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DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ARTHRITIS ADVISORY COMMITTEE
DAY II
Thursday, June 3, 2004
8:04 a.m.
ACS Conference Room
Room 1006
5630 Fishers Lane
Rockville, Maryland
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PARTICIPANTS
Allan Gibofsky, M.D., J.D., Chair
Jayne E. Peterson, R.Ph., J.D. Acting Executive
Secretary
Members
Jennifer Anderson, Ph.D.
Joan M. Bathon, M.D.
Dennis W. Boulware, M.D.
John J. Cush, M.D.
J. Michael Finley, D.O.
Steven G. Geis, Ph.D., M.D., Industry
Representative
Gary Stuart Hoffman, M.D.
Wendy W. McBriar, R.N., M.S., C.H.E.S., Consumer
Representative
Special Government Employee (SGE) Consultants
(Voting)
Bruce N. Cronstein, M.D.
Brian F. Mandell, M.D., Ph.D.
Michael H. Weisman, M.D.
H. James Williams, M.D.
Government Employee Participants/Discussants
(Voting)
Marc C. Hochberg, M.D., MPH
Robert Terkeltaub, M.D.
FDA
Brian Harvey, M.D., Ph.D.
Joel Schiffenbauer, M.D.
Sharon Hertz, M.D.
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C O N T E N T S
Issue: Trial Design and Endpoints
for Drugs for Acute Gout
Call to Order
Allan Gibofsky, M.D., J.D., Chair 4
Introductions 4
Conflict of Interest Statement:
Jayne Peterson, R.Ph., J.D. 8
Acting Executive Secretary, AAC, FDA
Welcome
Brian Harvey, M.D., Ph.D., FDA 11
Gout: Clinical Review and Trial Design Issues
Joel Schiffenbauer, M.D. 12
Management of Acute Gout
John J. Cush, M.D. 30
Merck Research Laboratories
Introduction
Agustin Melian, M.D. 94
Design Considerations in Acute
Gouty Arthritis Studies
David I. Daikh, M.D., Ph.D. 96
Experience of Etoricoxib and Indomethacin
n Acute Gouty Arthritis
Agustin Melian, M.D. 121
Lessons Learned
David I. Daikh, M.D., Ph.D. 139
Discussion 142
Committee Discussion and Questions 184
Open Public Hearing 218
Committee Discussion and Questions (Resumed) 219
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P R O C E E D I N G S
Call to Order
DR. GIBOFSKY: Good morning. I would like
to welcome everyone on the panel, as newly
constituted, together with the members of the
audience, to the Arthritis Advisory Committee
hearing. This is the second day of our meetings on
a very interesting topic, Chronic, and today, Acute
Gout.
My name is Allan Gibofsky, and I will be
chairing the meeting today. I would like to begin
by asking the members of the panel, as
reconstituted, to please introduce themselves
beginning on my right.
Introductions
DR. GEIS: I am Steve Geis. I am the
representative from the pharmaceutical industry. I
spent 18 years doing clinical research in that
industry.
DR. FINLEY: Michael Finley. I am
Associate Professor of Medicine at Western
University College of Osteopathic Medicine of the
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Pacific in Pomona, California, and I am a
rheumatologist.
DR. CUSH: Jack Cush, Presbyterian
Hospital of Dallas. I am a rheumatologist.
MS. McBRIAR: Wendy McBriar, Director of
Arthritis Services, Virtua Health, in New Jersey.
I am a nurse and health educator. I am the
Consumer Rep.
DR. BOULWARE: Dennis Boulware, Professor
of Medicine, University of Alabama at Birmingham,
and a rheumatologist.
DR. BATHON: Joan Bathon, Professor of
Medicine at Johns Hopkins University, and a
rheumatologist.
DR. MANDELL: Brian Mandell, Department of
Rheumatology, Cleveland Clinic, Cleveland.
DR. WILLIAMS: Jim Williams,
rheumatologist, University of Utah.
MS. PETERSON: I am Jayne Peterson. I am
the Acting Executive Secretary for the meeting
today.
DR. GIBOFSKY: Allan Gibofsky, Professor
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of Medicine and Public Health at Weill Medical
College of Cornell University, a rheumatologist.
DR. ANDERSON: Jennifer Anderson, Research
Professor Emeritus in Biostatistics at Boston
University School of Public Health.
DR. HOFFMAN: Gary Hoffman, Professor of
Medicine and Chair of Rheumatology at the Cleveland
Clinic, rheumatologist.
DR. HOCHBERG: Marc Hochberg,
rheumatologist, Maryland Veterans Affairs Health
Care System, and Professor of Medicine at the
University of Maryland School of Medicine,
Baltimore.
DR. WEISMAN: Michael Weisman, Chief,
Division of Rheumatology, Cedars-Sinai Medical
Center, Professor of Medicine at UCLA.
DR. TERKELTAUB: Robert Terkeltaub, VA
Medical Center, San Diego, UCSD, rheumatologist.
DR. CRONSTEIN: I am Bruce Cronstein, New
York University School of Medicine. I am Professor
of Medicine, Pathology, and Pharmacology.
DR. SCHIFFENBAUER: Joel Schiffenbauer,
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FDA, Division of Analgesic, Anti-inflammatory, and
Ophthalmic Drug Products.
DR. HARVEY: Brian Harvey, the Deputy
Office Director and currently Acting Division
Director, and I am not a rheumatologist.
DR. HERTZ: Sharon Hertz, Deputy Division
Director for the hosting division.
DR. GIBOFSKY: Thank you. I would like to
begin by apologizing to the committee and to the
audience, I did promise a prompt 8 o'clock start
today, however, we were subject to the vagaries of
Murphy's Law in getting here. As everyone on the
committee knows, rheumatologists and
non-rheumatologists included, Murphy was indeed an
optimist.
A couple of housekeeping announcement.
The committee, by consensus, has decided to shorten
its lunch from an hour and a half to only half an
hour, so as to have more time, if necessary, for
deliberation.
As a result, the public hearing will begin
one half-hour after the conclusion of the morning
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session, which may be close to the 1 o'clock time,
but may be somewhat before it. If there are any
individuals here who would like to be heard during
the open public hearing, please schedule that with
the Acting Executive Secretary or another member of
staff, so that we can queue them in, in an
appropriate and timely fashion.
With that, I would like to turn the
meeting over to Dr. Harvey for some opening
remarks, but before that, Ms. Peterson will read
the Conflict of Interest Statement.
Conflict of Interest Statement
MS. PETERSON: Thank you. 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 at this meeting.
Based on the submitted agenda and the
information provided by the participants, the
Agency has determined that all reported interests
in firms regulated by the Center for Drug
Evaluation and Research present no potential for a
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conflict of interest at this meeting with the
following exceptions:
Dr. Michael Weisman has been granted a
waiver under 18 U.S.C. Section 208(b)(3) for
consulting with a competitor on a matter unrelated
to the topics to be discussed at this meeting. He
receives less than $10,001 a year.
Dr. Bruce Cronstein has been granted a
waiver under 208(b)(3) for serving on a speakers
bureau for the sponsor of Arcoxia. He speaks on
topics unrelated to those being discussed today,
and receives more than $10,000 a year.
Dr. H. James Williams has been granted a
208(b)(3) waiver for serving on a speakers bureau
for the sponsor of Arcoxia. He speaks on unrelated
topics and receives from $5,001 to $10,000 a year.
Dr. J. Michael Finley has been granted a
208(b)(3) waiver for serving on a speakers bureau
for the sponsor of Arcoxia. He lectures on
unrelated topics and receives more than $10,001 a
year.
Dr. Marc Hochberg has been granted a
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208(b)(1) waiver for serving as a consultant and
speaker for the sponsor of Arcoxia. He consults on
unrelated issues and receives less than $10,001 a
year. His speaking is sometimes related to the use
of products in gout. He receives from $5,001 to
$10,000 a year for speaking.
Dr. Robert Terkeltaub has been granted a
208(b)(1) waiver for speaking for the sponsor of
Arcoxia in gout. He receives less than $5,001 a
year.
A copy of these waiver statements may be
obtained by submitting a written request to the
Agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building.
Lastly, we would like to also note for the
record that Dr. Steven Geis is participating in
this meeting as an industry representative acting
on behalf of regulated industry.
In the event that the discussions involve
any other products or firms not already on the
agenda for which FDA participants have a financial
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interest, the participants are aware of the need to
exclude themselves from such involvement, and
their exclusion will be noted for the record.
With respect to all other participants, we
ask in the interest of fairness that they address
any current or previous financial involvement with
any firm whose products they may wish to comment
upon.
Thank you.
DR. GIBOFSKY: Thank you, Ms. Peterson.
Now, Dr. Brian Harvey, Acting Director of
DAAODP of the Food and Drug Administration.
Dr. Harvey.
Welcome
DR. HARVEY: Good morning. Thank you once
again. I wanted to thank the Committee again for
their services today. Yesterday's discussion was
very lively and enlightening, and certainly what we
all were looking for today. Of course, we will be
talking about treatments for acute gout, and we are
looking forward once again to a lively and
thoughtful discussion.
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I would also like to thank, looking ahead
to the public speakers this afternoon and also to
our partners in industry who will be presenting
today, today we will be talking about clinical
trial designs for future clinical trials, as well
as what might currently be underway.
It is a general discussion that is going
to help FDA and our industry partners to sort of
chart future directions in treatments for gout.
So, with that, we actually will get
started and move on since we are on a fairly tight
schedule, and at this point I would like to
introduce Dr. Joel Schiffenbauer, who is a senior
medical officer here in the Division, for his
presentation Gout: Clinical Review and Trial Design
Issues.
Gout: Clinical Review and Trial Design Issues
DR. SCHIFFENBAUER: Good morning. My
topic for discussion this morning is Gout: Clinical
Review and Trial Design Issues. My presentation
will highlight issues for the Committee to consider
in the design of trials to study the treatment of
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acute gout.
Gout is caused by a deposition of
monosodium urate crystals around and in the tissues
of the joint. As was discussed yesterday, there
are three distinct stages: asymptomatic
hyperuricemia, followed by acute intermittent gout,
which is the focus of this morning's discussion,
and then subsequently, chronic tophaceous gout.
The initial episode of gout usually
follows decades of asymptomatic hyperuricemia. It
is characterized by intense pain and inflammation,
and this is an important point to consider in
determining the endpoints to study in any trial of
acute gout.
It usually begins as a monoarticular
involvement most often with the first metatarsal
phalangeal joint.
The natural course varies with improvement
and resolution in days to one to two weeks, and
this a second important point to consider from two
aspects of the trial design.
First, it will help determine how long the
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duration of trial should be in acute gout, and,
secondly, whether we consider using superiority or
non-inferiority designs, and I will come back to
this is a few slides.
During the intercritical periods, joints
are virtually free of symptoms although crystals
may be found.
This is an example of what we are dealing
with. This individual has swelling, redness at
both the ankle and the first MTP joint, and will
likely have extreme pain in both of those areas.
This is the inciting agent, the uric acid
crystal, which in this photomicrograph, is found
within a white blood cell.
Standard approaches to therapy are
summarized in this slide, and you will hear more
about this in detail from Dr. Cush following my
presentation, but there are several approaches to
therapy, and those include nonsteroidals of which
there are several that are approved for us in acute
gout, colchicine, which is approved for both oral
and intravenous use, as well as glucocorticoids,
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which are approved, and ACTH, which has been used
frequently, but is not approved for use in acute
gout.
The remainder of the presentation will
focus on specific trial design considerations, but
before I get to that, there is some general trial
design information that is available at the FDA web
site for individuals in the community to search.
The E9 and E10 documents, which cover
statistical principles and choice of control groups
in general trial design, and then specifically, two
guidances in rheumatoid arthritis and
osteoarthritis.
In addition, there are the CONSORT
recommendations which were mainly geared towards
reporting of clinical trials, but in which there is
useful clinical trial design information available,
and I have provided the reference for that.
So, focusing now on acute gout. Gout is a
unique medical disorder that deserves specific
studies and its own labeled indication or is a
model of acute pain. We would ask the Committee to
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discuss this as one of their initial questions,
because this discussion will influence what
outcomes we wish to look at in any trial of acute
gout.
The first consideration is who do we
recruit into these trials, what are the inclusion
and exclusion criteria. First, is documentation of
crystals critical? Should this be at the time of
flare, that is, when the patient presents to be
entered into the trial, or any previous
documentation, if they have had a joint tap within
a year or two, is that adequate?
If they have had crystals documented from
the knee, but now they present with an ankle that
is swollen, would that be acceptable?
Or are clinical criteria sufficient to
serve as entry criteria? For example, the ACR
classification of acute gouty arthritis in which 6
of 12 clinical, laboratory, and x-ray criteria may
be utilized. I have listed some of those criteria
on the next slide.
For example, more than one attack of acute
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arthritis, maximal inflammation developed within
one day, attack of monoarticular arthritis, first
MTP joint pain or swelling, suspected tophus, or
hyperuricemia, and there are additional clinical
criteria, and we would ask the Committee to
consider what the diagnostic criteria should be.
Let me turn now to the second
consideration, and that is whether the trial should
be a superiority or non-inferiority trial.
Superiority to placebo is preferable as this is the
most straightforward way of demonstrating efficacy,
but the question remains are placebo-controlled
trials in acute gout ethical.
This question arises because of the
severity of pain in acute gout, however, I would
like to point out one interesting fact. If one
examines baseline VAS pain scores from trials in
acute gout, and compares those to baseline VAS
scores in trials in acute pain, such as
postoperative trials that we see at the Agency,
there is, in fact, very little difference in the
baseline VAS pain scores. In trials for
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postoperative pain, we allow placebo controls to be
performed.
Now, the question remains, is a baseline
VAS pain score of 50 in a gout trial, the same as a
50 in a postoperative knee replacement or hip
replacement. I think that is a question that can't
be answered right now, but nevertheless, the
baseline pain scores seem to be very similar.
One approach to consider to incorporate
placebo would be examining the use of rescue or
time to treatment failure as a primary outcome.
This early escape design reduces exposure to
suboptimal therapy and may be acceptable to
incorporate placebo.
There are, however, several alternatives
to placebo-controlled trials, which I have listed
here. The first is a trial with an active
comparator with a demonstration of superiority of
the new drug to active comparator.
This might be a very acceptable approach
especially if we are interested in better and more
efficacious drugs.
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The second approach could be a
dose-controlled study. By this, I mean a study
where we examine several dose levels of the drug,
and we demonstrate superiority of the high dose of
that drug to the low dose. Again, this would allow
us not to incorporate placebo.
Lastly, is the active comparator and
non-inferiority design.
If the non-inferiority design is chosen,
the question is which comparator would we want to
compare if the new drug is a nonsteroidal, would we
want to compare a nonsteroidal comparator, or would
we allow a drug, such as colchicine, to be the
comparator in a nonsteroidal trial, and if so, what
is the non-inferiority margin.
Are there historical adequately controlled
trials, and by that, I mean placebo-controlled
trials, that are of similar design to support the
non-inferiority studies? Indeed, if you look in
the literature, there is only one true
placebo-controlled trial comparing the efficacy of
colchicine to placebo, and there are no
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placebo-controlled trials looking at nonsteroidals.
If no placebo is chosen and
non-inferiority design is considered, the issue is
always of sensitivity of the trial, that is, do we
know that both drugs work, or is it possible that
both drugs do not work.
In fact, since gout is a disorder in which
pain resolves spontaneously, this may have
implications on the choice and duration of the
trial using an non-inferiority design, and we would
like the Committee to consider this in their
discussions.
There are a number of domains that can be
examined in a gout trial. Certainly, pain I think
is a critically important domain, but there are
several others that can be examined, and those
include inflammation, some measure of function
whether it be walking, ability to walk, ability to
work, or some other function, patient or physician
global assessment of disease and/or treatment, and
then possibly some health-related quality of life
measure, although in a trial of short duration,
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this may not be as critical.
Let me turn now to some of the primary
outcomes or some of the outcomes to discuss.
The first question is: What is the value
of reduction in pain as the primary outcome? If
this is considered one of the primary outcomes,
then, we would anticipate measuring some of the
typical parameters that we measure in an acute
analgesia trial, and these include pain intensity
difference, pain relief, time to onset, time to
re-medication, multi-dose efficacy.
The second question is: Is there value in
additional endpoints beyond pain? If we feel that
gout is a unique clinical entity, and is
characterized by both pain and inflammation, then,
should we include inflammation as part of the
outcomes that are measured.
However, measurements of inflammation may
be difficult to standardize, and this should be
considered by the Committee.
There are some additional outcomes I would
like to suggest that may, in fact, allow us to
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capture the totality of the treatment experience.
For example, rescue, that I have already mentioned,
time to rescue could be one outcome, or the number
of individuals using rescue in a predefined period
of time, such as 24, 48 hours, or some other
specific time.
Alternatively, time to complete resolution
would be a possible outcome, or time to 80 percent
or 50 percent resolution, and then lastly, a form
of a responder index, such as the number of
subjects with good to excellent pain relief in some
prespecified period of time.
This raises the next question: What
should that time be, when should we seek to measure
response to therapy?
Again, if, as we all agree, that pain is a
hallmark of this disorder, and we would certainly
like to see patients improve within a relatively
short period of time, but can we ask for a response
within a hour, should it be within the first 8
hours, within the first 24 hours?
I would remind you also that gout will
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tend to improve spontaneously over a relatively
short period of time, and this may have impact on
something, such as a time-weighted average, or
should we consider a combination.
We would certainly want to capture some
efficacy measure early in the course of the
treatment, as well as possibly later in the course
of the treatment over a few days. We would ask you
to try and consider this in your deliberations.
There are several additional trial design
considerations that I would like to put forth.
Is there value in stratification by the
following: renal function, uric acid level--these
probably in a short-term trial will not be
critical--or by tophi, or by the number of joints
involved, such as polyarticular or monoarticular
arthritis.
If we consider the inclusion of
individuals with polyarticular arthritis, it may be
important to identify a signal joint, but then the
concern is how do we evaluate the totality of the
response in other joints.
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How should we deal with concomitant
medications, other nonsteroidals, other pain
medications? Should we allow pain medications to
be included during the efficacy trial, so as to
keep individuals in the trial and reduce the
dropout, and therefore, imputation of missing data?
How do we handle low-dose aspirin,
diuretics, or other drugs that may influence the
renal clearance of uric acid? Again, in a
short-term trial, these may not be critical issues,
but we would ask the Committee to consider this,
and then diet and alcohol intake, the same
concerns.
Some additional considerations. I have
already alluded to the evaluation of single and
multiple dose efficacy. This is analogous to the
requirements that we have for studying an acute
analgesic. We would like to know how the
individual fares within the first few hours of
therapy, as well as how they do over the subsequent
days.
How long should an attack be present
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before randomization? On a practical basis, it is
unlikely that we will be able to enter subjects
into a trial that have their attack present for
only a few hours. On the other hand, would we want
to enter someone that has had their attack present
for four, five, or six days?
On a practical basis, it would seem likely
that the most likely subjects would have their
attack present for one to three days.
Should we allow previous therapy? If an
individual self-medicates 24 to 48 hours before
randomization, is this acceptable? It may be
acceptable if they have self-medicated with a
short-acting analgesic that is completely washed
out by the time of randomization.
However, if we don't allow any previous
therapy because of the potential influence on the
outcome of the trial, then, I would ask you to
reconsider your concern for placebo-controlled
trials.
If an individual has had an attack for 24
to 48 hours, and has not self-medicated, is there a
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concern with entering them into a
placebo-controlled trial?
If a patient is on previous therapy,
should we withdraw them from that therapy, and can
that be associated with a worsening flare of their
disorder, and how would we handle that in a trial.
Lastly, the question, is there a
difference in a disease course in individuals that
have acute attacks on a background of chronic
tophaceous gout versus those individuals that just
have acute attacks?
So, the areas for discussion include the
following, which I have discussed already some.
Inclusion and exclusion criteria, superiority
versus non-inferiority trials, especially the issue
of placebo-controlled trials, what are the domains
to study, what outcome measures and timing of the
studies, and then other issues, such as
stratification, concomitant medications, et cetera.
So, in conclusion, gout is a common
disorder. You heard a lot about that yesterday.
New therapies that provide improved risk-benefit
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ratios should be studied and added to the
armamentarium, and rigorous trial design is needed.
You will be hearing next from Dr. Cush,
who will be discussing management of acute gout,
and following that, a presentation by a company and
their approach to a trial design in acute gout, and
I think, all together, should provide an
interesting background for today's discussion.
Thank you very much.
DR. GIBOFSKY: Thank you, Dr.
Schiffenbauer.
Are there questions from the panel for Dr.
Schiffenbauer? Just one from me, if I may.
In one of your slides, you asked us to
consider whether gout is a medical disorder or a
model of acute pain. Like light being a wave and a
particle, can gout not be both?
DR. SCHIFFENBAUER: It could. I was
asking the question because I think the implication
is what should we consider as the primary outcome.
If it is considered a model of acute pain, then, we
have certain parameters that we use in acute
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analgesia studies.
If it is considered its own entity, then,
I think pain, but we may wish then to consider
additional outcome measures, such as inflammation,
and I think that is kind of what I was trying to
set up and get from the Committee.
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: Thank you for an excellent
overview of the issues. I guess one question, and
I don't know if you will be able to respond to
this, on your next to the last slide, you said that
new therapies that provide improved risk-benefit
ratios should be studied and added to the
armamentarium.
I don't know what Dr. Cush is going to
say, but in the vast majority of people who have
gout, and I exclude from this the individuals who
have contraindications to the use of nonsteroidal
anti-inflammatory drugs either absolute or
relative, the drugs have a pretty good
benefit-to-risk ratio in this population.
So, does that imply that the Agency would
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like to see agents which have a better
benefit-to-risk ratio in the population which has
relative and absolute contraindications to the
drugs that are already in use, or would like to see
agents which are quantumly beyond NSAIDS in terms
of either efficacy or safety for the vast majority
of people who have acute gout?
DR. HARVEY: Did you want me to jump in on
this? Actually, we will see what the Agency sees,
and, of course, we want to make sure there is
safety and efficacy for the indication.
DR. SCHIFFENBAUER: We would always like
to see quantum leaps in therapies, but I actually
agree with Dr. Harvey's comment.
DR. GIBOFSKY: Any other questions from
the panel?
[No response.]
DR. GIBOFSKY: Thank you. We shall see
what we shall see, and now we shall see Dr. Cush,
who is a member of the panel and also Chief of
Rheumatology and Immunology at Presbyterian
Hospital of Dallas.
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Dr. Cush.
Management of Acute Gout
DR. CUSH: Good morning, everyone.
I have been asked to talk about the acute
management of classic gout or the acute gouty
attack, and it is my intention sort of to give a
little bit of overview, but to focus on what has
been done in trials and what are the outcomes and
how that impacts on clinical trial design in the
future.
A topic that was brought up yesterday by
Jim and others is, you know, where are these
patients and how do we get them in trials.
It is interesting to note firstoff, that
most rheumatologists love gout. I mean it is a
very interesting disease, it is easy to diagnose,
the impact of our intervention is great. We feel
good about ourselves when patients are very happy
with their outcomes.
In fact, most of the giants in
rheumatology, starting with Hippocrates and going
up to the time of McCarty and Hollander and
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Schumacher, and whatnot, have cut their teeth on
gout as a career, and I think it is because it's an
interesting disease, it has a direct cause, it has
a biochemical and immunologic basis, and we have
effective interventions, so this is why we love
this condition.
Interestingly, however, very few of us are
seeing a lot of patients with gout. We have
patients who have chronic tophaceous gout in our
clinic, we have an occasional patient who has
chronic intermittent gout, but the vast majority of
patients who have gout are being managed elsewhere,
so although I wish they were in my clinic, they are
not, and that is sort of a shame because we believe
that, as a discipline, we have a great impact on
these patients.
That was studied by Richard Panish in his
paper that showed when rheumatology intervention
was compared to a generalist approach to this
condition, there was a shorter duration of
symptoms, less hospitalization, lower cost overall,
suggesting the value of a rheumatologic
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consultation in such instances.
Hence, most of these patients are in the
care of the primary care and emergency physicians.
They are first line. That is, you know, people
that darken the boxes, they go to their family
doctor whenever they have a problem, and they don't
know enough to go to a rheumatologist obviously,
and if they did know, they probably couldn't get in
to see us anyway. That is another issue.
But there are significant hazards here in
that I think Marc's point about the effectiveness
of therapy is so accepted at this point, it is
absolutely true, however most rheumatologists are
very aware of the fact that there is a large
variability as to how patients are treated.
What I believe is the gold standard is
probably not the gold standard out in the general
community, and that varies, not only in our
country, but also in surveys done in France and in
Mexico and New Zealand, where there is considerable
variability between the general practitioner,
whether it be internist or family practitioner, and
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the rheumatologist, and the orthopedist as far as
their approach to gout.
What is unfortunate is that there is a
surprising amount of misuse of these medications
and inappropriate use of medications by the general
practicing physician, so I think that to foster
guidelines and new drug development is also to
foster better education and, hopefully, better
outcomes for patients who have this condition.
So, as stated, it is a disorder of
monosodium urate crystal deposition. It has been
around for years, started with Hippocrates in 450
B.C., when he described this as the king of
diseases and the disease of kings. The burden to
society is significantly great.
Roubenoff estimated 37 million lost days
of work in the United States in 1981. Kim and
cohorts, in their estimate of the burden of disease
on society, said that gout costs us 27 million-plus
dollars per annum for the management and care of
acute gout, and this tends us to underestimate the
true costs because this is mostly just men, it
34
doesn't include women, which are a significant
minority here that are affected by gout, and it
does not include a lot of the indirect and
intangible costs of having such an impactable
disease.
The epidemiology was reviewed yesterday
quite well by Dr. Terkeltaub, but this NHANES
survey, which was a telephone survey of the general
population, was a bit of a surprise.
Most of the epidemiologic studies on gout
suggested about 2.1 and 2.5 percent prevalence in
the general population. However, when this survey
was done--excuse me, 1 percent, going as high as
2.1 to 2.5 million people--when this survey was
done and people were asked on the phone, "Have you
had or do you have kidney stones," they found a
much higher than previously reported prevalence,
and they asked the same question of gout, and they
found 5 million people who claimed to have gout.
Now, it is hard to confuse a kidney stone.
It is a pretty certain diagnosis when a patient
reports that. Patient reports of gout, however, are
35
notoriously inaccurate because the diagnosis, as
made by their general practitioner, are
unfortunately sometimes inaccurate, as well.
So, this is probably an overestimation of
the true numbers, but it is probably somewhere
between 2 and 5 million as far as the prevalence in
society, and that prevalence does go up, as was
pointed out yesterday, according to age, that men
are mostly affected here, but that women in the
postmenopausal era are almost equally affected.
This is a dramatic disease, and it is
dramatic because of the abundance of inflammatory
mediators that are produced at the time of the
attack.
A wide number of mediators that cause this
intense pain and inflammation, redness, and warmth,
and whatnot, a number of cytokines, you can add
this TNF and interleukin-8, and again, the list
goes on and on and on as far as the amount of
mediators that are present here.
Finding an effective therapy that will
downregulate that and produce clinical symptoms is
36
really a gargantuan task, and it is actually
surprising that we do as well as we do given the
amount of inflammation that seems to emanate from
these joints.
So, today, we are talking about acute
gout, but, of course, gout is divided into several
different forms, acute intercritical gout that
appeared in between attacks when patients are
quiescent and have no symptoms, and they are often
not on therapy.
There is chronic tophaceous gout which was
discussed in some detail yesterday, and then there
is asymptomatic hyperuricemia, who has not yet had
an attack of gout or uric acid nephrolithiasis.
Then, lastly, there is renal effects of gout, as
well.
Other publications talk about another
distinction of acute or classic gout versus
atypical gout, and atypical gout is also prone to
having acute attacks, although they are not as
acute, they are more insidious. They are more in
women, they are more in older people who are on
37
diuretics and have hypertension and renal failure,
and whatnot.
So, it is a sort of quasi-group. They
tend to fall a little bit under this acute
umbrella, but their inclusion in clinical trials
could cloud things. So, again, the acute or
classic attack of gout really usually is often
referred to as acute podagra.
This is often a sudden severe onset of
pain, warmth, inflammation. There is severe
limitation of motion, patients are unable to walk,
they are unable to have a sheet on it. It is
really quite dramatic.
So, while Dr. Schiffenbauer points out
that pain scales in the acute predictive gout are
not much different than other pain models, it seems
that gout patients scream a little louder, and it
could be because men are wienies, I don't know. It
could be that really it is more severe in its pain.
I tend to like some of the pain scales
that are used in some of the clinical trials,
because they tend to represent this almost like a
38
spinal tap 11, and they have zero to 4, zero being
none, 1 being mild, 2 being moderate, 3 being
severe, and 4 being extreme. That is sort of I
think indicative of the severity of the attack.
Podagra historically was said to occur at
the first joint in 90 percent of cases. More
recent estimates are probably a little bit less,
but podagra is the involvement of an acute
inflammatory event that affects the first big toe
or the MTP joint.
Some joints commonly involved early on are
the tarsus, the ankle, and the knee, distinguishing
it from other crystalline arthropathies and other
acute onset of inflammatory events.
It is not uncommon for these people to
have low grade fevers, high white counts, high sed
rates and CRPs at presentation. Patients will
often have monoarthritis as the first attack, but
then with repeated attacks, will ascend from their
lower extremity upwards and may have oligoarticular
and polyarticular presentations later on in the
disease especially when tophi form.
39
The initial presentation of polyarthritis
is more often seen in the elderly, in women, and
those who have mild proliferative disorders, also,
in patients who have a transplant and are receiving
cyclosporine.
There are many precipitants to this -
inactivity, surgery, alcohol, infection, drugs, and
whatnot. Untreated attacks can last up to 14 days,
although there is quite a significant amount of
variability there according to who you read, but
that is what my experience is.
Those who have an attack are at high risk
for subsequent attacks. The majority will have
another attack within a year, and it is estimated
that 78 percent will have another attack within two
years.
An interesting study done by Bellamy and
coworkers in Canada, and published in 1987, looked
at the natural history of gout in 11 individuals
who had an acute attack of podagra. There were 11
volunteers who had this acute attack. Two withdrew
before the full course of therapy or of observation
40
I should say, because of severe attacks, and went
on to receive indomethacin.
It should be noted that these 11 patients
who had acute gout, there were 2 who had tophi at
entry, 5 who had a history of nephrolithiasis, 2
who had a history of both. All had prior attacks
with a median of 4 prior attacks in the 7 years
prior, and that occurred usually with a median of
within 4 years.
Nine were on allopurinol and 1 was on a
uricosuric agent. It is unclear as to whether
those drugs were continued during this trial. But,
nonetheless, when they observed these people, they
showed that pain was improved by Day 5 in the
majority of patients, that swelling was improved by
Day 7, that tenderness was improved in 7 out of 9
patients by Day 7, but 2 patients continued to have
persistent pain. But only 3 people had noted
complete resolution of their symptoms by the end of
the 7-day study.
So, again, pain and swelling and erythema
and warmth all began to improve after Day 3. A
41
significant improvement was really seen between
Days 5 and 7, although again complete resolution
was not had in all.
At entry, these patients had a mean pain
score of a little less than 4, a little less than
extreme, and at the end of the study, 7 days, the
mean value was only about 2 or moderate level. So,
again while these patients got better, this is not
complete resolution of the disease.
The implications here are significant for
trials, first, what is your endpoint for these
attacks and when will get pain get better on its
own, and what are the outcomes that we should do in
looking at that.
So, laboratorywise, again, we should note
that, you know, hyperuricemia is a hallmark of the
disease, however, studies have shown repeatedly
that up to 50 percent of patients will have normal
uric acid levels at the time of acute gouty
presentation.
Leukocytosis is common, elevated sed rates
and CRPs are seen, often because of an intermittent
42
inflammatory process, chronic inflammatory indices,
such as a low albumin, anemia are not seen.
Cytokine levels have been measured and
shown to be elevated in patients, and there are
classic x-ray findings that can be seen early on
with soft tissue swelling, later on with
development of punched-out sclerotic, overhanging
edge type erosions.
These are the patients who have tophi in
different forms, the helix of the ear, over the
elbow, and severe chronic tophaceous gout over the
hands. The difference between these and nodules is
that they seem to come to a head and have a
propensity to break through the skin and exude this
chalky substance that is very, very rich in
monosodium urate crystals.
Their incidence has decreased over
decades, presumably with better therapy, however,
they are seen in a significant minority of
individuals. It is estimated it takes up to 10
years for a patient to have gout, to develop
clinically manifest tophi.
43
They are most commonly seen over the
elbows, but can be seen in the hands, feet, and
ears. They will damage tissue and bone and
whatnot, and therefore, their presence is alarming,
not only because of their damaging potential, but
also because what they indicate as far as total
body urate load.
Uric acid, we talked about yesterday.
Again, up to 50 percent of patients will have
normal uric acid levels at the time of attack. The
mechanism of this are probably not understood.
They are probably mediated by inflammation,
suggesting that maybe inflammation, including IL-6
may enhance renal clearance of uric acid, and it's
possibly why we see that.
Another interesting factor is the negative
association between gout and rheumatoid arthritis,
a good teaching point for our residents and people
we teach, because often patients will come with
both diagnoses, and you can't have both, and there
are actually good reasons for that, or at least
there are some suggestions for that, some which
44
involve the role of rheumatoid factor possibly in
blocking interactions between IgG and Fc receptors,
possibly the role of just inflammation in cytokines
in enhancing uric acid excretion, that also is
somewhat protective, hence, the exclusion of
patients with a diagnosis of RA would make sense in
an acute gouty trial.
How does one diagnose gout? There are two
ways. One would be the American Rheumatism
Association criteria of 1977, as was reported by
Wallace, where you either have to have crystal
evidence of monosodium urate crystals in either the
joint or in a tophus, or any one of the 6 clinical
following features.
That would include more than one acute
attack, maximum inflammation within one day,
erythema over joint, acute podagra, history of
podagra, unilateral tarsal involvement, tophi,
hyperuricemia, asymmetric swelling on x-ray,
subcortical cysts without erosions, and
culture-negative inflammatory arthritis as a means
of a clinical diagnosis without evidence of crystal
45
identification.
In a more practical manner, this is what I
do in practice, I think most of us do, is patients
present with acute or recurrent mono or
oligoarthritis, and then you confirm the diagnosis
by crystal identification.
In the absence of crystal identification,
one can substitute with probably not to the same
degree of certainty, but I think enhanced
certainty, any one of the following. That would
include a history of recurrent disease, a history
or evidence of hyperuricemia, and lastly, x-ray
evidence of gouty damage with sort of typical x-ray
of gout seen on x-ray.
So, here again, the acute podagra episode
mediated by a urate crystal, in this case taken up
by a poly, and again, this is fairly miserable
arthritis. I mean the onset of many of the other
arthritides we take care of is often not as
dramatic as that seen, and we don't see rheumatoids
with faces like this. We tend to see only our gout
patients who look like this when they come in.
46
So, the management of gout, which was
discussed yesterday, mainly, the chronic
management, the acute management of gout is
nonsteroidals, steroids and colchicine.
There are some problems with this, and
this goes to I think what Marc Hochberg brought up
earlier is that our therapies work really well and
that the benefit-to-risk ratio seems to be quite
acceptable.
In fact, that is true, but there are risks
associated with this, and those risks are maybe
more compounded in patients who have risk factors,
who have baseline or background diseases that
enhance the toxicity of the agents that we commonly
rely upon to use in the management of gout.
So, I think this is sort of the reason why
one needs the development of newer and possibly
safer therapies with at least equal efficacy, if
not better efficacy, but again, if our past efforts
have been very good, then, why not shoot for that.
The management certainly should begin with
the confirmation of diagnosis. This is what we do
47
in rheumatology practices. This is what is not
often done in the emergency rooms and in the
general practitioner's office who may not have
again a detailed understanding of the condition.
Also, the management of acute gout also is
the beginning of the prevention of subsequent
attacks, and that is modification of behaviors and
drugs and whatnot that may contribute to such
activity.
There are FDA-approved therapies for the
management of gout, and there are a lot of
therapies that are unapproved, that have been tried
in trials, and obviously, during acute gout, you
would want to avoid drugs that lower uric acid
levels, such as uricosuric drugs and even
allopurinol.
There are regional differences as to how
this is managed. Nonsteroidals, if you read
publications and talk to physicians, are the
preferred drug of choice in the United States and
Canada, New Zealand, and Australia, however, in
print, there is a widespread preference for
48
colchicine in France, and many of the European
Union nations who also feel that the use of
colchicine is not only effective, but is also
diagnostic.
In many instances, for instance, in this
one survey in France, 61 percent of the physicians
preferred colchicine alone, but 32 percent of that
same cohort preferred the combined use of
colchicine with a nonsteroidal.
The duration of therapy is going to vary
according to the patient's symptoms, but could be
as long as a month. It is quite interesting,
though, as historic as this disease is, and as
prevalent as it is, that there are no formal
guidelines that have been tested and/or advocated,
although I was reading Dr. Terkeltaub's New England
Journal article last night and came across a Dutch
web site for general practitioners that has
guidelines out there, and several medical schools
have their guidelines for local use, but again,
none of these have actually been tested or been
even rigorously developed using evidence-based
49
methodology.
So, the drugs that we do use in the
management of acute gout have significant effects,
there are well-known dosing regimens that can be
used, but there are also well-known toxicities that
need to be kept in mind in the choice of one's
therapy.
This is a publication that I was involved
with in the management of acute gout. The first
question is nonsteroidals, can they be used or are
they contraindicated, does the patient have renal
insufficiency or history of peptic ulcer disease,
congestive heart failure, or intolerance to these
drugs, and, if not, then nonsteroidals are the
preferred agent of choice.
However, if those are contraindicated,
then, the next question is can you use the
corticosteroids, and, if not, then what you
probably should do is use the corticosteroids. The
question is how much and where and when and
whatnot. On this, you base your decision on how
many joints are involved.
50
If it's a monoarticular presentation, one
would consider the use of intra-articular steroids,
less toxic, more effective, rapid onset of effect.
However, if it's polyarticular presentation, one
could go to either oral or--excuse me--that is
supposed to be intramuscular administration.
If, however, corticosteroids were
contraindicated, brittle diabetes or brittle
congestive heart failure, one could advocate the
use of oral colchicine, and only oral colchicine.
So, colchicine is certainly the most
historic drug used in the management of gout. It
is talked about as the first drug for gout. It's
an alkaloid of the Colchicum species. It has
significant anti-inflammatory effects, thought to
be mediated by its ability to inhibit microtubule
formation and basically poly activity.
The half-life of this drug varies widely
according to who you read. It is as brief as a few
minutes. Its plasma half-life is certainly less
than an hour, it is as short as 19 minutes, but it
can be as long as 16 hours, because it does seem to
51
bind to tissues, especially polys and microtubules,
and stay around for as long as 10 days.
So, again, there is a wide variability
here. It is found, because it is lipid soluble, it
is found in other tissues in high concentrations
including the liver, spleen, and intestine. It is
excreted in the urine, in the bile, and undergoes
some degree of intrahepatic recirculation.
It is metabolized by demethylation using
cytochrome 3A4, which is also responsible for the
metabolism of other drugs which have been linked to
the toxicity of colchicine use especially
erythromycin, ketoconazole, cyclosporine, and most
recently, the statins.
These drugs do cross the placenta and are
found in breast milk. They are not dialyzable.
They have many off-label indications besides gout,
pseudogout, amyloidosis, FMF, many skin conditions
including Behcets and Sweets syndrome, and it goes
on and on.
The biologic effects of colchicine are
numerous, but again its mainly its effect on polys
52
and poly activities with adherence and
degranulation, but it does inhibit the expression
of adhesion molecules, the generation of cytokines
and chemokines that are probably involved in again
this inflammatory process.
There are many advantages to using
colchicine, it has a lost history. It works in
both acute gout, it works as prophylaxis in chronic
gout, and prophylaxis when starting hyperuricemic
therapy.
It is said to have a diagnostic
specificity of 96 percent and sensitivity of 70
percent. It has a very fast onset of action when
used IV, although it is longer when used in the PO
form, and this is said to be certainly faster than
what is seen with corticosteroids either as
intra-articular or intramuscular, which is
certainly better than PO corticosteroids.
Lastly, I think nonsteroidals tend to have
their effects a little longer. There is certainly
an advantage in the management of the patients who
are NPO and not able to take anything by mouth,
53
surgical patients and hospitalized patients, and
those who are intolerant or unable to take
nonsteroidals because of contraindications.
These drugs are cheap. Yu, in a
retrospective analysis of 540 patients, basically
showed that the results of colchicine therapy were
excellent in 82 percent of individuals and
satisfactory in 12 percent, and only poor in 5
percent, and there were few episodes of
intolerance, no cases of renal or hematologic
toxicity, and this was over an extended period of
time, over 20 years, in 540 patients.
It has been studied going back to 1939,
when Lockie tested colchicine in patients with
gout, 75 patients, and compared the effects of
colchicine in those patients to other rheumatic
disease including rheumatoid arthritis and
psoriatic arthritis, and whatnot.
Interestingly, all of the gout patients
responded to colchicine, whereas, none of the other
arthritides did. They do not talk about their
outcomes that were used in that trial, but it
54
nevertheless shows again the specificity and
selectivity of a colchicine response.
In 1967, Wallace tested 120 patients, 58
of whom had acute gout, which was originally
defined as an elevated uric acid level with a
current arthritis. Fifteen of these patients had
tophi, and they were treated with colchicine orally
or by IV, roughly split, in the total 120-patient
group.
Major resolution of joint inflammation
within 48 hours was the prime outcome with no
worsening in the next 7 days. In the gout
population, 76 percent of patients resolved,
whereas, in the other population, only 3.2 percent
of patients resolved, again suggesting the
specificity of response here.
Acute gout management, I don't think I
need to go through this a great deal, most of us
know this, but it is 1.2 or 1 mg initially, and
then a dose every 1 to 2 hours until GI symptoms
develop or until the patients are better.
Ahearn, in his publication, it was a
55
placebo-controlled trial comparing colchicine in
gout, showed that 64 percent of patients responded
within 48 hours. That compared to 23 percent in
the placebo arm.
They both had again progressive
improvement over the next 36 hours, however,
colchicine and related GI toxicity and diarrhea
developed within 24 hours in most patients, so
often the GI symptomatology and diarrhea, which was
really quite severe, has its onset before the onset
of clinical improvement.
I heard yesterday Marc's statement that
patients are still very happy with colchicine
outcomes because they would rather deal with GI
toxicity than the pain of gout, which is a
testimony to how severe the pain of gout really is.
Again acute use is reserved for patients
who cannot tolerate nonsteroidals and steroids.
Dr. Wortman has a recent publication where he
states, quite interestingly, that he prefers
nonsteroidals in the management of acute gout,
however, he does prefer the use of colchicine when
56
patients don't yet have an established diagnosis,
such that he can use colchicine almost as a
diagnostic test.
So, when would one use IV colchicine?
Well, in my estimation never, but it should be used
or advocated when a rapid response is needed, when
oral use is precluded and when nonsteroidals and
steroids are contraindicated.
The problem is that there are no warning
signs here as there is with oral colchicine. The
toxicity sort of depends upon how much you give
over time and what your doses are. The recommended
doses are either 2 mg initially, followed by 1 mg
every 6 hours, for a maximum of 4 to 5 mg.
Another regimen would be 2 mg IV as one
single dose, or a third regimen would be 3 mg as
one single IV dose.
The problem is that there is significant
amount of toxicity associated with this. It can be
as simple as extravasation into the local tissues,
which causes significant irritation if not tissue
necrosis, but it can be severe as death.
57
A report coming out of the Office of Drug
Safety here at FDA, they detailed 20 deaths that
occurred in a recent time period.
This is a listing of 23 publications, just
by literature search, that give evidence for severe
toxicity, episodes of suicide, and mortal outcomes
in patients who received IV colchicine, suggesting
that the utility and the use of this approach
should be severely questioned.
In this Bonnel article, well, actually
before that, I asked Joel to tell me, if he looked
at the Med Watch system, what did he come up with,
and just looking at just the Adverse Event
Reporting System, since 1990, in the system, there
are 90 deaths associated with IV colchicine.
Now, those are not confirmed, we don't
know if there is duplicates in there, we haven't
researched those, so that is just a ballpark figure
suggesting that this is a serious problem.
Interestingly, during the same period,
there were 429 deaths associated with allopurinol,
but again there are a lot more issues going on
58
there. Allopurinol has far greater uses, wider
uses than does colchicine.
In its report by the Office of Drug Safety
in Bonnel, there are 20 deaths over a 17-year
period. Most of these were taken from the Adverse
Event Reporting System, but some from the
literature.
There were mostly males, 11 males and 8
females, 17 patients, and they ranged from 50 to 90
years of age. There were two cases of FMF, and the
rest were gout. All exceeded the recommended doses
of 2 to 4 mg. The range went from 5.5 to over 19
mg as a total course.
Adverse reactions that were seen included
thrombocytopenia, leukopenia, pancytopenia,
agranulocytosis, aplastic anemia, tubule renal
failure, and DIC. Death occurred within 1 to 40
days, and 80 percent of these patients showed
evidence of bone marrow depression.
There were risk factors in 13 of these
patients including the elderly, pre-existing
medical conditions, the use of background
59
nonsteroidals, and recent oral colchicine use that
was then compounded by follow-up therapy with IV
colchicine use.
It was clear from their review of the
warnings, precautions, and contraindications listed
in the package insert or in prescribing guidelines
in any major publication were not followed or were
misinterpreted by the prescriber.
Acute toxicity with colchicine can be
again limited to just the skin. Many suggest that
this drug should not be given IV unless there is an
indwelling catheter that had been firmly
established.
Symptoms could begin as tightness in the
chest, difficulty swallowing, abdominal pain,
nausea, vomiting, diarrhea, arthralgias, myopathy,
and then lead to severe shock, oliguria, paralysis
and delirium.
The mechanisms by which these patients
develop these multi-organ involvement and
subsequent death has really not been fully
elucidated. Again, the labs are dramatic, often
60
with severe cytopenias and the development of renal
failure and DIC.
Fatalities have been seen with as little
as 1 mg IV in patients who have been on background
therapy and then received this and had obviously
other risk factors.
Rhabdomyolysis has been reported
especially in end-stage renal disease, and the
patients who were felt to be at risk are those
again who are older, who have renal failure, those
who have been previously taking PO colchicine and
now get switched over to the same dose of IV
colchicine, those who are on background
cyclosporine or tacrolimus, those on grapefruit
juice, and those on statins.
Again, you can see the different stages of
intoxication could begin with GI symptoms and
dehydration, and then progress to more severe
manifestations in the first two to three days. If
the patient is lucky enough to recover,
leukocytosis and allopecia will ensue.
So, guidelines for use I think should be
61
reviewed and always advocated. It should be
severely restricted as far as its use, whether
restricted to a particular discipline or an
individual, or to be banned outright either by
institutions or maybe even by this body.
In Great Britain, it has been removed from
the formulary totally. In many hospital systems
around the country, it has been removed from the
formulary totally. I was in a hospital last week
where a very well-known rheumatologist opened some
mail while I was sitting in his office, and he got
very upset. He said, "Darn, look at this, my
favorite drug has been taken off the formulary
because we had a recent death, because some
knucklehead inappropriately used IV colchicine."
A drug that he loved to use, that he was
very skillful at using, this is a very good
rheumatologist, I am sure he knows all these
guidelines, other people have now taken this drug
away from him, and he can no longer use it in his
hospital.
Again, single IV doses should not exceed 3
62
mg as a single dose, and 2 is probably a better
dose. Cumulative doses should not exceed 4 to 5 mg
over a total of 7 days. When one looks at the
patients who died and had serious toxicity, often
it was more than 1 mg per day over a 7-day period,
that patient got into trouble, and, in fact, going
higher than 0.5 mg per day for a 7-day period put
patients at risk.
It should be given by IV catheter. If IV
use is to follow chronic PO therapy, and used to
sustain the patient, it should be done at basically
half the dose. If you are going to follow up IV
therapy with PO therapy, you should wait 7 to 10
days before initiating PO therapy.
Reduced dosages should be used in the
elderly, in those with liver disease and renal
disease, those with prior PO colchicine, and it is
certainly contraindicated in those who are
pregnant, who have combined renal-hepatic disease,
who have very low creatinine clearances, and who
have evidence of biliary obstruction.
Treatment is often difficult obviously
63
with drug cessation, promoting intelligent use, it
is not dialyzable, cytopenias can be managed with
growth factors in some instance, rhabdomyolysis
should be managed, as it usually is, with fluids
and alkalization, if necessary, and there have been
some experimental therapies with Fab-2 fragments to
inhibit and to bind, but this is an experimental
tool that is being used.
Moving on to corticosteroids and
intra-articular and intramuscular use, they
certainly have benefits equal to nonsteroidals.
They are felt to be overall less toxic when used
acutely and intermittently, and again have
significant benefits.
There are, however, some issues, that
there is no standardization as far as dosing, which
form is best, what is the best route. It is often
good in patients who have contraindications to
receive nonsteroidals, and that includes heart
failure, renal failure, GI bleed, or patients who
have monoarticular presentations in whom a
intra-articular injection would make more sense.
64
Toxicity can be significant,
hyperglycemia, hypokalemia, fluid retention, and it
is frequently reported that patients who receive
corticosteroids get better, but then a few days
later or maybe a week or two later, they actually
rebound where they get another flare of gout.
Prednisone orally has been used with doses
of 30 to 50 mg being advocated for up to a week and
then tapered over the next week or so. Again,
there is this issue of rebound.
ACTH is probably the best studied of
these, either 40 or 80 mg--excuse me--international
use as in a single injection. Other dosage forms
include triamcinolone, acetonide, and
betamethasone, 7 mg.
I have listed a few studies here that look
at the value of ACTH therapy as compared to Indocin
or Diclofenac here, and you can see that basically,
ACTH seems to perform very well. It had a faster
onset than Indocin, and Indocin certainly had more
toxicity, was compared head to head over here.
When it was an uncontrolled trial, 97
65
percent of people were better by 5 1/2 days. When
compared to triamcinolone, both groups, the ACTH
group and the triamcinolone group, responded by Day
8, but the triamcinolone group had fewer rebound
episodes and required less re-treatment.
Then, Werlen showed that when comparing
these two different steroid forms, the Diclofenac
and steroids outperformed the nonsteroidals in
their trial.
So, nonsteroidals have been advocated, FDA
approved, including indomethacin, naproxen, and
sulindac. Many have been tested in clinical trials,
most of which have been open label. The benefits
of nonsteroidals are that they certainly have a
fast relief of onset compared with colchicine, PO
colchicine, not IV.
It is estimated that 2 to 4 hours it takes
for people to get better. With indomethacin, that
would not be complete improvement. It is less
toxic when prescribed appropriately and better
tolerated than certainly colchicine. They are
widespread in their use and most docs are more
66
familiar with the proper dosing and use of
nonsteroidals than they are with colchicine and IV
colchicine, and certainly in many instances, there
are very cost effective.
I believe the representative from Merck
will review the combined results of the etoricoxib
study that was reported recently at the American
Pain Society, but all of this to say that
etoricoxib and COX-2 inhibitors have been tested in
gout in two studies, and submitted an analysis of
both or a combination of both, and they have showed
using two primary outcomes here that etoricoxib
compared very well to Indocin, so while they both
had significant benefit, the real benefit was seen
with less toxicity in the etoricoxib group compare
to Indocin as far as hypertension, diarrhea, and
CNS or headache.
Analgesics have also been advocated in the
treatment of acute gout, and that includes the use
of topical ice where it has been shown that
patients who received ice had better outcomes as
far as swelling and pain, and ketorolac.
67
Actually, this fellow Shresta was one of
my residents at Parkland, he did both of these
trials at Parkland, and he used ketorolac, and his
time points were very short time points, 30
minutes, 60 minutes, 90 minutes, and 2 hours.
He showed in this open label trial and a
double-blinded, randomized, controlled trial
against Indocin that it performed very well, either
equal to Indocin or certainly significant by 90
minutes or 2 hours in both trials.
There was, however, in the second trial,
some rebound in patient who received the ketorolac
after 6 hours.
I have a listing for you in the next two
tables, the trials that have been done, open label
trials and controlled trials, in the management of
acute gout. This is basically for your education
to show you, number one, the design and the number
of patients, but to look at the primary outcomes
that were used in these trials and the time points
for evaluation.
You can see that most of these used pain
68
or joint exam findings, tender joints and swollen
joints, as outcomes, but pain usually in VAS or
Likert scales, and the days and times of evaluation
ranged from 24-hour evaluation to--or Shresta, he
did these at 30 minutes, 60 minutes, and 90
minutes, but one day all the way up to 7 days here.
In the next trial, these are controlled
trials, comparing mostly nonsteroidals, some of
these are steroid trials and ice trials, and
whatnot, and you can see again most of these
required pain outcomes and, the top one here, a 50
percent reduction in pain, mostly going to the
reduction in pain level, or reported just changes
in pain level, usually is reported by either VAS or
Likert scales.
Again, the time points that were usually
looked at were 1 to 8 days in most of these trials.
So, the considerations as we go forward is
how does one establish a diagnosis, would it be
solely based on prior evidence or current evidence
of crystals as a means for diagnosis.
Would you rely on ARA criteria, either
69
crystals or the clinical criteria, or would you use
the much more practical approaches as I do in
clinic, what is the duration, does someone come in
with two weeks of symptoms and new gout, or must
they have established gout over time, what does the
duration of attack have to be before they get in.
In some instances, patients had to wait 5
to 7 days to get in. This is sort of a problem,
because again that is the maximal amount of pain.
You want to get these patients in as soon as
possible.
Con meds are issues, as Joel talked about.
I think most patients will come to you on some
degree of pain medicine whether they be
nonsteroidals or other pain medicines. Steroids
obviously I think would compound things unless it
was a steroid trial, and allopurinol should be
stopped at entry.
Time assessments. The window here is much
shorter. This is not like the trials we were
talking about yesterday. We were looking at 3
months, 6 months, and 12 month outcomes. Here, I
70
think we are looking at 1-day, 2-day, 7-day
outcomes, and the extended outcome may be anywhere
from 14 to 30 days.
The primary outcome is always going to be
pain, I mean there is no doubt about this. I don't
know that there can be much argument here. This is
an incredibly painful condition, and that is what
patients want. That is what we accept clinically
when we see these patients.
There are other secondary measures that
one can look at and I list those for you there, and
I would advocate these are rescue medicines in any
regimen whether it be placebo-controlled or an
active-controlled regimen.
This is my suggestions for a clinical
trial. Number 1, I see as guidelines for actual
numbers, I think would be Smart in this instance.
Obviously, they would be short-term trials, so I
think that the first applies here. We are not going
to have many people treated with acute therapy for
over a year.
I believe an active controlled trial,
71
looking for a non-inferiority design largely
because of what Marc brought up earlier, which is
that the therapies we have are very effective. You
know, to go against a currently approved therapy
wouldn't make a great deal of sense, and use a
non-inferiority design, that you have obviously
double-blind and active controlled.
Patients should have a diagnosis of gout,
and I think that although I like my method of
diagnosis, I still think you have to go with
something that has been tested and held to be true.
ARA criteria have a sensitivity of 87 percent or 84
percent, and specificity of 100 percent if you
include crystals.
The acute gouty attack should be seen
within a certain period of time, certainly within
three days. The trial length could be up to two
weeks, and visit frequency I think would have to
depend on the expectations of the drug and its
onset of effect.
One thing that I was thinking about, that
is not on the slide, but is a common issue in
72
clinical trials, is that patients have a run-in
period. They are seen, they are screened, they are
consented. You get labs, they come back a week or
two, or three days or two days later, that is a
problem here. These people hurt today.
I think that inclusion criteria have to be
liberalized to allow for people who may be entered
into a trial who have renal failure and you don't
know about it, who have LFTs that you don't know
about, who have, you know, because they didn't
reveal the fact that they are an alcoholic, the
ideas that they need to get in, I think you should
protect the trial as best you can with Smart
criteria, but I don't think you should impair
enrollment in these trials by clinical inclusion
criteria.
Obviously, age greater than 18, the
diagnosis of gout, an acute attack should be
defined, and I think that should be one of the
outcomes here, not only how long an acute attack
lasts, but whether they have subsequent acute
attacks.
73
Mono/oligoarthritis are preferable at
entry. Polyarthritis I think should be excluded
for several reasons. One, it could be something
else. Two, the polyarthritis tends to fall more in
that atypical gouty group, older women, more
insidious, older, mostly women, more insidious
attacks, nodal osteoarthritis, a lot of other
factors going on there, and their response to
therapy may not be the same, so I would tend to
exclude polyarticular presentations of gout in such
trials.
Activity needs to be assessed, and
activity can be easily assessed by just using the
cardinal signs of inflammation, so tumor, rubor,
dolor, or calor, pain, swelling, redness, and
warmth, and improvement in two out of four, or
three out of four as very objective means of
outcome.
Exclusions, I think absolute exclusions
should include polyarthritis, an excessive alcohol
use, renal insufficiency, if known, background
aspirin, if known, cyclosporine, rheumatoid
74
arthritis, transplant, active infections, dietary
restrictions, and uncontrolled hypertension might
be certain obvious issues you would exclude.
What is on the table, and I think very
uncertain, are background use of nonsteroidals or
BC, diabetes, heart failure, tophi,
nephrolithiasis, previous or current narcotic use,
previous or current anticoagulants, background
nonsteroidals, allopurinol, probenecid,
sulfinpyrazone, hospitalized or immobilized
patients, those that are unwilling, and, my
favorite, those who are currently involved in
litigation.
So, primary outcomes I think are clearly
going to be patient derived and pain. I think that
pain can be self-reported measures of pain. We
heard presentations at our pain advisory meeting
about the use of PDAs and direct patient entry of
data.
It is real-time, more reliable, gives you
I think a true assessment of what is going on. It
can also give you a more reliable assessment of
75
time to onset that may not be easily achieved in a
recurrent physician visit kind of assessment.
Secondary outcomes can be both patient and
physician derived. That will include global
assessment of the disease, global response to the
drug, complete resolution of symptoms, time to
resolution of symptoms, what happens in an index
joint, if one can be identified as far as the four
cardinal signs of inflammation, swollen joint
score, tender joint scores on zero to 3 scale, the
need for rescue analgesics, inflammatory indices of
sed rate and CRP, uric acid could be also looked at
although I think less important, functional
measures, and then comparison with the active drug
as far as the safety and toxicity profile.
So, that was a mouthful. I will end
there.
Thank you very much.
DR. GIBOFSKY: Thank you very much, Dr.
Cush.
Are there questions for Dr. Cush from the
members of the panel?
76
Dr. Weisman.
DR. WEISMAN: Dr. Cush, what is your
formula for managing patients with acute gout that
is complicated? Transplantation comes in with a
creatinine of 2, already on steroids, and so forth.
DR. CUSH: Well, the more complicated they
are, the more I tend to rely on steroids in
management, so if they have transplants, and if
they have renal insufficiency, and they are
hospitalized and they are NPO, I think steroids is
the major issue.
It has often been advocated that in
patients who have contraindications to using
nonsteroidals, that you can still use them because
you are unlikely to get into the significant
trouble one sees with nonsteroidals, whether that
be GI or hematologic or renal, because you are
using short courses of therapy.
However, I think that is probably
overestimated and that most patients don't need
three days of therapy. They probably need more like
seven to 14 days of therapy, and there the risks
77
are real.
So, I think complicated gout may require
parenteral administration of medicines, more use of
steroids. I tend again not to want to use IV
colchicine.
I think getting smarter about prevention
of subsequent attacks and using combinations of
whatever the patient can tolerate to treat the
acute attack is the smartest way to go, but then
again, you know, complicated courses are often
because you can't get them under control.
The real struggle I don't think is as much
in the management of the acute episode as once you
get them under control, how do you keep them
control, because what complicates them are the
factors that bring out these more recurrent
attacks.
DR. WEISMAN: Would you include them in
clinical trials?
DR. CUSH: Well, again, I alluded to some
of that by saying no for transplant, no for
cyclosporine, no for a lot of difficult situations.
78
I think these acute trials could occur in patients
who have well-controlled intercritical gout on no
therapy, or well-controlled intercritical gout on
some therapy.
It could occur in well-controlled
tophaceous gout and then has an acute attack, but
patients who are chronically out of control with
inflammation and swollen joints and whatnot, that
can be a more problematic group, and they are more
likely to be in that tophaceous gout group. Again,
those might need to be excluded.
I think again to liberalize patients, so
that they don't have to undergo, for instance, a
lab screen, that requires them to return in 24
hours or a week, would be a horrible thing, because
it would deny those people access to treatment
which they desperately need today.
DR. GIBOFSKY: Dr. Hoffman.
DR. HOFFMAN: That was a great and very
thoughtful review, Jack. Thank you.
I would like to hear your thoughts on a
couple of points that you mentioned and guidelines
79
you suggested. If I understood you correctly, you
would stop allopurinol in patients who came in with
acute gout.
We have all seen patients who have
recently had allopurinol started and have
precipitated an acute attack, and I am not sure
that that attack is in any way, other than for that
association, different than other attacks or that
it would respond differently to the agent being
tested.
So, I am not sure why someone would change
the dose that the patient came in on, the
allopurinol dose rather than just continue what
they were on and treat the acute attack in testing
the agent of interest.
DR. CUSH: I think it is a matter of how
one is taught, I don't think there is a lot of
science here. I think there is a lot of
hand-me-downs as to what works. I mean I have
always been taught that it should be stopped mainly
because you want to stop the mobilization of tissue
stores as much as possible to give you the best
80
chance of acute resolution, that if they continue
on allopurinol, you may prolong the attack.
Again, I don't think that is as well
studied as I wish it were. That is certainly an
issue, whether or not patients should be continued
on whatever background therapy they are on, whether
it be allopurinol or diuretics. Obviously, there
are drugs that may contribute to either that event
or maybe even the prolongation of that event.
My view is if they can safely be stopped,
then, what is the hazard in it, are you hurting the
patient down the line as far as their ultimate
control, would they fall out of control by stopping
that 300 mg or 100 mg a day of allopurinol.
DR. HOFFMAN: I don't know the answer to
that either, but I think it is an issue that
remains perhaps contentious.
DR. CUSH: Right.
DR. HOFFMAN: Along the same lines, since
the significant minority of people, you have got a
great handle on the literature and can probably
inform us, but I am thinking that there are some
81
studies in the past that have suggested that when
you look at all gout, that perhaps as many as 30
percent of people have polyarticular gout.
You might comment on whether that is
accurate or not, but if it is a significant
minority, why would one want to exclude
polyarticular gout in a trial especially if one of
your standards for inclusion was crystal
demonstrated gout?
DR. CUSH: If crystals were your
identifying factor, I think that you would be a
little more certain, but you could identify
crystals, and still not know whether that is acute
polyarticular septic arthritis, as well. So, that
is an issue.
I think what is clear from what I have
read and looked at is that in the initial
presentations, not someone who has established gout
and has recurrent disease, but in the initial
presentation, polyarticular gout is very, very
uncommon except for in the population I mentioned -
women, mild proliferative disorders, elderly, and
82
those receiving cyclosporine.
Otherwise, it is actually really small, it
is probably in the single digits. By "poly," I
mean four or more joints. You know, mono and oligo
is really I think where 90-plus percent of the
patients exist. I think that there is more
diagnostic certainly in that restriction.
If one allows polyarticular gout, I think
you would need to make sure that you are not
dealing with other issues, whether it be another
crystal, whether it be background issues that may
complicate response to therapy.
So, I mainly exclude them because I think
it is an uncommon aspect to the disease, and there
are so many patients, you don't need those to do
the trial well.
DR. HOFFMAN: So, you wouldn't exclude
oligo.
DR. CUSH: No, I would not exclude oligo.
I think that is a very important inclusion.
DR. HOFFMAN: Finally, if the chairman
would allow me a final question, I would just like
83
perhaps your opinion and some of the other experts
on the panel about what I think is a bias in the
literature.
That is the nonassociation of gout and
rheumatoid arthritis. I actually don't believe
that at all from my own practice because I would
submit that most rheumatologists who see a patient
with a flare-up of RA, and are concerned about a
comorbidity, might or might not aspirate the joint
to rule out sepsis, but probably don't personally
do synovial fluid analysis.
DR. CUSH: Right.
DR. HOFFMAN: But having done that myself,
I have seen a number of cases of patients with RA
and gout, of course, as well as pseudogout, and I
am not sure how robust that literature is, and
since the notion has been in the literature, then,
there has been a story, perhaps fantasy, that has
grown up around it regarding rheumatoid factor and
inhibition.
DR. CUSH: Well, I would agree it is not a
well studied matter. I think it is somewhat urban
84
legend, rheumatology legend that has passed on.
My own belief is that it is true, and that
stems somewhat from observations and doing clinical
trials where I don't know why uric acid was being
done, but I have done several trials where RA
patients, uric acid levels were being done, and it
was clear that uric acid levels would go down when
RA was at its worst.
That was curious to me, and that is why I
think some of the more recent data about this
negative association and maybe why that occurs
associated with IL-6 and whatnot rings true.
I think it is an important teaching point
because I think in the general practice community
where people are seeing arthritis patients don't
know well how to diagnose these, patients come to
us all the time with, "Doctor, I have gout, lupus,
and rheumatoid arthritis."
"I am sorry, ma'am, you don't. Firstoff,
you are too young to have gout and you definitely
don't have lupus."
For me to propose that the two can
85
coexist, I do propose that septic arthritis and
gout often do coexist, I think would be misleading
and miss a prime teaching opportunity to the
general public, which is that you either have one
or the other, and if you have both, let's report
it.
In fact, if you looked at the reports in
the literature of combined gout and rheumatoid
arthritis, they are less in number than the numbers
of combined gout and septic arthritis.
I still think your point is right. I
think that most rheumatologists, when they see an
acute rheumatoid who has one or two swollen joints,
rather than aspirating that joint, treat it. And
how do they treat it? More nonsteroidals, more
steroids, and whatever.
So, the possibility I think still remains
and I think for someone to study in that matter by
vigilantly looking for it would be an important
contribution to our literature.
DR. GIBOFSKY: Dr. Cronstein.
DR. CRONSTEIN: Jack, again, that was a
86
terrific review and very thoughtful.
One of the things that you mentioned was
the need for very rapid assessment and enrollment
of patients, so this might preclude I guess a more
thorough evaluation of the medical status, but
since many of the drugs, whether they are
comparator agents, all the nonsteroidals, for
example, can exacerbate hypertension and renal
insufficiency, I am just wondering if you could
elaborate on how you might go about doing this,
because this is going to be a problem.
DR. CUSH: And figure this into the
equation. If this trial is done by me, and by
those of you around this table who do clinical
trials, this won't be as much of an issue, because
we will actually spend an hour with the patient, we
will do a very careful history, we will do a very
careful exam.
In that hour, we could actually have labs
back and see what the creatinine and LSCs are, and
whatnot. But the problem is I don't have these
patients in my clinic, I am not going to treat that
87
many acute gouts this year. If you are going to do
this in emergency rooms, in family practice clinics
where they are seeing patients every 8 to 10
minutes, you know, these guys don't have the time
to do this kind of detail, and so you are going to
get a real world view of these people including
some of their comorbidities and some of their
background therapies.
You know, the FDA and the product
manufacturers have to accept a higher degree of
toxicity that may be associated with such an
approach, but to not do that is to maybe deny
people who really need therapy right now some
intervention.
How long can someone who has acute gout,
where they can't have a sheet on their big toe, or
they can't walk, whether it's a mother who is
taking care of kids or a businessman who has a trip
tomorrow, and whatnot, I think it is cruel and
unjust.
I think that I would point to the higher
good, which is go for patient relief and now, and
88
accept again a more real life population except
that I will enroll them now, get my labs, and maybe
we have to stratify those people post hoc for
patients who had uncontrolled hypertension, for
patients who had renal insufficiency, people who
were diabetic, and whatnot.
DR. GIBOFSKY: Dr. Terkeltaub.
DR. TERKELTAUB: Thank you for that
review.
I wanted to point out one item about gouty
inflammation, and that is, that it actually,
pathogenically, is very well characterized. I mean
not only do we have the etiologic agent as opposed
to, you know, not knowing the primary etiology of
RA, but the major inflammatory mediators including
IL-1, TNF-alpha, IL-8, the signal transduction
cascades including P38 and of Kappa B inhibitors,
the effects of leukocyte adhesion molecules, Dr.
Cronstein having elucidated how colchicine works on
e-selectin, these are all well characterized, and
some of the actual targets are seen by specific
medications now in practice including IL-1
89
inhibitors, TNF-alpha inhibitors, and medications
being evaluated in the clinic for RA, that may not
work very well for RA, but may work for gout.
Are you aware of any anecdotal evidence
for some of these particular medications in trials
or in use for RA working for gouty inflammation?
DR. CUSH: I am not. As you were going
into this, I was going to turn around and ask you
that question. I would love to see if Kineret or a
TNF inhibitor has been tried in acute gout, and, if
so, I would like to know.
DR. TERKELTAUB: Dr. Cronstein has told me
that I shouldn't admit to using Kineret or Enbrel
for gout, that it wouldn't be seemly, but I will
admit to it, and there is some anecdotal evidence
for some of the biologics affecting gouty
inflammation, but obviously, it hasn't been done in
a controlled manner.
DR. CUSH: Would responses be as prompt?
DR. TERKELTAUB: Handfuls of patients, it
is very hard to tell, but there is some evidence
that some of the biologic agents might work for
90
gouty inflammation.
DR. CUSH: So, maybe going to Dr.
Weisman's question as to how do you manage someone
who is very difficult to manage, who maybe you
can't give colchicine, maybe you can't give
nonsteroidals, and maybe you can't even use a
steroid, maybe that is yet another alternative.
DR. TERKELTAUB: I think there is room for
trials, for careful trials, and again, you did a
tremendous job in the review. I think that one of
the issues is that I think we really are seeing
more complicated patients in terms of more
polyarthritis and more severe flares in the elderly
and patients with renal failure and transplants,
and so forth.
So, I would encourage, given that these
are the patients that we have a shortage of safe
medications to use, that we would at least study
these patients in trials.
DR. CUSH: And I think that they should be
studied because they are still a therapeutic
conundrum in many situations. Their inclusion in
91
an acute trial, for an acute indication, I think
would only tend to complicate matters for what
should be a relatively straightforward trial.
It is a different matter if you want to
study people who have established chronic
tophaceous gout, or renal failure, or one of these
very difficult kind of cases, and look for the
control of acute flares in those people. That is a
different kind of trial and maybe even a different
kind of drug is being developed.
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: I guess maybe your thoughts
on one other issue, and this sort of comes out of
what Dr. Terkeltaub just said. If you have
patients who can take established therapy, let's
say, NSAIDs, then, following your rationale, you
would say that the NSAIDs should be the comparator
agent, right?
DR. CUSH: Yes.
DR. HOCHBERG: Then, if you have people
who have contraindications to NSAIDs, and you want
to look at a new therapy for gout which might be
92
appropriate in that population, you know, do you
want to comment on the choice of comparators in
that situation?
Also, if you had something which was an
entirely new class of drugs, you know, this is not
necessarily a quantum leap, but a new class of drug
that might be used in this condition that hadn't
been used in gout before, where would the
appropriate role for a placebo control be?
DR. CUSH: To answer your last question, I
think in the latter instance, you know, a new
product line, a new biologic mechanism of action,
one not yet tested, I think would have to be tested
in a placebo population with obviously, a very
liberal policy as far as how to rescue those
people, so as not to subject them to unwarranted
degrees of pain and misery.
I think for a nonsteroidal head to head,
to use an approved nonsteroidal as your head to
head is what the FDA would require. My
understanding is that if you are going to go for
indication, you can go against an approved drug and
93
go for either non-inferiority or superiority, and
that would be acceptable.
In the case where nonsteroidals are
contraindicated, first, I would exclude those
people from a nonsteroidal trial if possible, but
then if you want to include them, then, you could
use either colchicine as your comparator or maybe
even steroids as your comparator.
ACTH steroids, are they approved? I don't
think they are.
DR. SCHIFFENBAUER: Corticosteroids have
acute gout as an indication, but ACTH, not.
DR. CUSH: Oral corticosteroids?
DR. SCHIFFENBAUER: I think it just says
like prednisone would be an example of that.
DR. CUSH: That is interesting because I
think there is far less evidence that that is
effective compared to ACTH.
DR. GIBOFSKY: Any further questions for
Dr. Cush from members of the panel? If not, Dr.
Cush, thank you for a superb presentation.
We will move on to a presentation at this
94
point from the members of the Merck Research
Laboratories.
Dr. Agustin Melian will introduce his
colleagues, who will make the presentation.
Dr. Melian.
Merck Research Laboratories
Introduction
DR. MELIAN: Thank you and good morning.
I am Dr. Agustin Melian and I am a Director of
Clinical Research at Merck Research Laboratories.
As Merck is one of the few sponsors to
have recently carried out studies in acute gouty
arthritis, the Agency has asked if we might come
here today to share some of our experiences with
the group. On behalf of Merck and Merck Research
Laboratories, I would like to thank the Agency for
this opportunity.
As I think the Committee is well aware of
here today, acute gouty arthritis is one of the
most common inflammatory arthropathies in men over
the age of 40. Despite this relatively common
clinical occurrence, there is a relative paucity of
95
data from clinical literature on acute gouty
arthritis studies.
Those studies that have been done for the
most part have had just a limited number of
patients, many haven't included a large number of
endpoints, and many haven't included a large amount
of information on the endpoints that they have
included.
So, the question faced by the Committee
today is the same question that was faced by Merck
when they first conceptualized and designed their
studies, that is, in the absence of extensive
clinical data, how best to conduct studies in acute
gouty arthritis.
In order to try to answer this question,
Merck scanned the available literature, reviewed
FDA guidance documents, and then brought together
experts in the field of clinical rheumatology.
Based upon the advice of these experts, we
then carried out two clinical studies. They were
replicate studies in acute gouty arthritis, Study
040, published in 2002, in the British Medical
96
Journal, and Study 049, published earlier this year
in Arthritis and Rheumatism.
Here to discuss key issues from the design
phase of the Merck studies is Dr. David Daikh. Dr.
Daikh, along with Dr. Ralph Schumacher, was one of
the key pivotal investigators who were first
involved with the design and conceptualization of
these studies.
After Dr. Daikh's presentation, I will
return to the podium to discuss and briefly
summarize the study results. Then, Dr. Daikh will
present a brief presentation on Lessons Learned.
With that, I would like to turn the podium
over to Dr. Daikh.
Thank you.
Design Considerations in Acute Gouty
Arthritis Studies
DR. DAIKH: Good morning. I appreciate
the opportunity to discuss with you and review some
of our experience in setting up these trials in
acute gout, and also, as a rheumatologist,
appreciate the interest of the FDA in studying this
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disease in more detail.
I will discuss with you design
considerations in acute gouty arthritis. I think
that given the previous presentations, I will just
touch briefly on issues of pathophysiology as they
relate to issues of study design.
I will then review briefly the extant
literature that was available and that we used to
guide our own design, and then really spend most of
the time talking in detail about some of the
considerations that, in fact, many of these were
actually outlined very nicely by Dr. Schiffenbauer.
I think you will see that we covered much of the
same ground in these deliberations.
I will also then talk in some detail about
the approach to data analysis that would be
required by different study designs.
Really, after the definitive presentation
on acute gout, there is nothing really I can add,
certainly given the collective experience of the
panel, except really to emphasize that this clearly
is, as we all know, a clinical syndrome that is the
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result of an immune response to monosodium urate
crystals.
Really, because of the inflammatory nature
of the disease and the clinical expression of that
inflammation, I would argue that we are really
dealing with a unique clinical entity.
The diagnostic criteria proposed by
Wallace and coworkers a number of years ago have
been alluded to in a number of ways, and I want to
spend a couple minutes going over these
specifically.
They really reflect the reality of
clinical practice, that once you have some
certainty of a history of crystal-induced
arthritis, the diagnosis in the acute setting is
greatly simplified, so the presence of
characteristic urate crystals in the joint at the
time of diagnosis in fluid is critically important
and allows you essentially to make a diagnosis of
acute gout, or indirect evidence of the presence of
crystals, that is, tophi either clinically apparent
or present on a radiograph.
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However, it is important to emphasize that
even with definitive diagnosis of crystals, either
directly or indirectly, one still needs the
subpoints which are, in these criteria, C1 and C4,
that is, the maximal inflammation developed within
one day, and that there is redness in the observed
joint, really emphasizing the importance of
inflammation in making this diagnosis.
In the absence of either immediate, direct
or indirect evidence of crystals, further, the
criteria allow a diagnosis with a number of points
that have been mentioned. I am just going to
emphasize them again because it makes the point
that this is a stereotypical clinical response and
you can make a diagnosis of acute gout on clinical
grounds.
So, in addition to maximal inflammation
within 24 hours, more than a history of acute
attacks, mononeuritis, in particular podagra,
involvement of the first MTP, unilateral
involvement of the first MTP, and then the others
that you see listed there.
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As has been very comprehensively reviewed,
we really divide our treatment of acute gout into
essentially what is preventative treatment of the
acute attacks and then treatment of the acute
attacks. We will be for the purpose of this
discussion really focusing on nonsteroidals and
similar drugs, colchicine and corticosteroids.
Before we get to the details of our own
study of a COX-2 specific inhibitor compared to a
standard nonsteroidal in acute gout, I just want to
address the issue of what quantitative studies were
available at the time of our own design to assist
in guidance.
Listed here are the total number of
studies. Now, these are with the exception of the
highlighted studies, double-blinded, controlled
trials in acute gout up to the time of our own
involvement in the study.
The highlighted studies have been alluded
to. I am going to discuss in detail the
observational study, as well as the
placebo-controlled trial of colchicine. The third
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highlighted study was a double-blinded, controlled
trial that will be discussed subsequently as we
address the issue of quantification of Indocin's
effect on this disease.
But I just want to emphasize, as you look
at this list, a number of points. One, it was a
remarkably short list. Secondly, most of these
studies have a very small number of patients, and a
number of them, most of them actually are quite
old. So, in fact, very little guidance as we will
see in terms of prior experience with these kinds
of studies.
Now, what study or studies do we have to
tell us about the natural history of gout, and what
I am really going to be addressing here is the
issue of spontaneous resolution of disease.
Well, we have one, the observational study
of Bellamy et al. in 1987, the rationale of which
was really to serve as a documentation of the
natural history of this disease with the express
goal of potentially guiding future studies, so
really what we need.
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As was noted, this was a small trial of 11
patients. These were patients who presented with
classic podagra or had a history of prior attacks.
The measurements were, as you might expect, pain,
tenderness, swelling, erythema, et cetera, but
importantly, these patients were observed in an
inpatient setting. They were hospitalized and
observed over the course of the study.
Now, also importantly, the mean time from
the onset of the patient's attack to their
enrollment in the study was 2.8 days. The baseline
level of pain in these patients was graded as
severe or very severe, and, in fact, the mean pain
at entry in study, in this group of 11 patients,
was 3.73. This was on a scale of zero to 4.
Here is the data. I want to emphasize a
couple of points on this graph. You see here mean
pain severity versus time. Now, there is actually
two plots of time here. The first x axis here is
study day, but here you see this is actually the
mean numbers of days since the onset of attack, so
Study Day 3 really corresponds to 5 days since the
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onset of attack. This will be important for us to
keep these two timelines in mind as we move forward
and look at this in other studies in acute gout.
You can see, then, for study days, up to
Study Day 3, which corresponds to 5 days since the
onset of attack, there was essentially no change in
the patient's pain severity. Then, beyond 5 days
into the attack, there was some diminishment of
pain.
Now, as I think noted previously, 2 of the
patients of the 11 dropped out during the course of
the study because of unbearable pain essentially,
and so this plot, also from the publication, shows
an intention to treat analysis with these 2
patients included. You can see really very little
difference, the conclusion remains the same.
So, from our single study, the natural
history of acute gout, we would conclude that there
is essentially no resolution in severe to very
severe pain over the first 5 days from the onset of
attack, and that really even at the point there
begin to be some resolution of pain, it was minimal
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over the course of 7 days. This, I think really
reflects our clinical experience.
Another study that potentially can guide
us in terms of understanding duration of attack and
response would be the single placebo-controlled
trial that was alluded to. This was also a study
which included patients who presented with podagra,
involvement of the first MTP, and this was a very
short-term study, 48-hour study, comparing
colchicine to placebo.
These are patients who had had
crystal-proven gout, and they again, importantly,
were observed in an inpatient setting. They were
basically put at bed rest.
The pain scale here, instead of a zero to
4 scale, is 100 mm Visual Analogue Scale with 100
being the patient's expression of maximal pain. In
addition, there was an overall clinical score
assigned, which was a composite of pain,
tenderness, swelling, and redness.
In terms of the baseline characteristics
for this group of patients, their mean time from
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the onset of their clinical attack to randomization
was 38 hours, and their estimated mean pain, as we
will see, at randomization was 60 to 70 mm on the
VAS.
You can see here the entry point in these
patients. Again, we have study days here, as well
as the mean number of days since the onset of
attack. Here again we see very little to no
resolution over the first couple of days of study,
2.5 days here you see no change.
The other point to make from this
placebo-controlled trial is essentially no placebo
response especially immediately upon entry into the
study. Remember this is days out from enrollment.
I think we can also contrast this placebo
curve to the kind of placebo responses that we are
used to seeing in studies of osteoarthritis and
rheumatoid arthritis, it's a very small placebo
response.
So, from these studies, we can at least
feel assured with our conventional wisdom in
clinical experience that at least moderate to
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severe attacks do not resolve spontaneously within
a 5 to 7 day time period, and that there really is
very little placebo response in this acute disease.
Let me move now to a number of issues that
could be considered, that were considered as we set
up the study. Well, as has been alluded to, an
important point is really control versus a
comparator design, placebo versus active
comparator, and if an active comparator design is
chosen, what should be the comparator drug, which
patients should be selected, what endpoints should
be chosen to measure outcome and when should those
measurements be made.
Let's consider the pros and cons of a
placebo design versus active comparator. In terms
of placebo control, obviously, the major major pro
is that this greatly simplifies the interpretation
of results.
The disadvantages, especially in acute
gout, I think are numerous, and issues that we
grappled with. Importantly, as has been alluded to
in some of the questions, patients and referring
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physicians know how painful this condition is, many
of the patients have had it before, and they also
know that effective therapies are readily
available.
I really want to emphasize that we are
dealing with both a practical approach and perhaps
an ethical approach, but certainly because of the
practical issues, raise the difficulty of enrolling
patients, and then the question is it really
ethical to withhold effective, readily available
treatment in these patients with highly
inflammatory, very severe pain.
In addition, not only a practical issue,
but an issue that would potentially confound the
data analysis is the issue of dropouts, patients
who maybe were willing to enroll in the study, but
then because they were receiving placebo, continued
to have severe pain, dropped out during the course
of the study or potentially required some rescue
medication, which we can discuss.
The other issue, as I think was addressed
in these prior studies, the potential need to have
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patients in an inpatient setting, to monitor
compliance and to prevent self-medication by
patients with readily available over-the-counter
medications.
If anything, remember the two studies that
I reviewed. Those were inpatient studies. I
think, if anything, those studies may have
overemphasized the speed to resolution because
those patients were not ambulatory.
Now, consider the active comparator
design. The advantages or pros of this design
certainly are that standard therapies,
nonsteroidals, corticosteroids, perhaps to a lesser
extent colchicine in the short term, are known to
be highly efficacious and obviously readily
available.
The ethical concerns do not apply, this is
a more humane approach, giving patients therapy at
the time that they need it, and this presumably
would also minimize the issue of enrollment
concerns, as well as dropout concerns during a
short-term study.
109
The cons to a active comparator controlled
trial are also potentially significant, that is,
more complex statistical requirements.
In particular, I am going to touch on
these points, the need really to demonstrate an
assay sensitivity, to demonstrate that the
comparator drug actually works, and, in addition,
the need to assign a comparability bound, to
compare the two drugs, to show that they actually
are clinically comparable or equal.
As you will see, the recommendation after
deliberation of all these issues really to the
sponsor was that this should be an active
comparator design and that the disadvantages or
cons of this design really are manageable compared
to those both practical and ethical that would
relate to a placebo-controlled trial.
Given the recommendation for an active
comparator design, what should be the comparator?
It was really essentially unanimous agreement that
that comparator drug should be indomethacin, 50
mg/3 times a day. This was an FDA-approved drug
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for the treatment of acute gout. It really is a
clinical gold standard widely used in practice and
historically, the first and longest used drug.
This is actually supported by the IMS
database in which, in the United States, Indocin is
the most widely prescribed drug for the treatment
of acute gout. You may recall from the review of
the active comparator-controlled trials, this was
the most common drug used in prior studies.
Now, moving to the issue of clinical
endpoints. Certainly, endpoints should address key
characteristics of the disease and should, to some
extent, reflect the global assessment of response
to therapy.
We certainly are in agreement with the
point advocated earlier that by far and away, pain
is the primary manifestation of this disease,
should be the primary endpoint, not only in terms
of ease of assessment, but importance to patients.
Secondary endpoints could be numerous, but
to the extent that this an inflammatory condition
and we are really looking for a response to
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inflammation, secondary importance, such as joint
tenderness, joint swelling, global assessments to
therapy or symptoms by both patients and
investigators would be appropriate.
Now, also, in terms of the issue of
inflammation, the cardinal signs of inflammation.
We consider the issue of erythema, and really judge
that this should probably be an exploratory
endpoint in this trial because of concern about the
difficulty of objectively assessing erythema in a
given patient, especially given that patients were
likely to have a variety of skin colors and may
make it difficult to assess erythema in a
comparative manner.
What about patient selection, should
patients have a minimum degree of pain before
entering the study?
Well, there is certainly concern that
patients who have mild pain may resolve more
quickly than what we saw in the two trials in which
patients were enrolled with moderate to very severe
pain. It very likely would be the case that some
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minimum degree of pain would be required in order
to demonstrate a measurable response.
So, the recommendation was that patients
who are enrolled in the study should have at least
moderate, severe, or extreme pain at baseline
enrollment.
Now, the important issue about the timing,
should a maximum amount of time since the onset of
the patient's symptoms be mandated in the study?
Really, here, the issue is the need to balance the
time required to seek medical attention versus the
time where we might see spontaneous resolution.
I showed you the prior studies that I
think define some of those parameters, and I think
they are well within our own clinical experience,
and the recommendation was specifically to require
enrollment within two days, 48 hours of the onset
of an attack.
What about the issue of self-medication?
Obviously, nonsteroidals are widely available.
Most patients have had attacks before, they know
what to use, they have it available, but there was
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very strong concern that prior treatment in an
acute setting would confound the analysis. So, the
recommendation was that no prior use of
nonsteroidals or corticosteroids would be allowed
for patients to be enrolled for their current
attack.
Now, in terms of the issue that was raised
from some of the questions, what about chronic
therapy? Really, the feeling was I think as
alluded to, that if a patient was on chronic
prophylactic or suppressive therapy and doing well,
now had a recent change in their medication, that
might be the cause of the current attack or might
prolong their current attack, that that would be
okay.
The recommendation was that if patients
were on stable allopurinol or colchicine, that they
actually could be enrolled for an acute attack.
Now, in terms of timing of the
assessments, certainly it is important in terms of
the time that you measure the response, that that
should be integrated over a clinically meaningful
114
time period. Certainly, in a disease like gout
where we know eventually, the attack will resolve,
that needs to be within a time period where we will
not be seeing spontaneous resolution.
In addition, given that this is such a
common disease and people are treating it
regularly, it would be important to look at the
assessment over a clinically meaningful or
practical time period that most people are
expecting a response.
Now, going back to the other end, the
outside of treatment or assessment period, but what
about the short end, what about measuring over a
very short time period?
Well, if we had limited data in terms of
the overall duration of an attack, there are even
less data to guide us in short-term measurements.
There are really very little data talking
about acute response to analgesics or nonsteroidals
in acute gout, but there certainly was at least
theoretical concern that for this highly
inflammatory condition, the onset of the effect of
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therapy might take longer than you would normally
see in an acute pain model because of the
inflammatory response, and not too much data to
guide us in predicting for a given nonsteroidal
when that response would occur.
So, the recommendations in terms of timing
were as follows: that the primary time period for
assessment would be over Study Days 2 to 5, and as
I have mentioned, the feeling was that this would
be within a time period where we would not expect
to see spontaneous resolution.
In addition, a secondary time period would
be used over Study Days 2 to 8 to capture that
period which is typical for patients being treated
for gout today in the clinic.
In terms of the short end or the front end
of therapy, the recommendation was to collect data
on pain assessment at a 4-hour time point after the
initial dose of Day 1 of enrollment.
So, given this clinical background and
those study design parameters, I want to just
briefly discuss the issues of statistical analysis
116
in a study like this.
One can imagine at least theoretically two
broad approaches to measuring assay sensitivity.
One, we might call a clinical approach or a
qualitative approach. The other would be a
quantitative approach.
I think if I could state in words the
qualitative approach, it would be really that if
the observed response is consistent with clinical
expectations, then, in a comparator design, the
effect would be attributed to the treatment.
Now, this qualitative or clinical approach
really requires a number of things to be in place.
One is to have a comparator drug that is reliable
and effective. That certainly is the case with
indomethacin, the clinical gold standard for
treatment as we discussed, and really, I think
indomethacin has a particular response.
I think that you will see, as you see the
presentation of data from this study, in fact, this
was borne out in the study, in fact, did have a
very predictive response.
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In addition, for this clinical comparison,
it would be important to be confident that gout
attacks would not resolve spontaneously over the
study period, and as I have shown you, we would
predict that that would not occur over the five
days of the study, especially if patients were
starting out with moderate to severe disease.
Finally, this would require that a placebo
effect be small, and as we have seen from the
placebo-controlled trial, there is a small placebo
effect in this disease.
On the other hand, a quantitative approach
would have a number of other requirements.
Unfortunately, we have about as little information
to guide us in this area, as well.
A quantitative approach would really
require that a boundary be established for response
to the gold standard drug, indomethacin, and that
would be the level of response at which
indomethacin would have to exceed.
One needs for this sufficient data from
the literature to determine the magnitude of
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indomethacin's effect. Unfortunately, that data is
very minimal, and we will see that in the next
presentation.
But, in fact, there really is no precedent
in the literature for establishing the minimal
effect size for indomethacin or any other
nonsteroidal.
So, because of these limitations, the
clinical experience, the nature of the disease, the
recommendations were that the clinical approach
would be acceptable in an assay, a study design of
this sort, but that a quantitative approach would
be included as supportive information to the extent
that it was supported in the literature and could
be measured in the clinical study.
Once the gold standard or active drug is
chosen and presumably an assay sensitivity could be
ascribed, the other important point then, and
requirement, would be that some boundary of
difference between the active comparator and the
study drug be established.
This would really be the boundaries for
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the difference between indomethacin and the study
drug within which those drugs must fall.
This, we felt really needed to be based on
not only extrapolation from other conditions or
information in the literature, but really based on
something that would be clinically relevant and
clinical judgment.
The recommendation here was that the
boundary for effect size of the two drugs be
established at 0.5 on a zero to 4-point scale.
This 0.5 threshold is somewhat more stringent than
the Delphi consensus, which has been established
for osteoarthritis, which is 0.7 on a zero to
4-point Likert scale.
I think it is also consistent with
clinical judgment about what is a clinically
relevant or important degree or pain relief, and
also a level that has been used in other clinical
trials, for example, osteoarthritis.
Finally, then, this is just a graphical
representation of what I am talking about in terms
of comparability.
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This just shows the mean difference over
Days 2 to 5 when we would just theoretically
conceptualize between two drugs, and the
requirement here would be that the mean difference,
as well as the 95 percent confidence intervals for
study drug compared to active comparator, would
have to be within the comparability bounds of 0.5.
So, I am going to conclude there with that
consideration of general study issues that pertain
to acute gout and those that we considered in this
talk.
I will just actually summarize here for
you, really, that because of our paucity of data,
this is a formidable challenge, and we really based
our design on information that was available, and
really to emphasize as we move forward and look at
the study specifically, to emphasize the key study
issues that we considered.
The issue of active versus placebo
controlled, the challenge that the comparator
control would be manageable while those of a
placebo control would not be approachable in a
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clinical study.
Issues of endpoint, that is, the need to
choose those that are relevant to the disease, and
finally, the timing of assessments, the need to
choose a period least likely to be affected by
spontaneous resolution.
I am now going to turn the podium back
over to Dr. Melian, who will present to you the
specific experience in these studies of etoricoxib
compared to indomethacin.
Experience of Etoricoxib and Indomethacin
in Acute Gouty Arthritis
DR. MELIAN: Thank you, David.
Now that Dr. Daikh has reviewed key issues
that went into the design of the etoricoxib versus
indomethacin studies, etoricoxib being the COX-2
inhibitor that was studied in the Merck studies, I
am next going to go over the study results.
As shown in this next slide, is a
schematic of the study design. The recommendations
of our rheumatology experts were followed in the
design of this study. The study had an active
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comparator design. Patients who met eligibility
criteria were randomized on a 1 to 1 ratio to
receive either etoricoxib 120 mg/once daily or
indomethacin 50 mg/3 times a day.
For the purposes of this study, the first
day of study treatment, which was also the day of
randomization, was defined as Day 1.
Day 1, by definition, had to occur within
48 hours of the onset of the attack, because this
was one of our inclusion criteria, so patients had
up to 48 hours, if they met inclusion criteria,
they were then randomized to one of these two study
treatment groups.
A study timeline showing day of study and
day relative to the onset of attack is shown on the
bottom of this slide.
The primary efficacy hypothesis of these
studies was that etoricoxib 100 mg/once daily would
demonstrate clinical efficacy comparable to
indomethacin 50 mg/3 times a day as assessed by the
patient's assessment of pain over a 4-day period,
Days 2 through 5.
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A secondary hypothesis was comparability
to indomethacin, the patient's assessment of pain
over Days 2 through 8.
The primary and key secondary endpoints
are shown here. The primary endpoint was the
patient's assessment of pain. The primary endpoint
was recorded on a zero to 4-point Likert scale
where zero reflected none or no pain, and 4
reflected extreme pain.
The primary assessment period was Days 2
through 5. The secondary assessment period was
Days 2 through 8, and there was additional
assessment period on Day 1, 4 hours after the
initial dose of the study medication.
Key secondary endpoints included the
patient's global assessment of response to therapy,
and assessment of study joint tenderness.
Additional endpoints included the
investigator's assessment of study joint swelling,
the proportion of patients discontinuing due to
lack of efficacy, and the exploratory endpoint,
proportion of patients exhibiting joint erythema.
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As noted, the latter was designated as
exploratory in this study over concerns that it
might be difficult to detect study joint erythema
in patients with distinct skin colorations. In
fact, as you will see later in this presentation,
that concern turned out to be unwarranted, and, in
fact, erythema was detectable in the majority of
patients.
The timing of the assessments during the
study period are shown here. Patients, for the
primary endpoint, were assessed at baseline, then
again at 4 hours after initial dosing, and then
once daily over a 7-day treatment period.
For the secondary and exploratory
endpoints, patients were assessed on Days 2, 5, and
8. All patients had baseline measurements except
for the patient's and investigator's global
assessments of response to therapy since, by
definition, patients needed to be on therapy in
order to answer this question.
The basic selection criteria are shown in
this slide here. All patients had to be randomized
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within 48 hours of the onset of their attack of
acute gouty arthritis. All patients had to have a
clinical diagnosis of gout as defined by the
Wallace criteria or the ARA criteria, which we have
heard about previously.
All patients also had to have moderate,
severe, or extreme pain at baseline.
Patients who took a COXIB, an NSAID, or
corticosteroid before coming into the trial were
excluded from randomization.
Patients who were on baseline preventive
gout medications, such as colchicine or
allopurinol, were allowed to come into the study as
long as the dose of this therapy had been stable
before they came to the study, and was not
anticipated to change during the time of the study.
Basic enrollment characteristics are shown
in this slide here. The first study enrolled 150
patients, and the second, 189. These are, to the
best of our knowledge, the largest gout studies
that have ever been performed.
In order to enroll this number of
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patients, it was actually a formidable task. We
used over 40 sites for each of these studies, and
over 10 countries.
The main reason, in discussion with
investigators, that we had difficulty recruiting
patients was, in fact, that most patients
self-medicate before they ever came into the
clinic.
Baseline characteristics and demographics
for the study are shown here. Patients who entered
the study were typical of those with acute gouty
arthritis. The mean age of entry was approximately
50. The majority of patients were men, and
patients were of diverse racial and ethnic
backgrounds.
As is typical for patients with acute
gouty arthritis, the majority of patients had
monoarticular disease. The most common site of
arthritis in these studies was the first toe, first
MTP.
Approximately 28 to 29 percent of patients
in this study had polyarticular disease, suggesting
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a slight bias towards patients with severe
symptomatology. Consistent with this hypothesis,
what we saw was that the majority of patients had
severe or extreme disease.
If we looked at the average time from the
onset of attack to when they entered the study, on
average, patients came in within one day of the
onset of their attack.
This time to onset of attack to when they
were enrolled in the study presumably reflects the
time required for the gout flare to flare
significantly enough that patients go to see their
physician, and also the logistics involved with
actually getting in to see one's physician or care
provider.
In the following slide are shown patient
disposition. The majority of patients who enrolled
in these studies continued to finish study period.
There were slightly more discontinuations due both
to lack of efficacy and due to adverse experiences
on indomethacin compared to etoricoxib, but, in
general, in both groups, the number of patients
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discontinuing was low.
Shown next is the treatment effects for
the primary endpoint, the patient assessment of
pain. What we can see here in blue is the response
amongst patients treated with indomethacin. Along
the y axis is change from baseline, and along the x
axis is mean days since the onset of their attack
of acute gouty arthritis.
What you can see here for indomethacin is
we see that most patients were, in fact, on
average, enrolled at the 24-hour period since the
onset of their attack, and we just what we expect
in terms of the treatment effect, a rapid and
marked treatment response seen within the first 24
to 48 hours.
Although one needs to be cautious when
comparing data across studies, it is helpful here
to compare what we saw in this study to the Bellamy
study, remembering again that the Bellamy study was
the observational study where patients were
followed over time in the absence of treatment.
What we saw in that study is that
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patients, on average, were enrolled approximately
three days after the onset of their attack, and for
the patient assessment of pain, they saw very
little to no response out to Day 5 since the onset
of their attack.
This is in marked contrast to what we saw
with indomethacin in terms of effect size in this
study. If we next look out over the subsequent
four days, what we see is small treatment effects
in the indomethacin group and small improvements
also in the observational study. However, the
relative magnitude of these effects compared to
that seen early on with treatment with indomethacin
was small.
Next, shown in yellow, is the response for
the primary endpoint for etoricoxib. What we can
see here is a very familiar pattern where the
response for etoricoxib over Days 2 to 5, the
primary assessment period of this study, Days 2
through 8, the secondary assessment period, and
also on Day 1, four hours after initial dosing, was
practically indistinguishable from that seen with
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indomethacin. This is for the first of our two
replicate studies.
If we next move on to the second of the
two replicate studies, shown here on the right, we
can see a very familiar pattern, once again looking
almost indistinguishable from that seen in the
initial study.
What this suggests to us is that gout
actually in appropriately designed trials is a
highly reproducible model and that with effective
inhibition of cyclooxygenase, either nonselectively
with indomethacin, or highly selectively with
etoricoxib, you can see these marked improvements.
So, now, let's next move on to secondary
and exploratory endpoints. If the scout study
design is truly robust, what we would expect to see
is similar effects across multiple endpoints, and
that is, in fact, exactly what we can see.
What we are looking at here is results for
joint tenderness and joint swelling. On the next
slide, we will see patient and investigator global
assessments, and we will see essentially the exact
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same response that we saw with the primary
endpoint, with a marked response occurring early on
during treatment and maintained throughout the
treatment period.
We see this again, tenderness and
swelling, and on the next slide, we are looking at
patient and investigator global assessments. For
the patient and investigator global assessments,
these are shown in a slightly different format
because there was no baseline measurement for this
endpoint.
So, what you are looking at here actually
is the percent of patients that had a good to
excellent response from either the patient's
perspective for the patient global assessment of
response to therapy, or the investigator's
perspective for the investigator global assessment
of response to therapy.
You can see that in each case, that by Day
2, the majority of patients from either the
patient's or the investigator's perspective had a
marked improvement in terms of response to therapy,
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and that these improvements are maintained through
the 8-day treatment period.
Lastly, moving on to the more objective
measurement of study joint erythema, the results
are shown here. What we can see here in these two
replicate studies is that the majority of patients
in both studies, over 90 percent had erythema at
baseline.
Thus, our concerns that this endpoint
might not be as easily detectable as some of the
others, in fact, in appropriately selected
patients, as we saw here, it turned out to be
unwarranted, and although I am not showing you, we
did subgroup analysis broken down by race, and what
we saw there is that in each racial subgroup,
approximately 90 percent or better of the patients
had detectable erythema at baseline.
Then, let's look at the response over time
where we can see here once again that same pattern,
by Day 2, 50 percent of the patient approximately
had complete resolution of their study joint
erythema, and by Day 5, only 10 to 20 percent of
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patients had any residual erythema detectable.
So, in summary, these results indicate
that both indomethacin and etoricoxib were highly
effective for the treatment of acute gouty
arthritis. We saw rapid treatment effects and we
saw improvements across multiple domains.
Now that we have reviewed the results of
this study, let's next review the methodology. In
order to have a successful study with an active
comparator, as Dr. Daikh went over for us, there
are two distinct criteria that need to be met.
The first is that the active comparator
needs to have been shown to have performed as
expected, and the second is that the test drugs
needs to have been shown to be comparable or
perform similarly to the active comparator.
In this study, indomethacin was chosen as
the active comparator control because it was
considered, based on clinical experience, to be
highly reliable and thus, the appropriate standard
for the treatment of gout.
So, based on the clinical approach, was
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indomethacin effective, so based on clinical
experience, was indomethacin effective in this
study?
The answer is yes, indomethacin performed
exactly as expected. There was a marked and rapid
treatment effect, it was seen across multiple
endpoints and multiple domains, and by Day 2, the
second day of dosing, the majority of patients had
a good to excellent response.
Moving next on from the clinical approach
to the analytical approach, how did indomethacin
perform compared to data generated in previous
clinical studies? In these analyses, the
analytical approach was considered secondary or
supplementary because it was complicated by a
number of factors.
First, was the relative paucity of data in
the clinical literature on which to base effect
size, and the second was the lack of any generally
accepted convention on how the minimal bound for
effect size should be calculated.
Despite these limitations, prespecified
135
criteria for the minimal bound for indomethacin
effect size were derived, such that at the end of
the day, there would be objective criteria to
ensure that the positive control had performed
well.
In order to do these analyses, the effect
size bound was derived from the only study in the
literature, a study of ketoprofen versus
indomethacin, which provided serial data on pain,
on the serial data, on the effect size, and
variability obtained over the appropriate time
period.
Because this study collected data on a
3-point Likert scale, and ours was a on 4-point
Likert scale, this data was rescaled to a zero- to
4-point Likert scale.
We then extrapolated recommendations from
previous FDA guidance on rheumatoid arthritis,
which suggested that in studies lacking placebo, a
test drug should maintain at least 60 percent of
the active comparator effect size, and applied this
general rule to the ketoprofen study, and arrived
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at a minimal effect size of negative 1.46 Likert
units.
We prespecified for our studies that both
the point estimate and the 95 percent confidence
interval for that point estimate for indomethacin
needed to surpass this 1.46 Likert unit bound.
Although these analyses required
substantial extrapolations, they did at least
provide some objective criteria to support the
subjective clinical assessment of efficacy provided
in these studies.
Shown here now are the results for
indomethacin compared to the 1.46 Likert unit
bound. Shown on the left are the results of the
first study 040, and on the right, the second study
049.
What we can see in both cases, both the
point estimate and the 95 percent confidence
interval for that point estimate surpassed or
passed the minimal effect size calculated from the
previous study.
That is whether you are using the
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quantitative approach shown here or the qualitative
approach which we reviewed in terms of looking at
the overall data from the studies and saying did
indomethacin perform as expected based on our
clinical experience and our clinical
interpretation.
The answer is the same, is yes, the active
comparator worked in these studies.
Now, once you have established that the
active comparator worked, the next question is did
your test drug work comparably or similar to your
active comparator, in this case being indomethacin.
In order to establish this, we followed
the recommendations of our experts and used the
comparability bounds of 0.5 Likert units. Once
again, the 0.5 Likert units was chosen because it
was smaller than the 0.7 Likert units suggested in
the Delphi experiment to be a clinically meaningful
difference, and it is also consistent with half the
distance between adjacent points on a Likert scale,
suggesting that if two values fell within this
difference, on average, they would score the same
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on the Likert scale.
Results here are displayed as difference
between means for etoricoxib versus indomethacin.
What we can see here is the point estimate in both
of these studies, whether we looked either over the
primary assessment period, 2 through 5 days, or 2
through 8 days, fell very close to the equivalence
mark here shown by the solid line, and
approximately 0.1 Likert units, and we see that
both the point estimates and the 95 percent
confidence intervals fall well within the 0.5
Likert unit boundaries shown by the dotted line
above and below in these grafts.
So, in summary, I think the data that is
generated in these studies actually demonstrates
that the acute study design used in them is robust.
Indomethacin performed reliably and as expected in
the studies, and the endpoints are highly
reproducible between studies, and results were
consistent across endpoints.
In replicate studies, etoricoxib and
indomethacin performed comparably based upon
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predefined criteria, and putting all of this
together, what it suggests is that meaningful
results can be obtained in the absence of placebo.
With that, what I would like to do is now
turn the podium back over the Dr. Daikh for a
discussion of lessons learned.
Lessons Learned
DR. DAIKH: So, you have had a review of
the issue of acute gout and we have talked about
some of the general and theoretical concerns of
study design, and now a review of the results from
these two studies.
Let me just leave a couple comments in
terms of what we did learn from the study and
perhaps provide a preview of a discussion in terms
of what we may talk about in the future.
Certainly, a major lesson, a major
conclusion from these studies was that recruitment
was very difficult. We had predicted that the
difficulty with a placebo-controlled trial would be
insurmountable from a practical standpoint, but, in
fact, even with an active comparator-controlled
140
trial, recruitment was very difficult.
I think as Dr. Melian planned out, this
required a number of centers around the world, and
I can speak from personal experience, I was
actually quite surprised. I was anticipating in a
VA setting that we would have a lot of ease in
getting patients.
I certainly agree with the point that we,
as rheumatologists, are seeing a minority of
patients, but I had very close working
relationships with the docs in the ER, with the
clinic docs, and obviously, in setting up the
study, there was a plan to have direct
communication, and even with all those efforts, it
was very difficult.
Patients were just taking medications
before they came in.
What about potential considerations
looking forward to future studies? Well, in
retrospect, looking at the reproducibility of the
data even in a very short time period, it seems
that it may be interesting and informative to
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collect additional data pertaining to the onset of
clinical signs and symptoms in acute gout. It may
be beneficial to look at earlier times.
I think it would be reasonable to explore
the use of pain measurements over perhaps multiple
parameters and early time points, perhaps even
considering the use of stop watches as has been
done in some acute pain models.
It is also very reasonable to explore the
use of alternative pain scales, perhaps to enhance
precision in other than the zero- to 4-point Likert
scale used in this study.
As you are all very familiar, a number of
different measures and instruments could be used,
whether they be a visual analogue or a broader
numerical scale.
I think it also, looking forward, would be
very useful to consider the inclusion of a
functional outcome measure in a disease like acute
gout, that would have a meaning both in terms of
patient outcomes and also the ability to assess
efficacy of a drug.
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So, with that, I am going to pause, and
that is the sum of our presentation in terms of
experience in the study of acute gout.
I appreciate the attention.
DR. GIBOFSKY: Thank you, gentleman.
At this point, what is the Committee's
pleasure, we are scheduled for a break, or we can
begin our discussion of this paper and then take a
break?
Discussion followed by a break seems to be
the consensus of the Committee.
Dr. Anderson, you have the first question.
Discussion
DR. ANDERSON: Those studies were very
nicely presented and very clearly presented. I
just have a couple of short questions.
I was wondering why you used the Likert
scale even though you would expect that VAS might
offer more precision, and what you had investigated
about that before deciding on the Likert.
The other question is about the use of
least squares means, which are in all of those
143
plots, and it wasn't described what you adjusted
for, and it sort of raises the issue of why that
was necessary and whether there were rather
different results for some subgroups of patients.
DR. DAIKH: I will just respond in
general. I think it is a very good point that
there are a number of scales that could be used,
and that is what I was trying to get at with the
summary slide, to open up the discussion.
We certainly did discuss the possibility
of using a visual analogue, for example, but I will
let Dr. Melian address this, as well, really
relating to the broad experience of the sponsor in
other pain models with this scale.
DR. MELIAN: We had used Likert scales in
a number of other pain models, and it seemed to
make sense for us to bring that forward. Also, in
sort of reviewing the literature, one of the main
studies we were looking back to was the Bellamy
study, and in that Bellamy study, they also used
the similar Likert scale for pain, so it at least
gave us a good anchor to use.
144
We know that in some studies, VAS's are
used, in other studies Likerts are used, and they
generally tend to correlate fairly well. Would it
have been wrong to use a VAS scale, probably not,
and it might be interesting for future studies to
actually VAS and Likert scales together an see how
well they correlate in acute gouty arthritis.
DR. GIBOFSKY: The second question before
we get to Dr. Hochberg, there was a question from
Dr. Anderson about least squares.
DR. MELIAN: I am actually going to bring
up Jim Bolognese, who was the statistician on this
study. Jim, if you could address the question on
least squares.
DR. BOLOGNESE: The study was stratified
by poly or monoarticular involvement, so that was a
factor in the model, and also baseline pain was a
factor in the model, so the results are adjusted
for those two factors in the analysis of variance
model.
DR. ANDERSON: But were there rather
different results?
145
DR. BOLOGNESE: No, the results were very
consistent across those two endpoints.
Interactions were not close to being significant.
DR. MELIAN: But this actually does bring
up a question or an issue that was raised earlier
amongst the panel with Dr. Cush's presentation,
which is polyarticular versus monoarticular.
Obviously, what we did in our study was we
enrolled both patient subtypes because, if not, we
really wouldn't have any data on the polyarticular
disease. What we saw was, in fact, there were
similar results between the two active treatment
groups in both groups.
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: Thank you, Dr. Gibofsky. I
am only going to ask--I have several questions, but
I am only going to ask one, and the one I am going
to ask deals with something which was brought up
during Dr. Cush's presentation, and the subsequent
discussion.
You enrolled patients within one day, so
patients came in, they were evaluated, and they
146
were randomized on the same day. So, what did you
do in terms of the screening of those subjects at
the time that they came in given the concerns that
were raised in the presentation that you might end
up enrolling people who had renal insufficiency,
other laboratory abnormalities that might be
relative contraindications to NSAID use?
DR. DAIKH: I will take that. Obviously,
very important considerations, and once again,
another way in which there was a need to balance
the practical considerations of enrollment with the
clinical concerns of the patients.
So, what we did specifically in the study,
in anticipation that the decision would need to be
made at the time of enroll and treat, or not enroll
and treat, for patients who had uncontrolled
hypertension, 165 and above, 95 and above, they
were excluded.
From the standpoint of renal function, we
issued guidelines to investigators that history of
significant renal insufficiency would be a
contraindication, and that was defined as greater
147
than 2 or a clearance of 30 or less.
Now, in terms of laboratory testing, that,
of course, the ease of that varies by study site,
if it was in a clinic versus a hospital setting,
but if there had been no laboratory testing within
the prior year that would guide the physician in
terms of their ability to conclude there was
significant renal involvement, mild dysplasia, et
cetera, then, it was required that they obtain
laboratory testing with results of CBC, creatinine
before enrollment.
If there were values available for the
preceding year that were reassuring, then, they
could be enrolled.
DR. MELIAN: Obviously, this is one of the
challenges with recruitment, and we worked very
closely with sites to try to make sure that, where
possible, they could turn over labs as quickly as
possible.
I think Dr. Cush said one hour. Our
experience is that most places can't get labs back
in one hour, but some places can, so this is where
148
we really had the interaction with the site, worked
closely with them, to try to get labs back as
quickly as possible, and in terms of those patients
we couldn't get labs back in time, we followed the
recommendations as Dr. Daikh has described.
DR. GIBOFSKY: Thank you, Dr. Hochberg. I
have put your name back on the queue for follow-up
questions later.
Dr. Weisman.
DR. WEISMAN: You mentioned that there
were difficulties in recruitment in spite of the
fact that you chose this study design.
What were those difficulties and how do
you relate them to the kinds of issues that Dr.
Cush brought up earlier about theoretical
difficulties in recruitment, what were the
practical difficulties and did they match what Dr.
Cush had mentioned earlier?
DR. MELIAN: I will let David give you
firsthand experience with that, and then I can give
you some of the secondary feedback we got from the
investigators.
149
DR. DAIKH: In my experience, I think they
matched very well with the concerns that Dr. Cush
raised. Even in a setting where rheumatologists
are actually involved in teaching other primary
care physicians and interacting with them, a lot of
these patients came to us from clinics and the
ambulatory walk-in ER.
So, sometimes there were issues of prompt
recognition of acute gout and sort of making the
call quickly to us, but by far and away, in my
experience, the difficulty was pretreatment.
Patients had come in having already taken an NSAID,
or having been given an NSAID by a doc in the box
before they came to our study site.
The other extreme, and I think it actually
probably pertains somewhat more to a VA site, the
other extreme we would see occasionally would be
the patient that actually had been holding out for
36 hours or longer before coming in, so by the time
they came in were evaluated as beyond the two days.
DR. WEISMAN: They spent a couple of days
in the emergency room?
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[Laughter.]
DR. DAIKH: No comment.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: Going back to the
polyarticular patients, for the physical exam
components, I was wondering if you could tell us
how you analyzed those data. Did you develop a
single chain score for swelling and tenderness and
erythema, which was an average of all the joints?
Secondly, how did you identify the
involved joints, was it patient report, or was it
based on tenderness on the exam?
DR. MELIAN: The involved joints were
essentially dependent upon whether the patient
reported symptoms, and it was confirmed by the
investigator that was present.
In terms of the actual scale used, it was
on a Likert scale, and if I could have that scale
pulled up for the swelling, I will show you
exactly--
DR. BATHON: One of the problems of
swelling in gout is you can have a single joint
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involved and have, as you know, really widespread
swelling with pitting edema, so it can sort of
obscure really uninvolved joints.
DR. MELIAN: Right.
DR. DAIKH: The guidelines were
specifically focusing on an index joint and
measuring swelling of the joint itself. For those
patients who had oligoarticular attack, then, the
guideline was to pick the most severely involved
joint, the most painful reported joint or most
tender joint, and then from time of enrollment on
down, that would be the single index joint that was
assessed.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: Two things. One, was this a VA
study, or were there other sites other than VA?
DR. MELIAN: We used VA sites, but we did
not explicitly use VA sites. In fact, each study
was performed in over 40 sites and over 10
countries each. So, we really scanned the world to
get appropriate patients.
DR. CUSH: I am confused by some of the
152
fuzzy math that you presented. What I am confused
by is you used Bellamy's paper and said that there
was two days of symptoms, and you added that on to
what they reported to give us some graph.
Firstoff, that was a mean of 2.8 days, and
it ranged from 1 to 5 and you don't know.
DR. MELIAN: That's correct.
DR. CUSH: You shouldn't be doing that.
You can only report what you know, and everything
else is extrapolation. Even in your own studies,
you have patient report of what happened, and I
think it is misleading.
I mean it is useful information to put in
the paper, but then to plot out and hazard a
separate x axis just confuses matters because then
later on in your presentation, you are telling us
you did things on Days 2, 3, 5. I am not sure
which days 2, 3, and 5 you are talking about.
So, is it the Patient Day 2, 3, 5, or is
it the chronological study day? I actually know,
but I am saying the ladder along the bottom needs
to be gone. It sort of obscures what is true and
153
what you can hang your hat on.
DR. MELIAN: Obviously, if you go the
paper, what we are showing is the study day. What
we did here, because the purpose of this meeting is
to discuss what is the natural course of acute
gouty arthritis, and the best we could do was try
to take an average of the data out there to try to
see what it would look like, and since, on average,
those patients came in 2.8 days after the onset of
attack, we used that.
We can show you the data the other way.
We have it the other way.
DR. CUSH: Again, it just obscures, I mean
you can have a limitation to duration of symptoms
at entry, and that is information. It is the same
for other trials, other diseases, but then when you
are reporting responses, you can't include that in
your time to response, because you really don't
know, and everybody's is different.
DR. DAIKH: I think that is absolutely an
appropriate point, that the 2.8 days are an
average. So, in fact, the data should be made more
154
fuzzy, that is, any defining line should have a
spread around it.
I think the point that I was trying to get
at in terms of general considerations in study
design, I think that it is very important to pick a
time within which you have got to look at the
patient, and I don't think it is necessarily
exactly in the 2- to 5-day period because of the
uncertainty in the Bellamy paper and the absence of
other papers, but I don't think it's 3 days either.
DR. GIBOFSKY: Dr. Geis.
DR. GEIS: On the Bellamy data, though, I
wouldn't suggest that it really reflects what a
placebo response would be.
DR. MELIAN: No, the only data we have on
placebo comes from the Ahearn data, which was the
colchicine comparator study, which Dr. Daikh
presented.
DR. GEIS: Because in my experience, when
you give a placebo in acute pain setting, you can
get an enormous response, it looks like an
effective drug, especially in the first few hours.
155
So, my question then is what was your
4-hour data? I know you referred to it, but I
don't see it here. Did you ever blow it up?
DR. MELIAN: If we can put up the slide
from the presentation, what you can see is that at
4 hours, there is actually pretty marked data,
pretty marked response in both treatment groups.
So, from the presentation, that is Slide No. 17.
We are looking at indomethacin, but etoricoxib
performed similarly.
At 4 hours, you see a response of
approximately 1 Likert unit, and then you see a
continued response over time. The largest response
occurs over the initial 24 to 48 hours.
DR. GEIS: Thank you.
DR. MELIAN: I think one of the things you
do see in the Ahearn paper, though, which is
consistent with what is discussed in the critical
literature, they are not always shown, is that the
placebo response there is relatively low, and I
think one of the things is when you have a disease
that is driven by inflammation, particularly fairly
156
potent inflammation, you probably get less of a
placebo response.
Do I have data to support that? Well, the
only data available is that from the Ahearn paper,
and that had a very little placebo response.
DR. GIBOFSKY: Thank you.
Dr. Cronstein.
DR. CRONSTEIN: Thank you. I had a
question about the way you presented the data,
which is the mean reduction in Likert score. I
guess the problem I am having is it looks like,
judging from starting with a mean score of about 3,
that none of these people got complete resolution
by 8 days. Is that correct?
DR. MELIAN: That is actually not correct.
We actually have some data showing the degree of
patients who had resolution. Well, I showed you
the degree of resolution for erythema, you
remember, by Day 2, approximately, 50 percent of
the patients had resolution of erythema by Day 5,
80 to 90 percent, and we also have data on percent
of patients who had complete resolution or had mild
157
to no pain.
Actually, it's very interesting. The
results are practically superimposable. Whether
you look at erythema or you look at percent of
patients who had mild to no pain, you get these bar
graphs that you could almost lay right on top of
each other, suggesting that overall, these endpoint
correlated extremely well.
The same thing is seen with tenderness,
same thing is seen with swelling. I think what it
is telling us is this really a disease that is
driven by inflammation.
So, even though NSAIDs and COX-2
inhibitors have an analgesic effect, that when you
look at the overall picture and you are looking at
improvement, what you are seeing is all the
endpoints corresponding sort of in the same pattern
or in line with each other, and I think what that
means is, well, yes, now you are starting to treat
the inflammation, and you are seeing the effect,
and the effect is across the board.
DR. CRONSTEIN: So, out of curiosity, who
158
are those people who didn't respond, that didn't
have complete resolution? You show about 20
percent of them still didn't. Were they the
polyarticular or the more severe, or did you break
it down that way?
DR. MELIAN: Well, if you would look over
time, the response in the polyarticular to the
monoarticular is very similar, but the
monoarticular has just a very smidgen is probably
not--I mean I know it is not statistically
significant, but the monoarticular has a very small
increase in response compared to the polyarticular.
What is really interesting is the
precision of the data, though, because if one looks
at the treatment groups for the monoarticular, they
respond almost exactly the same.
You saw how small the variability was in
the study, and when you look at the two after
treatment groups, the responses are almost exactly
the same, and then you see the slight bump-up, or
bump-up meaning slightly less response even though
not statistically significantly different in the
159
polyarticular group with the very tight confidence
intervals, it says there is probably a slight
difference here with polyarticular taking a little
bit longer to improve.
DR. GIBOFSKY: Gentlemen, please use the
microphone, or you will be asked to make a
significant contribution to the Chair's retirement
fund.
Dr. Harvey.
DR. HARVEY: Actually, I would just like
to say that the FDA is finding this discussion very
helpful, and if I could ask the Chair if we could
take a break now and then actually continue the
discussion after a short break?
DR. GIBOFSKY: We have several other
people in queue, I think. We will continue the
discussion after the break, but I would like to
give the colleagues who have been queued up, an
opportunity.
Dr. Boulware.
DR. BOULWARE: My question has to do with
the inclusion/exclusion criteria you used and
160
specifically colchicine. You, I think
appropriately, excluded people who may have
self-medicated themselves with COXIBs and NSAIDs
and steroids, but you didn't mention colchicine.
Was that inquired and was that prevalent,
and why did you not include that, too?
DR. MELIAN: Well, what we did was if a
patient was on stable base like colchicine for
preventive use, we allowed those patients into the
study, because those patients were flaring on top
of their colchicine.
They couldn't have changed their dose,
though, so of the patient was on colchicine, they
had a flare, and they said, oh, well, now I am
going to take 2 tablets instead of 1, that patient
was excluded.
Also, they weren't allowed to change their
dose during the study period, so they had to stay
on consistent or constant dosing throughout the
study period. What we were trying to do here was
really look at these drugs the way they would be
used in real life, and that is the way you
161
typically used drugs, or at least NSAIDs or
indomethacin in acute gouty arthritis.
DR. BOULWARE: But there are occasional
patients who keep their colchicine at home, and
they will start and self-initiate the treatment, so
I guess you excluded them because their baseline
was zero.
DR. MELIAN: If they started the
colchicine anytime within the previous--it was 2 to
4 weeks, I would have to check exactly--4 weeks,
sorry, 4 weeks, they weren't allowed into the
study.
DR. GIBOFSKY: There are two colleagues in
queue who we will continue now, and then we will
take our break.
Dr. Hochberg with a follow-up question?
DR. HOCHBERG: If I can follow up on
something which Dr. Cronstein started. The average
pain when patients began in the study was severe on
the 5-point Likert scale, and the average at the
end of the study was mild, and we know that there
are about 20 percent who don't respond with regard
162
to the good or excellent improvement on the global
assessment of response.
So, the first question is should one look
at what is really important to the patient is not
that they still have mild pain, is that the pain is
gone, resolution of pain as the outcome variable,
and the second, which that might happen, but you
don't see it often in a 7-day study, so should the
study, in fact, be longer than 7 days, and maybe
you can tell us what happened to these patients
after 7 days.
DR. DAIKH: I agree with you in general,
but again this is a balancing of a clinically
meaningful time period. Maybe 9 days would be
better if you get to complete resolution in 95
percent of those patients, but then you have to
start worrying about the spontaneous resolution
period.
Now, whether or not there should be an
outcome that would be setting a threshold for a
clinically meaningful degree of pain relief, that
is I think a very reasonable point and worth
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discussing.
In terms of whether or not the patient
really--I mean obviously they would prefer to have
no pain than mild pain--but I think mild pain
compared to placebo would be clinically meaningful
at 7 days, for example.
DR. GIBOFSKY: Dr. Hoffman.
DR. HOFFMAN: I think that the diligence
with which this study was designed and carried out
makes contributions beyond just setting a new
standard for rigor in trials with pharmaceutical
agents.
One of the things that I am wondering
about in terms of your exploratory endpoint of
erythema is fortuitous, that you look at it as an
exploratory endpoint in part because of what a soft
measurement it is, but also it raises questions
about whether erythema always is part of
inflammation, because we know in a variety of other
situations, such as studies of wound repair, tissue
regeneration and repair from trauma, that is either
surgical or accidental, that we often see erythema
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persist for extended periods of time even in the
absence of inflammation.
So, I would compliment you on having
brought that issue to further light and discussion,
and I would take that as evidence for us not to
include erythema as an important endpoint in
looking at gout or perhaps other inflammatory
conditions where indeed it may not be such an
accurate marker of inflammation as opposed to
tissue repair.
DR. MELIAN: I think what we heard from
Dr. Cush, and obviously we took the same approach
in our study, was that the primary symptom that the
patient is most concerned about is pain. We did,
as I mentioned, looked at erythema because it was a
potential marker of inflammation.
We had the same kinds of concerns that you
have. There were approximately 10 to 20 percent
that by Day 5 hadn't cleared the erythema, and
maybe those are the kinds of patients that you are
discussing, but in the majority of patients, it did
correlate extremely well with the other endpoints,
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and even if it is not a primary endpoint in
studies, I think it provides additional valuable
information at least in the sense that if you could
see that it correlates in general, not necessarily
on a per-patient basis, I think that would add to
one's interpretation of the data.
DR. HOFFMAN: I was speaking more to the
fact that at Day 8, there was still, in the absence
of significant pain, perhaps no pain, that there
was still erythema, and certainly we have seen in
our patients, people who still have very modest
erythema that may be there for a week in the
absence of any pain whatsoever. We see it in
surgical wounds all the time.
DR. MELIAN: And I would concur with you,
and I think even in an extremely inflammatory joint
sometimes, because, if for no other reason, you
have this infiltration, perhaps it has to do with
wound healing, but the infiltration of inflammatory
cells, and then you have got a residual.
Sometimes that erythema at the end, at
least in my own personal experience, probably has
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to do more with the tissue destruction and the
leftover effects of that, and that is probably what
you are getting to with wound healing.
DR. HOFFMAN: I was thinking more of the
neovascularization that we see and when.
DR. MELIAN: I am just curious, the
neovascularization of the wound healing, how
quickly that occurs, so if it is an acute attack of
acute gouty arthritis--
DR. GIBOFSKY: Presumably, your hand is in
your pocket because you are reaching for your
wallet to make the contribution for not using the
microphone.
DR. MELIAN: I was just curious as to how
quickly that neovascularization occurs.
DR. HOFFMAN: I can only speak to
experiments done in college many years ago, where
we actually saw neovascularization in the process
of wound healing within a week. That is not a
literature I follow anymore.
DR. GIBOFSKY: Very quick question before
we break. You told us about 8 patients, 7 have an
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adverse event, 1 had a laboratory adverse event.
Can you give us a little bit more detail
on those 8 patients?
DR. MELIAN: I am happy to. I just want
to make sure, because it doesn't have to do so much
with study design. In terms of discontinuations
and adverse experiences in this study, the most
common adverse experiences were just those that one
would expect to see with NSAID treatment, and
particularly with indomethacin.
Dr. Cush actually showed in his slide our
data on safety, and what you saw was that the
safety features, the adverse experiences, the most
common body system involved was actually the
neurologic, and you saw the same sorts of CNS kind
of adverse experiences that one would expect with
indomethacin - dizziness, lightheadedness, these
kinds of vague neurologic findings. Headaches were
extremely common, and you saw a marked difference
between the indomethacin group and the etoricoxib
group.
Other body systems, GI was a fairly common
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one. Once again, with a selective inhibitor, you
saw less of that than you did with indomethacin,
but overall, the number of events was low.
DR. GIBOFSKY: Thank you.
At this point, we will take our break. We
will come back and resume if there is further
discussion on this paper. If not, I am told that
there are no individuals queued up for public
comment. So, if there is no further discussion on
this paper, when we come back into the regular
session, we will go right into the questions that
have been posed to us by the Agency.
A 15-minute break. Let's resume at 11:13.
[Break.]
DR. GIBOFSKY: You will all note that a
floor mike has been put in that corner of the room,
so that that will diminish the Chair's retirement
fund in the event that people have to respond from
other parts of the room.
We are going to resume the morning
session. I would like to continue if there are
further comments about the presentation this
169
morning, I would like to continue that discussion.
I was told that the Agency found our discussion
particularly useful and would like to see if there
are any further comments from any other members of
the panel or additional comments from the members
of the panel who spoke on the presentation this
morning.
Are there further comments or discussion
from other members of the panel? Dr. Cush.
DR. CUSH: I would like to make I guess a
pitch for Likert scale evaluations. My concern
about a 10-centimeter Visual Analogue Scale, while
it gives you the presumption of greater spread and
ability to pick up finer degrees of change, in
fact, I think that it doesn't, because most people
are afraid of doing the extreme unless there they
have an extreme response meaning they are totally
well and they will go to zero.
Most people avoid the first centimeter or
two on this end, they tend to bunch up in the
middle anyway, and most Visual Analogue Scales
don't have descriptors whereas, the Likert scale,
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you know, on this zero to 4 scale with the
descriptors, I think is much more objective and I
think shows degree of change, which we can really
hang our hats on.
Again, it is less sensitive to lesser
degrees of change, but lesser degrees of change are
not important in a disease of this magnitude. I
mean I think we are looking for acute gout control
where you are looking to hit a home run in every
situation.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: I think the data would
support that either scale is equally effective, and
either one can be used and show similar results.
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: Well, I guess I want to
come back to the issue of outcomes, and maybe Dr.
Anderson would want to comment. I don't know if
you want to do this now or do this later, but in
terms of whether we want to look at this as a pain
model and measure improvement in pain, the way it
was done in the data that were presented to us, or
171
whether we want to look at, you know, sort of
reaching a level of no pain or reaching a level of
mild pain, or a certain degree of improvement.
Thinking about what exists now is outcomes
in rheumatoid arthritis trials, for example, where
one can reach a state, for instance, using the DAS
of low disease activity, or one can have an ACR50
improvement, something like that, whether we should
I guess think about that as moving in that
direction maybe for discussion with the Agency with
regard to gout studies, and whether the data that
were collected during the studies that were
presented to us would be useful in terms or
exploratory analyses in that way.
DR. GIBOFSKY: I am certainly comfortable
in entertaining discussion on that now, and then we
can formalize our discussion when we begin the
consideration of Question 1, since that is the
first question.
Dr. Anderson, would you like to comment or
respond to Dr. Hochberg?
DR. ANDERSON: Yes, I like the concept of
172
a composite outcome, but I don't know, in an acute
condition like this, I think it could be difficult,
but there are two things that I would like to say
on this.
One, I was impressed with the comment that
Dr. Melian made about the pain response probably
being driven by the inflammation response, so that
this would seem not to be solely a pain situation,
but there are these other components. It would
seem desirable to work with more than just pain in
looking at outcomes for acute gout.
The other thing, following from what you
said about there now being some data that would be
useful for exploring whether composite outcomes
could be useful here, it may be able to distinguish
between agents that you can't distinguish between
when you use just pain or just inflammation or
just, you know, whatever.
It is very valuable to have some good data
now that somebody, I don't know who, could use to
address this issue.
DR. GIBOFSKY: Dr. Cronstein.
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DR. CRONSTEIN: This is more in the nature
of a comment, I guess, again following up on the
question that I asked before about how there seemed
to be no complete resolution or many people did not
achieve complete resolution of symptoms in the
8-day follow-up period.
I guess the comment would be, and this
came out of some discussions with Dr. Hochberg
during the break, that one, perhaps a longer
follow-up should be included. I know this is
getting ahead of ourselves.
I think the omission of a functional
endpoint is important, and I think that that should
be included, as well, because I don't think you
would regain full function if you are still in the
Likert scale of 1.
DR. GIBOFSKY: Dr. Mandell.
DR. MANDELL: A comment and a question.
The comment is, you know, as we think about looking
at markers of inflammation clinically, we have to
be cognizant I think if we are picking an agent
that has some specific activity against one marker
174
more than another, if we have, you know, something
that specifically targets a molecule that
vasodilates, and we pick erythema heat, we may
selectively be picking one thing different, so we
just need to be looking at that.
I guess in the future, we have already
targeted drug therapy. We look at whether dropping
a sed rate, or dropping the IL-1 specifically would
be driving a composite marker of response.
I have a question for the presenters about
looking at the delayed outcoming following an acute
intervention. We know what the response was in
terms of a secondary flare or, quote, "rebound," or
anything two weeks afterwards.
Was that collected, was that standardized
in a way that we can make any sense of that, and is
that doable to be incorporated into an acute
treatment protocol design in the future that we
look for that specific question?
DR. GIBOFSKY: Dr. Daikh? Dr. Melian,
would you like to respond and take either the front
or the side microphone?
175
DR. MELIAN: In terms of following the
endpoints past the 8-day period, no, we did not do
that. We did collect adverse experiences after
that time point, and obviously, there were some
patients who would have had an adverse experience
that might have been associated with gout, such as
pain or gout flare or something of that sort.
We did see that in a small number of
patients, but it was relatively small. Now, in
terms of would it be helpful to look over that time
point, it may be in future studies.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: To speak to Dr. Mandell's
question, in fact, most of the acute gout trials do
not look at that. It has been rarely mentioned in
over 30 trials that I looked at, that there was a
mention of it, but it was obviously not well
studied.
It seemed to be almost an afterthought to
the design of these trials, suggesting that again
it was either not designed to look at that, or we
don't really want to know that, and if the goal of
176
therapy is to control the acute attack, you can do
that with the number of days to maybe a week or
two, but then what happens after you stop therapy
and go on is relevant to the treatment of the acute
attack.
I think as Dr. Mandell suggests, that may
need to be incorporated, so, you know, an acute
treatment period of one week to two weeks, where
the first week is full therapy, second week might
be withdrawal of therapy, and then an observation
period as we do in other trials certainly for
safety reasons, but also for the purposes of
looking at recurrence of disease, which would be
yet another secondary outcome that would be
important in gout.
A lot of new cases of gout will respond to
just one attack, but those who have chronic gout,
who have intermittent attacks, may have more
attacks subsequent to this, and we need to worry
about that.
Again, that could be six months from now,
that could also be in the next 30 days, so I think
177
that to fail the next 30 days would be a serious
indictment for any therapy.
DR. GIBOFSKY: The comment was made and
was kind of left undiscussed or unopposed, that for
short-term trials, patient-reported outcomes and
health-related quality of life indicators may be
less useful than for trials of a longer duration.
I would be interested in hearing how some
of the members of the panel feel about that.
Ms. McBriar, would you respond, please?
MS. McBRIAR: I think I agree that it is
less important when you have an acute situation,
the patient is just dealing with that, not really
worrying about too much else except getting rid of
their pain, but as time goes on, and when it is a
longer time, it starts to really impact their life,
and that is when you want to measure those issues.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: I think the patient-reported
outcome is the end-all here. It is the beginning
of the end, and everything else is sort of
interesting to the rheumatologist and the
178
practitioner, but, you know, patient pain, and let
them decide, and then after that, I mean there are
obvious impacts on quality of life here, it impacts
on work, that are easily measurable and dramatic in
scale when they are looked at.
You know, functional measures, we stopped
them a long time ago, button tests, and 50-foot
walk time, but as gout is a lower extremity
disease, you know, why is that not being measured
in patient with acute attacks? Just look at
50-foot walk time and resolution of that.
I think that these should be incorporated
in the short-term trials. I mean the perspective
of what you are looking to accomplish or analyze
are a little bit different than in safety and
long-term studies where you want to see maintenance
of quality of life, improvement in quality of life,
but again with a hyperuricemic, and I see that
acutely, with an acute gout regimen where it is the
control of inflammation to control pain, you will
see that acutely.
DR. GIBOFSKY: Dr. Geis.
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DR. GEIS: Just to comment, in my
experience in doing clinical trials in other
arthritides, we thought that in the acute setting,
we wouldn't see changes in function and quality of
life, but we collected it anyway, and surprisingly,
we did see it in a matter of a couple days, we
would see something happen.
So, it seemed to be useful, and when we
presented it to the physicians, they thought that
was good information to have.
DR. GIBOFSKY: Do you want to respond?
MS. McBRIAR: So, what you are saying is
that in a couple of days, you are seeing changes in
quality of life?
DR. GEIS: I am just saying in past
experience, but different arthritides, and that
people did not think we would see it, but we did
collect it, and we did see it, and that was kind of
a eye-opener as to, gee, this would be important to
get more information about function and quality of
life in the acute setting.
MS. McBRIAR: I think a baseline is always
180
important and helpful, and anything past that
really depends upon the goal of the medication,
what one would predict would be helpful to the
patient.
I am trying to look at it like surgery,
and if you have surgery, you kind of know you are
going to be not functioning real well for a couple
days. If you are still in that situation a week or
two weeks or three weeks down the line, it becomes
much more impactful.
DR. GIBOFSKY: Dr. Anderson.
DR. ANDERSON: Just to comment that if you
are using functional status or health-related
quality of life health status in the very short
term, after only a week of treatment, the
instruments would have to be specially designed
because things like the HAQ refer to longer periods
of time. I don't know what kinds of instruments
were used in the studies that you did, Dr. Geis.
DR. GEIS: I don't recall off the top of
my head, but we did use subsections of the HAQ, as
well as different measures in function, and they
181
were exploratory, they weren't really primary or
secondary endpoint, but they gave, it seemed, the
physicians information which surprised them at how
quickly it appeared the patients could get back to
doing some normal functioning.
DR. GIBOFSKY: Dr. Schiffenbauer.
DR. SCHIFFENBAUER: I actually agree with
Dr. Anderson's comment. I think in the short term,
I would be surprised if function, ability to work
didn't worsen. What would be surprising is if it
actually remained worse after the attack of gout
resolved.
I doubt that would be the case, and that
might be something to look at, but I think in the
short term, you are going to see such drastic
changes, I am not sure what to do with them except
if they persisted after the attack resolved, that
might be a useful bit of information to know.
DR. GIBOFSKY: Dr. Terkeltaub.
DR. TERKELTAUB: I want to remind the
panel of a general caveat, and that is that the
gouty joint is not normal between attacks. Elazea
182
Pasqual [ph] has published that the leukocyte count
is elevated.
The general caveat is that the gouty joint
is not expected to be normal even after a week of
an anti-inflammatory treatment. We are not
eradicating synovitis, we are not eradicating tophi
by giving NSAIDs or colchicine or other
medications.
It is not equivalent to treating pneumonia
where you are eradicating an infection that is
easily treatable with an antibiotic, and this
should factor into interpretation of residual
symptoms and completeness really of symptoms and of
function.
DR. GIBOFSKY: I think your comments also
address part of what I asked earlier, which is
whether we are dealing with an either/or situation
and whether we are dealing with an "and" situation,
and I think that is something we will get into in a
few minutes.
Dr. Weisman.
DR. WEISMAN: I think you have to remember
183
that these instruments reflect both pain and
damage, and I think what Bob is mentioning is that
there is something else going on with the joint
that could affect function afterwards.
But very clearly, when you relieve pain, I
think that is what Dr. Geis had mentioned before,
when you relieve pain with an anti-inflammatory
drug, you are going to see an effect on these
instruments within a week or two rather than
waiting three months.
But then other factors may influence the
instruments that have to do with the chronicity of
the disease.
DR. GIBOFSKY: Further discussion on the
presentation this morning? Are we ready to begin
the first of the questions?
We are going to begin the questions. We
will break for lunch. We will then come back and
continue the questions. I am reminded that we do
have to at least allow for the open public hearing
at 1 o'clock, so that our colleagues who may be
watching this live or watching it later or
184
following the broadcasts and the meeting are at
least advised that there is the opportunity for the
public hearing at the scheduled time, so that if
someone shows up at 1 o'clock, we can't say sorry,
the time is past, so we will have the opportunity
for the open public hearing at 1 o'clock, which
will interrupt whatever else we are doing.
But we will begin the questions now, we
will break for lunch, and then we will come back
with the open public hearing. If comments are made
at that time, we will hear them, otherwise, we will
resume the questions to the Committee.
So, at this point, we are ready for the
discussions of the questions that were posed to us.
We begin with an introductory statement.
Committee Discussion and Questions
DR. GIBOFSKY: Individuals with acute gout
often experience significant pain. Although
standard treatments include NSAIDs, colchicine and
glucocorticoids, none of these agents have been
demonstrated to be efficacious in
placebo-controlled, randomized, double-blind
185
studies. Therefore, it is important to carefully
assess any new therapy for efficacy.
I don't think this is a statement that
requires much discussion, so the first question is,
the first issue:
I. Please discuss whether gout is
considered a unique clinical entity or a model of
acute pain.
Who would like to tackle that first? Dr.
Williams.
DR. WILLIAMS: I don't think any of us
would treat an acute attack of gout with just
analgesics, so I think that I would consider it a
unique entity with which pain is a component.
DR. GIBOFSKY: I see nods. I see Dr.
Cush's hand, so we will go to Dr. Cush's hand, and
then those who are nodding.
DR. CUSH: Gout is a model of acute
inflammatory arthritis and, hence, should be
treated as a separate entity. Control the
inflammation, you control the pain, yet it is,
nonetheless, interesting that the use of
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analgesics, ketorolac and/or topical ice have an
additive effect here. The topical ice therapy was
added on top of colchicine and nonsteroidal
therapy, so again this should be taken into
account, but it was additive in its benefits.
DR. GIBOFSKY: I might pose a question to
Dr. Harvey. What are the differences in terms of
our finding whether it is a unique clinical entity
or a model of acute pain as opposed to finding that
it is both?
DR. HARVEY: I think the purpose of the
question was to stimulate discussion, and it has
been effective in that.
DR. GIBOFSKY: That answers my question.
So, does anyone else want to comment on
the statements that have been made thus far as to
the characterization of gout? I think the
consensus seems to be it is a clinical entity that
causes pain, but in and of itself, it is not a
model of acute pain.
Is that a fair summary? Dr. Cronstein.
DR. CRONSTEIN: Again, just based on the
187
discussion earlier about functional endpoints, et
cetera, I think it is very clear that we don't do
that for most analgesic trials, and I would just
like to reiterate that this is probably something
that wouldn't respond simply to analgesics,
although we obviously haven't tested that.
DR. GIBOFSKY: Anyone else? Dr. Geis.
DR. GEIS: I just want to be clear I am
understanding what people are saying, that even
though it is not just a model of pain, and it is a
separate functional entity, if it was studied like
classic pain studies are done, and it was shown to
be useful for understanding a drug's ability to
control pain, could it be considered an acceptable
pain model even though we accept that it is a
different functional entity and there is all kinds
of inflammation involved.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: I don't think I would enter
my patients into a trial with an acute attack of
gout if the only treatment were analgesia.
DR. GEIS: I guess what I am saying is so,
188
for example, if you had an NSAID was going to be
your active comparator, and you said we are going
to put a placebo arm in and we are going to measure
on an hourly basis from the first four hours after
you see the patient, and you can rescue them out of
the placebo group if nothing happens.
And you saw a separation from placebo
within an hour, my experience is that is sort of
considered a good pain model. If that seemed to
happen with gout, why not do it?
DR. WILLIAMS: If you are using an NSAID,
I think you are then confused by whether it's the
anti-inflammatory effects of the NSAID or the
analgesic effects of the NSAID, and I would
consider that, but if you are going to tell me you
are going to treat with demerol, I wouldn't be
interested.
DR. GIBOFSKY: Dr. Cronstein.
DR. CRONSTEIN: I guess i just wanted to
reiterate that colchicine, which is again one of
the standard therapies, is not, as far as I know,
particularly useful as an analgesic, and if that
189
were your comparator, I am not sure how you would
draw any conclusions from a trial if it were set up
as an analgesic trial.
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: I want to go back, I guess,
to Dr. Geis's comment here then. If gout was
considered a model of acute pain, you could then
apply the guidance document or the draft guidance
document for studies of agents in acute pain to
gout, and utilize those outcomes then.
My understanding--please refresh my memory
here--but these are predominantly short-term
studies in acute pain, and wouldn't necessarily
reflect the duration of the study and the time to
response that the clinicians would be interested
in, in terms of assessing the patient, or that you
would necessarily expect to see the so-called,
let's say moderate to excellent response if you are
looking at 5 days and 7 days, right? Because my
experience with the acute pain studies is that they
tend to be 8 hours, 24 hours.
So, sort of by definition, I mean while it
190
could be a model of acute pain for the acute
resolution of pain in the first 24 hours, clearly,
it is more than that.
DR. GIBOFSKY: Any further discussion on
point number 1? Okay, let move on to II.
II. Please comment on the use of the
following clinical measures: pain intensity, pain
relief, time to onset of analgesia, time to
re-medication.
Are there additional endpoints that should
be considered for these clinical trials, such as
evidence of local inflammation, erythema,
sensitivity to touch, assessment of function,
patient/physician and global assessment?
Please discuss the value of an endpoint,
such as time to good or excellent pain relief in a
defined period of time (a responder analysis).
Dr. Weisman.
DR. WEISMAN: I don't understand the
question very well. Maybe, Joel, you want to
explain this? In a pain model, you look for onset,
you look for magnitude, and you look for duration.
191
Is that what you are asking here? Okay.
The other, now you are asking about a
responder index. Are you talking about a good
responder, you know, a 20 percent responder? What
would be an index and how would you factor those
issues in, you know, an onset duration and
magnitude?
DR. SCHIFFENBAUER: Well, I hate to give
you a non-answer, but that is exactly what we would
like the Committee to consider. The question is
whether this should be studied with the acute
analgesia parameters that we apply to standard
acute analgesics, or is it more than that, is it
that plus inflammation or other measures?
I mean what we heard in the first question
was that it was a unique entity, but what I am
hearing, too, is that some people would just study
pain as the primary endpoint. That is the question
to the Committee.
DR. WEISMAN: The message is coming
through, to make it simple, no, there is more to it
than the pain model.
192
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: Well, I think pain is the
patient's primary concern, and probably the easiest
to measure, and it would be one of your primary
endpoints. The treatment of the pain is the
treatment of the arthritis, and I think you would
also want to study what has happened to the
inflammation, the redness, the swelling, the
tenderness, et cetera, and I wouldn't separate them
and say we will only look at the pain. The
treatment of the pain is the treatment of the
arthritis.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: I will flip what Dr. Williams
has said and say the treatment of the inflammation
is the treatment of the pain, and so I think that
inflammation measures are important in the outcome,
so I still think that again the primary endpoint
should always be pain as measured by the patient,
using a Likert scale or PDA or Visual Analogue, I
think that is all well and fine.
I do think there needs to be a
193
quantification of inflammation, and what is
inflammation in gout? It is really the attack. In
my talk, I said the attack really was the four
cardinal signs of inflammation.
You could say improvement is improvement
in two out of three, and the resolution is all four
are gone, and that is when the attack is over, and
that can be objectively measured when the patient
is enrolled, when the patient comes back for their
1-day visit, their 3-day visit, their 5, their 7,
whatever. That is the resolution of erythema,
swelling, warmth, and tenderness in the index
joint.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: I agree that we need measures
of pain and inflammation in our assessments, but I
do think that it is suggested by the Merck studies,
and pain may correlate extremely tightly and
extremely well over the short term with measures of
inflammation, which would be different from
something like rheumatoid arthritis where pain
doesn't necessarily correlate with the joint
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findings.
If, over time, every study demonstrated a
very unique tight correlation of pain with these
measures of inflammation, it is conceivable that
the pain could be the most important measure to
assess.
DR. GIBOFSKY: Dr. Cush, to add a fifth
cardinal sign of loss of function to the four
previously outlined, bullet 1 asks us whether we
would want to consider assessment of function in an
outcome study.
Your thoughts on that?
DR. CUSH: Again, I think a secondary
measure would be interesting and since most attacks
are lower extremity, I would advocate a 50-foot
walk time as a measure of that. Again, I did a lot
of those when I started doing clinical research,
and, in fact, it was kind of fun. I had a stop
watch, they were walking next to the guy in the
hallway, who was on his way to lunch.
But the patients themselves reported
satisfaction, you could see their improvement by
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doing this one test. They knew they were better by
the exam or by their reports, but how they are
going to do on their walk time was also an
interesting exercise.
Now, there may be other measures of
function one could do if it involved things other
than the lower extremity, but I would advocate a
50-foot walk time or some other maybe questionnaire
generated activity measure of function.
DR. GIBOFSKY: The second bullet: Please
discuss the value of an endpoint such as time to
good or excellent pain relief in a defined period
of time.
Dr. Hochberg, can I ask for your thoughts
on that?
DR. HOCHBERG: Sure, you are going to open
the well here, because I will comment again on the
first bullet, which I didn't do before.
I actually like the issue of achieving a
certain level of response in a defined period of
time, and I think that is helpful for the clinician
in terms of assessing a product and giving
196
information to a patient saying, you know, patients
like you, 50 percent will have a response over the
course of a week as opposed to on average, you will
have a 2-point improvement in your 4-point Likert
scale.
So, I like an endpoint of time to response
or the proportion of responders over a certain
period of time, and think that that should probably
be built in as a secondary outcome. At least the
measure of pain as the primary outcome, maybe this
could be modeled as a primary in terms of the
improvement in pain at a certain level.
If I could have your permission to go back
to the first bullet?
DR. GIBOFSKY: Please.
DR. HOCHBERG: Thank you. I am not
enamored of the physician-derived measures of
inflammation, erythema, tenderness here. I think I
am more enamored of the patient-derived measures.
Having had gout, I think the patient-derived
measure here for me would be more paramount in
terms of the amount of pain, the improvement in
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pain, and my global assessment.
I have no objections to an assessment of
function. You know, it could be both a
performance-based measure and a self-report
measure.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: I will pass for a second.
DR. GIBOFSKY: Dr. Anderson.
DR. ANDERSON: Do I take it, Dr. Hochberg,
that inflammation can't really be measured very
well, so it is not a good outcome?
DR. HOCHBERG: Well, you certainly have a
lot of experience with, let's say, assessing the
reliability of the measurements of inflammation,
and I think while inflammation could be measured in
a valid fashion, that there would need to be a lot
of training in terms of getting both the
inter-examiner reliability for the measurement of
inflammation, be it on a, let's say, a naught to 3
scale of redness, or the so-called naught to 3
scale of swelling, and I think it is obviously much
easier to do it on a present or absent scale.
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I think on a present or absent scale, yes,
it can be reliably measured.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: My memory has returned. I
think Dr. Hochberg is right. Most of the trials,
however, have looked at scores as opposed to counts
on joints as opposed to dichotomous, they do want
to do gradations, and ACR does have criteria for
how to do that, which there is some subjectivity
involved.
Marc, you had talked about patients who
had responded, 50 percent of people would respond
after five days. By that, do you mean a complete
response, complete resolution of symptoms, or do
you mean a responder index which would be some high
level response involving multiple things?
I know you, as I am, you are a fan of
pain, but I would call for complete resolution as
reported by the patient, and maybe that can be
fudged a little by saying, you know, greater than
90 percent resolution of your symptoms, and return
to normal activity, but would you want a composite
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measure, or would you just go with some other
measure of complete response?
DR. GIBOFSKY: Response, Dr. Hochberg.
DR. HOCHBERG: Ideally, it would be a
complete response. I think given what we know
clinically, and given that the data that we saw
this morning, which I think really inform our
discussion, it would be unlikely to anticipate
complete response with the sort of currently
available agents within the first five days of
therapy in a large percentage of patients.
So, one would need obviously a much larger
study if one was going to power the study on the
complete response and as a non-inferiority study.
DR. GIBOFSKY: Dr. Bathon, then Dr.
Williams.
DR. BATHON: We also might want to think
about whether it would be reasonable to incorporate
inflammatory indices in the measure, as well, and I
wondered if in the Merck study, there were any data
on sed rate or CRPs.
DR. GIBOFSKY: Would Dr. Daikh or Dr.
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Melian care to respond to the question of Dr.
Bathon?
DR. MELIAN: No, we did not collect
information on CRP or on sed rate. In clinical
studies of this kind, it is often hard to get sed
rate because it needs to be done locally.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: My comment goes back to Dr.
Hochberg's comments. I agree that I think pain is
the primary endpoint, however, I do think that we
can identify swelling of the joint.
I would make the comment that the
committee that developed the ACR20 criteria looked
at whether grading mild, moderate, severe helped,
and it did not appear that those gradations helped
over just presence or absence. However, if you ask
for those gradations, you often got a more careful
joint exam.
DR. GIBOFSKY: Dr. Hoffman.
DR. HOFFMAN: Bob Terkeltaub pointed out
how abnormal the joint may be after resolution of
the attack, and that emphasizes even more to me how
201
difficult it is to sort out the low-grade, ongoing
inflammatory process from what might be a response
to injury and repair, and how unrealistic it might
be to expect total resolution of all of the
classical features, with the most important feature
then being pain and function.
It would then seem that in designing
studies, that that would have to be the two
absolute, most important endpoints that are
included, total resolution of pain and restoration
of function.
DR. GIBOFSKY: Dr. Schiffenbauer, I am
going to pose this to you, are you comfortable that
we have commented appropriately on the first part
of the question, the use of the clinical measures
of pain intensity, pain relief, time to onset, and
time to re-medication?
DR. SCHIFFENBAUER: I would actually like
to get some further clarification. The question
is--I mean I heard pain being a primary symptom,
but then inflammation being important. I didn't
hear any discussion of the possibility of
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co-primary endpoints. That did not come up. Some
integration of pain and inflammation as co-primary,
I wonder if the Committee could address that.
The second part of it was there was some
discussion of time to resolution or improvement,
which seems to be an end-loaded endpoint, if you
will. It is an endpoint that you might look at it
three or four or five, six days, but since this an
acutely painful condition, I would like to hear
more about the front-loaded sort of analysis, which
gets back to the time to onset, those types of
issues. I didn't hear that specifically being
addressed.
DR. GIBOFSKY: Does everyone understand
the request from us? Would anyone like to address
some of those comments? Dr. Cush.
DR. CUSH: So, pain only as a primary
outcome, and everything else second. Pain only and
then patient reported, and everything else is
secondary. I do think that everything should be
front-loaded, as you suggest, and one day as your
first time assessment is probably too late.
203
I mean I think if you are going to go for
an acute gout indication, which is going to be the
relief of the pain associated with acute gout, one
should have a several hour determination, whether
that is a 30-60-90-120 minute assessment that is
done in a few trials, or whether that is a
four-hour assessment as was done in the etoricoxib
trial, or whether it is going to be a 6 or 12 hour
assessment.
I think it should be a less than one-day
assessment, and then some other intervals after
that to show, and it should be front-loaded. I
mean we shouldn't be looking at starting treatment
7 days and then 14 days. We have missed what is
most bothersome to the patient.
What is most bothersome to the patient is
how I am feeling the next 24 hours and maybe the
next 36 hours, and we should have therapies that
clearly show what the magnitude of response is in
that time frame.
DR. SCHIFFENBAUER: How does that gibe
with Dr. Williams' comment that he would not allow
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an individual to be entered in a trial for demerol?
Since you are just measuring acute pain, I am still
not getting clarification.
DR. CUSH: They are separate issues. I
mean I agree with what most people said, including
Dr. Williams, that it is inflammation that is
driving the pain here, and it is not pain alone,
so, in an acute trial, you might get--you know, and
as was seen in the ketorolac trials, in fact, they
did have improvement in 30, 60, 90 minutes, but
they didn't do so well after 6 hours, you know,
they weren't all that great.
So, it would have to have a good blend in
there because, yes, you could give narcotics to
cover up pain, but have you really controlled
inflammation. A lot of these would come out in the
secondary variables. I still don't know that I
would want to rank inflammation as a primary or
covariable here, because I think it is the more
difficult to measure.
We have heard some differences as to how
reliable the cardinal signs of inflammation are,
205
whether we should do swollen joint scores on a zero
to 3 scale, or just a yes and no scale. There is a
lot of variation there that hasn't been well tested
in this particular arena.
So, to make a secondary outcome to invite
exploratory investigations, as Merck has done with
erythema, just done by visual analysis as opposed
to doing laser doppler studies for blood flow as a
measure of erythema and inflammation could also be
done.
Again, I think those are all secondary
points.
DR. GIBOFSKY: Dr. Terkeltaub.
DR. TERKELTAUB: Are we going to address
chronic synovitis in this setting and how to
evaluate that in the trial modalities, because
basically, as a tertiary care rheumatologist
dealing with the worst gout, this is what is what I
see. You see chronic destructive synovitis that
isn't really appropriately evaluated in toto by
these sorts of measures.
DR. GIBOFSKY: I think the floor is
206
certainly open for discussion of any parameter that
the Committee considers important in the assessment
of an acute or chronic trial design. We certainly
can.
Dr. Cronstein.
DR. CRONSTEIN: This is going back to the
front-loading, if you will. I think clearly, if
you front-load everything that you are measuring
and look at those earliest time points, most
importantly, it is going to dictate the
comparators, so if you were to compare it to
glucocorticoids or to colchicine, you probably
wouldn't get any change at 4 hours.
So, this is clearly going to dictate the
way that you structure your trial with respect to
the drug that you are comparing it to, since we
have kind of written off placebo trials, and I
think that that needs to be kept in mind, as well.
DR. GIBOFSKY: Dr. Weisman.
DR. WEISMAN: It seems to me from the
discussion that the duration of the attack is
probably not affected terribly by the medications
207
that we have been discussing. It is the area under
the curve or the magnitude that seems to be
responding, and this gets back to what Bob has been
trying to tell us, that this is an ongoing process.
It is probably useful to look at it as an
issue of controlling inflammation or pain as
quickly and as completely as possible, but the
duration of it is probably not going to affected by
those specific therapies.
We all know about rebound, we all know, we
use steroids, we use these drugs, if we stop them
too quickly, the attack recurs. Even with ACTH,
you have to give patients maintenance colchicine,
so we see this from a clinical standpoint.
That probably relates again to what Bob is
saying, is that the process keeps going. So, it is
going to be very difficult for us, Joel, to I think
make this distinction because if we are treating
early and aggressively and actively, as quickly as
possible, all we are going to measure is pain
relief, but that is not all what is going on.
I have tried to put some kind of dressing
208
on this discussion in terms of pathophysiology.
Maybe Bob should comment on this issue about the
duration of the process, or if I am reading it
correctly.
DR. TERKELTAUB: I think you read it
correctly.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: I am not sure I agree with
that, Mike. I think that if we are talking about
an acute attack of gout as opposed to patients with
chronic gout, I think we do make an impact on the
duration of the attack, and that we do shorten the
duration.
DR. GIBOFSKY: Further comments? Does
anyone want to comment on Dr. Terkeltaub's question
about the assessment of chronic synovitis? I am
not sure that we explored that fully yesterday, and
perhaps we can revisit it.
Dr. Cronstein.
DR. CRONSTEIN: I guess the question is
how long, I mean how long is chronic. I know what
you are talking about as those people who have
209
months, but I think in terms of the sorts of
questions that have been posed, for the most part,
have to do with sort of life in the trenches as
opposed to the tertiary care center.
I think the questions are very different
at that point.
DR. GIBOFSKY: Comment, Dr. Terkeltaub?
DR. TERKELTAUB: I just want to know
whether we will address the chronic patients
because it is very much like RA, these types of
drugs that we are discussing today,
anti-inflammatory analgesics are not going to
really address the chronic entrenched disease.
DR. GIBOFSKY: I think much of the
discussion on chronic was yesterday, but I am
certainly willing to re-explore.
DR. TERKELTAUB: There is chronic
inflammatory, as well as chronic accumulation of
urate. There are many people that have tophi, that
don't have symptoms.
DR. GIBOFSKY: Is there some specific
comments that we should be considering in our
210
recommendations to the Agency to take into account?
DR. TERKELTAUB: I think we should be
looking at the possibility in terms of future
medications evaluated in this disease, are things
that may reduce the amount of destruction at the
cartilage level and the amount of synovitis, and
that some of these medications may not work quickly
vis-a-vis pain relief.
DR. GIBOFSKY: Back to the initial
characterization, Question I, that we are talking
about a unique clinical disorder rather than just a
painful condition, that approach?
DR. TERKELTAUB: Yes, it does, and I think
we are talking about a unique form of acute and
chronic disease.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: Yes, that relates to a
question I had earlier about whether you were going
to base the joints that you are targeting on,
patient report of pain, or the physician
assessment, because the patient can see a swollen
and painful hand, and it maybe is only the wrist
211
involved. On the physician exam, you find no
involvement of the MCPs, even though there is
diffuse swelling, and the patient can't necessarily
separate that.
On the other end, with chronic disease,
where there is acute on chronic inflammation, the
physician may find tenderness in a number of joints
that the patient doesn't think are involved. So, I
think there are issues there that are complex and
need to be sorted out.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: Well, again, we are speaking to
indications, and today's indication is acute.
Yesterday's indication that we spoke to was the
chronic one, but was really for the indication of
treating the hyperuricemia associated with gout and
how treatment of that would relate to the chronic
consequences of hyperuricemia and the disease.
So, it kind of gets to what Dr. Terkeltaub
was bringing up, but really doesn't, and today's
indication really is for the person with brand-new
gout for the first time, or a person with
212
intercritical gout and then gets a new attack, or a
person who has maybe some chronic tophaceous gout
that is well controlled and has attacks, but that
is a little bit different still than really a sole
separate indication, which is chronic tophaceous
gout and synovitis, and that would be a whole new
indication that we would really have to develop,
because I don't think pain would be an appropriate
primary outcome there.
I think that you are really looking at
more sort of rheumatoid arthritis-like outcomes
where you are looking at composite measures of
improvement. You are looking at synovial load, you
are looking at damage, you are looking at long-term
outcomes, and it may not be one regimen, it may be
new therapies, it may be combinations of therapies.
It really is a whole new can of worms that he has
opened up by that question, and I think it is an
important one because this is what we see as
rheumatologists.
It is unfortunately, or fortunately for
the populace, a minority of those 2.5 million
213
people with gout, but it is the ones that
concentrate in our offices. I think today's
indication is for the majority of those people who
have acute presentation of gout and the
intercritical exacerbations of gout.
DR. GIBOFSKY: Does everyone agree with
the concept that we probably, despite two days of
discussion, have not covered the universe of
patients with gout, particularly those whom we may
be seeing in our experience?
Dr. Terkeltaub.
DR. TERKELTAUB: Agree, and I think that
as we are able to remodel the tophi in joints by
more potent and more tolerated anti-hyperuricemics,
we are going to start to see new types of problems
with possibly accelerated destructive changes at
the cartilage level, and we may have to deal with
this.
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: I just wanted to get back
to Dr. Schiffenbauer's comment, if that is all
right.
214
DR. GIBOFSKY: Certainly.
DR. HOCHBERG: One can front-load the
studies in patients with acute gout or acute
exacerbations during intercritical gout for relief
of pain as a primary outcome and improvement in
inflammation as a secondary outcome, front-loading
these outcomes.
It still is important to I think follow
patients in study on treatment to look at the
resolution of the attack where they are, quote,
"back to baseline," for those who have maybe some
chronic smoldering symptoms and get an exacerbation
on top of it.
I am concerned that a 7-day study may not
be of long enough duration for such a study if one
wants to look at a secondary outcome of back to
baseline or complete resolution.
DR. GIBOFSKY: Further Comments? Dr.
Cush.
DR. CUSH: I would ask Dr. Hochberg and
other members of the committee, would you then
propose that all acute gout studies be at least 30
215
days in duration?
DR. GIBOFSKY: I think we will deal with
that in Question III. I would ask you to hold that
thought because we will come back and deal with the
duration.
Further discussion on point II? Dr.
Anderson.
DR. ANDERSON: I would just like to say
something about function, which has sort of
disappeared for the time being from our
discussions. That is the difficulty in assessing
whether a person has returned to baseline, because
the first measurement you are going to have on
people is when they are in the middle of an attack.
That is a difficulty there, I think.
DR. CUSH: But baseline status refers to
their baseline, not the chronological baseline at
study entry. A patient has their own perception of
what their baseline function is. I was working, I
was running. I think that is what the statement
was referring to.
DR. ANDERSON: Okay. So, if it's patient
216
report of their being back to what they used to do,
that's fine. I was thinking that you maybe were
talking about 50-foot walk time, which you wouldn't
have based on measurement.
DR. CUSH: Right. That would be a purely
subjective measure of, you know, time to resolution
of symptoms would be the day that the patients says
I have returned to my baseline status as far as my
function and my ability to function without pain,
you know, plus or minus 5 percent, something like
that.
DR. GIBOFSKY: If there are no further
comments on Question II at this point, we will
break at this point. We will resume at 1 o'clock
with the opportunity for the open public hearing.
We can continue the discussion on Question II
following the open public hearing, which we are
required to open at 1 o'clock, and then we will
continue with the remainder of the questions at
that time.
We will adjourn the morning session at
this time.
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[Whereupon, at 11:59 a.m., the proceedings
were recessed, to be resumed at 1:00 p.m.]
218
A F T E R N O O N P R O C E E D I N G S
[1:03 p.m.]
DR. GIBOFSKY: Ladies and gentlemen, we
are back on the record for the afternoon session.
Open Public Hearing
DR. GIBOFSKY: At this point in our
schedule, we are going to hold the open public
hearing.
Both the Food and Drug Administration and
the public believe in a transparent process for
information gathering and decisionmaking. To
ensure such transparency at the open public hearing
session of the advisory committee meeting, the FDA
believes that it is important to understand the
context of an individual's presentation.
For this reason, FDA encourages you, the
open public hearing speaker, at the beginning of
your written or oral statement, to advise the
committee of any financial relationship that you
may have with the sponsor, its product, and, if
known, its direct competitors.
For example, this financial information
219
may include the sponsor's payment of your travel,
lodging, or other expenses in connection with your
attendance at the meeting. Likewise, the FDA
encourages you at the beginning of your statement
to advise the committee if you do not have any such
financial relationships.
If you choose not to address this issue of
financial relationships at the beginning of your
statement, it will not preclude you from speaking.
Are there any members of the public who
would like to present or make a statement to the
Committee at this time?
[No response.]
DR. GIBOFSKY: Hearing none, we will
resume our deliberations on the questions as asked.
Committee Discussion and Questions (Resumed)
DR. GIBOFSKY: I believe we have completed
Question II, unless any member of the Committee
would like to further comment on Question II.
Seeing none, we will move to Question III.
We are waiting to move to Question III, which I
will read while we are waiting for it to be put up.
220
Question III. Attacks of gout may be
self-limited and resolve spontaneously over 1 to 2
weeks.
Then, there are three bullets.
Please discuss the duration of a trial for
acute gout.
What is the value of a demonstration of
efficacy within the first 8 hours? The first day?
Is there clinical meaning in an analysis
of average of pain over several days? How many
days?
Dr. Hochberg, can I impose upon you to
begin to address Roman III?
DR. HOCHBERG: Let me start with the
second bullet, and I think to summarize the way I
would distill our conversation and discussion prior
to the lunch break, is that there is very high
value to demonstrate efficacy within the first 8
hours and within the first day. I think there was
pretty much consensus on that.
Then, with regard to the clinical meaning
and an analysis of the average of pain, again, I
221
think there was consensus that the area under the
curve of pain relief was very important as well.
Let's say the cumulative amount of pain relief or
the less area under the curve of pain was very
important, as well, measured over several days.
How many days? I don't know.
In terms of the duration of the trial,
while we are again interested in front-loading the
assessment of efficacy, we are also concerned about
the resolution of the attack, and concerned that
based on the little that we know of the natural
history of gout from the observational studies and
the placebo group of the colchicine trial, and what
we learned from the trials conducted by Merck, that
either the majority of patients or a sizable
minority of the patients don't have resolution of
their attack by 7 days.
So, I would think that we would want to
see trials of longer than 7 days in duration. I am
not sure 30 days, which was the number that was
thrown out, but maybe 14 days.
DR. GIBOFSKY: Dr. Cronstein.
222
DR. CRONSTEIN: I guess I have a question
about the use of the area under the curve, and I am
not sure how much value that adds to what you
already saw, particularly inasmuch as the
comparators are probably going to be very similar
to the drugs under study just because we have
already ruled out, if you will, a placebo trial.
So, it is very likely that you are going
to see overlapping curves, and I don't know how
much difference that--I mean not to exclude it,
it's no big deal obviously to calculate that sort
of thing, but I don't know how much it adds.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: I actually like Marc's
suggestion of 14 days. I think in the interest of
patients who are feeling much better after a week,
I would think that the Merck model of one today for
seven days would be good, and then every other day
for another week, but I would like to see a couple
of weekly followups afterwards, just to make sure
we have captured the full effect, and not seen any
rebound.
223
DR. GIBOFSKY: So, I am hearing a sense
that there may be difference between the period of
time that the trial is conducted and the period of
time that data is collected following the trial in
order to get a more longitudinal picture of the
natural history of the event and the treatment of
event.
Dr. Cronstein.
DR. CRONSTEIN: I guess also since none of
the agents got back to zero, if you will, at the
8-day time point, it seems obvious to me that you
would want to get to a point where the patients are
back to their baseline, if you will.
DR. GIBOFSKY: Dr. Weisman.
DR. WEISMAN: It occurred to me that I am
sure Merck would have been happy to collect
additional data for, say, the second week, but the
problem is we are not listening to what they were
saying to us, which is this was a very difficult
trial to carry out. They had to go to how many
countries to do this--10 in one, 11 in the
other--to recruit patients in the trial with a huge
224
variety of different sites, I am sure, not just
rheumatologists.
How many rheumatology versus
non-rheumatology sites did you go to? So, half
their sites were non-rheumatologists. So, we heard
that they went to 10 or 11 different countries, 40
different sites, half the sites were
non-rheumatologists, and many of them, I am sure,
were not sites that normally do clinical trials.
So, there is going to be a huge variety of
data that is collected, very difficult to put this
trial together, and so I think we ought to
understand that before we come up with these kind
of ideal frameworks.
To do a trial of acute gout, for example,
can a trial of acute gout be done in the United
States? With the sites that we have in the United
States, given the disease, can we do that here?
Why don't we ask Merck to answer the question, can
we actually do that trial in the United States with
a sufficient N, not you, Dr. Cush, I want to ask
Merck.
225
DR. GIBOFSKY: I will allow you to ask
Merck if the representative will go to the
microphone. At the microphone if you care to
answer.
DR. WEISMAN: Given what you have told us
already and given the number of patients that you
need for a comparator trial to another agent, can
you successfully accomplish a study in the United
States?
DR. MELIAN: In the United States alone?
DR. WEISMAN: Yes.
DR. MELIAN: I think you could do it, but
I think you are going to have to work very hard to
do it.
DR. WEISMAN: Well, you obviously chose
not to do it alone in the United States, right?
DR. MELIAN: That is correct.
DR. WEISMAN: And the reason you chose not
to do it in the United States alone?
DR. MELIAN: How many years did we want to
take to enroll the trial.
DR. WEISMAN: Okay, so that's the answer.
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So, what I am saying is let's be realistic about
the number of patients that you need to do the
study, and the number of investigators that you can
get, and the fact that Dr. Cush is pushing very
hard on the microphone over there because he is
going to reject pretty much everything that I have
said.
Go ahead, Jack.
DR. GIBOFSKY: Not everything, Dr.
Weisman, just all of it.
Dr. Cush.
DR. CUSH: Dr. Weisman is right. I think
that it is difficult, but, you know, so is
recruiting for rheumatoid arthritis in this era
when we have many successful therapies currently
available. To recruit for rheumatoid arthritis
trials for drugs in development in 1980s and 1990s
was relatively easy because there were a lot of
patients, and a lot of them were not well treated,
and there weren't a lot of good therapies.
Now, we have a situation where we have a
lot of effective therapies, much like the situation
227
of gout, where there are a lot of effective
therapies, and people seem to think that they know
what they want to do.
But the fact still remains is that there
are millions of people, that there are no trials.
The main reason why this has been difficult is
because we haven't had the outcomes outlined, there
have been no methodology. There has not been a
significant push to have the gout trials.
All the trials that we saw in development
were done by interested individuals trying to
answer a question, as much as there were industries
trying to look at a pile of studies, whether, you
know, etoricoxib or Rofecoxib or sulindac might
possibly work, or might be an indication.
So, again, I think with guidelines for
outcomes, with education, I mean there are plenty
of researchers. It takes work, and it can be done,
but to say it can't be done, I mean then we have
just wasted this whole day. We have laid the
groundwork where this can be done, and the patients
are there.
228
If Merck couldn't find them, that is
Merck's fault. I think that there are a lot of
people who can find them.
DR. GIBOFSKY: A quick response, Dr.
Weisman?
DR. WEISMAN: My rebuttal, very quickly,
is that true true and unrelated, Jack, yes,
rheumatoid arthritis is difficult to recruit for
because we have many effective therapies. That is
not true for acute gout.
We have heard we don't have many effective
therapies here, as much as you think, otherwise,
they wouldn't be doing the study, and the problem
here is recruitment of physicians and patients in
the United States because of exactly what you said
this morning. It's the scattered number of
patients that are out there, that are seen in
emergency rooms and primary care offices, not seen
with rheumatologists. They are almost impossible
to capture.
I think that is the real reason, and that
is why I am trying to be realistic. That is not
229
going to change very much, and that is why I am
saying let's be realistic about study design
because who is going to be doing the studies.
DR. GIBOFSKY: Dr. Cronstein.
DR. CRONSTEIN: I think again we need to
query the people who have done this study and have
had the difficulty in recruitments, and according
to what they told us earlier, the major difficulty
was that people were taking over-the-counter
nonsteroidals or some other nonsteroidals that they
had, so adding onto a trial where you have patients
simply come back for over a longer period of time,
I don't think is going to add to the burden, but
maybe we could get that information from you guys.
DR. GIBOFSKY: I would share Dr.
Cronstein's comments in that recognizing the
difficulties in recruitment, once the patient is
recruited, I am not sure the period of observation
is as significant or raises additional difficulties
beyond the recruitment.
Certainly, there is some, there will be
some dropoff, but if the problem is in the
230
recruitment, that is at the front-load stage, but
once the patient is there, the observation is less
difficult to do.
If our colleague from Merck would care to
comment?
DR. MELIAN: I agree with you. Once you
have the patients in the trial, the major hurdle
has been handled. Yes, you have some patients who
discontinue throughout the trial, and we actually
went through that number when I showed you my
slides and a small number of patients in both
treatment groups discontinued during the 8-day
period.
You can imagine if you went to 14 days,
that it would be larger yet. That being said, the
major hurdle is in the first few days of
recruitment.
Now, the one thing that I do have to tell
you, because I am not sure it came through in my
presentation, is that when we looked at patients in
terms of pain, and if the system was set up I could
show you, because I actually do that this data, and
231
I can share it with anybody who wants to see it,
90-plus percent of patients at the end of the 8-day
period had mild or no pain.
So, you are really get down to what is
really minimal or no pain in that 8-day time frame.
I think that is consistent because when we treat
gout with Indocin, we don't usually go much beyond
an 8-day treatment period. Some patients do
require longer.
DR. GIBOFSKY: Dr. Finley.
DR. FINLEY: I wanted to follow up kind of
where we left the discussion before the break, and
it dovetails with our discussion about recruitment
that Dr. Weisman brought up.
I wondered, thinking about the work that
the folks at Merck did, are we really talking about
acute gout, or are we talking about acute episodes
of intercritical gout, which is kind of where we
left the discussion, and thinking about their
particular studies, they talked about the Wallace
criteria, and they talked about--I think I heard
during the presentation about all the patients met
232
the clinical criteria, and I wondered if they knew,
of the patients that they entered, how many were
the first episode of gout that they had ever had,
or were the preponderance intercritical patients.
Then, how many of them were diagnosed
based on chart review of prior evidence of
crystals, or, in fact, were diagnosed at the time
the crystals were identified at the time of
enrollment, or were the preponderance of their
entrants mostly meeting the other criteria, the 6
of 12, because that has implications, as Dr.
Weisman has talked about, for recruitment, and in
the real world, where are we going to do these
things.
Because we under these criteria as
rheumatologists, but my concern really is, as has
been mentioned, that we are going to create a
paradigm that no one could get through.
DR. GIBOFSKY: Is that data available that
can be shared in terms of first attack versus
intercritical?
DR. MELIAN: Yes. Now that I am becoming
233
an expert at microphonetology here, in terms of
first attacks, they were relatively rare in our
studies, 92, 93 percent, somewhere in the 90s, 92
percent range of patients had had previous attacks
of gout.
On average, most patients had 4 or
greater, or at least if you categorized in
different categories of how many attacks you had,
the majority fell under 4 or greater.
In terms of how many had crystals, in our
study, about 25 percent had documented crystals.
We did not require that patients had to have
documented crystals in our study. We used the ARA
or the Wallace criteria.
DR. GIBOFSKY: Follow-up, Dr. Finley?
DR. FINLEY: I would just ask, as you had
more and more difficulty recruiting, were you doing
more arthrocentesis to document or you mentioned
just there at the end that you were using the
clinical criteria more, but I just want to better
understand your answer.
DR. MELIAN: So, in our studies, what we
234
required is that they use the clinical criteria,
and we set that up per the ARA guidelines. If you
go through those actual clinical criteria, A and B
of those criteria are crystal-proven gout. C,
which is the 6 out of 12, is the additional
clinical criteria.
So, we kept the rules the same, and what
we got out at the end of the study were the numbers
that you saw. We did not undergo any protocol
changes to help recruitment in this regard.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: One of the things I think Dr.
Finley is getting at, and a concern I have, is if
you extend the time point out too long, make the
study too long, is that you are passing the acute
gout and entering the gray area of where recurrent
gout occurs, and it may be unfair to a sponsor to
hold them to a longer time point when we are
treating acute gout, because there is really a gray
area there, who is going to have an acute attack
within the next two weeks versus the next six
months.
235
So, I think while we all are interested
biologically in how long we exactly have to treat
and how long that treatment is good for, I think we
have to be cognizant of the fact that these are
acute gout trials, and not chronic gout, and we
have to make some kind of, albeit it arbitrary,
timeline as to where the end of acute gout is.
DR. GIBOFSKY: Ms. McBriar.
MS. McBRIAR: I think also for the
patient's perspective, they don't want to be tested
and tested and tested too often either, so we need
to do what we have to do to get good results, but I
don't think we need to go overboard because we want
to learn more.
DR. GIBOFSKY: I think we have discussed
the first bullet and probably the second. The
third one is a bit more technical.
Is there clinical meaning in an analysis
of average of pain over several days? I guess, if
so, how many days?
Thoughts or suggestions on that specific
bullet? Dr. Cush.
236
DR. CUSH: Again, it goes to the early
debate on area under the curve, more of how much
time patients spend in pain. I don't think the
subtleties of pain involved here require this type
of presentation of data. I think it is no more
valuable than the patient-derived Likert scales of
pain or VAS. I think it is going to be the same
thing, and again, an average over time.
I think I would rather see a magnitude or
an absolute, so the magnitude is what your pain is
and what is has fallen to, and then the absolute
being time to resolution of pain.
DR. GIBOFSKY: Any further comments on
Roman III or any of the sub-bullets? Dr. Anderson.
DR. ANDERSON: On the area under the
curve, the advantage that I see is that it is a
single test. The way that the pain seems to go
with treatment for acute gout is that there is an
initial improvement, and then the improvement
continues, so that if you do an area under the
curve, you are capturing the speed with which the
pain is reduced and the eventual amount that it is
237
reduced, as well, and you are doing a single test
for it.
So, that, I would think would be the
advantage of it.
DR. GIBOFSKY: Dr. Schiffenbauer.
DR. SCHIFFENBAUER: Could I just get
clarification? In using the area under the curve,
is there any implication if the trial is a
non-inferiority versus a superiority to placebo in
this instance where the disease, the acute flare
resolves spontaneously, would that tend to make the
two drugs look more similar? You see my question
there in that regard? Am I not making that clear?
No?
DR. GIBOFSKY: The question is if you use
the AUC, does it make a difference whether you use
a non-inferiority versus a superiority.
Dr. Hochberg.
DR. HOCHBERG: I think I understand your
question, and in order to have spontaneous
resolution, let's say, in a superiority trial to
placebo, where you would worry about this occurring
238
in the placebo group, you would probably have to
have a 30-day trial, and then look at sort of the
area under the curve for 30 days, or at least the
outcome at 30 days. So, I don't think it would be
a problem in a 7-day or even a 14-day trial.
DR. GIBOFSKY: Further discussion on that
topic? Dr. Cronstein.
DR. CRONSTEIN: Again, I guess we come
back to the comparator drugs, as well, because of
the onset of action. I guess I am having a little
trouble seeing the extra value aside from the fact
that it's easier to compare one number to another
number as opposed to comparing eight numbers or
however many measurements.
So, again, all of the graphs that we have
seen have been pretty much superimposable, and I
imagine that going forward, since presumably, most
of the comparisons are going to be made to other
nonsteroidals, that, again, the graphs should be
pretty much overlapping unless you guys decide to
go test something different, you know, colchicine
or something.
239
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: Unless there is a drug that
can work faster than indomethacin. I mean I think
the area under the curve is useful for speed, speed
of response, but indomethacin works fairly quickly.
DR. CRONSTEIN: Right, and steroids don't,
so I don't know that it tells you--I mean steroids
may get you deeper at your second measurement than
indomethacin, I don't know that for a fact, but
they certainly don't do anything at early time
points.
DR. GIBOFSKY: So, if you use the area
under the curve, it may be a function both of the
methodology and the comparator.
DR. CRONSTEIN: Right.
DR. GIBOFSKY: Dr. Hochberg. Withdrawn by
Dr. Hochberg.
Any further comments on this point? Dr.
Schiffenbauer, have you gotten the information, the
results of our wisdom? Okay.
Let's move to Roman IV.
The onset and duration of an acute attack
240
is unpredictable and the extent of pain during an
acute attack of gout is variable.
Please discuss the clinical trial
implications of enrollment of patients who have
already had symptoms of an acute attack for a
period of time, for example, 48 hours.
Please discuss the clinical trial
implications of enrolling patients who may be
untreated or partially treated.
Shall we deal with the second bullet first
since I think we have already discussed some of
that earlier? Would someone care to respond to
that? Dr. Cush.
DR. CUSH: I believe that the Merck
approach was an intelligent one to allow patients
on chronic therapy, chronic maintenance therapy
with allopurinol and colchicine to continue on
those therapies. I do think that there would be
confounding factors involved if they were to
include patients who were previously treated with
corticosteroids or nonsteroidals, especially in the
last four weeks.
241
I think that their guidelines and
operations make the most amount of sense as far as
enrollment criteria and allowing patients to easily
enter the trial without complication.
DR. GIBOFSKY: So, you are differentiating
between the patient who is on chronic maintenance
and the patient who might have taken an OTC within
a day of enrolling in the trial.
DR. CUSH: Chronic maintenance is okay
again for colchicine and allopurinol. Any chronic
use of nonsteroidals or steroids would be an
exclusion, and then intermittent or recent use of
colchicine or allopurinol--I am not sure how that
factors in--but colchicine especially would be a
contraindication to inclusion.
DR. GIBOFSKY: DR. Weisman.
DR. WEISMAN: I think this is entirely a
practical issue as we heard from Merck, is that
they were only able to capture patients under these
circumstances. They found too many patients that
had already started on these anti-inflammatory
agents at the beginning of their acute attack,
242
which had to be excluded.
Everybody else, depending on their level
of disease activity, was included, which is the
same thing we do with rheumatoid arthritis. It
depends on what level of disease activity they are
going into the trial. So, I think it is just a
practical issue.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: One thing that might make
enrollment easier is to allow patients who have
taken a dose of ibuprofen, but not in the last 8
hours, because that is probably the most commonly
used OTC NSAID, and it is relatively short acting,
so if you had an 8-hour gap, it seems to me like
that might be a reasonable patient that you could
still enroll.
DR. GIBOFSKY: Anything further on bullet
2?
Let's go back to bullet 1. The
implications of enrollment of patients who have
already had symptoms of an acute attack for a
period of time, presumably untreated during that
243
period of time.
I assume that is what you are looking for,
Dr. Schiffenbauer.
Any comments about this? Dr. Cush.
DR. CUSH: I think in a sense there is a
natural selection here. Patients will present or
won't present. They are not going to present
because they have dealt with this before, they have
a means of dealing with it now, so they are not
going to show up. They are only going to show up
when things don't get better after they
self-treated themselves, in which case they are
excluded from these kind of trials anyway.
But the vast majority of people who have
acute gouty attacks, who will then seek help, will
do so within the first 24 to 48 hours anyway, so I
think that that is reasonable.
Most of the trials that we looked at, that
I reviewed, would include patients for either 18
hours or 24 hours, or as long as even 3 days, 48
and even 3 days, but I think that the 48-hour time
limit is probably reasonable, because you want to
244
give the patient an ample opportunity to respond,
and not catch them at the tail end of their
symptoms.
But we learned I think from the way that
Merck was trying to represent the data, that there
was a lead-in period that they weren't truly
capturing in the time it took them to get better
anyway, which was, you know, again 5 days or so,
certainly in their 7-day study.
So, again, you would like to get them as
soon as you can, so they are going to be at their
peak when you treat them.
DR. GIBOFSKY: And you would establish an
arbitrary cutoff of, say, 48 hours. A patient who
is untreated for longer might be less likely to
show clinical effect because we know by Day 5 to
Day 7, there is already some amelioration of
symptoms.
DR. CUSH: Well, as in other disease, how
early is early? I like it early as possible, 48
hours is very good, 36 I think would even be
acceptable, but beyond 36, you are starting to get
245
into an area where symptoms might begin to improve.
The Bellamy study really showed that
patients didn't show any evidence of improvement
until after the 48-hour time period, that symptoms
really began to improve significantly by Day 3 to
5. Of course, that is recognizing that is 3 to 5
plus the 2.8 days they had for time to
presentation, so again, I say that up to even 3
days, you might even be safe, but 48 hours would be
ideal.
Hence, if there are issues of enrollment,
then, maybe allowing up to 72 hours might be
reasonable as a start point in a study.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: Actually, Jack covered it
right at the end there. I was going to say that 48
hours, I agree most of the patients will come
within that time anyway, but I don't know that
there is a real--it is an arbitrary time point, and
there is not a lot of difference between 48 and 72,
and I would have made it 72 hours because it would
make it easier for recruitment.
246
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: I think this may point us
to one of the reasons that the company had a
problem enrolling this trial in the U.S., and maybe
I am completely off base and you will tell me, but
a lot of patients with gout, who are followed by
primary care doctors, let alone rheumatologists,
have a bottle of indomethacin at home in their
medicine cabinet and have been told, and may know
from experience, that if they get an attack of gout
on the background of colchicine or allopurinol or
whatever, that they pop their indomethacin, and
they may do that before they call the doctor or
come into the office, which would exclude them from
participating in a trial as we are designing it and
as the sponsor had designed it, because they have
been treated or partially treated.
So, the duration of the attack is one
thing, but the fact that NSAIDs are prescribed,
NSAIDs were available over the counter, and it is
certainly true in other countries where you can go
and buy them even without a prescription, that
247
people who have had gout and have been treated for
gout, are likely to self-medicate themselves before
they come in.
DR. GIBOFSKY: Dr. Cronstein.
DR. CRONSTEIN: Again, I would like to go
back and revisit Dr. Bathon's statement at the end
of the last bullet about possibly admitting people
to trials who were taking the short-taking
nonsteroidal, but hadn't taken it for, say, 8
hours.
Forget about the indomethacin, but many
patients will just go to the drugstore and buy
Motrin or Advil or something. I think that might
improve recruitment. I don't know if you have the
numbers as to what drugs people were taking. Is it
broken down into over the counter versus
prescription nonsteroidals? In the screen?
DR. GIBOFSKY: Response if you have it.
DR. MELIAN: We don't have that
information with us, sorry.
DR. CRONSTEIN: But I think that is an
excellent idea of permitting--and that may
248
alleviate some of the problems with recruitment if
you permit short-acting nonsteroidals outside of a
certain time frame.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: When I look at Merck's data
on the time of onset to randomization, 80 percent
of the people presented within the first day, and
only 20 percent within the second 24-hour period,
so extending it to 72 hours is probably not going
to pick up a great deal of additional patients.
DR. GIBOFSKY: Further discussion on Roman
Numeral IV? Have we reached consensus, now
recommendations? Okay.
Let's move to Roman V.
Considering the extent of pain and
duration of attacks at trial entrance, please
discuss the advantages and disadvantages of
placebo-controlled studies versus active-controlled
trials. If placebo-controlled studies are not
recommended, are there data from studies of
existing therapies sufficient to define a margin of
non-inferiority?
249
I think we heard in Dr. Daikh's
presentation, I believe there were two slides
looking at the advantages and disadvantages of
placebo-controlled studies versus active-controlled
trials, and I think certainly that is worthy of
note to the answer or to the comment on the first
sentence.
Dr. Williams?
DR. WILLIAMS: I am a big believer in
placebo-controlled trials, but in this case, I
realize these treatments haven't been demonstrated
in randomized, controlled trials, but we certainly
feel that they are effective treatments, and I
think a placebo-controlled trial would be very
difficult to sell to the investigators, as well as
to the patients.
DR. GIBOFSKY: Any other comments? Dr.
Bathon.
DR BATHON: I agree with that. The other
complication is that a lot of times we don't know
these people. You can talk rheumatoid arthritis
patients into a placebo-controlled trial as long as
250
there is rescue, and you could argue that maybe you
could ask them to put up with--the gout patients to
put up with two days of placebo, and then have a
rescue, but because you don't have a relationship
with these people and they are coming in
desperately for treatment, I think it would be a
very difficult sell to give a placebo.
DR. GIBOFSKY: I'm getting a sense that in
this particular situation, we are not recommending
or at least we think that placebo-controlled trials
would be disadvantageous to the patient.
So, we can go to the second comment, the
second sentence, which is are there data from
studies of existing therapies sufficient to define
a margin of non-inferiority for an active
comparator.
Dr. Cush.
DR. CUSH: I wanted to add one caveat to
placebo-controlled trials, which was brought up
earlier by Dr. Hochberg, and that it is appropriate
for truly new compounds and novel compounds for
which an active comparator may not be a reasonable
251
comparator, I mean one that is currently approved
and marketed. So, that is the one caveat.
DR. GIBOFSKY: Dr. Harvey.
DR. HARVEY: Before you moved on, I didn't
know if you wanted there to be any further
discussion or any elaboration on the concept of
medication rescue, some of the variations on that
theme.
DR. GIBOFSKY: Dr. Cush.
DR. CUSH: Certainly, a placebo-controlled
trial, that would be the only way one could do
that, and I think that any out point where the
patient felt that the pain was extreme and
unbearable, and patients have to be told that, you
know, there is a chance that your condition could
get better by doing nothing and just resting.
You could have as a part of placebo
management, ice and whatnot, but anyway, they still
have to be told they could get worse, too, and
should they get worse, they could be offered either
an analgesic or a standard of care as rescue
therapy, and that becomes one of your arms, one of
252
your outcomes, your secondary outcomes.
DR. GIBOFSKY: In rheumatoid arthritis, we
are learning that leaving a patient untreated for
even a brief period of time may affect the ultimate
outcome in the clinical course of a disease.
Do we have any data that is either similar
or distinct in gout, whether leaving a patient
untreated for gout in the context of
placebo-controlled trial may be acceptable in the
short term, but may have implications for either
other manifestations, hyperuricemia, if present, or
their chronic intercritical gout?
Dr. Weisman.
DR. WEISMAN: Well, we heard from Bob
Terkeltaub earlier today that there is data
indicating that the process continues, and there
are many patients that go on with some kind of
smoldering disease, just even keeping aside the
concept of hyperuricemia, just the fact that the
joint disease appears to progress clinically even
in the intercritical periods.
Although you are not going to be able to
253
support this with MRI data, like you can--or early
erosion data in rheumatoid arthritis, because there
hasn't been any studies looking at this structural
damage issue, but I suspect there probably will be
at some point, there will be some data to document
this whether it's investigator initiated or
pharmaceutical company initiated, but there will be
some data.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: I think that because we are
convinced we have effective therapies, that if you
had a placebo-controlled trial with rescue, you
would end up without a placebo control.
DR. GIBOFSKY: Are there data from studies
of existing therapies sufficient to define a margin
of non-inferiority?
Anyone want to tackle that one? I think
we heard some of that in Dr. Daikh's presentation
as to why the study was designed the way it was
given the limitations of existing therapies and the
ability to define the margin of non-inferiority,
but anyone else want to comment on that?
254
[No response.]
DR. GIBOFSKY: Okay. Dr. Harvey, are you
comfortable with a response to your question about
rescue?
DR. HARVEY: I am never comfortable, but I
will--
DR. GIBOFSKY: Would you like a cushion?
DR. HARVEY: Dr. Schiffenbauer has an
elaboration.
DR. SCHIFFENBAUER: I didn't have a
specific issue about the rescue, but I just wanted
to get some clarification from the Committee.
If I have heard you correctly, you would
allow individuals to have an attack for 48 up to
possibly 72 hours, and I heard maybe some
disagreement as to whether they could or could not
take some therapy during that time, possibly
ibuprofen possibly, or nothing, and then you were
objecting or you were concerned about
placebo-controlled trials, and I am not quite
comfortable that I understand the difference there.
I guess the concern I have or the question
255
I have is if someone is untreated for 48 to 72
hours, if that is what we are saying is one way to
approach this, is there an objection to entering
them into a placebo-controlled trial that may
continue for an additional 6 or 8, 12, 24 hours of
that placebo-controlled period to evaluate in a
rigorous fashion the effects of a new therapy.
DR. GIBOFSKY: So, your question is if
someone has gone for two days on their own for
whatever reason, perhaps it's Friday night and they
can't get to their doctor until Monday, what is the
up side and down side to beginning the clock at T
zero and then putting them into a
placebo-controlled trial.
DR. SCHIFFENBAUER: Yes, and let me just
add although I think we do all think that Indocin
works effectively, I don't know that we truly have
any idea of when it starts to work, how effective
it really is, because we don't have those
placebo-controlled trials to document that. Maybe
someone could address that.
DR. GIBOFSKY: Dr. Hochberg, did I see
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your hand going for the microphone? I do now.
DR. HOCHBERG: Again, if we go back to
Question I, I guess we felt that gout was an
acutely painful condition, but it was more than
just pain. You know, there was a tremendous role
for inflammation.
Then, in one of the subsequent questions,
I don't remember whether it was II or III, that we
are front-loading the outcomes and looking at some
of the outcomes that are used to assess agents for
the treatment of acute pain.
So, clearly, there is a period in which
this could be placebo-controlled in order to define
the time course of the response in comparison to
placebo in this painful inflammatory condition.
But then you get into the issue in a
placebo-controlled study of rescue, and personally,
I mean I have had a lot of experience in
osteoarthritis trials, and I don't like rescue
because I think it sort of muddies the
interpretation of the results, and some of the
meta-analyses now suggest that the effect size that
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is seen with treatment in studies that do not allow
rescue is larger than the effect size which is seen
in studies which do allow rescue, suggesting that
there is an effective rescue.
Then, you have to decide, well, what is
the rescue going to be, does the patient stay in
the study and continue to get observed on rescue to
contribute to the analysis in the placebo group, or
once they go on rescue, are they a failure, and
then you are looking at time to failure as an
outcome. So, that gets real problematic from my
point of view.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: Your question about how
quickly things seem to respond, the data that was
presented to us by Merck would suggest that they
respond to both agents within the first few hours,
and I find that there will be some moral dilemma to
try and put patients on placebo if I can make them
better. Patients with gout are miserable, and to
ask them to hold off for treatment for 12 to 24
hours, I would find it a difficult ethical issue.
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DR. GIBOFSKY: Dr. Schiffenbauer.
DR. SCHIFFENBAUER: Again, that is in the
context of recruiting individuals that have gone
already 48 hours or up to 72 hours without therapy.
That is the point I want to clarify.
DR. WILLIAMS: They didn't come to me in
the first 48 hours. Once they have come to me,
they are then there to be treated, and that is when
my time clock started.
DR. GIBOFSKY: Does that answer your
question, Dr. Schiffenbauer? Okay.
Ms. McBriar.
MS. McBRIAR: It seems that a lot of
people have talked about the severe inflammation
that is going along with the severe pain in these
patients early on, and it just worries me if the
rheumatoid arthritis data is true about the early
damage, and we want to preserve joints and we want
to preserve function, that if we do a
placebo-controlled trial, that there could be this
damage to the joints early on, and, as the consumer
rep, if we don't have to go that way, I would be
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much happier.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: I prefer placebo-controlled
trials. We don't have control over when the
patient presents, so we can't be responsible for
that, but I think it is just really a practicality
measure. If they are presenting for treatment, and
it's an acutely severely painful condition like
this, it is very difficult to enroll people in
placebo-controlled trial.
I think we could try it, but I bet you it
would introduce yet another layer of recruitment
difficulty, so it may make it impractical. I think
that until we know data about damage, we can feel
reasonably ethically comfortable still that a
placebo-controlled trial is fairly ethical in terms
of lack of data on joint damage.
If we find down the road by MRI or
something that each single attack adds more and
more damage to the joint, then, we would have to
rethink that.
DR. GIBOFSKY: Dr. Cronstein.
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DR. CRONSTEIN: I realize that there is a
suspicion based on the RA trials, but the RA
trials, you are talking about months of
inflammation as opposed to here you are talking
about a difference of 12 to 24 or 48 hours. I
really don't think there is any reason to think
that delaying treatment is going to give you a
chronic or more of a chronic problem as far as
arthritis goes. I don't think there is any
evidence for that.
I think, in fact, there are many patients
who have one or two acute attacks over long
periods, not sufficient to require a prophylaxis,
and they don't have any specific joint injury. I
don't think that the worry about that is the main
issue.
I just find that if you have something--I
know we haven't done the placebo trials--but if you
have something that you know works at least as a
pain reliever, that depriving a patient with gout,
with an acute gouty attack, you know, depriving
them of any pain relief, I don't think that is
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feasible, and I don't think that we are going to
see the same placebo responses that we would
otherwise have seen, but obviously we can't do
that.
DR. GIBOFSKY: Dr. Boulware.
DR, BOULWARE: I think the
placebo-controlled observation for 8 hours would be
ideal, too, but I think another layer of
practicality is when you enter them, you have 8
hours to do the follow-up study, and unless there
is something that the patient is going to do, which
then becomes maybe unreliable, it is very
impractical to ask my staff to stick around until
midnight when you enter somebody at 4 o'clock in
the afternoon.
DR. GIBOFSKY: Dr. Geis.
DR. GEIS: Until I saw placebo data for
the first few hours after the first dose, I don't
know that I would conclude that you are seeing a
real effect of a drug or just a placebo effect. It
is after seeing just lots of data in different
conditions.
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You could build in a substudy where you
maybe have 50 patients per group where you are
looking for this short-term response comparing
placebo to the active, so you don't have to build
it in for all 150 patients, that you might need to
look for the total response over several days, so
that may be one way of doing it, and then have
specific sites who feel they have the staff to
follow up in the first 8 hours, and all of that, so
there may be a way you could work it and get both
things.
DR. GIBOFSKY: Any further comment on
Roman Numeral V? Dr. Schiffenbauer.
DR. SCHIFFENBAUER: The second part of
that was the non-inferiority margin and the effect
size of any comparator. Did anybody have any other
comments about that because that was left
unresolved.
DR. GIBOFSKY: I think the question as
posed is part of your data from studies of existing
therapies. I believe we heard that the data from
existing therapies are meager at best, and that
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resulted in the design trial that we heard earlier
today, which is probably as good as it gets based
on the data that is available.
Unless anyone has knowledge of a different
data set, but I suspect if there were, it would
have been factored by the consultants into the
trial design that we heard today.
Let's move to Roman VI. Please discuss
the following clinical trial issues: the use of
concomitant medications such as diuretics or low
dose aspirin. The entry inclusion criteria for an
acute gout trial, particularly the need for
documentation of the presence of crystals, and to
make it perhaps a bit simpler, let's talk about the
first attack of acute gout in a person's life
versus an attack of acute gout in a patient who is
known to have the diagnosis of gout, and then
enrollment of patients with polyarticular gout.
Should the trial be stratified by this
factor, are there other factors to consider for
stratification.
Who would like to begin the discussion on
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that? Dr. Cush.
DR. CUSH: I think we already covered the
con meds issue of colchicine and allopurinol as
background therapy. I think diuretics, I think
they are real world, they should be allowed.
Aspirin, I think is a confounder as is
nonsteroidals, and if at all possible, those
patients should be excluded or the low dose aspirin
be stopped for the period of study. I am not sure
that there is a significant acute risk to stopping
81 mg of prednisone a day.
I think that the entry criteria, I would
still advocate the use of the ACR criteria because
they are the best studied although I do think that
more liberalized criteria should be established
because that may be one of the factors that hampers
enrollment, and I don't think that crystal
identification has to be a part of the mix.
Obviously, it is factored into the
equation the ARA used in its deliberations to
arrive at criteria, but they are helpful, but not
required.
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In clinical practice, we all do this, we
don't absolutely have to have crystals, we would
like to see crystals, but we don't have to have
crystals to have a certain or incompetent diagnosis
of gout and to proceed with therapy, whether it be
acute therapy or more chronic hyperuricemic
therapy.
I would argue against polyarticular gout.
I think especially if it's first time attacks, Dr.
Gibofsky asked do we want to just only go after
nascent, brand-new onset gout, but I think that is
too restrictive, and those patients are going to be
even harder to find, and will require more of a
public health kind of campaign for advertising to
find those patients.
They are out there, and there is a certain
steady flow of them. We have well-defined incident
rates, but it will be harder to do. Especially in
that population, I would avoid polyarticular gout.
In more established populations, I think to include
them might be reasonable, but to get to an
assessment issue, as Dr. Bathon was talking about,
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is which joint do you go after, which becomes your
index joint.
Maybe the one you chose as your index
joint is really not your worst one, and will not
respond as maybe other joint will respond, and
there is always the worry of background therapy.
Stratification is only going to be I think
necessary if you have again a more rapid and
liberalized inclusion criteria that allow patients
to be seen, consented, screened by clinical
parameters, and then enrolled rapidly.
Then you have to basically do a post hoc
stratification for things that you might accept not
unknowingly, which might include uncontrolled
hypertension, renal disease, et cetera.
DR. GIBOFSKY: Dr. Cush, I think you may
have misunderstood my comments about crystal
analysis. I was referring to bullet 2, where the
question would be if you had a patient who is
presenting with gout de novo and no history of
gout, would you prefer the crystal analysis to the
six Wallace criteria as opposed to a patient who is
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known to have a diagnosis of gout, would not the
Wallace criteria suffice, in which case you would
not need the crystal analysis.
In other words, the first patient comes to
you in clinic with what looks like podagra despite
the discomfort of the arthrocentesis, wouldn't you
want to know that you are dealing with monosodium
urate as opposed to your patient who has been with
you for five years, who comes in and says here I am
again.
DR. CUSH: And I believe that the actual
paper, the Wallace criteria paper from 1977 deals
with this fact and comfortably allows you to make
the diagnosis in either situation, with or without
crystals. It is very clear by the inclusion of
crystal identification, you increase the
specificity of diagnosis to 100 percent. That is
absolutely true. But without it, you don't lose
that much, you are down 10, 15 percent I think at
the most was the number that was in the paper.
So, just by going like clinical criteria
alone, if you make it, then, you are going to be
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in. Of course, it is always great to have
crystals, but I don't think you need to do it from
the standpoint of having diagnostic criteria. I
think the diagnostic criteria were developed to
allow for that degree of leeway, but then again,
this is really a point most pertinent to going
after patients for first time attacks.
If that is the sole kind of study one
wants to do, you are going to have trouble, and it
is not the trouble in identifying crystals and
making the diagnosis, it is trouble in finding the
patients.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: I would argue that I would
like to see the diagnosis by the demonstration of
crystals at some point. There are so many patients
out there who say they have gout, who we can't
document they really have gout, that at some point
in the course, I would like to have crystals
demonstrated. After that, I am perfectly willing
to rely on the criteria that say that that current
attack is an attack of gout.
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DR. GIBOFSKY: Dr. Cronstein.
DR. CRONSTEIN: I think as Dr. Cush
pointed out, somebody who comes in with an acute
podagra, it is pretty unlikely it is going to be
anything else. The discomfort of the tap, you
know, adds to the difficulty in recruitment if that
is going to be an issue, and then finally, a lot of
emergency rooms are probably not going to be
equipped for appropriate crystal examination.
So, I think that even though it is a small
percentage of the patients, you said it was 10 or
20 percent, something like that, a small percentage
of the patients, I think that might hinder
recruitment, and I don't think that we necessarily
need that level of documentation.
DR. GIBOFSKY: Dr. Schiffenbauer.
DR. SCHIFFENBAUER: Would there be any
concern if there was an imbalance in the groups,
the treatment groups, for those that had crystal
identification versus those that don't because of
the false positive or false negative rate, that
issue, do you either require that everybody have it
270
or everybody use clinical criteria just to avoid
that possibility?
DR. GIBOFSKY: Dr. Hochberg.
DR. HOCHBERG: I would actually be
consistent with the way in which other rheumatic
conditions--I hate the word rheumatic--other
arthritis conditions are described in draft
guidance documents and in entry criteria, that the
patient has a clinical diagnosis of and fulfills
American College of Rheumatology classification
criteria for is often the way that studies are
recruited for, that protocols are written,
protocols are agreed upon by the sponsor and the
Agency, and papers are written.
That is how we do it for rheumatoid
arthritis and oftentimes for osteoarthritis, not
all the time for osteoarthritis, so I think
somebody with a clinical diagnosis of gout, who
fulfills what granted are old, but haven't been
revisited criteria for gout would buy somebody into
a study.
Some of those people will be aspirated for
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crystal identification, and that is how they will
fulfill them, some of them won't, and I think that
ought be reported in a paper, and that could be
compared as part of the table 1 baseline data in a
paper and clearly be reported in the report that
comes to the Agency for the Agency's review, and if
the Agency notes an imbalance, the statisticians
can look at it and decide how they want to deal
with it.
I would stratify on polyarticular gout if
I was designing a protocol, because I think, you
know, there is a suggestion that the time to
response may be different because of the burden of
disease and the number of joints involved.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: I agree strongly with what
Dr. Cronstein said earlier about not requiring an
arthrocentesis, but the only thing I am concerned
about is that if this trial were done heavily in
primary care practices or emergency rooms, I think
a lot of rheumatologists amongst us are skeptical
about the validity of joint exams done by
272
non-orthopedists and non-rheumatologists.
Many patients come to us with supposed
joint swelling and joint findings that we can't
corroborate, so that would be an issue, you are
just relying on clinical criteria.
DR. GIBOFSKY: What about Dr.
Schiffenbauer's question, should whatever criteria
that are adopted be uniformly applied, requiring
either crystals for all or crystals for none?
Dr. Williams.
DR. WILLIAMS: I agree with Marc. I think
that if you are going to accept the criteria, the
12 criteria, you allow them to have either way to
make the diagnosis, those are the guidelines.
DR. GIBOFSKY: Further comments on any of
the bullets listed here? Is the Committee
comfortable with the recommendations about
stratification, inclusion criteria, and the use of
concomitant medications?
Dr. Hochberg.
DR. HOCHBERG: I would like to ask a
question about concomitant medications. Are there
273
any data on whether low-dose aspirin, 81 mg, has an
analgesic effect?
DR. GIBOFSKY: Any data from the Agency
perhaps?
Dr. Cronstein.
DR. CRONSTEIN: I am not aware.
DR. GIBOFSKY: Well, you were sitting next
to Dr. Schiffenbauer. Guilt by association, Dr.
Cronstein.
DR. CRONSTEIN: I am not aware of any
data.
DR. HOCHBERG: There was a prior comment
made to discontinuing low-dose aspirin on entry
into a trial, and if there is not an analgesic
effect of low-dose aspirin, then, why would it be
discontinued in somebody who might be on it
especially, you know, somebody at risk for coronary
disease or has had a prior thrombotic event and has
gout, and comes into a trial. I mean I would
probably want to leave them on it.
DR. GIBOFSKY: I think that is a fair
question.
274
Dr. Williams.
DR. WILLIAMS: Actually, Jack was the one
that made that point and he has gone, but the
reason would be is because of its effect on uric
acid retention in low doses. I think that you
could make the case for just continuing their
medications at the same stable dose and make just
as much sense.
DR. GIBOFSKY: Dr. Cronstein.
DR. CRONSTEIN: I think the same could be
said for diuretics, and there you can lose control
of hypertension if you stop them, so I think that
things should just continue.
DR. GIBOFSKY: I think we would be
comfortable with continuing concomitant medications
at the stable dose that the patient is on at the
entry of the study. I believe we have discussed
bullet 2.
Any further comment on stratification by
other factors? I think we have talked about
polyarticular gout. Anyone want to make any other
comments about stratification?
275
DR. HOCHBERG: Could I ask you a question?
DR. GIBOFSKY: Please.
DR. HOCHBERG: Do we know whether there
are any other variables that affect the response to
treatment in patients with acute gout, that we
might want to stratify on because they might be
associated with response?
DR. GIBOFSKY: I am sorry Dr. Terkeltaub
isn't here and Dr. Cush has gone. Dr. Cronstein.
DR. CRONSTEIN: The question is whether
you have somebody who has an acute attack on top of
chronic tophaceous gout and whether they ever get
back to baseline, and I think that that is
problematic.
Were there many patients in your trial
that had chronic tophaceous gout or did you exclude
them?
DR. MELIAN: I don't have the exact
number, but I think we had about 10 to 20 percent
of patients that fell in that general category. I
don't have the numbers in front of me, so I am
stretching here a little bit, but I think it was in
276
that general ballpark.
DR. CRONSTEIN: Do you know if there was a
difference in response, because if they already
have structural damage to the joint, is that going
to interfere with your ability to--
DR. MELIAN: That is something that we
would have to go back and look at the database. We
think if anything is going to have an impact on the
things that we have looked at, it would be baseline
pain where patients with more severe pain tend to
have a greater improvement.
DR. GIBOFSKY: Dr. Williams.
DR. WILLIAMS: We did not address
allopurinol and I assume the patients who were on
chronic allopurinol would remain on like we do with
diuretics and aspirin.
There is some, I don't know if it's
evidence based, that starting allopurinol can
prolong the attacks of gout, and if they got put on
allopurinol, I assume they would have been put on
other medications and not qualify for the trial
anyway, but if someone were just put on allopurinol
277
acutely, or if that should be stopped or at least
stratified.
DR. GIBOFSKY: Dr. Bathon.
DR. BATHON: Apparently, some
complementary and alternative things that are out
on the market have steroids in them, so we might
just say restrict those kinds of things.
DR. GIBOFSKY: Any further comments about
Roman Numeral VI? Any further comments about any
of the issues we have been discussing this
afternoon in response to the questions posed to us
for consideration?
Any other questions from you, Dr.
Schiffenbauer, for our consideration? Anyone?
If there are no further questions from the
panel or issues to discuss, Dr. Harvey, would you
like to make some concluding remarks?
DR. HARVEY: First of all, I would like to
thank you all for your service to the Committee. I
really believe that these last two days have been
very productive and have had a lot of good
discussion on all the different areas that were
278
outlined in the agenda.
I really think that this discussion and
what we have done yesterday and today will lead to
future clinical trials for new therapies for
patients who are currently suffering, so I thank
you for your service.
DR. GIBOFSKY: Thank you. I would like to
thank the members of the panel for their spirited
and considered deliberations these last two days.
I would like to thank you once again for making my
job so easy and hopefully, yours so enjoyable.
I will declare this meeting adjourned.
[Whereupon, at 2:08 p.m., the meeting
adjourned.]
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