DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ARTHRITIS ADVISORY COMMITTEE
Wednesday, June 2, 2004
ACS Conference Room
5630 Fishers Lane
Allan Gibofsky, M.D., J.D. Chair
Jayne E. Peterson, R.Ph., J.D., Executive Secretary
Jennifer J. 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
Gary Stuart Hoffman, M.D.
Wendy W. McBriar, R.N., M.S., C.H.E.S.,
SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS (VOTING):
H. James Williams, M.D.
Brian F. Mandell, M.D., Ph.D.
David T. Felson, M.D., M.P.H.
GOVERNMENT EMPLOYEE PARTICIPANT (VOTING):
Marc C. Hochberg, M.D., M.P.H.
GOVERNMENT EMPLOYEE SPEAKER (NON-VOTING):
Robert Terkeltaub, M.D.
Brian Harvey, M.D., Ph.D.
Sharon Hertz, M.D.
James Witter, M.D., Ph.D.
Lourdes Villalba, M.D.
C O N T E N T S
Call to Order, Opening Remarks, Introductions,
Allan Gibofsky, M.D., J.D. 5
Conflict of Interest Statement,
Jayne E. Peterson, R.Ph., J.D. 8
Welcome, Brian E. Harvey, M.D., Ph.D., Acting
Director, DAAODP, FDA 12
Uric Acid and Gout, James P. Witter, M.D., Ph.D.,
Medical Team Leader, DAAODP, FDA 16
Gout: An Evolving Problem at a Therapeutic
Crossroads, Robert A. Terkeltaub, M.D., Chief,
VAMC Rheumatology Section, Professor of Medicine
in Residence, University of California,
San Diego 38
Cardiome Pharma, Inc. Presentation:
Introduction, Alan Moore, Ph.D., Executive Vice
President, Clinical Development and Regulatory
Gout: a Serious Progressive Disease,
Ralph Snyderman, M.D., Duke University
Health System 88
Oxypurinol Efficacy and Safety, Garth Dickinson,
M.D., University of Ottawa 96
OXPL213 Analysis, Robert W. Makuch, Ph.D.,
Yale University 106
Unmet Medical Need/Clinical Experience and
Post-Approval Issues, Leonard Calabrese, D.O.,
Cleveland Clinic Foundation 115
Oxypurinol for Symptomatic Gout in
Lourdes Villalba, M.D., Medical Officer,DAAODP, FDA 139
C O N T E N T S (Continued)
Open Public Hearing:
Edward G. Mihalo 175
Nancy Joseph-Ridge, M.D. 179
Jane T. Osterhaus, Ph.D. 184
Zeb Horowitz, M.D. 188
Walter J. Clifford Statement 193
(Read by Edward G. Mihalo)
Allyn Hamilton 198
Committee Discussions and Questions 200
P R O C E E D I N G S
Call to Order, Opening Remarks, Introductions
DR. GIBOFSKY: Good morning and welcome to
the first of a two-day meeting of the FDA Arthritis
Advisory Committee. My name is Allan Gibofsky,
from Cornell University Medical College, and it is
my privilege and honor to serve as chair of the
I would like to begin by welcoming
everyone here, our colleagues, our visitors and our
guests from the public to the first of two days of
what I know will be a very spirited and interesting
discussion focusing on an old disease and new
implications for its therapy in the public good.
I would like to begin by asking the
members of the table to please identify themselves
for the record and for the public who are observing
us, beginning on my far right, Dr. Geis.
DR. GEIS: I am Dr. Steve Geis. I am the
industry representative on the committee. I am a
now retired member of the community and previously
worked in the pharmaceutical industry.
DR. FINLEY: I am Michael Finley. I am
Associate Professor of Medicine at Western
University College of Osteopathic Medicine, Pacific
and Pomona, California. I am a member of the
committee and a rheumatologist.
DR. CUSH: Jack Cush. I am a
rheumatologist from Presbyterian Hospital in
MS. MCBRIAR: Wendy McBriar, Director of
Arthritis Services at Virtual Health in New Jersey,
DR. BOULWARE: Dennis Boulware, Professor
of Medicine, University of Alabama at Birmingham,
and I an a rheumatologist.
DR. BATHON: Joan Bathon. I am a
Professor of Medicine at Johns Hopkins University
and a rheumatologist.
DR. MANDELL: Brian Mandell, Vice Chairman
of Medicine at the Cleveland Clinic, Department of
DR. WILLIAMS: Jim Williams,
rheumatologist at the University of Utah.
MS. PETERSON: I am Jayne Peterson. I am
the Acting Executive Secretary of the Advisory
Committee meeting today.
DR. GIBOFSKY: Allan Gibofsky, Professor
of Medicine and Public Health Cornell University
and a rheumatologist.
DR. ANDERSON: Jennifer Anderson, Research
Professor Emeritus of Biostatistics at Boston
University School of Public Health.
DR. HOFFMAN: Gary Hoffman, Cleveland
clinic, rheumatology, Professor of Medicine and
Chairman of Rheumatology.
DR. FELSON: David Felson, Professor of
Medicine at Boston University School of Medicine
and a rheumatologist.
DR. VILLALBA: Lourdes Villalba. I am a
medical officer in the Division of Anti-Inflammatory,
Analgesic and Ophthalmic Drug
Products and I a rheumatologist.
DR. WITTER: Good morning. Jim Witter,
from the FDA.
DR. HERTZ: Good morning. Sharon Hertz, I
am Deputy Director for this Division of Anti-Inflammatory
and Analgesic Drug Products.
DR. HARVEY: I am Brian Harvey. I am the
Deputy Director of the Office of Drug Evaluation V,
and it is my pleasure to be the Acting Division
Director for this Division.
DR. GIBOFSKY: Thank you, all. Now I
would like to call on Jane Peterson, our Acting
Executive Secretary, to review the conflict of
interest statement. Jayne?
Conflict of Interest Statement
MS. PETERSON: Thank you. I am going to
read the conflict of interest statement now. 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
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
conflict of interest at this meeting, with the
Dr. Brian Mandell has been granted a
waiver under 18 USC Section 208(b)(3) for
consulting with a competitor on a general issue.
He receives less than $10,001 a year. Dr. Allan
Gibofsky has been granted a waiver under 208(b)(3)
for consulting and speaking for a firm that has an
interest in a competitor. He consults and speaks
on matters unrelated to those being discussed at
this meeting. He receives less than $10,001 a year
for consulting and greater than $10,000 a year for
speaking. Dr. John Cush has been granted a
208(b)(3) waiver for consulting and speaking for a
competitor on unrelated matters. He receives less
than $10,001 a year for consulting and less than
$5,001 a year for speaking. Dr. David Felson has
been granted a 208(b)(3) waiver because a colleague
has a research grant from a competitor to study
gout in general. The grant is less than $100,000 a
year. Wendy McBriar has been granted a 201(b)(3)
waiver for consulting with a competitor on an
unrelated matter. She receives less than $10,001 a
Dr. Robert Terkeltaub has been granted a
limited (208)(b)(1) waiver for consulting with two
competitors. He consults on unrelated matters for
one and on an unrelated matter for the other. He
receives less than $10,001 a year from each firm.
He also speaks for a competitor on gout and
receives less than $5,001 a year. Under the terms
of the limited waiver, Dr. Terkeltaub will be
permitted to make a presentation to the committee
and to answer any questions related to his
presentation, however, he is excluded from
participating in the committee's discussions.
Lastly, Dr. Marc Hochberg has been granted
a 208(b)(1) waiver for his consulting with two
competitor son unrelated matters. He receives less
than $10,001 a year from each firm.
A copy of these waiver statements may be
obtained by submitting a written request to the
agency's Freed of Information Office, Room 12A-30
of the Parklawn Building.
Lastly, we would also like to 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
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 product they may wish to comment upon. Thank
you. Dr. Gibofsky?
DR. GIBOFSKY: Thank you, Miss Peterson.
We are going to have a very full agenda today with
a number of distinguished speakers making
fascinating presentations. I would also like to
ask our colleagues in the audience to remember that
we do have a time schedule for the open public
hearing at which time, if any of them would like to
offer any comments on the presentations, they can
feel free to do so. Please schedule them through
the Acting Executive Secretary or through a member
of the FDA staff as we go into our deliberative and
At this point I would like to introduce
once again Dr. Harvey, the Acting Director of the
DAAODP, who will offer us some welcoming remarks
and introduce the first speaker of the program.
DR. HARVEY: Great! Thank you very much
and thank you all for being here. I would like to
say that I am pleased that under my watch the work
of many people, over many years, is coming together
for this two-day panel on the treatment of gout,
both acute and chronic. Of course, you all have
the agenda here and we will be getting to that in
just a second.
I would like to say it is my pleasure to
be the Acting Director of this Division. I am
currently at the Office level as well in the Office
of Drug Evaluation V. I took over back in November
from Lee Simon so I have some big shoes to fill.
This past fall, when I told my wife that Dr. Simon
was leaving and, I said, going to a better place,
she said, "oh my goodness, is he sick? Did he
die?" "No," I said, "he's going back to Harvard."
But I am glad to be here.
As we look over the agenda and we see that
we are dealing both with the issues of acute and
chronic gout, in my current position I have the
opportunity, as an outside activity, to still see
patients on weekends as an in-hospital medicine
physician. This past weekend--you know, federal
holiday, what better way to spend it than working
in a hospital! I actually did see a patient with
an acute attack of gout. I won't go into any
details. I don't want to violate HCFA, but it
amazed me that in the twenty years since I have
been in medical school the treatment options that
we have for this patient, just past Monday, really
have not changed much. You know, we have the same
basic medications that we had back when I was in
medical school in the '80s.
So, I think we really have an opportunity
to here to chart the future and we have the
expertise. We have all the important groups
represented and I think we can really do a lot to
sort of outline future clinical trial designs and
sort of a broad overview but also in some nuts and
bolts ways on the future of clinical trial designs
for both the acute treatment as well as chronic
treatment of gout.
In thinking about it, as part of the
mission statement of the FDA under the FDA
Modernization Act of 1997, affectionately known as
FDAMA, it actually outlines what our mission is,
and it is not only to protect the patients but it
is also to promote patient health, to paraphrase.
I think the two days of this panel meeting really
represent what that is all about.
So, at this time I would like to thank the
committee members, both the permanent members and
the consultants. I would like to thank the
presenters. I would like to thank the industry
representative and the patient representative for
their perspectives on things. Of course, I mean,
the reason we are all here is because of the
patients. I would like to thank those in the
audience for your attendance today because getting
information out, education, patient awareness,
public awareness is also an important part of that
puzzle as well. So, for those who are going to be
presenting at the open public hearing and those who
are in the audience listening, I think we are all
playing important roles and I would like to thank
you all for being here.
Actually, at this point I would like to
introduce the first presenter, Dr. Jim Witter who
is one of our senior medical officers in the
Division and a team leader. He is going to give
his presentation on uric acid and gout. Dr.
DR. GIBOFSKY: While Dr. Witter is coming
to the podium, could I ask the member of the panel
who just joined us to identify himself and
introduce himself for the record, please?
DR. HOCHBERG: Marc Hochberg, University
of Maryland, Baltimore and the Maryland Veterans
Affairs Healthcare System.
DR. GIBOFSKY: Thank you, Dr. Hochberg.
Uric Acid and Gout
DR. WITTER: Good morning. Thank you for
being here today, taking time out of your busy
schedules to help us with the topic today and
tomorrow, which is an area that is often ignored in
terms of public health, as Dr. Harvey has just
So, what we want to do over the next two
days is to really tap the resources that we have
here and gather input regarding issues that we
should consider as we think about clinical trials
intended to support the development and approval
for drugs that treat gout and/or hyperuricemia.
We will be focusing over the next two days
on both the acute situations and chronic
situations, somewhat of an artificial divide but we
thought it was necessary and was most effective to
do it that way. My comments will be particularly
towards a chronic setting.
So gout, what is the problem? Well, as I
indicated earlier, it is an important unmet medical
need because it causes both acute and chronic pain.
In certain settings, in certain situations it can
also cause joint and renal damage. There is an
increasing incidence and severity that has been
noted in the literature over the past few years.
Estimates, for example, have it at a little over 8
persons per 100,000 in the U.S. that are affected,
with a male to female ratio of approximately 1:6.
This increase has been commented on, that it is not
related to the overall use of diuretics which is
becoming more prevalent in the population as well.
It appears as though gout is presenting
itself at earlier age. This is particularly true
for males. In females the increase seems to be
mostly in the postmenopausal period. There also
appear to be, and I think we will hear about this
shortly, increases related to obesity, tying into
what has been called the insulin resistance
syndrome which, again, is something that we will be
hearing more about in a second.
Also as Dr. Harvey had indicated, there
are really not a lot of treatment options that are
available currently. So, one of the outcomes we
are hoping for from this meeting will be that in
the future there will, in fact, be more options.
But to list them, we have for example non-steroidal
anti-inflammatory drugs which, as you know, word at
the level of prostaglandins. We have colchicine
which work at the level of microtubules. This is
available both as an oral and as an intravenous
agent. We have allopurinol which works at the
level as an inhibitor of xanthine oxidase. We also
have probenecid which works at the level of the
As we then transition from a clinical
trial to look at the data that comes in-house, what
we are interested in ultimately is to write a
label. I would like to spend a little time on
discussing that. Label claims have various legal
and regulatory uses but their primary purpose is to
inform healthcare providers and patients about the
document that is underlined, both the documented
benefits and risks associated with the product.
These claims are intended to then describe the
clinical benefit and, in fact, once these are
approved, the sponsor can actually promote such
claims. What we hope for in any situation is that
we have as accurate as possible label because this
allows for effective risk management down the road.
We do not at the present time have a
specific guidance document for gout. We do for
many other areas, as you are aware. But if we did,
what should we be thinking through in terms of if
we tried to standardize the language in the labels
for chronic use, for example? Some of the options
may be for treatment of hyperuricemia associated
with gouty flares, gouty arthritis, tophi or renal
On the other hand, in an acute situation
or for prophylactic use the label might say for the
short-term treatment of uric acid-induced gout.
I will just take a second to remind
ourselves then what is some of the language that is
currently available for the various agents that are
approved: Indocin, one of the oldest of the
medicines maybe that is out there. The label under
the indication sections says this is effective in
active stages of acute gouty arthritis.
Benemid or probenecid reads for the
treatment of hyperuricemia associated with gout and
Zyloprim or allopurinol reads the
management of pats with sings and symptoms of
primary and secondary gout, and has in parentheses,
acute attacks, tophi, joint destruction, uric acid
lithiasis, and/or nephropathy. It also notes in
rather bold letters, although I haven't bolded it
here, that this is not an innocuous drug and it is
not for asymptomatic hyperuricemia, a topic that I
am sure we will get into today.
As mentioned, also we have colchicine.
This is probably the oldest drug. I believe it was
DESI; it didn't go through a formal NDA approval.
It has in its language for the treatment of gout,
relieving pain of acute attacks or as interval
therapy to prevent acute attacks of gout.
It is almost summertime so I thought it
would be appropriate to talk about the activities
that go on. In the older days of this field it
became clear that the gold standard in terms of
looking at this problem was something that has been
called the urate pool. So, I thought I would just
describe that and discuss that for a second as it
may apply to our situation here today.
In this cartoon we have a mechanism to
fill this pool, and that is the diet. We have a
mechanism to also drain this pool through the
urine. These can be impacted in various ways which
we will be discussing over the next couple of days.
But let's take it that we have the pool at a
certain level. What I have drawn here is kind of a
wave which represents the serum uric acid level.
It is intended to be a little bit bumpy because it
is not necessarily static. As every pool does, it
tells you how deep it is. So, I have given you
some numbers here of 10 mg/dl and 6 mg/dl.
Now, when we have a situation that is
appropriate under perhaps, you know, steady state
conditions--and this is really a poor man's version
of modeling. We have Dr. Meyer Katzper here in the
audience who can talk to you more if you are
interested in modeling and approaching this
situation through modeling, but we have an
equilibrium, let's say, with two other compartments
of this pool, the joint and a tophus. It may be
then that under situations of equivalence or when
things are equilibrated that there is a dynamic
interplay between these two, with exchanging in
both ways. But when the uric acid level then
rises, we have a situation that the joint, for
example, fills more rapidly and we have then an
acute attack. As you can see, I have drawn the
arrow going back to the pool to maintain again this
With a tophus it may not be exactly the
same situation. There may be mechanisms that can
allow this to form but there may not be as
effective mechanisms to allow it to be resorbed,
and that may be an issue that become important
clinically, especially in clinical trials.
So, as our little friend here is
encouraging us to do, let's jump in. In terms of
what we are trying to get at today, it is the issue
of clinical trials and how we should go about
thinking about them. One of the basic and first
questions we would want to ask then, particularly
in a chronic situation, is about the baseline serum
uric acid level.
It is interesting in the sense that the
prevalence of gout has been estimated to be 30
percent when the serum uric acid is 10 mg/dl, but
only 0.6 percent when it is 7 mg/dl and, yet, there
still is in general a poor correlation of serum
uric acid to gouty flares. So, this is something
that we would like you to comment on.
Also, the issue of prior flares at what we
call a target joint, the issue of the number of
flares that have occurred at this joint in order to
get somebody enrolled in a trial, the severity of
the flares at that joint and then how should these
be diagnosed? Should we require that these all be
diagnosed by crystal analysis for example? Is it
sufficient that a physician makes a diagnosis? Or,
is it even sufficient that the patient self-reports? We
would like your comment on these
With relationship to tophi, we would like
some comment about how we go about distinguishing,
for example, from nodules that might occur in RA or
nodes that might occur in OA, and the relationship
of size in terms of entry into clinical trial.
Renal status is also something that we
will be talking about over the next couple of days.
So, we would like you to think about the issue of
chronic renal insufficiency and how that should be
factored into any trials.
Regarding exclusion criteria then,
particularly for a chronic situation, we want to
make sure that at a minimum we exclude other
crystal-induced diseases, or that we make sure that
there are no other inflammatory diseases or
infections enrolled. We would like you to consider
what we should do with renal status, particularly
with use of diuretics; with the issue of co-morbid
diseases, as I mentioned earlier about obesity; and
any thoughts you may have on special populations
such as a transplant population or those with
genetic defects. The latter is probably applies
more to a younger population, as you are all aware.
In terms of efficacy issues then, we would
like some discussion on endpoints and the duration
of these endpoints. One of the questions that we
are going to be discussing today at length, I would
hope, is the issue of whether or not serum uric
acid is a valid surrogate or not. I will be
discussing more about surrogacy in a second.
We also would like to have comment about
the number of gouty attacks, particularly early on
in a chronic study--how much, how long should we
exclude these kinds of events from the analysis?
If the endpoint happens to be tophi, should we be
thinking in terms of the size or the number?
In other areas of medicine we have given a
lot of thought to the concept of disability and
quality of life domains so we would like you to
share any thoughts you may have in this area as
Then in terms of duration, how much, how
long should each area of the various trials be?
For example, if one is looking at the endpoint of
serum uric acid, is a trial of 6-12 month duration
sufficient? Whereas, if you are looking at tophi,
if that is the endpoint, do we need to have
something more in the range of 1-2 years?
As I indicated earlier, I would just like
to talk for a bit about what a surrogate is so that
we are on the same page, so to speak, as we go
forward with this area. If you look in the Code of
Federal Regulations under 314.510, Subpart H and it
has been dubbed affectionately the surrogate
approval, it reads as follows: FDA may grant
marketing approval for a new drug product on the
basis of adequate and well-controlled clinical
trials establishing that the drug product has an
effect on a surrogate endpoint that is reasonably
likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict
clinical benefit or on the basis of an effect on a
clinical endpoint other than survival or
Now, to dig down and drill down just a
little bit more, a definition that we use for a
surrogate endpoint is a surrogate endpoint of a
clinical trial is a laboratory measurement or a
physical sign used as a substitute for a clinically
meaningful endpoint that measures directly how a
patient feels, functions or survives. The idea of
a surrogate then is that changes induced by any
therapy on a surrogate endpoint are expected to
reflect changes in this clinically meaningful
There are some caveats to the Subpart H
approval process. One of those, for example, is
that there is a requirement that the applicant will
study the drug further to verify and describe its
clinical benefit where there is, in fact,
uncertainty of the relationships of the surrogate
to the clinical endpoint, or the observed clinical
benefit to the ultimate clinical outcome. It is
assumed, for example, that post-marketing studies
will usually be under way, that they will be
adequate and well controlled, and that they must be
carried out with due diligence.
Continuing with caveats a bit later in the
CFR, it notes that the FDA may withdraw approval
following a hearing if some of the following apply:
that a post-marketing clinical study, in fact,
fails to verify the clinical benefit; that the
applicant fails to perform the required post-marketing study
with due diligence; that
promotional materials are false or misleading; or
other evidence demonstrates that the drug product
is not shown to be safe or effective under its
conditions of use.
So, to give you some idea of surrogates
are currently are from an FDA perspective, I have
just listed some here--blood pressure lowering;
this should say lipid lowering, not lipid lowering
agents; the use of blood sugar levels; bone mineral
density levels and the HIV load. These are some
examples of currently accepted surrogate endpoints.
So, let me restate my question earlier
then in relationship to serum uric acid levels and
re-ask the question, are these both valid surrogate
endpoints? What I mean by that is when you look
at, for example, a change of serum uric acid
concentration--let's say you go from 10 to 8, is
that a valid surrogate endpoint? Or, is it a valid
surrogate endpoint when one approaches and attains
a selected endpoint, such as 5 mg/dl or 6 mg/dl?
So, we would like some discussion on that point
because it is a very important distinction.
Then, in terms of serum uric acid, we also
would like some discussion about the issue of
precision and, reflecting back to the pool idea,
that is, serum uric acid estimates can change, can
vary, so should we have multiple values done at
multiple times to make sure that we are getting the
best estimates of what is going on?
Looking again at the issue of targeted
versus non-targeted joints, should they be
evaluated together or separately? We would like
some discussion on that.
Then, if tophus happens to be one of the
endpoints in the trial, what is the best way to go
about looking at that? Is it with some kind of
imaging modality such as an MRI, or is a manual
method sufficient? And, should it be a percent
resolution or should it be a complete resolution?
Some of the design and statistical issues
that we would like comment on are the issue of the
initial titration to minimize flares. I think we
are all aware that in the early period this is a
problem so we would like your comment on this. We
would like you to comment also on the issue of a
placebo control. Should this be, for example,
during some or all of the trial? It gives us the
advantage of looking at superiority to placebo
issues to help us understand the effect sizes for
example. Or, should we be thinking more about an
active control or standard of care control?
Then we could enter into issues of non-inferiority
and that would engender a discussion of
how different can the test compound be from the
controlling agent. Obviously, the selection of any
kind of active control depends on the drug under
development. If you are looking at something that
works at the level of the kidney, that is different
than if you are looking at an enzyme inhibitor.
We would also like some comment on the
dose ranging that we should be looking at to
achieve various target serum uric acids, and any
comments you may have on the approach. Should we
have, for example, a means approach or a responder
approach, the latter being very important and used
a lot for example in rheumatoid arthritis? Then,
any comment you may have on this concept which is
evolving of a minimal important difference to get
some idea, again, of the clinical benefit.
Co-medications and diet issues,
particularly in a chronic situation, can be very
important and we would like your thoughts about
this. For example, use of low dose aspirin can
have an effect on renal clearance; the use of
colchicine; and then the concomitant use of NSAIDs
or COX-2 agents.
We would also like you to comment on the
issue of alcohol use and how we should approach
that. For example, is a patient diary a way to go
about that? Then, any thoughts you may have on
restrictions of diet to standardize.
So, the issue always, particularly for
approval, is, you know, how safe is safe? I think
it is particularly important for this topic today
in particular because generally when one goes and
decides that something is going to be employed to
lower uric acid levels, this is for the most part a
lifelong decision. So, the issue we would like you
to discuss today is whether this necessarily has to
be a daily long-term use or can it be intermittent,
and should we approach that.
We would like you to discuss the issues of
co-medications, as I just discussed, for either
gout prophylaxis or treatment. For example, is
there a possibility that a myopathic result could
be worsened if somebody is taking colchicine? We
would like any thoughts you have on special
populations. I had mentioned earlier the issue of
chronic renal insufficiency.
Then, comments about whether ICH
guidelines are adequate in this setting. To remind
you what that is, some minimum requirements in
terms of patient exposure that we look for when an
NDA comes in or BLA. In terms of patients then, it
looks something to the range of 300-600 patients
for 6 months, 100 patients for a year and 1500
total. We are generally interested in what will
ultimately be the highest dose.
So, the better that we have clinical
trials designed, the better that we have
information in these clinical trials, the better
decisions can be made at various different levels.
For example, at FDA we evaluate the risks and
benefits for a population. You can see in this
cartoon that the benefits seem to outweigh the
risks. The healthcare provider though also takes
that same information as is translated in the label
and makes a decision for a patient and, again, in
this cartoon it looks as though the benefits are
winning. Then the patient, importantly the most
important factor in anything, evaluates the
benefits and risks in terms of their personal
values. In this case, it looks like maybe this
person hasn't quite made up their mind but maybe it
isn't to their benefit.
So, there is lots to discuss today and
tomorrow and we are looking forward to it. Thank
DR. GIBOFSKY: Thank you, Dr. Witter. One
quick question, if I may, can you give us examples
of agents that have been approved under Subpart H
and also agents that have been withdrawn by the
agency under Subpart H?
DR. HARVEY: Hi, I will jump in--Brian
Harvey. The easy question is that to my knowledge
nothing has been withdrawn under Subpart H. There
was actually a public hearing a few years back,
under the auspices I think of the oncology group,
where they actually discussed--Dr. Pasteur? There
was a panel meeting, advisory panel, where these
various issues were discussed and that is a matter
of the public record of what things have been
approved under Subpart H, what has been done post-market and
what, if any, actions have been taken by
the agency. So, that is all available publicly
but, to my knowledge, nothing has been withdrawn
under Subpart H.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: Yes, regarding the slide on
current state surrogates, specifically with regard
to bone marrow density just a question, my
understanding is that for a new drug to be approved
it has to demonstrate fracture risk reduction, but
for a new form of a preparation, for instance, of
an already approved drug it can be approved with
comparability with regard to bone marrow density.
Is that correct, or am I incorrect?
DR. HARVEY: Well, I think the specifics
of what other divisions do in their risk/benefit
analysis--I would refer you to the various guidance
documents and policy documents in those specific
areas, and it is an evolving field and, of course,
those various divisions go to their expert panels
for input as well. So, we are sort of on a
parallel track with them. They may be a little bit
ahead, but I think some of those technical nuances
really all are on the FDA web.
But you raise some valid points and during
your discussion there may be some parallels and
sometimes those parallels are valid and sometimes
they are not. Of course, today's discussion will
be a general discussion about those gout issues but
with the specifics of gout that may supersede some
of the other areas as well.
DR. GIBOFSKY: Thank you, Dr. Harvey. Are
there any other questions from the panel about the
methodology? We will talk about pathophysiology
throughout the rest of the day. Dr. Geis?
DR. GEIS: Just quickly, is there any
history of a drug being approved based solely on a
surrogate marker without the sponsor collecting any
clinical relevant data?
DR. HARVEY: Brian Harvey, I will keep
jumping in because these really are big picture
questions you are asking and not really specific
for the gout issue. But I think we are all well
aware of the public record in the area of HIV
disease and how the approval of drugs in that area
have really been tied not only to clinical outcomes
but also the surrogate of viral load. Of course,
significance is always in the eye of the beholder,
but there really is a huge body of information out
there in the public record on those various areas.
We can look to HIV treatments as one area.
Oncological project is another where they have sort
of led the field of pharmaceutical development
using these surrogate endpoints. Of course, as you
know, there is a huge body of clinical literature
as well as a lot of FDA information, both in
formalized guidance as well as public record from
previous panels. So, it is a good question. I
think it is a good guiding principle but, as
always, significance is in the eye of the beholder.
DR. GIBOFSKY: Thank you, Dr. Harvey. At
this point, if there are no other questions from
the panel regarding Dr. Witter's presentation, I
would like to call up Dr. Robert Terkeltaub, who is
Chief of the Veterans Administration Rheumatology
Section and Professor of Medicine in Residence at
University of California, San Diego, who will
address us on gout as an evolving problem at a
therapeutic crossroads. Dr. Terkeltaub?
Gout: An Evolving Problem at a
DR. TERKELTAUB: I want to thank Jim for
inviting me and also to thank Brian for providing a
note to my chief of service so I could be excused
from my medical duties. It is a nice break from
that particular service right now.
I am really honored to be here. I am
going to talk about a problem that I have worked on
for many years and that I feel very strongly about
as a major public health problem. Basically, we
are dealing with the prototypical crystal
deposition disease. What you are seeing here, of
course, is an aggressive tophus deposited in the
toe that is destroying underlying connective
The issue is partly of the normal
metabolism of uric acid, the normal product of
purine metabolism. I am not going to belabor you
with all the steps involved in purine metabolism
but basically xanthine oxidase at the end stages of
purine metabolism generates uric acid and,
obviously, this has been a fruitful drug target and
allopurinol targets this particular enzyme.
We are dealing with a question of balance
and human uric acid balance is pretty precarious
because the size of the total miscible uric pool in
the typical male is a gram to 1200 mg. Our
production and intake of purines balances with our
elimination of purines on a daily basis. So, the
size of what flushes through a uric pool is about
the same size as the uric pool. So, you can see
that either excess purine production or even small
decreases in uric acid elimination will produce
hyperuricemia over time.
Basically, we are dealing with a disease
in which hyperuricemia is only one manifestation.
We have an increase in the total body urate pool
and ultimately the deposition of monosodium urate
crystals and clinical expression in these various
forms, including not only arthritic manifestations
but also urolithiasis with not only uric acid but
also calcium oxalate in some patients, and a rare
problem these days in the form of interstitial
nephropathy, most likely because of better control
of not only hypertension but also hyperuricemia.
So, we have a disease in which the
etiology is very well understood vis-a-vis the
monosodium urate crystal being pro-inflammatory,
depositing tophi, and we understand purine
metabolism very well. We have a disease in which
diagnosis and therapy are well developed but often
poorly applied, which is an issue which hasn't yet
been discussed but can be, and we have a common
disease in which we have approximately 3-5 million
affected subjects in the United States alone. We
have a high prevalence in certain minority groups
of a disease that is growing in numbers, and a
disease that is evolving clinically due to not only
socioeconomic factors but also iatrogenic factors
that must be considered. So, we have a major
public health problem.
If you look at the raw numbers, if you are
dealing with the NIH-IS survey and self-reported
prevalence, you are dealing nearly with a doubling
of the self-reported prevalence of gout between
1969 and 1996. If you are looking at the annual
case incidence in this study from Rochester, you
are dealing with approximately a 50 percent
increase. Now, these epidemiologic data are
subject to limitations in a disease that is
episodic, that is recurrent but, anyway, it appears
from the numbers that the disease is more common.
The reasons for this are complex. One is
almost certainly the increased of longevity of the
population. Sustained serum uric acid elevation
over time times longer time is going to lead to
more gout, in our view. An increase in the
prevalence of hypertension, increased use of
diuretic and aspirin therapy--and I will show you
our own evidence but basically the epidemiologic
evidence in certain studies argues that increased
diuretic use is a risk factor for more gout.
Dietary trends--increased obesity and
metabolic syndrome, demographic trends in the
United States, improved survival from coronary-artery
disease, congestive heart failure and
diabetes mellitus, and many of the patients who
have stents wouldn't be around to get gout in this
day and age, and basically increased end-stage
renal disease and increased survival from this, and
increased transplants as well as the limitations in
the current generation of anti-hyperuricemic drugs.
So, what are the numbers here? If we look
at hypertension alone, there has clearly been more
than a 10 percent rise over the 1990s. If we look
at hypertension treatment patterns, there has been
a major change. I wanted to cite the ALLHAT study
which is a study that was done on 42,000 subjects
in the United States and compared outcomes,
including non-fatal MI and also stroke and CHF, and
the results were interpreted to support the use of
inexpensive thiazides relative to ACE inhibitors,
calcium channel blockers, alpha-adrenergic blockers
for the treatment of mild to moderate hypertension.
So, this study has been quite influential.
For example, in my own healthcare system,
the VA, VISN-22 which is the desert Southwest VA,
we have reviewed a population of approximately a
quarter of a million and we have a very special
group of patients, obviously, about 90 percent
male. We are dealing also with about 40 percent of
the population in our VISN-22 population being 65
years of age or older. But in this 5-year period
that was reviewed, very generously by a pharmacist,
aspirin use was up approximately 10 percent.
Furosemide use was up approximately 4.7 percent and
hydrochlorothiazide use in the cost conscious VA
system was up 74 percent. Allopurinol was up 12
percent during this time period. This is in line
with national prescribing figures for allopurinol,
as I understand them. So, we are dealing with a
situation where the hydrochlorothiazide use is
exploding in the very cost conscious environment of
the VA and most likely cost conscious environments
elsewhere, which means almost everywhere.
I saw the movie "Supersize" this weekend
and I was very happy to see that hyperuricemia and
gout made it onto the radar screen of that movie.
Basically, Time magazine has covered this topic in
depth and this week's cover issue is on obesity as
well. We are very clear on the fact that obesity
is a big problem in America and increased body mass
index alone is associated with hyperuricemia but
insulin resistance clearly compounds the problem.
The principal features of the metabolic
syndrome are legion and they include hyperuricemia.
Basically, what we are dealing with is a number of
renal effects pure to insulin resistance alone and
then compounded by hypertension. But basically
hyperuricemia stimulates increased renal sodium
reabsorption and uric reabsorption as well. There
is an additional mild effect in renal ammonium
excretion associated with insulin resistance that
promotes an acid milieu. Basically, we realize
that the relative risk of urolithiasis in men who
carry a diagnosis of gout is at least 2. So, the
problems of insulin resistance certainly compound
hyperuricemia, and up to 20 percent of patients
with gout have a history of kidney stones and this
may also contribute to morbidity with gout.
So, what we are dealing with along the
lines of epidemiology is a problem that goes up
with aging. The age-adjusted prevalence of
metabolic syndrome rises steadily so that up to 35-40
percent of individuals greater than age 70 meet
the criteria for metabolic syndrome. You can see
when you look along ethnic lines and if you look at
men and women that the most rapidly growing ethnic
subpopulation, Hispanic subpopulation has the
highest age-adjusted prevalence of metabolic
Basically, what are the diet and alcohol
related trends that may be influencing the
incidence of gout? Choi has done a very impressive
large study in male health professionals aged 40-75, almost
50,000 people followed up for 12 years,
and 730 of these people developed new gout in this
time frame. So, these were people who did not have
gout at the beginning of the study. The relative
risk of incident gout was 1.41 in the highest
quintile for meat consumption; 1.51 for seafood;
and then almost half for dairy product consumption,
low fat dairy products; and any form of alcohol,
2.53. But when it was broken down to beer, 1.75
for 5 beers a week to 1 beer daily; 2.51 for 2 or
more beers daily; and then spirits, 1.15; and wine,
Now, you know, I view these data for dairy
products as maybe reflecting ascertainment bias
given that the people in the highest quintiles for
dairy product consumption in this study who had the
low incident gout risk were consuming 2 glasses of
skim milk per day or consuming a fair amount of
non-fat yoghurt per day and there has to be a
difference between people who drink a lot of skim
milk and other people.
Basically in terms of the multivariate
analysis, these differences were not immediately
obvious when hypertension diuretic use was factored
in and I think people recognize that there has to
be a difference between a beer drinker and a wine
drinker. So, I think there is also room for
interpretation of ascertainment bias in these data,
but these are very compelling studies that are
going to have to be addressed.
Basically, we have another issue in that
several popular diets that are high in fat and also
high in meat and seafood consumption and low in
carbohydrates have the potential to promote
hyperuricemia by ketosis and high meat and seafood
intake. I won't mention these diets by name
because I don't have to, everybody knows the names,
and people realize that there is a low carb frenzy
in this country that also has very high economic
The economic impact also is something that
is reflected in beer intake. If you look at the
alcohol consumption numbers in the United States,
alcohol consumption actually has been somewhat flat
or slightly declining over the last 20 years,
however, beer consumption--and beer of course
contains the very readily absorbed di-tetra purine
guanosine--beer consumption is the segment of the
alcohol market that has risen steadily. This is
the very hot-selling lite beer de jour, Michelob
Ultra, but basically what we are dealing with is
lite beer and low carb beers have markedly
increased in their market share and in their
overall consumption in this country and have been
promoted as health-conscious options. They
certainly are a bit lower in carbohydrates but they
are not lower in guanosine content. So, this is a
factor in terms of the public health problem that
has to be considered as well if one takes into
consideration the data on incident gout that I
The other issue in terms of the
epidemiology of this disease is that the classic
profile of a gout patient, including several people
in this room, I am sure, is illustrated here. We
are dealing with a disease in which the classic
profile is changing. There are many more females
that are involved and there appears to be a rise in
the 70-80 age group as well.
Gout in older women is increasing in
prevalence partly because of increased longevity.
That is the assumption, but also it is linked to
very common use of thiazide diuretics and currently
the numbers are that more than 25 percent of
individuals greater than the age of 65 are using
diuretics, mainly thiazides, and also linked to
chronic renal insufficiency and congestive heart
failure. Attending on internal medicine this
month, we realize that about 20 percent of our
admissions at the VA are for congestive heart
failure exacerbations. So, we are seeing a lot of
gout and CHF and a lot of gout in older women with
CHF at the University of California, San Diego and
at the VA in San Diego.
Will decreased use of estrogens ultimately
raise uric acid and gout prevalence? Estrogens are
uricosuric and estrogens are becoming somewhat more
out of favor given the recent data in press, and
there is a question about whether serum uric acid
and gout prevalence will rise in women because of
the anticipated decrease in the use of estrogens.
Also, gout in women can be different
clinically and this has to be factored into the
design and interpretation of clinical trials. As
opposed to the classic podagra, the gout in women
can masquerade as inflammatory hand osteoarthritis.
Uric crystals love to deposit in osteoarthritic
joints, most likely because of solubility issues
with respect to altered matrix integrity in the
osteoarthritic joint. Gout, presenting as tophi is
a common presentation in older women with
What about renal insufficiency? Renal
insufficiency promotes hyperuricemia and gout
clearly, and makes management of hyperuricemia and
gouty arthritis substantially more difficult. What
about the numbers? Well, we know that in 1987
there were 156 new cases per million of end-stage
renal disease. In 1997 there were 303 new cases
per million. And the prevalence of end-stage renal
disease is 4-5 times higher in African Americans
and in the elderly.
In terms of transplants, the number of
transplants has nearly doubled also in the same
time frame, partly because of improved transplant
donor networks and protocols. In addition to renal
transplants, we see more heart, liver and pancreas
transplants as well. We realize that transplants
and cyclosporine-induced gout is an emerging
problem in gout. In terms of cyclosporine-induced
gout in the setting of major organ transplantation,
hyperuricemia is present in more than 80 percent of
the cyclosporine-treated patients in this setting.
Mean serum urate levels are often spectacularly
high and the gout prevalence is between 8-13
percent by 3 years, typically more than 10 percent,
and a lot of this depends also on the cyclosporine
dosing which often is higher for the cardiac
So, what is going to happen with
transplant-associated gout, associated with
cyclosporine use clinically is that we see rapidly
expanding tophi refractory to therapy. There may
be some sort of extrarenal cyclosporine effect that
may affect urate solubility. This appears to be
beyond the pale in terms of the rapid expansion of
tophi relative to the urate levels, and the
arthritis may be refractory to steroids and other
anti-inflammatory therapeutics. We often see
patients with transplants who are on 10 mg, 15 mg
of prednisone a day and still come in with
polyarticular gout. Cyclosporine, of course, is
nephropathic and induces chronic renal
insufficiency, and cyclosporine and chronic renal
insufficiency can contribute to serious adverse
drug interactions. One of these is called
colchicine myopathy which may present very quickly
after oral colchicine initiation in this setting.
I have some good news. Cyclosporine and
gout will be a brief footnote in the long history
of gout. At the VA we looked at cyclosporine
prescriptions over the same time frame and we
looked at thiazide prescriptions and they were down
by approximately a third, and the prescriptions of
tacrolimus and sirolimus were way up in that time
frame. People are realizing that there are
alternatives with less hyperuricemic toxicity but
also principally less nephropathic toxicity. These
are being currently optimized for transplant
medicine and the cyclosporine alternatives include
tacrolimus. Another inhibitor of calcineurin like
cyclosporine, however, is marginally better for
hyperuricemia as well as hypertension and
nephropathy in my view, in reviewing the
literature, as well as sirolimus and mycophenolate.
Combination regimens with lower dose cyclosporines,
such as 25 mg twice a day of cyclosporine
microemulsion are clinically efficacious.
Eventually, clearly, advances in therapeutic new
intolerance will render cyclosporine fully obsolete
and we will get rid of any iatrogenic issue.
So, what we have here is the situation of
increased gout prevalence and increased clinical
complexity of gout in the United States. It is
very hard to measure gout clinical complexity but
from talking to my colleagues everywhere, people
generally agree that gout is more difficult to
manage; there is more tophaceous gout and the
problem of gout and chronic renal insufficiency
makes the disease more complex. This has clearly
evolved over the last 20 years and has accelerated
over the last 10 years. What we have is a "perfect
storm" so we have to try to deal with the numbers.
The IMS data for the rise in allopurinol-treated
patients is impressive. It is 25 percent
in this time frame. Basically, it is not because
of improved medical education, I am pretty certain.
The other problem is that refractory
tophaceous disease has not disappeared and appears
to be making a comeback, as I have mentioned.
Refractory gout is painful, destructive and
incapacitating, as you can see by these erosive
changes illustrated here. Joint erosions can
progress even with effective therapy that lowers
serum urate. Once you deposit urate crystals in a
joint, the crystals are very pro-inflammatory and
can promote matrix metalloprotease expression and
nitric oxide production and promote cartilage
destruction and connective tissue destruction. So,
we have to deal with this issue.
There are some larger issues here.
Sustained hyperuricemia, even in a very predisposed
population such as in Kinma, in Taiwan is
associated with incident gout in only 20 percent by
5 years, and we need to determine what factors,
other than serum urate, account for the clinical
crystal deposition as gout, and what are the
natural urate crystallization regulators. Can they
be harnessed in therapy? In the meantime, we are
dealing with measures to reduce inflammation and
reduce serum urate.
The extent of effectiveness of the non-
pharmacologic mechanisms directed to urate
metabolism, such as diet, alcohol, lifestyle and
anti-hypertension therapy, are not exactly clear,
to be kind. Clearly, the existing generation of
anti-hyperuricemics is antiquated and needs
What about diet because we are the FDA
and, you know, this is the Food and Drug
Administration? What about diet? Traditional low
purine diets that have been used in the past more
commonly are unpalatable and they only reduce serum
urate by up to 1 mg/dl or 15 percent about the max.
What about roles of other diets? There is a
customized 40/30/30 diet with caloric reduction.
It was a small open study with 13 patients. These
were all overweight or obese men with gout. When
you tailor a weight reduction diet for insulin
resistance and look at 16 weeks and achieve a lot
of weight loss--at 16 weeks you are achieving about
1 lb per week weight loss, which is pretty
impressive--urate levels decrease by 18 percent
with a 40/30/30 carb/protein/fat scheme. Caloric
restriction is the key here, but also replacing
refined carbohydrates with complex ones and
replacing saturated fat with monounsaturates and
olive oil, nuts and seafood. So, this argues that
some diets that are the same overall scheme as some
of the popular best-selling book low carb diets may
actually be okay for gout. So, not all low carb
diets may be adverse. The effects of diet and
alcohol modification on hyperuricemia and on gouty
arthritis itself need a careful controlled long-term study,
including the very popular low carb
diets right now which really have not been studied
at all in a controlled way, although there is a
hell of a lot of publicity on the Internet about
gout being worsened by several low carb diets.
In terms of the uric acid lowering
pharmaceuticals that are currently in use,
allopurinol, in terms of serum uric acid lowering
therapeutics, is dominating of course the use in
the U.S. market. Oxypurinol has been available on
a compassionate use basis and, of course, is a
major active metabolite of allopurinol.
Allopurinol has limitations and that is
why I think we are assembled here in part. Rash in
approximately 2 percent of subjects; intolerance,
and we will go over what defines intolerance, in up
to 10 percent of subjects. Major allopurinol
hypersensitivity is rare, approximately 100 cases
reported, but has a 20 percent mortality rate.
Oxypurinol cross-reactivity puts some limits on
alternative use. Then tophus reduction with
allopurinol is often slow so that raises another
bunch of issues because the optimum dosing of
allopurinol relative to label and relative to the
published guidelines for avoiding allopurinol
hypersensitivity syndrome is controversial. The
optimum dosing of allopurinol is particularly
controversial with chronic renal insufficiency.
If you look at drugs that are used to
promote uricosuria, probenecid is the most common
one used in the United States.
Sulfinpyrazone use is problematic.
Sulfinpyrazone is related to phenylbutazone and can
cause some of the same problems that phenylbutazone
causes hematologically at the level of the GI tract
and also the anti-platelet effect of sulfinpyrazone
can lead to adverse drug interactions.
Benzbromarone is not FDA approved and
hepatotoxicity can be serious with this drug and
has led to withdrawal from the marketplace in
France, as an example.
Losartan and fenofibrate are among drugs--every
two or three years there is some other drug
that is discovered to be mildly uricosuric. The
current ones are losartan and fenofibrate which
have relatively weak effects and questionable
extent of synergy with current drugs but can get in
the way in terms of clinical trial evaluation. We
are dealing with drugs that typically will reduce
serum urate on their own by 8-10 percent and up to
15 percent or 20 percent.
Can we develop pharmacogenomic approaches
to optimize uric lowering therapy based on
spectacular recent science in terms of
understanding renal urate handling? The classic
disorder of renal urate excretion in primary gout
is such that if you look at the gouty patients'
urinary uric acid relative to their plasma uric
acid at a level of, let's say, 8 mg percent of
plasma uric acid, the patients with gout will have
approximately half as much urinary uric acid put
out. Given that three-quarters of patients are
under-excreters, this is quite significant.
Basically, the most compelling development
in this field is the identification of this
molecule, URAT1, as the major mediator of proximal
tubule urate reabsorption in the kidney. URAT1 is
a member of the organic anion transporter family.
It has this multiple pass transmembrane protein
structure and it functions as an anion exchanger,
more active for organic anions than for inorganic
anions. It is thought that the anions in the
intracellular side of the proximal tubule cells are
triggering urate reabsorption by this exchange
mechanism. I only conceptualize that it goes
through the middle of this molecule. We are not
sure if that is the case.
URAT1 is to be contrasted with another
molecule, UAT, uric acid transporter, which is
actually a urate anion channeler and urate here is
thought to go through the middle of this membrane
protein, and this membrane protein is not a member
of the organic anion transport family. This is not
an exchange process. It is driven
electrochemically and is subject to regulation by a
number of mediators, including sugars, including
adenosine and including oxonic acid.
When one looks at what happens at the
level of the proximal tubule in the nephron, URAT1
sits on the luminal side and promotes urate
reabsorption, triggered by a number of organic
anions. Lactate includes some of the ketoacids
generated by burning fat with some of the popular
low carb diets, and includes metabolites of the
anti-tuberculous drug pyrazinamide and basically it
is inhibited at the luminal side by benzbromarone,
probenecid, losartan, sulfinpyrazone and actually
also high doses of salicylates. Urate reabsorption
into the circulation at the basolateral membrane is
mediated probably by UAT and by another member of
the organic anion transporter family.
It is important to remember that urate
movement at the proximal tubule is bidirectional so
there is a secretory pathway that probably has a
maximal capacity of about a quarter of that of the
reabsorption capacity in the proximal tubule.
There are potential mediators of this process that
are identified and we believe that UAT and a
sodium-dependent phosphate co-transporter and
another member of the OAT family carry out this
So, we have a situation where the organic
anion transporter family, also known as the SLC-22
family, is highly regulated, and gender is one of
the factors that regulates expression of these
proteins, as well as aging, development,
hypertension, hyperuricemia itself, renal failure
and the effects of certain drugs. So, we have a
situation where we know that almost all the serum
urate is filtered; that there is bidirectional
urate movement at the proximal tubule,
predominantly reabsorption but also secretion; and
that reabsorption is finely tuned, probably by
other OAT family members but also possibly by the
sodium hydrogen ion anti-porter whose activity goes
up in metabolic syndrome and normally only 10
percent of the filter load is increased.
But there has been a very important
development pharmacogenomically in that subjects
who have defective URAT1 expression--and these
subjects have a disorder that is known as
idiopathic familial renal hypouricemia and now it
is no longer idiopathic because it has been linked
to URAT1 mutations--these subjects do not
significantly alter their uric clearance if they
are given probenecid, pyrazinamide or
benzbromarone. So, we realize that URAT1 is an
interesting pharmacogenomic issue and also a very
compelling specific drug target.
The problem though with uricosurics is
that the effectiveness of altered uricosurics is
limited by chronic renal insufficiency. There is
an element of uric over-production in 10-25 percent
of patients with primary gout and that imparts
urolithiasis risk, and there are other side effects
and drug interactions at play.
So, there has been a lot of interest in
the potential therapeutic role of uricase for
patients with gout. Uricase oxidizes uric acid to
a much more soluble compound, lantoin, generating
hydrogen peroxide. Basically, it is a critical
means in lower species to convert the relatively
insoluble uric acid to highly soluble lantoin. If
you look at the serum urate of a normal mouse, it
is 1 mg percent but the uricase knockout mouse,
generated by Kowski and his coworkers, developed
serum uric levels of 10 mg percent and get
uricosuric tubulopathy and will die unless they are
given a xanthine oxidase inhibitor.
So, uricase gene silencing in human beings
renders human uric balance quite precarious because
urate is insoluble in vitro at about 7 mg percent.
So, recombinant uricase is actually FDA approved
for short-term, single course use in pediatric
hematologic malignancies, and produces profound
acute urate lowering, typically 10-15 mg/dl down to
1-2 mg/dl, and has been effective in preliminary
studies short-term in gout patients. It has the
potential for accelerated tophus dissolution in
terms of months.
The issues with recombinant uricase are
that it is highly immunogenic, being
transcriptionally silent in human beings, which
limits both its safety and efficacy, and some of
the side effects seen over years of use of non-recombinant
uricase in Europe and recombinant
uricase worldwide have been respiratory distress
and anaphylaxis. Then the hydrogen peroxide
generation limits safety in specific patients.
There are concerns about cell transformation in
vitro because of the hydrogen peroxide generation,
and in vivo hemolysis in patients with G6PD
deficiency and hemoglobinemia have been reported.
In patients with tumor lysis syndrome,
obviously a complicated thing to treat,
neutropenia, sepsis, hypocalcemia and
hypophosphatemia all have been reported in a few
percent of patients treated with rasburicase for
tumor lysis syndrome and alkalinization of the
urine can promote these electrolyte disturbance, it
appears, in association with uricase use. The drug
is potentially lethal and is not orally
bioavailable, and clearly clinical trials of less
immunogenic forms are of interest and are in
progress for gout.
I would propose that the therapeutic niche
for concomitant uricase in gout to be limited term
treatment, with a long-lasting recombinant uricase
preparation of low antigenicity for the reduction
of macroscopic destructive tophus burden in highly
What about asymptomatic hyperuricemia in
vascular disease? This topic has received a lot of
press of late and it is important because there are
many more patients with asymptomatic hyperuricemia
than there are with gout. The press is from a fair
amount of really good literature that tells you
that serum urate levels correlate with untreated
blood pressure in children between the age of 6-18,
and that hyperuricemia is a very powerful predictor
of atherosclerosis and arterial occlusive events
and adverse outcome in primary vascular diseases.
A striking example is a 12-fold higher
cardiac death rate in stroke survivors at 5 years,
adjusted for renal function in those who are
hyperuricemic. And, I am not saying that we should
ignore such data. And, serum urate may be--may be
and independent risk factor for atherosclerosis and
certain atherosclerotic vaso-occlusive
Basically, there is a large amount of
recent data that I have used, quite controversial,
that suggests direct linkage of hyperuricemia to
vascular smooth muscle dysfunction, increased
sodium reabsorption, hypertension, glomerulopathy,
cyclosporine nephropathy and chronic renal
insufficiency itself. The question has arisen is
markedly elevated normal serum urate in a human
being, such as the levels of 7, 8 that we see in a
human being, a beneficial or a harmful result of
evolutionary human uricase gene silencing?
Basically, if we are dealing with human
evolution, we realize that a key step was the
evolution of hominids to more upright posture and,
at about the same time uricase became silenced at
the transcriptional level in higher primates. What
has been done to address the issue of whether a
normal serum uric acid level of approximately 6 mg
percent or mildly elevated hyperuricemia, 7-8 mg
percent, in a human being may directly cause
vascular disease is to use a specific model where
oxonic acid, a uricase inhibitor, is given to rats.
The serum urate rises from approximately 1 mg
percent to 2-3 mg percent.
What happens in this model, which has been
developed primarily by Richard Johnson and
colleagues, is that the increased hyperuricemia
that is seen in this model correlates with
activation of the renin angiotensin system, more
sodium resorption, higher blood pressure, and there
is also some in vitro data that adding uric acid to
cultured cells will induce the proliferation of
these cells, induce COX-2, induce certain
chemokines and induce MAP kinase activation.
What are the flaws in interpreting this
model that we can bring up? One of the flaws is
that oxonic acid directly inhibits the function of
UAT which has an oxynate binding site. So, it has
the potential to promote intracellular retention of
urate and other solutes in cells of the
Then, the other limitation is that direct
uric acid infusion in healthy human adults, which
has been performed by Waring et al., did not alter
any hemodynamic or endothelial functions. Urate
handling as well as serum urate levels may differ
markedly in the rat and human and the cellular
effects of soluble uric acid in vitro are subject
to artifacts because of potential micro
Basically, what we have is a situation
where uric acid in humans has good effects in that
it is an antioxidant. It is 8 times more abundant
in human serum than ascorbate. Human ascorbate
production actually was lost in evolution in
parallel with uricase. And, uric acid actually
appears to protect against oxidant induced in
hypoxic brain and heart injury. Again, under
certain conditions uric acid may be a pro-oxidant
and soluble uric acid may turn on genes. So, the
good and the bad effects of hyperuricemia may
depend on the nature of the host, much as it
depends on the culture conditions in vitro.
Some food for thought before I talk about
surrogate endpoints for a couple of minutes--gout
is evolving clinically and clearly refractory gout
and gout are rising. Better preventative efforts
population-wide are needed, including patient
education. Development of new treatments has not
kept pace with medical needs. Typical asymptomatic
hyperuricemia has not been proven to directly cause
renal or vascular disease, and gout and
hyperuricemia are well understood in management but
not well enough.
So, we have a situation in which we have
uric acid, indicated by these stars, that is
physiologically kept in solution below about 7 mg
percent, and physiologically eliminated, and when
we have imbalance in either purine production or
intake or urate elimination, we get supersaturation
and tissues are supersaturated. Tophi are formed.
Our goal is to either apply dietary
measures, anti-oxidase inhibitors, uricosurics or
uricase in some circumstances to allow these tophi
to resorb. We will ultimately then see less
intense and less frequent gouty arthritis and we
will have less supersaturation in tissues that will
promote tophus resorption.
How do we do this in somebody who is,
let's say, hypersensitive to allopurinol or truly
allopurinol intolerant? Our options really are
limited. You know, the ideal situation is no
chronic renal insufficiency and urate under-excretion where
we can apply a uricosuric.
Allopurinol desensitization is a 50/50 proposition
in terms of success and oxypurinol is probably
better than that, as we will hear today from what I
have read. If a patient is allopurinol tolerant
and has refractory gout and we are not putting them
into a clinical trial, do we push allopurinol? Can
we combine allopurinol with probenecid? There is
very little data on these situations.
So, the issues regarding clinically
meaningful and optimal surrogate endpoints for
clinical trials include the synergistic role of
combinations of anti-hyperuricemic therapies. The
problem is that precipitation of gouty inflammation
of urolithiasis are side effects of effective serum
urate lowering, and allopurinol and uricosuric
intolerance and failure need firm definitions. For
example, too low or too high allopurinol dosing
does not constitute treatment failure.
Other issues are that serum urate is going
to be less informative than measuring the total
body urate pool, and I would propose that newer
fluorescent labeling protocols be developed by
targeted grants, I would hope, to add better
measures of body urate pool. And, we need to have
better simple measures of uric acid production
levels and uric acid excretion levels in the kidney
than what we have today.
How consistent is urate and how many times
to measure has been raised as an issue. Then,
there is the question of the percent drop in serum
level versus the absolute drop in serum level. Do
you drop to a target "sweet spot" level of, for
example, 5-6 mg percent? Or, do you try to go
slower or lower?
What do you do in terms of patients with
chronic renal failure? I think it is important to
point out that creatinine clearance is going to be
a superior measure than serum creatinine to
interpret results, particularly in elderly patients
in these trials.
Serum urate in disease phenotype becomes
an issue because of the effects of gender that I
have mentioned; the effects of diabetes itself; as
well as chronic renal insufficiency and CHF; as
well as all the other things patients are doing.
I bring up a few questions. One study of
a calcium channel blocker compared to beta blocker
for hypertension management in patients with
cyclosporine use showed that the calcium channel
blocker lowered serum urate by 10 percent, whereas
the beta blocker lowered urate by zero. So,
sometimes the way that hypertension is managed
alone can have an impact on hyperuricemia depending
on the clinical setting.
Then, the anti-inflammatory properties,
albeit somewhat low grade for statins, also may be
higher grade for PPAR gamma agonist anti-diabetic
agents may have to be factored into interpretation
of clinical trials with modification of gout.
Then, in terms of tophus size, we need
validation of parameters for size change and manual
measurement of superficial tophi, and the threshold
for change by radiographic assessment, such as MRI,
is really not defined, and we don't know whether to
measure both grossly uninvolved and involved joints
because with the uninvolved joints, if you aspirate
some of those joint fluids, you may see urate
crystals and that is not really rare.
Then the issue of needing quality of life
instruments and assessing the frequency and
severity of gouty attacks; the length of attacks;
the number of anti-inflammatories consumed--would
those be useful parameters to look at? And, which
shorter and longer specific times points to look
at? We need instruments like an ACR-50 or a HAQ
optimized for gout. The one that we are trying to
play with at UCSD is a drop in serum urate in
milligrams per deciliter, divided by the fraction
of gouty attacks per month between 3-12 months
relative to baseline, and then trying to come up
with some numbers for validating that particular
instrument. It is a very poor instrument but it is
Then, the role of pharmacogenomics and
optimal clinical trials of anti-hyperuricemic
drugs--is there a role for identifying patients who
have SNPs and URAT1 and other OATs, and UAT? Is it
important to identify hyperuricemia that is
possibly mediated by dysregulated tissue UAT as
distinct from a true increase in the body urate
pool? I think, as we will see maybe 5 or 10 years
from now, this will be a significant issue.
I want to think about identifying also
altered pyrimidine metabolism in non-immune
allopurinol toxicity as another pharmacogenomic
tool. Finally, identifying subject redox stress
may also help in pointing out who is more
susceptible to uricase toxicity.
So, thank you for your attention.
DR. GIBOFSKY: Thank you, Dr. Terkeltaub
for an excellent presentation. I would like to
take a moment, if there are any specific questions
from the panel for Dr. Terkeltaub before we go on.
DR. CUSH: You implied that we should be
looking at tophi as a measurable outcome. Can you
inform us as to the evidence that reducing tophi
improves quality of life and subsequent attacks?
You were sort of talking about tophi as sort of a
measurable pool or tangible measurable pool of
total body urate as opposed to just going to serum
uric acid levels. I mean, we would look to prevent
gout by looking at attacks. Clinically we usually
don't target tophi because when they show up they
have so many tophi--we would like them to go away
and we take that as a goal but we often don't see
that in practice.
DR. TERKELTAUB: That is a good question.
I think, you know, with modern imaging techniques
we may be able to see in a better manner
microscopic tophi in the synovium, and we will be
able to better understand how to reduce the urate
crystal burden at the joint level. Basically,
given that the disease includes connective tissue
destruction mediated by those deposits, I think
that is a large issue.
The problem here is that as you decrease
tophus size you may get more symptoms vis-a-vis
attacks of gouty inflammation. Whether it has been
studied adequately, clearly not. There have bee so
few clinical studies over the last 20 years.
DR. GIBOFSKY: Bob, you pointed out that
erosions can progress even with effective lowering
of serum uric acid. To what extent then ought we
to be considering imaging as an outcome measure in
clinical trials for any anti-gout agent?
DR. TERKELTAUB: Yes, thank you for the
question. I was referring to a study by Bob
Wartman and Geraldine McCarthy about 12 years ago.
Basically, they looked at the first toe and they
saw, with gross radiographs, that there was
progression over a fairly long time period with
adequate serum urate lowering and, basically I
think there is a lot of room for optimizing a
better trial today using more modern imaging
DR. GIBOFSKY: Dr. Bathon?
DR. BATHON: I was just remembering one of
the NSAIDs, etodolac, clinical trials that caused
significant lowering of uric acid. I was wondering
if it could be clinically efficacious.
DR. TERKELTAUB: Several of the NSAIDs can
modulate urate excretion, not huge effects. I
think they become more important to consider when
you are trying to understand what the etiology of
the hyperuricemia is, other than aspirin, of
course, and salicylates.
DR. GIBOFSKY: Dr. Felson?
DR. FELSON: Bob, that was a wonderful
comprehensive talk. If we are going to consider
uric acid as a surrogate marker, it seems that we
need to know a little bit more about the
repeatability of measurement, the sources of
variability over time of the day and from day to
day. When I was in medical school I learned that
there were a number of different assay techniques
for uric acid and that they weren't necessarily
consistent in their results. Could you start with
that? Is that still true or is there some real
consistency across various labs in given specimens
and what levels they produce?
DR. TERKELTAUB: The standard measure
right now for serum uric measurements is adopted
nationwide. There used to be a uricase method that
was used in some labs and a distinct method used in
other labs. In terms of the reproducibility
between patients, there haven't been terrific
studies done. Most of the studies have been done
on a population level to construct bell curves and
there haven't been terrific studies done vis-a-vis
DR. FELSON: Does uric acid vary by time
of day in a given person? It was hard to use
cholesterol, for example, as an outcome measure in
trials because there was a lot of variability from
hour to hour and from day to day in people; blood
pressure similarly. That is one of the reasons why
we get multiple measures of blood pressure to make
a diagnosis. Is there a similar variability in
DR. TERKELTAUB: Not to my knowledge.
DR. FELSON: But it sounds like it hasn't
been well studied.
DR. TERKELTAUB: It hasn't been well
studied since I have been a rheumatologist. That
is the problem.
DR. GIBOFSKY: Any other questions? Dr.
DR. HOFFMAN: The comments about the
Wartman study and continuing erosive changes after
normalization of uric acid, is that in part because
all gout is really micro tophaceous, it is the
product of so many years of laying down sodium
urate and normalization of serum uric acid is
really the curve towards gradual resorption of
tophi. So, when we look at clinical endpoints
using imaging, it really wouldn't be so meaningful
to look at radiographic endpoints for something
less than perhaps a year after the accrual of
increasing micro tophi within the joint was aborted
and resorption had meaningfully progressed.
DR. TERKELTAUB: Yes, I think we believe
that serum urate is the large tip of a large
iceberg, and I would challenge clinical
investigators to look at more sensitive methods of
imaging the synovium of joints to look at small
tophi and to try to calculate the size changes.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: If we are going to look at
the recurrence of acute attacks of gout, let's say,
in someone who has had prior gout and has
hyperuricemia to assess the efficacy of a long-term
therapy, would one do that in a patient who would
be entered into a trial who is on background
colchicine therapy, which is at least accepted
therapy to reduce the risk of recurrence of acute
attacks, and see whether an agent in addition to
colchicine was better than placebo in addition to
colchicine? Or, would you consider doing this
instead of colchicine?
DR. TERKELTAUB: I would consider doing it
with colchicine pretty much. I think that
basically the most common side effect we see with
allopurinol, for example, is precipitation of acute
gouty attacks. The data are not great for this. I
mean, we know that the gouty attacks are usually
precipitated most frequently in the first couple of
months of allopurinol treatment, but with
uricosuric treatment, which is titrated by
everybody out there more steadily, there is are few
gouty attacks precipitated. Has that been studied
in a really good quantitative clinical trial? No,
but I think people who are experienced clinicians
know that is probably the truth. I don't think
that withdrawal of colchicine would be a good thing
in terms of constructing clinical trials.
DR. GIBOFSKY: Thank you, Dr. Terkeltaub.
I think at this point we will move to the next
portion of the program which is a presentation by
Cardiome Pharma, Inc. We will ask Dr. Moore, the
Executive Vice President for Clinical Development
and Regulatory Affairs of Cardiome Pharma Corp. to
introduce the program and the speakers for that
portion. Dr. Moore?
Cardiome Pharma, Inc.
DR. MOORE: Well, good morning, ladies and
gentlemen. We are here to talk about oxypurinol
for gout. I am Alan Moore and I am the Executive
VP for Clinical Development and Regulatory Affairs
of Cardiome Pharma.
My role here basically is three-fold. I
am going to give you a very brief introduction to
Cardiome Pharma. Then I want to talk about the
regulatory history of oxypurinol because it is
really quite extensive, as I am sure you know, and
finally talk about the concepts of the agenda and
the agenda itself.
First of all, let me start with Cardiome
Pharma. We are an R&D company that is based in
Vancouver, Canada. We focus on cardiovascular drug
development. As I am sure you are aware, there is
a large component of anti-inflammatory in
cardiovascular so, consequently, we have frequent
interactions with both FDA's cardiorenal and anti-
inflammatory drug divisions as well.
Let me talk about oxypurinol regulatory
history. In 1966 Burroughs Wellcome filed an IND
for the compassionate use program for oxypurinol.
The reason was that in 1963 Burroughs Wellcome had
marketed allopurinol and had quickly observed
allopurinol-intolerant patients. Consequently, in
'66 this compassionate use program started, which
was designed to provide oxypurinol for allopurinol-
In 1996 ILEX acquired the IND for the use
of oxypurinol, and in 1998 the drug received an
orphan drug designation. As you will hear later,
this is a very small population of patients that we
are talking about.
In 1999 the pivotal study OXPL213 was
initiated, and you will hear a lot more about that
later on this morning. In 2002, Cardiome Pharma
acquired the IND for this drug and we filed the NDA
on December 23 of 2003 which is, of course, part of
the reason that we are here today.
Dr. Witter had talked about Subpart H and,
as I said, the way the majority of patients who
received this drug was by compassionate use. So,
let me talk about the benefits of Subpart H
approval, which we have been talking about
extensively today with the FDA, versus the current
compassionate use program.
First of all, Subpart H approval provides
patient education; provides restrictive patient
enrollment criteria; provides a patient registry;
provides physician education and training; provides
collection of safety data and fewer patients lost
to follow-up. Of course, the converse is true of
the compassionate use program.
So, the proposed indication that we are
looking for oxypurinol is--let me read it,
oxypurinol is indicated to treat hyperuricemia in
patients with symptomatic gout who are intolerant
to allopurinol and have failed either rechallenge
or desensitization with allopurinol. To be clear
then, this is a doubly intolerant patient
population, and what we are talking about here are
people who have not just failed allopurinol once
but have also failed twice because they failed
either a rechallenge or a desensitization, again,
making the population that much smaller than what
we have been talking about before.
Now, what does oxypurinol provide for
these allopurinol-intolerant gout patients? Well,
it addresses an important unmet medical need. We
have already heard from Dr. Terkeltaub that
allopurinol-intolerant patients have very limited
options and, clearly, oxypurinol provides an
option. Secondly, oxypurinol has demonstrated good
clinical efficacy, and we will talk about that
later on in the presentation. Next, it is well
tolerated in the majority of allopurinol-intolerant
patients. Not to emphasize the point here, but the
patients we are talking about are 100 percent
intolerant to allopurinol; they simply cannot take
it, whereas, 70 percent of them can take
oxypurinol, and we will talk about that later as
well. Finally, as Dr. Witter mentioned, under
Subpart H there will be additional safety and
efficacy issues addressed, first by the Subpart H
risk management program but, secondly, by a Phase 4
study, that we will also talk about later in some
detail, that is currently under way in our hands
that talks about clinical outcome and compares that
with serum uric acid as well.
So, let me introduce the speakers and
topics for today. First of all, with have Dr.
Ralph Snyderman, from Duke University, who will be
talking about gout as a serious progressive
disease. Secondly, we will have Dr. Garth
Dickinson, from the University of Ottawa, who will
be talking about oxypurinol efficacy and safety.
Thirdly, we have Dr. Robert Makuch, from Yale
University, who will be talking about OXPL213
analysis, and this is our key pivotal study.
Finally, Dr. Leonard Calabrese, from the Cleveland
Clinic, will be talking about his clinical
experience and post-approval issues with
oxypurinol. So, thank you for your attention. Dr.
Gout: a Serious Progressive Disease
DR. SNYDERMAN: Thank you, Alan. I would
like to thank the FDA and the Arthritis Advisory
Committee for giving us the option to talk but,
more importantly, for recognizing an important
serious, progressive metabolic disease which, as we
have heard from Dr. Terkeltaub--one of the best
presentations I have heard in a long time--this is
a problem that is not only with us, it is going to
be increasing as we go ahead, and it is an
important clinical problem.
Gout is probably one of the best described
and understood and characterized diseases virtually
in all the history of medicine, having been written
about by Hippocrates and his colleagues; being
discussed by Galain with a description of a tophus;
Garret, in 1844, beginning the revolution in
medical understanding of the metabolic basis of
disease; the development of uricosuric agents in
1950; and the development of allopurinol in the
very early '60s.
Now, given the fact that gout is a serious
metabolic disease for which there are a number of
treatments, I also feel it has been badly under-recognized,
the degree of the clinical problem that
it is. As I was hearing Dr. Terkeltaub talking, it
is almost the Rodney Dangerfield of rheumatology
diseases. It doesn't seem to get the respect that
I actually started at Duke in the
rheumatology division at the time that we had Jim
Weingarten, Bill Kelly, Ed Holmes, Wayne Rundells
who was in the hematology division, and Durham, as
many of you know, was a hotbed of moonshine, white
whiskey, and we had an incredible prevalence of
gout and it was very well studied.
Very recently, on an NPR show, public
radio in Durham, from the People's Pharmacy I heard
a physician say that gout was no longer a medical
problem, that it was so easily treated physicians
don't even think about it anymore. Just having
completed rounds at Duke doing my rheumatology
turn, I can tell you that this is a very prevalent
disease. Just seeing the patients that we are
seeing at Duke, I would agree with Dr. Terkeltaub,
not only is it common, not only is it prevalent but
the patients are much more complicated and usually
are admitted not because of their gout but because
of other serious diseases, but what is bothering
them the most, even though they may be dying from
something else, is their problem with chronic
So, gout is a serious metabolic disease.
In its untreated form it is chronic, progressive
and debilitating. It is the most common form of
inflammatory arthritis in men over 40, and we are
seeing it more and more in women. Many patients
with gout have renal insufficiency, with primary or
secondary but we suspect a substantial amount is
primary. We have also heard, and there is very
good epidemiological data, both from the Rochester
studies and in Taiwan, that gout is increasing
dramatically over the last few decades. It is
occurring at a much earlier age. It is increasing
in frequency even independent of other medications--primary
gout is increasing in frequency and it is
increasing in women. So, we need to deal with it.
This clearly is a problem.
The stages of gout are well described.
The first attack is usually following substantial
periods of hyperuricemia. I think the discussion
of whether or not there are developments of micro
tophi in certain joints, such as the first MTP, is
a very interesting question but we certainly know
from direct experiments that one does not need a
micro tophus, given the elegant studies of Dan
McCarthy and P. Phelps injecting monosodium urate
crystals directly in their joint and getting a very
hardy gouty attack. So, I think that is an
interesting question but, nonetheless, acute
recurring gout followed in some by inter-critical
period and then chronic tophaceous gout. What
differentiates these individuals is certainly a
matter of great interest.
I think one of the reasons gout has been
to some degree not given the respect that it truly
deserves is the fact that it has been associated
with conditions that people can bring on
themselves, at least seemingly so. This has been
called the disease of kings. I was interested to
hear that white wine doesn't increase gouty attacks
but maybe port wine does and individuals eating
sweetbreads and various other things. So, this was
called the disease of kings and many cartoons show
the obese individual, obviously wealthy, being
carried about by others with a swollen big toe.
But that is not the story of gout as we
are seeing it. We are seeing it as a debilitating
disease that causes a great deal of joint
destruction and the tophi, while difficult to
remove, what I would say is that tophi themselves
are debilitating in individuals with large tophi.
There is a lot of weight and bulk to carry around
and many people suffer from this.
As any rheumatologist knows, the way we
used to challenge ourselves sometimes at rounds is
where have you not seen a tophus? Tophi could
develop virtually anywhere and they certainly
develop in the kidney and many people with
prolonged hyperuricemia develop urate nephropathy.
Pathogenesis has already been described elegantly.
Again, this is a disease in which we know so much
and, yet, there are things that we still don't
know. Whether the monosodium urate crystal
provides a surface for complement activation or
other mechanisms of inflammation, nonetheless, it
is very pro-inflammatory in most individuals.
The management of gout has been very well
described. I will just say briefly that we are
often focused on treating the acute gouty attack,
whether it is monoarticular or oligo- or
polyarticular. But in individuals in Duke Hospital
this is sometimes the greatest problem by far that
a patient is facing, no matter what their other
We are virtually never able to use
colchicine. As much as I have used it as a
rheumatologist, I can tell you when somebody is in
the hospital there is always a good reason that you
cannot use colchicine. NSAIDs which work extremely
well also. It seems as though most of the patients
that we have, have a creatinine that is higher than
what we would like to see in somebody using Indocin
or some other nonsteroidal. Corticosteroids--at
least I see it all the time with the house staff
and it amazes me sometimes that the first-line drug
of choice seems to be the use of corticosteroids,
whether intra-articular or systemic.
The chronic treatment of gout to actually
affect the metabolic cause for development of
monosodium urate crystals is, as we heard,
primarily uricosuric agents, xanthine oxidase
inhibitors, uricase still being looked upon
experimentally, with the most common utilization
being allopurinol. I remember quite well when the
compassionate clearance became available for
oxypurinol, and I can tell you that for physicians
having to do this is burdensome, very hard to
develop follow-up and very rarely used even though
many clinicians would want to use oxypurinol, in my
So, the therapeutic goals in gout--we need
to decrease the frequency of attacks, the severity
of attacks but what we really want to do is
decrease the continued deposition of monosodium
urate crystals; decrease the frequency of gouty
attacks, tophi, urate nephropathies and renal
colic, and there are a number of different forms of
renal diseases associated with gout.
The major point I want to make, other than
that gout is under-appreciated as a national
problem which is going to be getting worse and it
affects a segment of the population that seem to
have the least options available to them. So, I
believe it is a matter of justice as well to give
this problem the attention it deserves.
The figure I have is 2.5 million. Dr.
Terkeltaub had 3-5 million. Clearly, this is a
large number of people. As best as we can tell,
roughly 1 million prescriptions of allopurinol are
made each year. There are up to 40,000 individuals
who, for one reason or another, cannot take
allopurinol. The data that will be presented by
others today is that within this population there
are going to be, let's say, up to 14,000
individuals whose condition could be satisfactorily
treated with oxypurinol. That is the argument that
will be made by the people at Cardiome.
I would just like to put this a bit into
perspective. If we look at the individuals who
then potentially could be treated effectively with
oxypurinol, we have allopurinol-intolerant gout
patients that have already failed desensitization
and are likely to be affected well by oxypurinol,
you are talking about a serious disease. We think
an awful lot about cystic fibrosis, as we should,
hemophilia, Gaucher's and others. I applaud the
FDA and the Arthritis Advisory Committee for
focusing specifically on those unfortunate
individuals that have chronic gout that have no
other option open to them. Thank you very much.
The next speaker is Dr. Garth Dickinson,
from the University of Ottawa, who is going to talk
about oxypurinol efficacy and safety.
Oxypurinol Efficacy and Safety
DR. DICKINSON: Thank you, Dr. Snyderman
and good morning, everyone.
In discussing the efficacy and safety of
oxypurinol I would like to focus on two main
trials. The first is the pivotal trial OXPL213 and
the second is the compassionate use program which
is called CUP3362-01. OXPL213 was an open-label,
single-arm, multicenter trial that enrolled 79
patients. The trial duration was 14 weeks.
Everyone enrolled in the trial had mild to moderate
allopurinol intolerance. Everyone enrolled in the
trial had relatively normal renal function. Their
creatinine had to be less than 2.
The primary efficacy endpoint for the
trial was a serum uric acid reduction of 2 mg/dl.
Oxypurinol was dosed in a graded fashion, starting
with 100 mg per day for the first week, 200 mg per
day for the second, 300 mg per day for the third
week. So, gradual titration in dose. Once a
reduction of 2 mg/dl was achieved in serum uric
acid there was no further dose escalation.
What were the results? You can see that
the patients started off with a mean serum uric
acid of 10.11 so they had significant hyperuricemia
and they were all symptomatic patients. In the
efficacy intent-to-treat population, as defined by
the protocol, of 77 individuals the mean reduction
was 1.90. This was just short of the primary
efficacy endpoint of 2 mg/dl. However, this
reduction was highly statistically significant
compared outcome to the baseline number, at a level
of p less than 0.0001. In the completer
population, the 54 individuals who were able to
complete the 14-week trial, the reduction in serum
uric acid was naturally higher. It was 2.32 mg/dl.
In addition, we looked at perhaps a more
clinically relevant endpoint, and that was what was
the number of patients whose serum uric acid
actually fell into the normal range, and we found
that in the total efficacy intent-to-treat
population 38 percent dropped into the normal
range. In the population that completed the trial,
50 percent of these individuals had their serum
uric acid reduced into the normal range.
The compassionate use program is not a
clinical trial. It started in 1966 as a result of
a need for patients who could not tolerate
allopurinol. Since that time there have been 533
patients enrolled in that trial. And, 533 patients
represents probably over 5 percent of the
allopurinol-intolerant population that this drug is
intended for so this represents a large component
of the allopurinol-intolerant patient population.
This was a real-world study and 38 percent
of our patients had renal failure as defined by a
creatinine of 2 or greater. Many of these patients
are transplant patients. The average dose that the
patients took at 1 year was 372 mg and there was a
fairly wide dose range, from 100-1800 mg per day.
One patient in particular took 1600 mg of
oxypurinol daily for 8 years without any
The problem with adverse reactions with
oxypurinol tends to be more idiosyncratic rather
than dose related. The average duration of
treatment with oxypurinol is 3.2 years, with 22
years being the maximum that any one individual has
been on the drug, and there are currently 162
patients taking oxypurinol in this compassionate
use program and in the one that followed the 213
Looking at longer-term serum uric acid
endpoints, you see that at 1 year in both the
extension to the 213 trial--these were patients who
were able to continue oxypurinol treatment after
completing the 213 trial--and those in the
compassionate use program, their serum uric acid
fell by about 2.9 mg/dl. This compares to about 3
mg/dl which occurs in patients who are given long-term
allopurinol therapy at 300 mg per day, again,
a highly statistically significant reduction.
Gout flares have been referred to already
a few times this morning, and they are a problem
when you are trying to measure the effectiveness of
any particular uric acid lowering therapy. In the
213 trial we had 24 gout flares experienced by 12
patients. So, our rate of flares was about 16
percent, which compares very closely to what is
experienced with allopurinol, the rate being quoted
as somewhere between 10-24 percent. So, treatment
with oxypurinol seems to mobilize uric acid and may
be associated with gout flares, just as is the case
In concluding about the efficacy of
oxypurinol, there is no question that oxypurinol is
effective in reducing serum uric acid in
allopurinol-intolerant patients. The magnitude of
the serum uric acid reductions are quite comparable
to those seen with allopurinol.
Let's move on now to safety. In
discussing safety I will be speaking again about
two trials, OXPL213 and the compassionate use
program. The safety issues relate primarily to the
30 percent of patients who cannot take oxypurinol,
100 percent of these patients cannot take
allopurinol. They are all allopurinol-intolerant.
Seventy percent can tolerate oxypurinol but 30
When you look at the adverse events that
occurred in trial 213, if you look over to the
column on the right side you will see that of the
oxypurinol-related events there were 30 events
considered to be related to oxypurinol and 21 of
these resulted in discontinuation of the drug.
There were no serious adverse events due to
oxypurinol. There was 1 death in the trial
unrelated--due to cancer of the pancreas. There
were no life-threatening adverse events due to
oxypurinol. There were 3 severe adverse events.
Two of these were severe skin rashes and one was a
significant elevation in liver function tests.
When we look at the adverse events that
prompted oxypurinol discontinuation, you can see a
recurring word here, dermatologic, dermatologic.
The vast majority of adverse events with oxypurinol
are skin rash, just as is seen with allopurinol.
The other thing that you see here is that
of these 21 patients that had to stop oxypurinol in
the trial, 19 of them had exactly the same reaction
to oxypurinol as they had with allopurinol. So, in
any one individual it is quite predictable what
kind of adverse event you are likely to come up
The final point here is that it is not
just skin rashes. There are other things that can
occur, there are other adverse events. These
typically are clinically silent so it could be
myelosuppression, thrombocytopenia or it could be
elevation in liver function tests. So, it is
important that patients who are started on
oxypurinol be carefully monitored both clinically
and by laboratory evaluation.
In terms of the adverse events that caused
discontinuation of oxypurinol, they occurred early
and 71 percent of them occurred in the first week,
while they are on 100 mg per day. They are
predictable. In any individual, if they are going
to have an adverse event, there is a 90 percent
chance it will be the same event they had with
allopurinol. So, if they had a rash you watch for
a rash. If they had liver function problems on
allopurinol you watch for liver function problems.
Ninety percent of them were mild or moderate and
all of the adverse events were entirely reversible.
Remember, in this trial we did not enroll anybody
who had had a severe reaction to allopurinol.
These are mild or moderate allopurinol reactions.
When we look at the compassionate use
program, we see that there are many more serious
adverse events. This is an elderly population with
multiple co-morbidities. Importantly though, look
again over at the column on your right side. Since
1966, investigators using oxypurinol have never
reported a serious adverse event related to
oxypurinol. That is a pretty astounding safety
record. There have been no life-threatening
adverse events reported either. Over 1500 years of
patient dosing are included here.
Let's turn now and look at hepatic adverse
events. In the 213 trial 6 patients had hepatic
adverse events to allopurinol who were enrolled in
the trial. Of these, 2 had the same type of mild
liver function abnormalities to oxypurinol. In the
compassionate use program we identified 20 patients
who had had liver function abnormalities on
allopurinol. When they took oxypurinol, 6 of them
again had the same type of liver function
abnormalities and had to be withdrawn. The
consistency here is that still about 33 percent of
individuals were having the same type of reactions;
30 percent of individuals who can't take
allopurinol also can't take oxypurinol.
When we look at this from a slightly
different angle and we look at all the hepatic
adverse events that occurred in the 213 trial or in
the years of the patients who continued on
oxypurinol, we found 6 episodes of hepatic
dysfunction. Two of these were considered to be
probably related to oxypurinol and in both those
instances the patient had experienced abnormal
liver functions while taking allopurinol. So,
these patients dropped out. One dropped out early
in the trial and one completed the trial but
dropped out after the end of the trial and didn't
continue on. All of the other hepatic
abnormalities that occurred in these patients were
considered unrelated to oxypurinol therapy by the
principal investigators. In three of the four
cases oxypurinol was continued for prolonged
periods and no further adverse events occurred.
So, for safety conclusions for oxypurinol,
70 percent of patients who are allopurinol-intolerant can
tolerate oxypurinol. The adverse
events that do occur with oxypurinol occur early.
They are predictable. They are reversible. There
is risk of hepatic toxicity and it is important
that any patient who is started on oxypurinol be
followed and managed in an appropriately structured
clinical environment. There has been no evidence
of significant harm with oxypurinol. There have
been no drug-related serious adverse events
reported with oxypurinol. So, in this population
who are 100 percent allopurinol-intolerant, in this
population oxypurinol is much safer than
Thank you. I would like to now introduce
Robert Makuch, from Yale University, who will look
at a statistical analysis of the 213 study. Thank
DR. MAKUCH: Good morning. I am here to
discuss the analysis of the pivotal trial for
oxypurinol, OXPL213. I would like to take a step
back just for a minute and summarize my recent
involvement in this effort. This included my
review of numerous documents, including the pivotal
study data, the study protocol, the analysis plan
and related documents. Based on my independent
assessment, there were certain limitations to the
study that included inconsistencies or
incompleteness of various efficacy endpoint
definitions in the analyses.
This led me to propose, prior to looking
at any of the data, alternative endpoints and
analytic methods. What I would like to do this
morning is review for you these alternatives with
two goals in mind. The first is to provide you
with additional information that may be useful in
your discussion today regarding guidelines for
chronic gout studies. Secondly, to help you
understand more fully the results from this pivotal
To review briefly, for the primary
efficacy objective for this pivotal study the goal
was to demonstrate the efficacy of oxypurinol in
lowering serum uric acid by at least 2 mg/dl after
14 weeks of its administration to symptomatic
hyperuricemic patients who have developed an
intolerance to allopurinol. This primary objective
was operationalized by defining the primary
efficacy endpoint as follows: One would consider
the mean of the 3 baseline assessments and from
that, for each subject, subtract the mean of the
assessments made at weeks 12, 13 and 14, or for
those subjects who did not have values at these
time points we would then consider the last
available assessment that would then be used for
This endpoint definition, as you can see,
is somewhat inconsistent in the sense that we used
the average of 3 values for patients at their
treatment termination for those who did make it to
the end of the study and we only used one value for
those who discontinued early. We will return to
this issue later.
I would like to just review for you
briefly the patients that will comprise the basis
for my analysis. There were initially 79 subjects
enrolled who took at least 1 dose. On the other
hand, there were 2 subjects for whom there were no
post-baseline serum uric acid values available.
They were discontinued for reasons unrelated to
study drug and so, per the protocol, the ITT or
intent-to-treat efficacy population then becomes 77
subjects. Of the 77 subjects, of those who
completed 14 weeks of they, we had a total of 54
subjects. The remainder discontinued early with 23
such subjects meeting that particular criterion.
Of those 23, there were 8, in fact, who had no
post-baseline serum uric acid values.
So, my analyses then will focus on two
groups. One will be the original ITT per protocol
population of 77 subjects. The other will be the
77 minus the 8 subjects who did not have post-baseline, or
69 subjects then who had at least 1
post-baseline SUA value. The reason, in part, is
that this often is used as the intent-to-treat
population in other studies.
To focus just for a minute on the 8
subjects who did not have a post-baseline SUA who
were unable to tolerate oxypurinol, we note in the
analysis that they were originally assigned a SUA
change value of zero. Clearly, this would
compromise the ability to detect a SUA reduction of
greater than or equal to 2.0 since we have 8
subjects of the 77 having a value imputed of zero.
This is not an optimal statistical approach for two
reasons. One, for these 8 patients we are imputing
a value of zero. More generally though, the change
value doesn't take into account all the data that
were collected on these patients. In fact, the
data were collected on these patients not only at
baseline and at weeks 12, 13 and 14 but, in
addition, we had data collected as well at week 6
and at week 9. So, in fact, we have a good set of
information available on all subjects as they
proceeded through their entire treatment course.
What I would like to then do is to just
briefly describe some of the alternative endpoints
that I considered prior to looking at the data, as
well as an additional analysis that I thought would
be meaningful in terms of getting a fuller
appreciation for these data. The alternative
endpoints included the proportion reverting to a
normal SUA level, and you have already heard Dr.
Dickinson present the results for that. The second
alternative endpoint is to consider the baseline
average for all the subjects but just minus the
last value. So, what we are then doing here is
applying a consistent definition to all the
subjects. Namely, we are going to take the last
value for all the subjects as opposed to taking
several values for some subjects and taking just
the last value for other subjects, as was done in
the original protocol and the original analysis
Secondly, I will also present the
regression analysis which takes into account all
the data. The reason I find this to be very useful
and perhaps the preferred method is that it does
use all the data in the full intent-to-treat
population of 77 subjects and, secondly, we do not
impute any data.
To summarize the results of this analysis,
again, we have the 77 intent-to-treat for the
population and here we are looking at the change
from average baseline to just the last value.
Therefore, upon the reduction in the SUA we get a
slightly different result than what was presented
to you earlier because it was based on somewhat
different data in terms of some patients--3 values
for some patients and other patients just 1 value.
Here we are taking just the last value for all the
subjects and then you do get a reduction of 1.95
with a confidence interval as seen and, again, a
highly statistically significant reduction in the
SUA values between baseline and week 24.
The second analysis includes all those for
whom we had at least 1 post-baseline SUA value, the
69 subjects. For that group we then get a
reduction in the SUA value of 2.12, again with the
corresponding confidence interval as you can see,
again a highly statistically significant reduction
in the SUA values over time associated with
oxypurinol. Clearly, the mean value then does
The best way I think to look at these data
is with a regression analysis since it uses all the
data for all the patients, with no data imputation.
At Yale I guess we call this the spaghetti plot.
It looks sort of like you threw spaghetti on the
graph but essentially this is all the data that we
have and, as you can see, it does point out the
information that we have at week 6, week 9, 12, 13
and 14 which are the values at which measurements
were taken, as well as all the information for all
The dark line is the regression line that
we will describe next. One point though is to note
that there is a market decline between baseline and
week 6 and then that levels out from week 6 out to
week 14. This is actually quite consistent with
the dose escalation scheme that was used in the
study, in which the doses were increased up until
the week 6 period and then modifications were made
for those who did not achieve a 2.0 mg/dl
reduction. So, in some sense, this trial was dosed
in a way that was titrated towards a reduction of
2.0, which I think has to be considered when
looking at the results at the end of the study
which, again, are around 2.0.
So, in the regression analysis, just to
describe it, we did a linear regression with both
linear and quadratic terms. When one applies it to
the data that we saw in the previous slide, at week
14 there is a mean drop of 2.37 mg/dl in the serum
uric acid level. Moreover, the 95 percent
confidence limit ranges from the low of 2.06 to
2.67. So, not only is the average drop in excess
of 2.0 but also the lower 95 percent confidence
limit for this mean also exceeds 2.0.
So, the conclusions are that using and
considering alternate endpoint analyses, whether we
look at the N of 77, which is the full intent-to-treat
population in which we have, for the last
value analysis, a value of 1.95 being the mean
drop, or the 69 subjects, all of whom have at least
1 post-baseline SUA value--again, an intent-to-treat
population often defined in protocols, or
whether we look at the regression analysis which
uses all 77 full intent-to-treat population per the
protocol and in which we have a significant drop
and you saw the confidence interval earlier which,
again, is in excess of 2.0, clearly all the
analyses show a highly statistically significant
reduction in the serum uric acid values.
In my opinion, future studies then should
consider at least regression analysis since they do
look at all the data for all patients with no data
imputation. Admittedly,; the current study, as
designed and analyzed originally, did not meet the
primary endpoint of a 2.0 or greater decrease.
However, these results should be considered in the
context of these alternative analyses, the dosing
schedule used in this particular study--you will
hear more about this, and you have heard a little
bit already, that a restrictive Subpart H risk
management program is being proposed, and that a
Phase 4 study has been designed to address
limitations of this current pivotal study.
Thank you. The next speaker will be Dr.
Calabrese who will discuss clinical experience and
Unmet Medical Need/Clinical Experience
and Post-Approval Issues
DR. CALABRESE: Good morning, Mr.
Chairman, members of the committee and members of
the FDA and guests, it is my charge to talk about
some practical clinical issues with oxypurinol. I
would like to start by saying that Dr. Terkeltaub
and Dr. Snyderman have already elegantly described
gout as a disease not only of antiquity but a
disease where there is considerable morbidity and
mortality. I like to tell house staff and students
that for the vast majority of cases of gout, it is
a very, very treatable disease, eminently
treatable, but for a small percentage of patients,
and a percentage that I think is increasing, as
previously described, with multiple co-morbidities,
particularly those with drug intolerance given the
few drugs that we have available, it is really a
One of the more particularly vexing
problems for clinicians is when we face patients
who are allopurinol-intolerant, particularly those
with high urate loads, chronic tophaceous gout
which is so often complicated by mild renal
insufficiency, leaving only two pathways to deal
with these patients. One is to pursue allopurinol.
One could rechallenge. One could subject them to
desensitization technique, which is complex and
laborious, not universally available and one that
is flawed given the sizeable number of patients who
will fail desensitization. Oxypurinol for this
population is the only option, and I will talk a
little bit about the experience with it, which will
actually treat the underlying metabolic disorder.
Otherwise, we are relegated to a treatment
path if symptomatic and supportive care. Yes, we
can reduce the number of gouty attacks. We can
reduce morbidity. We do nothing to affect the
metabolic problem that belies the disorder and to
forestall end-organ damage from this infiltrative,
destructive and inflammatory disease.
Now, at the Cleveland Clinic we have a
sizeable experience with oxypurinol. I reviewed
this in anticipation of this meeting and I was
surprised to find out that my experience with this
drug goes back over 20 years. It seems just like
the other day that I started putting patients on
this. Sixteen patients, including 13 in the
compassionate use and 3 in the pivotal trial, and
consistent with the data that was just presented,
of these patients, 2 were intolerant and had mild
cutaneous reactions and were withdrawn. The
remaining patients were treated from approximately
a month to over 10 years.
I would just like to share with you three
vignettes of patients that I currently have on
long-term oxypurinol, just to give you a flavor of
how I have come to understand this drug and utilize
it in my armamentarium of treating this disease.
One is a patient I have treated for a
number of years who had increasingly frequent gouty
attacks, intolerant to allopurinol, mild renal
insufficiency, and he has been totally controlled
on oxypurinol and has been gout-free for a number
The second patient I think is familiar to
all of the rheumatologists in this room. This is
an elderly woman who had a successful renal
transplant. She also has draining tophi. She is
highly allopurinol intolerant, and she is on long-term
calcineurin antagonist with cyclosporine that
maintains her creatinine in the mid-2s. I have had
her on oxy at a dose of about 300-400 mg a day and
she has been gout-free and has been experiencing
regression of her tophi over the past few years.
The final case is really instructive to me
and has meant a lot to me, and I want to share this
vignette in just a slight amount of detail. This
is a patient JH. He is a very robust, well-traveled civil
engineer who, in the early '90s,
became increasingly debilitated by gouty attacks,
increasing in frequency, tophaceous, and he had
reached a point where he had enlarging tophi,
including one on his foot, very similar to the one
Dr. Terkeltaub showed that graphic picture of. It
involved the toe, complexly involved the web space,
had eroded through the skin, was chronically
draining, was a site of recurrent cellulitis.
He was treated by a fine internist in
Cleveland who knew that this guy was an allopurinol
candidate and needed allopurinol, and he treated
him and he rashed. He also has a creatinine of
about 2.5. Knowing that he had no other options,
he retreated him and he rashed again. Knowing the
desperation of this individual with this
progressive course, he actually instituted low dose
graded desensitization, and with each gradation of
dose Mr. JH had progressively more severe rashes
and intolerance. He ultimately was referred to me.
I entered him on compassionate use and
escalated his oxy up to 400 mg a day under the
cover of colchicine. I can tell you the experience
summarily. One, this man has never had another
attack of gout in over a decade. Number two, his
tophi have either regressed; some have disappeared
but the largest ones are still there but totally
healed over. There is no doubt--you don't need a
statistical instrument to assess his quality of
Now, having seen this patient every three
months, giving him this drug over the years, we
have become friends and I talked to him about
coming to this hearing today. He kind of
sheepishly told me, he said, I want you to tell
them. He said because when I first came to see
you--you know, he had been engineering at all these
large dam projects, a really kind of a manly guy--he said, I
was depressed; I was nearly suicidal--because he was looking
at a transmetatarsal
amputation. It is a vignette but meaningful to me.
So, based upon this experience and
utilizing this drug with some comfort, you know, I
am trying to make a case that I think that
risk/benefit is favorable but there are still
outstanding issues with this drug clearly. One, it
would be highly desirable to obtain clinical data
from a study, a meaningful clinical endpoint. And,
should it reach regulatory approval, I would want
to see a system in place that limits access to this
to appropriate patients, used in a wise manner by
I believe there are two programs here,
including this Phase 4 trial that was alluded to
and the risk management program that I would just
like to briefly describe in closing.
The Phase 4 protocol, which is just
getting under way, was crafted with consultation
with the FDA, and this is a 2-year randomized,
placebo-controlled trial of oxy in 240 patients.
The primary endpoint of this study will be
reduction in gouty attacks. Patients have to have
at least 6 attacks during a calendar year coming
into the study. It will also assess reduction in
tophi. There are quality of life measures and
serum uric acid reduction.
I think all of us would agree that if this
study were completed it would provide meaningful
information about some issues that we just don't
have at the present time, correlating clinical
outcomes to serum uric acid.
In addition, the risk management program I
think is critical. What has been proposed is that
this drug would be distributed by a centralized
pharmacy and there would be a physician education
program that would ensure a knowledge base before
being able to write for this. This would be web-based.
There would also be a resource of patients
to help them understand their disease and its
Once a patient has met the criteria for
going into the study, a form would be
electronically transmitted and this would be
verified before dispensing drug. I think most
importantly, this type of risk management system
would allow the tracking of outcomes and ongoing
analysis of AEs.
So, overall when I consider risk/benefit
in this, first of all, I think that efficacy-wise
in my mind--I know that this drug works and it
clearly reduces serum uric acid. I am impressed
with its safety, recognizing the gravity of
allopurinol hypersensitivity states. These are
rare cases that were referred to but you don't have
to see more than one case of true hypersensitivity
syndrome to be humbled by this.
One of the points I would like to make is
that in patients who have been enrolled in this,
mild to moderate, which means patients with true
hypersensitivity syndrome, Stevens-Johnson and TEM,
are not candidates for this. There has been no
upgrading of toxicity in the entire oxy experience.
In other words, if you have a mild to moderate rash
with allopurinol you get a mild to moderate rash
and there has never been single case of
hypersensitivity syndrome, Steven-Johnson or TEM,
reported. So, I think this favorably influences my
willingness to subject patients to the prodrug of
the drug that they have been hypersensitive to.
Furthermore, I think this risk management program
So, to conclude, for the patients that I
have described to you, who are allopurinol
intolerant, I have no other therapeutic
alternatives for them and I think that this is a
valuable drug. I think that the data that have
been presented thus far, at least in what I
consider to be my experience with this drug, has a
positive ratio of benefits to risk. I do believe,
having been through this compassionate use program
for so many years, that the proposed risk
management program will be a better program. It
will make this more widely available to patients
because many patients have dropped out of the oxy
program when they have moved and they couldn't find
a physician to do this, and it certainly will allow
better monitoring of this overall issue. Thank
DR. GIBOFSKY: Thank you, Dr. Calabrese.
We are a few minutes behind, however, in the
interest of open discussion I would like to afford
the panel the opportunity to ask questions of any
of the previous speakers. If there are questions
from the panel, we will entertain them at this time
before we take our break. We will make up the time
later in the session. Dr. Felson?
DR. FELSON: A quick question for anyone,
I think Len Calabrese has laid out the design of
the Phase 4, which sounds like a randomized trial
with a placebo control, with a primary endpoint of
number of clinical attacks, it sounds like. Why
was that chosen as the primary endpoint, especially
given the discussion we have heard so far about
potential surrogates, as opposed to using uric
DR. MOORE: Let me start with that.
Basically, that was an extensive discussion we have
had with the FDA on acceptable parameters.
Clearly, we would have benefitted from discussion
with this panel, but a part of the requirement for
approval of this drug is that we had to get a Phase
4 study under way. So, that is how we designed it.
It seems a perfectly beneficial clinical outcome
that one would reduce tophi and so that is the
basis for the study design.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: When we go through our
training, those of us who train medical students,
residents and fellows, we recommend that the serum
uric acid be normalized often to below 5 mg/dl or 6
mg/dl. So, maybe somebody could comment on what is
a clinically important reduction or a clinically
meaningful reduction in serum uric acid for someone
who starts at 10? You know, what does it mean to
have a reduction of 2 mg/dl even if you are still
having an elevated serum uric acid level?
DR. CALABRESE: Marc, I think that is a
great question. First I would like to point out
that in most patients treated with oxy we have been
able to effect far more than 2. That trial is
biased by the fact that drug escalation was stopped
when they hit t 2 mg. In most patients that I have
treated we have got 3 or more.
Now, asking the question of what is
clinically meaningful, I think that this is a
subject of debate. You know, there are data from
Ralph Shoemacher that suggest that even the mere
fact of escalating frequency of gouty attacks may
be seen before even normalization. I have been
impressed by patients on oxy in whom we have
maximized their dose, keeping them in the range of
6, 7 or close to 8, the frequency of attacks have
been decreased. So, I think this is an issue that
needs to be addressed in a clinical study that will
correlate clinical outcomes with SUA. This hasn't
been done in any rigorous manner.
DR. GIBOFSKY: Dr. Geis?
DR. GEIS: Do you have anything in the
literature that says what if you gave placebo to a
bunch of patients, what would their uric acid
levels do? I mean, because this is open-label it
is kind of hard to interpret it but do we know
about historical data with placebo studies?
DR. MOORE: I think there is very little
literature data on that today. Clearly, we will be
studying that in our Phase 4 study and have a much
better handle on it then. But, as Dr. Snyderman
pointed out earlier, gout is a progressive disease
and so one would clearly expect it to get worse and
not better. So.
DR. GIBOFSKY: Dr. Finley?
DR. FINLEY: Dr. Calabrese, when you are
thinking about clinical endpoints, and you
mentioned tophi reduction and you described your
vignette, are we talking about size, the number,
healing? How do we do that? How do we validate
that between raters and those kinds of things?
DR. CALABRESE: I am just a clinical
rheumatologist taking care of people with sore
toes, and I will leave some of these discussions to
the experts here. But my experience, even with
allopurinol, is that, you know, you don't see these
things disappear over time, but certainly there is
an element of regression because I have seen these
draining areas receding. You don't see that cheesy
stuff through the skin. You see a decrease in
girth that could at least be palpated. What the
best way to measure this is, I would leave that to
DR. GIBOFSKY: Dr. Moore or Dr. Calabrese,
help me understand how a compassionate use program,
where the drug is restricted, would be less
effective or not as good as a Subpart H approval
where the drug would be restricted under your risk
DR. MOORE: Let me begin. Basically, our
experience has been with the compassionate use
program to date. It is a less than perfect
collection of data. So, what we are looking at is
a much more controlled situation, creating a
patient registry, which we don't have with
compassionate use. As you know, compassionate use
is more at the prerequisite of the individual
investigator and not the company. Whereas, with a
company controlled environment, which would be the
Subpart H, we get much better feedback on risk and
side effects to the patients. We would also get
less of this loss to follow-up issue. We would be
able to track the patients. So, I think I would
feel that we would have much better control of what
was going on.
DR. CALABRESE: I would just like to
mention that in addition to a smoother bureaucratic
process for the physician, it would be much easier
to register into this than become an investigator
and do this. The compassionate use program really
did not include any type of formal physician or
patient education and this actually has the
requirement for a knowledge base that a third party
would check off on, actually looking over these
report forms. You know, over 20 years ago they are
DR. MOORE: Thank you. One final point on
that as well is accessibility for patients. For a
compassionate use program people have to hear about
a drug one way or another and it is very hard for
them to get on this program. Whereas, if the drug
is actually marketed, albeit on a very limited
distribution program, they will know it is
available, physicians will know it is available.
DR. GIBOFSKY: I take that point, but the
concern in the back of my mind is if the drug is
available, albeit in a limited distribution, is
there not the concern that the drug will be used
beyond its primary indication by physicians who may
think, based on the data, that perhaps oxy is
superior to allo and why not start with oxy?
DR. MOORE: That is an excellent question
and that is one of our greatest concerns as we go
into this. So, in fact, what we have is that as
the physicians request the drug there will be a
very formal form, and in the NDA we have all of
this material described where there is not just
education material but the physician will have to
formally describe the patient, and there are
criteria which qualify them for receiving the drug
and part of this is double allo intolerance. So, I
think it is a very restricted system and it is a
very good way of controlling it.
DR. GIBOFSKY: Dr. Anderson?
DR. ANDERSON: I have a question going
back to the design of the study that is currently
under way, and it has to do with the eligibility
restriction that the patient has to have had at
least 6 attacks in the previous year. I was
wondering what is known about the distribution of
number of attacks per year in gout patients and
what drove that--you know, what made you decide
DR. MOORE: It is a matter of powering the
study, frankly, and what we are looking at is that
a lot of these people are sicker anyway because by
the time you get to an allopurinol-intolerant
patient population they have been trying other
treatments for a long while. So, often many of
them are very sick patients. It is not that
difficult to find people who have 6-8 gout attacks
a year. We have 6 patients right now who are ready
to come onto this study. But really it is a matter
of powering the study, showing the efficacy of the
drug in terms of this clinical outcome and, at the
same time, being able to compare this to lowering
serum uric acid, how much it goes down and where it
goes down to.
DR. ANDERSON: Can I just follow-up on
DR. GIBOFSKY: Sure.
DR. ANDERSON: This wasn't presented here
but it was in the background material we have, it
was indicated that you would need a hundred centers
to find those patients, which seems to run a bit
counter to what you just said.
DR. MOORE: No, no, if I gave the
impression they are easy to find, I didn't mean
that. What I should say is that we have access, of
course, to all of the physicians who have been
recruiting into a compassionate use program. We
are the only people who distribute oxypurinol. So,
it is easier for us to find these kinds of patients
because we already have access to the physicians
who have them.
No, my bet is that we will get about two
or three patients per site. This isn't your
average clinical study where you have one patient
per month per site. This is going to be much more
restrictive than that.
DR. GIBOFSKY: Dr. Geis?
DR. GEIS: You didn't present any
demographic data about the patients that you did
study. How do you know they are representative of
the intended patient population?
DR. MOORE: I am not sure I understand the
DR. GEIS: I mean, in most clinical trials
I have been involved in, you usually want to give
the demographics and show this really does
represent what the literature says the patients
will look like.
DR. MOORE: Oh, I see.
DR. GEIS: I think in one of the documents
that we were given in advance the ratio of males to
females was really not different from what I heard
historically is the ratio by gender in the gout
patients. So, it made me think who are you really
DR. MOORE: No, as Dr. Dickinson said
earlier, first of all, this is a rather small
patient population that we are looking at, the
allopurinol-intolerant gout patient population.
Secondly, we have the largest database of anyone on
these patients. So, we believe that our database
on 612 patients truly represents the demographics
of the broader patient population. We have
anywhere from 5-10 percent of them right now.
DR. GIBOFSKY: Dr. Mandell?
DR. MANDELL: In 213 the numbers that you
have, 9 of 77 by ITT had less or equal to 6. I
understand it wasn't pushed to do that. Since most
of us would be pushing, if we are going to be
treating, the uric acid down probably lower than
just the targeted 2 drop, what information do you
have on the safety or efficacy of the drug used in
that manner, pushed to really try to drop the uric
DR. MOORE: Let me start and then turn to
Dr. Dickinson. The most information we have is
from our compassionate use program where, as Dr.
Dickinson described, we have gone up to 1800 mg.
So, I think for safety we have good safety data for
prolonged periods of time at very high doses.
For efficacy, clearly the Phase 4 program
will fill in more of that, although we do have good
data from the compassionate use program, as Dr.
Calabrese described. We get lowering of 3-4 mg/dl
with these higher doses. Remember that the 213
study was designed to reach the endpoint of 2 only.
So, that was really limited titration.
DR. MANDELL: How many patients does that
include actually at those high levels?
DR. DICKINSON: The average serum uric
acid at start was 10.1. So, about half the
patients had higher than 10 and half had lower than
10 as a starting SUA. The oxypurinol maximum dose
in the 213 study was 800 mg. I believe there were
9 patients that went up to 800 mg. That was the
limit on that study. Again, once a patient had
dropped their serum uric acid, if they dropped it
from 11 to 9 they were not eligible for any further
dose escalation because they had achieved the
endpoint in that study, which was a 2 mg/dl decline
in serum uric acid.
DR. MANDELL: So, we don't have a lot of
patients actually treated with the higher doses
DR. DICKINSON: We do in the compassionate
use program, which is a real-world program where
there are patients with renal insufficiency, renal
transplantations. We have a number of patients who
have been treated with 1200 mg, 1400 mg, 1600 mg a
DR. MANDELL: Do you know how many those
DR. MOORE: The mean dose that was used in
the compassionate use program was 372 mg and we are
asking for approval up to 800 mg for this
indication. The vast majority of patients were in
the middle, between 300-400 mg so there was really
a distribution curve down on the other side. But
in that program were 533 patients. So, you have a
large distribution with the majority being in the
middle with 300-400 mg coming out on the slope.
So, we do have data on high doses.
DR. GIBOFSKY: Dr. Bathon, do I see your
hand up for the last question?
DR. BATHON: Yes, along that same line
just as a follow-up to that, how then are you
guiding physicians in the Phase 4 trial to dose the
drug since you are using a clinical endpoint as
DR. MOORE: It is a titration study and
that is the same way that allopurinol is dosed.
So, they would go up in 100 mg doses over a 16-week
period. There is a 2-week run-in placebo period
and then an 18-week titration study. Of course,
being that this is a double-blind study the serum
uric acid will be read by an unblinded outside
physician so that will be guided by that. The goal
is to lower the serum uric acid to 6 mg/dl. That
is the goal.
DR. GIBOFSKY: I would like to thank the
presenters for giving us some additional food for
thought this afternoon. At this point we will take
our break for exactly 15 minutes and resume at
11:08 by that clock.
DR. GIBOFSKY: We are ready to begin.
Will all the panel members please take their seats
and the audience find theirs? At this point we
have a presentation by Dr. Lourdes Villalba, who is
the medical officer for DAAODP of the Food and Drug
Administration, and she will speak on oxypurinol
for symptomatic gout in allopurinol-intolerant
patients. Dr. Villalba?
Oxypurinol for Symptomatic Gout
in Allopurinol-Intolerant Patients
DR. VILLALBA: Good morning. The goal of
my presentation is to show you data from a specific
new drug application, an example as a starting
point for discussion of clinical trial design
issues in chronic gout. The proposed indication
for this drug, oxypurinol, is a very specific one
in a very specific population. But when you go
through the data I would like you to think about
how these data may apply to other drugs and trial
design issues in general.
Allopurinol, as mentioned earlier, is the
first-line treatment of hyperuricemia in gout. The
active metabolite of allopurinol is oxypurinol and,
because of the short half-life of allopurinol and
long-life of oxypurinol, it is believed that the
pharmacodynamic effects of allopurinol reside in
the oxypurinol moiety.
There is limited data on comparison of
allopurinol and oxypurinol. There are some studies
in the literature that have compared them. For
example, there is a crossover study of allopurinol
and oxypurinol in close to 100 patients but those
studies were not adequate for comparison of the
efficacy or the safety. In any case, the
literature suggests that allopurinol is more
efficacious in reducing uric acid levels as
compared to oxypurinol. The limited data available
in the literature really has not shown a difference
in safety between the two.
We do have one pharmacokinetic study
looking at the conversion of allopurinol into
oxypurinol. This study was conducted by the
sponsor as part of the NDA and is an open-label
bioequivalence study of 42 patients that showed
that the relative bioavailability of single dose
oxypurinol is about 30 percent that of allopurinol
for the 100 mg dose. That means that a single dose
of oxypurinol levels is equivalent to 58 mg of
allopurinol. The pharmacokinetic characteristics
of oxypurinol non-linear. Therefore, the data in
this particular study shows that 800 mg of
oxypurinol produced oxypurinol serum levels
equivalent to 112 mg of allopurinol. This, again,
is single dose. We do not have data on multiple
Allopurinol is generally well tolerated,
however, up to 10 percent of patients present
intolerance. Despite the fact that the drug has
been used for decades, the mechanism of toxicity is
not well understood. There is some toxicity that
is immunologically mediated and 204 percent of
patients present with hypersensitivity reactions,
and that is the main limitation to the use of
allopurinol. As already explained earlier, most of
the events are skin reactions, mile to moderate,
occasionally severe including Steven-Johnson and
toxic epidermic necrolysis. Other hypersensitivity
reactions include fever, hepatitis, nephritis,
hematologic such as aplastic anemia and
thrombocytopenia, and a very rare form of the
hypersensitivity syndrome, and 20 percent of the
cases may be fatal, the allopurinol
hypersensitivity syndrome which involves all of the
above--skin, fever, hepatitis, nephritis. It is
usually associated with eosinophilia. The
mechanism is unclear. It seems to be type IV
hypersensitivity mediated, T-lymphocyte mediated
with production of cytokines, including IL-5.
However, there is also non-immunologic
toxicity that involves mainly renal and liver
toxicity. In animal studies, for example, the
toxicity is mainly liver, renal and cardiac and the
hypersensitivity syndrome is not reproduced in
I distinguish between these two forms of
toxicity, however, in the clinical setting
sometimes it is very difficult to distinguish one
from the other. For example, if we see a patient
with transaminase elevations, unless there is also
a rash or fever or eosinophilia it is going to be
very difficult to say that that was related to
hypersensitivity or not. It is unclear whether the
hypersensitivity reactions to allopurinol are
directed to allopurinol, oxypurinol or other
The literature suggests that allopurinol
desensitization may be of use or may have a role
for some patients with mild to moderate cutaneous
intolerance. There are some case reports in case
report series and the most persuasive one is one by
in arthritis and rheumatism that reports a
retrospective evaluation of 32 patients who
received allopurinol desensitization for over a
month period and then continued on allopurinol for
a mean follow-up of 32 months. Of those 32
patients, 28 tolerated doses up to 50-100 mg daily
and 21 of those patients did so without any adverse
reaction and 7 of those patients actually presented
with some form of cutaneous reaction that was
managed with symptomatic treatment and by modifying
the schedule of the desensitization program. Four
patients required discontinuation.
It is important to note that the serum
uric acid levels went from 10.4 mg/dl at entry to
5.3 mg/dl at the end for those patients who
tolerated allopurinol. Also, I would like to point
out that there were patients with renal
insufficiency included in this retrospective study,
with a mean creatinine level of 2.8 mg/dl. It is
also important to point out that there were no
patients with severe intolerance included in this
Regarding oxypurinol, the sponsor has
already talked about the compassionate use program.
Oxypurinol has been available for patients since
1966 as part of the compassionate use program. The
sponsor has collected a large amount of data from
approximately 500 patients in an open-label manner.
I would like to point out that it was not a study
that was prospectively designed to evaluate the
efficacy or the safety of oxypurinol.
This was actually a retrospective
evaluation of patients who were seen over a period
of 40 years. That is why there is less than
optimal documentation of, for example, allopurinol
intolerance prior to entry, also the efficacy and
safety during the study. Clinical laboratories
were not systematically collected, were collected
at the discretion of the investigator. There are
missing data. For example, serum uric acid
baseline levels were missing in 32 percent of
patients and post-baseline levels were missing in
24 percent of patients.
Regarding the demographics, up to 30
percent of patients were missing the age or the
ethnicity data. Also, 25 percent of patients were
missing baseline creatinine data. Regarding the
patient disposition, 28 patients were lost to
follow-up. Therefore, data from this program,
although encouraging, is not adequate to assess in
a robust way the efficacy or the safety of
Let me say that the day suggest that the
drug is effective in reducing serum uric acid
levels, and also that some patients develop who
develop allopurinol intolerance tolerate
oxypurinol. However, that was not enough for
marketing of the drug and the sponsor entered
discussions regarding additional data needed for
marketing. Protocol OXPL213 was started at the end
of 1999, beginning of 2000. It is important to
remember that this is an unmet medical need in a
population who is at high risk of developing
allopurinol intolerance and severe reactions; that
this drug was already available in compassionate
use. So, at that time and in that setting it was
thought that a 2 mg/dl change in serum uric acid,
used as a surrogate endpoint, would be something
reasonable. In addition to the uric acid levels,
the study needed to assess efficacy and, if
successful, a post-marketing study would be
conducted for evaluation of meaningful clinical
This is the study design, and you may have
an idea already because of the prior presentation.
This was a prospective, open-label, uncontrolled
dose-escalation study of 14 weeks. That was the
base study and it included 79 patients. Those
patients who completed the study were offered to
continue into the extension and 48 patients
continued into the extension. The extension is
Entry criteria included patients with
symptomatic hyperuricemia with documented
allopurinol intolerance. Documentation could be a
single episode of intolerance as documented by the
primary physician or rheumatologist or, in addition
to that, the patient could actually have a history
of rechallenge or desensitization. One-third of
those 79 patients approximately--there were 26
patients who had undergone rechallenge or
The exclusion criteria, as mentioned
earlier--those patients with severe prior reaction
to allopurinol did not enter the study. The use of
diuretics and uricosuric agents were also exclusion
criteria. Regarding renal function status,
patients with creatinines of 2 mg/dl or above and
liver function tests of 3 times the upper limit of
normal or higher were excluded from the study.
Again, I want you to think about all these entry
The treatment scheme, you already saw that
this is a fixed dose escalation study, starting
with 100 mg and going up to 800 mg daily according
to the fact if the patient achieved or not the
desired endpoint. Most of the patients, 60 percent
of the patients were on the 300 mg dose and I
believe 8 or 9 patients were on the 800 mg dose.
The others were on doses in between. Of course,
some patients received the 100 mg dose and
presented with reactions and were discontinued but
most of the patients were on 300 mg.
Regarding the endpoints, the primary
outcome was the serum uric acid level. However, I
would like to point out that there was not a
central laboratory. That means that each site
worked with different labs and those labs had a
different normal range.
The primary analysis was a landmark
analysis of comparison of the mean baseline and
mean final value of week 2, 13 and 14, and there
were also measurements of serum uric acids at week
6 and week 9 for those who had not achieved a 2
mg/dl drop by week 6. The primary analysis was to
be in the ITT population and it was to show a
decrease of at least 2 mg/dl.
These are the baseline characteristics of
the study. The mean age was 61 years. Fifty
percent of patients were male. The mean serum uric
acid was 10.1 mg/dl, with a range from 7.7-13.7
mg/dl. The mean creatinine at entry was 1.3 mg/dl,
with a range from 0.8 to 2.2. There were 26
patients who had failed prior rechallenge or
Regarding concomitant medication, 43
percent of patients were on colchicine,
prophylactic colchicine; 6 percent of the patients
were on low dose aspirin; 53 percent were taking
diuretics, although this was one of the exclusion
criteria for this study; and 49 percent of the
patients were taking NSAIDs or COX-2 inhibitors.
Regarding prior history of allopurinol
intolerance, most of the patients had skin
intolerance, 8 percent of the patients had skin
intolerance, and 20 percent had other
manifestations such as hepatic, renal, malaise, all
3 or fever. Again, these patients had mild to
moderate allopurinol intolerance, and there were no
patients with prior history of hematologic
intolerance or severe skin or liver intolerance.
The definition of intolerance for liver intolerance
was ALT elevation of 2.5 to 5 times the upper limit
of normal, and for renal it was BUN or creatinine
1.5 to 3 times the upper limit of normal. There
was no requirement for these to show eosinophilia.
I mean, the word of the investigator was taken who
thought these were allopurinol intolerance
The results of the FDA analysis are a
little different from the sponsor analysis. In the
ITT population at 14 weeks--and we looked at the 79
patients, all patients who were included in the
study and received at least 1 dose of medication--the mean
change from baseline was 1.78 mg/dl. In
the sponsor's analysis, in 77 patients it was 1.9
but in 79 patients when they looked at the whole
thing it was 1.85. But, actually, that doesn't
matter too much. I think that the important thing
here is that the study did not achieve the primary
efficacy endpoint. But even if it, let's say it
achieved 2 mg/dl, the issue is if 2 mg/dl is
something that one would like to see as the goal
for treatment for gout.
In the completer analysis the change in 54
patients was 2.32 mg/dl. This change was highly
statistically significant, with a p value of 0.001.
That means that the study rejects the null
hypothesis that the change of serum uric acid level
associated with oxypurinol is equal to zero.
Another way of looking at the data is by
looking at final mean serum uric acid. In the ITT
population it was 8 mg/dl. In the completer
population it was 7.5 mg/dl. By our analysis of
the data set, 10 patients achieved a serum uric
acid level of 6 mg/dl or below and 2 patients
achieved 5 mg/dl or below. This is the most
important difference, I would say, that I found
with the sponsor presentation. We have not
clarified yet why there is this difference. We
have to go through the data set again with the
There was no evidence of dose response and
that may have something to do with the study
design, the fixed dose escalation. Another factor
that may have something do with it is the
pharmacokinetic characteristics of oxypurinol. As
we saw, that is non-linear in a single dose and we
don't know the data for multiple dose.
There were 12 flares and 8 of them were
during the base study; 5 only during the base study
and 3 of them in the base and extension, and 4 were
only during the open extension. Four patients had
tophi complications, such as infection, drainage or
pain, 2 in the base study and 2 in the extension.
In the absence of a placebo-control arm this is
very difficult to interpret. Is this oxypurinol
effect on serum uric acid or is this spontaneous
flare that occurs despite the drop in uric acid?
We looked at the characteristics of the
patients in the base study. All patients with gout
flares dropped their uric acid levels, and the
range was from 1.5-3.9 in some patients. So, there
was a drop of uric acid level. Half of the
patients were on colchicine. None of the patients
were discontinued from the study. They were
treated with steroids or NSAIDs and continued and
completed the study. I don't have the data from
the extension. The extension is still ongoing so
data is incomplete.
I am going to show you a few slides about
the safety. There were 5 deaths. One during the
base study. That was a pancreatic carcinoma.
There were 4 during the extension. One patient
died of end-stage liver disease; one was found
dead. One patient had GI bleeding and worsening
COPD, and one patient died of sepsis after a
surgical procedure. All these events, in the
opinion of the investigators, were unrelated to
Regarding serious adverse events, non-fatal
serious adverse events, there were 7 in the
base study and 15 in the extension. Again, all of
them seemed to be unrelated to study drug. I would
like to point out 2 definitive myocardial
infarctions and 1 questionable myocardial
infarction in the base study. So, we see 3
patients with cardiac events in a 14-week study of
79 patients. Maybe this finding may be related to
the cardiovascular high risk population that is
under study with the co-morbidities and associated
factors like hypertension, obesity and diabetes
seen in patients with hyperuricemia, and also
hyperuricemia itself may be an independent risk
Regarding discontinuations, 54 patients
completed so 25 patients discontinued. Of those
discontinuations, most of them were due to skin
intolerance. Sixteen patients discontinued because
of skin intolerance. One patient was reported to
have discontinued because of liver intolerance.
One patient had thrombocytopenia. We had the
pancreatic carcinoma and one patient was a protocol
violator, and there were 5 cases that I classified
as miscellaneous and I would like to expand a
little bit more on these.
One of the patients was discontinued
because of monitor decision. After one dose of
oxypurinol, this patient developed a fever,
followed by chills, skin sensitivity,
polyarthalgias and viral syndrome. This patient
was excluded from the sponsor's analysis because it
was considered unrelated to study drug. However, I
think that it may have been related but, in any
case, in an efficacy ITT analysis I think it should
be included in the analysis.
One patient had a hypersensitivity
syndrome. It was described as hypersensitivity
NOS. That means no other symptoms and there is
nothing more in the case report form. So, it isn't
clear exactly what the reaction was of this
One patient had fever, chills, headache
and allergic rhinitis, probably unrelated. One
patient discontinued because of nausea and vomiting
after one dose and this patient had a prior history
of liver intolerance.
One patient developed elevation of ALT and
BUN and it was considered by the investigator to be
a protocol violation because the patient was not
complying with the medication. So, this may be
unrelated, this elevated ALT, but still should be
included in the analysis of safety.
In addition to the patients who
discontinued, there were 3 patients who completed
the base study but had hypersensitivity reactions
and did not enter the extension. Two of them had
liver function test elevations and one had a rash.
Therefore, in summary, approximately 30
percent of patients developed intolerance; 70
percent of patients with intolerance showed skin
intolerance--I am talking approximately, I am not
giving an exact number--70 percent within the first
week. Most of the patients showed the same kind of
intolerance as before and none of them was
considered serious. There were 2 cases that were
different from baseline, 1 with thrombocytopenia
and the other with LFT elevation.
This slide focuses on the patients who had
actually undergone and failed rechallenge or
desensitization. There were 26 patients. Of these
patients, 10 discontinued because of
hypersensitivity reactions again. The
hypersensitivity reactions were the same as they
had in the prior allopurinol experience. That is
40 percent of the patients. There were 3 deaths, 1
in the base study and 2 in the extension, and in
the extension that included the patient with end-stage liver
disease and 1 patient with sepsis.
Therefore, in summary, 79 patients were
enrolled; 54 completed the 14-week study; 48
entered the extension. At the time of the analysis
there were 37 patients available in the safety
population. Ten patients achieved serum uric acid
levels of 6 mg/dl or below and 5 mg/dl or below at
14 weeks. Eight patients had flares during the
Regarding adverse events, there were no
serious hypersensitivity reactions. Most of them
occurred within the first week. Most of them were
cutaneous and similar to what the patient had
presented before. Others, beside the skin,
included a few liver intolerance events; 1
thrombocytopenia; 1 viral syndrome. This was in a
population of patients with mild to moderate
intolerance to start with and with normal renal
function or mild renal insufficiency.
Therefore, our challenge is to define a
population for a favorable risk/benefit in which a
modest decrease in serum uric acid would outweigh
the risk of 30-40 percent intolerance in a
population which is at increased risk of
intolerance and in the setting of a not well-defined
So, all these data are for you to take and
help us in the discussion of the discussion points.
That is the end of my talk.
DR. GIBOFSKY: Thank you, Dr. Villalba.
Are there questions for Dr. Villalba? Dr. Hoffman?
DR. HOFFMAN: That was very helpful. I
was going back to the data that you showed us that
concluded that there was no evidence of dose
DR. VILLALBA: Yes?
DR. HOFFMAN: I was curious about the
rigor with which we come to conclusions about that
data because there were only 54 completers in that
trial, and it wasn't clear--well, we didn't see the
data on how many patients were at each dose level
and followed for what period of time, perhaps up to
14 weeks, perhaps longer, for us to know whether or
not there was adequate sample size at each dose
level to really address dose response. If it not
adequately addressed in this study, do we have from
the applicant additional data about dose response?
Do we also have the necessary data about dose
response in allopurinol to come to conclusions
about linearity of dose response?
DR. VILLALBA: Well, regarding the data
from the sponsor for oxypurinol, yes, we did the
analysis and we looked at the sponsor's analysis
with the data that we had. I can say that it
cannot be said that there is a dose response. I am
not saying that there is no dose response. That is
the database that we have.
DR. GIBOFSKY: Dr. Villalba, please use
the microphone. It is a bit difficult to hear you.
DR. VILLALBA: I am sorry. So, that is
the database we have and I think it is inadequate
to address that.
DR. HOFFMAN: I think it is a terribly
important issue if we are talking about a new
protocol in which our goal is to achieve a uric
acid of 6 or less by dose escalating. If there is
really no dose response, I think we need to clarify
that before we feel comfortable about a protocol
that uses a dose escalation strategy.
DR. VILLALBA: Yes, I agree.
DR. GIBOFSKY: Dr. Geis?
DR. GEIS: In your analyses did you look
at changes in other risk factors which could affect
uric acid levels, like blood pressure, weight,
alcohol use, thiazide changes?
DR. VILLALBA: We looked at concomitant
medications. We didn't look at other factors but
regarding concomitant medications--let me think--there were
8 patients who were started on NSAIDs or
COX-2 inhibitors but I don't think that would
affect the serum level but it may affect the
symptoms. There were 2 patients, I believe, that
started new diuretics but there was not much change
other than that. And, 4 patients started
colchicine in the study.
DR. GIBOFSKY: Dr. Mandell?
DR. MANDELL: Following further really on
the question of the pharmacokinetics and
pharmacodynamics of the drug, in looking at trying
to get a dose response in the multi-dosing setting,
was creatinine clearance taken into consideration
in that analysis or are the numbers too small,
number one, really relating to the pharmacokinetics
of why there might or might not be a dose response?
Two, do we know anything about the pharmacodynamics
in patients who are allopurinol sensitive as
opposed to non-allopurinol sensitive patients on
the sensitivity to oxypurinol?
DR. VILLALBA: I don't think we have any
data on that. Regarding the first question, the
data we have on pharmacokinetics is only single
dose. There is no data on multiple dose.
DR. MANDELL: So, what you said about the
non-dose response was the single dose analysis?
DR. VILLALBA: No, no, that was in the
study, the result of the study.
DR. MANDELL: So, some of those patients
had various levels of creatinine clearance in
DR. VILLALBA: Yes, but as per the entry
criteria, only patients with creatinine up to 2
mg/dl could enter and the mean creatinine at entry
DR. MANDELL: There is a wide spread of
DR. VILLALBA: Yes, but we don't have data
DR. GIBOFSKY: Dr. Anderson?
DR. ANDERSON: My concerns are only partly
to do with safety. I found it very disturbing that
the study was not placebo controlled because, as
you commented earlier, in the absence of a placebo
control or any kind of control you really cannot
interpret the safety results and even the efficacy
results. It is not clear from other discussions
that have been held here whether a drop of 2 mg is
clinically important and, given the lack of
knowledge about the reliability of this measure, is
it even a minimally important difference? It could
be that you need at least 3 mg or, if you are
starting high, 10; you need to have an even greater
milligram drop for it to be clinically important.
I guess those are just concerns that I
have about the study, and also about the revised
analysis, the revised analysis that was presented
by the sponsor. You know, this was an analysis
that was devised after the initial analysis didn't
quite work. So, those are all concerns I have.
DR. VILLALBA: Yes, regarding the first
concern, we agree completely. That was our concern
all along and the sponsor's concern too. That is
why it was agreed that a Phase 4 study would be
conducted. Regarding that change, it is precisely
what we wanted to decide because that is our issue
too. We are not sure that 2 mg/dl should be
considered acceptable as adequate evidence of
DR. GIBOFSKY: Dr. Boulware?
DR. BOULWARE: Regarding study 213, I am
sort of bothered by drawing conclusions about dose
responsiveness and the ability to hit the endpoint
of 5 mg/dl or 6 mg/dl which we considered desirable
when the study was designed, that you stop the dose
escalation once you dropped by 2. When I think
about that and I looked at the earlier spaghetti
gram provided to us by the sponsor, the number of
patients entered who had a baseline SUA within 2
points of the desired endpoint are very limited.
There are only about 2 or 3 patients. Anyone who
had a drop of 2 from their baseline had their dose
stopped. So, it is very difficult, in my mind, to
draw any conclusions about its inability to be dose
responsive and also its inability to achieve a
target of 5 mg and 6 mg. Is that appropriate?
DR. VILLALBA: I completely agree with
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: I would like to get your
comments about safety. I am a bit concerned, and
let me refer to a couple of your slides. First,
the proposed indication, which is your slide number
3, is for treatment of hyperuricemia in patients
who are intolerant and have failed either
rechallenge or desensitization with allopurinol.
In the 213 study, in your presentation only 26 of
the subjects had actually had a prior rechallenge
or desensitization so the majority had not.
It appears to me that there is an
imbalance in the incidence of adverse experiences
during 213, with a higher rate of adverse
experiences in those who had failed the prior
rechallenge or desensitization than in those who
had not had the desensitization or rechallenge.
The one death that occurred during the study
occurred in someone who had failed the rechallenge
or desensitization. Half of the deaths during the
follow-up extension occurred in that population.
So, does the lack of data, relative absence of data
in the people who actually would fulfill the
criteria for this indication concern you?
DR. VILLALBA: Yes, and I agree with you.
DR. GIBOFSKY: Dr. Felson?
DR. FELSON: I guess I am going to pose
this to you but I would also be happy to pose it to
the sponsor, the idea that you get exactly the same
side effects if you get oxypurinol reaction and
that the bioavailability of oxypurinol is
substantially lower than allopurinol might suggest--and also
that there is a good deal of literature
suggesting that the side effects of allopurinol are
often oxypurinol-mediated--that might suggest an
explanation of oxypurinol efficacy, that it is
simply administering lower dose allopurinol. Why
not just give lower dose allopurinol? Is that an
explanation that is consistent with the data
DR. VILLALBA: I agree with your concern.
That is all that I can say.
DR. GIBOFSKY: Are there further questions
from the committee? If not, at this point let me
make one brief announcement. Several members of
the committee have asked for additional information
to educate themselves, so we can do our job, about
Subpart H. As alluded to by Dr. Witter, 21 CFR
314.510 etc. I suspect many of my colleagues are
not adapt at reading the Code of Federal
Regulations so I have asked Dr. Harvey to please
provide us, sometime over the next 24 hours, with
either the website where that can be perused at
leisure--if anyone peruses the CFR at leisure--as
well as perhaps an executive summary and some
examples of where Subpart H has been invoked. With
that, we are at lunch. We will resume at exactly
[Whereupon, at 11:49 a.m., the proceedings
were recessed for lunch, to resume at 1:00 p.m.]
A F T E R N O O N P R O C E E D I N G S
DR. GIBOFSKY: Thank you, we will now
begin the afternoon session. Before we begin the
public hearing we have a couple of administrative
matters. Dr. Harvey has completed his homework
assignment that I gave him before the break and he
would like to present some comments to the
committee. Dr. Harvey?
DR. HARVEY: Thanks very much. I just
wanted to give you a quick blurb on Subpart H.
Actually, I really don't want to go into too much
detail but I want to be able to give you the
information you need to go and read all about it.
My memory did serve me correctly, there was a panel
meeting, an Oncological Drug Advisory Committee
meeting on March 12 and 13 of 2003 where they
actually spent a whole day on Subpart H. So, you
can see that this is an area where, if you wanted
to go into some depth, you could really spend
literally a whole meeting just on Subpart H.
The transcript of that, the summary, all
the related material is on the website. So, for
those of you who are not initiated to the web, you
just go to the FDA web page, so www.fda.gov and you
get the main page. There is a little box up on the
upper left-hand corner where you can actually do a
search. In this case you just put in Subpart H.
If you just put in that simple term, Subpart H, you
will get everything in the world you want to know
and, luckily, the first hit on that search is
actually a printout of all of the NDAs that have
ever been approved by FDA under Subpart H. As I
said this morning, the vast majority of those are
in the areas of HIV treatment where viral load was
the surrogate endpoint, and the other area was
oncology, as I said this morning, where tumor
response and variations in tumor response themes
were used as a surrogate endpoint.
So, really that resource, which is
publicly available, is really the best way to go
ahead and get your hands around the whole issue of
Subpart H. Really, in light of today's discussion,
it really is just sort of a peripheral part of what
we are discussing, which is really the clinical
aspects of clinical trial design and your expertise
in the area clinically as well as scientifically.
But I wanted to get you that information and that
is really the best resource to answer that
DR. GIBOFSKY: Thank you, Dr. Harvey.
Before the break there were some questions
addressed to the sponsor, Cardiome, and,
unfortunately, my back was turned and I did not see
them raise their hand. There was a specific
question I believe from Dr. Felson to them. So, in
the interest of collegial discourse I extend my
apologies for not recognizing that they had a
comment to make and would ask them to respond to
some of the discussion this morning. Dr. Moore?
DR. MOORE: No apology is necessary but
thank you very much for giving us the opportunity.
We are going to show you very quickly some data
that addresses the issue on rechallenge versus non-
rechallenge patients, and I will make a comment on
PK values as well. Dr. Dickinson?
DR. DICKINSON: Can I have the slide? One
of the questions that arose is the dosing in
patients in the CUP program. This just gives you
the range of doses. As you can see, the range is
from less than 100 and, in fact, goes up to 1800
and this is the range of dosing. So, is pretty
broad. Not everybody is at 300 mg, and it tends to
be higher than 300 mg, as you see, with
The next slide. The other question that
came up was about allopurinol rechallenge. In
fact, we did have information on 97 percent of all
our patients, whether they had been rechallenged or
not. Approximately 38 percent had been
rechallenged and the remainder, 62 percent, had
not. When we looked at safety data here we could
find no difference between these groups. When we
looked at the data in 213 as to whether or not
these patients could tolerate oxypurinol, it was
exactly the same, 28 percent could tolerate
oxypurinol whether they had been rechallenged or
whether they were just considered to be intolerant
on the basis of the usual one clinical reaction to
allopurinol. So, we didn't find that the
information about rechallenge was particularly
helpful. Thank you.
DR. MOORE: Finally, a comment on the PK,
is oxy low dose allo? In fact, the usual
literature statement is that oxy is half as
bioavailable as allopurinol. We have a chronic
dosing study in congestive heart failure where in
31 patients we have measured the blood levels to
600 mg to oxypurinol and that is 11.3 mcg/ml. What
you would expect from 300 mg of allopurinol is
between 6-10 mcg/ml. So, again, 600 oxy equals 300
allo seems to hold and we agree with Dr. Villalba
that we think those results were an artifact of the
single dose that was given on the PK. I mean, we
did it and those were the results but chronically
it looks quite different. So. Thank you very
DR. GIBOFSKY: Thank you. One small
administrative item, more for the guests in
attendance than the members of the committee,
outside there was a sheet showing the list of
tentative meeting dates for the Arthritis Advisory
Committee being 10/21 and 10/22/04. Staff was made
to realize several weeks ago that that is in
conflict with the American College of Rheumatology
meeting and so we are currently canvassing the
committee to determine when an appropriate next
date will be. As soon as that determination is
made it will be posted on the website for those of
you who are interested in attending that meeting,
but it will not be October 21 and 22 as posted on
the sheet outside.
We are going to move into the open public
hearing section at this time. Before we begin I
would just like to read a statement into the
record. Both the Food and Drug Administration and
the public believe in a transparent process for
information gathering and decision making. 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, the 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 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.
Our first speaker in the open public
hearing session is Mr. Edward G. Mihalo. Mr.
Open Public Hearing
MR. MIHALO: Good afternoon. My name is
Ed Mihalo and I am a pharmacist in the Pittsburgh,
Pennsylvania area. Cardiome has said that they
would pay me for travel and some lodging.
Besides being a pharmacist, I am a gout
patient and I currently use oxypurinol since I had
an allergic reaction to allopurinol. To fully
understand how my quality of life has improved, you
need to know a little about my history. I had my
first kidney stone at age 20. I continued having
stones periodically until urologist prescribed
allopurinol. My serum uric acid was already well
over 10 mg/dl but I had not yet experienced gout.
Three to four weeks into the treatment
with allopurinol I developed a rash from head to
toe. The allopurinol was discontinued and I was
treated with diet and increased fluid intake alone.
By age 35 both gout and kidney stones were causing
me a great deal of pain and suffering on a regular
basis. My wife and kids also had to endure my pain
and depressed moods. They watched me crawl into
the house because I was in such pain. I had to go
to work on crutches, which didn't help because one
gouty foot touched the ground and it does hurt. My
co-workers tried to help by moving me around the
pharmacy on a chair so I could get from station to
Finally, I was led to a rheumatologist who
had heard of oxypurinol. My treatments up to this
point included steroids, NSAIDs, mild narcotics and
colchicine which caused me great gastrointestinal
distress. For about eight years I was on
oxypurinol and I was well controlled both for gout
and kidney stones.
Unfortunately, when I was 43 my physician
moved out of the country and I could not find
anyone to replace him and the oxypurinol. There
was an immediate backslide into gout attacks,
kidney stones and incapacitating pain. At times I
would pass more than one kidney stone a week and
have a gouty attack concurrently. The incidence of
gout episodes was increasing as well as the
duration of the attacks. The kidney stones went
from the size of tiny grains of sand to something
that resembled small sea shells. I began
collecting the stones and in this small plastic bag
which contains about 40 stones in that period just
between the first treatment and the second--I
thought soon I would have enough for my own private
--but I wouldn't have been able to enjoy
it anyway. Believe me, there was no joy in life
during these attacks. It was during these years
without oxypurinol that I seriously thought that
amputation might be a better alternative to dealing
with the excruciating pain. Then I had a severe
episode in my knee so now I couldn't even crawl
around the house. Also, two of my fingers began to
develop tophi about the size of peas.
About three years ago my daughter located
Cardiome Pharma through an Internet search. They
helped me to locate a physician in the area who had
experience in treating a patient with oxypurinol.
He agreed to help me and now I can stand here to
speak to you pain-free. My serum uric acid is
normalizing so gout attacks have ceased. I haven't
added a kidney stone to my collection, which has
reduced my fear of impaired kidney function. The
tophi on my fingers are disappearing.
Additionally, I have had no rash or unusual blood
Without oxypurinol I merely existed. I
had no quality of life. I had reached the point of
desperation of many times. Now oxypurinol has
given me my life back. I am able to perform my job
as any professional would. I can also enjoy all
the social activities that I had in the past, and I
am grateful for the supply of oxypurinol and I
would like to thank all of you for being attentive
to my story.
I have also been asked to read a letter
from--You can come back for that.
MR. MIHALO: Come back for that? That is
fine. Thanks very much.
DR. GIBOFSKY: Thank you, Mr. Mihalo. Our
next presentations are going to be delivered
jointly, sharing some time, by Dr. Nancy Joseph
Ridge and Dr. Jane Osterhaus. They will be sharing
DR. JOSEPH-RIDGE: Thank you and good
afternoon. My name is Nancy Joseph-Ridge. I am a
rheumatologist and I work at TAP Pharmaceutical.
We are currently designing a clinical program
looking at a new xanthine oxidase inhibitor so we
would like to share our view as a proposed clinical
trial design for chronic gout.
As you heard this morning, the treatment
of hyperuricemia is indicated for gout; tophaceous
gout; and also renal calculi due not only to uric
acid but also calcium oxalate. The goal, we
believe, is to reduce and maintain serum urate to
less than 6 mg/dl--fairly well published and
I want to just go over a couple of
literature reports on observational studies that
have been done. The first one is by Lee Yu and Dr.
Schumacher from Pennsylvania, in General
Rheumatology in 2001, looking at the treatment of
hyperuricemia in patients with gout treated with
allopurinol. This was 57 subjects treated
prospectively for 10 years.
There were 2 groups divided from serum
urate of less than 6 mg/dl and those that were
greater than 6 mg/dl. Those with less than 6 were
noted to have reduction in tophi and tophi were
greater in those greater than 6, with 37 percent of
the subjects versus 16 percent of the subjects when
their serum urate was less than 6. Fewer crystals
were noted in the joint fluid of the aspirates in
44 percent of subjects with less than 6 mg/dl
versus 88 percent.
Then, something that we have been talking
about today, fewer gout attacks over a period of 2
years, and that went from a mean gout attack of 1
attack per year versus 6 attacks per year when
serum urate was greater than 6 mg/dl. So, we see
these three outcomes looking at reduction of serum
The next publication I would just like to
highlight is one from Perez-Ruiz. This was in
Arthritis Care Research, in 2002. He actually
looked at 63 patients who were treated with
allopurinol, benzbromarone or a combination of
both. What he did was look at tophi and measured
then using calipers to see how fast they reduce.
The mean duration of tophi resolution actually was
20 months and the time span was anywhere from 6
months to 64 months for the tophi to totally
What he noticed was that the resolution
rates of those tophaceous deposits were directly
related to how low your serum urate level was.
With allopurinol there was a 0.57 mm/month
resolution with a serum urate mean rate of 5.37.
Benzbromarone decreased tophi by 1.21 mm/month when
the serum urate was 4. With combined hyperuricemic
activity of both agents in combination, 1.53
mm/month and the serum rate was 3.97 mg/dl. So, a
direct correlation between decreasing serum urate
with reduction of tophi.
What we have seen in our current clinical
trials and what we are proposing as clinical trial
design for chronic gout is for the primary endpoint
to be the maintenance and reduction in serum rate
to less than 6. This is key and may take a while
before you can see clinical benefit up to one year
or maybe longer because of total body urate load
having to be decreased over that period of time.
The second endpoints being those of
clinical endpoints in tophi reduction. These
measures via either imaging MRI, ultrasound or the
way that Dr. Perez-Ruiz did using either calipers
or physical measurement. Reduction in gout flares
over a period of time, which would be a long-standing gout
flare reduction over at least a year
period. Inclusion of a comparator to look at
safety and efficacy of allopurinol and/or placebo.
Placebo is very important to look at adverse event
background rates, with adverse events being noted
with concomitant drugs that we give, such as
colchicine, NSAIDs or the other concomitant drugs
that our subjects have to be on. Minimally to
demonstrate equivalence to comparator is also key.
We also think that we should consider a safety dose
which would be 2 times the maximum clinical dose to
give you that idea as far as the adverse events.
Finally, long-term controlled studies, at
least one study having a one-year duration. The
older literature with carbon-14 radiolabeled uric
acid shows that it takes at least one year for
total body urate loads to sometimes normalize and
those subjects with tophaceous deposits may take
The study population should resemble the
gout population and include renal impairment and
those with other co-morbidities, and finally, a
proportion of subjects with higher baseline serum
urate or seeing with epidemiology data that higher
baseline serum urate is a factor and that efficacy
and safety of the drug should be analyzed with
DR. OSTERHAUS: Good afternoon. Jane
Osterhaus, I am a consultant to TAP in the area of
health outcomes. It has clearly been touched on a
lot already this morning, but I would like to
encourage the committee to consider the necessary
inclusion of humanistic information in gout
clinical trials. With the renewed interest in gout
treatments--we heard that there hasn't been a new
treatment in about three to four decades almost, so
I think we have this new increased interest in
gout. We also have heard this morning that the
prevalence of gout in the U.S. is certainly
expected to increase due to the aging population,
obesity, increasing rates of type 2 diabetes.
Coupled with the new interest in gout, I
think we have also learned a lot over the last
decade or so about patient-reported outcomes and
their importance in medical decision-making. When
I think about patient-reported outcomes I am
talking about health-related quality of life, work
productivity, functional status--things that are
quite important I think to the rheumatology
Currently there is no existing guidance on
patient-reported outcomes for gout clinical trials,
but if you think about gout and what we know about
it, it certainly isn't a silent disease. We have
pain. We have heard about swelling, tophi and some
of the long-term potentially emotional consequences
of gout as well. Given that, I think it is
reasonable to consider measuring outcomes such as
patient functioning, well-being, symptom relief and
satisfaction with treatment.
The types of measures that you can
consider recommending or including in clinical
trials range from general health status instruments
such as the SF-36 to disease specific ones. The
SF-36 I think would be a very reasonable choice for
a general health status assessment. It is
certainly well-known in the clinical trials
community. It is probably the most commonly used
health status measure that is a general measure.
Its reliability and validity are certainly well
established and, certainly, if you think about the
rheumatology committee it has certainly been used
in osteoarthritis and rheumatoid arthritis trials.
We also can compare across conditions.
In terms of disease-specific measures, the
HAQ is, again, a very frequently used and widely
recognized instrument that is used in RA clinical
trials. It has 8 domains and it may be useful in
got, although its usefulness may be limited by the
joints of the gout patients that are actually
affected. So, HAQ may or may not have some
validity in a gout population.
We have identified no disease-specific
gout measures in the literature and we thought that
it did make sense to probably think about an
instrument that actually focuses on specific
aspects of gout that are not captured in general
instruments like the SF-36. So, TAP has developed
a gout assessment questionnaire that currently
consists of 21 items and 7 domains. We just have
some information based on 2 cross-sectional data
sets. Within that cross-sectional setting we see
good internal consistency, and we see adequate
reliability for its initial use but there is
clearly work that needs to be done on going. We
need to confirm the hypothesized scales. We need
to gain some experience in different gout
populations and we really need to understand the
relationship between the measures in the GAQ with
clinical measures that people have talked about
today. We also need to understand things like
minimal clinical important difference and change
If you are going to be including
humanistic measures in clinical trials, it also
makes sense to think about the timing of those
measures. Given the comments that we have heard
earlier that the initiation of gout therapy might
result in more acute gout flares early on and that
it could take up to a year for total body urate
load to decrease to normal, we would recommend that
for patient-reported outcomes you evaluate longer-term data
with considering the impact of gout
treatment from patients' perspective as opposed to
very short-term data. Thank you.
DR. GIBOFSKY: Thank you, Dr. Osterhaus.
We will next hear from Dr. Zeb Horowitz. Dr.
DR. HOROWITZ: Members of the advisory
panel, members of the FDA, ladies and gentlemen,
thank you for this opportunity to make a brief
statement to the committee about issues we face in
the design of clinical trials for pipeline product
for refractory gout patients, puricase.
Puricase is a genetically engineered
recombinant porcine urate oxidase that we are
developing to control hyperuricemia in patients
with severe symptomatic gout in whom conventional
therapy is contraindicated or has been ineffective.
This recombinant uricase has been modified by
covalent detachment of methoxypolyethylene glycol,
which is expected to extend the duration in the
circulation and to reduce the potential for immune
In a Phase 1 study conducted at Duke
University, intravenous puricase appears to be
effective in achieving a dramatic and a prolonged
reduction in circulating uric acid to sell below
the solubility limit. A Phase 2 trial is ongoing
to confirm and extend these results.
We anticipate that rigorous and continuous
control of hyperuricemia throughout the dosing
interval is achievable in most patients with
otherwise refractory gout. Currently approved
agents for the treatment of chronic gout have
demonstrated efficacy in lowering circulating uric
acid but have no definitive evidence regarding
their effect on long-term clinical outcomes.
It is our hope that chronic administration
of puricase may prevent or eliminate the
accumulation of uric acid in joints and tissues
that leads to acute gout attacks and other long-term
consequences of chronic hyperuricemia,
including destruction of joints, bones, cartilage
and tissue. However, demonstration of these
clinical benefits within the context of a
registration program is impractical at this time.
We believe that the continuous control of uric acid
well below the solubility limit is the appropriate
registration endpoint for this product.
Major hurdles must be overcome before a
rigorous, well-controlled clinical endpoint trial
can be implemented in patients with refractory
gout. Some of these hurdles are heterogeneity of
patient symptoms in relation to circulating
concentration of uric acid; lack of reliable
information relating rate of change of circulating
uric acid to symptoms; unpredictability of gout
flare frequency and severity; lack of a validated
disease-specific instrument to assess clinical
severity and change; lack of a validated
methodology to assess tissue stores of uric acid
quantitatively; lack of a validated methodology to
assess gout tophi quantitatively; and, finally,
ethical concerns about placebo-controlled design in
long-term clinical trials in refractory gout
patients even though these patients are already
inadequately treated with available therapies.
In view of these hurdles in trial design
for the treatment of refractory gout, what is the
most appropriate efficacy endpoint in pivotal
trials today? The circulating concentration of
uric acid is the most reliable measure of drug
efficacy in hyperuricemic gout patients for whom
conventional therapy has failed to control disease,
or who are unable to use alternative therapies due
to intolerance. These refractory gout patients
have chronic hyperuricemia even while using
allopurinol or uricosuric agents. Such patients
suffer chronic, debilitating pain and deformity.
No spontaneous remissions occur.
We know that chronic hyperuricemia leads
to tissue accumulation of urate, but we cannot
directly correlate the degree of urate accumulation
with the effective drug treatment on urate
accumulation with clinical outcomes.
Puricase offers the possibility of
continuously and dramatically lowering circulating
uric acid levels on a chronic basis. We have
observed puricase to do this in the first day of
administration of a single dose, and to maintain a
very low level for up to one month. We anticipate
that very low levels of uric acid can be maintained
on a chronic basis in most patients upon multiple
dose administrations at multi-week intervals.
The effect of puricase on tissue levels of
uric acid is unknown. We hypothesize that over
periods of time, perhaps long periods of time,
tissue deposits of uric acid can become gradually
mobilized into the circulation where puricase will
safely destroy it. Over months or years a
beneficial reduction in painful symptoms of gout
may become observable in otherwise refractory gout
patients. The number, volume and symptoms of gout
tophi may become reduced.
As long as the maximum concentration of
circulating uric acid remains continuously below a
very conservative threshold, perhaps less than 6
mg/dl, over a long period of time it is reasonable
to expect a highly favorable clinical outcome. But
we cannot predict when and in what specific way
these benefits will accrue. In this context, we
believe that the most appropriate efficacy endpoint
for pivotal trials of a new agent, as effective as
puricase is in lowering the circulating uric acid
concentration, is the circulating acid
concentration. Thank you.
DR. GIBOFSKY: Thank you, Dr. Horowitz.
Dr. Horowitz is senior vice president and chief
medical officer of Savient Pharmaceuticals, Inc. in
East Brunswick, New Jersey. Our next presentation
will come from Mr. Edward Mihalo, reading a
statement from Mr. Walter J. Clifford who is unable
to attend due to travel problems. Mr. Mihalo?
MR. MIHALO: I am Walter Clifford, a
resident of Colorado Springs, Colorado, where I
reside with my wife of 37 years. We are the
parents of 8 children. I will shortly be 60 years
of age. My academic training and professional work
are in the areas of immunology and microbiology. I
own and operate a small specialty lab which
provides immunologic clinical testing and research.
Although I have been aware that gout has been a
problem to members of my extended family for
several generations, I did not personally recognize
the problem in myself until approximately the age
of 45 years.
Our family has an atypical manifestation
of the condition which strikes in the ankles,
knees, hips, shoulders, elbows, wrists and hands
but very seldom in the great toe. Fluid aspirates
from the wrist, elbow and knees have demonstrated
the abundance or classical uric acid crystals. The
outward manifestations of regional swelling, hot,
red tissue and severe restricted mobility have all
been present during flares.
Initial treatment with indomethacin and
colchicine were ineffective. For a period of about
six months allopurinol seemed to help. However, I
developed the classical allergic response to the
allopurinol, including swelling, hives on the
torso, back and face, elevated heart rate and
difficulty in breathing. Intolerance of
allopurinol required intermittent prescriptive
doses of benadryl and other histamines under the
direction of an allergist. Clinical effectiveness
of the allopurinol diminished until it was finally
Gout flares became frequent and severe and
could only be controlled with methyl prednisolone
in Medrol tapered dose packs. The Medrol is
usually restricted to three or at most four uses
per year. However, my condition became severe
enough that packs were used every four to six weeks
and, on a few occasions, back to back. My
rheumatologist worked with me to manage diet and
other considerations, as well as to try various
approaches to control the gout.
Nothing seemed to make much difference in
either frequency or severity of the flares. As I
began to lose mobility of my hands and wrists, it
became harder and harder to work at my profession
and in the lab. The flares in my knees and ankles
made it difficult to safely drive the car and I
became dependent on my wife to drive me where I
needed to go. I very seriously began to search for
an alternative as the flares became more frequent
When my doctor approached me about taking
part in a clinical trial study involving oxypurinol
I eagerly agreed in the hope that something might
be found to help me. I began the study in July,
2000. Within a few weeks I began to find
substantial relief from the gout and immobility.
Since time I have only had two flares, both of
which were substantially shorter and more moderate
than previously experienced. Both subsided quickly
with a single Medrol dose pack.
Today I seldom worry about gout. The
oxypurinol has worked well and seems to fit in well
with the medications being taken for unrelated
conditions. It has not only been highly
instrumental in my being able to perform my work
and to be self-reliant, but has made a monumental
difference in quality of life.
I have been a light aircraft pilot and an
organist for many years. Gout made both of these
pursuits virtually impossible. I could not manage
the communications and navigation equipment in the
plane and I lost the ability to safely operate the
controls in the aircraft. While serving in the
Army in Vietnam I provided volunteer musical
service to the various chapel services whenever my
duties permitted. I could handle service music,
including high mass, while wearing combat boots.
Sadly, at the height of the gout flares I could not
manage even simple service hymns due to loss of
mobility and agility. Since starting on the
oxypurinol program I have been able to regain
sufficient freedom of movement and again provide
volunteer musical services at the church and
elsewhere. I suspect my flying days are past.
For very selfish reasons, I wanted to be
able to continue in my profession, as well as to
enjoy an improved quality of life. I earnestly
hope that oxypurinol makes it to market. I cringe
at the thought of losing it, expecting that I might
well live out my remaining life as a cripple if the
gout returns. I am most appreciative of the folks
at Cardiome Pharma for their contribution to my
health and that of others. I also appreciate the
opportunity to have something to put before the
committee. Thank you, Walter J. Clifford.
DR. GIBOFSKY: Thank you, Mr. Mihalo. Our
next presentation will be from Mr. Allyn Hamilton.
MR. HAMILTON: I hate to bore you all
again with the crutches, and all that sort of
stuff. When I met Dr. Hustetter, who put me on
this, he was a new doctor in his arthritic office
in Chattanooga, Tennessee. He said, "what are you
doing about it?" I told him, I said, "well, I'm
drinking a lot of water and I've cut down"--I used
to eat liver, calves liver and cooked onions and I
could feel my knees swell up while eating this. I
told him I was quitting that. I was drinking a lot
of water, keeping my feet elevated, trying to build
up my legs because I a golfer. I couldn't even go
18 holes in the golf cart. Now I carry my own bag.
But some of the medicines that we tried,
colchicine, allopurinol, Benemid, Indocin which was
good for attacks, butazolidin, Clinoril, anturane,
cortisone--of course, he would shoot me with
cortisone every time he drained the thing, Zyloprim
and all my stuff is very dated because I have been
on oxypurinol for 20 years and it works like a
charm. So, I don't know anything about all these
things you all are talking about. I never had to
worry about them. But Zyloprim was the medicine of
choice for a maintenance drug when I was going
through this. The first pill I took, I didn't even
get home before I had violent swelling in this
shoulder and I think it created an attack. So, I
called the doctor back up and he said get back down
here. This was a different doctor, of course. I
went to about 20 doctors before I finally got on
oxypurinol. I went down there and he gave me a
shot of adrenaline and sent me home. He said I
don't know what you can do about it, outside of
just the normal eating colchicine by the handful,
dosing with a bunch of pain pills, with your feet
propped up on top of the sofa for days. Just
Real funny, Dr. Hustetter, when I started
with him, he said, "you know, you've got a
fantastic threshold for pain." Let me tell you how
painful this stuff is, when that pressure builds up
it is horrible. Anyhow--let me see, that is pretty
much it really. Thank you very much. Cardiome--how do you
pronounce it?--is covering my expenses
and stuff. Thank you.
Committee Discussion and Questions
DR. GIBOFSKY: Thank you, Mr. Hamilton.
That concludes the presentations during the open
public hearing. The committee will now begin its
consideration of the questions posed to us by the
members and staff of the FDA. You have before you
a list of questions. There are in eight broad
categories with multiple sub-bullets. In the
interest of clarity and efficiency, while many of
these issues appear to be inter-related in terms of
surrogacy endpoint clinical differences and what
patients should be enrolled in trials, I would ask
that we consider them in order seriatim rather than
kind of go back and forth. So, we will begin with
the first question.
Please discuss the utility of serum uric
acid as a surrogate marker for the chronic
treatment of gout. There are several sub-bullets:
If an appropriate surrogate, what level of serum
uric acid or amount of change would be considered
adequate v of efficacy?
Would an analysis comparing mean change
for treatment populations reflect efficacy? Would
analysis comparing numbers of individuals in each
treatment arm reaching a prespecified level or
amount of change adequately reflect efficacy?
Are there advantages to choosing an
analysis of either the uric acid levels at last
visit or the uric acid levels over time, based on
AUC? Does the choice of surrogate as the efficacy
endpoint influence the decision of what is
considered acceptable risk?
The question is now open for discussion by
the members of the panel. Come, come, don't be
shy! Dr. Cush?
DR. CUSH: I think for everyone who
practices rheumatology uric acid as a marker for
success makes incredible sense. It is, in fact,
what we look to do in the management of our
patients. But as a sole basis for a drug's
approval, withstanding other information, it
becomes a little bit difficult. Again, I think we
sort of make that leap of faith that if we control
uric acid we control the disease but I don't think
we have enough really quality data to tell us that
control of uric acid leads to better quality of
life, less joint destruction, better survival. For
attacks, I think there is probably enough evidence
to say that, but I think the idea is that it is a
large leap that this committee would have to make
to back that, and I think to accept that as a
surrogate and then require all this other stuff to
show these facts may be passable.
But I think, you know, really there is no
reason that a drug in development at this stage
can't have one of these surrogates as a primary
outcome along with the clinical outcome, and that
trials be constructed using both placebo and active
controls for extended periods of time to answer
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: I listened to all this and
it certainly isn't one percent of the population.
That would be as frequent as rheumatoid arthritis
and that is not true in my practice. I think that
while I would like to see as an endpoint the
decrease in joint destruction and decrease in the
number of acute attacks, I think as a practical
matter we need to use some sort of surrogate so you
can identify the disease by the presentation of
crystals. But I think you can use serum uric acid
level as a surrogate. We certainly do as we
monitor these patients. If we can get it down
below 6 we would anticipate that that would
decrease the frequency of attacks and improve the
DR. CUSH: It goes against the
anticipation that that would happen. I think what
we have done, we have been holding manufacturers to
a higher level of evidence and they need to show us
that in truly objective measures.
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: That would be the ideal,
but I think that you are going to have trouble
getting the number of patients necessary to really
get good data to show that you made that kind of
change. I hear them saying 6 attacks per year. It
is going to take 100 clinics to get 200 patients
and those trials are going to be very difficult to
do. So, in the meantime I would use it as a
surrogate because I think that that is the way we
use it now in practice.
DR. GIBOFSKY: To what extent is the serum
uric acid a surrogate for total uric acid? We have
all seen these pictures of tophi and the tophi can
be quite extensive and, yet, the serum uric acid
may be only mildly elevated. So, I guess the
question that has been coming up to me again and
again is while serum uric acid may be a marker, is
it an appropriate marker for total uric acid? Is
that what the gold standard should be? Dr.
DR. WILLIAMS: I think it is a marker of
the total serum uric acid. We can lower the serum
uric acid faster than we can lower the pool.
However, over time if you keep the uric acid low
you will gradually lower that pool. Rapid lowering
of the serum uric acid may have very little impact
on the total pool to start off.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: Earlier today we heard from Dr.
Terkeltaub that measuring total body urate by
looking at tophi would make some sense, or maybe
even more specialized means. Now we are examining,
you know, using a surrogate marker for a disease
and its activity, and now we are talking about a
laboratory test to look at a disease and its
activity. My point is gout is an easy disease.
They hurt. You know, clinical measures work. I
think everything else is going to be icing on the
cake and I don't see any reason why we can't
require strong clinical outcomes. I mean, this is
predominantly a disease of pain.
Going to Jim's point, I don't have these
people in my clinic either, and over 3600
practicing rheumatologists, we take care of a very
small minority of almost 5 million people who have
this disease. That means they are out in the
private sector. They are being treated by primary
carers and emergency room docs, and that is why we
don't see them. So, obviously, the trial is not
going to be done in my office as well as it is
going to be done in a hospital and its emergency
DR. GIBOFSKY: Dr. Felson?
DR. FELSON: I actually sketched out the
primary endpoints and the pros and cons of each of
them. Serum uric acid could be defined in one of
three ways as an endpoint, I guess. One is by the
regression, sort of continuous measure and does it
change on treatment more than in the comparator.
The good news about that is it is powerful because
it is continuous. The bad news about that is it
may be trivial and be significant.
Then, there is sort of the arrangement
that was made for what was called the pivotal trial
for oxypurinol, which was at least a 2 mg/dl
decrement as the lower bound of the 95 CI of
improvement. I actually have a bunch of problems
with that. One is that it suddenly dichotomizes
the continuous measure and, therefore, makes it
less powerful. Another, which I think has been
said a few times here, is that I am not sure
whether it is clinically important.
Then, the last one would be a reduction to
an arbitrary level on the part of a certain number
of patients. That is bullet number three, would an
analysis comparing the number of individuals in
treatment arm reaching a prespecified level or
amount of change--we just talked about the
prespecified amount of change; this is the
prespecified level. The obvious one, based on the
literature and based on the physicochemical
solubility of uric acid, sounds like it is less
than 6 over a period of time.
That seems to me the only supportable
primary efficacy measure that you would use for
serum uric acid, if you used one. Now, the problem
there is the ability to get to that level would
likely depend on the baseline level in a given
person or group of people, and it would be harder
to reach if some people start off with very high
levels. I think one could argue that since there
are effective therapies here already, even though
not maybe not in some subsets of patients, it might
be okay to ask for a high threshold level of proof,
which this would be.
Then, the alternative is the Jack Cush
alternative. You know, it is interesting, I came
here this morning thinking I would choose that.
Then as I listened to the serum uric acid
discussion I think you guys all convinced me we
should go to serum uric acid. Then I think as I
thought about what Jack was saying, I think I came
a little bit back towards that because it is such a
symptomatic, easily characterizable symptomatic
disease and attacks are the central manifestation.
The problems with using clinical attacks
are that they increase early in uric lowering
therapy so one would have to define it after a
certain period of time on treatment or start
enumerating them. I think there is another issue
in these particular types of patients who would be
eligible for these trials. Frankly, I see a lot of
these because I practice in a municipal hospital
and I am not sure when a given attack begins and
ends in any of these patients. They often have
very continuously active, smoldering disease and it
might be difficult to enumerate attacks in some of
Then the other thing I think Marc or
someone else brought up earlier is that the number
of attacks might be affected by co-therapy to
prevent attacks. I think you could probably get
around that design issue by just requiring
constancy of some co-therapy so that it doesn't
vary through the course of the trial. Then you
would have an outcome, so you would do number of
attacks sort of starting at three months or six
months after initiation of therapy per month, or
something, and that might work the best of all.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: Dr. Felson is always a hard
act to follow because he is so thoughtful in the
way he lays things out. I want to step back to the
issue of whether uric acid is a surrogate. I guess
when I think of a surrogate I think of sort of the
evidence-based medicine approach. There is
actually a paper that speaks directly to this as to
when something is a good surrogate and when it is
not a good surrogate. We know from the
epidemiological data that measurements of serum
uric acid predict the development of gout. So, it
is great for that.
We have some observational data, although
not from placebo-controlled, randomized trials,
that suggest that if you change the measure of uric
acid you get an improvement in some of the clinical
outcomes in terms of a decrease in size of
tophaceous deposits, as well as a decrease in the
number of attacks.
I think putting those two together, you
would say, yes, this behaves as a surrogate
endpoint. Now, the problem is that the drugs lower
serum uric acid so that you are treating
hyperuricemia, but the treatment of gout is
different because gout is arthritis, and gout is
painful and it is clinically characterizable, as
Jack, David and others have commented. In a trial
which is focused on a drug which would lower serum
uric acid the patients are not going to come in
naive to treatments for gout. They will either be
on colchicine or they will be on NSAIDs or they
will be on glucocorticoids. So, they will need to
have some background therapy and then one deals
with the issue of are you recruiting subjects for a
study who have failed previous hyperuricemic
therapy in order to determine whether a new agent
will lower serum uric acid levels as the primary
endpoint, or the secondary endpoint of will it
reduce the number of, let's say, attacks of gout or
the severity of arthritis during the course of time
in a population that is already being treated for
So, I would look at uric acid as, yes, it
is a surrogate marker for gout but it is something
which is an appropriate endpoint in and of itself
in the patient with recurrent attacks of gout or a
chronic gouty arthritis.
DR. GIBOFSKY: Dr. Williams, did you have
DR. WILLIAMS: As usual, I agree with
David Felson but if someone lowered their uric acid
by 2 degrees or by 30 percent and they still had a
uric acid of 8, I wouldn't find that very
satisfactory. So, I would agree that we would have
to set a fixed level, and from the data it would
appear to be 6 mg/dl.
However, I have one problem with using
acute attacks as an endpoint, besides those that
have been mentioned, and that is that the disease
is so episodic and so unpredictable. So, you are
going to have to follow them for a significant
period of time to get enough attacks or enough
expected attacks to make a difference. It is not a
continuous problem like rheumatoid arthritis and I
think that that makes the trial much more difficult
and longer and larger to get adequate numbers.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: Not to be a broken record, but
when my patients come back with gout the first
question I ask is not what is your acid, I don't
even care if I have the lab and the chart, you very
easily ask them what has happened since the last
time I saw you. The last time I saw you I may have
started you on allopurinol or on probenecid or
colchicine and loaded prednisone to the mix, and
successful therapy is whether you have had attacks
or not. Then I feel good about myself when I see
that uric acid went down. I don't actually have a
target. I mean, I would like them all to be less
than 6 but in practice that is not commonly
achievable. But what is achievable is control of
DR. GIBOFSKY: Dr. Hochberg, as you know
and as we heard, there is a poor correlation
between serum uric acid and gouty attacks. To what
extent would that factor into the assessment of
lowering serum uric acid as a surrogate marker?
DR. HOCHBERG: Well, I think in terms of
the prediction of the development of gout there is
actually probably a very good correlation, from the
population data at least, for having hyperuricemia
and having the subsequent risk of developing gout.
With regard to the individual patient who
comes in with acute gout, you know, you are right
in that there is a large proportion who will have
normal serum uric acid at the time that they
present with acute gout. So, I personally think
that uric acid has to be looked at separate from
the issue of gouty arthritis and go back at least
to the way I was taught to practice, which was to
treat the arthritis, probably the way Jack Cush
treats the arthritis--not too different from the
East Coast and Texas--but to focus on the serum
uric acid as a measure--and Dr. Terkeltaub can
correct me and maybe tell us how good a measure it
is--of total urate pool and the fact that probably
reduction in the uric acid will be associated with
reduction in the size of tophi, and that needs to
be addressed separately.
DR. GIBOFSKY: Dr. Hoffman?
DR. HOFFMAN: I would concur with Marc's
observations. While we have all seen patients with
normal or borderline uric acid levels come to us
with gout, I don't think the issue is so much is
there a direct linear relationship between the
serum uric acid at any one point in time and will
someone get gout. I think it is more of an issue
of being supersaturated over time--how long has
this patient been building micro tophaceous
deposits until the time comes when they actually
have what we think of as strip mining of sodium
uric crystals from those deposits. If somebody is
acutely hyperuricemic, that may not be terribly
relevant compared to the person who has been
sitting at a uric acid level of 8.5 for 15 years.
But to get more to the bullet point that
we are addressing, is serum uric acid an
appropriate surrogate, I think the alternative
question is what do we have as a better surrogate?
Unless you would like to call on Bob Terkeltaub
again to address this, but as far as I know we
don't have a means of measuring total body urate
pool so we can't use that as a surrogate. And, I
am not aware of any other surrogate that is going
to serve us better than serum uric acid. A change
in uric acid, is it an adequate measure of
efficacy? Well, it is one measure of efficacy. I
don't think we can use that as the only endpoint in
a study. I think we have to use it in conduction
with reduction in attacks of gout.
As Jim Williams pointed out, if we are
dealing with people who are not having very
frequent attacks of gout, that is going to be
difficult and going to require a very large number
of patients to do that study. So, there are some
logistic issues in study design there.
But I think the issue is very complicated
because we know it is not just a matter of what
your serum uric acid is or at what point at time,
but it is over time and then there are other
variables such as crystallization--perhaps there
are some that we know of and perhaps more that we
don't know of that determine why there are patients
whose serum uric acid maybe 10 for 10 years who
never get an attack again.
DR. GIBOFSKY: Well, we have heard from
the East Coast; we have heard from Texas; we have
heard from part of the Heartland. Comments from
the West Coast? Dr. Finley?
DR. FINLEY: Mr. Chairman, I share the
concern that we do need to have a clinical marker
as a surrogate as well as the serum uric acid. As
we have heard from the public comments, for the
patients, as Jack Cush mentioned, they are not
concerned about what their uric acid is. I also
share Jim Williams' concerns about us conceiving
and recommending to the FDA a study that, you know,
for the sponsors is not attainable in a fashion
that would be acceptable to the non-rheumatologists
who treat most of this disease.
DR. GIBOFSKY: I would hope that the FDA
would not allow us to recommend the perfect as the
enemy to the good, particularly for patients with
gout. How about the Deep South? Dr. Boulware?
DR. BOULWARE: I am actually very
comfortable with using serum uric acid as a
surrogate marker for this study. I am reading it
now more broadly in terms of this broad discussion
of a surrogate marker for the treatment of gout.
We started off by talking about a very select
population and we have boxed ourselves in, saying
we probably can't use clinical outcomes of patients
because it may be too small or restricted a patient
population. But if you really wanted to see if a
drug was effective for the chronic treatment of
gout and open it to all gout patients, not just
those who have intolerance to allopurinol, then we
maybe could answer this question. So, I would
favor using a clinical outcome marker too, but not
if it means that you essentially hamstring the
DR. GIBOFSKY: Any other comments from
other colleagues in Baltimore, Dr. Bathon?
DR. BATHON: I would agree that I think a
dual kind of outcome is appropriate. I like the
idea of serum uric acid but I think it should have
a clinical correlate. If I had to choose what
outcome of serum uric acid I would like, I think it
would be to hold it to the most rigorous
expectation, which would be to normalize uric acid
and ensure that correlates with reduction in
DR. GIBOFSKY: Dr. Terkeltaub, your name
was invoked for perhaps some clarification of one
of Dr. Hoffman's issues. I wonder if I could ask
you to address that at this time briefly.
DR. TERKELTAUB: I have some concern that
if trials aren't constructed properly, when looking
at serum uric acid levels we are going to be
impairing development of drugs to treat patients
with difficult gout and a high body burden of serum
uric acid. The numbers in terms of trying to use
serum urate to interpret effects on urate pool size
change, if you take a normal man that has a urate
pool of about a gram and that man has 5 L of
plasma, then what is in the plasma at a level of 7
mg percent reflects about a third of the total body
pool. Whereas, you know, some of the patients that
we see with really bad gout have 5, 10, 25, 30
grams of uric acid and then the serum urate
reflects really a couple of percent of the total
body urate pool.
So, my concern is that when trying to
evaluate urate lowering therapies, if we only use
serum urate and if we try to pigeonhole people to a
level that is considered normal, 6 mg percent, that
we are not going to be really looking at people
where they have a shrinking tumor burden of tophus
and that would be a great mistake.
DR. GIBOFSKY: Dr. Felson?
DR. FELSON: Bob, if the physicochemical
solubility is at 7 and we lower it to 6, they have
to be, at least at some rate, taking some of that
stuff that was out of solution and putting it back
into solution and if their kidneys are working, you
know, peeing it out or getting it converted to
something else. I mean, it has to be shrinking,
doesn't it? Aren't we messing with the dynamic
flows of their uric acid pool?
DR. TERKELTAUB: Yes. I think the
question is when you have a serum urate level of 10
and you reduce it to 8, are you failing to control
the disease? There, I think the serum urate is a
problem. You don't get urate crystallization in
plasma and serum; you get it in the tissues. And,
I don't think serum urate accurately reflects what
is going on at the tissue level in that
circumstance. You know, if you are reducing the
manufacturing of uric acid and you are reducing
tissue deposits, which clearly happens in many of
our patients who are stabilized on drugs such as
allopurinol, then you are not really getting an
accurate readout on the serum level.
DR. GIBOFSKY: Thank you, Dr. Terkeltaub.
DR. GEIS: I just want to clarify what I
think I am hearing. Are you saying if you powered
a clinical trial with a primary endpoint being some
measure of uric acid levels, then you would have a
manageable sample size to do a trial? And, if you
collected clinical outcomes and you weren't powered
to see a difference necessarily from placebo but
you saw numerical differences, and you were
statistically better with uric acid levels, are you
then saying you could interpret to mean that drug
treats gout? Is that what I am hearing people say?
And, if a sponsor replicated that, then you would
say, yes, the drug treats gout. It doesn't just
treat the uric acid, it treats the gout as long as
you had some measure of clinical outcome, although
not statistically significant? Is that what I am
DR. GIBOFSKY: I am not sure we have gone
that deep into trial design. We have just been
focusing on the utility of serum uric acid as a
surrogate marker based on the comments we heard
DR. GEIS: Okay.
DR. GIBOFSKY: To what degree a study is
powered, or should be powered, perhaps we will get
into with one of the other broader areas. Dr.
Williams, you were next with a comment or question.
DR. WILLIAMS: Actually, that addresses
exactly what I wanted to say, and that is, when I
was referring to an endpoint of less than 6 mg/dl
as an endpoint to show that you have efficacy, it
doesn't necessarily mean that it would be the total
approach that it is an effective treatment for
gout. I was trained that if I am trying to lower
the serum uric acid pool I would like to get the
uric acid to 3 or 4. However, I would not make
that the level to demonstrate that you are
effective in lowering uric acid.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: I guess before I ask my
question, which is really a question to Dr.
Terkeltaub, I would comment back to Dr. Geis'
question. In one of Dr. Witter's slides on the
approved indications for the products that we are
discussing, this sort of class, I like the
indication that says for the treatment of
hyperuricemia associated with gout. I think that
is what we are talking about now because I still
consider gout to be a form of arthritis and when I
am treating gout I am treating the attack of gout.
When I am treating hyperuricemia I am treating
So, I would sort of like to know if there
are relatively straightforward, reliable methods
which are not too expensive to measure the total
body burden or total body pool of urate that
function better than the serum uric acid level.
DR. GIBOFSKY: A quick replay, Dr.
DR. TERKELTAUB: No.
DR. GIBOFSKY: Thank you. That was quick.
DR. ANDERSON: I would just like to
comment on the relative power of an outcome as
change in uric acid level or reaching a certain
level in uric acid versus the clinical outcome of
the number of attacks in a time period like a year.
Actually, the power for an outcome where you would
be comparing two groups for number of attacks per
year is really pretty good. You know, it is fairly
reasonable to assume that these attacks follow a
Poisson distribution and I think that the study
that was proposed by Cardiome is actually
overpowered. You know, by the description that is
given, it is overpowered for the outcome of cutting
the number of attacks by 50 percent. So, really
just isn't such a hard thing to do. That is really
what I am trying to say.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: I like the way Marc has divided
it up. To make the analogy with rheumatoid
arthritis, you know, I treat the arthritis
utilization now I am also looking for treatment
that would focus on the CRP, treatment that would
lower CRP. CRP is a little bit different than uric
acid but they are pretty close. CRP is a direct
extension of IL-6. Anyway, I have a little bit of
a problem with that approach but I think we should
get to the real issue which, again, is a surrogate
marker, comparing to HIV and bone density and
lipids, where there are clear-cut, defined benefits
to control or lessening of those levels. Again,
what is the clear-cut evidence for taking a patient
who has defined gout--we certainly know that having
elevated uric acid levels increases one's risk of
having attacks but take it the other way around,
they have gout and I presume they have
hyperuricemia, what is the evidence that lowering
hyperuricemia gives you X benefit as far as quality
of life, attacks, extra-articular manifestations,
x-ray erosions, damage, disability, blah, blah,
blah? I am not aware that there is a lot there.
Is there anything there that hasn't been presented
So, again, it is a gigantic leap of faith
that we are making based on what we have done for
years and years and years, which is the problem
with the whole gout literature and the research.
It has been an empiric disease since Hippocrates.
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: However, in clinical
practice if we lower their uric acid we decrease
the frequency of their gout attacks.
DR. CUSH: We do?
DR. WILLIAMS: It seems to be so in my
practice and we heard from some people here today
who have done well on lowering of their uric acid.
DR. CUSH: I don't doubt that but the
evidence is what I am concerned about.
DR. WILLIAMS: I agree, we don't have
DR. CUSH: I don't know how I can tell FDA
and you, know, draw up a guidance document for this
to, you know, leap forward on leaps of faith rather
than good evidence.
DR. GIBOFSKY: Are you having a problem
with a faith-based initiative?
DR. CUSH: You are my lawyer, I can't ask
you for advice for how to answer that.
DR. WILLIAMS: However, we are not going
to have any more new treatments. If we don't move
ahead we are going to stay where we have been over
the last 30, 40 years.
DR. GIBOFSKY: Ms. McBriar?
MS. MCBRIAR: Yes, I think it is time to
do something. There hasn't been anything new for
quite a few years and the patients obviously have a
need, and we are seeing an increased prevalence and
I think we have to choose the best ideas that
people have here and move with them and see what we
DR. GIBOFSKY: Dr. Bathon?
DR. BATHON: I agree with what Dr. Cush
was saying but I think, drawing the analogy to
rheumatoid arthritis again, we learned a lot about
the natural history of the disease and the efficacy
of a drug that we have been using for a decade or
more, called methotrexate, when we did the clinical
trials of new TNF antagonists. I think we have
that opportunity here. We have to accept the fact
that we don't have a lot of data to base our design
on right now but if we design the best trial that
we can, given the data that we have, we might be
able to answer these questions a couple of years
down the road and have a better handle on the
natural history and the impact of allopurinol, much
less the new drugs.
DR. GIBOFSKY: Dr. Hoffman?
DR. HOFFMAN: I am trying in my own mind
to synthesize what we have been hearing from a
number of people, and I think what I am hearing,
including from Dr. Terkeltaub, is that there are
people who clearly have reduced frequency of gouty
attacks even if their uric acid is not brought down
to some magic number, perhaps 6 or less. We are
not sure about how adequate a serum uric acid
change of whatever amount you want to choose is in
being an absolutely adequate surrogate of efficacy--
decreased gouty attacks.
So, if we don't have that degree of
certainty, it would appear that the endpoints for a
gout study would have to be two-fold. On one
level, decreasing serum uric acid and on the other
level numbers of gouty attacks per patient over a
unit of time. I don't think I could advocate a
study that did not include both endpoints.
DR. GIBOFSKY: I think we have had
considerable discussion of question I. I would
like to drill down on the five bullets. There will
be ample opportunity for further discussion. Our
charge was to discuss the utility of serum uric
acid as a surrogate marker for the chronic
treatment of gout and now perhaps we can just try
and get some consensus, without formal vote, on the
five bullets. Is there a consensus there is an
appropriate surrogate? Is there anyone who would
disagree that it is an acceptable surrogate? Not
the acceptable surrogate but an acceptable
Then, what level of serum urate or amount
of change in serum uric acid level would be
considered adequate evidence of efficacy? Dr.
Cush, you had your hand up so I will let you tackle
DR. CUSH: I will reiterate that it is not
percentage change, it is absolute value and I will
stay with 6 as my target.
DR. GIBOFSKY: Okay. The second bullet,
would an analysis comparing the mean change in
serum urate for treatment populations adequately
reflect efficacy? Dr. Hochberg?
DR. HOCHBERG: No.
DR. GIBOFSKY: Discussion? Disagreement?
Would an analysis comparing the number of
individuals in each treatment arm reaching a
prespecified level or amount of change adequately
reflect efficacy? Dr. Anderson?
DR. ANDERSON: If it was a prespecified
DR. GIBOFSKY: Dr. Felson?
DR. FELSON: I didn't understand
DR. ANDERSON: Well, the question was
would an analysis comparing the number of
individuals in each treatment arm reaching a
prespecified level of SUA adequately reflect
efficacy? And, I said yes to that, but no if it
had been amount of change.
DR. GIBOFSKY: Are there advantages to
choosing--I am sorry, Dr. Cush?
DR. CUSH: Going to the prespecified
level, I want to get to a point I made earlier, the
cholesterol analogy. Cholesterol trials took off
because we had drugs to lower cholesterol levels
and we thought it was a good idea, and we had
prespecified levels we were shooting for. When we
did all that we actually didn't know what the long-term
benefits would be. That didn't happen until,
you know, 50,000 or 100,000 people were treated in
long-term trials and we saw reductions in
cardiovascular mortality, and what-not. So, there
it became a great surrogate. But when it was first
used it was probably assumed to be a good
DR. FELSON: I think, Jack, you made the
exact right point earlier when you said we don't
know what going to 8 mg means with respect to
clinical effect. In cholesterol there were a
variety of epidemiologic data that suggested that
if you lowered it to a certain amount you would get
a lower rate of the endpoint. That is why it was
acceptable. The only evidence we have that a
particular level is going to lower the risk of
attacks is the level of 6. Since that is what has
been studied, that is where we have the evidence.
It may well be, as Jim was saying, that if we lower
from 10 to 8 we get less attacks but there is no
evidence for that. I think it wouldn't be a good
idea to suggest that that be the endpoint because
it doesn't necessarily have any clinical meaning.
DR. GIBOFSKY: Don't go away from the
microphone, Dr. Felson. Are there advantages to
choosing an analysis of either the uric acid level
at last visit or the uric acid level over time,
based on the AUC?
DR. FELSON: There are always advantages
in terms of power--well, not always but almost
always, to choosing uric acid levels over time
because the average one might be a noisy thing. I
think the one exception is if the curve shows that
on treatment uric acid levels continue to decline,
perhaps be dose is going up, then if you pick the
very last level you will get the very best
reduction. So, I think it depends on the
particular treatment and what the curve of therapy
is doing to the uric acid level. I think the other
thing is, frankly, increasingly we are interested
in effects that have duration. So, I think doing
something over time is reasonable.
DR. GIBOFSKY: Let me introduce the last
bullet by referring you back to Dr. Villalba's
slide 27, entitled, the oxypurinol challenge.
Define a population for a favorable risk/benefit--benefit,
modest decrease in serum urate; risk,
intolerance. With that as background, is the
choice of a surrogate as the efficacy endpoint
influence the decision of what is considered
acceptable risk? Dr. Finley?
DR. FINLEY: The short answer is I think
yes. Even though we have been talking about the
surrogate as the serum uric acid, you know, in our
discussion we talked about who really treats these
folks and I think Jack mentioned where the studies
will be done, and I still concern myself that as we
ask the sponsors to aim for some target, whatever
surrogate we pick, and remember who is going to be
doing the studies, and probably not a preponderance
of them will be in the hands of rheumatologists
necessarily, that choice of surrogate is clearly
very important. I would advocate, you know, we
consider things beyond the serum urate.
DR. GIBOFSKY: I think we have adequately
discussed question I. I would like to move on to
question II. There will be much more time for
discussion as we go along. We have eight topic
areas to consider. So, if we can put up question
II, for a drug to be approved for the treatment of
hyperuricemia associated with gout, what additional
information besides uric acid levels are important
to collect? That topic is now open for discussion.
I think we have already alluded to some of that.
Perhaps we could just have a reiteration in the
context of this particular question. Anyone want
to tackle that one? Dr. Williams?
DR. WILLIAMS: Well, I think we have
discussed that we would like to see some clinical
change as well. So, I would like to see both
reducing the number of episodes of acute gout plus
decrease in the size of the tophi, two that are
mentioned up there.
DR. GIBOFSKY: Certainly, I think we have
also commented on renal function in our patients,
and to the extent that renal function can cause
gouty attacks and to the extent that gout and
hyperuricemia can cause decreased renal function,
that would be something that would be worth
assessing as well. Any other suggestions for
information? Dr. Cush?
DR. CUSH: As was mentioned earlier,
quality of life and humanistic outcomes I think are
important. Obviously, if we are going for this as
a surrogate marker we want to see long-term
benefits; these are long-term trials. So, joint
outcome, disability, work, humanistic function,
DR. GIBOFSKY: Ms. McBriar?
MS. MCBRIAR: I also would like to see
quality of life and also perhaps a pain scale,
looking at people's pain.
DR. GIBOFSKY: Any other comments? Dr.
DR. WILLIAMS: I would just raise a
question. Since we talked about radiographic
damage, I think most of that is done associated
with tophi. I think the damage is a little less
predictable maybe than in rheumatoid arthritis. I
personally think that we can't have trials that
will be long enough to see significant enough
changes but I would be interested if others feel
DR. GIBOFSKY: Let me pose a question to
Dr. Felson. Given the extensive co-morbidity in
patients with gout, to what extent would a disease-specific
instrument be preferable to a general
instrument measuring quality of life, or to what
extent would a general instrument be preferable to
the disease-specific instrument, and can you tease
out the effect of one co-morbid condition on
another, and which instrument should we be looking
at in health-related quality of life assessment?
DR. FELSON: No, I think disease-specific
instruments are both more sensitive to change and
evaluating the therapy of a given disease and in
this situation, where there are so many co-morbidities that
are affecting generic quality of
life, I think you almost have to use it. I think
it is a secondary outcome measure but I think some
kind of disease-specific or arthritis-specific
measure--I am not sure that HAQ and the AIMS are
such bad ideas here, but those would be better.
I think, by the way, it was shocking how
many people died of cardiovascular and other things
in some of these studies and I am wondering--you
know, we are talking about long-term studies here
so the attrition rates would be concerning. I
think trying to identify eligible patients not just
on the basis of their gout or their renal disease
but also who don't have class IV congestive heart
failure or even class III might not be a bad idea.
DR. GIBOFSKY: Ms. McBriar?
MS. MCBRIAR: I would also like to see a
general quality of life because it then can be
compared against other diseases and that is always
DR. GIBOFSKY: So, you would want to see
both disease specific and general health-related
quality of life?
MS. MCBRIAR: Yes.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: Since we are talking about
using a surrogate as a means of approval and
looking for other things downstream, I think you
have to also then be mindful that this should be a
study that really reflects real use, and not use
the usual restrictive entry and exclusion criteria
but have people who have obesity, and heart
failure, and renal insufficiency, and diabetes
included here because there are going to be real
life issues. You know, as Bob showed earlier about
hyperuricemia predicting cardiovascular problems
later on, and as David pointed out, I think that is
a real concern that one would have to answer by
doing these longer-term trials.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: I guess the other issue in
following up on this is because of the association
with cardiovascular disease you have a population
of people who should be, if they are not already,
taking low dose aspirin. One has to consider in
the design of the trial the effect of low dose
aspirin on urate handling and, if all the patients
aren't on it, whether that would need to be
stratified in terms of the randomized process as
DR. GIBOFSKY: Thank you, Dr. Hochberg.
That is category VIII, subsection 3 and I will come
back to you and ask for your comments specifically
when we get to that point as well. Are we ready to
drill down on the three bullets? Any further
discussion of the specific question II as to
whether additional information is needed to be
collected? If not, let's drill down.
Clinical endpoints of a reduced number of
gout attacks and decreased size of tophi in trials
of uric acid lowering drugs. Dr. Cush, want to
tackle that one?
DR. CUSH: I think that reduced number of
gout attacks can be done. There are some problems
with defining gout attacks but we probably anguish
over it more than we should. Our patients seem to
know exactly when they are. My secretary can
diagnose over the phone--
--but decreasing tophi sounds about as
intelligent as measuring nodules in rheumatoid
arthritis trials. It depends on the person doing
the assessments; it depends on the tools you have
and using calipers. I think there is a real value
in measuring tophi but, you know, it is only a
small reflection of total body urate load and maybe
we can only see it really well in the elbow and not
so well in the feet. As Dr. Terkeltaub mentioned
earlier, I think we need newer methods here.
Whether it is scintigraphy or labeling or MRI, or
what-not, I think that should be done.
DR. GIBOFSKY: I confess I am not sure
that there are many of us who actually take
calipers to a tophus when we see it.
DR. CUSH: I would be afraid to.
DR. GIBOFSKY: And I can understand why.
But that said, are there or ought there to be
preferred methods for measuring tophi? Dr.
DR. MANDELL: You can certainly do it with
calipers. I think, from a logistics side, that is
probably the most cost-effective way to do it. You
can certainly follow people who get reduction. But
the issue is can you find one that you can actually
measure at the same spot under that skin as it
moves each time, and I think that is going to be a
I would like to comment on the gouty
attack issue. You know, I didn't say much before
about it. I didn't say anything before about the
surrogate marker. I am comfortable with targeting
uric acid lowering as a marker, but I also think we
do have some issue relating to the arthritis, and
the design challenge I think is going to be the
unique part that when you give this drug, which
should decrease long-term attacks, has a very high
likelihood of increasing attacks in the short term.
That is going to need to be built in and I don't
think we really understand the timing of when that
window should be when we should not count that.
So, the drug looks worse or better based on the
likelihood of getting an attack early and I think
that is going to be a real challenge in trial
DR. GIBOFSKY: Dr. Hoffman?
DR. HOFFMAN: I think that is a terribly
important point but I think it could be
circumvented if you started counting attacks
perhaps three months after initiation of therapy.
But the major heading that we are addressing these
issues under are for a drug to be approved. I
think at looking at reduction of tophus size would
build into a study something that is untenable. We
would all like to know it but if you are going to
take a year or two or three to see a meaningful
change in tophus size at a point where we don't
have anything more sophisticated than calipers,
then I think that is not feasible to build into
these trials. But I can't imagine the trials not
taking into account frequency and number of gouty
attacks, perhaps starting three months after drug
has been initiated and we, hopefully, have achieved
equilibration perhaps also under cover of treatment
with a second agent, that is colchicine which is
the standard of care.
DR. GIBOFSKY: So let me pose the question
under bullet three to you, Dr. Hoffman--I am sorry,
there was a question or a comment before? Dr.
DR. BATHON: Yes, I think we do a lot of
very inaccurate methods of assessment, including
joint counts. So, calipers seem even more
sensitive to me than perhaps the feel of a finger
on a joint.
I want to come back to that point about
the early attacks after starting treatment. That
is another thing that we learned but are there data
that really support the fact that these drugs
increase the incidence of attacks? Do we know from
the data that before treatment there are X number
of attacks and after initiation of gout treatment
there is an increase in X number of attacks? I bet
there aren't real data to support that either.
DR. GIBOFSKY: Dr. Felson?
DR. FELSON: I guess, Joan, sometimes
there aren't data because it is reasonably clear.
I think it is reasonably clear but then, again, I
am not usually an anecdotal type guy.
I would like to paraphrase Nancy Reagan
with respect to her comment about measuring
tophaceous deposits--"just say no." It is going to
be very hard to measure reliably. We have many
other better measures here, and I think it is also
the time it would take to get change is unknown and
would be a mess.
There is one question we haven't
addressed, which is number of attacks or reduction
of attacks. I wanted to try to address that
briefly. I think number of attacks is a better
choice than reduction in attacks. The reason for
that is reduction in number of attacks is
contingent upon two things. One is knowing the
current number of attacks and the other is knowing
how many attacks occurred before this drug was
started, i.e., before the patient experienced the
three months worth of potential flares of attacks
they might have gotten. So, I think to ask them to
remember six months before, or something like that,
how many attacks they used to have last year and
whether they got a reduced number now is a problem.
The other way to do this would be a very
long run-in prior to therapy in which you enumerate
the attacks. I don't think that is a good way--I
mean, I think a run-in is nice but if we are
talking about a six-month run in to get enough
attacks to be able to enumerate and follow, I think
that is asking a lot of patients. So, I would be
inclined to measure or quantify the number of
attacks and not try to figure out whether they
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: I would agree once again
with David. I would like to throw out a question
about another potential measure, and that would be
radiographs of the feet to look at the metatarsal
phalangeal joint and look at erosions, and possibly
joint space narrowing. You know, we have very
good, reliable scales to assess damage to the MTP
joints in patients with rheumatoid arthritis, and I
am not sure there are any data that have applied
these scales to patients with gout but, in fact,
that might be something where one could generate
such data either as an exploratory outcome in
studies or even just for data collection in order
to move the field forward.
DR. GIBOFSKY: Marc, are you suggesting
that the Sharp score methodology could be applied
to a trial of gout treatment agents?
DR. HOCHBERG: Well, I think it would be
of interest to see if it could. I guess it is
something that Almarack and John Sharp might be
interested in doing.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: It is my understanding Almarack
has discussed that but I don't know the details.
Sort of to piggyback on what Marc said, fingers and
calipers--I agree with David, just say no to tophi,
but this may be one situation where ultrasound
might make sense. There are a few centers that do
them. Obviously, it would be a select sub-study
for any trial but I think that ultrasound could
easily identify and quantify tophi over a period of
DR. GIBOFSKY: Any other comments on
question II? I think we have covered all three
bullets. If there are no other comments on
question II, please put up question III.
Individuals with gout may demonstrate a
broad range of uric acid levels. We have two
discussion questions and two specific questions.
Please discuss the range of uric acid
levels that would reflect meaningful inclusion or
Are there any advantages to recruiting
patients with uric acid in a specified range, such
as 8-12 mg/dl?
Please discuss whether there is a
rationale for studying individuals with values of
uric acid over 12 medication/dl.
Is there value in stratifying patients by
uric acid level?
So, first bullet, please discuss the range
of uric acid levels--I think we have already
touched upon that. Does anyone want to come back
and discuss that again? Dr. Williams?
DR. WILLIAMS: Just to address this
question in general, I think that to include
patients they ought to have hyperuricemia and acute
gouty arthritis but I don't know that I would
stratify it further.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: Extremes in uric acid
determinations I think bring into play other
diseases. So, if we are just talking about gout I
don't think we will have these extremes. They will
be there but there will be so few of them I think
that going after a specific disease indication and
characterizing the disease on clinical grounds
rather than on uric acid levels I don't think this
becomes anything more than a moot point.
DR. GIBOFSKY: Everyone comfortable with
Are there any advantages to recruiting
patients with uric acid in a specified range such
as 8-12 mg/dl? Dr. Hochberg?
DR. HOCHBERG: I guess based on what Dr.
Terkeltaub has said, I am not sure we can assume
the statement that is in the parentheses is
correct. Probably based on the data that have been
shown to us and that which is in the literature,
most patients with gout who would be eligible for a
study in which they would receive a hyperuricemic
therapy would have uric acid levels above 7 and
would fall in the range between 8-12. So, it is
likely that with randomization one would achieve
some comparability between the groups. I think if
one got to the rationale for including people who
had levels above 12, they would be less likely to
reach the outcome just because they are starting at
a much higher level. So, you would probably want
to stratify prior to randomization to make sure
they were evenly distributed. So, you would
stratify patients above 12 and not necessarily
between 8-12--I mean, not necessarily but I don't
know enough to inform myself that that is a good
thing to do, to stratify between 8-12.
DR. GIBOFSKY: Is the committee
comfortable that the parenthetical statement in
bullet two is probably not accurate, given what we
have heard today, that the serum urate probably
does not represent the total body load of uric
Any other comments on bullet two or bullet
four, which we have kind of alluded to? Anyone
else on that or are we comfortable with the
comments that have been made? I think Dr. Hochberg
also indicated the issues that might be present in
patients with values of urate over 12 mg/dl, the
possibility of other conditions, but does anyone
feel that there might be a rationale for including
these individuals in a hyperuricemia related to
gout study? Dr. Bathon?
DR. BATHON: I am sort of antagonistic to
the idea of setting an upper limit of normal as
long as we exclude cancer patients and that type of
thing. I think we want a range of patients with
moderate disease and severe disease and we
shouldn't exclude those above 12.
DR. GIBOFSKY: Dr. Finley?
DR. FINLEY: I would agree with Dr. Bathon
and I would harken back to something that Dr.
Hochberg said earlier. We have a growing
population of patients who have undergone
transplantation and are going to fit this, and the
indication I think Marc spoke to was hyperuricemia
associated with gout. I have no notion of how big
the population might be that would come under
scrutiny but certainly would want to know that
data, especially when we are talking about
rheumatoid arthritis and other diseases that we all
treat, longitudinal disease, and perhaps the
indications for using these in those settings might
DR. GIBOFSKY: The Chair would have great
interest in following the data on uricemia in
transplant patients. Dr. Cush?
DR. CUSH: Just to make a statement in
favor of over 12 is that that is what the
indication is for, uric acid therapy. So,
competitors of allopurinol need to compete in that
market and those patients should be included and,
if need be, if there are enough of them to be sub-analyzed.
DR. GIBOFSKY: Any other comments or
discussion on question III? If not, I think we
will take one more question before our break. We
are running a bit ahead of schedule but we will
continue, nonetheless, and take question IV. I
think we can deal with question IV relatively
Patients with gout may have renal
insufficiency. Patients with renal insufficiency
may have gout. Discuss the value of including or
excluding such patients in clinical trials. If
they are to be included, what range of serum
creatinine levels would be important to consider
for inclusion? Dr. Boulware, do you want to take a
stab at that?
DR. BOULWARE: I think we should include
patients who have renal insufficiency because that
will represent a population of patients that we are
going to take care of. I am not really clear that
establishing serum creatinine levels is as useful
as creatinine clearance because that as a surrogate
marker of filtration is probably even worse than
what we are talking about. So, I don't know what
that level should be but I think we should include
DR. GIBOFSKY: Is the committee
comfortable with the notion of creatinine clearance
rather than serum creatinine as the more precise
measure of renal status? So, that should be the
recommendation? Dr. Cush?
DR. CUSH: More precise although not
ideal. Other measures of direct clearance are far
better than calculated or measured 24-hour urines
for creatinine clearance. There are obviously
going to be problems as far as how accurate those
are, especially in situations where there is some
mild to moderate impairment. It is better than
serum creatinines however. I think that is clear.
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: I agree it is better than
serum creatinine but I think as a practical issue
it doesn't make a lot of difference.
DR. GIBOFSKY: So, is there a general
consensus about including patients with renal
insufficiency in these trials as opposed to
excluding them? The inclusion is probably, as we
have heard, more real world. The exclusion might
be more pure but we are aiming for real world. I
see nods around the table so we would reaction the
inclusion of patients with renal insufficiency.
So, what range of creatinine or creatinine
clearance would be important to consider for
inclusion? How low can we go? Dr. Cush?
DR. CUSH: Or how high in serum creatinine
can we go? I think I would exclude patients who
have end-stage renal disease and patients on
dialysis. That is another can of worms. I am
comfortable up to 4 as far as the serum creatinine
and maybe as low as 30 cc on a 24-hour creatinine
clearance but, again, I think that I would be more
concrete and just make dialysis and end-stage renal
disease as a cut-off.
DR. GIBOFSKY: Anyone else? Dr. Felson?
DR. FELSON: Is this a generic set of
concerns or is this relevant to just the oxypurinol
trials? Because oxypurinol is renally cleared.
DR. GIBOFSKY: I think this is posed as a
generic question for incorporation in guidance by
the agency in any trial. Is that right, Dr.
Harvey? Dr. Witter? They are shaking their heads
so it is generic.
DR. CUSH: But David's point is that there
needs to be appropriate adjustment for renally
DR. GIBOFSKY: Right.
DR. FELSON: I think you might be inclined
to constrain eligibility for oxypurinol trials with
respect to renal insufficiency more than you might
for another therapy which is hepatically cleared
and where it might not matter so much.
DR. GIBOFSKY: Dr. Mandell?
DR. MANDELL: The other issue though was
that your creatinine clearance drops as your
ability to use prophylactic therapy to prevent
attacks so if that is going to be a primary
outcome, that is going to need to be stratified or
handled some place along the way.
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: With no more data than Jack
has, I would have said 3 as a creatinine.
DR. GIBOFSKY: Okay. You are agreeing
DR. CUSH: Yes.
DR. GIBOFSKY: Then he can't be right!
DR. HOFFMAN: I think trials generically,
as we are discussing them, have to include people
with renal insufficiency but perhaps not people on
dialysis because, again, we are talking about
application to real world situations and these are
often the people that we are treating. I think
while we can include people with varying degrees of
renal insufficiency, we just need to stratify them
in looking at outcome efficacy.
DR. GIBOFSKY: Any other comments on the
renal issue? Dr. Bathon?
DR. BATHON: I think Dr. Mandell's point
is really important. I think all of the medicines
that we use for acute attacks can have adverse
effects in patients with renal insufficiency and
the design of the trial would have to be really
careful in terms of spelling out how you could
manage acute attacks or how to analyze the data in
renal insufficient patients who couldn't get as
many ancillary acute management strategies like
colchicine and NSAIDs compared to those that could.
DR. GIBOFSKY: Dr. Hochberg?
DR. HOCHBERG: I would just raise the
question for discussion, would we want to know or
would the sponsor want to know the 24-hour urine
uric acid excretion in a subject at entry into a
DR. GIBOFSKY: Thoughts on that? Dr. Cush
is nodding his head.
DR. CUSH: Obviously it depends on the
mechanism of action of the drug, but it seems like
a smart thing to do. You know, the drug that we
are talking about here we are looking at long-term
outcomes over two years or five years and I am not
sure that is going to be as important as in a more
DR. GIBOFSKY: Dr. Hochberg, since you
posed the question, do you have some feelings on
DR. HOCHBERG: Well, I was thinking if we
are going to suggest that a sponsor collect a 24-hour urine
on every participant in order to
calculate the creatinine clearance as an estimate
of GFR, then you could use that urine to calculate
the 24-hour urine uric acid excretion. But it
would seem to me that most of the treatments that
are being discussed at least, that were discussed
this morning and around lunchtime, are focused on
decreasing production of the uric acid as opposed
to increasing excretion of uric acid. So, I am not
sure that it would inform us at all with regard to
the mechanism of action or provide useful
DR. GIBOFSKY: Good point. Any further
discussion on topic IV? If not, this is a perfect
segue, since we are talking about renal
insufficiency and urine flow, to take our break and
we will resume at exactly 3:02 by that clock for
the remaining four questions.
DR. GIBOFSKY: Can I ask the panelists and
guests to please take their seats so we can begin
the second half of the afternoon? Let's resume our
discussion with question V, which is a statement
followed by a short essay.
Uric acid lowering drugs such as
allopurinol are sometimes used at doses higher than
those labeled. Discuss the utility of studying
multiples, such as twice the higher dose, of the
proposed maximum efficacious dose of a new drug. Comment
from the panel? Discussion? Dr. Williams,
let me impose on you to kick off the discussion, if
DR. WILLIAMS: If we are looking at the
efficacy as bringing the uric acid to a specific
level, I think the dose that brought the uric acid
to that level would be the maximum efficacious
dose. I am not sure you need to go higher than
that. Since at least the drugs we have right now
seem to be relatively--their reaction seems to be
idiosyncratic rather than dose related--that you
push the dose to that which will bring it down to
the level you are searching for, and that would be
your maximum dose. You don't need to go higher
DR. GIBOFSKY: Dr. Geis, let me solicit
your feelings on this point.
DR. GEIS: I guess would that then raise
the question, if the sponsor did that and it
worked, that people would say, well, in the real
world physicians will keep pushing the dose if we
get the patients down to a certain level with a
therapeutic and do you, therefore, have efficacy
and safety at even higher doses. That is always
the struggle I have found that we run into.
DR. GIBOFSKY: So, the suggestion is that
a study at higher than the maximum efficacious dose
is likely to result in greater use of that greater
dose than a study that doesn't study the multiple
and efficacious dose.
DR. GEIS: Right.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: I was confused by your point.
Could you say that again?
DR. GIBOFSKY: I am suggesting that
hypothetically if there were a study in which more
than the maximum efficacious dose were studied and
found to be maximally efficacious, or minimally
more so, that could lead to greater use of a higher
dose than a study which did not study a higher
dose, if I understood Dr. Geis. If I didn't, then
we will move on to the next question. Any other
thoughts on this? Dr. Anderson?
DR. ANDERSON: Do I understand what you
are saying as being that whatever is the maximum
dose that you study, there will be doctors who will
double it in practice, with possibly accompanying
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: That is a natural tendency for
all drugs, or a lot of the drugs that we use that
are marketed. They come out with a marketed dose
with an acceptable toxicity profile and then, once
they get to the market, use tends to creep up.
Often that is met with some acceptable outcomes,
that there isn't much increase in toxicity and
there is more efficacy, as in the case of ibuprofen
for instance. In the case of methotrexate, we
started out with 7.5 mg and now it is a laughable
dose. So, time will determine what the real
maximally efficacious and acceptably safe drug dose
is going to be. Again, I don't know that we can
advocate this as a routine part of drug
development. I think that it is the responsibility
of the FDA to oversee the patient safety and for
the manufacturer to get the best possible efficacy
while maintaining that safety, and it is up to them
to figure out the dose. I don't think we should
tell them once you have figured out the dose, now
give us a double dose study. I think that is
something that can be done in post-marketing
studies by the manufacturer.
DR. GIBOFSKY: Dr. Geis?
DR. GEIS: I guess where I am going with
this is that in my experience in other arthrities
we would push the dose to show that you got to a
plateau, and that by keeping and pushing the dose
you didn't get a better, a greater effect.
Therefore, it sort of gave the physicians the data
that said there is no benefit in keeping on pushing
the dose. That is what I am saying here. Would we
want to do something like that?
DR. GIBOFSKY: Dr. Mandell?
DR. MANDELL: I am not sure in this
setting, where you are talking about an enzyme
inhibitor in a heterogeneous population, that you
are going to see a maximum efficacious dose. If in
a large percentage of your population you increase
and increase dose, you still may be lowering the
uric acid further. So, I think the maximal
efficacious is going to be a difficult thing to
define from early preclinical or Phase 1 trials.
DR. GIBOFSKY: Good point. Any other
comments on this? Dr. Hochberg?
DR. HOCHBERG: I guess part of develop, as
Dr. Geis says, is to determine the maximally
effective dosage with safety. I think that here,
even if it is an enzyme inhibitor, you will have
some doses, let's say, at the lower end of the
spectrum which may be effective in a certain
percentage of subjects but are ineffective in
another percentage of the subjects and then you
will have to do escalation as part of Phase 2 in
order to really find out what the sort of maximal
effective and safe dose is in order to get to the
top of the range. Because, if you never get to the
top of the range, then you are never sure you have
the right dose once you go into Phase 3. Then, if
you end up getting marketed, what will happen is
what Dr. Cush says, you know, the practitioner will
end up pushing the dose above that range unless
there is evidence that there is clear toxicity
associated with it.
I think another aspect that we have to
consider now and that the FDA may want to think
about in terms of advising companies is the whole
issue of pharmacogenomics and why people don't
respond to what might be the maximally effective
dose. Maybe they are never going to respond to
that agent. This ought to be something that maybe
companies should think about studying or collecting
data on in order to be able to study it as they
bring drugs from development towards the
DR. GIBOFSKY: Thank you, Dr. Hochberg.
Further comments on question V?
I think we will move on to question VI.
Please discuss the what could be considered an
optimal duration for these trials. Dr. Boulware,
may I ask you to begin the discussion?
DR. BOULWARE: This is one of those
questions that probably should have had bullets
under it because I think it depends on what your
endpoint is going to be. If you want to look just
for lowering of serum uric acid you probably could
achieve that quicker and, depending on what your
endpoint is and where you started from, maybe
within 12 weeks. If you want to look at the
reduction in the number of attacks, you probably
have to go longer and it would depend on what kind
of patients you entered into the study and how
frequent the attacks were.
Another outcome we didn't discuss earlier
but which probably is important is the severity of
their attacks. If we maintain the number but
reduce severity of attacks and duration of an
attack, that may be an important outcome that too
and my guess is that is going to take at least six
months of a trial.
Finally, if we are looking at reducing
tophi size, and we have talked about ways to do
that, we saw in earlier presentations a mean of 20
months I think, plus/minus 10 months in order to do
that, so that is going to take a long time to do,
at least a year to see an effective reduction, but
it depends on the sensitivity of the method you
use. With ultrasound maybe you could see a 50
percent reduction in--I don't know--six months.
DR. GIBOFSKY: So, the optimal duration
might be different for lowering serum uric acid,
for educing size of tophi and for reducing either
the incidence or severity of attacks of gout. Is
that what you are saying? Dr. Bathon?
DR. BATHON: Yes, but even within one
endpoint like reducing serum uric acid it is going
to depend on the mechanism of action possibly with
the rapidity with which the drug achieves that.
So, something that immediately inhibits xanthine
oxidase might be relatively quick whereas something
that is a uricosuric agent may take longer to have
an effect. So, I think it depends on mechanism,
the rapidity of the effect of the drug and then,
obviously, whether you are doing dose escalation
versus starting out with one single dose will make
a big impact.
DR. GIBOFSKY: Also depending on
concomitant therapies which we will get to in just
a few minutes. Dr. Cush?
DR. CUSH: I like Dr. Boulware's
stratification based on the surrogate marker only,
which would be a much shorter trial, you know, 24
weeks, as Joan says, depending on surrogate marker
plus the primary clinical outcome, which is attacks
being longer in 6 months or maybe longer. You
could use IC's guidelines for numbers to apply
this, you know, 300-600 I guess for a 6-month
trial. Then, they are going to have to do the
long-term trials if they are going to get the
surrogate marker indication and that is going to
have to be 2 years, and that is for quality of
life, humanistic outcomes, x-ray outcomes, nodular
outcomes even, morbidity, mortality stuff. I think
real long trials with larger numbers are going to
DR. GIBOFSKY: Ms. McBriar, do you think a
20-year period of time is appropriate or too long
for assessing changes in health-related quality of
life by patient-reported outcomes?
MS. MCBRIAR: I would think at least one
year and see it hold. I think it will be hard on
the sponsor but I do think it is important if you
want the long-term effect of these drugs to be
DR. GIBOFSKY: Other comments on point IV?
DR. ANDERSON: A comment more about the
number of attacks, and something that concerns me a
little about some of the discussion before about
that is that it was suggested that maybe the number
of attacks in the first three or six months of the
trial could be ignored. But I think it would be
better to just keep track of the number of attacks
per six-month period and take all of that into
account. Depending on the mode of action of the
drug, it seems conceivable that one drug might
increase them in the first six months and then
decrease them after and another one just sort of
decrease them slowly. So, that is a feature that
one would not want to lose sight of. It isn't
strictly speaking on this point.
DR. GIBOFSKY: Any further comments on VI?
Have we adequately discussed this to everyone's
satisfaction and provided some input for the staff
of the agency to consider?
We will move on to VIII, please.
DR. CUSH: Michael and I were just talking
about this, you know, over time for quality of life
outcome measures this is much more a saw-tooth
pattern of disease than even RA because they do
spike and the question is if their spikes are
infrequent and not that large, then the cumulative
hit to the being is going to be less and,
therefore, I think a lower duration of follow-up
for quality of life outcome is going to be
DR. GIBOFSKY: No argument there. Number
VII, please discuss the implications of placebo
versus active controls and superiority versus non-
inferiority designs for clinical trial of uric acid
lowering drugs. Is there sufficient data available
in the literature to establish a generally accepted
response rate for allopurinol--presumably the
appropriate comparator--that could be used for
calculating a non-inferiority margin? Dr. Felson,
can I ask you to kick off the discussion here,
DR. FELSON: Yes, I think we talked a lot
about patients who really have no other options
where allopurinol has failed them. I think in that
situation a placebo-controlled trial is appropriate
and a conventional design that is, you know, reject
the null hypothesis design, powered appropriately,
is also what you probably should be recommending.
If these were therapies that were going to be
tested as first-line urate lowering agents against
allopurinol I think a non-inferiority design would
be better. The only circumstance I was thinking
about where you could do a non-inferiority design
was if you decided--because it sounded like even
though the trial we heard about was supposed to be
in double failures--what you guys called double
failures--in fact, wasn't in double failures; it
was in single failures mostly, that is, people who
had some kind of trouble with allopurinol and
hadn't actually been rechallenged or desensitized.
So, one I guess non-inferiority design one could
conjure up which wouldn't be uninteresting would be
to test a new agent and compare it to
desensitization. So, what you could do is do a
randomized trial. You would have to sort of
desensitize to placebo, I guess, and that would
work. Then, that might be some kind of non-inferiority. I
guess that is a non-inferiority
design although you don't necessarily know what the
response rate for desensitization is. I think it
would be better probably initially to do a placebo-
controlled trial in people who can't take
allopurinol and just deal with it in a conventional
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: But, again, we are talking
about gout which is sort of maybe the most painful
condition that we manage so I really worry about
placebo-controlled trials and I don't want to use
them unless it is absolutely necessary. But I do
think that my education here at the FDA has been
that they like to see a placebo-controlled trial
and that might be the perfect instance, to have a
small trial for those kind of patients. I don't
know how small it would be. If it is 60-120
patients for a limited duration, maybe that is
acceptable. But for larger numbers, as you
suggested, a head-to-head comparison with
allopurinol would make more sense to me using a
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: I agree with David. If you
are looking at patients who are allopurinol toxic
so they can't use it, we don't have another
treatment so then I could see a placebo-controlled
trial because you are going to use pain relief as
your escape. But if you are looking at trying to
bring in a new drug, then I would compare it to the
standard which is allopurinol.
DR. GIBOFSKY: Along those lines, is there
sufficient evidence in the literature to establish
a generally accepted response rate for allopurinol
that could be used for calculating a non-inferiority margin?
Dr. Hochberg, are you aware of
the literature here?
DR. HOCHBERG: No, I am not aware of a
generally accepted response rate in terms of the
proportion of patients who would have a serum uric
acid level below 6 mg/dl with appropriate dosing of
DR. GIBOFSKY: And to the extent that we
have been talking about that level as an
appropriate surrogate marker, it would be important
to have that in the literature.
DR. HOCHBERG: I think so. One of the
papers that was referred to by a presenter earlier
in justifying that as a level of clinical
importance, only about a third of the patients who
were in that observational study actually reached
that level with treatment.
DR. GIBOFSKY: Any other comments on this
point about methodology of superiority versus non-
inferiority or placebo versus active control? I
think we have established that the answer to the
bullet is no, but that doesn't preclude us from
making those suggestions as outlined. Ms. McBriar?
MS. MCBRIAR: I would just want to make
sure that the sponsor had decided how to rescue
people. This is a pretty serious, potentially
damaging disease and it is obviously very painful
and I wouldn't want people to be in pain for too
DR. GIBOFSKY: I think you are echoing Dr.
Cush's concern about placebo trials in such an
acutely painful condition. Any other comments on
question VII? Dr. Hochberg?
DR. HOCHBERG: Just a comment about the
issue of rescue, if the number of recurrent attacks
of gout, let's say, is going to be a secondary
outcome, presumably in the protocol there would be
a standardized method of treatment of those acute
attacks when they occur with an agent which, let's
say, would not affect serum uric acid levels which
presumably would be the primary outcome measure.
So, again, if we are going to be looking at agents
which are designed to lower serum uric acid levels
in patients with gout, then we would anticipate
that those individuals in the study, whether they
be in the placebo group or in the active treatment
group, are going to have attacks of gout during the
course of the study and that they will need to be
DR. GIBOFSKY: Any other comments?
Let's move to VIII. Please discuss the
implications of concomitant therapies. Can
concomitant drugs such as colchicine or non-steroidals be
continued during clinical trials for
chronic gout? Discuss the implications of
permitting or prohibiting the use of concomitant
diuretics or low dose aspirin. Is there value in
recommending or prohibiting a particular diet? Is
it appropriate to restrict alcohol use--presumably
in the context of a clinical trial? Please discuss
issues concerning the enrollment of patients with
kidney stones and inclusion of transplant patients,
especially those on drugs such as cyclosporine.
Dr. Hochberg, I threatened earlier to call
on you to begin the discussion here so I will
fulfill my promise.
DR. HOCHBERG: Well, these are all
important areas and necessary to discuss. I don't
want to go at them bullet by bullet but starting
with bullet one, definitely, concomitant agents
should be continued during the trial. You know, I
think as Dr. Cush and others have mentioned here,
the hallmark of therapy in patients with recurrent
attacks of gout is chronic colchicine therapy in
order to prevent recurrent attacks of gout, and we
remember that that has sort of come into the
armamentarium not from randomized, placebo-controlled trials
but from before and after
studies. So, obviously colchicine should be
continued. There apparently is a sizeable
proportion of patients--again, we don't really know
what number it is--who are intolerant of colchicine
therapy who usually are on chronic NSAID they for
prevention of recurrent attacks of gout. So, I
think yes, that has to be included. Again, it
might be something that one wants to stratify on.
You don't want to stratify on too many variables
but you want to make sure that patients that are on
them are at least able to continue them in the
study, and certainly not washed out.
Do you want me to keep going?
DR. GIBOFSKY: Please.
DR. HOCHBERG: Bullet number two is
discuss the implications of concomitant diuretics
and low dose aspirin. Well, I guess that depends
on the co-morbid condition. Certainly, the
population with cardiovascular disease which should
be taking low dose aspirin, I think, again, should
be in the study. We, again, need to consider the
effects of low dose aspirin on renal handling of
urate, but since most of the compounds that have
been at least discussed earlier today and probably
would be in development would be focused on
inhibiting xanthine oxidase and production of uric
acid, I don't think that is a problem. Maybe
diuretics aren't a problem as well in that regard,
although if the diuretics are being used for the
management of hypertension in clinical practice
oftentimes you try and switch agents so that might
be a consideration. But I don't think that I would
exclude people who are on diuretic therapy and low
DR. GIBOFSKY: We will stop there and have
further discussion of those two bullets before we
go on to the other subheadings. Dr. Williams?
DR. WILLIAMS: I totally agree on bullet
number one. Bullet number two, I would think they
could continue on their diuretics and low dose
aspirin if they had been on them for a month prior
to the study and remained constant during the
study. I think any impact they had would wash out.
DR. GIBOFSKY: Dr. Bathon?
DR. BATHON: With regard to the first
bullet, with NSAIDs and colchicine, I wonder if it
wouldn't be a more sensible design to just have a
PRN mandate like a week of treatment for each acute
attack, or something where you could get them off
continuous treatment and just use it for acute
management. For renal failure patients where you
might not want to be using NSAIDs and colchicine,
have a third possibility of using steroids.
DR. GIBOFSKY: Dr. Hoffman?
DR. HOFFMAN: There is an old study--I was
discussing with Bob Terkeltaub earlier; I think it
probably goes back to the '60s--where people were
made normal uricemics who previously had gout and
were kept on colchicine, I think it was for six
months, or not placed on colchicine and there were
some recurrent attacks of gout in both groups
between there was clearly a difference of fewer
attacks of gout in the patients maintained on
colchicine. It is with that in mind that I have
always treated patients with colchicine for six
months and sometimes even up to a year, realizing
that urate stores were going to take a long time to
be mobilized. I would be more comfortable with a
protocol where, unless there was a contraindication
to colchicine or unless colchicine was not
tolerated, to have colchicine as the standard of
care along with starting a uric acid reducing
agent, and to use alternative therapies only if
colchicine was contraindicated.
As far as the other points are concerned,
other concomitant therapies including thiazides, I
agree with Jim on that. I think that is reasonable
clinical practice and should be part of protocols.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: Prior to this discussion I
would have excluded diuretics and low dose aspirin
because it would just complicate matters, but
certainly you could stratify for those patients
and, on further consideration, I think it is
actually better to include them because it is
common but, more importantly, such patients will be
primed to get in trouble; they will be more likely
to have hyperuricemia and troubles with that. You
know, it is basically selecting for a naturally
occurring high risk population and I think we will
see more numbers to make judgments as far as the
outcomes in efficacy and safety.
DR. GIBOFSKY: Any other comments on
bullets one and two? If not, we will move to
bullet three, is there value in recommending or
prohibiting a particular diet?
At Cornell we have the maxim "when all
else fails, find out what the patient likes to eat
and forbid it." I am wondering if that is
appropriate in this setting given what we heard
from Dr. Terkeltaub earlier. Comments?
DR. CUSH: The point would be to note make
the diet an issue. So, you could screen patients
if they are taking a particular diet, but I think
any diet restrictions should not be a part of the
clinical trial. I think you want to take a
population that does not have a dietary restriction
going in. That would be my guidance.
DR. GIBOFSKY: Other comments on this?
DR. FELSON: I think this and the next one
we can knock of probably at the same time. They
are both similar issues. Maybe alcohol is part of
the diet, maybe it is not. I think this is
probably a good clinical practice issue. I would
be inclined to let people know what the issues are
about diet and just proscribe dramatic changes in
diet. You know, if you are part of this trial, we
would like you not to adopt the Atkins diet in the
middle of it because that might affect your uric
acid and we might not be able to evaluate the
therapy we are trying to evaluate.
With alcohol, I think I would be inclined
to do more or less the same, with the exception of
trying to exclude, as we often do, patients who
tend to use excessively in part because that is
going to be very difficult for you to deal with for
uric acid levels and in part because they are
likely to be non-compliant and would introduce a
variety of other considerations and concerns.
DR. GIBOFSKY: Ms. McBriar, could I ask
you to comment on the feasibility of instituting
these kinds of life style or social habit changes
in patients with chronic disease?
MS. MCBRIAR: I think it is probably one
of the harder pieces to do. I think it is
important and I think it is part of the overall
care for patients and that should be a message that
we all get out, but I think if we are trying to
study the drug we are right not to throw too many
different things into it that might complicate the
DR. GIBOFSKY: Any further discussion on
those two bullets?
Let's go on. Discuss issues concerning
the enrollment of patients with kidney stones. Dr.
Boulware, your thoughts on that?
DR. BOULWARE: I guess I have always
thought of renal stones as being part of the whole
spectrum of gout so I would not think you would
want to restrict them but include them in there. I
guess it would require a separate stratification
for looking at success of treating stones and
recurrent stones, but we are all rheumatologists
treating gout and arthritis attacks separately too.
But I would think you would want to include them.
DR. GIBOFSKY: Any other comments? Dr.
DR. FINLEY: The question is phrased as
kidney stones generically. Is there a feeling--I
don't know, I thought it was in the slides that
there is an indication for this not only with uric
acid stones but calcium oxalate stones as well.
Would that have to be teased apart, or would there
be a recommendation to the sponsor, or would the
FDA be interested in defining what the stone is,
what the makeup of the stone is?
DR. GIBOFSKY: I suspect we would learn
that not all of our patients are as compulsive and
diligent as our colleague who came to us with his
stones for us to analyze, if need be. But the
question is should we stratify patients with or
without nephrolithiasis in a study looking at
reduction of serum urate as a surrogate marker for
gout. That is the question on the table. Anyone
else want to comment on that? Dr. Felson?
DR. FELSON: I think you let your patients
in. I think it becomes an interesting sub-study to
evaluate the effect of lowering uric acid on that
outcome, and I would hope that the sponsor,
whichever sponsor this would be for the studies,
would be inclined to fund that part of the sub-study, which
wouldn't be all that difficult to do.
It would be real interesting information.
DR. GIBOFSKY: Dr. Williams?
DR. WILLIAMS: I agree. I think it would
be interesting. I doubt you would have enough
power to make any decisions.
DR. GIBOFSKY: Dr. Hoffman?
DR. HOFFMAN: The type of stones becomes
something of a complicated issue because even
people who wind up having uric nephropathy--if I am
not mistaken and Bob Terkeltaub may want to
comment--often have calcium oxalate stones because
the initial crystallization is with urate on top of
which calcium oxalate is laid down.
DR. GIBOFSKY: Other comments on bullet
five? Dr. Hochberg?
DR. HOCHBERG: While I agree that people
with stones and hyperuricemia could be entered into
the studies that we have been discussing, they also
could serve as the population of a completely
separate study which I think would be relatively
easy to recruit from urologists who see patients
with recurrent stones and I am sure measure or at
least could be convinced to measure serum uric acid
levels. Allopurinol, if I remember correctly, is
the standard of care for patients with recurrent
stones with any etiology because of the point
brought up by Dr. Hoffman. So, people who are
intolerant of allopurinol would be candidates for
hyperuricemia therapy if they have hyperuricemia
and recurrent stones.
DR. GIBOFSKY: Everyone comfortable with
our discussion of bullet five? Any further
comment? If not, let's go on to bullet six, please
discuss inclusion of heart and/or renal transplant
patients, especially those on drugs such as
I think we heard from Dr. Terkeltaub this
morning that cyclosporine is going to be a footnote
to the gout story but, nevertheless, there are many
patients still on it. How does the committee feel
about offering input into the inclusion or
exclusion of these patients, who are receiving
transplants whether or not they are on
cyclosporine, for these kinds of studies? Dr.
DR. CUSH: I would exclude. I think it is
a problem for the transplant world. It is a
relatively small problem compared to the numbers we
are talking about in the issues above that, where
we are trying to include real-world patients. So,
I think that is a second study or post-marketing
study that has true value, but I am not sure it is
necessary for registration.
DR. GIBOFSKY: Are you suggesting that
renal transplant patients don't exist in the real
world, Dr. Cush?
DR. CUSH: Not in my real world.
DR. GIBOFSKY: They do in mine, Dr. Cush.
DR. CUSH: Oh, really!
DR. GIBOFSKY: Any other comments? It is
a small subset of patients, granted.
DR. WILLIAMS: I would just agree that I
think studying cyclosporine and uric acid is a
DR. GIBOFSKY: Dr. Hoffman, did you want
DR. HOFFMAN: I think it is in a sense a
separate study but if someone is looking at a new
agent, this is a group of people I think have
fairly serious problems when they do get gout and
they do need to be studied. I would lean more
towards including them as a subset for separate
DR. GIBOFSKY: Dr. Finley?
DR. FINLEY: Dr. Calabrese showed a couple
of patients and I think of the one patient that I
took care and his gout predated his
transplantation, and once he got transplanted and
was on cyclosporine his gout was immeasurably more
difficult to care for. I don't know that this is a
subtext for how we are discussing this but the
notion that there weren't individuals who were gout
patients predating their transplantation ought to
be thought of as we flavor this discussion. I
concern myself with those real-world patients.
Transplants used to be uncommon; used to be not
part of our practices. Now we see patients who
commonly have those.
DR. GIBOFSKY: Dr. Bathon?
DR. BATHON: I think the issue with
oxypurinol might be different from other drugs that
we might consider down the road. In general, a
brand-new drug that has not been tested in people
is probably not a drug that you would want to put
into patients who have a renal transplant
initially. So, I would think they would be a
later, separate study for most brand-new drugs that
are being evaluated.
DR. GIBOFSKY: Any other discussion on
bullet six? Dr. Hochberg?
DR. HOCHBERG: I would agree that patients
post-transplant should represent a separate
population for studies. Another consideration is
also because of the adverse events which would be
much higher in the population because of the co-therapy, the
potential risk of infection, etc.
which would be difficult to interpret if post-transplant
patients are intermingled with patients
who have primary gout in a large population and may
not be evenly distributed.
DR. GIBOFSKY: Any other comments?
I think we have adequately discussed all
of the materials presented to us in appropriate
depth and detail. However, are there any issues
that we either haven't discussed that any of the
members of the panel would like to bring up, or any
of the bullets that we have discussed that any
members of the panel would like to made additional
comments on or go back to for further discussion?
DR. GEIS: Would it be useful to just talk
for a few minutes about the definition or
identification of patients with chronic gout?
Because if we don't have that right in the
inclusion-exclusion criteria we will be in trouble
regardless of what we measure.
DR. GIBOFSKY: The question for us is the
issue of a definition of chronic gout. Do we want
to offer some suggestions as to what the term
"chronic" should mean in this setting? I think we
have considered frequency of attacks. We had a
brief discussion on severity of attacks. But do we
want to offer a little bit more guidance? Dr.
DR. FELSON: I actually wanted to bring up
a different issue but it is not unrelated to Dr.
Geis'. I think it would be reasonable, since we
are talking about therapy for people who can't take
allopurinol but for whom allopurinol would
otherwise be indicated, to use the same definition
that is published and accepted for allopurinol use.
I think Bob Terkeltaub went over it earlier today
and I am not sure I remember all the details, but
it is a particular uric acid level, but I think you
need three attacks per year as sort of the criteria
that are out there. That would seem like the right
thing to do, with some kind of good documentation
that there have been attacks.
What I wanted to raise, I have sort of
been thinking about how one would evaluate subjects
in trials or participants in trials and it wasn't
clear to me how you would get the number of
attacks. Would you see a patient every three
months and say how many attacks have you had since
we last saw you? Or, do you have them come to see
you with every attack, creating some chaos in your
practice, so you can document those attacks?
I am also mindful of the fact that we are
involved in an Internet study where we are finding
that people actually have attacks much more often
than they necessarily see doctors with. So, I am
not sure exactly what the answer to that question
is, but I think it is something worth discussing
and considering. If serum uric acid is a primary
outcome, then that is easy. You can just have them
come every three months and get a serum uric acid.
But if it is number of attacks in the interim, then
if you have them come every six months or three
months and ask them to remember, their memory may
not be all that accurate. You may want them to
come in with every attack if you want to have a
document or attack list. So, I don't know exactly
how that would occur.
DR. GIBOFSKY: Dr. Cush?
DR. CUSH: Tomorrow I was going to make
the proposal about what is an acute attack. I have
not read a really good definition of that but I
think we were all taught it in medical school,
using gout as an example of the four cardinal signs
of inflammation--redness, warmth, pain and
swelling--and that an acute attack could be three
our of four, two out of four. Hence, the ideal
situation would be that as defined by a healthcare
provider on direct examination, although it might
be interesting to also ascertain whether patients
could make the same judgment using the same rules.
I think we are all impressed that patients
who have gout often do return to the clinic and
say, "well, I had an attack last month" or "I've
had five attacks since I last saw you," but they
have no joint swelling and you find out it was just
that they had a little more pain in the instep.
They just jump on it with prednisone or colchicine
or something. You are not sure if it was a true
attack but they define it as an attack. It is
certainly not like those first few attacks where
they couldn't walk and they were on crutches, and
they were in the emergency room and the sheet was
bothering me--you know, the classic gouty thing. I
think sticking to the four cardinal signs of
inflammation as a measure of attacks makes most
DR. GIBOFSKY: Dr. Cush, how would you
deal with or how do you deal with the frequent
coexistence of gout with pseudo-gout in terms of
defining what the etiology of the inflammation was?
DR. CUSH: Well, I think it depends on the
nature of the therapy that is used to treat that
individual. You could discount the fact that they
could exist together, as could septic arthritis be
in the mix there as well. I think if my therapy
wasn't working when it should be, that is when I
start the existence of another background condition
such as pseudo-gout. But talking about uric acid
lowering therapies, theoretically they should not
be effective in preventing attacks, whereas
colchicine and non-steroidals and steroids would
certainly have effect on both conditions.
DR. GIBOFSKY: But the question implicit
in Dr. Felson's statement is what would the gold
standard be for identifying those attacks. Should
it be the physician observation, the patient self-report?
If it is the physician observation, should
there be a demonstration of uric acid crystals in
the fluid each time?
DR. CUSH: No, my suggestion is that it
should be by direct examination by a physician or
someone in the trial to assess the patients on a
PRN basis as it arises. I don't think crystal
identification is necessary. Again, I threw out
that maybe patients could ascertain this having
some very defined rules about what a true attack
was, but that would be a study for someone to do to
show patient-derived variables compared to
physician-derived variables, hopefully, with the
idea of coming away with easier ways of doing long-term
trials in the future.
DR. GIBOFSKY: Dr. Williams, you have a
DR. WILLIAMS: Jack covered much of it but
I am a little concerned about self-reported attacks
of gout because I have gout patients who tell me
they had an attack that lasted several hours or a
day and without treatment went away, and I suspect
those really weren't attacks of out. I think if
you are going to use that as one of your measures
you have to have them evaluated by an investigator.
DR. GIBOFSKY: Any other comments from
members of the panel regarding the information we
have covered today, or any other topics you would
like to raise in this context? Dr. Hochberg?
DR. HOCHBERG: Well, just for completeness
sake in this context I guess, there is the push and
pull here. While it would be nice to have subjects
who would call in to the study nurse, let's say, at
the time that they are having an attack of gout so
they could be seen in order to have a health
professional concur that this is, in fact, an
attack of gout, that may impact on recruitment and
retention, particularly for a study where if you
are looking for people who are intolerant of
allopurinol, let's say, they may be widely
dispersed; they may not live necessarily close to
the individual physician. Or, if we are going to
recruit in general from a large population in the
VA healthcare system we may have problems getting
those individuals in.
So, there are validated criteria which
have been published for survey purposes to validate
a diagnosis of acute gout by the American
Rheumatism Association, now the American College of
Rheumatology. So, sponsors may want to think about
using those in conjunction with some type of
telephone monitoring on a frequent interval in
order to eliminate the problem of recall over three
months between visits, let's say, with monthly
telephone monitoring--"have you had an attack of
gout in the past month?" If the answer is yes, try
and collect some information about it. If not,
"thank you very much. We'll call you in another
month and we'll see you for your uric serum acid
monitoring visit in three months."
DR. GIBOFSKY: Any further discussion or
comment? If not, let me thank you all for your
participation. Dr. Witter, Dr. Harvey, did you get
the input that you were looking for from the group?
Dr. Harvey, any concluding remarks?
DR. HARVEY: I think that there has been a
lively and a thoughtful discussion on all of the
topics by the committee, and I think there is a lot
here for FDA to think about and I would like to
thank the committee for all of your work and
especially thank the Chairman today. Thank you.
DR. GIBOFSKY: Thank you all very much for
your input and hard work and making my role here
particularly easy. Tomorrow morning we will begin
at 8:00 sharp. Please bring your luggage with you
if you are staying at the hotel. It will be stored
here in the FDA offices, and we will depart from
here tomorrow evening to our respective homes or
wherever else we are sojourning. The hotel shuttle
should be here momentarily to take those of us who
are staying at the DoubleTree back there. This
concludes the formal part of the meeting. I will
see you all tomorrow morning.
[Whereupon, at 4:50 p.m., the proceedings
were recessed until 8:00 a.m., Thursday, June 3,