
Okay.
Does that help, Arthur? All right.
Dr.
Cush?
DR. CUSH: I'll pass.
DR. WOOD: Any other discussion? Dr.
Nissen?
DR. NISSEN: I want to be reassured that
ibuprofen and diclofenac are not worse.
DR. WOOD: We don't have that data. I
205
would like to be reassured, too. Bob Temple
designed the study. We would all want reassurance.
But we are sitting here at whatever time
it is,
11:00, 12:00--
DR. NISSEN: I understand.
I am being
provocative for a reason and the reason
is that
there is a lot of uncertainty about those
other two
agents.
I think that, as we think about
changing
the landscape of the use of NSAIDs, there
are some
risks we are taking. Some of the risks are that we
shift use to agents that may actually
turn out, in
the final analysis, to be less safe. I think we
have to understand that.
DR. WOOD: We understand that. But I
think we are faced with the data we have
right now
and we need to act and decide on that
which is the
position the FDA was in as well and why
they found
it tough.
Okay. In the absence of any other
206
comments--oh; I'm sorry. Dr. Manzi.
DR. MANZI: This is prior to voting for
Letter b.
I want to make sure it is clear that we
are voting on risk:benefit in the
population that
there is an indicated use for. Is that
correct--not the prevention population.
DR. WOOD: Right.
I mean, if someone
comes in and demonstrates that this drug
cures
cancer 100 percent of the time, then,
obviously,
they will come back and have a very
different
risk:benefit ratio than we would be
discussing
here. So I think all we can
discuss right now are
the indications for which it is being
used right
now.
If someone comes back with
colon polyp
prevention or some other, a curing of
Alzheimer's,
the individual risk:benefit analysis that
people
would take into account then I think
would be
different. Then I think that would be reasonable.
DR. MANZI: I just think it is important
because, although we are extrapolating
risk from a
population that it wasn't indicated as
far as
207
usage, we can't extrapolate risk:benefit.
DR. WOOD: The population--I mean, one
question is do you think, as you take
this into
account, you should consider is, do you
think the
outcome for risk would be fundamentally
different
based on some biologically plausible
probability in
different populations. If it does, you might take
that into account, I guess.
DR. MANZI: I don't think we have the
answer to that. I think it is unknown. But I
think the benefit may be very different.
DR. WOOD: It is not entirely unknown.
The studies that were done in arthritis
patients
which were not placebo-controlled, done
against
active controls, showed the same kind of
signal.
Now, we impute in them a
placebo which is
always risky, of course. But we would have to come
up with some very convoluted kind of
argument, I
think, to do. But I hear your point.
Any other comments? Are we totally
satisfied, as the auctioneer would
say? Then let's
start the vote and we will start it on
the other
208
side this time. I would remind you, again, to
state your name.
DR. SHAFER: Steve Shafer.
I,
unexpectedly, cast my vote last night
when my
father, an 89-year-old man with no other
risk
factors for heart disease but a sensitive
stomach,
asked me if he should stay on his
Celebrex. I said
yes.
DR. HENNEKENS: Charles Hennekens. Yes.
DR. FRIEDMAN: Larry Friedman. Yes.
DR. PAGANINI: Emil Paganini. Yes.
MS. SHAPIRO: Robyn Shapiro. Yes.
DR. CANNON: Richard Cannon. Yes.
DR. MORRIS: Lou Morris.
Yes.
DR. D'AGOSTINO: Ralph D'Agostino. Yes.
DR. ILOWITE: Norm Ilowite.
Yes.
MR. LEVIN: Arthur Levin.
No.
MS. MALONE: Leona Malone.
Yes.
DR. BATHON: Joan Bathon.
Yes.
DR. CUSH: Jack Cush.
Yes. No "buts."
DR. CRAWFORD: Stephanie Crawford. Yes.
DR. GIBOFSKY: Allan Gibofsky. Yes.
DR. WOOD: Alastair Wood. Yes.
DR. GROSS:
Peter Gross. Yes.
DR. HOLMBOE: Eric Holmboe.
Yes.
209
DR. FARRAR: John Farrar.
Yes.
DR. MANZI: Susan Manzi.
Yes.
DR. HOFFMAN: Gary Hoffman.
Yes.
DR. DWORKIN: Robert Dworkin. Yes.
DR. BOULWARE: Dennis Boulware. Yes.
DR. DOMANSKI: Michael Domanski. Yes.
DR. FLEMING: Fleming.
Yes.
DR. FURBERG: Furberg.
Yes.
DR. DAY: Ruth Day.
Yes.
DR. PLATT: Richard Platt. Yes.
DR. GARDNER: Gardner.
Yes.
DR. ELASHOFF: Janet Elashoff. Yes.
DR. NISSEN:
Steve Nissen. Yes.
DR. ABRAMSON: Steve Abramson. Yes.
DR. WOOD: Okay.
To allow everybody to go
off and file their stories now, we will
break for
lunch and be back to start again promptly
at 1
o'clock.
Thanks a lot.
(Lunch recess.)
210
A F T E R N O O N P R O C E E D I N G S
(1:02 p.m.)
DR. WOOD: Let's get into our seats and
let's begin. I have taken the chair's prerogative
to change the program. What I have asked is Dr.
Anne Trontell from the FDA to give us a
short
presentation on what the FDA's regulatory
armamentarium looks like in terms of the
potential
restrictions or other changes they could
make to a
drug that might be relevant to this
discussion in
order that, as we go through the next
question, and
subsequent questions, we can do that in
the most
informed, thoughtful way.
Anne has very kindly agreed to
do this
very quickly--I mean, to prepare it very
quickly,
not to go through it very quickly. When we finish,
I will ask her to stay up there and we
will have
the opportunity to discuss the various
options with
her in some detail so that we have got a
really
good handle on what the various issues
are.
Anne.
DR. TRONTELL: Thank you.
This is a list
211
of some of the options that have been
outlined or
experienced by the agency. I am going to present
them quickly sort of in a rough
progression from
those that are voluntary and least
intrusive to
those that are most intrusive.
One option that I will start
off by
listing is not, in fact, one that is
under the
agency's purview to require but,
certainly, a
number of the sponsors have come forth
and made
voluntary limitations on marketing of
their
products perhaps by offering not to
market it
directly to consumers or, in some
instances, some
companies have voluntarily limited the
detailing of
their product to certain specialty groups
or
advertising, perhaps, to only certain
specialty
journals.
But let me turn now into the
arena where
FDA starts to have some regulatory
purview. The
first area is in the area of
labeling. There, in a
black-box warning, FDA can make quite
salient
certain risk information, certain
contraindications
or other conditions that they feel are
appropriate
212
to the safe use of a product.
One consequence of giving a
product a
black-box warning is that it limits the
use of what
we call reminder ads, those that simply
have the
product's name. In practice, it makes marketing of
these products directly to consumers
rather
difficult, it is actually mentioning that
drug
product.
Other options available in labeling
or
relabeling a product might to be to
change its
indication to some form of second-line
use or,
perhaps, to actually go so far as to
contraindicate
its use in certain patient populations.
Another broad tier of
interventions that
might be taken would be in the form of
some kind of
targeted education or outreach. This can go to
clinicians and/or to patients. This can come in
the form of public announcements or
"Dear
Healthcare Practitioner" letters as
has been done
repeatedly in the past.
One form of education directed
to patients
are medication guides which are, in fact,
forms of
213
patient-friendly labeling informing of
risks or of
the methods to avoid risks directed to
proteins
and, in point of fact, required to be
dispensed
with each prescription of that product.
There are other forms of
academic
detailing that have been shown in some
settings to
be quite successful in targeting
prescribers to
direct their prescribing of a product to
appropriate conditions felt to support
its safe
use.
The next broad category that I would
suggest would be what we have termed, in
draft
guidance, reminder systems. These have ways of
reinforcing or prompting people to seek
appropriate
use of the product. One candidate in this area
might be some form of a patient agreement
or
informed consent where the patient
acknowledges the
risks of the product and notes that they
accept
them.
There have been several systems
in this
category also put forth where the
physician makes
some form of attestation on paper or
otherwise that
214
some appropriate-use condition is being met. This
is the case for the drug product
alosetron that has
been mentioned here previously. This might be
attestation in the case of these products
that some
form of second-line use is being followed
that the
patient is otherwise intolerant of other
therapies.
Other reminder systems may also
take the
form of some limitation put on the amount
of the
product that is supplied in any one
particular
prescription or, perhaps, limitations
placed on
whether or not refills can be obtained.
DR. FARRAR: By physician attestation, do
you mean they have to write on the
prescription
what it is for?
DR. TRONTELL: I can give you the details
of the two systems--there may now be
three--where
there is usually some form the physician
fills out
to attest that the patient meets the
appropriate
conditions that might be kept on file or
that
might, in fact, be some condition of the
product
being dispensed. So, in the case of alosetron, a
sticker is placed on the
prescription. The
215
pharmacist is to look for that sticker to
be in
place before they actually dispense the
product.
The last category, short of
marketing
suspension, is what we have termed
performance-linked access systems which,
really,
might otherwise be termed some form of
restricted
distribution of the product. In this setting, one
sets forth some defined population,
either of
providers or patients, and sets up a
process or
system that restricts access to the
product to
those individuals.
Pharmacists may be involved if
this is a
product that is available through
outpatient
departments. These basically imply that not every
physician, pharmacist or patient is able
to get the
product without going through certain
conditions.
Those conditions are required for access
and,
hence, the term performance-linked
access.
Examples that may be known to
many in this
room include the drug product clozapine,
sometimes
abbreviated no blood, no drug. People are required
to present proof of inadequate white
count before
216
obtaining the product. Thalidomide has an
extensive system of registering patients,
providers
and pharmacists that require input from
several
parties to assure that the woman
obtaining the
product isn't pregnant at the time of
dispensing.
There are some others.
In these, just to reinforce the
point,
which is that the product is not
dispensed, not
shipped or otherwise made available to
the patient
unless defined conditions of minimal risk
have been
met.
That is a very quick
run-through. I will
be happy to entertain further questions.
DR. WOOD: Thanks for preparing that so
quickly.
Anne, a number of people have asked to
have a printed preparation of that
made. I wonder
if we could do that as soon as we have
finished.
Are there points of discussion
or
questions from the Committee? Yes, Arthur?
MR. LEVIN: Anne, how many drugs do we
have registries for now. It is more than one,
isn't it?
DR. TRONTELL:
I'm sorry. You said
registries?
MR. LEVIN: Right.
With Accutane, didn't
217
we get to a registry?
DR. TRONTELL: There is not one currently
in place with Accutane or isotretinoin,
but some of
the discussions by the Drug Safety
Advisory
Committee had made recommendations that
one be put
in place.
Traditionally, when you get into this
last category of restricted distribution,
it is
very difficult to put one in place
without some
form of registration. You really need a list of
who can and who may not, in fact,
prescribe the
product.
So registration is almost a condition of
putting up the restrictions.
MR. LEVIN: Just one other question. In
the beginning, you labeled something as
voluntary.
How would you characterize all of these
other
risks.
Is this a negotiated--in other words, you
have voluntary limitations on marking,
but
voluntary doesn't appear anywhere else,
such as
with labeling or anything else. But isn't all this
218
really a negotiation? Or does the agency have the
power to say, this is the way it is going
to be or
it comes off the market.
DR. TRONTELL: I think that is a difficult
question to answer directly. The distinction of
voluntary limitations were placed here
because, to
my knowledge, these agreements that have
been put
in place relative to marketing have been
ones that
have been offered by the drug companies
opposed to
FDA trying to make any restrictions upon
marketing.
Generally, all of these matters
of risk
management or risk minimization, there is
a
back-and-forth process that is directed
to the
feasibility of actually putting some of
these
systems into place.
DR. WOOD: But, in fairness, if this
committee makes strong recommendations
that
something should be done, it would be
pretty tough
not to follow them, I would have
thought. Dr.
Platt?
DR. PLATT: Anne, questions about
black-box warnings and academic
detailing; does the
219
agency have a sense overall about how
well
black-box warnings work? I am mindful of the fact
that cisapride was withdrawn from the
market after
several revisions of the black box failed
to reduce
inappropriate prescribing below something
like
25 percent of all cisapride recipients.
So that is Question No. 1. Why don't you
answer that and then I will ask you about
academic
detailing.
DR. TRONTELL: You know, evaluations of
the effectiveness of any of these
programs are
really limited and cisapride was
certainly an
instance where we saw persistence of the
undesired
behavior despite repeated labeling.
It is difficult to say. There are some
products, I was telling Dr. Wood at the
break--ketorolac has a black-box warning
and
indications that it should be used for a
very
circumscribed length of time. Our examinations of
prescription-use data would suggest that
there is
actually very high conformance in that
particular
instance.
So I am not sure we have enough
220
information to predict the effectiveness
of these,
in particular the black-box warning.
Again, looking at the black-box
warning
put in place for the drug product Seldane
and the
occurrence of torsade de pointes in its
concomitant
administration with other products, there
were some
evaluations of that labeling intervention
suggesting that upwards to 90 percent or more
of an
appropriate co-prescribing had been
eliminated but
it had not eliminated entirely and that
there were
still unacceptable levels persisting.
So it is a mixed picture and I
would like
to emphasize to everyone that, perhaps,
with the
exception of the restricted systems,
which are put
in place on a relatively limited basis
because they
are really quite a large undertaking and
do
restrict access as well as minimize
risks, that we
have very poor information.
The systems that register
individuals, by
the nature of the fact that we now have a
defined
population of people receiving the
product, we can
better estimate the adverse events and other
events
221
that are reported to us. In the case of clozapine,
we can actually look at how many low
white counts
have been observed.
DR. WOOD: But there are other examples.
The Rezulin example with multiple changes
in the
label to invoke different liver-function
test
frequencies, there is good data on the
fact that
that was not followed, I guess. And the cisapride
example is also true. Wasn't it bromfenac that was
supposed to be for ten days and most of
the
patients got it for longer. So there are a lot of
examples that, at best, don't provide you
with much
reassurance that labeling changes work.
That is not to say we shouldn't
do them,
but, certainly, just labeling change on
their own
have not been extraordinarily effective.
DR. PLATT: Right.
So can I ask you about
what mandatory academic detailing
means. Who is
responsible for developing the
content? Who is
responsible for delivering it? Who is responsible
for overseeing compliance with an
effective
academic-detailing regimen?
DR. TRONTELL: This is something that I
put down for--to my knowledge, I don't
believe we
have any mandatory academic detailing
positions in
222
place but, as one example of a form of
education
that, in some settings has been shown
effective to
alter prescribing behavior. But, to my knowledge,
that is not in place.
If you go back to some of the voluntary
programs, some products are largely, if
not solely,
limited to certain specialty groups. Some of the
human-growth hormones are largely
confined to
pediatric endocrinologists. So that has--I don't
know the particulars of how those
products are
detailed to those prescribers.
DR. PLATT: Right.
So it is not an option
for us to recommend that the agency
require an
academic detailing program.
DR. TRONTELL: In this component, again,
these slides were assembled hastily--I
think the
question might be, it still fits into
some realm
where we might define some targeted
prescribing
group that we thought would be
appropriate to
223
determine which patients should receive
this
product.
So I believe it is not an easy option to
identify.
It really probably relates a little bit
more to some of these issues which is if
there is
some form of limited promotion directed
toward one
specialty group or a specially trained
group in
being able to prescribe these products.
DR. WOOD: Dr. Manzi.
DR. MANZI: Actually, my questions were
answered.
Thanks.
DR. WOOD: Okay.
Great. Dr. Day?
DR. DAY: I just wanted to mention that,
in addition to the attestation option,
having
people sign a piece of paper, either the
physician
but especially the patient, that they
have read and
"understand," we don't know
that they really
understand until we give them a
comprehension test.
So, this could take the form of
a very
brief survey. This has been tried in Accutane. To
start out with, it was a voluntary
survey. Under a
voluntary survey, I believe that 20
percent of the
patients actually filled out the
survey. I don't
224
think that the new guidelines for what is
going to
happen on Accutane have been released
yet, but
there was some talk that that might
become
mandatory.
So it doesn't need to be onerous. It can
be very brief. But there might be some patients
who are in such pain on a given day, give
them
anything, they will sign it to get their
relief.
But if they are going to be taking these
products
over the long term, we really do want to
be sure
they understand what the consequences are
going to
be.
DR. WOOD: You might sign something when
you were getting your wisdom teeth out
that might
not be applicable later; right? Dr. D'Agostino?
DR. D'AGOSTINO: Could you just reiterate
what you mean by the black box makes
direct-to-consumer very hard. I thought it
eliminated it. So could you explain what it
actually does?
DR. TRONTELL: I will actually defer to
Dr. Temple to give you those details.
DR. TEMPLE: The black box makes reminder
ads impossible. How big a deal that is depends on
how much reminder advertising there
is. I think
225
that is not a major thing.
But the ad to be considered
appropriately
balanced would have to convey the
contents of the
black box in all its full
unpleasantness. I think
that is what Anne meant. It is hard to write an ad
that is appealing to people when you are
telling
them about all this bad news, and that
would have
to be right up front.
I don't know how much you pay
attention to
ads, but you can't just stick it over in
the place
where all the small print is. It would have to be
part of the main ad, whether that is a
written ad
or a t.v. administration.
DR. PLATT: These ads you see on
television, at the end telling you may
die from
this.
DR. TEMPLE: Things like that. It would
have to say the bad news.
DR. MORRIS: But, Bob, that is why there
226
is no oral contraceptive ads on
t.v.? That's the
point.
That is black-box drug.
DR. TEMPLE: I wouldn't allege for a
minute that all black boxes make it
unattractive to
do them.
But those ads have to tell you this bad
news and, if that is so unattractive, the
ad
doesn't appeal anymore, that is what
would make it
difficult.
DR. MORRIS: But, even if there is no
black box, it has to tell you the bad
news.
DR. TEMPLE: The contents of a black box
are scary and unpleasant and that is all
Anne
meant, that it might be hard to get an
appealing
ad.
DR. MORRIS: I don't want to get off the
impression that, if there is a black box,
we don't
have to worry about DTC.
DR. TEMPLE: No; I wouldn't say that.
DR. WOOD: No; that is exactly right.
There are certainly ways to do DTC in
print ads,
particularly, that would be permissible
with the
black-box warning. They might not be pictures of
227
young ladies skipping through pretty
fields, but
they would be unlikely to have just skull
and
crossbones on their either.
DR. TEMPLE: Right.
The only thing I
would allege is that we would ask that
the contents
of the box be featured prominently in the
ad. So
it still might be possible.
DR. WOOD: So one way to summarize what
Anne is saying about this would be that
restricting
DTC should be a separate or additional
issue to
black-box warnings. Is that fair, Bob, even though
I understand restricting DTC is not
within your--
DR. TEMPLE: Right.
DR. WOOD: But it is within the rubric of
the commission's recommendations.
DR. TEMPLE: It is.
I think what Anne
said is we can negotiate on those
things. We don't
think we can ban DTC. Not everybody thinks that is
true, but we don't think we can.
DR. WOOD: But we did hear yesterday that
voluntary agreements can be changed
pretty fast.
DR. TEMPLE: Right.
Can I mention one
228
other thing?
DR. WOOD: Sure.
DR. TEMPLE: We do have one actual rule
that does allow us to impose restricted
distribution under what is called Subpart
H for
drugs that are important and that you
could only be
satisfied that they were safe for use in
that
setting.
We have not, to my knowledge,
imposed such
as Subpart H restriction after
approval. I could
be wrong about that. I am sure it would involve
what you have been calling
negotiation. But I
don't think it is impossible
DR. WOOD: But that was mainly applied to
oncology drugs; right? No?
DR. TEMPLE: No.
Subpart H has two parts.
One is approval on the basis of a
surrogate. That
one part.
The other part is approval with limits
on distribution that also make you--you
would have
to believe that drug couldn't be
distributed safely
without it. It is only supposed to refer to drugs
that you really need to.
DR. WOOD: Dr. Gross?
DR. GROSS: Since direct-to-consumer
advertising has been so effective for the
229
pharmaceutical companies, have you
considered doing
direct-to-consumer education from the
FDA's point
of view, either pairing it with the ad
from the
pharmaceutical companies, doing it
separately. I
know it costs money. Maybe you could have a PDUFA
extended to cover the cost for that. But I think,
since it has been so effective for them,
why not
consider it for you?
DR. WOOD: Which one of the three of you
wants to take that?
DR. TEMPLE: Actually, I am embarrassed to
say I didn't hear the very beginning of
the
question.
DR. WOOD: The suggestion is that, in
addition to direct-to-consumer
advertising by drug
companies, there could be
direct-to-consumer
advertising by the FDA to put the other
ads in
perspective, I guess.
DR. TEMPLE: Ah.
That takes money beyond
230
what we usually feel we have.
DR. GROSS: That is why I suggested PDUFA
funding.
DR. TEMPLE: That's okay with--never mind.
I am not allowed to say that.
DR. TRONTELL: What FDA does have is the
opportunity, through its own broadcast
resources,
through MedWatch, through public-health
advisories,
the opportunity to speak. But, certainly, any kind
of commensurate advertising campaign has
largely
been restricted to broad messages; you
know,
generics are safe, et cetera, like that.
DR. WOOD: Dr. Dworkin.
DR. DWORKIN: Are there other levels of
warning in addition to black-box
warnings?
DR. TRONTELL: Well, a black-box warning,
or a boxed warning, is really--attaches
to some of
the marketing restricts that Dr. Temple
described,
but there is, certainly, as part of the
package
insert or physician labeling, a warning
section
that information can be placed. The black box is
often set off in heavy type to make it
prominent or
231
salient to the physician, anyone looking
at this
product, that there is some special risk
that
deserves attention.
DR. WOOD: Dr. Morris?
Oh; okay.
MR. LEVIN: A couple of things. One of
the reasons for my no vote was this
concern and
that is the ability of FDA to insist on
and enforce
conditions which will limit the
distribution and
use of the drug to appropriate
populations.
That said, some of the
risk-management
experiences we have had actually have
been
positive.
For example, with lotrinex, we did
manage to reduce the population being
prescribed
the drug considerably and, I think, into
the range
of what experts estimated was the
appropriate
population.
My problem here is the time it
takes to
work through this. I can't remember when we had
that Accutane meeting but it was over a
year ago.
Accutane meetings have occurred regularly
over the
last several decades and it just take
forever, in
this negotiated process, to get the
things in place
232
that are recommended and then accepted by
the FDA.
So I am very concerned about the time-lag
issue
here, that whatever we recommend today,
in terms
of--if we do, in terms of these kinds of
options
for limiting risk, that you are not going
to see
this in the next couple of months based
on prior
experience. It is going to be a long haul.
DR. WOOD: I think part of the committee's
job
should be to make a recommendation about how
fast we should see it and light a fire
under these
guys.
That will provide some ammunition to the FDA
in their negotiations and will provide
some focus
to others. If they are not doing it fast enough,
then we--the other option, I suppose, is
to put a
more restrictive position until whatever
issues are
resolved.
Sorry. John?
DR. JENKINS: I think, as Dr. Galson said
on
Wednesday morning in the Introduction, we are
committed to making our decision our your
recommendations on these applications and
these
products very quickly after this
meeting. We will
233
do everything we can to implement
whatever those
changes are as quickly as possible
recognizing
there are, sometimes, some just
logistical issues
that have to worked through. But we are committed
to
doing the action and getting it implemented as
quickly as possible in this case.
DR. WOOD: There is nothing beats setting
a time line, so we will probably do
that. Any
other comments?
DR. NISSEN: Quick question. If we think
the dose is a particularly important
issue, could
one restrict the--could we change this
label or
change the doses that are marketed; for
example,
celecoxib is available in 100 and
200-milligram
capsules.
Could we limit it to the 100-milligram
capsules as a way to avoid the exposure
to higher
doses.
Is there a way to do that for the FDA?
DR. TRONTELL: That would fall in the
category of what would be a reminder
system; in
other words, to make it difficult for
people to
take the higher dose. By requiring them to take
more pills, they would use it up more
quickly. So
234
that would be an option that I think we
would be
eager to hear from the committee if that
was what
they thought would be the best to do.
DR. NISSEN: What I am getting is to get
800 milligrams, you would have to take 8
capsules
which, obviously, would have an effect on
patients
not doing that.
DR. JENKINS: If I could just make a
comment on that. We have to be careful that, when
we make our changes, that we don't have
unintended
consequences of our changes. One of the things
that catches people off guard sometimes
is that
drug prices are not reflected, or based
on the
number of milligrams that are in the
capsule. So
100 and a 200-milligram capsule often are
very
close to being the same price.
So you can have an unintended
consequence
for patients who need that higher dose of
substantially increasing their cost by
limiting the
dosage that is available.
DR. WOOD: I agree with that and that is
an important point, but one way, I guess,
to
235
implement that kind of change would be to
have a
different restriction for a different
dose. You
could have the 200-milligram dose with
different
restrictions on it than the 100-milligram
dose.
But we will get to that point.
DR. JENKINS: Right.
Stephanie?
DR. CRAWFORD: Dr. Trontell, could the
options for action from a regulatory
perspective
include the requirement for definitive,
well-designed postmarketing surveillance
studies or
is that not an option?
DR. TRONTELL: I think that is something
that can enter into some of the
regulatory options
that FDA would consider, but they are not
what we
have classically described as an
intervention to
minimize risk. So that might be a way to better
characterize the risk but that is
something I think
I will let Dr. Jenkins reply to more
definitively.
DR. JENKINS: We could clearly have the
companies enter into an agreement to do a
postmarketing commitment study based on
your
recommendations. So postmarketing commitments are
236
not only made at the time of approval,
they can
also be made after approval when a new
issue comes
up.
We probably haven't used those as much in the
past as we should have in the
post-approval arena,
but it is certainly something we could do
based on
your recommendation to what studies are
essential.
DR. WOOD: And your success in getting
these studies completed has not been
terrific;
right?
DR. JENKINS: I think that is a
misstatement on a lot of levels. I think the
record is much better than it is
portrayed often in
the media. Part of the problem in the past has
been record keeping as well as the agency
was not
as diligent in the past as we should have
been in
setting time lines for when the studies
should be
done.
We are much more strict now that we set
rigorous time lines for every aspect of a
study
including protocol submission,
enrollment,
completion. That information is now publicly
available on our website so you can see
if
companies are meeting their obligations
or if they
237
are falling behind.
DR. WOOD: Okay.
Well, I have got us back
on time before lunch and now we have lost
some of
that.
So, unless there are some really important
questions--oh; Dr. Shafer. All right.
Dr. Shafer,
is this really important?
DR. SHAFER: Yes. I
think so. But I just
want to say that I don't support the idea
of
limiting the drug by placing the burden
and the
hassle on patients, things that require
the
patient--
DR. WOOD: We will get to that issue.
Just questions for Dr. Trontell.
DR. SHAFER:
I am coming to the very last
point on the slide here. The efforts that place
the burden on the patients, themselves, I
think are
misdirected.
DR. WOOD: All right.
Thank you very
much, and thanks very much for preparing
that at
such short notice over your lunchtime.
MS. MALONE: I just wanted to thank him
for that comment.
DR. WOOD: I beg your pardon, Dr.
Trontell.
There is one more question.
MS. MALONE: I just wanted to thank the
238
last speaker for that comment.
DR. WOOD: Let's return to where we were
before lunch. We were about to begin the
discussion--oh; before we do that, I
should
announce the vote. Like in Iraq, it takes a long
time for the votes to be counted. The results of
Question 1.a. were 32 to 0, in case any
of you
missed that, and, for Question 1.b., 31
to 1.
Let's go on to Question 1.c.
which is, if
yes, and it was yes, please describe the
patient
populations in which the potential
benefits of
celecoxib outweigh the potential risks
and what
actions you would recommend.
The reason that we had the
immediately
preceding talk was it seemed to me, at
least, as I
looked at that question, that the
potential actions
obviously included a raft of the various
options
that we heard from the last speaker.
So, do we have discussion on
this point?
239
Dr. Cush?
DR. CUSH: The populations where the
potential benefits outweigh the risks
were, I
believe, those that are currently
indicated;
osteoarthritis, rheumatoid arthritis and
a few pain
indications. I do think that we should make a call
for additional study. I do think that there should
be additions to the warnings within the
label under
Precautions or Warnings, although not a
black box
for celecoxib.
I do think that there should
be, in those
warnings, or in the study designs that
have come
forward, a risk-reduction strategy so
that patients
who may be at risk, that risk is
minimized as much
as possible.
DR. WOOD: Other discussion? Arthur?
MR. LEVIN: Could I just ask why you
oppose a black-box warning?
DR. CUSH: In this instance and this
compound, I don't think there is a
preponderance of
evidence that argues in favor of that.
DR. WOOD: I didn't hear that last
240
comment.
DR. CUSH: I believe, for this compound,
there is not a preponderance of evidence
that would
suggest the need for a black-box warning
for this
compound.
DR. WOOD: All right.
Other comments?
Dr. Shafer?
DR. SHAFER: I think for indications the
drug should be indicated for individuals
who cannot
tolerate NSAIDs with a proton-pump
inhibitor. I
think the drug should be started at the
lowest
possible dose as part of the indications.
I oppose a standardized
black-box warning
for the class because I think that can
result in a
dilution of the message by implying that
the risk
across the class is identical. But I think each
drug should be evaluated
individually. In the case
of celecoxib, I think the FDA should
mandate a
black-box warning clearly stating the
increased
likelihood of cardiovascular adverse
events
including death. But I also think there should be
a black-box warning that contraindicates
the drug
241
following cardiopulmonary bypass based
upon the
pareoxib, valdecoxib, data. I think that
part--these drugs should all not be used
following
cardiopulmonary bypass.
Pfizer has voluntarily
suspended marketing
of celecoxib. I believe they should continue to do
that, although it is not in our purview,
until the
FDA has implemented the recommendations.
DR. WOOD: Other comments? Dr. Domanski?
DR. DOMANSKI: You know, I wonder--this is
a small point, probably. I think they all ought to
get a black box. I think there is something to be
said for--you know, if the message is
substantially
the same for having substantially the
same message
in that black box, though, because it
underscores
the fact that we think there is a class
effect,
admitting that there is probably some
variation
among the drugs.
DR. WOOD: I think we may have to circle
back to the class effect at the end. So I think,
right now, we should just focus on the
risk-management strategy for celecoxib
and not take
242
in the other ones.
I also think there should be a
black-box
warning.
I think there should be severe
restrictions on the prescribing of the
drugs at
both the dose and the patient
population. Curt?
DR. FURBERG: I agree with that. I think
if you are consistent. We unanimously said the
drug carries risks. So we have an obligation to be
more specific obligation to be more
specific about
that, and the way to do it is to have a
black-box
warning and warn against use in high-risk
people
and in the use of high doses.
DR. WOOD: I mean, we could have
direct-to-consumer advertising that had
people,
well-known skaters skating around an ice
rink and
then dropping dead, or something rather
than
just--okay.
DR. PLATT: So yes to black-box warning.
I am very impressed by the seeming
consensus we
have had that naproxen appears to be a
relatively
safe drug. So I would favor considering the label
and the instruction to clinicians being
that this
243
be a drug to be used as a drug of second
choice;
that is, for individuals who have either
failed a
comparator--and I am toying with the idea
of
suggesting the we actually name
naproxen--or who
are intolerant for some reason.
I favor the attestation
requirement
because I think there is an important
piece of risk
communication that we could do but I
think we won't
do without having that. I think there is a lot of
information living in the datasets that
were
presented to us that hasn't been put in a
form that
is most useful to patients and that is I
think that
I would have the attestation actually
specify the
incremental risk that patients might
expect based
on the accumulated literature and that
incremental
risk would be patient-specific based on
fairly
standard risk factors.
So I would really hope that the
committee
would support a request to FDA to
collaborate with
NIH to use the accumulated data to
develop much
more informative information for patients
and
physicians to allow them to estimate
their
244
incremental risk.
I think there is a huge
difference between
a patient agreeing to take an incremental
risk that
might be a half a percent per year versus
an
incremental risk that might be 10 percent
per year.
We have the information to allow patients
to know
what size risk they are taking on.
DR. WOOD: Dr. Nissen?
DR. NISSEN: The problem with that, of
course, is we don't have robust enough
data to
actually know that in an individual
patient's
situation. But let me come back--the thing is what
do we really want here? What we want is to make
certain that therapy is available for
those people
in whom it is appropriate and to make
certain that
people in whom it is inappropriate don't
get it.
Now, a black box is a good way
to
communicate things. The question is what does it
say?
I think what it has to say is that there is
evidence of an increased risk of
cardiovascular and
cerebrovascular and, obviously, in
language that is
very clearly written.
I also think that it is
important to
discuss--we have seen some pretty good
evidence of
a dose-response relationship with
cardiovascular
245
toxicity.
So, to say to physicians, you should
limit the dose and you should limit the
duration
whenever possible is also very important
to
communicate.
I don't think
direct-to-consumer
advertising is appropriate at this point,
given the
fact that direct-to-consumer advertising
tends to
stimulate the use of a drug, excessive
use of the
drug.
I think a patient guide is very helpful
here.
I think that patients--you have to respect
the ability of patients to also make
decisions. I
think a patient guide that explains in
lay language
what our conclusions are about the extent
of risk
that must be dispensed with the drug is a
very
helpful way to educate the public about
what these
risks look like.
I would also say that we ought
to offer a
strategy for the sponsor here for getting
these
warnings removed. In my view, an adequately sized
246
trial against a comparator that we are
comfortable
with--namely, naproxen, at the
200-milligram
dose--would be--we can set what those
upper bounds
are, but I think if someone can
demonstrate, if the
sponsor can demonstrate, that the
200-milligram
dose does not produce excess
cardiovascular risk
versus naproxen, that we ought to give
that option.
That would be an incentive, a
strong
incentive, to do that very pivotal trial
because
what we don't have is we don't have good
data on
what the 200-milligram dose, what its
risks look
like, compared to a very good
comparator. So those
are some of the thoughts I had.
DR. WOOD: I agree with that. I would say
that, from my personal perspective, that
it should
have a restricted black-box warning. It should be
given to very restricted patient
populations in
limited dose and for limited
duration. There
should be absolutely no
direct-to-consumer
advertising.
I would add that if a patient
guide or
even if the package insert, itself, was
to try to
247
specify risk, we should do that in a more
helpful
way than we do that right now. I don't know what 1
percent increase means to me, even. So we should
put it in some contextual basis like it
is the same
increased risk as you would get from
smoking so
many cigarettes a day. Or it is the same increased
risk as you get from whatever it is,
having
diabetes or something.
You could give multiple
different
examples.
So patients have some kind of sense of
what they are talking about here because
I don't
see how any of us, certainly not people
who don't
think about risk every day, can really
put that
into a meaningful contextual basis.
You know, people worry about
flying and
then get in their car and drive
drunk. So people
have a relatively poor ability, I think,
to assess
risk and we need to help them do that
with
meaningful statements rather than other
risks.
Are there any other--I'm sorry.
Yes?
DR. MORRIS: Let me argue against a ban on
DTC.
Firstly, I am against a ban for three
248
reasons.
One is I am not sure it is enforceable.
Secondly, philosophically, I am against
the idea of
banning information. Thirdly, it won't work.
There are too many other ways
of getting
to the patient and I think what you will
have is a
big influx of money into public-relations
efforts
in which we won't even see what is being
communicated to patients.
On the other hand, I would
argue very
strongly for a totally different way of
communicating the risks of these drugs to
patients.
Right now, what you have in all these
commercials,
is about a third of the ad having some
kind of
message that no one understands and
nobody takes
away.
It clearly just isn't coming across to
people.
What I would suggest is that
what we do is
we break out the risk information on this
drug into
a single commercial and that, for every
three
benefit commercials, we play this risk
commercial
so people can have a whole story in which
we can
put this into a better context, not put
together by
249
people whose job it is to market and sell
the drug
but let these commercials be put together
by an
independent group reporting to the FDA
that meets
the standards of fair balance for both
the company
and the FDA but which provides a full
message to
people about how the risks and benefits
of the drug
have to be carefully understood and
whatever other
message it is.
But I think that we need to
think of--I
mean, I have been--of all this whole
story, the
public reaction to the withdrawal of Vioxx
just
astounded me. I have to believe that part of their
reaction was due to the
direct-to-consumer
advertising that was done for this class
of drugs.
I think, unless we have a
fundamental
change and do a better job of educating
the public
and communicating better risks in the
same way we
communicate benefits, I think this is
going to
happen again in another class of drugs.
DR. WOOD: People who look at consumer ads
apparently interpret toxicity statements as
implying the drug is more toxic. The surveys of
250
the effects of the erectile dysfunction
ads and the
ones that have, because of the way they
chose to
advertise them--the ones that say, beware
of a
four-hour erection, are assumed by
patients to
imply more potency. No pun intended.
DR. MORRIS: But if there is a very vivid
risk, like, for Xenical, or, for some
reason, I
have learned people love their
livers. If you say
it causes liver disease, it really upsets
people.
But, for the most part, this--if you look
at the
research on consumer takeaways, what they
remember
from seeing an ad, risk information is
way down on
the list.
It just doesn't get through to people
with the same prominence as the benefit
information.
If we really want a balanced
ad, I think
we have to have a dedicated ad that
balances all
the benefit information.
DR. WOOD: Dr. Day?
DR. DAY: I agree with Dr. Morris'
intended outcome but I do not think we
need to go
to separated ads at this time. I apologize for
251
bringing in results that are not yet
published but
I feel morally obligated to at this
time. We have
produced our own t.v. ad for a fake drug
and, after
analysis of what is going on in all the
t.v.
ads--for example, the location of where
they put
the side effect and showing that that is
the least
optimal place for memory and
comprehension based on
separate laboratory studies on other
kinds of
materials--we then did experiments where
you put
the side effects in where they normally
come and
people don't remember or understand them.
You relocate them somewhere
else where all
the lab studies say people will remember
and you at
least double what they take away. In some of our
experiments, it has been even higher than
that. So
if we look at what the nature of
cognitive
processing is for a 60-second, 45-second
ad, amount
of information and put the information in
an
appropriate location, as well as adjust
the
language--we have done an extensive
analysis of the
readability level of what is being said
for the
benefits versus the risks.
We found that you need to have
three grade
levels more education to understand the
risks than
the benefits. If we can have fair balance on these
252
two things I have mentioned as well as
others that
we have looked at, then we will have more
of a
chance to have all the information at the
same
point in time.
DR. MORRIS: Ruth, I am not saying you
could not build an ad to do this. When we first
did the initial experiments on DTC, we
actually
varied different ways of presenting risk
information and, yeah; you can
communicate risk
information.
But if you look at the way ads are
produced, it is clear that the people who
create
these ads, their primary goal is to
market the
drug.
It is not to produce information that is
equally balanced. I don't think you can set up a
structure that people can't get around.
It would be fairly easy for
them to figure
out a way to get around it. Also, this was a t.v.
ad you did, or print?
DR. DAY: This is a t.v. ad.
DR. MORRIS: So, okay; you can do it. It
just won't work.
DR. WOOD: We are getting--I understand.
Let's move on. Dr. Elashoff?
DR. ELASHOFF: No.
253
DR. WOOD: No?
Let's look at my list
here.
Dr. Bathon?
DR. BATHON: If we do recommend the black
box, I am pretty strongly opposed to the
idea of
putting a dose and duration warning in
that. I
would say that, if you consider the four
indications right now for these drugs,
some don't
have all four indications, three of the
four
conditions are chronic; R.A., O.A., and
FAP. The
exclusion is acute pain.
So, to come in and say, use for
the
shortest duration possible, contradicts
the
indications. Secondly, if you put in an indication
to use the lowest dose possible, you are
negating
the fact that efficacy is better for some
of these
drugs at the higher doses for people with
254
rheumatoid arthritis in particular, and
they need
those higher doses. That is one of the four
indications.
I would suggest, if we decide
on a black
box, that we ought to have the underlying
theme be
avoidance in patients with high
cardiovascular risk
profiles.
That would be the underlying unifying
theme.
DR. WOOD: Although the risks also appear
in people with low underlying risk
profiles in the
studies.
DR. BATHON: The studies do show, the ones
that we reviewed over these past few
days, pretty
clearly, in a number of them, that those
people who
have higher cardiovascular risk profiles,
and who
are on aspirin, have higher event rates
than those
not.
DR. WOOD: Right.
They have higher event
rates, but the others had a significant
effect as
well.
DR. BATHON: We have to play probability
somewhere. We can't cover all of our bases.
DR. WOOD: Okay.
Let's go on. Dr.
Gibofsky?
DR. GIBOFSKY: No.
255
DR. WOOD: Dr. Manzi?
DR. MANZI: First of all, I agree with
Joan on most of the comments but I wanted
to get
back to the suggestion that we regulate
the order
in which we are recommending prescribing
the
medications where they have to fail the
tradition
or "nonselective, nonsteroidal"
first. I would say
I would be opposed to that because I think,
for
various reasons, there may be reasons to
go to
these agents first-line, whether it is
G.I. issues
or anticoagulation issues or whatever the
situation
may be.
DR. WOOD: Dr. Abramson?
DR. ABRAMSON: Yes. I
just want to
express an overall concern that we are
making
fairly draconian recommendations for the
drug that
we thought had the least robust evidence,
although
we all agreed it had evidence.
DR. WOOD:
We might make more draconian
256
recommendations for the others.
DR. ABRAMSON: I understand that. But I
think we are doing it out of context because
the
notion that you put a black box to say
that you
can't use this primarily without failing
other
drugs is not data-driven. We saw in, even ADAPT,
that there was increased negative
outcomes on the
Naprosyn group. So, while I agree with the
consensus that Naprosyn does seem to be
protective,
an unintended consequence of making
Naprosyn the
first choice without being very careful
is more
G.I. bleeding.
We all understand the PPIs
might protect
but this becomes a very complex
risk:benefit
decision.
I also think that, to say that,
therefore, diclofenac, meloxicam, et
cetera, look
very much like the celecoxib, should be
used before
celecoxib is not data-driven.
So I think we have to be
careful not to
make decisions that are driven by our
sense that
there is something terribly wrong with
this class
that supports the use of other drugs that
is going
257
to give us unintended consequences.
So I think we are going to end
up needing
a very serious warning, maybe a black-box
warning.
I think it is hazardous to discuss each
of these
drugs right now without defining what the
nature of
the class is because I am going to
suggest that
whatever we say for celecoxib it is going
to be
hard not to say for diclofenac and a
couple of
other drugs.
DR. WOOD: Dr. Domanski?
DR. DOMANSKI: I think that saying that
something is a second-line drug doesn't
necessarily
mean that you have got to try a different
drug if
it is clear to the physician that that
drug is
inappropriate. I mean, it forces you to consider
it as a second-line drug only but not
necessarily
to give something else.
I do think these should be a
second-line
drug, though, and I would just reiterate
that I
think that the warning should be a strong
one and I
entirely agree that that should apply to
the other
drugs in this class.
DR. WOOD: Dr. Dworkin?
DR. DWORKIN: I completely agree with Dr.
Abramson.
I am really uncomfortable with the
258
notion of giving this drug a black-box
warning or
considering it second-line because we
have seen no
data in the last two-and-a-half days that
would
warrant the huge migration of patients
away from
this drug to traditional NSAIDs. We just don't
know that the cardiovascular risks of
traditional
NSAIDs are less than celecoxib, but there
will be a
huge number of patients, both because of
clinical
and patient decisions, migrating away
from this
drug to other drugs where we don't have
an evidence
base in support of that.
Now, while we have seen some
data
suggesting that naproxen has less of a
risk than
these other drugs, I think none of us
would feel
comfortable enough with that data to give
naproxen,
for example, an indication of having less
cardiovascular risk. So I think we have to be very
aware of the kind of very meager evidence
base that
we have here and the risk that we are
going to
259
bring about an enormous migration of
patients from
one drug to other drugs where we don't
really know
much.
DR. WOOD: Dr. Gross.
DR. GROSS: I sense a discomfort in the
group about committing ourselves to
celecoxib and
whether there should be a black-box warning or
not.
Maybe the solution is to consider what we
want to
say about all the NSAIDs including the
coxibs, do
we want to have a warning for all of them
or a
black-box warning for all of them, and
then it
might be easier to deal with the
individuals.
DR. WOOD: The problem with that is we
have to vote, first of all, whether--what
the
actions we take for each of the
drugs. I think we
should do that first because we haven't
done that
yet with the others.
Dr. Nissen?
DR. NISSEN: The reason everybody is
uncomfortable, of course, is that we know
so much
less about the comparator drugs. We don't have
robust cardiovascular safety data, for
example, for
260
diclofenac. One of the things that is really
troubling me about this, and I think you
made some
very good points, Steve, is that if you
look at a
trial like CLASS, you see, basically, the
same
cardiovascular event rates with
diclofenac as you
see with 800 milligrams of celecoxib.
So if, in fact, we do
precipitate a
migration away from celecoxib to
diclofenac, we may
not actually be doing good. We may actually be
doing potentially harm. I am concerned that we
don't have the evidence.
So I think we have to keep our
warnings to
what we know. What we do know is, and we have
agreed, that celecoxib, compared to
placebo, has
excess risk. But we don't know whether that risk
is excess in comparison to ibuprofen of
diclofenac.
So any statement that would tend to
suggest using
those alternative agents first is
probably not
warranted by the data because we simply
don't have
the data to make such a conclusion.
So I think we have to limit our
statements
to what has been proven within a
reasonable doubt
261
here and that is that celecoxib is
probably riskier
than placebo.
DR. WOOD: Dr. Gardner.
DR. GARDNER:
I am having similar
discomfort about the benefit side when we
look at
all of these drugs in a group like
this. So my
comments will apply to everything that we
are doing
here today.
I think that we are not, this
afternoon,
going to get a whole lot more information
about
benefit.
We have been focused on risk. But
I
would echo Rich Platt's request to the
FDA to dig
into all of the information we have on
the various
products including the observational data
which can
be very helpful here in helping to
specify.
For example, we are all, now,
very
sensitive to the fact that R.A. patients
and
elderly patients tend to be, thanks especially
to
Dr. Cryer's presentations--we know that
they are at
higher risk both of cardiovascular and of
G.I.
bleeds.
We know that. But the
observational
studies, at least in some of the clinical
trials,
262
were done on much younger folks.
We heard yesterday from the
Military that
they have got very fit people who need
these drugs.
So I would like to--before we start
specifying who
are the populations that have need and
what we
should do to help them restrict, I would
like to
ask that, at least the FDA if not we,
this
afternoon, pay attention to better
specification of
the risks and benefits for communication
of risks
to other people besides the elderly R.A.
patients
whom we know are at higher risk and then
find ways
to communicate them appropriately.
I am in favor of med
guides. I just want
to comment, as someone who fills
prescriptions,
that when you put a med guide in a
packaging, the
way to get it to the patients is to have
it
packaged in the containers that you are
going to
distribute to the patients. That affects bulk
packaging.
Any time you design a med guide
that is
supposed to be handed out by a pharmacist
in a
chain pharmacy after you have taken bulk
drug out
263
and repackaged it is not going to get
there. So
think, as well, when we are talking about
med
guides, that you want to individualize
them to the
dispensing.
DR. WOOD: I think we have exhausted the
discussion. Do we want to move to the vote on
this.
DR. CRYER: Dr. Wood, over here in the
corner.
DR. WOOD: I have been told that, as you
are not a voting member of the committee,
you are
not allowed to comment during the
discussion at
this stage. Thanks.
DR. CUSH: Should not the first vote,
then, be whether this is no warning,
warning or
black box?
DR. WOOD: I think what we could do--let
me ask the FDA. It seems to me that there are
multiple issues here so I would suggest
that we go
around the panel and ask each panel
member what
they think should be done, what is their
kind of
list of things that they would like to
see done.
264
Is that reasonable?
DR. JENKINS: The intent of Question c.
was not to have a specific vote. It was more to
give a sense, from the committee, about
the goals
for the risk-management program and any
specific
ideas you have about how that should be
implemented
but not to take a vote on the exact
wording of a
box or whatever.
DR. WOOD: Sure.
But would it be helpful
to go around and ask each person what
they think or
have you got a sense of that already,
John?
DR. JENKINS: Wait a minute, one of my
colleagues is telling me--I don't know
that you
have to go around to every individual
member, but
if that is what you choose, that would be
fine. We
are always interested in hearing
everyone's ideas.
DR. WOOD: Okay.
Let's do that. Was that
acceptable to the committee? Let's start with Dr.
Abramson.
DR. ABRAMSON: I guess my bias on this is
that we have to, as I have said several
times,
define what we mean by the class and what
we think
265
the pathophysiology is here. I think we all agree
that there is a risk from sustained,
high-level
COX-2 inhibition.
I think the challenge before
us, and I
will ultimately believe in some sort of
serious
warning, perhaps a black-box warning, is
that we
agree that we are talking apples to
apples. My
bias will be, as I have said, to include
drugs
other than the coxibs, drugs that fall
into COX-2
preferential categories similar to
celecoxib.
Just as a final point, I would
remind the
panel that when meloxicam was first
marketed, in
the U.S., it was marketed as a COX-2
inhibitor.
After VIGOR, the company was prescient
enough to
stop marketing that way. It is, I believe, still
the only COX-2 selective drug available
in Japan.
So, had they continued to market that
drug as a
COX-2 inhibitor, that would be among our
four drugs
of discussion.
So my plea is that we decide
first, before
we get into too much detail on the
individual
warnings and labeling, what it is we mean
as a
266
group as COX-2 and try and draw a line
somewhere
that extends, in my view, beyond the
three coxibs
that we are discussing.
DR. WOOD: Let's just go around. And
let's try and just list the things and
not discuss
it
all again. Otherwise, we will take
forever.
Just list your recommendations.
DR. NISSEN: I am in favor of a black-box
warning which basically says that there
is
dose-dependent increase in cardiovascular
risk with
the drug.
I am in favor of no DTC advertising and
I am in favor of a patient guide, a
patient
handout, that would inform the patient
about the
risks of the drug.
DR. ELASHOFF: I have no additional
comments.
DR. GARDNER: I am in favor of no DTC
advertising, a patient guide, a med
guide, to
communicate to the patient as well as the
physician, and warnings that are
appropriate to the
risk group.
DR. WOOD:
Richard?
DR. PLATT: I favor a substantially
upgraded postmarketing-surveillance
program,
black-box warning. I would favor recommending this
267
drug be treated as a second-line drug and
I would
favor mentioning the suggestive evidence
about
naproxen possibly being a preferred
alternative. I
personally would favor attestation that
requires
the patient to acknowledge the magnitude
of the
risk and I was persuaded by the argument
about
putting that risk in the context of other
easily,
relatively easily, understood risks.
DR. DAY: I am for a black-box warning and
I think that they can be differential
across the
different products and whatever the
minimum is,
this one might get that. The upper limit may still
be high but I don't think we need to
decide on this
one, given defining the class and so
forth, at this
time.
I would be in favor of the medication guide.
Also, I know a lot of people say the
"Dear
Healthcare Professional" letter
isn't read, but
sometimes it is, so I think that both
physicians,
healthcare providers and patients should
get this
268
information.
I am not necessarily in favor
of
suspending DTC at this time as long as it
is done
in a way that provides fair balance
between
benefits and risks if that can be
achieved. I am
open to having the patient attestation
part,
perhaps with a small survey for
comprehension.
DR. FURBERG: I am for the black box. I
agree with the contraindication for high
dose. I
would like to be more specific about the
population
by contraindicating the drug for patients
with
known coronary heart disease and stroke
and for
patients at increased risk.
I am also in favor of some form
of patient
agreement or consent. If we had any way of barring
direct-to-consumer advertising, I would
be in favor
of that because I think that action, in
itself,
would prevent more serious adverse events
than
anything else we can do other than taking
that drug
off the market.
DR. FLEMING: I favor a black-box warning
regarding the increased cardiovascular
and
269
cerebrovascular risks. I am inclined to also agree
with noting the particular concerns with
those
patients that have high cardiovascular
risk and
toward encouraging minimizing dose and
duration,
appreciating the comment that that is
more
challenging in certain settings, and yet
it still
doesn't preclude use for a longer term
but it just
notes that there are potentially
increased risks
with that.
I am in agreement with barring
direct-to-consumer advertising unless Dr.
Morris
strategy that could be more effective is
achievable--I don't have a clear sense
about
that--and the concept of the patient
guide as well.
DR. WOOD: Okay.
Let's just keep going.
Dr. Domanski.
DR. DOMANSKI: Black-box warning that puts
for the increased cardiovascular risk of
the drug,
patient pamphlet, second-line drug.
DR. BOULWARE: I favor a black-box warning
expressing the known cardiovascular risk
when used
in the doses that were excessive of the
approved
270
levels of 400 milligrams but also
stipulating it is
not quite clear what the relative risk is
to the
other known nonsteroidals.
DR. WOOD: Next?
DR. DWORKIN: I am not in favor of a
black-box warning unless it is given to
all NSAIDs,
traditional and selective. I am in favor of a
detailed and comprehensive cardiovascular
warning
for celecoxib. I will pass on the other stuff.
DR. WOOD: Dr. Hoffman.
DR. HOFFMAN: I am in favor of a black-box
warning to be in place until more
definitive
studies are done and that warning
should--well, we
are not supposed to address the direct
wordage but
it was mentioned that there should be a
limitation
on duration.
I think that is impractical
because most
of the patients using this drug have
chronic
diseases that don't go away. But there definitely
should be, within the guidances, doses
not to
exceed 200 milligrams a day. I would be against
direct-to-consumer advertising and I
would advocate
271
a patient guide with this being
second-line
therapy.
DR. WOOD: Dr. Manzi.
DR. MANZI: I am not opposed to a
black-box warning. I think it should clearly state
the cardiovascular risk with higher doses
for
longer duration but not directly advocate
low doses
for short duration. I am vehemently opposed to it
being a second-line agent and I think a
patient
guide is sufficient.
DR. WOOD: Dr. Farrar.
DR. FARRAR: I am in favor of a black-box
warning specifying cardiac risk factors. I am
vehemently against direct advertising on
this and
all of the COX drugs. I feel strongly that a
patient guide should be designed so that
it can be
read and understood by patients. I will pass on
the rest.
DR. WOOD: Dr. Holmboe.
DR. HOLMBOE: I am in favor of a black-box
warning.
Again, I had some discomfort with regard
to the nonselective NSAIDs. There should be a
272
warning for those as well. I am in favor of a
patient medication guide, particularly
one that
should try to address not only health
literacy
issues but also health numeracy
issues. I hope
that the FDA will undertake study of
these guides
as well as, say, the medication
themselves. I am
also in favor of also adding to this some
academic
detailing to make sure the word gets out
to the
physicians who are using these drugs. I will pass
on the others.
DR. WOOD: Peter?
DR. GROSS: I am in favor of a warning
related to the dose-dependent toxicity
and that a
similar warning should be on all coxibs
and
nonselective NSAIDs. I favor a medication guide
for patients and a consent for patients
when they
will be taking higher doses. I would favor
direct-to-consumer advertising only if
combined
with FDA-approved education on the
putative risks
and I am opposed to it being a
second-line agent.
DR. WOOD: Thank you.
I am in favor of
the black-box warning. I am in favor of a very
273
restricted patient group to exclude
people who are
likely at risk for cardiovascular
disease. It is
not just those who have previously
identified
themselves by having cardiovascular
disease. It
would include the elderly patients with
high-risk
factors and probably some others. I am against
direct-to-consumer advertising, strongly.
I think a patient guide has to
be useful
and should be done. I think however we articulate
risk to patients, it needs to be done in
a way that
is immediately obvious what we are
talking about.
I think it is hard for me and for most
people to
understand what a 1 percent increase in
risk means
to me or to anyone else. So I think it needs to be
put in some contextual way that relates
to people's
regular daily lives.
I think one other thing I am in
favor of
that has not been said is I am in favor
of the
company having the opportunity to have
the
black-box warning removed if they can
demonstrate
in well-designed, well-controlled,
double-blind
trials that the drug, at any particular
dose or on
274
any particular group, does not, indeed,
have these
risks.
So I think I am favor of
viewing this as a
step that we are taking right now based
on the
evidence we have but we are prepared to
consider
changing that if they come up with
evidence, good
evidence, excellent evidence, that
overwhelms what
we have got right now.
DR. GIBOFSKY: There are four indications
for celecoxib, two short-term and two
long-term. I
think the population should be the
intended
populations, the indicated populations,
to be used
at the lowest effective dose. I oppose a black-box
warning.
I am in favor of patient handout.
I
oppose the use of or designation as a
second-line
agent.
I am not opposed to DTC advertising so long
as it is informative and educational and
consistent
with the message above.
DR. WOOD: Dr. Crawford.
DR. CRAWFORD: Thank you.
I am strongly
in favor of a black-box warning about the
cardiovascular risks. Also, I feel strongly the
275
need for postmarketing commitment
studies. I share
the Chairman's thoughts about the
possibility of
such studies removing the need for a
black-box
warning in the future. Also, I am very much
against direct-to-consumer advertising,
but it if
is not possible to make that a regulatory
action,
to say that there needs to be appropriate
communication of the risk in that
direct-to-consumer advertising.
DR. WOOD: Dr. Cush.
DR. CUSH: Jack Cush.
I am opposed to a
black-box warning. I am in favor of a general
warning that stipulates some strategy for
risk
reduction and risk minimization. I am strongly in
favor of direct-to-consumer advertising
as long as
the major statement significantly
outlines this
cardiovascular risk and that D.V.MAC take
particular attention and making sure that
that is
highlighted. I am also in favor of further study
of cardiovascular risk in the target
population.
DR. WOOD: Dr. Bathon.
DR. BATHON: I am opposed to a black-box
276
warning but I am in favor of a strong
warning that
advises the association of cardiovascular
risk and
in the target population. I am very opposed to DTC
advertising and I think that, if there
were not DTC
advertising and a strong warning, we
would be more
likely to target these drugs to the
appropriate
populations.
DR. WOOD: Ms. Malone.
MS. MALONE: Yes. I
am opposed to a
black-box warning. I think there should be a
serious warning about cardiovascular risk
and
dose-dependency. I think there should be a limit
on direct-to-consumer advertising. I don't like
the idea of calling this a second-line
drug. I
think what that is going to do is have
insurance
companies require--it is not going to
leave the
decision with the physician and the
consumer. It
is going to make insurance companies say,
you have
to try these other drugs first.
I think there should be a
patient guide
that is readable, understandable, easily
accessible
and I think there should be very good
education for
277
the doctors so that this dialogue can
take place.
And I am not opposed at all to a patient
consent or
attestation and I actually think that
that will
lead to a better communication between
the doctor
and the patient.
DR. WOOD: Arthur?
MR. LEVIN: Black box with the
cardiovascular risk; medication guide, of
course;
some sort of informed consent or assent
or
agreement. But I agree with the Chairman that we
have to learn how to convey risk in ways
that are
meaningful to consumers.
I would also argue that we have
to learn
how to convey benefit. We are only talking
convening risk. We need to figure out how to
convey realistically what we know about
the
benefits so that the balance can be
made. Academic
detailing, I think, has been shown to be
effective
and it would be intriguing. I just think it is an
intriguing idea to tie black-box removal
as a stick
and carrot to encourage further study.
Until we figure out how
direct-to-consumer
278
advertising can tell the truthful story
about
drugs, I would at least suspend it for
now.
DR. WOOD: Dr. Ilowite.
DR. ILOWITE: I favor a black-box warning
advising of the increased cardiovascular
risk which
is duration and dose-dependent. I favor a
statement saying that it is relatively
contraindicated in patients with high
cardiovascular risk. I am opposed to calling it a
second-line drug. I am opposed to
direct-to-consumer advertising. I am in favor of a
medication guide. And I wouldn't mention Naprosyn
as the preferred NSAID.
DR. WOOD: Ralph?
DR. D'AGOSTINO: I am in favor of a
black-box warning. I don't think there should be
direct-to-consumer advertising. I think the
evaluation of the cardiovascular risk is
important
and, as a matter of fact, I don't think
it would be
very hard to do with the clinical-trial
data plus
some things like we have at
Framingham. There are
comparators compared to--sort of the
optimal person
279
compared to your average population. It is
equivalent to being diabetic. There are lots of
ways of doing this and I think it should
definitely
be done.
DR. WOOD: Dr. Morris.
DR. MORRIS: I am in favor of a black-box
warning.
I would like to see it for the broadest
definition of class and every drug get
the
black-box warning in this class. Information can
vary, but within that, there should be
statements
about the class because I am real
concerned about
switching when there is nothing known and
I would
like to include some kind of statement in
that
black-box warning about what is not known
as well
as what is known.
Obviously, I am in favor of DTC
but
restructuring it in favor of a really
strong
postmarketing-surveillance program and
probably
studies like Dr. Temple suggested. I am actually
not in favor of a medication guide but I
am in
favor of a unitive-use patient package
insert. I
think some of the information in that should
also
280
be broad and classwide so people can
understand
that the concerns extend beyond just
COX-2s as they
think of COX-2s.
I am also in favor of an insert
for
over-the-counter drugs in this class that
also
talks about the use of this drug. I guess that is
it.
DR. WOOD: Dr. Cannon?
DR. CANNON: I am in favor of a black-box
warning, a warning of increasing
cardiovascular
risk that is dose and duration
dependent. I am
also in agreement no DTC. I think a medication
guide for patients is fine. I don't think this
drug, though, should be prohibited for
use in
patients who have cardiovascular risk
factors. I
don't think we have the data to say that
they are
at particularly higher risk than those
without risk
factors.
I would say something that
hasn't been
mentioned and, in my view, should be
included and
that is, for those patients who do have
cardiovascular risk factors, that the
concomitant
281
use of aspirin will likely not reduce the
risk that
may be imparted by the use of Celebrex
and that, in
fact, it may negate the G.I. benefit of
the drug.
DR. WOOD: Dr. Shapiro?
MS. SHAPIRO: I, too, favor a black-box
warning; no direct-to-consumer; a patient
guide;
and prescribing restrictions that would
assure
lowest possible dose; and, also,
second-line not in
the sense that something else would have
had to
have been tried but that the physician
would had to
have considered and then discounted a
non-COX
alternative.
DR. WOOD: Dr. Paganini?
DR. PAGANINI: I favor a black box. I
believe that it should contain a
cardiovascular
warning in understandable terms. I believe that
there should be a statement of probable
dose and
time relationship, that it should be a
second-line
for those with G.I. failure to other
options; there
should be no direct advertising and there
should be
developed a patient brochure.
DR. WOOD: Dr. Friedman.
DR. FRIEDMAN: I favor a bar to
direct-to-consumer advertising. I favor enhanced
education both for patients and, frankly,
for the
282
medical community. I favor a black-box warning
mentioning the high-group, the problem
with
cardiovascular disease, the concern with
the high
dose.
I also favor mentioning the uncertainties
with regard to all of the NSAIDs. I assume that,
under Question 5, we will discuss
additional
research activity which I see as
absolutely
essential.
DR. WOOD: Charlie?
DR. HENNEKENS: I would want all
healthcare providers and patients to be
aware that
coxibs increase cardiovascular risk by
about 40
percent.
I would want them also to know that, in
the comparator trials, naproxen compares
favorably
to all the coxibs. I would also want them to know
that the short-acting NSAIDs appear to be
at least
as hazardous as the coxibs. I would want basically
that all arthritis patients and all other
patients
treated with coxibs or the short-acting
NSAIDs,
283
especially, as well as naproxen, should
have their
global cardiovascular risk assessed as the
NHLBI
has recommended in general, and they
should have
aggressive management of all their
cardiovascular
risks.
I am not in favor of this being
a
second-line drug. I am not in favor of
direct-to-consumer advertising. I am not actually
in favor of a black box but I am in favor
of a
strong warning that should be applied
equally to
all coxibs and all short-acting NSAIDs.
DR. WOOD: Steve?
DR. SHAFER: I believe it should be
indicated for second-line therapy. I favor a
black-box warning on dose- and
duration-dependent
cardiovascular risk. I concur with potentially
removing the black box for certain doses
in
comparator NSAIDs as is supported by
clinical-trial
data in the future. It should be contraindicated
following cardiopulmonary bypass. I would actually
permit DTC advertising as we have
understood what
that would mean with the black-box
warning. I like
284
the idea of the patient guide and I would
oppose to
mandatory physician and patient
attestation.
DR. WOOD: Okay.
Just in case you thought
you had finished, let's move on to
Question No. 2.
Question No. 2:
Valdecoxib
DR. WOOD: Question No. 2 addresses
valdecoxib. The first question is, do the
available data support a conclusion that
valdecoxib
significantly increases the risk of
cardiovascular
events.
I think we have probably had a
lot of the
discussion on this so let's see if there
is any new
discussion that we would like to have and
then we
can, perhaps, go around the table and get
everybody's brief individual comments on
this.
Is there discussion first? Then let's go
around the table--I beg your pardon. Yes?
DR. SHAFER: One point of discussion. Can
we also discuss parecoxib, or think about
parecoxib
concurrently. I know it is not an approved drug
but at least some of my thinking about
this relates
to my thoughts about parecoxib as
well. Or is that
285
not appropriate?
DR. WOOD: Sure.
I mean parecoxib is
converted to valdecoxib in the body. Do you think
there is a difference?
DR. SHAFER:
That answers my question.
DR. WOOD: Pardon?
DR. SHAFER: That answers my question when
it comes time for the vote.
DR. WOOD: Okay.
Go ahead. We will start
with you this time, Steve.
DR. SHAFER: All right.
The question
before us is do the available data
support a
conclusion that it significantly
increases the risk
of cardiovascular events. Yes, after
cardiopulmonary bypass. I point out that CABG is
just one type of cardiopulmonary bypass
but it is
probably common to all forms of
cardiopulmonary
bypass because the common thread is the
bypass
machine, itself. I don't think the cardiovascular
signal is clear otherwise so I would say
yes in the
setting of cardiopulmonary bypass.
DR. WOOD: Let me just ask you. Why did
286
you not see a signal anywhere else given
that there
wasn't any evidence anywhere else.
DR. SHAFER: That is what you just said.
There was no signal anywhere else because
there was
no evidence anywhere else.
DR. WOOD: So it is not that you think
that it is safe in other settings. It is just that
you don't know.
DR. SHAFER: The other places where they
have looked at it, the signal has been
weaker than
other studies of approximately the same
size as I
interpreted the data, although Study 047,
there was
some increase in C.V. events versus
naproxen.
DR. WOOD: Charlie?
DR. HENNEKENS: Hennekens.
Yes.
DR. FRIEDMAN: Friedman. Yes.
DR. PAGANINI: Paganini.
Yes.
MS. SHAPIRO: Shapiro.
Yes.
DR. CANNON: Cannon.
Yes.
DR. MORRIS: Morris.
Yes.
DR. D'AGOSTINO: D'Agostino.
Yes.
DR. ILOWITE:
Ilowite. Yes.
MR. LEVIN: Levin.
Yes.
MS. MALONE: Malone.
Yes.
DR. BATHON: Joan Bathon.
Yes.
287
DR. CUSH: Cush.
Yes.
DR. CRAWFORD: Crawford.
No relation to
Lester.
Yes.
DR. GIBOFSKY: Gibofsky.
Yes.
DR. WOOD: Wood.
Yes.
DR. GROSS: Gross.
Yes.
DR. HOLMBOE: Holmboe.
Yes.
DR. FARRAR: John Farrar.
Yes.
DR. MANZI: Sue Manzi.
Yes.
DR. HOFFMAN: Gary Hoffman.
Yes.
DR. DWORKIN: Dworkin.
Yes.
DR. BOULWARE: Boulware.
Yes.
DR. DOMANSKI: Domanski.
Yes.
DR. FLEMING: Fleming.
Yes.
DR. FURBERG: Furberg.
Yes.
DR. DAY: Day.
Yes.
DR. PLATT: Platt.
Yes.
DR. GARDNER: Gardner.
Yes.
DR. ELASHOFF: Elashoff.
Yes.
DR. NISSEN: Nissen.
Yes.
DR. ABRAMSON: Abramson.
Yes.
DR. WOOD: With our new computerized
system, it is 32 to 0.
The second question is, does
the overall
risk versus benefit profile for
valdecoxib support
288
marketing in the U.S.? I think we should do some
discussion on that first. Comments on that? I
guess I would comment. I am not sure that the
current data we have does support
continued
marketing in the U.S. In fact, I think it probably
does not.
We have got a very clear and
replicated
signal of cardiovascular lack of safety
in two
studies and we have got a lack of clear
G.I.
benefit in terms of complicated
risks. And we have
already approved one drug which appears
to have a
lower signal than the others. It would seem to me
that, if this drug were to be continued
to be
marketed, we would need a lot better data
to
justify its continued availability
Dr. Nissen?
DR. NISSEN: This one is really tough
because there is just not any data in the
population to which this drug is being
used. The
only data we have is two studies, one of
which was
small, the other of which was, I think,
pretty
clear after cardiopulmonary bypass and
that signal
was very strong really only in the arm
that got the
I.V. product.
So what really have is an
absence of
289
information. Now, the question I think you are
asking, Alastair, is was there a mistake
made in
actually approving this drug with the
limited data
that was available because that is really
what you
are saying, that in the absence of proof
that it is
safe, that it should be
deregistered. I think that
is really tough.
So I have a lot of trouble with
this one
because I don't see evidence one way or
the other
for valdecoxib. Now, maybe somebody can help me.
Tom, you can do some mathematical
highjinks over
there and maybe you can convince me to
the
contrary, or Ralph or Charlie, but I
don't have
290
evidence.
DR. WOOD: Just to respond to that, I
think we have heard the argument many
times that
people need choices. I agree with that. But it
seems highly improbable to me that this
drug is
safer than celecoxib. It is almost inconceivable
to me why somebody would prescribe this
drug over
celecoxib if you were going to use that.
I am not arguing whether you
should use
celecoxib or not. We have been through that
discussion. But, given the size of the signal and
somebody used the expression before, the
CAB
studies may be a canary in a coal
mine. It is a
high platelet-activated group and that
may be just
reflecting a model in which it is easier
to see a
signal than it is in other models and it was
possible, remember, to see it with a
relatively
small number of patients, 500 patients,
or
something.
So this was a very strong
signal in a very
small number of patients, a fifth of the
number of
patients seen in the approved study, for
example.
DR. HENNEKENS: Alastair, you are quite
right that there is no evidence that it
is safer
than celecoxib, but there is also no
evidence that
291
it is more harmful than celecoxib.
DR. NISSEN: Exactly.
DR. WOOD: Dr. Abramson.
DR. ABRAMSON: I would agree. I think
there is a strong database in terms of
the clinical
trials.
What we are lacking are large outcome
trials that show a VIGOR-like or a
TARGET-like
effect.
So, therefore, it would be not a good
precedent, in my view, to remove a drug
because
there is an alternative without a more
serious
safety signal.
I think there is a caveat with
these CABG
trials that we have to talk about which
is that
these patients, as we stressed yesterday,
or the
other day, were given low-dos
aspirin. So, in
effect, they had both COX-1 and COX-2
inhibition.
It may be that, in that acute event, the
platelets
are so intensely clotting that the
aspirin may have
been overridden. But, in effect, these patients
292
were given a COX-mixed inhibition.
So since there was no
comparator arm in
that valdecoxib/parecoxib study, I don't
know that
we can draw a lot of conclusions about
the
intrinsic safety of this drug in
arthritis use over
time.
I think that was a flawed study to draw
specific conclusions about isolated COX-2
inhibition.
DR. WOOD:
But the company had so little
faith in the safety of the drug that they
gave it
with aspirin in the general surgery
study.
DR. ABRAMSON: Nevertheless, it was a
mixed compound.
DR. WOOD: They didn't feel it was safe to
give to patients who were undergoing
general
surgery without aspirin.
DR. ABRAMSON: Right.
But if we are doing
clinical pharmacology and using that to
make
projections on safety of drugs, those
patients were
given mixed inhibitor.
DR. WOOD: Sure.
Dr. Furberg?
DR. FURBERG: I agree with Dr. Nissen that
293
we have an absence of good evidence but I
come down
on the other side, and that is not a
reason for
leaving it on the market, a lack of
evidence. So I
think we need to face up to the fact that
we don't
have good evidence and take it off the
market and
the manufacturer can come back when they
have good
data.
DR. WOOD: Yes; motivate them. Dr.
Elashoff?
DR. ELASHOFF: Doesn't this drug already
have a black-box warning that the others
do not?
DR. WOOD: No; a black-box warning for
skin, not for cardiovascular.
DR. ELASHOFF: Yes, but I mean isn't that
something that should be taken into
account in
terms of the risk:benefit for this
particular drug.
DR. WOOD: Right.
So there are additional
risks, you are saying. Yes; that's right. Any
other comments? Dr. Farrar?
DR. FARRAR: I think that this drug, in
particular, also points out another
suggestion that
should be made and would make me feel a
lot better.
294
I think it is much harder to take a drug
off the
market without evidence than not to put
it on
without evidence. That makes it a quandary for me
but it also suggests, in fact, that drugs
ought to
have a renewal date. Our grants have a renewal
date, lord knows. and we have to show
that we have
made progress. I would actually strongly recommend
consideration of that. Obviously, that discussion
is later but it would make me feel a lot
better
about this.
DR. WOOD: Dr. Cush?
DR. CUSH: This question speaks to
risk:benefit and there is, obviously,
demonstrated
benefit as these drugs are, again,
equipotent to
available drugs. I am not convinced that there is
a signal that says that there is a
potential risk,
a significant risk, when the drug is used
as
indicated.
DR. WOOD: Any other comments? Then let's
go around the room--oh; sorry. Dr. Fleming?
Let
Tom go first and then Dr. Manzi next.
DR. FLEMING: Go ahead.
DR. WOOD: Dr. Manzi, you have been
deferred to.
DR. MANZI: I just wanted to respond to
295
the comment that we need to wait until
they can
prove safety. I would say that we put the same
charge to Celebrex in removal of the
black-box
warning, that we saw a signal, we felt
that there
was clearly a risk and now we want
long-term safety
data.
I think we should do the same with this
drug.
DR. WOOD: Dr. Fleming?
DR. FLEMING: I appreciate the fact that
we have much more limited data here, I
think about
3,000 patients. It is predominantly in the CABG
setting.
The signal, though, here, really
impresses me with the magnitude of the
signal. We
are looking at the 035 trial at a 15 to 2
on events
and that is 1-1 on M.I. It doesn't reflect the
fact that the investigators called 9 to 2
on those
M.I.s.
When we are looking at the
other data as
well, we have got quite a strong
signal. The 069
296
trial was in general surgery and that was
more
neutral at 5-5, although DVTs were 2 to 1
for
placebo.
I know these are really small numbers but
when you are looking at the events that
are of
greater interest, the M.I.s, the arrests,
the
cardiac deaths and the strokes, it is 3
to 2 so,
again, it is really small data. But I don't
consider that favorable. It is in the wrong
direction.
Essentially, we have the 035
trial and the
Nussmeier trial. Steve Nissen pointed out that it
is relevant to look at the fact that we
had the
three arms. The combination arm had a relative
risk of 3.7. The valdecoxib had a relative risk of
2.
So it was less striking although, when you
looked at all of the events, it was a
relative risk
of 1.9 in both.
So, essentially, there is very
strong
evidence here in the setting where it has
been
studied.
What we are struggling with is that there
is very limited evidence, though, in
being able to
look beyond. So what do you say?
I mean essentially where there
is
evidence, it is of significant concern,
but this is
understudied relative to other
agents. And so do
297
we give it the benefit of the doubt, or
do we view
that in the absence of reliable evidence
here?
Continued marketing is of serious
concerns, and we
should wait until we have more reliable
evidence to
restore marketing. To me that's the debate.
DR. WOOD: And the drug clearly gives
bigger signals than you see anywhere
else. The
general surgery study was so underpowered
you
couldn't possibly have seen anything,
given the
agent and so on.
DR. FLEMING: And I guess my point there
is it's not a reassuringly positive
study.
DR. WOOD: Right, not reassuring, and they
were on aspirin.
DR. FLEMING: The key events are 3 to 2 in
the wrong direction, and it's in the
context of
aspirin.
DR. WOOD: Right.
I mean, you know, come
on.
Okay.
DR. :
You know, I think that
given the extensiveness of the review
that we've
had, I think it's reasonable not to
accept the
precedent that it's already on the market
and to
make an independent recommendation about
whether it
298
should be regardless of what that turns
out to be.
But I think we--you know, given again the
extent of
this review, it's appropriate to give it
that kind
of de novo review and decide whether it
should be
there.
DR. :
Okay. Dr. Gibofsky?
DR. GIBOFSKY: I have a question for Dr.
Fleming.
Is it possible?
DR. :
Sorry. Yes, go ahead.
DR. GIBOFSKY: Dr. Fleming, in light of
what Dr. Packer taught us this morning,
if you
apply, again, having only one time point
to look
at, and you're applying a second level of
discrimination at a .05 level, do we have
enough of
a power--or a signal here that it does
become
significant? I mean I'm impressed by some of the
participants say that this is a much
bigger signal
299
we are seeing in other situations, which
admittedly
is lower at 1.4, as many of you said, but
I'm not
impressed that it's such a large signal,
one-time
signal, that it merits the drug being
dropped from
the market.
DR. FLEMING:
Let me respond to that in
one minute.
DR. :
Okay, all right. And
other questions? Yes, Dr.
(?).
DR. :
Yes. I share Dr.
Abramson's and Nissen's concerns. I also am
mindful of the volumes of data that we
have
reviewed.
However, at the end of the day, as we've
heard from one speaker in particular,
we're obliged
to make our decisions based on the weight
of the
evidence, and we practice evidence-based
medicine.
We don't practice the absence of
evidence-based
medicine.
So consequently I think we have to look
at the data that we have, be cautious, be
concerned, have that discomfort in our
gut, but go
with the evidence and the data that we have.
DR. WOOD: I agree with that and we have
300
no evidence of G.I. safety. We have evidence of
cardiovascular toxicity and that, to me,
is
compelling. Dr. Shafer?
DR. SHAFER: I just want to respond to the
canary in the coal mine and the
cardiovascular
safety concerns because it really was the
two CABG
studies.
The level of physiologic trespass imposed
by cardiopulmonary bypass should not be
underestimated or the effects of that on
the entire
immune and thrombotic systems.
So, if the message to a company
is don't
ever study a drug in in cardiopulmonary
bypass
patients because, if you get a bad
outcome, it will
be assumed to be a representative of your
class of
drugs and there will be no more studies
of
analgesic possibilities in patients on
cardiopulmonary bypass.
So I totally rejected the
concept that the
naproxen studies should be separated out
as a
different sort of funny class
effect. But in the
case of cardiopulmonary bypass, I really
do think
that is a very different kettle of
fish. I don't
301
think it is a canary in a coal mine
although I
could be proven wrong by future data.
But do not underestimate the
level of
trespass that that represents and the
limits that
that puts on the extrapolalatability of
those data
to patients on arthritis, or with
arthritis.
DR. WOOD: Any other comments? Dr.
Abramson?
DR. ABRAMSON: The point I was making
about the aspirin is that I am not sure
that we can
use this CABG study as a surrogate for
the safety
of these drugs in the long term because
there was
no nonselective comparator. Had we done the same
study with Motrin at high doses, because
the COX-2
effect seems to be driving it and aspirin
did not
prevent the adverse event, I am concerned
that,
alone, without a comparator, it doesn't
help us say
what this drug does in the non-acute
coronary-syndrome setting because this
was a
dual-inhibiting setting.
So I think we have to be
cautious in
extrapolating that as a surrogate study.
DR. WOOD: Although it is interesting that
the general-surgery patients also got
aspirin.
DR. ABRAMSON: But they did not have the
302
same strength of signal.
DR. WOOD: Oh, no; but that there was a
need to give them aspirin.
DR. ABRAMSON: We don't know, Alastair, if
there was a need to give it or not. They gave it.
That is all we can say. We don't know what would
happen without aspirin.
Steve, your points are
well-taken. I am
very troubled by this one because, as a
cardiologist, I know what happens when
you open a
chest and stop the heart and put people
on bypass
pumps and blood circulating
extracorporeally. It
is a really very big insult. So it is very hard
for me to extrapolate results in that
population to
a general population.
I agree with everything that
has been
said.
It is a very strong signal and I was the one
that said, the other day, that this
happened with
10 days of exposure in the face of
aspirin. That
303
is a very compelling result. But I don't know how
to apply that knowledge to patients that
are going
to get 10 or 20 milligrams of the drug
with
arthritis. What I do know is that giving 40
milligrams right after cardiopulmonary
bypass is
not a good idea. I know that for certain. But I
don't know what that needs for taking 10
or 21
milligrams with arthritis.
So what it really comes down to
is how
much weight do you all give to this
notion of the
class effect? If you really, really believe that
there is unequivocal evidence of a class
effect,
then if see it in any population for any
drug in
the class, then, you got to do that.
But I must point out to you
that we don't
have long-term safety data on ibuprofen
or
diclofenac. Does that mean we should deregister
those drugs? I think it is a really interesting
issue.
DR. WOOD: Let's go to the question, then.
The question is, does the overall
risk:benefit
profile for valdecoxib support--remember,
the
304
question asked does it support marketing
in the
U.S., not just is it neutral. Let's start with Dr.
Abramson.
DR. CUSH: Wait.
Dr. Fleming was going to
give us an answer, maybe.
DR. WOOD: Oh, I'm sorry. You're right.
Sorry, Tom.
DR. FLEMING: I just was looking at the
evidence in the totality. Essentially, the
totality of the evidence, the problem is
it is very
limited.
We have got, in what has been presented
to us, three trials; the Nussmeier 071
trial, 035
trial, the 069. By my crude summary here, the
relative risk is slightly more than 2.5
and, in
terms of strength of evidence, the
standard error
is more than 3.0.
So, to my way of thinking, that
is quite
strong evidence. I would surely like to have a lot
more data and my biggest uncertainty is
how does
this extrapolate to other settings. But there is
quite strong data here in the CABG
setting, in the
surgery setting.
DR. SHAFER: How much of that is driven by
the CABG study?
DR. FLEMING: Well, there are two and
305
almost all the data are from those
two. The
general-surgery study, I counted as 5.5
although,
really, the events we are interested in
are 3 to 2.
So this is a slightly--it is.
DR. WOOD: But the question we are being
asked here is does the data support
marketing the
U.S. So it is not just a
question--if we have no
data at all, that surely wouldn't support
marketing
in the United States. So, absence of data is
important here, I think, particularly in
the
presence of a safety signal, a strong
safety
signal.
DR. CUSH: Absence of data means you take
a drug off the market?
DR. WOOD: That is what we will have to
decide.
Dr. Gibofsky.
DR. GIBOFSKY: I have made my comments..
DR. WOOD: Sorry.
Dr. Hennekens?
DR. HENNEKENS: I believe there is a class
306
effect which is similar for all the
coxibs and the
short-acting NSAIDs. As such, I interpret the
valdecoxib signal to be that these
classes of
agents should not be used in
cardiac-surgery
patients, but they don't bear directly on
their
utilization in arthritis patients, in my
view.
DR. WOOD: Dr. Ilowite?
DR. ILOWITE: Dr. Wood, you are, I think,
getting back to Dr. Temple's wording of
the
questions. The only reason it says "support
marketing" is because he didn't want
to change the
format of the questions for the three
drugs. So it
might have easily said, "does it
support
withdrawal?" The reason that wasn't done was
because--
DR. WOOD: But it doesn't. I mean, he
didn't want to change--well, that is
fine. I think
people know what we are voting on so I
don't think
it makes much difference. Do we want to have a
discussion on this point? Go ahead, Dr. Ilowite,
again.
DR. ILOWITE: One is more of a passive
307
effect.
The hurdle is lower if you say, does it
support marketing than if you say, does
it support
withdrawal.
DR. WOOD: That's right.
But if we think
that is truly different, then what we are
saying is
that the hurdle to remove a drug that we
see as
being unsafe, we are going to make that
hurdle
substantially higher than the hurdle to
get it on
the market in the first place. That is an
interesting concept and one that we
should,
perhaps, discuss, but I am not sure that
is--do you
think, Bob--Bob Temple--do you think--Dr.
Jenkins
do you think the hurdle to remove a drug
from the
market should be higher than the hurdle
to get it
on the market?
DR. JENKINS: That is a very interesting
and difficult question because,
obviously, the
product is already on the market. You are
fundamentally being asked, given that you
voted in
2.a. that you think that the drug
increases the
risk of cardiovascular events, should
that have any
impact on whether it remains on the
market.
DR. WOOD: Is your proposal, Dr. Ilowite,
that we change the question to should--or
do you
just want us--
308
DR. ILOWITE: No; the question was fine.
DR. WOOD: Then let's call the question.
DR. TEMPLE: Alastair, just one thing.
DR. WOOD: Yes, Bob.
DR. TEMPLE: In legal terms, as opposed
to practical terms, it is fairly clear
that the
standard for approval says, all tests
reasonably
applicable have been done to evaluate
safety and it
is safe, and it has got to be
effective. It is
very clear from the law and court
decisions that
one of the things you could do, if you
got more
information that make you doubt that the
risk:benefit calculus you made at the
time of
approval was still true, you could seek
to withdraw
it from the market.
These rules and the law doesn't
give
quantitative differences there. Of course, to take
something off the market against the
company's
will, you have to go through a legal set
of
309
proceedings. Therefore, you queried about the
evidence arguably more than you are when
you first
do the approval decision. So there is a fair
amount of evidence that you need to take
a drug off
the market as a practical matter.
Now, you know, in a different world where,
at five years, you reconsider it just as
though you
didn't know anything, starting from the
beginning,
maybe the standards would be different.
DR. WOOD: But, from a patient's
perspective, it is probably the same
thing.
DR. TEMPLE: You, certainly,
intellectually want to think of it as
roughly the
same thing. There is, of course, the fact that
after a drug is marketed, you have
certain
assurances from spontaneous reports that
you didn't
have before you marketed that is
irrelevant to
these considerations, I would say.
DR. WOOD: Okay.
Let's start the vote
from Dr. Abramson. So the question is, still as
written, does the overall risk support
marketing in
the U.S.
A yes would mean leaving it on the
310
market.
A no would mean taking it off the market,
just to make sure.
DR. ABRAMSON: Yes.
DR. NISSEN: Yes.
DR. ELASHOFF: I am concerned that we are
adding a new risk to something that
already has a
black-box warning. So I am unclear here.
DR. GARDNER: Pass.
DR. PLATT: Yes.
DR. DAY: Abstain.
DR. FURBERG: Furberg.
No.
DR. FLEMING: Fleming.
Abstain.
DR. DOMANSKI: Domanski.
Abstain.
DR. BOULWARE: Boulware.
Yes.
DR. DWORKIN: Dworkin.
Yes.
DR. HOFFMAN: Abstain.
DR. MANZI: Manzi.
Yes.
DR. FARRAR: Farrar.
Yes.
DR. HOLMBOE: Holmboe.
No, because of the
sulfonamide issue and the other black box
for
cardiovascular.
DR. GROSS: Gross.
No.
DR. WOOD: Wood.
No.
DR. GIBOFSKY: Gibofsky.
Yes.
DR. CRAWFORD: Crawford.
No, based on the
311
paucity of evidence.
DR. CUSH: Cush.
Yes.
DR. BATHON: Bathon.
Yes.
MS. MALONE: Malone.
Yes.
MR. LEVIN: Levin.
No.
DR. ILOWITE: Ilowite.
Abstain
DR. D'AGOSTINO: D'Agostino.
Abstain.
DR. MORRIS: Morris.
Yes.
DR. CANNON: Cannon.
Yes.
MS. SHAPIRO: Shapiro.
No.
DR. PAGANINI: Paganini.
Abstain.
DR. FRIEDMAN: Friedman.
Abstain.
DR. HENNEKENS: Hennekens.
Yes.
DR. SHAFER: Shafer.
Yes.
DR. WOOD: If yes, and all those who
abstained and voted no can participate in
this as
well, describe the patient population in
which the
potential benefits of valdecoxib outweigh
the
potential risks and what actions you
recommend that
312
FDA should consider implementing to
ensure safe use
of valdecoxib?
Let's see if there is
discussion on this
or whether we want to do the same as we did
with
the last one and go around again and each
person
give their recommendations as to what
restrictions,
if any, they would like to see on the
prescribing.
Is that acceptable to the committee?
DR. HENNEKENS: Could I ask a question
about procedure, Alastair?
DR. WOOD: Of course.
Go ahead.
DR. HENNEKENS: If a person feels that
they don't have enough information the
really make
a judgment about whether the drug should
be on the
market or not and, therefore, abstain,
are they
necessarily in a position that they could
then say
which patient populations would benefit
from it?
DR. WOOD: Yes; I think they are. I think
they can provide us with guidance to what
should be
done if the drug were to stay on the
market. They
could still provide us with guidance,
yes. So I
think we should be encompassing. Everybody has the
313
chance to respond.
Yes, Dr. Nissen?
DR. NISSEN: I am disappointed in the
abstentions. We all sat here and listened to the
evidence.
DR. WOOD: Steve, I don't think we should
badger people into voting
DR. NISSEN: I actually do want to ask
people, as we move forward, to think
about making a
commitment one way or the other because
what you
have is a minority of us making a
decision. I
think it is appropriate that people weigh
in. So,
one man's opinion.
DR. WOOD: Assuming that there is no
objection to that, let's go around the
table again
and ask for suggestions as to how you
would manage
this.
I guess what I would do here
is, I am
going to--if people are agreeable, I will
assume
that we would do at least what we would
do with
celecoxib unless someone sees an objection
to that.
Let's only produce incremental changes,
if any,
314
that you would like to see to this.
Bob?
DR. TEMPLE: You are going to discuss this
in a later question, No. 5, like what
studies
should people do. I just wonder whether you want
to speculate on that a little bit so that
people
can think about that as they give this
answer. For
example, do you mean a comparison with
naproxen? Or
what?
DR. WOOD: The committee, you mean, or me?
DR. TEMPLE: Huh?
DR. WOOD: The committee or me?
DR. TEMPLE: Everybody.
I am only asking
now, even though it is there later,
because maybe
that is relevant to the discussion that
goes on as
it might have been the celecoxib
discussion, too.
DR. WOOD: Okay. Boy, that might make it
complicated, I mean, because we--
DR. TEMPLE: You can duck it if you really
want to.
DR. WOOD: Let's go around and make the
recommendations here and then--we are not
going to
315
forget that--because I want to keep us
moving.
Otherwise, we will never get to these
other things.
Let's start with Steve Shafer
and go
around.
Steve, to save time, set the tone by
adding to your previous comments rather
than--if
there are things you want to add, add
them.
Otherwise, we will just with what you
said before.
DR. SHAFER: My comments are the same as
my previous comments with the one addition
that, in
anesthesia, we do desperately need better
options
in the immediate post-operative period
for which
the intravenous form is an intriguing
opportunity.
I will just say that.
DR. HENNEKENS: Hennekens.
I make the
same recommendations as for celecoxib.
DR. FRIEDMAN: Friedman.
Same
recommendations.
DR. PAGANINI: Paganini.
I would alter
the black box to include only
post-cardiac surgery.
I don't see that there is any other data
on there
for anything else.
DR. WOOD: Dr. Shapiro?
MS. SHAPIRO: I would mimic what I had
said before and exclude its use ever in
316
post-cardiac surgery.
DR. WOOD: Dr. Cannon?
DR. CANNON: Same as my comments for
celecoxib.
DR. WOOD: Dr. Morris?
DR. MORRIS: I would make some changes.
For this one, I would suggest a
medication guide.
I would also suggest a contraindication
that would
be both in the contraindications section
and the
black box in cardiac surgery. I would also try to
develop some kind of special program that
would be
coordinated with patients undergoing
cardiac
surgery that would have some kind of
extra warning.
DR. WOOD: Dr. D'Agostino.
DR. D'AGOSTINO: D'Agostino.
Nothing to
add.
DR. ILOWITE: Ilowite.
Nothing to add
except discussion of the CABG data.
DR. WOOD: Arthur?
MR. LEVIN: Levin.
Nothing to add.
DR. WOOD: Ms. Malone.
MS. MALONE:
Malone. Much the same as
with Celebrex but to also emphasize the
need for
postmarketing surveillance.
DR. WOOD: Dr. Bathon.
317
DR. BATHON:
I would be in favor of a
black-box warning for this drug with the
advisory
about the CABG patients and against
chronic use
until further safety data are available
in the
target populations.
DR. WOOD: Dr. Cush.
DR. CUSH: The same but I would then
change the warning to a black box
regarding CABG
and any other acute cardiac situation.
DR. WOOD: Dr. Crawford.
DR. CRAWFORD: Same as my comments with
celecoxib.
DR. WOOD: Dr. Gibofsky.
DR. GIBOFSKY: No change from previous
comments.
DR. WOOD: I would say the same as before
318
but I would have a triple black-box
warning and I
would, again, offer the company the
option to get
back off probation if they can come up
with clear
and unequivocal safety data.
Dr. Gross?
DR. GROSS: Same as Celebrex but I would
make valdecoxib a second-line selective
COX-2
inhibitor.
DR. HOLMBOE: I would contraindicate this
drug for use in post-CABG surgery. I would
strongly recommend banning it to consumer
advertising and I clearly would make this
a
second-line drug.
DR. WOOD: Dr. Farrar?
DR. FARRAR: As opposed to what I said
about Celebrex, I think I would provide
in the
black box an absolute contraindication in
cardiac
surgery, a contraindication stating that
the
long-term-use risk is unknown in the
black box and
that it is second-line with a clear
indication
that, if the company produces data
obviating those,
then those could be removed.
DR. WOOD: Dr. Manzi?
DR. MANZI: In addition to the Celebrex
information I provided before, I agree
with the
319
contraindication in any revascularization
procedure.
DR. WOOD: Dr. Hoffman?
DR. HOFFMAN: I would repeat the concerns
I had about Celebrex in a black-box
warning for
this agent but, whereas I was not in favor of
a
duration limitation for Celebrex, I am in
favor of
a duration limitation for this agent for
which we
only have six-month data.
DR. WOOD: Dr. Dworkin?
DR. DWORKIN: For this agent, I would be
in favor of a black-box warning and also
stipulating that it should only be used
third-line,
I think, and then with the
contraindications that
other people have mentioned.
DR. WOOD:
Dr. Boulware.
DR. BOULWARE: The same warning I had
listed for the black box for
celecoxib. I would
also add a contraindication for CABG
surgery and
320
also an listing that we don't know the
long-term
use in cardiovascular risk.
DR. WOOD: Dr. Domanski.
DR. DOMANSKI: Number one, I am going to
ask that I be allowed--I am given pangs
of
conscience by Dr. Nissen. I think he is right. I
don't think the data are there and I
would like to
change my abstain to a no, if I am
permitted to.
With regard to the box, same as
Celebrex
but would add that it is contraindicated
in the
setting of post-bypass.
DR. WOOD: Dr. Fleming?
DR. FLEMING: I would add that it should
be contraindicated in cardiac
surgery. As I was
thinking through this further, I was
thinking there
ought to be some mandated requirement,
and we are
going to get to this in Question 5, for
trials that
would give us the broader insight that we
are
lacking.
I am troubled by the fact that when we
look at the other four coxibs, they have
all had,
on average, 20,000 patients. We have three here.
Dr. Nissen has persuaded me
that we do
321
need to be more forthcoming. We can't probably be
as persuasive in mandating that as we can
in voting
no.
So, with that logic, I would like to also
change my abstain to a no.
DR. WOOD: Dr. Furberg.
DR. FURBERG: Same recommendation but I
would add a limitation in use to 1 to 2
weeks
mentioning in the black box or somewhere
in the
labeling that there is a lack of evidence
for sort-
and long-term benefit and safety in
low-risk
patients.
DR. WOOD: Dr. Day?
DR. DAY: Same as before except the
contraindications that others have
mentioned and
also no DTC.
DR. WOOD: Richard?
DR. PLATT: I would add a contraindication
for
patients undergoing cardiovascular surgery.
Even though we will talk about additional
trials
later, I would make continued marketing
of this
drug conditional on an appropriately
designed
randomized trial being undertaken
forthwith.
DR. WOOD: Dr. Gardner?
DR. GARDNER: I will join my colleagues in
converting from an abstain to a no and,
therefore,
322
not make recommendations for continued.
DR. WOOD: That was another change in the
vote.
Did you get that? You can see how
hanging
chads come; right? Dr. Gardner changed her vote
from an abstain to a no.
Dr. Elashoff?
DR. ELASHOFF: Elashoff.
I would add a
limitation to second-line therapy if this
stays on
the market.
DR. WOOD: Dr. Nissen?
DR. NISSEN: I would offer a stronger
warning than we put on celecoxib which
particularly
emphasizes that longer-term safety has
not been
established and that the drug should not
be used
long-term until further data are
forthcoming.
DR. GIBOFSKY: Excuse me.
You said
celecoxib; don't you mean--we are
discussing
valdecoxib.
DR. NISSEN: Similar to, similar warnings
323
to, is what I said. So I wanted similar warnings
but stronger with the proviso that we
don't have
the long-term safety data established
and,
therefore, the drug should not be used
long-term.
DR. WOOD: Dr. Abramson?
DR. ABRAMSON: I would keep mine the same.
DR. WOOD: Let's take a break We will
return at five past 3:00. That is ten minutes from
now.
And we will get started on the next question.
(Break.)
DR. WOOD: Okay.
Let's get started.
Question No. 3:
Rofecoxib
DR. WOOD: We are going to move on to
Question No. 3. I think we have got the system
down pat now. We know what we are doing here,
hopefully. The first question is, do the available
data support a conclusion that rofecoxib
significantly increases the risk of
cardiovascular
events.
We have been over this a lot, I
think, so
we probably don't need a lot of discussion. But I
will entertain discussion if there is
any. Seeing
324
no hands, we will--which side did we
start on last
time?
Over here.
Yes, Dr. Ilowite.
DR. ILOWITE: Just to remind everybody
that this is the only celecoxib that has
been
approved for JRA and was available as a
liquid.
DR. WOOD: Can we just hold for a moment.
DR. GARDNER: Would you say that again. I
didn't hear what you said.
DR. ILOWITE: We are talking about
Question 3; right?
DR. WOOD: Right.
DR. ILOWITE: I was just going to remind
everybody, this is the only COX-2
inhibitor that
has been approved for treatment of
juvenile
rheumatoid arthritis and was available as
a liquid.
DR. WOOD: Dr. Elashoff's vote was not
properly recorded because it was unclear
what she
said, apparently. Would she like to vote?
DR. ELASHOFF: I was told I had to say
something other than "unclear,"
so I said no.
DR. WOOD: So you said no. That being the
325
case, roll of the drum, the vote is 14
yes, 5
abstain and 12 no.
DR. HENNEKENS: Alastair, a point of
information. I think we run the risk of giving a
bad message here. If we are saying that valdecoxib
is contraindicated in cardiac surgery
patients when
we haven't acknowledged that, if there
really is a
class effect, we wouldn't want doctors to
get the
mistaken impression that they should use
another
coxib or another NSAID instead of
valdecoxib.
DR. WOOD: I am assuming that the FDA will
take that into account and contraindicate
all of
them in cardiac surgery. Am I wrong about that,
Dr. Temple? Dr. Jenkins?
DR. JENKINS: That would certainly seem to
be the logical conclusion since
valdecoxib is only
in oral dosage form and the others are
oral as
well.
DR. WOOD: So does that reassure you,
Charlie?
I know that someone said consistency is
the hobgoblin of small minds, but I guess
I have
got one.
DR. WOOD: Let's move on, then. Which
side did we start on last time. I have forgotten.
You started last time? All right.
Let's start
326
with Dr. Abramson. Do the available data support a
conclusion that rofecoxib significantly
increases
the risk of cardiovascular events.
DR. ABRAMSON: Yes.
DR. NISSEN: Nissen.
Yes.
DR. WOOD: Hang on.
I have been asked to
ask each of you to give your name before
you give
the vote.
Sorry. So, Dr. Abramson?
DR. ABRAMSON:
Abramson. Yes.
DR. WOOD: Nissen?
DR. NISSEN: Nissen.
Yes.
DR. ELASHOFF: Elashoff.
Yes; both
against placebo and against naproxen.
DR. GARDNER: Gardner.
Yes.
DR. PLATT: Platt.
Yes.
DR. DAY: Day.
Yes.
DR. FURBERG: Furberg.
Yes.
DR. FLEMING: Fleming.
Yes.
DR. BOULWARE: Boulware.
Yes.
DR. DWORKIN: Dworkin.
Yes.
DR. HOFFMAN: Hoffman.
Yes.
DR. MANZI: Manzi.
Yes.
DR. FARRAR: Farrar.
Yes.
DR. HOLMBOE: Holmboe.
Yes.
DR. WOOD: Wood.
Yes.
327
DR. GIBOFSKY: Gibofsky.
Yes.
DR. CRAWFORD: Crawford.
Yes.
DR. CUSH: Cush.
Yes.
DR. BATHON: Bathon.
Yes.
MS. MALONE: Malone.
Yes.
MR. LEVIN: Levin.
Yes.
DR. ILOWITE: Ilowite.
Yes.
DR. D'AGOSTINO: D'Agostino.
Yes.
DR. MORRIS: Morris.
Yes.
DR. CANNON: Cannon.
Yes.
MS. SHAPIRO: Shapiro.
Yes.
DR. PAGANINI: Paganini.
Yes.
DR. FRIEDMAN: Friedman.
Yes.
DR. HENNEKENS: Hennekens.
Yes.
DR. SHAFER: Shafer.
Yes.
DR. WOOD: Dr. Gross has returned.
DR. GROSS: Yes.
DR. WOOD: Dr. Domanski has returned. The
question we are voting on is, does the
available
data support a conclusion that rofecoxib
significantly increases the risk of cardiovascular
events.
DR. DOMANSKI: Yes.
DR. WOOD: Okay.
The vote is 32 yes.
Let's move on to the next question; does
the
328
overall risk versus benefit profile for
rofecoxib
support marketing in the U.S. We will start
with--do you want discussion on that
first?
DR. HENNEKENS: Yes.
DR. WOOD: All right.
Charlie.
DR. HENNEKENS: I think it is important to
point out that, in the placebo-controlled
trials,
the point estimates for rofecoxib are
practically
identical to that for celecoxib. Where there
appears to be a discrepancy is the
rofecoxib trials
use naproxen as a comparator which always
compares
favorably. Some of the celecoxib trials use the
short-acting NSAIDs which I continue to
believe has
329
been an issue that we, I know, will
discuss. But I
think the overall placebo-controlled
comparisons
are pretty much identical to one another.
DR. WOOD: Any other discussion? Dr.
Nissen?
DR. NISSEN: There are some troubling
things, however. If you look at all the evidence
including the meta-analysis, the
blood-pressure
effects for the drug are clearly outside
of other
drugs in the class including celecoxib
and so on.
So one of the things that troubles me is
I happen
to think that the prostacycline factor is
not the
only one.
I share Bob Temple's concern that a 5-
or 6-millimeter average blood-pressure
increase
over a period of time is very undesirable
since
there are other drugs in the NSAID and
coxib class
that do not appear to have that very
large signal
on blood pressure.
There is another signal here as
well that
I think it is important that we
understand and that
is the heart-failure signal. Compare the
heart-failure events in the APC and
approved
330
trials.
What you see is almost no heart-failure
events.
Now, you don't know if they are the same
definitions, but you would like to
believe they
are.
And you see this pulmonary edema, heart
failure, very, very strong signal, as
evidenced by
the Kaplan Meier curve that was in the
New England
Journal of Medicine.
So I think there are
differences within
the class. I think the problem emerges much more
clearly with rofecoxib, particularly on
the
blood-pressure, heart-failure, side. So my
thinking is that there are safer
alternatives and,
therefore, it isn't the same. It isn't identical.
DR. HENNEKENS: A quick question on that.
If you think there is more hypertension
and heart
failure, then in the APT collaboration
events of
non-fatal M.I., non-fatal stroke and
vascular
death, in the placebo-controlled trials,
why
doesn't that added hazard translate into
a higher
risk estimate?
DR. NISSEN: What you are saying is heart
failure and edema don't immediately
translate to
331
thrombotic events.
DR. HENNEKENS: No; but blood pressure
does on stroke and on M.I.
DR. NISSEN: There is a latency, of
course.
It takes a while for hypertension to yield
an excess of events. So there may be some latency
issues here as well. But I do think the signal on
blood pressure is different for this
age. I think,
you know, if you look at the data
dispassionately,
you come to that conclusion. So it makes me more
concerned.
DR. WOOD: I also have a view on this. I
think the data here are very
compelling. There are
two trials, as Steve just said. There is not only
the cardiovascular risk in the approved
trial,
there is also the very large risk from
heart
failure which separates very early. So there is a
clear signal this drug appears
substantially worse
than the others. I can't see any reason to keep it
on the market.
Curt?
DR. FURBERG: I don't think that is
332
correct for heart failure. In the
placebo-controlled trials of Celebrex had
a risk
ratio of 6. The risk ratio in the approved study
was 4.
So there is no indication that Vioxx is
worse than Celebrex for causing heart
failure.
DR. WOOD: Dr. Paganini.
DR. PAGANINI: I think this drug really
has a much stronger dose relationship
than the
others have. I think if you take a look at the
doses, at the higher doses, you get a much higher
response.
The studies showed clearly that 50
milligrams is probably not very good, 25
a little
bit better, but 12-and-a-half came back
to where
the other NSAIDs seemed to be.
So I would sort of strongly
look at dose
response in this particular drug versus
the others.
I think it is much more apparent here
than the
others.
DR. WOOD: Dr. Shafer.
No? Any other
comments?
Sorry, Dr. Manzi. It is hard to
see
over in this corner.
DR. MANZI: I just wanted to point out in
333
the interest of a risk:benefit way,
number one,
that, as Dr. Ilowite pointed out, this is
the only
drug approved for pediatrics, for JRA,
too. It is
the only one with a G.I. safety proven
indication.
Other than its efficacy, I would also
point out
that the once-day dosing, whether it be
25
milligrams or whatever, has been a very
favorable
component for patients as far as
compliance issues.
DR. WOOD: Of course, it might be related
to its toxicity, even, the once-day
dosing.
Any other comments?
DR. BATHON: It is also the only drug
available that can be used in people who
are
sulfa-allergic.
DR. WOOD: Was there somebody else? Dr.
Fleming?
DR. FLEMING: In addition to the excesses
that are strongly seen in the VIGOR and
the APPROVe
trial, the APPROVe trial, Charlie, is
placebo-controlled so maybe I missed the
essence of
what you were saying. The APPROVe trial does show
a substantial increase in a
placebo-controlled
334
setting and also shows, in that context,
that the
excesses are cardiac events as well as
cerebrovascular events.
The most favorable of these is
the
Alzheimer's study if you are just looking
at
cardiovascular events and yet, that is
the
study--if that is our positive study,
that is the
study that shows a statistically significant
increase in mortality at 41 against
23. So we have
got some significant concerns in each of
the
trials.
Even with the trial that is favorable, or
neutral is a better term, in terms of the
cardiovascular events, is very
unfavorable in
mortality.
DR. WOOD: Are we ready to go around the
room?
I think so. We would like to
start with Dr.
Abramson.
I'm sorry. Dr. Shafer.
DR. SHAFER: I would say overwhelmingly
no, although if individual patients can
petition
the company under some mechanism, I would
support
that.
DR. WOOD: Dr. Hennekens.
DR. HENNEKENS: Hennekens.
Yes.
DR. FRIEDMAN: Friedman.
No.
DR. PAGANINI: Paganini.
Yes.
335
MS. SHAPIRO: Shapiro.
No.
DR. CANNON: Cannon.
No.
DR. MORRIS: Morris.
Yes, but.
DR. D'AGOSTINO: D'Agostino.
No.
DR. ILOWITE: Ilowite.
Yes.
MR. LEVIN: Levin.
No.
MS. MALONE: Malone.
Yes, with
reservation.
DR. BATHON: Bathon.
Yes, but at lower
dose, 50 milligrams.
DR. CUSH: Cush.
Yes.
DR. CRAWFORD: Crawford.
Yes.
DR. GIBOFSKY: Gibofsky.
Yes.
DR. WOOD: Wood.
No.
DR. GROSS: Gross.
No.
DR. HOLMBOE: Holmboe.
Yes, but only for
children.
DR. FARRAR: Farrar.
Yes.
DR. MANZI: Manzi.
Yes.
DR. HOFFMAN: Hoffman.
No.
DR. DWORKIN: Dworkin. Yes, with
restrictions.
DR. BOULWARE: Boulware.
Yes.
DR. DOMANSKI: Domanski.
No.
DR. FLEMING: Fleming.
No.
336
DR. FURBERG:
Furberg. No.
DR. DAY: Day.
No.
DR. PLATT: Platt.
Yes.
DR. GARDNER: Gardner.
Yes, with
restrictions.
DR. ELASHOFF: Elashoff.
No.
DR. NISSEN: Nissen.
No, but with a
possible compassionate-use program.
DR. ABRAMSON: Abramson.
Yes.
DR. WOOD: Okay.
While we are doing our
counting, let's go on and review the
restrictions
we would want to have on this if it were
on the
market.
This time, we will start with
Dr.
Abramson.
DR. ABRAMSON: I think the concern with
337
rofecoxib is the dose response and the
hypertension. I think there should be some
addressing of the maximum dose--
DR. WOOD: Dr. Abramson, sorry. Could I
interrupt you. The hanging chads have raised their
head.
They want to go back. We can't
agree on the
vote, apparently, for 2.b. So the question for
2.b. was, does the overall risk versus
benefit
profile for valdecoxib support marketing
in the
U.S.
Even though we announced the vote, and
everybody rushed out to file the story,
it was
premature. We are going to have to retake the vote
because we are not sure what the vote
was,
apparently.
So, I have forgotten which side
we started
on now.
Who started? Steve? Let's go around
again and let me remind everybody what we
are
voting here. We are voting for valdecoxib. Does
the overall risk versus benefit profile
for
valdecoxib--we are going back to retake
the vote
for valdecoxib for Question 2.b. because
there is
some discrepancy, apparently, in the vote
counting.
338
Remember Florida? You thought I was kidding.
DR. NISSEN:
Where is Katherine Harris now
that we need her.
DR. WOOD: So we are going to go back and
retake--isn't that right? We are going back to
2.b.
We are going back to Question 2.b. and we are
taking the vote on 2.b. The question is, for
valdecoxib, Bextra, does the overall risk
versus
benefit profile for valdecoxib support
marketing in
the U.S.
A yes would keep it on the market.
A no
would take it off the market. Steve are you--which
one was it?
COMMITTEE MEMBER: Is it not on the tape
recorder?
DR. ABRAMSON: Abramson.
Yes.
DR. NISSEN: Nissen.
Yes.
DR. ELASHOFF: Elashoff.
No.
DR. GARDNER: Gardner.
No.
DR. PLATT: Platt.
Yes.
DR. DAY: Day, the hanging chad. I have
to abstain because the question is based
on the
available evidence. That is the basis for my
339
abstention.
DR. FURBERG: Furberg.
No.
DR. FLEMING: Fleming.
No.
DR. DOMANSKI: Domanski.
No.
DR. BOULWARE: Boulware.
Yes.
DR. DWORKIN: Dworkin.
Yes.
DR. HOFFMAN: Hoffman.
Yes, with
restrictions on dose and duration.
DR. MANZI: Manzi.
Yes.
DR. FARRAR: Farrar.
Yes, with
limitations on dose and duration.
DR. HOLMBOE: Holmboe.
No.
DR. GROSS: Gross.
No.
DR. WOOD: Wood.
No.
DR. GIBOFSKY: Gibofsky.
Yes.
DR. CRAWFORD: Crawford.
No.
DR. CUSH:
Cush. Yes.
DR. BATHON: Bathon.
Yes. I had
restrictions, also.
MS. MALONE: Malone.
Yes.
MR. LEVIN: Levin.
No.
DR. ILOWITE: Ilowite.
I am one of the
340
abstainers before. I will change it to yes.
DR. D'AGOSTINO: D'Agostino.
I will
balance that and change it to no.
DR. MORRIS: Morris.
Yes.
DR. CANNON: Cannon. Yes.
MS. SHAPIRO: Shapiro.
No.
DR. PAGANINI: Paganini continues
abstaining.
DR. FRIEDMAN: Friedman.
I will go to a
no.
DR. HENNEKENS: Hennekens.
Yes.
DR. SHAFER: Shafer.
Yes.
DR. WOOD: Okay.
While we are counting
that, we will go back to No. 3. We were about to
take the vote on 3.b. Oh; we can't vote yet.
While we are waiting, is there
discussion
on 3.c.?
3.c. is what we would done in terms of
restrictions were rofecoxib to come back
on the
market.
Is there someone else that could do the
count if we could vote? I beg your pardon. Go
ahead.
DR. HOLMBOE: I just wanted to make a
341
comment that it sounds like Vioxx is
really the
only thing that is available for
pediatric JRA.
Since our major concern is cardiovascular
risk, I
am persuaded by the arguments that you
have made
that I would hate to remove something
that may be
of benefit to a population likely to be
at very low
cardiovascular risk.
DR. WOOD: But we could keep it on the
market just for GRA if we wanted. All other drugs
could get approval for that, I
guess. So that is
your comment. Any other comments? Sorry; Dr.
Farrar?
DR. FARRAR: A comment about thinking
about these drugs in general which is
that,
although hypertension risk and the edema
risk may
be higher in terms of the studies that we
have
looked at, they clearly occur with the
other drugs
in
this category. In fact, a part of the
labeling
of the drugs ought to be recommendations
about
monitoring for those issues.
I think, in this particular
case, perhaps
one of the restrictions would be added to
some more
342
formal warning. But I think the point is that,
even a low risk of increased hypertension
which may
go unnoticed in a young, healthy person,
would be
an important criteria for long-term use
of any of
these drugs and clearly for this one.
DR. WOOD: Any other comments? Dr.
Morris?
DR. MORRIS: This is a case where, even
though I am in favor of the marketing of
the drug,
I am not in favor of the marketing of the
highest
dose.
I think that should be removed from
marketing. I also would very heavily support some
kind of really bold warning on duration
of use for
this drug as well.
DR. WOOD: Dr. Paganini.
DR. PAGANINI: I would second those
sentiments.
DR. WOOD: Dr. Hoffman?
DR. HOFFMAN: I am concerned about the
pediatric issue for two reasons, one,
that Norm
Ilowite stated in regards to lack of a
lot of other
options, but also the concern about
silent,
343
insidiously progressive, cardiovascular
injury. I
would be very interested in Dr. Nissen's
comments
even though they may be entire
theoretical about
what we might be buying into in approving
this for
chronic use in children.
DR. WOOD: Okay.
Let's--
DR. PLATT: One more.
DR. WOOD: Okay.
Dr. Platt first and then
Dr. Nissen.
DR. NISSEN: It seems to me, to the extent
that we believe there are differences
between drugs
in this class, that rofecoxib is the
extreme, both
in terms of its potential danger and its
potential
benefit.
So I think that the onus on informed
choice is greater for this drug than for
the
others.
DR. WOOD: Dr. Nissen?
DR. NISSEN: I am concerned. Part of it
comes from a long history of studies with
blood
pressure that show that it is a
continuous risk
factor.
It extends really way down into the normal
range and part of the reason why I was
arguing
344
against bringing the drug back is that,
while it
may be true that it is the only drug
approved for
JRA, there is not any reason to believe
that other
agents could not, in fact, be developed
for use in
that population.
I am worried that, if you
increase blood
pressure 5 or 6 millimeters of mercury
over a long
period of time, you will have a very
adverse effect
on the health of individuals. So, because I
believe the blood pressure is such an
important
surrogate endpoint in cardiovascular
risk, it puts
the rofecoxib data in a different
perspective.
I guess the other thing I want
to make
sure everybody understands, is that there
are some
differences in what was seen. The dose that was
used and approved was the 25-milligram
dose, not
the 50-milligram dose. There is a very, very
strong signal there.
That kind of signal is only
seen at 800
milligrams in the APC trial. So I think that there
is a much greater effect here with this
agent even
at doses that are not
supratherapeutic. So, if we
345
do bring the drug back, I think that the
12-and-a-half-milligram dose is the only
dose that
I would be comfortable with because we
have seen a
pretty strong signal at 25.
If you recall, we haven't seen
signals at
200 for celecoxib. So it is quantitatively and
qualitatively quite a different signal
with
rofecoxib than celecoxib. So I just hope everybody
understands the implications of a
decision to put
this drug back on the market.
DR. MORRIS: What is the effect, if blood
pressure is raised, like you say, for,
let's say
six months, what is the effect if someone
is taken
off the drug? Does that effect go on or does blood
pressure return to normal? Do we know?
DR. NISSEN: I don't have any data to that
effect.
I would believe that it would be likely,
at least in large part reversible, but I
am not
sure anyone has such data.
DR. WOOD: Dr. Ilowite?
DR. ILOWITE: So, if there were a way to
make approval in children contingent upon
further
346
study on effects on blood pressure and
other
mechanisms of atherogenesis that might
have
long-term use, I would certainly be in
favor of
that.
DR. NISSEN: It is pretty difficult to
study because the latency--you know, if
you are
going to say, well, I am going to
increase the
life-long risk of cardiovascular disease
in a young
person, you are going to have to wait a
long time
and do an awful big study to see it. So it is just
not a studyable phenomenon. You have to accept the
importance of blood pressure as a
surrogate measure
and make the decision on that basis.
DR. ILOWITE: If I could just comment.
Certainly, blood pressure, which would be
easy to
study.
Secondly, there are trials in existence now
looking at surrogate early markers of
atherosclerosis in adolescents an older
children,
not preadolescents, that might be useful.
DR. WOOD: That was Dr. Ilowite again.
Are we ready to take a vote?
DR. FARRAR: One more.
DR. WOOD: Sorry, Dr. Farrar.
DR. FARRAR: This is Dr. Farrar. It
actually is a very opportune time to
think about
347
this kind of long-term study. As many of you know,
the NIH is in the process of putting
together
approximately a billion dollars worth of
money to
study pediatric diseases. Perhaps, the advice of
this committee could be used to sway them
in terms
of looking at those issues.
DR. WOOD: Dr. Manzi?
DR. MANZI: I just had a question because
we
didn't have, really, access to the data in JRA
as far as efficacy with Vioxx. Were there
blood-pressure issues in those trials?
DR. ILOWITE: There were no blood-pressure
issues to my knowledge. I think it was a study
against naproxen and showing--
DR. WOOD: Do we know there were no
blood-pressure issues, or do we just not
know?
DR. ILOWITE: I would know if there were
blood-pressure issues.
DR. WOOD:
Bob, do you know?
DR. TEMPLE: No; I don't know. But what I
wanted to ask Steve was whether he
thought seeing
whether you could manage the blood
pressure and how
you could manage the blood pressure would
be of
interest.
Blood pressure is something we
ordinarily think of as treatable.
348
DR. WOOD: It was managed and approved,
though, wasn't it? And you still ended up with a
higher blood pressure. I forget the data now.
Steve, isn't that right?
DR. NISSEN: Yes.
What was observed was
there was a blood-pressure
differential. But, in
addition, there was a greater use of
antihypertensive agents.
DR. WOOD: There was a greater dropout
because of hypertension, too.
DR. NISSEN: One of the problems is that
if you actually look at the data very,
very
carefully and maybe Ralph may be able to
comment on
this, that treated hypertension still
confers a
risk over no hypertension; that is to
say, bringing
the blood pressure down to the same level
with a
349
drug does not neutralize the risk of
hypertension
in all the epidemiological--
DR. D'AGOSTINO: Certainly, the Framingham
data says that. You have a 160 systolic on
treatment, you are at higher risk than a
160
systolic natural.
DR. NISSEN: That's right.
DR. D'AGOSTINO: You are presumably coming
down from a much higher level and pulling
it down.
But it definitely does not restore
you. You have
to bring it down to something like 120
where you
don't see a difference.
DR. WOOD: Okay.
Let's go around the room
starting with Dr. Abramson.
DR. ABRAMSON: On 3.c.?
DR. WOOD: We are on 3.c. I guess, again,
the issue is are there incremental
changes you want
to make over your previous votes here.
DR. ABRAMSON: I think this is a tougher
one and Dr. Nissen articulated the
concerns. So I
would have a stronger label in terms of
hypertension and potential cardiovascular
outcomes.
350
I would have a restriction of upper dose
to be
determined. And I would leave open the possibility
of some change of this with future
studies. This
is one drug, based on the evidence right
now, that
I might make a second choice if I had
to--given the
evidence that we have.
DR. NISSEN: Because we have
evidence both
at 25 and 50 milligrams that is really
quite
robust, if anything is done with the
drug, it
should be at a dose of
12-and-a-half. Again, I am
concerned. I would also just want to make sure
everybody understands that if you look at
all the
observational studies, this was the
outlier. So,
if you really want to make this
evidence-based, you
have got to look at all the evidence.
You have got two trials and
observational
data that are telling you the same thing,
that this
is not a safe alternative. So I don't want to go
there.
But, if we do go there, I would put the
most difficult and most complex warning
on there
possible.
DR. ELASHOFF: Elashoff.
Stronger than
351
either of the two previous cases.
DR. GARDNER: Gardner.
Stronger as well.
This may be the drug that we ask to
register
patients or otherwise bring attestation
into the
risk-management program as well as a
good, strong
postmarketing or continued marketing
ongoing
evaluation.
DR. PLATT: Platt.
I started off at the
extreme with the other drugs. So I stay there,
though I would add the dose restriction
for this
drug.
DR. DAY: More restriction, except I must
say, were they unlucky that they used
higher doses
to begin with? They were the first one that
entered, as I recall, the marketing fray.
DR. WOOD: No, no.
DR. DAY: Oh; that's right. So, if they
had come in at 12-and-a-half and 25, it
might have
been different. But, okay; more restrictions, if
it were to come back.
DR. FURBERG: Furberg.
Stronger black-box
warnings.
DR. FLEMING: Fleming.
I would add the
same conditions and concerns that Steve
Nissen
indicated.
352
DR. DOMANSKI: Domanski.
I would use the
same recommendations I did for
Celebrex. I would
underscore second-line drug.
DR. BOULWARE: I have nothing further to
add.
Boulware.
DR. DWORKIN: I agree with what has been
said.
I would actually think about making this
third-line, but a patient will have had
to have
failed two NSAIDs, whether selective or
not, before
they try this drug.
DR. HOFFMAN: Hoffman.
I agree with the
black-box warning should this be
remarketed with
restriction in dose to 12.5 milligrams.
DR. MANZI: I agree with the black-box
label.
I would restrict only the 50-milligram
dose.
If there were a choice, I would rather have
patient consent versus not having the
drug
available.
DR. FARRAR:
John Farrar. A strong
353
black-box warning including an indication
of
ongoing monitoring of blood pressure in
all
patients including children. I am conflicted about
the idea of registration but feel that
some sort of
patient consent to indicate the knowledge
of the
potential risks be made but that the drug
be made
available. I also agree with the restriction in
dose.
DR. HOLMBOE: Eric Holmboe.
I agree with
what has been said previously. I also feel that,
if this drug is to be used in adults,
there should
be some sort of informed-consent process.
DR. GROSS: Peter Gross. A strong
black-box warning, second-line drug and
restricted
to 12-and-a-half-milligram dose.
DR. WOOD: Alastair Wood. I would say the
same thing, black-box warning. I would have a very
restricted access program in which
consent would be
obtained and, if it were to come back on
the
market, there would have to be such
limited access
that there would be an attestation and
some clear
ability of patients to consent.
Similarly, in children, I think we should
be careful not to just assume children
are not at
risk here. While I understand the sentiment to
354
promote the drug in children, I think we
need to be
careful that we don't, then, put them at
even
greater risk with their lifelong
hypertension risk,
their lifelong exposure to cardiovascular
risk
factor, and so on when there might be
safer drugs
available.
DR. GIBOFSKY: Gibofsky.
I would agree
for restricting the dose to not above
12.5
milligrams in patients who need it for
chronic use,
not for acute use. I would favor a very strong
black-box warning to emphasize the
hypertension,
cardiovascular, at the higher dose. I would favor
language making this a less preferable
agent,
whether it is second or third choice, to
be
determined.
I question whether this is
something that
might be handled, if it comes back, under
a Subpart
H where there would be very strong
restrictions on
who would have access to it based on need
and
355
determination of physician and patient.
DR. CRAWFORD: Crawford.
In addition to
what I stated with the other two, I think
there
should be a stronger black-box warning,
dose limits
as appropriate, duration limits,
second-line and
informed consent.
DR. CUSH: Cush.
I would be in favor of
retention of all current
indications. However, I
would strongly recommend removal of the
50-milligram dose from the market and its
omission
from the package insert as a potential
dose for use
in acute pain. I would strongly encourage a
black-box warning.
DR. BATHON: Bathon.
I am strongly in
favor of a strong black-box warning with
elimination of the 50-milligram and this
drug as a
second choice.
MS. MALONE: Malone.
I have no problem
with the black-box warning. I think, if it does
come back on a market, that there have to
be
ongoing studies. And I am in favor of a patient
consent that they acknowledge the risks
that are
356
involved.
MR. LEVIN: Black-box warnings
strengthened and I am intrigued by the
notion of a
Subpart H approach to limit prescribing
and
distribution of the drug.
DR. WOOD: That was Mr. Levin.
DR. ILOWITE: Ilowite.
A strong black-box
warning, elimination of the 50-milligram
dose. I
would encourage reexamination of the dose
in
children in addition to the studies of
blood
pressure and atherogenesis that were
talked about
before.
DR. D'AGOSTINO: D'Agostino.
Stronger
black-box warning, dose restriction to
12-and-a-half and restricted access.
DR. MORRIS: Morris.
Black box,
withdrawal of the highest dose. I would like to
see a consent, initially, but also, based
on that
consent, a reminder sent to the patient
about
either six months or a year, depending
upon issues
related to duration to remind them about
the risks
of long-term use.
DR. CANNON: Cannon.
I favor a strong
black-box warning, no direct-to-consumer
advertising. I would limit its use to a short-term
357
use for pain in adults and for chronic
use in
children and young adults with JRA with
careful
monitoring of blood pressure.
MS. SHAPIRO: Shapiro.
I agree with what
Dr. Cannon just said with some dose
limitations,
appropriate dose limitations.
DR. PAGANINI: Paganini.
Black box to
include very strong and severe dose and
time
restrictions as well as cardiovascular,
to spell
out the cardiovascular clearly to include
blood
pressure and congestive heart failure, no
direct
advertising and move from a patient
brochure as a
patient consent.
DR. FRIEDMAN: I agree with what has just
been said with the elimination of the
high 50 dose.
DR. HENNEKENS: Hennekens.
I share
Steve's concern that blood pressure is a
greater
potential issue here but Richard's that
it is
likely that higher doses of this drug
lead to
358
greater benefits. This may offer one plausible
explanation for the higher risk seen in
observational studies.
As I said, with regard to the
coxib, I
think global risk assessment and
aggressive
management of cardiovascular risk is
important. I
would expand that I would definitely
think we ought
to be thinking about Ralph D'Agostino
Framingham
Risk Score and the aggressive management
based on
federal an AHA guidelines which are
mandated based
on these assessments for both statins and
aspirin.
DR. SHAFER: Steve Shafer.
If it is to be
marketed, I think it should only be
indicated for
children not adequately treated with
conventional
NSAIDs.
The black-box warning should state that
the
cardiovascular effects in children are unknown
and that the use in adults is not
recommended.
The adult use should be limited
to
compassionate use only which, I believe,
is the
Subpart H restriction.
DR. WOOD: Okay.
I am now in a position
to read you the votes for Question 2.b.
and 3.b.,
359
at least for now. The vote for 2.b., which was the
vote on valdecoxib, for those of you who
have
forgotten already, was 17 yes, 2 abstain
and 13 no.
The vote on 3.b., which was the rofecoxib
vote, was
15 no, 17 yes.
Question No. 4
So let's move on the Question
No. 4; if
the available data support a conclusion
that one or
more COX-2 selective agents increase the
risk of
cardiovascular events, and we have
clearly made
that decision already, then please
comment on the
role, if any, of concomitant use of
low-dose
aspirin in reducing cardiovascular events
in
patients treated with COX-2-selective
NSAIDs.
I am not sure how we can do
that, apart
from the sort of biological basis. There are not
any randomized trials in which we have
got data
from that, are there? Ones that are on the market
here?
DR. HENNEKENS: If we accepted a global
risk assessment and aggressive management
of
cardiovascular risk based on federal and
AHA
360
guidelines, that embedded in both of
those sets of
guidelines are guidelines for the
aggressive
management with statins and aspirin
rather than a
recommendation that is for a specific
drug in
specific response to this class of drug.
DR. WOOD: No; but I think the question
here, Charlie, is that if we accept that
this drug,
in itself, carries a risk of
cardiovascular
disease--let me rephrase the
question. I think the
question that is being asked here is do
we think
that the cardiovascular risk produced by
these
drugs, or any one of these drugs, can be
reversed
by
the administration of aspirin. That is
what we
are trying to get at.
DR. HENNEKENS: I wanted to rephrase the
answer and say that I think aggressive
assessment
and management of all cardiovascular
risks of these
patients is what is indicated. I think it would be
a mistake to limit it based on a
pharmacologic
argument to this one particular
agent. And, in
addition, there are exiting federal and
NIH
guidelines--AHA guidelines; I'm
sorry--for the
361
management of these patients for both
statins and
aspirin which would kick in. That, to me, makes
much more rational sense.
DR. WOOD: No, no.
I understand that.
But let me just correct it. This could apply to a
patient independently of their--a patient
who was
not eligible for aspirin under AHA or
federal
guidelines. So the question that is being put here
is whether a patient who is taking these
drugs who
would not otherwise be eligible for
aspirin under
federal AHA guidelines should take
aspirin to
counteract the adverse effects of this
drug. Am I
right; John?
DR. JENKINS: Yes.
That is exactly
correct.
That would be a logical place you might
go if you think these drugs have a
cardiovascular
risk.
Based on the mechanisms proposed, you might
think you can take a low-dose aspirin and
reverse
it.
But we want to know your thoughts about
whether that has any value in reversing
the
cardiovascular risk and what the impact
is on the
G.I. benefit because this will come down
to a
362
question we will have to address in the
labeling
for these products whether there should
be any
comment about use of low-dose aspirin.
DR. WOOD: So I guess the study that
speaks to that most, I suppose, would be
the CLASS
study.
It wasn't a randomized comparison, although
it does give some evidence that the G.I.
benefit
was antagonized by aspirin and the
cardiovascular
benefit was reversed as well, I suppose.
Steve?
DR. NISSEN: I understand the spirit of
what you are asking here and let me see
if I can
frame this. You are asking whether we have
evidence that the mechanism-specific
effect of
these drugs can be reversed by
concomitant
administration of aspirin. I have looked at all
the data.
I looked at that APC data. I
looked at
everything else. Just there is no compelling
evidence of it.
It goes both ways and this is
actually one
of the biggest disappointments for the
whole class
because, when this whole hypothesis was
first
363
raised, there were people who said, don't
worry
about these drugs. Just give everybody a baby
aspirin every day and you can reverse the
cardiovascular toxicity of the COX-2
inhibitors.
It turns out that that
hypothesis, and I
have said a number of times, the road to
hell is
paved with biological plausibility, and
this is
another example of that the, in fact, it
was
plausible but it appears to be
wrong. Having said
that, the amount of data we have upon
which to make
that judgment is limited. It would be useful, at
some point in the future, if this class
of drugs is
to survive in the long run, to study this
in a more
formal way with larger sample sizes that
will let
people like Ralph and Tom and others
calculate with
more precision whether, in fact, aspirin
is an
effective antagonist to the toxicity of
this class
of drugs.
DR. WOOD: Dr. Bathon.
DR. BATHON: I agree with Steve that, with
the available data that we have so far,
the
addition of aspirin not only does not
appear to
364
reduce the cardiotoxicity but it also
seems to undo
the G.I. benefit. But, more importantly, if
somebody is on an aspirin with a COX-2,
you no
longer have COX-2 selectivity anyway, so
it doesn't
make rational sense to put the two
together. If
somebody needs aspirin, then there is no
particular
advantage to them being on a COX-2 drug
unless one
argues that aspirin plus a nonselective
NSAID has
higher G.I. toxicity, perhaps, than
aspirin plus a
COX-2 selective agent and I don't know
that we have
those data.
DR. WOOD: Dr. Domanski.
DR. DOMANSKI: I think it is important to
paraphrase Dr. FitzGerald--he may still
be
here--but I have learned from him. It is clear
that there is--at least it seems clear
that there
is a derangement caused by these drugs
and no
particular reason to believe that aspirin
mitigates
the derangement.
DR. WOOD: It is always dangerous to
paraphrase Garret. I will tell you that. Dr.
Platt?
DR. PLATT: It seems to me the arguments
for aspirin, if we accept them, could
clearly move
these drugs into second-line status. Those who
365
didn't think so before, I think, lose the
rationale
there is for treating these drugs as just
regular
NSAIDs.
DR. WOOD: Dr. Gross?
DR. GROSS: I think there is just not
enough good evidence to comment on this
one way or
the other and the question raised was not
a primary
endpoint on any of the studies we used.
DR. WOOD: Dr. Farrar.
DR. FARRAR: I think we need to be
careful.
Aspirin is not a panacea for cardiac
vascular disease. I think the cardiologists would
know better than I but, in my discussions
with a
couple of people last night and in the
past with
some of my colleagues at the University
of
Pennsylvania, it is clear that, in people
with
cardiac risk, serious cardiac risk,
aspirin is
probably useful in the general
population. It is
not at all clear and the benefit is
actually
366
reasonably small.
So I am not sure why there is a
sense of
loss that it doesn't work. But it is clear to me
that it doesn't work. The only evidence that
seemed to suggest it at all was the
approved study
and it was the outlier.
DR. WOOD: Any other comments? Dr. Cush?
DR. CUSH: To, again, paraphrase and
reinforce what Joan said in that, if you
probably
need aspirin for cardiovascular
prophylaxis and its
modest effects on that, then you
certainly
shouldn't be on a COX-2 inhibitor.
DR. NISSEN: There was one question I had
for our G.I. colleagues that never got
answered and
maybe you can help with this. Is there a
comparison of a conventional NSAID plus
aspirin for
cardiac protection versus a COX-2
inhibitor plus
aspirin.
Is there a quantitative difference in the
risk of G.I. toxicity?
DR. CRYER:
It depends on how you make the
comparison. If you derive your comparison--and I
am speaking about data that, to my
knowledge, has
367
not yet hit the peer-review published
world. If
you make the determination,
epidemiologically,
based upon hospitalizations for upper
G.I.
bleeding, the data would suggest that a
COX-2
specific inhibitor plus aspirin appears
to be a
regimen that is associated with a lower
rate of
hospitalizations than nonselective NSAID
plus
aspirin.
If you make the determination
based upon
the traditional characterization of G.I.
events,
the two arms appear equivalent.
DR. WOOD: At a personal level, I agree
with Dr. Gross. I don't think there is any
evidence base that we can answer that on,
however
attractive the underlying hypothesis
might be.
I don't think we need to go
around and
vote on that. Does anyone else have anything they
want to say on that that has not been
said? Yes,
Ralph?
DR. D'AGOSTINO: Maybe the FDA could
remind us. There was--I can't find it quickly, but
there was concern in one of the
noninferiority
368
trials that, if the study had too many
individuals
that were taking aspirin, not randomized
to aspirin
but taking aspirin, it was going to pull
the two
groups together. Could somebody from the FDA just
remind us where that concern--
DR. VILLALBA: In the lumiracoxib studies,
the subgroup on aspirin showed that--in
the
non-aspirin group, there is a clear
signal for
lumiracoxib versus naproxen. There were, like, 10
to 2 myocardial infarctions, while in the
subgroup
using aspirin, there was no difference.
DR. CRYER: I had forgotten about the
TARGET--this is Cryer, again, to answer
Dr.
Nissen's question. I had forgotten about the
TARGET trial and I will just remind the
group of
yesterday's presentation. In the 18,000 patients,
there were no differences with respect to
low-dose
aspirin and G.I. events, no statistically
significant differences.
DR. WOOD: Any other comments on that?
Yes?
DR. FLEMING: Fleming.
The data are
369
pretty limited. If you look at all 18,000
patients, it was 24, 23 in those that are
aspirin
users but it was 35, 27 in those that
were not. So
it is rather fragile while, in other
studies like
APPROVe, there was no evidence of
interaction.
DR. WOOD: I am going to jump to Question
6 because Question 6 we have to take a
vote on. So
I want to make sure we get that under our
belt and
then we will come back to Question 5.
Question 6 is, do you recommend
that the
labeling for these products include
information
regarding the absence of long-term
controlled
clinical-trial data to assess the potential
cardiovascular effects of these
drugs. If so,
please describe how you recommend that
information
be conveyed, warning, precaution.
I have a sense, John, that we
have already
covered that, to some extent, haven't we?
DR. JENKINS: Again, noting that this
question is about the agent other than
the three we
just discussed. This is about the other twenty.
DR. WOOD: I'm sorry. Then we will keep
370
going on 5, then. I beg your pardon. So we have
dealt with 4. Let's go on to 5.
Question No. 5
What additional clinical trials
or
observational studies, if any, do you
recommend as
essential to further evaluate the
potential
cardiovascular risks of celecoxib,
rofecoxib and
valdecoxib. What additional clinical trials or
observational studies, if any, to you recommend
as
essential to further evaluate the
potential
benefits--reduced G.I. risk--of
celecoxib,
rofecoxib and valdecoxib. Please be specific with
regard to which COX-2 selective agent to
study,
trial design, patient population, control
groups,
endpoints, duration, sample size, et
cetera. And
it is five to 4:00.
There is a three-day task right
there, it
seems to me. Do you really want that before we
leave?
Bob?
DR. TEMPLE: I guess I was struck by the
fact that several of you, but not
everybody, said
that celecoxib or valdecoxib has to do
something to
371
get rid of a certain nasty thing in the
labeling,
get rid of the box. So it raises immediately the
question what would they have to do to do
that;
comparison with some other drug, not be
worse than
naproxen?
What do they have to do?
That is why this deserves some
attention.
Nobody expects you to design the whole
trial
perfectly or fully in five minutes.
DR. WOOD: Four-and-a-half, now. Comments
on that?
How are we going to design a trial?
Can
we break it out easily? What would we need to
evaluate the potential cardiovascular
risk if we
think there is a cardiovascular risk of
celecoxib,
rofecoxib and valdecoxib.
Comments on that? Yes, Dr. Farrar.
DR. FARRAR: I think this
actually begs an
issue that we ought to address which is
that we
cannot possibly, in the half an hour or forty-five
minutes that is left do all of the issues
that are
being requested here. But it does suggest--
DR. WOOD: Did you think you were going
home at 5:00?
DR. FARRAR: My mother is down the road.
It's fine.
DR. WOOD: She'll be glad to see you
372
tonight.
We're all coming. (Laughter.)
DR. FARRAR: But it suggests, in fact,
that there needs to be a process that,
perhaps,
even expands beyond this particular class
of drugs
to really examine the issue of how the
safety of
drugs needs to be considered with regards
to the
patient populations that in whom the
drugs are
likely to be used and with regards to the
potential
uses for a particular drug.
I actually would strongly
recommend that,
for those of us who--I was one of those
who
recommended that there should be some
trials or
some studies done to try and remove some
of the
black-box labeling that, at least, I was
in favor
of.
Rather than trying to design all of that now,
what, really, I would suggest is that a
group of
academic folks made up of some of the
people here
but, clearly, including people with
pharmoepidemiology, statistical, epidemiological
373
skills as well as the particular
specialty skills
of arthritis, pain or whatever is
necessary, be put
together to formulate a really good
design based on
the type and the discussions here and
that the
recommendation of this group ought to be
that, not
just the folks at the FDA, but that there
should be
an ongoing process with a group of academic
advisors to really formulate an
appropriate study.
DR. WOOD: I guess I was the person that
suggested the sort of "get of out
jail free" card
if they came out with the studies. It seems to me
the studies break into two different
broad groups.
There are studies that would be
potentially against
placebo that would establish whether the
drug had
an absolute risk and there are studies
against some
other comparator that would establish
whether the
drugs were superior or inferior or the
same as the
other comparator.
It seems to me the choice of
the
comparator would depend, first, on the
indication,
clearly, and one would like at least to be
able to
get some information on what the
comparator looks
374
like on its own. So I am sort of going back to the
question that Tom Fleming raised
yesterday, or
whatever day it was, not it all merging.
But, with so many of these
studies, we are
in the position of trying to impute what
we would
expect to see with a placebo or what we
would
expect to see--yes; what we would expect
to see
with the placebo--in the absence of the
placebo, or
even we are trying to impute what this
drug would
do versus that drug based on another
study.
So it would be important to
know, for
example, unequivocally, whether naproxen
plus, I
would think, a PPI inhibitor does
something good or
bad in terms of cardiovascular risk. If we knew
that, we might be in better shape to make
judgements about how to design the
trials.
So I am not sure I would jump in
immediately to all these
comparisons. We are going
to get to some of that, I guess, in the
next series
of questions that look at the other
nonsteroidals.
But I think it is a complicated issue
that would
need to be addressed for both the
375
placebo-controlled group and the active
control
group and would need, actually, a third
comparison
which is a research program that looks at
the
active comparator so that we establish
what it is
we are actually looking at there because
a lot of
that we have imputed.
Bob?
DR. TEMPLE: Suppose you knew--there are a
bunch of nonsteroidal anti-inflammatory
drugs out
there.
Everybody agrees somebody is going to--you
are going to treat pain with
something. Several of
you said that staying on the market with
this box
places you under some--that, ideally, at
least,
there would be some further studies
designed to
show something.
So, just to pose a couple of
questions,
suppose an adequately sized study of
adequate
duration showed that this drug was no
worse than
ibuprofen, a standard treatment, would
that be
reassuring up to a point even though you
have never
had a placebo-controlled trial of
ibuprofen and you
probably never will.
Or would you have to use
naproxen which
people sort of have an inclination to
think is a
little better. Or do you have to try to dream up
376
another placebo-controlled trial which is
not easy
to think how you do these days unless
sort of polyp
reduction raised its head again, maybe at
a lower
dose.
It would helpful not to design
the whole
trial but to think a little bit about
some of those
things and what is possible. If you can't do
anything until you have the definitive
naproxen
versus placebo study, we are talking
almost never
because we don't have any of that.
DR. WOOD: Of course, the other issue that
is on the table is that some of us
believe these
drugs were risky. And so inherent in that
assumption is that you would be cautious
about
recommending a trial to be done because
the
likelihood is it would revalidate or
replicate what
has already been shown. So there is some hazard in
suggesting that, I think.
But I actually think there is a
value in
377
trying to demonstrate an effect against
naproxen.
I don't see a problem with that. Naproxen may be
beneficial. We ought to know that, though, and we
ought to be able to find that out fairly
quickly, I
would have thought. And let's get that.
After all, it is not that we
are trying to
define the origin of life or something
here. This
is not some fundamental discovery we are
trying to
make.
We are trying to divine what the optimal
therapy is for something. If we can evaluate
naproxen plus a PPI and work out how that
stacks up
against placebo, and then move on from
there, we
could get a lot of information fairly
quickly, I
think, that would be very valuable.
DR. TEMPLE: So at least the initial
study, perhaps you would add other groups
like one
of the other selective ones that isn't so
named,
but the first study would be a study of
reasonable
duration.
You also--I hope you will say something
about just how long it needs to be,
too. I mean,
is it a one-year or a three-year study?
The initial comparison might be
against
378
naproxen and some dose of celecoxib. They already
have a study against ibuprofen so that
wouldn't be
too helpful to do again, I guess. Is that the sort
of thing you are thinking of ?
DR. WOOD: Yes. I
would be unimpressed
with a study against another selective
COX-2
inhibitor. I think that is likely to be negative.
DR. TEMPLE: And it has been done.
DR. WOOD: And it is being done right now.
I am not sure of what that will teach
me. At the
end of that study, if you gave two doses
of the
same drug, you would expect to see the
same effect
in both groups. If you give two drugs that are
very similar in their pharmaceutical effect,
you
are unlikely to see a difference between
them and I
am not sure what that would tell me.
DR. TEMPLE: So, so far, at least, your
thinking naproxen, if I hear you.
DR. WOOD: Right.
Dr. Cush?
DR. CUSH: I think, by going through this
data in the last few days, that we have
acknowledged that there are a number of
signals
379
that exist--that are worrisome that exist
for the
nonselective nonsteroidals especially for
ibuprofen
and diclofenac which have been often
comparators in
these trials. I think we also have been impressed
by the performance of the naproxen.
Hence, I would say that, really, the
whole
class, all nonsteroidals, should have a
warning
that would include some lesser version of
what may
be in the black-box warning about
cardiovascular
risk and that everyone should basically
carry that
forward, maybe with the only pass being
provided to
naproxen which becomes a comparator drug
for future
trials.
I think that, to get off the
list, to get
that warning removed, you basically have
to, as a
sponsor, do a trial against naproxen or,
in some
other manner, show that you do not show a
significant cardiovascular hypertensive
risk to
your patients.
I would also favor the
performance of an
NIH and/or FDA-funded--ALLHAT trial has
been
proposed--and such a trial should be two
years
380
duration.
DR. WOOD: Dr. Nissen?
DR. NISSEN: Let me see if I can get very
specific here. For each of the marketed COX-2s
which I assume, at least for the moment,
will
be--who knows? Actually, I am not sure what we
decided.
But let me say that, in arthritis, it is
very clear you can't do a
placebo-controlled trial.
While it might seem appealing to do your
acetaminophen codeine control group, I
just don't
think it is a practical approach.
I think we need to have some clarity
and
some consistency in comparators because,
if we
don't, if every sponsor compares to a
different
active comparator, we will have no
clarity at all.
So I happen to think that the evidence is
pretty
good that naproxen is no worse than
neutral. So I
would like to see a celecoxib 200
milligrams, a
dose that has not, at this point, been
shown to
have excess cardiovascular risk, against
naproxen,
500 BID, with adequate size, and Tom has
mentioned
some numbers--we are talking about around
100
381
events, at least, maybe a little bit
more--to get
the upper limit of the hazard ratio to be
at a
level that would provide some comfort.
If you are going to do that
trial, then it
makes a lot sense to add a third arm to
the trial
which includes a conventional and
non-naproxen
NSAID.
I happen to like diclofenac because it is
an agent that looked, in CLASS, an awful
lot like
celecoxib.
So now you have clarity in a
single trial
of acceptable size on how a low dose of
celecoxib,
the most commonly prescribed dose,
compares to an
agent that you believe is, at worst, neutral
and to
an agent that has some potential
suspicion to be
worse than neutral. When you are done with that
trial, you will know a lot more.
Now, Merck has already set up a
diclofenac
comparator with their agent and that is
helpful.
The problem is--
DR. TEMPLE: Not naproxen.
DR. NISSEN: Not naproxen.
You know,
obviously, is it very costly to redesign
that trial
382
but there is a problem for me. If Garret
FitzGerald is right, that diclofenac is
similar to
celecoxib in selectivity and, therefore,
in
cardiovascular risk, then the comparator
to
etoricoxib could be a comparator that is
not
neutral.
It is not a naproxen comparator.
So we may not have clarity, the
clarity
that we would need. So I think that, in the
absence of being able to do
placebo-controlled
trials, you have got to pick an agent
that you
think is probably no worse than neutral
and try to
show whether new drugs that are proposed
and
existing drugs are not worse than that
agent on
cardiovascular risk.
So that is one guy's
opinion. But I am
not an epidemiologist. I am just a
knuckle-dragging cardiologist.
DR. TEMPLE: That sounds good. Actually,
that is getting close to the ALLHAT study
that we
are hoping for.
DR. WOOD: Dr. Dworkin.
DR. DWORKIN: I was going to say much of
383
what Dr. Nissen said except that what I
would
prefer is a third comparator, ibuprofen,
because I
think we have this large class of
traditional
NSAIDs and, if we had a series of studies
with
these COX-2-selective drugs, whether it
is
celecoxib, rofecoxib, valdecoxib, and
each of those
studies had a comparator of naproxen and
ibuprofen,
while we wouldn't have a placebo baseline
at the
end of the day, we would have a lot of
information
about naproxen, which we would all like
to know a
lot more about, and, with the ibuprofen
arms across
all these studies, we would have a lot of
information about the traditional NSAIDs
that we
know very little about at this
point. Of course,
we would also then know a lot about our
coxibs as
the third arm.
DR. TEMPLE: Not to state the obvious,
there is a difference between what you
can
reasonably ask a company to do and what
you could
ask a larger group to do. We all want to know
about diclofenac but it is not clear that some
company wants to know about
diclofenac. So it
384
could be slightly different, but this is
a very
helpful discussion.
DR. DWORKIN: Could I say one thing, Bob,
about that. Isn't it the case that, in Europe, the
European regulatory authorities really
require a
comparator arm. So you would not be doing much
more than is done in Europe by saying
that we would
like to see at least one trial with an
ibuprofen
arm and also a naproxen arm, in addition
to your
drug.
I don't think that is unreasonable.
DR. TEMPLE: That is fair.
But if they
were to come back and tell us, if we are as
good as
naproxen, aren't we okay? It would be hard to say
the answer to that is no.
DR. WOOD: Dr. Fleming.
DR. FLEMING: I will defer discussion
about ibuprofen and diclofenac until we
get to the
later questions. My sense is there is a trial that
I believe should be done with celecoxib
although it
is optional, although I would tie it to
the black
boxes, as you have previously.
I believe that there are,
however, studies
385
that should be viewed as essential for
valdecoxib
and rofecoxib. Relative to the celecoxib, what I
had written down parallels what Steve
Nissen had
said with a few extra specifics. The design that
Bob Temple had put forward, to me, makes
a lot of
sense.
It would seem logical as one approach here
that for celecoxib could lead to the kind
of
evidence that would remove the black box,
is to do
a trial.
I would urge that the
comparator be
naproxen or aspirin plus PPI, agents for
which
there is a considerable sense that the
effect on
cardiovascular excess risk is minimal, and it
be a
noninferiority design, essentially ruling
out the
magnitude of effect sizes that we are
seeing
overall which is actually going an
achievable task;
that is,
ruling out a 50 percent increase.
Basically, if truth is no
increase, you
can rule out a 50 percent increase with
90 percent
power with only a 2-and-a-half percent
false-positive error rate with 250 events
which,
essentially, is a trial that would have
about
386
10,000 people per arm. That would be the basic
target that I would put forward. That trial is
positive if your observed excess risk is
in the
neighborhood of 17 percent.
So anything that is not worse
than about a
17 percent increase in the trial of that
size would
rule out a 50 percent increase.
In may view, if that type of
evidence were
available, and I would be inclined to
think it
would be the OA or RA setting and I would
like to
see it for two, to two-to-three years
follow up.
You had staggered entry and then
additional follow
up so we are looking at at least a couple
of years
of follow up. We are looking at duration of
outcome.
That is the kind of evidence that, from
my perspective, would provide a
considerable
reassurance. I don't consider it
mandatory, but I
would link it to the black-box issue.
On the other hand, for
valdecoxib and
rofecoxib, linked to the fact that I
voted no, to
my way of thinking, if these product are
going to
be on the market, it should be essential
that we
387
get additional evidence. I am very troubled that,
that, for valdecoxib, we have 3,000
patients. We
have minimal evidence here upon which to
base a
clear sense of whether or not there is
excess risk.
I believe the FDA should
consider it
essential, within an acceptable time
frame, to
perform a study that allows us to get a
clear sense
of whether there is an excess risk. The dose
should be chosen according to what the
sponsor
believes would be an appropriate
marketable dose
that we would want to be able to
establish safety.
For rofecoxib, my sense is
that, what we
are hearing is that Vioxx may have gone
forward
with an improper dose. I think, if we are, in
fact, going to get it back onto the
market, there
should be studies done at a dose that is,
in fact,
going to be marketed that needs to be established
to be safe.
Similarly, as for the
celecoxib, if these
studies are done, and I believe they
should be
considered essential, they should be done
in a
manner to allow us to rule out a 50
percent
388
increase using a proper control and that
control
would depend on the indication, but
either a
placebo control, and aspirin plus PPI or
a naproxen
control would seem acceptable.
DR. WOOD: Okay.
Dr. Hennekens.
DR. HENNEKENS: The randomized comparisons
of the short-acting NSAIDs suggest to me
that they
are at least as hazardous as the
coxibs. These are
over-the-counter drugs that have
direct-to-consumer
advertising. I think there is a signal here that
we should not ignore, so I would not
limit the
comparisons to naproxen.
DR. WOOD: We are getting to that, though,
in a second. Dr. D'Agostino?
DR. D'AGOSTINO: Many of the comments I
was going to make have been already made,
but I
think that, if you shift the indication
to
something away from arthritis, you can
get a
placebo as a third arm. I think the naproxen is a
good idea.
I am concerned. I agree 100 percent that
it should be noninferiority. I am concerned about
389
the 1.5 because some of the drugs that we
have
condemned may have something like a 1.5
or even
smaller.
So that may be too generous. I
think
that takes a lot of discussion and I
don't know the
answer.
The other point that I visited
a few times
and don't want to leave is that I think
the follow
up is very important, that people can
leave because
their blood pressure is building up, they
are
getting hypertensive, or they could leave
because
of G.I. problems. But those individuals need to be
followed.
They can get off the drug but they need
to be followed.
Should the analysis be
intent-to-treat or
should it be something else, one can
argue that
again.
But I think it is very important that it
is, as much as possible, a complete
follow up.
There is also--it goes without saying,
but we need
a long enough time because we don't seem
to have a
constant hazard over time. So we have to make sure
the studies do go the two or three years
and the
ascertainment adjudication of these CBD
events has
390
to be a prime item in the particular
studies.
DR. WOOD: Dr. Hoffman?
DR. HOFFMAN: I liked what I have heard
from Steve and Tom about suggestions for
a study, a
long-term study, going 1.5 to three years
for
arthritis. But I think we fall into potential
traps here when we talk generically about
arthritis. I think rheumatoid arthritis, being a
systemic disease, which has an increased
risk of
cardiovascular disease to start with,
becomes a
very difficult situation to deal with if
one uses
that cohort in a long-term study.
These people are constantly
having their
multiple therapies tweaked to find the
sweet spot
which sometimes we find, sometimes we
don't.
However, if the study is done with a mild
to
moderate OA, a degree of osteoarthritis
that is
significant enough for which someone
would take
medication, then you don't run into the
problems of
multiple other medications and systemic
illness.
So I like the idea. I think with mild to
moderate OA, you can have an analgesic
arm. You
391
can start with acetaminophen. You could even
increase from acetaminophen to
acetaminophen with
codeine, if necessary. There are no known
cardiovascular risks with that. You can compare
that to the NSAID group, naproxen, if you
like, or
ibuprofen with a PPI, and then look at
your COX-2.
I think that becomes a much cleaner
study.
DR. WOOD: Dr. Cush?
DR. CUSH: I want to echo some of the same
comments but then specifically speak to
some of the
impracticalities of what Dr. Temple and
Dr. Fleming
had suggested, very good ideas, good
plans, but,
again, as Gary stated, we need a team of
drugs to
manage these people over the long
haul. They don't
stay on any one drug. So, to expect someone to
stay on aspirin, 4 grams a day for two or
three
years, is not going to happen on any
drug, in fact.
It is just not going to happen.
Moreover, aspirin, 4 grams a
day, is not
used at all ever anymore by anybody who
knows what
they are doing. The gastroenterologists would have
a field day with this. Okay?
So to try to provide
392
some modicum of protection by putting a
PPI on top
of that is not going to be practical and
this would
never work in a clinical-trial situation.
As Dr. Hoffman has suggested,
an analgesic
class makes sense, whether that be
acetaminophen,
tramadol or propoxyphene, and if you want
to throw
in the added benefit of 81 milligrams of
aspirin a
day as a control, that probably would
work.
DR. WOOD: Dr. Fleming.
DR. FLEMING: Under their proposal, there
are, certainly options that were put
forward and an
alternative to the aspirin PPI would be
to use
naproxen as the control arm. Just to get back to
Ralph's point, he is right that it is
difficult to
know exactly what the margin is
here. What is an
unacceptable level of increased risk.
I had mentioned that I would
want us to
rule out at 50 percent increase and that
would take
10,000 per arm. If we, in fact, asked to rule out
a 33 percent increase, it would be 20,000
per arm
and, to rule out a 20 percent increase
would be
60,000 per arm.
A reassuring aspect, though, is
that if we
are ruling out a 50 percent increase,
which is
10,000 per arm or, in essence, 250 events
in the
393
pairwise comparison, what one is doing to
be
successful there is getting an estimate
that is far
less than a 50 percent increase. It is an estimate
of about 15 to 17 percent. It would have to be
better than that to be a success.
Thereby, what one would be
getting is, for
that study to be positive, a result that
would
indicate that the estimated excess risk
is, at
most, one third what we are estimating it
to be in
the aggregate here and, hopefully, even
better.
So, keep in mind that, in that
trial
design, it is not success if you see
1.5. It is
success if you rule out 1.5 and that is
going to
take something that is an estimate of
only about a
15 percent increase.
DR. WOOD: I am going to move us along to
next that as we have already started to
lose people
and I think we have given them advice on
this.
Question No. 6
There are more than 20
nonselective NSAIDs
currently approved for marketing in the
United
States.
Unlike the situation with COX-2-selective
agents, large, long-term, placebo-controlled
clinical trials have not been conducted
to evaluate
long-term risks including cardiovascular
risks.
394
Based on the data presented
interesting
background package and during the
committee
meeting, please address the following
questions
regarding the approved nonselective
NSAIDs.
The first one is No. 6; do you
recommend
that the labeling for these products include
information regarding the absence of
long-term
controlled clinical-trial data to assess
the
potential cardiovascular effects of these
drugs.
If so, please describe how you recommend that
this
information be conveyed; for example,
warning,
precaution, and so on.
Fine. Let's put it in. But what does
that do for anybody? There are lots of things that
haven't been evaluated for. I certainly think it
should be evaluated, but they haven't
been
395
evaluated for carcinogenicity in long-term trials,
or whatever. So I am not sure of what that would
actually do.
But let's go. Richard?
DR. PLATT: It seems to me, in the absence
of clinical-trial data, it is worth
making use of
the observational data we have and it is
worth
collecting more and better observational
data
pronto.
I think Bob O'Neill made some
excellent
comments about the things you would want
of
observational trials to provide the
guidance we
would like to have. I think that, in a relatively
short time, reasonably good information
could guide
the agency in the absence of clinical
trials.
DR. WOOD: Dr. Domanski.
DR. DOMANSKI: You know, I actually think
the effect that it has is it does provide
immediate
education for people, not necessarily
working with
these things all the time. We have been through
three days of this now and we probably
have heard
what there is to hear about it. But folks are
396
going to hear about the problems with
these other
drugs, but there are clearly issues with
the other
nonsteroidals.
I think it would actually be
quite
informative to physicians making these
prescriptions who are not necessarily
rheumatologists to have that in there
counterbalancing it. I don't know whether it
should be a warning or a precaution but I
think
that is actually a useful thing go have.
DR. WOOD: Dr. Nissen?
DR. NISSEN: Houston, we have a problem.
Let me tell you what it is. It is really very
clear what it is. If you read the financial
literature, or media, they will tell you
that the
biggest beneficiary of this controversy
has been
the so-called COX-2-selective NSAIDs that
are not
called coxibs. An example would be miloxicam.
Apparently, miloxicam has something like
doubled
its
marketshare in the wake of all this
controversy.
Now, do we know that an agent
like
397
miloxicam that is approximately the same
in terms
of COX-2 selectivity as celecoxib isn't
going to
produce exactly the same outcomes. The answer is,
we don't know. So, if the arguments that I heard a
little while ago that said, well, we
don't have a
big enough database on valdecoxib to keep
in on the
market, and I was very sensitive to
that. I voted
the other way, but I understood where
people were
coming from.
Well, if that is true, isn't it
true for
other agents? So, at the very least, we have to
tell prescribing physicians and the
public that we
don't know whether these agents that are
in that
cluster of partially COX-2-selective
agents, that
they don't have the same hazard ratio
that we saw
for celecoxib.
So I think that we ought to
demand the
same level of evidence. Now, how do you do that,
particularly if an agent is now
generic? I haven't
the faintest idea. But, at the very least, we need
the same warnings and we need the same
level of
evidence.
Otherwise, we could actually shift
398
people from celecoxib, let's say, to
miloxicam and
they would have the false reassurance
that there is
not a problem.
And we don't know that there is
not a
problem.
We just don't know. So I am
worried
about this, what we have done today, and
I think
there has to be equality in labeling
across this
class until proven otherwise.
DR. PLATT: Do you include naproxen in
that class?
DR. NISSEN: I guess I don't because I
think we know more. Let me just tell you why I
think we know that. I mean, naproxen has beat
COX-2 inhibitors pretty handily in some
pretty
well-designed clinical trials. So I think we have
got some evidence. We have got very good epi data
on naproxen. So I don't put it in that class.
But I am talking about the
partially
COX-2-selective class. You have mentioned several
times the groups that are in that. We know what
these drugs are. I think we have got to look at
them individually and see what the
database that we
399
have for safety--my guess is you don't
have very
much inside FDA to not document an excess
in
cardiovascular risk for those agents.
So I think we could be just hiding the
problem under a great big rug rather than
solving
it by the actions we take today unless we
act more
broadly.
DR. WOOD: Just a question to the FDA.
Many of these nonsteroidals are available
over-the-counter. Labeling changes there have
different kinds of implications;
right? Charley
Ganley is here. He is always putting me on the
spot.
DR. TEMPLE: I think it is only two,
though, Charley; right? Only two; right?
DR. WOOD: Aleve is available.
DR. TEMPLE: Naproxen is and ibuprofen is.
What else? Ketoprofen.
The nominal labeling, of
course, for OTC all says short-term
use--not that
we believe that anybody limits it. So that has to
be coped with.
DR. WOOD: Right.
That is a different
400
issue.
Maybe that is too complicated in the next
30 minutes, 32 minutes. Any other comments? We
have got Dr. Morris.
DR. MORRIS: I want to reinforce what
Steve said because you have to look at
the black
box in two ways. One is what is in the black box
as information that should try to inform
the
physician. But there is a huge symbolic value of a
black box in and of itself.
Once a drug has a black box, it
is just
viewed, by physicians, as something
totally
different than a drug without a black
box. If we
could just inadvertently send this huge
signal to
people that certain drugs have black
boxes, certain
drugs don't, I think that is why I am
favor of a
black box for the whole broad
category. But if
there is no information, what is in the
black box
is, we don't know. But it still gives the same
symbolic value that this problem
exists--we think
it exists across the whole class.
DR. WOOD: Dr. Crawford.
DR. CRAWFORD: Thank you.
I just have a
401
question for FDA. Would you please remind us of
the difference between--not a black box
but a
regular warning versus a precaution?
DR. TEMPLE: I am not sure what you mean
by the difference.
DR. CRAWFORD: No. I
understand the black
box.
But there is also a level in the labeling of
warning, a labeling of precaution. Those I am not
clear on.
DR. TEMPLE: Okay.
Warning information
shows up in various places in the
labeling. If
there is a black box, it is going to be
the first
thing in labeling, so it is
prominent. We try not
to make it too lengthy, but it really
targets the
thing.
Under current labeling
guidance, which is
under review, the next thing that comes
is a lot of
description and clinical trials and then
you get to
the indications. Then you get to warnings. If
there is a warning, that is where it
goes. It
could be in dark print if you want to
emphasize it
and that is where the warning goes.
If it is of less concern, you
generally
put it under precautions. Frankly, the distinction
between warnings and precautions is not
always as
402
clear as we would like it and, in a
recent
proposal, not yet final, we propose
calling them
warnings and precautions and not trying
to make
that distinction anymore.
DR. WOOD: But, Bob, isn't the major
difference that, if you have a black-box
warning,
you have to deliver all of the
information every
time you deliver anything.
DR. TEMPLE: Well, you do.
But I would
say, in dark print--
DR. WOOD: For example, it means you
can't--I used to say it meant that you
couldn't
give out pens with just the name of the
drug on it.
DR. TEMPLE: That's reminder ads. A
black-box warning absolutely bars
reminder ads.
DR. WOOD: But then somebody showed me a
pen in which the end unscrewed and the
entire thing
was stuffed in like stuffed into a
bottle. So I am
not so sure even that is true
anymore. But that is
403
the fundamental difference.
DR. TEMPLE: Well, no.
It is the visual
quality of it and the--
DR. WOOD: For companies, that is the
difference.
DR. TEMPLE: It depends on how important
reminder ads is.
DR. WOOD: No yellow stickers. No pens.
DR. TEMPLE: But an ad would have to give
prominence to a dark-print warning, too.
DR. WOOD: Right.
Dr. Gross?
DR. GROSS: I think if we walk out of here
with just a black-box warning for the
COX-2
inhibitors and not for all the NSAIDs, it
is going
to extremely limit the use of the COX-2
inhibitors
and a lot of people who would benefit by
their use
over the NSAIDs will not get that
benefit.
I think we need to have a
black-box
warning for all of them. The nature of what is
said in the black box can vary somewhat,
but we are
going to be giving the wrong message if
we don't do
it for all the NSAIDs.
DR. WOOD: Dr. Shafer?
DR. SHAFER: First, specifically, I am
afraid--I think we do have a purpose in
trying to
404
channel people to safer drugs. I am afraid that if
we put a black-box warning on everything,
we are
actually going to dilute the message that
we are
trying to give people.
I think we specifically know
four drugs
that are COX-2-like; etdolac, miloxicam,
diclofenac, sulinac. The observational data would
suggest that three of those, in
particular, showed
up; miloxicam, diclofenac and sulinac. So
I would
propose that, logically, the same
black-box warning
and the same concerns expressed about
valdecoxib,
exactly echoing your concepts, should
apply to
those four drugs specifically
DR. WOOD: Just to respond to that, I
would be dead against that. I think it is one
thing to put a black-box warning on
something that
says we don't have data. I think it is a very
different thing to put a black-box
warning on drugs
for
which we have no data that implies we have
405
data.
I think we will undercut the strength of
black-box warnings if we do that.
DR. SHAFER: What do we do with
valdecoxib, though?
DR. WOOD: We know, absolutely not.
Valdecoxib has two trials that show
absolutely
clear signal. It is not the same at all.
Richard?
DR. PLATT: Whether they are black box or
not I think is not so much an issue as
the fact
that I think it would be a mistake to
attach the
same warning to all the other noncoxib
nonsteroidals, absent naproxen which I
think we
have excluded from any warning. It seems to me we
ought to use the information we have to
produce an
appropriately graded warning while the
agency is
ensuring that better data is collected.
It seems to me, for drugs like
miloxicam,
it would make good sense to require the
same kind
of RCT that we have been talking about
for
valdecoxib and for some of these other
agents. It
may be better observational data is all
you will
406
have.
But the better observational data can come
sooner than we ever have hope of getting
the RCT
data.
DR. WOOD: Last comment on this from Steve
Nissen.
DR. NISSEN: I feel compelled to point out
that, in the CLASS trial, diclofenac was
indistinguishable from 800 milligrams of
celecoxib.
So, yes; it is not the same but, you
know, we have
labeling--we put a black box on celecoxib
for all
doses.
It is perfectly plausible that it is
exactly equivalent to celecoxib. Diclofenac and
celecoxib could be equivalent in
cardiovascular
risk.
They were in a pretty big trial, one of the
bigger trials we had to look at.
And Tom Fleming makes the
argument that if
A equals B, B doesn't necessarily equal
C. And I
believe that. But I am worried. I am worried
about this because we will, by our
actions today,
cause a shift in prescribing
practices. That shift
should, to the best of our ability, be a
shift
toward greater safety. That is why we were called
407
together for three days.
I don't have clarity here about
whether we
are going to induce a favorable or an
unfavorable
shift.
The only way to have some clarity is to
require the same thing of all the drugs.
DR. WOOD: Then let's take a vote on 6.
I'm sorry; where is there someone
else? All right.
DR. ABRAMSON: I just wanted to, very
importantly, echo some of the comments,
particularly Steve's, that we do have
data. We
have it in TARGET and in EDGE and in
CLASS, that
diclofenac and, in some cases, ibuprofen,
looks
very much like the drugs that we consider
warranting a black-box label. So I think it is
very important that we be broad in our
thinking
enough not to send the message that we don't
think
there is concern.
Now, the black boxes don't have
to be
identical but there has to be some
message sent
that we have some data to suggest these
drugs also
carry a cardiovascular risk.
DR. WOOD: So we have to vote, apparently,
408
on 6.
DR. HENNEKENS: May I make one statement,
please.
DR. WOOD:
Charlie? Yes.
DR. HENNEKENS: In direct, randomized
comparisons against placebo, there is a
41 percent
hazard of the coxibs. Against naproxen, there is a
56 percent hazard of the coxibs. Against
diclofenac and ketoprofen, there is a 14
percent
possible lower risk.
I think we can't ignore
this. And I think
that just saying a black box for the
entire class
is ignoring some of these direct
randomized
comparisons.
DR. WOOD: We have to vote on that so your
vote can reflect these differences. I am not sure
how, exactly, we are going to vote. Bob?
DR. WOOD: Alastair, just one thing. The
question, as written, doesn't make any
distinction
between one or another of the so-called
nonselective ones. In other words, it doesn't
recognize even the possibility that some
of the
409
ones not identified as coxibs are
selective. So,
somehow, I think you need to--and that is
what
Steve's whole comment was related to.
So the question, itself,
doesn't really
break that out.
DR. WOOD:
So we could break the question
out to say whether we think other
putatively
selective nonsteroidals may carry the
same risk and
should carry some warning. So that would be first
question.
Whether the putatively nonselective
drugs should carry the same or a
different warning
and, I guess, the third question would
be, if so,
describe how you recommend that
information be
conveyed.
Is that fair, Bob? John?
DR. JENKINS: The concern I have with that
approach is I think we heard, throughout
the
meeting, that this issue of which one is
a
selective and which one is not a
selective is very
dependent upon who did the assay and
whose table
you are using. So I don't know which table you
would refer to to say, these are the
selective
ones, even though they are not coxibs,
and these
410
are the nonselective ones.
DR. WOOD: I agree with that. I am trying
to respond to Bob's request.
DR. TEMPLE: It is okay to tell us what
your doubts are. One of the things we might be
able to do, or have to do, is try to
refine the
statement about which ones are selective
or not.
DR. WOOD: My concern about responding too
definitively to this is that we spend a
lot of time
reviewing the data on the specific drugs
that were
on the table. While I agree that the other drugs
were there sort of as mirror images, if
you will,
at times, I am not sure that the
committee has put
that much effort into reviewing all these
other
drugs.
I have a certain sense of
caution before
we rush into other labeling changes.
Dr. Ilowite?
DR. ILOWITE: The FDA people have informed
me that we should know the consequences
of our
actions.
They say if we put a black-box warning on
something that is over-the-counter, it
would no
411
longer be over-the-counter.
DR. WOOD: Right.
I realize that. I was
actually going to bring that up. It doesn't
actually say that--I mean, this question
does not
imply that we put a black-box warning on
it. But
if people feel that, they would a
black-box warning
on it, then that will be the consequence. That is
absolutely right.
Bob and John, do you think you
have got
enough from the discussion or do you
really want to
force this to a vote?
DR. CUSH: Mr. Chairman, I would like to
suggest that we not divide this up as
selective and
nonselective for reasons that have been
stated,
that we just say the remainder of the
nonsteroidal
class, excluding COX-2-specific drugs for
which we
have already discussion and vote on, if
we could
say just the remainder nonsteroidals and
then
comment individually on naproxen as there
seems
there is a sentiment that that may merit
some
special consideration.
DR. WOOD: So we take the position that,
412
apart from the three drugs we have talked
about,
the other drugs as a group, and naproxen
as a
separate drug.
DR. CUSH: From Indocin all the way up to
miloxicam.
DR. WOOD: All right.
Do people want to
go around? Is there any more discussion on that?
DR. CUSH: And the vote would be whether
or not there should be a warning or a
black box or
need for research and no warning.
DR. WOOD: Lots of comments on that. Dr.
Nissen?
DR. NISSEN: It is the nature of the
warning that I want to be clear
about. I think the
warning can be worded in such a way that
it says
that some drugs in this class of agents
have been
shown to increase the risk of
cardiovascular and
cerebrovascular events. Long-term data on the
cardiovascular safety of this agent has
not been
established.
What you are telling people is,
we don't
know.
That is a warning that says, we can't
413
demonstrate one way or the other, not a
warning
that says, we know that the drug is
harmful but
simply that we don't know. I think that is
informative and I think it is helpful so
that
people know that there is at least some
reason to
be cautious.
Now, what you do after that, in
terms of
what kinds of trials should be done, we
have
already talked about. But I think you have to tell
people that we suspect there may be a
problem here.
DR. WOOD: John?
DR. JENKINS:
I might suggest that we come
back and just vote on the question the
way it is
written because if you look at the
question the way
we wrote it, it would be useful to hear
whether you
think we should add, as it says, do you
recommend
that the labeling for these products
include
information regarding the absence of
long-term
controlled clinical-trial data to assess
the
potential cardiovascular effects on these
drugs.
Probably, you want to have a yes or no
there and
let your discussion stand to let us,
then, go back
414
and decide whether it is going to be a
warning, a
precaution or a box.
But I think it would be useful to hear
if
you think these other drugs, where we
don't have
data or we have limited data, we should
say
something to the effect that the question
asks you
about lack of data.
DR. WOOD:
And you would be comfortable
with the second sentence being conveyed
from the
discussion.
DR. JENKINS: Yes.
DR. WOOD: Okay.
Good. Then let's
start--I have lost touch with where we
started last
time.
Steve Abramson. Let's start with
you.
DR. ABRAMSON: Okay.
I would answer yes
to that first question.
DR. NISSEN: Nissen.
Yes.
DR. ELASHOFF: Elashoff.
Yes.
DR. GARDNER: Gardner.
Yes.
DR. PLATT: Platt.
Yes. Please don't use
a blanket approach to this class.
DR. DAY: Day.
Yes. I echo Platt.
DR. FURBERG: Furberg.
Yes to precaution.
DR. FLEMING: Fleming.
Yes to the first
question.
I haven't commented on the second so let
415
me do so.
I am uncomfortable having a blanket
approach to the second because I do think
there is
considerably different evidence, for
example, on
diclofenac versus naproxen. So I would hope that
the agency approaches this thoughtfully
looking at
the totality of the data with agents that
are in
the diclofenac category getting a much
clearer
indication, potentially a black-box
warning, with
agents in the naproxen category looked at
in a very
different magnitude and a very different
context,
certainly without a black box.
DR. DOMANSKI: Domanski.
Yes to the first
question and I agree with Dr. Fleming for
the
second.
DR. BOULWARE: Boulware.
Yes.
DR. DWORKIN: Dworkin.
Yes. And I think,
for
the second question, it should be comparable or
consistent with whatever is decided about
celecoxib
with respect to whether it is a warning
or
416
black-box warning.
DR. MANZI: Yes to the first question.
DR. FARRAR: Yes to the first question
with the advice that it be linked to the
consideration of G.I. versus
cardiovascular
toxicity.
Yes to the second in terms of a warning
for the agents that have more of a
COX-2. I
understand that it is hard to determine
that but I
think we have to do that and I would
strongly
recommend against making them all the
same, in
fact, a strong plea to leave the current
generation
of NSAIDs with a warning.
DR. HOLMBOE: Holmboe.
Yes. Also, I
would consider a black box for those that
are found
to have similar data to the coxibs.
DR. GROSS: Gross.
Yes to the first one
and, to the second one, I would be in
favor of a
black-box warning where the language
varies
depending on the strength of the evidence
or lack
thereof referring to a possible class
effect.
DR. WOOD:
Wood. Yes to the first
question and with exactly the same
comments as Tom
417
Fleming made.
DR. CRAWFORD: Crawford.
Yes to the first
question.
I would be against, at this point--based
on the available evidence, I would be
against a
black box but yes to a warning or a
precaution.
DR. CUSH: Yes.
There is a need for a
warning label for all nonsteroidals with
regard to
cardiovascular risk and that, to get that
warning
removed, there should be a trial, I
guess, with
naproxen showing superiority or
nonsuperiority, I
guess.
DR. BATHON: Bathon.
Yes to the first
question.
I would approach them as a class with
the exception of naproxen.
MS. MALONE: Malone.
Yes to the first
question.
I do not think it should be a blanket
black box. I think it should be a warning of an
individualized nature. But I think what we have to
be extremely, extremely, careful of is
setting off
some hysteria with the public because
here we are
going from concern about three coxib
drugs and now
we are warning against almost anything
that these
418
people are taking.
DR. LEVIN: Yes to the first.
DR. ILOWITE: Ilowite.
Yes to the first.
I would be against a black-box warning
for either
naproxen or ibuprofen.
DR. D'AGOSTINO: D'Agostino.
Yes to the
first with precautions.
DR. MORRIS: Morris.
I would say yes in
the method that Peter has outlined for
prescription
drugs.
For over-the-counter drugs, I would suggest
that there be a warning about long-term
use at
higher doses and the potential for
cardiovascular
risk.
DR. WOOD: That was Dr. Morris.
DR. CANNON: Cannon. Yes with a warning
regarding long-term use.
DR. FRIEDMAN: Friedman.
Yes to the first
part and, obviously, as others have said,
tailored
to the individual drug. The implications, of
course, of saying that we don't have
adequate
research is that we are going to try to
get it
done.
So, when we put that in there, we have to
419
follow through.
DR. HENNEKENS: Yes to the first question
with the caveats that the short-acting
NSAIDs,
specifically ibuprofen, ketoprofen,
diclofenac
appear to be at least as hazardous as the
coxibs
and that naproxen is neutral to maybe
slightly
favorable on cardiovascular risk and,
secondly,
that the warning would be the same as for
the
coxibs.
DR. SHAFER: Yes with a graded warning
based on both the available data and the
pharmacologically established COX-2
selectivity.
DR. WOOD: Okay.
DR. WOOD: Question No. 7; what additional
clinical trials or observational studies,
if any,
do you recommend as essential to further
evaluate
the potential cardiovascular risk of the
nonselective NSAIDs. Please be specific with
regard to which nonselective NSAIDs--all,
or only
selected agents--trial design, et cetera,
et
cetera.
DR. JENKINS: Dr. Wood, if I can make a
420
comment.
In the interest of getting to what I
think is probably our most important
remaining
question and making sure we address that
before we
lose too many of the committee members
because I am
seeing we are losing some already, I
think No. 8 is
probably the next most important question
which is
what the databases need to be for new
agents.
DR. WOOD: Okay.
Before we move on to
that, I have got the vote on Question 6;
28 yes, no
abstentions, no no's.
DR. FLEMING: If we are jumping to 8, just
very quickly, in 10 seconds, I would
certainly
urge, from a public-health perspective,
that if
there was any way possible to include
ibuprofen and
diclofenac in the Temple trial, that
would be an
extremely important added insight.
DR. WOOD: In the Temple ALLHAT trial.
Okay.
Question No. 8
DR. WOOD: Question 8; with regard to
evaluation of cardiovascular risk, what
studies do
you recommend as essential to be
completed and
421
reviewed prior to approval of new
NSAIDs. With
regard to the evaluation of the potential
benefits--for example, reduced G.I.
risk--what
studies do you recommend as essential to
be
completed and reviewed prior to approval
of new
NSAIDs?
Please be specific with regard to trial
design, patient placebo, control groups,
endpoints,
duration, sample size, safety monitoring
and
patient protections, et cetera?
Some of this, actually, John, we have
already covered. I think, in the studies that we
recommended for the "get out of jail
free" cards,
we have covered that. So we could go back over
that, I think, and see if there are
additional
things we wanted to do. We have covered some of
these already. Yes?
DR. HOLMBOE: I just want to reiterate one
thing I would suggest that applies to the
previous
studies discussed and to new studies. Again, I
want to emphasize that, if we are going
to do a
randomized controlled trial, our
hypothesis is that
these drugs are causing harm. Therefore, you are
422
being randomized to harm, not benefit.
I would just make a plea that,
if you are
going to do these studies, as has been
discussed
using the various comparators, that we
maximize, as
part of that trial, the cardiovascular-risk-factor
reduction, getting to Dr. Hennekens'
point. I
think not to do that would be unethical.
DR. GROSS: Any other comments? Yes; Dr.
Nissen?
DR. NISSEN: Again, this is really
challenging.
I know what I am going to say isn't
going to be population with the Merck
folks, but I
just don't think that--I think you have
got to have
a comparator that is neutral or better
than
neutral.
So I want the new drugs to show an upper
confidence boundary in the range of what
Tom
Fleming talked about against naproxen.
That is a high enough standard
to protect
the public which is what we are all
talking about
here today. So I am willing to accept that
naproxen is no worse than neutral. So, if you are
not 50 percent worse than naproxen, then
you meet a
423
standard that I would consider acceptable
and then
that is going to be a point estimate that
is no
more than about a 15 or 17 percent worse
than
naproxen.
That is a safe and secure way to
proceed.
Now, that means restarting some
development programs. I know it is very painful,
but I don't think that being as good as
diclofenac
when we don't know how good diclofenac
is, is the
right standard.
DR. HENNEKENS: I agree with you,
completely, Steve. I think the same bar should
hold for any of the new NSAIDs.
DR. GROSS: Dr. Gardner?
DR. GARDNER: I think all the studies
should be powered adequately for subgroup
analysis
and to have duration of use taken into
account so
that we can make some of these
distinctions that we
have been struggling with.
DR. GROSS: Dr. Farrar.
DR. FARRAR: Two quick but different
points.
One is that we need to be very careful
424
that the drugs are tested in populations
in whom
they are likely to be used, namely
patients who are
older and have either hidden or, perhaps,
some mild
known cardiovascular risk, obviously
limiting it to
people with mild risk, but in the group
in which it
is likely to be used.
The second issue is, you ask
about the
G.I. benefit. I do think that, given all the talk
that we have gone through these three
days, that it
would be appropriate for any new drug to
have a
comparison against naproxen or one of the
other
COX-1s in combination with a protective
agent for
stomach ulcers. That combination, obviously, would
need to be discussed.
DR. WOOD: I would say that we should
certainly insist on at least the studies
that we
recommended before and that we should
consider
comparisons to naproxen and, if there is
an
appropriate indication, and to placebo if
we can do
that.
Once we have got a naproxen PPI and placebo
study in our bag, we would be in a lot
better shape
to interpret what we are actually looking
at, I
425
think.
Dr. Fleming?
DR. FLEMING: I would just echo what has
been said previously that I would want to
see,
depending on the indication, it could be
placebo
control, it could be naproxen control,
evidence
that essentially allows us to rule out a
50 percent
increase in the relative risk for
cardiovascular
events.
DR. WOOD: Dr. Cush?
DR. CUSH: I think it is important to be
practical. So, for new drugs not yet on the
market, they should be required to do
these trials
just like APPROVe and CABG II with
valdecoxib
except these must be done in the indications
for
which a drug is being sought, so in
osteoarthritis,
in rheumatoid arthritis, or whatever, and
that
those trials should be done in low-risk
individuals, that they should not be done
in
high-risk individuals, because,
otherwise, you
really shouldn't be using these drugs in
high-risk
individuals.
So they should be done in
low-risk
populations and they should be done with
an
appropriate active control group over a
long period
426
of time, which is at least a year, but I
think it
would be preferable to do two years. These will be
difficult and expensive trials to do but
they must
be
done for those who want to come into the market.
For those that are currently in
the
market, I think that the answer could
probably be
helped a great deal by Dr. Temple's
ALLHAT design
or a modification thereof.
DR. WOOD: Any other comment on that? Is
that helpful, John?
DR. JENKINS: Yes.
DR. WOOD: What is your pleasure? We are
losing people so what is your pleasure
for the next
question?
9?
DR. JENKINS: I think 9 is getting us into
the area of--it is fairly speculative
and, in many
ways, linked to No. 6 where you have
already
recommended that there be something in
the labeling
about products that don't have data. So I don't
427
know that 9 is critical because,
obviously, any
future NSAID that we get is likely to
come back to
this committee for your recommendation
before we
make an approval decision. So then we would
actually have the data in front of us to
decide
what the labeling should say.
DR. WOOD: So do you want to go back to 7,
then?
DR. FLEMING: Before we do, can I make one
comment?
DR. WOOD: Yes; Tom.
DR. FLEMING: Basically, on 9, you are
putting forward a potential condition
upon which,
if satisfied, could lead to the absence
of a label
indicating a warning. The critical distinction
here is this is worded as, if there is
absence of
establishing an increase, which is very
different
from evidence against an increase, and
that is
basically failure to achieve
statistically
significant establishing an increase is
not ruling
out an increase. So this first sentence here--if
you do trials that fail to show
significant
428
increases, that is not a reassurance
against an
increase.
What you want is evidence
sufficiently
powered and sufficiently neutral ruling
out
unacceptable increases. That is a critical
distinction. So the essence here is--I think the
first sentence is very misleading as to
the basis
for removing the need for a black box.
It is what we have been saying
when we
have been talking about Question No.
7. What we
would want is evidence sufficiently favorable
and
adequately precise that you can rule out
an
unacceptable increase. And some of us have put
forward a suggestion that that could be a
relative
risk of 1.5.
So if studies are done of
sufficient
quality and sufficient size and
sufficient
precision with sufficiently favorable
results that
you can rule out a 50 percent increase,
then I
think it logically follows to then
suggest that
that would justify a substantial weakening of
the
precautions that would have to be in the
label.
DR. JENKINS: Thanks for that
clarification. The idea was that whatever studies
you recommended in Question 8 carried
over to the
429
findings that would then impact on the
labeling in
Question 9. So maybe the wording is imprecise but,
if you are recommending that rule out 50
percent
increase in Question 8, then 9 is--if we
get that
rule-out 50 percent increase, would that,
then,
result in something less in labeling than
the
others have.
DR. FLEMING: The essence of my point is
it is not persuasive simply to say that
we did
trials that failed to show an
excess. Rather, we
need trials that rule out unacceptable
increases.
DR. WOOD: I think we were saying, also,
John that the studies we recommended in
Question 5
all that we learned from that would carry
over to
this as well. At least that is what I thought we
were saying. I was sort of, I guess, piggy-backing
onto Tom's and my comments at that stage.
Richard?
DR. PLATT: I would like to make a comment
430
about Question No. 7, if I may.
DR. WOOD: No. which?
DR. PLATT: Question No. 7.
DR. WOOD: Wait a minute. Before we do
that, are we finished? We are not going to do 9.
Is that what you are saying, John?
DR. JENKINS: I think you are having some
discussion about 9 now. You have kind of clarified
what you would like to see as far as the
preapproval databases. Dr. Fleming just helped
clarify his thoughts, at least, on if
those
preapproval databases meet the criteria
that he
established, it sounds like he wouldn't
think that
they would have to carry the same level
of warning
that the approved products are going to
be getting.
DR. WOOD: I think the other point, which
I think he made as well, but just in case
it was
missed, is there is also a duration
period. We
would expect to see sufficient sample
size and
sufficient duration of exposure in these
trials
before approval which is not the case
with some of
the drugs we have right now.
DR. JENKINS: Right.
DR. WOOD: Dr. Cush?
DR. CUSH: I just want to ask Dr. Jenkins
431
and Dr. Temple, you are now suggesting,
by this
question, as a condition of future
approval for
future agents that this cardiovascular
safety study
would have to be completed prior to
granting and
considering a new drug application.
DR. WOOD: Absolutely, I think.
DR. CUSH: Because that is, obviously, a
departure from what we have done. These are
usually--of course, this trials would
have safety
issues as the primary endpoint, not
efficacy, so it
may take a longer time to do. Again, that is a
departure in process, is it not?
DR. JENKINS: I think what the committee,
so far, seems to be recommending for new
products
in this class of NSAIDs, you are
essentially saying
there needs to be an outcome study prior
to
approval, outcome meaning that
cardiovascular and
probably also the G.I. outcome study so
you can
really assess benefit:risk before the
approval
432
decision.
So that is a departure from
what was
required in the past for this class of
drugs where
we heard people did 3, 6 or 12-month
efficacy
trials and had databases of 4,000, 5,000
patients.
But they didn't have an outcome study
specifically
powered to rule out some degree of
cardiovascular
risk or to specifically evaluate the
complicated
G.I. leading issues.
DR. WOOD: It is not just cardiovascular
risk.
It is heart failure. It is G.I.
bleeds. It
is complicated ulcers. It is the whole gestalt of
risk that we are talking about, it seems
to me.
DR. TEMPLE: You can see from some of the
presentations that some companies marketing
COX-2-selective drugs have already seen
that
particular handwriting on the wall and
have done
those very studies, not necessarily
perfectly.
DR. CUSH: I agree.
But my concern is it
is setting a new paradigm for clinical
trials in
the United States, that we actually now
have to do
trials for severe and worrisome, albeit
common,
433
side effects prior to the approval of a
drug. I am
not so concerned about
nonsteroidals. I am
concerned about future drug development
in other
areas where novel medicines may be
delayed and
curtailed as far as development because
of this new
paradigm.
DR. NISSEN: Let me answer that and say
that this is different. The reason it is different
is that the disease we are talking about
is the
leading cause of death in the United
States. It is
vascular disease. So it is very common. We have
got a lot of evidence that several drugs
in this
class can substantially elevate the risk
of that
very common and lethal disease.
We are not saying this is the
regulatory
standard for every product and every
class. The
other reason why we can afford to do this
is we
have alternatives here. There are 20 drugs on the
market.
We are leaving on the market some coxibs
with some warnings. So the patient and the
physician have a lot of choices.
So it is okay to now set a
pretty high bar
434
because that is what we really need to do,
now that
we know what we know. We learned it the hard way.
We learned it via a very, very difficult
process
that took place last fall. Now that we know that,
we know where to set the bar for this
class of
drugs and it has to be set pretty high.
DR. TEMPLE: There is a lot of public
discussion going on about how safe things
have to
be.
But what Steven said is absolutely right. You
have got priors here. There are other examples of
this.
I will very briefly give you two.
If you want a drug for heart
failure other
than, perhaps, an ACE inhibitor or
something like
that that we think we understand, we will
expect an
outcome study, a survival study, because
so many
drugs for heart failure have had adverse
outcomes
while improving exercise tolerance.
Similarly, any new
antiarrhythmic drug has
to provide similar data before it can be
approved.
That is not a good situation--it is not a
good
thing for drug development of those
drugs, but we
have had a disastrous outcome, CAST. So where you
435
have priors, you modify your
expectations.
DR. WOOD: These were the examples I was
going to give. I think we are in exactly the same
situation here, Bob. We have been through the
process.
We have gained the experience.
And we
are in the same way as we are with
phosphodiesterase inhibitors. If another
phosphodiesterase inhibitor came along,
we would
view it somewhat skeptically.
DR. TEMPLE: Right.
I think that is the
point Steve was making, too.
DR. WOOD: Exactly.
DR. TEMPLE: We know something here.
DR. WOOD: We are going to move, then, to
Question No. 7 and start with that.
Question No. 7
DR. WOOD: Dr. Platt was first on deck.
DR. PLATT: It seems to me unlikely that
it will be possible to do conventional
randomized
trials for many of the now generic
nonsteroidals,
particularly the ones for which you are
unlikely to
put a very strong warning.
Therefore, I suggest that you
consider a
variation of the large simple trial. Specifically,
I think that there is an opportunity to
something
436
that is essentially new which is to do
large-scale
cluster randomized trials in the kinds of
environments that Dave Graham described
as being
good ones in which to do observational
studies.
The basic logic would be that
practices or
larger groups would be randomized to
prefer
ibuprofen as the first drug among a class
prefer
indomethacin, or for some other
others. Those are
just examples. That provides good randomization.
It provides the opportunity to use the
kinds of
observational strengths of completely
representative populations using the
drugs as they
are used in regular practice and it is an
extremely
efficient way to collect the exposure and
the
outcome data.
It would be efficient and it
would provide
an opportunity to do--it is essentially a
new way
to study important questions and I think
it would
be ideally suited to this kind of
question for
437
which I don't think you are going to have
another
good trial approach.
DR. WOOD: We could take approaches where
we actually examine people who were going
on
therapy in the real world. There are other
approaches, as you discussed before.
The one caution I would say
about
using--about just taking away everything
that David
said is David, himself, acknowledged the
Medi-Cal
database is not well validated yet and it
is has
been hard to track deaths in that; right,
David?
The validity and the mortality.
DR. GRAHAM: Actually, California Medicaid
does have linkage to death certificates
up through
2002 so, for the older NSAIDs, you could
theoretically obtain that data. Kaiser Permanente
has linkage to death-certificate
data. Tennessee
Medicaid, with Wayne Ray, whom you know
very well,
Alastair, he has linkage to
death-certificate data.
Then, in Canada, several of the
large
databases there also have linkage to
death-certificate data.
DR. WOOD: I was talking about the
Medi-Cal one specifically because of its
relevance
to this question. That is why.
438
Steve?
DR. NISSEN: On these other agents,
probably the key is to create incentives
for
companies to do this. That means that the way you
word the warnings that we suggested will
have some
impact.
I think that one of the ways you get rid
of that warning is to do an adequate
trial.
This creates an incentive for
companies
that have popular currently branded
agents which
are being used a lot to do some more
studies, do
appropriate studies, so that they can
lose that
cardiovascular warning.
Now, if the warnings are really
weak,
there won't be any incentive at all to do
that. So
I think--I am just arguing in favor or
your being a
little tough on this one because these
are drugs
taken by tens of millions of people and,
if they
really do increase by a factor of 1.5 or
1.6, the
risk of myocardial infarction and stroke
on a
439
population basis, that is a really big
deal.
So we need clarity here. The only way you
get clarity, I think, is with randomized
controlled
trials.
So I think you have got to create an
environment that incentivizes people to do
those
randomized controlled trials.
DR. WOOD: There's one point we've not
discussed and I guess, as the Chairman of
the NDAC
Committee, I think it should come
up. It does seem
to me that new NSAIDs should not go OTC
in the
absence of clear safety data. So if somebody's
patent expired on that COX-2 right now, I
don't
think we should let that go OTC without
really good
safety data that we could evaluate before
it went
OTC.
So that might encourage people to get some
of these studies done if they want to
switch.
Any other comments? I agree with Dr.
Nissen.
Just to be sure that there is some
incentive because, if we make all of
these rules
more stringent, there has to be some
reason for the
pharmaceutical companies to continue to
develop new
440
drugs.
What we want is a win, a double win, a
triple win. We want the patient to win.
DR. WOOD: Right.
Although, just to
respond to that, Ms. Malone, I agree with
that.
Actually, in some ways, we are opening up
a whole
new opportunity for pharmaceutical
companies to
develop new drugs in that you won't be
the fourth
COX-2 inhibitor on the market. You may be
something that has a safety signal that
would be
better than someone else.
So there actually are huge incentives
now
to encourage the development of novel
compounds
that are safer and effective.
Yes? Dr. Bathon?
DR. BATHON: In follow up to your comment,
I would like to say that one thing that
hasn't been
said, I think, in three days, is it is
nice to know
that, if we can keep these drugs on the
market,
that we will be able to continue to
explore the
importance of COX-2 in other pathological
processes
because there may, as yet, be
undiscovered
applications for these drugs.
We are in an era of really
targeted
treatment to have these kinds of specific
inhibitors still available to continue to
study new
441
applications is important as well.
DR. WOOD: Of course, people can
study--would study--new applications
under and IND
and they wouldn't need to be available to
do that.
I mean, all the ones that we saw in the
second day
were not currently available.
DR. BATHON: Yes, but if you take a drug
like thalidomide or something, if you
remove it
from the market, you give it a pretty bad
press and
then people aren't too crazy about being
in
clinical trials.
DR. WOOD: It is back on the market.
Any other comments? Then I think--have we
anything else that we need to discuss
pressingly?
If not, and the most important piece of
information
I need to give you is one that Kimberly
has which
is--where is it? The travel agency that you can
change your flights to has changed,
apparently.
That has vanished. So that means you are out of
442
luck.
I think we are through. Thanks very much
for everybody who stayed to the end and
it has been
a tough three days. Thank you very much.
(Whereupon, at 5:14 p.m., the
meeting was
adjourned.)
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