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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ARTHRITIS ADVISORY COMMITTEE

DAY II

Thursday, June 3, 2004

8:04 a.m.

ACS Conference Room

Room 1006

5630 Fishers Lane

Rockville, Maryland

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PARTICIPANTS

Allan Gibofsky, M.D., J.D., Chair

Jayne E. Peterson, R.Ph., J.D. Acting Executive

Secretary

Members

Jennifer Anderson, Ph.D.

Joan M. Bathon, M.D.

Dennis W. Boulware, M.D.

John J. Cush, M.D.

J. Michael Finley, D.O.

Steven G. Geis, Ph.D., M.D., Industry

Representative

Gary Stuart Hoffman, M.D.

Wendy W. McBriar, R.N., M.S., C.H.E.S., Consumer

Representative

Special Government Employee (SGE) Consultants

(Voting)

Bruce N. Cronstein, M.D.

Brian F. Mandell, M.D., Ph.D.

Michael H. Weisman, M.D.

H. James Williams, M.D.

Government Employee Participants/Discussants

(Voting)

Marc C. Hochberg, M.D., MPH

Robert Terkeltaub, M.D.

FDA

Brian Harvey, M.D., Ph.D.

Joel Schiffenbauer, M.D.

Sharon Hertz, M.D.

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C O N T E N T S

Issue: Trial Design and Endpoints

for Drugs for Acute Gout

Call to Order

Allan Gibofsky, M.D., J.D., Chair 4

Introductions 4

Conflict of Interest Statement:

Jayne Peterson, R.Ph., J.D. 8

Acting Executive Secretary, AAC, FDA

Welcome

Brian Harvey, M.D., Ph.D., FDA 11

Gout: Clinical Review and Trial Design Issues

Joel Schiffenbauer, M.D. 12

Management of Acute Gout

John J. Cush, M.D. 30

Merck Research Laboratories

Introduction

Agustin Melian, M.D. 94

Design Considerations in Acute

Gouty Arthritis Studies

David I. Daikh, M.D., Ph.D. 96

Experience of Etoricoxib and Indomethacin

n Acute Gouty Arthritis

Agustin Melian, M.D. 121

Lessons Learned

David I. Daikh, M.D., Ph.D. 139

Discussion 142

Committee Discussion and Questions 184

Open Public Hearing 218

Committee Discussion and Questions (Resumed) 219

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P R O C E E D I N G S

Call to Order

DR. GIBOFSKY: Good morning. I would like

to welcome everyone on the panel, as newly

constituted, together with the members of the

audience, to the Arthritis Advisory Committee

hearing. This is the second day of our meetings on

a very interesting topic, Chronic, and today, Acute

Gout.

My name is Allan Gibofsky, and I will be

chairing the meeting today. I would like to begin

by asking the members of the panel, as

reconstituted, to please introduce themselves

beginning on my right.

Introductions

DR. GEIS: I am Steve Geis. I am the

representative from the pharmaceutical industry. I

spent 18 years doing clinical research in that

industry.

DR. FINLEY: Michael Finley. I am

Associate Professor of Medicine at Western

University College of Osteopathic Medicine of the

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Pacific in Pomona, California, and I am a

rheumatologist.

DR. CUSH: Jack Cush, Presbyterian

Hospital of Dallas. I am a rheumatologist.

MS. McBRIAR: Wendy McBriar, Director of

Arthritis Services, Virtua Health, in New Jersey.

I am a nurse and health educator. I am the

Consumer Rep.

DR. BOULWARE: Dennis Boulware, Professor

of Medicine, University of Alabama at Birmingham,

and a rheumatologist.

DR. BATHON: Joan Bathon, Professor of

Medicine at Johns Hopkins University, and a

rheumatologist.

DR. MANDELL: Brian Mandell, Department of

Rheumatology, Cleveland Clinic, Cleveland.

DR. WILLIAMS: Jim Williams,

rheumatologist, University of Utah.

MS. PETERSON: I am Jayne Peterson. I am

the Acting Executive Secretary for the meeting

today.

DR. GIBOFSKY: Allan Gibofsky, Professor

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of Medicine and Public Health at Weill Medical

College of Cornell University, a rheumatologist.

DR. ANDERSON: Jennifer Anderson, Research

Professor Emeritus in Biostatistics at Boston

University School of Public Health.

DR. HOFFMAN: Gary Hoffman, Professor of

Medicine and Chair of Rheumatology at the Cleveland

Clinic, rheumatologist.

DR. HOCHBERG: Marc Hochberg,

rheumatologist, Maryland Veterans Affairs Health

Care System, and Professor of Medicine at the

University of Maryland School of Medicine,

Baltimore.

DR. WEISMAN: Michael Weisman, Chief,

Division of Rheumatology, Cedars-Sinai Medical

Center, Professor of Medicine at UCLA.

DR. TERKELTAUB: Robert Terkeltaub, VA

Medical Center, San Diego, UCSD, rheumatologist.

DR. CRONSTEIN: I am Bruce Cronstein, New

York University School of Medicine. I am Professor

of Medicine, Pathology, and Pharmacology.

DR. SCHIFFENBAUER: Joel Schiffenbauer,

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FDA, Division of Analgesic, Anti-inflammatory, and

Ophthalmic Drug Products.

DR. HARVEY: Brian Harvey, the Deputy

Office Director and currently Acting Division

Director, and I am not a rheumatologist.

DR. HERTZ: Sharon Hertz, Deputy Division

Director for the hosting division.

DR. GIBOFSKY: Thank you. I would like to

begin by apologizing to the committee and to the

audience, I did promise a prompt 8 o\'clock start

today, however, we were subject to the vagaries of

Murphy\'s Law in getting here. As everyone on the

committee knows, rheumatologists and

non-rheumatologists included, Murphy was indeed an

optimist.

A couple of housekeeping announcement.

The committee, by consensus, has decided to shorten

its lunch from an hour and a half to only half an

hour, so as to have more time, if necessary, for

deliberation.

As a result, the public hearing will begin

one half-hour after the conclusion of the morning

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session, which may be close to the 1 o\'clock time,

but may be somewhat before it. If there are any

individuals here who would like to be heard during

the open public hearing, please schedule that with

the Acting Executive Secretary or another member of

staff, so that we can queue them in, in an

appropriate and timely fashion.

With that, I would like to turn the

meeting over to Dr. Harvey for some opening

remarks, but before that, Ms. Peterson will read

the Conflict of Interest Statement.

Conflict of Interest Statement

MS. PETERSON: Thank you. The following

announcement addresses the issue of conflict of

interest with respect to this meeting and is made a

part of the record to preclude even the appearance

of such at this meeting.

Based on the submitted agenda and the

information provided by the participants, the

Agency has determined that all reported interests

in firms regulated by the Center for Drug

Evaluation and Research present no potential for a

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conflict of interest at this meeting with the

following exceptions:

Dr. Michael Weisman has been granted a

waiver under 18 U.S.C. Section 208(b)(3) for

consulting with a competitor on a matter unrelated

to the topics to be discussed at this meeting. He

receives less than \$10,001 a year.

Dr. Bruce Cronstein has been granted a

waiver under 208(b)(3) for serving on a speakers

bureau for the sponsor of Arcoxia. He speaks on

topics unrelated to those being discussed today,

and receives more than \$10,000 a year.

Dr. H. James Williams has been granted a

208(b)(3) waiver for serving on a speakers bureau

for the sponsor of Arcoxia. He speaks on unrelated

topics and receives from \$5,001 to \$10,000 a year.

Dr. J. Michael Finley has been granted a

208(b)(3) waiver for serving on a speakers bureau

for the sponsor of Arcoxia. He lectures on

unrelated topics and receives more than \$10,001 a

year.

Dr. Marc Hochberg has been granted a

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208(b)(1) waiver for serving as a consultant and

speaker for the sponsor of Arcoxia. He consults on

unrelated issues and receives less than \$10,001 a

year. His speaking is sometimes related to the use

of products in gout. He receives from \$5,001 to

\$10,000 a year for speaking.

Dr. Robert Terkeltaub has been granted a

208(b)(1) waiver for speaking for the sponsor of

Arcoxia in gout. He receives less than \$5,001 a

year.

A copy of these waiver statements may be

obtained by submitting a written request to the

Agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn Building.

Lastly, we would like to also note for the

record that Dr. Steven Geis is participating in

this meeting as an industry representative acting

on behalf of regulated industry.

In the event that the discussions involve

any other products or firms not already on the

agenda for which FDA participants have a financial

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interest, the participants are aware of the need to

exclude themselves from such involvement, and

their exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

upon.

Thank you.

DR. GIBOFSKY: Thank you, Ms. Peterson.

Now, Dr. Brian Harvey, Acting Director of

DAAODP of the Food and Drug Administration.

Dr. Harvey.

Welcome

DR. HARVEY: Good morning. Thank you once

again. I wanted to thank the Committee again for

their services today. Yesterday\'s discussion was

very lively and enlightening, and certainly what we

all were looking for today. Of course, we will be

talking about treatments for acute gout, and we are

looking forward once again to a lively and

thoughtful discussion.

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I would also like to thank, looking ahead

to the public speakers this afternoon and also to

our partners in industry who will be presenting

today, today we will be talking about clinical

trial designs for future clinical trials, as well

as what might currently be underway.

It is a general discussion that is going

to help FDA and our industry partners to sort of

chart future directions in treatments for gout.

So, with that, we actually will get

started and move on since we are on a fairly tight

schedule, and at this point I would like to

introduce Dr. Joel Schiffenbauer, who is a senior

medical officer here in the Division, for his

presentation Gout: Clinical Review and Trial Design

Issues.

Gout: Clinical Review and Trial Design Issues

DR. SCHIFFENBAUER: Good morning. My

topic for discussion this morning is Gout: Clinical

Review and Trial Design Issues. My presentation

will highlight issues for the Committee to consider

in the design of trials to study the treatment of

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acute gout.

Gout is caused by a deposition of

monosodium urate crystals around and in the tissues

of the joint. As was discussed yesterday, there

are three distinct stages: asymptomatic

hyperuricemia, followed by acute intermittent gout,

which is the focus of this morning\'s discussion,

and then subsequently, chronic tophaceous gout.

The initial episode of gout usually

follows decades of asymptomatic hyperuricemia. It

is characterized by intense pain and inflammation,

and this is an important point to consider in

determining the endpoints to study in any trial of

acute gout.

It usually begins as a monoarticular

involvement most often with the first metatarsal

phalangeal joint.

The natural course varies with improvement

and resolution in days to one to two weeks, and

this a second important point to consider from two

aspects of the trial design.

First, it will help determine how long the

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duration of trial should be in acute gout, and,

secondly, whether we consider using superiority or

non-inferiority designs, and I will come back to

this is a few slides.

During the intercritical periods, joints

are virtually free of symptoms although crystals

may be found.

This is an example of what we are dealing

with. This individual has swelling, redness at

both the ankle and the first MTP joint, and will

likely have extreme pain in both of those areas.

This is the inciting agent, the uric acid

crystal, which in this photomicrograph, is found

within a white blood cell.

Standard approaches to therapy are

summarized in this slide, and you will hear more

about this in detail from Dr. Cush following my

presentation, but there are several approaches to

therapy, and those include nonsteroidals of which

there are several that are approved for us in acute

gout, colchicine, which is approved for both oral

and intravenous use, as well as glucocorticoids,

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which are approved, and ACTH, which has been used

frequently, but is not approved for use in acute

gout.

The remainder of the presentation will

focus on specific trial design considerations, but

before I get to that, there is some general trial

design information that is available at the FDA web

site for individuals in the community to search.

The E9 and E10 documents, which cover

statistical principles and choice of control groups

in general trial design, and then specifically, two

guidances in rheumatoid arthritis and

osteoarthritis.

In addition, there are the CONSORT

recommendations which were mainly geared towards

reporting of clinical trials, but in which there is

useful clinical trial design information available,

and I have provided the reference for that.

So, focusing now on acute gout. Gout is a

unique medical disorder that deserves specific

studies and its own labeled indication or is a

model of acute pain. We would ask the Committee to

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discuss this as one of their initial questions,

because this discussion will influence what

outcomes we wish to look at in any trial of acute

gout.

The first consideration is who do we

recruit into these trials, what are the inclusion

and exclusion criteria. First, is documentation of

crystals critical? Should this be at the time of

flare, that is, when the patient presents to be

entered into the trial, or any previous

documentation, if they have had a joint tap within

a year or two, is that adequate?

If they have had crystals documented from

the knee, but now they present with an ankle that

is swollen, would that be acceptable?

Or are clinical criteria sufficient to

serve as entry criteria? For example, the ACR

classification of acute gouty arthritis in which 6

of 12 clinical, laboratory, and x-ray criteria may

be utilized. I have listed some of those criteria

on the next slide.

For example, more than one attack of acute

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arthritis, maximal inflammation developed within

one day, attack of monoarticular arthritis, first

MTP joint pain or swelling, suspected tophus, or

hyperuricemia, and there are additional clinical

criteria, and we would ask the Committee to

consider what the diagnostic criteria should be.

Let me turn now to the second

consideration, and that is whether the trial should

be a superiority or non-inferiority trial.

Superiority to placebo is preferable as this is the

most straightforward way of demonstrating efficacy,

but the question remains are placebo-controlled

trials in acute gout ethical.

This question arises because of the

severity of pain in acute gout, however, I would

like to point out one interesting fact. If one

examines baseline VAS pain scores from trials in

acute gout, and compares those to baseline VAS

scores in trials in acute pain, such as

postoperative trials that we see at the Agency,

there is, in fact, very little difference in the

baseline VAS pain scores. In trials for

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postoperative pain, we allow placebo controls to be

performed.

Now, the question remains, is a baseline

VAS pain score of 50 in a gout trial, the same as a

50 in a postoperative knee replacement or hip

replacement. I think that is a question that can\'t

be answered right now, but nevertheless, the

baseline pain scores seem to be very similar.

One approach to consider to incorporate

placebo would be examining the use of rescue or

time to treatment failure as a primary outcome.

This early escape design reduces exposure to

suboptimal therapy and may be acceptable to

incorporate placebo.

There are, however, several alternatives

to placebo-controlled trials, which I have listed

here. The first is a trial with an active

comparator with a demonstration of superiority of

the new drug to active comparator.

This might be a very acceptable approach

especially if we are interested in better and more

efficacious drugs.

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The second approach could be a

dose-controlled study. By this, I mean a study

where we examine several dose levels of the drug,

and we demonstrate superiority of the high dose of

that drug to the low dose. Again, this would allow

us not to incorporate placebo.

Lastly, is the active comparator and

non-inferiority design.

If the non-inferiority design is chosen,

the question is which comparator would we want to

compare if the new drug is a nonsteroidal, would we

want to compare a nonsteroidal comparator, or would

we allow a drug, such as colchicine, to be the

comparator in a nonsteroidal trial, and if so, what

is the non-inferiority margin.

Are there historical adequately controlled

trials, and by that, I mean placebo-controlled

trials, that are of similar design to support the

non-inferiority studies? Indeed, if you look in

the literature, there is only one true

placebo-controlled trial comparing the efficacy of

colchicine to placebo, and there are no

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placebo-controlled trials looking at nonsteroidals.

If no placebo is chosen and

non-inferiority design is considered, the issue is

always of sensitivity of the trial, that is, do we

know that both drugs work, or is it possible that

both drugs do not work.

In fact, since gout is a disorder in which

pain resolves spontaneously, this may have

implications on the choice and duration of the

trial using an non-inferiority design, and we would

like the Committee to consider this in their

discussions.

There are a number of domains that can be

examined in a gout trial. Certainly, pain I think

is a critically important domain, but there are

several others that can be examined, and those

include inflammation, some measure of function

whether it be walking, ability to walk, ability to

work, or some other function, patient or physician

global assessment of disease and/or treatment, and

then possibly some health-related quality of life

measure, although in a trial of short duration,

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this may not be as critical.

Let me turn now to some of the primary

outcomes or some of the outcomes to discuss.

The first question is: What is the value

of reduction in pain as the primary outcome? If

this is considered one of the primary outcomes,

then, we would anticipate measuring some of the

typical parameters that we measure in an acute

analgesia trial, and these include pain intensity

difference, pain relief, time to onset, time to

re-medication, multi-dose efficacy.

The second question is: Is there value in

additional endpoints beyond pain? If we feel that

gout is a unique clinical entity, and is

characterized by both pain and inflammation, then,

should we include inflammation as part of the

outcomes that are measured.

However, measurements of inflammation may

be difficult to standardize, and this should be

considered by the Committee.

There are some additional outcomes I would

like to suggest that may, in fact, allow us to

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capture the totality of the treatment experience.

For example, rescue, that I have already mentioned,

time to rescue could be one outcome, or the number

of individuals using rescue in a predefined period

of time, such as 24, 48 hours, or some other

specific time.

Alternatively, time to complete resolution

would be a possible outcome, or time to 80 percent

or 50 percent resolution, and then lastly, a form

of a responder index, such as the number of

subjects with good to excellent pain relief in some

prespecified period of time.

This raises the next question: What

should that time be, when should we seek to measure

response to therapy?

Again, if, as we all agree, that pain is a

hallmark of this disorder, and we would certainly

like to see patients improve within a relatively

short period of time, but can we ask for a response

within a hour, should it be within the first 8

hours, within the first 24 hours?

I would remind you also that gout will

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tend to improve spontaneously over a relatively

short period of time, and this may have impact on

something, such as a time-weighted average, or

should we consider a combination.

We would certainly want to capture some

efficacy measure early in the course of the

treatment, as well as possibly later in the course

of the treatment over a few days. We would ask you

to try and consider this in your deliberations.

There are several additional trial design

considerations that I would like to put forth.

Is there value in stratification by the

following: renal function, uric acid level\--these

probably in a short-term trial will not be

critical\--or by tophi, or by the number of joints

involved, such as polyarticular or monoarticular

arthritis.

If we consider the inclusion of

individuals with polyarticular arthritis, it may be

important to identify a signal joint, but then the

concern is how do we evaluate the totality of the

response in other joints.

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How should we deal with concomitant

medications, other nonsteroidals, other pain

medications? Should we allow pain medications to

be included during the efficacy trial, so as to

keep individuals in the trial and reduce the

dropout, and therefore, imputation of missing data?

How do we handle low-dose aspirin,

diuretics, or other drugs that may influence the

renal clearance of uric acid? Again, in a

short-term trial, these may not be critical issues,

but we would ask the Committee to consider this,

and then diet and alcohol intake, the same

concerns.

Some additional considerations. I have

already alluded to the evaluation of single and

multiple dose efficacy. This is analogous to the

requirements that we have for studying an acute

analgesic. We would like to know how the

individual fares within the first few hours of

therapy, as well as how they do over the subsequent

days.

How long should an attack be present

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before randomization? On a practical basis, it is

unlikely that we will be able to enter subjects

into a trial that have their attack present for

only a few hours. On the other hand, would we want

to enter someone that has had their attack present

for four, five, or six days?

On a practical basis, it would seem likely

that the most likely subjects would have their

attack present for one to three days.

Should we allow previous therapy? If an

individual self-medicates 24 to 48 hours before

randomization, is this acceptable? It may be

acceptable if they have self-medicated with a

short-acting analgesic that is completely washed

out by the time of randomization.

However, if we don\'t allow any previous

therapy because of the potential influence on the

outcome of the trial, then, I would ask you to

reconsider your concern for placebo-controlled

trials.

If an individual has had an attack for 24

to 48 hours, and has not self-medicated, is there a

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concern with entering them into a

placebo-controlled trial?

If a patient is on previous therapy,

should we withdraw them from that therapy, and can

that be associated with a worsening flare of their

disorder, and how would we handle that in a trial.

Lastly, the question, is there a

difference in a disease course in individuals that

have acute attacks on a background of chronic

tophaceous gout versus those individuals that just

have acute attacks?

So, the areas for discussion include the

following, which I have discussed already some.

Inclusion and exclusion criteria, superiority

versus non-inferiority trials, especially the issue

of placebo-controlled trials, what are the domains

to study, what outcome measures and timing of the

studies, and then other issues, such as

stratification, concomitant medications, et cetera.

So, in conclusion, gout is a common

disorder. You heard a lot about that yesterday.

New therapies that provide improved risk-benefit

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ratios should be studied and added to the

armamentarium, and rigorous trial design is needed.

You will be hearing next from Dr. Cush,

who will be discussing management of acute gout,

and following that, a presentation by a company and

their approach to a trial design in acute gout, and

I think, all together, should provide an

interesting background for today\'s discussion.

Thank you very much.

DR. GIBOFSKY: Thank you, Dr.

Schiffenbauer.

Are there questions from the panel for Dr.

Schiffenbauer? Just one from me, if I may.

In one of your slides, you asked us to

consider whether gout is a medical disorder or a

model of acute pain. Like light being a wave and a

particle, can gout not be both?

DR. SCHIFFENBAUER: It could. I was

asking the question because I think the implication

is what should we consider as the primary outcome.

If it is considered a model of acute pain, then, we

have certain parameters that we use in acute

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analgesia studies.

If it is considered its own entity, then,

I think pain, but we may wish then to consider

additional outcome measures, such as inflammation,

and I think that is kind of what I was trying to

set up and get from the Committee.

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: Thank you for an excellent

overview of the issues. I guess one question, and

I don\'t know if you will be able to respond to

this, on your next to the last slide, you said that

new therapies that provide improved risk-benefit

ratios should be studied and added to the

armamentarium.

I don\'t know what Dr. Cush is going to

say, but in the vast majority of people who have

gout, and I exclude from this the individuals who

have contraindications to the use of nonsteroidal

anti-inflammatory drugs either absolute or

relative, the drugs have a pretty good

benefit-to-risk ratio in this population.

So, does that imply that the Agency would

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like to see agents which have a better

benefit-to-risk ratio in the population which has

relative and absolute contraindications to the

drugs that are already in use, or would like to see

agents which are quantumly beyond NSAIDS in terms

of either efficacy or safety for the vast majority

of people who have acute gout?

DR. HARVEY: Did you want me to jump in on

this? Actually, we will see what the Agency sees,

and, of course, we want to make sure there is

safety and efficacy for the indication.

DR. SCHIFFENBAUER: We would always like

to see quantum leaps in therapies, but I actually

agree with Dr. Harvey\'s comment.

DR. GIBOFSKY: Any other questions from

the panel?

\[No response.\]

DR. GIBOFSKY: Thank you. We shall see

what we shall see, and now we shall see Dr. Cush,

who is a member of the panel and also Chief of

Rheumatology and Immunology at Presbyterian

Hospital of Dallas.

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Dr. Cush.

Management of Acute Gout

DR. CUSH: Good morning, everyone.

I have been asked to talk about the acute

management of classic gout or the acute gouty

attack, and it is my intention sort of to give a

little bit of overview, but to focus on what has

been done in trials and what are the outcomes and

how that impacts on clinical trial design in the

future.

A topic that was brought up yesterday by

Jim and others is, you know, where are these

patients and how do we get them in trials.

It is interesting to note firstoff, that

most rheumatologists love gout. I mean it is a

very interesting disease, it is easy to diagnose,

the impact of our intervention is great. We feel

good about ourselves when patients are very happy

with their outcomes.

In fact, most of the giants in

rheumatology, starting with Hippocrates and going

up to the time of McCarty and Hollander and

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Schumacher, and whatnot, have cut their teeth on

gout as a career, and I think it is because it\'s an

interesting disease, it has a direct cause, it has

a biochemical and immunologic basis, and we have

effective interventions, so this is why we love

this condition.

Interestingly, however, very few of us are

seeing a lot of patients with gout. We have

patients who have chronic tophaceous gout in our

clinic, we have an occasional patient who has

chronic intermittent gout, but the vast majority of

patients who have gout are being managed elsewhere,

so although I wish they were in my clinic, they are

not, and that is sort of a shame because we believe

that, as a discipline, we have a great impact on

these patients.

That was studied by Richard Panish in his

paper that showed when rheumatology intervention

was compared to a generalist approach to this

condition, there was a shorter duration of

symptoms, less hospitalization, lower cost overall,

suggesting the value of a rheumatologic

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consultation in such instances.

Hence, most of these patients are in the

care of the primary care and emergency physicians.

They are first line. That is, you know, people

that darken the boxes, they go to their family

doctor whenever they have a problem, and they don\'t

know enough to go to a rheumatologist obviously,

and if they did know, they probably couldn\'t get in

to see us anyway. That is another issue.

But there are significant hazards here in

that I think Marc\'s point about the effectiveness

of therapy is so accepted at this point, it is

absolutely true, however most rheumatologists are

very aware of the fact that there is a large

variability as to how patients are treated.

What I believe is the gold standard is

probably not the gold standard out in the general

community, and that varies, not only in our

country, but also in surveys done in France and in

Mexico and New Zealand, where there is considerable

variability between the general practitioner,

whether it be internist or family practitioner, and

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the rheumatologist, and the orthopedist as far as

their approach to gout.

What is unfortunate is that there is a

surprising amount of misuse of these medications

and inappropriate use of medications by the general

practicing physician, so I think that to foster

guidelines and new drug development is also to

foster better education and, hopefully, better

outcomes for patients who have this condition.

So, as stated, it is a disorder of

monosodium urate crystal deposition. It has been

around for years, started with Hippocrates in 450

B.C., when he described this as the king of

diseases and the disease of kings. The burden to

society is significantly great.

Roubenoff estimated 37 million lost days

of work in the United States in 1981. Kim and

cohorts, in their estimate of the burden of disease

on society, said that gout costs us 27 million-plus

dollars per annum for the management and care of

acute gout, and this tends us to underestimate the

true costs because this is mostly just men, it

34

doesn\'t include women, which are a significant

minority here that are affected by gout, and it

does not include a lot of the indirect and

intangible costs of having such an impactable

disease.

The epidemiology was reviewed yesterday

quite well by Dr. Terkeltaub, but this NHANES

survey, which was a telephone survey of the general

population, was a bit of a surprise.

Most of the epidemiologic studies on gout

suggested about 2.1 and 2.5 percent prevalence in

the general population. However, when this survey

was done\--excuse me, 1 percent, going as high as

2.1 to 2.5 million people\--when this survey was

done and people were asked on the phone, \"Have you

had or do you have kidney stones,\" they found a

much higher than previously reported prevalence,

and they asked the same question of gout, and they

found 5 million people who claimed to have gout.

Now, it is hard to confuse a kidney stone.

It is a pretty certain diagnosis when a patient

reports that. Patient reports of gout, however, are

35

notoriously inaccurate because the diagnosis, as

made by their general practitioner, are

unfortunately sometimes inaccurate, as well.

So, this is probably an overestimation of

the true numbers, but it is probably somewhere

between 2 and 5 million as far as the prevalence in

society, and that prevalence does go up, as was

pointed out yesterday, according to age, that men

are mostly affected here, but that women in the

postmenopausal era are almost equally affected.

This is a dramatic disease, and it is

dramatic because of the abundance of inflammatory

mediators that are produced at the time of the

attack.

A wide number of mediators that cause this

intense pain and inflammation, redness, and warmth,

and whatnot, a number of cytokines, you can add

this TNF and interleukin-8, and again, the list

goes on and on and on as far as the amount of

mediators that are present here.

Finding an effective therapy that will

downregulate that and produce clinical symptoms is

36

really a gargantuan task, and it is actually

surprising that we do as well as we do given the

amount of inflammation that seems to emanate from

these joints.

So, today, we are talking about acute

gout, but, of course, gout is divided into several

different forms, acute intercritical gout that

appeared in between attacks when patients are

quiescent and have no symptoms, and they are often

not on therapy.

There is chronic tophaceous gout which was

discussed in some detail yesterday, and then there

is asymptomatic hyperuricemia, who has not yet had

an attack of gout or uric acid nephrolithiasis.

Then, lastly, there is renal effects of gout, as

well.

Other publications talk about another

distinction of acute or classic gout versus

atypical gout, and atypical gout is also prone to

having acute attacks, although they are not as

acute, they are more insidious. They are more in

women, they are more in older people who are on

37

diuretics and have hypertension and renal failure,

and whatnot.

So, it is a sort of quasi-group. They

tend to fall a little bit under this acute

umbrella, but their inclusion in clinical trials

could cloud things. So, again, the acute or

classic attack of gout really usually is often

referred to as acute podagra.

This is often a sudden severe onset of

pain, warmth, inflammation. There is severe

limitation of motion, patients are unable to walk,

they are unable to have a sheet on it. It is

really quite dramatic.

So, while Dr. Schiffenbauer points out

that pain scales in the acute predictive gout are

not much different than other pain models, it seems

that gout patients scream a little louder, and it

could be because men are wienies, I don\'t know. It

could be that really it is more severe in its pain.

I tend to like some of the pain scales

that are used in some of the clinical trials,

because they tend to represent this almost like a

38

spinal tap 11, and they have zero to 4, zero being

none, 1 being mild, 2 being moderate, 3 being

severe, and 4 being extreme. That is sort of I

think indicative of the severity of the attack.

Podagra historically was said to occur at

the first joint in 90 percent of cases. More

recent estimates are probably a little bit less,

but podagra is the involvement of an acute

inflammatory event that affects the first big toe

or the MTP joint.

Some joints commonly involved early on are

the tarsus, the ankle, and the knee, distinguishing

it from other crystalline arthropathies and other

acute onset of inflammatory events.

It is not uncommon for these people to

have low grade fevers, high white counts, high sed

rates and CRPs at presentation. Patients will

often have monoarthritis as the first attack, but

then with repeated attacks, will ascend from their

lower extremity upwards and may have oligoarticular

and polyarticular presentations later on in the

disease especially when tophi form.

39

The initial presentation of polyarthritis

is more often seen in the elderly, in women, and

those who have mild proliferative disorders, also,

in patients who have a transplant and are receiving

cyclosporine.

There are many precipitants to this -

inactivity, surgery, alcohol, infection, drugs, and

whatnot. Untreated attacks can last up to 14 days,

although there is quite a significant amount of

variability there according to who you read, but

that is what my experience is.

Those who have an attack are at high risk

for subsequent attacks. The majority will have

another attack within a year, and it is estimated

that 78 percent will have another attack within two

years.

An interesting study done by Bellamy and

coworkers in Canada, and published in 1987, looked

at the natural history of gout in 11 individuals

who had an acute attack of podagra. There were 11

volunteers who had this acute attack. Two withdrew

before the full course of therapy or of observation

40

I should say, because of severe attacks, and went

on to receive indomethacin.

It should be noted that these 11 patients

who had acute gout, there were 2 who had tophi at

entry, 5 who had a history of nephrolithiasis, 2

who had a history of both. All had prior attacks

with a median of 4 prior attacks in the 7 years

prior, and that occurred usually with a median of

within 4 years.

Nine were on allopurinol and 1 was on a

uricosuric agent. It is unclear as to whether

those drugs were continued during this trial. But,

nonetheless, when they observed these people, they

showed that pain was improved by Day 5 in the

majority of patients, that swelling was improved by

Day 7, that tenderness was improved in 7 out of 9

patients by Day 7, but 2 patients continued to have

persistent pain. But only 3 people had noted

complete resolution of their symptoms by the end of

the 7-day study.

So, again, pain and swelling and erythema

and warmth all began to improve after Day 3. A

41

significant improvement was really seen between

Days 5 and 7, although again complete resolution

was not had in all.

At entry, these patients had a mean pain

score of a little less than 4, a little less than

extreme, and at the end of the study, 7 days, the

mean value was only about 2 or moderate level. So,

again while these patients got better, this is not

complete resolution of the disease.

The implications here are significant for

trials, first, what is your endpoint for these

attacks and when will get pain get better on its

own, and what are the outcomes that we should do in

looking at that.

So, laboratorywise, again, we should note

that, you know, hyperuricemia is a hallmark of the

disease, however, studies have shown repeatedly

that up to 50 percent of patients will have normal

uric acid levels at the time of acute gouty

presentation.

Leukocytosis is common, elevated sed rates

and CRPs are seen, often because of an intermittent

42

inflammatory process, chronic inflammatory indices,

such as a low albumin, anemia are not seen.

Cytokine levels have been measured and

shown to be elevated in patients, and there are

classic x-ray findings that can be seen early on

with soft tissue swelling, later on with

development of punched-out sclerotic, overhanging

edge type erosions.

These are the patients who have tophi in

different forms, the helix of the ear, over the

elbow, and severe chronic tophaceous gout over the

hands. The difference between these and nodules is

that they seem to come to a head and have a

propensity to break through the skin and exude this

chalky substance that is very, very rich in

monosodium urate crystals.

Their incidence has decreased over

decades, presumably with better therapy, however,

they are seen in a significant minority of

individuals. It is estimated it takes up to 10

years for a patient to have gout, to develop

clinically manifest tophi.

43

They are most commonly seen over the

elbows, but can be seen in the hands, feet, and

ears. They will damage tissue and bone and

whatnot, and therefore, their presence is alarming,

not only because of their damaging potential, but

also because what they indicate as far as total

body urate load.

Uric acid, we talked about yesterday.

Again, up to 50 percent of patients will have

normal uric acid levels at the time of attack. The

mechanism of this are probably not understood.

They are probably mediated by inflammation,

suggesting that maybe inflammation, including IL-6

may enhance renal clearance of uric acid, and it\'s

possibly why we see that.

Another interesting factor is the negative

association between gout and rheumatoid arthritis,

a good teaching point for our residents and people

we teach, because often patients will come with

both diagnoses, and you can\'t have both, and there

are actually good reasons for that, or at least

there are some suggestions for that, some which

44

involve the role of rheumatoid factor possibly in

blocking interactions between IgG and Fc receptors,

possibly the role of just inflammation in cytokines

in enhancing uric acid excretion, that also is

somewhat protective, hence, the exclusion of

patients with a diagnosis of RA would make sense in

an acute gouty trial.

How does one diagnose gout? There are two

ways. One would be the American Rheumatism

Association criteria of 1977, as was reported by

Wallace, where you either have to have crystal

evidence of monosodium urate crystals in either the

joint or in a tophus, or any one of the 6 clinical

following features.

That would include more than one acute

attack, maximum inflammation within one day,

erythema over joint, acute podagra, history of

podagra, unilateral tarsal involvement, tophi,

hyperuricemia, asymmetric swelling on x-ray,

subcortical cysts without erosions, and

culture-negative inflammatory arthritis as a means

of a clinical diagnosis without evidence of crystal

45

identification.

In a more practical manner, this is what I

do in practice, I think most of us do, is patients

present with acute or recurrent mono or

oligoarthritis, and then you confirm the diagnosis

by crystal identification.

In the absence of crystal identification,

one can substitute with probably not to the same

degree of certainty, but I think enhanced

certainty, any one of the following. That would

include a history of recurrent disease, a history

or evidence of hyperuricemia, and lastly, x-ray

evidence of gouty damage with sort of typical x-ray

of gout seen on x-ray.

So, here again, the acute podagra episode

mediated by a urate crystal, in this case taken up

by a poly, and again, this is fairly miserable

arthritis. I mean the onset of many of the other

arthritides we take care of is often not as

dramatic as that seen, and we don\'t see rheumatoids

with faces like this. We tend to see only our gout

patients who look like this when they come in.

46

So, the management of gout, which was

discussed yesterday, mainly, the chronic

management, the acute management of gout is

nonsteroidals, steroids and colchicine.

There are some problems with this, and

this goes to I think what Marc Hochberg brought up

earlier is that our therapies work really well and

that the benefit-to-risk ratio seems to be quite

acceptable.

In fact, that is true, but there are risks

associated with this, and those risks are maybe

more compounded in patients who have risk factors,

who have baseline or background diseases that

enhance the toxicity of the agents that we commonly

rely upon to use in the management of gout.

So, I think this is sort of the reason why

one needs the development of newer and possibly

safer therapies with at least equal efficacy, if

not better efficacy, but again, if our past efforts

have been very good, then, why not shoot for that.

The management certainly should begin with

the confirmation of diagnosis. This is what we do

47

in rheumatology practices. This is what is not

often done in the emergency rooms and in the

general practitioner\'s office who may not have

again a detailed understanding of the condition.

Also, the management of acute gout also is

the beginning of the prevention of subsequent

attacks, and that is modification of behaviors and

drugs and whatnot that may contribute to such

activity.

There are FDA-approved therapies for the

management of gout, and there are a lot of

therapies that are unapproved, that have been tried

in trials, and obviously, during acute gout, you

would want to avoid drugs that lower uric acid

levels, such as uricosuric drugs and even

allopurinol.

There are regional differences as to how

this is managed. Nonsteroidals, if you read

publications and talk to physicians, are the

preferred drug of choice in the United States and

Canada, New Zealand, and Australia, however, in

print, there is a widespread preference for

48

colchicine in France, and many of the European

Union nations who also feel that the use of

colchicine is not only effective, but is also

diagnostic.

In many instances, for instance, in this

one survey in France, 61 percent of the physicians

preferred colchicine alone, but 32 percent of that

same cohort preferred the combined use of

colchicine with a nonsteroidal.

The duration of therapy is going to vary

according to the patient\'s symptoms, but could be

as long as a month. It is quite interesting,

though, as historic as this disease is, and as

prevalent as it is, that there are no formal

guidelines that have been tested and/or advocated,

although I was reading Dr. Terkeltaub\'s New England

Journal article last night and came across a Dutch

web site for general practitioners that has

guidelines out there, and several medical schools

have their guidelines for local use, but again,

none of these have actually been tested or been

even rigorously developed using evidence-based

49

methodology.

So, the drugs that we do use in the

management of acute gout have significant effects,

there are well-known dosing regimens that can be

used, but there are also well-known toxicities that

need to be kept in mind in the choice of one\'s

therapy.

This is a publication that I was involved

with in the management of acute gout. The first

question is nonsteroidals, can they be used or are

they contraindicated, does the patient have renal

insufficiency or history of peptic ulcer disease,

congestive heart failure, or intolerance to these

drugs, and, if not, then nonsteroidals are the

preferred agent of choice.

However, if those are contraindicated,

then, the next question is can you use the

corticosteroids, and, if not, then what you

probably should do is use the corticosteroids. The

question is how much and where and when and

whatnot. On this, you base your decision on how

many joints are involved.

50

If it\'s a monoarticular presentation, one

would consider the use of intra-articular steroids,

less toxic, more effective, rapid onset of effect.

However, if it\'s polyarticular presentation, one

could go to either oral or\--excuse me\--that is

supposed to be intramuscular administration.

If, however, corticosteroids were

contraindicated, brittle diabetes or brittle

congestive heart failure, one could advocate the

use of oral colchicine, and only oral colchicine.

So, colchicine is certainly the most

historic drug used in the management of gout. It

is talked about as the first drug for gout. It\'s

an alkaloid of the Colchicum species. It has

significant anti-inflammatory effects, thought to

be mediated by its ability to inhibit microtubule

formation and basically poly activity.

The half-life of this drug varies widely

according to who you read. It is as brief as a few

minutes. Its plasma half-life is certainly less

than an hour, it is as short as 19 minutes, but it

can be as long as 16 hours, because it does seem to

51

bind to tissues, especially polys and microtubules,

and stay around for as long as 10 days.

So, again, there is a wide variability

here. It is found, because it is lipid soluble, it

is found in other tissues in high concentrations

including the liver, spleen, and intestine. It is

excreted in the urine, in the bile, and undergoes

some degree of intrahepatic recirculation.

It is metabolized by demethylation using

cytochrome 3A4, which is also responsible for the

metabolism of other drugs which have been linked to

the toxicity of colchicine use especially

erythromycin, ketoconazole, cyclosporine, and most

recently, the statins.

These drugs do cross the placenta and are

found in breast milk. They are not dialyzable.

They have many off-label indications besides gout,

pseudogout, amyloidosis, FMF, many skin conditions

including Behcets and Sweets syndrome, and it goes

on and on.

The biologic effects of colchicine are

numerous, but again its mainly its effect on polys

52

and poly activities with adherence and

degranulation, but it does inhibit the expression

of adhesion molecules, the generation of cytokines

and chemokines that are probably involved in again

this inflammatory process.

There are many advantages to using

colchicine, it has a lost history. It works in

both acute gout, it works as prophylaxis in chronic

gout, and prophylaxis when starting hyperuricemic

therapy.

It is said to have a diagnostic

specificity of 96 percent and sensitivity of 70

percent. It has a very fast onset of action when

used IV, although it is longer when used in the PO

form, and this is said to be certainly faster than

what is seen with corticosteroids either as

intra-articular or intramuscular, which is

certainly better than PO corticosteroids.

Lastly, I think nonsteroidals tend to have

their effects a little longer. There is certainly

an advantage in the management of the patients who

are NPO and not able to take anything by mouth,

53

surgical patients and hospitalized patients, and

those who are intolerant or unable to take

nonsteroidals because of contraindications.

These drugs are cheap. Yu, in a

retrospective analysis of 540 patients, basically

showed that the results of colchicine therapy were

excellent in 82 percent of individuals and

satisfactory in 12 percent, and only poor in 5

percent, and there were few episodes of

intolerance, no cases of renal or hematologic

toxicity, and this was over an extended period of

time, over 20 years, in 540 patients.

It has been studied going back to 1939,

when Lockie tested colchicine in patients with

gout, 75 patients, and compared the effects of

colchicine in those patients to other rheumatic

disease including rheumatoid arthritis and

psoriatic arthritis, and whatnot.

Interestingly, all of the gout patients

responded to colchicine, whereas, none of the other

arthritides did. They do not talk about their

outcomes that were used in that trial, but it

54

nevertheless shows again the specificity and

selectivity of a colchicine response.

In 1967, Wallace tested 120 patients, 58

of whom had acute gout, which was originally

defined as an elevated uric acid level with a

current arthritis. Fifteen of these patients had

tophi, and they were treated with colchicine orally

or by IV, roughly split, in the total 120-patient

group.

Major resolution of joint inflammation

within 48 hours was the prime outcome with no

worsening in the next 7 days. In the gout

population, 76 percent of patients resolved,

whereas, in the other population, only 3.2 percent

of patients resolved, again suggesting the

specificity of response here.

Acute gout management, I don\'t think I

need to go through this a great deal, most of us

know this, but it is 1.2 or 1 mg initially, and

then a dose every 1 to 2 hours until GI symptoms

develop or until the patients are better.

Ahearn, in his publication, it was a

55

placebo-controlled trial comparing colchicine in

gout, showed that 64 percent of patients responded

within 48 hours. That compared to 23 percent in

the placebo arm.

They both had again progressive

improvement over the next 36 hours, however,

colchicine and related GI toxicity and diarrhea

developed within 24 hours in most patients, so

often the GI symptomatology and diarrhea, which was

really quite severe, has its onset before the onset

of clinical improvement.

I heard yesterday Marc\'s statement that

patients are still very happy with colchicine

outcomes because they would rather deal with GI

toxicity than the pain of gout, which is a

testimony to how severe the pain of gout really is.

Again acute use is reserved for patients

who cannot tolerate nonsteroidals and steroids.

Dr. Wortman has a recent publication where he

states, quite interestingly, that he prefers

nonsteroidals in the management of acute gout,

however, he does prefer the use of colchicine when

56

patients don\'t yet have an established diagnosis,

such that he can use colchicine almost as a

diagnostic test.

So, when would one use IV colchicine?

Well, in my estimation never, but it should be used

or advocated when a rapid response is needed, when

oral use is precluded and when nonsteroidals and

steroids are contraindicated.

The problem is that there are no warning

signs here as there is with oral colchicine. The

toxicity sort of depends upon how much you give

over time and what your doses are. The recommended

doses are either 2 mg initially, followed by 1 mg

every 6 hours, for a maximum of 4 to 5 mg.

Another regimen would be 2 mg IV as one

single dose, or a third regimen would be 3 mg as

one single IV dose.

The problem is that there is significant

amount of toxicity associated with this. It can be

as simple as extravasation into the local tissues,

which causes significant irritation if not tissue

necrosis, but it can be severe as death.

57

A report coming out of the Office of Drug

Safety here at FDA, they detailed 20 deaths that

occurred in a recent time period.

This is a listing of 23 publications, just

by literature search, that give evidence for severe

toxicity, episodes of suicide, and mortal outcomes

in patients who received IV colchicine, suggesting

that the utility and the use of this approach

should be severely questioned.

In this Bonnel article, well, actually

before that, I asked Joel to tell me, if he looked

at the Med Watch system, what did he come up with,

and just looking at just the Adverse Event

Reporting System, since 1990, in the system, there

are 90 deaths associated with IV colchicine.

Now, those are not confirmed, we don\'t

know if there is duplicates in there, we haven\'t

researched those, so that is just a ballpark figure

suggesting that this is a serious problem.

Interestingly, during the same period,

there were 429 deaths associated with allopurinol,

but again there are a lot more issues going on

58

there. Allopurinol has far greater uses, wider

uses than does colchicine.

In its report by the Office of Drug Safety

in Bonnel, there are 20 deaths over a 17-year

period. Most of these were taken from the Adverse

Event Reporting System, but some from the

literature.

There were mostly males, 11 males and 8

females, 17 patients, and they ranged from 50 to 90

years of age. There were two cases of FMF, and the

rest were gout. All exceeded the recommended doses

of 2 to 4 mg. The range went from 5.5 to over 19

mg as a total course.

Adverse reactions that were seen included

thrombocytopenia, leukopenia, pancytopenia,

agranulocytosis, aplastic anemia, tubule renal

failure, and DIC. Death occurred within 1 to 40

days, and 80 percent of these patients showed

evidence of bone marrow depression.

There were risk factors in 13 of these

patients including the elderly, pre-existing

medical conditions, the use of background

59

nonsteroidals, and recent oral colchicine use that

was then compounded by follow-up therapy with IV

colchicine use.

It was clear from their review of the

warnings, precautions, and contraindications listed

in the package insert or in prescribing guidelines

in any major publication were not followed or were

misinterpreted by the prescriber.

Acute toxicity with colchicine can be

again limited to just the skin. Many suggest that

this drug should not be given IV unless there is an

indwelling catheter that had been firmly

established.

Symptoms could begin as tightness in the

chest, difficulty swallowing, abdominal pain,

nausea, vomiting, diarrhea, arthralgias, myopathy,

and then lead to severe shock, oliguria, paralysis

and delirium.

The mechanisms by which these patients

develop these multi-organ involvement and

subsequent death has really not been fully

elucidated. Again, the labs are dramatic, often

60

with severe cytopenias and the development of renal

failure and DIC.

Fatalities have been seen with as little

as 1 mg IV in patients who have been on background

therapy and then received this and had obviously

other risk factors.

Rhabdomyolysis has been reported

especially in end-stage renal disease, and the

patients who were felt to be at risk are those

again who are older, who have renal failure, those

who have been previously taking PO colchicine and

now get switched over to the same dose of IV

colchicine, those who are on background

cyclosporine or tacrolimus, those on grapefruit

juice, and those on statins.

Again, you can see the different stages of

intoxication could begin with GI symptoms and

dehydration, and then progress to more severe

manifestations in the first two to three days. If

the patient is lucky enough to recover,

leukocytosis and allopecia will ensue.

So, guidelines for use I think should be

61

reviewed and always advocated. It should be

severely restricted as far as its use, whether

restricted to a particular discipline or an

individual, or to be banned outright either by

institutions or maybe even by this body.

In Great Britain, it has been removed from

the formulary totally. In many hospital systems

around the country, it has been removed from the

formulary totally. I was in a hospital last week

where a very well-known rheumatologist opened some

mail while I was sitting in his office, and he got

very upset. He said, \"Darn, look at this, my

favorite drug has been taken off the formulary

because we had a recent death, because some

knucklehead inappropriately used IV colchicine.\"

A drug that he loved to use, that he was

very skillful at using, this is a very good

rheumatologist, I am sure he knows all these

guidelines, other people have now taken this drug

away from him, and he can no longer use it in his

hospital.

Again, single IV doses should not exceed 3

62

mg as a single dose, and 2 is probably a better

dose. Cumulative doses should not exceed 4 to 5 mg

over a total of 7 days. When one looks at the

patients who died and had serious toxicity, often

it was more than 1 mg per day over a 7-day period,

that patient got into trouble, and, in fact, going

higher than 0.5 mg per day for a 7-day period put

patients at risk.

It should be given by IV catheter. If IV

use is to follow chronic PO therapy, and used to

sustain the patient, it should be done at basically

half the dose. If you are going to follow up IV

therapy with PO therapy, you should wait 7 to 10

days before initiating PO therapy.

Reduced dosages should be used in the

elderly, in those with liver disease and renal

disease, those with prior PO colchicine, and it is

certainly contraindicated in those who are

pregnant, who have combined renal-hepatic disease,

who have very low creatinine clearances, and who

have evidence of biliary obstruction.

Treatment is often difficult obviously

63

with drug cessation, promoting intelligent use, it

is not dialyzable, cytopenias can be managed with

growth factors in some instance, rhabdomyolysis

should be managed, as it usually is, with fluids

and alkalization, if necessary, and there have been

some experimental therapies with Fab-2 fragments to

inhibit and to bind, but this is an experimental

tool that is being used.

Moving on to corticosteroids and

intra-articular and intramuscular use, they

certainly have benefits equal to nonsteroidals.

They are felt to be overall less toxic when used

acutely and intermittently, and again have

significant benefits.

There are, however, some issues, that

there is no standardization as far as dosing, which

form is best, what is the best route. It is often

good in patients who have contraindications to

receive nonsteroidals, and that includes heart

failure, renal failure, GI bleed, or patients who

have monoarticular presentations in whom a

intra-articular injection would make more sense.

64

Toxicity can be significant,

hyperglycemia, hypokalemia, fluid retention, and it

is frequently reported that patients who receive

corticosteroids get better, but then a few days

later or maybe a week or two later, they actually

rebound where they get another flare of gout.

Prednisone orally has been used with doses

of 30 to 50 mg being advocated for up to a week and

then tapered over the next week or so. Again,

there is this issue of rebound.

ACTH is probably the best studied of

these, either 40 or 80 mg\--excuse me\--international

use as in a single injection. Other dosage forms

include triamcinolone, acetonide, and

betamethasone, 7 mg.

I have listed a few studies here that look

at the value of ACTH therapy as compared to Indocin

or Diclofenac here, and you can see that basically,

ACTH seems to perform very well. It had a faster

onset than Indocin, and Indocin certainly had more

toxicity, was compared head to head over here.

When it was an uncontrolled trial, 97

65

percent of people were better by 5 1/2 days. When

compared to triamcinolone, both groups, the ACTH

group and the triamcinolone group, responded by Day

8, but the triamcinolone group had fewer rebound

episodes and required less re-treatment.

Then, Werlen showed that when comparing

these two different steroid forms, the Diclofenac

and steroids outperformed the nonsteroidals in

their trial.

So, nonsteroidals have been advocated, FDA

approved, including indomethacin, naproxen, and

sulindac. Many have been tested in clinical trials,

most of which have been open label. The benefits

of nonsteroidals are that they certainly have a

fast relief of onset compared with colchicine, PO

colchicine, not IV.

It is estimated that 2 to 4 hours it takes

for people to get better. With indomethacin, that

would not be complete improvement. It is less

toxic when prescribed appropriately and better

tolerated than certainly colchicine. They are

widespread in their use and most docs are more

66

familiar with the proper dosing and use of

nonsteroidals than they are with colchicine and IV

colchicine, and certainly in many instances, there

are very cost effective.

I believe the representative from Merck

will review the combined results of the etoricoxib

study that was reported recently at the American

Pain Society, but all of this to say that

etoricoxib and COX-2 inhibitors have been tested in

gout in two studies, and submitted an analysis of

both or a combination of both, and they have showed

using two primary outcomes here that etoricoxib

compared very well to Indocin, so while they both

had significant benefit, the real benefit was seen

with less toxicity in the etoricoxib group compare

to Indocin as far as hypertension, diarrhea, and

CNS or headache.

Analgesics have also been advocated in the

treatment of acute gout, and that includes the use

of topical ice where it has been shown that

patients who received ice had better outcomes as

far as swelling and pain, and ketorolac.

67

Actually, this fellow Shresta was one of

my residents at Parkland, he did both of these

trials at Parkland, and he used ketorolac, and his

time points were very short time points, 30

minutes, 60 minutes, 90 minutes, and 2 hours.

He showed in this open label trial and a

double-blinded, randomized, controlled trial

against Indocin that it performed very well, either

equal to Indocin or certainly significant by 90

minutes or 2 hours in both trials.

There was, however, in the second trial,

some rebound in patient who received the ketorolac

after 6 hours.

I have a listing for you in the next two

tables, the trials that have been done, open label

trials and controlled trials, in the management of

acute gout. This is basically for your education

to show you, number one, the design and the number

of patients, but to look at the primary outcomes

that were used in these trials and the time points

for evaluation.

You can see that most of these used pain

68

or joint exam findings, tender joints and swollen

joints, as outcomes, but pain usually in VAS or

Likert scales, and the days and times of evaluation

ranged from 24-hour evaluation to\--or Shresta, he

did these at 30 minutes, 60 minutes, and 90

minutes, but one day all the way up to 7 days here.

In the next trial, these are controlled

trials, comparing mostly nonsteroidals, some of

these are steroid trials and ice trials, and

whatnot, and you can see again most of these

required pain outcomes and, the top one here, a 50

percent reduction in pain, mostly going to the

reduction in pain level, or reported just changes

in pain level, usually is reported by either VAS or

Likert scales.

Again, the time points that were usually

looked at were 1 to 8 days in most of these trials.

So, the considerations as we go forward is

how does one establish a diagnosis, would it be

solely based on prior evidence or current evidence

of crystals as a means for diagnosis.

Would you rely on ARA criteria, either

69

crystals or the clinical criteria, or would you use

the much more practical approaches as I do in

clinic, what is the duration, does someone come in

with two weeks of symptoms and new gout, or must

they have established gout over time, what does the

duration of attack have to be before they get in.

In some instances, patients had to wait 5

to 7 days to get in. This is sort of a problem,

because again that is the maximal amount of pain.

You want to get these patients in as soon as

possible.

Con meds are issues, as Joel talked about.

I think most patients will come to you on some

degree of pain medicine whether they be

nonsteroidals or other pain medicines. Steroids

obviously I think would compound things unless it

was a steroid trial, and allopurinol should be

stopped at entry.

Time assessments. The window here is much

shorter. This is not like the trials we were

talking about yesterday. We were looking at 3

months, 6 months, and 12 month outcomes. Here, I

70

think we are looking at 1-day, 2-day, 7-day

outcomes, and the extended outcome may be anywhere

from 14 to 30 days.

The primary outcome is always going to be

pain, I mean there is no doubt about this. I don\'t

know that there can be much argument here. This is

an incredibly painful condition, and that is what

patients want. That is what we accept clinically

when we see these patients.

There are other secondary measures that

one can look at and I list those for you there, and

I would advocate these are rescue medicines in any

regimen whether it be placebo-controlled or an

active-controlled regimen.

This is my suggestions for a clinical

trial. Number 1, I see as guidelines for actual

numbers, I think would be Smart in this instance.

Obviously, they would be short-term trials, so I

think that the first applies here. We are not going

to have many people treated with acute therapy for

over a year.

I believe an active controlled trial,

71

looking for a non-inferiority design largely

because of what Marc brought up earlier, which is

that the therapies we have are very effective. You

know, to go against a currently approved therapy

wouldn\'t make a great deal of sense, and use a

non-inferiority design, that you have obviously

double-blind and active controlled.

Patients should have a diagnosis of gout,

and I think that although I like my method of

diagnosis, I still think you have to go with

something that has been tested and held to be true.

ARA criteria have a sensitivity of 87 percent or 84

percent, and specificity of 100 percent if you

include crystals.

The acute gouty attack should be seen

within a certain period of time, certainly within

three days. The trial length could be up to two

weeks, and visit frequency I think would have to

depend on the expectations of the drug and its

onset of effect.

One thing that I was thinking about, that

is not on the slide, but is a common issue in

72

clinical trials, is that patients have a run-in

period. They are seen, they are screened, they are

consented. You get labs, they come back a week or

two, or three days or two days later, that is a

problem here. These people hurt today.

I think that inclusion criteria have to be

liberalized to allow for people who may be entered

into a trial who have renal failure and you don\'t

know about it, who have LFTs that you don\'t know

about, who have, you know, because they didn\'t

reveal the fact that they are an alcoholic, the

ideas that they need to get in, I think you should

protect the trial as best you can with Smart

criteria, but I don\'t think you should impair

enrollment in these trials by clinical inclusion

criteria.

Obviously, age greater than 18, the

diagnosis of gout, an acute attack should be

defined, and I think that should be one of the

outcomes here, not only how long an acute attack

lasts, but whether they have subsequent acute

attacks.

73

Mono/oligoarthritis are preferable at

entry. Polyarthritis I think should be excluded

for several reasons. One, it could be something

else. Two, the polyarthritis tends to fall more in

that atypical gouty group, older women, more

insidious, older, mostly women, more insidious

attacks, nodal osteoarthritis, a lot of other

factors going on there, and their response to

therapy may not be the same, so I would tend to

exclude polyarticular presentations of gout in such

trials.

Activity needs to be assessed, and

activity can be easily assessed by just using the

cardinal signs of inflammation, so tumor, rubor,

dolor, or calor, pain, swelling, redness, and

warmth, and improvement in two out of four, or

three out of four as very objective means of

outcome.

Exclusions, I think absolute exclusions

should include polyarthritis, an excessive alcohol

use, renal insufficiency, if known, background

aspirin, if known, cyclosporine, rheumatoid

74

arthritis, transplant, active infections, dietary

restrictions, and uncontrolled hypertension might

be certain obvious issues you would exclude.

What is on the table, and I think very

uncertain, are background use of nonsteroidals or

BC, diabetes, heart failure, tophi,

nephrolithiasis, previous or current narcotic use,

previous or current anticoagulants, background

nonsteroidals, allopurinol, probenecid,

sulfinpyrazone, hospitalized or immobilized

patients, those that are unwilling, and, my

favorite, those who are currently involved in

litigation.

So, primary outcomes I think are clearly

going to be patient derived and pain. I think that

pain can be self-reported measures of pain. We

heard presentations at our pain advisory meeting

about the use of PDAs and direct patient entry of

data.

It is real-time, more reliable, gives you

I think a true assessment of what is going on. It

can also give you a more reliable assessment of

75

time to onset that may not be easily achieved in a

recurrent physician visit kind of assessment.

Secondary outcomes can be both patient and

physician derived. That will include global

assessment of the disease, global response to the

drug, complete resolution of symptoms, time to

resolution of symptoms, what happens in an index

joint, if one can be identified as far as the four

cardinal signs of inflammation, swollen joint

score, tender joint scores on zero to 3 scale, the

need for rescue analgesics, inflammatory indices of

sed rate and CRP, uric acid could be also looked at

although I think less important, functional

measures, and then comparison with the active drug

as far as the safety and toxicity profile.

So, that was a mouthful. I will end

there.

Thank you very much.

DR. GIBOFSKY: Thank you very much, Dr.

Cush.

Are there questions for Dr. Cush from the

members of the panel?

76

Dr. Weisman.

DR. WEISMAN: Dr. Cush, what is your

formula for managing patients with acute gout that

is complicated? Transplantation comes in with a

creatinine of 2, already on steroids, and so forth.

DR. CUSH: Well, the more complicated they

are, the more I tend to rely on steroids in

management, so if they have transplants, and if

they have renal insufficiency, and they are

hospitalized and they are NPO, I think steroids is

the major issue.

It has often been advocated that in

patients who have contraindications to using

nonsteroidals, that you can still use them because

you are unlikely to get into the significant

trouble one sees with nonsteroidals, whether that

be GI or hematologic or renal, because you are

using short courses of therapy.

However, I think that is probably

overestimated and that most patients don\'t need

three days of therapy. They probably need more like

seven to 14 days of therapy, and there the risks

77

are real.

So, I think complicated gout may require

parenteral administration of medicines, more use of

steroids. I tend again not to want to use IV

colchicine.

I think getting smarter about prevention

of subsequent attacks and using combinations of

whatever the patient can tolerate to treat the

acute attack is the smartest way to go, but then

again, you know, complicated courses are often

because you can\'t get them under control.

The real struggle I don\'t think is as much

in the management of the acute episode as once you

get them under control, how do you keep them

control, because what complicates them are the

factors that bring out these more recurrent

attacks.

DR. WEISMAN: Would you include them in

clinical trials?

DR. CUSH: Well, again, I alluded to some

of that by saying no for transplant, no for

cyclosporine, no for a lot of difficult situations.

78

I think these acute trials could occur in patients

who have well-controlled intercritical gout on no

therapy, or well-controlled intercritical gout on

some therapy.

It could occur in well-controlled

tophaceous gout and then has an acute attack, but

patients who are chronically out of control with

inflammation and swollen joints and whatnot, that

can be a more problematic group, and they are more

likely to be in that tophaceous gout group. Again,

those might need to be excluded.

I think again to liberalize patients, so

that they don\'t have to undergo, for instance, a

lab screen, that requires them to return in 24

hours or a week, would be a horrible thing, because

it would deny those people access to treatment

which they desperately need today.

DR. GIBOFSKY: Dr. Hoffman.

DR. HOFFMAN: That was a great and very

thoughtful review, Jack. Thank you.

I would like to hear your thoughts on a

couple of points that you mentioned and guidelines

79

you suggested. If I understood you correctly, you

would stop allopurinol in patients who came in with

acute gout.

We have all seen patients who have

recently had allopurinol started and have

precipitated an acute attack, and I am not sure

that that attack is in any way, other than for that

association, different than other attacks or that

it would respond differently to the agent being

tested.

So, I am not sure why someone would change

the dose that the patient came in on, the

allopurinol dose rather than just continue what

they were on and treat the acute attack in testing

the agent of interest.

DR. CUSH: I think it is a matter of how

one is taught, I don\'t think there is a lot of

science here. I think there is a lot of

hand-me-downs as to what works. I mean I have

always been taught that it should be stopped mainly

because you want to stop the mobilization of tissue

stores as much as possible to give you the best

80

chance of acute resolution, that if they continue

on allopurinol, you may prolong the attack.

Again, I don\'t think that is as well

studied as I wish it were. That is certainly an

issue, whether or not patients should be continued

on whatever background therapy they are on, whether

it be allopurinol or diuretics. Obviously, there

are drugs that may contribute to either that event

or maybe even the prolongation of that event.

My view is if they can safely be stopped,

then, what is the hazard in it, are you hurting the

patient down the line as far as their ultimate

control, would they fall out of control by stopping

that 300 mg or 100 mg a day of allopurinol.

DR. HOFFMAN: I don\'t know the answer to

that either, but I think it is an issue that

remains perhaps contentious.

DR. CUSH: Right.

DR. HOFFMAN: Along the same lines, since

the significant minority of people, you have got a

great handle on the literature and can probably

inform us, but I am thinking that there are some

81

studies in the past that have suggested that when

you look at all gout, that perhaps as many as 30

percent of people have polyarticular gout.

You might comment on whether that is

accurate or not, but if it is a significant

minority, why would one want to exclude

polyarticular gout in a trial especially if one of

your standards for inclusion was crystal

demonstrated gout?

DR. CUSH: If crystals were your

identifying factor, I think that you would be a

little more certain, but you could identify

crystals, and still not know whether that is acute

polyarticular septic arthritis, as well. So, that

is an issue.

I think what is clear from what I have

read and looked at is that in the initial

presentations, not someone who has established gout

and has recurrent disease, but in the initial

presentation, polyarticular gout is very, very

uncommon except for in the population I mentioned -

women, mild proliferative disorders, elderly, and

82

those receiving cyclosporine.

Otherwise, it is actually really small, it

is probably in the single digits. By \"poly,\" I

mean four or more joints. You know, mono and oligo

is really I think where 90-plus percent of the

patients exist. I think that there is more

diagnostic certainly in that restriction.

If one allows polyarticular gout, I think

you would need to make sure that you are not

dealing with other issues, whether it be another

crystal, whether it be background issues that may

complicate response to therapy.

So, I mainly exclude them because I think

it is an uncommon aspect to the disease, and there

are so many patients, you don\'t need those to do

the trial well.

DR. HOFFMAN: So, you wouldn\'t exclude

oligo.

DR. CUSH: No, I would not exclude oligo.

I think that is a very important inclusion.

DR. HOFFMAN: Finally, if the chairman

would allow me a final question, I would just like

83

perhaps your opinion and some of the other experts

on the panel about what I think is a bias in the

literature.

That is the nonassociation of gout and

rheumatoid arthritis. I actually don\'t believe

that at all from my own practice because I would

submit that most rheumatologists who see a patient

with a flare-up of RA, and are concerned about a

comorbidity, might or might not aspirate the joint

to rule out sepsis, but probably don\'t personally

do synovial fluid analysis.

DR. CUSH: Right.

DR. HOFFMAN: But having done that myself,

I have seen a number of cases of patients with RA

and gout, of course, as well as pseudogout, and I

am not sure how robust that literature is, and

since the notion has been in the literature, then,

there has been a story, perhaps fantasy, that has

grown up around it regarding rheumatoid factor and

inhibition.

DR. CUSH: Well, I would agree it is not a

well studied matter. I think it is somewhat urban

84

legend, rheumatology legend that has passed on.

My own belief is that it is true, and that

stems somewhat from observations and doing clinical

trials where I don\'t know why uric acid was being

done, but I have done several trials where RA

patients, uric acid levels were being done, and it

was clear that uric acid levels would go down when

RA was at its worst.

That was curious to me, and that is why I

think some of the more recent data about this

negative association and maybe why that occurs

associated with IL-6 and whatnot rings true.

I think it is an important teaching point

because I think in the general practice community

where people are seeing arthritis patients don\'t

know well how to diagnose these, patients come to

us all the time with, \"Doctor, I have gout, lupus,

and rheumatoid arthritis.\"

\"I am sorry, ma\'am, you don\'t. Firstoff,

you are too young to have gout and you definitely

don\'t have lupus.\"

For me to propose that the two can

85

coexist, I do propose that septic arthritis and

gout often do coexist, I think would be misleading

and miss a prime teaching opportunity to the

general public, which is that you either have one

or the other, and if you have both, let\'s report

it.

In fact, if you looked at the reports in

the literature of combined gout and rheumatoid

arthritis, they are less in number than the numbers

of combined gout and septic arthritis.

I still think your point is right. I

think that most rheumatologists, when they see an

acute rheumatoid who has one or two swollen joints,

rather than aspirating that joint, treat it. And

how do they treat it? More nonsteroidals, more

steroids, and whatever.

So, the possibility I think still remains

and I think for someone to study in that matter by

vigilantly looking for it would be an important

contribution to our literature.

DR. GIBOFSKY: Dr. Cronstein.

DR. CRONSTEIN: Jack, again, that was a

86

terrific review and very thoughtful.

One of the things that you mentioned was

the need for very rapid assessment and enrollment

of patients, so this might preclude I guess a more

thorough evaluation of the medical status, but

since many of the drugs, whether they are

comparator agents, all the nonsteroidals, for

example, can exacerbate hypertension and renal

insufficiency, I am just wondering if you could

elaborate on how you might go about doing this,

because this is going to be a problem.

DR. CUSH: And figure this into the

equation. If this trial is done by me, and by

those of you around this table who do clinical

trials, this won\'t be as much of an issue, because

we will actually spend an hour with the patient, we

will do a very careful history, we will do a very

careful exam.

In that hour, we could actually have labs

back and see what the creatinine and LSCs are, and

whatnot. But the problem is I don\'t have these

patients in my clinic, I am not going to treat that

87

many acute gouts this year. If you are going to do

this in emergency rooms, in family practice clinics

where they are seeing patients every 8 to 10

minutes, you know, these guys don\'t have the time

to do this kind of detail, and so you are going to

get a real world view of these people including

some of their comorbidities and some of their

background therapies.

You know, the FDA and the product

manufacturers have to accept a higher degree of

toxicity that may be associated with such an

approach, but to not do that is to maybe deny

people who really need therapy right now some

intervention.

How long can someone who has acute gout,

where they can\'t have a sheet on their big toe, or

they can\'t walk, whether it\'s a mother who is

taking care of kids or a businessman who has a trip

tomorrow, and whatnot, I think it is cruel and

unjust.

I think that I would point to the higher

good, which is go for patient relief and now, and

88

accept again a more real life population except

that I will enroll them now, get my labs, and maybe

we have to stratify those people post hoc for

patients who had uncontrolled hypertension, for

patients who had renal insufficiency, people who

were diabetic, and whatnot.

DR. GIBOFSKY: Dr. Terkeltaub.

DR. TERKELTAUB: Thank you for that

review.

I wanted to point out one item about gouty

inflammation, and that is, that it actually,

pathogenically, is very well characterized. I mean

not only do we have the etiologic agent as opposed

to, you know, not knowing the primary etiology of

RA, but the major inflammatory mediators including

IL-1, TNF-alpha, IL-8, the signal transduction

cascades including P38 and of Kappa B inhibitors,

the effects of leukocyte adhesion molecules, Dr.

Cronstein having elucidated how colchicine works on

e-selectin, these are all well characterized, and

some of the actual targets are seen by specific

medications now in practice including IL-1

89

inhibitors, TNF-alpha inhibitors, and medications

being evaluated in the clinic for RA, that may not

work very well for RA, but may work for gout.

Are you aware of any anecdotal evidence

for some of these particular medications in trials

or in use for RA working for gouty inflammation?

DR. CUSH: I am not. As you were going

into this, I was going to turn around and ask you

that question. I would love to see if Kineret or a

TNF inhibitor has been tried in acute gout, and, if

so, I would like to know.

DR. TERKELTAUB: Dr. Cronstein has told me

that I shouldn\'t admit to using Kineret or Enbrel

for gout, that it wouldn\'t be seemly, but I will

admit to it, and there is some anecdotal evidence

for some of the biologics affecting gouty

inflammation, but obviously, it hasn\'t been done in

a controlled manner.

DR. CUSH: Would responses be as prompt?

DR. TERKELTAUB: Handfuls of patients, it

is very hard to tell, but there is some evidence

that some of the biologic agents might work for

90

gouty inflammation.

DR. CUSH: So, maybe going to Dr.

Weisman\'s question as to how do you manage someone

who is very difficult to manage, who maybe you

can\'t give colchicine, maybe you can\'t give

nonsteroidals, and maybe you can\'t even use a

steroid, maybe that is yet another alternative.

DR. TERKELTAUB: I think there is room for

trials, for careful trials, and again, you did a

tremendous job in the review. I think that one of

the issues is that I think we really are seeing

more complicated patients in terms of more

polyarthritis and more severe flares in the elderly

and patients with renal failure and transplants,

and so forth.

So, I would encourage, given that these

are the patients that we have a shortage of safe

medications to use, that we would at least study

these patients in trials.

DR. CUSH: And I think that they should be

studied because they are still a therapeutic

conundrum in many situations. Their inclusion in

91

an acute trial, for an acute indication, I think

would only tend to complicate matters for what

should be a relatively straightforward trial.

It is a different matter if you want to

study people who have established chronic

tophaceous gout, or renal failure, or one of these

very difficult kind of cases, and look for the

control of acute flares in those people. That is a

different kind of trial and maybe even a different

kind of drug is being developed.

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: I guess maybe your thoughts

on one other issue, and this sort of comes out of

what Dr. Terkeltaub just said. If you have

patients who can take established therapy, let\'s

say, NSAIDs, then, following your rationale, you

would say that the NSAIDs should be the comparator

agent, right?

DR. CUSH: Yes.

DR. HOCHBERG: Then, if you have people

who have contraindications to NSAIDs, and you want

to look at a new therapy for gout which might be

92

appropriate in that population, you know, do you

want to comment on the choice of comparators in

that situation?

Also, if you had something which was an

entirely new class of drugs, you know, this is not

necessarily a quantum leap, but a new class of drug

that might be used in this condition that hadn\'t

been used in gout before, where would the

appropriate role for a placebo control be?

DR. CUSH: To answer your last question, I

think in the latter instance, you know, a new

product line, a new biologic mechanism of action,

one not yet tested, I think would have to be tested

in a placebo population with obviously, a very

liberal policy as far as how to rescue those

people, so as not to subject them to unwarranted

degrees of pain and misery.

I think for a nonsteroidal head to head,

to use an approved nonsteroidal as your head to

head is what the FDA would require. My

understanding is that if you are going to go for

indication, you can go against an approved drug and

93

go for either non-inferiority or superiority, and

that would be acceptable.

In the case where nonsteroidals are

contraindicated, first, I would exclude those

people from a nonsteroidal trial if possible, but

then if you want to include them, then, you could

use either colchicine as your comparator or maybe

even steroids as your comparator.

ACTH steroids, are they approved? I don\'t

think they are.

DR. SCHIFFENBAUER: Corticosteroids have

acute gout as an indication, but ACTH, not.

DR. CUSH: Oral corticosteroids?

DR. SCHIFFENBAUER: I think it just says

like prednisone would be an example of that.

DR. CUSH: That is interesting because I

think there is far less evidence that that is

effective compared to ACTH.

DR. GIBOFSKY: Any further questions for

Dr. Cush from members of the panel? If not, Dr.

Cush, thank you for a superb presentation.

We will move on to a presentation at this

94

point from the members of the Merck Research

Laboratories.

Dr. Agustin Melian will introduce his

colleagues, who will make the presentation.

Dr. Melian.

Merck Research Laboratories

Introduction

DR. MELIAN: Thank you and good morning.

I am Dr. Agustin Melian and I am a Director of

Clinical Research at Merck Research Laboratories.

As Merck is one of the few sponsors to

have recently carried out studies in acute gouty

arthritis, the Agency has asked if we might come

here today to share some of our experiences with

the group. On behalf of Merck and Merck Research

Laboratories, I would like to thank the Agency for

this opportunity.

As I think the Committee is well aware of

here today, acute gouty arthritis is one of the

most common inflammatory arthropathies in men over

the age of 40. Despite this relatively common

clinical occurrence, there is a relative paucity of

95

data from clinical literature on acute gouty

arthritis studies.

Those studies that have been done for the

most part have had just a limited number of

patients, many haven\'t included a large number of

endpoints, and many haven\'t included a large amount

of information on the endpoints that they have

included.

So, the question faced by the Committee

today is the same question that was faced by Merck

when they first conceptualized and designed their

studies, that is, in the absence of extensive

clinical data, how best to conduct studies in acute

gouty arthritis.

In order to try to answer this question,

Merck scanned the available literature, reviewed

FDA guidance documents, and then brought together

experts in the field of clinical rheumatology.

Based upon the advice of these experts, we

then carried out two clinical studies. They were

replicate studies in acute gouty arthritis, Study

040, published in 2002, in the British Medical

96

Journal, and Study 049, published earlier this year

in Arthritis and Rheumatism.

Here to discuss key issues from the design

phase of the Merck studies is Dr. David Daikh. Dr.

Daikh, along with Dr. Ralph Schumacher, was one of

the key pivotal investigators who were first

involved with the design and conceptualization of

these studies.

After Dr. Daikh\'s presentation, I will

return to the podium to discuss and briefly

summarize the study results. Then, Dr. Daikh will

present a brief presentation on Lessons Learned.

With that, I would like to turn the podium

over to Dr. Daikh.

Thank you.

Design Considerations in Acute Gouty

Arthritis Studies

DR. DAIKH: Good morning. I appreciate

the opportunity to discuss with you and review some

of our experience in setting up these trials in

acute gout, and also, as a rheumatologist,

appreciate the interest of the FDA in studying this

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disease in more detail.

I will discuss with you design

considerations in acute gouty arthritis. I think

that given the previous presentations, I will just

touch briefly on issues of pathophysiology as they

relate to issues of study design.

I will then review briefly the extant

literature that was available and that we used to

guide our own design, and then really spend most of

the time talking in detail about some of the

considerations that, in fact, many of these were

actually outlined very nicely by Dr. Schiffenbauer.

I think you will see that we covered much of the

same ground in these deliberations.

I will also then talk in some detail about

the approach to data analysis that would be

required by different study designs.

Really, after the definitive presentation

on acute gout, there is nothing really I can add,

certainly given the collective experience of the

panel, except really to emphasize that this clearly

is, as we all know, a clinical syndrome that is the

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result of an immune response to monosodium urate

crystals.

Really, because of the inflammatory nature

of the disease and the clinical expression of that

inflammation, I would argue that we are really

dealing with a unique clinical entity.

The diagnostic criteria proposed by

Wallace and coworkers a number of years ago have

been alluded to in a number of ways, and I want to

spend a couple minutes going over these

specifically.

They really reflect the reality of

clinical practice, that once you have some

certainty of a history of crystal-induced

arthritis, the diagnosis in the acute setting is

greatly simplified, so the presence of

characteristic urate crystals in the joint at the

time of diagnosis in fluid is critically important

and allows you essentially to make a diagnosis of

acute gout, or indirect evidence of the presence of

crystals, that is, tophi either clinically apparent

or present on a radiograph.

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However, it is important to emphasize that

even with definitive diagnosis of crystals, either

directly or indirectly, one still needs the

subpoints which are, in these criteria, C1 and C4,

that is, the maximal inflammation developed within

one day, and that there is redness in the observed

joint, really emphasizing the importance of

inflammation in making this diagnosis.

In the absence of either immediate, direct

or indirect evidence of crystals, further, the

criteria allow a diagnosis with a number of points

that have been mentioned. I am just going to

emphasize them again because it makes the point

that this is a stereotypical clinical response and

you can make a diagnosis of acute gout on clinical

grounds.

So, in addition to maximal inflammation

within 24 hours, more than a history of acute

attacks, mononeuritis, in particular podagra,

involvement of the first MTP, unilateral

involvement of the first MTP, and then the others

that you see listed there.

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As has been very comprehensively reviewed,

we really divide our treatment of acute gout into

essentially what is preventative treatment of the

acute attacks and then treatment of the acute

attacks. We will be for the purpose of this

discussion really focusing on nonsteroidals and

similar drugs, colchicine and corticosteroids.

Before we get to the details of our own

study of a COX-2 specific inhibitor compared to a

standard nonsteroidal in acute gout, I just want to

address the issue of what quantitative studies were

available at the time of our own design to assist

in guidance.

Listed here are the total number of

studies. Now, these are with the exception of the

highlighted studies, double-blinded, controlled

trials in acute gout up to the time of our own

involvement in the study.

The highlighted studies have been alluded

to. I am going to discuss in detail the

observational study, as well as the

placebo-controlled trial of colchicine. The third

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highlighted study was a double-blinded, controlled

trial that will be discussed subsequently as we

address the issue of quantification of Indocin\'s

effect on this disease.

But I just want to emphasize, as you look

at this list, a number of points. One, it was a

remarkably short list. Secondly, most of these

studies have a very small number of patients, and a

number of them, most of them actually are quite

old. So, in fact, very little guidance as we will

see in terms of prior experience with these kinds

of studies.

Now, what study or studies do we have to

tell us about the natural history of gout, and what

I am really going to be addressing here is the

issue of spontaneous resolution of disease.

Well, we have one, the observational study

of Bellamy et al. in 1987, the rationale of which

was really to serve as a documentation of the

natural history of this disease with the express

goal of potentially guiding future studies, so

really what we need.

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As was noted, this was a small trial of 11

patients. These were patients who presented with

classic podagra or had a history of prior attacks.

The measurements were, as you might expect, pain,

tenderness, swelling, erythema, et cetera, but

importantly, these patients were observed in an

inpatient setting. They were hospitalized and

observed over the course of the study.

Now, also importantly, the mean time from

the onset of the patient\'s attack to their

enrollment in the study was 2.8 days. The baseline

level of pain in these patients was graded as

severe or very severe, and, in fact, the mean pain

at entry in study, in this group of 11 patients,

was 3.73. This was on a scale of zero to 4.

Here is the data. I want to emphasize a

couple of points on this graph. You see here mean

pain severity versus time. Now, there is actually

two plots of time here. The first x axis here is

study day, but here you see this is actually the

mean numbers of days since the onset of attack, so

Study Day 3 really corresponds to 5 days since the

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onset of attack. This will be important for us to

keep these two timelines in mind as we move forward

and look at this in other studies in acute gout.

You can see, then, for study days, up to

Study Day 3, which corresponds to 5 days since the

onset of attack, there was essentially no change in

the patient\'s pain severity. Then, beyond 5 days

into the attack, there was some diminishment of

pain.

Now, as I think noted previously, 2 of the

patients of the 11 dropped out during the course of

the study because of unbearable pain essentially,

and so this plot, also from the publication, shows

an intention to treat analysis with these 2

patients included. You can see really very little

difference, the conclusion remains the same.

So, from our single study, the natural

history of acute gout, we would conclude that there

is essentially no resolution in severe to very

severe pain over the first 5 days from the onset of

attack, and that really even at the point there

begin to be some resolution of pain, it was minimal

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over the course of 7 days. This, I think really

reflects our clinical experience.

Another study that potentially can guide

us in terms of understanding duration of attack and

response would be the single placebo-controlled

trial that was alluded to. This was also a study

which included patients who presented with podagra,

involvement of the first MTP, and this was a very

short-term study, 48-hour study, comparing

colchicine to placebo.

These are patients who had had

crystal-proven gout, and they again, importantly,

were observed in an inpatient setting. They were

basically put at bed rest.

The pain scale here, instead of a zero to

4 scale, is 100 mm Visual Analogue Scale with 100

being the patient\'s expression of maximal pain. In

addition, there was an overall clinical score

assigned, which was a composite of pain,

tenderness, swelling, and redness.

In terms of the baseline characteristics

for this group of patients, their mean time from

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the onset of their clinical attack to randomization

was 38 hours, and their estimated mean pain, as we

will see, at randomization was 60 to 70 mm on the

VAS.

You can see here the entry point in these

patients. Again, we have study days here, as well

as the mean number of days since the onset of

attack. Here again we see very little to no

resolution over the first couple of days of study,

2.5 days here you see no change.

The other point to make from this

placebo-controlled trial is essentially no placebo

response especially immediately upon entry into the

study. Remember this is days out from enrollment.

I think we can also contrast this placebo

curve to the kind of placebo responses that we are

used to seeing in studies of osteoarthritis and

rheumatoid arthritis, it\'s a very small placebo

response.

So, from these studies, we can at least

feel assured with our conventional wisdom in

clinical experience that at least moderate to

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severe attacks do not resolve spontaneously within

a 5 to 7 day time period, and that there really is

very little placebo response in this acute disease.

Let me move now to a number of issues that

could be considered, that were considered as we set

up the study. Well, as has been alluded to, an

important point is really control versus a

comparator design, placebo versus active

comparator, and if an active comparator design is

chosen, what should be the comparator drug, which

patients should be selected, what endpoints should

be chosen to measure outcome and when should those

measurements be made.

Let\'s consider the pros and cons of a

placebo design versus active comparator. In terms

of placebo control, obviously, the major major pro

is that this greatly simplifies the interpretation

of results.

The disadvantages, especially in acute

gout, I think are numerous, and issues that we

grappled with. Importantly, as has been alluded to

in some of the questions, patients and referring

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physicians know how painful this condition is, many

of the patients have had it before, and they also

know that effective therapies are readily

available.

I really want to emphasize that we are

dealing with both a practical approach and perhaps

an ethical approach, but certainly because of the

practical issues, raise the difficulty of enrolling

patients, and then the question is it really

ethical to withhold effective, readily available

treatment in these patients with highly

inflammatory, very severe pain.

In addition, not only a practical issue,

but an issue that would potentially confound the

data analysis is the issue of dropouts, patients

who maybe were willing to enroll in the study, but

then because they were receiving placebo, continued

to have severe pain, dropped out during the course

of the study or potentially required some rescue

medication, which we can discuss.

The other issue, as I think was addressed

in these prior studies, the potential need to have

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patients in an inpatient setting, to monitor

compliance and to prevent self-medication by

patients with readily available over-the-counter

medications.

If anything, remember the two studies that

I reviewed. Those were inpatient studies. I

think, if anything, those studies may have

overemphasized the speed to resolution because

those patients were not ambulatory.

Now, consider the active comparator

design. The advantages or pros of this design

certainly are that standard therapies,

nonsteroidals, corticosteroids, perhaps to a lesser

extent colchicine in the short term, are known to

be highly efficacious and obviously readily

available.

The ethical concerns do not apply, this is

a more humane approach, giving patients therapy at

the time that they need it, and this presumably

would also minimize the issue of enrollment

concerns, as well as dropout concerns during a

short-term study.

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The cons to a active comparator controlled

trial are also potentially significant, that is,

more complex statistical requirements.

In particular, I am going to touch on

these points, the need really to demonstrate an

assay sensitivity, to demonstrate that the

comparator drug actually works, and, in addition,

the need to assign a comparability bound, to

compare the two drugs, to show that they actually

are clinically comparable or equal.

As you will see, the recommendation after

deliberation of all these issues really to the

sponsor was that this should be an active

comparator design and that the disadvantages or

cons of this design really are manageable compared

to those both practical and ethical that would

relate to a placebo-controlled trial.

Given the recommendation for an active

comparator design, what should be the comparator?

It was really essentially unanimous agreement that

that comparator drug should be indomethacin, 50

mg/3 times a day. This was an FDA-approved drug

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for the treatment of acute gout. It really is a

clinical gold standard widely used in practice and

historically, the first and longest used drug.

This is actually supported by the IMS

database in which, in the United States, Indocin is

the most widely prescribed drug for the treatment

of acute gout. You may recall from the review of

the active comparator-controlled trials, this was

the most common drug used in prior studies.

Now, moving to the issue of clinical

endpoints. Certainly, endpoints should address key

characteristics of the disease and should, to some

extent, reflect the global assessment of response

to therapy.

We certainly are in agreement with the

point advocated earlier that by far and away, pain

is the primary manifestation of this disease,

should be the primary endpoint, not only in terms

of ease of assessment, but importance to patients.

Secondary endpoints could be numerous, but

to the extent that this an inflammatory condition

and we are really looking for a response to

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inflammation, secondary importance, such as joint

tenderness, joint swelling, global assessments to

therapy or symptoms by both patients and

investigators would be appropriate.

Now, also, in terms of the issue of

inflammation, the cardinal signs of inflammation.

We consider the issue of erythema, and really judge

that this should probably be an exploratory

endpoint in this trial because of concern about the

difficulty of objectively assessing erythema in a

given patient, especially given that patients were

likely to have a variety of skin colors and may

make it difficult to assess erythema in a

comparative manner.

What about patient selection, should

patients have a minimum degree of pain before

entering the study?

Well, there is certainly concern that

patients who have mild pain may resolve more

quickly than what we saw in the two trials in which

patients were enrolled with moderate to very severe

pain. It very likely would be the case that some

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minimum degree of pain would be required in order

to demonstrate a measurable response.

So, the recommendation was that patients

who are enrolled in the study should have at least

moderate, severe, or extreme pain at baseline

enrollment.

Now, the important issue about the timing,

should a maximum amount of time since the onset of

the patient\'s symptoms be mandated in the study?

Really, here, the issue is the need to balance the

time required to seek medical attention versus the

time where we might see spontaneous resolution.

I showed you the prior studies that I

think define some of those parameters, and I think

they are well within our own clinical experience,

and the recommendation was specifically to require

enrollment within two days, 48 hours of the onset

of an attack.

What about the issue of self-medication?

Obviously, nonsteroidals are widely available.

Most patients have had attacks before, they know

what to use, they have it available, but there was

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very strong concern that prior treatment in an

acute setting would confound the analysis. So, the

recommendation was that no prior use of

nonsteroidals or corticosteroids would be allowed

for patients to be enrolled for their current

attack.

Now, in terms of the issue that was raised

from some of the questions, what about chronic

therapy? Really, the feeling was I think as

alluded to, that if a patient was on chronic

prophylactic or suppressive therapy and doing well,

now had a recent change in their medication, that

might be the cause of the current attack or might

prolong their current attack, that that would be

okay.

The recommendation was that if patients

were on stable allopurinol or colchicine, that they

actually could be enrolled for an acute attack.

Now, in terms of timing of the

assessments, certainly it is important in terms of

the time that you measure the response, that that

should be integrated over a clinically meaningful

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time period. Certainly, in a disease like gout

where we know eventually, the attack will resolve,

that needs to be within a time period where we will

not be seeing spontaneous resolution.

In addition, given that this is such a

common disease and people are treating it

regularly, it would be important to look at the

assessment over a clinically meaningful or

practical time period that most people are

expecting a response.

Now, going back to the other end, the

outside of treatment or assessment period, but what

about the short end, what about measuring over a

very short time period?

Well, if we had limited data in terms of

the overall duration of an attack, there are even

less data to guide us in short-term measurements.

There are really very little data talking

about acute response to analgesics or nonsteroidals

in acute gout, but there certainly was at least

theoretical concern that for this highly

inflammatory condition, the onset of the effect of

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therapy might take longer than you would normally

see in an acute pain model because of the

inflammatory response, and not too much data to

guide us in predicting for a given nonsteroidal

when that response would occur.

So, the recommendations in terms of timing

were as follows: that the primary time period for

assessment would be over Study Days 2 to 5, and as

I have mentioned, the feeling was that this would

be within a time period where we would not expect

to see spontaneous resolution.

In addition, a secondary time period would

be used over Study Days 2 to 8 to capture that

period which is typical for patients being treated

for gout today in the clinic.

In terms of the short end or the front end

of therapy, the recommendation was to collect data

on pain assessment at a 4-hour time point after the

initial dose of Day 1 of enrollment.

So, given this clinical background and

those study design parameters, I want to just

briefly discuss the issues of statistical analysis

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in a study like this.

One can imagine at least theoretically two

broad approaches to measuring assay sensitivity.

One, we might call a clinical approach or a

qualitative approach. The other would be a

quantitative approach.

I think if I could state in words the

qualitative approach, it would be really that if

the observed response is consistent with clinical

expectations, then, in a comparator design, the

effect would be attributed to the treatment.

Now, this qualitative or clinical approach

really requires a number of things to be in place.

One is to have a comparator drug that is reliable

and effective. That certainly is the case with

indomethacin, the clinical gold standard for

treatment as we discussed, and really, I think

indomethacin has a particular response.

I think that you will see, as you see the

presentation of data from this study, in fact, this

was borne out in the study, in fact, did have a

very predictive response.

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In addition, for this clinical comparison,

it would be important to be confident that gout

attacks would not resolve spontaneously over the

study period, and as I have shown you, we would

predict that that would not occur over the five

days of the study, especially if patients were

starting out with moderate to severe disease.

Finally, this would require that a placebo

effect be small, and as we have seen from the

placebo-controlled trial, there is a small placebo

effect in this disease.

On the other hand, a quantitative approach

would have a number of other requirements.

Unfortunately, we have about as little information

to guide us in this area, as well.

A quantitative approach would really

require that a boundary be established for response

to the gold standard drug, indomethacin, and that

would be the level of response at which

indomethacin would have to exceed.

One needs for this sufficient data from

the literature to determine the magnitude of

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indomethacin\'s effect. Unfortunately, that data is

very minimal, and we will see that in the next

presentation.

But, in fact, there really is no precedent

in the literature for establishing the minimal

effect size for indomethacin or any other

nonsteroidal.

So, because of these limitations, the

clinical experience, the nature of the disease, the

recommendations were that the clinical approach

would be acceptable in an assay, a study design of

this sort, but that a quantitative approach would

be included as supportive information to the extent

that it was supported in the literature and could

be measured in the clinical study.

Once the gold standard or active drug is

chosen and presumably an assay sensitivity could be

ascribed, the other important point then, and

requirement, would be that some boundary of

difference between the active comparator and the

study drug be established.

This would really be the boundaries for

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the difference between indomethacin and the study

drug within which those drugs must fall.

This, we felt really needed to be based on

not only extrapolation from other conditions or

information in the literature, but really based on

something that would be clinically relevant and

clinical judgment.

The recommendation here was that the

boundary for effect size of the two drugs be

established at 0.5 on a zero to 4-point scale.

This 0.5 threshold is somewhat more stringent than

the Delphi consensus, which has been established

for osteoarthritis, which is 0.7 on a zero to

4-point Likert scale.

I think it is also consistent with

clinical judgment about what is a clinically

relevant or important degree or pain relief, and

also a level that has been used in other clinical

trials, for example, osteoarthritis.

Finally, then, this is just a graphical

representation of what I am talking about in terms

of comparability.

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This just shows the mean difference over

Days 2 to 5 when we would just theoretically

conceptualize between two drugs, and the

requirement here would be that the mean difference,

as well as the 95 percent confidence intervals for

study drug compared to active comparator, would

have to be within the comparability bounds of 0.5.

So, I am going to conclude there with that

consideration of general study issues that pertain

to acute gout and those that we considered in this

talk.

I will just actually summarize here for

you, really, that because of our paucity of data,

this is a formidable challenge, and we really based

our design on information that was available, and

really to emphasize as we move forward and look at

the study specifically, to emphasize the key study

issues that we considered.

The issue of active versus placebo

controlled, the challenge that the comparator

control would be manageable while those of a

placebo control would not be approachable in a

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clinical study.

Issues of endpoint, that is, the need to

choose those that are relevant to the disease, and

finally, the timing of assessments, the need to

choose a period least likely to be affected by

spontaneous resolution.

I am now going to turn the podium back

over to Dr. Melian, who will present to you the

specific experience in these studies of etoricoxib

compared to indomethacin.

Experience of Etoricoxib and Indomethacin

in Acute Gouty Arthritis

DR. MELIAN: Thank you, David.

Now that Dr. Daikh has reviewed key issues

that went into the design of the etoricoxib versus

indomethacin studies, etoricoxib being the COX-2

inhibitor that was studied in the Merck studies, I

am next going to go over the study results.

As shown in this next slide, is a

schematic of the study design. The recommendations

of our rheumatology experts were followed in the

design of this study. The study had an active

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comparator design. Patients who met eligibility

criteria were randomized on a 1 to 1 ratio to

receive either etoricoxib 120 mg/once daily or

indomethacin 50 mg/3 times a day.

For the purposes of this study, the first

day of study treatment, which was also the day of

randomization, was defined as Day 1.

Day 1, by definition, had to occur within

48 hours of the onset of the attack, because this

was one of our inclusion criteria, so patients had

up to 48 hours, if they met inclusion criteria,

they were then randomized to one of these two study

treatment groups.

A study timeline showing day of study and

day relative to the onset of attack is shown on the

bottom of this slide.

The primary efficacy hypothesis of these

studies was that etoricoxib 100 mg/once daily would

demonstrate clinical efficacy comparable to

indomethacin 50 mg/3 times a day as assessed by the

patient\'s assessment of pain over a 4-day period,

Days 2 through 5.

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A secondary hypothesis was comparability

to indomethacin, the patient\'s assessment of pain

over Days 2 through 8.

The primary and key secondary endpoints

are shown here. The primary endpoint was the

patient\'s assessment of pain. The primary endpoint

was recorded on a zero to 4-point Likert scale

where zero reflected none or no pain, and 4

reflected extreme pain.

The primary assessment period was Days 2

through 5. The secondary assessment period was

Days 2 through 8, and there was additional

assessment period on Day 1, 4 hours after the

initial dose of the study medication.

Key secondary endpoints included the

patient\'s global assessment of response to therapy,

and assessment of study joint tenderness.

Additional endpoints included the

investigator\'s assessment of study joint swelling,

the proportion of patients discontinuing due to

lack of efficacy, and the exploratory endpoint,

proportion of patients exhibiting joint erythema.

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As noted, the latter was designated as

exploratory in this study over concerns that it

might be difficult to detect study joint erythema

in patients with distinct skin colorations. In

fact, as you will see later in this presentation,

that concern turned out to be unwarranted, and, in

fact, erythema was detectable in the majority of

patients.

The timing of the assessments during the

study period are shown here. Patients, for the

primary endpoint, were assessed at baseline, then

again at 4 hours after initial dosing, and then

once daily over a 7-day treatment period.

For the secondary and exploratory

endpoints, patients were assessed on Days 2, 5, and

8\. All patients had baseline measurements except

for the patient\'s and investigator\'s global

assessments of response to therapy since, by

definition, patients needed to be on therapy in

order to answer this question.

The basic selection criteria are shown in

this slide here. All patients had to be randomized

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within 48 hours of the onset of their attack of

acute gouty arthritis. All patients had to have a

clinical diagnosis of gout as defined by the

Wallace criteria or the ARA criteria, which we have

heard about previously.

All patients also had to have moderate,

severe, or extreme pain at baseline.

Patients who took a COXIB, an NSAID, or

corticosteroid before coming into the trial were

excluded from randomization.

Patients who were on baseline preventive

gout medications, such as colchicine or

allopurinol, were allowed to come into the study as

long as the dose of this therapy had been stable

before they came to the study, and was not

anticipated to change during the time of the study.

Basic enrollment characteristics are shown

in this slide here. The first study enrolled 150

patients, and the second, 189. These are, to the

best of our knowledge, the largest gout studies

that have ever been performed.

In order to enroll this number of

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patients, it was actually a formidable task. We

used over 40 sites for each of these studies, and

over 10 countries.

The main reason, in discussion with

investigators, that we had difficulty recruiting

patients was, in fact, that most patients

self-medicate before they ever came into the

clinic.

Baseline characteristics and demographics

for the study are shown here. Patients who entered

the study were typical of those with acute gouty

arthritis. The mean age of entry was approximately

50\. The majority of patients were men, and

patients were of diverse racial and ethnic

backgrounds.

As is typical for patients with acute

gouty arthritis, the majority of patients had

monoarticular disease. The most common site of

arthritis in these studies was the first toe, first

MTP.

Approximately 28 to 29 percent of patients

in this study had polyarticular disease, suggesting

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a slight bias towards patients with severe

symptomatology. Consistent with this hypothesis,

what we saw was that the majority of patients had

severe or extreme disease.

If we looked at the average time from the

onset of attack to when they entered the study, on

average, patients came in within one day of the

onset of their attack.

This time to onset of attack to when they

were enrolled in the study presumably reflects the

time required for the gout flare to flare

significantly enough that patients go to see their

physician, and also the logistics involved with

actually getting in to see one\'s physician or care

provider.

In the following slide are shown patient

disposition. The majority of patients who enrolled

in these studies continued to finish study period.

There were slightly more discontinuations due both

to lack of efficacy and due to adverse experiences

on indomethacin compared to etoricoxib, but, in

general, in both groups, the number of patients

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discontinuing was low.

Shown next is the treatment effects for

the primary endpoint, the patient assessment of

pain. What we can see here in blue is the response

amongst patients treated with indomethacin. Along

the y axis is change from baseline, and along the x

axis is mean days since the onset of their attack

of acute gouty arthritis.

What you can see here for indomethacin is

we see that most patients were, in fact, on

average, enrolled at the 24-hour period since the

onset of their attack, and we just what we expect

in terms of the treatment effect, a rapid and

marked treatment response seen within the first 24

to 48 hours.

Although one needs to be cautious when

comparing data across studies, it is helpful here

to compare what we saw in this study to the Bellamy

study, remembering again that the Bellamy study was

the observational study where patients were

followed over time in the absence of treatment.

What we saw in that study is that

129

patients, on average, were enrolled approximately

three days after the onset of their attack, and for

the patient assessment of pain, they saw very

little to no response out to Day 5 since the onset

of their attack.

This is in marked contrast to what we saw

with indomethacin in terms of effect size in this

study. If we next look out over the subsequent

four days, what we see is small treatment effects

in the indomethacin group and small improvements

also in the observational study. However, the

relative magnitude of these effects compared to

that seen early on with treatment with indomethacin

was small.

Next, shown in yellow, is the response for

the primary endpoint for etoricoxib. What we can

see here is a very familiar pattern where the

response for etoricoxib over Days 2 to 5, the

primary assessment period of this study, Days 2

through 8, the secondary assessment period, and

also on Day 1, four hours after initial dosing, was

practically indistinguishable from that seen with

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indomethacin. This is for the first of our two

replicate studies.

If we next move on to the second of the

two replicate studies, shown here on the right, we

can see a very familiar pattern, once again looking

almost indistinguishable from that seen in the

initial study.

What this suggests to us is that gout

actually in appropriately designed trials is a

highly reproducible model and that with effective

inhibition of cyclooxygenase, either nonselectively

with indomethacin, or highly selectively with

etoricoxib, you can see these marked improvements.

So, now, let\'s next move on to secondary

and exploratory endpoints. If the scout study

design is truly robust, what we would expect to see

is similar effects across multiple endpoints, and

that is, in fact, exactly what we can see.

What we are looking at here is results for

joint tenderness and joint swelling. On the next

slide, we will see patient and investigator global

assessments, and we will see essentially the exact

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same response that we saw with the primary

endpoint, with a marked response occurring early on

during treatment and maintained throughout the

treatment period.

We see this again, tenderness and

swelling, and on the next slide, we are looking at

patient and investigator global assessments. For

the patient and investigator global assessments,

these are shown in a slightly different format

because there was no baseline measurement for this

endpoint.

So, what you are looking at here actually

is the percent of patients that had a good to

excellent response from either the patient\'s

perspective for the patient global assessment of

response to therapy, or the investigator\'s

perspective for the investigator global assessment

of response to therapy.

You can see that in each case, that by Day

2, the majority of patients from either the

patient\'s or the investigator\'s perspective had a

marked improvement in terms of response to therapy,

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and that these improvements are maintained through

the 8-day treatment period.

Lastly, moving on to the more objective

measurement of study joint erythema, the results

are shown here. What we can see here in these two

replicate studies is that the majority of patients

in both studies, over 90 percent had erythema at

baseline.

Thus, our concerns that this endpoint

might not be as easily detectable as some of the

others, in fact, in appropriately selected

patients, as we saw here, it turned out to be

unwarranted, and although I am not showing you, we

did subgroup analysis broken down by race, and what

we saw there is that in each racial subgroup,

approximately 90 percent or better of the patients

had detectable erythema at baseline.

Then, let\'s look at the response over time

where we can see here once again that same pattern,

by Day 2, 50 percent of the patient approximately

had complete resolution of their study joint

erythema, and by Day 5, only 10 to 20 percent of

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patients had any residual erythema detectable.

So, in summary, these results indicate

that both indomethacin and etoricoxib were highly

effective for the treatment of acute gouty

arthritis. We saw rapid treatment effects and we

saw improvements across multiple domains.

Now that we have reviewed the results of

this study, let\'s next review the methodology. In

order to have a successful study with an active

comparator, as Dr. Daikh went over for us, there

are two distinct criteria that need to be met.

The first is that the active comparator

needs to have been shown to have performed as

expected, and the second is that the test drugs

needs to have been shown to be comparable or

perform similarly to the active comparator.

In this study, indomethacin was chosen as

the active comparator control because it was

considered, based on clinical experience, to be

highly reliable and thus, the appropriate standard

for the treatment of gout.

So, based on the clinical approach, was

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indomethacin effective, so based on clinical

experience, was indomethacin effective in this

study?

The answer is yes, indomethacin performed

exactly as expected. There was a marked and rapid

treatment effect, it was seen across multiple

endpoints and multiple domains, and by Day 2, the

second day of dosing, the majority of patients had

a good to excellent response.

Moving next on from the clinical approach

to the analytical approach, how did indomethacin

perform compared to data generated in previous

clinical studies? In these analyses, the

analytical approach was considered secondary or

supplementary because it was complicated by a

number of factors.

First, was the relative paucity of data in

the clinical literature on which to base effect

size, and the second was the lack of any generally

accepted convention on how the minimal bound for

effect size should be calculated.

Despite these limitations, prespecified

135

criteria for the minimal bound for indomethacin

effect size were derived, such that at the end of

the day, there would be objective criteria to

ensure that the positive control had performed

well.

In order to do these analyses, the effect

size bound was derived from the only study in the

literature, a study of ketoprofen versus

indomethacin, which provided serial data on pain,

on the serial data, on the effect size, and

variability obtained over the appropriate time

period.

Because this study collected data on a

3-point Likert scale, and ours was a on 4-point

Likert scale, this data was rescaled to a zero- to

4-point Likert scale.

We then extrapolated recommendations from

previous FDA guidance on rheumatoid arthritis,

which suggested that in studies lacking placebo, a

test drug should maintain at least 60 percent of

the active comparator effect size, and applied this

general rule to the ketoprofen study, and arrived

136

at a minimal effect size of negative 1.46 Likert

units.

We prespecified for our studies that both

the point estimate and the 95 percent confidence

interval for that point estimate for indomethacin

needed to surpass this 1.46 Likert unit bound.

Although these analyses required

substantial extrapolations, they did at least

provide some objective criteria to support the

subjective clinical assessment of efficacy provided

in these studies.

Shown here now are the results for

indomethacin compared to the 1.46 Likert unit

bound. Shown on the left are the results of the

first study 040, and on the right, the second study

049\.

What we can see in both cases, both the

point estimate and the 95 percent confidence

interval for that point estimate surpassed or

passed the minimal effect size calculated from the

previous study.

That is whether you are using the

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quantitative approach shown here or the qualitative

approach which we reviewed in terms of looking at

the overall data from the studies and saying did

indomethacin perform as expected based on our

clinical experience and our clinical

interpretation.

The answer is the same, is yes, the active

comparator worked in these studies.

Now, once you have established that the

active comparator worked, the next question is did

your test drug work comparably or similar to your

active comparator, in this case being indomethacin.

In order to establish this, we followed

the recommendations of our experts and used the

comparability bounds of 0.5 Likert units. Once

again, the 0.5 Likert units was chosen because it

was smaller than the 0.7 Likert units suggested in

the Delphi experiment to be a clinically meaningful

difference, and it is also consistent with half the

distance between adjacent points on a Likert scale,

suggesting that if two values fell within this

difference, on average, they would score the same

138

on the Likert scale.

Results here are displayed as difference

between means for etoricoxib versus indomethacin.

What we can see here is the point estimate in both

of these studies, whether we looked either over the

primary assessment period, 2 through 5 days, or 2

through 8 days, fell very close to the equivalence

mark here shown by the solid line, and

approximately 0.1 Likert units, and we see that

both the point estimates and the 95 percent

confidence intervals fall well within the 0.5

Likert unit boundaries shown by the dotted line

above and below in these grafts.

So, in summary, I think the data that is

generated in these studies actually demonstrates

that the acute study design used in them is robust.

Indomethacin performed reliably and as expected in

the studies, and the endpoints are highly

reproducible between studies, and results were

consistent across endpoints.

In replicate studies, etoricoxib and

indomethacin performed comparably based upon

139

predefined criteria, and putting all of this

together, what it suggests is that meaningful

results can be obtained in the absence of placebo.

With that, what I would like to do is now

turn the podium back over the Dr. Daikh for a

discussion of lessons learned.

Lessons Learned

DR. DAIKH: So, you have had a review of

the issue of acute gout and we have talked about

some of the general and theoretical concerns of

study design, and now a review of the results from

these two studies.

Let me just leave a couple comments in

terms of what we did learn from the study and

perhaps provide a preview of a discussion in terms

of what we may talk about in the future.

Certainly, a major lesson, a major

conclusion from these studies was that recruitment

was very difficult. We had predicted that the

difficulty with a placebo-controlled trial would be

insurmountable from a practical standpoint, but, in

fact, even with an active comparator-controlled

140

trial, recruitment was very difficult.

I think as Dr. Melian planned out, this

required a number of centers around the world, and

I can speak from personal experience, I was

actually quite surprised. I was anticipating in a

VA setting that we would have a lot of ease in

getting patients.

I certainly agree with the point that we,

as rheumatologists, are seeing a minority of

patients, but I had very close working

relationships with the docs in the ER, with the

clinic docs, and obviously, in setting up the

study, there was a plan to have direct

communication, and even with all those efforts, it

was very difficult.

Patients were just taking medications

before they came in.

What about potential considerations

looking forward to future studies? Well, in

retrospect, looking at the reproducibility of the

data even in a very short time period, it seems

that it may be interesting and informative to

141

collect additional data pertaining to the onset of

clinical signs and symptoms in acute gout. It may

be beneficial to look at earlier times.

I think it would be reasonable to explore

the use of pain measurements over perhaps multiple

parameters and early time points, perhaps even

considering the use of stop watches as has been

done in some acute pain models.

It is also very reasonable to explore the

use of alternative pain scales, perhaps to enhance

precision in other than the zero- to 4-point Likert

scale used in this study.

As you are all very familiar, a number of

different measures and instruments could be used,

whether they be a visual analogue or a broader

numerical scale.

I think it also, looking forward, would be

very useful to consider the inclusion of a

functional outcome measure in a disease like acute

gout, that would have a meaning both in terms of

patient outcomes and also the ability to assess

efficacy of a drug.

142

So, with that, I am going to pause, and

that is the sum of our presentation in terms of

experience in the study of acute gout.

I appreciate the attention.

DR. GIBOFSKY: Thank you, gentleman.

At this point, what is the Committee\'s

pleasure, we are scheduled for a break, or we can

begin our discussion of this paper and then take a

break?

Discussion followed by a break seems to be

the consensus of the Committee.

Dr. Anderson, you have the first question.

Discussion

DR. ANDERSON: Those studies were very

nicely presented and very clearly presented. I

just have a couple of short questions.

I was wondering why you used the Likert

scale even though you would expect that VAS might

offer more precision, and what you had investigated

about that before deciding on the Likert.

The other question is about the use of

least squares means, which are in all of those

143

plots, and it wasn\'t described what you adjusted

for, and it sort of raises the issue of why that

was necessary and whether there were rather

different results for some subgroups of patients.

DR. DAIKH: I will just respond in

general. I think it is a very good point that

there are a number of scales that could be used,

and that is what I was trying to get at with the

summary slide, to open up the discussion.

We certainly did discuss the possibility

of using a visual analogue, for example, but I will

let Dr. Melian address this, as well, really

relating to the broad experience of the sponsor in

other pain models with this scale.

DR. MELIAN: We had used Likert scales in

a number of other pain models, and it seemed to

make sense for us to bring that forward. Also, in

sort of reviewing the literature, one of the main

studies we were looking back to was the Bellamy

study, and in that Bellamy study, they also used

the similar Likert scale for pain, so it at least

gave us a good anchor to use.

144

We know that in some studies, VAS\'s are

used, in other studies Likerts are used, and they

generally tend to correlate fairly well. Would it

have been wrong to use a VAS scale, probably not,

and it might be interesting for future studies to

actually VAS and Likert scales together an see how

well they correlate in acute gouty arthritis.

DR. GIBOFSKY: The second question before

we get to Dr. Hochberg, there was a question from

Dr. Anderson about least squares.

DR. MELIAN: I am actually going to bring

up Jim Bolognese, who was the statistician on this

study. Jim, if you could address the question on

least squares.

DR. BOLOGNESE: The study was stratified

by poly or monoarticular involvement, so that was a

factor in the model, and also baseline pain was a

factor in the model, so the results are adjusted

for those two factors in the analysis of variance

model.

DR. ANDERSON: But were there rather

different results?

145

DR. BOLOGNESE: No, the results were very

consistent across those two endpoints.

Interactions were not close to being significant.

DR. MELIAN: But this actually does bring

up a question or an issue that was raised earlier

amongst the panel with Dr. Cush\'s presentation,

which is polyarticular versus monoarticular.

Obviously, what we did in our study was we

enrolled both patient subtypes because, if not, we

really wouldn\'t have any data on the polyarticular

disease. What we saw was, in fact, there were

similar results between the two active treatment

groups in both groups.

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: Thank you, Dr. Gibofsky. I

am only going to ask\--I have several questions, but

I am only going to ask one, and the one I am going

to ask deals with something which was brought up

during Dr. Cush\'s presentation, and the subsequent

discussion.

You enrolled patients within one day, so

patients came in, they were evaluated, and they

146

were randomized on the same day. So, what did you

do in terms of the screening of those subjects at

the time that they came in given the concerns that

were raised in the presentation that you might end

up enrolling people who had renal insufficiency,

other laboratory abnormalities that might be

relative contraindications to NSAID use?

DR. DAIKH: I will take that. Obviously,

very important considerations, and once again,

another way in which there was a need to balance

the practical considerations of enrollment with the

clinical concerns of the patients.

So, what we did specifically in the study,

in anticipation that the decision would need to be

made at the time of enroll and treat, or not enroll

and treat, for patients who had uncontrolled

hypertension, 165 and above, 95 and above, they

were excluded.

From the standpoint of renal function, we

issued guidelines to investigators that history of

significant renal insufficiency would be a

contraindication, and that was defined as greater

147

than 2 or a clearance of 30 or less.

Now, in terms of laboratory testing, that,

of course, the ease of that varies by study site,

if it was in a clinic versus a hospital setting,

but if there had been no laboratory testing within

the prior year that would guide the physician in

terms of their ability to conclude there was

significant renal involvement, mild dysplasia, et

cetera, then, it was required that they obtain

laboratory testing with results of CBC, creatinine

before enrollment.

If there were values available for the

preceding year that were reassuring, then, they

could be enrolled.

DR. MELIAN: Obviously, this is one of the

challenges with recruitment, and we worked very

closely with sites to try to make sure that, where

possible, they could turn over labs as quickly as

possible.

I think Dr. Cush said one hour. Our

experience is that most places can\'t get labs back

in one hour, but some places can, so this is where

148

we really had the interaction with the site, worked

closely with them, to try to get labs back as

quickly as possible, and in terms of those patients

we couldn\'t get labs back in time, we followed the

recommendations as Dr. Daikh has described.

DR. GIBOFSKY: Thank you, Dr. Hochberg. I

have put your name back on the queue for follow-up

questions later.

Dr. Weisman.

DR. WEISMAN: You mentioned that there

were difficulties in recruitment in spite of the

fact that you chose this study design.

What were those difficulties and how do

you relate them to the kinds of issues that Dr.

Cush brought up earlier about theoretical

difficulties in recruitment, what were the

practical difficulties and did they match what Dr.

Cush had mentioned earlier?

DR. MELIAN: I will let David give you

firsthand experience with that, and then I can give

you some of the secondary feedback we got from the

investigators.

149

DR. DAIKH: In my experience, I think they

matched very well with the concerns that Dr. Cush

raised. Even in a setting where rheumatologists

are actually involved in teaching other primary

care physicians and interacting with them, a lot of

these patients came to us from clinics and the

ambulatory walk-in ER.

So, sometimes there were issues of prompt

recognition of acute gout and sort of making the

call quickly to us, but by far and away, in my

experience, the difficulty was pretreatment.

Patients had come in having already taken an NSAID,

or having been given an NSAID by a doc in the box

before they came to our study site.

The other extreme, and I think it actually

probably pertains somewhat more to a VA site, the

other extreme we would see occasionally would be

the patient that actually had been holding out for

36 hours or longer before coming in, so by the time

they came in were evaluated as beyond the two days.

DR. WEISMAN: They spent a couple of days

in the emergency room?

150

\[Laughter.\]

DR. DAIKH: No comment.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: Going back to the

polyarticular patients, for the physical exam

components, I was wondering if you could tell us

how you analyzed those data. Did you develop a

single chain score for swelling and tenderness and

erythema, which was an average of all the joints?

Secondly, how did you identify the

involved joints, was it patient report, or was it

based on tenderness on the exam?

DR. MELIAN: The involved joints were

essentially dependent upon whether the patient

reported symptoms, and it was confirmed by the

investigator that was present.

In terms of the actual scale used, it was

on a Likert scale, and if I could have that scale

pulled up for the swelling, I will show you

exactly\--

DR. BATHON: One of the problems of

swelling in gout is you can have a single joint

151

involved and have, as you know, really widespread

swelling with pitting edema, so it can sort of

obscure really uninvolved joints.

DR. MELIAN: Right.

DR. DAIKH: The guidelines were

specifically focusing on an index joint and

measuring swelling of the joint itself. For those

patients who had oligoarticular attack, then, the

guideline was to pick the most severely involved

joint, the most painful reported joint or most

tender joint, and then from time of enrollment on

down, that would be the single index joint that was

assessed.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: Two things. One, was this a VA

study, or were there other sites other than VA?

DR. MELIAN: We used VA sites, but we did

not explicitly use VA sites. In fact, each study

was performed in over 40 sites and over 10

countries each. So, we really scanned the world to

get appropriate patients.

DR. CUSH: I am confused by some of the

152

fuzzy math that you presented. What I am confused

by is you used Bellamy\'s paper and said that there

was two days of symptoms, and you added that on to

what they reported to give us some graph.

Firstoff, that was a mean of 2.8 days, and

it ranged from 1 to 5 and you don\'t know.

DR. MELIAN: That\'s correct.

DR. CUSH: You shouldn\'t be doing that.

You can only report what you know, and everything

else is extrapolation. Even in your own studies,

you have patient report of what happened, and I

think it is misleading.

I mean it is useful information to put in

the paper, but then to plot out and hazard a

separate x axis just confuses matters because then

later on in your presentation, you are telling us

you did things on Days 2, 3, 5. I am not sure

which days 2, 3, and 5 you are talking about.

So, is it the Patient Day 2, 3, 5, or is

it the chronological study day? I actually know,

but I am saying the ladder along the bottom needs

to be gone. It sort of obscures what is true and

153

what you can hang your hat on.

DR. MELIAN: Obviously, if you go the

paper, what we are showing is the study day. What

we did here, because the purpose of this meeting is

to discuss what is the natural course of acute

gouty arthritis, and the best we could do was try

to take an average of the data out there to try to

see what it would look like, and since, on average,

those patients came in 2.8 days after the onset of

attack, we used that.

We can show you the data the other way.

We have it the other way.

DR. CUSH: Again, it just obscures, I mean

you can have a limitation to duration of symptoms

at entry, and that is information. It is the same

for other trials, other diseases, but then when you

are reporting responses, you can\'t include that in

your time to response, because you really don\'t

know, and everybody\'s is different.

DR. DAIKH: I think that is absolutely an

appropriate point, that the 2.8 days are an

average. So, in fact, the data should be made more

154

fuzzy, that is, any defining line should have a

spread around it.

I think the point that I was trying to get

at in terms of general considerations in study

design, I think that it is very important to pick a

time within which you have got to look at the

patient, and I don\'t think it is necessarily

exactly in the 2- to 5-day period because of the

uncertainty in the Bellamy paper and the absence of

other papers, but I don\'t think it\'s 3 days either.

DR. GIBOFSKY: Dr. Geis.

DR. GEIS: On the Bellamy data, though, I

wouldn\'t suggest that it really reflects what a

placebo response would be.

DR. MELIAN: No, the only data we have on

placebo comes from the Ahearn data, which was the

colchicine comparator study, which Dr. Daikh

presented.

DR. GEIS: Because in my experience, when

you give a placebo in acute pain setting, you can

get an enormous response, it looks like an

effective drug, especially in the first few hours.

155

So, my question then is what was your

4-hour data? I know you referred to it, but I

don\'t see it here. Did you ever blow it up?

DR. MELIAN: If we can put up the slide

from the presentation, what you can see is that at

4 hours, there is actually pretty marked data,

pretty marked response in both treatment groups.

So, from the presentation, that is Slide No. 17.

We are looking at indomethacin, but etoricoxib

performed similarly.

At 4 hours, you see a response of

approximately 1 Likert unit, and then you see a

continued response over time. The largest response

occurs over the initial 24 to 48 hours.

DR. GEIS: Thank you.

DR. MELIAN: I think one of the things you

do see in the Ahearn paper, though, which is

consistent with what is discussed in the critical

literature, they are not always shown, is that the

placebo response there is relatively low, and I

think one of the things is when you have a disease

that is driven by inflammation, particularly fairly

156

potent inflammation, you probably get less of a

placebo response.

Do I have data to support that? Well, the

only data available is that from the Ahearn paper,

and that had a very little placebo response.

DR. GIBOFSKY: Thank you.

Dr. Cronstein.

DR. CRONSTEIN: Thank you. I had a

question about the way you presented the data,

which is the mean reduction in Likert score. I

guess the problem I am having is it looks like,

judging from starting with a mean score of about 3,

that none of these people got complete resolution

by 8 days. Is that correct?

DR. MELIAN: That is actually not correct.

We actually have some data showing the degree of

patients who had resolution. Well, I showed you

the degree of resolution for erythema, you

remember, by Day 2, approximately, 50 percent of

the patients had resolution of erythema by Day 5,

80 to 90 percent, and we also have data on percent

of patients who had complete resolution or had mild

157

to no pain.

Actually, it\'s very interesting. The

results are practically superimposable. Whether

you look at erythema or you look at percent of

patients who had mild to no pain, you get these bar

graphs that you could almost lay right on top of

each other, suggesting that overall, these endpoint

correlated extremely well.

The same thing is seen with tenderness,

same thing is seen with swelling. I think what it

is telling us is this really a disease that is

driven by inflammation.

So, even though NSAIDs and COX-2

inhibitors have an analgesic effect, that when you

look at the overall picture and you are looking at

improvement, what you are seeing is all the

endpoints corresponding sort of in the same pattern

or in line with each other, and I think what that

means is, well, yes, now you are starting to treat

the inflammation, and you are seeing the effect,

and the effect is across the board.

DR. CRONSTEIN: So, out of curiosity, who

158

are those people who didn\'t respond, that didn\'t

have complete resolution? You show about 20

percent of them still didn\'t. Were they the

polyarticular or the more severe, or did you break

it down that way?

DR. MELIAN: Well, if you would look over

time, the response in the polyarticular to the

monoarticular is very similar, but the

monoarticular has just a very smidgen is probably

not\--I mean I know it is not statistically

significant, but the monoarticular has a very small

increase in response compared to the polyarticular.

What is really interesting is the

precision of the data, though, because if one looks

at the treatment groups for the monoarticular, they

respond almost exactly the same.

You saw how small the variability was in

the study, and when you look at the two after

treatment groups, the responses are almost exactly

the same, and then you see the slight bump-up, or

bump-up meaning slightly less response even though

not statistically significantly different in the

159

polyarticular group with the very tight confidence

intervals, it says there is probably a slight

difference here with polyarticular taking a little

bit longer to improve.

DR. GIBOFSKY: Gentlemen, please use the

microphone, or you will be asked to make a

significant contribution to the Chair\'s retirement

fund.

Dr. Harvey.

DR. HARVEY: Actually, I would just like

to say that the FDA is finding this discussion very

helpful, and if I could ask the Chair if we could

take a break now and then actually continue the

discussion after a short break?

DR. GIBOFSKY: We have several other

people in queue, I think. We will continue the

discussion after the break, but I would like to

give the colleagues who have been queued up, an

opportunity.

Dr. Boulware.

DR. BOULWARE: My question has to do with

the inclusion/exclusion criteria you used and

160

specifically colchicine. You, I think

appropriately, excluded people who may have

self-medicated themselves with COXIBs and NSAIDs

and steroids, but you didn\'t mention colchicine.

Was that inquired and was that prevalent,

and why did you not include that, too?

DR. MELIAN: Well, what we did was if a

patient was on stable base like colchicine for

preventive use, we allowed those patients into the

study, because those patients were flaring on top

of their colchicine.

They couldn\'t have changed their dose,

though, so of the patient was on colchicine, they

had a flare, and they said, oh, well, now I am

going to take 2 tablets instead of 1, that patient

was excluded.

Also, they weren\'t allowed to change their

dose during the study period, so they had to stay

on consistent or constant dosing throughout the

study period. What we were trying to do here was

really look at these drugs the way they would be

used in real life, and that is the way you

161

typically used drugs, or at least NSAIDs or

indomethacin in acute gouty arthritis.

DR. BOULWARE: But there are occasional

patients who keep their colchicine at home, and

they will start and self-initiate the treatment, so

I guess you excluded them because their baseline

was zero.

DR. MELIAN: If they started the

colchicine anytime within the previous\--it was 2 to

4 weeks, I would have to check exactly\--4 weeks,

sorry, 4 weeks, they weren\'t allowed into the

study.

DR. GIBOFSKY: There are two colleagues in

queue who we will continue now, and then we will

take our break.

Dr. Hochberg with a follow-up question?

DR. HOCHBERG: If I can follow up on

something which Dr. Cronstein started. The average

pain when patients began in the study was severe on

the 5-point Likert scale, and the average at the

end of the study was mild, and we know that there

are about 20 percent who don\'t respond with regard

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to the good or excellent improvement on the global

assessment of response.

So, the first question is should one look

at what is really important to the patient is not

that they still have mild pain, is that the pain is

gone, resolution of pain as the outcome variable,

and the second, which that might happen, but you

don\'t see it often in a 7-day study, so should the

study, in fact, be longer than 7 days, and maybe

you can tell us what happened to these patients

after 7 days.

DR. DAIKH: I agree with you in general,

but again this is a balancing of a clinically

meaningful time period. Maybe 9 days would be

better if you get to complete resolution in 95

percent of those patients, but then you have to

start worrying about the spontaneous resolution

period.

Now, whether or not there should be an

outcome that would be setting a threshold for a

clinically meaningful degree of pain relief, that

is I think a very reasonable point and worth

163

discussing.

In terms of whether or not the patient

really\--I mean obviously they would prefer to have

no pain than mild pain\--but I think mild pain

compared to placebo would be clinically meaningful

at 7 days, for example.

DR. GIBOFSKY: Dr. Hoffman.

DR. HOFFMAN: I think that the diligence

with which this study was designed and carried out

makes contributions beyond just setting a new

standard for rigor in trials with pharmaceutical

agents.

One of the things that I am wondering

about in terms of your exploratory endpoint of

erythema is fortuitous, that you look at it as an

exploratory endpoint in part because of what a soft

measurement it is, but also it raises questions

about whether erythema always is part of

inflammation, because we know in a variety of other

situations, such as studies of wound repair, tissue

regeneration and repair from trauma, that is either

surgical or accidental, that we often see erythema

164

persist for extended periods of time even in the

absence of inflammation.

So, I would compliment you on having

brought that issue to further light and discussion,

and I would take that as evidence for us not to

include erythema as an important endpoint in

looking at gout or perhaps other inflammatory

conditions where indeed it may not be such an

accurate marker of inflammation as opposed to

tissue repair.

DR. MELIAN: I think what we heard from

Dr. Cush, and obviously we took the same approach

in our study, was that the primary symptom that the

patient is most concerned about is pain. We did,

as I mentioned, looked at erythema because it was a

potential marker of inflammation.

We had the same kinds of concerns that you

have. There were approximately 10 to 20 percent

that by Day 5 hadn\'t cleared the erythema, and

maybe those are the kinds of patients that you are

discussing, but in the majority of patients, it did

correlate extremely well with the other endpoints,

165

and even if it is not a primary endpoint in

studies, I think it provides additional valuable

information at least in the sense that if you could

see that it correlates in general, not necessarily

on a per-patient basis, I think that would add to

one\'s interpretation of the data.

DR. HOFFMAN: I was speaking more to the

fact that at Day 8, there was still, in the absence

of significant pain, perhaps no pain, that there

was still erythema, and certainly we have seen in

our patients, people who still have very modest

erythema that may be there for a week in the

absence of any pain whatsoever. We see it in

surgical wounds all the time.

DR. MELIAN: And I would concur with you,

and I think even in an extremely inflammatory joint

sometimes, because, if for no other reason, you

have this infiltration, perhaps it has to do with

wound healing, but the infiltration of inflammatory

cells, and then you have got a residual.

Sometimes that erythema at the end, at

least in my own personal experience, probably has

166

to do more with the tissue destruction and the

leftover effects of that, and that is probably what

you are getting to with wound healing.

DR. HOFFMAN: I was thinking more of the

neovascularization that we see and when.

DR. MELIAN: I am just curious, the

neovascularization of the wound healing, how

quickly that occurs, so if it is an acute attack of

acute gouty arthritis\--

DR. GIBOFSKY: Presumably, your hand is in

your pocket because you are reaching for your

wallet to make the contribution for not using the

microphone.

DR. MELIAN: I was just curious as to how

quickly that neovascularization occurs.

DR. HOFFMAN: I can only speak to

experiments done in college many years ago, where

we actually saw neovascularization in the process

of wound healing within a week. That is not a

literature I follow anymore.

DR. GIBOFSKY: Very quick question before

we break. You told us about 8 patients, 7 have an

167

adverse event, 1 had a laboratory adverse event.

Can you give us a little bit more detail

on those 8 patients?

DR. MELIAN: I am happy to. I just want

to make sure, because it doesn\'t have to do so much

with study design. In terms of discontinuations

and adverse experiences in this study, the most

common adverse experiences were just those that one

would expect to see with NSAID treatment, and

particularly with indomethacin.

Dr. Cush actually showed in his slide our

data on safety, and what you saw was that the

safety features, the adverse experiences, the most

common body system involved was actually the

neurologic, and you saw the same sorts of CNS kind

of adverse experiences that one would expect with

indomethacin - dizziness, lightheadedness, these

kinds of vague neurologic findings. Headaches were

extremely common, and you saw a marked difference

between the indomethacin group and the etoricoxib

group.

Other body systems, GI was a fairly common

168

one. Once again, with a selective inhibitor, you

saw less of that than you did with indomethacin,

but overall, the number of events was low.

DR. GIBOFSKY: Thank you.

At this point, we will take our break. We

will come back and resume if there is further

discussion on this paper. If not, I am told that

there are no individuals queued up for public

comment. So, if there is no further discussion on

this paper, when we come back into the regular

session, we will go right into the questions that

have been posed to us by the Agency.

A 15-minute break. Let\'s resume at 11:13.

\[Break.\]

DR. GIBOFSKY: You will all note that a

floor mike has been put in that corner of the room,

so that that will diminish the Chair\'s retirement

fund in the event that people have to respond from

other parts of the room.

We are going to resume the morning

session. I would like to continue if there are

further comments about the presentation this

169

morning, I would like to continue that discussion.

I was told that the Agency found our discussion

particularly useful and would like to see if there

are any further comments from any other members of

the panel or additional comments from the members

of the panel who spoke on the presentation this

morning.

Are there further comments or discussion

from other members of the panel? Dr. Cush.

DR. CUSH: I would like to make I guess a

pitch for Likert scale evaluations. My concern

about a 10-centimeter Visual Analogue Scale, while

it gives you the presumption of greater spread and

ability to pick up finer degrees of change, in

fact, I think that it doesn\'t, because most people

are afraid of doing the extreme unless there they

have an extreme response meaning they are totally

well and they will go to zero.

Most people avoid the first centimeter or

two on this end, they tend to bunch up in the

middle anyway, and most Visual Analogue Scales

don\'t have descriptors whereas, the Likert scale,

170

you know, on this zero to 4 scale with the

descriptors, I think is much more objective and I

think shows degree of change, which we can really

hang our hats on.

Again, it is less sensitive to lesser

degrees of change, but lesser degrees of change are

not important in a disease of this magnitude. I

mean I think we are looking for acute gout control

where you are looking to hit a home run in every

situation.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: I think the data would

support that either scale is equally effective, and

either one can be used and show similar results.

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: Well, I guess I want to

come back to the issue of outcomes, and maybe Dr.

Anderson would want to comment. I don\'t know if

you want to do this now or do this later, but in

terms of whether we want to look at this as a pain

model and measure improvement in pain, the way it

was done in the data that were presented to us, or

171

whether we want to look at, you know, sort of

reaching a level of no pain or reaching a level of

mild pain, or a certain degree of improvement.

Thinking about what exists now is outcomes

in rheumatoid arthritis trials, for example, where

one can reach a state, for instance, using the DAS

of low disease activity, or one can have an ACR50

improvement, something like that, whether we should

I guess think about that as moving in that

direction maybe for discussion with the Agency with

regard to gout studies, and whether the data that

were collected during the studies that were

presented to us would be useful in terms or

exploratory analyses in that way.

DR. GIBOFSKY: I am certainly comfortable

in entertaining discussion on that now, and then we

can formalize our discussion when we begin the

consideration of Question 1, since that is the

first question.

Dr. Anderson, would you like to comment or

respond to Dr. Hochberg?

DR. ANDERSON: Yes, I like the concept of

172

a composite outcome, but I don\'t know, in an acute

condition like this, I think it could be difficult,

but there are two things that I would like to say

on this.

One, I was impressed with the comment that

Dr. Melian made about the pain response probably

being driven by the inflammation response, so that

this would seem not to be solely a pain situation,

but there are these other components. It would

seem desirable to work with more than just pain in

looking at outcomes for acute gout.

The other thing, following from what you

said about there now being some data that would be

useful for exploring whether composite outcomes

could be useful here, it may be able to distinguish

between agents that you can\'t distinguish between

when you use just pain or just inflammation or

just, you know, whatever.

It is very valuable to have some good data

now that somebody, I don\'t know who, could use to

address this issue.

DR. GIBOFSKY: Dr. Cronstein.

173

DR. CRONSTEIN: This is more in the nature

of a comment, I guess, again following up on the

question that I asked before about how there seemed

to be no complete resolution or many people did not

achieve complete resolution of symptoms in the

8-day follow-up period.

I guess the comment would be, and this

came out of some discussions with Dr. Hochberg

during the break, that one, perhaps a longer

follow-up should be included. I know this is

getting ahead of ourselves.

I think the omission of a functional

endpoint is important, and I think that that should

be included, as well, because I don\'t think you

would regain full function if you are still in the

Likert scale of 1.

DR. GIBOFSKY: Dr. Mandell.

DR. MANDELL: A comment and a question.

The comment is, you know, as we think about looking

at markers of inflammation clinically, we have to

be cognizant I think if we are picking an agent

that has some specific activity against one marker

174

more than another, if we have, you know, something

that specifically targets a molecule that

vasodilates, and we pick erythema heat, we may

selectively be picking one thing different, so we

just need to be looking at that.

I guess in the future, we have already

targeted drug therapy. We look at whether dropping

a sed rate, or dropping the IL-1 specifically would

be driving a composite marker of response.

I have a question for the presenters about

looking at the delayed outcoming following an acute

intervention. We know what the response was in

terms of a secondary flare or, quote, \"rebound,\" or

anything two weeks afterwards.

Was that collected, was that standardized

in a way that we can make any sense of that, and is

that doable to be incorporated into an acute

treatment protocol design in the future that we

look for that specific question?

DR. GIBOFSKY: Dr. Daikh? Dr. Melian,

would you like to respond and take either the front

or the side microphone?

175

DR. MELIAN: In terms of following the

endpoints past the 8-day period, no, we did not do

that. We did collect adverse experiences after

that time point, and obviously, there were some

patients who would have had an adverse experience

that might have been associated with gout, such as

pain or gout flare or something of that sort.

We did see that in a small number of

patients, but it was relatively small. Now, in

terms of would it be helpful to look over that time

point, it may be in future studies.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: To speak to Dr. Mandell\'s

question, in fact, most of the acute gout trials do

not look at that. It has been rarely mentioned in

over 30 trials that I looked at, that there was a

mention of it, but it was obviously not well

studied.

It seemed to be almost an afterthought to

the design of these trials, suggesting that again

it was either not designed to look at that, or we

don\'t really want to know that, and if the goal of

176

therapy is to control the acute attack, you can do

that with the number of days to maybe a week or

two, but then what happens after you stop therapy

and go on is relevant to the treatment of the acute

attack.

I think as Dr. Mandell suggests, that may

need to be incorporated, so, you know, an acute

treatment period of one week to two weeks, where

the first week is full therapy, second week might

be withdrawal of therapy, and then an observation

period as we do in other trials certainly for

safety reasons, but also for the purposes of

looking at recurrence of disease, which would be

yet another secondary outcome that would be

important in gout.

A lot of new cases of gout will respond to

just one attack, but those who have chronic gout,

who have intermittent attacks, may have more

attacks subsequent to this, and we need to worry

about that.

Again, that could be six months from now,

that could also be in the next 30 days, so I think

177

that to fail the next 30 days would be a serious

indictment for any therapy.

DR. GIBOFSKY: The comment was made and

was kind of left undiscussed or unopposed, that for

short-term trials, patient-reported outcomes and

health-related quality of life indicators may be

less useful than for trials of a longer duration.

I would be interested in hearing how some

of the members of the panel feel about that.

Ms. McBriar, would you respond, please?

MS. McBRIAR: I think I agree that it is

less important when you have an acute situation,

the patient is just dealing with that, not really

worrying about too much else except getting rid of

their pain, but as time goes on, and when it is a

longer time, it starts to really impact their life,

and that is when you want to measure those issues.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: I think the patient-reported

outcome is the end-all here. It is the beginning

of the end, and everything else is sort of

interesting to the rheumatologist and the

178

practitioner, but, you know, patient pain, and let

them decide, and then after that, I mean there are

obvious impacts on quality of life here, it impacts

on work, that are easily measurable and dramatic in

scale when they are looked at.

You know, functional measures, we stopped

them a long time ago, button tests, and 50-foot

walk time, but as gout is a lower extremity

disease, you know, why is that not being measured

in patient with acute attacks? Just look at

50-foot walk time and resolution of that.

I think that these should be incorporated

in the short-term trials. I mean the perspective

of what you are looking to accomplish or analyze

are a little bit different than in safety and

long-term studies where you want to see maintenance

of quality of life, improvement in quality of life,

but again with a hyperuricemic, and I see that

acutely, with an acute gout regimen where it is the

control of inflammation to control pain, you will

see that acutely.

DR. GIBOFSKY: Dr. Geis.

179

DR. GEIS: Just to comment, in my

experience in doing clinical trials in other

arthritides, we thought that in the acute setting,

we wouldn\'t see changes in function and quality of

life, but we collected it anyway, and surprisingly,

we did see it in a matter of a couple days, we

would see something happen.

So, it seemed to be useful, and when we

presented it to the physicians, they thought that

was good information to have.

DR. GIBOFSKY: Do you want to respond?

MS. McBRIAR: So, what you are saying is

that in a couple of days, you are seeing changes in

quality of life?

DR. GEIS: I am just saying in past

experience, but different arthritides, and that

people did not think we would see it, but we did

collect it, and we did see it, and that was kind of

a eye-opener as to, gee, this would be important to

get more information about function and quality of

life in the acute setting.

MS. McBRIAR: I think a baseline is always

180

important and helpful, and anything past that

really depends upon the goal of the medication,

what one would predict would be helpful to the

patient.

I am trying to look at it like surgery,

and if you have surgery, you kind of know you are

going to be not functioning real well for a couple

days. If you are still in that situation a week or

two weeks or three weeks down the line, it becomes

much more impactful.

DR. GIBOFSKY: Dr. Anderson.

DR. ANDERSON: Just to comment that if you

are using functional status or health-related

quality of life health status in the very short

term, after only a week of treatment, the

instruments would have to be specially designed

because things like the HAQ refer to longer periods

of time. I don\'t know what kinds of instruments

were used in the studies that you did, Dr. Geis.

DR. GEIS: I don\'t recall off the top of

my head, but we did use subsections of the HAQ, as

well as different measures in function, and they

181

were exploratory, they weren\'t really primary or

secondary endpoint, but they gave, it seemed, the

physicians information which surprised them at how

quickly it appeared the patients could get back to

doing some normal functioning.

DR. GIBOFSKY: Dr. Schiffenbauer.

DR. SCHIFFENBAUER: I actually agree with

Dr. Anderson\'s comment. I think in the short term,

I would be surprised if function, ability to work

didn\'t worsen. What would be surprising is if it

actually remained worse after the attack of gout

resolved.

I doubt that would be the case, and that

might be something to look at, but I think in the

short term, you are going to see such drastic

changes, I am not sure what to do with them except

if they persisted after the attack resolved, that

might be a useful bit of information to know.

DR. GIBOFSKY: Dr. Terkeltaub.

DR. TERKELTAUB: I want to remind the

panel of a general caveat, and that is that the

gouty joint is not normal between attacks. Elazea

182

Pasqual \[ph\] has published that the leukocyte count

is elevated.

The general caveat is that the gouty joint

is not expected to be normal even after a week of

an anti-inflammatory treatment. We are not

eradicating synovitis, we are not eradicating tophi

by giving NSAIDs or colchicine or other

medications.

It is not equivalent to treating pneumonia

where you are eradicating an infection that is

easily treatable with an antibiotic, and this

should factor into interpretation of residual

symptoms and completeness really of symptoms and of

function.

DR. GIBOFSKY: I think your comments also

address part of what I asked earlier, which is

whether we are dealing with an either/or situation

and whether we are dealing with an \"and\" situation,

and I think that is something we will get into in a

few minutes.

Dr. Weisman.

DR. WEISMAN: I think you have to remember

183

that these instruments reflect both pain and

damage, and I think what Bob is mentioning is that

there is something else going on with the joint

that could affect function afterwards.

But very clearly, when you relieve pain, I

think that is what Dr. Geis had mentioned before,

when you relieve pain with an anti-inflammatory

drug, you are going to see an effect on these

instruments within a week or two rather than

waiting three months.

But then other factors may influence the

instruments that have to do with the chronicity of

the disease.

DR. GIBOFSKY: Further discussion on the

presentation this morning? Are we ready to begin

the first of the questions?

We are going to begin the questions. We

will break for lunch. We will then come back and

continue the questions. I am reminded that we do

have to at least allow for the open public hearing

at 1 o\'clock, so that our colleagues who may be

watching this live or watching it later or

184

following the broadcasts and the meeting are at

least advised that there is the opportunity for the

public hearing at the scheduled time, so that if

someone shows up at 1 o\'clock, we can\'t say sorry,

the time is past, so we will have the opportunity

for the open public hearing at 1 o\'clock, which

will interrupt whatever else we are doing.

But we will begin the questions now, we

will break for lunch, and then we will come back

with the open public hearing. If comments are made

at that time, we will hear them, otherwise, we will

resume the questions to the Committee.

So, at this point, we are ready for the

discussions of the questions that were posed to us.

We begin with an introductory statement.

Committee Discussion and Questions

DR. GIBOFSKY: Individuals with acute gout

often experience significant pain. Although

standard treatments include NSAIDs, colchicine and

glucocorticoids, none of these agents have been

demonstrated to be efficacious in

placebo-controlled, randomized, double-blind

185

studies. Therefore, it is important to carefully

assess any new therapy for efficacy.

I don\'t think this is a statement that

requires much discussion, so the first question is,

the first issue:

I. Please discuss whether gout is

considered a unique clinical entity or a model of

acute pain.

Who would like to tackle that first? Dr.

Williams.

DR. WILLIAMS: I don\'t think any of us

would treat an acute attack of gout with just

analgesics, so I think that I would consider it a

unique entity with which pain is a component.

DR. GIBOFSKY: I see nods. I see Dr.

Cush\'s hand, so we will go to Dr. Cush\'s hand, and

then those who are nodding.

DR. CUSH: Gout is a model of acute

inflammatory arthritis and, hence, should be

treated as a separate entity. Control the

inflammation, you control the pain, yet it is,

nonetheless, interesting that the use of

186

analgesics, ketorolac and/or topical ice have an

additive effect here. The topical ice therapy was

added on top of colchicine and nonsteroidal

therapy, so again this should be taken into

account, but it was additive in its benefits.

DR. GIBOFSKY: I might pose a question to

Dr. Harvey. What are the differences in terms of

our finding whether it is a unique clinical entity

or a model of acute pain as opposed to finding that

it is both?

DR. HARVEY: I think the purpose of the

question was to stimulate discussion, and it has

been effective in that.

DR. GIBOFSKY: That answers my question.

So, does anyone else want to comment on

the statements that have been made thus far as to

the characterization of gout? I think the

consensus seems to be it is a clinical entity that

causes pain, but in and of itself, it is not a

model of acute pain.

Is that a fair summary? Dr. Cronstein.

DR. CRONSTEIN: Again, just based on the

187

discussion earlier about functional endpoints, et

cetera, I think it is very clear that we don\'t do

that for most analgesic trials, and I would just

like to reiterate that this is probably something

that wouldn\'t respond simply to analgesics,

although we obviously haven\'t tested that.

DR. GIBOFSKY: Anyone else? Dr. Geis.

DR. GEIS: I just want to be clear I am

understanding what people are saying, that even

though it is not just a model of pain, and it is a

separate functional entity, if it was studied like

classic pain studies are done, and it was shown to

be useful for understanding a drug\'s ability to

control pain, could it be considered an acceptable

pain model even though we accept that it is a

different functional entity and there is all kinds

of inflammation involved.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: I don\'t think I would enter

my patients into a trial with an acute attack of

gout if the only treatment were analgesia.

DR. GEIS: I guess what I am saying is so,

188

for example, if you had an NSAID was going to be

your active comparator, and you said we are going

to put a placebo arm in and we are going to measure

on an hourly basis from the first four hours after

you see the patient, and you can rescue them out of

the placebo group if nothing happens.

And you saw a separation from placebo

within an hour, my experience is that is sort of

considered a good pain model. If that seemed to

happen with gout, why not do it?

DR. WILLIAMS: If you are using an NSAID,

I think you are then confused by whether it\'s the

anti-inflammatory effects of the NSAID or the

analgesic effects of the NSAID, and I would

consider that, but if you are going to tell me you

are going to treat with demerol, I wouldn\'t be

interested.

DR. GIBOFSKY: Dr. Cronstein.

DR. CRONSTEIN: I guess i just wanted to

reiterate that colchicine, which is again one of

the standard therapies, is not, as far as I know,

particularly useful as an analgesic, and if that

189

were your comparator, I am not sure how you would

draw any conclusions from a trial if it were set up

as an analgesic trial.

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: I want to go back, I guess,

to Dr. Geis\'s comment here then. If gout was

considered a model of acute pain, you could then

apply the guidance document or the draft guidance

document for studies of agents in acute pain to

gout, and utilize those outcomes then.

My understanding\--please refresh my memory

here\--but these are predominantly short-term

studies in acute pain, and wouldn\'t necessarily

reflect the duration of the study and the time to

response that the clinicians would be interested

in, in terms of assessing the patient, or that you

would necessarily expect to see the so-called,

let\'s say moderate to excellent response if you are

looking at 5 days and 7 days, right? Because my

experience with the acute pain studies is that they

tend to be 8 hours, 24 hours.

So, sort of by definition, I mean while it

190

could be a model of acute pain for the acute

resolution of pain in the first 24 hours, clearly,

it is more than that.

DR. GIBOFSKY: Any further discussion on

point number 1? Okay, let move on to II.

II\. Please comment on the use of the

following clinical measures: pain intensity, pain

relief, time to onset of analgesia, time to

re-medication.

Are there additional endpoints that should

be considered for these clinical trials, such as

evidence of local inflammation, erythema,

sensitivity to touch, assessment of function,

patient/physician and global assessment?

Please discuss the value of an endpoint,

such as time to good or excellent pain relief in a

defined period of time (a responder analysis).

Dr. Weisman.

DR. WEISMAN: I don\'t understand the

question very well. Maybe, Joel, you want to

explain this? In a pain model, you look for onset,

you look for magnitude, and you look for duration.

191

Is that what you are asking here? Okay.

The other, now you are asking about a

responder index. Are you talking about a good

responder, you know, a 20 percent responder? What

would be an index and how would you factor those

issues in, you know, an onset duration and

magnitude?

DR. SCHIFFENBAUER: Well, I hate to give

you a non-answer, but that is exactly what we would

like the Committee to consider. The question is

whether this should be studied with the acute

analgesia parameters that we apply to standard

acute analgesics, or is it more than that, is it

that plus inflammation or other measures?

I mean what we heard in the first question

was that it was a unique entity, but what I am

hearing, too, is that some people would just study

pain as the primary endpoint. That is the question

to the Committee.

DR. WEISMAN: The message is coming

through, to make it simple, no, there is more to it

than the pain model.

192

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: Well, I think pain is the

patient\'s primary concern, and probably the easiest

to measure, and it would be one of your primary

endpoints. The treatment of the pain is the

treatment of the arthritis, and I think you would

also want to study what has happened to the

inflammation, the redness, the swelling, the

tenderness, et cetera, and I wouldn\'t separate them

and say we will only look at the pain. The

treatment of the pain is the treatment of the

arthritis.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: I will flip what Dr. Williams

has said and say the treatment of the inflammation

is the treatment of the pain, and so I think that

inflammation measures are important in the outcome,

so I still think that again the primary endpoint

should always be pain as measured by the patient,

using a Likert scale or PDA or Visual Analogue, I

think that is all well and fine.

I do think there needs to be a

193

quantification of inflammation, and what is

inflammation in gout? It is really the attack. In

my talk, I said the attack really was the four

cardinal signs of inflammation.

You could say improvement is improvement

in two out of three, and the resolution is all four

are gone, and that is when the attack is over, and

that can be objectively measured when the patient

is enrolled, when the patient comes back for their

1-day visit, their 3-day visit, their 5, their 7,

whatever. That is the resolution of erythema,

swelling, warmth, and tenderness in the index

joint.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: I agree that we need measures

of pain and inflammation in our assessments, but I

do think that it is suggested by the Merck studies,

and pain may correlate extremely tightly and

extremely well over the short term with measures of

inflammation, which would be different from

something like rheumatoid arthritis where pain

doesn\'t necessarily correlate with the joint

194

findings.

If, over time, every study demonstrated a

very unique tight correlation of pain with these

measures of inflammation, it is conceivable that

the pain could be the most important measure to

assess.

DR. GIBOFSKY: Dr. Cush, to add a fifth

cardinal sign of loss of function to the four

previously outlined, bullet 1 asks us whether we

would want to consider assessment of function in an

outcome study.

Your thoughts on that?

DR. CUSH: Again, I think a secondary

measure would be interesting and since most attacks

are lower extremity, I would advocate a 50-foot

walk time as a measure of that. Again, I did a lot

of those when I started doing clinical research,

and, in fact, it was kind of fun. I had a stop

watch, they were walking next to the guy in the

hallway, who was on his way to lunch.

But the patients themselves reported

satisfaction, you could see their improvement by

195

doing this one test. They knew they were better by

the exam or by their reports, but how they are

going to do on their walk time was also an

interesting exercise.

Now, there may be other measures of

function one could do if it involved things other

than the lower extremity, but I would advocate a

50-foot walk time or some other maybe questionnaire

generated activity measure of function.

DR. GIBOFSKY: The second bullet: Please

discuss the value of an endpoint such as time to

good or excellent pain relief in a defined period

of time.

Dr. Hochberg, can I ask for your thoughts

on that?

DR. HOCHBERG: Sure, you are going to open

the well here, because I will comment again on the

first bullet, which I didn\'t do before.

I actually like the issue of achieving a

certain level of response in a defined period of

time, and I think that is helpful for the clinician

in terms of assessing a product and giving

196

information to a patient saying, you know, patients

like you, 50 percent will have a response over the

course of a week as opposed to on average, you will

have a 2-point improvement in your 4-point Likert

scale.

So, I like an endpoint of time to response

or the proportion of responders over a certain

period of time, and think that that should probably

be built in as a secondary outcome. At least the

measure of pain as the primary outcome, maybe this

could be modeled as a primary in terms of the

improvement in pain at a certain level.

If I could have your permission to go back

to the first bullet?

DR. GIBOFSKY: Please.

DR. HOCHBERG: Thank you. I am not

enamored of the physician-derived measures of

inflammation, erythema, tenderness here. I think I

am more enamored of the patient-derived measures.

Having had gout, I think the patient-derived

measure here for me would be more paramount in

terms of the amount of pain, the improvement in

197

pain, and my global assessment.

I have no objections to an assessment of

function. You know, it could be both a

performance-based measure and a self-report

measure.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: I will pass for a second.

DR. GIBOFSKY: Dr. Anderson.

DR. ANDERSON: Do I take it, Dr. Hochberg,

that inflammation can\'t really be measured very

well, so it is not a good outcome?

DR. HOCHBERG: Well, you certainly have a

lot of experience with, let\'s say, assessing the

reliability of the measurements of inflammation,

and I think while inflammation could be measured in

a valid fashion, that there would need to be a lot

of training in terms of getting both the

inter-examiner reliability for the measurement of

inflammation, be it on a, let\'s say, a naught to 3

scale of redness, or the so-called naught to 3

scale of swelling, and I think it is obviously much

easier to do it on a present or absent scale.

198

I think on a present or absent scale, yes,

it can be reliably measured.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: My memory has returned. I

think Dr. Hochberg is right. Most of the trials,

however, have looked at scores as opposed to counts

on joints as opposed to dichotomous, they do want

to do gradations, and ACR does have criteria for

how to do that, which there is some subjectivity

involved.

Marc, you had talked about patients who

had responded, 50 percent of people would respond

after five days. By that, do you mean a complete

response, complete resolution of symptoms, or do

you mean a responder index which would be some high

level response involving multiple things?

I know you, as I am, you are a fan of

pain, but I would call for complete resolution as

reported by the patient, and maybe that can be

fudged a little by saying, you know, greater than

90 percent resolution of your symptoms, and return

to normal activity, but would you want a composite

199

measure, or would you just go with some other

measure of complete response?

DR. GIBOFSKY: Response, Dr. Hochberg.

DR. HOCHBERG: Ideally, it would be a

complete response. I think given what we know

clinically, and given that the data that we saw

this morning, which I think really inform our

discussion, it would be unlikely to anticipate

complete response with the sort of currently

available agents within the first five days of

therapy in a large percentage of patients.

So, one would need obviously a much larger

study if one was going to power the study on the

complete response and as a non-inferiority study.

DR. GIBOFSKY: Dr. Bathon, then Dr.

Williams.

DR. BATHON: We also might want to think

about whether it would be reasonable to incorporate

inflammatory indices in the measure, as well, and I

wondered if in the Merck study, there were any data

on sed rate or CRPs.

DR. GIBOFSKY: Would Dr. Daikh or Dr.

200

Melian care to respond to the question of Dr.

Bathon?

DR. MELIAN: No, we did not collect

information on CRP or on sed rate. In clinical

studies of this kind, it is often hard to get sed

rate because it needs to be done locally.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: My comment goes back to Dr.

Hochberg\'s comments. I agree that I think pain is

the primary endpoint, however, I do think that we

can identify swelling of the joint.

I would make the comment that the

committee that developed the ACR20 criteria looked

at whether grading mild, moderate, severe helped,

and it did not appear that those gradations helped

over just presence or absence. However, if you ask

for those gradations, you often got a more careful

joint exam.

DR. GIBOFSKY: Dr. Hoffman.

DR. HOFFMAN: Bob Terkeltaub pointed out

how abnormal the joint may be after resolution of

the attack, and that emphasizes even more to me how

201

difficult it is to sort out the low-grade, ongoing

inflammatory process from what might be a response

to injury and repair, and how unrealistic it might

be to expect total resolution of all of the

classical features, with the most important feature

then being pain and function.

It would then seem that in designing

studies, that that would have to be the two

absolute, most important endpoints that are

included, total resolution of pain and restoration

of function.

DR. GIBOFSKY: Dr. Schiffenbauer, I am

going to pose this to you, are you comfortable that

we have commented appropriately on the first part

of the question, the use of the clinical measures

of pain intensity, pain relief, time to onset, and

time to re-medication?

DR. SCHIFFENBAUER: I would actually like

to get some further clarification. The question

is\--I mean I heard pain being a primary symptom,

but then inflammation being important. I didn\'t

hear any discussion of the possibility of

202

co-primary endpoints. That did not come up. Some

integration of pain and inflammation as co-primary,

I wonder if the Committee could address that.

The second part of it was there was some

discussion of time to resolution or improvement,

which seems to be an end-loaded endpoint, if you

will. It is an endpoint that you might look at it

three or four or five, six days, but since this an

acutely painful condition, I would like to hear

more about the front-loaded sort of analysis, which

gets back to the time to onset, those types of

issues. I didn\'t hear that specifically being

addressed.

DR. GIBOFSKY: Does everyone understand

the request from us? Would anyone like to address

some of those comments? Dr. Cush.

DR. CUSH: So, pain only as a primary

outcome, and everything else second. Pain only and

then patient reported, and everything else is

secondary. I do think that everything should be

front-loaded, as you suggest, and one day as your

first time assessment is probably too late.

203

I mean I think if you are going to go for

an acute gout indication, which is going to be the

relief of the pain associated with acute gout, one

should have a several hour determination, whether

that is a 30-60-90-120 minute assessment that is

done in a few trials, or whether that is a

four-hour assessment as was done in the etoricoxib

trial, or whether it is going to be a 6 or 12 hour

assessment.

I think it should be a less than one-day

assessment, and then some other intervals after

that to show, and it should be front-loaded. I

mean we shouldn\'t be looking at starting treatment

7 days and then 14 days. We have missed what is

most bothersome to the patient.

What is most bothersome to the patient is

how I am feeling the next 24 hours and maybe the

next 36 hours, and we should have therapies that

clearly show what the magnitude of response is in

that time frame.

DR. SCHIFFENBAUER: How does that gibe

with Dr. Williams\' comment that he would not allow

204

an individual to be entered in a trial for demerol?

Since you are just measuring acute pain, I am still

not getting clarification.

DR. CUSH: They are separate issues. I

mean I agree with what most people said, including

Dr. Williams, that it is inflammation that is

driving the pain here, and it is not pain alone,

so, in an acute trial, you might get\--you know, and

as was seen in the ketorolac trials, in fact, they

did have improvement in 30, 60, 90 minutes, but

they didn\'t do so well after 6 hours, you know,

they weren\'t all that great.

So, it would have to have a good blend in

there because, yes, you could give narcotics to

cover up pain, but have you really controlled

inflammation. A lot of these would come out in the

secondary variables. I still don\'t know that I

would want to rank inflammation as a primary or

covariable here, because I think it is the more

difficult to measure.

We have heard some differences as to how

reliable the cardinal signs of inflammation are,

205

whether we should do swollen joint scores on a zero

to 3 scale, or just a yes and no scale. There is a

lot of variation there that hasn\'t been well tested

in this particular arena.

So, to make a secondary outcome to invite

exploratory investigations, as Merck has done with

erythema, just done by visual analysis as opposed

to doing laser doppler studies for blood flow as a

measure of erythema and inflammation could also be

done.

Again, I think those are all secondary

points.

DR. GIBOFSKY: Dr. Terkeltaub.

DR. TERKELTAUB: Are we going to address

chronic synovitis in this setting and how to

evaluate that in the trial modalities, because

basically, as a tertiary care rheumatologist

dealing with the worst gout, this is what is what I

see. You see chronic destructive synovitis that

isn\'t really appropriately evaluated in toto by

these sorts of measures.

DR. GIBOFSKY: I think the floor is

206

certainly open for discussion of any parameter that

the Committee considers important in the assessment

of an acute or chronic trial design. We certainly

can.

Dr. Cronstein.

DR. CRONSTEIN: This is going back to the

front-loading, if you will. I think clearly, if

you front-load everything that you are measuring

and look at those earliest time points, most

importantly, it is going to dictate the

comparators, so if you were to compare it to

glucocorticoids or to colchicine, you probably

wouldn\'t get any change at 4 hours.

So, this is clearly going to dictate the

way that you structure your trial with respect to

the drug that you are comparing it to, since we

have kind of written off placebo trials, and I

think that that needs to be kept in mind, as well.

DR. GIBOFSKY: Dr. Weisman.

DR. WEISMAN: It seems to me from the

discussion that the duration of the attack is

probably not affected terribly by the medications

207

that we have been discussing. It is the area under

the curve or the magnitude that seems to be

responding, and this gets back to what Bob has been

trying to tell us, that this is an ongoing process.

It is probably useful to look at it as an

issue of controlling inflammation or pain as

quickly and as completely as possible, but the

duration of it is probably not going to affected by

those specific therapies.

We all know about rebound, we all know, we

use steroids, we use these drugs, if we stop them

too quickly, the attack recurs. Even with ACTH,

you have to give patients maintenance colchicine,

so we see this from a clinical standpoint.

That probably relates again to what Bob is

saying, is that the process keeps going. So, it is

going to be very difficult for us, Joel, to I think

make this distinction because if we are treating

early and aggressively and actively, as quickly as

possible, all we are going to measure is pain

relief, but that is not all what is going on.

I have tried to put some kind of dressing

208

on this discussion in terms of pathophysiology.

Maybe Bob should comment on this issue about the

duration of the process, or if I am reading it

correctly.

DR. TERKELTAUB: I think you read it

correctly.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: I am not sure I agree with

that, Mike. I think that if we are talking about

an acute attack of gout as opposed to patients with

chronic gout, I think we do make an impact on the

duration of the attack, and that we do shorten the

duration.

DR. GIBOFSKY: Further comments? Does

anyone want to comment on Dr. Terkeltaub\'s question

about the assessment of chronic synovitis? I am

not sure that we explored that fully yesterday, and

perhaps we can revisit it.

Dr. Cronstein.

DR. CRONSTEIN: I guess the question is

how long, I mean how long is chronic. I know what

you are talking about as those people who have

209

months, but I think in terms of the sorts of

questions that have been posed, for the most part,

have to do with sort of life in the trenches as

opposed to the tertiary care center.

I think the questions are very different

at that point.

DR. GIBOFSKY: Comment, Dr. Terkeltaub?

DR. TERKELTAUB: I just want to know

whether we will address the chronic patients

because it is very much like RA, these types of

drugs that we are discussing today,

anti-inflammatory analgesics are not going to

really address the chronic entrenched disease.

DR. GIBOFSKY: I think much of the

discussion on chronic was yesterday, but I am

certainly willing to re-explore.

DR. TERKELTAUB: There is chronic

inflammatory, as well as chronic accumulation of

urate. There are many people that have tophi, that

don\'t have symptoms.

DR. GIBOFSKY: Is there some specific

comments that we should be considering in our

210

recommendations to the Agency to take into account?

DR. TERKELTAUB: I think we should be

looking at the possibility in terms of future

medications evaluated in this disease, are things

that may reduce the amount of destruction at the

cartilage level and the amount of synovitis, and

that some of these medications may not work quickly

vis-a-vis pain relief.

DR. GIBOFSKY: Back to the initial

characterization, Question I, that we are talking

about a unique clinical disorder rather than just a

painful condition, that approach?

DR. TERKELTAUB: Yes, it does, and I think

we are talking about a unique form of acute and

chronic disease.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: Yes, that relates to a

question I had earlier about whether you were going

to base the joints that you are targeting on,

patient report of pain, or the physician

assessment, because the patient can see a swollen

and painful hand, and it maybe is only the wrist

211

involved. On the physician exam, you find no

involvement of the MCPs, even though there is

diffuse swelling, and the patient can\'t necessarily

separate that.

On the other end, with chronic disease,

where there is acute on chronic inflammation, the

physician may find tenderness in a number of joints

that the patient doesn\'t think are involved. So, I

think there are issues there that are complex and

need to be sorted out.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: Well, again, we are speaking to

indications, and today\'s indication is acute.

Yesterday\'s indication that we spoke to was the

chronic one, but was really for the indication of

treating the hyperuricemia associated with gout and

how treatment of that would relate to the chronic

consequences of hyperuricemia and the disease.

So, it kind of gets to what Dr. Terkeltaub

was bringing up, but really doesn\'t, and today\'s

indication really is for the person with brand-new

gout for the first time, or a person with

212

intercritical gout and then gets a new attack, or a

person who has maybe some chronic tophaceous gout

that is well controlled and has attacks, but that

is a little bit different still than really a sole

separate indication, which is chronic tophaceous

gout and synovitis, and that would be a whole new

indication that we would really have to develop,

because I don\'t think pain would be an appropriate

primary outcome there.

I think that you are really looking at

more sort of rheumatoid arthritis-like outcomes

where you are looking at composite measures of

improvement. You are looking at synovial load, you

are looking at damage, you are looking at long-term

outcomes, and it may not be one regimen, it may be

new therapies, it may be combinations of therapies.

It really is a whole new can of worms that he has

opened up by that question, and I think it is an

important one because this is what we see as

rheumatologists.

It is unfortunately, or fortunately for

the populace, a minority of those 2.5 million

213

people with gout, but it is the ones that

concentrate in our offices. I think today\'s

indication is for the majority of those people who

have acute presentation of gout and the

intercritical exacerbations of gout.

DR. GIBOFSKY: Does everyone agree with

the concept that we probably, despite two days of

discussion, have not covered the universe of

patients with gout, particularly those whom we may

be seeing in our experience?

Dr. Terkeltaub.

DR. TERKELTAUB: Agree, and I think that

as we are able to remodel the tophi in joints by

more potent and more tolerated anti-hyperuricemics,

we are going to start to see new types of problems

with possibly accelerated destructive changes at

the cartilage level, and we may have to deal with

this.

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: I just wanted to get back

to Dr. Schiffenbauer\'s comment, if that is all

right.

214

DR. GIBOFSKY: Certainly.

DR. HOCHBERG: One can front-load the

studies in patients with acute gout or acute

exacerbations during intercritical gout for relief

of pain as a primary outcome and improvement in

inflammation as a secondary outcome, front-loading

these outcomes.

It still is important to I think follow

patients in study on treatment to look at the

resolution of the attack where they are, quote,

\"back to baseline,\" for those who have maybe some

chronic smoldering symptoms and get an exacerbation

on top of it.

I am concerned that a 7-day study may not

be of long enough duration for such a study if one

wants to look at a secondary outcome of back to

baseline or complete resolution.

DR. GIBOFSKY: Further Comments? Dr.

Cush.

DR. CUSH: I would ask Dr. Hochberg and

other members of the committee, would you then

propose that all acute gout studies be at least 30

215

days in duration?

DR. GIBOFSKY: I think we will deal with

that in Question III. I would ask you to hold that

thought because we will come back and deal with the

duration.

Further discussion on point II? Dr.

Anderson.

DR. ANDERSON: I would just like to say

something about function, which has sort of

disappeared for the time being from our

discussions. That is the difficulty in assessing

whether a person has returned to baseline, because

the first measurement you are going to have on

people is when they are in the middle of an attack.

That is a difficulty there, I think.

DR. CUSH: But baseline status refers to

their baseline, not the chronological baseline at

study entry. A patient has their own perception of

what their baseline function is. I was working, I

was running. I think that is what the statement

was referring to.

DR. ANDERSON: Okay. So, if it\'s patient

216

report of their being back to what they used to do,

that\'s fine. I was thinking that you maybe were

talking about 50-foot walk time, which you wouldn\'t

have based on measurement.

DR. CUSH: Right. That would be a purely

subjective measure of, you know, time to resolution

of symptoms would be the day that the patients says

I have returned to my baseline status as far as my

function and my ability to function without pain,

you know, plus or minus 5 percent, something like

that.

DR. GIBOFSKY: If there are no further

comments on Question II at this point, we will

break at this point. We will resume at 1 o\'clock

with the opportunity for the open public hearing.

We can continue the discussion on Question II

following the open public hearing, which we are

required to open at 1 o\'clock, and then we will

continue with the remainder of the questions at

that time.

We will adjourn the morning session at

this time.

217

\[Whereupon, at 11:59 a.m., the proceedings

were recessed, to be resumed at 1:00 p.m.\]

218

A F T E R N O O N P R O C E E D I N G S

\[1:03 p.m.\]

DR. GIBOFSKY: Ladies and gentlemen, we

are back on the record for the afternoon session.

Open Public Hearing

DR. GIBOFSKY: At this point in our

schedule, we are going to hold the open public

hearing.

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decisionmaking. To

ensure such transparency at the open public hearing

session of the advisory committee meeting, the FDA

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, FDA encourages you, the

open public hearing speaker, at the beginning of

your written or oral statement, to advise the

committee of any financial relationship that you

may have with the sponsor, its product, and, if

known, its direct competitors.

For example, this financial information

219

may include the sponsor\'s payment of your travel,

lodging, or other expenses in connection with your

attendance at the meeting. Likewise, the FDA

encourages you at the beginning of your statement

to advise the committee if you do not have any such

financial relationships.

If you choose not to address this issue of

financial relationships at the beginning of your

statement, it will not preclude you from speaking.

Are there any members of the public who

would like to present or make a statement to the

Committee at this time?

\[No response.\]

DR. GIBOFSKY: Hearing none, we will

resume our deliberations on the questions as asked.

Committee Discussion and Questions (Resumed)

DR. GIBOFSKY: I believe we have completed

Question II, unless any member of the Committee

would like to further comment on Question II.

Seeing none, we will move to Question III.

We are waiting to move to Question III, which I

will read while we are waiting for it to be put up.

220

Question III. Attacks of gout may be

self-limited and resolve spontaneously over 1 to 2

weeks.

Then, there are three bullets.

Please discuss the duration of a trial for

acute gout.

What is the value of a demonstration of

efficacy within the first 8 hours? The first day?

Is there clinical meaning in an analysis

of average of pain over several days? How many

days?

Dr. Hochberg, can I impose upon you to

begin to address Roman III?

DR. HOCHBERG: Let me start with the

second bullet, and I think to summarize the way I

would distill our conversation and discussion prior

to the lunch break, is that there is very high

value to demonstrate efficacy within the first 8

hours and within the first day. I think there was

pretty much consensus on that.

Then, with regard to the clinical meaning

and an analysis of the average of pain, again, I

221

think there was consensus that the area under the

curve of pain relief was very important as well.

Let\'s say the cumulative amount of pain relief or

the less area under the curve of pain was very

important, as well, measured over several days.

How many days? I don\'t know.

In terms of the duration of the trial,

while we are again interested in front-loading the

assessment of efficacy, we are also concerned about

the resolution of the attack, and concerned that

based on the little that we know of the natural

history of gout from the observational studies and

the placebo group of the colchicine trial, and what

we learned from the trials conducted by Merck, that

either the majority of patients or a sizable

minority of the patients don\'t have resolution of

their attack by 7 days.

So, I would think that we would want to

see trials of longer than 7 days in duration. I am

not sure 30 days, which was the number that was

thrown out, but maybe 14 days.

DR. GIBOFSKY: Dr. Cronstein.

222

DR. CRONSTEIN: I guess I have a question

about the use of the area under the curve, and I am

not sure how much value that adds to what you

already saw, particularly inasmuch as the

comparators are probably going to be very similar

to the drugs under study just because we have

already ruled out, if you will, a placebo trial.

So, it is very likely that you are going

to see overlapping curves, and I don\'t know how

much difference that\--I mean not to exclude it,

it\'s no big deal obviously to calculate that sort

of thing, but I don\'t know how much it adds.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: I actually like Marc\'s

suggestion of 14 days. I think in the interest of

patients who are feeling much better after a week,

I would think that the Merck model of one today for

seven days would be good, and then every other day

for another week, but I would like to see a couple

of weekly followups afterwards, just to make sure

we have captured the full effect, and not seen any

rebound.

223

DR. GIBOFSKY: So, I am hearing a sense

that there may be difference between the period of

time that the trial is conducted and the period of

time that data is collected following the trial in

order to get a more longitudinal picture of the

natural history of the event and the treatment of

event.

Dr. Cronstein.

DR. CRONSTEIN: I guess also since none of

the agents got back to zero, if you will, at the

8-day time point, it seems obvious to me that you

would want to get to a point where the patients are

back to their baseline, if you will.

DR. GIBOFSKY: Dr. Weisman.

DR. WEISMAN: It occurred to me that I am

sure Merck would have been happy to collect

additional data for, say, the second week, but the

problem is we are not listening to what they were

saying to us, which is this was a very difficult

trial to carry out. They had to go to how many

countries to do this\--10 in one, 11 in the

other\--to recruit patients in the trial with a huge

224

variety of different sites, I am sure, not just

rheumatologists.

How many rheumatology versus

non-rheumatology sites did you go to? So, half

their sites were non-rheumatologists. So, we heard

that they went to 10 or 11 different countries, 40

different sites, half the sites were

non-rheumatologists, and many of them, I am sure,

were not sites that normally do clinical trials.

So, there is going to be a huge variety of

data that is collected, very difficult to put this

trial together, and so I think we ought to

understand that before we come up with these kind

of ideal frameworks.

To do a trial of acute gout, for example,

can a trial of acute gout be done in the United

States? With the sites that we have in the United

States, given the disease, can we do that here?

Why don\'t we ask Merck to answer the question, can

we actually do that trial in the United States with

a sufficient N, not you, Dr. Cush, I want to ask

Merck.

225

DR. GIBOFSKY: I will allow you to ask

Merck if the representative will go to the

microphone. At the microphone if you care to

answer.

DR. WEISMAN: Given what you have told us

already and given the number of patients that you

need for a comparator trial to another agent, can

you successfully accomplish a study in the United

States?

DR. MELIAN: In the United States alone?

DR. WEISMAN: Yes.

DR. MELIAN: I think you could do it, but

I think you are going to have to work very hard to

do it.

DR. WEISMAN: Well, you obviously chose

not to do it alone in the United States, right?

DR. MELIAN: That is correct.

DR. WEISMAN: And the reason you chose not

to do it in the United States alone?

DR. MELIAN: How many years did we want to

take to enroll the trial.

DR. WEISMAN: Okay, so that\'s the answer.

226

So, what I am saying is let\'s be realistic about

the number of patients that you need to do the

study, and the number of investigators that you can

get, and the fact that Dr. Cush is pushing very

hard on the microphone over there because he is

going to reject pretty much everything that I have

said.

Go ahead, Jack.

DR. GIBOFSKY: Not everything, Dr.

Weisman, just all of it.

Dr. Cush.

DR. CUSH: Dr. Weisman is right. I think

that it is difficult, but, you know, so is

recruiting for rheumatoid arthritis in this era

when we have many successful therapies currently

available. To recruit for rheumatoid arthritis

trials for drugs in development in 1980s and 1990s

was relatively easy because there were a lot of

patients, and a lot of them were not well treated,

and there weren\'t a lot of good therapies.

Now, we have a situation where we have a

lot of effective therapies, much like the situation

227

of gout, where there are a lot of effective

therapies, and people seem to think that they know

what they want to do.

But the fact still remains is that there

are millions of people, that there are no trials.

The main reason why this has been difficult is

because we haven\'t had the outcomes outlined, there

have been no methodology. There has not been a

significant push to have the gout trials.

All the trials that we saw in development

were done by interested individuals trying to

answer a question, as much as there were industries

trying to look at a pile of studies, whether, you

know, etoricoxib or Rofecoxib or sulindac might

possibly work, or might be an indication.

So, again, I think with guidelines for

outcomes, with education, I mean there are plenty

of researchers. It takes work, and it can be done,

but to say it can\'t be done, I mean then we have

just wasted this whole day. We have laid the

groundwork where this can be done, and the patients

are there.

228

If Merck couldn\'t find them, that is

Merck\'s fault. I think that there are a lot of

people who can find them.

DR. GIBOFSKY: A quick response, Dr.

Weisman?

DR. WEISMAN: My rebuttal, very quickly,

is that true true and unrelated, Jack, yes,

rheumatoid arthritis is difficult to recruit for

because we have many effective therapies. That is

not true for acute gout.

We have heard we don\'t have many effective

therapies here, as much as you think, otherwise,

they wouldn\'t be doing the study, and the problem

here is recruitment of physicians and patients in

the United States because of exactly what you said

this morning. It\'s the scattered number of

patients that are out there, that are seen in

emergency rooms and primary care offices, not seen

with rheumatologists. They are almost impossible

to capture.

I think that is the real reason, and that

is why I am trying to be realistic. That is not

229

going to change very much, and that is why I am

saying let\'s be realistic about study design

because who is going to be doing the studies.

DR. GIBOFSKY: Dr. Cronstein.

DR. CRONSTEIN: I think again we need to

query the people who have done this study and have

had the difficulty in recruitments, and according

to what they told us earlier, the major difficulty

was that people were taking over-the-counter

nonsteroidals or some other nonsteroidals that they

had, so adding onto a trial where you have patients

simply come back for over a longer period of time,

I don\'t think is going to add to the burden, but

maybe we could get that information from you guys.

DR. GIBOFSKY: I would share Dr.

Cronstein\'s comments in that recognizing the

difficulties in recruitment, once the patient is

recruited, I am not sure the period of observation

is as significant or raises additional difficulties

beyond the recruitment.

Certainly, there is some, there will be

some dropoff, but if the problem is in the

230

recruitment, that is at the front-load stage, but

once the patient is there, the observation is less

difficult to do.

If our colleague from Merck would care to

comment?

DR. MELIAN: I agree with you. Once you

have the patients in the trial, the major hurdle

has been handled. Yes, you have some patients who

discontinue throughout the trial, and we actually

went through that number when I showed you my

slides and a small number of patients in both

treatment groups discontinued during the 8-day

period.

You can imagine if you went to 14 days,

that it would be larger yet. That being said, the

major hurdle is in the first few days of

recruitment.

Now, the one thing that I do have to tell

you, because I am not sure it came through in my

presentation, is that when we looked at patients in

terms of pain, and if the system was set up I could

show you, because I actually do that this data, and

231

I can share it with anybody who wants to see it,

90-plus percent of patients at the end of the 8-day

period had mild or no pain.

So, you are really get down to what is

really minimal or no pain in that 8-day time frame.

I think that is consistent because when we treat

gout with Indocin, we don\'t usually go much beyond

an 8-day treatment period. Some patients do

require longer.

DR. GIBOFSKY: Dr. Finley.

DR. FINLEY: I wanted to follow up kind of

where we left the discussion before the break, and

it dovetails with our discussion about recruitment

that Dr. Weisman brought up.

I wondered, thinking about the work that

the folks at Merck did, are we really talking about

acute gout, or are we talking about acute episodes

of intercritical gout, which is kind of where we

left the discussion, and thinking about their

particular studies, they talked about the Wallace

criteria, and they talked about\--I think I heard

during the presentation about all the patients met

232

the clinical criteria, and I wondered if they knew,

of the patients that they entered, how many were

the first episode of gout that they had ever had,

or were the preponderance intercritical patients.

Then, how many of them were diagnosed

based on chart review of prior evidence of

crystals, or, in fact, were diagnosed at the time

the crystals were identified at the time of

enrollment, or were the preponderance of their

entrants mostly meeting the other criteria, the 6

of 12, because that has implications, as Dr.

Weisman has talked about, for recruitment, and in

the real world, where are we going to do these

things.

Because we under these criteria as

rheumatologists, but my concern really is, as has

been mentioned, that we are going to create a

paradigm that no one could get through.

DR. GIBOFSKY: Is that data available that

can be shared in terms of first attack versus

intercritical?

DR. MELIAN: Yes. Now that I am becoming

233

an expert at microphonetology here, in terms of

first attacks, they were relatively rare in our

studies, 92, 93 percent, somewhere in the 90s, 92

percent range of patients had had previous attacks

of gout.

On average, most patients had 4 or

greater, or at least if you categorized in

different categories of how many attacks you had,

the majority fell under 4 or greater.

In terms of how many had crystals, in our

study, about 25 percent had documented crystals.

We did not require that patients had to have

documented crystals in our study. We used the ARA

or the Wallace criteria.

DR. GIBOFSKY: Follow-up, Dr. Finley?

DR. FINLEY: I would just ask, as you had

more and more difficulty recruiting, were you doing

more arthrocentesis to document or you mentioned

just there at the end that you were using the

clinical criteria more, but I just want to better

understand your answer.

DR. MELIAN: So, in our studies, what we

234

required is that they use the clinical criteria,

and we set that up per the ARA guidelines. If you

go through those actual clinical criteria, A and B

of those criteria are crystal-proven gout. C,

which is the 6 out of 12, is the additional

clinical criteria.

So, we kept the rules the same, and what

we got out at the end of the study were the numbers

that you saw. We did not undergo any protocol

changes to help recruitment in this regard.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: One of the things I think Dr.

Finley is getting at, and a concern I have, is if

you extend the time point out too long, make the

study too long, is that you are passing the acute

gout and entering the gray area of where recurrent

gout occurs, and it may be unfair to a sponsor to

hold them to a longer time point when we are

treating acute gout, because there is really a gray

area there, who is going to have an acute attack

within the next two weeks versus the next six

months.

235

So, I think while we all are interested

biologically in how long we exactly have to treat

and how long that treatment is good for, I think we

have to be cognizant of the fact that these are

acute gout trials, and not chronic gout, and we

have to make some kind of, albeit it arbitrary,

timeline as to where the end of acute gout is.

DR. GIBOFSKY: Ms. McBriar.

MS. McBRIAR: I think also for the

patient\'s perspective, they don\'t want to be tested

and tested and tested too often either, so we need

to do what we have to do to get good results, but I

don\'t think we need to go overboard because we want

to learn more.

DR. GIBOFSKY: I think we have discussed

the first bullet and probably the second. The

third one is a bit more technical.

Is there clinical meaning in an analysis

of average of pain over several days? I guess, if

so, how many days?

Thoughts or suggestions on that specific

bullet? Dr. Cush.

236

DR. CUSH: Again, it goes to the early

debate on area under the curve, more of how much

time patients spend in pain. I don\'t think the

subtleties of pain involved here require this type

of presentation of data. I think it is no more

valuable than the patient-derived Likert scales of

pain or VAS. I think it is going to be the same

thing, and again, an average over time.

I think I would rather see a magnitude or

an absolute, so the magnitude is what your pain is

and what is has fallen to, and then the absolute

being time to resolution of pain.

DR. GIBOFSKY: Any further comments on

Roman III or any of the sub-bullets? Dr. Anderson.

DR. ANDERSON: On the area under the

curve, the advantage that I see is that it is a

single test. The way that the pain seems to go

with treatment for acute gout is that there is an

initial improvement, and then the improvement

continues, so that if you do an area under the

curve, you are capturing the speed with which the

pain is reduced and the eventual amount that it is

237

reduced, as well, and you are doing a single test

for it.

So, that, I would think would be the

advantage of it.

DR. GIBOFSKY: Dr. Schiffenbauer.

DR. SCHIFFENBAUER: Could I just get

clarification? In using the area under the curve,

is there any implication if the trial is a

non-inferiority versus a superiority to placebo in

this instance where the disease, the acute flare

resolves spontaneously, would that tend to make the

two drugs look more similar? You see my question

there in that regard? Am I not making that clear?

No?

DR. GIBOFSKY: The question is if you use

the AUC, does it make a difference whether you use

a non-inferiority versus a superiority.

Dr. Hochberg.

DR. HOCHBERG: I think I understand your

question, and in order to have spontaneous

resolution, let\'s say, in a superiority trial to

placebo, where you would worry about this occurring

238

in the placebo group, you would probably have to

have a 30-day trial, and then look at sort of the

area under the curve for 30 days, or at least the

outcome at 30 days. So, I don\'t think it would be

a problem in a 7-day or even a 14-day trial.

DR. GIBOFSKY: Further discussion on that

topic? Dr. Cronstein.

DR. CRONSTEIN: Again, I guess we come

back to the comparator drugs, as well, because of

the onset of action. I guess I am having a little

trouble seeing the extra value aside from the fact

that it\'s easier to compare one number to another

number as opposed to comparing eight numbers or

however many measurements.

So, again, all of the graphs that we have

seen have been pretty much superimposable, and I

imagine that going forward, since presumably, most

of the comparisons are going to be made to other

nonsteroidals, that, again, the graphs should be

pretty much overlapping unless you guys decide to

go test something different, you know, colchicine

or something.

239

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: Unless there is a drug that

can work faster than indomethacin. I mean I think

the area under the curve is useful for speed, speed

of response, but indomethacin works fairly quickly.

DR. CRONSTEIN: Right, and steroids don\'t,

so I don\'t know that it tells you\--I mean steroids

may get you deeper at your second measurement than

indomethacin, I don\'t know that for a fact, but

they certainly don\'t do anything at early time

points.

DR. GIBOFSKY: So, if you use the area

under the curve, it may be a function both of the

methodology and the comparator.

DR. CRONSTEIN: Right.

DR. GIBOFSKY: Dr. Hochberg. Withdrawn by

Dr. Hochberg.

Any further comments on this point? Dr.

Schiffenbauer, have you gotten the information, the

results of our wisdom? Okay.

Let\'s move to Roman IV.

The onset and duration of an acute attack

240

is unpredictable and the extent of pain during an

acute attack of gout is variable.

Please discuss the clinical trial

implications of enrollment of patients who have

already had symptoms of an acute attack for a

period of time, for example, 48 hours.

Please discuss the clinical trial

implications of enrolling patients who may be

untreated or partially treated.

Shall we deal with the second bullet first

since I think we have already discussed some of

that earlier? Would someone care to respond to

that? Dr. Cush.

DR. CUSH: I believe that the Merck

approach was an intelligent one to allow patients

on chronic therapy, chronic maintenance therapy

with allopurinol and colchicine to continue on

those therapies. I do think that there would be

confounding factors involved if they were to

include patients who were previously treated with

corticosteroids or nonsteroidals, especially in the

last four weeks.

241

I think that their guidelines and

operations make the most amount of sense as far as

enrollment criteria and allowing patients to easily

enter the trial without complication.

DR. GIBOFSKY: So, you are differentiating

between the patient who is on chronic maintenance

and the patient who might have taken an OTC within

a day of enrolling in the trial.

DR. CUSH: Chronic maintenance is okay

again for colchicine and allopurinol. Any chronic

use of nonsteroidals or steroids would be an

exclusion, and then intermittent or recent use of

colchicine or allopurinol\--I am not sure how that

factors in\--but colchicine especially would be a

contraindication to inclusion.

DR. GIBOFSKY: DR. Weisman.

DR. WEISMAN: I think this is entirely a

practical issue as we heard from Merck, is that

they were only able to capture patients under these

circumstances. They found too many patients that

had already started on these anti-inflammatory

agents at the beginning of their acute attack,

242

which had to be excluded.

Everybody else, depending on their level

of disease activity, was included, which is the

same thing we do with rheumatoid arthritis. It

depends on what level of disease activity they are

going into the trial. So, I think it is just a

practical issue.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: One thing that might make

enrollment easier is to allow patients who have

taken a dose of ibuprofen, but not in the last 8

hours, because that is probably the most commonly

used OTC NSAID, and it is relatively short acting,

so if you had an 8-hour gap, it seems to me like

that might be a reasonable patient that you could

still enroll.

DR. GIBOFSKY: Anything further on bullet

2?

Let\'s go back to bullet 1. The

implications of enrollment of patients who have

already had symptoms of an acute attack for a

period of time, presumably untreated during that

243

period of time.

I assume that is what you are looking for,

Dr. Schiffenbauer.

Any comments about this? Dr. Cush.

DR. CUSH: I think in a sense there is a

natural selection here. Patients will present or

won\'t present. They are not going to present

because they have dealt with this before, they have

a means of dealing with it now, so they are not

going to show up. They are only going to show up

when things don\'t get better after they

self-treated themselves, in which case they are

excluded from these kind of trials anyway.

But the vast majority of people who have

acute gouty attacks, who will then seek help, will

do so within the first 24 to 48 hours anyway, so I

think that that is reasonable.

Most of the trials that we looked at, that

I reviewed, would include patients for either 18

hours or 24 hours, or as long as even 3 days, 48

and even 3 days, but I think that the 48-hour time

limit is probably reasonable, because you want to

244

give the patient an ample opportunity to respond,

and not catch them at the tail end of their

symptoms.

But we learned I think from the way that

Merck was trying to represent the data, that there

was a lead-in period that they weren\'t truly

capturing in the time it took them to get better

anyway, which was, you know, again 5 days or so,

certainly in their 7-day study.

So, again, you would like to get them as

soon as you can, so they are going to be at their

peak when you treat them.

DR. GIBOFSKY: And you would establish an

arbitrary cutoff of, say, 48 hours. A patient who

is untreated for longer might be less likely to

show clinical effect because we know by Day 5 to

Day 7, there is already some amelioration of

symptoms.

DR. CUSH: Well, as in other disease, how

early is early? I like it early as possible, 48

hours is very good, 36 I think would even be

acceptable, but beyond 36, you are starting to get

245

into an area where symptoms might begin to improve.

The Bellamy study really showed that

patients didn\'t show any evidence of improvement

until after the 48-hour time period, that symptoms

really began to improve significantly by Day 3 to

5\. Of course, that is recognizing that is 3 to 5

plus the 2.8 days they had for time to

presentation, so again, I say that up to even 3

days, you might even be safe, but 48 hours would be

ideal.

Hence, if there are issues of enrollment,

then, maybe allowing up to 72 hours might be

reasonable as a start point in a study.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: Actually, Jack covered it

right at the end there. I was going to say that 48

hours, I agree most of the patients will come

within that time anyway, but I don\'t know that

there is a real\--it is an arbitrary time point, and

there is not a lot of difference between 48 and 72,

and I would have made it 72 hours because it would

make it easier for recruitment.

246

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: I think this may point us

to one of the reasons that the company had a

problem enrolling this trial in the U.S., and maybe

I am completely off base and you will tell me, but

a lot of patients with gout, who are followed by

primary care doctors, let alone rheumatologists,

have a bottle of indomethacin at home in their

medicine cabinet and have been told, and may know

from experience, that if they get an attack of gout

on the background of colchicine or allopurinol or

whatever, that they pop their indomethacin, and

they may do that before they call the doctor or

come into the office, which would exclude them from

participating in a trial as we are designing it and

as the sponsor had designed it, because they have

been treated or partially treated.

So, the duration of the attack is one

thing, but the fact that NSAIDs are prescribed,

NSAIDs were available over the counter, and it is

certainly true in other countries where you can go

and buy them even without a prescription, that

247

people who have had gout and have been treated for

gout, are likely to self-medicate themselves before

they come in.

DR. GIBOFSKY: Dr. Cronstein.

DR. CRONSTEIN: Again, I would like to go

back and revisit Dr. Bathon\'s statement at the end

of the last bullet about possibly admitting people

to trials who were taking the short-taking

nonsteroidal, but hadn\'t taken it for, say, 8

hours.

Forget about the indomethacin, but many

patients will just go to the drugstore and buy

Motrin or Advil or something. I think that might

improve recruitment. I don\'t know if you have the

numbers as to what drugs people were taking. Is it

broken down into over the counter versus

prescription nonsteroidals? In the screen?

DR. GIBOFSKY: Response if you have it.

DR. MELIAN: We don\'t have that

information with us, sorry.

DR. CRONSTEIN: But I think that is an

excellent idea of permitting\--and that may

248

alleviate some of the problems with recruitment if

you permit short-acting nonsteroidals outside of a

certain time frame.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: When I look at Merck\'s data

on the time of onset to randomization, 80 percent

of the people presented within the first day, and

only 20 percent within the second 24-hour period,

so extending it to 72 hours is probably not going

to pick up a great deal of additional patients.

DR. GIBOFSKY: Further discussion on Roman

Numeral IV? Have we reached consensus, now

recommendations? Okay.

Let\'s move to Roman V.

Considering the extent of pain and

duration of attacks at trial entrance, please

discuss the advantages and disadvantages of

placebo-controlled studies versus active-controlled

trials. If placebo-controlled studies are not

recommended, are there data from studies of

existing therapies sufficient to define a margin of

non-inferiority?

249

I think we heard in Dr. Daikh\'s

presentation, I believe there were two slides

looking at the advantages and disadvantages of

placebo-controlled studies versus active-controlled

trials, and I think certainly that is worthy of

note to the answer or to the comment on the first

sentence.

Dr. Williams?

DR. WILLIAMS: I am a big believer in

placebo-controlled trials, but in this case, I

realize these treatments haven\'t been demonstrated

in randomized, controlled trials, but we certainly

feel that they are effective treatments, and I

think a placebo-controlled trial would be very

difficult to sell to the investigators, as well as

to the patients.

DR. GIBOFSKY: Any other comments? Dr.

Bathon.

DR BATHON: I agree with that. The other

complication is that a lot of times we don\'t know

these people. You can talk rheumatoid arthritis

patients into a placebo-controlled trial as long as

250

there is rescue, and you could argue that maybe you

could ask them to put up with\--the gout patients to

put up with two days of placebo, and then have a

rescue, but because you don\'t have a relationship

with these people and they are coming in

desperately for treatment, I think it would be a

very difficult sell to give a placebo.

DR. GIBOFSKY: I\'m getting a sense that in

this particular situation, we are not recommending

or at least we think that placebo-controlled trials

would be disadvantageous to the patient.

So, we can go to the second comment, the

second sentence, which is are there data from

studies of existing therapies sufficient to define

a margin of non-inferiority for an active

comparator.

Dr. Cush.

DR. CUSH: I wanted to add one caveat to

placebo-controlled trials, which was brought up

earlier by Dr. Hochberg, and that it is appropriate

for truly new compounds and novel compounds for

which an active comparator may not be a reasonable

251

comparator, I mean one that is currently approved

and marketed. So, that is the one caveat.

DR. GIBOFSKY: Dr. Harvey.

DR. HARVEY: Before you moved on, I didn\'t

know if you wanted there to be any further

discussion or any elaboration on the concept of

medication rescue, some of the variations on that

theme.

DR. GIBOFSKY: Dr. Cush.

DR. CUSH: Certainly, a placebo-controlled

trial, that would be the only way one could do

that, and I think that any out point where the

patient felt that the pain was extreme and

unbearable, and patients have to be told that, you

know, there is a chance that your condition could

get better by doing nothing and just resting.

You could have as a part of placebo

management, ice and whatnot, but anyway, they still

have to be told they could get worse, too, and

should they get worse, they could be offered either

an analgesic or a standard of care as rescue

therapy, and that becomes one of your arms, one of

252

your outcomes, your secondary outcomes.

DR. GIBOFSKY: In rheumatoid arthritis, we

are learning that leaving a patient untreated for

even a brief period of time may affect the ultimate

outcome in the clinical course of a disease.

Do we have any data that is either similar

or distinct in gout, whether leaving a patient

untreated for gout in the context of

placebo-controlled trial may be acceptable in the

short term, but may have implications for either

other manifestations, hyperuricemia, if present, or

their chronic intercritical gout?

Dr. Weisman.

DR. WEISMAN: Well, we heard from Bob

Terkeltaub earlier today that there is data

indicating that the process continues, and there

are many patients that go on with some kind of

smoldering disease, just even keeping aside the

concept of hyperuricemia, just the fact that the

joint disease appears to progress clinically even

in the intercritical periods.

Although you are not going to be able to

253

support this with MRI data, like you can\--or early

erosion data in rheumatoid arthritis, because there

hasn\'t been any studies looking at this structural

damage issue, but I suspect there probably will be

at some point, there will be some data to document

this whether it\'s investigator initiated or

pharmaceutical company initiated, but there will be

some data.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: I think that because we are

convinced we have effective therapies, that if you

had a placebo-controlled trial with rescue, you

would end up without a placebo control.

DR. GIBOFSKY: Are there data from studies

of existing therapies sufficient to define a margin

of non-inferiority?

Anyone want to tackle that one? I think

we heard some of that in Dr. Daikh\'s presentation

as to why the study was designed the way it was

given the limitations of existing therapies and the

ability to define the margin of non-inferiority,

but anyone else want to comment on that?

254

\[No response.\]

DR. GIBOFSKY: Okay. Dr. Harvey, are you

comfortable with a response to your question about

rescue?

DR. HARVEY: I am never comfortable, but I

will\--

DR. GIBOFSKY: Would you like a cushion?

DR. HARVEY: Dr. Schiffenbauer has an

elaboration.

DR. SCHIFFENBAUER: I didn\'t have a

specific issue about the rescue, but I just wanted

to get some clarification from the Committee.

If I have heard you correctly, you would

allow individuals to have an attack for 48 up to

possibly 72 hours, and I heard maybe some

disagreement as to whether they could or could not

take some therapy during that time, possibly

ibuprofen possibly, or nothing, and then you were

objecting or you were concerned about

placebo-controlled trials, and I am not quite

comfortable that I understand the difference there.

I guess the concern I have or the question

255

I have is if someone is untreated for 48 to 72

hours, if that is what we are saying is one way to

approach this, is there an objection to entering

them into a placebo-controlled trial that may

continue for an additional 6 or 8, 12, 24 hours of

that placebo-controlled period to evaluate in a

rigorous fashion the effects of a new therapy.

DR. GIBOFSKY: So, your question is if

someone has gone for two days on their own for

whatever reason, perhaps it\'s Friday night and they

can\'t get to their doctor until Monday, what is the

up side and down side to beginning the clock at T

zero and then putting them into a

placebo-controlled trial.

DR. SCHIFFENBAUER: Yes, and let me just

add although I think we do all think that Indocin

works effectively, I don\'t know that we truly have

any idea of when it starts to work, how effective

it really is, because we don\'t have those

placebo-controlled trials to document that. Maybe

someone could address that.

DR. GIBOFSKY: Dr. Hochberg, did I see

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your hand going for the microphone? I do now.

DR. HOCHBERG: Again, if we go back to

Question I, I guess we felt that gout was an

acutely painful condition, but it was more than

just pain. You know, there was a tremendous role

for inflammation.

Then, in one of the subsequent questions,

I don\'t remember whether it was II or III, that we

are front-loading the outcomes and looking at some

of the outcomes that are used to assess agents for

the treatment of acute pain.

So, clearly, there is a period in which

this could be placebo-controlled in order to define

the time course of the response in comparison to

placebo in this painful inflammatory condition.

But then you get into the issue in a

placebo-controlled study of rescue, and personally,

I mean I have had a lot of experience in

osteoarthritis trials, and I don\'t like rescue

because I think it sort of muddies the

interpretation of the results, and some of the

meta-analyses now suggest that the effect size that

257

is seen with treatment in studies that do not allow

rescue is larger than the effect size which is seen

in studies which do allow rescue, suggesting that

there is an effective rescue.

Then, you have to decide, well, what is

the rescue going to be, does the patient stay in

the study and continue to get observed on rescue to

contribute to the analysis in the placebo group, or

once they go on rescue, are they a failure, and

then you are looking at time to failure as an

outcome. So, that gets real problematic from my

point of view.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: Your question about how

quickly things seem to respond, the data that was

presented to us by Merck would suggest that they

respond to both agents within the first few hours,

and I find that there will be some moral dilemma to

try and put patients on placebo if I can make them

better. Patients with gout are miserable, and to

ask them to hold off for treatment for 12 to 24

hours, I would find it a difficult ethical issue.

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DR. GIBOFSKY: Dr. Schiffenbauer.

DR. SCHIFFENBAUER: Again, that is in the

context of recruiting individuals that have gone

already 48 hours or up to 72 hours without therapy.

That is the point I want to clarify.

DR. WILLIAMS: They didn\'t come to me in

the first 48 hours. Once they have come to me,

they are then there to be treated, and that is when

my time clock started.

DR. GIBOFSKY: Does that answer your

question, Dr. Schiffenbauer? Okay.

Ms. McBriar.

MS. McBRIAR: It seems that a lot of

people have talked about the severe inflammation

that is going along with the severe pain in these

patients early on, and it just worries me if the

rheumatoid arthritis data is true about the early

damage, and we want to preserve joints and we want

to preserve function, that if we do a

placebo-controlled trial, that there could be this

damage to the joints early on, and, as the consumer

rep, if we don\'t have to go that way, I would be

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much happier.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: I prefer placebo-controlled

trials. We don\'t have control over when the

patient presents, so we can\'t be responsible for

that, but I think it is just really a practicality

measure. If they are presenting for treatment, and

it\'s an acutely severely painful condition like

this, it is very difficult to enroll people in

placebo-controlled trial.

I think we could try it, but I bet you it

would introduce yet another layer of recruitment

difficulty, so it may make it impractical. I think

that until we know data about damage, we can feel

reasonably ethically comfortable still that a

placebo-controlled trial is fairly ethical in terms

of lack of data on joint damage.

If we find down the road by MRI or

something that each single attack adds more and

more damage to the joint, then, we would have to

rethink that.

DR. GIBOFSKY: Dr. Cronstein.

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DR. CRONSTEIN: I realize that there is a

suspicion based on the RA trials, but the RA

trials, you are talking about months of

inflammation as opposed to here you are talking

about a difference of 12 to 24 or 48 hours. I

really don\'t think there is any reason to think

that delaying treatment is going to give you a

chronic or more of a chronic problem as far as

arthritis goes. I don\'t think there is any

evidence for that.

I think, in fact, there are many patients

who have one or two acute attacks over long

periods, not sufficient to require a prophylaxis,

and they don\'t have any specific joint injury. I

don\'t think that the worry about that is the main

issue.

I just find that if you have something\--I

know we haven\'t done the placebo trials\--but if you

have something that you know works at least as a

pain reliever, that depriving a patient with gout,

with an acute gouty attack, you know, depriving

them of any pain relief, I don\'t think that is

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feasible, and I don\'t think that we are going to

see the same placebo responses that we would

otherwise have seen, but obviously we can\'t do

that.

DR. GIBOFSKY: Dr. Boulware.

DR, BOULWARE: I think the

placebo-controlled observation for 8 hours would be

ideal, too, but I think another layer of

practicality is when you enter them, you have 8

hours to do the follow-up study, and unless there

is something that the patient is going to do, which

then becomes maybe unreliable, it is very

impractical to ask my staff to stick around until

midnight when you enter somebody at 4 o\'clock in

the afternoon.

DR. GIBOFSKY: Dr. Geis.

DR. GEIS: Until I saw placebo data for

the first few hours after the first dose, I don\'t

know that I would conclude that you are seeing a

real effect of a drug or just a placebo effect. It

is after seeing just lots of data in different

conditions.

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You could build in a substudy where you

maybe have 50 patients per group where you are

looking for this short-term response comparing

placebo to the active, so you don\'t have to build

it in for all 150 patients, that you might need to

look for the total response over several days, so

that may be one way of doing it, and then have

specific sites who feel they have the staff to

follow up in the first 8 hours, and all of that, so

there may be a way you could work it and get both

things.

DR. GIBOFSKY: Any further comment on

Roman Numeral V? Dr. Schiffenbauer.

DR. SCHIFFENBAUER: The second part of

that was the non-inferiority margin and the effect

size of any comparator. Did anybody have any other

comments about that because that was left

unresolved.

DR. GIBOFSKY: I think the question as

posed is part of your data from studies of existing

therapies. I believe we heard that the data from

existing therapies are meager at best, and that

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resulted in the design trial that we heard earlier

today, which is probably as good as it gets based

on the data that is available.

Unless anyone has knowledge of a different

data set, but I suspect if there were, it would

have been factored by the consultants into the

trial design that we heard today.

Let\'s move to Roman VI. Please discuss

the following clinical trial issues: the use of

concomitant medications such as diuretics or low

dose aspirin. The entry inclusion criteria for an

acute gout trial, particularly the need for

documentation of the presence of crystals, and to

make it perhaps a bit simpler, let\'s talk about the

first attack of acute gout in a person\'s life

versus an attack of acute gout in a patient who is

known to have the diagnosis of gout, and then

enrollment of patients with polyarticular gout.

Should the trial be stratified by this

factor, are there other factors to consider for

stratification.

Who would like to begin the discussion on

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that? Dr. Cush.

DR. CUSH: I think we already covered the

con meds issue of colchicine and allopurinol as

background therapy. I think diuretics, I think

they are real world, they should be allowed.

Aspirin, I think is a confounder as is

nonsteroidals, and if at all possible, those

patients should be excluded or the low dose aspirin

be stopped for the period of study. I am not sure

that there is a significant acute risk to stopping

81 mg of prednisone a day.

I think that the entry criteria, I would

still advocate the use of the ACR criteria because

they are the best studied although I do think that

more liberalized criteria should be established

because that may be one of the factors that hampers

enrollment, and I don\'t think that crystal

identification has to be a part of the mix.

Obviously, it is factored into the

equation the ARA used in its deliberations to

arrive at criteria, but they are helpful, but not

required.

265

In clinical practice, we all do this, we

don\'t absolutely have to have crystals, we would

like to see crystals, but we don\'t have to have

crystals to have a certain or incompetent diagnosis

of gout and to proceed with therapy, whether it be

acute therapy or more chronic hyperuricemic

therapy.

I would argue against polyarticular gout.

I think especially if it\'s first time attacks, Dr.

Gibofsky asked do we want to just only go after

nascent, brand-new onset gout, but I think that is

too restrictive, and those patients are going to be

even harder to find, and will require more of a

public health kind of campaign for advertising to

find those patients.

They are out there, and there is a certain

steady flow of them. We have well-defined incident

rates, but it will be harder to do. Especially in

that population, I would avoid polyarticular gout.

In more established populations, I think to include

them might be reasonable, but to get to an

assessment issue, as Dr. Bathon was talking about,

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is which joint do you go after, which becomes your

index joint.

Maybe the one you chose as your index

joint is really not your worst one, and will not

respond as maybe other joint will respond, and

there is always the worry of background therapy.

Stratification is only going to be I think

necessary if you have again a more rapid and

liberalized inclusion criteria that allow patients

to be seen, consented, screened by clinical

parameters, and then enrolled rapidly.

Then you have to basically do a post hoc

stratification for things that you might accept not

unknowingly, which might include uncontrolled

hypertension, renal disease, et cetera.

DR. GIBOFSKY: Dr. Cush, I think you may

have misunderstood my comments about crystal

analysis. I was referring to bullet 2, where the

question would be if you had a patient who is

presenting with gout de novo and no history of

gout, would you prefer the crystal analysis to the

six Wallace criteria as opposed to a patient who is

267

known to have a diagnosis of gout, would not the

Wallace criteria suffice, in which case you would

not need the crystal analysis.

In other words, the first patient comes to

you in clinic with what looks like podagra despite

the discomfort of the arthrocentesis, wouldn\'t you

want to know that you are dealing with monosodium

urate as opposed to your patient who has been with

you for five years, who comes in and says here I am

again.

DR. CUSH: And I believe that the actual

paper, the Wallace criteria paper from 1977 deals

with this fact and comfortably allows you to make

the diagnosis in either situation, with or without

crystals. It is very clear by the inclusion of

crystal identification, you increase the

specificity of diagnosis to 100 percent. That is

absolutely true. But without it, you don\'t lose

that much, you are down 10, 15 percent I think at

the most was the number that was in the paper.

So, just by going like clinical criteria

alone, if you make it, then, you are going to be

268

in. Of course, it is always great to have

crystals, but I don\'t think you need to do it from

the standpoint of having diagnostic criteria. I

think the diagnostic criteria were developed to

allow for that degree of leeway, but then again,

this is really a point most pertinent to going

after patients for first time attacks.

If that is the sole kind of study one

wants to do, you are going to have trouble, and it

is not the trouble in identifying crystals and

making the diagnosis, it is trouble in finding the

patients.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: I would argue that I would

like to see the diagnosis by the demonstration of

crystals at some point. There are so many patients

out there who say they have gout, who we can\'t

document they really have gout, that at some point

in the course, I would like to have crystals

demonstrated. After that, I am perfectly willing

to rely on the criteria that say that that current

attack is an attack of gout.

269

DR. GIBOFSKY: Dr. Cronstein.

DR. CRONSTEIN: I think as Dr. Cush

pointed out, somebody who comes in with an acute

podagra, it is pretty unlikely it is going to be

anything else. The discomfort of the tap, you

know, adds to the difficulty in recruitment if that

is going to be an issue, and then finally, a lot of

emergency rooms are probably not going to be

equipped for appropriate crystal examination.

So, I think that even though it is a small

percentage of the patients, you said it was 10 or

20 percent, something like that, a small percentage

of the patients, I think that might hinder

recruitment, and I don\'t think that we necessarily

need that level of documentation.

DR. GIBOFSKY: Dr. Schiffenbauer.

DR. SCHIFFENBAUER: Would there be any

concern if there was an imbalance in the groups,

the treatment groups, for those that had crystal

identification versus those that don\'t because of

the false positive or false negative rate, that

issue, do you either require that everybody have it

270

or everybody use clinical criteria just to avoid

that possibility?

DR. GIBOFSKY: Dr. Hochberg.

DR. HOCHBERG: I would actually be

consistent with the way in which other rheumatic

conditions\--I hate the word rheumatic\--other

arthritis conditions are described in draft

guidance documents and in entry criteria, that the

patient has a clinical diagnosis of and fulfills

American College of Rheumatology classification

criteria for is often the way that studies are

recruited for, that protocols are written,

protocols are agreed upon by the sponsor and the

Agency, and papers are written.

That is how we do it for rheumatoid

arthritis and oftentimes for osteoarthritis, not

all the time for osteoarthritis, so I think

somebody with a clinical diagnosis of gout, who

fulfills what granted are old, but haven\'t been

revisited criteria for gout would buy somebody into

a study.

Some of those people will be aspirated for

271

crystal identification, and that is how they will

fulfill them, some of them won\'t, and I think that

ought be reported in a paper, and that could be

compared as part of the table 1 baseline data in a

paper and clearly be reported in the report that

comes to the Agency for the Agency\'s review, and if

the Agency notes an imbalance, the statisticians

can look at it and decide how they want to deal

with it.

I would stratify on polyarticular gout if

I was designing a protocol, because I think, you

know, there is a suggestion that the time to

response may be different because of the burden of

disease and the number of joints involved.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: I agree strongly with what

Dr. Cronstein said earlier about not requiring an

arthrocentesis, but the only thing I am concerned

about is that if this trial were done heavily in

primary care practices or emergency rooms, I think

a lot of rheumatologists amongst us are skeptical

about the validity of joint exams done by

272

non-orthopedists and non-rheumatologists.

Many patients come to us with supposed

joint swelling and joint findings that we can\'t

corroborate, so that would be an issue, you are

just relying on clinical criteria.

DR. GIBOFSKY: What about Dr.

Schiffenbauer\'s question, should whatever criteria

that are adopted be uniformly applied, requiring

either crystals for all or crystals for none?

Dr. Williams.

DR. WILLIAMS: I agree with Marc. I think

that if you are going to accept the criteria, the

12 criteria, you allow them to have either way to

make the diagnosis, those are the guidelines.

DR. GIBOFSKY: Further comments on any of

the bullets listed here? Is the Committee

comfortable with the recommendations about

stratification, inclusion criteria, and the use of

concomitant medications?

Dr. Hochberg.

DR. HOCHBERG: I would like to ask a

question about concomitant medications. Are there

273

any data on whether low-dose aspirin, 81 mg, has an

analgesic effect?

DR. GIBOFSKY: Any data from the Agency

perhaps?

Dr. Cronstein.

DR. CRONSTEIN: I am not aware.

DR. GIBOFSKY: Well, you were sitting next

to Dr. Schiffenbauer. Guilt by association, Dr.

Cronstein.

DR. CRONSTEIN: I am not aware of any

data.

DR. HOCHBERG: There was a prior comment

made to discontinuing low-dose aspirin on entry

into a trial, and if there is not an analgesic

effect of low-dose aspirin, then, why would it be

discontinued in somebody who might be on it

especially, you know, somebody at risk for coronary

disease or has had a prior thrombotic event and has

gout, and comes into a trial. I mean I would

probably want to leave them on it.

DR. GIBOFSKY: I think that is a fair

question.

274

Dr. Williams.

DR. WILLIAMS: Actually, Jack was the one

that made that point and he has gone, but the

reason would be is because of its effect on uric

acid retention in low doses. I think that you

could make the case for just continuing their

medications at the same stable dose and make just

as much sense.

DR. GIBOFSKY: Dr. Cronstein.

DR. CRONSTEIN: I think the same could be

said for diuretics, and there you can lose control

of hypertension if you stop them, so I think that

things should just continue.

DR. GIBOFSKY: I think we would be

comfortable with continuing concomitant medications

at the stable dose that the patient is on at the

entry of the study. I believe we have discussed

bullet 2.

Any further comment on stratification by

other factors? I think we have talked about

polyarticular gout. Anyone want to make any other

comments about stratification?

275

DR. HOCHBERG: Could I ask you a question?

DR. GIBOFSKY: Please.

DR. HOCHBERG: Do we know whether there

are any other variables that affect the response to

treatment in patients with acute gout, that we

might want to stratify on because they might be

associated with response?

DR. GIBOFSKY: I am sorry Dr. Terkeltaub

isn\'t here and Dr. Cush has gone. Dr. Cronstein.

DR. CRONSTEIN: The question is whether

you have somebody who has an acute attack on top of

chronic tophaceous gout and whether they ever get

back to baseline, and I think that that is

problematic.

Were there many patients in your trial

that had chronic tophaceous gout or did you exclude

them?

DR. MELIAN: I don\'t have the exact

number, but I think we had about 10 to 20 percent

of patients that fell in that general category. I

don\'t have the numbers in front of me, so I am

stretching here a little bit, but I think it was in

276

that general ballpark.

DR. CRONSTEIN: Do you know if there was a

difference in response, because if they already

have structural damage to the joint, is that going

to interfere with your ability to\--

DR. MELIAN: That is something that we

would have to go back and look at the database. We

think if anything is going to have an impact on the

things that we have looked at, it would be baseline

pain where patients with more severe pain tend to

have a greater improvement.

DR. GIBOFSKY: Dr. Williams.

DR. WILLIAMS: We did not address

allopurinol and I assume the patients who were on

chronic allopurinol would remain on like we do with

diuretics and aspirin.

There is some, I don\'t know if it\'s

evidence based, that starting allopurinol can

prolong the attacks of gout, and if they got put on

allopurinol, I assume they would have been put on

other medications and not qualify for the trial

anyway, but if someone were just put on allopurinol

277

acutely, or if that should be stopped or at least

stratified.

DR. GIBOFSKY: Dr. Bathon.

DR. BATHON: Apparently, some

complementary and alternative things that are out

on the market have steroids in them, so we might

just say restrict those kinds of things.

DR. GIBOFSKY: Any further comments about

Roman Numeral VI? Any further comments about any

of the issues we have been discussing this

afternoon in response to the questions posed to us

for consideration?

Any other questions from you, Dr.

Schiffenbauer, for our consideration? Anyone?

If there are no further questions from the

panel or issues to discuss, Dr. Harvey, would you

like to make some concluding remarks?

DR. HARVEY: First of all, I would like to

thank you all for your service to the Committee. I

really believe that these last two days have been

very productive and have had a lot of good

discussion on all the different areas that were

278

outlined in the agenda.

I really think that this discussion and

what we have done yesterday and today will lead to

future clinical trials for new therapies for

patients who are currently suffering, so I thank

you for your service.

DR. GIBOFSKY: Thank you. I would like to

thank the members of the panel for their spirited

and considered deliberations these last two days.

I would like to thank you once again for making my

job so easy and hopefully, yours so enjoyable.

I will declare this meeting adjourned.

\[Whereupon, at 2:08 p.m., the meeting

adjourned.\]

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